WO2020148780A1 - Process for preparation of 4,4,4- trifluorobut-2-en-1-ol and intermediate thereof - Google Patents

Process for preparation of 4,4,4- trifluorobut-2-en-1-ol and intermediate thereof Download PDF

Info

Publication number
WO2020148780A1
WO2020148780A1 PCT/IN2020/050042 IN2020050042W WO2020148780A1 WO 2020148780 A1 WO2020148780 A1 WO 2020148780A1 IN 2020050042 W IN2020050042 W IN 2020050042W WO 2020148780 A1 WO2020148780 A1 WO 2020148780A1
Authority
WO
WIPO (PCT)
Prior art keywords
trifluorobut
alkyl
enoate
amine
trifluoro
Prior art date
Application number
PCT/IN2020/050042
Other languages
French (fr)
Inventor
Mridul MISHRA
Sameer Prasad PANDEY
Somaning KURLE
Hanuman GUPTA
Kapil Kumar
Anurag Jain
Original Assignee
Srf Limited
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 Srf Limited filed Critical Srf Limited
Publication of WO2020148780A1 publication Critical patent/WO2020148780A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups

Definitions

  • the present invention provides a process for preparation of 4,4,4- trifluorobut-2-en-l- ol from alkyl 4,4,4-trifluorobut-2-enoate and also provides one step process for preparation of alkyl 4,4,4-trifluorobut-2-enoate from corresponding hydroxy derivative using mild and easily available reagents.
  • Alkyl 4,4,4-trifluorobut-2-enoate is an important intermediate for preparing prostaglandin derivatives. A few methods are known in the prior art for preparation of alkyl 4,4,4-trifluorobut-2-enoates.
  • U.S. Pat. No. 4,563,525 discloses a two-step preparation of ethyl 4,4,4- trifluorobutenoate using l,8-diazabi-cyclo[5.4.0]undec-7-ene (DBU).
  • DBU is an expensive reagent and its use at a commercial scale would be non-viable.
  • present invention develops a cost effective and robust process for preparation of alkyl 4,4,4-trifluorobut-2-enoate.
  • the present invention provides a process for preparation of 4,4,4- trifluorobut-2-en-l- ol from alkyl 4,4,4-trifluorobut-2-enoate using mild and easily available reagents.
  • the present invention provides a process for preparation of 4,4,4- trifluorobut-2-en- 1 -ol, comprising the steps of: a) reacting an alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride in presence of an amine to obtain alkyl 4,4,4-trifluorobut-2-enoate; and b) reducing alkyl 4,4,4-trifluorobut-2-enoate to obtain 4,4,4-trifluorobut-2-en-l- ol.
  • the present invention provides a process for preparation of 4,4,4- trifluorobut-2-en- 1 -ol, comprising the steps of:
  • the present invention provides a process for preparation of 4,4,4- trifluorobut-2-en- 1 -ol, comprising the steps of:
  • the“alkyl” refers to a branched or unbranched aliphatic hydrocarbon chain selected from a group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, sec -butyl, pentyl or the like.
  • “amine” refers to an aliphatic amine and selected from a group consisting of methyl amine, dimethyl amine, ethylamine, diethyl amine, triethyl amine, diisopropyl amine, diisopropylethyl amine, propyl amine, butyl amine or like.
  • the amine for present invention is used in pure form or in solution form.
  • the solution form refers to a solution of amine in a solvent selected from dichloromethane, chloroform, carbon tetrachloride, toluene, acetonitrile, N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), sulfolane or the like.
  • alkyl 4,4,4-trifluorobut-2-enoate and 4,4,4- trifluorobut-2-en- 1 -ol refers to corresponding E-isomer, Z-isomer or a racemic mixture thereof.
  • Alkyl 4,4,4-trifluorobut-2-enoate and 4,4,4-trifluorobut-2-en-l-ol preferably refers to E-isomer.
  • the reducing agents for present invention can be selected from a group consisting of metal-based hydrogenation catalyst such as Pd-C/Fb, Ni-C/Fb, 5% Pt- C/Fb, Pt0 , lithium aluminium hydride, sodium borohydride, sodium triacetoxy borohydride, diisobutylaluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride or like.
  • the reducing agent for present invention may be used in solid, powder or solution form.
  • the solution form refers to a solution of reducing agent in an organic solvent selected from toluene, hexane, methyltetrahydrofuran, tetrahydrofuran, pentane, diethyl ether or like.
  • the reduction reaction in present invention is carried out in a solvent selected from a group consisting of dichloromethane, carbon tetrachloride, diethyl ether, methyltertiarybutyl ether, tetrahydrofuran, methyltetrahydrofuran, monoglyme, toluene or the like.
  • the present invention provides a process for preparation of (2E)- 4,4,4-trifluorobut-2-en-l-ol, comprising the steps of: a) reacting an alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride in presence of an amine to obtain (2E)-alkyl 4,4,4-trifluorobut-2- enoate; and
  • the present invention provides a process for preparation of (2E)-4,4,4-trifluorobut-2-en-l-ol, comprising the steps of:
  • the present invention provides a process for preparation of (2E)-4,4,4-trifluorobut-2-en-l-ol, comprising the steps of:
