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[ CAS No. 274693-26-4 ] {[proInfo.proName]}

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Chemical Structure| 274693-26-4
Chemical Structure| 274693-26-4
Structure of 274693-26-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 274693-26-4 ]

CAS No. :274693-26-4 MDL No. :MFCD23160137
Formula : C26H32F2N6O4S Boiling Point : -
Linear Structure Formula :- InChI Key :WLEOHEIRUFTYCF-FYEBJQQMSA-N
M.W : 562.63 Pubchem ID :67289290
Synonyms :

Calculated chemistry of [ 274693-26-4 ]

Physicochemical Properties

Num. heavy atoms : 39
Num. arom. heavy atoms : 15
Fraction Csp3 : 0.62
Num. rotatable bonds : 10
Num. H-bond acceptors : 10.0
Num. H-bond donors : 2.0
Molar Refractivity : 140.41
TPSA : 141.74 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -7.18 cm/s

Lipophilicity

Log Po/w (iLOGP) : 5.45
Log Po/w (XLOGP3) : 3.59
Log Po/w (WLOGP) : 4.46
Log Po/w (MLOGP) : 3.14
Log Po/w (SILICOS-IT) : 3.2
Consensus Log Po/w : 3.97

Druglikeness

Lipinski : 1.0
Ghose : None
Veber : 1.0
Egan : 1.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -5.21
Solubility : 0.00343 mg/ml ; 0.0000061 mol/l
Class : Moderately soluble
Log S (Ali) : -6.25
Solubility : 0.000314 mg/ml ; 0.000000558 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -6.48
Solubility : 0.000188 mg/ml ; 0.000000334 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 5.82

Safety of [ 274693-26-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 274693-26-4 ]

* 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 [ 274693-26-4 ]

