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[ CAS No. 274693-27-5 ] {[proInfo.proName]}

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Chemical Structure| 274693-27-5
Chemical Structure| 274693-27-5
Structure of 274693-27-5 * Storage: {[proInfo.prStorage]}
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Product Details of [ 274693-27-5 ]

CAS No. :274693-27-5 MDL No. :
Formula : C23H28F2N6O4S Boiling Point : -
Linear Structure Formula :- InChI Key :OEKWJQXRCDYSHL-FNOIDJSQSA-N
M.W : 522.57 Pubchem ID :9871419
Synonyms :
AZD6140;AR-C 126532XX;Possia;Brilique;brand name: Brilinta

Calculated chemistry of [ 274693-27-5 ]

Physicochemical Properties

Num. heavy atoms : 36
Num. arom. heavy atoms : 15
Fraction Csp3 : 0.57
Num. rotatable bonds : 10
Num. H-bond acceptors : 10.0
Num. H-bond donors : 4.0
Molar Refractivity : 128.22
TPSA : 163.74 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -8.05 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.89
Log Po/w (XLOGP3) : 2.03
Log Po/w (WLOGP) : 2.66
Log Po/w (MLOGP) : 2.12
Log Po/w (SILICOS-IT) : 1.79
Consensus Log Po/w : 2.5

Druglikeness

Lipinski : 1.0
Ghose : None
Veber : 1.0
Egan : 1.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -4.01
Solubility : 0.0514 mg/ml ; 0.0000984 mol/l
Class : Moderately soluble
Log S (Ali) : -5.1
Solubility : 0.00419 mg/ml ; 0.00000801 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -4.86
Solubility : 0.00723 mg/ml ; 0.0000138 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 5.41

Safety of [ 274693-27-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 274693-27-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 274693-27-5 ]

[ 274693-27-5 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 274693-26-4 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
97.1% With hydrogenchloride; In methanol; at -3 - 20℃; for 3h;Large scale; Methanol (105 L) and Stage II (21 kg) were charged to the reaction kettle at room temperature,Cool to -3 C at -3 CConcentrate hydrochloric acid (107.1 kg) in batches in two hours and below,Stir for 1 hour. Methyl tert-butyl ether was charged to the reaction vessel at -3 C105L,207 L sodium hydroxide solution was added to adjust the pH of the reaction mass to 8.0. After the reaction mass was stirred at 10 C for 30 minutes,Warm to room temperature and stir for another 30 minutes.Static stratification,The organic and aqueous phases are separated,The lower aqueous phase was extracted with methyl tert-butyl ether,The organic phase was washed with saturated sodium chloride solution and then extracted with methanol.Combined organic phase,Put into activated carbon 2.10kg,Heated to 40 C,Stir for 30 minutes,filter,Rinse with methyl tert-butyl ether.Vacuum distillation,The resulting residue was recrystallized from ethyl acetate and cyclohexane,Centrifuge,Vacuum dried at 55 C for 6 hours,Ticagrelor.The yield is about 97.1%Purity is about 99.6%.
94.1% With hydrogenchloride; In water; ethyl acetate; (c) dissolving intermediate (iii) (500 g, 0.89 mol) in ethyl acetate, thenAdd hydrochloric acid for deprotection,Tegrelillo (436.5 g, yield 94.1%) was obtained.
93% With hydrogenchloride; In methanol; water; toluene; at 10 - 20℃;Large scale; 3) Operation process(1) cooling the toluene solution of the upper step product remaining in the 200L reaction vessel to 10 to 20 C;(2) adding 37.062 kg of hydrochloric acid and 55 L of methanol mixed solution cooled to 10 to 20 C into the reaction kettle under stirring;After the addition is completed, the mixture is kept at 10 to 20 C for 3 to 4 hours;(3) TLC detection reaction was completed, ethyl acetate: isooctane=1:1, taking the upper organic phase point plate;Stop stirring, let stand for stratification, and separate the lower methanol water phase for use;(4) Add 500 ml of the lower methanol aqueous phase separated in the above step, and add 20% potassium carbonate aqueous solution with stirring.(25.406 kg of potassium carbonate and 101.64 L of purified water); finally adjusted pH between 7-9;(5) adding 55 L of ethyl acetate under stirring, and stirring for 30 min;Stop stirring, let stand layering, separate the lower layer of water, and transfer the upper organic phase to the PE barrel for use;(6) The lower aqueous phase was transferred to the reaction vessel, 55 L of ethyl acetate was added, and the mixture was stirred for 30 min; the stirring was stopped, and the layer was allowed to stand.Divide the lower aqueous phase;(7) Combine the two organic phases, add 200L reaction kettle, add 55L purified water with stirring, stir for 30 minutes; stopStirring, standing layering, separating the lower aqueous phase; adding 55 L of purified water to the reactor, stirring for 30 minutes; stopping stirring, quenchingLayering, separating the lower aqueous phase;(8) Add 686 g of activated carbon to the organic phase (the amount of activated carbon is 5% of the crude product, and the crude product is 100% yield)Calculated), heated to 40 ~ 50 C, stirred for 30 minutes;(9) Filter the filter pad with diatomaceous earth (about 100g of diatomaceous earth), distill off the solvent under reduced pressure at 50 C, steam until no more liquidThe body is effluent; add 11 L of ethyl acetate to distill off the solvent, repeat 2 times until the solid is produced, no more liquid will flow out;Add 68.61 L of ethyl acetate and heat to 50-60 C to dissolve (the amount of ethyl acetate is 5 times the mass of the crude product, the crude product is100% yield calculation); transfer the solution into a 50L reaction kettle, heated to 50 ~ 60 C;(10) Add 82.33L of isooctane preheated to 50-60 C under stirring (the amount of isooctane is ethyl acetate volume)1.2 times); control the addition speed to keep the internal temperature above 50 C, and gradually precipitate solids during the addition;(11) After the addition is completed, the temperature is lowered by stirring to a temperature of 20 to 30 C, and stirred for 1 hour;(12) further cooling to 0 to 10 C and stirring for 2 hours;(13) Centrifugal filtration, the reaction kettle and the filter cake were pretreated to 13.72 L of ethyl acetate and 16.47 L of isothermally cooled to 0 to 10 C.Washed with octane mixed solvent;(14) The filter cake is dried under vacuum at 45-55 C for 8 to 12 hours to obtain 11.6 kg of crude tigrilo (Im-4);85; 1) Add 45 L of dichloromethane and 108 L of tert-butanol to a 200 L crystallizer; stir and add 11.5 kg of ticagrelor.Product,(2) heating to 50 ~ 60 C under stirring for 1 hour; cooling to 20 ~ 30 C, stirring for 1 hour;(3) further cooling to 0 to 10 C for 2 hours;(5) centrifugal filtration, the reaction kettle and the filter cake are rinsed with water precooled to 0 to 10 C;(6) The filter cake was dried under vacuum at 45-55 C for 8 to 12 hours to obtain 10.7 kg of ticagrelor; the weight yield was 93%.
93.3% With hydrogenchloride; In methanol; water; at 2℃; for 2h;Inert atmosphere; The intermediate TG-3 obtained in the step S3 is added to the reactor, and then dissolved in methanol, and the temperature is lowered to 2 C, and nitrogen gas is added thereto, and the methanol solution of hydrochloric acid is added dropwise under the temperature control for 2 hours. Water and ethyl acetate were added, the system was temperature-controlled at 15 C, and the liquid phase was separated. The aqueous phase was extracted twice with 5 times TG-3 weight of ethyl acetate. The organic phase was washed once with saturated aqueous sodium hydrogencarbonate and the organic layer was evaporated to dryness. After adding ethyl acetate, stirring to complete dissolution, heating to reflux, adding n-hexane dropwise, stirring and cooling to 22 C, stirring was continued for 1.5 h, filtration, and vacuum drying to obtain white solid TG-4 as a crude product; The mass ratio of TG-3, methanol, methanolic hydrochloric acid solution, water, ethyl acetate and n-hexane was 1:2.5:2.5:3:2:4.
90.5% With hydrogenchloride; water; In methanol; for 1h; Two drops of concentrated aqueous hydrochloric acid was added to a solution of 7 (23 mg, 0.041 mmol, 1.0 eq) in methanol(1.5 mL), the reaction solution was stirred for about 1 h, saturated solution of potassium carbonate was added to the reaction solution until the pH value reached to 8, then extracted with EtOAc, the organic layer was dried and evaporated under vacuum to give the title product as a brown oil (19 mg, 90.5%). 1H NMR (300 MHz, CDCl3) delta 6.95~7.12 (m, 3 H), 4.98~5.03 (q, 1 H), 4.74~4.75 (t, 1 H), 4.31 (s, 1 H), 4.00 (s, 1 H), 3.67~3.75 (dd, 4 H), 2.93~2.96 (m, 2 H), 2.53 (q, 1 H), 2.34 (s, 1 H), 1.57~1.60 (q, 2 H), 1.25~1.41 (m, 2 H), 0.87~0.94 (t, 3 H). EI-MS m/z 523.3 (M+H)+ .
90% With phosphoric acid; In methanol; at 20℃; for 24h; To a solution of CPATAMA (0.21 g, 0.38 mmol) in MeOH (10 mL) at room temperature orthophosphoric acid (85%, 1.5 mL) was slowly added. Resulting reaction mixture was stirred at room temperature for 24 h, then water was added (20 mL), and reaction mixture was neutralized with 1 M NaOH. Product was extracted to EtOAc (5 x 10 mL), combined organic phases were dried over Na2SO4, then concentrated to afford crude product, which was purified by chromatography (SiO2, EtOAc) to afford title compound as a white powder (0.18 g, 90 % yield). 19F NMR (CD3OD, 470.5 MHz) delta -141.9--142.1 (m, 1F), -145.6--145.9 (m, 1F); MS (ESI) m/z: 523 [MH]+.
90% With phosphoric acid; water; In methanol; at 20℃; for 24h; To a solution of CP ATA MA (0.21 g, 0.38 mmol) in MeOH (10 mL) at room temperature orffto-phosphoric acid (85%, 1.5 mL) was slowly added. Resulting reaction mixture was stirred at room temperature for 24 h, then water was added (20 mL), and reaction mixture was neutralized with 1 M NaOH. Product was extracted to EtOAc (5 x 10 mL), combined organic phases were dried over Na2S04, then concentrated to afford crude product, which was purified by chromatography (Si02. EtOAc) to afford title compound as a white powder (0.18 g, 90 % yield). 19F NMR (CD3OD, 470.5 MHz) delta -141 .9- 142.1 (m, 1 F), -145.6-145.9 (m, 1 F): MS (ESI) mlz: 523 [MH]
90% With hydrogenchloride; In methanol; water; at 20℃; for 15h; 2 g of compound h, 50 mL of methanol, 3 mol/L of HCl 48 mL were added to the reaction flask at room temperature, and magnetically stirred until dissolved.Solution, the ice bath was cooled to below 20 C, and the reaction was stirred for 15 h. After the reaction of co is completed, 20 mL of a 1 mol/L NaOH aqueous solution is added thereto. The pH was adjusted to about 7.2, methanol was distilled off, and 50 mL of ethyl acetate was added. The aqueous layer was separated and the organic layer was washed with brine. Evaporate 20 mL of ethyl acetate, replenish 30 mL of ethyl acetate, repeat the operation twice, combine the filtrates, and distill off part of the acetic acid.Ethyl ester, 200 mL of isooctane was added thereto, and the temperature was slowly raised to 50 C by an oil bath, stirred at a constant temperature for 30 min, and cooled to 20 C.The product j was precipitated, and dried by filtration to obtain 1.2 g of a pale yellow powder. The yield was 90%, and the HPLC purity was 97.88%. Compound j Chemical name: (1S, 2S, 3R, 5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-( Propylthio)-3H-[1,2,3]-triazole[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-dialcohol.
88% With hydrogenchloride; In methanol; water; at 10℃; for 6h; (4) To 500g compound VI, add methanol and water mixture (1500 ml) with volume ratio of 4:1. Then, add 450 ml of concentrated hydrochloric acid. At 10 C react for 6h. is added to the reaction product 1000 ml ethyl acetate, stirring 5 min later, the liquid, aqueous phase for the 500 ml ethyl acetate extraction a, combined organic phase, the organic phase by adding 100 ml normal heptane, stirring to wash-out when a large amount of white solid, continue to stir 1h, filtering, is to obtain compound VII for standard auspicious Luo river, product after drying 408g, the yield is 88%, the purity is 99%.
87% With hydrogenchloride; In methanol; at 20℃; for 4h;Industrial scale; (1) The toluene solution of the previous product left in the 100L glass reactor was cooled to 20 C;(2) stirring was cooled to 20 C 21.409kg of hydrochloric acid and 30.75L of methanol was added to the reaction mixture of the reaction vessel; addition was completed and maintained at 20 C for 4h;(3) TLC (ethyl acetate: isooctane = 1: 1, take the upper organic point plate), FTG-3 raw material point disappears, the reaction is complete; stop stirring,Static stratification, separation of the lower methanol aqueous standby;(4) 500L reactor was added to the lower part of the lower methanol aqueous phase,With stirring, 20% aqueous potassium carbonate was added(14.202 kg of potassium carbonate and 56.81 L of purified water);Finally adjust the pH between 9;(5) adding 30.75L of ethyl acetate with stirring, stirring for 30min;Stop stirring, standing stratification, separation of the lower aqueous phase,The upper organic phase into the PE barrel backup;(6) into the lower aqueous phase reactor, 30.75L of ethyl acetate was added,Stirring 30min; stop stirring, standing stratification, separation of the lower aqueous phase;(7) The two organic phases were combined, added to a 100L glass reactor,30.75L purified water was added with stirring, stirred for 30min; stop stirring, standing stratification, separation of the lower aqueous phase;30.75L of purified water was added to the reaction kettle and stirred for 30 minutes;Stop stirring, stratification, leaving the lower aqueous phase;(8) To the organic phase, 384 g of activated carbon (5% of the amount of active carbon is used as crude product and the crude product is calculated in 100% yield) is heated to 50 C,Stir for 30min;(9) was filtered, the filtrate was evaporated under reduced pressure at 50 C solvent,Steamed until there is no liquid outflow; then add ethyl acetate 6.15L steamIn addition to the solvent, repeat 2 times, until the solid is generated, there is no liquid outflow;(10) To the residue was added 38.40L of ethyl acetate was heated to 60 C dissolved (ethyl acetate was used in an amount of 5 times the volume of the crude product, the crude product in 100% yield); The solution was transferred to a 100L glass reactor, heated To 60 C;(11) 46.08 L isooctane (isooctane in an amount of 1.2 times the volume of ethyl acetate) preheated to 60 C was added with stirring; the addition rate was controlled,Keep the internal temperature above 50 C ,During the process of solid precipitation gradually;(12) is added, cooled to 30 C with stirring, stirred for 1h;(13) and then cooled to 10 C and stirred for 2h;(14) was filtered, the reactor and the filter cake with precooled to 0 ~ 10 C of 7.68L ethyl acetate and 9.22L isooctane mixed solvent leaching;(15) The filter cake was dried under reduced pressure at 60 C for 12h to obtain crude product of ticagrelor, with white or almost white crystalline powder 6.577kg; yield 87%.
75% With hydrogenchloride; In methanol; at 20℃; To a reaction mixture of 7.7 g (0.01368 moles) 2-[[(3aR,4S,6R,6aS)-6-[7-[[(1 R,2S)-2-(3,4- difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1 ,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,2- dimethyltetrahydro-3aH-cyclopenta[d][1 ,3]dioxol-4-yl]oxy]-1-ethanol of formula VII in 15 ml methanol, 15 ml concentrated hydrochloric acid was charged and the reaction mixture was stirred at room temperature for 2-3 hours. The reaction mixture was cooled to 0C to 5C and neutralized with 30 ml aqueous ammonia and extracted two times with 25 ml ethyl acetate, ethyl acetate layers were combined and washed with 25 ml water. Ethyl acetate layer was distilled under reduced pressure at 40C. Ticagrelor was isolated from 20% acetone in heptane mixture and dried under vacuum at 45C to 50C. Yield = 5.36g (Efficiency - 75%, HPLC -99.4%).
65.4% With hydrogenchloride; water; In methanol; at 20℃; for 24h; 1.41 g of 9-[3aR-(3aalpha,4alpha,6alpha,6aalpha)-[[2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxole-4-oxo-]ethanol]-6-yl]-6-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-2-mercapto-8-aza purine (2.5 mmol) was added to a reaction flask at room temperature, and dissolved in 20 mL of methanol, added 10 mL of hydrochloric acid (3N) to react 24 hour while stirring at room temperature. The solution was adjusted to pH=7.0-7.5 with 30% sodium hydroxide solution, concentrated under reduced pressure to remove methanol, and extracted three times with ethyl acetate. The organic phases were combined and dried, and distilled under reduced pressure to recover the solvent, to obtain the crude product, which was recrystallized from ethyl acetate and n-hexane to get 0.85 g of white solid Ticagrelor (I) 0.85 g, with a yield of 65.4%.
57% With hydrogenchloride; In methanol; water; toluene; at 5℃; for 3h;Large scale; TGRL-6 (16 mol) in toluene was added dropwise a mixture of concentrated hydrochloric acid (17.88 kg) and methanol (28.6 L). The addition was complete, the reaction was stirred at 5 C 3h. Phase, remove the toluene phase. Configure sodium bicarbonate(18. lkg), water (26.6kg) and ethyl acetate (24kg) was added dropwise to a mixture of methanol phase and sodium bicarbonate. Dropping is completed, phase, retaining the upper organic phase. Add organic phase activated carbon bleaching. Filter and concentrate the organic phase to a solid. Got ticagrelor 5.7kg, The total yield of 57%, purity96.85%, impurity N 1.2%
Example 9. Preparation of [lS-[lalpha,2alpha,3beta(lS*,2R*),5beta]]-3-[7-[2-(3,4-difluorophenyl)- cyclopropylamino] -5-(propylthio)-3H-l ,2,3-triazolo [4,5-</] pyrimidin-3-yl] -5-(2- hydroxyethoxy)cyclopentane-l,2-diolThe 2-({(3ai?,4lS,6i?,6a5)-6-[7-[(li?,25)-2-(3,4-Difiuorophenyl)cyclopropyl]amino}-5- (propylthio)-3/f-[l,2,3]triazolo[4,5-J]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3a/f- cyclopenta[J][l,3]dioxol-4-yl}oxy)ethanol solution from above was cooled to 15C, a solution of concentrated aqueous hydrochloric acid (465 kg) in methanol (623 kg), also tempered to 15C, was charged. The reaction was stirred at 15C until the conversion criterion was fulfilled (> 97%) and the phases were allowed to separate. The methanol- water layer, containing the product, was added to sodium bicarbonate (404 kg) in water (749 kg), keeping the temperature below 22C. When pEta > 6 the aqueous layer was extracted with ethylacetate (756 kg) and the phases were separated. The water layer was again washed with ethylacetate (1080 kg) whereafter the aqueous layer was discharged. The ethylacetate layers were combined and washed once with water (490 kg). The water content in the remaining ethylacetate solution was decreased to ?0.8% (w/w) by vacuum distillation at 5O0C, followed by a clear filtration and the concentration was adjusted to 6.2 L/kg 2-[((3ai?,45',6i?,6a5)-6-[5-Amino-6-chloro-2-(propylthio)pyrimidin- 4-yl] amino } -2,2-dimethyltetrahydro-3 aH-cyclopenta[<i] [1,3] dioxol-4-yl)oxy] ethanol. The mixture was heated to 500C and then iso-octane was added (1152 kg) during 45 minutes. The slurry was cooled to O0C during 2.5 hours and then kept at this temperature for 3.5 hours. The product was isolated and washed with a cold (<5C) mixture of ethylacetate (722 kg) and iso-octane (828 kg). Finally, the isolated product was dried under vacuum to give the title compound as a white solid (203 kg, 90% calculated from 2- [((3ai?,45',6i?,6a5)-6-[5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl]amino}-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)oxy]ethanol).
[00129] (1S,2S,3R,5S)-3-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (ticagrelor-d0): A solution of 2-((3aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol (450 mg, 0.80 mmol, 1.00 equiv.) in methanol (4 mL) and 12N hydrochloric acid (1.5 mL) was stirred at ambient temperature for about 3 hours. The pH value of the solution was adjusted to 8-9 by adding potassium carbonate. Following standard extractive workup with ethyl acetate (3 x 20 mL), the resulting crude residue was purified by silica gel column chromatography(dichloromethane / methanol (50: 1)) to give a semi-crude product (200 mg; yield = 48 %). The semi-crude product, which contained about 5 % of other diastereoisomers, was then further purified by chiral-prep EtaPLC (column: Chiralpak IA2 x 25cm, 5umChiral- P(IA)004IA00CJ-MB003) to afford the title compound (100 mg). [alpha] D 24 ] -43.2 (c, 0.2 g / 100 mL in MeOH). LC-MS: m/z = 523.0 (MH)+, Retention time : 1.58 minute. 1H NMR (300 MHz, CD3OD) delta: 7.08-7.23 (m, 3 H), 5.13 (q,l H), 4.75-4.79 (m, 1 H), 4.17-4.20 (m, 1 H), 3.91-3.95 (m, 1 H), 3.63-3.73 (m, 4 H), 3.06-3.26 (m, 2 H), 2.90-3.00 (m, 1 H), 2.70-2.80 (m, 1 H), 2.05-2.29 (m, 2 H), 1.60-1.88 (m, 2 H), 1.38-1.59 (m, 2 H), 0.94 (t, /=7.5 Hz, 3 H).
To a solution of compound 12 (1.56 g) in methanol (10 vol) was added a solution of hydrochloric acid (1.24 ml) in water (2 mL) at 25-30C. The reaction mixture was stirred at 25-30C for 4-6 hrs. The reaction was monitored by TLC. After completion, the methanol was distilled off under reduced pressure. The obtained residue was taken up in water and extracted with ethyl acetate (100 mL). The extract was washed with aqueous sodium bicarbonate (50 mL) and then the ethyl acetate was removed by distillation to provide the crude product. The crude product was crystallized from a mixture of ethyl acetate and diisopropylether to provide a white solid.
7 g With hydrogenchloride; In dichloromethane; water; 2-({(3af?,4S,6R,6aS)-6-[7-[(1 2S)-2-(3,4-diflurophenyl)-cyclopropyl]amino}- 5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-cy]pyrimidin-3-yl]-2,2-dimethyltetrahydro- 3aH-cyclopenta [d ][1 ,3]dioxal-4-yl}oxy)-1 -ethanol (10.0 gm) was dissolved in methylene dichloride (100.0 ml) and the solution was stirred for 10-15 minutes to the same solution was added concentrated hydrochloric acid (3.33 gm) and reaction mass was stirred for stirred for 60-90 min. The progress of reaction was monitored by HPLC. After completion of reaction, purified water (150 ml) was charged to the reaction mass, solution was basified to pH 8-9 using sodium hydroxide solution, stirred, and layers were separated. Methylene dichloride layer was washed using purified water (100.0 ml) and then 10 % W V sodium chloride solution. The methylene dichloride was evaporated at 30-35C under reduced pressure to produce 8.0 gm of (1 S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl] aminoJ-Sipropylthioi-SH-ll ^.SHriazolo^.S-dlpyrimidin-S-yll-S^- hydroxyethoxy) cyclopentane-1 , 2-diol (ticagrelor) as oil. To the same oil ethyl acetate (40.0 ml) was added, the solution was stirred and heated to 50- 55 C followed by addition of n-heptane (50.0 ml) and the solution was maintained at same temperature for 30 min. The resulting solution was gradually cooled to room temperature and further cooled and maintained at 0-5C, for 30-40 min. Obtained solid was filtered, washed with pre-chilled n- heptane (8 ml), suck dried and dried at 50-55C to give pure white crystalline solid of ticagrelor, 8.0 gm. (HPLC purity: 98.2 % by area). Purification: Above obtained solid (8.0 gm) was dissolved in ethyl acetate (40 ml), stirred and heated to 50C followed by addition of n-heptane (50 ml) with stirring at 50C and maintained for 30 min. The resulting solution was gradually cooled to room temperature and further cooled and maintained at 0-5C for 30-40 min. Obtained solid was filtered, washed with pre-chilled n-heptane (8.0 ml), suck dried and dried at 50-55X to give pure white crystalline powder of ticagrelor. Crystalline form of ticagrelor of formula (I) is characterized by its PXRD as illustrated in Figure 3. The IR spectrum of crystalline form of ticagrelor of formula (I) having characteristic peaks at IR (KBr): 457.75, 536.32, 579.54, 618.83, 642.34, 671.61 , 714.13, 753.65, 771.86, 790.62, 808.82, 826.94, 890.70, 934.77, 993.68, 1050.52, 1071.86, 1093.04, 1114.20, 1170.46, 1 196.11 , 1209.08, 1275.67, 1329.10, 1384.24, 1426.75, 1453.39, 1521.02, 1588.92, 1625.30, 2931.85, 2963.75, 3293.51 , 3390.76 cm'1 , and having characteristic peaks at IR (KBr) 579.54, 618.83, 671.61 , 771.86, 826.94, 993.68, 1050.52, 1093.04, 1114.20, 1196.1 1 , 1275.67, 1329.10, 1426.75, 1453.39, 1521.02, 1588.92, 1625.30, 2931.85, 2963.75, 3293.51 , 3390.76 cm-1 as illustrated in Figure 4. 1H NMR (CDCI3) : delta= ppm 9.38-9.37 (d, NH), 7.37-7.25 (dd, 2H), 7.07 (s, 1 H), 5.13-5.12 (s, 1 H), 5.07-5.06 (d, 1 H), 4.98-4.92 (q, 1 H), 4.63-4.60 (t, 1 H), 5.57-5.52 (q, 1 H), 3.75-3.73 (t, 1H), 3.51-3.49 (t, 4H), 3.16-3.13 (q, 1 H), 2.95- 2.90 (q, 1 H), 2.88-2.81 (q, 1 H), 2.64-2.61 (q, 1 H), 2.13-2.10 (q, 1 H), 2.05- 2.00 (q, 1 H) 1.56-1.51 (q, 1 H), 1.50-1.46 (m, 2H), 1.39-1.36 (q, 1 H), 0.82- 0.78 (t, 3H) ppm. 13C NMR (100. MHz, CDCI3): delta= 169.17, 153.95, 149.43, 139.40, 123.17, 122.82, 1 17.13, 116.96, 114.85, 114.72, 81.78 (CH2), 74.38 (CH2), 73.68 (CH2), 70.86 (CH2), 60.30 (CH2), 60. i5 (CH), 35.70 (CH), 32.11 (CH), 24.06 (CH2), 22.30 (CH2), 13.21 (CH2), 12.98 (CH3), 62.48, 71.7 (CH2), 35.10, 62.48, 112.41 , 121.32, 125.35, 129.33, 135.99, 145.47, 149.5, 151.7, 155.15, 157.2, 157.69, 161.30 (CH) ppm. MS m/z (%): 523.0 [M+1]+ (100). Anal. Calcd. for CHNOS (250.01): C, 52.81 ; H, 5.35; N, 16.07. Found: C, 52.69; H, 5.34; N, 15.93 % [Yield = 7.0 gm (75.27%); Purity (HPLC) = 99.5%]
23 g With hydrogenchloride; In methanol; at 20℃; for 3.41667h; (3aR-(3aa,4a,6a(lR*,2S*)6aa)-2-[6-({7-[2-(3,4-difluorophenyl)cyclopropyl] amino-5-^ropylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3yl)tetrahydro-2,2-dimethyl-4H- cyclopenta-l,3-dioxol-4yl)oxy]ethanol (30 gm) was dissolved in methanol (240 ml) and then added concentrated hydrochloric acid (90 ml) slowly for 15 minutes. The reaction mass was stirred for 3 hours at room temperature and the solvent was distilled off under vacuum to obtain a residual mass. The residual mass was adjusted to pH to 8 with sodium hydroxide (25%) and then extracted with ethyl acetate. The layers were separated and the organic layer was dried with sodium sulfate. The solvent was distilled off under vacuum at below 40C to obtain a solid. To the solid was added acetonitrile (300 ml) at 55C to obtain a clear solution. To the solution was then cooled to 10 to 15C for 1 hour, filtered and then dried to obtain 23 gm of ticagrelor.
With hydrogenchloride; In methanol; water; at 20℃; for 24h; Charge (2.6 gm) of compound 28 in (8-10 Vol.) of Methanol at Room temperature. Charge dilute HC1 (1.4 gm) at RT. Stir the reaction mass for 24 hours at RT. Upon completion of the reaction checked by TLC, the reaction mass was brought to slightly acidic pH of 6-6.5 by using dilute aq. NaOH. Upon removal of methanol under vacuum and extracting organic mass with ethyl acetate and further washing this organic layer with brine and concentration of ethyl acetate under vacuum gave crude Ticagrelor 1. Further purification of Ticagrelor 1. was carried out by crystallization from a mixture of ethyl acetate and heptane to provide white to off-white solid. The purity of Ticagrelor 1 was 99.6% (HPLC). Some of the characteristic and selective peaks (delta value) in -NMR (CDG13) for 1 are 7.5 (s, 1H), 6.83 - 7.2 (m, 3H), 5.67 (m, 1 H), 5.04 (m, 1H), 4.82 (m, 1H), 4.13 (m, 1H), 3.6 - 3.9 (m, 4H), 3.2 (t, 2H), 1.57 (m, 2H), 0.79 (t, 3H).
With hydrogenchloride; In water; at 20℃; for 48h; A flask is charged with organic layer containing 2-(((3aR,4S,6R,6aS)-6-(7- (((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3] triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4- yl)oxy)ethan-1 -ol (1 10 mL) and 2% hydrochloric acid solution (75 mL). The reaction mixture is stirred at room temperature for 48 hours and progress of the reaction is monitored by TLC. Then the reaction mixture is diluted with ethyl acetate (50 mL), layers are separated. The organic layer is sequentially washed with water (50 mL), brine solution (50 mL) followed by complete distillation under vacuum at 45C. The crude compound is dissolved in ethyl acetate (12 mL) and then hexane (50 mL) is added. The mixture is stirred for 2 hours followed by isolation of solid by filtration. The obtained solid is dissolved in ethyl acetate (12 mL) and treated with charcoal followed by filtration. The filtrate is subjected to complete distillation and obtained solid is purified by column chromatography using ethyl acetate:hexane (1 :1 ) and methanohdichloromethane (5:95) to afford the title compound
4.16 g With hydrogenchloride; In methanol; water; at 35 - 40℃; for 16h; Hydrochloric acid (3N, 24 mL) was added to a solution of <strong>[274693-26-4]2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d](1,3)dioxol-4-yl)oxy)ethanol</strong> (6 g, Formula XI as obtained from Example 10) in methanol (30 mL). The reaction mixture was heated to 35C to 40C. The reaction mixture was stirred for 16 hours at 35C to 40C. Methanol was distilled off completely under vacuum at 30C to 35C to obtain a residue. The residue was extracted with dichloromethane (36 mL). The organic layer was washed with aqueous hydrochloric acid (IN, 30 mL) followed by washing with aqueous sodium bicarbonate solution (3 g in 30 mL) and deionized water (30 mL). The organic layer was distilled off to dryness to obtain a crude material. The crude material was purified with acetonitrile (30 mL) to afford the title compound. Yield: 4.16 g
With pyridinium p-toluenesulfonate; In methanol; water; at 72℃; for 4h;Green chemistry; Example-3: Preparation of Ticagrelor (I) A mixture of methanol (1000 ml), solid resulted in example-2 (200 gm), pyridinium p- toluene sulphonate (178 gm) and water (400 ml) was heated to 72C and maintained for about 4 hours. The progress of the reaction was monitored by HPLC. On completion of the reaction, the reaction mixture was cooled to 30C followed by the addition of water (1600 ml). The resultant reaction mass was maintained for about 4 hours. The solid thus obtained was filtered, washed with a mixture of methanol (133 ml) and water (266 ml), washed with water (400 ml) and dried. Yield: 350 gm
169 g With hydrogenchloride; In methanol; toluene; at 15 - 20℃; for 1h; <strong>[274693-26-4]2-({(3aR,4S,6R,6aS)-6-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxolan-4-yl}oxy)ethanol</strong> (VII) in toluene was cooled to 15 to 20 C, Then, 465 g of concentrated hydrochloric acid cooled to 15 to 20 C and 625 g of methanol were added and the reaction mixture was stirred at about 15 to 20 C for about 1 hour. The aqueous solution containing the product was added to 400 g of sodium bicarbonate and water at a temperature below 20 & lt; 0 & gt; C 750 g of the dubbed solution, extracted twice with ethyl acetate, 800 g each time; The organic phases were combined, washed with water, dried over anhydrous sodium sulfate and concentrated. The concentrate was crystallized from a mixed solvent of ethyl acetate / isooctane (720 g / 830 g) to give 169 g of the title compound.
With hydrogenchloride; In water; at 100℃; for 2h; 1 g (4 mmol) of 4,6-dichloro-2- (propylthio) -5-aminopyrimidine, 11.5 g (4 mmol) of NH2-R and 1.7 g (16 mmol) of triethylamine were added to a reaction flask,After stirring at 100 C for 12h under stirring, the mixture was cooled to room temperature and added with 30mL of water. Each was washed with ethyl acetate and saturated brine three times, and the solvent was removed by rotary evaporation to give Compound 5 as a pink powder.To 0.42 g (1 mmol) of compound 5, 10 mL of glacial acetic acid and 0.14 g (2 mmol) of sodium nitrite were added and refluxed for 3 hours at 100 C. After cooling to room temperature, ammonia water was added to neutrality, extracted with ethyl acetate and evaporated to dryness to give compound 6;To 0.45 g (1 mmol) of compound 6, 30 mL of toluene, 0.58 g (5 mmol) of potassium carbonate and 0.17 g (1 mmol) of NH2-R were added and refluxed at 210 C for 2 hours.Cooled to room temperature, filtered and the filtrate was evaporated to dryness to give compound 7; Compound 7 was refluxed in hydrochloric acid at 100 C for 2 hours to obtain the compound ticagrelor.
10.9 g With hydrogenchloride; In methanol; water; at 20 - 25℃; 12.4 g (22.1 mmol, 1.0 eq) of the compound of formula II obtained in Example 8,Was dissolved in 200 ml of methanol, 73.7 ml (221.1 mmol, 10.0 eq) of 3 mol / L aqueous hydrochloric acid was added at 20-25 C, and the mixture was stirred at 20-25 C,TLC showed the reaction was neutralized with 45% aqueous sodium hydroxide to pH = 7 after completion of the reaction and concentrated under reduced pressure. The residue was added with water100ml, extracted with ethyl acetate (300ml × 2) and saturated aqueous sodium chloride solution (100ml), concentrated under reduced pressure to dryness, and crystallized from ethyl acetate / isooctane to give 10.9g of ticagrelor (I) ; White solid; HPLC purity: 99.4%.
6.95 kg Step 4: The organic phase containing Compound 6 was added with diisopropylethylamine, 0.3 kg, stirred at room temperature for 30 minutes, and then concentrated under reduced pressure at a temperature of 45 C. to give Compound 6 as an oil, 7.8 kg, which was directly used in the next step. One-step reactionStep 5: Add 200L reaction tank to methanol, turn on stirring under nitrogen protection, add compound 6, cool to 0C-5C, add 2.61kg concentrated hydrochloric acid and 3.4kg methanol mixture, and incubate at 5C-15C for 3 hours. Stop stirring, set aside for 15 minutes, separate the liquid, discard the organic phase;Step 6: The aqueous phase was added with ethyl acetate, 50 L, extracted, and the liquid was separated. The resulting organic phase was added with diisopropylethylamine, 0.3 kg, and was concentrated under reduced pressure at a temperature of 40 C. When decompression concentrated to a level of about 10 L remaining. At the time, n-heptane was added, and 30 L of solid was precipitated, and the mixture was stirred at room temperature for 1 hour, then cooled to 0-10 DEG C., stirred for 1 hour, centrifuged, and the resulting product was dried under reduced pressure at 40 DEG C. to obtain the final product ticagrelor, 6.95 kg. .The final product NMR data is as follows:H(d6-DMSO): 8.95 (d, 1H), 7.39-7.21 (m, 2H), 7.10-7.00 (m, 1H), 5.12 (d, 1H), 5.05 (d, 1H), 4.96 (q, 1H), 4.62-4.54 (m, 2H), 3.95 (brs, 1H), 3.79-3.73 (m, 1H), 3.55-3.47 (m, 4H), 3.20-3.13 (m, 1H), 2.98-2.81 (m, 2H) ), 2.63 (d, 1H), 2.29-2.21 and 2.16-2.09 (m, 1H), 2.07-2.00 (m, 1H), 1.73-1.33 (m, 4H), 0.99 (t, 3H).MS(APCI)m/e 523[M+H]+After testing, the content of ticagrelor in the obtained product is: 99.8%Oxidation Impurities (Sulfoxide and Sulfone) Content: Not Detected
0.69 g With hydrogenchloride; In methanol; water; at 15℃; for 8h; 7 ml of hydrochloric acid and 28 ml of methanol were added to the reaction solution prepared in Example 7.Stir at 15C for 8 hours, after the reaction is over,The organic layer was separated and an appropriate amount of potassium carbonate was added to the aqueous layer to a pH of about 8.Then it is extracted with ethyl acetate (30 ml x 3).The organic layer is concentrated.Yellow solid product ticagrelor 0.69g.
10.7 kg With hydrogenchloride; In water; toluene; at 10 - 20℃;Large scale; (1) cooling the toluene solution of the upper step product remaining in the 200L reaction vessel to 10 to 20 C;(2) adding 37.062 kg of hydrochloric acid and 55 L of methanol mixed solution cooled to 10 to 20 C into the reaction kettle under stirring;After the addition is completed, the mixture is kept at 10 to 20 C for 3 to 4 hours;(3) TLC detection reaction was completed, ethyl acetate: isooctane = 1:1, and the upper organic phase plate was taken;Stop stirring, let stand for stratification, and separate the lower methanol water phase for use;(4) adding a lower methanol aqueous phase separated in the above step to a 500 L reaction kettle, and adding 20% potassium carbonate aqueous solution (25.406 kg of potassium carbonate and 101.64 L of purified water) under stirring;Finally adjust the pH between 7-9;(5) adding 55 L of ethyl acetate under stirring, and stirring for 30 min;Stop stirring, let stand layering, separate the lower layer of water, and transfer the upper organic phase to the PE barrel for use;(6) The lower aqueous phase was transferred to the reaction vessel, 55 L of ethyl acetate was added, and the mixture was stirred for 30 minutes; the stirring was stopped, the layer was allowed to stand, and the lower aqueous phase was separated; (7) Combine the two organic phases, add 200L reaction kettle, add 55L purified water under stirring, and stir for 30 minutes;Stop stirring, let stand for stratification, and separate the lower aqueous phase;Then, 55 L of purified water was added to the reaction vessel, and the mixture was stirred for 30 minutes; the stirring was stopped, the layer was allowed to stand, and the lower aqueous phase was separated;(8) adding 686 g of activated carbon to the organic phase (the amount of activated carbon is 5% of the crude product, the crude product is calculated in 100% yield), heating to 40-50 C, stirring for 30 minutes;(9) Filter the filter pad with diatomaceous earth (about 100 g of diatomaceous earth), distill off the solvent under reduced pressure at 50 C, and steam until no more liquid flows out;Then add 11 L of ethyl acetate to distill off the solvent, repeat 2 times until the solid is produced, no more liquid will flow out;To the residue, 68.61 L of ethyl acetate was added and heated to 50-60 C to dissolve (the amount of ethyl acetate was 5 times the mass of the crude product, and the crude product was calculated in 100% yield);Transfer the solution to a 50L reactor and heat to 50-60 C; (10) adding 82.33 L of isooctane preheated to 50-60 C under stirring (the amount of isooctane is 1.2 times the volume of ethyl acetate);Control the addition speed to keep the internal temperature above 50 C, and gradually precipitate solids during the addition;(11) After the addition is completed, the temperature is lowered by stirring to a temperature of 20 to 30 C, and stirred for 1 hour;(12) further cooling to 0 to 10 C and stirring for 2 hours;(13) centrifugal filtration, the reaction kettle and the filter cake are washed with a mixture of 13.72 L of ethyl acetate and 16.47 L of isooctane precooled to 0 to 10 C;(14) The filter cake was dried under vacuum at 45 to 55 C for 8 to 12 hours to obtain 11.6 kg of ticagrelor crude product (Im-4); the yield was 85%. (1) Add 45 L of dichloromethane and 108 L of t-butanol to a 200 L crystallizer; add 11.5 kg of ticagrelor crude by stirring. (2) heating to 50 ~ 60 C under stirring for 1 hour; cooling to 20 ~ 30 C, stirring for 1 hour;(3) further cooling to 0 to 10 C for 2 hours;(4) centrifugal filtration, the reaction kettle and the filter cake are rinsed with water precooled to 0 to 10 C;(5) The filter cake was dried under vacuum at 45-55 C for 8 to 12 hours to obtain 10.7 kg of ticagrelor; the weight yield was 93%. After testing total impurities of 0.74%, SM1: 0.09%, Im-1: 0.08%
9.8 g With trifluoroacetic acid; In dichloromethane; at 0 - 10℃; for 1h; a, preparation of crude ticagreride: 56gIsopropyl ticagreIntermediate(0.1 mol, 1.0 eq) was placed in 500 mL of dichloromethane and stirred to dissolve;1.1 g of trifluoroacetic acid (0.01 mol, 0.1 eq) was added dropwise at 0-5 C.The dichloromethane solution was dripped in 30 minutes; after the dropwise addition, the reaction was carried out at 5-10 C.The reaction was monitored by TLC; after 1 hour, TLC showed the reaction of the starting material was completed and 200 mL of water was added.The pH was adjusted to 6-7 with potassium carbonate, and the aqueous layer was extracted with dichloromethane (200 mL×2). The organic phase was combined and then water (300 mL×2).Wash with saturated brine (300 mL × 2), dry over anhydrous sodium sulfate, and filter.Evaporated to dryness under reduced pressure to give 45.8 g of crude ticagrei, yield 88%b, the preparation of ticagrelor amorphous: take 10g crude ticagrei,Placed in 100 ml of tetrahydrofuran solvent, stirred, and warmed to 65-70 C,Maintain this temperature for 30 min, add 1 g of activated carbon, stir for 10 min, filter with hot heat, rinse the filter cake with tetrahydrofuran, and gradually cool the filtrate to 30-35 C with stirring.Then slowly distill off the solvent under reduced pressure, and recycle the tetrahydrofuran.Made a foamy solid, crushed, dried,9.8 g of ticagrelor amorphous product was obtained.Its X-ray powder diffraction pattern is shown in Figure 1.
With hydrogenchloride; In methanol; water; Ticagrelor precursor 2-(((3aR, 4S, 6R, 6aS) -6- (7-(((1R, 2S) -2- (3,4-difluorophenyl) cyclopropyl) amino) -5 -(Propylthio) -3H- [1,2,3] triazolo [4,5-d] pyrimidin-3-yl) -2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1 , 3] dioxol-4-yl) oxy) ethanol was added to a mixture of 9.5 g of concentrated hydrochloric acid and 100 mL of methanol. After the reaction was completed, 150 mL of ethyl acetate was added and neutralized with an aqueous sodium bicarbonate solution. The organic layer was separated and washed with brine. The organic layer was concentrated to obtain a ticagrelor free base that is an oil phase.

