CN110872230B - Preparation method of 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compound and intermediate thereof - Google Patents
Preparation method of 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compound and intermediate thereof Download PDFInfo
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/093—Preparation of carboxylic acids or their salts, halides or anhydrides by hydrolysis of —CX3 groups, X being halogen
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
- C07C45/676—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton by elimination of carboxyl groups
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Abstract
The invention relates to a preparation method of a 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compound shown in a formula I, which is a novel, effective, safe and environment-friendly preparation method. The 1- (trifluoromethyl) cyclopropane-1-carboxylic acid disclosed by the invention can be used as a medical intermediate for preparing a final medicament.
Description
Technical Field
The present invention relates to a novel, efficient, safe and environmentally friendly process for the preparation of 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compounds, which are useful intermediates for the preparation of pharmaceutical products.
Background
1- (trifluoromethyl) cyclopropane-1-carboxylic acid compounds are important pharmaceutical intermediates, which have been reported in the literature as intermediates in the preparation and development of pharmaceutical products (see, for example, pct applications, 2018038667,2018038668,2017102091,2017106607,2017135472,2017106872, 201620533, 2017078352;2017018924,2017055473,2017011776, 201685423, etc.).
The reported methods for preparing 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compounds are known as follows: (step 1) the metal salt of diethyl malonic acid reacts with 1, 2-dibromoethane in a phase transfer catalyst and dimethyl sulfoxide to prepare diethyl cyclopropane-1, 1-dicarboxylic acid; (step 2) diethyl cyclopropane-1, 1-dicarboxylic acid is treated by 15% liquid alkali sodium hydroxide solution, and cyclopropane-1, 1-dicarboxylic acid is prepared by acidification; (step 3) further reacting the cyclopropane-1, 1-dicarboxylic acid with sulfur tetrafluoride; (step 4) after the reaction solution was heat-treated with a saturated sodium hydrogencarbonate solution and further acidified, 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compound was obtained.
However, in commercial mass production of 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compounds, step 3 in the above-mentioned production method has serious drawbacks and problems: (problem 1) the reaction yield of step 3 is low (36%); (problem 2) highly toxic gaseous sulfur tetrafluoride is used, so that high pressure is required for the reaction conditions; (problem 3) a large dose of sulfur tetrafluoride was used in the reaction, with 1 molar equivalent of cyclopropane-1, 1-dicarboxylic acid requiring 6 molar equivalents of sulfur tetrafluoride; (problem 4) after reaction with Sulfur tetrafluoride, the byproduct is gaseous thionyl fluoride (SOF) 2 ) And Hydrogen Fluoride (HF), by-products are toxic; (problem 5) sulfur tetrafluoride and byproduct hydrogen fluoride corrode metals; (problem 6) after the completion of the reaction, hydrogen fluoride is also formed during the water treatment of sulfur tetrafluoride and thionyl fluoride, which makes the waste of step 3 contain a large amount of hydrogen fluoride. In addition, the above known preparation methods have other problems. (problem 7) the product from step 2, cyclopropane-1, 1-dicarboxylic acid, is a thermally unstable compound that decomposes as the gas changes its gas-liquid phase at a melting point of 136-137 ℃.
Thus, problems (1) and (3) have caused a large problem that the yield is not efficient and a large amount of waste is generated. Problems (2) and (4) relate to the problem of how to ensure safety, and require a large investment in operation, during the reaction and in the storage of sulfur tetrafluoride to ensure safety of commercial production in the factory. To solve problem (5) expensive corrosion-resistant metals such as hastelloy or the use of fluoropolymer precious materials for industrial reuse are required. To solve the problem (6), a large amount of investment in three-waste treatment such as HF and fluoride ion treatment is required, and the emission of HF and fluoride ion harmful to the environment is strictly prohibited. Problem (7) relates to the safety problem of cyclopropane 1, 1-dicarboxylic acid compounds in storage and handling because cyclopropane 1, 1-dicarboxylic acid compounds are explosive at high temperatures. In general, the above known preparation methods have the problem of low production efficiency, and bring about great safety and environmental protection risks.
Disclosure of Invention
The invention provides a novel, effective, safe and environment-friendly preparation method for preparing an important and practical intermediate 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compound.
In order to solve the above problems, the inventors have made extensive studies and have desired a method for industrially producing a 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compound. As a result, the inventors have succeeded in obtaining a novel preparation method comprising a safe and effective process for the fluoromethylation step of α -acetyl- γ -butyrolactone, which is a commercially economical and practical compound. This would overcome the problems of the prior art. This new method can be used in equipment and instruments of the organic synthesis standard. Without handling SF as in the prior art 4 As with HF, special equipment and instrumentation is required.
The preparation process (scheme 1) of the present invention comprises three steps, processes (A), (B) and (C), for preparing a compound of formula (I) which is 1- (trifluoromethyl) cyclopropane-1-carboxylic acid.
Process/step (A), (B) and (C) for preparing compounds of formula (I) by reaction of formula 1
Step (a)(A) (B) and (C)
Step (A)
Step (a) involves the reaction process of a-acetyl-gamma-butyrolactone salt of a compound of formula (II) with S- (trifluoromethyl) -dibenzothiophene salt of a compound of formula (III) (reaction formula 2).
