Continuous large-scale production of ethyl 2,2-difluoro-4-pentenoate and 2-fluorinated methyl aminoacetonitriles by use of a flow reactor

• US 4,847,401 A
• Filed: 01/15/1988
• Issued: 07/11/1989
• Est. Priority Date: 12/31/1985
• Status: Expired due to Term

• Current Assignee: Aventis Incorporated (Sanofi )
• Original Assignee: Merrell Pharmaceuticals Incorporated (Dow, Inc.)
• Inventors: Kolb, Michael, Gerhart, Fritz
• Primary Examiner(s): BRUST, JOSEPH
• Application Number:
  US07/145,694
• Time in Patent Office: 543 Days
• Field of Search: 560/219, 558/378, 558/452
• US Class Current: 558/378
• CPC Class Codes: B01J 19/0013 Controlling the temperature of the process
• CPC Class Codes: B01J 19/18 Stationary reactors having moving elements inside B01J19/08, B01J19/26 take precedence
• CPC Class Codes: B01J 2219/00058 Temperature measurement

Abstract

The large scale preparation of ethyl 2,2-difluoro-4- pentenoate and 2-fluorinated methyl aminoacetonitriles by reaction of 2-H-perfluoroethyl allyl ether and n-butyl lithium and fluoromethylacetonitrile and a Grignard reagent, respectively, is largly unsuccessful because of side reactions which convert intermediate products and reactants to undesired products. Applicants have overcome these problems by performing the reactions with cooling in a continuous manner in a flow reactor with short residence time.

Claims

1. A method for the production of ethyl 2,2-difluoro-4-pentenoate, wherein the improvement comprises the continuous preparation of 1,2,2-trifluorovinyl allyl ether via the dehydrofluorination of 2-H-perfluoroethyl allyl ether with n-butyl lithium at low temperatures and short residence times in a flow reactor system comprising,

a closed tubular flow reactor comprising at least two inlet ports and an outlet port;

respective fluid supply conduits communicating with said inlet ports;

at least one of said fluid supply conduits being thermally conductive and coiled proximate to said flow reactor;

a fluid outlet communicating with said outlet port; and

pump means for controlling the flow of fluid through said flow reactor;

and which comprises the spontaneous arrangement of said 1,2,2-trifluorovinyl allyl ether in the presence of ethanol to form said ethyl 2,2-difluoro-4-pentenoate.

2. A method for the production of 2-fluorinated methyl aminoacetronitriles, wherein the improvement comprises the continuous preparation of a fluorinated methyl ketimine magnesium halide via the reaction of a Grignard reagent with fluoroacetonitrile at low temperatures and short residence times in a flow reactor system comprising,

a closed tubular flow reactor comprising at least two inlet ports and an outlet port;

respective fluid supply conduits communicating with said inlet ports;

at least one of said fluid supply conduits being thermally conductive and coiled proximate to said flow reactor;

a fluid outlet conduit communicating with said outlet port; and

pump means for controlling the flow of fluid through said flow reactor;

which comprises the reaction of said ketimine magnesium halide salt with hydrogen cyanide, or aqueous ammonium cyanide, or an aqueous solution of an alkali metal cyanide and a proton source to form said 2-fluorinated methyl aminoacetonitrile.

3. A process for the preparation of 2-fluoro-methyl-2-amino-3-pentenonitrile according to claim 2, wherein the Grignard reagent is propenylmagnesium bromide.