Hydrochloric Acid → 1,1-Dimethylethyl N-[(1S)-2-[(1S,3S,5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-2-oxoethyl]carbamate

HRID 1431910Notes

Reaction equation

HRID 1431910 reaction equation
[CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@@H:8]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2)[C:9]([OH:11])=O)=[O:6])[CH3:3].[C@H:24]12[CH2:29][C@H:28]1[CH2:27][C@@H:26]([C:30]([NH2:32])=[O:31])[NH:25]2.CS(O)(=O)=O.Cl.ON1C2C=CC=CC=2N=N1>>[NH2:32][C:30]([C@@H:26]1[CH2:27][C@H:28]2[C@H:24]([CH2:29]2)[N:25]1[C:9](=[O:11])[C@H:8]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2)[NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:23])=[O:6])=[O:31]

Participants

6

Reactant 5

HCID 313Hydrochloric AcidHCID 6395Methanesulfonic AcidHCID 757711-HydroxybenzotriazoleHCID 11506821(1S,3S,5S)-2-Azabicyclo(3.1.0)hexane-3-carboxamideHCID 11723843(2S)-((tert-Butoxycarbonyl)amino)(3-hydroxytricyclo(3.3.1.1 3,7)dec-1-yl)acetic acid

Product 1

HCID 566049201,1-Dimethylethyl N-[(1S)-2-[(1S,3S,5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-2-oxoethyl]carbamate

Procedure

A coupling reaction is then used to couple (αS)-α[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, (Formula VI) to (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Formula J) methanesulfonic acid salt or HCl salt in the presence of 1-hydroxybenzotriazole (HOBT) or other known coupling agent to produce 3-(aminocarbonyl)-(αS)-α-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-β-oxo-(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid, 1,1-dimethylethyl ester (Formula K). Formula K compound is subjected to dehydration by treating compound K with organic base such as pyridine or triethylamine, and trifluoroacetic anhydride or other dehydrating agent such as phosphorus oxychloride (POCl3) or cyanuric chloride, and then subjecting the reaction to hydrolysis by cooling to from about 25 to about 40° C. and treating with sodium hydroxide or other strong base such as KOH or LiOH to form Compound L. 3-cyano-(αS)-α-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-β-oxo-(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid, 1,1-dimethylethyl ester (Formula L), which is then deprotected to form the dipeptidyl peptidase IV inhibitor (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile (Formula M).

Workup

  1. customA coupling reaction

Sources & evidence

ORD record
ord-544f7242cffb4414a16e9cfafad6f016
Source dataset
uspto-grants-2009_11
Patent number
US07611880B2

Reaction notes

Loading…