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[ CAS No. 170729-80-3 ] {[proInfo.proName]}

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Chemical Structure| 170729-80-3
Chemical Structure| 170729-80-3
Structure of 170729-80-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 170729-80-3 ]

CAS No. :170729-80-3 MDL No. :
Formula : C23H21F7N4O3 Boiling Point : -
Linear Structure Formula :- InChI Key :ATALOFNDEOCMKK-OITMNORJSA-N
M.W : 534.43 Pubchem ID :135413536
Synonyms :
MK-0869;MK-869;US brand name: Emend;ONO-7436;Emend;L-754030
Chemical Name :5-(((2R,3S)-2-((R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-1H-1,2,4-triazol-3(2H)-one

Calculated chemistry of [ 170729-80-3 ]

Physicochemical Properties

Num. heavy atoms : 37
Num. arom. heavy atoms : 17
Fraction Csp3 : 0.39
Num. rotatable bonds : 8
Num. H-bond acceptors : 12.0
Num. H-bond donors : 2.0
Molar Refractivity : 118.82
TPSA : 83.24 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.58 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.24
Log Po/w (XLOGP3) : 4.2
Log Po/w (WLOGP) : 6.5
Log Po/w (MLOGP) : 4.05
Log Po/w (SILICOS-IT) : 5.77
Consensus Log Po/w : 4.75

Druglikeness

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

Water Solubility

Log S (ESOL) : -5.61
Solubility : 0.00131 mg/ml ; 0.00000245 mol/l
Class : Moderately soluble
Log S (Ali) : -5.66
Solubility : 0.00118 mg/ml ; 0.0000022 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -7.94
Solubility : 0.00000609 mg/ml ; 0.0000000114 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 4.57

Safety of [ 170729-80-3 ]

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 [ 170729-80-3 ]

* 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 [ 170729-80-3 ]

[ 170729-80-3 ] Synthesis Path-Downstream   1~61

  • 1
  • [ 990-91-0 ]
  • [ 170729-80-3 ]
  • [ 265121-01-5 ]
YieldReaction ConditionsOperation in experiment
81.1% Add 300 ml of tetrahydrofuran to the reaction flask in turn,14.0g <strong>[170729-80-3]aprepitant</strong>,22.3 g of tetrabenzyl pyrophosphate,Nitrogen protection,Cool down to 0 ~ 10 C.A temperature control of 0 to 10 C was added to 33.6 kg of sodium hexamethyldisilazane solution.Plus,The reaction was kept for 1 hour.The reaction is quenched with saturated sodium bicarbonate solution.Extraction with methyl tert-butyl ether.The organic layer was respectively treated with 0.5 M potassium hydrogen sulfate solution,Saturated sodium bicarbonate solution,Washed with saturated sodium chloride solution,Dry over anhydrous sodium sulfate.filter,And concentrated to give a yellow oil.Add 300ml of cyclohexane,Stir at 5 to 15 C for 2 to 3 hours.filter,The filter cake is dried in vacuum for 2 to 3 hours.Obtained a white solid of 16.9 g,The yield was 81.1%.
With sodium hexamethyldisilazane; In tetrahydrofuran; at -5 - 5℃; for 1h; A 12 L round-bottomed flask was equipped with an overhead stirrer, a thermocouple and a N2 inlet. The vessel was charged with <strong>[170729-80-3]aprepitant</strong>, 5-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (300 g), tetrabenzyl pyrophosphate (393 g), and 3.85 L of dry THF. The batch was then cooled under N2 to an internal temperature of between -5 and 5 C. NaHMDS (1.37 L of a 1.0 M solution in THF) was added via an addition funnel at such a rate that the internal temperature remained <5 C. Typical addition times were 25-35 minutes and the reaction was typically complete in 60 minutes. Upon completion, the reaction was poured into a rapidly stirred mixture of t-butyl methyl ether (10.4 L) and saturated sodium bicarbonate (10.4 L). The two phase system was separated and the organic layer washed with saturated sodium bicarbonate (1×10.4 L), 10% sodium bisulfate (1×5.2 L) and water (2×5.2 L). The batch was concentrated in vacuo (100 torr) to approximately half its original volume and then solvent switched to methanol (the final batch volume was 3.0 L). The internal batch temperature during the solvent switch was maintained at <25 C. This solution was transferred to a 5 L round-bottomed flask and heated to 45 C. while stirring under nitrogen. After 30 minutes, mono-O-benzylphosphate (3.0 g) was added and a seed bed should persist. The slurry was aged 18 hours at 45 C. The slurry was allowed to cool to room temperature and then aged one hour. The slurry was filtered through a sintered glass funnel and washed with methanol (2×1.2 L). The wet cake was dried in vacuo at room temperature, yielding 307 g (78%, adjusted for seed) mono-O-benzylphosphate intermediate as a white crystalline solid.
Example 1Preparation of Dibenzylester Fos<strong>[170729-80-3]aprepitant</strong>250 ml of tetrahydrofuran (THF), 10 gm of <strong>[170729-80-3]aprepitant</strong> and 14 gm of tetrabenzylpyrophosphate were charged into a clean and dry 4 neck round bottom flask. The reaction mixture was cooled to about -20 C. 47 ml of 1.0M sodium bis-(trimethylsilyl)amide in THF was added at about -20 C. over about 3 hours. The resultant reaction mixture was stirred for about 30 minutes. After completion of the reaction, the reaction mass was quenched by adding 250 ml of saturated sodium bicarbonate solution. 250 ml of isopropyl ether was charged and stirred for about 15 minutes. Organic and aqueous layers were separated and the organic layer washed with 250 ml of 0.5 M potassium hydrogen sulfate solution. Organic and aqueous layers were separated and the organic layer washed with 250 ml of saturated sodium bicarbonate solution. Organic and aqueous layers were separated and the organic layer was washed with 250 ml of purified water. Organic and aqueous layers were separated and the organic layer was dried over anhydrous sodium sulfate. The organic layer was distilled completely under vacuum to afford the residue. To the residue 30 ml of ethyl acetate was charged and the suspension was stirred for about 30 minutes to get a clear solution. 100 ml of cyclohexane was charged and stirred for about 2 hours. The separated solid was filtered and the solid was washed with cyclohexane. The solid (Formula (II)) obtained was dried at about 30 C. under vacuum for about 1 hour to yield 10 gm of the title compound.Purity by HPLC: 93.74% with monobenzyl fos<strong>[170729-80-3]aprepitant</strong> (III): 1.39% and <strong>[170729-80-3]aprepitant</strong>: 1.0%, other unknown impurities: 3.83%.
With sodium hexamethyldisilazane; In tetrahydrofuran; at 0 - 5℃; for 1.25h;Inert atmosphere; <strong>[170729-80-3]Aprepitant</strong> (50 gm), tetrabenzyl pyrophosphate (75 gm) and teterahydrofuran (635 ml) were added under nitrogen atmosphere at room temperature. The contents were then cooled to 0 to 5C and then added sodium hexamethyldisilazane (266.6 ml) slowly for 45 minutes. The reaction mass was stirred for 30 minutes at 0 to 5C and then added sodium bicarbonate solution (8%, 1700 ml) and methyl tert-butyl ether (1700 ml) at room temperature. The layers were separated and the organic layer was washed with saturated sodium hydrogen sulfite solution. Again the layers were separated and the organic layer was washed with water. The organic layer was dried with sodium sulfate and the solvent was distilled off under vacuum at 30 to 35C to obtain 68 gm of dibenzyl fos<strong>[170729-80-3]aprepitant</strong>.
190 g With water; sodium hydride; In tetrahydrofuran; mineral oil; at 8 - 15℃;Inert atmosphere; 37.50 gm of sodium hydride (60% disperse in oil) was added in 4-5 equal lots to a solution of 150gm of <strong>[170729-80-3]aprepitant</strong> and 218gm of tetrabenzyl pyrophosphate in mixture of 3000ml tetrahydrofuran and 3ml water (0.10% w/v) under nitrogen atmosphere at about 8C-15C. The reaction mass was stirred for about 5-15 minutes, then ethyl acetate and methylene dichloride was added to reaction mass at about 0C to 5C. The reaction mass was stirred for about 5 minutes and organic layer was washed with 10% aqueous sodium bicarbonate solution followed by aqueous sodium chloride solution. The organic layer was dried over sodium sulphate, distilled out solvent and degassed. Cyclohexane was added in solution of degassed mass in ethyl acetate at 25 to 30C to obtain a white solid. The slurry mass was stirred, filtered and dried at about 30C. Crude product obtained further purified by ethyl acetate and cyclohexane to yield pure titled compound. Dry wt: 190gm. Purity: 99.80%; <strong>[170729-80-3]Aprepitant</strong> (Formula III): Not detected; Impurity F: Not detected.