Reaction 2, step (A)
Wherein M is an alkali metal atom or an ammonium group; r is R 1 、R 2 、R 3 And R is 4 Each independently is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 4 carbons; x is X - Is a conjugate base of an acid.
The salts of α -acetyl- γ -butyrolactone represented by the compound of formula (II) can be readily prepared quantitatively from commercially inexpensive available reactions of α -acetyl- γ -butyrolactone, around which equimolar amounts of the base can react with protons to form salts at the α -position of α -acetyl- γ -butyrolactone. More preferably, the reaction is carried out at a temperature ranging from-30℃to room temperature for several hours. Preferred bases are listed below: alkali metal hydroxides such as sodium hydroxide NaOH, potassium hydroxide KOH, lithium hydroxide LiOH, cesium hydroxide CsOH, or the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium tert-butoxide, lithium methoxide, lithium ethoxide, lithium tert-butoxide, and the like; alkali metal hydrides such as sodium hydride, potassium hydride and lithium hydride; alkali metals such as lithium, sodium or potassium; ammonium hydroxide compounds such as tetramethylammonium hydroxide, tetraethylammonium hydroxide; tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, benzyltriethylammonium hydroxide, and the like.
M in the compound of formula (II) + Is the cationic part of the base used. When the base is an alkali metal hydroxide, an alkali metal alkoxide, an alkali metal hydride or an alkali metal, M + Is an alkali metal cation. When the base is ammonium hydroxide, M + Is ammonium cation.
The α -acetyl- γ -butyrolactone salt of the compound of formula (II) may be in equilibrium with its tautomer of formula (II') (as follows):
r in the compound of formula (III) 1-4 May be a halogen atom or an alkyl group, the halogen atom is preferably a fluorine atom, and the alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group or a tert-butyl group, and is preferably a methyl group or a tert-butyl group.
A compound of formula (II) - Is a conjugate base of an acid, more preferably a conjugate base of a strong acid. The conjugate base of the acid may be X - ,CF 3 SO 3 - ,BF 4 - ,Cl - ,Br - ,PF 6 - ,HSO 4 - ,C 4 F 9 SO 3 - ,CCl 3 SO 3 - ,CH 3 SO 3 - ,C 6 H 5 SO 3 - (benzenesulfonic acid ion), 4-CH 3 C 6 H 4 SO 3 - (4-methylbenzenesulfonic acid ion), 4-BrC 6 H 4 SO 3 - (4-Bromobenzenesulfonic acid ion), 4-NO 2 C 6 H 4 SO 3 - (4-nitrobenzenesulfonic acid ion). Of these, CF is most preferred 3 SO 3 - ,BF 4 - ,Cl - ,Br - 。
S- (trifluoromethyl) dibenzothiophene salt the compounds of formula (III) are commercially available or can be prepared according to the preparation methods reported in the journal literature (see J.Org.chem.,2017,82,7708-7719; WO2016/146040; eur.J.Org.chem.,2009,1390-1397; J.am.chem.; 1993,115,2156-2164;J.Fluorine Chem; 1999,98,75-81) the following list are all suitable S- (trifluoromethyl) dibenzothiophene salts, for example S- (trifluoromethyl) dibenzothiophene triflate, S- (trifluoromethyl) dibenzothiophene tetrafluoroborate, 2, 8-difluoro-S- (trifluoromethyl) dibenzothiophene triflate, 2, 8-difluoro-S- (trifluoromethyl) dibenzothiophene tetrafluorosulfonate, 2, 8-difluoro-S- (trifluoromethyl) dibenzothiophene tetrafluoroate, 2, 8-difluoro-S- (trifluoromethyl) dibenzothiophene chloride, 2, 8-difluoro-S- (trifluoromethyl) dibenzothiophene complex, 2, 8-difluoro-S- (trifluoromethyl) dibenzothiophene sulfonate, 2, 8-difluoro-S- (trifluoromethyl) thiophene complex, 2, 8-difluoro-S- (trifluoromethyl) thiophene sulfonate, 2, 8-difluoro-S- (trifluoromethyl) thiophene sulfonate, 2,3,7, 8-tetrafluoro-S- (trifluoromethyl) dibenzothiophene tetrafluoroborate, 2,3,7, 8-tetrafluoro-S- (trifluoromethyl) dibenzothiophene chloride, 2, 8-dimethyl-S- (trifluoromethyl) dibenzothiophene triflate, 3, 7-di (tert-butyl) -S- (trifluoromethyl) dibenzothiophene triflate, 2,4,6, 8-tetramethyl-S- (trifluoromethyl) dibenzothiophene triflate, and the like.