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  • [ 145783-12-6 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: nitric acid / 2 h / 20 °C 1.2: 0.5 h / 0 °C 2.1: N,N-diethylaniline; trichlorophosphate / 3 h / Reflux 3.1: tetrahydrofuran / 2 h / 0 - 10 °C 4.1: acetic acid; iron / ethanol; water / 0.33 h / 60 °C 5.1: sodium nitrite; acetic acid / toluene; water / 0.5 h / 20 °C 5.2: pH 8 - 9 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C 7.1: hydrogenchloride / water; methanol / 3 h / 20 °C 7.2: pH 8 - 9
Multi-step reaction with 8 steps 1.1: sodium acetate; sodium hydroxide / ethanol; water / 20 °C 1.2: 0.5 h / 0 °C 1.3: 0 - 5 °C 2.1: pyridine; trichlorophosphate / toluene / 4.75 h / 70 °C 3.1: ammonium formate; zinc / methanol; isopropyl alcohol / 0.33 h 4.1: hydrogen / 11 h / 20 °C 5.1: triethylamine; sodium iodide / 1,4-dioxane / 7 h / 120 °C 6.1: sodium nitrite / water; acetic acid; ethyl acetate / 30 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h 8.1: hydrogenchloride; water / methanol / 1 h
Multi-step reaction with 10 steps 1.1: nitric acid; acetic acid / 2 h / 25 - 30 °C 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 3 h / 115 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 3.2: 1.5 h / -25 - -15 °C 3.3: 0.08 h 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 5.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 6.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 7.1: iodine / acetone / 2 h / 25 - 60 °C 8.1: potassium carbonate / acetone / 20 h / 55 - 60 °C 9.1: hydrogenchloride; water / methanol / 5 h / 20 - 25 °C 9.2: 25 - 30 °C / pH 10 10.1: formic acid / palladium 10% on activated carbon / 50 °C
Multi-step reaction with 7 steps 1.1: nitric acid; acetic acid / 2 h / 25 - 30 °C 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 3 h / 115 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 3.2: 1.5 h / -25 - -15 °C 3.3: 0.08 h 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 5.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 6.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 7.1: hydrogenchloride; water / toluene; methanol / 2 h / 25 - 30 °C 7.2: pH > 8
Multi-step reaction with 8 steps 1.1: nitric acid; acetic acid / 2 h / 25 - 30 °C 2.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 3 h / 115 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 3.2: 1.5 h / -25 - -15 °C 3.3: 0.08 h 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 5.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 6.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 7.1: potassium carbonate / acetone / 24 h / 25 - 60 °C 8.1: hydrogenchloride; water / methanol / 5.5 h / 20 - 55 °C 8.2: 25 - 30 °C / pH 10
Multi-step reaction with 7 steps 1.1: sodium hydroxide; sodium acetate / 0 - 20 °C 1.2: 0.5 h / 0 - 8 °C 2.1: trichlorophosphate / toluene / 4.5 h / 70 - 94 °C 3.1: triethylamine / ethanol / 5 h / 5 - 35 °C / Cooling with ice 4.1: hydrogenchloride / methanol / 24 h / 20 °C 5.1: palladium on activated charcoal; hydrogen / methanol; tetrahydrofuran / 3 h / 20 °C / 7500.75 Torr 6.1: sodium nitrite; acetic acid / water; methanol; acetonitrile / 4 h / 5 °C 7.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 5 h / 5 - 20 °C

  • 3
  • [ 145783-13-7 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: N,N-diethylaniline; trichlorophosphate / 3 h / Reflux 2.1: tetrahydrofuran / 2 h / 0 - 10 °C 3.1: acetic acid; iron / ethanol; water / 0.33 h / 60 °C 4.1: sodium nitrite; acetic acid / toluene; water / 0.5 h / 20 °C 4.2: pH 8 - 9 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C 6.1: hydrogenchloride / water; methanol / 3 h / 20 °C 6.2: pH 8 - 9
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 3 h / 115 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 2.2: 1.5 h / -25 - -15 °C 2.3: 0.08 h 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 6.1: hydrogenchloride; water / toluene; methanol / 2 h / 25 - 30 °C 6.2: pH > 8
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 3 h / 115 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 2.2: 1.5 h / -25 - -15 °C 2.3: 0.08 h 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 6.1: potassium carbonate / acetone / 24 h / 25 - 60 °C 7.1: hydrogenchloride; water / methanol / 5.5 h / 20 - 55 °C 7.2: 25 - 30 °C / pH 10
Multi-step reaction with 9 steps 1.1: N-ethyl-N,N-diisopropylamine; trichlorophosphate / toluene / 3 h / 115 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 2.2: 1.5 h / -25 - -15 °C 2.3: 0.08 h 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 4.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 5.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 6.1: iodine / acetone / 2 h / 25 - 60 °C 7.1: potassium carbonate / acetone / 20 h / 55 - 60 °C 8.1: hydrogenchloride; water / methanol / 5 h / 20 - 25 °C 8.2: 25 - 30 °C / pH 10 9.1: formic acid / palladium 10% on activated carbon / 50 °C
Multi-step reaction with 9 steps 1: triethylamine; dmap / dichloromethane / 2 h / 10 - 20 °C 2: sodium hydrogencarbonate / dichloromethane; water / 5 h / 60 - 65 °C 3: palladium on activated charcoal / methanol / 16 h / 25 - 30 °C / 2625.26 Torr 4: hydrogenchloride; sodium nitrite / dichloromethane; water / 2 h / 0 - 5 °C 5: toluene-4-sulfonic acid / 4 h / 35 - 40 °C 6: triethylamine; dmap / dichloromethane / 2 h / -5 - 0 °C 7: triethylamine / 1 h / 25 - 30 °C 8: lithium borohydride / tetrahydrofuran / 16 h / 20 - 25 °C / Inert atmosphere 9: hydrogenchloride / water; methanol / 16 h / 35 - 40 °C
Multi-step reaction with 6 steps 1: tetrabutylammomium bromide; phosphorus(V) oxybromide / acetonitrile / Reflux 2: acetic acid; iron / methanol / 20 - 60 °C 3: triethylamine / 1-methyl-pyrrolidin-2-one / 6 h / 85 - 90 °C 4: acetic acid; sodium nitrite / water / 0 - 5 °C 5: triethylamine / acetonitrile / 1 h / 20 - 25 °C 6: hydrogenchloride / methanol; water / 20 - 25 °C