  • 2
  • [ 990-91-0 ]
  • [ 170729-80-3 ]
  • [ 265121-01-5 ]
  • C44H41F7N4O9P2 [ No CAS ]
  • 3
  • [ 252742-72-6 ]
  • 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine p-toluenesulfonate [ No CAS ]
  • [ 170729-80-3 ]
  • 4
  • [ 252742-72-6 ]
  • [ 171338-27-5 ]
  • [ 170729-80-3 ]
YieldReaction ConditionsOperation in experiment
68% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 0.5h; Example 8: Synthesis of I5-Chloromethyl-2,4-dihydro-[1 ,2,4]triazol-3-one-variant:To a solution of 0.6Og (1.48mmol, 1 equivalent) of III in 3.1 mL of DMF were added 226mg (1.64mmol, 1.1 equivalents) of potassium carbonate at ambient temperature. The mixture was stirred at 209C and a solution of 238mg (1.78mmol, 1.2 equivalents) of 5-Chloromethyl-2,4-dihydro-[1 ,2,4]triazol-3-one in 1.5ml_ of DMF was added dropwise within 15min. The reaction was stirred for 15min at 209C before 1 OmL of water were added dropwise while the product started to crystallize. The resulting suspension was stirred for 10min at 259C before it is cooled to 00C and stirred for 1 h. The crystals was collected by filtration and washed with cold water to give 416mg (68percent) of the title compound after drying under reduced pressure (400C, 10mbar) as a white crystalline product.Example 8a: Synthesis of I lambda^I -Amino^-chloro-eth-^-ylideneJ-hydrazinecarboxylic acid methyl ester-variant: To a solution of 500mg (1.14mmol, 1 equivalent) of III in 4.2mL of acetonitrile were added 546muL (3.29mmol, 2.9 equivalents) of lambda/,lambda/-diisopropylethylamine and 244mg (1.48mmol, 1.29 equivalents) of /V- [1 -Amino-2-chloro-eth-(Z)-ylidene]-hydrazinecarboxylic acid methyl ester. The resulting suspension was stirred at ambient temperature for 3h while a clear solution was formed. The reaction mixture was concentrated under reduced pressure (450C, 100mbar) and the residue was dissolved in 1 OmL of dichloromethane and washed with 1 OmL of a 26.5percent aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure (459C, 100mbar). Then 4.2mL of acetonitrile were added to the residue and the mixture was transferred to a reactor where it was stirred for 55h at 1109C and 1.5bar. Then the reaction mixture was concentrated under reduced pressure (450C, 10 mbar) and the residue was dissolved in 5.6mL of methanol. The reaction mixture was heated to reflux and charcoal was added. <n="20"/>The reaction mixture was kept at reflux for 30min before it was filtered over a bed of celite and washed with methanol. The filtrate was concentrated under reduced pressure and then suspended in acetonitrile. The resulting crystalline product I was collected by filtration and washed with cold acetonitrile to give 324mg (53percent) of the title compound as a white crystalline product.Example 9: Synthesis of I without isolation of intermediates:A mixture of 33.5g (77mmol, 1 equivalent) of Xl dissolved in 496ml_ of methanol and 6.69g of Pd/C (10percent) was charged with hydrogen and stirred for 2h at ambient temperature. The catalyst was filtered off and washed three times with 5OmL of methanol. The filtrate was concentrated under reduced pressure (450C, 10mbar) to yield in 34g of III as a colourless oil. This oil was dissolved in 278ml_ of acetonitrile and 28g (218mmol, 2.9 equivalents) of lambda/,lambda/-diisopropylethylamine and 16g (97,8mmol, 1.3 equivalents) of /V-[1 - Amino-2-chloro-eth-(Z)-ylidene]-hydrazinecarboxylic acid methyl ester were added. The mixture was stirred at ambient temperature for three hours and then concentrated under reduced pressure. The residue was dissolved in 30OmL of dichloromethane and washed with 30OmL of a 26.5percent aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure (45°C, 10mbar). Then 13OmL acetonitrile were added and the resulting mixture was transferred to a reactor where it was stirred for 45h at 1100C and 1.5 bar. The reaction mixture was then concentrated under reduced pressure (450C, 10mbar) and the residue was dissolved in 371 mL methanol. The reaction mixture was heated to reflux and charcoal was added. The reaction mixture was kept at reflux for 30min before it was filtered over a bed of celite and washed with methanol. The filtrate was concentrated under reduced pressure and then suspended in 278mL of acetonitrile. The resulting crystals were collected by filtration and washed with acetonitrile to give 377g (69percent) of the title compound as a white crystalline product.NMR: 1H-NMR (DMSOd6, 300MHz) delta (ppm) = 1.36 (d, CH3, 3H, J 6.5Hz), 2.39(dt, CH2, 1 H, J 11.7Hz, J 3.1 Hz), 2.75 (d, CH2, 1 H, J 14.2Hz), 2.84 (d, CH2, 1 H, J 11.7Hz), 3.38 (d, CH2, 1 H, J 13.9Hz), 3.49 (d, CH, 1 H, J 2.54), 3.62 (d, CH2, 1 H, J 10.9Hz), 4.12 (t, CH2, 1 H, J 9.9Hz), 4.33 (d, CH, 1 H, J 2.7Hz), 4.94 (q, CH, 1 H, J 6.5Hz), 7.07 (t, CH, 2H, J 8.8Hz), 7.37 (s, CH, 2H), 7.51 (t, CH, 2H, J 6.1 Hz), 7.83 (S, CH, 1 H), 11.29 (bs, NH, 2H). 13C-NMR (DMSOd6, 75.47MHz) delta (ppm) = 24.75, 50.79, 51.88, 59.07, 68.02, 71.87, 95.77, 114.79, 115.07, 121.39, 121.60, 125.22, 126.87, 128.83, 129.88, 130.31 , 130.74, 131.18, 131.37, 131.47, 133.52, 133.56, 144.24, 146.87, 156.72, 160.45, 163.68.
  • 5
  • [ 252742-72-6 ]
  • [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride [ No CAS ]
  • [ 170729-80-3 ]
  • 6
  • [ 219821-37-1 ]
  • [ 170729-80-3 ]
YieldReaction ConditionsOperation in experiment
In toluene; at 140℃; for 3h; EXAMPLE 1 [2R- [2oc (R*), 3cc]]-5- [ [2- [1- [3, 5-bis (trifluoromethyl) phenyl] ethoxy]-3- (4- fluorophenyl)-4-morpholinyllmethyll-1, 2-dihydro-3H-1, 2, 4-triazol-3-one A mixture of the starting material as the hydrochloride salt of (2R, 2- alpha-R, 3a)-2- [l- [3, 5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl)-1, 4- oxazine (2a) (1.00 kg; 2.11 mol) and potassium carbonate (1.02 kg; 7.39 mol) in DMSO (2.2 L) and toluene (1.0 L) was cooled to 15C. A slurry of amidrazone 3 (367 g; 2.22 mol) in toluene (1.5 L) was added. The mixture was stirred and then partitioned between toluene (4.0 L) and water (5.0 L). The phases were separated at 40C. The organic layer (containing 4a) was washed with water (5.0 L) at 40C and then partially concentrated at atmospheric pressure, providing intermediate 4a, which is used in the next step without isolation. The resulting solution containing intermediate 4a was heated to 140C for 3 h and then allowed to cool to RT. The solids were filtered and dried in vacuo at 40 C. The product (1.00 kg) was dissolved in methanol (10.0 L) and 50 g of Darco was added. The mixture was heated at 60C for 1 h and then filtered at this temperature. The filtrates were allowed to cool slowly to RT. Water (5.0 L) was added slowly over 1 h. The slurry was cooled to 5 C and the solids were filtered and dried in vacuo at 40 C to yield 0.96 kg (85% overall yield) of the product [2R- [2oc (R*), 3cc]]-5- [ [2- [1- [3, 5-bis (trifluoromethyl) phenyl]- ethoxy]-3- (4-fluorophenyl)-4-morpholinyl] methyl]-1, 2-dihydro-3H-1, 2,4-triazol-3- one (i. e. 5- [ [2 (R)- [l (R)- [3, 5-bis (trifluoromethyl) phenyl]ethoxy]-3(S)-(4-fluorophenyl) -4-morpholinyl] methyl]-1, 2-dihydro-3H-1, 2, 4-triazol-3-one). Intermediate 4a: [a] D25=+84 (c=1.02, methanol) ;'H NMR (400 MHz, CDC13) 8 7. 64 (s, 2H), 7.34 (brt, J~7, 2H), 7.16 (s, 1H), 7.03 (t, J = 8. 4,2H), 5.8 (very br s, 2H), 4.88 (q, J = 6. 