In the step (A), the molar ratio of the S- (trifluoromethyl) dibenzothiophene salt compound of formula (III) to the alpha-acetyl-gamma-butyrolactone compound of formula (I) is in the range of 0.5-2: 1, more preferably 0.8 to 1.5:1.
in step (a), the reaction is more preferably carried out in the presence of a solvent. The solvent may be an amide such as N, N-dimethylformamide, N-methylformamide, N-dimethylacetamide, N-methylacetamide, 1-methyl-2-pyrrolidone, hexamethylphosphoric triamide, etc.; nitriles such as acetonitrile, propionitrile, etc.; ethers such as diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane, dioxane, etc.; sulfoxides or sulfones such as dimethyl sulfoxide, tetramethylsulfone (sulfolane), and the like; lactones such as gamma-butyrolactone, delta-valerolactone, gamma-valerolactone, etc.; carbonates such as dimethyl carbonate, diethyl carbonate, ethyl methyl carbonate, ethylene carbonate, propylene carbonate, and the like; ketones such as acetone, ethyl methyl ketone, cyclohexanone, etc.; esters such as methyl acetate, ethyl acetate, and the like; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, isobutanol, tert-butanol and the like; or water, etc. The solvent may be a single solvent or a mixed solvent of the above-listed solvents.
In step (a), the reaction temperature may be between-80 ℃ and +80 ℃, preferably between-60 ℃ and +30 ℃. The reaction time may be appropriately selected so that the reaction is completed. It may be from about 0.1 hours to several days, preferably within a day.
The α -acetyl- γ -butyrolactone salt compounds of formula (II) may also be prepared in situ in solution by α -acetyl- γ -butyrolactone with about equimolar amounts of a base. The preferred solvents and bases are the same as described in method (A) above. The salt of α -acetyl- γ -butyrolactone represented by formula (II) prepared by in situ reaction may react with S- (trifluoromethyl) dibenzothiophene salt represented by formula (III) (reaction formula 3).
In-situ reaction of alpha-acetyl-gamma-butyrolactone in reaction formula 3 to prepare its salt compound of formula (II)
Step (B)
Step (B) comprises a process of reacting an alpha-acetyl-alpha- (trifluoromethyl) -gamma-butyrolactone compound of formula (IV) with a halide salt represented by formula (V) (reaction formula 4)
Reaction 4, step (B)
Wherein Y is an alkali metal atom, an ammonium moiety, or a phosphorus atom moiety; z is a halogen atom.
Z in the compound of formula (V) may be more preferably an iodine atom, a bromine atom and a chlorine atom. More preferred are iodine atoms and bromine atoms, among which iodine atoms are most preferred from the viewpoint of high yield and milder reaction conditions. As preferred halide salts of the formula (V) (Y) + Z - ) Alkali metal iodides such as lithium iodide, sodium iodide, potassium iodide, cesium iodide, and the like; alkali metal bromides such as lithium bromide, sodium bromide, potassium bromide, cesium bromide, and the like; alkali metal chlorides such as lithium chloride, sodium chloride, potassium chloride, cesium chloride, and the like. Amine iodides such as trimethyl ammonium iodide, tetramethyl ammonium iodide, triethyl ammonium iodide, tetraethyl ammonium iodide, tetrapropyl ammonium iodide, tetrabutyl ammonium iodide, benzylAnd benzyltriethylammonium iodide; ammonium bromide compounds such as tetramethyl ammonium bromide, tetraethyl ammonium bromide, tetrapropyl ammonium bromide, tetrabutyl ammonium bromide, benzyl trimethyl ammonium bromide, benzyl triethyl ammonium bromide, and the like; ammonium chloride compounds such as tetramethyl ammonium chloride, tetraethyl ammonium chloride, tetrapropyl ammonium chloride, tetrabutyl ammonium chloride, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, and the like; phosphonium iodide compounds such as tetraphenyl phosphonium iodide, tetraphosphorus iodide and the like; phosphonium bromide compounds such as tetraphenyl phosphonium bromide, tetramethylphosphonium bromide and the like; phosphonium chloride compounds such as tetraphenyl phosphonium chloride, tetramethyl phosphonium chloride and the like. Among them, alkali metal iodides and bromides and ammonium iodides and bromides are more preferable, and alkali metal iodides and ammonium iodides are more preferable from the viewpoint of high yield and mild reaction conditions.
In step (B), the ratio of the amount of the halogenated salt compound of formula (V) to the amount of the compound of formula (IV) of alpha-acetyl-alpha- (trifluoromethyl) -gamma-butyrolactone may be selected to be slightly excessive from the catalytic amount. Preferably, about 0.05 mole to about 1 mole, more preferably about 0.1 mole to about 0.7 mole, may be selected for 1 mole of α -acetyl- α - (trifluoromethyl) - γ -butyrolactone.
In step (B), the reaction is more preferably carried out in the presence of a solvent. The reaction solvent may be: amides such as 1-methyl-2-pyrrolidone, N-dimethylformamide, N-dimethylacetamide, N-methylacetamide, hexamethylphosphoric triamide and the like; sulfoxides or sulfones such as dimethylsulfoxide, tetramethylsulfone (sulfone), and the like. Lactones such as gamma-butyrolactone, delta-valerolactone, gamma-valerolactone, etc.; carbonates such as ethylene carbonate, propylene carbonate, and the like; the solvent may be a single solvent or a mixture of the illustrated solvents.
In step (B), the reaction temperature may be suitably selected in the range of about 80 ℃ to about 25 ℃, preferably in the range of about 100 ℃ to about 200 ℃. The reaction time may be appropriately selected so that the reaction is completed. It may be from about 0.1 hours to several days, preferably within a day.
