FR2663032A1 - PROCESS FOR THE PREPARATION OF 2-PHENYL-6- (PYRIMIDIN-2-YL) PYRIDINE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of a compound of formula (V): (CF DRAWING IN BOPI) in which W, Y and Z independently represent hydrogen, chlorine, fluorine, an alkyl or alkoxy group. The process consists in reacting a compound of formula (IV) (CF DRAWING IN BOPI) in which W, Y and Z are as defined above, with zinc (II) chloride. This process can be included in the preparation of (6- (2-chlorophenyl) pyrid-2-yl) -pyrimidines.

Description

The present invention relates to a method of

  preparation of derivatives of 2-phenyl-6- (pyrimidine-2-

  yl) pyridine, intermediate compounds used in this process and processes for preparing the intermediate compounds. According to the present invention, there is provided a process for preparing a compound of formula (V) wherein W, Y and Z independently represent hydrogen, chlorine, fluorine, alkyl or alkoxy, the process comprising treating a compound of formula (IV) wherein W, Y and Z are as defined

  above, with zinc chloride (II).

  According to one of its aspects, the present invention provides a process for preparing a compound of formula (V), wherein W, Y and Z are as defined above, the process comprising the steps of: a) combining in lithium a compound of formula (VIII) wherein W, Y and Z are as defined above and X is bromine or iodine; and b) treating the product formed in (a) with the

zinc chloride (II).

  According to another of its aspects, the present invention provides a process for preparing a compound of general formula (I), wherein, W, Y and

  Z are as defined above, R 1, R 2 and R 3 represent

  independently, hydrogen, alkyl, haloalkyl or alkoxy and R 4, R 5 and R 6 independently represent hydrogen, chlorine, fluorine, alkyl, haloalkyl or alkoxy, or R 4 t R 5 form

  together a polymethylene group of formula -CH 2) n

  in which m is 3 or 4; the process comprising the steps of: a) combining lithium with a compound of formula (VIII) wherein X, W, Y and Z are as defined above; b) treating the product thus formed in (a) with zine (II) chloride; and c) reacting the product thus formed in (b) with a compound of formula (III) in the presence

a suitable catalyst.

  The invention comprises steps (b) and (c)

individually or in combination.

  The process is particularly useful for the preparation of compounds of general formula (I) wherein W, Y, Z, R 1, R 2, R 3, R 5 and R 6 are all

  hydrogen and R 4 is a methyl group.

  A suitable compound of formula (VIII) is 2-chlorobromobenzene. The alkyl group and the alkyl portions of the alkoxy and haloalkyl groups contain 1 to 6, preferably 1 to 4, carbon atoms and are straight-chain or branched-chain groups, for example methyl,

  ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, dry -

butyl or tert-butyl.

  Compounds of general formula (I) are disclosed in EP-A-259,139 and are

useful as fungicides.

  The method of the invention is illustrated in Scheme A. In Scheme A, the variables W, Y, Z, X, R 1,

  R 2, R 3, R 4, R 5 and R 6 have the definitions given above.

  In step (a), a compound of formula (VIII) is preferably lithium combined with an alkyl lithium (e.g., n-butyllithium) in a suitable solvent (such as tetrahydrofuran) at a suitable temperature (e.g. -70 to -100 ° C., preferably from -70 ° to -78 ° C.) to form a product (IV).

  (IV) corresponds to the general formula (IV).

  In step (b), the product formed in step (a) (product IV) is reacted with zinc (II) chloride in a suitable solvent (for example diethyl ether) at a temperature of suitable (for example in the range of -60 to -80 ° C, preferably in the range of -70 to -78 ° C) to form a product (V). The product (V) is considered to have the general formula (V). ). In step (c), the product (V) is reacted with a compound of the general formula (III) in the presence of a suitable catalyst (for example tetrakis (triphenylphosphine) palladium) in a suitable solvent (for example tetrahydrofuran) and at a

suitable temperature.

  Compounds of general formula (III), in

  which R 1, R 2, R 3, R 4, R 5 and R 6 are as defined above.

  above can be prepared by coupling a dibromo-

  pyridine of general formula (VI), wherein R 1, R 2 and

  R 3 are as defined above, with a bromine

  pyrimidine of general formula (VII), wherein R 4, R 5 and R 6 are as defined above The reaction of

  Coupling can be carried out by treatment of the dibromo-

  pyridine (VI) with butyllithium in tetrahydro-

  furan, followed by zinc (II) chloride in the ether of

  diethyl and then the addition of tetrakis (triphenylphosphine)

  with bromopyrimidine (VII) The reaction is

  driving at temperatures between -70 and 20 C.