6,1H), 4.33 (d, J = 2. 8, 1H), 4.24 (td, J = 11. 6,2. 0, 1H), 3.77 (s, 2H), 3.66 (ddd, J= 11.6, 3.2, 1.6, 1H), 3.46 (d, J= 2.8, 1H), 3.31 (d, J = 14.5, 1H), 2.96 (brd, J= 11.6, 1H), 2.59 (d, J = 14.5, 1H), 2.50 (td, J = 12.1, 3.2, 1H), 1.47 (d, J = 6.6, 3H). Anal. Calc. for C24H2sF7N404 : C, 50.89 ; H, 4.45 ; F, 23.48 ; N, 9.89. Found: C, 50.48 ; H, 4.40 ; F, 23.43 ; N, 9.84. Final product la : Mp: 255 C ; [alpha] = +69 (c=1.00, methanol) ;'H NMR (400 MHz, CD30D) 8 7.70 (s, 1H), 7.51 (m, 2H), 7.32 (s, 2H), 7.04 (t, J= 8.7, 2H), 4.94 (q, J= 6.3, 1H), 4.35 (d, J= 2.8, 1H), 4.28 (td, J = 11. 5,2. 8, 1H), 3.66 (ddd, J = 11. 5,3. 3,1. 6, 1H), 3.54 (d, J = 14. 3, 1H), 3.48 (d, J = 2.8, 1H), 2. 88 (br d, J = 11. 9,1H), 2.86 (d, J = 14.3, 1H), 2.49 (td, J = 11. 9,3. 6, 1H), 1.44 (d, J = 6.3, 3H) ;"C NMR (100 MHz, CD30D) 8 164.1 (d, J = 245.9), 158. 7,147. 6,147. 0,134. 1 (d, J= 3.1), 132.7 (d, J= 33.4), 132.4 (d, J= 8.0), 127.8 (m), 124.6 (q, J= 272.0), 122.3 (m), 116.1 (d, J = 21.6), 97.1, 73.7, 70.5, 60.4, 53.6, 52.2, 24.7. Anal. Calc. for C23H2lF7N403 : C, 51.69 ; H, 3.96 ; F, 24.88 ; N, 10.48. Found: C, 51.50 ; H, 3.82 ; F, 24.73 ; N, 10.44. HRMS : 534. 1480 (meas. ); 534.1502 (calc. for C23H21F7N4O3).
at 135 - 137℃; for 2h; To a stirred mixture of (2R,3S)-2-{(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy} -3-(4-fluorophenyl) morpholine 4- methylbenzenesulphonate (10 g), powdered potassium carbonate (8 g) in dimethyl sulfoxide (40 ml) was added a solution of N-methylcarboxyl-2-chloroacetamidrazone (2.9 g) in dimethyl sulfoxide (40 ml) at 20-230C over 20-30 minutes. After stirring the reaction mixture at the same temperature for 1 hour, the reaction mixture was quenched with water (80 ml) and extracted with toluene (100 ml). The organic layer was washed twice with water (50 ml) and concentrated at atmospheric pressure upto maximum extent. The viscous liquid residue was heated at 135-1370C for 2 hours to get the solid residue. After completion of reaction , toluene (50 ml) was added and the slurry was cooled to room temperature. Then it was filtered, washed with toluene (20 ml). The wet solid was dissolved in methanol (70 ml) at 5O0C and treated with activated carbon (1 g) at 60-620C for 1 hour, filtered and washed with methanol (30 ml). The combined filtrate was cooled to 250C and water (50 ml) was added slowly over I hour. The slurry was stirred at 25-3O0C for 1 hour and filtered. The wet solid was washed with 2:1 mixture of methanol : water (30 ml) and dried at 5O0C under reduced pressure to get the title compound. Yield: 6 g HPLC purity:99.8 %
  • 7
  • (2R,3S)-4-benzyl-2-[1R-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine p-toluenesulfonate salt [ No CAS ]
  • N-methoxycarbonyl-2-chloroacetamidrazone [ No CAS ]
  • [ 170729-80-3 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In dimethyl sulfoxide; at 20 - 23℃; for 1.5h;Product distribution / selectivity; Step- V: [2R-[2a(R*), 3a]]-5-[[2-[1-[3, 5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4- fluorophenyl)-4-morpholinly]methyl]-1, 2-dihydro-3H-1 , 2, 4-triazole-3- one, (or) 2-(R)-(1-(R)-(3,5-bis(trifluoro-methyl)-phenyl)ethoxy)-3-(S)-(4- fluoro)phenyl-4-(3-(5-oxo-1H, 4H- 1, 2, 4-triazolo)methylmorpholine); i. e. aprepitant; Potassium carbonate (10.7 gm) and dimethylsulfoxide (80 ml) are added to [2R-[2a(f?*),3a]]-2-[1-[3,5-bis(trifluoromethyl)-phenyl]ethoxy]-3-(4-fluorophenyl) morpholine p-toluene sulfonate salt (19 gm, diastereomeric impurity: 1.6%) under N2 atmosphere under stirring, the contents are cooled to 200C and then the solution of N-methylcarboxyl-2-chloroacetamidrazone (6 gm) in <n="11"/>dimethylsulfoxide (77 ml) is slowly added during 30 minutes at 20 - 230C. The contents are stirred for 1 hour at 20 - 230C, the reaction mass is quenched into the mixture of water (150 ml) and methyl tert-butyl ether (300 ml) at 25 - 300C and then separated the layers. The organic layer is washed with water (230 ml) followed by washings with saturated sodium bicarbonate solution (230 ml), water (230 ml) and saturated sodium chloride solution (230 ml), dried over sodium sulfate and then concentrated at 40 - 500C. The resulting residue is dissolved in xylene (250 ml), diisopropylethyl amine (62.5 ml) is added at 25 - 300C, the contents are heated to 1350C and then stirred for 3 hours. The reaction mass is cooled to 25 - 300C and stirred for over night at 25 - 300C. Filtered the material and washed with xylene (10 ml) followed by n-hexane (100 ml) to give 6 gm of aprepitant (diastereomeric impurity: 1.1%).Reference Example 2; To a suspension of [2R-[2a(R*),3a]]-2-[1-[3,5-bis(trifluoromethyl)- phenyl]ethoxy]-3-(4-fluoropheny.)morpholine p-toluene sulfonate salt and powder K2CO3 in DMSO (7.8 Lt) at 2O0C is added a solution of N- methylcarboxyl-2-chloroacetamidrazone in DMSO(7.8 Lt). The first half of the solution is added quickly, (with slightly cooling with ice water bath) then the remaining half is added over a period of 1 hour. After the addition, the reaction is checked by LC, and the reaction is quenched with cold water (15 Lt) and methyl- t-butyl ether (MTBE) (30 Lt) solution. The organic layer is separated, and washed with water, sat. NaHCO3, brine, and water (20Lt/each) respectively. The aqueous layer is back extracted with additional MTBE (15Lt). The combined MTBE solution is concentrated to an oil. The resulting crude product is dissolved in xylene (25 Lt) and diisopropylethylamine (6.25 Lt) and is heated to reflux (~135C) and the reaction is monitored by LC. The reaction takes 4 - 6 hours to complete, the reaction solution is cooled down to room temperature overnight and filter to get [2R-[2a(R*),3a]]-5-[[2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3- (4-fluorophenyl)-4-morpholinly]methyl]-1 ,2-dihydro-3H-1 ,2,4-triazole-3-one (expect 1.33 Kg, -80%, typically purity 98.5A%). The resulting crude product is dissolved in hot methanol (13.3 Lt), added charcoal 133 gm, then filtered and the charcoal is washed with hot methanol (3.3 Lt). The methanol solution is cooled down to room temperature, then water (7 Lt) is added drop wise. After being stirred at room temperature for 2 hrs, the suspension is filtered to pure <n="12"/>aprepitant as a white crystalline compound (Purity, 99.5%, diastereomeric impurity: 0.4%).
  • 8
  • [ 219821-37-1 ]
  • [ 170729-80-3 ]
YieldReaction ConditionsOperation in experiment
98.4% In 5,5-dimethyl-1,3-cyclohexadiene; for 3h;Reflux; The product of the previous step is xylene (30ml) Reflux 3h to complete reaction. Cooled with stirring, filtered and washed with toluene. Filter cake and methanol (100ml), reflux to the solution, stirring cooling, ice bath stirring 20min, filtration, washing, drying white solid V (11.1 g, 98.4%).
97.7% In 5,5-dimethyl-1,3-cyclohexadiene; at 130 - 139℃; for 4h; The reaction bottle (II) compound is added (100.0 g), anhydrous potassium carbonate (102.0 g), dimethyl sulfoxide (200 ml), xylene (200 ml), 0 - 10 C stirring for 10 - 15 minutes, adding the compound (III) (39.0 g), stirring for about 16 hours, plus xylene and water, stirring 10 minutes, layered, the organic layer is washed with water, dried with anhydrous sodium sulfate, filtered, washing the filter cake for xylene, filtrate 130 C -139 C reaction 4 hours. Stirring cooling to 0 C -10 C, filtering, the filter cake is xylene washing. Solid vacuum drying 20 hours, to obtain compound (I) 109.0 g, molar yield 97.7%. HPLC: 99.97%, total isomer 0.017%.