  • 4
  • [ 112897-97-9 ]
  • [ 274693-27-5 ]
  • 5
  • 2-[((3aR,4S,6R,6aS)-6-[[5-amino-6-chloro-2-(propylsulfanyl)-4-pyrimidinyl]amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy]-1-ethanol [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sodium nitrite; acetic acid / toluene; water / 0.5 h / 20 °C 1.2: pH 8 - 9 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C 3.1: hydrogenchloride / water; methanol / 3 h / 20 °C 3.2: pH 8 - 9
Multi-step reaction with 3 steps 1: sodium nitrite / water; acetic acid; ethyl acetate / 30 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h 3: hydrogenchloride; water / methanol / 1 h
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / water; acetonitrile / 20 °C 2: potassium carbonate / acetonitrile / 25 - 30 °C 3: hydrogenchloride / water; dichloromethane
Multi-step reaction with 2 steps 1.1: hydrogenchloride / water 1.2: 0.01 h 2.1: N-ethyl-N,N-diisopropylamine; sodium hydroxide / water; ethyl acetate / 15 - 20 °C 2.2: 1 h / 20 °C
Multi-step reaction with 2 steps 1: isopentyl nitrite / isopropyl alcohol / 20 - 30 °C 2: hydrogenchloride / methanol / 20 °C
Multi-step reaction with 3 steps 1: isopentyl nitrite / isopropyl alcohol / 25 - 30 °C 2: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 20 °C 3: hydrogenchloride / methanol / 20 °C
Multi-step reaction with 3 steps 1: sodium nitrite / water; acetic acid / 2 h / 0 °C 2: N-ethyl-N,N-diisopropylamine / ethyl acetate / 4 h / 20 °C 3: hydrogenchloride / water; methanol / 6 h / 10 °C
Multi-step reaction with 3 steps 1: sodium nitrite; acetic acid / toluene; water / 2 h / 0 - 10 °C 2: potassium carbonate / toluene; water / 2 h / 20 - 30 °C 3: hydrogenchloride / toluene; methanol / 1 h / 15 - 20 °C
Multi-step reaction with 3 steps 1.1: oxalic acid / tetrahydrofuran / 0.17 h / 20 °C / Large scale 1.2: 1 h / 10 - 40 °C / Large scale 2.1: N-ethyl-N,N-diisopropylamine / 2 h / 43 °C / Large scale 3.1: hydrogenchloride / methanol / 3 h / -3 - 20 °C / Large scale
Multi-step reaction with 3 steps 1: acetic acid; sodium nitrite / toluene; water / 1 h / Large scale 2: potassium carbonate / toluene; water / 3 h / 20 °C / Large scale 3: hydrogenchloride / toluene; water; methanol / 3 h / 5 °C / Large scale
Multi-step reaction with 3 steps 1: sodium nitrite; acetic acid / toluene; water / 1 h / 10 - 20 °C 2: potassium carbonate / toluene; water / 1 h / 10 °C 3: hydrogenchloride / methanol / 4 h / 20 °C / Industrial scale
Multi-step reaction with 3 steps 1: sodium nitrite / acetic acid / 3 h / 100 °C 2: potassium carbonate / toluene / 2 h / 210 °C 3: hydrogenchloride / water / 2 h / 100 °C
Multi-step reaction with 3 steps 1.1: acetic acid; sodium nitrite / toluene; water / 1 h / 0 - 10 °C / Inert atmosphere; Large scale 2.1: potassium carbonate / toluene; water / 2 h / 0 - 20 °C / Inert atmosphere; Large scale 3.1: N-ethyl-N,N-diisopropylamine / toluene; water / 0.5 h / 45 °C / Large scale 3.2: 3 h / 0 - 15 °C / Inert atmosphere; Large scale
Multi-step reaction with 3 steps 1: sodium nitrite; acetic acid / toluene; water / 10 - 20 °C / Large scale 2: potassium carbonate / toluene; water / 10 - 20 °C / Large scale 3: hydrogenchloride / toluene; water / 10 - 20 °C / Large scale
Multi-step reaction with 3 steps 1: sodium nitrite; acetic acid / toluene; water / 10 - 20 °C / Large scale 2: potassium carbonate / toluene; water / 10 - 20 °C / Large scale 3: hydrogenchloride / toluene; water; methanol / 10 - 20 °C / Large scale
Multi-step reaction with 3 steps 1: sodium nitrite; hydrogenchloride / ethyl acetate; water / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / ethyl acetate / 3 h / 20 °C / Inert atmosphere 3: hydrogenchloride / water; methanol / 2 h / 2 °C / Inert atmosphere
Multi-step reaction with 3 steps 1: hydrogenchloride; sodium nitrite / ethyl acetate; water / 1 h / 0 °C 2: ethyl acetate / 2 h / 40 °C 3: hydrogenchloride / ethyl acetate; water
Multi-step reaction with 3 steps 1: acetic acid; sodium nitrite / 0 - 20 °C 2: triethylamine / acetonitrile / 2 h / 80 °C 3: hydrogenchloride / methanol; water / 0.5 h / 20 °C
Multi-step reaction with 3 steps 1: sodium nitrite; acetic acid / water; toluene / 1 h / 0 - 2 °C 2: potassium carbonate / water 3: hydrogenchloride / methanol / 2 h / 0 - 10 °C / Large scale
Multi-step reaction with 3 steps 1: acetic acid; sodium nitrite / dichloromethane; water / 2 h / 0 - 5 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 0 - 25 °C 3: hydrogenchloride / water; methanol / 25 - 35 °C

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  • 6
  • [ 145783-14-8 ]
  • [ 274693-27-5 ]
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[2]Patent: WO2012/85665,2012,A2
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  • 7
  • (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h 2: hydrogenchloride; water / methanol / 1 h
Multi-step reaction with 10 steps 1.1: methanol / 12 h / 20 - 25 °C 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 2.2: 3 h / 20 - 25 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 3.2: 1.5 h / -25 - -15 °C 3.3: 0.08 h 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 5.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 6.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 7.1: iodine / acetone / 2 h / 25 - 60 °C 8.1: potassium carbonate / acetone / 20 h / 55 - 60 °C 9.1: hydrogenchloride; water / methanol / 5 h / 20 - 25 °C 9.2: 25 - 30 °C / pH 10 10.1: formic acid / palladium 10% on activated carbon / 50 °C
Multi-step reaction with 7 steps 1.1: methanol / 12 h / 20 - 25 °C 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 2.2: 3 h / 20 - 25 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 3.2: 1.5 h / -25 - -15 °C 3.3: 0.08 h 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 5.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 6.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 7.1: hydrogenchloride; water / toluene; methanol / 2 h / 25 - 30 °C 7.2: pH > 8
Multi-step reaction with 8 steps 1.1: methanol / 12 h / 20 - 25 °C 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 2.2: 3 h / 20 - 25 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 3.2: 1.5 h / -25 - -15 °C 3.3: 0.08 h 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 5.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 6.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 7.1: potassium carbonate / acetone / 24 h / 25 - 60 °C 8.1: hydrogenchloride; water / methanol / 5.5 h / 20 - 55 °C 8.2: 25 - 30 °C / pH 10
Multi-step reaction with 5 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: N,N-dimethyl-formamide / 60 °C 3.1: sodium hydride / tetrahydrofuran / 1 h / -20 °C 3.2: 16 h / -20 °C 4.1: lithium borohydride / tetrahydrofuran / 16 h / 0 °C 5.1: phosphoric acid / ethanol / 24 h / 20 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 1 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 16 h / 20 °C 3.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 4.1: sodium dithionite; sodium carbonate / methanol; water / 16 h / 40 °C 5.1: isopentyl nitrite / acetonitrile / 2 h / 70 °C 6.1: sodium hydride / tetrahydrofuran / 1 h / -20 °C 6.2: 16 h / -20 °C 7.1: lithium borohydride / tetrahydrofuran / 16 h / 0 °C 8.1: phosphoric acid / ethanol / 24 h / 20 °C
Multi-step reaction with 5 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: N,N-dimethyl-formamide / 60 °C 3.1: sodium hydride / tetrahydrofuran / 1 h / -20 °C 3.2: 16 h / -20 °C 4.1: lithium borohydride / tetrahydrofuran / 16 h / 0 °C 5.1: phosphoric acid / water; ethanol / 24 h / 20 °C
Multi-step reaction with 5 steps 1.1: tetrahydrofuran / 1 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 16 h / 20 °C 2.2: 2 h / 20 °C 3.1: hydrogen; 5%-palladium/activated carbon / methanol / 16 h / 7500.75 Torr 4.1: sodium nitrite; acetic acid / 0.5 h / 20 °C 5.1: phosphoric acid / methanol; water / 24 h / 20 °C
Multi-step reaction with 5 steps 1.1: tetrahydrofuran / 1 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 16 h / 20 °C 2.2: 2 h / 20 °C 3.1: hydrogen; 5%-palladium/activated carbon / methanol / 16 h / 7500.75 Torr 4.1: sodium nitrite; acetic acid / 1 h / 20 °C 5.1: hydrogenchloride / methanol; water / 20 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 1 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 16 h / 20 °C 3.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 4.1: sodium dithionite; sodium carbonate / methanol; water / 16 h / 40 °C 5.1: isopentyl nitrite / acetonitrile / 2 h / 70 °C 6.1: sodium hydride / tetrahydrofuran / 1 h / -20 °C 6.2: 16 h / -20 °C 7.1: lithium borohydride / tetrahydrofuran / 16 h / 0 °C 8.1: phosphoric acid / water; ethanol / 24 h / 20 °C
Multi-step reaction with 7 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl acetamide / 1 h / 0 - 5 °C / Inert atmosphere 1.2: 5 h / 50 °C / Inert atmosphere 2.1: potassium <i>tert</i>-butylate / N,N-dimethyl acetamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 2 h / 50 °C / Inert atmosphere 3.1: N,N-dimethyl-formamide / 8.5 h / 60 °C / Inert atmosphere 4.1: osmium(VIII) oxide; 4-methylmorpholine N-oxide; 1,4-bis(9-O-dihydroquinidine)phthalazine / acetone; water / 18.5 h / 0 - 25 °C 5.1: toluene-4-sulfonic acid / ethanol / 12.5 h / Reflux 6.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 1 h / 0 - 5 °C / Inert atmosphere 6.2: 2 h / 50 °C / Inert atmosphere 7.1: hydrogenchloride / water; methanol / 2 h / 0 - 20 °C / Inert atmosphere

  • 8
  • 2-({(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopentadiene[d][1,3]dioxolene-4-yl}oxy)ethanol [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h 2: hydrogenchloride; water / methanol / 1 h
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 25 - 30 °C 2: hydrogenchloride / water; dichloromethane
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 20 °C 2: hydrogenchloride / methanol / 20 °C
Multi-step reaction with 2 steps 1: triethylamine / acetonitrile / 2 h / 80 °C 2: hydrogenchloride / methanol; water / 0.5 h / 20 °C

  • 9
  • [ 145783-15-9 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: triethylamine; sodium iodide / 1,4-dioxane / 7 h / 120 °C 2: sodium nitrite / water; acetic acid; ethyl acetate / 30 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h 4: hydrogenchloride; water / methanol / 1 h
Multi-step reaction with 4 steps 1: triethylamine / 1-methyl-pyrrolidin-2-one / 30 - 90 °C / Inert atmosphere 2: sodium nitrite; acetic acid / toluene; water / 25 - 30 °C 3: potassium carbonate / toluene; water / 25 - 30 °C 4: hydrogenchloride; water / toluene; methanol / 0 - 20 °C
Multi-step reaction with 5 steps 1: acetic anhydride / toluene / 0 - 20 °C 2: triethylamine / ethanol / 40 - 80 °C / Inert atmosphere 3: hydrogenchloride; water / methanol / 35 °C 4: sodium nitrite / water; methanol / 0 - 5 °C 5: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C
Multi-step reaction with 5 steps 1: acetic anhydride / toluene / 0 - 20 °C 2: triethylamine / ethanol / 40 - 80 °C / Inert atmosphere 3: hydrogenchloride; water / methanol / 35 °C 4: sodium nitrite / water; methanol / 0 - 5 °C 5: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C
Multi-step reaction with 5 steps 1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 2: isopentyl nitrite / acetonitrile / 50 - 70 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C 4: lithium borohydride / tetrahydrofuran / 0 - 30 °C 5: hydrogenchloride; water / methanol / 25 - 30 °C
Multi-step reaction with 6 steps 1: acetic anhydride / toluene / 0 - 20 °C 2: triethylamine / ethanol / 50 - 60 °C / Inert atmosphere 3: hydrogenchloride; water / methanol / 35 °C 4: isopentyl nitrite / acetonitrile / 30 - 60 °C 5: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C 6: lithium borohydride / tetrahydrofuran / -10 - 20 °C
Multi-step reaction with 6 steps 1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 2: sodium hydroxide; water / methanol / 0 - 30 °C 3: isopentyl nitrite / acetonitrile / 10 - 70 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 5: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C 6: hydrogenchloride; water / methanol / 25 - 30 °C
Multi-step reaction with 6 steps 1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 2: sodium hydroxide; water / methanol / 0 - 30 °C 3: isopentyl nitrite / acetonitrile / 10 - 70 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 5: hydrogenchloride; water / 16 h / 20 °C 6: lithium borohydride / tetrahydrofuran / -10 - 20 °C
Multi-step reaction with 7 steps 1.1: triethylamine / tetrahydrofuran / 24 h / Reflux 2.1: acetic acid; sodium nitrite / 1 h / 20 °C 3.1: potassium carbonate / 2 h 4.1: sodium hydride / tetrahydrofuran; mineral oil / 0.25 h / -10 °C 4.2: 16 h / -10 °C 5.1: lithium borohydride / tetrahydrofuran / 16 h / 20 °C 6.1: dimethyl sulfoxide / 16 h / 60 °C 7.1: phosphoric acid / methanol / 24 h / 20 °C
Multi-step reaction with 5 steps 1.1: potassium phosphate / tetrahydrofuran / 24 h / 20 °C / Reflux 1.2: 1 h / 20 °C 2.1: methanol / 0.25 h / 20 °C 3.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 3.2: 2 h / -10 °C 3.3: 2 h / 20 °C 4.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 5.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 5 steps 1.1: potassium phosphate / tetrahydrofuran / 24 h / 20 °C / Reflux 1.2: 1 h / 20 °C 2.1: potassium carbonate / 2 h / 20 °C 3.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 3.2: 2 h / -10 °C 3.3: 2 h / 20 °C 4.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 5.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 6 steps 1.1: potassium phosphate / tetrahydrofuran / 24 h / 20 °C / Reflux 1.2: 1 h / 20 °C 2.1: potassium phosphate / 88 h / 70 °C 3.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 3.2: 2 h / -10 °C 4.1: lithium borohydride / tetrahydrofuran / 1 h / 20 °C 5.1: dimethyl sulfoxide / 72 h / 20 - 70 °C 6.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 6 steps 1.1: potassium phosphate / tetrahydrofuran / 24 h / 20 °C / Reflux 1.2: 1 h / 20 °C 2.1: methanol / 0.25 h / 20 °C 3.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 3.2: 2 h / -10 °C 4.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C 5.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 6.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 6 steps 1.1: triethylamine / tetrahydrofuran / 24 h / 20 °C / Reflux 2.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 3.1: methanol / 0.25 h / 20 °C 4.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 4.2: 2 h / -10 °C 4.3: 2 h / 20 °C 5.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 6.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 6 steps 1.1: potassium phosphate / tetrahydrofuran / 24 h / 20 °C / Reflux 1.2: 1 h / 20 °C 2.1: potassium carbonate / 2 h / 20 °C 3.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 3.2: 2 h / -10 °C 4.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C 5.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 6.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 6 steps 1.1: triethylamine / tetrahydrofuran / 24 h / 20 °C / Reflux 2.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 3.1: potassium carbonate / 2 h / 20 °C 4.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 4.2: 2 h / -10 °C 4.3: 2 h / 20 °C 5.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 6.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 7 steps 1.1: triethylamine / tetrahydrofuran / 24 h / 20 °C / Reflux 2.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 3.1: methanol / 0.25 h / 20 °C 4.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 4.2: 2 h / -10 °C 5.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C 6.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 7.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 7 steps 1.1: triethylamine / tetrahydrofuran / 24 h / 20 °C / Reflux 2.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 3.1: potassium carbonate / 2 h / 20 °C 4.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 4.2: 2 h / -10 °C 5.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C 6.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 7.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 7 steps 1.1: triethylamine / tetrahydrofuran / 24 h / 20 °C / Reflux 2.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 3.1: potassium phosphate / 88 h / 70 °C 4.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 4.2: 2 h / -10 °C 5.1: lithium borohydride / tetrahydrofuran / 1 h / 20 °C 6.1: dimethyl sulfoxide / 72 h / 20 - 70 °C 7.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 3 steps 1.1: triethylamine / 48 h / 75 °C 2.1: water; acetic acid; sodium nitrite / 20 h / 25 °C 3.1: 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / 25 °C / Inert atmosphere 3.2: 16 h / 25 °C / Inert atmosphere
Multi-step reaction with 3 steps 1: triethylamine / 48 h / 75 °C 2: acetic acid; sodium nitrite / 0.5 h / 20 - 30 °C 3: triethylamine / tetrahydrofuran / 2 h / 20 °C
Multi-step reaction with 3 steps 1: triethylamine / 48 h / 75 °C 2: acetic acid; sodium nitrite / 0.5 h / 20 - 30 °C 3: sodium carbonate / acetonitrile / 20 h / 20 °C
Multi-step reaction with 3 steps 1: triethylamine / 48 h / 75 °C 2: acetic acid; sodium nitrite / 0.5 h / 20 - 30 °C 3: triethylamine / tetrahydrofuran / 2 h / 20 °C
Multi-step reaction with 3 steps 1: triethylamine / 48 h / 75 °C 2: acetic acid; sodium nitrite / 0.5 h / 20 - 30 °C 3: sodium carbonate / acetonitrile / 20 h / 20 °C
Multi-step reaction with 4 steps 1: triethylamine / ethylene glycol / 9 h / 90 °C 2: acetic acid; sodium nitrite / water; toluene / 10 h / 20 °C 3: potassium carbonate / water / 5 h / 20 - 30 °C 4: hydrogenchloride / methanol; water / 11 h / 10 - 15 °C
Multi-step reaction with 4 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene; N-ethyl-N,N-diisopropylamine / ethylene glycol / 120 - 125 °C 2: toluene-4-sulfonic acid / water; acetonitrile / 20 °C 3: potassium carbonate / acetonitrile / 25 - 30 °C 4: hydrogenchloride / water; dichloromethane
Multi-step reaction with 3 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene; N-ethyl-N,N-diisopropylamine / ethylene glycol / 120 - 125 °C 2: toluene-4-sulfonic acid / water; acetonitrile / 20 °C 3: potassium carbonate / acetonitrile / 25 - 30 °C
Multi-step reaction with 3 steps 1.1: sodium hydrogencarbonate / water / 0.14 h / 100 °C 2.1: hydrogenchloride / water 2.2: 0.01 h 3.1: N-ethyl-N,N-diisopropylamine; sodium hydroxide / water; ethyl acetate / 15 - 20 °C 3.2: 1 h / 20 °C
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; tetra-(n-butyl)ammonium iodide / sulfolane / 95 - 105 °C 2: isopentyl nitrite / isopropyl alcohol / 20 - 30 °C 3: hydrogenchloride / methanol / 20 °C
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; tetra-(n-butyl)ammonium iodide / sulfolane / 95 - 105 °C 2: isopentyl nitrite / isopropyl alcohol / 25 - 30 °C 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 20 °C 4: hydrogenchloride / methanol / 20 °C
Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / water / 20 h / 100 °C 2: sodium nitrite / water; acetic acid / 2 h / 0 °C 3: N-ethyl-N,N-diisopropylamine / ethyl acetate / 4 h / 20 °C 4: hydrogenchloride / water; methanol / 6 h / 10 °C
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / 6 h / 128 °C / Green chemistry 2.1: acetic acid; sodium nitrite / toluene; water / 1 h / 3 - 30 °C / Green chemistry 2.2: 2.5 h / 30 °C / Green chemistry 3.1: pyridinium p-toluenesulfonate / water; methanol / 4 h / 72 °C / Green chemistry
Multi-step reaction with 4 steps 1: triethylamine / 11 h / 100 °C / Inert atmosphere 2: sodium nitrite; acetic acid / toluene; water / 2 h / 0 - 10 °C 3: potassium carbonate / toluene; water / 2 h / 20 - 30 °C 4: hydrogenchloride / toluene; methanol / 1 h / 15 - 20 °C
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / sulfolane / 3 h / 107 °C / Large scale 2.1: oxalic acid / tetrahydrofuran / 0.17 h / 20 °C / Large scale 2.2: 1 h / 10 - 40 °C / Large scale 3.1: N-ethyl-N,N-diisopropylamine / 2 h / 43 °C / Large scale 4.1: hydrogenchloride / methanol / 3 h / -3 - 20 °C / Large scale
Multi-step reaction with 4 steps 1: triethylamine / ethylene glycol / 8 h / 100 °C / Large scale 2: acetic acid; sodium nitrite / toluene; water / 1 h / Large scale 3: potassium carbonate / toluene; water / 3 h / 20 °C / Large scale 4: hydrogenchloride / toluene; water; methanol / 3 h / 5 °C / Large scale
Multi-step reaction with 4 steps 1: triethylamine; ethylene glycol / 1,2-dimethoxyethane / 9 h / 100 °C / Industrial scale 2: sodium nitrite; acetic acid / toluene; water / 1 h / 10 - 20 °C 3: potassium carbonate / toluene; water / 1 h / 10 °C 4: hydrogenchloride / methanol / 4 h / 20 °C / Industrial scale
Multi-step reaction with 4 steps 1: triethylamine / 12 h / 100 °C 2: sodium nitrite / acetic acid / 3 h / 100 °C 3: potassium carbonate / toluene / 2 h / 210 °C 4: hydrogenchloride / water / 2 h / 100 °C
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / ethanol / 20 - 100 °C 2: acetic acid; sodium nitrite / water; toluene / 4 h / 15 - 20 °C 3: potassium carbonate / water / 15 °C 4: trifluoroacetic acid / methanol; toluene / 8 h / 15 °C
Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine / ethanol / 20 - 100 °C 2: acetic acid; sodium nitrite / water; toluene / 4 h / 15 - 20 °C 3: potassium carbonate / water / 15 °C 4: sodium methylate; methanol / 20 °C 5: hydrogenchloride / water; methanol / 8 h / 15 °C
Multi-step reaction with 6 steps 1: triethylamine / dichloromethane / 1 h / 10 - 20 °C 2: triethylamine / 1,4-dioxane / 12 h / Reflux 3: potassium carbonate; ethanol / 24 h / Reflux 4: acetic acid; sodium nitrite / water / 10 - 20 °C 5: potassium carbonate / toluene / 24 h / 20 °C 6: hydrogenchloride / water; methanol / 24 h / 30 °C
Multi-step reaction with 6 steps 1: triethylamine / dichloromethane / 1 h / 10 - 20 °C 2: triethylamine / 1,4-dioxane / 12 h / Reflux 3: trifluoroacetic acid / methanol / 24 h / 20 - 50 °C 4: potassium carbonate; ethanol / 24 h / Reflux 5: acetic acid; sodium nitrite / water / 10 - 20 °C 6: potassium carbonate / tetrahydrofuran / 24 h / 20 °C
Multi-step reaction with 6 steps 1: pyridine / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 2: triethylamine / 1,4-dioxane / 12 h / Reflux 3: trifluoroacetic acid / methanol / 24 h / 20 - 50 °C 4: potassium carbonate; ethanol / 24 h / Reflux 5: acetic acid; sodium nitrite / water / 10 - 20 °C 6: potassium carbonate / tetrahydrofuran / 24 h / 20 °C
Multi-step reaction with 6 steps 1: pyridine / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 2: triethylamine / 1,4-dioxane / 12 h / Reflux 3: potassium carbonate; ethanol / 24 h / Reflux 4: acetic acid; sodium nitrite / water / 10 - 20 °C 5: potassium carbonate / toluene / 24 h / 20 °C 6: hydrogenchloride / water; methanol / 24 h / 30 °C
Multi-step reaction with 4 steps 1: triethylamine / ethylene glycol / 90 - 100 °C / Large scale 2: sodium nitrite; acetic acid / toluene; water / 10 - 20 °C / Large scale 3: potassium carbonate / toluene; water / 10 - 20 °C / Large scale 4: hydrogenchloride / toluene; water / 10 - 20 °C / Large scale
Multi-step reaction with 4 steps 1: triethylamine / ethylene glycol / 0.5 h / 9 - 100 °C / Large scale 2: sodium nitrite; acetic acid / toluene; water / 10 - 20 °C / Large scale 3: potassium carbonate / toluene; water / 10 - 20 °C / Large scale 4: hydrogenchloride / toluene; water; methanol / 10 - 20 °C / Large scale
Multi-step reaction with 4 steps 1: triethylamine / ethanol / 100 - 130 °C / Sealed tube; Inert atmosphere 2: acetic acid; sodium nitrite / acetonitrile; water / 0.5 h / 0 - 5 °C 3: potassium carbonate / acetonitrile; water / 3 h / 15 - 20 °C 4: hydrogenchloride / water; methanol / 3 h / 15 - 25 °C
Multi-step reaction with 4 steps 1: triethylamine / ethanol / 100 - 130 °C / Sealed tube; Inert atmosphere 2: acetic acid; sodium nitrite / acetonitrile; water / 0.5 h / 0 - 5 °C 3: potassium carbonate / acetonitrile; water / 3 h / 15 - 20 °C 4: hydrogenchloride / water; methanol / 3 h / 15 - 25 °C
Multi-step reaction with 4 steps 1: triethylamine / ethanol / 100 - 130 °C / Sealed tube; Inert atmosphere 2: acetic acid; sodium nitrite / acetonitrile; water / 0.5 h / 0 - 5 °C 3: potassium carbonate / acetonitrile; water / 3 h / 15 - 20 °C 4: hydrogenchloride / water; methanol / 3 h / 15 - 25 °C
Multi-step reaction with 4 steps 1: triethylamine / ethanol / 100 - 130 °C / Sealed tube; Inert atmosphere 2: acetic acid; sodium nitrite / acetonitrile; water / 0.5 h / 0 - 5 °C 3: potassium carbonate / acetonitrile; water / 3 h / 15 - 20 °C 4: hydrogenchloride / water; methanol / 3 h / 15 - 25 °C
Multi-step reaction with 4 steps 1: sodium tosylate; sodium iodide; N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 10 h / 100 °C / Inert atmosphere 2: sodium nitrite; hydrogenchloride / ethyl acetate; water / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / ethyl acetate / 3 h / 20 °C / Inert atmosphere 4: hydrogenchloride / water; methanol / 2 h / 2 °C / Inert atmosphere
Multi-step reaction with 4 steps 1: sodium hydroxide / ethyl acetate / 20 h / 90 °C 2: hydrogenchloride; sodium nitrite / ethyl acetate; water / 1 h / 0 °C 3: ethyl acetate / 2 h / 40 °C 4: hydrogenchloride / ethyl acetate; water
Multi-step reaction with 4 steps 1: triethylamine / isopropyl alcohol / 30 h / 80 °C / Industrial scale 2: isopentyl nitrite / acetonitrile / 12 h / 75 °C / Industrial scale 3: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 12 h / 20 °C 4: pyridine hydrochloride / 0 °C
Multi-step reaction with 4 steps 1: triethylamine / 110 °C / Sealed tube 2: acetic acid; sodium nitrite / 0 - 20 °C 3: triethylamine / acetonitrile / 2 h / 80 °C 4: hydrogenchloride / methanol; water / 0.5 h / 20 °C
Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / water / 87 °C / Large scale 2: sodium nitrite; acetic acid / water; toluene / 1 h / 0 - 2 °C 3: potassium carbonate / water 4: hydrogenchloride / methanol / 2 h / 0 - 10 °C / Large scale

