Title of Invention

PROCESS FOR THE PREPARATION OF (PYRIMIDIN-2-YL) METHYL KETONES

Abstract PROCESS FOR THE PREPARATION OF (PYRIMIDIN-2-YL) METHYL KETONES The present invention relates to a process for the preparation of (pyrimidin-2-y1)methyl ketones of the general formula wherein the substituent groups are as herein described
Full Text

Process for the preparation of (pyrimidm-2-yl)methyI ketones
The invention relates to a process for the preparation of (pyrimidin-2-yl)methyl ketones of the general formula

in which R1 is in each case a C1_10-alkyl groups a Ca-s-cycloalkyl group, an allyl group or an aryl-C1-4-allgii group, aria R2 is a C1-10-alsiLgroup or aryl group. Ci-io-Alkyl groups are understood here and below as meaning aH linear or branched primary, secondary or tertiary alkyl groups having 1 to 10 carbon atoms, thus, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, fert-pentyl, neopentyl, hexyl, hepryl, octyl, nonyl or decyl.
C3-8-Cycloalkyl are to be understood as meaning, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Aryl-Ci-4-alkyl groups are the groups composed of an aryl group and an alkyl group having 1 to 4 carbon atoms, aryl groups being understood as meaning, in particular, phenyl or naphthyl groups. The aryl groups may also be substituted by one or more Ci_4-alkyl groups, Ci^t-alkoxy groups or halogen atoms. Examples of aryl-Ci-4-aIkyl groups are, in particular, benzyl, 1-phenylethyl, 2-phenylethyl and 3-phenylpropyl.
Compounds of the formula I, in particular l-(4,6-dimemoxypyrimidin-2-yl)propan-2-one (R1=R2 = Me) are potential intermediates in the synthesis of agrochemical active ingredients.
Syntheses of these compounds have hitherto not been described in the prior art.
It was an object of the present invention to provide a preparation process which is simple and suitable for an industrial scale.
According to the invention, the object is achieved by the process of Claim 1. It has been found that the malondiimidates, which are readily available from malodinitrile and the corresponding alcohols (DE-A-24 26 913, EP-A-0 024 200), of the general formula


in which R1 has the meaning given above, react with P-keto esters of the general formula

in which R2 has the meaning given above, and R3 is a Ci_io-alkyl group, directly and in a good yield to give the desired compounds (T).
The reaction is advantageously carried out in such a wayIhat the water formed during the reaction is removed from the reaction mixture. This can be achieved, for example, by adding a dehydrating agent or by azeotropic distillation with a suitable entrainer. The malondiirnidates (IT) can either be used without a diluent (as free base) or else be formed in situ from a corresponding salt and a base. They are preferably used without a diluent. For this, they can, for example, be extracted with a solvent of low polarity, such as dichloromethane or diethyl ether, from a neutralized solution of one of their salts and be isolated by evaporating the solvent (EP-A-0 024 200).
The salts of the malondiirnidates (13) used are preferably the dihydrochlorides.
The process according to the invention is preferably used for the preparation of (4,6^-dimemoxypyrirnidin-2-yl)methyl ketones, by using dimethyl malondiimidate (R1 = Me) as malondiimidate (U).
The P-keto esters (ID) used are preferably acetoacetic esters (R2 = Me), 3-oxopentanoic esters (R2 = Et) or benzoylacetic esters (R2 = Ph).
Preferred P-keto esters are the methyl and ethyl esters (R3 = Me, Et).
The process according to the invention is advantageously carried out in an inert solvent, such as, for example, toluene or xylene. The reaction temperature is advantageously -50 to 150 °C.