Steps (a) and (B) may be performed by a continuous process using one reactor, referred to as a one-pot reaction process. In the reactor used in the step (A), the compound salt of the formula (II) is reacted with the S- (trifluoromethyl) dibenzothiophene salt compound of the formula (III) in the presence of a solvent, and after the reaction in the step (A) is finished, the halide salt compound of the formula (V) is added to the reaction mixture of the reactor, and the reaction in the synthetic route (B) proceeds smoothly in the reactor.
Alternatively, salts of the compounds of formula II can be prepared by one-pot methods using α -acetyl- γ -butyrolactone (as already mentioned in equation 3 above), and also 1-acetyl-1- (trifluoromethyl) cyclopropane compounds of formula (VI) can be prepared by one-pot methods using α -acetyl- γ -butyrolactone (see example 7, steps 1-3).
Step (C)
Step (C) involves a haloform reaction of a compound of formula (VI) 1-acetyl-1- (trifluoromethyl) cyclopropane (formula 5)
Reaction 5, step (C)
The haloform reaction is a chemical reaction in which haloform is a reaction in which a methyl ketone moiety (R-CO-CH 3 Radical) is fully halogenated. The haloform reaction of method (C) may be carried out by the same reaction conditions as the well-known haloform reaction (see "The Haloform Reaction", chemical Reviews,1934,15 (3), 275-309). In general, compounds of formula (VI) which may be 1-acetyl-1- (trifluoromethyl) cyclopropane are prepared by haloform reaction with a halogenating reagent in the presence of a base. When the halogenating agent is a hypohalite, no base is required as the hypohalite can be both a halogenating agent and a base.
Examples of the halogenating agent include halogen, halogen complex, hypohalous acid, hypohalite, tri-or dihaloisocyanuric acid or a salt thereof, dihalodimethylhydantoin, N-halosuccinimide, N-halophthalimide, ammonium halide compound, chloramines, and the like. Preferred exemplary halogens such as chlorine (Cl) 2 ) Bromine(Br 2 ) Or iodine (I) 2 ) The method comprises the steps of carrying out a first treatment on the surface of the Halogen complexes such as bromine (Br) 2 ) -dioxane complex and the like; hypohalous acids such as hypochlorous acid, hypobromous acid or hypoiodic acid; hypohalites such as sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium hypobromite, potassium hypobromite, sodium hypoiodite, or potassium hypoiodite, etc.; tri-or dihalogenated isocyanuric acid and salts thereof such as trichloroisocyanuric acid, sodium dichloroisocyanurate, dibromocyanuric acid or sodium dibromocyanuric acid and hydrates thereof, and the like. Dihalodimethylhydantoin such as 1, 3-dichloro-5, 5-dimethylhydantoin, 1, 3-dibromo-5, 5-dimethylhydantoin, 1, 3-diiodo-5, 5-dimethylhydantoin, etc.; n-halogenated succinimides such as N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide; n-halophthalimides such as N-chlorophthalimide, N-bromophthalimide or N-iodophthalimide; n-halophthaloyl-benzoyl-imides such as N-chlorophthalide-benzoyl-imine, N-bromophthaloyl-benzoyl-imine or N-iodophthaloyl-benzoyl-imine; halogen ammonium compounds such as benzyl trimethylammonium perchlorate, tetrabutylammonium tribromide, trimethylphenyl ammonium tribromide, benzyl trimethylammonium tribromide, pyridinium tribromide, tetramethylammonium dichloroiodate, benzyl trimethylammonium dichloroiodate, and the like; chloramines such as chloramine hydrate B, o-dichloramine T dihydrate, chloramine T trihydrate, dichloramine B, dichloramine T, and the like. Among them, halogen or hypohalite is more preferable because of low cost and easy post-treatment.
In the method (C), the base used may be, as preferable, a metal hydroxide such as sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), cesium hydroxide (CsOH), or the like: metal alcohol oxides such as sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium tert-butoxide, lithium methoxide, lithium ethoxide, lithium tert-butoxide, and the like; tetraalkylammonium hydroxides such as tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, and the like. Among them, naOH and KOH are more preferable because of cost and availability.
In the method (C), the solvent used is preferably water. The solvent for dissolving the 1-acetyl-1- (trifluoromethyl) cyclopropane compound of formula (VI) is a quantitative dioxane or tetrahydrofuran as co-solvent.
In the method (C), the amount of the halogen may be appropriately determined in the range of about 2 moles to about 15 moles, more preferably about 3 moles to about 12 moles, and further, for 1 mole of the 1-acetyl-1- (trifluoromethyl) cyclopropane compound of the formula (VI), the amount of the halogen is about 3 moles to about 9 moles. The other halogenating agents are used in an amount of about 2 to about 15 moles, preferably about 3 to about 12 moles, further preferably about 3 to about 9 moles of active halogen are required relative to 1 mole of the 1-acetyl-1- (trifluoromethyl) cyclopropane compound of formula (VI). For example, the amount of hypohalous acid, hypohalite, N-halosuccinimide, N-halobenzoylimine, N-halophthalimide, ammonium halide compound, or chloramine used in process (C) may be suitably determined in the range of about 2 moles to about 15 moles, preferably about 3 moles to about 12 moles. More preferably from 3 moles to about 9 moles. The amount of dihalocyanuric acid or dihalodimethylhydantoin used in process (C) may be suitably determined in the range of from about 1.3 to about 7.5 moles, preferably from about 1.5 to about 6 moles, more preferably from about 1.5 to about 4.5 moles. The amount of trihalocyanuric acid used in process (C) can be suitably determined in the range of about 0.7 mole to about 5 mole, preferably about 1 mole to about 4 mole, more preferably about 1 mole to about 3 mole.