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  • 12
  • ethyl 2-(6-(benzyloxycarbonylamino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy) acetate [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: lithium borohydride / tetrahydrofuran / 5 h / 0 °C 2: 5%-palladium/activated carbon / methanol / 1 h / 20 °C 3: triethylamine; sodium iodide / 1,4-dioxane / 7 h / 120 °C 4: sodium nitrite / water; acetic acid; ethyl acetate / 30 °C 5: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h 6: hydrogenchloride; water / methanol / 1 h
Multi-step reaction with 6 steps 1.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 1.2: 20 °C 1.3: pH 6 - 7 2.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 2.2: 20 - 70 °C 3.1: triethylamine / ethanol / 40 - 80 °C / Inert atmosphere 4.1: hydrogenchloride; water / methanol / 35 °C 5.1: sodium nitrite / water; methanol / 0 - 5 °C 6.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C
Multi-step reaction with 6 steps 1.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 1.2: 20 °C 1.3: pH 6 - 7 2.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 3.1: triethylamine / ethanol / 40 - 80 °C / Inert atmosphere 4.1: hydrogenchloride; water / methanol / 35 °C 5.1: sodium nitrite / water; methanol / 0 - 5 °C 6.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C
Multi-step reaction with 6 steps 1.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 1.2: 20 - 60 °C 2.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 3.1: isopentyl nitrite / acetonitrile / 50 - 70 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C 5.1: lithium borohydride / tetrahydrofuran / 0 - 30 °C 6.1: hydrogenchloride; water / methanol / 25 - 30 °C
Multi-step reaction with 7 steps 1.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 1.2: 20 - 60 °C 2.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 3.1: sodium hydroxide; water / methanol / 0 - 30 °C 4.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 6.1: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C 7.1: hydrogenchloride; water / methanol / 25 - 30 °C
Multi-step reaction with 7 steps 1.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 1.2: 20 - 60 °C 2.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 3.1: sodium hydroxide; water / methanol / 0 - 30 °C 4.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 6.1: hydrogenchloride; water / 16 h / 20 °C 7.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
Multi-step reaction with 7 steps 1.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 1.2: 20 - 60 °C 2.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 3.1: hydrogenchloride; water / 20 - 70 °C 4.1: acetic acid / methanol / 0 - 30 °C 5.1: isopentyl nitrite / acetonitrile / 30 - 60 °C 6.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C 7.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
Multi-step reaction with 7 steps 1.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 1.2: 20 - 60 °C 2.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 3.1: acetic acid; iron / methanol / 20 - 35 °C 4.1: isopentyl nitrite / acetonitrile / 50 - 70 °C 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C 6.1: lithium borohydride / tetrahydrofuran / 0 - 30 °C 7.1: hydrogenchloride; water / methanol / 25 - 30 °C
Multi-step reaction with 7 steps 1: sodium hydroxide; water / tetrahydrofuran / 10 - 20 °C 2: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 3: triethylamine / ethanol / 50 - 60 °C / Inert atmosphere 4: hydrogenchloride; water / methanol / 35 °C 5: isopentyl nitrite / acetonitrile / 30 - 60 °C 6: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C 7: lithium borohydride / tetrahydrofuran / -10 - 20 °C
Multi-step reaction with 8 steps 1.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 1.2: 20 - 60 °C 2.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 3.1: acetic acid; iron / methanol / 20 - 35 °C 4.1: sodium hydroxide; water / methanol / 0 - 30 °C 5.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 7.1: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C 8.1: hydrogenchloride; water / methanol / 25 - 30 °C
Multi-step reaction with 8 steps 1.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 1.2: 20 - 60 °C 2.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 3.1: acetic acid; iron / methanol / 20 - 35 °C 4.1: sodium hydroxide; water / methanol / 0 - 30 °C 5.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 7.1: hydrogenchloride; water / 16 h / 20 °C 8.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
Multi-step reaction with 8 steps 1.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 1.2: 20 °C 1.3: pH 6 - 7 2.1: hydrogenchloride; water / methanol / 25 - 30 °C 3.1: toluene-4-sulfonic acid 4.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 4.2: 20 - 70 °C 5.1: triethylamine / 1-methyl-pyrrolidin-2-one / 30 - 90 °C / Inert atmosphere 6.1: sodium nitrite; acetic acid / toluene; water / 25 - 30 °C 7.1: potassium carbonate / toluene; water / 25 - 30 °C 8.1: hydrogenchloride; water / toluene; methanol / 0 - 20 °C
Multi-step reaction with 12 steps 1: hydrogenchloride / ethanol; water / 20 °C 2: pyridine / dichloromethane / -80 - 20 °C / Inert atmosphere 3: lithium borohydride / tetrahydrofuran / 2 h / -10 °C 4: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 750.08 Torr 5: triethylamine; dmap / dichloromethane / 20 °C / Inert atmosphere 6: silver(l) oxide / dichloromethane / 0 - 30 °C / Inert atmosphere; Molecular sieve 7: trifluoroacetic acid / dichloromethane / 20 °C 8: sodium hydrogencarbonate / N,N-dimethyl-formamide / 90 - 95 °C / Inert atmosphere 9: acetic acid; sodium nitrite / water; toluene / 20 - 30 °C 10: dichloromethane / 20 - 30 °C 11: sodium hydroxide; water / 1,4-dioxane / 30 °C / Cooling with ice 12: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 3000.3 Torr
Multi-step reaction with 13 steps 1: hydrogenchloride / ethanol; water / 20 °C 2: pyridine / dichloromethane / -80 - 20 °C / Inert atmosphere 3: lithium borohydride / tetrahydrofuran / 2 h / -10 °C 4: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 750.08 Torr 5: triethylamine; dmap / dichloromethane / 20 °C / Inert atmosphere 6: silver(l) oxide / dichloromethane / 0 - 30 °C / Inert atmosphere; Molecular sieve 7: trifluoroacetic acid / dichloromethane / 20 °C 8: hydrogenchloride / methanol; ethyl acetate; water 9: sodium hydrogencarbonate / N,N-dimethyl-formamide / 90 - 95 °C / Inert atmosphere 10: acetic acid; sodium nitrite / water; toluene / 20 - 30 °C 11: dichloromethane / 20 - 30 °C 12: sodium hydroxide; water / 1,4-dioxane / 30 °C / Cooling with ice 13: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 3000.3 Torr
Multi-step reaction with 8 steps 1: hydrogenchloride / ethanol; water / 20 °C 2: pyridine / dichloromethane / -80 - 20 °C / Inert atmosphere 3: lithium borohydride / tetrahydrofuran / 2 h / -10 °C 4: hydrogenchloride; hydrogen; palladium 10% on activated carbon / methanol; water / 2 h / 750.08 Torr 5: sodium hydrogencarbonate / N,N-dimethyl-formamide / 90 - 95 °C / Inert atmosphere 6: acetic acid; sodium nitrite / water; toluene / 20 - 30 °C 7: dichloromethane / 20 - 30 °C 8: sodium hydroxide; water / 1,4-dioxane / 30 °C / Cooling with ice
Multi-step reaction with 8 steps 1: hydrogenchloride / ethanol; water / 20 °C 2: pyridine / dichloromethane / -80 - 20 °C / Inert atmosphere 3: lithium borohydride / tetrahydrofuran / 2 h / -10 °C 4: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 750.08 Torr 5: sodium hydrogencarbonate / N,N-dimethyl-formamide / 90 - 95 °C / Inert atmosphere 6: acetic acid; sodium nitrite / water; toluene / 20 - 30 °C 7: dichloromethane / 20 - 30 °C 8: sodium hydroxide; water / 1,4-dioxane / 30 °C / Cooling with ice
Multi-step reaction with 9 steps 1: hydrogenchloride / ethanol; water / 20 °C 2: pyridine / dichloromethane / -80 - 20 °C / Inert atmosphere 3: lithium borohydride / tetrahydrofuran / 2 h / -10 °C 4: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 750.08 Torr 5: tetrahydrofuran / 0 - 10 °C 6: acetic acid; iron / ethanol; water / 60 - 70 °C / Inert atmosphere 7: acetic acid; sodium nitrite / water; toluene / 20 - 30 °C 8: dichloromethane / 20 - 30 °C 9: sodium hydroxide; water / 1,4-dioxane / 30 °C / Cooling with ice

Reference: [1]Zhang, Hao; Liu, Jun; Zhang, Luyong; Kong, Lingyi; Yao, Hequan; Sun, Hongbin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3598 - 3602]
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[4]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[5]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[6]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[7]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[8]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[9]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[10]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[11]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[12]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[13]Current Patent Assignee: BRIGHTGENE BIO MEDICAL TECHNOLOGY CO LTD - US2015/322071, 2015, A1
[14]Current Patent Assignee: BRIGHTGENE BIO MEDICAL TECHNOLOGY CO LTD - US2015/322071, 2015, A1
[15]Current Patent Assignee: BRIGHTGENE BIO MEDICAL TECHNOLOGY CO LTD - US2015/322071, 2015, A1
[16]Current Patent Assignee: BRIGHTGENE BIO MEDICAL TECHNOLOGY CO LTD - US2015/322071, 2015, A1
[17]Current Patent Assignee: BRIGHTGENE BIO MEDICAL TECHNOLOGY CO LTD - US2015/322071, 2015, A1
  • 14
  • [ 1006376-60-8 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1: sodium hydroxide / water; toluene / 1 h / 40 °C 2: sodium t-butanolate / toluene / 11 h / 60 - 80 °C 3: water; sodium hydroxide / methanol / 1 h / 65 °C 4: thionyl chloride / 8 h / 35 °C 5: ammonia; water / ethyl acetate / 1 h / 10 °C 6: sodium hypochlorite; water; sodium hydroxide / 14 h / 40 °C 7: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h 8: hydrogenchloride; water / methanol / 1 h
  • 15
  • [ 1006376-61-9 ]
  • [ 274693-27-5 ]
  • 16
  • [ 367-11-3 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 10 steps 1: aluminum (III) chloride / 1.33 h / 50 °C 2: Trimethyl borate; (S)-diphenylprolinol; dimethylsulfide borane complex / tetrahydrofuran; toluene / 1.5 h / 35 - 45 °C 3: sodium hydroxide / water; toluene / 1 h / 40 °C 4: sodium t-butanolate / toluene / 11 h / 60 - 80 °C 5: water; sodium hydroxide / methanol / 1 h / 65 °C 6: thionyl chloride / 8 h / 35 °C 7: ammonia; water / ethyl acetate / 1 h / 10 °C 8: sodium hypochlorite; water; sodium hydroxide / 14 h / 40 °C 9: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h 10: hydrogenchloride; water / methanol / 1 h
Multi-step reaction with 12 steps 1.1: aluminum (III) chloride / dichloromethane / 30 h / 20 - 25 °C / Industry scale 2.1: sodium iodide; sodium azide; 3,5-dihydroxyphenol / N,N-dimethyl-formamide / 5 - 30 °C / Inert atmosphere 3.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane Ν,Ν-diethylaniline complex / toluene / 1.5 h / 15 - 20 °C / Inert atmosphere 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene / 5 - 10 °C 5.1: hydrogenchloride; zinc / methanol / -5 - 0 °C 5.2: 0.25 h / 10 - 30 °C 6.1: methanol / 12 h / 20 - 25 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 7.2: 3 h / 20 - 25 °C 8.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 8.2: 1.5 h / -25 - -15 °C 8.3: 0.08 h 9.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 10.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 11.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 12.1: hydrogenchloride; water / toluene; methanol / 2 h / 25 - 30 °C 12.2: pH > 8
Multi-step reaction with 13 steps 1.1: aluminum (III) chloride / dichloromethane / 30 h / 20 - 25 °C / Industry scale 2.1: sodium iodide; sodium azide; 3,5-dihydroxyphenol / N,N-dimethyl-formamide / 5 - 30 °C / Inert atmosphere 3.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane Ν,Ν-diethylaniline complex / toluene / 1.5 h / 15 - 20 °C / Inert atmosphere 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene / 5 - 10 °C 5.1: hydrogenchloride; zinc / methanol / -5 - 0 °C 5.2: 0.25 h / 10 - 30 °C 6.1: methanol / 12 h / 20 - 25 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 7.2: 3 h / 20 - 25 °C 8.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 8.2: 1.5 h / -25 - -15 °C 8.3: 0.08 h 9.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 10.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 11.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 12.1: potassium carbonate / acetone / 24 h / 25 - 60 °C 13.1: hydrogenchloride; water / methanol / 5.5 h / 20 - 55 °C 13.2: 25 - 30 °C / pH 10
Multi-step reaction with 15 steps 1.1: aluminum (III) chloride / dichloromethane / 30 h / 20 - 25 °C / Industry scale 2.1: sodium iodide; sodium azide; 3,5-dihydroxyphenol / N,N-dimethyl-formamide / 5 - 30 °C / Inert atmosphere 3.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane Ν,Ν-diethylaniline complex / toluene / 1.5 h / 15 - 20 °C / Inert atmosphere 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene / 5 - 10 °C 5.1: hydrogenchloride; zinc / methanol / -5 - 0 °C 5.2: 0.25 h / 10 - 30 °C 6.1: methanol / 12 h / 20 - 25 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 25 °C 7.2: 3 h / 20 - 25 °C 8.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 8.2: 1.5 h / -25 - -15 °C 8.3: 0.08 h 9.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 10.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 11.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 12.1: iodine / acetone / 2 h / 25 - 60 °C 13.1: potassium carbonate / acetone / 20 h / 55 - 60 °C 14.1: hydrogenchloride; water / methanol / 5 h / 20 - 25 °C 14.2: 25 - 30 °C / pH 10 15.1: formic acid / palladium 10% on activated carbon / 50 °C

  • 17
  • [ 51336-95-9 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1: Trimethyl borate; (S)-diphenylprolinol; dimethylsulfide borane complex / tetrahydrofuran; toluene / 1.5 h / 35 - 45 °C 2: sodium hydroxide / water; toluene / 1 h / 40 °C 3: sodium t-butanolate / toluene / 11 h / 60 - 80 °C 4: water; sodium hydroxide / methanol / 1 h / 65 °C 5: thionyl chloride / 8 h / 35 °C 6: ammonia; water / ethyl acetate / 1 h / 10 °C 7: sodium hypochlorite; water; sodium hydroxide / 14 h / 40 °C 8: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h 9: hydrogenchloride; water / methanol / 1 h
  • 18
  • [ 155899-66-4 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1.1: N-ethyl-N,N-diisopropylamine / 4-methyl-2-pentanone / 2 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / -30 °C 2.2: 3 h / 20 °C 3.1: lithium borohydride / tetrahydrofuran / 5 h / 0 °C 4.1: 5%-palladium/activated carbon / methanol / 1 h / 20 °C 5.1: triethylamine; sodium iodide / 1,4-dioxane / 7 h / 120 °C 6.1: sodium nitrite / water; acetic acid; ethyl acetate / 30 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h 8.1: hydrogenchloride; water / methanol / 1 h
Multi-step reaction with 11 steps 1.1: potassium carbonate / ethanol; water / 3 h / 60 - 65 °C 1.2: 0.25 h 2.1: sodium t-butanolate / N,N-dimethyl-formamide; tetrahydrofuran / 2 h / -10 - 5 °C 3.1: diisobutylaluminium hydride / toluene / 2.5 h / -25 - -20 °C 3.2: 0.25 h 4.1: hydrogen / 20% palladium hydroxide-activated charcoal / methanol / 10 h / 20 - 25 °C / 2327.23 Torr / Autoclave; Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 6.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 7.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 8.1: iodine / acetone / 2 h / 25 - 60 °C 9.1: potassium carbonate / acetone / 20 h / 55 - 60 °C 10.1: hydrogenchloride; water / methanol / 5 h / 20 - 25 °C 10.2: 25 - 30 °C / pH 10 11.1: formic acid / palladium 10% on activated carbon / 50 °C
Multi-step reaction with 8 steps 1.1: potassium carbonate / ethanol; water / 3 h / 60 - 65 °C 1.2: 0.25 h 2.1: sodium t-butanolate / N,N-dimethyl-formamide; tetrahydrofuran / 2 h / -10 - 5 °C 3.1: diisobutylaluminium hydride / toluene / 2.5 h / -25 - -20 °C 3.2: 0.25 h 4.1: hydrogen / 20% palladium hydroxide-activated charcoal / methanol / 10 h / 20 - 25 °C / 2327.23 Torr / Autoclave; Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 6.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 7.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 8.1: hydrogenchloride; water / toluene; methanol / 2 h / 25 - 30 °C 8.2: pH > 8
Multi-step reaction with 9 steps 1.1: potassium carbonate / ethanol; water / 3 h / 60 - 65 °C 1.2: 0.25 h 2.1: sodium t-butanolate / N,N-dimethyl-formamide; tetrahydrofuran / 2 h / -10 - 5 °C 3.1: diisobutylaluminium hydride / toluene / 2.5 h / -25 - -20 °C 3.2: 0.25 h 4.1: hydrogen / 20% palladium hydroxide-activated charcoal / methanol / 10 h / 20 - 25 °C / 2327.23 Torr / Autoclave; Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 6.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 7.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 8.1: potassium carbonate / acetone / 24 h / 25 - 60 °C 9.1: hydrogenchloride; water / methanol / 5.5 h / 20 - 55 °C 9.2: 25 - 30 °C / pH 10
Multi-step reaction with 10 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 8.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 9.1: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C 10.1: hydrogenchloride; water / methanol / 25 - 30 °C
Multi-step reaction with 10 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 8.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 9.1: hydrogenchloride; water / 16 h / 20 °C 10.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
Multi-step reaction with 10 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 8.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 9.1: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C 10.1: hydrogenchloride; water / methanol / 25 - 30 °C
Multi-step reaction with 10 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: sodium hydroxide; water / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 8.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 9.1: hydrogenchloride; water / 16 h / 20 °C 10.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
Multi-step reaction with 10 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 3.2: 20 °C 3.3: pH 6 - 7 4.1: hydrogenchloride; water / methanol / 25 - 30 °C 5.1: toluene-4-sulfonic acid 6.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 6.2: 20 - 70 °C 7.1: triethylamine / 1-methyl-pyrrolidin-2-one / 30 - 90 °C / Inert atmosphere 8.1: sodium nitrite; acetic acid / toluene; water / 25 - 30 °C 9.1: potassium carbonate / toluene; water / 25 - 30 °C 10.1: hydrogenchloride; water / toluene; methanol / 0 - 20 °C
Multi-step reaction with 8 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: isopentyl nitrite / acetonitrile / 50 - 70 °C 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C 7.1: lithium borohydride / tetrahydrofuran / 0 - 30 °C 8.1: hydrogenchloride; water / methanol / 25 - 30 °C
Multi-step reaction with 8 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: isopentyl nitrite / acetonitrile / 50 - 70 °C 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C 7.1: lithium borohydride / tetrahydrofuran / 0 - 30 °C 8.1: hydrogenchloride; water / methanol / 25 - 30 °C
Multi-step reaction with 8 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 3.2: 20 °C 3.3: pH 6 - 7 4.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 4.2: 20 - 70 °C 5.1: triethylamine / ethanol / 40 - 80 °C / Inert atmosphere 6.1: hydrogenchloride; water / methanol / 35 °C 7.1: sodium nitrite / water; methanol / 0 - 5 °C 8.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C
Multi-step reaction with 8 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: lithium borohydride / tetrahydrofuran / 0 - 20 °C 3.2: 20 °C 3.3: pH 6 - 7 4.1: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 5.1: triethylamine / ethanol / 40 - 80 °C / Inert atmosphere 6.1: hydrogenchloride; water / methanol / 35 °C 7.1: sodium nitrite / water; methanol / 0 - 5 °C 8.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C
Multi-step reaction with 9 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: isopentyl nitrite / acetonitrile / 50 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C 8.1: lithium borohydride / tetrahydrofuran / 0 - 30 °C 9.1: hydrogenchloride; water / methanol / 25 - 30 °C
Multi-step reaction with 9 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: acetic acid; iron / methanol / 20 - 35 °C 6.1: isopentyl nitrite / acetonitrile / 50 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 35 °C 8.1: lithium borohydride / tetrahydrofuran / 0 - 30 °C 9.1: hydrogenchloride; water / methanol / 25 - 30 °C
Multi-step reaction with 9 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C 6.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 8.1: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C 9.1: hydrogenchloride; water / methanol / 25 - 30 °C
Multi-step reaction with 9 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C 6.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 8.1: hydrogenchloride; water / 16 h / 20 °C 9.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
Multi-step reaction with 9 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C 6.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 8.1: lithium aluminium tetrahydride / tetrahydrofuran / -10 - 0 °C 9.1: hydrogenchloride; water / methanol / 25 - 30 °C
Multi-step reaction with 9 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: triethylamine / ethanol / 36 h / 125 °C / 3677.86 Torr / Autoclave; Inert atmosphere 5.1: sodium hydroxide; water / methanol / 0 - 30 °C 6.1: isopentyl nitrite / acetonitrile / 10 - 70 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 30 °C 8.1: hydrogenchloride; water / 16 h / 20 °C 9.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
Multi-step reaction with 9 steps 1.1: sodium carbonate / water; tetrahydrofuran / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ethanol; ammonium cerium (IV) nitrate / 50 - 70 °C 3.2: 20 - 70 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: hydrogenchloride; water / 20 - 70 °C 6.1: acetic acid / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 30 - 60 °C 8.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C 9.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
Multi-step reaction with 9 steps 1.1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 50 - 60 °C 3.2: 20 - 60 °C 4.1: sodium hydrogencarbonate / water; tetrahydrofuran / 0 - 35 °C 5.1: hydrogenchloride; water / 20 - 70 °C 6.1: acetic acid / methanol / 0 - 30 °C 7.1: isopentyl nitrite / acetonitrile / 30 - 60 °C 8.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C 9.1: lithium borohydride / tetrahydrofuran / -10 - 20 °C
Multi-step reaction with 9 steps 1: sodium carbonate / water; 4-methyl-2-pentanone / 20 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C 3: sodium hydroxide; water / tetrahydrofuran / 10 - 20 °C 4: ammonium formate / palladium 10% on activated carbon / ethanol / 30 - 70 °C 5: triethylamine / ethanol / 50 - 60 °C / Inert atmosphere 6: hydrogenchloride; water / methanol / 35 °C 7: isopentyl nitrite / acetonitrile / 30 - 60 °C 8: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 - 35 °C 9: lithium borohydride / tetrahydrofuran / -10 - 20 °C
Multi-step reaction with 8 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: iron; acetic acid / 2 h / 20 °C 3.1: acetic acid; sodium nitrite / 1 h / 20 °C 4.1: potassium carbonate / 2 h 5.1: sodium hydride / tetrahydrofuran; mineral oil / 0.25 h / -10 °C 5.2: 16 h / -10 °C 6.1: lithium borohydride / tetrahydrofuran / 16 h / 20 °C 7.1: dimethyl sulfoxide / 16 h / 60 °C 8.1: phosphoric acid / methanol / 24 h / 20 °C
Multi-step reaction with 8 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: methanol / 1 h / 20 °C 3.1: sodium carbonate; Aminoiminomethanesulfinic acid / methanol; water / 1 h / 60 °C 4.1: acetic acid; sodium nitrite / 1 h / 20 °C 5.1: sodium hydride / tetrahydrofuran; mineral oil / 0.25 h / -10 °C 5.2: 16 h / -10 °C 6.1: lithium borohydride / tetrahydrofuran / 16 h / 20 °C 7.1: dimethyl sulfoxide / 16 h / 60 °C 8.1: phosphoric acid / methanol / 24 h / 20 °C
Multi-step reaction with 4 steps 1.1: methanol / 1 h / 20 °C 1.2: 2 h / 20 - 60 °C 1.3: 1 h / 20 °C 2.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 2.2: 2 h / -10 °C 2.3: 2 h / 20 °C 3.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 4.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 5 steps 1.1: methanol / 1 h / 20 °C 1.2: 2 h / 20 - 60 °C 1.3: 1 h / 20 °C 2.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 2.2: 2 h / -10 °C 3.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C 4.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 5.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 7 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: methanol / 1 h / 20 °C 3.1: sodium carbonate; Aminoiminomethanesulfinic acid / methanol; water / 1 h / 60 °C 4.1: sodium nitrite; acetic acid / 1 h / 20 °C 5.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 5.2: 2 h / -10 °C 5.3: 2 h / 20 °C 6.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 7.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 7 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: iron; acetic acid / 2 h / 20 °C 3.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 4.1: potassium carbonate / 2 h / 20 °C 5.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 5.2: 2 h / -10 °C 5.3: 2 h / 20 °C 6.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 7.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 7 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: iron; acetic acid / 2 h / 20 °C 3.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 4.1: methanol / 0.25 h / 20 °C 5.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 5.2: 2 h / -10 °C 5.3: 2 h / 20 °C 6.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 7.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 8 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: iron; acetic acid / 2 h / 20 °C 3.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 4.1: methanol / 0.25 h / 20 °C 5.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 5.2: 2 h / -10 °C 6.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C 7.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 8.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 8 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: methanol / 1 h / 20 °C 3.1: sodium carbonate; Aminoiminomethanesulfinic acid / methanol; water / 1 h / 60 °C 4.1: sodium nitrite; acetic acid / 1 h / 20 °C 5.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 5.2: 2 h / -10 °C 6.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C 7.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 8.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 8 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: iron; acetic acid / 2 h / 20 °C 3.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 4.1: potassium carbonate / 2 h / 20 °C 5.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 5.2: 2 h / -10 °C 6.1: lithium borohydride / tetrahydrofuran / 16 h / 0 - 20 °C 7.1: dimethyl sulfoxide / 16 h / 20 - 60 °C 8.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 8 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: iron; acetic acid / 2 h / 20 °C 3.1: isopentyl nitrite / acetonitrile / 1 h / 70 °C 4.1: potassium phosphate / 88 h / 70 °C 5.1: sodium hydride / tetrahydrofuran / 0.25 h / -10 °C 5.2: 2 h / -10 °C 6.1: lithium borohydride / tetrahydrofuran / 1 h / 20 °C 7.1: dimethyl sulfoxide / 72 h / 20 - 70 °C 8.1: phosphoric acid; water / methanol / 24 h / 20 °C
Multi-step reaction with 7 steps 1: potassium carbonate / ethyl acetate; water / 3 h / 0 - 20 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 2 h / -10 °C 3: palladium on activated charcoal; hydrogen / methanol / 20 °C 4: N-ethyl-N,N-diisopropylamine / ethanol / 20 - 100 °C 5: acetic acid; sodium nitrite / water; toluene / 4 h / 15 - 20 °C 6: potassium carbonate / water / 15 °C 7: trifluoroacetic acid / methanol; toluene / 8 h / 15 °C
Multi-step reaction with 8 steps 1: potassium carbonate / ethyl acetate; water / 3 h / 0 - 20 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 2 h / -10 °C 3: palladium on activated charcoal; hydrogen / methanol / 20 °C 4: N-ethyl-N,N-diisopropylamine / ethanol / 20 - 100 °C 5: acetic acid; sodium nitrite / water; toluene / 4 h / 15 - 20 °C 6: potassium carbonate / water / 15 °C 7: sodium methylate; methanol / 20 °C 8: hydrogenchloride / water; methanol / 8 h / 15 °C

