Process for preparation of sulfonylurea bile acid derivatives

1. A process for preparing an amorphous solid form of a compound of Formula I:

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 2 R 3 ; wherein, R 2 and R 3 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 2 and R 3 are taken together with the nitrogen atom to which they attached to form a 3- to 12-membered hetercyclic ring;

said process comprising the steps of:

a) reacting 7-keto lithocholic acid with a hydroxyl protecting reagent to produce compound 2;

wherein PG 1 is a hydroxyl protecting group;

b) reacting compound 2 with an acyl azide formation reagent in the presence of R 4 CH 2 OH to produce compound 3:

wherein R 4 is substituted or unsubstituted phenyl;

c) deprotecting compound 3 to produce compound 4:

d) reacting compound 4 with a silylating agent in the presence of a base to produce compound 5:

wherein PG 2 is a silyl group;

e) reacting compound 5 with acetaldehyde in the presence of a Lewis acid to produce compound 6:

f) hydrogenating compound 6 to produce compound 7:

g) reacting compound 7 with a base in a protic solvent or a mixture of a protic solvent and a non-protic solvent to produce compound 8:

h) reducing compound 8 to produce the compound (II):

i) optionally reacting compound (II) with HA, wherein HA is an acid, to form the salt 9,

j) reacting compound (II) or the salt 9 with a compound of formula 10E,

wherein R′ is imidazol-1-yl, alkyl-O- aryl-O-, Cl, or CCl 3 , in the presence of an organic base, to form the compound of Formula (I):

k) treating the compound of Formula (I) with diethyl amine to produce a compound of Formula (IV):

and

l) treating the compound of Formula (IV) with an acid, thereby producing the amorphous form of the compound of Formula (I).

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

3. The process of claim 1 , wherein in step a), the hydroxyl protecting reagent is tert-butyl(dimethyl)silyl chloride.

4. The process of claim 1 , wherein in step b), the acyl azide formation reagent is diphenylphosphoryl azide.

5. The process of claim 1 , wherein in step c), compound 3 is deprotected by reaction with HCl in methanol.

6. The process of claim 1 , wherein in step d), the silylating agent is trimethylsilyl trifluoromethanesulfonate.

7. The process of claim 1 , wherein in step e), the Lewis acid is BF 3 .Et 2 O.

8. The process of claim 1 , wherein in step g), the base is NaOH.

9. The process of claim 1 , wherein in step h), the reducing agent is NaBH 4 .

10. The process of claim 1 , wherein in step j) the compound of Formula 10E is of the formula

wherein R 1 is as defined in claim 1 .

11. The process of claim 2 , wherein in step j), the compound of Formula 10E is selected from compounds of formulas 10A, 10B, 10C and 10D:

wherein R 5 is alkyl or aryl.

12. A process for preparing an amorphous solid form of a compound of Formula I:

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 2 R 3 ; wherein, R 2 and R 3 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 2 and R 3 are taken together with the nitrogen atom to which they attached to form a 3- to 12-membered hetercyclic ring;

said process comprising the steps of:

a) treating the compound of Formula (I) with diethyl amine to produce a compound of Formula (IV):

and

b) treating the compound of Formula (IV) with an acid, thereby producing an amorphous form of the compound of Formula (I).

13. A process for producing compound (II),

comprising the steps of

a) reacting 7-keto lithocholic acid with a hydroxyl protecting reagent to produce compound 2;

wherein PG 1 is a hydroxyl protecting group;

b) reacting compound 2 with an acyl azide formation reagent in the presence of R 4 CH 2 OH to produce compound 3:

wherein R 4 is substituted or unsubstituted phenyl;

c) deprotecting compound 3 to produce compound 4:

d) reacting compound 4 with a silylating agent in the presence of a base to produce compound 5:

wherein PG 2 is a silyl group;

e) reacting compound 5 with acetaldehyde in the presence of a Lewis to produce compound 6:

f) hydrogenating compound 6 to produce compound 7:

g) reacting compound 7 with a base in a protic solvent or a mixture of a protic solvent and a non-protic solvent to produce compound 8:

and

h) reducing compound 8, thereby producing compound (II).

14. The process of claim 12 , wherein R 1 is