In the process (C), the amount of the base may be suitably determined in the range of about 2 moles to about 30 moles, preferably about 3 moles to about 25 moles, further preferably, for 1 mole of the compound of formula (VI), the amount of the base is about 3 moles to about 20 moles.
The reaction temperature of step (C) may be suitably selected to be between-10℃and 80℃and preferably between about 0℃and 50℃and more preferably between about 0℃and room temperature. The reaction time may be appropriately selected so that the reaction is completed. It may be from about 0.1 hours to several days, preferably within a day.
The crude product from step (B) can be used as starting material for step (C) (see example 7, step 4).
The invention further includes a process for preparing a compound of formula (I) 1- (trifluoromethyl) cyclopropane-1-carboxylic acid via steps (B) and (C) (see equation 6).
Process for the preparation of compounds of formula 6, formula (I) steps (B) and (C)
Steps (B) and (C) are as above.
The invention further includes a process for preparing a compound of formula (I) 1- (trifluoromethyl) cyclopropane-1-carboxylic acid via step (C) (scheme 7).
Process for preparing 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compounds of formula (I) via step (C) in reaction formula 7
The description of step (C) is as above.
The invention also includes a process (equation 8) for preparing a 1-acetyl-1- (trifluoromethyl) cyclopropane compound of formula (VI) via steps (a) and (B).
Process for preparing 1-acetyl-1- (trifluoromethyl) cyclopropane compound of formula (VI) via steps (A) and (B) in reaction scheme 8
The description of steps (a) and (B) is as above. The reactions of steps (a) and (B) may be carried out in a continuous process in one reactor, which, as already described above, is referred to as a one-pot reaction. Alternatively, salts of the compounds of formula II can be prepared by one-pot methods using α -acetyl- γ -butyrolactone (as already mentioned in equation 3 above), and also 1-acetyl-1- (trifluoromethyl) cyclopropane compounds of formula (VI) can be prepared by one-pot methods using α -acetyl- γ -butyrolactone (see example 7, steps 1-3).
The invention further includes a process (equation 9) for preparing a compound of formula (IV) 1-acetyl-1- (trifluoromethyl) cyclopropane via step (B).
Reaction 9, step (B)
The description of step (B) is as above.
The invention further includes a process (scheme 10) for preparing the α -acetyl- α - (trifluoromethyl) - γ -butyrolactone compound of formula (IV) via step (a).
Process for preparing alpha-acetyl-alpha- (trifluoromethyl) -gamma-butyrolactone compounds of formula (IV) via step (A) in reaction scheme 10
The description of step (a) is as above.
In another aspect, the invention also includes a novel compound, an α -acetyl- α - (trifluoromethyl) - γ -butyrolactone compound of formula (IV), which is a useful intermediate in the preparation of 1-acetyl-1- (trifluoromethyl) cyclopropane compounds of formula (VI) and 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compounds of formula (I).
1- (trifluoromethyl) cyclopropane-1-carboxylic acid the compounds of formula (I) are important intermediates in the production and development of many pharmaceuticals. The invention provides a novel, efficient, safe and environment-friendly method and novel intermediates for producing 1- (trifluoromethyl) cyclopropane-1-carboxylic acid. These compounds are very useful for the industrial production of the compounds of formula (I).
Detailed Description
In order to further understand the present invention, a method for producing a 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compound and an intermediate thereof according to the present invention will be described in detail with reference to examples. It should be understood that these examples are presented merely to further illustrate the features of the present invention and are not intended to limit the scope of the invention or the scope of the claims.
Example 1: preparation of alpha-acetyl-alpha- (trifluoromethyl) -gamma-butyrolactone
Under nitrogen protection, 12.8 g (0.1 mole) of α -acetyl- γ -butyrolactone and 300mL of N, N-Dimethylformamide (DMF) were added to the flask. After the mixture was cooled to-28℃13.4g (0.12 mol) of potassium tert-butoxide was added and the reaction mixture was stirred at this temperature for 0.5h to give potassium salt of α -acetyl- γ -butyrolactone in DMF solution. Then, 48.2g (1.11 mol) of a 2, 8-difluoro-S- (trifluoromethyl) dibenzothiophene triflate solution was added dropwise to a-25-30℃solution containing potassium salt of α -acetyl- γ -butyrolactone, followed by stirring for 2 hours. The resulting mixture was stirred at-25-30 ℃ for 1 hour, then warmed to room temperature and stirred at room temperature for 1 hour. For the reaction mixture 19 FNMR nuclear magnetic analysis showed that the yield of the product α -acetyl- α - (trifluoromethyl) - γ -butyrolactone was 81%. The reaction mixture was mixed with a large amount of water and the precipitate of the by-product 2, 8-difluorodibenzothiophene was removed by filtration. The filtrate was extracted with ethyl acetate several times, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the product, which was purified by distillation under reduced pressure. The physical and spectral data of α -acetyl- α - (trifluoromethyl) - γ -butyrolactone are as follows: colorless liquid, melting point 104 ℃/26mmHg; 19 F-NMR(376MHz,CDCl 3 ,CFCl 3 delta-67.98 ppm (s, CF) as a Standard 3 )； 1 H NMR(400MHz,CDCl 3 )δ2.53ppm(s,3H,CH 3 ),2.60(m,1H,CH),3.04(m,1H,CH),4.28(m,1H,CH),4.43ppm(m,1H,CH)； 13 CNMR(100MHz,CDCl 3 )δ26.9ppm(s,CH 3 ) 27.4 (quartet, j=2hz, ch) 2 ) 64.7[ quartet, J=27 Hz, four groups C), 65.9 (s, CH 2 O), 123.1 (quartet, j=280 hz, cf 3 ) 167.5 (quartet, j=2 Hz, (c=o) O), 194.7 (s, c=o).