Reference: [1]Zhang, Hao; Liu, Jun; Zhang, Luyong; Kong, Lingyi; Yao, Hequan; Sun, Hongbin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3598 - 3602]
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/85665, 2012, A2
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/85665, 2012, A2
[4]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/85665, 2012, A2
[5]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[6]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[7]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[8]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[9]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[10]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[11]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[12]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[13]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[14]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[15]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[16]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[17]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[18]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[19]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[20]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[21]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[22]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2012/138981, 2012, A2
[23]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2586773, 2013, A1
[24]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2586773, 2013, A1
[25]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[26]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[27]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[28]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[29]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[30]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[31]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[32]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[33]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/60837, 2013, A1
[34]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN103626743, 2018, B
[35]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN103626743, 2018, B
  • 21
  • [ 1350749-64-2 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 1.2: 1.5 h / -25 - -15 °C 1.3: 0.08 h 2.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 3.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 4.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 5.1: hydrogenchloride; water / toluene; methanol / 2 h / 25 - 30 °C 5.2: pH > 8
Multi-step reaction with 6 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 1.2: 1.5 h / -25 - -15 °C 1.3: 0.08 h 2.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 3.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 4.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 5.1: potassium carbonate / acetone / 24 h / 25 - 60 °C 6.1: hydrogenchloride; water / methanol / 5.5 h / 20 - 55 °C 6.2: 25 - 30 °C / pH 10
Multi-step reaction with 8 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -25 - -15 °C 1.2: 1.5 h / -25 - -15 °C 1.3: 0.08 h 2.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 3.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 4.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 5.1: iodine / acetone / 2 h / 25 - 60 °C 6.1: potassium carbonate / acetone / 20 h / 55 - 60 °C 7.1: hydrogenchloride; water / methanol / 5 h / 20 - 25 °C 7.2: 25 - 30 °C / pH 10 8.1: formic acid / palladium 10% on activated carbon / 50 °C
Multi-step reaction with 7 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 16 h / 20 °C 2.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 3.1: sodium dithionite; sodium carbonate / methanol; water / 16 h / 40 °C 4.1: isopentyl nitrite / acetonitrile / 2 h / 70 °C 5.1: sodium hydride / tetrahydrofuran / 1 h / -20 °C 5.2: 16 h / -20 °C 6.1: lithium borohydride / tetrahydrofuran / 16 h / 0 °C 7.1: phosphoric acid / ethanol / 24 h / 20 °C
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 16 h / 20 °C 1.2: 2 h / 20 °C 2.1: hydrogen; 5%-palladium/activated carbon / methanol / 16 h / 7500.75 Torr 3.1: sodium nitrite; acetic acid / 0.5 h / 20 °C 4.1: phosphoric acid / methanol; water / 24 h / 20 °C
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 16 h / 20 °C 1.2: 2 h / 20 °C 2.1: hydrogen; 5%-palladium/activated carbon / methanol / 16 h / 7500.75 Torr 3.1: sodium nitrite; acetic acid / 1 h / 20 °C 4.1: hydrogenchloride / methanol; water / 20 °C
Multi-step reaction with 7 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 16 h / 20 °C 2.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 3.1: sodium dithionite; sodium carbonate / methanol; water / 16 h / 40 °C 4.1: isopentyl nitrite / acetonitrile / 2 h / 70 °C 5.1: sodium hydride / tetrahydrofuran / 1 h / -20 °C 5.2: 16 h / -20 °C 6.1: lithium borohydride / tetrahydrofuran / 16 h / 0 °C 7.1: phosphoric acid / water; ethanol / 24 h / 20 °C
Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -80 - -75 °C / Inert atmosphere 2.1: potassium carbonate / tetrahydrofuran / 3 h / 10 - 20 °C / pH 9 3.1: zinc; acetic acid / dichloromethane / 2 h / 5 - 10 °C 3.2: 2 h / 0 - 3 °C 3.3: 4 h
Multi-step reaction with 3 steps 1: potassium carbonate / water; toluene / 20 °C 2: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 20 °C / Cooling with ice 3: hydrogenchloride / water; methanol / 50 °C
Multi-step reaction with 3 steps 1: potassium carbonate / water; toluene / 20 °C 2: triphenylphosphine; diethylazodicarboxylate / 1,4-dioxane / 20 °C / Cooling with ice 3: hydrogenchloride / water; methanol / 55 °C
Multi-step reaction with 3 steps 1: potassium carbonate / water; toluene / 20 °C 2: triphenylphosphine; diethylazodicarboxylate / 1,4-dioxane / 20 °C / Cooling with ice 3: trifluoroacetic acid / methanol / 60 °C

  • 22
  • [ 1383715-58-9 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 2.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 3.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 4.1: hydrogenchloride; water / toluene; methanol / 2 h / 25 - 30 °C 4.2: pH > 8
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 2.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 3.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 4.1: potassium carbonate / acetone / 24 h / 25 - 60 °C 5.1: hydrogenchloride; water / methanol / 5.5 h / 20 - 55 °C 5.2: 25 - 30 °C / pH 10
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 20 - 25 °C 2.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 3.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 4.1: iodine / acetone / 2 h / 25 - 60 °C 5.1: potassium carbonate / acetone / 20 h / 55 - 60 °C 6.1: hydrogenchloride; water / methanol / 5 h / 20 - 25 °C 6.2: 25 - 30 °C / pH 10 7.1: formic acid / palladium 10% on activated carbon / 50 °C
Multi-step reaction with 6 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: sodium dithionite; sodium carbonate / methanol; water / 16 h / 40 °C 3.1: isopentyl nitrite / acetonitrile / 2 h / 70 °C 4.1: sodium hydride / tetrahydrofuran / 1 h / -20 °C 4.2: 16 h / -20 °C 5.1: lithium borohydride / tetrahydrofuran / 16 h / 0 °C 6.1: phosphoric acid / ethanol / 24 h / 20 °C
Multi-step reaction with 6 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2.1: sodium dithionite; sodium carbonate / methanol; water / 16 h / 40 °C 3.1: isopentyl nitrite / acetonitrile / 2 h / 70 °C 4.1: sodium hydride / tetrahydrofuran / 1 h / -20 °C 4.2: 16 h / -20 °C 5.1: lithium borohydride / tetrahydrofuran / 16 h / 0 °C 6.1: phosphoric acid / water; ethanol / 24 h / 20 °C

  • 23
  • [ 1383715-59-0 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
74% Stage #1: 2-[[(3aR,4S,6R,6aS)-6-[[4-[N-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-yl]-N-tert-butoxycarbonyl]amino]-2-(propylthio)-5-nitropyrimidin-6-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy] ethanol With acetic acid; zinc In dichloromethane at 5 - 10℃; for 2h; Stage #2: With acetic acid; sodium nitrite In dichloromethane; water at 0 - 3℃; for 2h; Stage #3: With hydrogenchloride In methanol; water for 4h; 4 synthesis of ticagrelor 90 g of the compound of formula 7 prepared in Example 3 was added to a 2000 ml three-necked flask,400 ml of dichloromethane was added,43g zinc powder,Stirring to reduce the temperature to 5 ,39.6 g of acetic acid was added dropwise,Control the internal temperature between 10 . Plus,The reaction was stirred at this temperature for 2 hours,After the reaction,The filtrate was added to 250 ml of potassium carbonate solution,Take the organic layer,And concentrated under reduced pressure to give a pale yellow solid.The solid was charged into a 2000 ml three-necked flask,Add 1000ml of methylene chloride, stirring down to 0 ~ 3 ,Add 40 g of acetic acid.Plus,A solution of sodium nitrate (14 g of sodium nitrite dissolved in 60 ml of water) was added dropwise at a rate of 1 drop / 5 s.The reaction was stirred at this temperature for 2 hours.After the reaction, add potassium carbonate solution,Take the organic layer,Evaporated to dryness under reduced pressure to give a pale yellow concentrate.The concentrate was added to a 2000 ml three-necked flask,Add 560 ml of methanol,280 ml of concentrated hydrochloric acid was added dropwise,Stir for 4 hours.Adding 600 ml of n-heptane to extract impurities,Discarded.500 ml of dichloromethane was added,With potassium carbonate solution to adjust the pH of 10 or so,Take the organic layer,Placed in a clean three-necked flask,Add 2g activated carbon,30 g of anhydrous sodium sulfate,Stir for 30 minutes,Diatomaceous earth filter,The filtrate is evaporated under reduced pressure,A white solid.Recrystallization from 200 ml of isopropanol,A white powder was added to the solid.35 vacuum drying overnight,Weighing 51g,Mole yield: 74%.
Multi-step reaction with 3 steps 1.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 2.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 3.1: hydrogenchloride; water / toluene; methanol / 2 h / 25 - 30 °C 3.2: pH > 8
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 2.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 3.1: potassium carbonate / acetone / 24 h / 25 - 60 °C 4.1: hydrogenchloride; water / methanol / 5.5 h / 20 - 55 °C 4.2: 25 - 30 °C / pH 10
Multi-step reaction with 6 steps 1.1: sodium hydrogencarbonate; sodium dithionite / water; acetone / 2 h / 20 - 25 °C 2.1: sodium azide; acetic acid / toluene; water / 1 h / 5 - 10 °C 3.1: iodine / acetone / 2 h / 25 - 60 °C 4.1: potassium carbonate / acetone / 20 h / 55 - 60 °C 5.1: hydrogenchloride; water / methanol / 5 h / 20 - 25 °C 5.2: 25 - 30 °C / pH 10 6.1: formic acid / palladium 10% on activated carbon / 50 °C

  • 24
  • [ 1383715-61-4 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
87% With phosphoric acid In ethanol at 20℃; for 24h; 8 Example 8: Preparation of (1S,2S,3R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl) amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy) cyclopentane-1,2-diol (TCG, ticagrelor) To a solution of BATAMA (0.25 g, 0.38 mmol) in EtOH (10 mL) at room temperature orthophosphoric acid (85%, 1.5 mL) was slowly added. The resulting reaction mixture was stirred at room temperature for 24 h. Water was then added (20 mL) and the reaction mixture neutralized with 1M NaOH. The product was extracted to ethyl acetate (5 x 10 mL), the combined organic phases were dried over Na2SO4, then concentrated to give a crude product, which was purified by chromatography (SiO2, EtOAc) to afford title compound as a white powder (0.17 g, 87% yield). 19F NMR (CD3OD, 470.5 MHz) δ -141.9 - -142.1 (m, 1F), -145.6 - -145.9 (m, 1F); MS (ESI) m/z: 523 [MH]+.
87% With phosphoric acid In ethanol; water at 20℃; for 24h; 8 Preparation of (1 S,2S,3F?,5S)-3-(7-(((1 F?,2S)-2-(3,4-difluorophenyl)cyclopropyl) amino)-5 (propylthio)-3/-/-[1 ,2,3]triazolo[4,5-G|pyrimidin-3-yl)-5-(2-hydroxyethoxy) cyclopentane-1 ,2 diol (TCG, ticagrelor) To a solution of BATAMA (0.25 g, 0.38 mmol) in EtOH (10 m L) at room temperature orffto-phosphoric acid (85%, 1 .5 mL) was slowly added. The resulting reaction mixture was stirred at room temperature for 24 h. Water was then added (20 m L) and the reaction mixture neutralized with 1 M NaOH. The product was extracted to ethyl acetate (5 x 10 mL), the combined organic phases were dried over Na2S04, then concentrated to give a crude product, which was purified by chromatography (Si02, EtOAc) to afford title compound as a white powder (0.17 g, 87% yield).19F NMR (CD3OD, 470.5 MHz) 6-141.9 - -142.1 (m, 1F), -145.6- -145.9 (m, 1F); MS (ESI) mlz: 523 [MH]+.
Stage #1: tert-butyl N-[3-[(3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-N-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]carbamate With hydrogenchloride; water In methanol; toluene at 25 - 30℃; for 2h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate 10.6 Step-6: Preparation of [lS-(la,2a,3 (lS*,2R.i:),5 )]-3-[7-[2-(3,4-difluorophenyl) cyclopropyl]amino]-5-(propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2- hydroxyethoxy)-cyclopentane- 1 ,2-diol (Ticagrelor)A mixture of 2-[[(3aR,4S,6R,6aS)-6-[7-[[[N-(lR,2S)-2-(3,4-difiuorophenyl)-cyclopropan-l- yl]-N-tert-butoxycarbonyl]amino]-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl]- 2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl]oxy]ethanol (0.5 g), methanol (1.5 ml), concentrated hydrochloric acid (1.2 ml) and toluene (2.5 ml) was stirred for 2 hours while maintaining the temperature at about 25-30°C. After completion of the reaction, toluene (5 ml) and water (5 ml) were added to the reaction mass, followed by the layer separation and washing the aqueous layer containing product with toluene (10 ml). To the aqueous layer was added a solution of sodium carbonate in water to adjust the pH to more than 8, followed by extracting twice with ethyl acetate (2 x 15 ml). The combined organic layer containing the product was washed with saturated sodium chloride (10 ml). The resulting organic layer was dried over sodium sulfate and then evaporated to dryness under reduced pressure to produce 0.3 g of ticagrelor.Mass [M-H]: 521.2.
Multi-step reaction with 4 steps 1.1: iodine / acetone / 2 h / 25 - 60 °C 2.1: potassium carbonate / acetone / 20 h / 55 - 60 °C 3.1: hydrogenchloride; water / methanol / 5 h / 20 - 25 °C 3.2: 25 - 30 °C / pH 10 4.1: formic acid / palladium 10% on activated carbon / 50 °C