The examples below illustrate how the process according to the invention is carried out, but are not intended to impose any limitation.
Example 1 l-(4,6-Dimethoxypyrimidin-2-yl)propan-2-one
a,R1=R2 = Me)
A solution of dimethyl malondiimidate (6.51 g, 0.61 mol) in xylene (20 ml) was added to a solution, heated to 135 °C (reflux), of methyl acetoacetate (5.92 g, 50 mmol) in xylene (80 ml) over the course of 135 min in a flask fitted with reflux condenser and water separator such that the reaction mixture continued to reflux. After refluxing for a further 90 min, the reaction mixture was firstly filtered at 70 °C, the filtrate was further cooled to room temperature and then evaporated. The orange-brown oily crude product (8.35 g) was purified by column chromatography with hexane/ethyl acetate (v:v = 5:1) over silica gel 60. Yield: 5.56 g (56%, based on the diimidate) of a yellowish oil, which solidifies after a while.
*HNMR (CDC13): 8 = 5.92 (s, 1H); 3.91 (s, 6H); 3.86 (s, 2H); 2.27 (s, 3H). The spectrum additionally has signals for the enol form.
Example 2 1^4,6-Dimethoxypyrimidin-2-yl)butan-2-one
(I,R1=Me,R2 = Et)
The procedure was as described in Example 1, except that the methyl acetoacetate was
replaced by an equivalent amount of methyl 3-oxopentanoate, the addition period was
150 min with an after-reaction time of 120 min, and the reaction mixture was filtered at
90 °C.
Yield: 6.7 g (64%) of a yellow oil
'HNMR (CDCI3): 8 = 5.91 (s, 1H); 3.91 (s, 6H); 2.59 (q, 2H); 1.09 (t, 3H). The spectrum
additionally has signals for the enol form.

Example 3 l-(4,6-Dimethoxypyrimidin-2-yI)propan-2-one
Cr,Rls=R2 = Me)
The procedure was as described in Example 1, except that the methyl acetoacetate was
replaced by an equivalent amount of ethyl acetoacetate, the addition time was 130 min with
an after-reaction time of 280 min, and the reaction mixture was filtered at 90 °C.
Yield: 5.18 g (54%, based on the diimidate) of a yellowish oil, which solidifies after a
while.



Claims
1. Process for the preparation of (pyrimidin-2-yl)methyl ketones of the general
formula

in which R1 is in each case a C1_10-alkyl group, a C3_8-cycloalkyl group, an aflyl group or an aryl-C1-4-alkyl group, and R2 is a C1_10-alkyl group or aryl group, characterized in that a malondiimidate of the general formula

in which R1 has the meaning given above, is reacted with a {5-keto ester of the general formula

in which R2 has the meaning given above, and R3 is a C1-10-alkyl group.
2. Process according to Claim 1, characterized in that the water formed during the reaction is removed from the reaction mixture during the reaction.
3. Process according to Claim 1 or 2, characterized in that the malondiimidate (D) is prepared in situ from a corresponding salt and a base.
t

4. Process according to Claim 3, characterized in that the salt of the malondiimidate (II) used is the dihydrochloride.
5. Process according to one of Claims 1 to 4, characterized in that the malondiimidate (H) used is dimethyl malondiimidate.
6. Process according to one of Claims 1 to 5, characterized in that the p-keto ester (ID) used is an acetoacetic ester, 3-oxopentanoic ester or benzoylacetic ester.

7. A process for the prepartion of (pyrimmidin-2-yl) methyl ketones substantially as herein
described and exemplified.


Documents:

776-chenp-2004 abstract.pdf

776-chenp-2004 claims.pdf

776-chenp-2004 correspondence-others.pdf

776-chenp-2004 description (complete).pdf

776-chenp-2004 form-26.pdf

776-chenp-2004 form-3.pdf

776-chenp-2004 others.pdf

776-chenp-2004 pct.pdf

776-chenp-2004 petition.pdf

776-chenp-2004-abstract .jpg

776-chenp-2004-claims.pdf

776-chenp-2004-correspondence others.pdf

776-chenp-2004-correspondence po.pdf

776-chenp-2004-description complete.pdf

776-chenp-2004-form 1.pdf

776-chenp-2004-form 3.pdf

776-chenp-2004-form 5.pdf

776-chenp-2004-pct.pdf

776-CHENP-2004.pdf


Patent Number 236634
Indian Patent Application Number 776/CHENP/2004
PG Journal Number 47/2009
Publication Date 20-Nov-2009
Grant Date 13-Nov-2009
Date of Filing 15-Apr-2004
Name of Patentee LONZA LTD
Applicant Address MUNCHENSTEINERSTRASSE 38 CH-4052 BASEL
Inventors:
# Inventor's Name Inventor's Address
1 HIYOSHI, HIDETAKA C/O IHARA CHEMICAL INDUSTRY CO LTD KENKYUSHO 2256 NAKANOGO FUJIKAWA-CHO IHARA-GUN SHIZUOKA 421-3306
2 GRIFFITHS, GARETH, J BARETSTRASSE 2A CH-3930 VISP
PCT International Classification Number C07D239/52
PCT International Application Number PCT/EP02/11279
PCT International Filing date 2002-10-09
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 01124728.5 2001-10-17 EUROPEAN UNION