[ 274693-26-4 ] Synthesis Path-Downstream   1~49

  • 1
  • 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 ]
  • [ 376608-71-8 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
84% With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; 8.44 g (0.02626 moles) of (1 fi,2S)-2-(3,4-difluorophenyl)cyclopropanamine (R)-Mandelic acid) of Formula VI in 25ml dimethyl sulfoxide and 14ml (0.08036moles) Nu,Nu-diisopropylethylamine were charged and stirred for 15 minutes followed by addition of solution of 1 1.3 g 2-[[(3a ?,4S,6 ?,6aS)- 6-[7-chloro-5-(propylthio)-3H-1 ,2,3-triazolo[4,5-c/]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3a -- cyclopenta-[d][1 ,3]dioxol-4-yl]oxy]-1 -ethanol) formula V dissolved in 15 ml dimethyl sulfoxide at room temperature for 2-3 hours. The reaction mixture was quenched with 100ml water at 10-15°C and extracted two times each with 50 ml ethyl acetate. The organic layer was washed two times each with 25ml 1 N HCI solution followed by 25ml water followed by 50ml 5percent sodium bicarbonate solution. The organic layer was separated and distilled under reduced vacuum at 40°C to obtain residue. The residue was stirred with 30ml heptane for 4-5 hours at 25°C to 30°C, filtered and dried under vacuum at 50°C to 55°C for 12 hours to obtain compound of formula VII. Yield =12.4 g (efficiency -84percent, HPLC -99percent)
With potassium carbonate; In water; at 30℃;Product distribution / selectivity; Example 7. Preparation of 2-({(3aR,4S,6R,6aS)-6-[7-[(lR,25)-2-(3,4- Difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]triazolo[4,5- d\\ pyrimidin-3-yl] -2,2-dimethyltetrahydro-3aH-cyclopenta [d\\ [ 1 ,3] dioxol-4- yl}oxy)ethanoltrans-(lR,2S)-2-(3 ,4-Difluorophenyl)cyclopropanaminium (2i?)-2-hydroxy-2- phenylethanoate (146 kg, prepared as described in WO2008/018822, WO2008/018823, WOO 1/92200) and potassium carbonate (156 kg) were dissolved in water (576 kg) and charged to the 2-({(3ai?,45f,6i?,6a5)-6-[7-Chloro-5-(propylthio)-3/f-[l,2,3]triazolo[4,5- <i]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta[(i][l,3]dioxol-4-yl}oxy)ethanol solution with a rate that kept the temperature of the reaction <30°C. After the conversion criterion was reached (> 99percent) the water layer was separated off. The organic layer was washed twice with acetic acid (18 kg) and sodium chloride (13 kg) in water (560 kg) and then twice with sodium chloride (54 kg) in water (438 kg), whereafter the organic layer was used in the next step.
With potassium carbonate; In acetonitrile; at 25 - 30℃; To the solution of 2-({(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylthio)-3H-[1 ,2,3] triazolo[4,5-(^pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta[d] [1 ,3] dioxal-4-yl} oxy)-1 -ethanol (10.0 gm, 0.023 mol) in acetonitrile (70.0 ml) was added trans-^ R,2S)-2-(3,4-Difluorophenyl) cyclopropanamine \2R)-2- hydroxy-2-phenylethanoate (7.50 gm, 0.023 mol), followed by addition of anhydrous potassium carbonate (6.46.0 gm, 0.046 mol) under stirring at 25- 30°C and maintained for 2-3 hrs (progress of reaction was monitored by HPLC). After completion of reaction, resulting mass was diluted with water (200 ml), extracted 2-({(3aR,4S,6R,6aS)-6-[7-[(1 R,2S)-2-(3,4-diflurophenyl)- cyclopropyl]amino}-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl]- 2,2- dimethyltetrahydro-3aH-cyclopenta[d][1 ,3]dioxal-4-yl}oxy)-1 -ethanol compound twice with MDC ( 00 ml + 50 ml), separate the aqueous and MDC layer, washing the MDC layer with water (100 ml). The MDG was evaporated at 35-40X under reduced pressure to produce 13.0 gm of 2- ({(3a ,4S,6 6aS)-6-[7-[(1 2S)-2-(3,4-diflurophenyl)-cyclopropyl]amino}-5- (propylthio)-3H-[1 ,2,3]triazolo[4,5-Gf]pyrimidin-3-yl]-2,2-dimethyltetrahydro- 3aH-cyclopenta [cfl[1 ,3]dioxal-4-yl}oxy)-1 -ethanol as an oil. [Yield = 13.0 gm (98.85percent); Purity (HPLC) = 94.0percent]
With potassium carbonate; In water; toluene; at 20 - 30℃; for 2h; A solution of (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine (R) -mandelate (VI, according to CN1431992A, CN101495442A, WO2011132083A, etc.) 146 g or more And 156 g of potassium carbonate were dissolved in 580 g of water and added to step B at 20 to 30 ° C (3-chloro-5- (propylthio) -3H- [1,2,3] triazolo [4,5-d] pyrimidin-4- Pyrimidin-3-yl] -2,2-dimethyltetrahydro-3aaH-cyclopenta [d] [1,3] dioxolan-4-yl} oxy) ethanol (V) Toluene solution; Followed by stirring at 20 to 30 ° C for about 2 hours, The organic layer was washed with a mixture of 18 g of acetic acid and a saturated aqueous solution of sodium chloride to give the toluene solution of the title compound (VII), which was used directly in the next step.
With potassium carbonate; In water; toluene; at 20℃; for 3h;Large scale; To a solution of TGRL-5 (16 mol) in toluene was added a three-membered ring (5.54 kg)Stir at room temperature. The temperature was controlled to drop an aqueous solution of potassium carbonate. End reaction 3h. Phase, retaining the upper organic phase. The organic phase is used directly in the next section.
With potassium carbonate; In water; toluene; at 10℃; for 1h; (1) 100L glass reactor was added 31.00L of purified water, 4.464kg of potassium carbonate and 5.190kg FTG-SM3,Cooled to 10 ° C with stirring;(2) adding the toluene solution containing FTG-2 in the reaction kettle under stirring;(3) is added, the reaction temperature is controlled at 10 ° C for 1 h;(4) TLC detection (developing solvent: ethyl acetate / isooctane = 1: 1) FTG-2 raw material point disappears, the reaction is completed;Stop stirring, stratification, leaving the lower aqueous phase;(5) A solution of 3percent acetic acid (922 g) and 2percent sodium chloride (615 g) in purified water (29.20 L) was added to the organic phase and stirred for 30 min;Still stratification, separation of the lower aqueous phase;(6) A solution of 3percent acetic acid (922 g) and 2percent sodium chloride (615 g) in purified water (29.20 L) was added to the organic phase and stirred for 30 min;Still stratification, separation of the lower aqueous phase;(7) adding 10percent sodium chloride (3.070kg) of purified water (27.66L) to the organic phase, stirring for 30min; stopping stirring, standing stratification,Separate the lower aqueous phase;(8) adding 10percent sodium chloride (3.070kg) of purified water (27.66L) to the organic phase, stirring for 30min; stopping stirring, standing stratification,Separate the lower aqueous phase;(9) The upper organic phase left in the reactor directly into the next step.
With potassium carbonate; In water; toluene; at 10 - 20℃;Large scale; (1) Adding 55 L of purified water, 10.88 g of potassium carbonate and 9.282 kg of SM3 in a 200 L reactor, stirring and descending to a temperature of 10 to 20 ° C;(2) adding the toluene solution containing the above Im-2 to the reaction kettle under stirring;(3) After the addition is completed, the reaction is stirred at room temperature 10 to 20 ° C for 1 to 2 hours;(4) TLC detection reaction was completed, the developing solvent ethyl acetate: isooctane = 1:1; the stirring was stopped, the layer was allowed to stand, and the lower aqueous phase was separated;(5) adding 3percent acetic acid (1.65 kg) and 2percent sodium chloride (1.10 kg) of purified water (52.25 L) to the organic phase, stirring for 30 min; stopping the stirring, standing to separate the layers, and separating the lower aqueous phase; (6) adding 3percent acetic acid (1.65 kg) and 2percent sodium chloride (1.10 kg) in purified water (52.25 L) to the organic phase, stirring for 30 min; stopping the stirring, standing to separate the layers, and separating the lower aqueous phase;(7) adding 10percent sodium chloride (5.50 kg) of purified water (49.5 L) to the organic phase, stirring for 30 min; stopping the stirring, standing to separate the layers, and separating the lower aqueous phase;(8) adding 10percent sodium chloride (5.50 kg) of purified water (49.5 L) solution to the organic phase, stirring for 30 min; stopping the stirring, standing to separate the layers, and separating the lower aqueous phase;(9) The upper organic phase (Im-3 toluene solution) is left in the reaction vessel and directly proceeds to the next step.
With potassium carbonate; In water; toluene; at 10 - 20℃;Large scale; 3) Operation process(1) Adding 55 L of purified water, 10.88 g of potassium carbonate and 9.282 kg of SM3 in a 200 L reactor, stirring and descending to a temperature of 10 to 20 ° C;(2) adding the toluene solution containing the above Im-2 to the reaction kettle under stirring;(3) After the addition is completed, the reaction is stirred at room temperature 10 to 20 ° C for 1 to 2 hours;(4) TLC the reaction was complete, ethyl acetate expand solvent: isooctane = 1: 1; stirring was stopped, allowed to stand stratification, the lower aqueous phase was separated;(5)A solution of 3percent acetic acid (1.65 kg) and 2percent sodium chloride (1.10 kg) in purified water (52.25 L) was added to the organic phase.Stir for 30 min; stop stirring, let stand for stratification, and separate the lower aqueous phase;(6) Adding 3percent acetic acid (1.65 kg) and 2percent sodium chloride (1.10 kg) of purified water (52.25 L) to the organic phaseThe liquid was stirred for 30 minutes; the stirring was stopped, the layer was allowed to stand, and the lower aqueous phase was separated;(7) Add 10percent sodium chloride (5.50 kg) in purified water (49.5 L) to the organic phase, stir for 30 min; stop stirringMix, let stand layering, and separate the lower layer of water;(8) adding 10percent sodium chloride (5.50 kg) of purified water (49.5 L) to the organic phase, and stirring for 30 min;Stop stirring,Let stand layering,Divide the lower aqueous phase;(9) The upper organic phase (Im-3 toluene solution) is left in the reaction vessel and directly proceeds to the next step.
With N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 20℃; for 3h;Inert atmosphere; The intermediate TG-2 obtained in the step S2 was added to the reactor, dissolved in ethyl acetate, and then TG-SM-1 was added thereto, stirred, and then N,N-diisopropylethylamine was added thereto, and the reaction was carried out by introducing nitrogen gas. The temperature is 20 ° C, the reaction time is 3 h, and 5 times TG-2 mass of water is added at the end of the reaction. The pH is adjusted with 10percent acetic acid solution, and the organic phase is washed successively with water and a saturated aqueous solution of sodium hydrogencarbonate. Layer to dry TG-3; Among them, the mass ratio of TG-2, TG-SM-1, ethyl acetate, and N,N-diisopropylethylamine was 1:1.0:10:1.0.