  • the present invention provides a process for preparation of (2E)- alkyl 4,4,4-trifluorobut-2-enoate, comprising the steps of: a) reducing alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3- hydroxybutanoate; and
  • the step of reducing alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3-hydroxybutanoate is carried out in presence of metal based hydrogenation catalyst selected from a group consisting of Pd-C/Ph, Ni-C/Ph, 5% Pt- C/Ph, Pt0 2 , sodium borohydride, sodium triacetoxy borohydride.
  • metal based hydrogenation catalyst selected from a group consisting of Pd-C/Ph, Ni-C/Ph, 5% Pt- C/Ph, Pt0 2 , sodium borohydride, sodium triacetoxy borohydride.
  • the step of reducing alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3-hydroxybutanoate is carried out in presence of sodium borohydride as reducing agent.
  • alkyl 4,4,4-trifluoro-3-oxobutanoate is preferably carried out in a solvent selected from dichlorome thane, carbon tetrachloride, toluene, diethyl ether, methyltertiarybutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or the like.
  • the step of reducing alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3-hydroxybutanoate is carried out by slowly adding 4,4,4-trifluoro-3- oxobutanoate to a solution of reducing agent.
  • the step of reducing alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3-hydroxybutanoate is carried out by slowly adding 4,4,4- trifluoro-3-oxobutanoate to a solution of sodium borohydride.
  • alkyl 4,4,4-trifluoro-3-hydroxybutanoate is reacted with methane sulfonyl chloride in presence of an amine to obtain alkyl 4,4,4-trifluorobut-2- enoate.
  • reaction of alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride is carried out in presence of an aliphatic amine.
  • alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride is carried out using 2 to 3 molar equivalents of an amine.
  • the amine assists in removal of hydrogen chloride liberated during reaction of alkyl 4,4,4-trifluoro-3- hydroxybutanoate with methane sulfonyl chloride.
  • the reaction of alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride is optionally carried out in an organic solvent selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, toluene, acetonitrile, N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), sulfolane or the like.
  • the reaction of alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride is carried out at a temperature ranging from 0 °C to 50°C.
  • the present invention provides a yield of greater than 84 % for preparation of alkyl 4,4,4-trifluorobut-2-enoate.
  • the present invention provides a process for preparation of alkyl (2E)-4,4,4-trifluorobut-2-enoate having purity greater than 90%, preferably 95% and more preferably 98%.
  • the present invention provides a process for preparation of ethyl-(2E)-4,4,4-trifluorobut-2-enoate comprising the steps of reacting ethyl 4,4,4- trifluoro-3-hydroxybutanoate and methanesulfonyl chloride in presence of trimethylamine.
  • present invention provides a process for preparation of ethyl- (2E)-4,4,4-trifluorobut-2-enoate comprising the steps of reacting ethyl 4,4,4-trifluoro- 3 -hydroxy butanoate and methanesulfonyl chloride in presence of diisopropylethyl amine.
  • alkyl-(2E)-4,4,4-trifluorobut-2-enoate is reduced to obtain 4,4,4-trifluorobut-2-en-l-ol.
  • the reduction of alkyl 4,4,4-trifluorobut-2-enoate to obtain 4,4,4-trifluorobut-2-en-l- ol is preferably carried out in a solvent selected from a group consisting of dichlorome thane, carbon tetrachloride, toluene, diethyl ether, methyltertiarybutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or the like.
  • the step of reducing alkyl 4,4,4-trifluorobut-2-enoate to 4,4,4- trifluorobut-2-en- 1 -ol is carried out in presence of a reducing agent selected from lithium aluminium hydride, sodium borohydride, sodium triacetoxy borohydride, diisobutylaluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride.
  • a reducing agent selected from lithium aluminium hydride, sodium borohydride, sodium triacetoxy borohydride, diisobutylaluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride.
  • the step of reducing alkyl 4,4,4-trifluorobut-2-enoate to 4,4,4- trifluorobut-2-en- 1 -ol is preferably carried out in presence of diisobutylaluminium hydride.
  • the step of reducing alkyl 4,4,4-trifluorobut-2-enoate to 4,4,4-trifluorobut-2-en-l-ol is carried out using a solution of diisobutylaluminium hydride in toluene.
  • the step of reducing alkyl 4,4,4-trifluorobut-2-enoate to 4,4,4- trifluorobut-2-en- 1 -ol is carried out by slowly adding alkyl 4,4,4-trifluorobut-2-enoate or its solution to a solution of reducing agent.
  • the solvent may be selected from a group consisting of dichlorome thane, carbon tetrachloride, toluene, diethyl ether, methyltertiarybutyl ether, tetrahydrofuran, 2- methyltetrahydrofuran or the like.
  • the step of reducing alkyl 4,4,4-trifluorobut-2-enoate to 4,4,4- trifluorobut-2-en- 1 -ol is carried out by slowly adding a solution of alkyl 4,4,4- trifluorobut-2-enoate to a solution of diisobutylaluminium hydride in toluene.
