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With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 30℃; Inert atmosphere
COMPARATIVE EXAMPLE 2: Preparation of compound of Formula VII A mixture of 70percent trifluoro acetic acid/methylene chloride (150 ml) was allowed to cool to 0°C. To the reaction mass compound of Formula IV (25g, leq) was added at same temperature. Then the reaction mass was heated to 25-30°C and stirred for 2 hr at same temperature. After completion of reaction, distilled the reaction mass completely under vacuum and the obtained trifluoroacetic acid salt of Formula V was dissolved in acetonitrile (550 ml). To the reaction mass N-boc-homo phenyl alanine (25g, leq) and diisopropyl ethyl amine (27.5g, 4eq) were added at 25-30°C. Reaction mass was allowed to cool to 0°C and HOBt (11.5g, 1.6eq), PyBOP (44.4g, 1.6eq) were added in lot wise over 5 min at same temperature and stirred for overnight under nitrogen at 25-30°C. Then the reaction mass was allowed to cool to 0°C and the solid obtained was filtered, washed with chilled acetonitrile to get the title compound. Yield: 24.8 g; Chemical purity by HPLC: 89.35percent; HOBt: 9.9percent, PyBOP: 0.02percent and tris(pyrrolidino phosphine) oxide: 0.24percent by HPLC.
Stage #1: With trifluoroacetic acid In dichloromethane at 2 - 30℃; for 2 h; Stage #2: With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 2 - 30℃;
EXAMPLE 2: Preparation of compound of Formula VII A mixture of methylene chloride (90 ml) and trifluoro acetic acid (210 ml) was allowed to cool to 2-6°C and compound of Formula IV (100 g, leq) was added at same temperature. Then the reaction mass was heated to 25-30°C and stirred for 2 hr at same temperature. To the reaction mass methylene chloride (1.51it) was added and pH adjusted to 7-8 with 20percent sodium carbonate at 25-30°C and stirred for 20 min at same temperature. Separated the organic layer and washed with water (300ml) and 10percent sodium chloride (300 ml) sequentially. Organic layer was separated and concentrated under vacuum at below 35°C to obtain residue. The obtained residue was dissolved in dimethyl formamide (500 ml) and allowed to cool to 2-6°C. To the reaction mass HOBt (2.9g, O.leq), PyBOP (133.5g, 1.2eq), N-boc-homo phenyl alanine (59.7g, leq) were added slowly at 2-6°C. To the reaction mass HOBt (2.9g, O.leq), PyBOP (133.5g, 1.2eq), N-boc-homo phenyl alanine (59.7g, leq) and diisopropyl ethyl amine (110.5g, 4eq) were added slowly at 2-6°C. Then the reaction mass was heated to 25-30°C and stirred for 2-3 hr at same temperature. After completion of the reaction, reaction mass was quenched in to water (51it) at 25-30°C and stirred for 2-3 hr at same temperature and the precipitated solid was filtered, washed with water (500 ml) and dried to get the title compound. Yield: 130g; PXRD: Fig. 2; DSC: endothermic peak at about 150°C; Chemical purity by HPLC: 99.97percent; HOBt: 0.1percent, PyBOP: Not detected and tris(pyrrolidino phosphine) oxide: 0.02percent by HPLC.
Compound (V) (0.25 g, 0.39 mmol) was mixed with 12 mL of TFA/DCM (80%) and was stirred at room temperature for 1 hr at which time the mixture was concentrated and placed under high vacuum for 2 hr giving the TFA salt of the tri-peptide amine. The crude amine salt was dissolved in 6 mL DMF and 2-morpholino acetic acid (0.074 g, 0.507 mmol) was added followed by DIEA (0.504 g, 0.68 mL, 3.90 mmol). The mixture was cooled to 0 C. in an ice bath and PyBOP (0.32 g, 0.62 mmol) was added and stirred under an atmosphere of argon while warming to room temperature overnight. The mixture was diluted with brine (50 mL) and extracted with EtOAc (5×20 mL). The organic layers were combined, washed with sat. NaHCO3 (5×15 mL) and brine (1×25 mL) and dried over MgSO4. The MgSO4 was removed by filtration and the volatiles removed under reduced pressure to give the intermediate ester (0.195 g). To (0.150g, 0.23 mmol) of the intermediate ester was added 10% Pd/C (0.05g) followed by 5 mL of 1:1 mixture of MeOH and EtOAc and the mixture was placed under an atmosphere of hydrogen. After 2 hr, the contents were filtered through a plug of Celite and concentrated under vacuum to give (W) (0.12 g).
In dichloromethane; at 20℃; for 1.0h;
Compound (Y) (0.023 mol, 14.5 g) was mixed with TFA/DCM (80%) and stirred at room temperature for 1 hr at which time the mixture was concentrated and placed under high vacuum for 2 hr giving the TFA salt of the tri-peptide amine. To a solution of the TFA salt (0.023 mol, 1 eq.) in MeCN (120 mL) was added 4-chlorobutyryl chloride (1.2 eq., 0.028 mol, 0.32 mL) and DIEA (4 eq., 0.092 mol, 16 mL). The mixture was stirred at room temperature for 2 hr and then concentrated and purified by flash chromatography to afford (Z) (8 g).
