# US 2013/0280768 A1 · Process for preparing an enantiomerically enriched, deuterated secondary alcohol from a corresponding ketone without reducing deuterium incorporation

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- Number: US 2013/0280768 A1
- Document ID: US20130280768A1
- Status: Published application
- Kind: A1
- Application number: 13/819,985
- Filed: 2011-09-01
- Published: 2013-10-24
- Earliest claimed: 2010-09-01
- Assignees: Concert Pharmaceuticals, Inc.
- Inventors: Ramanaiah C. Kanamarlapudi; Steven A. Weissman; Emerich Eisenreich; Xuejun Liu
- Web page: https://patentgrep.com/patent/US20130280768A1

## CPC

- C12P 17/182: {Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system (alloxazine or isoalloxazine, e.g. riboflavine C12P25/00)}
- C07B 59/002: {Heterocyclic compounds}
- C07D 473/10: with methyl radicals in positions 3 and 7, e.g. theobromine
- C12P: FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE {(brewing of beer C12C; producing vinegar C12J; producing specific peptides or proteins C07K; producing enzymes C12N9/00; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; measuring or testing processes involving enzymes or microorganisms C12Q; measuring or testing processes involving nucleic acid amplification reactions C12Q1/6844; fermentation processes to form a food composition, A21 or A23; compounds in general, see the relevant compound class, e.g. C01, C07)}
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention provides a process for the preparation of enantiomerically enriched, deuterated secondary alcohols of Formula 1-A by employing ketoreductases or carbonyl reductases without reducing deuterium incorporation.

## Claims

### Claim 1

A process for the preparation of a compound of Formula I-A
comprising the step of reacting a compound of Formula II-A:
or a salt thereof, with a hydride source or a deuteride source in the presence of a ketoreductase or carbonyl reductase to form a compound of formula I with an enantiomeric excess of at least 80%, wherein:
each of R4, R6 and R7 is independently selected from —CH3 and —CD3;
each R5 is hydrogen or deuterium or a combination thereof;
each Z2 is the same and is hydrogen or deuterium;
each Z3 is the same and is hydrogen or deuterium;
each Z4 is the same and is hydrogen or deuterium;
each Z5 is the same and is hydrogen or deuterium; and
Y is H when a compound of Formula II-A is reacted with a hydride source; or
Y is D when a compound of Formula II-A is reacted with a deuteride source, wherein either R7 is —CD3 or at least one of Z2, Z3, Z4 and Z5 is deuterium, and wherein the amount of deuterium incorporation at each deuterium in R7, Z2, Z3, Z4 and Z5 in the compound of formula I is substantially equal to the amount of deuterium incorporation at corresponding deuterium atoms in R7, Z2, Z3, Z4 and Z5 in the compound of formula II.

### Claim 2 (depends on 1)

The process of claim 1, wherein each R7 is —CD3.

### Claim 3 (depends on 1)

The process of claim 1, wherein each Z2 is deuterium.

### Claim 4 (depends on 1)

The process of claim 1, wherein each Z2 is hydrogen.

### Claim 5 (depends on 1)

The process of claim 1, wherein each R5 is deuterium.

### Claim 6 (depends on 1)

The process of claim 1, wherein each R5 is hydrogen.

### Claim 7 (depends on 1)

The process of claim 1, wherein each Z3, Z4 and Z5 is hydrogen.

### Claim 8 (depends on 7)

The process of claim 7, wherein R6 is —CH3 and R7 is —CD3.

### Claim 9 (depends on 8)

The process of claim 8, wherein R4 is —CH3.

### Claim 10 (depends on 7)

The process of claim 7, wherein R6 is —CD3 and R7 is —CD3.

### Claim 11 (depends on 1)

The process of claim 1, wherein each Z3, Z4 and Z5 is deuterium.

### Claim 12 (depends on 11)

The process of claim 11, wherein each R6 and each R4 is —CD3.

### Claim 13 (depends on 1)

The process of claim 1, wherein:
a. the compound of Formula II-A is selected from any one of:
and
b. the compound of Formula I-A is selected from any one of the following:

### Claim 14 (depends on 1)

The process of claim 1, wherein:
the compound of Formula II-A is
and the compound of Formula I-A is

### Claim 15 (depends on 14)

The process of claim 14, further comprising the step of converting Compound 421(S) to Compound 121(S):

### Claim 16 (depends on 1)

The process of claim 1, wherein the hydride source or deuteride source is (i) a cofactor selected from NAD, NADH, NADP and NADPH, (ii) a reducing sugar and (iii) a dehydrogenase that dehydrogenates the reducing sugar.

### Claim 17 (depends on 16)

The process of claim 16, wherein Y is H; and the hydride source is (i) a cofactor selected from NAD, NADH, NADP and NADPH, (ii) glucose and (iii) glucose hydrogenase.

### Claim 18 (depends on 16)

The process of claim 16, wherein Y is D; and the deuteride source is (i) a cofactor selected from NAD and NADP, (ii) deuterated glucose, and (iii) glucose hydrogenase.

### Claim 19 (depends on 18)

The process of claim 18, wherein the deuteride source is (i) a cofactor selected from NAD and NADP, (ii) D-glucono-δ-lactone, and (iii) a metal deuteride or a mixed metal deuteride.

### Claim 20 (depends on 19)

The process of claim 19, wherein the metal deuteride or mixed metal deuteride is NaBD4.

### Claim 21 (depends on 1)

The process of claim 1, wherein the step of reacting a compound of Formula II-A or a salt thereof with a hydride source or a deuteride source is performed at a pH between 6.0 and 7.5.

### Claim 22 (depends on 21)

The process of claim 21, wherein the pH is between 6.90 and 7.05.

### Claim 23 (depends on 1)

The process of claim 1, wherein the ketoreductase or carbonyl reductase is selected from CRED A131, CRED A251, and KRED-NAD 101.