  • the slow addition of alkyl 4,4,4-trifluorobut-2-enoate in a reducing agent increases the selectivity of formation of (2E)- 4,4,4-trifluorobut-2-en-l-ol and minimised impurities formation.
  • the said addition sequence also helps to reduce reactor choking and controlling exothermicity of the reaction. Thus, the said addition sequence makes process more industrially satisfactory.
  • the reduction of ethyl 4,4,4-trifluorobut-2-enoate to obtain 4,4,4-trifluorobut-2-en-l-ol is preferably carried out using a solution of diisobutylaluminium hydride in toluene.
  • the reduction of ethyl 4,4,4-trifluorobut-2-enoate to obtain 4,4,4-trifluorobut-2-en-l-ol is preferably carried out using a solution of diisobutylaluminium hydride in hexane.
  • present invention provides a yield of greater than 90% for preparation of 4,4,4-trifluorobut-2-en-l-ol from alkyl 4,4,4-trifluorobut-2-enoate.
  • a solution of ethyl (2E)-4,4,4-trifluorobut-2-enoate in methyl tertiary butyl ether is dropwise added to a solution of diisobutyl aluminium hydride in toluene.
  • present invention provides a process for preparation of 4,4,4- trifluorobut-2-en- 1 -ol comprising a steps of reducing ethyl-(2E)-4,4,4-trifluorobut-2- enoate using diisobutylaluminium hydride as reducing agent in presence of methyltertiarybutyl ether.
  • present invention provides a process for preparation of 4,4,4- trifluorobut-2-en- 1 -ol comprising a steps of reducing methyl-(2E)-4,4,4-trifluorobut- 2-enoate using diisobutylaluminium hydride as reducing agent in presence of dichlorome thane .
  • isolation of 4,4,4-trifluorobut-2-en-l-ol is carried out by azeotropic distillation by using an entrainer.
  • the entrainer is selected from methanol, ethanol, tetrahydrofuran or 2-methyltetrahydrofuran or the like and mixture thereof.
  • the isolation of 4,4,4-trifluorobut-2-en-l-ol is carried out by azeotropic distillation using methanol as an entrainer.
  • the isolation of 4,4,4-trifluorobut-2-en-l-ol is carried out by azeotropic distillation using 2-methyltetrahydrofuran as an entrainer.
  • the present invention provides a process for preparation of (2E)-
  • the alkyl 4,4,4-trifluoro-3-oxobutanoate is selected from a group comprising of methyl
  • alkyl 4,4,4-trifluoro-3-hydroxybutanoate refers to methyl 4,4,4-trifluoro-3- hydroxybutanoate, ethyl 4,4,4-trifluoro-3-hydroxybutanoate, propyl 4,4,4-trifluoro-3- hydroxybutanoate, isopropyl 4,4,4-trifluoro-3-hydroxybutanoate, tert-butyl 4,4,4- trifluoro-3-hydroxybutanoate or like.
  • alkyl 4,4,4-trifluorobut-2-enoate refers to methyl 4,4,4-trifluorobut-2-enoate, ethyl
  • the present process for preparation of (2E)-4,4,4-trifluorobut- 2-en-l-ol is carried out in a single pot without isolation of the intermediates.
  • the compounds of the invention are isolated by any method known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
  • the completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), Gas chromatography (GC), liquid chromatography (LC) and alike.
  • TLC thin layer chromatography
  • HPLC high pressure liquid chromatography
  • UPLC ultra-pressure liquid chromatography
  • GC Gas chromatography
  • LC liquid chromatography
  • Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations.
  • the described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
  • Methane sulfonyl chloride (138.47 g, 0.74 mole) was added to a solution of ethyl 4,4,4- trifluoro-3-hydroxybutanoate (150 g, 0.80 mole) in dichloromethane (150 ml) and triethyl amine (244.2 g, 2.41 mole) at -70 °C.
  • the reaction mixture was warmed to a temperature of 20°C to 25 °C and stirred for 1 hour and later cooled to 0 °C. The progress of the reaction was monitored and after completion of the reaction, de-ionized water (250 ml) was added to the reaction mixture at 0 °C to 5 °C.
  • Methane sulfonyl chloride (138.47 g, 0.74 mole) was added to a solution of ethyl 4,4,4- trifluoro-3-hydroxybutanoate (150 g, 0.80 mole) in dichloromethane (150 ml) and diisopropylethyl amine (2.5 moles) at -70 °C.
  • the reaction mixture was warmed to a temperature of 20°C to 25 °C and stirred for 1 hour and later cooled to 0 °C. The progress of the reaction was monitored and after completion of the reaction, de-ionized water (250 ml) was added to the reaction mixture 0 °C to 5 °C.
  • reaction mixture was cooled to 0 °C and an aqueous solution of hydrochloric acid (250 ml, 10%) was drop wise added to the reaction mixture at 0 °C, maintaining the temperature below 15 °C.
  • Reaction mass stirred for 30 to 45 minutes at 10 °C to 15 °C.
  • An aqueous solution of hydrochloric acid 300 ml, 12 N was added dropwise at 0 °C and then stirred at 20 °C to 25 °C for an hour.
  • Organic layer was separated and aqueous layer was washed with methyltertiarybutyl ether (100 ml).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides a process for preparation of 4,4,4- trifluorobut-2-en-1-ol from alkyl 4,4,4-trifluorobut-2-enoate and also provides one step process for preparation of alkyl 4,4,4-trifluorobut-2-enoate from corresponding hydroxy derivative using mild and easily available reagents.

