Process for preparation of sulfonyl carbamate bile acid derivatives

1. A process for preparing a compound of Formula (II):

wherein

R 1 is selected from the group consisting of:

1) substituted or unsubstituted —C 1 -C 8 alkyl;

2) substituted or unsubstituted —C 2 -C 8 alkenyl;

3) substituted or unsubstituted —C 2 -C 8 alkynyl;

4) substituted or unsubstituted —C 3 -C 8 cycloalkyl;

5) substituted or unsubstituted aryl;

6) substituted or unsubstituted arylalkyl;

7) substituted or unsubstituted 3- to 12-membered heterocycloalkyl;

8) substituted or unsubstituted heteroaryl;

9) substituted or unsubstituted heteroarylalkyl; and

10) NR a R b , wherein, R a and R b are each independently selected from hydrogen, substituted or unsubstituted —C 1 -C 8 alkyl, substituted or unsubstituted —C 2 -C 8 alkenyl, substituted or unsubstituted —C 2 -C 8 alkynyl, substituted or unsubstituted —C 3 -C 8 cycloalkyl; alternatively R a and R b are taken together with the nitrogen atom to which they are attached to form a 3- to 12-membered hetercyclic ring;

said process comprising the steps of:

(1ai) reacting compound 1,

with a C 1 -C 6 -alkanol under acid catalysis to produce compound 2,

wherein R 6 is C 1 -C 6 -alkyl;

(1aii) reacting compound 2 with a strong base in the presence of a hydroxyl protecting agent to produce a compound of Formula 2a,

and reacting the compound of Formula 2a with a halogenating agent to produce compound 3,

wherein

PG 1 is a hydroxyl protecting group; and

R 2 is selected from Br, I, and C 1 ;

(1aiii) reacting compound 3 with an organic base to eliminate HR 2 and produce compound 4,

(1aiv) deprotecting compound 4 to produce compound 5,

(1av) reacting compound 5 with a hydroxyl protecting agent to produce compound 6:

(1avi) oxidatively cleaving and oxidizing compound 6 in the presence of a base to produce a compound of Formula (III):

(2bi) reacting the compound of Formula (III) with a C 1 -C 6 -alkanol under acid catalysis to produce compound 8,

(2bii) reacting compound 8 with a silylating agent in the presence of a base to produce compound 9:

wherein PG 3 is a silyl group;

(2biii) reacting compound 9 with acetaldehyde in the presence of a Lewis acid to produce compound 10:

(2biv) hydrogenating compound 10 to produce compound 11:

(2bv) reacting compound 11 with a base in a protic solvent or a mixture of a protic solvent and a non-protic solvent to produce compound 12:

2b(vi) reacting compound 12 with a hydroxyl protecting agent to produce the compound of Formula (V),

(3bi) reacting the compound of Formula (V) with a compound of the formula R 3 OC(O)Cl to produce compound 13:

wherein R 3 is an alkyl group; and

(3bii) reducing compound 13 to produce the compound of Formula (VI),

(4bi) reacting the compound of Formula (VI) with a compound of Formula 15E,

wherein R 4 is imidazol-1-yl, alkyl-O, aryl-O, Cl, or —CCl 3 , in the presence of an organic base, to produce compound 17,

and

(4bii) deprotecting the compound of Formula 17 to produce the compound of Formula (II).

2. The process of claim 1 , wherein R 1 is

3. The process of claim 1 , wherein step (4bii) is conducted in an aprotic solvent at a temperature from about 0° C. to about 80° C.

4. The process of claim 1 , wherein the compound of Formula 15E is selected from compounds 15B, 15C and 15D:

wherein R 5 is alkyl or aryl.

5. The process of claim 1 , wherein the compound of Formula 15E is selected from compounds 20B, 20C and 20D:

wherein R 5 is alkyl or aryl.

6. The process of claim 1 wherein PG is TBS.

7. The process of claim 1 wherein R 6 is methyl.

8. The process according to claim 1 wherein R 6 is methyl and PG 1 is TBS.