  • 2
  • [ 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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  • 3
  • [ 145783-12-6 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 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
Multi-step reaction with 7 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
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: iodine / acetone / 2 h / 25 - 60 °C
  • 4
  • (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine [ No CAS ]
  • 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 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
93% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h; [00128] 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: A solution of 2-((3aR,4S,6R,6aS)-6-(7-chloro-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 (370 mg, 0.86 mmol, 1.00 equiv) (15 mL), (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (145.6 mg, 0.86 mmol, 1.00 equiv.) and N,N-diisopropylethylamine (155.7 mg, 1.21 mmol, 1.20 equiv.) in dichloromethane was stirred at ambient temperature for about 16 hours, and then water (10 mL) was added. Standard extractive workup with dichloromethane (3 x 10 mL) gave the title product as a yellow oil (450 mg; yield = 93 %). m/z = 563 (MH)+.
89.5% With N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 20℃; for 4h; (3) To above-mentioned product dissolved in ethyl acetate, add in 180g compound V. Then, add 325g diisopropyl ethylamine. After completion of the addition, at 20 C react 4h. Finally add the reaction product is 2 times of the volume of the ethyl acetate extraction, the resulting aqueous phase and then into the aqueous phase 2 times of the volume of the ethyl acetate extraction, combined with the phase, saturated sodium bicarbonate solution used for washing 2-3 time, then wash with water 2-3 time, in 35-40 C concentrated under reduced pressure, then dried to obtain 539g compound VI, the yield is 89.5%, purity of 99.1%;
69.3% With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 16h; Compound 4 (12 mg, 0.071 mmol, 1.0 eq) and DIPEA (11 mg, 0.085 mmol, 1.2 eq) were charged to 6 in DCM (1.5 mL), the resulting solution was stirred for 16 h, then adjusted pH value to 7, then the organic layer was washed with water and brine, dried and evaporated under vacuum to give the title product as a brown oil (27 mg, 69.3%). 1H NMR (300 MHz, CDCl3) delta 7.05~7.26 (m, 3 H), 5.49~5.51 (dd, 1 H), 5.15 (s, 1 H), 4.85~4.87(d, 1 H), 4.08~4.15 (q, 2 H), 4.01 (s, 1 H), 3.51~3.62 (m, 4 H), 2.60~2.67(m, 1 H), 2.32~2.48(m, 1 H), 1.53 (s, 3 H), 1.35 (s, 3 H), 1.23~1.27 (t, 3 H). EI-MS m/z 563.2 (M+H)+ .
It has been verified that using the salts according to the invention with the purity of at least 96 % ee makes it possible to obtain, in any of the further steps of the synthesis of ticagrelor, the final product containing less than 0.15 % of the isomeric impurity IV with a configuration derived from the undesired diastereoiso ier la, without the necessity to use chromatographic purification.The salts of compound I with D-(-)-mandelic and R-(-)-3-chloromandelic acid in the purities mentioned in Examples 1 and 2 were used for the preparation of ticagrelor, which is illustrated in Scheme 1. The salts of the compound I with the said acids are marked I * HA therein. ticagrelorSCHEME 1Abbreviations used:CBz = benzyloxycarbonyl,MIBK methyl isobutyl ketone,DIPEA diisopropylethylamine.The total yield of the method described in Scheme 1 was 16 %. The quality of the obtained product was determined using the liquid chromatography method and amounted to 99.5 % with the content of impurity IV lower than 0.1 %. The method of preparation of ticagrelor according to Scheme 1 did not require the use of chromatographic purification in any of the steps of its synthesis.

