WO2000044703A2

WO2000044703A2 - A novel synthetic route for obtaining 1-(4-chlorophenyl)-4,4-dimethyl-pentane-3-one

Info

Publication number: WO2000044703A2
Application number: PCT/IL2000/000063
Authority: WO
Inventors: Yoel Sasson; David Ovadia; Raya Sturkovich
Original assignee: Makhteshim Chemical Works Ltd.
Priority date: 1999-01-31
Filing date: 2000-01-30
Publication date: 2000-08-03
Also published as: WO2000044703A3; AU2317000A; IL128290A0

Abstract

1-(4-chlorophenyl)-4,4-dimethyl-pentane-3-one of formula (I) is prepared by the alkylation of pinacolone (3,3-dimethyl-2-butanone) with p-chlorobenzylchloride where the pinacolone is used both as a reagent and the solvent. The alkylation is done under either Phase Transfer Catalysis conditions in the presence of a base or in the presence of a strong base.

Description

A Novci Synthetic Route For Obtaining H4<M)rophe-rιyl>4 -Diιndhyl-Paιtanfr-3-One

Field of the Invention

The present invention concerns an improved process for preparing l-(4-chlorophenyl)- 4,4-dimethyl-pentane-3-one, an intermediate for the synthesis of the fungicide tebuconazole.

Background of the Invention

The synthesis of l-(4-chlorophenyl)-4,4-dimethyl-pentane-3-one is described in European patent number 354,991. The basic process is done by first condensing pinacolone with p-chlorobenzaldehyde and isolating the resulting l-(4-chlorophenyl)-4,4-dimethyl-l- pentene-3-one. This pentene is then hydrogenized under pressure using Raney nickel as a catalyst. Since then a few synthetic routes along these lines (e.g. a two step process) have been described in EP 355,350, DE 3,921,167 and DE 4,004,031.

Alkylation of pinacolone is known and described in the literature. Langhals, E & Langhals, H. describe (Tetrahedron Letters 31, 859-862 1990) the alkylation of pinacolone with methyliodide. However the main products aredi and tri alkylated products. Only a low amount of rnonoalkylated product are obtained.

Galli, C, & Gentili, P. describe (J. Chem. Soc. Perkin Trans, 5. 1135-1 170 1993) the alkylation of pinacolone with phenyl bromide or iodide in the presence of a 4 fold excess of t-BuOK and a catalytic amount of FeCl₂. However by conducting this reaction where the alkylating agent is p-chlorobenzylchloride the diarylated product prevailed 48 % vs. 41% ofthe mono alkylated product.

Montignoul, M. J. et al. describe (J. Heterocyclic Chem. 21, 1509-1519 1984) the alkylation of pinacolone with benzylchloride using NaNH₂ in ether resulting in a 56% of the mono alkylated product. However using the same conditions, where p-chlorobenzylchloride was the alkylating agent of pinacolone resulted in a ratio of 2: 1 of di to mono alkylated products.

Objectives of the Invention

It is the objective of the present invention to provide a new and improved method for the preparation of l-(4-chlorophenyl)-4,4-dimethyl-pentane-3-one in one step reaction rather than in two steps.

It is a further objective ofthe present invention to provide a method for the preparation of this compound without using a very high pressure (up to ca. 150 bar) that is necessary for the selective hydrogenation of l-(4-chlorophenyl)-4,4-dimethyl-l- pentene-3-one.

An additional objective of the present invention is obtaining the desired product without having to use the Raney nickel hydrogenation catalyst known to be a carcinogenic and a highly flammable material.

Other objects ofthe invention will become apparent as the description proceeds.

Summary of the Invention

The present invention provides a process for preparing l-(4-chlorophenyl)-4,4-dimethyl-pentane-3-one ofthe formula

by the alkylation of pinacolone (3,3-dimethyl-2-butanone) with p- cWorobenzylchloride where the pinacolone is used both as a reagent and the solvent. The alkylation is done under either Phase Transfer Catalysis conditions in the presence of a base or in the presence of a strong base. Detailed Description of a Preferred Embodiment ofthe Invention

The reaction of the present invention may optionally be carried out in one of two ways: a) In the presence of a strong base b) Under phase transfer catalysis (PTC) conditions.

Both routes are most successful by using pinacolone in an excess of 10 to 50 fold relative to the alkylating agent. Thus pinacolone in both routes is used both as the reagent and the solvent.

Examples of strong bases are sodium or potassium tetraalkyl alkoxides containing straight or branched Ci to C6 alkyl groups. The preferred catalyst is sodium or potassium tertbutoxide.

