METHODS AND COMPOUNDS FOR PRODUCING DIPEPTIDYL PEPTIDASE IV INHIBITORS AND INTERMEDIATES THEREOF

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