50 - 60% With sodium carbonate; In N,N-dimethyl-formamide; xylene; at 120 - 130℃; for 3h;Product distribution / selectivity; Alternate process for APT-5:APT-4 was dissolved in 3V of xylene:DMF (2.5:0.5) and 0.25g sodium carbonate was added to the reaction mass and heated to 120 to 130 0C for 3 hours. After completion of reaction the reaction mass was cooled to 30 0C and 20 mL of ethyl acetate was added. *The pH of organic layer was adjusted to 6 with dil.HCl (1 :10). The organic layer was washed with water followed by brine. Charcoal (0.05 g) was added to the organic layer, stirred, filtered through hyflow and distilled to the syrupy mass. Heptane (30 mL) was added to the mass and heated to 500C. and stirred. The mass was cooled to 30 0C and filtered and washed the wet cake with hexane .Wet wt=0.6g.0.6g of crude aprepitant and 6 mL of ethyl acetate: methanol (1.5:0.15) was stirred, heated to reflux for dissolution and cooled to 500C. 18mL of hexane was added slowly for 30 minutes and stirred for 30hours. The reaction mass cooled to room temperature and stirred for 2hours. The solid was filtered and washed with hexane. The solid was dried under vacuum for 8hours.Wt=0.35gPurity: 99.5 % Yiled=50-60%
With N-ethyl-N,N-diisopropylamine; In xylene;Reflux; Compound of formula- VIII (10 grams) was taken in a mixture of xylene (55.5 ml) and N,N-diisopropylethyl amine (34.4 ml) and then refluxed for 4-6 hrs then cooled the reaction mixture. Filtered the precipitated compound and washed with xylene (5 ml) to get the crude Aprepitant. The crude compound was crystallized from a mixture of methanol and water to get Aprepitant. Yield: 6.5 grams.
In xylene; at 135 - 140℃; for 5h;Product distribution / selectivity; Example 6; Process for the preparation 5-[2(R)-[l(R)-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]- 3(S)-(4-fluorophenyl)morpholin-4-ylmethyl]-3,4-dihydro-2H-l,2,4-triazol-3-one :APT-4 was dissolved in xylene and heated the reaction mass to 135 to 140 0C for about 5 hours. After completion of reaction the reaction mass was cooled to 30 0C. The solid was filtered and washed with 300 mL of heptane to get APT-5 as crude. Wet wt=75g
With potassium hydroxide; In ethanol; water; at 90 - 100℃; for 0.2h; EXAMPLE 8 A mixture of starting materials (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride 2 (5 g; 10.5 mmol) and potassium carbonate (2.7 g; 20 mmol) was cooled to about 10 C. in tha solvent DMF. A slurry of amidrazone 3c (1.91 g; 11.6 mol) dissolved in DMF was added. The reaction mixture was stirred at room temperature. The mixture was extracted with ethyl acetate and water and phases were separated after the reaction was completed. The layer of ethyl acetate was washed with saturated aqueous solution of NaCl and combined. Ethyl acetate was concentrated under reduced pressure to obtain oily substance 4c, which was dissolved in a mixed solution of ethanol and water (1:1) and 2 g of solid potassium hydroxide was added. The reaction was performed at 90-100 C. for about 2 hours. The majority of ethanol was removed by concentrating under reduced pressure. The solution left was poured into a large amount of ice water, and a large amount of solid precipitated, which was then purified according to the method of Example 1 to obtain aprepitant (336 g, yield 60%).
With water; In dimethyl sulfoxide; at 90 - 110℃; To a 1L round bottom flask charged the compound of formula II (40g), dimethylsulfoxide (100ml) and potassium carbonate (35g) and stirred the reaction mixture for 15 minutes at a temperature of 20C to 30C. The reaction mixture is then cooled to a temperature of 10C to 30C. To the reaction mixture then charged the compound of formula III (14.9g) and stirred the reaction mixture at a temperature of 10C to 30C for 4 to 5 hour. Then charged water (195 ml) to the reaction mixture and heated at a temperature of 90C to 110C and maintained for 6-10 hours. To the resulting reaction mixture then added water and stirred for 15 minutes at a temperature of 90C to 95C. The reaction mixture is then cooled to the temperature of 40C to 45C and then added 50% acetic acid solution in water (~41ml) to the reaction mixture and stirred for 15 minutes, at this stage pH of the reaction mixture is 6 to 7. The reaction mixture is then heated at a temperature of 65 C to 90C with stirring for 30 minutes and then cooled to a temperature of 20C to 30C and maintained with stirring for 1 hour to obtain the solid. Filter the solid obtained under vacuum and washed with water and suck dry to obtain the solid. To the solid then add toluene (280ml) and heated the reaction mixture at a temperature of 75C to 95C for 1 hour. The reaction mixture is then cooled to a temperature of 20C to 35 C with stirring for 30 minutes to yield the solid. Filter the solid obtained under vacuum and washed with toluene and suck dry to obtain aprepitant. Yield 79% and purity 99.8%.
8.15 g With 4-methyl-2-pentanone; for 7h;Reflux; Potash (5. 10g, 36.90 mmol, 1.75 equiv.) was added to a suspension of the hydrochloride 11 ( 10 g, 21 . 10 mmol) in DMF (20 ml) at the laboratory temperature and the suspension was stirred for 30 mins and then addition of a suspension of amidrazone (3.83 g, 23.19 mmol, 1 .1 equiv.) in DMF (10 mL) was started within ca. 10 min. Stirring at the laboratory temperature followed for 4 h. The reaction was monitored with HPLC. The reaction mixture was then diluted with MIBK ( 100 ml) and water ( 100 ml) and brine (20 ml) were added under intensive stirring; the phases were thoroughly mixed and then separated. The aqueous phase was still washed with MIBK (50 ml). The combined organic phase was washed with water (50 ml) and brine (20 ml). The solution of the intermediate obtained this way was heated up to boil and the residual water was removed by azeotropic distillation. Reflux for 17 h, the mixture was concentrated by distillation, ca. 85 mL of MIBK removed. The solution was slowly cooled to the laboratory temperature while being stirred and then cooled to 5 C; crystals were removed by filtration and washed with cold MIBK (3 x 10 ml) and air-dried. 8. 15 g (72%) of crystals were obtained, purity 99.80 %, polymorph form I.
In 5,5-dimethyl-1,3-cyclohexadiene; at 135 - 141℃; for 2h;Inert atmosphere; The specific process of step (2) is:1) The 2R- [1R- [3,5- bis (trifluoromethyl) phenyl] ethoxy] -3S- (4- fluorophenyl) -4- (N- methoxycarbonyl Ki -2-amino Ethylhydrazone) - morpholine in toluene was transferred to a 50 L reactor and heated under nitrogen atmosphere and stirred at 135-141 C for 2 hours. After the reaction, the solution was slowly cooled to 2-8 C and stirred for 60 min.2) filter, wash the cake with xylene, dry, and then mixed with methanol and purified water, washing cake, white towhite crystalline powder;3) The resulting crystalline powder was transferred to a vacuum oven for drying, vacuum ?-0.08Mp, temperature 52-58 C, drying under reduced pressure 8-10h to constant weight, regular rolling, 2h recording of primary temperature, vacuum , Received a sharp piclidine

