WO2007000759A2 - SYNTHESIS OF SUBSTITUTED l-HALOMETHYL-2-PHENYL-l-PHENYL OXIRANE - Google Patents

SYNTHESIS OF SUBSTITUTED l-HALOMETHYL-2-PHENYL-l-PHENYL OXIRANE Download PDF

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Publication number
WO2007000759A2
WO2007000759A2 PCT/IL2006/000729 IL2006000729W WO2007000759A2 WO 2007000759 A2 WO2007000759 A2 WO 2007000759A2 IL 2006000729 W IL2006000729 W IL 2006000729W WO 2007000759 A2 WO2007000759 A2 WO 2007000759A2
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WIPO (PCT)
Prior art keywords
phenyl
oxirane
chlorophenyl
propene
halomethyl
Prior art date
Application number
PCT/IL2006/000729
Other languages
French (fr)
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WO2007000759A3 (en
Inventor
Raya Sturkovich
David Ovadia
David Leonov
Original Assignee
Makhteshim Chemical Works Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Makhteshim Chemical Works Ltd. filed Critical Makhteshim Chemical Works Ltd.
Priority to BRPI0613843-8A priority Critical patent/BRPI0613843A2/en
Priority to EP06745168A priority patent/EP1899312A2/en
Publication of WO2007000759A2 publication Critical patent/WO2007000759A2/en
Publication of WO2007000759A3 publication Critical patent/WO2007000759A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C07D301/14—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic peracids, or salts, anhydrides or esters thereof
    • C07D301/16—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic peracids, or salts, anhydrides or esters thereof formed in situ, e.g. from carboxylic acids and hydrogen peroxide
    • C07D301/18—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic peracids, or salts, anhydrides or esters thereof formed in situ, e.g. from carboxylic acids and hydrogen peroxide from polybasic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals

Definitions

  • the present invention is from the field of chemical synthesis, particularly the field of the synthesis of substituted methyl oxirane compounds, e.g. cis- l-(chloromethyl)-2-(2- chlorophenyl)- 1 -(4-fluorophenyl) oxirane.
  • the present invention provides a process for the preparation of l-halomethyl-2-phenyl-l- phenyl oxirane, wherein the phenyl substituents may be mono-, di- or poly- halo substituted, wherein 3-halo-2-phenyl- 1-phenyl propene is reacted with an anhydride and hydrogen peroxide in a solvent selected from among alkyl esters, followed by subsequent extraction and separation of the organic phase and isolation of the oxirane.
  • l-halomethyl-2-phenyl-l -phenyl oxirane wherein the phenyl substituents may be mono-, di- or poly- halo substituted, is prepared by reacting 3-halo-2-phenyl- 1 -phenyl propene with an anhydride and hydrogen peroxide in a solvent selected from among alkyl esters, followed by subsequent extraction and separation of the organic phase and isolation of the oxirane.
  • suitable anydrides include acetic anhydride and maleic anhydride.
  • Suitable solvents are alkyl acetates, preferably butyl acetate and ethyl acetate.
  • the reaction time is between 2 and 25 hours and the reaction temperature is from 5°C and 70 0 C.
  • the isolation and purification of the oxirane is carried out subsequent to the reaction and includes extraction and crystallization in single, multiple or repeated stages.
  • cis-l-(chloromethyl)-2-(2-chlorophenyl)-l-(4-fluorophenyl) oxirane is prepared wherein Z-3-chloro-2-(4-fluorophenyl)-l-(2-chlorophenyl) propene is reacted with maleic anhydride and hydrogen peroxide wherein the solvent is selected from among butyl acetate and ethyl acetate.
  • the reaction time is between 2 to 25 hours, preferably 8 to 13 hours, and the reaction temperature is from 15°C to 7O 0 C, preferably 25 0 C to 5O 0 C.
  • the organic phase of the reaction is extracted with water to remove all the water miscible reagents and the remaining organic phase is then subject to purification of the oxirane derivative therefrom.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epoxy Compounds (AREA)

Abstract

The present invention provides a process for the preparation of l-halomethyl-2-phenyl-l-phenyl oxirane, wherein the phenyl substituents may be mono-, di- or poly- halo substituted, wherein 3 -halo- 2 -phenyl- 1-phenyl propene is reacted with an anhydride and hydrogen peroxide in a solvent selected from among alkyl esters, followed by subsequent extraction and separation of the organic phase and isolation of the oxirane . The isolation and purification of the oxirane is carried out subsequent to the reaction and includes extraction and crystallization in single, multiple or repeated stages .

