EP1899312A2 - Improved synthesis of substituted 1-halomethyl-2-phenyl-1-phenyl oxirane - Google Patents

Improved synthesis of substituted 1-halomethyl-2-phenyl-1-phenyl oxirane

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Publication number
EP1899312A2
EP1899312A2 EP06745168A EP06745168A EP1899312A2 EP 1899312 A2 EP1899312 A2 EP 1899312A2 EP 06745168 A EP06745168 A EP 06745168A EP 06745168 A EP06745168 A EP 06745168A EP 1899312 A2 EP1899312 A2 EP 1899312A2
Authority
EP
European Patent Office
Prior art keywords
phenyl
oxirane
halomethyl
chlorophenyl
propene
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP06745168A
Other languages
German (de)
French (fr)
Inventor
David Leonov
David Ovadia
Raya Sturkovich
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Adama Makhteshim Ltd
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
Publication of EP1899312A2 publication Critical patent/EP1899312A2/en
Withdrawn legal-status Critical Current

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Classifications

    • 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.

Landscapes

  • 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.
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-
EP06745168A 2005-06-27 2006-06-22 Improved synthesis of substituted 1-halomethyl-2-phenyl-1-phenyl oxirane Withdrawn EP1899312A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL16942005 2005-06-27
PCT/IL2006/000729 WO2007000759A2 (en) 2005-06-27 2006-06-22 SYNTHESIS OF SUBSTITUTED l-HALOMETHYL-2-PHENYL-l-PHENYL OXIRANE

Publications (1)

Publication Number Publication Date
EP1899312A2 true EP1899312A2 (en) 2008-03-19

Family

ID=37547032

Family Applications (1)

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EP06745168A Withdrawn EP1899312A2 (en) 2005-06-27 2006-06-22 Improved synthesis of substituted 1-halomethyl-2-phenyl-1-phenyl oxirane

Country Status (5)

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

Citations (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

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3218130A1 (en) * 1982-05-14 1983-11-17 Basf Ag, 6700 Ludwigshafen AZOLYL METHYLOXIRANES, METHOD FOR THE PRODUCTION THEREOF AND FUNGICIDES CONTAINING THEM
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

Patent Citations (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

Also Published As

Publication number Publication date
BRPI0613843A2 (en) 2011-02-15
WO2007000759A3 (en) 2007-04-05
CN101208322A (en) 2008-06-25
KR20080024207A (en) 2008-03-17
WO2007000759A2 (en) 2007-01-04

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