  • 13
  • [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride [ No CAS ]
  • [ 170729-80-3 ]
  • 19
  • [ 472968-68-6 ]
  • [ 170729-80-3 ]
  • 20
  • (3R)-[3-(4-fluorophenyl)]-4-[(1R)-1-phenylethyl]-2-morpholinone [ No CAS ]
  • [ 170729-80-3 ]
  • 21
  • [ 472968-69-7 ]
  • [ 170729-80-3 ]
  • 24
  • (2R,3R)-2-[(R)-1-(3,5-Bis-trifluoromethyl-phenyl)-ethoxy]-4-chloro-3-(4-fluoro-phenyl)-morpholine [ No CAS ]
  • [ 170729-80-3 ]
  • 25
  • [ 472968-70-0 ]
  • [ 170729-80-3 ]
  • 26
  • [ 170729-80-3 ]
  • 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(1-phosphoryl-3-oxo-4H,-1,2,4-triazol-5-yl)methylmorpholine dipotassium salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
50 - 60% Purification:Crude aprepitant (75 g), 750 mL of methanol and 25% charcoal were added and heated to 50 0C and stirred for 30 minutes. The reaction mass was filtered through hyflow and washed with 12V of hot methanol. The reaction mass was cooled to 300C and water was added slowly for about 30 minutes. The solid was stirred for 2 hours and cooled to 20 0C and stirred for 30minutes. The solid was filtered and washed with chilled methanol: water (1 : 1) 2 V. The solid was dried under vacuum at 500C for deltahours.Wt=50-65gPurity=99.6% Yield=50-60%
50 - 60% Second Purification of Aprepitant using MDC: Methanol: HeptaneCrude aprepitant (0.6 g) and 6 mL of MDC: Methanol (1.5:0.15) were stirred and heated to reflux for dissolution for 1 hour and cooled to 500C. Heptane (18 mL) was added slowly for 30 minutes at the same temp and stirred for 30 hours. The reaction mass was cooled to room temperature and stirred for 2 hours. The solid was filtered and washed with heptane. The solid was dried under vacuum for 8 hours Wt=0.35g Purity: 99.5 % Yield=50-60%
In tert-butyl alcohol;Purification / work up; EXAMPLE 2; [0079] Preparation of Amorphous Form of Aprepitant[0080] Aprepitant (250 mg) was dissolved in t-butanol (50 ml) and the sample was filtered through a 0.45 mum PTFE syringe filter. The solution was added dropwise to liquid nitrogen and the sample was freeze dried.[0081] The XRD of the final product is set forth in Figure 4 and was recorded and identified as aprepitant in an amorphous form.
  • 29
  • N'-(1-amino-2-chloroethylidene)hydrazinecarboxylic acid methyl ester [ No CAS ]
  • [ 171338-27-5 ]
  • [ 170729-80-3 ]
YieldReaction ConditionsOperation in experiment
53% Example 8a: Synthesis of I lambda^I -Amino^-chloro-eth-^-ylideneJ-hydrazinecarboxylic acid methyl ester-variant: To a solution of 500mg (1.14mmol, 1 equivalent) of III in 4.2mL of acetonitrile were added 546muL (3.29mmol, 2.9 equivalents) of lambda/,lambda/-diisopropylethylamine and 244mg (1.48mmol, 1.29 equivalents) of /V- [1 -Amino-2-chloro-eth-(Z)-ylidene]-hydrazinecarboxylic acid methyl ester. The resulting suspension was stirred at ambient temperature for 3h while a clear solution was formed. The reaction mixture was concentrated under reduced pressure (450C, 100mbar) and the residue was dissolved in 1 OmL of dichloromethane and washed with 1 OmL of a 26.5% aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure (459C, 100mbar). Then 4.2mL of acetonitrile were added to the residue and the mixture was transferred to a reactor where it was stirred for 55h at 1109C and 1.5bar. Then the reaction mixture was concentrated under reduced pressure (450C, 10 mbar) and the residue was dissolved in 5.6mL of methanol. The reaction mixture was heated to reflux and charcoal was added. <n="20"/>The reaction mixture was kept at reflux for 30min before it was filtered over a bed of celite and washed with methanol. The filtrate was concentrated under reduced pressure and then suspended in acetonitrile. The resulting crystalline product I was collected by filtration and washed with cold acetonitrile to give 324mg (53%) of the title compound as a white crystalline product.Example 9: Synthesis of I without isolation of intermediates:A mixture of 33.5g (77mmol, 1 equivalent) of Xl dissolved in 496ml_ of methanol and 6.69g of Pd/C (10%) was charged with hydrogen and stirred for 2h at ambient temperature. The catalyst was filtered off and washed three times with 5OmL of methanol. The filtrate was concentrated under reduced pressure (450C, 10mbar) to yield in 34g of III as a colourless oil. This oil was dissolved in 278ml_ of acetonitrile and 28g (218mmol, 2.9 equivalents) of lambda/,lambda/-diisopropylethylamine and 16g (97,8mmol, 1.3 equivalents) of /V-[1 - Amino-2-chloro-eth-(Z)-ylidene]-hydrazinecarboxylic acid methyl ester were added. The mixture was stirred at ambient temperature for three hours and then concentrated under reduced pressure. The residue was dissolved in 30OmL of dichloromethane and washed with 30OmL of a 26.5% aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure (45C, 10mbar). Then 13OmL acetonitrile were added and the resulting mixture was transferred to a reactor where it was stirred for 45h at 1100C and 1.5 bar. The reaction mixture was then concentrated under reduced pressure (450C, 10mbar) and the residue was dissolved in 371 mL methanol. The reaction mixture was heated to reflux and charcoal was added. The reaction mixture was kept at reflux for 30min before it was filtered over a bed of celite and washed with methanol. The filtrate was concentrated under reduced pressure and then suspended in 278mL of acetonitrile. The resulting crystals were collected by filtration and washed with acetonitrile to give 377g (69%) of the title compound as a white crystalline product.NMR: 1H-NMR (DMSOd6, 300MHz) delta (ppm) = 1.36 (d, CH3, 3H, J 6.5Hz), 2.39(dt, CH2, 1 H, J 11.7Hz, J 3.1 Hz), 2.75 (d, CH2, 1 H, J 14.2Hz), 2.84 (d, CH2, 1 H, J 11.7Hz), 3.38 (d, CH2, 1 H, J 13.9Hz), 3.49 (d, CH, 1 H, J 2.54), 3.62 (d, CH2, 1 H, J 10.9Hz), 4.12 (t, CH2, 1 H, J 9.9Hz), 4.33 (d, CH, 1 H, J 2.7Hz), 4.94 (q, CH, 1 H, J 6.5Hz), 7.07 (t, CH, 2H, J 8.8Hz), 7.37 (s, CH, 2H), 7.51 (t, CH, 2H, J 6.1 Hz), 7.83 (S, CH, 1 H), 11.29 (bs, NH, 2H). 13C-NMR (DMSOd6, 75.47MHz) delta (ppm) = 24.75, 50.79, 51.88, 59.07, 68.02, 71.87, 95.77, 114.79, 115.07, 121.39, 121.60, 125.22, 126.87, 128.83, 129.88, 130.31 , 130.74, 131.18, 131.37, 131.47, 133.52, 133.56, 144.24, 146.87, 156.72, 160.45, 163.68.
  • 30
  • [ 265121-04-8 ]
  • [ 170729-80-3 ]
YieldReaction ConditionsOperation in experiment
With water at 90℃; Neat (no solvent);
YieldReaction ConditionsOperation in experiment
In methanol; water; at 11 - 65℃; for 3.41667h;Purification / work up; <strong>[170729-80-3]Aprepitant</strong> (200 g) and methanol (3000 ml) were charged at 25-300C and the mixture was heated to 60-650C and maintained for 30 minutes. The solution was cooled to 300C in about 50 minutes and then further cooled to 110C in about 50 minutes. Seed crystals of <strong>[170729-80-3]aprepitant</strong> (Form I) (0.5 g) was added to the solution. Pre-cooled water (1600 ml) (8-100C) was added in 60 minutes maintaining the temperature of reaction mass in the range of 11-13C. The reaction mixture was stirred for 15 minutes. The solid was filtered and washed with methanol: water (2:1) mixture, suck dried for 15 minutes and further dried in vacuum tray drier at 48C for 10-12 hours to obtain the title compound.Yield: 190 gContent of Form I: 12.1% by weight.
  • 32
  • [ 990-91-0 ]
  • [ 170729-80-3 ]
  • dibenzyl fosaprepitant [ No CAS ]
YieldReaction ConditionsOperation in experiment
87.4% Process for the Preparation of phosphorylated <strong>[170729-80-3]aprepitant</strong> using NMP and Lithium hydroxide monohydrate.Taken 10 ml of NMP under stirring and added 0.23 gm (5.47 mmole) lithium hydroxide monohydrate at ambient temperature. Added 0.5 gm (0.93 mmole) of <strong>[170729-80-3]aprepitant</strong> and stirred for 30 mins to get clear solution. Added 0.56 gm of (1.04 mmole) tetra benzyl pyrophosphate under stirring. Stirred the clear solution for 30 mins at 25-30C. Monitored reaction progress by HPLC. After completion of reaction (<strong>[170729-80-3]aprepitant</strong> < 0.5 %), cooled the reaction mass to 10- 15 C. Added 20 ml DCM under stirring. Separated the layers. Washed organic layer with (4x 25 ml) water and (2x 10 ml) saturated sodium bi-carbonate solution. Dryed DCM layer over 1.0 gm anhydrous sodium sulphate and concentrated under vacuum at ambient temperature to give yellow colored oil.Yield-0.65gm (87.4% theory).
  • 33
  • [ 170729-80-3 ]
  • fosaprepitant [ No CAS ]
YieldReaction ConditionsOperation in experiment