Description

PROCESS FOR PREPARATION OF 4,4,4- TRIFLUOROBUT-2-EN-1-OL AND INTERMEDIATE THEREOF
FIELD OF THE INVENTION
The present invention provides a process for preparation of 4,4,4- trifluorobut-2-en-l- ol from alkyl 4,4,4-trifluorobut-2-enoate and also provides one step process for preparation of alkyl 4,4,4-trifluorobut-2-enoate from corresponding hydroxy derivative using mild and easily available reagents. BACKGROUND OF THE INVENTION
Unsaturated alkyl esters are important intermediates for the preparation of different pharmaceutical and agrochemical products. Alkyl 4,4,4-trifluorobut-2-enoate is an important intermediate for preparing prostaglandin derivatives. A few methods are known in the prior art for preparation of alkyl 4,4,4-trifluorobut-2-enoates.
U.S. Pat. No. 4,563,525 discloses a two-step preparation of ethyl 4,4,4- trifluorobutenoate using l,8-diazabi-cyclo[5.4.0]undec-7-ene (DBU). DBU is an expensive reagent and its use at a commercial scale would be non-viable.
Therefore, present invention develops a cost effective and robust process for preparation of alkyl 4,4,4-trifluorobut-2-enoate.
OBJECT OF THE INVENTION
The present invention provides a process for preparation of 4,4,4- trifluorobut-2-en-l- ol from alkyl 4,4,4-trifluorobut-2-enoate using mild and easily available reagents. SUMMARY OF THE INVENTION
In first aspect, the present invention provides a process for preparation of 4,4,4- trifluorobut-2-en- 1 -ol, comprising the steps of: a) reacting an alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride in presence of an amine to obtain alkyl 4,4,4-trifluorobut-2-enoate; and b) reducing alkyl 4,4,4-trifluorobut-2-enoate to obtain 4,4,4-trifluorobut-2-en-l- ol.
In second aspect, the present invention provides a process for preparation of 4,4,4- trifluorobut-2-en- 1 -ol, comprising the steps of:
a) reducing alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3- hydroxybutanoate ;
b) reacting alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride in presence of an amine to obtain alkyl 4,4,4-trifluorobut-2-enoate; and c) reducing alkyl 4,4,4-trifluorobut-2-enoate to obtain 4,4,4-trifluorobut-2-en-l- ol.
In third aspect, the present invention provides a process for preparation of 4,4,4- trifluorobut-2-en- 1 -ol, comprising the steps of:
a) reducing alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3- hydroxybutanoate ;
b) reacting an alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride in presence of an amine to obtain alkyl 4,4,4-trifluorobut-2-enoate; c) reducing alkyl 4,4,4-trifluorobut-2-enoate to obtain 4,4,4-trifluorobut-2-en-l- ol; and
d) isolating 4,4,4-trifluorobut-2-en-l-ol using an entrainer.
DESCRIPTION OF THE INVENTION
As used herein, the“alkyl” refers to a branched or unbranched aliphatic hydrocarbon chain selected from a group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, sec -butyl, pentyl or the like. As used herein“amine” refers to an aliphatic amine and selected from a group consisting of methyl amine, dimethyl amine, ethylamine, diethyl amine, triethyl amine, diisopropyl amine, diisopropylethyl amine, propyl amine, butyl amine or like. The amine for present invention is used in pure form or in solution form. The solution form refers to a solution of amine in a solvent selected from dichloromethane, chloroform, carbon tetrachloride, toluene, acetonitrile, N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), sulfolane or the like.
As used herein, the compounds alkyl 4,4,4-trifluorobut-2-enoate and 4,4,4- trifluorobut-2-en- 1 -ol refers to corresponding E-isomer, Z-isomer or a racemic mixture thereof. Alkyl 4,4,4-trifluorobut-2-enoate and 4,4,4-trifluorobut-2-en-l-ol preferably refers to E-isomer.
As used herein, the reducing agents for present invention can be selected from a group consisting of metal-based hydrogenation catalyst such as Pd-C/Fb, Ni-C/Fb, 5% Pt- C/Fb, Pt0 , lithium aluminium hydride, sodium borohydride, sodium triacetoxy borohydride, diisobutylaluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride or like. The reducing agent for present invention may be used in solid, powder or solution form. The solution form refers to a solution of reducing agent in an organic solvent selected from toluene, hexane, methyltetrahydrofuran, tetrahydrofuran, pentane, diethyl ether or like.
The reduction reaction in present invention is carried out in a solvent selected from a group consisting of dichloromethane, carbon tetrachloride, diethyl ether, methyltertiarybutyl ether, tetrahydrofuran, methyltetrahydrofuran, monoglyme, toluene or the like.
In an embodiment, the present invention provides a process for preparation of (2E)- 4,4,4-trifluorobut-2-en-l-ol, comprising the steps of: a) reacting an alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride in presence of an amine to obtain (2E)-alkyl 4,4,4-trifluorobut-2- enoate; and
b) reducing (2E)-alkyl 4,4,4-trifluorobut-2-enoate to obtain (2E)-4,4,4- trifluorobut-2-en-l-ol.
In another embodiment, the present invention provides a process for preparation of (2E)-4,4,4-trifluorobut-2-en-l-ol, comprising the steps of:
a) reducing alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3- hydroxybutanoate ;
b) reacting alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride in presence of an amine to obtain (2E)-alkyl 4,4,4-trifluorobut-2- enoate; and
c) reducing (2E)-alkyl 4,4,4-trifluorobut-2-enoate to obtain (2E)-4,4,4- trifluorobut-2-en- 1 -ol.
In another embodiment, the present invention provides a process for preparation of (2E)-4,4,4-trifluorobut-2-en-l-ol, comprising the steps of:
a) reducing alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3- hydroxybutanoate ;
b) reacting an alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride in presence of an amine to obtain (2E)-alkyl 4,4,4-trifluorobut-2- enoate;
c) reducing (2E)-alkyl 4,4,4-trifluorobut-2-enoate to obtain (2E)-4,4,4- trifluorobut-2-en-l-ol; and
d) isolating 4,4,4-trifluorobut-2-en-l-ol using entrainer.
In an embodiment, the present invention provides a process for preparation of (2E)- alkyl 4,4,4-trifluorobut-2-enoate, comprising the steps of: a) reducing alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3- hydroxybutanoate; and
b) reacting alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride in presence of an amine to obtain (2E)-alkyl 4,4,4-trifluorobut-2- enoate.
