IIIHIIII US005202462A United States Patent (19) (11) Patent Number: 5,202,462 Yazawa et al. 45) Date of Patent: Apr. 13, 1993 (54) PROCESS FOR PRODUCING A HALOMETHYL PVALATE FOREIGN PATENT DOCUMENTS 75) Inventors: Naoto Yazawa, Shizuoka; Keinosuke 224.5457 3/1973 Fed. Rep. of Germany . Ishikame, Tokyo, both of Japan 3152341 6/1988 Japan ................................... 560/236 73) Assignee: hara Chemical Industry Co., Ltd., OTHER PUBLICATIONS Tokyo, Japan Chemical Abstracts, vol. 107, No. 17, Oct. 26, 1987, Andreev et al: "Chloromethyl pivalate." p. 664, Ab (21) Appl. No.: 920,529 stract No. 153938q. (22 Filed: Jul. 28, 1992 Chemical Abstracts, vol. 101, No. 23, Dec. 3, 1984, Binderup et al: "Chlorosulfates as reagents in the syn Related U.S. Application Data thesis of carboxylic acid esters . ', p. 563, Abstract 63 Continuation of Ser. No. 686,921, Apr. 18, 1991, aban No. 210 048b. doned. Primary Examiner-Arthur C. Prescott (30) Foreign Application Priority Data Attorney, Agent, or Firm-Oblon, Spivak, McClelland, Maier & Neustadt Apr. 20, 1990 JP Japan .................................. 2-104544 (51) Int. Cl* ... co7C 69/62 57 ABSTRACT 52) U.S. C. ............... A process for producing a halomethyl pivalate which 58) Field of Search ......................................... S60/236 comprises reacting an aqueous solution of a metal salt of pivalic acid with a dihalomethane selected from the (56) References Cited group consisting of bromochloromethane, chloroi U.S. PATENT DOCUMENTS odomethane and bromoiodomethane in the presence of 3,992,432 11/1976 Napier ................................. 560/236 a phase transfer catalyst. 4,421,675 12/1983 Sawicki. ... 560/236 4,699,991 0/1987 Arkles ................................. 560/236 14 Claims, No Drawings 5,202,462 1 2 According to the present invention, it is essential to PROCESS FOR PRODUCING A HALOMETHYL have a phase transfer catalyst present during the reac PVALATE tion of the aqueous solution of metal salt of pivalic acid with the dihalomethane. As the phase transfer catalyst, This application is a continuation of application Ser. 5 any catalyst which is usually called a phase transfer No. 07/686,921, filed Apr. 18, 1991 now abandoned. catalyst can be employed. For example, quaternary The present invention relates to a process for produc onium salts such as a quaternary ammonium salt, a qua ing a halomethyl pivalate which is useful as a starting ternary pyridinium salt and a quaternary phosphonium material for cephem antibiotics (which are disclosed, salt are usually used. They may be used alone or in for example, in Japanese Unexamined Patent Publica 10 combination. Among them, preferred are tetrabutylam tion No. 19593/1987). monium bromide, tetrabutylammonium chloride, trioc Heretofore, as a process for producing a halomethyl tylmethylammonium chloride and trioctylmethylam pivalate, it has been known to conduct so-called Blanc monium bromide which are readily obtainable from the Quelet reaction wherein formaldehyde and a hydrogen industrial viewpoint. halide are reacted with pivalic acid in the presence of a 15 In the process of the present invention, the phase catalyst such as aluminum chloride or zinc chloride. transfer catalyst is used in an amount of from 0.001 to 1 However, such a process has a problem that highly mol, preferably from 0.005 to 0.2 mol, per mol of the poisonous chloromethyl methyl ether and bis(- metal salt of pivalic acid. chloromethyl)ether (hereinafter referred to simply as Further, the dihalomethane selected from the group halomethyl ethers) are produced as by-products. 20 consisting of bromochloromethane, chloroiodomethane It is an object of the present invention to provide a and bromoiodomethane, which is to be reacted with the process for producing a halomethyl pivalate which does aqueous solution of the metal salt of pivalic acid, is used not produce highly poisonous halomethyl ethers as in an amount of from 1 to 100 mols, preferably from 10 byproducts produced in conventional methods and to 50 mols, per mol of the aqueous solution of the metal which is useful for practical industrial application. 25 salt of pivalic acid. The present inventors have conducted extensive re In the process of the present invention, a nonaqueous searches to develop a process for producing a halo inert organic solvent such as benzene, toluene and di methyl pivalate which does not produce highly poison ethyl ether can be used as the case requires. ous halomethyl ethers. As a result, it has been found Now, a specific embodiment suitable for the process that the object of the present invention can be attained of the present invention, will be described. Firstly, a by using a dihalomethane having halogen atoms differ phase transfer catalyst, an aqueous solution of a metal ent from each other in a process for producing a halo salt of pivalic acid and a dihalomethane selected from methyl pivalate by reacting an aqueous solution of a the group consisting