86.7% With dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate; sodium hexamethyldisilazane; In tetrahydrofuran; at -3℃; for 2h; A solution of 5 - [[2 (R) - [1 (R) - [3,5-bis (trifluoromethyl) phenyl] ethoxy] -3 (S) - (4-fluorophenyl) -4 - morpholineYl] methyl] -1,2-dihydro-3H-1,2,4-triazol-3-one (5.3 g, 10 mmol)Tetragenzyl pyrophosphate (7.0 g, 13 mmol) was dissolved in THF (60 mL)Ice water bath cooling,2.0M NaHMDS (12 ml, 24 mmol) was added dropwise to control the reaction temperature at about -3 C.Dripping 2 h to complete the reaction,(150 ml), sodium bicarbonate solution (150 ml), water (150 ml), and concentrated to dryness, dried over anhydrous sodium bicarbonate solution (150 ml) and saturated sodium bicarbonate solution (150 ml) Dried to give 5.9 g of a white solid, the yield was 86.7%.
  • 34
  • [ 1349902-81-3 ]
  • [ 170729-80-3 ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide; In ethanol; water; at 90 - 100℃; for 1h;Large scale; [0027] [0028] A mixture of starting materials (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride 2 (2 kg; 4.23 mol) and potassium carbonate (1.75 kg; 12.7 mol) was cooled to about 10 C. in the solvent N,N-dimethyl formamide (DMF). A slurry of amidrazone 3a (962 g; 4.65 mol) dissolved in DMF (4 L) was added. The reaction mixture was stirred at room temperature. The mixture was extracted with ethyl acetate (6 L) and water (8 L) and then phases weere separated after the reaction was completed, the layer of ethyl acetate was washed with saturated aqueous solution of NaCl (8 L×3) and combined, the majority of organic solvent ethyl acetate (about 20 L) was recovered under normal pressure, to obtain intermediate 4a. The intermediate 4a was directly put into the next step of reaction without separation. A water-ethanol mixed solvent and about 400 g potassium hydroxide was added into a reaction bottle, the reaction solution was reacted for about 1 hour at about 90-100 C., the majority of organic solvent ethanol was recovered under normal pressure after the reaction was completed. The reaction solution was cooled to room temperature, and a large amount of solid precipitated. Purifying steps: the above-mentioned solid was filtrated, and dried in vacuum at 40 C. The resultant product was dissolved in methanol (10 L), decolorized by adding appropriate amount of activated carbon, the mixture was heated and refluxed for 1 hour at about 60 C., and filtrated at the same temperature. The filtrate was cooled to room temperature, and a large amount of water was added slowly to the filtrate. The slurry was cooled to about 5 C. Solid was filtrated and dried in vacuum at 40 C., to obtain the product aprepitant (1940 g, 86%). [0029] Spectroscopic date of the intermediate 4a: [0030] 1HNMR (600 MHz, CDCl3): delta 7.64 (s, 1H), 7.35 (brs, 2H), 7.16 (s, 2H), 7.03 (t, J=8.4 Hz, 2H), 5.47 (s, 1H), 4.88 (dd, J=12.8, 6.6 Hz, 1H), 4.34 (d, J=2.22 Hz, 1H), 4.23 (t, J=11.6 Hz, 1H), 3.64 (d, J=10.7 Hz, 1H), 3.43 (s, 1H), 3.27 (d, J=14.3 Hz, 1H), 2.95 (d, J=12.1 Hz, 1H), 253-2.44 (m, 2H), 1.45 (s, 9H). 13CNMR (150 MHz, CDCl3): delta 163.5, 161.8, 154.9, 145.4, 132.4, 132.0, 131.7, 131.5, 131.3, 130.7, 130.6, 126.2, 123.9, 122.1, 121.4, 115.4, 115.2, 95.4, 72,3, 68.8, 59.4, 56.4, 52.4, 28.3, 24.4, MS (EI) m/z: 608.81 (M+1). [0031] Spectroscopic data of aprepitant: [0032] 1H NMR (CD3OD, 600 MHz): delta 7.69 (s, 1H), 7.41 (br, s, 2H), 7.22 (s, 2H), 6.95 (t, J=8.7 Hz, 2H), 4.85 (q, J=6.6 Hz, 1H), 4.27 (d, J=2.9 Hz, 1H), 4.19 (dt, J=2.3, 11.6 Hz, 1H) 3.57 (d, J=6.6 Hz, 1H), 3.44 (d, J=14.3 Hz, 1H), 2.78 (m, 2H), 2.40 (dt, J=3.5, 11.8 Hz, 1H), 1.35 (d, J=6.6 Hz, 3H), 13C NMR (CD3OD, 150 MHz): delta 163.4, 161.8, 157.2, 146.1, 145.5, 132.7, 131.6, 131.4, 131.0, 130.9, 126.4, 124.1, 122.3, 120.8, 114.7, 114.6, 95.7, 72.3, 69.0, 59.0, 52.2, 50.8, 23.2. HR-ESI-MS: 557.1389, (C23H21F7N4NaO3 cal. 557.1399).
  • 35
  • C25H27F7N4O4 [ No CAS ]
  • [ 170729-80-3 ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide; In ethanol; water; at 90 - 100℃; for 0.2h; EXAMPLE 7 A mixture of starting materials (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride 2 (5 g; 10.5 mmol) and potassium carbonate (2.7 g; 20 mmol) was cooled to about 10 C., in the solvent DMF. A slurry of amidrazone 3b (2.07 g; 11.6 mol) dissolved in DMF was added. The reaction mixture was stirred at room temperature. The mixture was extracted with ethyl acetate and water and phases were separated after the reaction was completed. The layer of ethyl acetate was washed with saturated aqueous solution of NaCl and combined. Ethyl acetate was concentrated under reduced pressure to obtain oil substance 4b, which was dissolved in a mixed solution of ethanol and water (1:1), and 2 g of solid potassium hydroxide was added. The reaction was performed at 90-100 C. for about 2 hours. The majority of ethanol was removed by concentrating under reduced pressure. The solution left was poured into a large amount of ice water, and a large amount of solid precipitated, which was then purified according to the method of Example 1 to obtain aprepitant (2.92 g, yield 52%).
  • 36
  • [ 6284-40-8 ]
  • [ 170729-80-3 ]
  • Fosaprepitant dimeglumine [ No CAS ]
YieldReaction ConditionsOperation in experiment
98% Step The formula V compound 5 - [[2 (R) - [1 (R) - [3,5- bis (trifluoromethyl) phenyl] ethoxy] -3 (S) - (4- fluorophenyl ) -4-morpholinyl] methyl] -1,2-dihydro--3H-1,2,4- triazol-3-(5.3g, 10mmol), pyrophosphoric acid tetrabenzyl ester (7.0g, 13mmol ) was dissolved in THF (60ml), ice-water bath, a solution of NaHMDS 2.0M (12ml, 24mmol), controlling the reaction temperature at about -3 . Dropwise to a stirred for 2h the reaction was complete, methyl tert-butyl ether was added (150ml) and saturated sodium bicarbonate solution (150ml), separated, saturated sodium bicarbonate solution (150ml), sodium bisulfite solution (150ml), water ( 150ml) washed, and concentrated to dryness, dried to obtain 5.9 g of a white solid, a yield of 86.7%. Step B The resulting product from the previous step (5.9g, 8.4mmol), N- methyl-glucamine -D- (2.2g, 11.3mmol) was dissolved in methanol (25ml) / water (1ml), was added 10% Pd / C (0.1 g), to atmospheric hydrogenation 4h the reaction was complete. Filtered and washed with methanol, concentrated to dryness, methanol (15ml), tributylphosphine (0.03 ml of), stirred overnight, isopropanol precipitated solid was filtered and washed with methanol (1ml). Added dropwise to ethanol (30ml) / acetonitrile (30ml), stirred IH, filtered and washed with acetonitrile, and dried in vacuo to give a white solid 7.5g. The solid was dissolved in methanol (50ml), added dropwise to acetone (150ml), stirred for 2h, filtered, washed with acetone and dried in vacuo to give a white solid 5.7g, yield 98%, proven a compound of formula I, the purity of the product 99.9%.
  • 37
  • [ 170729-80-3 ]
  • 5-(((2R,3S)-2-((R)-1-(3-(difluoromethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
  • 38
  • [ 170729-80-3 ]
  • 5-(((2R,3S)-2-((R)-1-(3-(fluoromethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
  • 5-(((2R,3S)-2-((R)-1-(3-(difluoromethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
  • 39
  • [ 170729-80-3 ]
  • 5-(((2R,3S)-2-((R)-1-(3-(difluoromethyl-d)-5-(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
  • 40
  • C26H22ClO3P [ No CAS ]
  • [ 170729-80-3 ]
  • C49H42F7N4O6P [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% To a 500 mL three-necked flask was added 15.0 g of compound II (28.1 mmol) under nitrogen,Add 120mL of tetrahydrofuran to dissolve, ice salt bath to -5oC,A solution of 73 mL of 1 M sodium bis (trimethylsilyl) amide (73.0 mmol)Temperature control below 5oC, after the addition of stirring 30min,Then, 12.9 g of compound III (28.7 mmol) in tetrahydrofuran (80 mL) was added dropwise to the flask at a temperature below 5 C. After completion of the dropwise addition, the ice salt bath was removed and allowed to warm to room temperature,Continue stirring for 1 h.Ice bath cooling, dropping 400mL saturated ammonium chloride aqueous solution quenching reaction,The mixture was extracted with 400 mL of methyl tert-butyl ether,The organic phases were washed with 200 mL of water and 200 mL of saturated brine, respectively,Dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure,To give 21.8 g of the title compound as a yellow oil in 82% yield.
  • 41
  • [ 170729-80-3 ]
  • aprepitant [ No CAS ]
YieldReaction ConditionsOperation in experiment
With pyrographite; In methanol; water; at 60 - 66℃; for 0.5h; The specific process of step 3 is:) to the 50L reactor by adding methanol and aripipine crude, heated to 60-66 C reflux, and then add activated carbon reflux decolorization 30min, filtration, washing with methanol;2) The filtrate was transferred to the IOOL reactor and stirred at 60-66 C. The purified water was added dropwise to precipitate a solid, slowly cooled to 19-25 Gamma and stirred for 12 h. The filter cake was washed with methanol and purified water to give a white or off-white solid;3) filter cake transferred to a vacuum oven for drying, vacuum -0.08Mp, the temperature at 52_58 C, vacuum drying S-IOh to constant weight, per hour, 2h record a temperature, vacuum Degree, after drying, crushing, packaging that was made arabican finished.
