USOO6278O15B1 (12) United States Patent (10) Patent No.: US 6,278,015 B1 Spangler et al. (45) Date of Patent: Aug. 21, 2001 (54) PROCESS FOR TRIFLUOROACETATE 4,701,551 10/1987 DesBois et al. ..................... 560/226 ESTERS AND THOESTERS 4,730,082 3/1988 Amiet et al. ......................... 560/227 4,879,407 11/1989 Amiet et al. ......................... 560/227 (75) Inventors: Lori Ann Spangler, Churchville; 4,916,256 * 4/1990 Grego et al. ......................... 560/227 Fereydon Abdesaken, Dresher; Joshua 5,405,991 4/1995 Feist et al. ........................... 560/239 Anthony Chong, Lansdale, all of PA (US) FOREIGN PATENT DOCUMENTS (73) Assignee: Rohm and Haas Company, WO 96/26.185 8/1996 (WO). Philadelphia, PA (US) * cited by examiner (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. Primary Examiner-Gary Geist Assistant Examiner Hector M. Reyes (74) Attorney, Agent, or Firm-Clark R. Carpenter (21) Appl. No.: 09/617,381 (22) Filed: Jul. 17, 2000 (57) ABSTRACT O O The present invention provides a proceSS for preparing esters Related U.S. Application Data or thioesters of trifluoroacetic acid from trifluoroacetylchlo (60) Provisional application No. 60/144,803, filed on Jul. 21, ride and an alcohol or a thiol with the ester or thioester being 1999. present as the Solvent. Esters and thioesters of trifluoroacetic (51) Int. Cl." ................................................. C07C 69/63 acid are fine chemical intermediates which can be used in the (52) U.S. Cl. .......................... 560/227; 560/265; 560/239; manufacture of pharmaceuticals, agricultural chemicals, liq 560/226; 560/228; 560/203 uid crystals, dyes and industrial chemicals. Trifluoroacetate (58) Field of Search ...................................... 560,227, 255 esters and thioesters can also be used as Solvents in the manufacture of other fine chemicals, pharmaceuticals, agri (56) References Cited cultural chemicals, liquid crystals, industrial chemicals and dyes. U.S. PATENT DOCUMENTS 2,012,812 8/1935 Guinot et al. ........................ 560/265 10 Claims, No Drawings US 6,278,015 B1 1 PROCESS FOR TRIFLUOROACETATE ESTERS AND THOESTERS This application claims benefit of provisional application 60/144,803, filed Jul. 21, 1999. us l The present invention relates to a process for preparing FC C - RXH esters or thioesters of trifluoroacetic acid from trifluoro (II) acetyl chloride and an alcohol or a thiol. Esters or thioesters of trifluoroacetic acid are fine chemical intermediates which can be used in the manufacture of pharmaceuticals, agricul FC ul XR + HCl, tural chemicals, liquid crystals, dyes and industrial chemi (I) cals. Trifluoroacetate esters can also be used as Solvents in the manufacture of other fine chemicals, pharmaceuticals, agricultural chemicals, liquid crystals, dyes and industrial wherein chemicals. 15 R is alkyl or alkyl Substituted with alkoxy or haloalkoxy, and There are Several processes previously disclosed which X is an oxygen or a Sulfur atom which comprises the Steps can be used to produce trifluoroacetate esters. U.S. Pat. No. of 4,916,256 teaches vapor phase reactions which must employ (i) reacting trifluoroacetyl chloride with a compound of a Substantial Stoichiometric excess of the toxic and relatively formula (II) in the initial presence of an amount of expensive trifluoroacetylchloride to react with an alcohol to said trifluoroacetate compound of formula (I) at a produce a trifluoroacetate ester. U.S. Pat. No. 5,405,991 temperature of 20° C. or less to produce the trifluo teaches the reaction of an acid chloride with an alcohol to roacetate compound of formula (I) and form a trifluoroacetate ester but with the necessity of having (ii) degassing the mixture at ambient temperature to a catalyst present which is an alkali metal Salt or an onium remove the HCl by-product and any residual trifluo Salt of the carboxylic acid corresponding to the acid chloride 25 roacetyl chloride. starting material. U.S. Pat. No. 4,701,551 discloses reaction AS used herein, the term “alkyl refers to Straight and of trifluoroacetic acid with an alcohol to form trifluoroac branched aliphatic hydrocarbon chains, for example, methyl, etate esters but liquid HF is required as a catalyst. U.S. Pat. ethyl, n-propyl, isopropyl, it-butyl, Sec-butyl, tert-butyl, No. 4,730,082 discloses a multi-step process to produce isoamyl and n-hexyl. When the alkyl group possesses an methyl trifluoroacetate from trifluoroacetic acid and metha asymmetric carbon atom, the term alkyl is meant to include nol; a catalytic amount of a strong acid is required in one of either enantiomeric form or a mixture thereof The term the steps. WO 96/26185A1 discloses formation of thioesters “alkoxy' refers to a Straight or a branched aliphatic hydro by reacting trifluoroacetic anhydride with thiols in the carbon chain attached to an OXygen atom, for example, presence of pyridine and 