* 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.
Stage #1: With water; lithium hydroxide In tetrahydrofuran at 20℃; for 18 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water
General Procedure VI-ETo a solution of compound VI-IIB (1.63 g, 5.7 mmol) in THF (20 mL) and water (2 mL) was added LiOH (246 mg, 10.26 mmol). The mixture was stirred at r.t. for 18 hrs. The reaction mixture was acidified with aq.HCl (1 M), and extracted with EtOAc (50 mL.x.3), washed with water (30 mL.x.2) and brine (30 mL.x.2). The organic layer was dried over anhydrous Na2SO4, and concentrated in vacuo to a compound I-IIh (1.42 g, yield 90percent).
Reference:
[1] Patent: US2011/152246, 2011, A1, . Location in patent: Page/Page column 238
[2] Patent: CN106220617, 2016, A, . Location in patent: Paragraph 0081; 0084
[3] Patent: CN107235884, 2017, A, . Location in patent: Paragraph 0032; 0069; 0070; 0105; 0106; 0117; 0118
[4] Patent: CN107235965, 2017, A, . Location in patent: Paragraph 0080; 0081; 0116; 0117; 0128; 0129
Stage #1: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water for 0.0833333 h; Cooling with ice Stage #2: With benzotriazol-1-ol In water for 1 h; Cooling with ice Stage #3: With sodium hydroxide In water at 0 - 5℃;
100g MOC-L- valine in 2L three-necked reaction flask was added 600mL of water, with mechanical stirring. In an ice bath was added 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride 111.61g, stirred for 5 minutes, to the system was added 1-hydroxybenzotriazole 39.33g, in an ice bath with stirring for about 1h, the system has a viscous white precipitate, the white viscous material as reactive intermediates. L-proline 69.01g into a conical flask then dissolved with 120mL water, then transferred to a pressure-equalizing dropping funnel, weigh 28.7percent aqueous sodium hydroxide 192g on the other pressure-equalizing dropping funnel. The two solutions were simultaneously added dropwise to the above reaction system. Dropwise addition of about one hour. The temperature of the system was kept at 0-5 degrees. The reaction was continued until the active ester content was less than 0.5percent. After completion of the reaction, white floc precipitates appeared. After completion of the reaction it was added with 2.4N hydrochloric acid to adjust the pH to 1-2, large amount of solid precipitated was filtered. The filtrate was extracted three times with dichloromethane. The organic phase was concentrated to give the product MOC-L-valinyl-L-proline 150g, 96percent yield.
Reference:
[1] Patent: CN105753844, 2016, A, . Location in patent: Paragraph 0035; 0036; 0037; 0038; 0039
4
[ 147-85-3 ]
[ 181827-47-4 ]
Yield
Reaction Conditions
Operation in experiment
10.67 g
With N-ethyl-N,N-diisopropylamine In water; acetonitrile at 20℃;
To a mixture of L-proline (4.44g, 38.6 mmol), water (20 ml), acetonitrile (20 ml) and DIEA (9.5 g, 73.5 mmol) was added a solution of (S)-2,5-dioxopyrrolidin-l-yl 2- (methoxycarbonylamino)-3-methylbutanoate (lOg, 36.7 mmol) in acetonitrile (20 mL) over 10 minutes. The reaction mixture was stirred overnight at room temperature. The solution was concentrated under vacuum to remove the acetonitrile. To the resulting clear water solution was added 6N HC1 (9 ml) until pH ~ 2 .The solution was transferred to a separatory funnel and 25percent NaCl (10 ml) was added and the mixture was extracted with ethyl acetate (75 ml), and then again with ethyl acetate (6 x 20 ml), and the combined extracts were washed with 25percent NaCl (2 x 10ml). The solvent was evaporated to give a thick oil. Heptane was added and the solvent was evaporated to give a foam, which was dried under high vacuum. Diethyl ether was added and the solvent was evaporated to give a foam, which was dried under high vacuum to give (S)-l-((S)-2- (methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (10.67g) as a white solid.