  • 42
  • [ 170729-80-3 ]
  • [ 265121-04-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sodium hexamethyldisilazane / tetrahydrofuran / 0 °C / Large scale 2: boron trichloride / tert-butyl methyl ether; dichloromethane / -5 °C / Inert atmosphere; Large scale 3: isopropyl alcohol / 2.5 h / Large scale
  • 43
  • [ 1185503-10-9 ]
  • [ 170729-80-3 ]
  • 44
  • [ 1185503-15-4 ]
  • [ 170729-80-3 ]
  • 45
  • [ 1185503-03-0 ]
  • [ 170729-80-3 ]
  • 46
  • C17H18FNO2*C19H16O8 [ No CAS ]
  • [ 170729-80-3 ]
  • 47
  • [ 1765-93-1 ]
  • [ 170729-80-3 ]
  • 48
  • C3H4BrN3O [ No CAS ]
  • [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride [ No CAS ]
  • [ 170729-80-3 ]
YieldReaction ConditionsOperation in experiment
97.9% With diethyl sulfate; triethylamine; lithium diisopropyl amide; In dimethylsulfoxide-d6; 5,5-dimethyl-1,3-cyclohexadiene; at 33℃; for 14h;Inert atmosphere; This embodiment provides a preparation process of aprepitant, comprising the following steps:Setp1, firstly add compound A and compound B to a mixed solvent of N,N-dimethylformamide and triethylamine.Mixing and dissolving to obtain a mixed solution; wherein, the mass ratio of the compound A to the compound B is 1.6; the mass ratio of the mixed solvent of N,N-dimethylformamide and triethylamine in the mixed solvent is 1:0.3, the mixed solution The solute mass fraction was 34%.Setp2, under a nitrogen atmosphere,Adding diisopropylamine lithium to the mixed solution for uniform mixing;The addition mass of lithium diisopropylamide is 1/3 of the sum of the masses of the compound A and the compound B.Setp3, nitrogen gas protection, stirring, adding a solution of diethyl sulfate in xylene; diethyl sulfate is added in a mass of 0.07% of the sum of the mass of compound A and compound B, and a solution of diethyl sulfate in xylene The mass percent concentration was 76%, and the drop rate of the solution of diethyl sulfate in xylene was 28 ml/min.Setp4, after the end of the dropwise addition, under nitrogen protection, the reaction was stirred at 33 C for 14 h;Setp5, the reaction product of the Setp4 is separated and purified to obtain the final product of aprepitant; the specific steps of separation and purification include:Setp51, extraction and recovery: Add the reaction solution produced by Setp4 to n-butanol, dichloromethane and water, the mass ratio of n-butanol to methylene chloride is 1:3; stir at 35 C for 60 min, then add saturation The organic layer obtained by the layering treatment of the brine is dried and dried by anhydrous magnesium sulfate;Setp52, dissolving: dissolving the crude aprepitant in an acetone solvent;Setp53, reflux decolorization: adding 1% diatomaceous earth of the crude quality of aprepitant, vacuum distillation, reflux decolorization for 20 min;Setp54, crystallization: the decolorizing solution is added to the acetone washing, and then the decolorizing solution recovered after the filtration treatment is subjected to crystallization treatment; the specific operation of the crystallization is as follows: first, the filtered decolorizing solution is heated to 55 C; secondly, under stirring, Water at a temperature of 20 C was added dropwise at a rate of 16 ml/min, and the stirring speed was 50 r/min. Finally, after the completion of the dropwise addition, the solution was cooled to 0 to 5 C for crystallization for 0.6 h.Setp55, filtration, washing: the crystallization liquid is filtered, and the mixture is washed with acetone and water at a mass ratio of 1:0.6, and the filter cake is washed to obtain aprepitant wet product;Setp56, drying: vacuum drying of aprepitant wet product to obtain aprepitant dry product, vacuum degree 0.05Mpa, drying temperature 40 C, drying time 12h, turning once every hour; finally crushed , screening, packaging to obtain finished products.Wherein the reaction of the compound A and the compound B is as shown in the formula (1):The yield of the final product obtained from aprepitant was 97.9%, the purity (HPLC) was 99.9%, and the maximum single impurity content was0.02%.
  • 49
  • [ 17176-77-1 ]
  • [ 170729-80-3 ]
  • [ 265121-01-5 ]
YieldReaction ConditionsOperation in experiment
92.4% With triethylamine; In tetrachloromethane; dichloromethane; at 0 - 10℃; Into a 500 mL reaction flask, 200 mL of dichloromethane and 20 g of <strong>[170729-80-3]aprepitant</strong> (I) were added, and the mixture was stirred until dissolved at 25 C. Then 9.8 g of dibenzyl phosphite and 11.5 g of carbon tetrachloride were added successively, the reaction was cooled to 0-5 C., 3.79 g of triethylamine was added dropwise, and the reaction was kept at 0-10 C. for 16-24 hours until TLC showed that the starting materials disappeared. Dilute hydrochloric acid was added to the reaction solution to adjust the pH to neutral, 100 mL of water was added thereto, followed by two times of extraction with 200 mL of dichloromethane for each time. The dichloromethane layers were combined and washed with 100 mL of 5% NaCl solution for two times, dried over anhydrous magnesium sulfate and then pulped with methyl tert-butyl ether to obtain 27.5 g of fos<strong>[170729-80-3]aprepitant</strong> phosphate intermediate (IV) in a yield of 92.4%. 1H NMR (400 MHz, CDC13): delta 1.15-1.25 (m, 2H), 1.45 (d, 3H), 2.48 (td, 1H), 2.75 (d, 1H), 2.86 (d, 2H), 3.2 (m, 1H), 3.46 (m, 2H), 3.64 (m, 1H), 4.19 (td, 1H), 4.30 (d, 1H), 4.87 (q, 1H), 5.22 (m, 4H), 7.07 (d, 2H), 7.12 (s, 2H), 7.28 (m, 4H), 7.34 (m, 4H), 7.63 (s, 1H), 9.44 (s, 1H).Mass:795.2 [M+H]+.
  • 50
  • [ 868-85-9 ]
  • [ 170729-80-3 ]
  • C25H26F7N4O6P [ No CAS ]
YieldReaction ConditionsOperation in experiment
90.6% With N-ethyl-N,N-diisopropylamine; In tert-butyl methyl ether; at 0 - 30℃; Into a 500 mL reaction flask, 100 mL of 3 methyl tert-butyl ether and 10 g of 4 <strong>[170729-80-3]aprepitant</strong> (I) were added, and the mixture was stirred until dissolved at 25 C. Then 3.1 g of 5 dimethyl phosphite and 18.6 g of 6 trichlorobromomethane were added successively, the reaction was cooled to 0-5 C., 3.6 g of 7 diisopropylethylamine was added dropwise, the temperature of the reaction was raised to 20-30 C. and the reaction was kept at the temperature for 16-24 hours until TLC showed that the starting materials disappeared. Dilute 8 hydrochloric acid was added to the reaction solution to adjust the pH to neutral, 50 mL of 9 water was added thereto, followed by two times of extraction with 100 mL of 10 dichloromethane for each time. The dichloromethane layers were combined and washed with 50 mL of 5% 11 NaCl solution for two times, dried over anhydrous magnesium sulfate and then pulped with methyl tert-butyl ether to obtain 10.9 g of 12 fos<strong>[170729-80-3]aprepitant</strong> phosphate intermediate (IV, wherein R1 and R2 are methyls) in a yield of 90.6%. 1H NMR (400 MHz, CDC13) delta 8.08 (s, 1H), 7.77 (q, J=1.8 Hz, 1H), 7.64 (t, J=2.1 Hz, 1H), 7.37 (dt, J=3.0, 1.5 Hz, 1H), 7.31 (ddd, J=7.1, 5.8, 1.1 Hz, 2H), 7.18-7.10 (m, 2H), 5.58 (d, J=7.0 Hz, 1H), 4.68 (qt, J=6.8, 1.0 Hz, 1H), 4.17-4.00 (m, 3H), 3.98 (dt, J=7.0, 1.0 Hz, 1H), 3.81 (d, J=12.5 Hz, 1H), 3.39 (d, J=10.8 Hz, 6H), 2.93 (ddd, J=12.5, 11.2, 3.5 Hz, 1H), 2.44 (dt, J=12.6, 1.8 Hz, 1H), 1.49 (d, J=6.9 Hz, 3H). Mass: 643.1 [M+H]+.
  • 51
  • [ 762-04-9 ]
  • [ 170729-80-3 ]
  • C27H30F7N4O6P [ No CAS ]
YieldReaction ConditionsOperation in experiment
90.4% With dmap; In chloroform; at 0 - 20℃; Into a 500 mL reaction flask, 133 mL of 14 chloroform and 13.3 g of 4 <strong>[170729-80-3]aprepitant</strong> (I) were added, and the mixture was stirred until dissolved at 25 C. Then 6.87 g of 15 diethyl phosphite and 98.0 g of 16 triiodomethane were added successively, and the reaction was cooled to 0-5 C., 6.1 g of 17 4-dimethylaminopyridine was added dropwise, the temperature of the reaction was raised to 10-20 C. and the reaction was kept at the temperature for 16-24 hours until TLC showed that starting materials disappeared. Dilute 8 hydrochloric acid was added to the reaction solution to adjust the pH to neutral, 130 mL of 9 water was added thereto, followed by two times of extraction with 270 mL of 10 dichloromethane for each time. The dichloromethane layers were combined and washed with 130 mL of 5% 11 NaCl solution for two times, dried over anhydrous magnesium sulfate and then pulped with methyl tert-butyl ether to obtain 15.1 g of 12 fos<strong>[170729-80-3]aprepitant</strong> phosphate intermediate (IV, wherein R1 and R2 are ethyls) in a yield of 90.4%. 1H NMR (400 MHz, CDC13)delta 8.13 (s, 1H), 7.77 (q, J=1.7 Hz, 1H), 7.64 (q, J=2.5, 2.0 Hz, 1H), 7.37 (t, J=1.8 Hz, 1H), 7.31 (ddd, J=7.0, 5.8, 1.1 Hz, 2H), 7.14 (dd, J=8.9, 7.5 Hz, 2H), 5.59 (d, J=6.9 Hz, 1H), 4.73-4.64 (m, 1H), 4.18-4.02 (m, 5H), 4.04-3.95 (m, 2H), 3.92-3.78 (m, 2H), 3.64 (dp, J=12.5, 8.1 Hz, 1H), 2.94 (ddd, J=12.5, 11.1, 3.5 Hz, 1H), 2.43 (dt, J=12.7, 1.9 Hz, 1H), 1.49 (d, J=6.9 Hz, 3H), 1.20 (t, J=8.0 Hz, 3H), 1.12 (t, J=7.9 Hz, 3H). Mass: 671.2 [M+H]+.
