DD262021A1 - METHOD FOR THE PRODUCTION OF HYDROCHLORIDES OF LENGTH-STRINGED ALKYLESTER RINGS-SUPPORTED DL-PHENYLAMINOSAURES - Google Patents

Abstract

The invention relates to a process for the preparation of hydrochlorides of long-chain alkyl esters of ring-substituted DL-Phenylaminosaeuren by reaction of corresponding amino acids, primary alcohols and thionyl chloride. The aim of the invention is to find a simple and effective process for the preparation of the title compounds, in particular also such representatives, which can not be obtained by previous methods, which can be used as potentially biologically active compounds. Formulas I to III

Description

embodiments

The invention is illustrated by the following characteristic examples, without being limited thereto:

Example 1: DL ^ p-Hexoxyphenyl oglycine heptyl ester hydrochloride.

To a suspension of 12.6 g (0.05 mol) of DL-2- (p-hexoxyphenyl) -glycine and 85.0 g (0.73 mol) of heptyl alcohol is slowly added dropwise 9.8 g (0.08 mol) with stirring. Given thionyl chloride. The mixture is heated to 45 ⁰ C and then heated to 80 ⁰ C for 3h. After cooling, 3.3 g (0.03 mol) of thionyl chloride are again added and the mixture heated for a further 2 Freq 80 ⁰ C. The filtered reaction solution is evaporated in vacuo at 80-85 ⁰ C to syrupy residue and with 150 ml of abs. Ether added. At -25 ⁰ C, a fine crystalline precipitate formed, which is recrystallized from ethyl acetate

 Yield: 14.2 g (73.6% of theory), mp 104 ° C

C ₂ IH ₃₅ NO ₃ · HCl (386.0) Analysis: calc. C 65.34% H 9.40% N 3.63%

gef. C 65.55% H 9.40% N 3.63%

Example 2: DL ^ -fp-dimethylaminophenyglycinoctyl ester dihydrochloride

To a suspension of 9.7 g (0.05 mol) of DL-2- (p-dimethylaminophenyl) glycine and 98.0 g (0.75 mol) of octyl alcohol is added slowly and dropwise 11.9 g (0.10 mol) of thionyl chloride with stirring , The mixture is heated to 50 ⁰ C and then heated to 9O ⁰ C for 5h. After cooling, 5.9 g (0.05 mol) of thionyl chloride are added again and the mixture is again heated to 9O ⁰ C for 3 h.

The filtered reaction solution is evaporated in vacuo at 85-90X to syrupy residue. The residue will be. taken up in 150 ml of saturated Natriumhydrogenca.brbonatlösung and extracted twice with 100 ml of ether. Hydrogen chloride is introduced into the ethereal solution dried with sodium sulfate. After 12 h standing at +4 ⁰ C, the precipitate is filtered off with suction and recrystallized from propanol / ether

 Yield: 9.1 g (48.0% of theory), m.p. 173-175 ° C

C ₁₈ H ₃₀ N ₂ O ₂ 2 HCl (379.4) Analysis: calc. C 56.99% H 8.50% N 7.38% Cl 18.69%

gef. C 57.04% H 8.51% N 7.37% Cl 18.68%

Claims (1)