In an embodiment, the step of reducing alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3-hydroxybutanoate is carried out in presence of metal based hydrogenation catalyst selected from a group consisting of Pd-C/Ph, Ni-C/Ph, 5% Pt- C/Ph, Pt02, sodium borohydride, sodium triacetoxy borohydride.
In a preferred embodiment, the step of reducing alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3-hydroxybutanoate is carried out in presence of sodium borohydride as reducing agent.
The reduction of alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3- hydroxybutanoate is preferably carried out in a solvent selected from dichlorome thane, carbon tetrachloride, toluene, diethyl ether, methyltertiarybutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or the like.
In an embodiment, the step of reducing alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3-hydroxybutanoate is carried out by slowly adding 4,4,4-trifluoro-3- oxobutanoate to a solution of reducing agent.
The slow addition of alkyl 4,4,4-trifluoro-3-oxobutanoate in a reducing agent helps to reduce reactor choking and controlling exothermicity of the reaction. Thus, the said addition sequence makes process more industrially satisfactory.
In another embodiment, the step of reducing alkyl 4,4,4-trifluoro-3-oxobutanoate to alkyl 4,4,4-trifluoro-3-hydroxybutanoate is carried out by slowly adding 4,4,4- trifluoro-3-oxobutanoate to a solution of sodium borohydride. In another embodiment, alkyl 4,4,4-trifluoro-3-hydroxybutanoate is reacted with methane sulfonyl chloride in presence of an amine to obtain alkyl 4,4,4-trifluorobut-2- enoate.
In another embodiment, the reaction of alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride is carried out in presence of an aliphatic amine.
The reaction of alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride is carried out using 2 to 3 molar equivalents of an amine. The amine assists in removal of hydrogen chloride liberated during reaction of alkyl 4,4,4-trifluoro-3- hydroxybutanoate with methane sulfonyl chloride.
The reaction of alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride is optionally carried out in an organic solvent selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, toluene, acetonitrile, N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), sulfolane or the like. The reaction of alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride is carried out at a temperature ranging from 0 °C to 50°C.
In another embodiment, the present invention provides a yield of greater than 84 % for preparation of alkyl 4,4,4-trifluorobut-2-enoate.
In another embodiment, the present invention provides a process for preparation of alkyl (2E)-4,4,4-trifluorobut-2-enoate having purity greater than 90%, preferably 95% and more preferably 98%.
In another embodiment, the present invention provides a process for preparation of ethyl-(2E)-4,4,4-trifluorobut-2-enoate comprising the steps of reacting ethyl 4,4,4- trifluoro-3-hydroxybutanoate and methanesulfonyl chloride in presence of trimethylamine.
In another embodiment, present invention provides a process for preparation of ethyl- (2E)-4,4,4-trifluorobut-2-enoate comprising the steps of reacting ethyl 4,4,4-trifluoro- 3 -hydroxy butanoate and methanesulfonyl chloride in presence of diisopropylethyl amine.
In another embodiment of present invention, alkyl-(2E)-4,4,4-trifluorobut-2-enoate is reduced to obtain 4,4,4-trifluorobut-2-en-l-ol.
The reduction of alkyl 4,4,4-trifluorobut-2-enoate to obtain 4,4,4-trifluorobut-2-en-l- ol is preferably carried out in a solvent selected from a group consisting of dichlorome thane, carbon tetrachloride, toluene, diethyl ether, methyltertiarybutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or the like.
In an embodiment, the step of reducing alkyl 4,4,4-trifluorobut-2-enoate to 4,4,4- trifluorobut-2-en- 1 -ol is carried out in presence of a reducing agent selected from lithium aluminium hydride, sodium borohydride, sodium triacetoxy borohydride, diisobutylaluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride.
In another embodiment, the step of reducing alkyl 4,4,4-trifluorobut-2-enoate to 4,4,4- trifluorobut-2-en- 1 -ol is preferably carried out in presence of diisobutylaluminium hydride.
In a preferred embodiment, the step of reducing alkyl 4,4,4-trifluorobut-2-enoate to 4,4,4-trifluorobut-2-en-l-ol is carried out using a solution of diisobutylaluminium hydride in toluene.
In another embodiment, the step of reducing alkyl 4,4,4-trifluorobut-2-enoate to 4,4,4- trifluorobut-2-en- 1 -ol is carried out by slowly adding alkyl 4,4,4-trifluorobut-2-enoate or its solution to a solution of reducing agent.
The solvent may be selected from a group consisting of dichlorome thane, carbon tetrachloride, toluene, diethyl ether, methyltertiarybutyl ether, tetrahydrofuran, 2- methyltetrahydrofuran or the like.
In another embodiment, the step of reducing alkyl 4,4,4-trifluorobut-2-enoate to 4,4,4- trifluorobut-2-en- 1 -ol is carried out by slowly adding a solution of alkyl 4,4,4- trifluorobut-2-enoate to a solution of diisobutylaluminium hydride in toluene. The slow addition of alkyl 4,4,4-trifluorobut-2-enoate in a reducing agent increases the selectivity of formation of (2E)- 4,4,4-trifluorobut-2-en-l-ol and minimised impurities formation. The said addition sequence also helps to reduce reactor choking and controlling exothermicity of the reaction. Thus, the said addition sequence makes process more industrially satisfactory.
In a specific embodiment, the reduction of ethyl 4,4,4-trifluorobut-2-enoate to obtain 4,4,4-trifluorobut-2-en-l-ol is preferably carried out using a solution of diisobutylaluminium hydride in toluene.
In a specific embodiment, the reduction of ethyl 4,4,4-trifluorobut-2-enoate to obtain 4,4,4-trifluorobut-2-en-l-ol is preferably carried out using a solution of diisobutylaluminium hydride in hexane.
In an embodiment, present invention provides a yield of greater than 90% for preparation of 4,4,4-trifluorobut-2-en-l-ol from alkyl 4,4,4-trifluorobut-2-enoate.
In a specific embodiment, a solution of ethyl (2E)-4,4,4-trifluorobut-2-enoate in methyl tertiary butyl ether is dropwise added to a solution of diisobutyl aluminium hydride in toluene.
In an embodiment, present invention provides a process for preparation of 4,4,4- trifluorobut-2-en- 1 -ol comprising a steps of reducing ethyl-(2E)-4,4,4-trifluorobut-2- enoate using diisobutylaluminium hydride as reducing agent in presence of methyltertiarybutyl ether.
