Phenylboronic acid compounds and intermediates and processes for the preparation thereof

• US 7,659,421 B2
• Filed: 06/19/2006
• Issued: 02/09/2010
• Est. Priority Date: 12/18/2003
• Status: Expired due to Fees

• Current Assignee: Galderma Research And Development Snc (Nestle SA)
• Original Assignee: Galderma Research And Development Snc (Nestle SA)
• Inventors: Pascal, Jean-Claude, Terranova, Eric
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US11/454,859
• Publication Number:
  US 20070015931A1
• Time in Patent Office: 1,331 Days
• Field of Search: 558/287, 562/7
• 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 of 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 radical is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl and tert-butyl radicals.

4. 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);

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

6. The process as defined by claims 4 or 5, 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.

7. The process as defined by claim 6, wherein step a) is carried out in the presence of N-bromosuccinimide in dichloromethane.

8. The process as defined by claims 4 or 5, wherein step a) is carried out in the presence of a free-radical initiator.

9. The process as defined by claims 4 or 5, wherein step b) is carried out in the presence of an organometallic reagent R′

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

10. The process as defined by claim 9, 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.

11. The process as defined by claims 4 or 5, wherein step b) is carried out in an ethereal solvent.

12. The process as defined by claims 4 or 5, wherein step b) is carried out at a temperature of from −

40°

C. to −

20°

C.

13. The process as defined by claims 4 or 5, wherein step c) is carried out in an ethereal solvent at a temperature of from −

10°

C. to +10°

C.

14. The process as defined by claim 4, wherein step d) is carried out in the presence of an ethereal solvent, a strong base and a trialkyl borate.

15. The process as defined by claim 14, 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.

16. The process as defined by claim 5, 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 triethylarnine base, and pinacolborane or pinacoldiborane.