Methods for preparation of bile acids and derivatives thereof

Patent metadata

Field	Value
Publication number	US-2019010184-A1
Application number	US-201615748716-A
Country	US
Kind code	A1
Filing date	Jul 22, 2016
Priority date	Jul 30, 2015
Publication date	Jan 10, 2019
Grant date	—

Abstract

The present application relates to a method of preparing compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, R 1 is H, α-OH, β-OH, or an oxo group.

First claim

1 . A method of preparing a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R 1 is H, α-OH, β-OH, or an oxo group, comprising the steps of:
(1) converting 2 to 3

(2) selectively oxidizing 3 to yield 4

(3) converting 4 to 5

(4) converting 5 to oxime 6

(5) converting oxime 6 to 7

(6) converting 7 to ketone 8

(7) deprotecting ketone 8 to form ketone 9;

(8) olefinating 9 to yield 10

(9) alkylating olefin 10 regioselectively and stereoselectively to yield 11

wherein P 1 is a protecting group or H;
(10) converting 11 to yield 12

wherein P 2 is a protecting group;
(11) regioselectively and stereoselectively reducing 12 to yield 13

 and
(12) deprotecting and selectively reducing 13 to yield the compound of formula (I).

2 . A method of preparing a compound of Formula (Ia):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, comprising the steps of:
(1) stereoselectively reducing 13 to yield 14

wherein P 1 is a protecting group or H and P 2 is a protecting group;
(2) selectively deprotecting 14 to yield 14a

 and
(3) hydrolyzing 14a to form the compound of Formula (Ia)

3 . The method of claim 2 , wherein the deprotecting in step 2 and the hydrolyzing in step 3 occur in a single step.

4 . A method of preparing a compound of Formula (Ib):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, comprising the steps of:
(1) oxidizing 13 regioselectively to yield 15

wherein P 1 is a protecting group or H and P 2 is a protecting group;
(2) stereoselectively reducing 15 to yield 16A

(3) stereoselectively reducing 16A to yield 17

(4) selectively deprotecting 17 to yield 17A

(5) hydrolyzing 17A to yield the compound of Formula (Ib)

5 . A method of preparing a compound of Formula (Ic):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, comprising the steps of:
(1) oxidizing 13 regioselectively to yield 15

wherein P 1 is a protecting group or H and P 2 is a protecting group;
(2) stereoselectively reducing 15 to yield 16B

(3) stereoselectively reducing 16B to yield 18

(4) deprotecting 18 to yield 18A

 and
(5) hydrolyzing 18A to yield the compound of Formula (Ic)

6 . The method of claim 4 or 5 , wherein the deprotecting in step 4 and the hydrolyzing in step 5 occur in a single step.

7 . A method of preparing a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R 1 is H, α-OH, β-OH, or an oxo group, comprising the steps of:
stereoselectively reducing 13 to yield 14

wherein P 1 is a protecting group and P 2 is a protecting group; and
deprotecting 14 to yield the compound of Formula (I).

8 . The method of claim 7 , wherein the stereoselective reduction comprises hydrogenation.

9 . The method of claim 8 , wherein the hydrogenation is conducted with a catalyst and hydrogen gas.

10 . A method of preparing a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R 1 is α-OH, comprising the step of:
stereoselectively reducing 16A to yield 17

wherein P 1 is a protecting group or H and P 2 is a protecting group; and deprotecting 17 to yield the compound of Formula (I) wherein R 1 is α-OH.

11 . The method of claim 10 , wherein the stereoselective reduction comprises hydrogenation.

12 . The method of claim 11 , wherein the hydrogenation is conducted with a catalyst and hydrogen gas.

13 . A method of preparing a compound of Formula (I):

Assignees

• Intercept Pharmaceuticals Inc

Inventors

• Pellicciari Roberto
• Gioiello Antimo

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07J13/005

  with double bond in position 16 (17) · CPC title

• C07J13/007

  with double bond in position 17 (20) · CPC title

• C07J9/005 Primary

  containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton · CPC title