In an embodiment, present invention provides a process for preparation of 4,4,4- trifluorobut-2-en- 1 -ol comprising a steps of reducing methyl-(2E)-4,4,4-trifluorobut- 2-enoate using diisobutylaluminium hydride as reducing agent in presence of dichlorome thane .
In an embodiment, isolation of 4,4,4-trifluorobut-2-en-l-ol is carried out by azeotropic distillation by using an entrainer. The entrainer is selected from methanol, ethanol, tetrahydrofuran or 2-methyltetrahydrofuran or the like and mixture thereof. In an embodiment, the isolation of 4,4,4-trifluorobut-2-en-l-ol is carried out by azeotropic distillation using methanol as an entrainer.
In preferred embodiment, the isolation of 4,4,4-trifluorobut-2-en-l-ol is carried out by azeotropic distillation using 2-methyltetrahydrofuran as an entrainer.
In an embodiment, the present invention provides a process for preparation of (2E)-
4.4.4-trifluorobut-2-en-l-ol having purity greater than 90% and preferably 95% and more preferably 98%.
The alkyl 4,4,4-trifluoro-3-oxobutanoate is selected from a group comprising of methyl
4.4.4-trifluoro-3-oxobutanoate, ethyl 4,4,4-trifluoro-3-oxobutanoate, propyl 4,4,4- trifluoro-3-oxobutanoate, isopropyl 4,4,4-trifluoro-3-oxobutanoate, tert-butyl 4,4,4- trifluoro-3-oxobutanoate or like.
The alkyl 4,4,4-trifluoro-3-hydroxybutanoate refers to methyl 4,4,4-trifluoro-3- hydroxybutanoate, ethyl 4,4,4-trifluoro-3-hydroxybutanoate, propyl 4,4,4-trifluoro-3- hydroxybutanoate, isopropyl 4,4,4-trifluoro-3-hydroxybutanoate, tert-butyl 4,4,4- trifluoro-3-hydroxybutanoate or like.
The alkyl 4,4,4-trifluorobut-2-enoate refers to methyl 4,4,4-trifluorobut-2-enoate, ethyl
4.4.4-trifluorobut-2-enoate, propyl 4,4,4-trifluorobut-2-enoate, isopropyl 4,4,4- trifluorobut-2-enoate, tert-butyl 4,4,4-trifluorobut-2-enoate or like.
In another embodiment, the present process for preparation of (2E)-4,4,4-trifluorobut- 2-en-l-ol is carried out in a single pot without isolation of the intermediates.
The compounds of the invention are isolated by any method known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
The completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), Gas chromatography (GC), liquid chromatography (LC) and alike. The reagents used in the above process are obtained commercially.
Unless stated to the contrary, any of the words“comprising”,“comprises” and includes mean“including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1: Preparation of Ethyl 4, 4, 4-trifluoro-3-hydroxybutanoate
A solution of methyltertiarybutyl ether (200 ml) and ethyl 4,4,4-trifluoro-3- oxobutanoate (500 g, 2.71 moles) was added to a solution of methyltertiarybutyl ether (1000 ml, 2T) and sodium borohydride (50.24 g, 1.35 moles) at 0 °C. Reaction mass was stirred for 2 hours at 20°C to 25 °C and subsequently cooled to 0°C. The progress of the reaction was monitored and after completion of the reaction, aqueous hydrochloric acid (250 ml, 2 N) was dropwise added to the reaction mixture at 0°C maintaining the temperature below 5 °C. Organic layer was separated and aqueous layer was washed with methyltertiarybutyl ether (200 ml). The organic layer was evaporated under vacuum at 40 °C to give ethyl 4,4,4-trifluoro-3-hydroxybutanoate as colourless oil (462 g).
Yield: 91.4 %; Purity: 98.2% Example 2: Preparation of Ethyl (2E)-4,4,4-trifluorobut-2-enoate
Methane sulfonyl chloride (138.47 g, 0.74 mole) was added to a solution of ethyl 4,4,4- trifluoro-3-hydroxybutanoate (150 g, 0.80 mole) in dichloromethane (150 ml) and triethyl amine (244.2 g, 2.41 mole) at -70 °C. The reaction mixture was warmed to a temperature of 20°C to 25 °C and stirred for 1 hour and later cooled to 0 °C. The progress of the reaction was monitored and after completion of the reaction, de-ionized water (250 ml) was added to the reaction mixture at 0 °C to 5 °C. Temperature of reaction mixture raised to 20 °C to 25 °C and stirred for 1 hour at the same temperature. Organic layer was separated and the aqueous layer was washed with dichloromethane (100 ml). The organic layers were combined and washed with hydrochloric acid solution (100 ml of 12 N ) at 20-25 °C and distilled under vacuum (200 mm of Hg) at 40 °C to give ethyl (2E)-4,4,4-trifluorobut-2-enoate as colourless oil.
Yield: 87 %; Purity: 99.3% Example 3: Preparation of Ethyl (2E)-4,4,4-trifluorobut-2-enoate
Methane sulfonyl chloride (138.47 g, 0.74 mole) was added to a solution of ethyl 4,4,4- trifluoro-3-hydroxybutanoate (150 g, 0.80 mole) in dichloromethane (150 ml) and diisopropylethyl amine (2.5 moles) at -70 °C. The reaction mixture was warmed to a temperature of 20°C to 25 °C and stirred for 1 hour and later cooled to 0 °C. The progress of the reaction was monitored and after completion of the reaction, de-ionized water (250 ml) was added to the reaction mixture 0 °C to 5 °C. Temperature of reaction mixture was raised to 20 °C to 25 °C and stirred for 1 hour at the same temperature. Organic layer was separated and the aqueous layer was washed with dichloromethane (100 ml). The organic layers were combined and washed with hydrochloric acid solution (100 ml of 12 N ) at 20-25 °C and distilled under vacuum (200 mm of Hg) at 40 °C to give ethyl (2E)-4,4,4-trifluorobut-2-enoate as colourless oil.
Yield: 85 %; Purity: 99% Example 4: Preparation of (2E)-4,4,4-trifluorobut-2-en-l-ol
A solution of ethyl (2E)-4,4,4-trifluorobut-2-enoate (100 g, 0.59 mole) in methyltertiarybutyl ether (150 ml) was added to a solution of diisobutylaluminium hydride in toluene (25%, 681 .2 ml, 1.12 moles) at -70 °C under nitrogen atmosphere. Reaction mixture was warmed to a temperature of 0 °C and later slowly to 20-25 °C. Reaction mixture was stirred for an hour at 20°C to 25 °C. The progress of the reaction was monitored and after completion of the reaction, reaction mixture was cooled to 0 °C and an aqueous solution of hydrochloric acid (250 ml, 10%) was drop wise added to the reaction mixture at 0 °C, maintaining the temperature below 15 °C. Reaction mass stirred for 30 to 45 minutes at 10 °C to 15 °C. An aqueous solution of hydrochloric acid (300 ml, 12 N) was added dropwise at 0 °C and then stirred at 20 °C to 25 °C for an hour. Organic layer was separated and aqueous layer was washed with methyltertiarybutyl ether (100 ml). The combined organic layers were subjected for azeotropic distillation using methanol and 2-methyltetrahydrofuran as entrainer at 120- 128 °C under atmospheric pressure, to give selectively (2E)-4,4,4-trifluorobut-2-en-l- ol as oil.
Yield: 90%; Purity: 97%

