# US 7,612,215 B2 · Process for preparing 2-oxo-1-pyrrolidine derivatives by intramolecular allylation

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

- Number: US 7,612,215 B2
- Document ID: US7612215B2
- Status: Granted
- Kind: B2
- Application number: 11/570,143
- Filed: 2005-05-26
- Published: 2008-05-29
- Granted: 2009-11-03
- Earliest claimed: 2004-06-11
- Assignees: UCB Pharma S.A.
- Inventors: Françoise Lurquin; Frank Driessens; Michel Callaert
- Web page: https://patentgrep.com/patent/US7612215B2

## CPC

- C07D 207/26: 2-Pyrrolidones
- C07C 237/22: having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K)
- C07D 207/277: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention relates to a new process for preparing 2-oxo-1-pyrrolidine derivatives of general formula (I), comprising the cyclisation of an intermediate of general formula (II) wherein the substituents are as defined in the specification.

## Claims

### Claim 1

A process for the preparation of compounds of general formula (I)
wherein
R2 and R3 are the same or different and each is, independently, hydrogen, C1-4 alkyl, cyano, aryl, —COOR7, halogen, R8COO—, R9SO3O— or R10SO2O—;
R1 is Ra, Rb or C2-20 alkenyl optionally substituted by aryl;
X is —CONR11R12, —COOR13 or —CN;
R7, R8, R9 and R10 are each independently chosen from hydrogen, Ra′ and Rb′;
R11, R12 and R13 are the same or different and each is, independently, hydrogen, C1-4 alkyl, aryl, arylalkyl, heteroaryl or heterocycloalkyl;
Ra and Ra′ each independently represent C1-20 alkyl or C1-20 alkyl substituted by one or more halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, carboxy, sulfonic acid, Rb, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxy, aryloxy, sulfonamide, acyl, ester, amido, azido, acyloxy, esteroxy and/or amidooxy;
Rb and Rb′ each independently represent aryl, heterocycloalkyl, heteroaryl or the same substituted by one or more halogen, Ra, hydroxy, thiol, amino, nitro, cyano, thiocyanato, carboxy, sulfonic acid, aryl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxy, aryloxy, sulfonamide, heterocycloalkyl, heteroaryl, acyl, ester, amido, azido, acyloxy, esteroxy and/or amidooxy;
comprising the cyclisation of an intermediate of general formula (II)
wherein
Y is a leaving group selected from halogen, —OC(O)R14, —OSO2—R15 and —OClO3;
R14 and R15 represent halogen or alkyl, arylalkyl, aryl, each optionally substituted by one or more halogen, alkyl, nitro and/or tertiary amino group;
X1 is as defined for X;
W is an electron withdrawing group selected from —COOR4, —COMe, —CN, —PO(OEt)2, —SO2aryl, —COaryl;
R4 represents hydrogen, C1-6 alkyl, aryl, arylalkyl, wherein each aryl and arylalkyl may be substituted by one or more halogen, nitro, and/or methoxy;
in the presence of one or more organic and/or inorganic bases.

### Claim 2 (depends on 1)

The process according to claim 1, wherein Y is halogen, —OC(O)R14, —OSO2—C6H4—CH3, —OSO2—C6H4—Br, —OSO2—C6H4—NO2, —OSO2—CH3, —OSO2—CF3, —OSO2—C4F9, —OSO2—CH2—CF3, —OSO2—(CH2)n—N+Me3, —OSO2—F or —OClO3.

### Claim 3 (depends on 1)

The process according to claim 1, wherein the base is selected from 1,1,3,3-tetramethylguanidine, sparteine, 1,5,7-triazabicyclo(4.4.0)dec-5-ene, bis(trimethylsilyl)acetamide, 1,8-diazabicyclo[5.4.0]undec-7-ene, tert-butylimino-tri(pyrrolidino)phosphorane, 1,5-diazabicyclo(4.3.0)non-5-ene, Na2CO3, K2CO3, Cs2CO3, NaH or tert-BuOK, optionally in the presence of a phase transfer catalyst.

### Claim 4 (depends on 1)

The process according to claim 1, comprising the hydrolysis of an intermediate of general formula (VII a)
wherein
R4a is a C1-6 alkyl;
X1 is as defined for X is claim 1;
R1, R2 and R3 are as defined in claim 1.