of bronochloromethane, chloroi metal salt of pivalic acid with a dihalomethane in the odomethane and bromoiodomethane are mixed and presence of a phase transfer catalyst. The present inven 35 reacted in predetermined proportions. There is no par tion is based on this discovery. ticular restriction on the reaction temperature, and it is Namely, the present invention provides a process for usually from 0 C, to the reflux temperature of the reac producing a halomethyl pivalate which comprises re tion system. The reaction time depends on the starting acting an aqueous solution of a metal salt of pivalic acid materials employed, the reaction temperature, the cata with a dihalomethane selected from the group consist lyst, etc., and it is usually about from 1 to 10 hours. The ing of bromochloromethane, chloroiodomethane and reaction can be conducted under atmospheric pressure bromoiodomethane in the presence of a phase transfer or elevated pressure. After completion of the reaction, catalyst. the reaction mixture is allowed to stand to have an Now, the present invention will be described in detail aqueous phase and an oil phase separated. Then, only with reference to the preferred embodiments. 45 the oil phase is collected, washed and distilled off, As the aqueous solution of a metal salt of pivalic acid whereby a halomethyl pivalate is obtained. to be used as a starting material in the present invention, In the process of the present invention, the pivalic an aqueous solution of an alkali metal or alkaline earth acid can be quantitatively recovered from the distilla metal salt of pivalic acid may be mentioned. As the tion residue by subjecting bis(pivaloyloxy)methane pro alkali metal or alkaline earth metal salt of pivalic acid, duced as by-product to hydrolysis with an alkali or acid, sodium, potassium, magnesium or barium salt of pivalic and the pivalic acid recovered can be reused. Accord acid may be mentioned. ingly, the process of the present invention is so efficient Such a metal salt of pivalic acid can be readily pro that the pivalic acid is consumed only for the formation duced by reacting pivalic acid with an aqueous solution of the halomethyl pivalate. of a hydroxide, carbonate or hydrogen carbonate of an 55 According to the process of the present invention alkali metal or alkaline earth metal. The aqueous solu wherein an aqueous solution of a metal salt of pivalic tion of a metal salt of pivalic acid thus obtained may be acid is reacted with a dihalomethane selected from the used as it is in the form of the aqueous solution. Alterna group consisting of bromochloromethane, chloroi tively, pivalic acid and a metal salt of an alkali metal or odomethane and bromoiodomethane in the presence of alkaline earth metal are reacted directly in the reaction 60 a phase transfer catalyst, it is possible to produce halo system to obtain an aqueous solution of the metal salt of methyl pivalate in good yield and without production pivalic acid. of halomethyl ethers as by-products. Further, the pi Further, water is used at least in an amount capable of valic acid can be recovered quantitatively by means of stirring, preferably at least in an amount capable of hydrolysis of bis(pivaloyloxy)methane produced as dissolving the inorganic salt formed. by-product, and the recovered pivalic acid can be re Moreover, there is no particular restriction as to the used. Thus, the process of the present invention is suit order to add pivalic acid, the base, the dihalomethane able as an industrial process for the production of halo and the phase transfer catalyst. methyl pivalate. 5,202,462 3 4. Now, the present invention will be described in fur TABLE 2-continued ther detail with reference to examples. However, it COMPARA should be understood that the present invention is by no TIVE means restricted by these specific examples. Example 6 7 8 EXAMPLE Selectivity for 28.0 29.6 31.2 100 EXAMPLE 1. Bis-product') Into a 200 ml reaction flask equipped with a con (%) denser, a thermometer and a stirrer, 161.7 g of bromo 48% sodium hydroxide aqueous solution Tributylammonium bromide chloromethane, 5.1 g of pivalic acid, a 48% sodium Trioctylmethylammonium chloride hydroxide aqueous solution and 0.5 of tetrabutylam O Bis(pivakoyloxy)methane monium bromide were introduced and reacted for 2.5 hours. The conversion and the selectivity for chloro In Tables 1 and 2, the selectivity and the selectivity methyl pivalate are shown in Table 1. (Neither chloro for bis product were calculated as follows: methyl methyl ether nor bis(chloromethyl)ether was detected from the above reaction solution.) 15 After completion of the reaction, the reaction solu Selectivity = -eirii;Yield of halomethyl pivalate tion was allowed to stand, and the oil phase separated, was collected, washed and distilled off to obtain 153.6g Selectivity for Yield of bis-product of bromochloromethane as a fraction having a boiling bis-product Conversion of pivalic acid point of 67 C.