  According to another of its aspects, the invention comprises the product of the process involving the steps of: a) combining lithium with a compound of formula (VIII) wherein X, W, Y and Z are as defined above; and (b) to take the product thus formed and to do so

  react with zinc (II) chloride.

  According to another of its aspects, the present invention comprises the product of the process for treating a compound of formula (IV) in which W, Y and Z are such

  as defined above with zinc chloride (II).

  According to yet another of its aspects, the present invention comprises a compound corresponding to the

general formula (V).

  The following example illustrates the present invention. The NMR values that are given are not selective; no attempt has been made to enumerate all the absorptions The following abbreviations are used in all cases: THF = tetrahydrofuran dd = doublet of doublets d = doublet t = triplet s = singlet

EXAMPLE 1

  This example illustrates the preparation of the 4-

  methyl-2- (6- (2-chlorophenyl) pyrid-2-yl) pyrimidine, as shown in Scheme B. 2-Chlorobromobenzene (Aldrich) reaction groups 0.57 g (2.98 mM) n-buyllithium, 2.5 M in hexanes (Aldrich) 1.7 ml (4.27 mM), zinc (II) chloride 1, OM in ether (Aldrich) 10 ml (10 mM) 4-methyl-2 - (6-bromopyrid-2-yl) pyrimidine, 0.5 g (2 mM)

  tetrakis (triphenylphosphine) palladium, 0.05 g (catalyst

  sor). Process 2-Chlorobromobenzene (dried over a 4 A molecular sieve) was dissolved in tetrahydrofuran (10 ml freshly distilled from sodium and benzophenone) in a dry apparatus under a nitrogen atmosphere. The resulting solution was then cooled with stirring (using a bath of solid CO 2 and acetone) to -78 C and a solution of n-butyllithium was added in 15 minutes at a temperature below C The colorless solution was then stirred at At -78 ° C. for 15 minutes before the addition of anhydrous zinc (II) chloride solution below -70 ° C. over a period of 20 minutes. The resulting white suspension was stirred at -78 ° C. for 30 minutes before the addition of a solution of 4-methyl-2- (6-bromopyrid-2-yl) pyrimidine and tetrakis (triphenylphosphine) palladium in THF

  (10 ml, freshly distilled from sodium / benzo

  phenone) The reaction mixture was then allowed to warm to room temperature to obtain a pale yellow solution in which a white solid began to precipitate. The mixture was then refluxed for 30 minutes before being cooled and quenched. the addition of a 10% aqueous solution of ethylenediamine tetra-acetic acid sodium salt (150 ml at pH 8). The two phases were separated and the aqueous solution was extracted with ethyl acetate. (2 x ml) The organic solutions were combined, dried over magnesium sulphate (anhydrous) and

  evaporated to give a bright yellow gum yield 0.9 g.

  The gum was purified by flash chromatography under vacuum on a 40 mm × 40 mm diameter silica gel pad (Merck 7729) eluting with a portion of ml of dichloromethane and then 4 portions of 50 ml of methyl ether. The fractions 3-5 were pooled to give a pale yellow gum, in a yield of 0.397 g (70.5%), which solidified on standing. The solid was recrystallized from acetate. 10% ethyl in hexane to give

slats of a lustrous white.

Melting point 123.8 124.3 C.

  Proton magnetic resonance in C 13 CD at 270 MHz: 7.47 (dd); 7, 36 (m); 7.77 (d); 7.92 (t);

  8.48 (d); 8.79 (d); 7.28 (d); 2.66 (s) ppm.

  Synthesis of 4-methyl-2- (6-bromopyrid-2-yl) pyrimidine 2,6-Dibromopyridine (9.48 g, 40 mM) was dissolved in tetrahydrofuran (100 ml, freshly distilled from sodium The solution was then cooled in a bath of solid CO 2 and acetone and n-butyllithium (2.5M solution in hexane 24 mL, 60 mM) was added with stirring. 30 minutes below -70 ° C. The dark green solution was then stirred at -78 ° C. for 1 hour, after which a small sample was taken, deactivated by the addition of water and extracted with ethyl acetate. The analysis by gas chromatography showed that there was only 2-bromopyridine at this stage, an anhydrous solution of zinc (II) chloride (1.0 M in 120 ml of diethyl ether, 120 m M) was added in 30 minutes, the reaction temperature being below -70 ° C. During the addition, the color took on a tinge of a duller green the and a green gum precipitated A solution of