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-methyl-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-Hydroxy-(4-methyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-isopropyl-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-Hydroxy-(4-isopropyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-isobutyl-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-Hydroxy-(4-isobutyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(3-methyl-butyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-Hydroxy-[4-(3-methyl-butyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-ethoxymethyl-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-(4-Ethoxymethyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-[(2S,1R)-2-amino-1-hydroxy-3-methylbutyl]-3-butyl-1,3,4-oxadiazolin-2-one p-toluenesulfonate[ No CAS ]
N-[(1S)-2-((2S)-2-{N-[(1S,2R)-2-(3-butyl-2-oxo-1,3,4-oxadiazolin-5-yl)-2-hydroxy-1-(methylethyl)ethyl]carbamoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]methoxycarboxamide[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(2-methoxy-ethyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-Hydroxy-[4-(2-methoxy-ethyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(2,2-dimethyl-propyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-[4-(2,2-Dimethyl-propyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-hydroxy-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-benzyl-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-(4-Benzyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-cyclopropylmethyl-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-(4-Cyclopropylmethyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-thiophen-2-ylmethyl-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-Hydroxy-(5-oxo-4-thiophen-2-ylmethyl-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-(2-amino-1-hydroxy-3-methyl-butyl)-3-<i>m</i>-tolyl-3<i>H</i>-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-Hydroxy-(5-oxo-4-m-tolyl-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-(2-amino-1-hydroxy-3-methyl-butyl)-3-<i>p</i>-tolyl-3<i>H</i>-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-Hydroxy-(5-oxo-4-p-tolyl-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(4-chloro-phenyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-[4-(4-Chloro-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-hydroxy-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(2-cyclopropyl-ethyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-[4-(2-Cyclopropyl-ethyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-hydroxy-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-cyclobutylmethyl-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-(4-Cyclobutylmethyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-(2-amino-1-hydroxy-3-methyl-butyl)-3-<i>o</i>-tolyl-3<i>H</i>-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-Hydroxy-(5-oxo-4-o-tolyl-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(4-fluoro-phenyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-[4-(4-Fluoro-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-hydroxy-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-phenethyl-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-Hydroxy-(5-oxo-4-phenethyl-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(4-methoxy-phenyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-Hydroxy-[4-(4-methoxy-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(2-methoxy-phenyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-Hydroxy-[4-(2-methoxy-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-cyclohexyl-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-(4-Cyclohexyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(2,4-dimethyl-phenyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-[4-(2,4-Dimethyl-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-hydroxy-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(4-fluoro-benzyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-[4-(4-Fluoro-benzyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-hydroxy-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
4-[5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-2-oxo-[1,3,4]oxadiazol-3-yl]-benzonitrile; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-[4-(4-Cyano-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-hydroxy-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(4-ethoxy-phenyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-[4-(4-Ethoxy-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-hydroxy-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(4-fluoro-2-methyl-phenyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-[4-(4-Fluoro-2-methyl-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-hydroxy-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(2,4-dimethoxy-phenyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-[4-(2,4-Dimethoxy-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-hydroxy-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-cyclohexylmethyl-