Claims

WE CLAIM
1. A process for preparation of 4,4,4-trifluorobut-2-en-l-ol, comprising the steps of: a) reducing an alkyl 4,4,4-trifluoro-3-oxobutanoate to an alkyl 4,4,4-trifluoro-3- hydroxybutanoate ;
b) reacting the alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride in presence of an amine to obtain an alkyl 4,4,4-trifluorobut-2-enoate; and
c) reducing the alkyl 4,4,4-trifluorobut-2-enoate to obtain 4,4,4-trifluorobut-2-en- l-ol,
wherein alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec- butyl, and pentyl.
2. A process for preparation of 4,4,4-trifluorobut-2-en-l-ol, comprising the steps of: a) reacting an alkyl 4,4,4-trifluoro-3-hydroxybutanoate with methane sulfonyl chloride in presence of an amine to obtain alkyl 4,4,4-trifluorobut-2-enoate; and b) reducing alkyl 4,4,4-trifluorobut-2-enoate to obtain 4,4,4-trifluorobut-2-en-l- ol,
wherein alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec- butyl, and pentyl.
3. The process as claimed in claims 1 and 2, wherein an amine is an aliphatic amine selected from a group consisting of methyl amine, dimethyl amine, ethylamine, diethyl amine, triethyl amine, diisopropyl amine, diisopropylethyl amine, propyl amine and butyl amine.
4. The process as claimed in claims 1 and 2, wherein 4,4,4-trifluorobut-2-en-l-ol is obtained by isolating by azeotropic distillation using an entrainer selected from a group consisting of methanol, ethanol, tetrahydrofuran and methyltetrahydrofuran or a mixture thereof.
5. The process as claimed in claims 1 and 2, wherein the step of reduction is carried out by slowly adding alkyl 4,4,4-trifluorobut-2-enoate or alkyl 4,4,4-trifluoro-3- oxobutanoate to reducing agent.
6. The process as claimed in claim 1 , wherein the step of reducing alkyl 4,4,4-trifluoro- 3-oxobutanoate to alkyl 4,4,4-trifluoro-3-hydroxybutanoate is carried out in presence of a reducing agent selected from Pd-C/Ph, Ni-C/Ph, 5% Pt-C/Ph, PtCE, sodium borohydride, sodium triacetoxy borohydride.
7. The process as claimed in claims 1 and 2, wherein the step of reducing alkyl 4,4,4- trifluorobut-2-enoate to obtain 4,4,4-trifluorobut-2-en-l-ol is carried out in presence of a reducing agent selected from lithium aluminium hydride, sodium borohydride, sodium triacetoxy borohydride, sodium bis(2-methoxyethoxy)aluminium hydride, diisobutylaluminium hydride.
8. The process as claimed in claims 1 and 2, wherein reduction step is carried out in a solvent, selected from a group consisting of dichlorome thane, carbon tetrachloride, diethyl ether, methyltertiarybutyl ether, tetrahydrofuran, methyltetrahydrofuran, monoglyme and toluene.
9. The process as claimed in claim 1 and 2, wherein alkyl 4,4,4-trifluorobut-2-enoate is (2E) - alkyl 4,4,4-trifluorobut-2-enoate.
10. The process as claimed in claim 1 and 2, wherein 4,4,4-trifluorobut-2-en-l-ol is (2E) - 4,4,4-trifluorobut-2-en-l-ol.
PCT/IN2020/050042 2019-01-17 2020-01-15 Process for preparation of 4,4,4- trifluorobut-2-en-1-ol and intermediate thereof WO2020148780A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201911002025 2019-01-17
IN201911002025 2019-01-17