Description

Improved Synthesis of Substituted l-haIomethyl-2-phenyI-l-phenyl oxirane
Field of the Invention
The present invention is from the field of chemical synthesis, particularly the field of the synthesis of substituted methyl oxirane compounds, e.g. cis- l-(chloromethyl)-2-(2- chlorophenyl)- 1 -(4-fluorophenyl) oxirane.
Background of the Invention
There are several synthetic schemes for the preparation of substituted halo-methyl oxiranes. The synthesis of cis- l-(chloromethyl)-2-(2-chlorophenyl)-l -(4-fluorophenyl) oxirane, which is an important intermediary for the synthesis of the important agrochemical products such as epoxiconazole, is disclosed in U.S. 5,268,517, however, the process described therein uses a water miscible organic acid as a solvent which makes the isolation process of the final product extremely difficult and provides poor yields. Furthermore the process is hazardous as it involves the handling of hydrogen peroxide.
Accordingly there is a need for a safe, efficient process for the preparation of substituted halo-methyl-oxirane which facilitates the isolation of the substituted halo-methyl oxirane.
It is the objective of the present invention to provide a safe, efficient process for the preparation of substituted halo-methyl oxiranes.
Summary of the Invention
The present invention provides a process for the preparation of l-halomethyl-2-phenyl-l- phenyl oxirane, wherein the phenyl substituents may be mono-, di- or poly- halo substituted, wherein 3-halo-2-phenyl- 1-phenyl propene is reacted with an anhydride and hydrogen peroxide in a solvent selected from among alkyl esters, followed by subsequent extraction and separation of the organic phase and isolation of the oxirane.
Detailed Description of the Invention
The following description is illustrative of embodiments of the invention. The following description is not to be construed as limiting, it being understood that the skilled person may carry out many obvious variations to the invention. According to the present invention there is provided a process for the preparation of substituted l-halomethyl-2-phenyl-l -phenyl oxirane. The present invention provides an improved process wherein said improvements are in yield, isolation procedure and safety.
According to a particular aspect of the invention l-halomethyl-2-phenyl-l -phenyl oxirane, wherein the phenyl substituents may be mono-, di- or poly- halo substituted, is prepared by reacting 3-halo-2-phenyl- 1 -phenyl propene with an anhydride and hydrogen peroxide in a solvent selected from among alkyl esters, followed by subsequent extraction and separation of the organic phase and isolation of the oxirane. Non-limiting examples of suitable anydrides include acetic anhydride and maleic anhydride. Suitable solvents are alkyl acetates, preferably butyl acetate and ethyl acetate. The reaction time is between 2 and 25 hours and the reaction temperature is from 5°C and 700C. The isolation and purification of the oxirane is carried out subsequent to the reaction and includes extraction and crystallization in single, multiple or repeated stages.
According to a specific embodiment of the present invention with reference to Scheme 1, cis-l-(chloromethyl)-2-(2-chlorophenyl)-l-(4-fluorophenyl) oxirane is prepared wherein Z-3-chloro-2-(4-fluorophenyl)-l-(2-chlorophenyl) propene is reacted with maleic anhydride and hydrogen peroxide wherein the solvent is selected from among butyl acetate and ethyl acetate. The reaction time is between 2 to 25 hours, preferably 8 to 13 hours, and the reaction temperature is from 15°C to 7O0C, preferably 250C to 5O0C. Upon completion of the reaction, the organic phase of the reaction is extracted with water to remove all the water miscible reagents and the remaining organic phase is then subject to purification of the oxirane derivative therefrom.
Figure imgf000004_0001
Scheme 1
Examples Example No. 1:
28.1 g (0.1 mol) of Z-3-chloro-2-(4-fluorophenyl)-l-(2-chlorophenyl) propene in 236g of ethyl acetate are mixed with 98 g (1 mol) of maleic anhydride, and 34g (0.6 mol) of 60% strength hydrogen peroxide solution is added at 30°C within 2 hour. The temperature is increased to 40° C and the mixture is stirred at 4O0C for a further 10 to 11 hours (conversion 95-96%, HPLC control).
The organic phase is washed twice with water at ambient temperature. Ethyl acetate is distilled. Crystallization can be done from hexane or chlorinated hydrocarbons, cis-1- (chloromethyl)-2-(2-chlorophenyl)-l-(4-fluorophenyl) oxirane with purity 97% & yield 86-87% is obtained.
Example No. 2:
28.1 g (0.1 mol) of Z-3-chloro-2-(4-fluorophenyl)-l-(2-chlorophenyl) propene in 25Og of butyl acetate are mixed with 73.5 g (0.75 mol) of maleic anhydride, and 25.5g (0.45 mol) of 60% strength hydrogen peroxide solution is added at 300C within 2 hour. The temperature is increased to 400C and the mixture is stirred at 400C for a further 16 to 17 hours (conversion 97-98%, HPLC control).
Butyl acetate is distilled. Crystallization can be done from hexane or chlorinated hydrocarbons. cis-l-(chloromethyl)-2-(2-chlorophenyl)-l-(4-fluoro-phenyl) oxirane with purity 97% & yield 86-87% is obtained. While embodiments of the 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 of the claims.
-A-

