BACKGROUND OF THE INVENTION
The invention relates to a method for the preparation of organo-catalyst of formula (X)
and Pinaki S Bhadury, et al, "An effective route to fluorine containing asymettric [alpha]-aminophosphonates using chiral Bronsted acid catalyst", chirality, 21,(5), 1 May 2009, pages 547-557
describe the synthesis catalyst of formula (X). Qing Zhao, et al, "An efficient method for sterically demanding Suzuki-Miyaura coupling reactions", Chemistry - A European journal, 19(7), 11 feb 2013, pages 2261-2265
describes Suzuki-Miyaura couplings using phosphor ligands.
The problem of the present invention is to provide an improved process for preparing catalyst of formula (X).
DESCRIPTION OF THE INVENTION
USED TERMS AND DEFINITIONS
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-6
-alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
In general in single groups like HO, H2
N, S(O), S(O)2
, NC (cyano), HOOC, F3
C or the like, the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself. For combined groups comprising two or more subgroups, the first or last named subgroup, where the free valence is indicated, for example, the substituent "aryl-C1-3
-alkyl-" means an aryl group which is bound to a C1-3
-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail. An asterisk or a broken line may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
For example, the term "3-carboxypropyl-group" represents the following substituent:
wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms "1-methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" group represent the following groups:
The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
Many of the following terms may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.
The term "substituted" as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
The invention contemplates enantiomers mentioned herein, e.g. in substantially pure form, in enriched form (e.g. substantially free of any or all other undesired enantiomers and/or diastereomers and/or in any mixing ratio, including the racemic forms, as well as the salts thereof.
In general, substantially pure stereoisomers can be obtained according to synthetic principles known to a person skilled in the field, e.g. by separation of corresponding mixtures, by using stereochemically pure starting materials and/or by stereoselective synthesis. It is known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, e.g. starting from optically active starting materials and/or by using chiral reagents.
Enantiomerically pure compounds of this invention or intermediates may be prepared via asymmetric synthesis, for example by preparation and subsequent separation of appropriate diastereomeric compounds or intermediates which can be separated by known methods (e.g. by chromatographic separation or crystallization) and/or by using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries.
Further, it is known to the person skilled in the art how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases; or by resolution of a racemic mixture using an appropriate resolving agent, e.g. by means of diastereomeric salt formation of the racemic compound with optically active acids or bases, subsequent resolution of the salts and release of the desired compound from the salt; or by derivatization of the corresponding racemic compounds with optically active chiral auxiliary reagents, subsequent diastereomer separation and removal of the chiral auxiliary group; or by kinetic resolution of a racemate (e.g. by enzymatic resolution); by enantioselective crystallization from a conglomerate of enantiomorphous crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.
DETAILED DESCRIPTION OF THE INVENTION
The present invention solves the problem stated above by means of the method of synthesis described hereinafter.
An embodiment of the invention relates to a method for the preparation of organo-catalyst of formula (X), see scheme 1
characterised in that the method comprises a Suzuki-Miyaura coupling of unprotected 3,3'-dibromo-1,1-bi-2-napthol with 3,5-bis-(trifluoromethyl)phenyl boronic acid in the presence of palladium diacetate and a ligand of formula (Y)
Starting materials are commercially available or may be prepared by methods that are described in the literature or herein, or may be prepared in an analogous or similar manner. Any functional groups in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the one skilled in the art.
The following abbreviations are used in the experimental section:
THF - Tetrahydrofuran
DMF - Dimethylformamide
Me-THF - 2-Methyl-tetrahydrofuran
HPLC - High performance liquid chromatography
ee - Enantiomer excess
ESI - Electrospray ionization
MS - Mass spectroscopy
CAS - Chemical abstract service
NMR - Nuclear magnetic resonance spectroscopy
MPLC - Medium pressure liquid chromatography
HCl - Hydrochloric acid
The synthesis according to the invention is illustrated in scheme 1.
Synthesis of (R)-3,3'-bis[3,5-bis(trifluormethyl)phenyl]-1,1'-binaphthyl-2,2'-dihy-drogenphosphate
)-di-bromo-BINOL (6.0 g, 12.5 mmol), (3,5-bis(trifluoromethyl)phenyl)boronic acid (8.067 g, 31.3 mmol), Na2
(3.98 g, 38.0 mmol), MeTHF (45 mL) and H2
O (15 mL) to a 250-mL reactor. Purge the mixture with N2
for 20 min, then add Pd(OAc)2
(14.6 mg, 0.065 mmol) and racemic 4-(2,6-dimethoxyphenyl)-3-(1,1-dimethylethyl)-2,3-dihydro-1,3-benzoxaphosphole (Angew Chem Int Ed 49 (2010), 5879-83,
24.7 mg, 0.075 mmol). Heat the reaction to 70 °C for 2 h, cool down to 20 °C then add 15 mL H2
O. Separate the layers then wash the organic fraction with water (20 mL). Treat the organic fraction with Darco 60 (0.3 h), filter then solvent switch to MeOH (45 mL). Heat the solution to 60 °C then crystallize the product by slow addition of water (45 mL). Cool down to 20 °C, filter the product then dry under reduced pressure at 70 °C for 20h.
Yield: 8.57 g (91%)
ee >99.5% (Method O)
H NMR (400 MHz, CDCl3
): δ 8.23 (s, 4H), 8.11 (s, 2H), 7.99 (d, J
= 8.2 Hz, 2H), 7.91 (s, 2H), 7.47 (dt, J
= 7.2, 1.0 Hz, 2H), 7.41 (dt, J
= 8.0, 1.4 Hz, 2H), 7.22 (d, J
= 8.5 Hz, 2H), 5.46 (s, 2H)
)-3,3'-bis(3,5-bis(trifluoromethyl)phenyl)-[1,1'-binaphthalene]-2,2'-dial (1) (5.5 g, 7.40 mmol), and pyridine (15 mL) to a 250-mL reactor. Slowly add a solution of phosphorus oxychloride (1.71 g, 11.152 mmol) in pyridine (7.5 mL while maintaining the reaction temperature below 30 °C. Stir the reaction mixture at 80 °C for 1.5 h, cool down to 40 °C then add water (7.5 mL) followed after 10 min by addition of HCl (6N) solution (37 mL). Heat the reaction to 100 °C for 1 h, cool down to 20 °C then filter the solids. Wash the solids with water (15 mL) then return them to the reactor. Add toluene (60 mL) and HCl (6N) (15 mL). Heat the mixture to 40 °C for 20 min then separate the aqueous fraction. Wash the organic fraction at 30-40 °C with 2 x 15 mL 6N HCl then with water (20 mL). Distill toluene to reach 17 mL of product solution, Heat to 60 °C then add heptane (60 mL) to crystallize the product. Cool down to 20 °C then filter, wash with heptane then dry under reduced pressure at 70 °C for 20 h.
Yield: 3.82 g (66.4 %)
ee >99.5% (Method P)
H NMR (400 MHz, CDCl3
): δ 8.01 (m, 8H), 7.57 (m, 4H), 7.42 (m, 4H), 6.28 (s, 1H).