Methods for preparation of bile acids and derivatives thereof
AssigneeIntercept Pharmaceuticals, Inc.
InventorsRoberto Pellicciari, Antimo Gioiello
Life of this patent
Estimating the term…
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, R1 is H, α-OH, β-OH, or an oxo group.
Claims39
A method of preparing a compound of Formula (I):
- or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1 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 P1 is a protecting group or H;
- (10) converting 11 to yield 12
- wherein P2 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).
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 P1 is a protecting group or H and P2 is a protecting group;
- (2) selectively deprotecting 14 to yield 14a
- and
- (3) hydrolyzing 14a to form the compound of Formula (Ia)
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 P1 is a protecting group or H and P2 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)
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 P1 is a protecting group or H and P2 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)
A method of preparing a compound of Formula (I):
- or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1 is H, α-OH, β-OH, or an oxo group, comprising the steps of:
- stereoselectively reducing 13 to yield 14
- wherein P1 is a protecting group and P2 is a protecting group;
- and
- deprotecting 14 to yield the compound of Formula (I).
A method of preparing a compound of Formula (I):
- or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1 is α-OH, comprising the step of:
- stereoselectively reducing 16A to yield 17
- wherein P1 is a protecting group or H and P2 is a protecting group;
- and deprotecting 17 to yield the compound of Formula (I) wherein R1 is α-OH.
A method of preparing a compound of Formula (I):
- or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1 is β-OH, comprising the step of:
- stereoselectively reducing 16B to yield 18
- wherein P1 is a protecting group or H and P2 is a protecting group;
- and
- deprotecting 18 to yield the compound of Formula (I) wherein R1 is β-OH.
A method of preparing a compound of Formula (I):
- or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1 is α-OH, comprising the steps of:
- (1) stereoselectively reducing 16A to yield 17
- wherein P1 is a protecting group or H and P2 is a protecting group;
- (2) selectively deprotecting 17 to yield 17A
- and
- (3) hydrolyzing 17A to yield the compound of Formula (I) wherein R1 is α-OH
A method of preparing a compound of Formula (I):
- or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1 is β-OH, comprising the steps of:
- (1) stereoselectively reducing 16B to yield 18
- wherein P1 is a protecting group or H and P2 is a protecting group;
- (2) selectively deprotecting 18 to yield 18A
- and
- (3) hydrolyzing 18A to yield the compound of Formula (I) wherein R1 is β-OH
A method of preparing a compound of Formula (I):
- or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1 is α-OH, comprising the steps of:
- (1) stereoselectively reducing 15 to yield 16A
- wherein P1 is a protecting group or H and P2 is a protecting group;
- (2) stereoselectively reducing 16A to yield 17
- and
- (3) deprotecting 17 to yield the compound of formula (I) wherein R1 is α-OH.
A method of preparing a compound of Formula (I):
- or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1 is β-OH, comprising the steps of:
- (1) stereoselectively reducing 15 to yield 16B
- wherein P1 is a protecting group or H and P2 is a protecting group;
- (2) stereoselectively reducing 16B to yield 18
- and
- (3) deprotecting 18 to yield the compound of formula (I) wherein R1 is β-OH.
A method of preparing a compound of Formula (I):
- or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1 is H, 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 P1 is a protecting group or H;
- (10) protecting 11 to yield 12
- wherein P2 is a protecting group;
- (11) regioselectively and stereoselectively reducing 12 to yield 13
- (12) stereoselectively reducing 13 to yield 14
- (13) selectively deprotecting 14 to yield 14a
- and
- (14) hydrolyzing 14a to form the compound of Formula (I)
A method preparing a compound of Formula (I):
- or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1 is α-OH, 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 P1 is a protecting group or H;
- (10) protecting 11 to yield 12
- wherein P2 is a protecting group;
- (11) regioselectively and stereoselectively reducing 12 to yield 13
- (12) oxidizing 13 regioselectively to yield 15
- (13) stereoselectively reducing 15 to yield 16A
- (14) stereoselectively reducing 16A to yield 17
- (15) selectively deprotecting 17 to yield 17A
- and
- (16) converting 17A to yield a compound of Formula (I) wherein R1 is α-OH
A method of preparing a compound of Formula (I):
- or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1 is β-OH, 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 P1 is a protecting group or H;
- (10) converting 11 to yield 12
- wherein P2 is a protecting group;
- (11) regioselectively and stereoselectively reducing 12 to yield 13
- (12) oxidizing 13 regioselectively to yield 15
- (13) stereoselectively reducing 15 to yield 16B
- (14) stereoselectively reducing 16B to yield 18
- (15) deprotecting 18 to yield 18A
- and
- (16) hydrolyzing 18A to yield a compound of Formula (I) wherein R1 is β-OH
A method of preparing Compound 7:
- Wherein R1 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
- and
- (5) converting oxime 6 to 7
A method of preparing Compound 4 wherein R1 is H, α-OH, β-OH, or an oxo group, comprising selectively oxidizing 3 to 4,
A method of preparing Compound 5 wherein R1 is H, α-OH, β-OH, or an oxo group, comprising converting 4 to 5,
A method of preparing Compound 8 wherein R1 is H, α-OH, β-OH, or an oxo group, comprising converting 7 to 8,
A method of preparing Compound 11 wherein R1 is H, α-OH, β-OH, or an oxo group;
- and P1 is H or a protecting group, comprising alkylating olefin 10 regioselectively and stereoselectively to yield 11,
A method of preparing Compound 13 wherein P1 is H or a protecting group and P2 is a protecting group, comprising regioselectively and stereoselectively reducing 12 to 13,
A method of preparing Compound 14 wherein P1 is H or a protecting group and P2 is a protecting group, comprising oxidizing 13 to 14,
A method of preparing Compound 15 wherein P1 is H or a protecting group and P2 is a protecting group, comprising selectively oxidizing 13 to 15
A method of preparing Compound 16A or 16B wherein P1 is H or a protecting group and P2 is a protecting group, comprising selectively reducing 15 to 16A or 16B,
A method of preparing Compound 18 wherein P1 is H or a protecting group and P2 is a protecting group, comprising selectively reducing 16B to 18,
A method of preparing compound 19 wherein P1 is H or a protecting group and P2 is a protecting group, comprising selectively reducing 15 to 19,
Dependencies are inferred from the claim text.