Claims

Claims
1. A process for the preparation of l-halomethyl-2-phenyl-l -phenyl oxirane, wherein the phenyl substituents may be mono-, di- or poly- halo substituted, wherein 3-halo-2- phenyl- 1 -phenyl propene is reacted with an anhydride and hydrogen peroxide in a solvent selected from among alkyl esters, followed by subsequent extraction and separation of the organic phase and isolation of the oxirane.
2. A process according to claim 1 wherein the l-halomethyl-2-phenyl-l -phenyl oxirane is cis-l-(chloromethyl)-2-(2-chlorophenyl)-l- (4-fluorophenyl) oxirane.
3. A process according to claim 1 wherein the 3-halo-2-phenyl- 1-phenyl propene is Z-3- chloro-2-(4-fluorophenyl)- 1 -(2-chlorophenyl) propene.
4. A process according to claim 1 wherein the solvent is selected from among ethyl acetate and butyl acetate.
5. A process according to claim 1 wherein said anhydride is selected from among acetic anhydride and maleic anhydride.
6. A process according to claim 1 for preparing cis-l-(chloromethyl)-2-(2-chlorophenyl)- 1- (4-fluorophenyl) oxirane by reacting Z-3-chloro-2-(4-fmorophenyl)-l-(2- chlorophenyl) propene with maleic anhydride and hydrogen peroxide in butyl or ethyl acetate.
S-
PCT/IL2006/000729 2005-06-27 2006-06-22 SYNTHESIS OF SUBSTITUTED l-HALOMETHYL-2-PHENYL-l-PHENYL OXIRANE WO2007000759A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
BRPI0613843-8A BRPI0613843A2 (en) 2005-06-27 2006-06-22 Method for the preparation of 1-halomethyl-2-phenyl-1-phenyl oxirane
EP06745168A EP1899312A2 (en) 2005-06-27 2006-06-22 Improved synthesis of substituted 1-halomethyl-2-phenyl-1-phenyl oxirane

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL169420 2005-06-27
IL16942005 2005-06-27

Publications (2)

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WO2007000759A2 true WO2007000759A2 (en) 2007-01-04
WO2007000759A3 WO2007000759A3 (en) 2007-04-05

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EP (1) EP1899312A2 (en)
KR (1) KR20080024207A (en)
CN (1) CN101208322A (en)
BR (1) BRPI0613843A2 (en)
WO (1) WO2007000759A2 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4464381A (en) * 1982-05-14 1984-08-07 Basf Aktiengesellschaft Fungicides containing azolylmethyloxiranes
US5268517A (en) * 1989-07-14 1993-12-07 Basf Aktiengesellschaft Stereoselective preparation of Z-1,2-diarylallyl chlorides and the conversion thereof into azolylmethyloxiranes, and novel intermediates

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3218129A1 (en) * 1982-05-14 1983-11-17 Basf Ag, 6700 Ludwigshafen Azolylmethyloxiranes, their preparation and use as medicaments

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4464381A (en) * 1982-05-14 1984-08-07 Basf Aktiengesellschaft Fungicides containing azolylmethyloxiranes
US5268517A (en) * 1989-07-14 1993-12-07 Basf Aktiengesellschaft Stereoselective preparation of Z-1,2-diarylallyl chlorides and the conversion thereof into azolylmethyloxiranes, and novel intermediates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1899312A2 *

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CN101208322A (en) 2008-06-25
KR20080024207A (en) 2008-03-17
EP1899312A2 (en) 2008-03-19
WO2007000759A3 (en) 2007-04-05
BRPI0613843A2 (en) 2011-02-15

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