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United States Patent (19) (11) 4,428,887 Tou Et Al United States Patent (19) (11) 4,428,887 Tou et al. 45) Jan. 31, 1984 54 METHOD OF PRODUCING MONO-SUBSTITUTED TERMINAL FOREIGN PATENT DOCUMENTS DESTERS 146496 7/1902 Fed. Rep. of Germany . (75) Inventors: Jacob S. Tou; Alfred A. Schleppnik, 1059M 1/1962 France . both of St. Louis, Mo. 940533 10/1963 United Kingdom. 73 Assignee: Monsanto Company, St. Louis, Mo. OTHER PUBLICATIONS 21 C. A. Bischoff, Ber. 29 (1), 966–967, (1896). Appl. No.: 398,060 D. A. White, S. Synthetic Comm. 7 (8), 559-568, (1977). (22) Filed: Jul. 14, 1982 Holden and Lapworth, J. Chem. Soc., 2368-2373, 51 Int. Cl. ..................... CO7C 120/00; CO7C 67/34 (1931). (52) U.S. Cl. ............................. 260/465 D; 260/465.4; Primary Examiner-Natalie Trousof 560/81; 560/190; 560/203 Assistant Examiner-Vera C. Clarke (58) Field of Search ................. 560/190, 193, 203, 81; Attorney, Agent, or Firm-Scott J. Meyer; James W. 260/465 D, 465.4 Williams, Jr, (56) References Cited 57 ABSTRACT U.S. PATENT DOCUMENTS Mono-substituted terminal diesters of malonic acid are 1,869,666 8/1932 Chaux et al. ........................ 544/304 prepared by reaction of the corresponding substituted 1,954,429 4/1934 Shonle ................................. 544/306 1,2-diesters with alkali metal hydride in the presence of 2,153,730 4/1939 Volwiler et al. 544/305 X organic solvent medium. 2,872,448 2/1959 Doran ................ ... 544/306 2,876,225 3/1959 Donnison ............................ 260/257 4 Claims, No Drawings 4,428,887 1. 2 5-Ethyl-5-(1-methylbutyl)barbiturate, (Nembutal (R), METHOD OF PRODUCING . pentobarbital), can be prepared by the reaction of ethyl MONO-SUBSTITUTED TERMINALDIESTERS 1-methylbutyl malonate in the above reaction system. 5-Allyl-5-(1-methylbutyl)barbiturate, (Seconal (R), BACKGROUND OF THE INVENTION 5 secobarbital), can be prepared by the reaction of allyl-1- This invention relates to a novel process for the pro methylbutyl malonate in the same reaction system. See duction of mono-substituted terminal diesters of ma U.S. Patent 1,954,429. lonic acid. These diesters have utility as starting materi 5-Ethyl-5-(1-methylbutyl)-2-thiobarbiturate, (Pento als and intermediates for the synthesis of pharmacologi thal (R), thiopental), can be prepared condensing ethyl cally active compounds such as the barbituates and 10 1-methylbutyl malonate with thiourea in the presence of related hypnotics, sedatives, tranquilizers, and anesthet. strong base. This compound is a useful anesthetic agent. 1CS. See U.S. Pat. No. 2,876,225. In 1903 Emil Fischer and J. von Mering synthesized 5-Allyl-5-(2-cyclohexen-1-yl)-2-thiobarbituric acid, a number of derivatives of barbituric acid by condens (Intranarcon (E), thialbarbital), can be prepared by con ing urea with diethyl malonate (commonly called ma 15. densation of phenyl propenyl malonate with thiourea. lonic ester) under the influence of sodium ethoxide as a The sodium salt is a useful anesthetic agent. See U.S. condensing agent. Some of these derivatives were Pat. No. 2,153,730. found by these scientists to be valuable as soporifics. Alkylation of diethyl malonate with a propargyl hal The preparation of the lead compound of these 5,5'- ide, followed by alkylation with allyl bromide yields the disubstituted barbiturates, namely 5,5'-diethylbarbituric 20 following organo-substituted diester of malonic acid: acid (Veronal (R), barbital), as described in German Patent No. 146,496 (1903), can be illustrated as follows: CH2=CHCH2 CO2CO2H5 C 25 / N -- CO(NH2) - A Ge. CH3 The above diester is a suitable intermediate for the pro Diethyl malonate Urea. 30. duction of 5-allyl-1-methyl-5-(1-methyl-2-pentynyl) diethyl ester barbituric acid, (Brevital (R), methohexital), which is a useful anesthetic agent as the sodium salt. See U.S. Pat. No. 2,872,448. v. The malonic ester required for the synthesis of the 35 hypnotic and sedative agent, 5-allyl-5-(2-cyclopenten I 1-yl) barbituric acid, (Cyclopal (R), can be obtained by O appropriate alkylation of diethyl allylmalonate 5,5'-Diethyl barbituric acid fochs Several hundreds of these barbiturate derivatives CH=CHCH-h having various hypnotic, sedative, tranquilizing and CO2C2H5 anesthetic activities have since been synthesized. See Blicke and Cox, Medicinal Chemistry, Vol. IV, page 1, 45. with 1,2-dibromocyclopentane and excess base. See John Wiley & Sons, New York, 1963. These com U.S. Pat. No. 1,869,666. pounds are especially useful as the sodium salts for The carbamate sedative, carbamic ester of 5-butyl-5- absorption from the gastrointestinal tract or for admin (2-hydroxyethyl)barbituric acid (Nogexan (E), carbubar istration through the parenteral route. bital), can be prepared from the intermediate compound The derivatives of barbituric acid now constitute one 50 diethylbutylmalonate of the more venerable families of medicinal agents. The