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃;
To a 0 C. cooled solution of 70% TFA/DCM (150 mL) was added (X) (25.0 g, 53.35 mmol, 1.0 eq.). The solution was stirred and allowed to warm to room temperature over 2 hr at which time the mixture was concentrated and placed under high vacuum for 2 hr giving the TFA salt of the di-peptide amine. To the resulting oil was added BocNHhPhe (14.68 g, 53.35 mmol, 1.0 eq.), 550 mL of MeCN, and DIEA (27.58 g, 37.2 mL, 213.4 mmol, 4.0 eq.) and the mixture was cooled to 0 C. in an ice bath. To the cooled mixture was added HOBT (11.53 g, 85.36 mmol, 1.6 eq.) followed by PyBOP (44.42 g, 85.36 mmol, 1.6 eq.) which was added in several portions over five minutes. The reaction was placed under argon and allowed to warm to room temperature overnight at which time a white precipitate had formed. The reaction mixture was cooled and the solids were collected by filtration and then washed with cold MeCN to give (Y) (24.86 g).
With hydrogen;5%-palladium/activated carbon; In methanol; ethyl acetate; at 20℃; for 2.0h;
Compound (Y) (1.55 g, 0.0023 mol) was dissolved in MeOH/EtOAc (1:1, 40 mL) and Pd-C (5%, 500 mg) was added. The mixture was stirred at room temperature under hydrogen for 2 hr, and then filtered through Celite and concentrated to get the carboxylic acid intermediate. To a stirred solution of (F) [see: Bioorg. Med. Chem. Letter 1999, 9, 2283-88] (1.2 eq., 2.55 mmol, 436 mg) in DMF (50 mL) was added the carboxylic acid intermediate (1 eq., 2.12 mmol, 1.24 g), DIEA (4 eq., 8.48 mmol, 1.5 mL) and HOBT (1.6 eq., 3.39 mmol, 458 mg). The mixture was cooled to 0 C. in an ice bath and PyBOP (1.6 eq., 3.39 mmol, 1.76 g) was added in several portions. The mixture was stirred at 5 C. under an atmosphere of nitrogen overnight. The reaction was diluted with sat. NaCl and extracted with EtOAc. The organic layer was washed with water and brine and dried over anhydrous MgSO4 and concentrated to an oil that was purified by flash chromatography to afford (CC) (356 mg).
24 g
With palladium 10% on activated carbon; hydrogen; In methanol; dichloromethane; at 25 - 30℃; for 36.0h;Autoclave;
EXAMPLE 3: Preparation of compound of Formula VIII A mixture of methanol (150 ml), methylene chloride (150 ml), compound of Formula VII (30 g) and 10% Pd/C (6g) were charged in to 2 lit auto clave at 25-35C and purged hydrogen gas at 25-30C for a period of 36 hr. After completion of the reaction, filtered the reaction mass and filterate was distilled under vacuum at below 40C. To the obtained compound n-heptane (120 ml) was added at 25-35C and stirred for 1-2 hr at same temperature. The solid obtained was filtered and dissolved in ethyl acetate (120 ml) at 25- 35C. The obtained solution was added in to n-heptane (450 ml) at 25-35C and stirred for 2 hr at same temperature. Precipitated solid was filtered, washed with n-heptane (90 ml) and dried to get the title compound. Yield: 24g; PXRD: Fig. 3; DSC: endothermic peak at about 64C; Chemical purity by HPLC: 97.2%.