### Claim 5 (depends on 1, 4)

The process according to claim 1, comprising the decarbalkoxylation of an intermediate of formula (VIIa) as defined in claim 4 or comprising the decarboxylation of an intermediate of general formula (VII b),
wherein
X2 is as defined for X in claim 1;
R1, R2 and R3 are as defined in claim 1.

### Claim 6 (depends on 1)

The process according to claim 1, wherein the intermediate of formula (II) is obtained by a method comprising the reaction of an intermediate of formula (III)
wherein
X3 is as defined for X in claim 1;
Y, R1, R2 and R3 are as defined in claim 1;
with a compound of formula (IV)
wherein
R5 is methoxy, ethoxy, chlorine, hydroxy, —ONa or —OK;
W1 is as defined for W in claim 1.

### Claim 7 (depends on 6)

The process according to claim 6, wherein W1 represents a group of formula —COOR4b, wherein R4b represents a C1-6 alkyl.

### Claim 8 (depends on 1, 6)

The process according to claim 6, wherein intermediate (III) is obtained by a method comprising the reaction of a compound of formula (V)
wherein Y, R2 and R3 are as defined in claim 1 and R6 is a leaving group such as defined for Y in claim 1;
with a compound of formula (VI);
wherein X4 is as defined for X in claim 1 and R1 is as defined in claim 1.

### Claim 9 (depends on 8)

The process according to claim 8, wherein R6 is —OSO2—C6H4—CH3.

### Claim 10 (depends on 1)

The process according to claim 1, comprising a step of separation of one or more of the different diastereoisomers of any of the compounds of formula (I), (VIIa) and (VIIb).

### Claim 11 (depends on 1)

The process according to claim 1, wherein the carbon atom indicated by (1*) is in the (S)-form.

### Claim 12 (depends on 1)

The process according to claim 1, wherein the carbon atom indicated by (2*) is in the (S)-form.

### Claim 13 (depends on 5)

The process according to claim 5, comprising a step of isolation of the compound of formula (VII b) wherein the carbon atom indicated by (2*) is in the (S)-form.

### Claim 14 (depends on 1)

The process according to claim 1, wherein W represents a group of formula —COOR4.

### Claim 15 (depends on 14)

The process according to claim 14, wherein R4 represents a C1-6 alkyl.

### Claim 16 (depends on 1)

The process according to claim 1, wherein R1 is a C1-6 alkyl.

### Claim 17 (depends on 16)

The process according to claim 16, wherein R1 is ethyl.

### Claim 18 (depends on 1)

The process according to claim 1, wherein X, X1, X2, X3 and X4 are —CONR11R12.

### Claim 19 (depends on 18)

The process according to claim 18, wherein X, X1, X2, X3 and X4 are —CONH2.

### Claim 20 (depends on 1)

The process according to claim 1, wherein R2 and R3 are halogens.

### Claim 21 (depends on 20)

The process according to claim 20, wherein R2 and R3 are fluorine.

### Claim 22 (depends on 1)

The process according to claim 1, wherein Y is halogen.

### Claim 23 (depends on 22)

The process according to claim 22, wherein Y is fluorine.

### Claim 24 (depends on 1)

The process according to claim 1, wherein the compound of formula (I) is (2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide.

### Claim 25 (depends on 1, 4)

Synthesis intermediates of formula (II a), (III), (VII a), (VII b) and salts thereof
wherein
X1, X2 and X3 are independently as defined for X in claim 1;
R1, R2, R3, R4 and Y are as defined in claim 1;
and R4a is as defined in claim 4.

### Claim 26 (depends on 25)

Synthesis intermediates according to claim 25 wherein R1 is ethyl, X1, X2 and X3 are —CONH2; R2, R3 and Y are F; R4 and R4a are methyl or ethyl.

### Claim 27 (depends on 25)

Synthesis intermediates according to claim 25, wherein the carbon atom indicated by (1*) is in the (S)-form.

### Claim 28 (depends on 26)

Synthesis intermediate of formula (VII b) according to claim 26, wherein the carbon atom indicated by (2*) is in the (S)-form.