Example 2: preparation of alpha-acetyl-alpha- (trifluoromethyl) -gamma-butyrolactone
640mg (5 mmol) of α -acetyl- γ -butyrolactone and 5mL of 1-methyl-2-pyrrolidone (NMP) are added to the flask under nitrogen. 616 mg (5.5 mmol) of potassium tert-butoxide was added under ice-bath cooling, and the reaction mixture was stirred for 20 minutes to obtain potassium salt of α -acetyl- γ -butyrolactone in NMP solution. After cooling the mixture to-20℃a solution of 2.41g (5.5 mol) of 2, 8-difluoro-S- (trifluoromethyl) dibenzothiophene triflate in 50mL of NMP was added dropwise with stirring for 10 minutes. The resulting reaction mixture was stirred at-20 ℃ for 1 hour, then warmed to room temperature and stirred at room temperature for 1 hour. For the reaction mixture 19 F NMR nuclear magnetic analysis showed that the yield of the product α -acetyl- α - (trifluoromethyl) - γ -butyrolactone was 60%. The product was identified by spectroscopic analysis.
Example 3: preparation of alpha-acetyl-alpha- (trifluoromethyl) -gamma-butyrolactone
640 milligrams (5 mmol) of α -acetyl- γ -butyrolactone and 5mL of dimethyl sulfoxide (DMSO) were added to the flask under nitrogen. 616 mg (5.5 mmol) of potassium tert-butoxide are added, the reaction mixture is stirred for 10 minutes, and the potassium salt of α -acetyl- γ -butyrolactone is obtained in DMSO solution, cooled in a water bath (room temperature). A solution of 2.41g (5.5 mol) of 2, 8-difluoro-S- (trifluoromethyl) dibenzothiophene triflate in 5mL of DMSO was added dropwise with stirring for 10 minutes. The resulting reaction mixture was stirred in a water bath for 1 hour. For the reaction mixture 19 F NMR nuclear magnetic analysis showed that the yield of the product α -acetyl- α - (trifluoromethyl) - γ -butyrolactone was54%. The product was identified by spectroscopic analysis.
Example 4: preparation of 1-acetyl-1- (trifluoromethyl) cyclopropane
In a reactor equipped with a condenser and a drying tube, 17.3g (88.2 mmol) of α -acetyl- α - (trifluoromethyl) - γ -butyrolactone and 6.5g (17.6 mmol) of tetrabutylammonium iodide and 18mL of dried 1-methyl-2-pyrrolidone (NMP) were charged. The reaction mixture was stirred with a magnetic stirrer in an oil bath at 135 ℃ for 3 hours. During the reaction, gas (CO) 2 ) After the evolution, the reaction proceeds. After the reaction, the reactor was separated from the condenser and the drying tube, and then connected to a trap bottle. After cooling the trapping bottle with liquid nitrogen, the trapping bottle was connected to an aspirator (reduced pressure). The reaction mixture of 1-acetyl-1-trifluoromethyl cyclopropane, which was stirred and heated to 120℃at 45℃was then transferred under reduced pressure (92 mmHg) to a trap bottle cooled by liquid nitrogen. The product obtained in the trapping bottle was 11.7 g (yield 87%). The physical and spectroscopic data are as follows: a colorless liquid; melting point 94-96 ℃; 19 F NMR(376MHz,CDCl 3 ,CFCl 3 as a standard)δ-64.89ppm(s,CF 3 )； 1 H NMR(400MHz,CDCl 3 )δ1.25～1.45(m,2xCH 2 ),2.41ppm(s,CH 3 )； 13 C NMR(100MHz,CDCl 3 )δ14.8(quartet,J＝2Hz,CH 3 ),28.1(quartet,J＝3Hz,CH 2 CH 2 ),33.6(quartet,J＝33Hz,quaternaryC),125.7(quartet,J＝271Hz,CF 3 ) 200.4 (s, c=o). GC-MS (EI method) 152 (M + ).