  • 5
  • [ 112897-97-9 ]
  • [ 274693-26-4 ]
  • 6
  • [ 106-31-0 ]
  • [ 274693-26-4 ]
  • C30H38F2N6O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
General procedure: TEA (90 mg, 0.889 mmol, 5 eq) was added to a solution of 7 (100 mg, 0.177 mmol, 1 eq) in acetonitrile (1 mL) and the mixture was stirred at room temperature for 30 min, then n-butyric anhydride (56 mg, 0.354 mmol, 2 eq) was added dropwise to the stirred solution. After 2 h, TLC analysis showed that the reaction was complete. The solvent was evaporated under vacuum to give a brown oil, which was dissolved in EtOAc (5 ml), and washed with water and brine, dried over Na2SO4 and evaporated to dryness. The residue was dissolved in a solution of 1% iodine in methanol (w/v) (2 mL), and was refluxed for 4 h, TLC analysis showed that the reaction was complete. The solvent was evaporated under vacuum to give the crude product, which was purified by chromatography on silica gel (PE : EtOAc =1:5) to give the title product as a colorless oil (15 mg).
  • 10
  • [ 274693-26-4 ]
  • [ 541-41-3 ]
  • C29H36F2N6O6S [ No CAS ]
YieldReaction ConditionsOperation in experiment
General procedure: TEA (90 mg, 0.889 mmol, 5 eq) was added to a solution of 7 (100 mg, 0.177 mmol, 1 eq) in acetonitrile (1 mL) and the mixture was stirred at room temperature for 30 min, then n-butyric anhydride (56 mg, 0.354 mmol, 2 eq) was added dropwise to the stirred solution. After 2 h, TLC analysis showed that the reaction was complete. The solvent was evaporated under vacuum to give a brown oil, which was dissolved in EtOAc (5 ml), and washed with water and brine, dried over Na2SO4 and evaporated to dryness. The residue was dissolved in a solution of 1% iodine in methanol (w/v) (2 mL), and was refluxed for 4 h, TLC analysis showed that the reaction was complete. The solvent was evaporated under vacuum to give the crude product, which was purified by chromatography on silica gel (PE : EtOAc =1:5) to give the title product as a colorless oil (15 mg).
  • 11
  • [ 274693-26-4 ]
  • [ 543-27-1 ]
  • C31H40F2N6O6S [ No CAS ]
YieldReaction ConditionsOperation in experiment
General procedure: TEA (90 mg, 0.889 mmol, 5 eq) was added to a solution of 7 (100 mg, 0.177 mmol, 1 eq) in acetonitrile (1 mL) and the mixture was stirred at room temperature for 30 min, then n-butyric anhydride (56 mg, 0.354 mmol, 2 eq) was added dropwise to the stirred solution. After 2 h, TLC analysis showed that the reaction was complete. The solvent was evaporated under vacuum to give a brown oil, which was dissolved in EtOAc (5 ml), and washed with water and brine, dried over Na2SO4 and evaporated to dryness. The residue was dissolved in a solution of 1% iodine in methanol (w/v) (2 mL), and was refluxed for 4 h, TLC analysis showed that the reaction was complete. The solvent was evaporated under vacuum to give the crude product, which was purified by chromatography on silica gel (PE : EtOAc =1:5) to give the title product as a colorless oil (15 mg).
  • 12
  • [ 1006376-60-8 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 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
  • 13
  • [ 1006376-61-9 ]
  • [ 274693-26-4 ]
  • 14
  • [ 51336-95-9 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 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
  • 16
  • [ 50600-40-3 ]
  • [ 274693-26-4 ]
  • 17
  • [ 274693-26-4 ]
  • [ 100-39-0 ]
  • [ 1383715-62-5 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In acetone; at 55 - 60℃; for 20h; Step 2: Preparation of 2-({(3aR,4S,6R,6aS)-6-[7-[[N-(lR,2S)-2-(3,4-difiuorophenyl)- cyclopropan-l-yl]-N-benzyl]amino}-5-(propylthio)-3H-[l ,2,3] triazolo [4,5-d]pyrimidin-3- yl]-2,2-dimethyl-tetrahydro-3aH-c clopenta[d] [1,3] dioxol-4-yl} oxy)ethanolBenzyl bromide (1.568 gm) and powdered potassium carbonate (4.912 gm) were added to a solution of 2-({(3aR,4S,6R,6aS)-6-[7- [[N-(lR,2S)-2-(3,4-difluorophenyl)- cyclopropylamino}-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 (4 gm) in acetone (120 ml). The reaction mixture was heated to 55 to 60C and continuously stirred for 20 hours at the same temperature. After completion of the reaction, the acetone was distilled out under vacuum and the residue was cooled to 25-30 C. Water (40 ml) and dichloromethane (40 ml) were added in to solution and stirred for 15 minutes at 25-30C. The layers were separated and the organic layer was distilled under vacuum at 40C and degassed to get 2- ({(3aR,4S,6R,6aS)-6-[7-[[N-(lR,2S)-2-(3,4-difiuorophenyl)- cyclopropan-l-yl]-N- benzyl]amino}-5-(propylthio)-3H- [1,2,3] triazolo [4,5-d]pyrimidin-3-yl]-2,2-dimethyl- tetrahydro-3aH-cyclopenta[d][l ,3] dioxol-4-yl} oxy)ethanol (5.5 gm).
  • 18
  • [ 376608-71-8 ]
  • [ 274693-26-4 ]
  • 19
  • [ 1383715-61-4 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
With iodine; In acetone; at 25 - 60℃; for 2h; Step 1 : Preparation of 2-({(3aR,4S,6R,6aS)-6-[7-[[N-(lR,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][l ,3] dioxol-4-yl} oxy)ethanol To a solution 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- [ 1 ,2,3] triazolo [4,5- d]pyrimidin-3-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][l ,3] dioxol-4-yl} oxy)ethanol (5 gm) in acetone (50 ml) was added iodine crystal (2 gm) at 25 to 30 C. The resulting solution was heated to 55 to 60 C with continuous stirring for 2 hrs. After completion of the reaction, the reaction mixture was cooled to 40C, followed by distillation of acetone under vacuum below 40C. The residue was cooled to 25-30C and water (50 ml) and dichloro methane (50 ml) were added at 25-30C followed by addition of sodium thiosulphate (10 gm). The resulting solution was stirred for 30 minutes followed by layer separation. The organic layer was washed with water (50 ml). The organic layer was distilled out under vacuum below 40C and degassed to provide 2-({(3aR,4S,6R,6aS)-6-[7- [[N-(lR,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-yl} oxy)ethanol (4 gm).
  • 20
  • [ 1402150-05-3 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
75% With lithium aluminium tetrahydride; In tetrahydrofuran; at -10 - 0℃;Product distribution / selectivity; L1AIH4 (0.2g) was added to THF (10 vol) slowly at 0 to -10C. To this mixture was added a solution of compound 11a (3g) in THF (15 mL) slowly over 30 min at 0 to -10C. The reaction mixture was stirred at 0 to -10C for 4-12 hrs. The reaction was monitored by TLC. When the reaction was complete, it was quenched and the product was isolated by routine work up. The filtrate was concentrated under reduced pressure, and compound 12 was isolated as an oily mass; yield 14g, 70-75%.
  • 21
  • [ 1427524-33-1 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
68% With bis(cyclopentadienyl)titanium dichloride; sodium bis(2-methoxyethoxy)aluminium dihydride; In tetrahydrofuran; toluene; at 25℃; for 3h;Cooling with ice; To a solution of TATAME (370 mg, 0.5 mmol) and titanocene dichloride (6 mg, 5 mol%) in THF (5 mL) stirring on an ice bath was added sodium bis(2-methoxyethoxy)aluminumhydride (3.5 M solution in toluene, 0.36 m L, 1 .25 mmol). The mixture was stirred for 1 h in an ice bath and then 2 h at about 25 C. The reaction mixture was poured into 0.1 M NaOH(aq) (50 mL), extracted with MTBE (50 m L), the extract washed with water (2 50 mL), concentrated and the residue purified by chromatography (Si02, hexane:EtOAc) to give the title compound as a resinous product (0.19 g, 68% yield).