4-dimethylaminopyridine methoxy, ethoxy, isopropoxy, n-butoxy and the like. The (DMAP). None of these references, either individually or 35 term “haloalkoxy' refers to an alkoxy group Substituted with collectively, teach or Suggest the process of the present one or more halo groups, for example, chloromethoxy, invention. chlorodifluoromethoxy, trifluoromethoxy, perfluoroethoxy, We have found in the process of the present invention 2-bromoethoxy and the like. The term “halo” refers to a that the product trifluoroacetate ester or thioester itself is an fluorine, chlorine or a bromine atom. excellent Solvent for the reaction. The reaction is run at 40 In a preferred process of this invention, R is (C-C)alkyl relatively low temperature, from about ambient to Somewhat or (C-C)alkyl substituted with (C-C)alkoxy. below the boiling point of trifluoroacetyl chloride. No other In a more preferred process of this invention, R is catalyst or reagent is required. Hydrogen chloride, which is (C-C)alkyl. a by-product of the reaction, is removed at the end of the In an even more preferred process of this invention, R is reaction by warming the reaction mixture to room tempera 45 methyl, ethyl or isopropyl. ture with stirring. The ester or thioester product obtained by In the most preferred process of this invention, R is ethyl. this proceSS is of already high purity, but purity can be More Specifically, the proceSS for the preparation of esters increased to >99% by distillation. The resultant advantages or thioesters of trifluoroacetic acid of this invention involves of the process of the present invention include: reacting trifluoroacetyl chloride with an alcohol or a thiol at 50 a low temperature in the presence of the desired product of (i) an ease of purification of the desired ester or thioester formula (I) as a Solvent in a first step and, at the end of the product Since no other Solvent is present which must be desired reaction, degassing the mixture at room temperature removed using distillation or other techniques, to remove hydrogen chloride by-product and any residual (ii) the solubility of trifluoroacetyl chloride in the desired trifluoroacetyl chloride. These gasses are treated, usually by ester or thioester is high which leads to concentrated 55 passing them through a Scrubber or, in the case of trifluo reaction mixtures and more pounds of product ester or roacetyl chloride, the gasses can be recycled, for example, thioester per reactor, by either capturing in a scrubber filled with the ester or (iii) the high solubility of trifluoroacetyl chloride in the thioester of trifluoroacetic acid which will be used as solvent desired ester or thioester results in a Safer proceSS Since in the Subsequent reaction or by condensation. The ester or the process control of the toxic trifluoroacetyl chloride 60 thioester of trifluoroacetic acid produced in this reaction is to prevent it from boiling away (b.p. is -27 C.) is not already of high purity, but the purity can be increased to just dependent on the reactor cooling, and >99% by distillation. (iv) no other reagents or catalysts are required for the The alcohol (ROH) or thiol (RSH) can be selected from desired ester or thioester formation. alcohols or thiols having from 1 to 6 carbon atoms. The alkyl Accordingly, this invention provides a proceSS for the 65 groupS R can be Straight chain or branched chain. The R preparation of a trifluoroacetate compound of formula (I) group can be Substituted with alkoxy groupS and with from trifluoroacetylchloride and a compound of formula (II) haloalkoxy groups. US 6,278,015 B1 3 4 The reaction step (i) is carried out at a temperature which EXAMPLE 1. is near the boiling point of trifluoroacetyl chloride. Typical Preparation of Ethyl Trifluoroacetate reaction temperatures range from about -40°C. to about 20 A heel of 187 g of ethyl trifluoroacetate was cooled to C., preferably from about -30° C. to about 0°C., and more -19 C. To this was added 199 g of trifluoroacetyl chloride, preferably from about -25 C. to about -15 C. and the mixture was maintained at -190 to -25 C. To this The proceSS is performed as follows: the dry reactor is was added 55.8 g of ethanol over 60 min, followed by an charged with a heel (recycled material, most usually from additional 14 g of ethanol over 45 min. The mixture was then the previous reaction batch) of the desired product ester or allowed to warm to room temperature with Stirring and using thioester and cooled to the low temperature. The first a scrubber filled with 10% aqueous sodium hydroxide. The reagent, which can be either trifluoroacetyl chloride or the resulting 396 g of ethyl trifluoroacetate was transferred to a compound of formula (II), is added. The Second reagent is still and distilled at atmospheric pressure to yield 360 g of added at a rate to keep the internal temperature of the reactor ethyl trifluoroacetate, >99% pure.