Examples of PTC are halogenated tetraalkylammonium salts containing straight or branched Ci to Cβ alkyl groups. The preferred catalysts are tetrabutylammonium iodide or the cheaper catalyst tetramethylammonium chloride in the presence of a catalytic amount of potassium iodide.

In the first route using potassium tertbutoxide as the strong base, the alkylating agent is added to the pinacolone potassium tertbutoxide mixture, where the mixture is either cooled, heated or at room temperature. The addition ofthe alkylating agent can be done in small portions during a time interval or at once. Thus the reaction can be carried out at a temperature of O°C to 100°C, preferably in the range of 5°C to 70°C and most preferably in the range of 10'C to 50'C. Best results are obtained by cooling the reaction to lO°C - 15°C where the yield is 85-86 %. In the latter case pinacolone self condensation is reduced and the quantity of small impurities is very low. In the second route, the phase transfer catalysis is done under basic conditions where the preferred base is NAOH. Reaction temperature is in the range of 100°C - 105°C resulting in a yield of 80%.

Examples

Example 1: In the Presence of a Strong Base

Potassium t-butoxide (73 g, 0.65 mole) and pinacolone (1000 g, 10 mole) were placed in a four-necked reaction flask equipped with a stirrer, condenser, thermometer and a dropping funnel, and the flask was cooled to a temperature of 15°C. p- Chlorobenzylchloride (81 g, 0.5 mole) was quickly added and the reaction mixture was stirred for 4-5 hours while mamtaining the temperature. The reaction rnixture was worked up with 200 ml. of water, stirred for 5 min. and the phases were separated. Excess pinacolone was removed by distillation, where 84 g of 1 -(4-chlorophenyl)-

4,4-dimethyl-pentane-3-one (purity 98%) was obtained by high vacuum distillation.

Example 2: Under Phase Transfer Catalysis Conditions

Sodium hydroxide (0.6 g, 0.15 mole), tetramethylammonium chloride (0.27 g, 2.5 mole), KI (I g, 0.6 mmole) and pinacolone (200 g, 2 mole) were placed in a four necked reaction flask equipped with a stirrer, condenser, thermometer and a dropping funnel and mixed for 5 min. at room temperature. p-Chlorobenzylchloride (16 g, 0.1 mole) was quickly added and the reaction mixture was heated to reflux (102-103°C) for a period of 6-10 hours. Conversion of p-chlorobenzylchloride is 98-100 %. The reaction rnixture was worked up with water (50 ml), stirred for 5 min. and the phases were separated. Pinacolone was removed by distillation and 18 g of l-(4- chlorophenyl)-4,4-dimethyl- pentane-3-one (purity 98%) was obtained by high vacuum distillation. While embodiments ofthe invention have been described by way of illustration, it will be apparent that the invention may be carried out with many modifications, variations and adaptations, without departing from its spirit or exceeding the scope ofthe claims.

Claims

A process for the preparation of l-(4-chlorophenyl)-4,4-dimethyl-pentane-3-one ofthe formula (I)

(I) which comprises the alkylation of 3,3-dimethyl-2-butanone (pinacolone) with p-chlorobenzylchloride wherein the pinacolone is also the solvent.

2. A process according to Claim 1 , where the reaction is run in the presence of a base.

3. A process according to Claim 1 wherein the base is selected from the group consisting of G to C₆ alkoxides and phase transfer catalysis conditions.

4. A process according to Claim 3 wherein the base is selected from the group consisting of G - Cβ straight or branched alkoxides and mixtures thereof.

5. A process according to Claim 3 wherein the strong base is sodium or potassium tert-butoxide.

6. A process according to Claim 1 wherein the ratio of p-chlorobenzaidehyde to pinacolone is from 1 to 10 to 1 to 50.

7. A process according to Claim 6 wherein the ratio of p-chlorobenzaidehyde to pinacolone is from 1 to 15 to 1 to 30

8. A process according to Claims 1 - 7 where the reaction temperature is in the range ofO°C to l20°C.

9. A process according to Claim 8 wherein the reaction temperature is in the range of5°C to 60°C.

10. A process according to Claim 1 wherein the reaction time is from 30 min. to 10 hours.

11. A process according to Claim 10 wherein the reaction time is from 1 hour to 8 hours.

12. A process according to Claim 1 wherein the phase transfer catalyst is a tetraalkylammonium halide.

13. A process according to Claim 12 wherein the tetraalkylammonium halide is selected from the group consisting of tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetraethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrapentylammonium iodie and mixtures of these.

14. A process according to Claim 12 wherein the tetraaUcylammonium halides are selected from the group consisting of tetrabutylammonium iodide and tetramethylammonium chloride in the presence of potassium iodide.