  • 22
  • (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine [ No CAS ]
  • [ 1431867-57-0 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
78% In dimethyl sulfoxide; at 60℃; for 16h; To a solution of MOTAMA (0.70 g, 1.65 mmol) in dry DMSO (5 mL) at room temperature CPA (0.29 g, 1.73 mmol) was added and reaction mixture was stirred at 60C for 16 h. Water was added (50 mL), and product was extracted to MeTHF (3 x 10 mL). Combined organic layers were dried over MgSO4, and concentrated to afford crude product, which was then purified by chromatography (SiO2, hexane:EtOAc) to afford colorless syrup (0.72 g, 78% yield). MS (ESI) m/z: 563 [MH]+.
78% In dimethyl sulfoxide; at 20 - 60℃; for 16h; To a solution of MOTAMA (0.70 g, 1 .65 mmol) in dry DMSO (5 mL) at room temperature CPA (0.29 g, 1.73 mmol) was added and reaction mixture was stirred at 60C for 16 h. Water was added (50 mL), and product was extracted to MeTHF (3 x 10 mL). Combined organic layers were dried over MgS04, and concentrated to afford crude product, which was then purified by chromatography (Si02, hexane:EtOAc) to afford colorless syrup (0.72 g, 78% yield). MS (ESI) mlz: 563 [MH]'.
  • 23
  • (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine [ No CAS ]
  • [ 1431867-58-1 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
72% In dimethyl sulfoxide; at 20 - 70℃; for 72h; To a solution of BOTAMA (0.20 g, 0.40 mmol) in dry DMSO (2 mL) at room temperature CPA (74 mg, 0.44 mmol) was added and reaction mixture was stirred at 70"C for 3 days. Water was added (20 mL), and product was extracted to MeTHF (3 x 5 mL). Combined organic layers were dried over MgS04, and concentrated to afford crude product, which was then purified by chromatography (Si02. hexane:EtOAc) to afford colorless syrup (0.16 g, 72% yield). MS (ESI) mlz: 563 [MH]' .
  • 25
  • 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 ]
  • [ 1444301-72-7 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
A flask was charged with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine mandelate (36.2 g) and ethyl acetate (50 mL) followed by addition of diisopropyl ethylamine (69 g). The mixture was stirred for about 25 minutes at room temperature followed by addition of organic layer (500 mL) from previous example 11 over a period of 30 minutes at the same temperature. The mixture was stirred for about 90 minutes at room temperature for completion of reaction as verified by TLC. After completion of reaction, water was charged to the mixture and layers were separated. The organic layer was washed with 2% aqueous hydrochloric acid solution (2*250 mL) followed by 20% sodium chloride solution (250 mL). The organic layer was subjected to distillation under vacuum at 55 C. to afford the title compound in about 97% yield.
  • 26
  • 2-(((3aR,4S,6R,6aS)-6-(5-chloro-7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol [ No CAS ]
  • [ 6898-84-6 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
30% In methanol; at 20℃; for 6h;Inert atmosphere; To a solution of 2-(((3aR,4S,6R,6aS)-6-(5-chloro-7-(((l R,2S)-2-(3,4- difluorophenyl)cyclopropyl)amino)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxoI-4-yl)oxy)ethanol (solid) 35 (5.2gm, O.Olmol) in 70ml methanol, sodium salt of propanethiol (CH3CH2CH2SNa, O.O lmol) was added and the reaction mixture was stirred for 6 hr at room temperature, under nitrogen atmosphere. The progress of reaction was monitored by TLC. On completion of reaction, the solvent was removed under vacuum and the residue was treated with ethyl acetate and water. The layer were separated, organic layer was separated and washed with brine. Drying of organic layer over anhydrous sodium sulfate, filtering and removal of ethyl acetate gave a residue, which on treatment with a suitable solvent and addition of anti solvent (discussed in detail in the text) gave 1.68gm (30% yield) of protected ketal of Ticagrelor 28. Some of the characteristic and selective peaks (delta value) in -NMR (CDC13) for 28 are 7.5 (s, lH), 6.8 - 7.3 (m, 3H), 5.42 (m, 1H), 5.1 (m, 1H), 4.8 (m, 1H), 4.1 (m, 1H), 3.4 - 3.7 (m, 4H), 3.1 (t, 2H), 1.45 (s, 3H), 1.26 (s, 3H), 1.15 (t, 3H), 0.87 (m, 1H).
  • 27
  • 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)-N,N-diphenylacetamide [ No CAS ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 6.16667h; A flask is charged with 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)-N,N- diphenylacetamide (3 g), THF (90 mL) and mixture is cooled to 0C. Then portion wise, Lithium aluminium hydride (940 mg) is added over a period of 10 minutes and mixture is stirred at 0C for 1 hour. The reaction mixture is then stirred at room temperature for 5 hours and progress of the reaction is monitored by TLC. Then mixture is cooled to 0-5C and quenched with ice cold water (100 mL) and then diluted with ethyl acetate (30 mL). The layers are separated and organic layer after drying is used for next step.
  • 28
  • 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)-1-morpholinoethan-1-one [ No CAS ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
With sodium bis(2-methoxyethoxy)aluminium dihydride; In tetrahydrofuran; at 20℃; for 1.16667h;Inert atmosphere; A flask is charged with 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)-1 - morpholinoethan-1 -one (1 g) in tetrahydrofuran (20 mL) and stirred under nitrogen atmosphere followed by addition of vitride (1 .53 mL) over a period of 10 minutes. The reaction mixture is stirred for 1 hour at room temperature and progress of the reaction is monitored by TLC. On completion, the mixture is quenched with sodium potassium tartrate (5 mL). The mixture is extracted with ethyl acetate (10 mL), then layers are separated and organic layer is subjected to distillation under vacuum at 45C. The obtained material is dissolved in THF (20 mL) and slowly lithium aluminiumhydride (0.1 17 g) is added to the mixture at 0-5C. Then mixture is stirred at room temperature for 1 hour and progress of the reaction is monitored by TLC. On completion of reaction, it is quenched with ice-cold water (20 mL) and extracted with ethyl acetate (15 mL). The layers are separated and organic layer is used for next step.
  • 29
  • [ 274693-25-3 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