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-(4-Cyclohexylmethyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(2,4-difluoro-phenyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-[4-(2,4-Difluoro-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-hydroxy-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(4-fluoro-2-methoxy-phenyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-[4-(4-Fluoro-2-methoxy-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-hydroxy-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(4-trifluoromethyl-phenyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-Hydroxy-[5-oxo-4-(4-trifluoromethyl-phenyl)-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(2-trifluoromethyl-phenyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-Hydroxy-[5-oxo-4-(2-trifluoromethyl-phenyl)-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(4-trifluoromethoxy-phenyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-Hydroxy-[5-oxo-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-benzo[1,3]dioxol-5-ylmethyl-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[(R)-(4-Benzo[1,3]dioxol-5-ylmethyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
5-((1R,2S)-2-Amino-1-hydroxy-3-methyl-butyl)-3-(4-benzyloxy-phenyl)-3H-[1,3,4]oxadiazol-2-one; compound with toluene-4-sulfonic acid[ No CAS ]
{(S)-1-[(S)-2-((S)-1-{(R)-[4-(4-Benzyloxy-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl]-hydroxy-methyl}-2-methyl-propylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester[ No CAS ]
((S)-2-Methyl-1-{(S)-2-[(S)-2-methyl-1-(4-methyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-propylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester[ No CAS ]
((S)-1-{(S)-2-[(S)-1-(4-Isopropyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-2-methyl-propylcarbamoyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester[ No CAS ]
((S)-1-{(S)-2-[(S)-1-(4-Isobutyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-2-methyl-propylcarbamoyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester[ No CAS ]
((S)-1-{(S)-2-[(S)-1-(4-Ethoxymethyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-2-methyl-propylcarbamoyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(2-Methoxy-ethyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(2,2-Dimethyl-propyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-2-Methyl-1-((S)-2-{(S)-2-methyl-1-[4-(3-methyl-butyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-propylcarbamoyl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester[ No CAS ]
((S)-2-Methyl-1-{(S)-2-[(S)-2-methyl-1-(5-oxo-4-phenyl-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-propylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester[ No CAS ]
((S)-1-{(S)-2-[(S)-1-(4-Butyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-2-methyl-propylcarbamoyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester[ No CAS ]
((S)-1-{(S)-2-[(S)-1-(4-Cyclopropylmethyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-2-methyl-propylcarbamoyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester[ No CAS ]
((S)-2-Methyl-1-{(S)-2-[(S)-2-methyl-1-(5-oxo-4-thiophen-2-ylmethyl-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-propylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester[ No CAS ]
((S)-2-Methyl-1-{(S)-2-[(S)-2-methyl-1-(5-oxo-4-thiophen-3-ylmethyl-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-propylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester[ No CAS ]
((S)-2-Methyl-1-{(S)-2-[(S)-2-methyl-1-(5-oxo-4-m-tolyl-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-propylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester[ No CAS ]
((S)-2-Methyl-1-{(S)-2-[(S)-2-methyl-1-(5-oxo-4-o-tolyl-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-propylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester[ No CAS ]
((S)-1-{(S)-2-[(S)-1-(4-Benzyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-2-methyl-propylcarbamoyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester[ No CAS ]
((S)-2-Methyl-1-{(S)-2-[(S)-2-methyl-1-(5-oxo-4-p-tolyl-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-propylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(4-Methoxy-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
((S)-2-Methyl-1-{(S)-2-[(S)-2-methyl-1-(5-oxo-4-phenethyl-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-propylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(2-Cyclopropyl-ethyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(4-Fluoro-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(2-Methoxy-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
((S)-1-{(S)-2-[(S)-1-(4-Cyclobutylmethyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-2-methyl-propylcarbamoyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(4-Hydroxy-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(4-Chloro-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(2,4-Dimethyl-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(4-Fluoro-benzyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(4-Cyano-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
