Synthesis of δ-aminolevulinic acid hydrochloride

SYNTHESIS OF 6-AMINOLEVULINIC ACID HYDROCHLORIDE S. I. Zav'yalov, N. I. Aronova, N. N. Makhova, and Yu. B. Vol'kenshtein UDC 542.91:547.484.451:547.466 6-Aminolevulinic acid (I) is a bioprecursor of the porphyrins and has a stimulating effect on the bio- synthesis of vitamin BI2 [1]. For a further study of the biochemical properties of (I), in the present paper we accomplished the direct synthesis of hydrocbloride (II) by the reaction of hippuric acid (III) with C1CO (CH2)2COOCH3(IV) in 7-picoline and the subsequent acid hydrolysis of the intermediate 2-phenyl-4-(fl-carbomethoxypr opionyl)-5-oxaz olinone (V) C0(CH~)~COOCH3 CsH~CONHGH2COOH(III) (iV} ' 1 oI=O H,oHC -]-* HC1 .H2NCH~CO(CH2)2COOH(II) --~(v) The preparation of (V) from (III) and (IV) represents the first case of using (HI) in the Dakin-West reaction with an acid chloride. The chemical synthesis of (II) accomplished by us is similar to the biogenesis of (I) from ~ycocoll and succinic acid [1]. EXPERIMENTAL METHOD preparation of (II). With stirring, to a solution of 40 g of (III) in 200 ml of T-picoline was added 56 ml of (IV) at such a rate that the temperature remained at 5-0~ (~ 2 h), after which the mixture was stirred at this temperature for another 5 h. With stirring, the reaction mass was poured into a mixture of 1 kg of ice and 160 ml of conc. HC1, and the obtained precipitate was washed in succession with water and ethyl ace- tale. We obtained 41 g (65%) of (V), mp 176-178 ~ , which did not depress the mixed melting point with an authentic specimen [2]. The obtained (V) was mixed with 1 liter of dilute HC1 solution (1 : 1), refluxed for 10 h, and cooled to ~20 ~ The obtained benzoic acid was filtered, while the mother liquor was refluxed for 30 min in the pres- ence of active carbon, which was removed by filtration and the filtrate was evaporated in vacuo to dryness. The residue was dissolved in 20 ml of conc. HC1 at ~100 ~ after which 200 ml of acetone was added with stirring, and the mixture was kept at ~20 ~ for 3 h. The obtained crystals were filtered, washed with acetone, and dried in a vacuum-desiccator over KOH. We obtained 19 g (51%) of (II), mp 148-151 ~ , which did not depress the mixed melting point with an authentic specimen. CONCLUSIONS A method was developed for the synthesis of 6-aminolevulinic acid by the reaction of the acid chloride of monomethyl succinate with hippuric acid in 7-pic~ and subsequent acid hydrolysis of the intermediate 2-phenyl-4-(fi -carbomethoxypr opionyl) -5-oxazolinone. LITERATURE CITED i. V. Ya. Bykhovskii, N. I. Zaitseva, and V. N. Bukin, Progress in Biological Chemistry, Vol. i0, Nauka (1969), p. 199. 2. W.R. Hearnand M. E. Wfldfeuer, Anal. Biochem., 2, 140 (1961). N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences of the USSR. Izvestiya AkademiiNauk SSSR, Seriya Khimicheskaya, No. 3, pp. 657-658, March, 1973. submitted May 17, 1972. Translated from Original article 1973 Consultants Bureau, a division of Plenum Publishing Corporation, 227 West 17th Street, New York, N. Y. 10011. All rights reserved. This article cannot be reproduced for any purpose whatsoever without permission of the publisher. A copy of this article is available from the publisher for $15.00. 632

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Transcript of Synthesis of δ-aminolevulinic acid hydrochloride