(2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran2-yl)-1-oxopentan-2-yl-carbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide maleate salt[ No CAS ]
(S)-2-((S)-2-amino-4-phenylbutanamido)-4-methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)pentanamide[ No CAS ]
EXAMPLE 6: Preparation of compound of Formula XIV A mixture of methylene chloride (60 ml) and trifluoro acetic acid (240 ml) was allowed to cool to 2-6C. To the reaction mass compound of Formula VII (lOOg, leq) was added at same temperature. Then the reaction mass was heated to 25-30C and stirred for 2 hr at same temperature. To the reaction mass methylene chloride (1.51it) was added and pH adjusted to 7-8 with 20% sodium carbonate at 25-30C and stirred for 20 min at same temperature. Separated the organic layer and washed with water (300 ml) and 10% sodium chloride (300 ml) sequentially. Organic layer was separated and concentrated under vacuum at 25-35C to obtain residue. The obtained residue was dissolved in dimethyl formamide (500 ml) and allowed to cool to 2-6C. To the reaction mass HOBt (2.2g, O. leq), PyBOP (99.2g, 1.2eq), morpholine acetic acid (29.5g, 1.2eq) and diisopropyl ethyl amine (82. lg, 4eq) were slowly added sequentially at 2-6C. Then the reaction mass was heated to 25-30C and stirred for 2-3 hr at same temperature. After completion of the reaction, reaction mass was quenched in to water (51it) at 25-30C and stirred for 2 hr at same temperature and the solid precipitated was filtered, washed with water (500 ml) and dried to get the title compound. Yield: 94 g; Chemical purity by HPLC: 97.6%; HOBt: 0.35%, PyBOP: 0.01% and tris(pyrrolidino phosphine) oxide: 0.04% by HPLC.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 30℃;Inert atmosphere;
COMPARATIVE EXAMPLE 2: Preparation of compound of Formula VII A mixture of 70% trifluoro acetic acid/methylene chloride (150 ml) was allowed to cool to 0C. To the reaction mass compound of Formula IV (25g, leq) was added at same temperature. Then the reaction mass was heated to 25-30C and stirred for 2 hr at same temperature. After completion of reaction, distilled the reaction mass completely under vacuum and the obtained trifluoroacetic acid salt of Formula V was dissolved in acetonitrile (550 ml). To the reaction mass N-boc-homo phenyl alanine (25g, leq) and diisopropyl ethyl amine (27.5g, 4eq) were added at 25-30C. Reaction mass was allowed to cool to 0C and HOBt (11.5g, 1.6eq), PyBOP (44.4g, 1.6eq) were added in lot wise over 5 min at same temperature and stirred for overnight under nitrogen at 25-30C. Then the reaction mass was allowed to cool to 0C and the solid obtained was filtered, washed with chilled acetonitrile to get the title compound. Yield: 24.8 g; Chemical purity by HPLC: 89.35%; HOBt: 9.9%, PyBOP: 0.02% and tris(pyrrolidino phosphine) oxide: 0.24% by HPLC.
EXAMPLE 2: Preparation of compound of Formula VII A mixture of methylene chloride (90 ml) and trifluoro acetic acid (210 ml) was allowed to cool to 2-6C and compound of Formula IV (100 g, leq) was added at same temperature. Then the reaction mass was heated to 25-30C and stirred for 2 hr at same temperature. To the reaction mass methylene chloride (1.51it) was added and pH adjusted to 7-8 with 20% sodium carbonate at 25-30C and stirred for 20 min at same temperature. Separated the organic layer and washed with water (300ml) and 10% sodium chloride (300 ml) sequentially. Organic layer was separated and concentrated under vacuum at below 35C to obtain residue. The obtained residue was dissolved in dimethyl formamide (500 ml) and allowed to cool to 2-6C. To the reaction mass HOBt (2.9g, O.leq), PyBOP (133.5g, 1.2eq), N-boc-homo phenyl alanine (59.7g, leq) were added slowly at 2-6C. To the reaction mass HOBt (2.9g, O.leq), PyBOP (133.5g, 1.2eq), N-boc-homo phenyl alanine (59.7g, leq) and diisopropyl ethyl amine (110.5g, 4eq) were added slowly at 2-6C. Then the reaction mass was heated to 25-30C and stirred for 2-3 hr at same temperature. After completion of the reaction, reaction mass was quenched in to water (51it) at 25-30C and stirred for 2-3 hr at same temperature and the precipitated solid was filtered, washed with water (500 ml) and dried to get the title compound. Yield: 130g; PXRD: Fig. 2; DSC: endothermic peak at about 150C; Chemical purity by HPLC: 99.97%; HOBt: 0.1%, PyBOP: Not detected and tris(pyrrolidino phosphine) oxide: 0.02% by HPLC.
(S)-N-((S)-1-((S)-1-((S)-2-((tert-butyldiphenylsilyloxy)methyl)oxiran-2-yl)-4-methyl-1-oxopentan-2-ylamino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide[ No CAS ]
(S)-N-((S)-1-((S)-1-((S)-2-(methoxymethyl)oxiran-2-yl)-4-methyl-1-oxopentan-2-ylamino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide[ No CAS ]
(S)-N-((S)-1-((S)-1-((R)-2-(hydroxymethyl)oxiran-2-yl)-4-methyl-1-oxopentan-2-ylamino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide[ No CAS ]
(S)-N-((S)-1-((S)-1-((S)-2-((methoxymethoxy)methyl)oxiran-2-yl)-4-methyl-1-oxopentan-2-ylamino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide[ No CAS ]
(S)-N-((S)-1-((S)-1-((S)-2-(((2-methoxyethoxy)methoxy)methyl)-oxiran-2-yl)-4-methyl-1-oxopentan-2-ylamino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide[ No CAS ]
((S)-2-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-1-morpholino-2,5,8,11-tetraoxo-4-phenethyl-3,6,9,12-tetraazahexadecanecarbonyl)oxiran-2-yl)methylmethanesulfonate[ No CAS ]
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