A process for the preparation of hydrochlorides of relatively long-chain alkyl esters of ring-substituted DL-phenylamino acids of the general formula III in which X ¹ and X ^{2 may be} identical or different and denote H, halogen, dialkylamino, alkyl or alkoxy in different positions and m and η = 0 to 4 be characterized in that ringsubstituierte DL-Phenylaminosäuren of the general formula I, in which X ¹ , X ² , m and η have the above meaning, with the 10-15fachen molar amount of a longer-chain primary alcohol of the general formula II, in the R a branched or unbranched alkyl group having a C number> 5, and 2-3 times the molar amount of thionyl chloride at temperatures between 70 and 9O ⁰ C are reacted. For this 1 page formulas Field of application of the invention The invention relates to a process for the preparation of hydrochlorides ring-substituted DL-Phenylaminosäureester by reaction of DL-Phenylaminosäuren with longer-chain primary alcohols and thionyl chloride. These DL-Phenylaminosäurealkylester are anti-inflammatory, analgesic and spasmolytically effective and are potential drugs. Characteristic of the known state of the art Longer chain alkyl ester hydrochlorides of DL-phenylamino acids have hitherto been prepared by reacting the amino acids with alcohols in the presence of dry hydrogen chloride at temperatures between 120 and 140 ° C (E. Schulz, W.-D. Sprung, G. Kröning, G. Vietinghoff: Pharmazie 33 [1978 ] 749). The disadvantage of this method is that with longer-chain alkoxy groups as ring substituents of Phenylaminosäuren an ether cleavage occurs and diaminocarboxylic acids are not esterified. According to the known thionyl chloride method (M. Brenner, HR Müller, RW Pfister: HeIv.Chim.Acta 33 [1950] 568, M. Brenner, W. Huber: HeIv. Chim. Acta 36 [1953] 1109), longer-chain alkyl ester hydrochlorides of ring-substituted DL were used -Phenylamino acids not previously synthesized. In the latter method, only lower alkyl and benzyl ester hydrochlorides of various amino acids were prepared under different conditions (WJHumphlett, CVWilson: J. Org. Chemistry 26 [1961] 2507, RPPatel, S.Price: J. Org. Chemistry 30 [1965 3575; NA Brusentov, VSGruzdew, VANovoselov, Yu.P.Shvachkin: SU Pat. 320,483; M.Portelli, G.Renzi, A.Gazzaniga: DD-WP 108,978; A.Tanaka: JP Pat. 192,345; SP Company Filho, G. Goissis: J. Chromatogr. 236 [1982] 197). Object of the invention The object of the invention is to find a process for the preparation of ring-substituted DL-Phenylaminosäurealkylesterhydrochloride after a single-step synthesis of the corresponding DL-amino acids and longer-chain primary alcohols (C number £ 5) in high yields and high purity. Explanation of the essence of the invention The object was to find a process for producing hitherto unknown long-chain ringsubstituierter DL-Phenylaminosäurealkylesterhydrochloride. According to the invention the object is achieved in that ring-substituted DL-phenyl amino acids are reacted with longer-chain primary alcohols and thionyl chloride. As DL-phenylamino acids, it is possible to use compounds of the general formula I where X ¹ and X ^{2 may be} identical or different and denote H, halogen, dialkylamino, alkyl or alkoxy in different positions and m and η = 0 to 4. The alkyl groups R of the primary alcohols of the general formula II can be branched or unbranched, their C number being S5. In the esterification reaction, 1 mol of DL-phenylamino acid is suspended in 10 to 15 mol of the primary alcohol at room temperature. After addition of 1.5 to 2 mol of thionyl chloride with stirring within 15-30 minutes, the reaction mixture is warmed to 40 to 50 ° C and then heated to 70 to 90 ⁰ C for 3 to 5 hours. After cooling the reaction mixture, 0.5 to 1 mole of thionyl chloride is again added over 10 minutes and stirred at 70 to 90 ° C for 2 to 3 hours. If necessary, a residue is filtered off immediately. The cooled reaction solution is with its double volume of abs. Ether mixed and stored at -25 ° C. Occurs in this case no crystallized crude product, the solvent is completely distilled off in vacuo. The crude product is checked by thin layer chromatography for unreacted amino acid. In case of incomplete reaction of the amino acid, the crude product is treated with sodium bicarbonate solution and the ester is extracted with ether. From the dried ethereal solution, the ester hydrochloride of general formula III, in which X ¹ , X ² , R, m and η have the above meaning, is obtained by introducing hydrogen chloride. The advantage of this invention over the previous methods is that some longer chain alkyl ester hydrochlorides of DL-phenyl amino acids, especially with longer chain alkoxy groups or with the dimethylamino group as ring substituents, can be made. In addition, the esterification can be carried out at lower temperature and with commercial, non-absolute alcohols. Another advantage is that no reaction water, but gaseous by-products and thereby the Aminosäureesterhydrochloride the general formula III are formed in relatively higher yield and greater purity.