Methods and compounds for producing dipeptidyl peptidase iv inhibitors and intermediates thereof

Abstract

Methods and compounds for production of cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV are provided.

1 . A compound of Formula IV 
       
         
           
           
               
               
           
         
       
     
     
         2 . A method for preparing (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-tricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo-[3.1.0]hexane-3-carbonitrile comprising:
 (a) treating (S)-α[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.1 3,7 ]decane-1-acetic acid (Formula VI) or its 1,4-diazabicyclo[2.2.2]octane salt with (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide to provide (1S,3S,5S)-2-[(2S)-2-(1,1-dimethylethoxycarbonyl)amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonylamine (Formula K);   (b) dehydrating (1S,3S,5S)-2-[(2S)-2-(1,1-dimethylethoxycarbonyl)amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonylamine to provide (1S,3S,5S)-2-[(2S)-2-(1,1-dimethylethoxycarbonyl)amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile (Formula L); and   (c) deprotecting (1S,3S,5S)-2-[(2S)-2-(1,1-dimethylethoxycarbonyl)amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile to provide (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-tricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo-[3.1.0]hexane-3-carbonitrile.   
     
     
         3 . The method according to  claim 2  further comprising treating (S)-α-amino-3-hydroxytricyclo[3.3.1.1 3,7 ]decane-1-acetic acid with Boc anhydride to provide (S)-α[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.1 3,7 ]decane-1-acetic acid (Formula VI). 
     
     
         4 . The method according to  claim 3  further comprising treating 3-hydroxy-α-oxotricyclo[3.3.1.1 3,7 ]decane-1-acetic acid to asymmetric reductive amination or transamination to provide (S)-α-amino-3-hydroxytricyclo[3.3.1.1 3,7 ]decane-1-acetic acid. 
     
     
         5 . The method according to  claim 2  further comprising
 (a) brominating tricyclo[3.3.1.1 3,7 ]decane-1-acetic acid to provide α-bromotricyclo[3.3.1.1 3,7 ]decane-1-acetic acid; 
 (b) treating α-bromotricyclo[3.3.1.1 3,7 ]decane-1-acetic acid with H 2 SO 4  and HNO 3  to provide α-bromo-3-hydroxytricyclo[3.3.1.1 3,7 ]decane-1-acetic acid; 
 (c) treating α-bromo-3-hydroxytricyclo[3.3.1.1 3,7 ]decane-1-acetic acid with ammonium hydroxide and heat to provide α-amino-3-hydroxytricyclo[3.3.1.1 3,7 ]decane-1-acetic acid; 
 (d) treating α-amino-3-hydroxytricyclo[3.3.1.1 3,7 ]decane-1-acetic acid with Boc anhydride and sodium hydroxide to provide α-[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.1 3,7 ]decane-1-acetic acid; 
 (e) treating α-[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.1 3,7 ]decane-1-acetic acid with a chiral base such as [1R,2S]-(−)-1,2-diphenylhydroxy ethylamine, 1,7,7-trimethylbicyclo[2.2.1]heptane-2-amine, or S-(−)-1-1(1-naphthyl)ethylamine; and 
 (f) isolating (S)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.1 3,7 ]decane-1-acetic acid from step (e). 
 
     
     
         6 . The method according to  claim 2  further comprising deprotecting (1S,3S,5S)-3-aminocarbonyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester to provide (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide. 
     
     
         7 . The method according to  claim 6  further comprising treating (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid, 1,1-dimethylethyl ester to Simmons-Smith conditions to provide (1S,3S,5S)-3-aminocarbonyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester. 
     
     
         8 . The method according to  claim 7  further comprising
 (a) treating (S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester with aqueous lithium hydroxide to provide N-Boc dehydroproline; and 
 (b) treating N-Boc dehydroproline with mesyl chloride, diisopropylethylamine, and ammonia to provide (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid, 1,1-dimethylethyl ester. 
 