  • 25
  • [ 1383715-63-6 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
With formic acid at 50℃; 11.4 Step 4: Preparation of [lS-[la,2a,3b(lS*,2R.i:),5b]]-3-[7-[2-(3,4-difluorophenyl)- cyclopropylamino]-5-(propylthio)-3H-l,2,3-triazolo[4,5-d] pyrimidin-3-yl]-5-(2 -hydroxy ethoxy)cyclopentane-l,2-diol (Ticagrelor)10% palladium on carbon and formic acid in ethanol were added to [1S- [la,2a,3b(lS*,2R.i:),5b]]-3-[7-[2-(3,4-difluorophenyl)- cyclopropyl-lyl]-N-benzyl]amino]-5- (propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane -1,2- diol (5 gm) at 50°C in three portions. The catalyst was filtered through high-low bed and the ethanol was distilled out under vacuum to get [lS-[la,2a,3b(lS*,2R*),5b]]-3-[7-[2-(3,4- difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-l,2,3-triazolo[4,5-d] pyrimidin-3-yl]- 5-(2-hydroxy ethoxy)cyclopentane-l,2-diol (4 gm).HPLC purity - 99.7 %
  • 26
  • [ 1383715-64-7 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-({(3aR,45,6R,6aS)-6-[7-[[N-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropan-1-yl]-N-tert-butoxycarbonyl]amino}-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}oxy)-O-tertbutoxycarbonylethanol With hydrogenchloride; water In methanol at 20 - 55℃; for 5.5h; Stage #2: With potassium carbonate In methanol; water at 25 - 30℃; 12.2 Step 2: Preparation of [lS-[la,2a,3b(lS*,2R.i:),5b]]-3-[7-[2-(3,4-difluorophenyl)- cyclopropylamino]-5-(propylthio)-3H-l,2,3-triazolo[4,5-d] pyrimidin-3-yl]-5-(2 -hydroxy ethoxy)cyclopentane-l,2-diol (Ticagrelor)To the solution of 2-({(3aR,4S,6R,6aS)-6-[7-[[N-(lR,2S)-2-(3,4-difiuorophenyl)- cyclopropan-l-yl]-N-tertbutoxycarbonyl]amino}-5-(propylthio)-3H- [ 1 ,2,3] triazolo [4,5- d]pyrimidin-3-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d] [ 1 ,3]dioxol-4-yl} oxy)-0-tert- butoxycarbonylethanol (6 gm) in methanol (40 ml) at 20-25°C concentrated hydrochloric acid (15 ml) was added in 30 minutes maintaining the temperature at 20-25°C. T he reaction mixture was heated at 50°C and stirred at 50-55°C for 5 hours. After the completion of the reaction, the reaction mixture was cooled to 25-30°C and washed with toluene (2X20 ml) at 25-30°C. Aqueous potassium carbonate was added to resulting solution and pH was adjusted to 10 at 25-30°C. The reaction mass was extracted with dichloromethane (50 ml) and the organic layer was washed with water (50 ml). The dichloromethane layer containing the product was distilled out under vacuum below 40°C and degassed to provide [1S- [la,2a,3b(lS*,2R*),5b]]-3-[7-[2-(3 ,4-difluorophenyl)- cyclopropylamino]-5-(propylthio)-3H- l,2,3-triazolo[4,5-d] pyrimidin-3-yl]-5-(2-hydroxy ethoxy)cyclopentane-l,2-diol (4 gm).HPLC purity- 99.7%.
  • 27
  • C9H9F2N*ClH [ No CAS ]
  • [ 1354945-69-9 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
95.5% With N-ethyl-N,N-diisopropylamine In acetonitrile at 25 - 35℃; 62 To a solution of compound XIII (5.80g) in acetonitrile (5-10V) was added diisopropyletliylamine (7.63 g). A solution of compound XII (10 g) in acetonitrile (3-5 V) was added. The reaction mixture was stirred at 25-35 °C for 1-5 hours. The reaction was stopped by adding brine solution (250 mL) and the resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic fraction was washed with brine (200 mL) and concentrated to dryness. The crude product was purified by crystallization from a mixture of MTBE and cyclohexane to give the product (12.8g, 95.5%).
  • 28
  • [ 1402150-11-1 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
54.5% Stage #1: methyl 2-((1S,2S,3S,4R)-4-(7-((1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,3-dihydroxycyclopentyloxy)acetate With lithium borohydride In tetrahydrofuran at -10 - 20℃; Stage #2: With hydrogenchloride; water In tetrahydrofuran 27 To a solution of TCG-15 DPT (3.5 g, 0.0063 mol) in THF (70 ml) was added L1BH4 (0.415 g, 0.019 mol) at -10°C. The mixture was stirred at RT for one hour. After the reaction was complete by TLC monitoring, 100 ml of water was added and the mixture was acidified with HCl solution and extracted with ethyl acetate (2 x 100 ml). The extract was dried over anhydrous NaaSC , filtered and concentrated under vacuum below 45°C to provide the crude product. The crude product was crystallized from a mixture of ethyl acetate and hexane to provide 1.80g (54.5%) of the pure product.
  • 29
  • [ 1402150-23-5 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-(((3aS,4R,6S,6aR)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-3aH-spiro[cyclopenta[d][1,3]dioxole-2,1'-cyclopentan]-6-yl)oxy)ethanol With hydrogenchloride; water In methanol; toluene at 0 - 20℃; Stage #2: With sodium hydrogencarbonate In water; toluene 39 Compound 10 in toluene is cooled to 0-20°C, and Cone. HC1 (26.24 g) and methanol (2- 10V) are added at 0-20°C. The reaction mixture is stirred at 0-20°C for 8-20 hrs. The reaction is monitored by TLC. After completion, the methanol is distilled off under reduced pressure. The obtained residue is diluted with water and the mixture is neutralized with saturated aqueous NaHCO3 and extracted with ethyl acetate (2 x 150 mL). The organic fraction is washed with aqueous sodium bicarbonate (50 mL) and concentrated to provide the crude product, which is crystallized from a mixture of ethyl acetate and heptane to provide a white solid (8.23 g).
1.1 g With hydrogenchloride In methanol; water at 20℃; for 4h; 32 Example 32: Synthesis of Ticagrelor 1 To a cooled solution of protected ticagrelor 42 (1.4 g) in methanol (14 mL) was added a solution of HC1 (1.2 mL) in water (2 mL). The reaction mixture was stirred at rt for 3-4 h. After completion the methanol was distilled off under reduced pressure. The residue was added water (70 mL) and extracted with ethyl acetate (2* 100 mL). The combined organic layers was dried over anhydrous sodium sulfate, filtered, treated with small amount of charcoal, and again filtered through hyflo. The filtrate was concentrated to give 1.1 g of Ticagrelor 1 as off- white solid. The sample of 1 was found to be identical in all respect i.e. TLC, HPLC-RT purity and spectroscopically to the sample of Example 1 1 and 12.
  • 30
  • [ 274693-27-5 ]
  • [ 50-78-2 ]
  • C9H8O4*C23H28F2N6O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% In hexane; dichloromethane at 20℃; for 264h; 2 Compound A Form III was produced by slurrying Form II (see WO 01/92262) in dichloromethane with Form III seed material (prepared, for example, as described in WO 01/92262) for 2 days at room temperature.Hexanes (0.75 mL) was added to a mixture of 3.3 mg (0.00631 mmol) ofCompound A Form III (produced as described above) and 3.6 mg (0.0120 mmol) of aspirin. The resulting mixture was treated with 50- /L portions of dichloromethane, with sonication between additions, until all of the solid dissolved (1.4 mL was required). That solution was added to a mixture of 31.1 mg (0.0595 mmol) of Compound A Form III (produced as described above) and 10.7 mg (0.0594 mmol) of aspirin. The resulting slurry was stirred at ambient temperature for 11 days and centrifuged. The liquid was removed by decantation and the solid was dried in a stream of dry air to give 35.2 mg) of Compound A: acetyl salicylic acid co-crystal (78% yield based on a co-crystal stoichiometry of 3:2 Compound A: acetyl salicylic acid - see Example 3).The resulting solid gave a diffractogram consistent with peaks listed in Example 4 (see Figure 1)
  • 31
  • [ 1444301-60-3 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 16 h / 20 °C 1.2: 2 h / 20 °C 2.1: hydrogen; 5%-palladium/activated carbon / methanol / 16 h / 7500.75 Torr 3.1: sodium nitrite; acetic acid / 0.5 h / 20 °C 4.1: phosphoric acid / methanol; water / 24 h / 20 °C
Multi-step reaction with 3 steps 1.1: triethylamine / 48 h / 75 °C 2.1: water; acetic acid; sodium nitrite / 20 h / 25 °C 3.1: 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / 25 °C / Inert atmosphere 3.2: 16 h / 25 °C / Inert atmosphere
Multi-step reaction with 3 steps 1: triethylamine / 48 h / 75 °C 2: acetic acid; sodium nitrite / 0.5 h / 20 - 30 °C 3: triethylamine / tetrahydrofuran / 2 h / 20 °C
Multi-step reaction with 3 steps 1: triethylamine / 48 h / 75 °C 2: acetic acid; sodium nitrite / 0.5 h / 20 - 30 °C 3: sodium carbonate / acetonitrile / 20 h / 20 °C
Multi-step reaction with 4 steps 1.1: triethylamine / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 19 h / 0 - 20 °C 2.1: hydrogen; 5%-palladium/activated carbon / acetic acid / 5 h / 7500.75 Torr 3.1: water; acetic acid; sodium nitrite / 20 h / 25 °C 4.1: 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / 25 °C / Inert atmosphere 4.2: 16 h / 25 °C / Inert atmosphere
Multi-step reaction with 4 steps 1: triethylamine / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 19 h / 0 - 20 °C 2: hydrogen; 5%-palladium/activated carbon / acetic acid / 5 h / 7500.75 Torr 3: acetic acid; sodium nitrite / 0.5 h / 20 - 30 °C 4: triethylamine / tetrahydrofuran / 2 h / 20 °C
Multi-step reaction with 4 steps 1: triethylamine / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 19 h / 0 - 20 °C 2: hydrogen; 5%-palladium/activated carbon / acetic acid / 5 h / 7500.75 Torr 3: acetic acid; sodium nitrite / 0.5 h / 20 - 30 °C 4: sodium carbonate / acetonitrile / 20 h / 20 °C
Multi-step reaction with 3 steps 1: triethylamine / 48 h / 75 °C 2: acetic acid; sodium nitrite / 0.5 h / 20 - 30 °C 3: triethylamine / tetrahydrofuran / 2 h / 20 °C
Multi-step reaction with 3 steps 1: triethylamine / 48 h / 75 °C 2: acetic acid; sodium nitrite / 0.5 h / 20 - 30 °C 3: sodium carbonate / acetonitrile / 20 h / 20 °C
Multi-step reaction with 4 steps 1: triethylamine / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 19 h / 0 - 20 °C 2: hydrogen; platinum on carbon / acetic acid / 5 h / 7500.75 Torr 3: acetic acid; sodium nitrite / 0.5 h / 20 - 30 °C 4: triethylamine / tetrahydrofuran / 2 h / 20 °C
Multi-step reaction with 4 steps 1: triethylamine / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 19 h / 0 - 20 °C 2: hydrogen; platinum on carbon / acetic acid / 5 h / 7500.75 Torr 3: acetic acid; sodium nitrite / 0.5 h / 20 - 30 °C 4: sodium carbonate / acetonitrile / 20 h / 20 °C
Multi-step reaction with 3 steps 1: triethylamine / methanol; water / 40 h / 100 °C 2: isopentyl nitrite / acetonitrile / 4 h / 50 °C 3: N-ethyl-N,N-diisopropylamine / acetonitrile / 4 h / 25 - 30 °C
Multi-step reaction with 5 steps 1.1: methanol; toluene / 20 °C 2.1: triethylamine / ethylene glycol; 1-methyl-pyrrolidin-2-one / 90 - 100 °C 3.1: acetic acid; sodium nitrite / toluene; water / 3 h / 20 °C 3.2: 0.17 h 4.1: potassium carbonate / toluene / 3 h / 20 °C 5.1: dihydrogen peroxide / ethyl acetate / 1 h / 20 °C

  • 32
  • [ 1427524-43-3 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
84% With phosphoric acid In methanol; water at 20℃; for 24h; 24 Example 24: Preparation of (1 S,2S,3F?,5S)-3-(7-(((1 F?,2S)-2-(3,4-difluorophenyl)cyclopropyl) amino)-5- (propylthio)-3/7-[1 ,2,3]triazolo[4,5-G|pyrimidin-3-yl)-5-(2-hydroxyethoxy) cyclopentane-1 ,2- diol (TCG) BATOMA To a solution of BATOMA (0.10 g, 0.15 mmol) in MeOH (4 mL) at room temperature ortho-phosphoric acid (85%, 1 .5 mL) was added. Resulting reaction mixture was stirred at room temperature for 24 h, then water was added (10 m L), and reaction mixture was neutralized with 1 M NaOH. The product was extracted to EtOAc (5 x 5 m L), combined organic phases were dried over Na2S04, and then concentrated to afford crude product, which was purified by chromatography (Si02, EtOAc) to afford title compound a white powder (66 mg, 84% yield). MS (ESI) m/z: 523 [MH]+.
  • 33
  • [ 1451195-46-2 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
63% With hydrogenchloride In methanol; water at 20℃; 30 Example 30: Preparation of (1 S,2S,3R,5S)-3-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl) amino)-5- (propylthio)-3/-/-[1 ,2,3]triazolo[4,5-G|pyrimidin-3-yl)-5-(2-hydroxy ethoxy)cyclopentane-1 ,2- diol (TCG) To a solution of BATAMAT (0.10 g, 0.14 mmol) in MeOH (4 mL) at room temperature 37% HCI (1 mL) was added. Resulting reaction mixture was stirred at room temperature and monitored by TLC and HPLC. After total conversion (several days) water was added (10 mL), and reaction mixture was neutralized with 1 M NaOH. The product was extracted to EtOAc (5 x 5 mL), combined organic phases were dried over Na2S04, and then concentrated to afford crude product, which was purified by chromatography (Si02, EtOAc) to afford title compound as a white powder (50 mg, 63% yield). MS (ESI) m/z: 523 [MH]+.
  • 34
  • (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine [ No CAS ]
  • [ 1354945-69-9 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
96% With triethylamine In tetrahydrofuran at 20℃; for 2h; 44 Example 44: Preparation of ticagrelor (TCG) To a stirring solution of (1 S,2S,3fl,5S)-3-(7-(((1 fl,2S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3/-/-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2- hydroxyethoxy)cyclopentane-1 ,2-diol (CLTOL; 1 .56 g, 4 mmol) in tetrahydrofuran (20 mL) at 20 °C was added a mixture of (1 ft,2S)-2-(3,4-difluorophenyl)cyclopropanamine (CPA; 0.68 g, 4 mmol) and triethylamine (0.70 mL, 5 mmol). After 2 h, the mixture was diluted with methyl fert-butyl ether (30 mL) and washed with 1 % aqueous acetic acid (100 mL), water (75 mL) and evaporated under reduced pressure. The residue was triturated under n-hexane (20 mL) and filtered to give ticagrelor (2.00 g, 96% yield): 19F NMR (CDCI3, 470.5 MHz) δ -142.4 (m, 1 F), -139.0 (m, 1 F); MS (ESI) m/z: 523 [MH]+.
96% With triethylamine In tetrahydrofuran at 20℃; for 2h; 19 Example 19: Preparation of ticagrelor (TCG) To a stirring solution of (1S,2S,3R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (CLTOL; 1.56 g, 4 mmol) in tetrahydrofuran (20 mL) at 20 °C was added a mixture of (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (CPA; 0.68 g, 4 mmol) and triethylamine (0.70 mL, 5 mmol). After 2 h, the mixture was diluted with methyl tert-butyl ether (30 mL) and washed with 1% aqueous acetic acid (100 mL), water (75 mL) and evaporated under reduced pressure. The residue was triturated under n-hexane (20 mL) and filtered to give ticagrelor (2.00 g, 96% yield): 19F NMR (CDCl3, 470.5 MHz) δ-142.4 (m, 1F), -139.0 (m, 1F); MS (ESI) m/z: 523 [MH]+.
  • 35
  • [ 1354945-69-9 ]
  • [ 1444301-72-7 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
93% With sodium carbonate In acetonitrile at 20℃; for 20h; 45 Example 45: Preparation of ticagrelor (TCG) To a stirring suspension of (1 fl,2S)-2-(3,4-difluorophenyl)cyclopropanamonium mandelate (0.33 g, 1 .03 mmol) and sodium carbonate (0.27 g, 2.5 mmol) in acetonitrile (12 mL) at 20 °C was added (1 S,2S,3fl,5S)-3-(7-(((1 ft,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5- (propylthio)-3/-/-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1 ,2-diol (CLTOL; 0.39 g, 1 mmol). The mixture was stirred for 20 h, diluted with water (50 mL) and extracted with ethyl acetate (60 mL). The extract was washed with water (50 mL), 0.1 M aqueous acetic acid (50 mL), again water (50 mL) and evaporated under reduced pressure to give ticagrelor (0.50 g, 93% yield): 19F NMR (CDCI3, 470.5 MHz) δ -142.5 (m, 1 F), -139.0 (m, 1 F); MS (ESI) m/z: 523 [MH]+.
93% With sodium carbonate In acetonitrile at 20℃; for 20h; 20 Example 20: Preparation of ticagrelor (TCG) To a stirring suspension of (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamonium mandelate (0.33 g, 1.03 mmol) and sodium carbonate (0.27 g, 2.5 mmol) in acetonitrile (12 mL) at 20 °C was added (1S,2S,3R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (CLTOL; 0.39 g, 1 mmol). The mixture was stirred for 20 h, diluted with water (50 mL) and extracted with ethyl acetate (60 mL). The extract was washed with water (50 mL), 0.1M aqueous acetic acid (50 mL), again water (50 mL) and evaporated under reduced pressure to give ticagrelor (0.50 g, 93% yield): 19F NMR (CDCl3, 470.5 MHz) δ -142.5 (m, 1 F), -139.0 (m, 1 F); MS (ESI) m/z: 523 [MH]+.
80.24% With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 5 - 20℃; for 5h; 6 Example 6 preparation of a compound of formula I Formula III compound 1.3 g is added to the bottle, adding tetrahydrofuran 13 ml, stirring and dissolving, ball point pen II - 1 compound 1.3 g, cooling to about 5 °C, dropwise N, N - diisopropyl trifluoroethylamine 1.3 g, the completion of the dropping, raising the temperature to room temperature, stirring the reaction 5 h, completion of the reaction. Evaporate the solvent under reduced pressure, the residue in ethyl acetate is added 20 ml, washing the organic phase (30 ml × 3), then the saturated salt water for washing (30 ml × 3), pressure reducing evaporate the organic phase, solid for isopropyl acetate/cyclohexane mixed solvent 6 ml (ethyl acetate/cyclohexane=3 ml/3 ml) recrystallization, resulting in white with slightly pink crystalline solid 1.4 g, yield 80.24%, a high-efficiency liquid phase analysis has a purity of 99.7%
67% Stage #1: (1R,2S)-2-(3,4-difluorophenyl)cyclopropanammonium mandelate With N-ethyl-N,N-diisopropylamine; sodium hydroxide In water; ethyl acetate at 15 - 20℃; Stage #2: 9-[(1’R,2’S,3’S,4’S)-2’,3’-dihydroxyl-4'-hydroxyethoxycyclopenta-1'-yl]-9H-2-thiopropyl-6-chloro-8-azepine With N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 1h; 8 Preparation of Ticagrelor (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine mandelate (1.8 g) and ethyl acetate (20 mL) were charged in a flask. The mixture was stirred at 15-20° C. for 10 minutes followed by addition of 20% aqueous sodium hydroxide solution (25 mL). The mixture was stirred and then the layers were separated. The organic layer was taken in another flak and to it diisopropyl ethylamine (1.5 mL) and (1S,2S,3R,5S)-3-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxyl) cyclopentane-1,2-diol were added. The mixture was stirred at room temperature for 1 hour and completion of the reaction was monitored by TLC. To the mixture water (5 mL) was added and the layers were separated. The organic layer was washed with 2% aqueous hydrochloric acid solution (10 mL) followed by complete distillation of organic solvent under vacuum. To the mass obtained ethyl acetate (10 mL) was added and then completely distilled under vacuum followed by cooling of mass to room temperature. Then ethyl acetate (10 mL) and n-hexane (50 mL) were added to the mass and mixture was stirred. The solid obtained was isolated by filtration and washed with n-hexane (5 mL) followed by drying under vacuum to afford the title compound in about 67% yield.

