# US 10,246,481 B2 · Bile acid derivatives and methods for synthesis and use

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- Number: US 10,246,481 B2
- Document ID: US10246481B2
- Status: Granted
- Kind: B2
- Application number: 15/983,859
- Filed: 2018-05-18
- Published: 2018-11-08
- Granted: 2019-04-02
- Earliest claimed: 2016-02-17
- Assignees: City of Hope
- Applicants: City of Hope
- Inventors: Donna Yu; Barry Forman
- Web page: https://patentgrep.com/patent/US10246481B2

## CPC

- C07J 9/005: {containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton}
- C07J: STEROIDS (seco-steroids C07C)

## Abstract

Provided herein, inter alia, are methods for the preparation of modulators of farnesoid X receptor (FXR), and compositions and uses of the modulators of FXR.

## Claims

### Claim 1

A method of synthesizing a compound having the following structure,
the method comprising,
(i) contacting a compound of formula (II)
wherein R11 is R11A or R11B, with an oxidizing reagent to provide a compound of formula (III-A) or (III-B),
or
(ii) when the product of step (i) has a structure according to formula (III-A), contacting the compound of formula (III-A) with an alcohol protecting agent to provide a compound of formula (III-B);
(iii) contacting a compound of formula (III-B) with an alkylating agent in the presence of a sterically hindered base to provide a compound of formula (IV),
(iv) optionally contacting the compound of formula (IV) with an alcohol deprotecting agent to provide a compound of formula (IV-A),
(v) treatment of the compound of formula (IV) or (IV-A) with a reducing agent to provide a compound of formula (I) or (I-A),
or
and
(vi) when the product of step (v) has a structure according to formula (I-A), contacting the compound of formula with an alcohol deprotecting agent to provide a compound of formula (I-A);
wherein,
L1 is —C(O)—, —C(O)O—, —C(O)NH—, or —CH2—;
R1 is hydrogen, halogen, —N3, —CF3, —CCl3, —CBr3, —CI3, —CN, —CHO, —OR1A, —NHR1A, —COOH, —CONH2, —NO2, —SH, —SO2Cl, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a carboxylate protecting group;
R2 is hydrogen or unsubstituted alkyl;
R3 is hydrogen, unsubstituted alkyl, or —OR3A;
R4 is hydrogen, unsubstituted alkyl, or —OR4A;
R5 is hydrogen, unsubstituted alkyl, or —OR5A;
R6 is hydrogen, unsubstituted alkyl, or —OR6A;
R7 is hydrogen, unsubstituted alkyl, or —OR7A;
R8 is hydrogen, unsubstituted alkyl, or —OR8A;
R9 is hydrogen, unsubstituted alkyl, or —OR9A;
R10 is hydrogen, unsubstituted alkyl, or —OR10A;
R11A is hydrogen;
R11B is an alcohol protecting group;
R12 is hydrogen, unsubstituted alkyl, or —OR12A;
R13 is unsubstituted alkyl;
R1A, R3A, R4A, R5A, R6A, R7A, R8A, R9A, R10A, R12A and R13A are independently hydrogen, unsubstituted alkyl, or an alcohol protecting group.

### Claim 2 (depends on 1)

The method of claim 1, the method comprising,
(i) contacting a compound of formula (II)
wherein R11 is R11A, with an oxidizing reagent to provide a compound of formula (III-A),
(ii) contacting the compound of formula (III-A) with an alcohol protecting agent to provide a compound of formula (III-B),
(iii) contacting a compound of formula (III-B) with an alkylating agent in the presence of a sterically hindered base to provide a compound of formula (IV),
(iv) contacting the compound of formula (IV) with an alcohol deprotecting agent to provide a compound of formula (IV-A),
(v) treatment of the compound of formula (IV-A) with a reducing agent to provide a compound of formula (I),

### Claim 3 (depends on 1)

The method of claim 1, the method comprising,
(i) contacting a compound of formula (II)
wherein R11 is R11B, with an oxidizing reagent to provide a compound of formula (III-B),
(ii) contacting a compound of formula (III-B) with an alkylating agent in the presence of a sterically hindered base to provide a compound of formula (IV),
(iii) contacting the compound of formula (IV) with an alcohol deprotecting agent to provide a compound of formula (IV-A),
(iv) treatment of the compound of formula (IV-A) with a reducing agent to provide a compound of formula (I)

### Claim 4 (depends on 1)

The method of claim 1, wherein R11B is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, or —SiR11CR11DR11E, wherein R11C, R11D, and R11E are independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl.

### Claim 5 (depends on 4)

The method of claim 4, wherein R11B is tetrahydropyranyl (THP).

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound of formula (I) has the following structure,

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound of formula (I) has the following structure,

### Claim 8 (depends on 7)

The method of claim 7, wherein
R1 is hydrogen;
R2 is hydrogen or unsubstituted alkyl; and
R4 is hydrogen or unsubstituted alkyl.

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound of formula (I) has the following structure,

### Claim 10 (depends on 9)

The method of claim 9, wherein the compound of formula (I) is 6-α-ethyl-ursodeoxycholic acid (6-EUDCA) having the following structure,

### Claim 11 (depends on 1)

The method of claim 1, wherein the oxidizing reagent of step (a) is a chromium oxidant, a ruthenium oxidant, a manganese oxidant, an activated dimethylsulfoxide oxidant, or a hypervalent iodine oxidant.

### Claim 12 (depends on 11)

The method of claim 11, wherein the oxidizing reagent is pyridinium chlorochromate (PCC).

### Claim 13 (depends on 1)

The method of claim 1, wherein the alcohol oxidation proceeds with greater than about 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1 regioselectivity.

### Claim 14 (depends on 1)

The method of claim 1, wherein said sterically hindered base of step (iii) is lithium diisopropylamide (LDA), (M+1)HMDS, (M+1)tBuO, (M+1)TMP, (M+1)PhO, (M+1)MeO, (M+1)EtO, DBU, Dabco, N,N-dichlorohexylmethylamine, N,N-diisopropyl-2-ethylbutylamine, 2,6-di-tert-butyl-4-methylpyridine, pentamethylpiperidine, MTBD, PMDBD, TBD, or tri-tert-butylpyridine, wherein (M+1) is Na, K, or Li.

### Claim 15 (depends on 14)

The method of claim 14, wherein said sterically hindered base is lithium diisopropylamide (LDA).

### Claim 16 (depends on 1)

The method of claim 1, wherein step (iii) comprises a second base.

### Claim 17 (depends on 16)

The method of claim 16, wherein said base is an alkyllithium reagent.

### Claim 18 (depends on 1)

The method of claim 1, wherein said alkylation agent of step (iii) is an alkyl halide.

### Claim 19 (depends on 18)

The method of claim 18, wherein said alkylation agent is an alkyl iodide.

### Claim 20 (depends on 1)

The method of claim 1, wherein step (iii) is performed in the presence of a polar aprotic solvent.

### Claim 21 (depends on 20)

The method of claim 20, wherein said polar aprotic solvent is HMPA, HMPT, DMF, DMSO, MeCN, dioxane, methylpyrrolidone, DMPU, or a tetra-alkyl urea.

### Claim 22 (depends on 1)

The method of claim 1, wherein the reducing agent of step (v) comprises an aluminum alkoxide and an alcohol.

### Claim 23 (depends on 22)

The method of claim 22, wherein the reducing agent comprises aluminum isopropoxide and isopropyl alcohol.

### Claim 24 (depends on 1)

The method of claim 1, wherein step (v) proceeds with greater than about 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, or 20:1 stereoselectivity.