Example 5: preparation of 1-acetyl-1- (trifluoromethyl) cyclopropane
1.0g (5.1 mmol) of alpha-acetyl-alpha- (trifluoromethyl) -gamma-butyrolactone, 423mg (2.55 mmol) of potassium iodide and 10mL of dryDry 1-methyl-2-pyrrolidone (NMP) was placed in a reactor equipped with a condenser and a drying tube. The reaction mixture was stirred with a magnetic stirrer at 150 ℃ in an oil bath for 50 minutes. For the reaction mixture 19 F NMR nuclear magnetic analysis shows that the yield of the product 1-acetyl-1- (trifluoromethyl) cyclopropane is high. The product is identified by spectral analysis and separation.
Example 6: preparation of 1- (trifluoromethyl) cyclopropane-1-carboxylic acid
In the flask, 5.79 g (145 mmol) sodium hydroxide and 40 ml water were added and the mixture was cooled in an ice bath. 9.48g (59.2 mmol) of bromine (Br) were added dropwise over 10 minutes with cooling on an ice bath to the stirred mixture 2 ). After addition, the reaction mixture was cooled on an ice bath and stirred for an additional 10 minutes. A solution of 1.0g (6.58 mmol) of 1-acetyl-1- (trifluoromethyl) cyclopropane in 4.6mL of dioxane was added dropwise over 10 minutes, and after the addition, the reaction mixture was stirred under ice-bath cooling for 2 hours and then at room temperature overnight. The reaction mixture is reacted with an amount of NaHSO 3 The aqueous solution is mixed to neutralize excess Br 2 The mixture was extracted with chloroform (20 mL. Times.2) and the organic layer was removed. The aqueous layer was acidified to ph=3 with 6N HCl and extracted with chloroform (20 ml×2). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 1.07g (quantitative yield) of 1- (trifluoromethyl) cyclopropane-1-carboxylic acid as a white solid. The product was identical to a standard sample of 1- (trifluoromethyl) cyclopropane-1-carboxylic acid. Spectral data of the product: 19 F NMR(376MHz,CDCl 3 ,CFCl 3 delta-65.51 ppm (s, CF) as a Standard 3 )； 1 H NMR(400MHz,CDCl 3 )δ1.40～1.56ppm(m,2xCH 2 ).
Example 7:
preparation of 1-acetyl-1- (trifluoromethyl) cyclopropane from α -acetyl- γ -butyrolactone via one-pot process of steps 1-3, and continuous haloform reaction in step 4
(step 1) in 25.6 g (0.20 mol) of α -acetyl- γ -butyrolactone and 250mL of dry N, N-Dimethylformamide (DMF) under nitrogen protection, 24.6g (0.22 mol) of potassium tert-butoxide are added in portions at a temperature of ice bath. The reaction mixture was stirred at 0 ℃ for 30 minutes and then cooled to-55 ℃.
(step 2) 96.4g (0.22 mol) of 2, 8-difluoro-S- (trifluoromethyl) dibenzothiophene triflate and 250ml of dry DMF solution were added to the reaction mixture of step 1 at a rate and the reaction temperature was controlled between-55 and-50 ℃. The reaction mixture was then stirred at-50 ℃ for 1 hour and then gradually warmed to room temperature over 2.5 hours. For the reaction mixture 19 F NMR nuclear magnetic analysis showed CF as 2, 8-difluoro-S- (trifluoromethyl) dibenzothiophene triflate 3 SO 3 Part of the label was used as a label, and the conversion of α -acetyl- α -trifluoromethyl- γ -butyrolactone to α -acetyl- α -trifluoromethyl- γ -butyrolactone was 91%.
(step 3) to the reaction mixture of step 2, 18g (0.12 mol) of sodium iodide was added, and the reaction mixture was heated to 135 ℃. The reaction mixture was stirred at 135℃for 7 hours, and the reaction mixture was distilled under reduced pressure to give a fraction containing 1-acetyl-1- (trifluoromethyl) cyclopropane. Fraction warp 19 F NMR analysis, using 4-chlorobenzotrifluoride as an internal standard, showed that 0.14mol of 1-acetyl-1- (trifluoromethyl) cyclopropane was prepared. The yield was 70% calculated from the starting material α -acetyl- γ -butyrolactone.
(step 4) the fraction containing 1-acetyl-1- (trifluoromethyl) cyclopropane was added to 426 g of a 10% aqueous potassium hypochlorite solution (KOCl, 0.471 mol) at 0 to 5℃and the reaction mixture was stirred at room temperature for 2 hours. Excess hypochlorite was degraded by the addition of sodium sulfite, and then the reaction mixture was acidified with 6 equivalents of hydrochloric acid and extracted with methyl tert-butyl ether (100 ml x 3). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate obtained by suction filtration was concentrated by evaporation and dried in vacuo to give 20.5 g of 1- (trifluoromethyl) cyclopropane-1-carboxylic acid as a white solid. Calculated as 1-acetyl-1- (trifluoromethyl) cyclopropane, the yield was 95%. The yield was 67% calculated from the starting α -acetyl- γ -butyrolactone. The spectrum of the product is consistent with that of a standard sample.