  • 36
  • [ 1445580-43-7 ]
  • [ 1402222-66-5 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
0.9 g Stage #1: (1S,2S,3R,5S)-3-(7-hydroxy-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol With 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 0.25h; Inert atmosphere; Stage #2: trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride In N,N-dimethyl-formamide at 25℃; for 16h; Inert atmosphere; 46 Example 46: Preparation of ticagrelor (TCG) To a solution of OHTOL (0.74 g), O-ie-chlorobenzotriazol-l -y -N./V./V./V-tetramethyluronium hexafluorophosphate (HCTU, 0.99 g) in dry DMF (2.5 mL) under nitrogen atmosphere was added N,N-diisopropylethylamine at 25 °C, stirred for 15 min and (1 R,2S)-2-(3,4- difluorophenyl)cyclopropanamine hydrochloride (0.50 g) was added. The resulting solution was stirred at 25 °C for 16 hours and the solvent was removed under reduced pressure. The product was purified by chromatography (silica gel; ethyl acetate) to give ticagrelor (0.9 g).
  • 37
  • 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-diethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
1.22 g With hydrogenchloride In methanol; water at 10 - 15℃; for 11h; 6.4 Step 4: the preparation of (I S, 2S, 3R. 5S)-3-[7-[(l R, 2S)-2-(3,4-difluorophenyl yl)-cyclopropylamino]-5-(thio-propyl)-3H-[-l ,2,3]triazolo[4,5-d]pyrimidine-3-yl]-5- (2-hydroxyethoxy) cyclopentane-l ,2-diol (formula A). Step 4: the preparation of (I S, 2S, 3R. 5S)-3-[7-[(l R, 2S)-2-(3,4-difluorophenyl yl)-cyclopropylamino]-5-(thio-propyl)-3H-[-l ,2,3]triazolo[4,5-d]pyrimidine-3-yl]-5- (2-hydroxyethoxy) cyclopentane-l ,2-diol (formula A). Concentrated hydrochloric acid (3.3 ml) was dissolved in methanol (10 ml), then the mixture was added dropwise to the solution prepared in step 3 at 15 °C, after the mixture was stirred for 1 1 hours at 10 °C, the aqueous layer was separated, the organic layer was adjusted to pH 8.0 and extracted with Ethyl acetate three times, then combined the organic layers, concentrated under reduced pressure to obtain the title compound 1.22g.
  • 38
  • [ 274693-27-5 ]
  • C23H28F2N6O4S*MgBr2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With magnesium bromide In acetonitrile at 50℃; for 0.25h; 3 Example 3: Preparation of an adduct of TOG with Mg Br2 (Ic) To a solution of TOG (0.20 g) in dry MeCN (5 mL) at 50C MgBr2 (74 mg) was added in one portion, and the resulting reaction mixture was stirred at 50°O for 15 mm. Salts were filtered offunder nitrogen to give Ic as a white powder (hygroscopic on air)
  • 39
  • [ 274693-27-5 ]
  • C23H28F2N6O4S*2C2H3O2(1-)*Fe(2+) [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.14g With iron(II) acetate In acetonitrile at 50℃; for 16h; 4 Example 4: Preparation of an adduct of TOG with Fe(OAc)2 (Id) To a solution of TOG (0.20 g) in dry MeON (4 mL) at 50°O Fe(OAc)2 (70 mg) was added in oneportion, and the resulting reaction mixture was stirred at 50°O for 16 h. Salts were filtered off,washed with MeON, and dried to afford Id as a yellow powder (0.14 g). DSO: no peaks; XRD analysis: no peaks (amorphous solid); IR (KBr): 3426, 2962, 2932, 2873, 1608, 1522, 1446, 1324,1276,1211,1115, 1061,666cm1.
  • 40
  • [ 274693-27-5 ]
  • C23H28F2N6O4S*(x)CaCl2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
6.7g With calcium(II) chloride dihydrate In ethyl acetate at 60℃; for 20h; 1 The adduct TOGxOaOl2 (Ia) was also prepared using 0a0l2x2H20 in EtOAc: Mixture of TOG (5.22 g) and 0a0l2x2H20 (1.54 g) in EtOAc (25 mL) was stirred at 60°O for 20h. White solid was filtered off, washed with EtOAc, and dried to afford Ia as a white powder (6.7g). IR (KBr): 3382, 2964, 2934, 2873, 1615, 1522, 1456, 1431, 1379, 1324, 1300, 1277, 1212,1115, 1057, 772, 689, 668, 644, 618, 581 cm1.
  • 41
  • [ 274693-27-5 ]
  • C23H28F2N6O4S*(x)Cl2Mg [ No CAS ]
YieldReaction ConditionsOperation in experiment
With magnesium chloride In acetonitrile at 60℃; for 16h; 2 Example 2: Preparation of an adduct of TOG with Mg012 (Ib) To a solution of TOG (0.30 g) in dry MeON (4 mL) at 60°O Mg012 (60 mg) was added in oneportion, and the resulting reaction mixture was stirred at 60°O for 16 h. Salts were filtered offunder nitrogen to give lb as a white powder (hygroscopic on air).
  • 42
  • C23H28F2N6O4S*(x)CaCl2 [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
0.12g In methanol; water at 25℃; for 16h; 5 Example 5: Preparation of TOG from the adduct of TOG with 0a012 (Ia) Mixture of Ia (0.20 g), H20 (3 mL) and MeOH (1 mL) was stirred at 25°O for 16 h. White powder was filtered off, washed with water and dried to afford 0.12 g of TOG. DSO: Onset 132.2°O, Peak 135.8°O; 19F NMR (OD3OD, 470.5 MHz) 6 -141.9 --142.1 (m, iF), -145.6 --145.9 (m,iF); IR (KBr): 3392, 3293, 2963, 2931, 1625, 1589, 1521, 1452, 1427, 1329, 1291, 1276, 1208,1196, 1114, 1072, 1050, 994, 891, 771, 668, 618, 579 cm1 MS (ESI) m/z: 523 [MH]+.
  • 43
  • [ 376608-71-8 ]
  • [ 1354945-69-9 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
87% With N-ethyl-N,N-diisopropylamine; In 2-methyltetrahydrofuran; at 20 - 30℃; for 3h; 2-Methyl-tetrahydrofuran (160 ml) and (l ,2S)-2-(354-difluoroplienyl)-cyclopropanamine R- mandelate (16.5 g, 51 mmol) were added to the compound Via (20 g, 50 mmol) N,N- diisopropyl-ethylamine (26 ml, 150 mmol) was added dropwise at 20 to 30°C. The mixture was agitated at 20 to 30°C for 3 hours. Then, water (150 ml) was added and 36percent hydrochloric acid (3.8 ml) was added dropwise. The phases were separated after stirring for 10 minutes. The top organic phase was evaporated in an evaporator at a reduced pressure, producing 28 g of a wet solid substance. This crude product was recrystallized from acetonitrile (200 ml). 23 g (87percent) of the compound I (ticagrelor) was obtained at a HPLC purity higher than 99.5percent.MW of 522.57 (C23H28F2N604S) was verified with HR MS.lHNMR (500 MHz, dmso-d6, 100°C): delta 8.84 (b, 1H); 7.27 (m52H); 7.07 (m, 1H); 4.98 (quartet, J=8.7Hz, 1H); 4.73 (m, 1H); 4.62 (m, 2H); 4.16 (m, 1H); 4.01 (m, 1H); 3.84 (m, 1H); 3.55 (m, 4H); 2.97-3.10 (m, 2H); 2.96 (m, 1H); 2.64 (m, 1H); 2.23 (m, 1H); 2.10 (m, 1H); 1.64 (m;2H); 1.53 (m, 1H); 1.36 (m, 1H); 0.93 (t, J=7.1Hz, 3H).
62.19% With potassium carbonate; In acetonitrile; at 25 - 30℃; To a solution of (1 ,2 ?,3S,5 ?)-3-[7-chloro-5-(propylthio)-3H- [1 , 2, 3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1 ,2-diol (3.0 gm 0.008 mol) in acetonitrile (60.0 ml) was added trans-(1 R,2S)-2-(3,4- Difluorophenyl) cyclopropanamine (2f?)-2-hydroxy-2-phenylethanoate (2.47 gm, 0.008 mol) followed by addition of Anhydrous potassium carbonate (2.13 gm, 0.015 mol) under stirring at 25-30°C. The resultant mass was maintained at 25-30°C under stirring for 2-3 hrs, and the progress of reaction was monitored by TLC. After completion of reaction, resulting mass was diluted with water (60 ml). From same solution (1 S,2S,3R,5S)-3-[7-[(1 R,2S)- 2-(3,4-difluorophenyl) cyclopropyl] amino}-5(propylthio)-3H-[1 ,2,3]- triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1 ,2-diol was extracted twice with ethyl acetate (60 ml + 30 ml), followed by washing the organic layer with water (100 ml), 15percent WA/ sodium chloride solution (100 ml). Ethyl acetate was evaporated at 50-55°C under reduced pressure to produce an oil of (1S,2S,3R,5S)-3-[7-[(1R2S)-2-(3,4-difluorophenyl) cyclopropyl] amino}-5(propylthio)-3H-[1 ,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5- (2-hydroxyethoxy) cyclopentane-1 , 2-diol (3.5 gm)(ticagrelor). To the same oil was added ethyl acetate (17.5 ml), the solution was stirred and heated to 50-55 °C, followed by addition of n-heptane (17.5 ml) and solution was maintained at 50-55°C for 30 min. The resulting solution was gradually cooled to room temperature, further cooled and maintained at 0-5°C for 30- 40 min. obtained solid was filtered and washed with pre-chilled n-heptane (3.5 ml), suck dried and dried at 50-55°C to give pure white crystalline solid of ticagrelor, 3.0 gm. (HPLC purity: 96.0 percent by area). Purification: Above obtained solid (3.0 grh) was dissolved in ethyl acetate (15 ml) stirred and heated to 50°C, followed by addition of n-heptane (15 ml). The solution was stirred at 50°C for 30 min. The resulting solution was gradually cooled to room temperature, further cooled and maintained at 0-5°C for 30-40 min. Obtained solid was filtered and washed with pre-chilled n-heptane (3.0 ml), suck dried and dried at 50-55°C to give pure white crystalline powder of ticagrelor, 2.5 gm. [Yield = 2.5 gm (62.19percent); Purity (HPLC) = 98.5percent]
2.29 g With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 25 - 30℃; for 4h; Acetonitrile (20ml) and (lR,2S)-2-(3,4-difluorophenyl)-cyclopropane amine R-mandelate (1.64 g, 5.1 mmol) were added to the compound Va (1.95 g, 5 mmol). Diisopropylethylamine (1.61 g, 12.5 mmol) was added dropwise at 25 to 30 °C. The mixture was stirred at 25 to 30°C for 4 hours. Then, water (30 ml) was added. Acetonitrile was evaporated in an evaporator at a reduced pressure. The mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic phase was washed with water (20 ml) and evaporated in an evaporator at a reduced pressure, providing 2.54 g of a solid substance. The crude product was re-crystallized from acetonitrile. 2.29g (88percent) of the compound I (Ticagrelor) was obtained with HPLC purity higher than 99percent. MW of 522.57 (C23H28F2N604S) was verified by means of HR MS. 1H NMR (500 MHz, dmso-d6, 100 °C): delta 8.84 (b, 1H); 7.27 (m, 2H); 7.07 (m, 1H); 4.98 (quartet, J=8.7Hz, 1H); 4.73 (m, 1H); 4.62 (m, 2H); 4.16 (m, 1H); 4.01 (m, 1H); 3.84 (m, 1H); 3.55 (m, 4H); 2.97-3.10 (m, 2H); 2.96 (m, 1H); 2.64 (m, 1H); 2.23 (m, 1H); 2.10 (m, 1H); 1.64 (m, 2H); 1.53 (m, 1H); 1.36 (m, 1H); 0.93 (t, J=7.1Hz, 3H).
  • 45
  • C23H26F2N6O4S [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
80 mg With sodium tetrahydroborate In methanol at 0 - 20℃; for 16.5h; 4 Preparation of Ticagrelor In this example, Ticagrelor is prepared starting from compound (3) produced as described in example 2, and following the synthetic scheme B.i). Compound (3) (170 mg, 0.28 mmol) is dissolved in a mixture of acetic acid and water (1 :1 , 1 .7 mL) and heated to reflux for two hours, monitoring the reaction by TLC (AcOEt, Rf (3) = 0.87; Rf (product) = 0.25). The mixture is cooled to room temperature, ethyl acetate is added (5 mL), the phases are separated, the organic phase is washed with water (2 x 5 mL) and with a saturated solution of sodium bicarbonate (2 x 5 mL), then again with water (2 x 5 mL) and finally with brine (5 mL). The organic phase is dried over sodium sulfate, the solvent is evaporated to a residue, which is taken up in methanol (1 mL) and cooled to 0 °C. To the resultant solution, NaBH4 is added (10 mg, 0.28 mmol). The mixture is stirred for 30 minutes at 0 °C then for 16 hours at room temperature. Afterwards, a saturated solution of ammonium chloride (2 mL) and ethyl acetate (10 mL) are added. The mixture is stirred for 30 minutes, the phases are separated, the organic phase is washed with brine (2 mL), dried over sodium sulfate and concentrated to a residue which is purified by flash chromatography eluting with dichloromethane/methanol 95:5, obtaining Ticagrelor (80 mg, 55%) as a white solid.
  • 46
  • N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-3-((3aS,4R,6S,6aR)-2,2-dimethyl-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazol[4,5-d]pyrimidin-7-amine [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
97% With hydrogenchloride In methanol; water at 0 - 20℃; for 4.5h; 3 Preparation of Ticagrelor In this example, Ticagrelor is prepared starting from compound (2) produced as described in e B.ii). A solution of compound (2) (500 mg, 0.77 mmol) in methanol (5 mL) is prepared and kept at 0 °C; to this solution, aqueous HCI 6N (1 .0 mL) is slowly added. At the end of the addition, the mixture is warmed to room temperature and stirred at this temperature for 4 hours and 30 minutes, then it is neutralized (pH = 7) with 1 N NaOH, methanol is removed under reduced pressure, the residue is taken up in ethyl acetate (5 mL) and washed with water (5 mL); the phases are separated, the aqueous phase is extracted again with ethyl acetate (3 x 10 mL). The organic phase is washed with water (2 x 10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated to a residue obtaining Ticagrelor (390 mg, 97%) as a white solid.
86% With hydrogenchloride In methanol; water at 15 - 25℃; for 3h; 3 Preparation of Compound I: IIc (71.14 g, 0.11 mol) was dissolved in a mixed solution of 260.00 g of methanol and 108.51 g of concentrated hydrochloric acid, maintaining the temperature at 15 to 25 ° C, and the reaction was stirred for 3 hours, and the reaction was confirmed by TLC. The reaction liquid was adjusted to pH 7 with a 30% sodium hydroxide solution, and methanol was evaporated under reduced pressure, ethyl acetate (500 mL) was added, and the organic phase was separated, washed with saturated sodium chloride solution (200 mL × 3), dried over anhydrous sodium sulfate After 8 hours, the temperature was raised to 50 ° C, and 300 mL of isooctane was added dropwise with stirring. After the completion of the dropwise addition, the temperature was lowered to 0 ° C, and the mixture was stirred for 4 hours to precipitate a solid, which was dried to obtain 49.43 g of crude compound I, yield 86%, HPLC. The purity was 98.8%.
  • 47
  • [ 274693-27-5 ]
  • [ 110-16-7 ]
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol maleate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In acetone at 0.3℃; for 0.1h; 30 Preparation of Ticagrelor Maleate Ticagrelor (2 g) and acetone (40 mL) were charged into a round bottom flask and stirred at about 30° C. for about 15 minutes. The reaction mixture was filtered through hyflow bed followed by washing of the bed with acetone (10 mL). Then maleic acid (0.49 g) was added to the above filtrate at about 30° C. and mixture was stirred for about 1 hour. The reaction mixture was concentrated up to 20% of its initial volume at 45° C. under reduced pressure. Then n-hexane (100 mL) was added to the reaction mixture at about 35° C. and mixture was stirred for about 3 hours to afford the title compound.
  • 48
  • [ 274693-27-5 ]
  • [ 77-92-9 ]
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol citrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In acetone at 0.3℃; for 0.1h; 31 Preparation of Ticagrelor Citrate Ticagrelor (1 g) and acetone (20 mL) were charged into a round bottom flask and stirred at about 30° C. for about 20 minutes. The reaction mixture was filtered through hyflow bed followed by washing of the bed with acetone (5 mL). Then citric acid (0.44 g) was added to the above filtrate at about 30° C. and mixture was stirred for about 1 hour. The reaction mixture was concentrated up to 20% of its initial volume at about 40° C. under reduced pressure. Then n-hexane (50 mL) was added to the reaction mixture at about 30° C. and mixture was stirred for about 2 hours to afford the title compound.
  • 49
  • [ 274693-27-5 ]
  • [ 87-69-4 ]
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol L-tartrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.41% In acetone at 30℃; for 0.2h; 26 Preparation of Ticagrelor L-Tartrate Ticagrelor (3 g) and acetone (60 mL) were charged into a round bottom flask and stirred at about 30° C. for about 10 minutes. The reaction mixture was filtered through hyflow bed followed by washing of the bed with acetone (10 mL). Then L (+)-tartaric acid (0.95 g) was added to the above filtrate at 30° C. and mixture was stirred for about 2 hours. The reaction mixture was cooled to 0-5° C. and maintained for about 30 minutes at the same temperature. The reaction mixture was concentrated up to 20% of its initial volume at 45° C. under reduced pressure. Then n-hexane (70 mL) was added to the reaction mixture and stirred for about 60 minutes for solid separation. The solid was isolated by filtration and dried at below 50° C. to afford the title compound in about 41.5% yield.
  • 50
  • [ 274693-27-5 ]
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol hydrochloride salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.75% With hydrogenchloride In water; ethyl acetate at 25 - 30℃; for 0.2h; 19 Preparation of Form I of Ticagrelor Hydrochloride Ticagrelor (0.5 g) and ethyl acetate (15 mL) were charged into a round bottom flask and the mixture was stirred at about 25-30° C. for about 15 minutes for clear solution. Then aqueous hydrochloric acid (0.12 mL, 35%) was added to the above reaction mixture at 25-35° C. and stirred for solid separation for about 2 hours. The solid was filtered, washed with ethyl acetate (5 mL) and dried to afford the title compound in about 75% yield having chiral HPLC purity of 99.55%.
  • 51
  • [ 274693-27-5 ]
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol hydrogenbromide salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
69.6% With hydrogen bromide In water; ethyl acetate at 0.3℃; for 0.1h; 21 Preparation of Ticagrelor Hydrobromide Ticagrelor (1 g) and ethyl acetate (30 mL) were charged into a round bottom flask and stirred at about 30° C. for 15 minutes. The reaction mixture was filtered through hyflow bed followed by washing of the bed with ethyl acetate (5 mL). Then aqueous hydrobromic acid (0.37 mL, 48%) was added to the above filtrate at same temperature and stirred for about 1 hour. The reaction mixture was concentrated up to 20% of its initial volume at 45° C. under reduced pressure. Then petroleum ether (70 mL) was added to the reaction mixture at 30° C. and stirred for about 90 minutes for solid separation. The solid obtained was isolated by filtration and dried at below 50° C. to afford the title compound in about 69.6% yield.
  • 52
  • [ 274693-27-5 ]
  • [ 110-15-6 ]
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol succinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% In acetone at 25 - 30℃; 22 Preparation of Form I of Ticagrelor Succinate Ticagrelor (0.5 g) and acetone (10 mL) were charged into a round bottom flask and the mixture was stirred at about 25-30° C. for about 15 minutes for clear solution. Then succinic acid (0.12 g) was added to the above reaction mixture at 25-35° C. and stirred overnight. To the clear solution, n-hexane (50 mL) was added and stirred for about 90 minutes for solid separation. The solid was isolated by filtration, washed with n-hexane (5 mL) and dried to afford the title compound in about 81% yield having chiral HPLC purity of about 99%.
  • 53
  • [ 274693-27-5 ]
  • [ 110-17-8 ]
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol fumarate [ No CAS ]
YieldReaction ConditionsOperation in experiment
94.4% In n-heptane; acetone at 0 - 35℃; for 1h; 1-2 Example 1 Ticagrelor precursor 2-(((3aR, 4S, 6R, 6aS) -6- (7-(((1R, 2S) -2- (3,4-difluorophenyl) cyclopropyl) amino) -5 -(Propylthio) -3H- [1,2,3] triazolo [4,5-d] pyrimidin-3-yl) -2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1 , 3] diox-4-yl) oxy) ethanol was added to a mixture of 9.5 g of concentrated hydrochloric acid and 100 mL of methanol. After the reaction was completed, 150 mL of ethyl acetate was added and neutralized with an aqueous sodium bicarbonate solution. The organic layer was separated and washed with brine. The organic layer was concentrated to obtain a ticagrelor free base that is an oil phase. 2.4 g of fumaric acid and 260 mL of acetone were added thereto and completely dissolved at 35 ° C. 1 L of n-heptane was dripped gradually, the reaction solution was cooled to 0-5 degreeC, and it stirred for 1 hour. The resulting white crystalline solid was filtered off. Thereafter, the mixture was washed with 100 mL of n-heptane and dried under vacuum at 40 ° C. for 12 hours to obtain 11.7 g of ticagrelor fumaric acid Form I crystal. (Yield 94.4%, Purity: 99.88%).
65% In acetone at 25 - 30℃; 24 Preparation of Ticagrelor Fumarate Ticagrelor (0.5 g) and acetone (13 mL) were charged into a round bottom flask and the mixture was stirred at about 25-30° C. for about 15 minutes for clear solution. Then fumaric acid (0.12 g) was added to the above reaction mixture at 25-35° C. and mixture was stirred for 4-5 hours. To the clear solution, n-hexane (50 mL) was added and stirred for about 90 minutes for solid separation. The solid was filtered, washed with n-hexane (5 mL) and dried to afford the title compound in about 65% yield having chiral HPLC purity of about 99.8%.
  • 54
  • [ 274693-27-5 ]
  • [ 147-71-7 ]
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol D-tartrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.93% In acetone at 0.3℃; 25 Preparation of Ticagrelor D-Tartrate Ticagrelor (0.5 g) and acetone (10 mL) were charged into a round bottom flask and the mixture was stirred at about 30° C. for about 15 minutes for clear solution. Then D (-)-tartaric acid (0.16 g) was added to the above reaction mixture at about 30° C. and mixture was stirred for overnight. To the clear solution, n-hexane (35 mL) was added and stirred for about 1 hour at 25-30° C. for solid separation. The solid was filtered, washed with n-hexane (5 mL) and dried to afford the title compound in about 93% yield having chiral HPLC purity of about 98%.
  • 55
  • [ 274693-27-5 ]
  • [ 32634-66-5 ]
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol O,O'-di-p-toluoyl-(2R,3R)-tartaric acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
34.6% In acetone at 0.3℃; for 0.1h; 27 Preparation of Ticagrelor O,O'-Di-P-Toluoyl-(2R,3R)-Tartaric Acid Salt Ticagrelor (2 g) and acetone (40 mL) were charged into a round bottom flask and stirred at about 30° C. for about 15 minutes. The reaction mixture was filtered through hyflow bed followed by washing of the bed with acetone (10 mL). Then anhydrous (-) O,O'-di-p-toluoyl-(2R,3R)-tartaric acid (1.6 g) was added to the above filtrate at about 30° C. and mixture was stirred for about 1 hour. The reaction mixture was concentrated up to 20% of its initial volume at 45° C. under reduced pressure. Then n-hexane (100 mL) was added to the reaction mixture at 30° C. and stirred for about 2 hours for solid separation. The solid was isolated by filtration and dried at below 50° C. to afford the title compound in about 34.6% yield.
  • 56
  • [ 274693-27-5 ]
  • [ 141-82-2 ]
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol malonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.46% In acetone at 0.3℃; for 0.1h; 28 Preparation of Ticagrelor Malonate Ticagrelor (2 g) and acetone (40 mL) were charged into a round bottom flask and stirred at 30° C. for about 15 minutes. The reaction mixture was filtered through hyflow bed followed by washing of the bed with acetone (10 mL). Then malonic acid (0.44 g) was added to the above filtrate at about 30° C. and mixture was stirred for about 1 hour. The reaction mixture was concentrated up to 20% of its initial volume at 45° C. under reduced pressure. Then n-hexane (100 mL) was added to the reaction mixture at about 30° C. and stirred for about 90 minutes for solid separation. The solid was isolated by filtration and dried at below 50° C. to afford the title compound in about 46% yield having HPLC purity of about 98%.
  • 57
  • [ 274693-27-5 ]
  • [ 144-62-7 ]
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol oxalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In acetone at 0.3℃; for 0.1h; 29 Preparation of Ticagrelor Oxalate Ticagrelor (2 g) and acetone (40 mL) were charged into a round bottom flask and stirred at about 30° C. for about 15 minutes. The reaction mixture was filtered through hyflow bed followed by washing of the bed with acetone (10 mL). Then oxalic acid (0.38 g) was added to the above filtrate at about 30° C. and mixture was stirred for about 1 hour. The reaction mixture was concentrated up to 20% of its initial volume at 45° C. under reduced pressure. Then n-hexane (100 mL) was added to the reaction mixture at about 30° C. and mixture was stirred for about 3 hours to afford the title compound.
  • 58
  • (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol malonate [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In water; ethyl acetate for 0.25h; 32 Preparation of Ticagrelor Ticagrelor malonate (0.5 g) and ethyl acetate (10 mL) were charged into round bottom flask. To the mixture 10% aqueous sodium carbonate solution (50 mL) was added and mixture was stirred for 15 minutes. The layers were separated and organic layer was subjected to distillation under vacuum to afford the title compound.
  • 59
  • 2-[(3aR,4S,6R,6aS)-6-(7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylsulfanyl)-3H-[1,2,3 ]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]oxy}ethyl acetate [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
With water; sodium hydroxide In methanol at 20 - 25℃; for 1h; 12; 13 [0090] EXAMPLE 12 Preparation of dimethyl formamide solvate of ticagrelor A mixture of 2- { [(3 aR,4S,6R,6a5)-6-(7- { [(1R,25)-2-(3 ,4-difluorophenyl)cyclopropyl] amino } - 5-(propylsulfanyl)-3H- [1,2,3 ]triazolo[4, 5-d]pyrimidin-3 -yl)-2,2-dimethyl- hexahydrocyclopenta[d] [1,31 dioxol-4-yl] oxy} ethyl acetate, compound of formula III(lOg), methanol and aqueous sodium hydroxide was stirred at about 20°C to about 25°Cfor about lh. Amberlite JR 120 H resin was added to the reaction mixture. The reactionmixture was concentrated under vacuum at about 30°C to about 35°C. Water and ethylacetate was added to the reaction mixture. The organic layer was separated, washed withauueous sodium carbonate solution, concentrated and degassed. The residue obtained wasdissolved in dimethyl formamide (1 OmL) at about 45°C to about 50°C and methyl tertbutyl ether (300mL) was added to it at about the same temperature. The mixture wasstirred for about 30mm. The mixture was then cooled to about 0°C to about 5°C and wasstirred for about 6h. The solid obtained was filtered at about 0°C to about 5°C, washedwith chilled methyl tert-butyl ether and dried at about 30°C to about 35°C for about 24h.
  • 60
  • (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine hydrochloride [ No CAS ]
  • 2-[(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]oxy}ethyl acetate [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine hydrochloride; 2-[(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]oxy}ethyl acetate With N-ethyl-N,N-diisopropylamine In dichloromethane at 20 - 25℃; Stage #2: With hydrogenchloride In water at 0 - 10℃; 30 EXAMPLE 30 Preparation of dimethyl formamide solvate of Ticagrelor A mixture of 2- { [(3 aR,4S,6R,6a5)-6- [7-chloro- 5-(propylsulfanyl)-3H- [1,2,3 ]triazolo[4, 5-d]pyrimidin-3 -yl] -2,2-dimethyl-hexahydrocyclopenta[d] [1,31 dioxol-4-yl] oxy} ethylacetate (1 5g), (1R,25)-2-(3 ,4-difluorophenyl)cyclopropanamine hydrochloride (7. 2g) anddiisopropyl ethyl amine (14.4g) in dichloromethane was stirred at about 20°C to about25°C. Water was then added to the reaction mixture. The organic layer was separated,washed with aqueous sodium carbonate solution, concentrated and degassed. Methanolwas then added to the above residue. The reaction mixture was cooled and concentratedhydrochloric acid was added to it under stirring. The reaction was stirred for about 20h toabout 24h at about 0°C to about 10°C. Water and dichloromethane was added to thereaction mixture. The organic layer was separated, washed with aqueous sodiumbicarbonate solution, concentrated and degassed. The residue obtained was dissolved indimethyl formamide (9mL) at about 40°C to about 50°C and toluene (142mL) was addedto it at about the same temperature. The mixture was stirred for about 3 0mm. The mixturewas then cooled to about 0°C to about -10°C and was stirred for about 6h to about 8h.The solid obtained was filtered at about 0°C to about -10°C, washed with toluene anddried at about 30°C to about 35°C for about 24h.TGA analysis of dimethyl formamide solvate of ticagrelor:Solvent % loss up to 100°CDimethyl formamide 10.06%
  • 61
  • C24H26F2N6O5S [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
85.2% With water; sodium hydroxide In 1,4-dioxane at 30℃; Cooling with ice; 18 Example 18 Preparation of compound 1 (Ticagrelor) A solution of sodium hydroxide (0.88 g, 22 mmol) in water (20 mml) was added slowly to a solution of compound (1-e′) (0.6 g, 1.1 mmol) in 1,4-dioxane (15 ml) cooling the temperature during the addition with an ice bath. After addition, the temperature of the reaction mixture was slowly heated to 20-30° C. and stirring for 2-3 hours. The reaction was monitored with TLC. After completion, aqueous ammonium chloride was added to adjust the pH of the mixture to 7-8. The organic layer was extracted by ethyl acetate (20 ml*3). Then the combined ethyl acetate was dried with anhydrous sodium sulfate, then filtered and the ethyl acetate was removed by distillation at reduced pressure to obtain crude product. The crude product was purified with column chromatography on silica (dichloromethane:methanol 100:150:1 gradient elution) to obtain compound 1 (Ticagrelor) as a white solid (0.48 g, yield 85.2%). HPLC purification is above 99%. 1H NMR (400M, MEOD) δ: 7.06-7.23 (m, 3H), 5.12 (q, 1H), 4.73-4.77 (m, 1H), 4.16-4.18 (m, 1H), 3.89-3.93 (m, 1H), 3.60-3.71 (m, 4H), 3.04-3.31 (m, 2H), 2.89-2.93 (m, 1H), 2.73-2.80 (m, 1H), 2.19-2.26 (m, 1H), 2.10-2.18 (m, 1H), 1.58-1.64 (m, 2H), 1.45-1.48 (m, 1H), 1.36-1.39 (m, 1H), 0.93 (t, J=14.8 Hz, 3H). MS (m/z): [M+H]+=523.00.
