Process for the preparation of substituted pyrrolidine derivatives and intermediates

1. A process for the preparation of compound (Ia) where R and R 1 are trans to each other in formula (1)

wherein

R is selected from the group consisting of H, OR 2 , N 3 , NHR 2 and F;

R 1 is selected from the group consisting of CH 3 , CH 2 OR 2 , CH 2 N 3 , CH 2 NHR 2 , CH 2 F, CHO, CH═NR 2 , CO 2 H, CO 2 alkyl, CONHR 2 , CH 2 CH 2 OR 2 , CH═CHCO 2 R 3 , CH 2 CH 2 CO 2 R 3 and CH 2 CH 2 CH 2 OR 2 ;

R 2 is selected from the group consisting of H, R 3 , CH 2 R 3 , C(O)R 3 and C(O)OR 3 ; and

R 3 is selected from the group consisting of alkyl and aryl; and pharmaceutically acceptable salts thereof;

which comprises:

i) reacting camphor sulfonic acid with thionyl chloride; further contacting the resultant camphor sulfonyl chloride with ammonia to generate camphor sulfonamide; and eliminating water from the amide under acidic conditions to produce an imine; and hydrogenating the resultant imine with hydrogen in the presence of a suitable catalyst to produce camphor sultam;

ii) further reacting (E)-3-benzyloxyacrylic acid chloride with camphor sultam and a base to yield the addition product (E)-3-benzyloxypropenoyl-(2′S)-borane-10,2-sultam

iii) contacting chloromethyltrimethylsilane with benzylamine to generate N-(trimethylsilylmethyl)benzylamine and further reacting N-(trimethylsilylmethyl)benzylamine with formaldehyde and methanol to produce N-(benzyl)-N-(methoxymethyl)-N-(trimethylsilylmethyl)amine;

iv) reacting compound (E)-3-benzyloxypropenoyl-(2′S)-borane-10,2-sultam with N-(benzyl)-N-(methoxymethyl)-N-(trimethylsilylmethyl)amine in the presence of a acid catalyst to produce pyrrolidine derivatives N-[[3S,4R)-4-Benzyloxy-1-(benzyl)pyrrolidin-3-yl]carbonyl]-(2′S)-bornane-10,2-sultam and N-[[3R,4S)-4-Benzyloxy-1-(benzyl)pyrrolidin-3-yl]carbonyl]-(2′S)-bornane-10,2-sultam as a mixture of isomers and isolating the desired isomer N-[[3S,4R)-4-Benzyloxy-1-(benzyl)pyrrolidin-3-yl]carbonyl]-(2′S)-bornane-10,2-sultam;

v) reducing compound N-[[3S,4R)-4-Benzyloxy-1-(benzyl)pyrrolidin-3-yl]carbonyl]-(2′S)-bornane-10,2-sultam with a reducing agent, and isolating the pyrrolidine derivative (3R,4R)-(1-Benzyl-4-benzyloxypyrrolidin-3-yl)methanol;

vi) deprotecting the (3R,4R)-(1-Benzyl-4-benzyloxypyrrolidin-3-yl)methanol through hydrogenation in the presence of a catalyst to produce the desired compound of formula (Ia).

2. The process of claim 1 wherein the base comprises methyl magnesium bromide.

3. The process of claim 1 wherein the acid catalyst comprises trifluoroacetic acid.

4. The process of claim 1 wherein the reducing agent comprises lithium aluminum hydride.

5. The process of claim 1 wherein the hydrogenation catalyst comprises Pd/C.

6. A process for the preparation of compound (Ia), where R═OH, R 1 ═CH 2 OH and R 2 ═H and R and R 1 are trans to each other in formula (I)

which comprises:

i) reacting camphor sulfonic acid with thionyl chloride; further contacting the resultant camphor sulfonyl chloride with ammonia to generate camphor sulfonamide; eliminating water from the amide under acidic conditions to produce an imine; and hydrogenating the resultant imine with hydrogen to produce camphor sultam;

ii) further reacting (E)-3-benzyloxyacrylic acid chloride with camphor sultam and a base to yield the addition product (E)-3-benzyloxypropenoyl-(2′S)-borane-10,2-sultam;

iii) contacting chloromethyltrimethylsilane with benzylamine to generate N-(trimethylsilylmethyl)benzylamine and further reacting N-(trimethylsilylmethyl)benzylamine with formaldehyde and methanol to produce N-(benzyl)-N-(methoxymethyl)-N-(trimethylsilylmethyl)amine;

iv) reacting compound (E)-3-benzyloxypropenoyl-(2′S)-borane-10,2-sultam with N-(benzyl)-N-(methoxymethyl)-N-(trimethylsilylmethyl)amine in the presence of a acid catalyst to produce pyrrolidine derivatives N-[[3S,4R)-4-Benzyloxy-1-(benzyl)pyrrolidin-3-yl]carbonyl]-(2′S)-bornane-10,2-sultam and N-[[3R,4S)-4-Benzyloxy-1-(benzyl)pyrrolidin-3-yl]carbonyl]-(2′S)-bornane-10,2-sultam as a mixture of isomers and isolating the desired isomer N-[[3S,4R)-4-Benzyloxy-1-(benzyl)pyrrolidin-3-yl]carbonyl]-(2′S)-bornane-10,2-sultam;

v) reducing compound N-[[3S,4R)-4-Benzyloxy-1-(benzyl)pyrrolidin-3-yl]carbonyl]-(2′S)-bornane-10,2-sultam with a reducing agent and isolating the pyrrolidine derivative (3R,4R)-(1-Benzyl-4-benzyloxypyrrolidin-3-yl)methanol;

vi) deprotecting compound (3R,4R)-(1-Benzyl-4-benzyloxypyrrolidin-3-yl)methanol through hydrogenation in the presence of a catalyst to produce the desired compound of formula (Ia).

7. The process of claim 6 wherein the base comprises methyl magnesium bromide.

8. The process of claim 6 wherein the acid catalyst comprises trifluoroacetic acid.

9. The process of claim 6 wherein the reducing agent comprises lithium aluminum hydride.

10. The process of claim 6 wherein the hydrogenation catalyst comprises Pd/C.