((S)-1-{(S)-2-[(S)-1-(4-Cyclohexyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-2-methyl-propylcarbamoyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(4-Ethoxy-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(4-Fluoro-2-methoxy-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(2,4-Dimethoxy-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(4-Fluoro-2-methyl-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(2,4-Difluoro-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-1-((S)-2-{(S)-1-[4-(4-Methoxy-2-methyl-phenyl)-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-2-Methyl-1-((S)-2-{(S)-2-methyl-1-[5-oxo-4-(2-trifluoromethyl-phenyl)-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-propylcarbamoyl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester[ No CAS ]
[(S)-2-Methyl-1-((S)-2-{(S)-2-methyl-1-[5-oxo-4-(4-trifluoromethyl-phenyl)-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-propylcarbamoyl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester[ No CAS ]
((S)-1-{(S)-2-[(S)-1-(4-Cyclohexylmethyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-2-methyl-propylcarbamoyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester[ No CAS ]
[(S)-2-Methyl-1-((S)-2-{(S)-2-methyl-1-[5-oxo-4-(4-trifluoromethoxy-phenyl)-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl]-propylcarbamoyl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester[ No CAS ]
((S)-1-{(S)-2-[(S)-1-(4-Benzo[1,3]dioxol-5-ylmethyl-5-oxo-4,5-dihydro-[1,3,4]oxadiazole-2-carbonyl)-2-methyl-propylcarbamoyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester[ No CAS ]
(2S)-2-((((2S)-2-(((1,1-dimethylethyl)oxy)carbonyl)-1-pyrrolidinyl)carbonyl)amino)-3-methylbutanoic acid[ No CAS ]
[ 144-55-8 ]
[ 181827-47-4 ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; water; ethyl acetate; toluene;
(iii) To a solution of N-[methoxycarbonyl]-L-valyl-L-proline tert-butyl ester (813 g) in toluene (3 litres) was added Amberlyst-15 ion exchange resin (190 g). The reaction was heated at 120 C. to distill off water present in the resin via a water/toluene azeotrope. Approximately 400 ml of distillate was collected. Heating was then continued at reflux for 1.5 hours. The reaction was cooled to 0 C. and the resin was removed by filtration. The filtrate was extracted with 1M NaOH (2.5 litres) followed by saturated aqueous sodium bicarbonate solution. The combined basic extracts were extracted with a mixture of THF/ethyl acetate (1:1, 1 litre), and then cooled in an ice bath. The aqueous solution was made acidic to pH 1.5 using cold 3M hydrocloric acid (1 litre) and extracted twice with THF/ethyl acetate (1:1, 1.5 litres and 1 litre). The extracts were combined and washed with brine, dried (MgSO4), and the solvent removed by evaporation. The resulting material was dissolved in ether (1 litre) and allowed to crystallize at 0 C. over 48 hours. The resulting solid was collected by filtration, washed with cold ether and dried under vacuum to give N-[methoxycarbonyl]-L-valyl-L-proline (373 g); 1 H NMR (300 MHz, DMSO) 12.4 (s, 1H), 7.37 (d, 1H), 4.25 (dd, 1H), 4.00 (t, 1H), 3.79 (m, 1H), 3.55 (m, 1H), 3.51 (s, 3H), 2.11 (m, 1H), 1.85 (m, 4H), 0.91 (d, 3H), 0.87 (d, 3H); MS m/z=273 (M+1).
(2R,3S)-3-amino-4-methyl-1,1,1-trifluoro-2-pentanol hemioxalate salt[ No CAS ]
[ 181827-47-4 ]
[ 543-27-1 ]
(S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[(S)-2-methyl-1-(S)-(2,2,2-trifluoro-1-hydroxyethyl)propyl]-pyrrolidine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 4-methyl-morpholine; In tetrahydrofuran;
(iv) N-Hethylmorpholine (8.5 ml) was added to a solution of <strong>[181827-47-4]N-(methoxycarbonyl)-L-valyl-L-proline</strong> (12.5 g) in THF (150 ml) and the solution was cooled to -15 C. in an ice/acetone bath. Isobutyl chloroformate (6.6 ml) was added dropwise and the mixture was stirred for 1 hour. A second portion of N-methylmorpholine (8.5 ml) was added, followed by (2R,3S)-3-amino-4-methyl-1,1,1-trifluoro-2-pentanol hemioxalate salt (10 g). The reaction mixture was then allowed to stir for 12 hours while allowing to warm to ambient temperature. The reaction mixture was diluted with ether (500 ml) and washed successively with saturated aqueous sodium bicarbonate solution, 1M HCl and brine. The aqueous layers were extracted with ether and all organic phases were combined and dried (MgSO4). The solution was filtered and the solvent removed by evaporation. The resulting material was filtered through silica gel using ether as the eluant. The ether fractions containing the product were combined and the solvent removed by evaporation. The product was dried under vacuum to give (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[(S)-2-methyl-1-(S)-(2,2,2-trifluoro-1-hydroxyethyl)propyl]-pyrrolidine-2-carboxamide (16.1 g); 1 H NMR (300 MHz, DMSO): 7.61 (d, 1H), 7.28 (d, 1H), 6.44 (d, 1H),4.44 (m, 1H), -4.05 (m, 1H), 3.98 (m, 1H), 3.75 (m, 2H), 3.55 (m, 1H), 3.50 (s, 3H), 1.83 (m, 6H), 0.90 (d, 3H), 0.86 (d, 3H); MS: m/z=426.