Claims (14)
1. A process for the preparation of a 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compound of formula (I), comprising the steps of: (step 1) reacting an alpha-acetyl-gamma-butyrolactone salt compound of formula (II) with an S- (trifluoromethyl) dibenzothiophene salt compound of formula (III), (step 2) reacting an alpha-acetyl-alpha- (trifluoromethyl) -gamma-butyrolactone compound of formula (IV) prepared in step 1 with a halide salt compound of formula (V), and (step 3) reacting a 1-acetyl-1- (trifluoromethyl) cyclopropane compound of formula (VI) prepared in step 2 to prepare a 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compound of formula (I) through haloform reaction;
Y + Z - -----------------(V)
wherein M is an alkali metal atom or an ammonium group; r is R 1 ,R 2 ,R 3 And R is 4 Each independently is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 4 carbons; x-is the conjugate base of an acid; y is an alkali metal atom, an ammonium group or a phosphorus group; z is a halogen atom.
2. A process for the preparation of a 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compound of formula (I), comprising the steps of: (step 1) reacting an alpha-acetyl-alpha- (trifluoromethyl) -gamma-butyrolactone compound of formula (IV) with a halogenated salt compound of formula (V), (step 2) reacting the 1-acetyl-1- (trifluoromethyl) cyclopropane compound of formula (VI) prepared in step 1 with haloform to obtain a 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compound of formula (I),
Y + Z - ----------------(V)
wherein Y is an alkali metal atom, an ammonium moiety or a phosphorus atom moiety; z is a halogen atom.
3. A process for the preparation of a 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compound of formula (I), comprising the steps of: the 1- (trifluoromethyl) cyclopropane-1-carboxylic acid compound of formula (I) is prepared by haloform reaction of the 1-acetyl-1- (trifluoromethyl) cyclopropane of formula (VI),
4. a process according to claim 1,2 or 3, wherein the haloform reaction is a reaction of 1-acetyl-1- (trifluoromethyl) cyclopropane with a halogenating agent in the presence of a base.
5. The method of claim 4, wherein the halogenating agent is chlorine, bromine or iodine.
6. A process according to claim 1,2 or 3, wherein the haloform reaction is prepared by reacting 1-acetyl-1- (trifluoromethyl) cyclopropane with a hypohalite.
7. The method of claim 6, wherein the hypohalite is sodium hypochlorite or potassium hypochlorite.
8. A process for the preparation of a 1-acetyl-1- (trifluoromethyl) cyclopropane compound of formula (VI), comprising the steps of: (step 1) reacting the alpha-acetyl-gamma-butyrolactone salt formula (II) compound with S- (trifluoromethyl) dibenzothiophene salt formula (III), reacting the alpha-acetyl-alpha- (trifluoromethyl) -gamma-butyrolactone formula (IV) compound prepared in step 1 with a halide salt formula (V) compound to obtain the 1-acetyl-1- (trifluoromethyl) cyclopropane formula (VI),
Y + Z - ----------------(V)
wherein M is an alkali metal atom or an ammonium group; r is R 1 ,R 2 ,R 3 And R is 4 Each independently is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 4 carbons; x-is the conjugate base of an acid; y is an alkali metal atom, an ammonium group or a phosphorus group; z is a halogen atom.
9. The method of claim 1 or 8, wherein steps 1 and 2 are performed by a one-pot reaction process.
10. A process for the preparation of a 1-acetyl-1- (trifluoromethyl) cyclopropane compound of formula (VI), comprising the steps of: the alpha-acetyl-alpha- (trifluoromethyl) -gamma-butyrolactone compound of formula (IV) reacts with a halide salt compound of formula (V) to prepare a 1-acetyl-1- (trifluoromethyl) cyclopropane compound of formula (VI),
Y + Z - (v)
wherein Y is an alkali metal atom, an ammonium moiety or a phosphorus atom moiety; z is a halogen atom.
11. The process according to claim 1,2,8 or 10, wherein Z in the compound of formula (V) is an iodine atom, a bromine atom or a chlorine atom.
12. A process for the preparation of an α -acetyl- α - (trifluoromethyl) - γ -butyrolactone compound of formula (IV), comprising the steps of: the alpha-acetyl-gamma-butyrolactone salt compound is reacted with S- (trifluoromethyl) dibenzothiophene salt compound of formula (III) to prepare alpha-acetyl-alpha- (trifluoromethyl) -gamma-butyrolactone compound of formula (IV);
wherein M is an alkali metal atom or an ammonium group; r is R 1 ,R 2 ,R 3 And R is 4 Each independently is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 4 carbons; x is X - Is a conjugate base of an acid.
13. The process according to claim 1,8 or 12, wherein the halogen atom of the compound of formula (III) is a fluorine atom or an alkyl group, the alkyl group is a methyl group or a tert-butyl group, and X in the compound of formula (III) - Is CF (CF) 3 SO 3 - ,BF 4 - ,Cl - Or Br (Br) - 。
14. A compound of formula (IV) α -acetyl- α - (trifluoromethyl) - γ -butyrolactone having the formula:
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| US5208353A (en) * | 1989-06-14 | 1993-05-04 | Smithkline Beecham Corp. | Intermediates for preparing epoxy esters |
| US5336809A (en) * | 1992-03-05 | 1994-08-09 | Bayer Aktiengesellschaft | Process for preparing 1-fluorocyclopropyl methyl ketone |
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