Method for preparing 6-alkylated steroidal derivatives and corresponding alkylated 5,6,7,8-tetrahydronaphthalene-2(4 alpha.H)-ones

Patent metadata

Field	Value
Publication number	US-9783569-B2
Application number	US-201415032251-A
Country	US
Kind code	B2
Filing date	Oct 28, 2014
Priority date	Oct 28, 2013
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

The present invention concerns a method for preparing certain steroidal derivatives alkylated in position 6, comprising a step of alkylating the corresponding compound halogenated in position 6 with an organometallic alkylating agent.

First claim

The invention claimed is:

1. A process for the preparation of a compound of formula (I):

wherein for the compound of formula (I):
R 1 and R 2 together form C and D rings of a steroidal carbon-based backbone, wherein said C and D rings optionally comprise one or more double bonds and are optionally substituted by one or more moieties selected from the group consisting of:
linear or branched alkyl groups comprising from 1 to 12 carbon atoms,
acyl groups comprising from 1 to 12 carbon atoms and optionally substituted by one or more hydroxyl groups,
carboxyl, hydroxyl or oxo groups, and
halogen atoms,

wherein the acyl, carboxyl, hydroxyl, and oxo groups are in free or protected form, and wherein each position of said C and D rings is optionally substituted with one or, where possible, two said moieties;
R′ 1 is a hydrogen or halogen atom, and R 1 and R′ 1 are located on either side of the plane of the A and B rings;
R 3 is an alkyl group comprising from 1 to 4 carbon atoms;
is a single bond or a double bond; and
is a single bond in the α or β position of the A and B rings, or a double bond in the plane of the A and B rings,

wherein said process comprises alkylation of a compound of formula (II):

wherein for the compound of formula (II), R 1 , R′ 1 , R 2 , and are as defined for the compound of formula (I), and X is a halogen atom;
with an organometallic alkylating agent, optionally in the presence of a metal catalyst, wherein the group R 3 , present in the organometallic alkylating agent, replaces group X of the compound of formula (II), to obtain the compound of formula (I).

2. The process according to claim 1 , wherein the organometallic alkylating agent is selected from the group consisting of organolithium compounds of formula R 3 Li, organomagnesium compounds of formula R 3 MgX′, organozinc compounds of formula R 3 ZnX′, where X′ is a halogen atom, organocopper compounds of formula R 3 Cu, lithium organocuprates of formula (R 3 ) 2 CuLi, organocyanocuprates of formula R 3 CuCNLi or (R 3 ) 2 CuCN(Li) 2 , halocuprates of formula R 3 CuLiX″, where X″ is a halogen atom, organoboron compounds of formula R 3 B(OH) 2 and organotrifluoroborates of formula R 3 BF 3 K.

3. The process according to claim 2 , wherein the organometallic alkylating agent is selected from the group consisting of organomagnesium compounds of formula R 3 MgX′, where X′ is a halogen atom, organocopper compounds of formula R 3 Cu, lithium organocuprates of formula (R 3 ) 2 CuLi, organocyanocuprates of formula R 3 CuCNLi or (R 3 ) 2 CuCN(Li) 2 , and halocuprates of formula R 3 CuLiX″, where X″ is a halogen atom.

4. The process according to claim 3 , wherein the organometallic alkylating agent is an organomagnesium compound of formula R 3 MgX′, where X′ is a halogen atom, and wherein the alkylation is carried out in the presence of a copper catalyst.

5. The process according to claim 3 , wherein the organometallic alkylating agent is a halocuprate of formula R 3 CuLiX″, where X″ is a halogen atom.

6. The process according to claim 3 , wherein the organometallic alkylating agent is a lithium organocuprate of formula (R 3 ) 2 CuLi or an organocyanocuprate of formula (R 3 ) 2 CuCN(Li) 2 .

7. The process according to claim 3 , wherein the organometallic alkylating agent is a lithium organocuprate of formula (R 3 ) 2 CuLi, and
wherein the alkylation comprises reaction of the compound of formula (II) with said lithium organocuprate,
followed by reaction of the resulting compound with a second alkylating agent of formula R 3 X′″, where X′″ is a halogen atom.

8. The process according to claim 1 , wherein the compound of formula (II) is obtained by halogenation of a compound of formula (III):

wherein for the compound of formula (III), R 1 , R′ 1 , R 2 , and are as defined in claim 1 .

9. The process according to claim 1 , wherein X is a bromine atom.

10. The process according to claim 9 , wherein the compound of formula (II) is obtained by reaction of the compound of formula (III) with an N-bromoimide in the presence of a radical initiator.

11. The process according to claim 1 , wherein the compound of formula (I) is a steroidal compound of formula (IA):

wherein for the compound of formula (IA):
R 3 is an alkyl group comprising from 1 to 4 carbon atoms;
R 4 is hydrogen, or a hydroxyl or oxo group, wherein the hydroxyl or oxo group is in free or protected form;
R 5 is hydrogen or a halogen atom;
R 6 is hydrogen or a hydroxyl group, in free or protected form;
R 7 is hydrogen or a —C(O)R 7 ′ or —C(OR) 2 R 7 ′ group, where R is a protective group for the carbonyl functional group and where R 7 ′ is selected from the group consisting of hydrogen, an alkyl group comprising from 1 to 3 carbon atoms, a hydroxyl group, in free or protected form, and a hydroxyalkyl group comprising from 1 to 3 carbon atoms, in free or protected form, or
R 6 and R 7 together form an oxo group in the 17 position of the steroidal backbone of the compound of formula (IA);
R 8 is hydrogen or an alkyl group comprising from 1 to 3 carbon atoms;
wherein the R 6 and R 7 groups are located on either side of the plane of the A, B, C and D rings;
is a single bond or a double bond;
is a single bond in the α or β position or in the plane of the A, B, C and D rings or, where possible, a double bond in the plane of the A, B, C and D rings; and

wherein the compound of formula (II) is a compound of formula (IIA):

 wherein for the compound of formula (IIA), R 4 , R 5 , R 6 , R 7 , R 8 , and are as defined for the compound of formula (IA), and X is a halogen atom.

12. The process according to claim 11 , wherein the compound of formula (I) is a steroidal compound of formula (IA):

wherein for the compound of formula (IA):
R 3 is an alkyl group comprising from 1 to 4 carbon atoms;
R 4 is hydrogen, or a hydroxyl or oxo group, wherein the hydroxyl or oxo group is in free or protected form;
R 5 is hydrogen or a halogen atom;
R 6 is hydrogen, or a hydroxyl group, in free or protected form;
R 7 ′ is selected from the group consisting of hydrogen, an alkyl group comprising from 1 to 3 carbon atoms, a hydroxyl group, in free or protected form, and a hydroxyalkyl group comprising from 1 to 3 carbon atoms, in free or protected form;
R 8 is hydrogen or an alkyl group comprising from 1 to 3 carbon atoms;
wherein the R 6 and —C(O)R 7 ′ groups are located on either side of the plane of the A, B, C and D rings;
the oxo group located on the carbon in the 20 position of the steroidal backbone is in free or protected form;
is a single bond or a double bond;
is a single bond in the α or β position or in the plane of the A, B, C and D rings or, where possible, a double bond in the plane of the A, B, C and D rings; and

wherein the compound of formula (II) is a compound of formula (IIA):

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Assignees

• Sanofi Sa

Inventors

• Duez Stéphanie
• Haesslein Jean-Luc
• Lhermitte Frédéric
• Quinio Pauline

Classifications

• C07C2602/28

  Hydrogenated naphthalenes · CPC title

• C07J9/005

  containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton · CPC title

• C07J21/008 Primary

  at position 17 · CPC title

• C07C45/68

  by increase in the number of carbon atoms · CPC title

• C07J5/0076 Primary

  by an alkyl group · CPC title