aforesaid lead member of the series, barbital, has been in continuous use since its discovery in 1903. The final step ochs in the synthesis of many of the barbiturates consists in CHCH)h either condensation of an organo-substituted malonic or 55 cyanoacetic ester with urea by means of sodium ethox ide or analogous condensation of such an ester with See French Patent No. M1059(1962); British Patent No. guanidine followed by hydrolysis of the imine thus 940,533. produced. The chemistry of this class of medicinal The diesters of malonic acid also can be converted to agents thus devolves in part on the preparation of suit the corresponding glycols which are intermediates for able organo-substituted malonic acid esters. the production of compounds that have found extensive Illustrative examples of other well-known members use as drugs to relieve mild anxiety. For example, re of the barbiturate family of hypnotics and sedatives duction of malonic ester with lithium aluminum hydride derived from organo-substituted diesters of, malonic gives the corresponding glycol. Reaction of the glycol acid are as follows: 65 with phosgene produces an intermediate which on 5-Ethyl-5-phenylbarbiturate, (Luminal (R), phenobar treatment with ammonia gives the tranquilizer, 2-meth bital), can be prepared by the reaction of ethyl phenyl yl-2-propyl-1,3-propanediol dicarbamate, (Equanil (R), malonate with urea in the presence of sodium ethoxide. Miltown (R), meprobamate), as follows: 4,428,887 4. invention provides a new method for the production of CH3 CH3 CH2OH organo-substituted malonic acid diesters which are use N / C ful starting materials and intermediates for the produc / N tion of barbiturates and other such pharmaceutical CH3(CH2)2 CH2OH agents which are known to be synthesized from such diesters. The inventors are not aware of any 1,2-ester migra tion reaction having been previously described. How CH3 CH2OCNH2 10 ever, a 1,3-ester migration, namely the "abnormal' Mi C chael addition, has been reported by Holder and Lap / N worth, J. Chem. Soc., 2368 (1931). CH3(CH2)2 Cho NH The invention can be illustrated by the reaction of O substituted trimethyl ethane-1,1,2-tricarboxylates and 15 substituted dimethyl cyanoethane-1,2-dicarboxylates See U.S. Pat. No. 2,724,720. with potassium hydride in 1,2-dimethoxyethane (glyme) A similar sequence using another malonic ester, solvent medium. The unsubstituted tricarboxylate is a known compound described by C. A. Bischoff, Ber. 29 CH3 CO2C2H5 (1), 966-967 (1896), with mp34.5 C., and has a chemi C cal structure as follows: / N CHCH-H CO2C2H5 CH3 o:CH: HC CH2 as the starting material, yields the hypnotic and tran 25 quilizer, 2-methyl-2-(1-methylpropyl)-1,3-propanediol dicarbamate, (Butatensin (R), Carbuten (E), mebutamate). It can be prepared by the reaction of methyl chloroace See U.S. Pat. No. 2,878,280. tate and dimethyl malonate in the presence of sodium The present invention is directed to a novel method methoxide in methanol solvent. of making terminal diesters of malonic acid of the fore 30 going general type which can be used as starting materi The unsubstituted dicarboxylate has bp 73-74 C. (1 als and intermediates for the production of hypnotics, mm Hg) and a chemical structure as follows: sedatives, tranquilizers and anesthetics by methods simi lar to the above illustrative methods. N DESCRIPTION OF THE INVENTION 35 H-H, In accordance with the method of the present inven CO2CH3CO2CH3 tion, mono-substituted terminal diesters of malonic acid are prepared by reaction of the corresponding substi It can be prepared by the reaction of methyl cyano tuted 1,2-diesters with alkali metal hydride in the pres acetate and methyl chloroacetate in the presence of ence of organic solvent medium. This novel 1,2-ester potassium carbonate in dimethylformamide solvent by transposition reaction can be illustrated by the follow procedures analogous to the method for alkylation of ing general reaction scheme: methyl 2-cyanopropionate described by D. A. White, Synthetic Comm. 7 (8), 559-568 (1977). The substituted derivatives of the aforesaid tricar for for boxylates and dicarboxylates can be obtained by con R--H, -i >R,--h densation reactions of said carboxylates with the corre k coR1 solv. X CO2R sponding alkyl, aryl and alkaryl halides such as, for example, methyl iodide, ethyl bromide, benzyl bromide, Wherein: 50, o-methylbenzyl bromide and the like alkylation com Ms Na, K, Li pounds. X=CN, CO2R, CO2R1 R and R1 = C1-4 alkyl Treatment of the alkylation adducts of the tricar R2=C1-6 alkyl, alkenyl, alkynyl; benzyl and C1-4 alkyl boxylates and dicarboxylates with KH in glyme leads to substituted benzyl. 55 the 1,2-ester transposition to provide the corresponding. Preferably, isomers. The resulting terminal malonic acid diesters can then be recovered as essentially pure compounds R2 = CH3, C2H5, benzyl, ot-methylbenzyl after acidic workup.
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