  tetrakis (triphenylphosphine) palladium (1.0 g of catalytic

  and 2-bromo-4-methylpyrimidine (9.6 g, 39.9 mM) in tetrahydrofuran (100 mL, freshly distilled from sodium / benzophenone) was then added in 30 minutes below The reaction mixture was allowed to warm to room temperature before refluxing for 1 hour. After cooling to room temperature, the reaction mixture was quenched by pouring into a 10% solution of ethylenediamine tetra- sodium acetate in water at pH 8 (500 ml) and extracting with ethyl acetate (3 x 500

  ml) The extraction phases with ethyl acetate

  The extracts were washed once with water (100 ml), dried over magnesium sulphate and evaporated to dryness.

giving a brown gum (12.1 g).

  The gum was purified by preparative medium pressure liquid chromatography using silica gel 60 (40-60 micron) and eluting with ethyl acetate to obtain the product as a brown solid. pale Yield

3.15 g (31.5%).

  The solid substance was recrystallized from

  ethyl acetate, m.p. 134.5 to 135.1 ° C.

  Displacements of the protons in the analysis R M N in CD C 13 at 270 M Hz: 7.60 (dd); 7.71 (t); 8.46 (dd); 8.78 (d);

7.19 (d); 2.76 (s) ppm.

CHEMICAL FORMULAS

R 3 R 4 (I) R 5 R 6

X C 1

(VIII)

(III) Br R 4 R 5 R 6 R 1 C 1

Y Z

CHEMICAL FORMULAS

  Li (IV) z Zn Cl YR 2 R 1 Br Ci WR 3 Br Br (V) (VI) (VII) Br R 4 δ NR 5 R 6 Diagram AXC 1 W y ftape (a) N v, Product (IV) step (b) Product (V) (c) R 5

Z R 6

z R (I) Z

(VIII)

  Cl R 4 Y (I) Scheme B Br Li Ci C 1 n-Bu Li / THF

Zn C 1 26ther of di-

ethy 1 e -70 n C CH 3 Zn Cl Ci C 1

Claims (5)

  Process for the preparation of a compound of formula (V): wherein W, Y and Z independently represent hydrogen, chlorine, fluorine, an alkyl or alkoxy group, characterized in that it consists in treating a compound of formula (IV): Li - Cl (IV) WY in which W, Y and Z are as defined above, with zinc chloride (II).   Process according to Claim 1 for the preparation of a compound of the formula (V): ZnCl Cl (v) Z I W   wherein W, Y and Z are as defined in claim 1, characterized in that it comprises the steps of: a) combining lithium with a compound of formula (VIII): X Ci Z (VIII)   W Y wherein W, Y and Z are as defined in claim 1 and X is bromine or iodine; and b) treating the product formed in (a) with the zinc chloride (II).   Process for the preparation of a compound of general formula (I) R 1 R 2 R 3   In which W, Y and Z independently represent hydrogen, chlorine, fluorine, an alkyl group or   alkoxy, R 1, R 2 and R 3 independently represent hydro-   gene, an alkyl, haloalkyl or alkoxy group, and R 4, R 5 and R 6 independently represent hydrogen, chlorine, fluorine, an alkyl, haloalkyl or alkoxy group, or R 4 and R 5 together form a group polymethylene of the formula - (CH 2) m wherein m is 3 or 4; process characterized in that it comprises the steps of: a) combining lithium with a compound of formula (VIII): X Cl (VIII) Z W Z   Wherein W, Y and Z are as defined above and X is bromine or iodine; b) treating the product thus formed in (a) with zinc (II) chloride and (c) reacting the product thus formed in (b) with a compound of formula (III): R 2 R 3 (III) R 4 R 5 R 6   in the presence of a suitable catalyst.   4 Process according to claim 1, 2 or 3,   characterized in that W, Y and Z all represent hydro-   gene. Product, characterized in that it is obtained by the process which comprises the steps of: a) combining lithium with a compound of formula (VIII): Cl (VIII)   wherein W, Y and Z independently represent hydrogen, chlorine, fluorine, an alkyl or alkoxy group and X is chlorine or bromine; and (b) to take the product thus formed and to do so   react with zinc (II) chloride.   Compound, characterized in that it corresponds to the general formula (V): Zn C 1 Cl (v) Y -W in which W, Y and Z independently represent hydrogen, fluorine, chlorine, an alkyl group or alkoxy. A product, characterized in that it is obtained by the process of treating a compound of formula (IV): Li Cl (IV) Z w wherein W, Y and Z are as defined in   Claim 1 with zinc chloride (II).