# US 2019/0375699 A1 · Processes for preparing (r)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethanol and 1-(5- chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethanone

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- Number: US 2019/0375699 A1
- Document ID: US20190375699A1
- Status: Published application
- Kind: A1
- Application number: 16/546,906
- Filed: 2019-08-21
- Published: 2019-12-12
- Earliest claimed: 2015-03-05
- Assignees: Roivant Sciences GmbH
- Applicants: Roivant Sciences GmbH
- Inventors: Stéphane De Lombaert; Daniel R. Goldberg
- Web page: https://patentgrep.com/patent/US20190375699A1

## CPC

- C07C 29/32: increasing the number of carbon atoms by reactions without formation of -OH groups
- C07C 29/143: of ketones
- C07C 45/455: {with carboxylic acids or their derivatives}
- C07C 49/80: containing halogen
- C07C 259/10: having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
- C07B 2200/07: Optical isomers
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention relates to processes for the preparation of (R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol, 1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone, and intermediates thereof, which are useful in the preparation of inhibitors of TPH1 for the treatment of, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, low bone mass diseases, serotonin syndrome, and cancer.

## Claims

### Claim 1

A process for preparing a compound of Formula A:
comprising reacting a compound of Formula 1-4:
wherein X is I,
with phenylboronic acid to produce the compound of Formula A.

### Claim 2 (depends on 1)

The process of claim 1, wherein said reacting is carried out under Suzuki coupling conditions.

### Claim 3 (depends on 1)

The process of claim 1, wherein said reacting is carried out in the presence of a Pd catalyst.

### Claim 4 (depends on 3)

The process of claim 3 wherein said Pd catalyst is Pd2(dppf)Cl2.

### Claim 5 (depends on 1)

The process of claim 1, wherein said reacting is carried out in the presence of a solvent.

### Claim 6 (depends on 5)

The process of claim 5 wherein said solvent comprises dioxane.

### Claim 7 (depends on 5)

The process of claim 5 wherein said solvent comprises aqueous sodium carbonate.

### Claim 8 (depends on 1)

The process of claim 1, wherein said reacting is carried out at elevated temperature.

### Claim 9 (depends on 8)

The process of claim 8, wherein said elevated temperature is about 90° C.

### Claim 10 (depends on 1)

The process of claim 1 wherein said compound of Formula 1-4:
is prepared by the process comprising reducing a compound of Formula 1-3:
in the presence of a chiral catalyst.

### Claim 11 (depends on 10)

The process of claim 10, wherein said chiral catalyst comprises iridium.

### Claim 12 (depends on 10)

The process of claim 10, wherein said chiral catalyst is prepared by combining dichloro(pentamethylcyclopentadienyl)iridium(III) dimer with (1R, 2R)-(−)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine.

### Claim 13 (depends on 10)

The process of claim 10, wherein said reducing is carried out at elevated temperature.

### Claim 14 (depends on 13)

The process of claim 13 wherein said elevated temperature is about 40° C.

### Claim 15 (depends on 10)

The process of claim 10, wherein said reducing is carried out in the presence of formate.

### Claim 16 (depends on 15)

The process of claim 15, wherein said formate is potassium formate.

### Claim 17 (depends on 10)

The process of claim 10, wherein said reducing is carried out in the presence of a solvent.

### Claim 18 (depends on 17)

The process of claim 17, wherein said solvent comprises acetonitrile.

### Claim 19 (depends on 10)

The process of claim 10 wherein said compound of Formula 1-3:
is prepared by the process comprising combining a compound of Formula 1-2:
with trifluoromethyltrimethylsilane.

### Claim 20 (depends on 19)

The process of claim 19, wherein said combining is carried out in the presence of CsF.

### Claim 21 (depends on 19)

The process of claim 19, wherein said combining is carried out at reduced temperature.

### Claim 22 (depends on 21)

The process of claim 21, wherein said reduced temperature is about 0° C.

### Claim 23 (depends on 19)

The process of claim 19, wherein said combining is carried out in the presence of a solvent.

### Claim 24 (depends on 23)

The process of claim 23, wherein said solvent comprises toluene.

### Claim 25 (depends on 19)

The process of claim 19, further comprising the step of adding tetra-n-butylammonium fluoride (TBAF).

