# US 2019/0375707 A1 · Process for the preparation of chiral pyrollidine-2-yl- methanol derivatives

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2019/0375707 A1
- Document ID: US20190375707A1
- Status: Published application
- Kind: A1
- Application number: 16/547,134
- Filed: 2019-08-21
- Published: 2019-12-12
- Earliest claimed: 2017-02-21
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Raffael Josef Koller; Christophe Pfleger
- Web page: https://patentgrep.com/patent/US20190375707A1

## CPC

- C07D 207/08: with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The invention relates to a novel process for the preparation of a chiral pyrollidine-2-yl-methanol derivative or a salt thereof of the formula I wherein R1 is aryl or heteroaryl and both aryl or heteroaryl are optionally substituted by C1-4-alkyl, halo-C1-4-alkyl, C1-4-alkoxy or halogen. The chiral pyrollidine-2-yl-methanol derivatives of the formula I are versatile building blocks in the synthesis of pharmacologically active compounds, such as for the stereospecific synthesis of oligonucleotides carrying chiral phosphonate moieties (see e.g. Int. PCT Publication WO 2010/064146).

## Claims

### Claim 1

A process for the preparation of a chiral pyrollidine-2-yl-methanol derivative of formula I
or a salt thereof, wherein
R1 is aryl or heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of C1-4-alkyl, halo-C1-4-alkyl, C1-4-alkoxy and halogen,
said process comprising
a) transforming a pyrrolidine carboxylic acid derivative of formula II
with an N,O-dialkylhydroxylamine of formula V
R4ONHR3 V
into the carbamoyl pyrrolidine derivative of formula III
wherein R2 is an amino protecting group; and R3 and R4 are each independently C1-4-alkyl;
b) reacting the carbamoyl pyrrolidine derivative of formula III with a Grignard reagent of the formula
R1MgHal
to form the aroyl pyrrolidine derivative of formula IV
wherein
R1 is aryl or heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of C1-4-alkyl, halo-C1-4-alkyl, C1-4-alkoxy and halogen;
Hal is halogen; and
R2 is an amino protecting group; and
c) removing the amino protecting group R2 from the aroyl pyrrolidine derivative of formula IV, and subsequently hydrogenating the aroyl pyrrolidine derivative in the presence of a hydrogenation catalyst to form the chiral pyrollidine-2-yl-methanol derivative of formula I.

### Claim 2 (depends on 1)

The process of claim 1, wherein the chiral pyrollidine-2-yl-methanol derivative has the structure of formula Ia.
wherein R1 is aryl or heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of C1-4-alkyl, halo-C1-4-alkyl, C1-4-alkoxy and halogen.

### Claim 3 (depends on 1)

The process of claim 1, wherein the chiral pyrollidine-2-yl-methanol derivative the structure of formula Ib.
wherein R1 is aryl or heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of C1-4-alkyl, halo-C1-4-alkyl, C1-4-alkoxy and halogen.

### Claim 4 (depends on 1)

The process of claim 1, wherein R1 is aryl, optionally substituted with one or more substituents selected from the group consisting of C1-4-alkyl, halo-C1-4-alkyl and C1-4-alkoxy.

### Claim 5 (depends on 4)

The process of claim 4, wherein R1 is phenyl.

### Claim 6 (depends on 1)

The process of claim 1, wherein the transformation in step a) is performed in the presence of a coupling agent, an amine base and an organic solvent at a reaction temperature between 0° C. and 60° C.

### Claim 7 (depends on 6)

The process of claim 6, wherein the coupling agent is selected from the group consisting of n-propylphosphonic acid anhydride (T3P®), N,N′-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide-hydrochloride (EDC), N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (TBTU), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU).

### Claim 8 (depends on 7)

The process of claim 7, wherein the coupling agent is combined with an additive selected from the group consisting of 1-hydroxybenztriazole (HOBt), N-hydroxysuccinimide (HOSu), and 1-hydroxy-7-azabenzotriazole (HOAt) and combinations thereof.

### Claim 9 (depends on 6)

The process of claim 6, wherein the amine base is a tertiary amine, and the organic solvent is a polar aprotic solvent.

### Claim 10 (depends on 1)

The process of claim 1, wherein step b) is performed in an organic solvent at a reaction temperature between −10° C. and 50° C.

### Claim 11 (depends on 10)

The process of claim 10, wherein the organic solvent is an ethereal or aromatic hydrocarbon solvent or mixtures thereof.

### Claim 12 (depends on 1)

The process of claim 1, wherein the amino protecting group R2 is cleavable under acidic conditions.

### Claim 13 (depends on 1)

The process of claim 1, wherein R2 is tert-butoxycarbonyl (BOC).

### Claim 14 (depends on 1)

The process of claim 1, wherein removing the amino protecting group R2 from the aroyl pyrrolidine derivative of formula IV is performed with a strong acid.

### Claim 15 (depends on 14)

The process of claim 14, wherein the strong acid is hydrochloric acid.

### Claim 16 (depends on 1)

The process of claim 1, wherein the hydrogenation in step c) is performed in the presence of a hydrogenation catalyst comprising a platinum group metal selected from the group consisting of ruthenium, osmium, rhodium, iridium, palladium and platinum.

### Claim 17 (depends on 1)

The process of claim 1, wherein the platinum group metal is palladium.

### Claim 18 (depends on 1)

The process of claim 1, wherein the hydrogenation in step c) is performed in a polar protic solvent at a reaction temperature between 0° C. and 60° C. and a hydrogen pressure between 1 and 10 bar.

### Claim 19 (depends on 1)

The process of claim 1, wherein the chiral pyrollidine-2-yl-methanol derivative is obtained in the form of its hydrochloride salt.

### Claim 20 (depends on 1)

The process of claim 1, wherein the chiral pyrollidine-2-yl-methanol derivative is selected from the group consisting of