  • 52
  • [ 53148-24-6 ]
  • [ 170729-80-3 ]
  • C31H30F7N4O6P [ No CAS ]
YieldReaction ConditionsOperation in experiment
81.1% With triethylamine; In tetrachloromethane; dichloromethane; at 0 - 10℃; Into a 500 mL reaction flask, 200 mL of 10 dichloromethane and 20 g of 4 <strong>[170729-80-3]aprepitant</strong> (I) were added, and the mixture was stirred until dissolved at 25 C. Then 9.8 g of 28 benzyl-methyl phosphite and 15.0 g of 21 carbon tetrachloride were added successively, the reaction was cooled to 0-5 C., 3.8 g of 29 triethylamine was added dropwise, and the reaction was kept at 0-10 C. for 16-24 hours until TLC showed that starting materials disappeared. Dilute 8 hydrochloric acid was added to the reaction solution to adjust the pH to neutral, 100 mL of 9 water was added thereto, followed by two times of extraction with 200 mL of dichloromethane for each time. The dichloromethane layers were combined and washed with 100 mL of 5% 11 NaCl solution for two times, dried over anhydrous magnesium sulfate and then pulped with methyl tert-butyl ether to obtain 21.7 g of 12 fos<strong>[170729-80-3]aprepitant</strong> phosphate intermediate (IV, wherein R1 is benzyl and R2 is methyl) in a yield of 81.1%. 1H NMR (500 MHz, Chloroform-d) delta 8.01 (s, 1H), 7.77 (t, J=1.8 Hz, 1H), 7.65-7.61 (m, 1H), 7.50 (dq, J=1.9, 1.0 Hz, 1H), 7.47-7.41 (m, 2H), 7.41-7.29 (m, 5H), 7.26-7.18 (m, 2H), 5.51 (d, J=6.9 Hz, 1H), 5.03 (dd, J=8.5, 1.7 Hz, 2H), 4.73 (dd, J=6.9, 1.0 Hz, 1H), 3.95 (dd, J=15.9, 12.0 Hz, 2H), 3.73 (dt, J=6.9, 1.1 Hz, 1H), 3.66 (d, J=12.2 Hz, 1H), 3.39 (d, J=10.8 Hz, 3H), 1.52 (d, J=6.8 Hz, 3H). Mass: 719.2 [M+H]+.
  • 53
  • C23H21F7N4O4 [ No CAS ]
  • [ 170729-80-3 ]
YieldReaction ConditionsOperation in experiment
94% With triethylsilane; boron trifluoride diethyl etherate; In acetonitrile; at 0 - 35℃; for 5h; 100.00 g (0.138 mol) of the compound V prepared in the above steps, 32.18 g (0.279 mol) of triethylsilane and 800 mL of acetonitrile were added to the reaction flask, and the temperature was reduced to 0 C. after being stirred and dissolved. 39.28g (0.277mol) of boron trifluoride ether solution was added dropwise at 0 10 , and the temperature was kept at 25 35 for 5h. A large amount of solid was precipitated, filtered, the filter cake was washed with a small amount of acetonitrile, and dried to obtain 69.65 g of a crude aprepitant as a white solid with a yield of 94%, which was directly used in the next step.(5) Refining crude aprepitant;520.00 g of methanol was added to 65.00 g (0.122 mol) of the crude aprepitant prepared in the above steps, and the temperature was raised to 55 C, and the mixture was stirred until the material solution was dissolved. After the material solution was dissolved, the temperature was controlled at 50 to 60 C under stirring. 325.00 g of purified water was added dropwise to the feed solution, and a large amount of solids were precipitated. The temperature was lowered to 20 C, and the temperature was maintained at 15-25 C for 1 hour. The cake was dried and placed in a vacuum drying box at 50 C. for 7 hours to obtain 61.86 g of a white solid with a yield of 95%, HPLC purity ?99.50% and a total product yield of 68%.
  • 54
  • C17H16F6N4O4 [ No CAS ]
  • [ 170729-80-3 ]
  • 55
  • C14H13F6NO3 [ No CAS ]
  • [ 170729-80-3 ]
  • 56
  • [ 574-98-1 ]
  • [ 170729-80-3 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In N,N-dimethyl-formamide at 50℃; 3.1.1. General Procedure of Syntheses of Aprepitant Derivatives with Alkyl Linker, 2A-C General procedure: The slight molar excess of the selected n-(terminal-bromoalkyl) phthalimide was added into anequimolar mixture of APT and sodium carbonate in dimethylformamide (DMF). The reaction mixturewas vigorously stirred in about 50 C for 12-18 h. Then, the triple molar excess of hydrazine wasadded into the reaction mixture for an additional 3 h. The progress of the reaction was monitored byHPLC. The crude reaction mixture was evaporated, dissolved in the HPLC mobile phase, purified bythe HPLC method, and lyophilized. The isolated main product was identified as a mono-substitutedAPT-alkylamine derivative (2A-C, ~75% reaction yield) by MS analysis confirmation.
  • 57
  • [ 5460-29-7 ]
  • [ 170729-80-3 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In N,N-dimethyl-formamide at 50℃; 3.1.1. General Procedure of Syntheses of Aprepitant Derivatives with Alkyl Linker, 2A-C General procedure: The slight molar excess of the selected n-(terminal-bromoalkyl) phthalimide was added into anequimolar mixture of APT and sodium carbonate in dimethylformamide (DMF). The reaction mixturewas vigorously stirred in about 50 C for 12-18 h. Then, the triple molar excess of hydrazine wasadded into the reaction mixture for an additional 3 h. The progress of the reaction was monitored byHPLC. The crude reaction mixture was evaporated, dissolved in the HPLC mobile phase, purified bythe HPLC method, and lyophilized. The isolated main product was identified as a mono-substitutedAPT-alkylamine derivative (2A-C, ~75% reaction yield) by MS analysis confirmation.
  • 58
  • [ 5394-18-3 ]
  • [ 170729-80-3 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In N,N-dimethyl-formamide at 50℃; 3.1.1. General Procedure of Syntheses of Aprepitant Derivatives with Alkyl Linker, 2A-C General procedure: The slight molar excess of the selected n-(terminal-bromoalkyl) phthalimide was added into anequimolar mixture of APT and sodium carbonate in dimethylformamide (DMF). The reaction mixturewas vigorously stirred in about 50 C for 12-18 h. Then, the triple molar excess of hydrazine wasadded into the reaction mixture for an additional 3 h. The progress of the reaction was monitored byHPLC. The crude reaction mixture was evaporated, dissolved in the HPLC mobile phase, purified bythe HPLC method, and lyophilized. The isolated main product was identified as a mono-substitutedAPT-alkylamine derivative (2A-C, ~75% reaction yield) by MS analysis confirmation.
  • 59
  • [ 105-36-2 ]
  • [ 170729-80-3 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In N,N-dimethyl-formamide at 50℃; for 24h; 3.1.2. General Procedure of Syntheses of Aprepitant Derivatives with Acetamide Linker, 4D and 4E General procedure: The slight molar excess of ethyl 2-bromoacetate was added into an equimolar mixture of APTand sodium carbonate in DMF. The reaction mixture was vigorously stirred in about 50 °C for 24 h.Then, the triple molar excess of hydrazine or ethylenediamine was added into the reaction mixture foran additional 3 h. The progress of the reaction was monitored by HPLC. The crude reaction mixturewas evaporated, dissolved in the HPLC mobile phase, purified by the HPLC method, and lyophilized.The isolated main product was identied as a mono-substituted amino-terminated APT-acetamidederivative (4D and 4E, 65-70% reaction yield) by MS analysis confirmation.
  • 60
  • [ 24021-90-7 ]
  • [ 171338-27-5 ]
  • [ 170729-80-3 ]
YieldReaction ConditionsOperation in experiment
91.1% With 1,8-diazabicyclo[5.4.0]undec-7-ene In methanol; ethyl acetate; acetone for 2h; Reflux; 1-5; 5 Dissolve 43.74g of compound II, 5-hydroxymethyl-2,4-dihydro-[1,2,4]triazol-3-one 12.66g, and dissolve it in 175mL ethyl acetate-acetone-methanol (105mL+35mL+ 35mL) mixed solvent, add 3.04g of 1,8-diazabicyclo[5,4,0-7-undecene], heat to reflux, react for 2h, add anhydrous sodium sulfate, stir for 15min, filter, 40 Distill under reduced pressure, add 260 mL of purified water, stir and crystallize at room temperature, filter and dry to obtain 47.35 g of aprepitant with a yield of 88.6% and a purity of 99.9% as determined by HPLC.
  • 61
  • [ CAS Unavailable ]
  • [ 170729-80-3 ]
  • [ 2170124-05-5 ]
YieldReaction ConditionsOperation in experiment
81% With 4-Methoxybenzenethiol; lithium formate In dimethyl sulfoxide at 20℃; for 24h; Irradiation; Inert atmosphere; chemoselective reaction;
Same Skeleton Products
Historical Records

Pharmaceutical Intermediates of
[ 170729-80-3 ]

Fosaprepitant Related Intermediates

Chemical Structure| 405-50-5

[ 405-50-5 ]

2-(4-Fluorophenyl)acetic acid