With palladium on carbon; hydrogen; In ethanol; under 760.051 Torr; for 3h;
General procedure: A mixture of compound 2a (2 mmol) and Pd/C (20 w%) in ethanol (30 mL) was hydrogenated for 3 hrs at atmospheric pressure.The reaction mixture was filtered off and concentrated in vacuo. The crude was taken in toluene and concentrated again,and then in Et2O/petroleum ether and concentrated once more to give compound 3a as a glassy solid in 62% yield overtwo steps. MS (ESI, EI-) m/z = 347 (MH-).
84
[ 4072-67-7 ]
[ 181827-47-4 ]
C28H31BrN2O7[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37.3%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 1.75h;Inert atmosphere;
Intermediate 70 1 ,1 '-(4,4'-biphenyldiyl)bis(2-bromoethanone) (37.8g, 95 mmol) was dissolved in DMF (800ml_) and degassed for 15 min (N2). Intermediate 61 (21.99 g, 81 mmol) was dissolved in DMF (100ml_), followed by careful addition of NaH (2.94 g, 73.4 mmol, 60% in oil) under nitrogen over 15 min. The solution was stirred under N2 for 15 min, then slowly added over 15 min drop-wise to a solution of 1 , 1 '-(4,4'- biphenyldiyl)bis(2-bromoethanone), followed by stirring for 1 h at RT. Solvent volume was then reduced in vacuo to ~100ml_ and cooled to 20C. 100ml_ of water was slowly added and resulting slight grey-yellow solid was filtered and washed with water (200ml_), hexane (200ml_) and dried under the vacuum (12h). The crude compound was purified on 500g of silica with hexane/ethyl acetate (increasing gradient from 50% to 100% EA), yielding 14.5g (37.3%) of Intermediate 70, 1H NMR (400 MHz, DMSO-c/6) delta ppm 8.1 1 (dd, J=12.0, 8.5 Hz, 4 H) 7.96 (d, J=8.4 Hz, 4 H) 7.41 (d, J=8.4 Hz, 1 H) 5.43 - 5.75 (m, 2 H) 4.99 (s, 2 H) 4.53 (dd, J=8.6, 4.7 Hz, 1 H) 4.03 (t, J=8.6 Hz, 1 H) 3.76 - 3.90 (m, 1 H) 3.60 - 3.73 (m, 1 H) 3.53 (s, 3 H) 2.22 - 2.37 (m, 1 H) 2.12 - 2.21 (m, 1 H) 1.85 - 2.06 (m, 3 H) 0.90 (dd, J=10.7, 6.6 Hz, 6 H).
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 4h;
General Procedure VII-BTo a solution of compound 4-aminophenylboronic acid (VII-IC) (101 mg, 0.74 mmol) in anhydrous dichloromethane (5 mL) was added compound VI-IC (200 mg, 0.74 mmol), HATU (421 mg, 1.11 mmol) and DIEA (320 mg, 2.5 mmol). The mixture was stirred at r.t. for 4 hrs. After completion of the reaction, the mixture was extracted with EtOAc (100 mL×2), and water (20 mL×2). The organic layer was dried over anhydrous Na2SO4, and concentrated. The residue was purified by prep-TLC (MeOH/EA=10:1) to give compound VII-ID (240 mg, yield 83%). MS (ESI) m/z (M+H)+ 392.
With N-ethyl-N,N-diisopropylamine; HATU; at 20℃; for 1h;
General ProcedureTo a solution of compound I-IIh (0.27 g, 1 mmol), HATU (0.38 g, 1 mmol) and DIEA (0.5 mL) was added 2-(4-aminophenyl)benzo[d]thiazol-6-amine (VIII-IIId) (72 mg, 0.3 mmol). The mixture was stirred at r.t. for 1 h. The mixture was washed with aqueous K2CO3 (2 mL). The organic layer was separated and concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford compound 403 (190 mg, yield 84.8%). MS (ESI) m/z (M+H)+ 750.3.