Publications (1)

Publication Number Publication Date
WO2020148780A1 true WO2020148780A1 (en) 2020-07-23

Family

ID=71613255

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2020/050042 WO2020148780A1 (en) 2019-01-17 2020-01-15 Process for preparation of 4,4,4- trifluorobut-2-en-1-ol and intermediate thereof

Country Status (1)

Country Link
WO (1) WO2020148780A1 (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015177179A1 (en) * 2014-05-21 2015-11-26 Intervet International B.V. Improved process for preparing substituted crotonic acids

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015177179A1 (en) * 2014-05-21 2015-11-26 Intervet International B.V. Improved process for preparing substituted crotonic acids

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ELSA ET AL.: "Systematic Study of the Reactivity of (E)-4,4,4-trifluorobut-2-en-1-yl 4-methylbenzenesulfonate Towards Different Classes of Nucleophiles", JOURNAL OF FLUORINE CHEMISTRY, vol. 180, 6 October 2015 (2015-10-06), pages 216 - 221, XP029304174, DOI: 10.1016/j.jfluchem.2015.10.006 *
NICOLA POHL ET AL.: "Chiral Compounds and Green Chemistry in Undergraduate Organic Laboratories: Reduction of a Ketone by Sodium Borohydride and Baker's Yeast", JOURNAL OF CHEMICAL EDUCATION, vol. 79, 6 June 2002 (2002-06-06), pages 727, XP055727339, DOI: 10.1021/ed079p727 *

Similar Documents

Publication Publication Date Title
EP1854788B1 (en) Method for producing 1-substituted-3-fluoroalkyl pyrazole-4-carboxylate
CN107417505B (en) Preparation method of alpha-halogenated tetramethyl cyclohexanone and (2,3,4, 4-tetramethylcyclopentyl) methyl carboxylic ester
JP5021470B2 (en) Method for preparing 4,4-difluoro-3-oxobutanoic acid ester
US10428012B2 (en) Method of preparation of 4-isopropylamino-1-butanol
EP1078921B1 (en) Novel intermediates and processes for the preparation of optically active octanoic acid derivatives
US9732056B2 (en) 2-(alkoxy or aryloxy carbonyl)-4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-2-enoic acid compounds, its preparation and use
WO2020148780A1 (en) Process for preparation of 4,4,4- trifluorobut-2-en-1-ol and intermediate thereof
US8097746B2 (en) Method for producing 2-isopropenyl-5-methyl-4-hexen-1-yl 3-methyl-2-butenoate
JP5448572B2 (en) Acetyl compound, method for producing the acetyl compound, and method for producing a naphthol compound using the acetyl compound
EP2880008B1 (en) Process for preparing spiro[2.5]octane-5,7-dione
US20070043107A1 (en) Processes for preparing alkyl 3-(4-tetrahydropyranyl)-3-oxopropanoate compound and 4-acyltetrahydropyrane
EP2448916B1 (en) Production of trans-4-aminocyclopent-2-ene-1-carboxylic acid derivatives
US10472312B2 (en) Method for producing phenoxyethanol derivative
US8816123B2 (en) Method for producing alkyl 5-methyl-5-hexenoate
KR20230154213A (en) Process for producing alkyl-4-oxotetrahydrofuran-2-carboxylate
CN116724030A (en) Method for producing an intermediate
JP2008120759A (en) METHOD FOR PRODUCING beta-DIKETONE COMPOUND HAVING ETHER GROUP
MX2007012329A (en) Method for producing 2-isopropenyl-5-methyl-4-hexen-1-yl 3-methyl-2-butenoate.
JP2002201169A (en) Method for producing 4-cyano-3-oxobutanoic acid ester
KR20070031394A (en) Process for the preparation of 4,4-difluoro-3-oxobutanoic acid esters

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20740955

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20740955

Country of ref document: EP

Kind code of ref document: A1