### Claim 26 (depends on 19)

The process of claim 19 wherein said compound of Formula 1-2 is prepared by the process comprising coupling a compound of Formula 1-1:
with N,O-dimethylhydroxylamine hydrochloride.

### Claim 27 (depends on 26)

The process of claim 26, wherein said coupling is carried out in the presence of triethyl amine (TEA).

### Claim 28 (depends on 26)

The process of claim 26, wherein said coupling is carried out in the presence of (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (HATU).

### Claim 29 (depends on 26)

The process of claim 26, wherein said coupling is carried out using oxalyl chloride.

### Claim 30 (depends on 26)

The process of claim 26, wherein said coupling is carried out in the presence of a solvent.

### Claim 31 (depends on 30)

The process of claim 30, wherein said solvent comprises dimethylformamide (DMF).

### Claim 32 (depends on 30)

The process of claim 30, wherein said solvent comprises dichloromethane (CH2Cl2).

### Claim 33 (depends on 1)

A compound of Formula A which is prepared by the process of claim 1.

### Claim 34

A process of preparing a compound of Formula A:
comprising reducing a compound of Formula B:
in the presence of a chiral catalyst.

### Claim 35 (depends on 34)

The process of claim 34, wherein said chiral catalyst comprises iridium.

### Claim 36 (depends on 34)

The process of claim 34, wherein said chiral catalyst is prepared by combining dichloro(pentamethylcyclopentadienyl)iridium(III) dimer with (1R, 2R)-(−)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine.

### Claim 37 (depends on 34)

The process of claim 34, wherein said reducing is carried out at elevated temperature.

### Claim 38 (depends on 37)

The process of claim 37, wherein said elevated temperature is about 40° C.

### Claim 39 (depends on 34)

The process of claim 34, wherein said reducing is carried out in the presence of formate.

### Claim 40 (depends on 39)

The process of claim 39, wherein said formate is potassium formate.

### Claim 41 (depends on 34)

The process of claim 34, wherein said reducing is carried out in the presence of a solvent.

### Claim 42 (depends on 41)

The process of claim 41, wherein said solvent comprises acetonitrile.

### Claim 43 (depends on 34)

A compound of Formula A which is prepared by the process of claim 34.

### Claim at position 44

44-52. (canceled)

### Claim 53

A process for preparing a compound of Formula 1-3:
wherein X is selected from Br and I,
comprising combining a compound of Formula 1-2:
with trifluoromethyltrimethylsilane.

### Claim 54 (depends on 53)

The process of claim 53, wherein X is I.

### Claim 55 (depends on 53)

The process of claim 53, wherein X is Br.

### Claim 56 (depends on 53)

The process of claim 53, wherein said combining is carried out in the presence of CsF.

### Claim 57 (depends on 53)

The process of claim 53, wherein said combining is carried out at reduced temperature.

### Claim 58 (depends on 57)

The process of claim 57, wherein said reduced temperature is about 0° C.

### Claim 59 (depends on 53)

The process of claim 53, wherein said combining is carried out in the presence of a solvent.

### Claim 60 (depends on 59)

The process of claim 59, wherein said solvent comprises toluene.

### Claim 61 (depends on 53)

The process of claim 53, further comprising the step of adding tetra-n-butylammonium fluoride (TBAF).

### Claim 62

A process for preparing a compound of Formula 1-2:
wherein X is selected from Br and I,
comprising coupling a compound of Formula 1-1:
with N,O-dimethylhydroxylamine hydrochloride.

### Claim 63 (depends on 62)

The process of claim 62, wherein X is I.

### Claim 64 (depends on 62)

The process of claim 62, wherein X is Br.

### Claim 65 (depends on 62)

The process of claim 62, wherein said coupling is carried out in the presence of triethyl amine (TEA).

### Claim 66 (depends on 62)

The process of claim 62, wherein said coupling is carried out in the presence of (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU).

### Claim 67 (depends on 62)

The process of claim 62, wherein said coupling is carried out using oxalyl chloride.

### Claim 68 (depends on 62)

The process of claim 62, wherein said coupling is carried out in the presence of a solvent.

### Claim 69 (depends on 68)

The process of claim 68, wherein said solvent comprises dimethylformamide (DMF).

### Claim 70 (depends on 68)

The process of claim 68, wherein said solvent comprises dichloromethane (CH2Cl2).

### Claim 71

A compound which is a compound of Formula B: