Novel phenylboronic acid compounds and intermediates and processes for the preparation thereof

• US 20070015931A1
• Filed: 06/19/2006
• Published: 01/18/2007
• Est. Priority Date: 12/18/2003
• Status: Active Grant

• Current Assignee: Galderma Research And Development Snc (Nestle SA)
• Original Assignee: Galderma Research And Development Snc (Nestle SA)
• Inventors: Pascal, Jean-Claude, Terranova, Eric
• Granted Patent: US 7,659,421 B2
• Time in Patent Office: Days
• US Class Current: 558/287
• CPC Class Codes: C07C 33/20 monocyclic
• CPC Class Codes: C07C 39/15 with all hydroxy groups on non-condensed rings , e.g. phenylphenol
• CPC Class Codes: C07C 401/00 Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
• CPC Class Codes: C07C 43/23 containing hydroxy or O-metal groups
• CPC Class Codes: C07C 69/76 Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

Abstract

Vitamin D derivatives, notably non-steroidal vitamin D derivatives, are prepared from novel disubstituted phenylboronic acid compounds having the formula (I):
and also from the novel intermediates having the formulae (1), (2), (3) and (10):

Claims

1. A disubstituted phenylboronic acid compound having the following structural formula (I):

2. The disubstituted phenylboronic acid compound as defined by claim 1, wherein formula (I), each alkyl radical having from 1 to 4 carbon atoms is a saturated or unsaturated, linear or cyclic, optionally branched such radical and can be interrupted by a heteroatom.

3. The disubstituted phenylboronic acid compound as defined by claim 2, wherein formula (I), each alkyl radial is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl and tert-butyl radicals.

8. A process for the preparation of a disubstituted phenylboronic acid compound (I) as defined by claim 1 wherein formula (I) R4 is the B(OH)₂ radical, comprising:

a) bromination of methyl 4-bromo-3-methylbenzoate into the compound (1);

b) substituting the bromine atom introduced in step a) by an alkyl radical R5 having from 1 to 4 carbon atoms to obtain a compound (2);

c) converting the ester function of the intermediate (2) or of methyl 4-bromo-3-methylbenzoate into a tertiary alcohol function by reaction with an organomagnesium compound of formula R2-MgX wherein X is a halogen and R2 is a methyl, ethyl, propyl or butyl radical, to obtain a compound (3);

d) converting the intermediate (3) into said disubstituted phenylboronic acid compound (I) in the presence of a base and a trialkyl borate, with the proviso that the steps a) and b) are omitted in the event that R1 is a hydrogen atom.

9. A process for the preparation of a disubstituted phenylboronic acid compound as defined by claim 1 wherein formula (I) R4 is the

10. The process as defined by claims 8 or 9, wherein step a) is carried out in the presence of at least one brominating agent selected from the group consisting of bromine, N-bromosuccinimide, sodium bromate and 1,3-dibromo-5,5-dimethylhydantoin and in a chlorinated or ether solvent.

11. The process as defined by claim 10, wherein step a) is carried out in the presence of N-bromosuccinimide in dichloromethane.

12. The process as defined by claims 8 or 9, wherein step a) is carried out in the presence of a free-radical initiator.

13. The process as defined by claims 8 or 9, wherein step b) is carried out in the presence of an organometallic reagent R′

1-M in which M is magnesium, copper or zinc.

14. The process as defined by claim 13, wherein step b) is carried out in the presence of copper iodide and an organomagnesium compound R′

1-MgX in which X is a bromine, chlorine or iodine atom.

15. The process as defined by claims 8 or 9, wherein step b) is carried out in an ethereal solvent.

16. The process as defined by claims 8 or 9, wherein step b) is carried out at a temperature of from 40°

C. to −

20°

C.

17. The process as defined by claims 8 or 9, wherein step c) is carried out in an ethereal solvent at a temperature of from −

10°

C. to +10°

C.

18. The process as defined by claim 8, wherein step d) is carried out in the presence of an ethereal solvent, a strong base and a trialkyl borate.

19. The process as defined by claim 18, wherein step d) is carried out in the presence of tetrahydrofuran, butyllithium and triisopropyl borate, at a temperature of from −

78°

C. to 40°

C.

20. The process as defined by claim 9, wherein step d) is carried out in the presence of a DMF, tetrahydrofuran, DMSO or dioxane solvent, a dichloro[1,1′

-ferrocenylbis(diphenylphosphane)]palladium(II) dichloromethane or Pd(dppf)Cl₂ catalyst, a potassium acetate or triethylamine base, and pinacolborane or pinacoldiborane.

21. A non-steroidal vitamin D analogue prepared from a disubstituted phenylboronic acid compound as defined by claim 1.

22. The non-steroidal vitamin D analogue as defined by claim 21, having the structural formula (IV):

23. A process for the preparation of a non-steroidal vitamin D analogue as defined by claim 22, comprising:

a) Suzuki coupling a compound having the formula (I);

in which;

R1 is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms,

R2 and R3, which may be identical or different, are each an alkyl radical having from 1 to 4 carbon atoms, and

R4 is the —

B(OH)₂ radical or the radical of formula;

and an aryl bromide having the formula (II);

in which;

R′

₁ is an alkyl radical having from 1 to 4 carbon atoms, to obtain a compound of formula (10);

b) fusing the Suzuki reaction compound (1) with the benzyl bromide (11) in the presence of a base;

c) liberating the alcohol functions of the compound (11) to obtain the compound (IV).

4. The compound having the following structural formula (1):

5. A compound having the following structural formula (2):

6. A compound having the following structural formula (3):

7. A compound having the following structural formula (10):