Synthesis of 5-AminoIevulinic Acid

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1593

Synthesis of 5-AminoIevulinic Acid

Materials and M ethods

Eva Benedikt* and Hans-Peter Köst+

Melting points are uncorrected and measured with a Kofler hot stage m icroscope (R eichert). IR spectra were taken on a Perkin Elmer 599 Infrared Spec­ trophotom eter, the intensity of absorption is indi­ cated as follows: s = strong, m = medium , w = weak, br = broad. N M R spectra were recorded on a Bruker AM 360 instrument equipped with an A spect 3000 computer. MS spectra were measured on a VG 7070 E spectrom eter.

Botanisches Institut der U niversität München, M enzinger Straße 67, D-8000 München 19, FRG Z. N aturforsch. 41b, 1593-1594 (1986); received June 18, 1986 5-Aminolevulinic Acid A 3-step synthesis of 5-aminolevulinic acid is de­ scribed.

5-Phthalimidolevulinic acid methyl ester (4) Introduction

80 g 5-brom olevulinic acid methyl ester (2) [4] were dissolved in 300 ml dimethyl formamide and 80 g potassium phthalimide were slowly added under stirring. The solution was stirred for 1 h at room tem perature, filtered and worked up with

5-A m inolevulinic acid is the first common precur­ sor in the biosynthesis o f all tetrapyrroles (Fig. 1).

COOH

COOH HOOC

chlorophyll porph yrin s

\ 5-a m in o levulinic acid

heme ----- — cytochrom s

->

vitamin B12

t

bile pigments

porphobilinogen

Therefore, it is often used for biochemical investiga­ tions and a simple synthesis would be useful. Till now, a number of synthesis have been described, which are m ostly tim e-consum ing or result in difficult to clean product(s) (for a com plete list see [1 —3]). Som e years ago, M cD onald [4] published the bromination of levulinic acid yielding 3-bromo- and 5-brom olevulinic acid which can be separated by dis­ tillation. We obtained 5-aminolevulinic acid from 5-brom olevulinic acid by a 2-step sequence (Gabrielsynthesis and hydrolysis) in 33% overall yield (Fig. 2).

* Present address; Institut de Chimie Organique l'U niversite, Perolles, CH-1700 Fribourg. Schweiz. + Reprint requests to Dr. H .-P. Köst.

+

Br2 C HjO H

COOH

COOCH3

COOCH3

COOH

COOCHj

de

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chloroform and water. The organic layer was washed with 0.2 M N aO H ( 4 x ) and water ( 3 x ) . A fter dry­ ing over anhydrous sodium sulfate, the solvent was removed with a rotatory evaporator and (4) recrys­ tallized from m ethanol. Yield: 62 g (59% ) of white crystals, m .p. 97 °C. IR (KBr) (cm -1): 2955 w, 2920 w, 2850 w, 1775 m. 1740 s, 1730 s, 1710 s, 1468 w, 1445 w, 1415 s, 1387 w, 1350 m, 1310 m, 1268 w, 1200 m, 1180 m, 1102 m, 1015 w, 990 w, 970 w, 925 w, 905 w, 795 w, 745 w, 710 m, 605 w, 530 w, 340 w. 1H N M R (360 M H z) (C D C l3) (ppm): 2.67 (t, J = 6.6 Hz, 2 H , H 2C (2)), 2.85 (t, J = 6.6 Hz, 2 H , H?C(3)), 3.69 (s, 3 H , H 3C O (6)), 4.56 (s, 2 H , H 2C (5)), 7 .7 1 -7 .7 6 (A A 'X X '-system , 2H , HC(10) + H C (10')), 7 .8 5 -7 .9 0 (A A 'X X '-system , 2 H , H C (9) + H C (9')). 13C N M R (100 M H z ) (C D C l3) (ppm): 27.60 (t, C (2)), 34.51 (t, C (3)), 46.52 (t, C (5)), 51.91 (q, C (6)), 123.51 (d, C(9) + C (9')), 132.03 (s, C(8) + C (8 ')), 134.13 (d, C(10) + C (10')), 167.50 (s, C(7) + C (7 ')), 172.47 (s, C (l)), 200.61 (s, C(4)). MS (70 eV) m/e (%): 275(3), M +; 244(10), M +- O C H 3; 216(18), M +- C 0 2C H 3; 160(69), C8H 40 2N - C H 2+; 115(100), H 3C 0 2C C H 2C H 2C 0 +,

[1] D. Shem in, in S. P. Colowick and N. C. Kaplan (eds.): M ethods of Enzymology, Vol. 4, Academic Press, New Y ork 1957, p. 648. [2] A. Pfaltz and S. A nw ar. T etrahedron Lett. 25, 2977 (1984).

5 -Aminolevulinic acid hydrochloride (5) 20 g of 4 were refluxed with 200 ml o f 6 M HC1 for 8 - 1 0 h. A fter cooling to —20 °C, the precipitated phthalic acid was rem oved by suction filtration and the clear filtrate brought to dryness in a vacuum d e­ siccator over KOH. The dry product was recrystal­ lized from m ethanol/isopropanol. Yield: 11.2 g (92%) of white crystals, m .p. 147 °C. IR (KBr) (c m '1): 3000 br, 2710 w, 2620 w, 1715 s, 1580 w, 1470 m, 1400 w, 1370 s, 1348 m, 1300 m, 1227 w, 1213 m, 1175 w, 1140 m, 1090 m, 1035 w, 985 w, 970 w, 935 m, 850 m, 765 m, 645 w, 615 w. I3C N M R (100 M H z) (D 6-D M SO ) (ppm): 27.34 (t, C (2)), 34.40 (t, C (3)), 46.53 (t, C (5)), 173.27 (s, C (l)), 202.66 (s, C (4)). MS (70 eV) m/e (%): 131(9), M +-H C 1; 115(25), M +- N H 2HC1.

We thank Prof. A. G ossauer for the support of this work. We also thank Miss E. Trieschm ann and Dr. G. Holze for measuring the NM R and mass spectra, re­ spectively. as w'ell as Dr. R. N eier for discussion. A grant from the D eutsche Forschungsgemeinschaft (D FG ) is gratefully acknowledged.

[3] C. H erdeis and A. Dimm erling. Arch. Pharm . 317, 304 (1984). [4] S. F. M cDonald. Can. J. Chem. 52, 3257 (1974).

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