8 g With lithium borohydride; In tetrahydrofuran; at 20 - 25℃; for 16h;Inert atmosphere; A solution of methyl(((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) acetate(10 g, Formula X as obtained from Example 9) in tetrahydrofuran (80 mL) was cooled to 0C to 5C. Lithium borohydride (60% in tetrahydrofuran, 15 mL) was added slowly under a nitrogen atmosphere. The resulting mixture was warmed to 20C to 25 C, and then stirred for 16 hours. The reaction mixture was cooled to 0C to 5C, and quenched slowly with deionized water (60 mL). The reaction mixture was extracted with ethyl acetate (60 mL) and re-extracted with ethyl acetate (20 mL). The combined organic layers were washed with aqueous sodium bicarbonate solution (5 g in 50 mL deionized water). The solvent was distilled off completely to obtain a solid material. The solid material was crystallized with a mixture of methyl tert butyl ether (10 mL) and cyclohexane (60 mL) to afford the title compound. Yield: 8 g
  • 30
  • [ 107-03-9 ]
  • 2-(((3aR,4S,6R,6aS)-6-(5-chloro-7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol [ No CAS ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
90.4% With potassium hydroxide; In ethanol; at 20℃; 2.61 g of 9-[3aR-(3alpha,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-chloro-8-aza purine (5 mmol), 0.46 g propanethiol (6 mmol) and 0.34 g potassium hydroxide (6 mmol) and 25 mL of ethanol were added to a reaction flask, to start reaction under room temperature while stirring, then the reaction ended with the TLC detection. The solution was concentrated under reduced pressure, and the residue was added dichloromethane and water, and adjusted with dilute acid to pH=6. The organic phase was separated, and the aqueous phase was extracted 3 times using dichloromethane. The organic phases were combined, dried and distilled under reduced pressure to recover the solvent, to get 2.54 g of oily substance 9-[3aR-(3aalpha,4alpha,6alpha6aalpha)-[[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 (or named: 2-[(3aR,4S,6R,6aS)-6-{7-[[(1R,2S)-2 (3,4-difluorophenyl)cyclopropyl]amino]-5-propyl-mercapto-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl]oxy}-1-ethanol (VIII), with a yield of 90.4%.
  • 31
  • [ 274693-26-4 ]
  • [ 110-17-8 ]
  • 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]-1-ethanol fumarate [ No CAS ]
YieldReaction ConditionsOperation in experiment
80.91% In isopropyl alcohol; at 70 - 75℃; for 0.5h; 4g (0.007109moles) of formula VII was charged in 25ml isopropanol followed by addition of 1.6gm (0.01379moles) of fumaric acid and the reaction mixture was heated to 70-75C for 30 minutes. The mixture was cooled to room temperature, filtered, dried under reduced pressure at 50-55C to obtain Formula VII fumarate salt. Yield= 3.9g. (Efficiency = 80.91 , HPLC-99.38%)
  • 32
  • [ 110-15-6 ]
  • [ 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-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy]-1-ethanol succinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
81.05% In isopropyl alcohol; at 70 - 75℃; for 0.5h; 4.5g (0.007998moles) of formula VII was charged in 25ml isopropanol followed by addition of 1.8g (0.01524moles) of succinic acid and the reaction mixture was heated to 70-75C for 30 minutes. The mixture was cooled to room temperature, filtered, dried under reduced pressure at 50-55C to obtain Formula VII succinate salt. Yield= 4.0g. (Efficiency = 81.05, HPLC-99.45%)
  • 33
  • 2-[((3aR,4S,6R,6aS)-6-[5-amino-6-chloro-2-(mercaptopropyl)pyrimidin-4-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxolan-4-yl)oxy]ethanol [ No CAS ]
  • [ 376608-71-8 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
28 g To a reaction mixture of 25 g of 2-[[(3aR,4S,6R,6aS)-6-[[5-amino-6-chloro-2-(propylthio)-4- pyrimidinyl]amino]-2,2-dimethyltetrahydro-3a --cyclopenta[d][1 ,3]dioxol-4-yl]oxy]1-ethanol of formula IV, 125 ml isopropyl alcohol were charged, followed by dropwise addition of 20 ml of isoamyl nitrite at 20°C to 30°C. The reaction mass was stirred to complete the reaction. To this reaction mass, 18.9 g of (1 ?,2S)-2-(3,4-difluorophenyl)cyclopropanamine (R)-Mandelic acid) of Formula VI was added and stirred for 10 minutes followed by addition of14ml (0.08036moles) Nu,Nu-diisopropylethylamine and stirred for 1 to 2 hours. N,N-diisopropylethylamine was charged and stirred. Isopropyl alcohol was distilled. Water and toluene were charged to the reaction mass. The reaction mass extracted with toluene. Toluene then distilled out and replaced with cyclohexane and stirred. The seed was added followed by addition of n-heptane and stirred at 20 to 30°C. Solid obtained was filtered and dried under vacuum Yield = 28 g (Efficiency - 83percent, HPLC -99.0percent).
Example-2: Preparation of 2-(((3aR,4S,6R,6aS)-(6-(7-(((lR,2S)-2-(3,4-difluorophenyl)- cyclopropyl)amino)-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl)-2,2- dimethyl-tetrahydro-4H-cyclopenta[d][l,3]-dioxol-4-yl)oxy)-ethan-l-ol (II) Step-A:To a mixture of the compound obtained in example- 1 (225 gm) and toluene (1125 ml), acetic acid (190 gm) was added at 30°C and cooled to a temperature of 3°C. Aqueous sodium nitrite solution was slowly added to the resultant mixture and maintained for about 1 hour at 3°C. The progress of the reaction was monitored by HPLC. On completion of the reaction, aqueous potassium carbonate solution was slowly added to the reaction mass and stirred at 5°C. The organic layer was separated from biphasic reaction mass and stored at 3°C. Step-B:The compound (lR,2S)-2-(3,4-difluorophenyl)-cyclopropanaminium-(2R)-hydroxy (phenyl)ethanoate (188 gm) was added to aqueous potassium carbonate solution and stirred for about 30 minutes at 30°C. To this reaction mixture, the separated organic layer obtained in step- A and stirred for about 2 hours. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was allowed for layer separation and the organic layer was separated. The separated organic layer was washed with a mixture of acetic acid, sodium chloride and water and with sodium chloride solution. The washed organic layer was distilled at about 53°C under vacuum to get a residue. Step-C:The residue resulted in step-B was mixed with diisopropyl ether (2250 ml) and heated to 53°C. The contents were maintained for about 30 minutes at 53°C resulting in a solution. The obtained solution was cooled to 30°C, maintained for 3 hours and then the solution was further cooled to 3°C and maintained for 2 hours. The resultant solid was filtered, washed with a mixture of diisopropylether (45 ml) and cyclohexane (180 ml), washed with cyclohexane (225 ml) and dried under vacuum. Yield: 250 g
  • 34
  • [ 274693-26-4 ]
  • [ 124-63-0 ]
  • 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)ethyl methanesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dichloromethane; at 0 - 5℃; for 3h; [00141] Methanesulfonyl chloride (0.086 mL, 1.10 mmol) was added dropwise to a solution of 2-(((3 aR,4S,6R,6aS)-6-(7-((( 1 R,2S)-2-(3 ,4-difluorophenyl)cyclopropyl)amino)-5- (propylthio)-3H- [1,2,3 ltriazolo[4,5-dlpyrimidin-3 -yl)-2,2-dimethyltetrahydro-3aH- cyclopenta[dl [1 ,3ldioxol-4-yl)oxy)ethanol (See Springthorpe, B. et. al. Bioorg.Med. Chem. Lett., 2007, 17, 6013-6018) (0.563 g, 1.0 mmol) and TEA (0.209 mL, 1.50 mmol) in DCM (5 mL) at 0C. The mixture was stirred from 0 C to about 5 C over 3 h. The reaction mixture was diluted with DCM (30 mL) and washed with water (5 mL). The mixture was dried by passing through a phase separator. Evaporation of the solvent and co-evaporation from toluene gave the title compound (1.a) (714 mg, 111% ) as a yellow thick oil, which was used as crude without further purification.[00142] ?H NMR (400 MHz, CDC13) oe 1.02 (dd, 3H), 1.3 - 1.47 (m, 5H), 1.55 (s, 3H), 1.72 (d, 2H), 2.20 (d, 1H), 2.6 - 2.71 (m, 2H), 2.97 (s, 3H), 3 - 3.19 (m, 3H), 3.57 - 3.68 (m, 1H), 3.69 - 3.79 (m, 1H), 4.02 (td, 1H), 4.13 - 4.24 (m, 2H), 4.78 (dd, 1H), 5.13 (td, 1H), 5.57 (s, 1H), 6.50 (s, 1H), 7.03 (s, 1H), 7.07 - 7.16 (m, 2H).[00143] ?9F NMR (376 MHz, CDC13) oe -141.37 (J = 21.3), -138.10 (J = 21.3).