S Y N T H E S I S O F 6 - A M I N O L E V U L I N I C

A C I D H Y D R O C H L O R I D E

S. I . Z a v ' y a l o v , N. I . A r o n o v a , N . N . M a k h o v a , a n d Y u . B . V o l ' k e n s h t e i n

UDC 542.91:547.484.451:547.466

6-Aminolevulinic acid (I) is a b i o p r e c u r s o r of the porphyr ins and has a s t imulat ing effect on the b io- synthes is of v i tamin BI2 [1]. F o r a fur ther study of the b iochemica l p rope r t i e s of (I), in the p r e sen t pape r we accompl i shed the d i rec t synthes is of hydrocblor ide (II) by the reac t ion of hippuric acid (III) with C1CO �9 (CH2)2COOCH3(IV) in 7-picol ine and the subsequent acid hydro lys i s of the in te rmedia te 2 - p h e n y l - 4 - ( f l - c a r - bomethoxypr opionyl)-5-oxaz olinone (V)

C0(CH~)~COOCH3

CsH~CONHGH2COOH(III) (iV} '1 oI=O H,oHC------]-* HC1 .H2NCH~CO(CH2)2COOH(II)

- - ~ ( v )

The p repa ra t ion of (V) f rom (III) and (IV) r e p r e s e n t s the f i r s t case of using (HI) in the D a k i n - W e s t reac t ion with an acid chloride. The chemical synthes is of (II) accompl ished by us is s im i l a r to the biogenesis of (I) f rom ~ycoco l l and succinic acid [1].

E X P E R I M E N T A L M E T H O D

p r e p a r a t i o n of (II). With s t i r r ing , to a solution of 40 g of (III) in 200 ml of T-p ico l ine was added 56 ml of (IV) a t such a r a t e that the t e m p e r a t u r e r emained a t 5-0~ (~ 2 h), a f t e r which the mix tu re was s t i r r e d a t this t e m p e r a t u r e for another 5 h. With s t i r r i ng , the reac t ion m a s s was poured into a mix tu re of 1 kg of ice and 160 ml of conc. HC1, and the obtained p rec ip i t a te was washed in success ion with wa te r and ethyl a c e - tale. We obtained 41 g (65%) of (V), mp 176-178 ~ , which did not depress the mixed mel t ing point with an authentic spec imen [2].

The obtained (V) was mixed with 1 l i t e r of dilute HC1 solution (1 : 1), ref luxed for 10 h, and cooled to ~20 ~ The obtained benzoic acid was f i l te red, while the mothe r l iquor was ref luxed for 30 min in the p r e s - ence of ac t ive carbon, which was r emoved by f i l t ra t ion and the f i l t ra te was evapora ted in vacuo to d ryness . The res idue was dissolved in 20 ml of conc. HC1 a t ~100 ~ a f t e r which 200 ml of acetone was added with s t i r r i ng , and the mix tu re was kept a t ~20 ~ for 3 h. The obtained c ry s t a l s were f i l te red , washed with a c e - tone, and dr ied in a v a c u u m - d e s i c c a t o r over KOH. We obtained 19 g (51%) of (II), mp 148-151 ~ , which did not dep re s s the mixed mel t ing point with an authentic spec imen.

CONCLUSIONS

A method was developed for the synthesis of 6-aminolevul inic acid by the reac t ion of the acid chlor ide of monomethyl succinate with hippuric acid in 7 -p i c~ and subsequent acid hydro lys i s of the in te rmedia te 2-phenyl-4-( f i - ca rbomethoxypr opionyl) -5-oxazol inone.

LITERATURE CITED

i. V. Ya. Bykhovskii, N. I. Zaitseva, and V. N. Bukin, Progress in Biological Chemistry, Vol. i0, Nauka (1969), p. 199.

2. W.R. Hearnand M. E. Wfldfeuer, Anal. Biochem., 2, 140 (1961).

N. D. Zel inski i Inst i tute of Organic Chemis t ry , Academy of Sciences of the USSR. Izves t iya A k a d e m i i N a u k SSSR, Seriya Khimicheskaya , No. 3, pp. 657-658, March , 1973. submit ted May 17, 1972.

Translated from Original article

�9 1973 Consultants Bureau, a division of Plenum Publishing Corporation, 227 West 17th Street, New York, N. Y. 10011. All rights reserved. This article cannot be reproduced for any purpose whatsoever without permission of the publisher. A copy of this article is available from the publisher for $15.00.

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