     
     
         9 . A cell line capable of producing (S)-α-amino-3-hydroxytricyclo[3.3.1.1 3,7 ]decane-1-acetic acid by asymmetric reductive amination or transamination of 3-hydroxy-α-oxotricyclo[3.3.1.1 3,7 ]decane-1-acetic acid (Formula II). 
     
     
         10 . A method for preparing 3-hydroxy-α-oxotricyclo[3.3.1.1 3,7 ]decane-1-acetic acid, which comprises
 (a) treating dichloro-(3-hydroxy-adamantan-1-yl)-acetic acid alkyl ester with an alkali metal base in the presence of an organic solvent to provide the sodium salt of 3-hydroxy-α-oxotricyclo[3.3.1.1 3,7 ]decane-1-acetic acid; and 
 (b) treating (a) with an acid to provide 3-hydroxy-α-oxotricyclo[3.3.1.1 3,7 ]decane-1-acetic acid. 
 
     
     
         11 . The method according to  claim 10  wherein the steps (a) and (b) are carried out in a single pot procedure. 
     
     
         12 . The method according to  claim 11  wherein the alkali metal base is sodium hydroxide and the acid is hydrochloric acid. 
     
     
         13 . A method for preparing (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid, 1-(1,1-dimethylethyl)ester which comprises treating a solution of an alkali metal salt of (S) 4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)ester with 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride and a base at a pH below 7 to provide (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid, 1-(1,1-dimethylethyl) ester. 
     
     
         14 . The method according to  claim 13  wherein the base is ammonia. 
     
     
         15 . The method according to  claim 13  further comprising treating the dicyclohexylamine salt of (S) 4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)ester with an alkali metal base to provide the alkali metal salt of (S) 4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)ester. 
     
     
         16 . The method according to  claim 13  further comprising treating the ethyl ester of (S) 4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)ester with ethanol and sodium hydroxide to provide the sodium metal salt of (S) 4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)ester. 
     
     
         17 . The method according to  claim 15  further comprising
 (a) treating (S) 4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)ester in ethanol and toluene with sodium hydroxide to provide the sodium salt of (S) 4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid 1-(1,1-dimethylethyl)ester; and 
 (b) treating the product of (a) with dicyclohexylamine in t-butyl methyl ether and heptane at a pH of about 2.5 to about 3 at a temperature of <5° C. to provide dicyclohexylamine salt of (S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)ester. 
 
     
     
         18 . A method for preparing (1S,3S,5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid, 1,1-dimethylethyl ester 
       
         
           
           
               
               
           
         
         which comprises 
         (a) treating (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid, 1-(1,1-dimethylethyl) ester with diethyl zinc and chloro iodomethane at a temperature of about −30° C. to about 0° C. to provide a mixture of syn- and anti-isomers; 
         (b) treating the product of (a) with an aqueous solution of methyl amine to provide the syn isomer; 
         (c) treating the syn-isomer with a strong base to provide syn-N—BOC-4,5-methanoproline; and 
         (d) treating syn-N—BOC-4,5-methanoproline with N-methylmorpholine isobutyl chloroformate, and ammonia to provide (1S,3S,5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid, 1,1-dimethylethyl ester. 
       
     
     
         19 . A method for preparing compound M′ 
       
         
           
           
               
               
           
         
         which comprises 
         (a) treating compound L 
       
       
         
           
           
               
               
           
         
         with hydrochloric acid to provide compound L′ 
       
       
         
           
           
               
               
           
         
       
       and
 (b) treating compound L′ with sodium hydroxide to provide compound M′. 
 
     
     
         20 . The method according to  claim 21  further comprising treating compound K 
       
         
           
           
               
               
           
         
       
       with trifluoroacetic anhydride in the presence of pyridine or triethylamine followed by treatment with a strong base such as sodium hydroxide, potassium hydroxide, or lithium hydroxide to provide compound L. 
     
     
         21 . A compound M