  • 35
  • [ 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.
  • 36
  • [ 24424-99-5 ]
  • [ 274693-26-4 ]
  • [ 1383715-61-4 ]
YieldReaction ConditionsOperation in experiment
25% With dmap; triethylamine; In dichloromethane; at -5 - 0℃; for 8h;Inert atmosphere; Under an inert nitrogen atmosphere, washed 250mL three neck round bottom flask was placed 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 methyl - hexahydro-cyclopenta [d] [1,3] dioxol-4-yl] oxy] ethyl-1-ol (2g, 3.52mmol, 1.00 eq., 99%), three ethylamine (700mg, 6.85mmol, 1.95 eq., 99%), N, N- dimethyl-4-amine (20mg, 0.16mmol, 0.05 eq., 99%) in methylene chloride (120mL), then was added dropwise with stirring di-t-butyl dicarbonate (780mg, 3.54mmol, 1.01 eq) in methylene chloride (20mL).The resulting solution was stirred at -5 ~ 0 8 hours added 250mL of water / ice to terminate the reaction, and extracted three times with 100mL dichloromethane.100mL organic layer was washed once with concentrated hydrochloric acid, the organic layer was dried over anhydrous sodium sulfate, combined and concentrated in vacuo.The residue was purified on silica gel column with ethyl acetate: petroleum ether (1:50 to 1: 2) to afford 600mg (25%) tert-butyl N- [3 - [(3aS, 4R, 6S, 6aR) 6- (2-hydroxyethoxy) -2,2-dimethyl - hexahydro-cyclopenta [d] [1,3] dioxol-4-yl] -5- (propyl mercapto) -3H- [1,2,3] triazolo [4,5-d] pyrimidin-7-yl] -N - [(2S) -2- (3,4- difluorophenyl) cyclopropyl ] carbamate as a white solid.
  • 37
  • 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 ]
  • trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine tartrate salt [ No CAS ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; at 43℃; for 2h;Large scale; Preparation of ticagrelor stage II:Tetrahydrofuran (100 L) was charged at room temperature,Oxalic acid dihydrate (6.62 kg) and ticagrelor phase I (20 kg)To the reactor,After stirring for 10 minutes,Reaction mass was cooled to 10 C.Into the reaction kettle sodium nitrite solution,The reaction mass was heated to 40 C,Stir for 1 hour. The reaction mass was cooled to room temperature,filter.The residue is washed with 100 L of dichloromethane.The above filtrate and sodium bicarbonate solution were charged at room temperature,Stir for 30 minutes.Isolated,The upper aqueous phase is extracted with dichloromethane.in room temperatureThe organic phase, compound III (15.28 kg) and diisopropylethylamine (30.8 kg) were charged to a reaction vessel,Stir for 2 hours.100L water into the reactor,Stir at room temperature for 30 minutes.After standing for 30 minutes,Isolated,The upper aqueous phase is extracted with dichloromethane.The organic phase is washed with acetic acid solution, water and sodium bicarbonate solution,Decolorized with activated carbon.The organic phase is distilled under reduced pressure and degassed for 1 hour,Ethyl acetate 20 L and n-heptane 300 L were charged at 50 C,Stir for 1 hour. Cool to room temperature,Input stage II seed 0.01kg,Stir for 2 hours.Heated to 43 C,Stir for 2 hours.After cooling to room temperature, it was stirred for another 2 hours. Centrifuge,Rinse with 40L n-heptanewash. Vacuum dried at 55 C for 4 hours,Ticagrelor stage II.The yield is about 90.7%Purity is about 95.2%.
  • 38
  • (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine [ No CAS ]
  • [ 274693-55-9 ]
  • C8H10ClN5S [ No CAS ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In toluene; at 210℃; 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-R1 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.
  • 39
  • [ 376608-71-8 ]
  • [ 220354-21-2 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
13.1 g With triethylamine; In acetonitrile; at 20 - 25℃; for 1h; 11.6 g (24.5 mmol, 1.0 eq) of the compound of the formula IV-1 obtained in Example 7 was dissolved in 150 ml of acetonitrile and (1R, 2S) -2- (3,4-difluoro Phenyl) cyclopropylamine (III), 7.9 g (24.5 mmol,(85.8 mmol, 3.5 eq) of triethylamine, followed by stirring for 1 hour at 20-25 ° C. The reaction was completed by TLC. The reaction mixture was concentrated under reduced pressure. The residue was added with 150 ml of water and extracted with 300 ml of ethyl acetate The organic phase was concentrated under reduced pressure to give 13.1 g of the title compound (molar yield to 95.3percent) which was used for the next reaction.
  • 40
  • 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 ]
  • (x)C8H8O3*C9H9F2N [ No CAS ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In water; toluene; at 0 - 20℃; for 2h;Inert atmosphere; Large scale; A 200 L reactor is pumped with a purified aqueous solution containing 5.6 kg of anhydrous potassium carbonate, 25 kg, and compound 5, 6.5 kg is added under stirring. Under nitrogen protection, the system is cooled to 0 C. to 10 C., and the organic phase of step 2 is added dropwise. To 200L system, temperature control 0 C ~ 10 C, dropping is completed, temperature control 10 C ~ 20 C insulation reaction for 2 hours; stop stirring, liquid separation, discarding the aqueous phase; organic phase added containing 1.5kg of sodium chloride The purified aqueous solution, 21.2kg, was stirred and separated, and the aqueous phase was discarded; the organic phase containing Compound 6 was directly used for the next reaction;
  • 41
  • 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-dimethytetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy}-1-benzoic acid ethyl ester [ No CAS ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
With methanol; sodium methylate; at 20℃; Sodium methoxide(1.5g) Into the reaction solution prepared in Example 6,After adding 10ml of methanol,Stir overnight at room temperature.Stably layered,The aqueous layer is extracted once with 20 ml of toluene.Combine organic layers,Then wash with 20ml water,The resulting organic layer was used directly for the next reaction.
  • 42
  • [ 67-56-1 ]
  • [ 274693-26-4 ]
  • C25H33F2N6O7PS [ No CAS ]
YieldReaction ConditionsOperation in experiment
90.11% Under nitrogen, the reaction flask were added isopropylidene ticagrelor, N,N- diisopropylethylamine (2.30g, 17.8mmol) and tetrahydrofuran 10mL, stirring (1.00g, 1.78mmol) 5 C to clarification, cooled to -5 C ~ 0 C. 5ml of tetrahydrofuran was added dropwise to the reaction solution phosphorus oxychloride (2.72g, 17.7mmol), the reaction solution is controlled temperature 0 C~ 5 C, 10min dropwise addition, the reaction temperature 0 C ~ 5 C for 2h. Under nitrogen, the reaction solution was slowly added dropwise 20ml of methanol, 0 C ~ 5 C reaction 1h, warmed to 10 C~ 15 C reaction was continued for 1h. To the reaction was added dropwise 30ml of water, temperature 5 C ~ 15C, addition was complete, warmed to 25 C ~ 30 C reaction 1h. 60ml of ethyl acetate twice. The combined organic phase was washed with 30ml water and 30ml saturated brine the organic phase, the resulting organic phase was dried over anhydrous sodium sulfate 1g IH, suction filtered, the filtrate was distilled off under reduced pressure, to give as a white solid 1.01g, yield 90.11%.