85.2% With sodium hydroxide In 1,4-dioxane; water at 20 - 30℃; 9.5 5) Preparation of ticagrelor 0.88 g (22 mmol) of sodium hydroxide was dissolved in 20 ml of water.Compound 1-e' 0.6 g (1.1 mmol) was dissolved in 15 ml of 1,4-dioxane.The above sodium hydroxide solution was slowly added dropwise under ice bath.After the completion of the dropwise addition, the temperature was slowly raised to room temperature 20-30 ° C, and stirring was continued for 2-3 hours.The TLC test compound 1-e' was reacted after completion of the reaction.A saturated aqueous solution of ammonium chloride was slowly added dropwise to adjust the pH to 7-8.The reaction solution was extracted with ethyl acetate 20 ml × 3 times.The ethyl acetate phases were combined, dried over anhydrous sodium sulfate and filtered and evaporated.The crude product was subjected to column chromatography (silica gel column,Eluent dichloromethane: methanol = 100:1 to 50:1 gradient elution)After isolation, compound 1 (Ticagrelor) white solid 0.48 g was obtained.The yield was 85.2%, and the HPLC purity was greater than 99%.
  • 62
  • C30H34F2N6O4S [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
95.2% With palladium 10% on activated carbon; hydrogen In methanol for 2h; 21 Preparation of compound 1 (Ticagrelor) from compound (1-f"):
Compound (1-f") (11.0 g, 18 mmol) was dissolved in anhydrous methanol (300 ml) to form a mixture. 10% Pd/C (1.1 g) and methanol (200 ml) were added to the above mixture. Under a pressurized hydrogen atmosphere (0.4 MPa), a suspension of the resulting mixture was stirred for 2 hours. The reaction was monitored with TLC. After completion, the mixture was filtered. The solvent of the filtration was removed by distillation to get crud product. The crude product was crystallized from a mixture of isopropanol and n-heptane to obtain compound 1 as a white solid (8.9 g, yield 95.2%). HPLC purification is above 98%. 1HNMR (400M, MeOD) δ: 7.06-7.23 (m, 3H), 5.11 (q, 1H), 4.72-4.76 (m, 1H), 4.15-4.18 (m, 1H), 3.89-3.92 (m, 1H), 3.60-3.72 (m, 4H), 3.05-3.31 (m, 2H), 2.89-2.94 (m, 1H), 2.72-2.80 (m, 1H), 2.18-2.26 (m, 1H), 2.11-2.18 (m, 1H), 1.58-1.65 (m, 2H), 1.46-1.48 (m, 1H), 1.36-1.40 (m, 1H), 0.95 (t, J=14.8 Hz, 3H). MS (m/z): [M+H]+=523.01.
  • 63
  • N-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]-N-{3-[(3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl}-N’,N’-dimethylsulfuric diamide [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
67% With hydrogenchloride In water at 20℃; for 6.5h; 7 Example 7(1 S,2S,3R,5S)-3-[7- { [(1 R,2S)-2-(3,4-difIuorophenyl)cyclopropylamino} -5- (propylsuLfanyl)-3H-[ I ,2,3]triazolo[4,5-dlpyrimidin-3-yl]-5-(2- hydroxyethoxy)cyclopentane- 1 ,2-diol (ticagrelor) In a glass reactor, a precooled at 0°C, hydrochloric acid solution (124 mL, 37%) was added to crude N-ft I R,2S)-2-(3,4-difluorophenyl)cyclopropyl]-N- {3- ft3aS,4R,6S,6aR)-6-{2-hydroxyethoxy)-2,2-dimethyltetrahydro-3 aHcyc Lopenta[d] [I ,3]dioxol-4-yl] -5 -(propylsulfanyl)-3H- [1,2,3] triazolo[4, 5- d]pyrimidin-7-yL} -N’,N’-dimethylsulfuric diamide achieved according to the procedure of example 5 (7.80 g, 0.010 mol). The mixture was stirred at room temperature for 6.5 hours. Water (300 mE) and methyl tert-butyl ether (200 mE), were added and the mixture was stirred for 10 mm. The organic layer was separated and the aqueous phase was extracted twice with methyl tert-butyl ether (200 mL). Combined organic layer were washed with water (200 mL) and with satd. sodium bicarbonate solution (2x 100 mL). The organic layer was separated and concentrated to give a brown oil. Acetonitrile (2x50 mL) was added and evaporated under reduced pressure, the crude was suspended in acetonitrile (21 mL) heated at 60°C until complete dissolution of the solid. Upon cooling the mixture at room temperature, title compound precipitates as an off-white solid. The solid was recovered by filtration and dried in vacuo at 40°C for 16 hours, affording ticagreLor (3.50 g, 67% yield). LC-MS (ESI) m/z 523.193 (MU) +
  • 64
  • [ 274693-27-5 ]
  • [ 77-76-9 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
93% With toluene-4-sulfonic acid; In acetone; at 20 - 30℃; for 12h;Inert atmosphere; Under an inert nitrogen atmosphere, washed 50mL three-necked round bottom flask was placed (1S, 2S, 3R, 5S) -3- (7 - [[(2S) -2- (3,4- difluorophenyl ) cyclopropyl] amino] -5- (mercapto propyl) -3H- [1,2,3] triazolo [4,5-d] pyrimidin-3-yl) -5- (2-hydroxyethoxy ) 2-diol (2g, 3.79mmol, 1.00 eq., 99%) and 4-methylbenzenesulfonate (20mg, 0.12mmol, 0.03 eq., 99%) in acetone (50 mL), then stirring at room temperature was added dropwise 2,2-dimethoxy propane (800mg, 7.68mmol, 2.03 eq).The resulting solution was stirred at 30 12 hours.Sodium bicarbonate pH-value of the solution was adjusted to 7.The mixture was filtered and the filtrate was concentrated in vacuo.The residue was purified by silica gel column with ethyl acetate: petroleum ether (1:50 to 1: 3) to afford 2g (93%) 2 - [[(3aR, 4S, 6R, 6aS) -6- (7 - [[(2S) -2- (3,4- difluorophenyl) cyclopropyl] amino] -5- (mercapto propyl) -3H- [1,2,3] triazolo [4, 5-d] pyrimidin-3-yl) -2,2-dimethyl - hexahydro-cyclopenta [d] [1,3] dioxol-4-yl] oxy] -1-ethyl - alcohol white oil.
  • 65
  • 2-(((3aS,4S,6R,6aS)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-phenyltetrahydro-4H-cyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
81% With dihydrogen peroxide In ethyl acetate at 20℃; for 1h; 1.5 5) Synthesis of ticagrelor (step d in scheme 3) 2-(((3aS,4S,6R,6aS)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-phenyltetrahydrocyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol (3 g)Was added ethyl acetate (30 ml), 35% hydrogen peroxide(1.1 ml), and the mixture was stirred at room temperature for 1 hour.Water (30 ml) was added and stirred for 15 minutes, followed by layer separation, and the organic layer was washed with water(24 ml) and washed twice with saturated brine (30 ml).The organic layer was dehydrated, filtered, and concentrated. To the concentrate was added ethyl acetate (18 ml)The mixture was heated and stirred at an internal temperature of 50°C for 30 minutes to dissolve completely, Iso-octane (18 ml) was slowly added dropwise thereto, followed by heating and stirring for 30 minutes.The reactor was cooled to room temperature and stirred at 0~5°C for 3 hours.The precipitated solid was filtered and dried to obtain ticagrelor (2.1 g, 81%).
  • 66
  • 2-(((3aS,4S,6R,6aS)-2-(4-chlorophenyl)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-4H-cyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
71% With dihydrogen peroxide In ethyl acetate at 20℃; for 1h; 1.5 5) Synthesis of ticagrelor (step d in scheme 3) 2-(((3aS,4S,6R,6aS)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-phenyltetrahydrocyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol (3 g)Was added ethyl acetate (30 ml), 35% hydrogen peroxide(1.1 ml), and the mixture was stirred at room temperature for 1 hour.Water (30 ml) was added and stirred for 15 minutes, followed by layer separation, and the organic layer was washed with water(24 ml) and washed twice with saturated brine (30 ml).The organic layer was dehydrated, filtered, and concentrated. To the concentrate was added ethyl acetate (18 ml)The mixture was heated and stirred at an internal temperature of 50°C for 30 minutes to dissolve completely, Iso-octane (18 ml) was slowly added dropwise thereto, followed by heating and stirring for 30 minutes.The reactor was cooled to room temperature and stirred at 0~5°C for 3 hours.The precipitated solid was filtered and dried to obtain ticagrelor (2.1 g, 81%). The product was obtained in 71% yield in the same manner as in step 5) of Example 1, using the product of the step 4.
  • 67
  • 2-(((3aS,4S,6R,6aS)-2-(3-(benzyloxy)phenyl)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-4H-cyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
77% With dihydrogen peroxide In ethyl acetate at 20℃; for 1h; 3.5 5) Synthesis of ticagrelor (step d in scheme 3) 2-(((3aS,4S,6R,6aS)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-phenyltetrahydrocyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol (3 g)Was added ethyl acetate (30 ml), 35% hydrogen peroxide(1.1 ml), and the mixture was stirred at room temperature for 1 hour.Water (30 ml) was added and stirred for 15 minutes, followed by layer separation, and the organic layer was washed with water(24 ml) and washed twice with saturated brine (30 ml).The organic layer was dehydrated, filtered, and concentrated. To the concentrate was added ethyl acetate (18 ml)The mixture was heated and stirred at an internal temperature of 50°C for 30 minutes to dissolve completely, Iso-octane (18 ml) was slowly added dropwise thereto, followed by heating and stirring for 30 minutes.The reactor was cooled to room temperature and stirred at 0~5°C for 3 hours.The precipitated solid was filtered and dried to obtain ticagrelor (2.1 g, 81%). It was obtained in a yield of 77% in the same manner as in the step 5) of Example 1, using the product of the above step 4.
  • 68
  • 2-(((3aS,4S,6R,6aS)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(naphthalen-2-yl)tetrahydro-4H-cyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
48% With dihydrogen peroxide In ethyl acetate at 20℃; for 1h; 4.5 5) Synthesis of ticagrelor (step d in scheme 3) 2-(((3aS,4S,6R,6aS)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-phenyltetrahydrocyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol (3 g)Was added ethyl acetate (30 ml), 35% hydrogen peroxide(1.1 ml), and the mixture was stirred at room temperature for 1 hour.Water (30 ml) was added and stirred for 15 minutes, followed by layer separation, and the organic layer was washed with water(24 ml) and washed twice with saturated brine (30 ml).The organic layer was dehydrated, filtered, and concentrated. To the concentrate was added ethyl acetate (18 ml)The mixture was heated and stirred at an internal temperature of 50°C for 30 minutes to dissolve completely, Iso-octane (18 ml) was slowly added dropwise thereto, followed by heating and stirring for 30 minutes.The reactor was cooled to room temperature and stirred at 0~5°C for 3 hours.The precipitated solid was filtered and dried to obtain ticagrelor (2.1 g, 81%).
  • 69
  • 2-(((3aS,4S,6R,6aS)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(thiophen-3-yl)tetrahydro-4H-cyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
65% With dihydrogen peroxide In ethyl acetate at 20℃; for 1h; 5.5 5) Synthesis of ticagrelor (step d in scheme 3) 2-(((3aS,4S,6R,6aS)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-phenyltetrahydrocyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol (3 g)Was added ethyl acetate (30 ml), 35% hydrogen peroxide(1.1 ml), and the mixture was stirred at room temperature for 1 hour.Water (30 ml) was added and stirred for 15 minutes, followed by layer separation, and the organic layer was washed with water(24 ml) and washed twice with saturated brine (30 ml).The organic layer was dehydrated, filtered, and concentrated. To the concentrate was added ethyl acetate (18 ml)The mixture was heated and stirred at an internal temperature of 50°C for 30 minutes to dissolve completely, Iso-octane (18 ml) was slowly added dropwise thereto, followed by heating and stirring for 30 minutes.The reactor was cooled to room temperature and stirred at 0~5°C for 3 hours.The precipitated solid was filtered and dried to obtain ticagrelor (2.1 g, 81%).
  • 70
  • 2-(((3aS,4S,6R,6aS)-2-butyl-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-4H-cyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
66% With dihydrogen peroxide In ethyl acetate at 20℃; for 1h; 6.5 5) Synthesis of ticagrelor (step d in scheme 3) 2-(((3aS,4S,6R,6aS)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-phenyltetrahydrocyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol (3 g)Was added ethyl acetate (30 ml), 35% hydrogen peroxide(1.1 ml), and the mixture was stirred at room temperature for 1 hour.Water (30 ml) was added and stirred for 15 minutes, followed by layer separation, and the organic layer was washed with water(24 ml) and washed twice with saturated brine (30 ml).The organic layer was dehydrated, filtered, and concentrated. To the concentrate was added ethyl acetate (18 ml)The mixture was heated and stirred at an internal temperature of 50°C for 30 minutes to dissolve completely, Iso-octane (18 ml) was slowly added dropwise thereto, followed by heating and stirring for 30 minutes.The reactor was cooled to room temperature and stirred at 0~5°C for 3 hours.The precipitated solid was filtered and dried to obtain ticagrelor (2.1 g, 81%). It was obtained in 66% yield in the same manner as in step 5 of Example 1, using the product of step 4.
  • 71
  • 2-(((3aS,4S,6R,6aS)-2-cyclohexyl-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-4H-cyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
76% With dihydrogen peroxide In ethyl acetate at 20℃; for 1h; 7.5 5) Synthesis of ticagrelor (step d in scheme 3) 2-(((3aS,4S,6R,6aS)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-phenyltetrahydrocyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol (3 g)Was added ethyl acetate (30 ml), 35% hydrogen peroxide(1.1 ml), and the mixture was stirred at room temperature for 1 hour.Water (30 ml) was added and stirred for 15 minutes, followed by layer separation, and the organic layer was washed with water(24 ml) and washed twice with saturated brine (30 ml).The organic layer was dehydrated, filtered, and concentrated. To the concentrate was added ethyl acetate (18 ml)The mixture was heated and stirred at an internal temperature of 50°C for 30 minutes to dissolve completely, Iso-octane (18 ml) was slowly added dropwise thereto, followed by heating and stirring for 30 minutes.The reactor was cooled to room temperature and stirred at 0~5°C for 3 hours.The precipitated solid was filtered and dried to obtain ticagrelor (2.1 g, 81%). Using the product obtained in the above step 4, the title compound was obtained in a yield of 76% in the same manner as in step 5 of Example 1.
  • 72
  • 3-((3aS,4R,6S,6aS)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-6-(2-hydroxyethoxy)tetrahydro-4H-cyclopenta[d][1,3,2]dioxaborol-2-yl)benzoic acid [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
54% With dihydrogen peroxide In ethyl acetate at 20℃; for 1h; 8.5 5) Synthesis of ticagrelor (step d in scheme 3) 2-(((3aS,4S,6R,6aS)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-phenyltetrahydrocyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol (3 g)Was added ethyl acetate (30 ml), 35% hydrogen peroxide(1.1 ml), and the mixture was stirred at room temperature for 1 hour.Water (30 ml) was added and stirred for 15 minutes, followed by layer separation, and the organic layer was washed with water(24 ml) and washed twice with saturated brine (30 ml).The organic layer was dehydrated, filtered, and concentrated. To the concentrate was added ethyl acetate (18 ml)The mixture was heated and stirred at an internal temperature of 50°C for 30 minutes to dissolve completely, Iso-octane (18 ml) was slowly added dropwise thereto, followed by heating and stirring for 30 minutes.The reactor was cooled to room temperature and stirred at 0~5°C for 3 hours.The precipitated solid was filtered and dried to obtain ticagrelor (2.1 g, 81%). Using the product of step 4), 54% of the product was obtained in the same manner as in step 5) of Example 1.
  • 73
  • 2-(((3aS,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(4-ethoxyphenyl)tetrahydro-4H-cyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
62% With dihydrogen peroxide In ethyl acetate at 20℃; for 1h; 9.5 5) Synthesis of ticagrelor (step d in scheme 3) 2-(((3aS,4S,6R,6aS)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-phenyltetrahydrocyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol (3 g)Was added ethyl acetate (30 ml), 35% hydrogen peroxide(1.1 ml), and the mixture was stirred at room temperature for 1 hour.Water (30 ml) was added and stirred for 15 minutes, followed by layer separation, and the organic layer was washed with water(24 ml) and washed twice with saturated brine (30 ml).The organic layer was dehydrated, filtered, and concentrated. To the concentrate was added ethyl acetate (18 ml)The mixture was heated and stirred at an internal temperature of 50°C for 30 minutes to dissolve completely, Iso-octane (18 ml) was slowly added dropwise thereto, followed by heating and stirring for 30 minutes.The reactor was cooled to room temperature and stirred at 0~5°C for 3 hours.The precipitated solid was filtered and dried to obtain ticagrelor (2.1 g, 81%). Product was obtained in 62% yield in the same manner as in 5) of Example 1, using the product of the above step 4).
  • 74
  • 2-(((3aS,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(2,4-dimethoxyphenyl)tetrahydro-4H-cyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
59% With dihydrogen peroxide In ethyl acetate at 20℃; for 1h; 10.5 5) Synthesis of ticagrelor (step d in scheme 3) 2-(((3aS,4S,6R,6aS)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-phenyltetrahydrocyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol (3 g)Was added ethyl acetate (30 ml), 35% hydrogen peroxide(1.1 ml), and the mixture was stirred at room temperature for 1 hour.Water (30 ml) was added and stirred for 15 minutes, followed by layer separation, and the organic layer was washed with water(24 ml) and washed twice with saturated brine (30 ml).The organic layer was dehydrated, filtered, and concentrated. To the concentrate was added ethyl acetate (18 ml)The mixture was heated and stirred at an internal temperature of 50°C for 30 minutes to dissolve completely, Iso-octane (18 ml) was slowly added dropwise thereto, followed by heating and stirring for 30 minutes.The reactor was cooled to room temperature and stirred at 0~5°C for 3 hours.The precipitated solid was filtered and dried to obtain ticagrelor (2.1 g, 81%). Product was obtained in 59% yield in the same manner as in step 5) of Example 1, using the product of step 4).
  • 75
  • N-(4-((3aS,4R,6S,6aS)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-6-(2-hydroxyethoxy)tetrahydro-4H-cyclopenta[d][1,3,2]dioxaborol-2-yl)phenyl)methanesulfonamide [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
63% With dihydrogen peroxide In ethyl acetate at 20℃; for 1h; 11.5 5) Synthesis of ticagrelor (step d in scheme 3) 2-(((3aS,4S,6R,6aS)-6-(7-((2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-phenyltetrahydrocyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethan-1-ol (3 g)Was added ethyl acetate (30 ml), 35% hydrogen peroxide(1.1 ml), and the mixture was stirred at room temperature for 1 hour.Water (30 ml) was added and stirred for 15 minutes, followed by layer separation, and the organic layer was washed with water(24 ml) and washed twice with saturated brine (30 ml).The organic layer was dehydrated, filtered, and concentrated. To the concentrate was added ethyl acetate (18 ml)The mixture was heated and stirred at an internal temperature of 50°C for 30 minutes to dissolve completely, Iso-octane (18 ml) was slowly added dropwise thereto, followed by heating and stirring for 30 minutes.The reactor was cooled to room temperature and stirred at 0~5°C for 3 hours.The precipitated solid was filtered and dried to obtain ticagrelor (2.1 g, 81%).
  • 76
  • [ 274693-27-5 ]
  • AR-C133913XX [ No CAS ]
  • C14H20N4O4S [ No CAS ]
  • C12H16N4O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
In water; acetonitrile UV-irradiation; 2.6 Photodegradation studies An aliquot of 2mL from sample stock solution (2.3.2) was transferred to covered disposable plastic cells, which were exposed to mirror chamber (100×18×17cm) equipped with UVC (254nm) lamp. After 2h, an aliquot of 1.0mL from the solution was diluted in a 5mL volumetric flask using a mixture composed by acetonitrile: water (57:43, v/v). The degraded sample was filtered through a 0.45μm membrane and then analyzed by HPLC
  • 77
  • [ 1354945-69-9 ]
  • (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine mandelate [ No CAS ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
86.2% With potassium carbonate In dichloromethane; water at 20℃; for 4h; 4.10 Example 10 Into a 25 ml three-neck flask was added formula VI compound (0.39 g, 1 mmol), potassium carbonate (0.41 g, 3 mmol), mandelic acid salt of formula VII compound (trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine) (0.35 g, 1.1 mmol), water (3 ml), dichloromethane (20 ml). Stir at room temperature for 4 hours. Drop methylene chloride level, anhydrous sodium sulfate drying, filtering, the rotary evaporating off the solvent, column chromatography (eluent is: ethyl acetate: dichloromethane volume ratio=0 - 10%: 1 gradient elution), to obtain the colorless solid ticagrelor 450 mg, yield: 86.2%.
  • 78
  • [ 1402150-10-0 ]
  • [ 274693-27-5 ]
YieldReaction ConditionsOperation in experiment
93.8% With sodium tetrahydroborate In water at 20℃; for 3h; 8 Preparation of tiagrelol (I) In a 250 ml round bottom flask, the compound 34.26 and 150 ml of water were added, and 5.67 g of sodium borohydride was added thereto. The mixture was stirred at room temperature for 3 hours. When the TLC was detected, the stirring was stopped and the mixture was washed with methylene chloride (100 ml x 3 ), The extract was combined, dried over anhydrous sodium sulfate, and the solvent was distilled off to recrystallize (V isopropanol: V petroleum ether = 1: 1) to give 30.88 g of tigrolipine (I) 93.8%, HPLC purity 95.25%
0.5 kg With sodium tetrahydroborate In diethylene glycol dimethyl ether at 50 - 60℃; for 3h; Large scale; 1 Preparation of Ticagr&or To a stirred cooled 1525°C solution of roxycyclopentyloxy)acetic acid ethyl ester (1.0 Kg) in diglyme (10.0 L) was added sodium borohydride (0.134 Kg) in five lots.The reaction mixture was heated to 50-60°C and stirred for 3h, The progress of the reaction was monitored by HPLC, After competion of the reaction, acetic acid (0.5 L) was added dropwise to the reaction mixture and stirred for 15m, The reaction mixture was added to mixture of water and ethy acetate (1:2) (30.0 L) and extracted. The organic ayer is separated. To the organic ayer was added methano’ (2.0 L) and aq. potassium bicarbonate soution (10% w/v) (5.0 L) and extracted. The organic ayer was separated. The above extraction and separation of organic ayer step was repeated twice. The organic ayer was washed with brine (10%) (5.0 L) and evaporated to dryness to give residue. The residue was stripped with ethy’ acetate (1.0 L), To the residue was added ethy acetate (3.5 L) and heated to 60-70°C tiM dissove, To the above soution, cydohexane (5.25 L) was added at the same temperature and stirred for 30m. The reaction mixture was cooed to 25-35°C for 3h. The sohd obtained was fi[tered, washed with mixture of ethy acetate and cydohexane (2:3) (1.0 L) and suck dried. The wet cake was stripped with ethy acetate (2.0 L) to give residue. The residue was dissoved in the mixture of ethy acetate and water (95:5) (2.2 L). n another round bottom flask cydohexane (10.5 L) and seed quantity of ticagr&or (Form AM) (0.02 Kg) was taken. Above prepared ethy acetate soution was added sowy to this mixture at 25-35°C. The reaction mixture was stirred at the same temperature for 4h. The obtained crystafline sohd was ffltered, washed with mixture of ethy acetate and cydohexane (15:85) (1.0 L), surry wash with water (10.0 L) and suck dried. The sohd was dried in vacuum dryer at 55-65°C for 12-16h to give ticagreor (0.5 Kg) as crystafline Form-AM.Purity by HPLC: 99.5%The XRPD of above obtained Ticagr&or is given in fig 1.
  • 79
  • [ 274693-27-5 ]
  • ticagrelor monohydrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.96 g With water In ethanol at 15 - 40℃; for 16h; 2 Example 2 Preparation of ticagrelor monohydrate 1.0g ticagrelor, add 2.0 ml anhydrous ethanol, then add purified water 1.0 ml, form suspended solution stirring 5 minutes. At water bath 30-40 °C conditions, suspension becomes clear solution. Placed under reduced pressure conditions at 15-20 °C slowly volatilize, crystallization 16h, and then separating, reduced-pressure drying about obtaining white crystalline 0.96g. The resulting product moisture is: 3.4% (ticagrelor monohydrate is the theoretical value of the water content of 3.3%), purity of 99.8%.
  • 80
  • [ 274693-27-5 ]
  • ticagrelor dihydrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.92 g With water In butanone at 15 - 40℃; for 18h; 3 Example 3 Preparation of ticagrelor dihydrate 1.0g ticagrelor, add 2.0ml 2-butanone, add purified water 2.0 ml, form suspended solution stirring 10 minutes. Under water bath 30-40 °C conditions the suspension becomes clear solution. Placed under reduced pressure conditions is 15-20 °C slowly volatilize, crystallization 18h, and then separating, reduced-pressure drying about obtaining white crystalline 0.92g. The resulting product moisture is: 6.4% (ticagrelor dihydrate is the theoretical value of the water content of 6.4%), purity of 99.6%.
  • 81
  • [ 274693-27-5 ]
  • [ 81-04-9 ]
  • C10H8O6S2*2C23H28F2N6O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
20.7 g at 20℃; for 16h; Inert atmosphere; 1 Preparation of ticagrelor heminapadic acid salt Under nitrogen, 323 mL of isopropyl ether, 16.17 g of ticagrella and 5.69 g of 1.5-naphthalenedisulfonic acid dihydrate were added and stirred at room temperature for 16 hours. After salt formation and filtration under nitrogen, the obtained solid was vacuum-dried at 40 °C for 16 hours to give 20.7 g of ticagrelor heminafadisilate.
  • 82
  • [ 274693-27-5 ]
  • ticagrelor sulfuric acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
420 mg With sulfuric acid at 20℃; for 12h; Inert atmosphere; 5 Preparation of ticagrelor sulfuric acid salt Under nitrogen, 10 mL of isopropyl ether was added with 500 mg of ticagrelor and 57mul of sulfuric acid,And the mixture was stirred at room temperature for 2 hours.After salt formation, by filtration under nitrogen,The resulting solidAnd vacuum dried at 30°C for 16 hours to obtain 420 mg of a ticagrelor sulfuric acid salt.
  • 83
  • [ 274693-27-5 ]
  • [ 98-11-3 ]
  • ticagrelor benzenesulfonic acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
4.95 g In dichloromethane for 0.5h; 3 Preparation of ticagrelor benzenesulfonic acid salt To 4.0 g of ticagrelor was added dichloromethaneAnd 1.23 g of benzenesulfonic acid was added thereto.The mixed solution was slowly poured into 600 mL of isopropyl etherAnd stirred for 30 minutes.After all of the solid was precipitated, it was obtained by filtration under nitrogen,The obtained solid was vacuum-dried at 40°C for 16 hours to obtain 4.95 g of ticagrelor benzenesulfonate.
  • 84
  • [ 274693-27-5 ]
  • [ 3144-16-9 ]
  • ticagrelor camphorsulfonic acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
13.72 g In hexane at 20℃; for 20h; Inert atmosphere; 2 Preparation of ticagrelor camphorsulfonic acid salt 10.0 g of ticagrelor and 4.45 g of (+)-10-camphorsulfonic acid were added to 200 mL of heptane under nitrogen,And the mixture was stirred at room temperature for 20 hours.After salt formation, by filtration under nitrogen,The resulting solid was vacuum-dried at 30°C for 16 hours to give 13.72 g of ticagrella camphor sulfonate.
  • 85
  • [ 274693-27-5 ]
  • [ 120-18-3 ]
  • ticagrelor naphthalenesulfonic acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
5.32 g In dichloromethane for 0.5h; 4 Preparation of ticagrelor naphthalene sulfonic acid salt ticagrelor in 4.0 g40 mL of dichloromethane is injected1.73 g of 2-naphthalene sulfonic acid hydrate was added.This mixed solution was added to isopropyl etherSlowly injected into 400 mL, and stirred for 30 minutes. After all of the solid was precipitated, it was obtained by filtration under nitrogen,The obtained solid was vacuum-dried at 40°C for 16 hours to obtain 5.32 g of ticagrelor naphthalene sulfonate.
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