  • 43
  • [ 274693-26-4 ]
  • C26H33F2N6O7PS [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; In tetrahydrofuran; at 5℃; for 3.25h;Inert atmosphere; Under nitrogen, the reaction flask was added starting material (5.01g, 8.90mmol), DIPEA (11.4g, 88.9mmol), THF 50mL, 5 stirred until clear. Slowly dropped freshly distilled POCl3 (13.6g, 88.9mmol), dropwise for about 15min, the reaction 3h. TLC [CH2Cl2:CH3OH = 4: 1] detection reaction is substantially complete, water was added with stirring 100mL homogeneous. 100mL extracted three times with ethyl acetate, washed with saturated saline water 50mL. The organic layer was collected, dried over anhydrous sodium sulfate. The organic solvent was evaporated to give the crude compound as a yellow solid 5.69 g, yield 99.4%.
  • 44
  • 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-2-(propylmercapto)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-1-ethanol [ No CAS ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
1.5 g With acetic acid; sodium nitrite; In water; at 0 - 5℃; for 3.5h; Eg 2: 5 C was added to the reaction flask, 3 g of compound g, 30 ml of acetic acid and 100 ml of water, dissolved by magnetic stirring, cooled to 0 C in an ice bath, and 20 g of NaNO 2 / 100 ml of H 2 O was added thereto under controlled temperature. After the addition, the reaction was magnetically stirred for 3.5 hours. 250 ml of ethyl acetate and 250% aqueous potassium carbonate solution 250 ml were added, the mixture was separated, and the mixture was separated, washed with water (500 mL), concentrated, and then recrystallized from 20 mL of n-octane / 110 mL of acetic acid to give the desired product 1.5 g, HPLC purity 99.88%. The by-product i content was 0.03%.
  • 45
  • 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 ]
  • C9H9F2N*C10H12O3 [ No CAS ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
89.8% In ethyl acetate; at 40℃; for 2h; Then, trimethylamine is added to the ethyl acetate solution.Adding a ring-forming reaction product (385.2 g, 0.9 mol) and(1R,2S)-2-(3,4-difluorophenyl)cyclopropanyl-2-hydroxy-4-phenyl-butyrate (350 g, 1 mol), and reacted at 40 C for 2 h,Intermediate (455.2 g, yield 89.8%) was obtained;
  • 46
  • [ 274693-26-4 ]
  • C26H32F2N6O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
13.24 g With tert.-butylhydroperoxide; bis(acetylacetonate)oxovanadium; (S,S)-tartaric acid ethyl ester; water; In tetrachloromethane; at 0℃; for 24h; (3) Dissolve 0.57 g (2.76 mmol) of (S, S) -ethyl tartrate in 100 mL of carbon tetrachloride, stir and add 0.36 g (1.36 mmol) of vanadyl acetylacetonate at 25 C, and add 247 muL (13.72 mmol) dropwise. Water, cooled to 0 C, stirred for 1 h, added 15.43 g (27.42 mmol) of compound IV obtained in step (2), and slowly added 15 mL of a carbon tetrachloride peroxybutanol solution (containing 3.71 g of hydrogen peroxide peroxybutanol, 41.17 mmol), reacted at 0 C for 24 hours, added a 1.00mol / L thiosulfuric acid solution, washed twice with 100 mL of deionized water, added 500 mL of n-pentane dropwise at 4 C, filtered, and concentrated to dryness under vacuum at 30 C to obtain a compound V crude product; the obtained crude compound V was added to 30 mL of acetone, heated to 45 C. to dissolve, 100 mL of ice water was added dropwise, left at 4 C. for 2 h, filtered, and dried under vacuum to obtain 13.24 g of compound V;
  • 47
  • [ 274693-26-4 ]
  • [ 64-19-7 ]
  • C28H34F2N6O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
77.14% With azodicarboxylic acid bis(2-methoxyethyl) ester; triphenylphosphine; In tetrahydrofuran; at 4 - 25℃; for 10h; S1. 10.00 g of compound I,9.32g of triphenylphosphine is dissolved in 200mL of tetrahydrofuran,2.13 g of glacial acetic acid and 8.32 g of di-2-methoxyethyl azodicarboxylate were added dropwise with stirring at 4 C.After the dropwise addition, the reaction was carried out at 25 C for 10 hours.Remove excess tetrahydrofuran under reduced pressure,When about 50mL of tetrahydrofuran remains or a small amount of crystals precipitates,Let stand for 2h at 4 , filter out some white crystals,The filtrate was dried to 10 mL, and 50 mL of methyl tertiary ether at 4 C was added.Mixing, filtering, vacuum drying at room temperature,8.29 g of compound II was obtained with a yield of 77.14% and a purity of 95.47%,
  • 48
  • 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 ]
  • [ 1402222-66-5 ]
  • [ 274693-26-4 ]
YieldReaction ConditionsOperation in experiment
94% With N-ethyl-N,N-diisopropylamine In water at 30 - 35℃; for 0.116667h; Flow reactor; 1.2; 2.2; 3.2 2) Preparation of TGI The TGM-2 material liquid is placed in the third material storage tank and stirred as the third material;Weigh 16g TGC (0.078mol, 1.1eq) and 14.2g N,N-diisopropylethylamine (0.11mol, 1.5eq), measure 200mL of water,Place it in the fourth raw material storage tank and stir evenly as the fourth raw material.The temperature of the second microchannel reactor is controlled at 30-35 through the integrated high and low temperature machine, and the third material is pumped into the second microchannel reactor through the metering pump 3, and the pumping flow rate is 4mL/min;The fourth material is pumped into the second microchannel reactor through the metering pump 4, and the pumping flow rate is 3 mL/min. The docking coupling reaction was carried out in the second microchannel reactor, the reaction time was 7 minutes, and the reaction temperature was 33°C.The effluent was collected, stirred, and allowed to stand for liquid separation. The aqueous layer was extracted with ethyl acetate (300mL×2),The organic phases were combined, washed with dilute hydrochloric acid solution (200 mL×1), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 39.9 g of crude product.80 mL of ethyl acetate and 200 mL of petroleum ether were added to the crude product, dissolved by heating, and crystallized by cooling to obtain 37.9 g of white TGI product.The yield was 94%.
  • 49
  • [ 274693-26-4 ]
  • [ 1895006-01-5 ]
  • [ 2795140-09-7 ]
YieldReaction ConditionsOperation in experiment
55% Stage #1: 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)-1-ethanol With pyridine; 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate In 2-methoxy-2-methylpropane at 20℃; for 1h; Inert atmosphere; Stage #2: Umemoto’s reagent With Quinuclidine; C36H22F10IrN4O2(1+)*F6P(1-); tetra-n-butyl-ammonium chloride; copper chloride (II) In dimethyl sulfoxide at 20℃; for 8h; Irradiation; Inert atmosphere; Sealed tube;
Same Skeleton Products
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