A new synthesis of DL-l-(p-hydroxyphenyl)- 2- aminobutan-3-one (la) is given. The optically active B-keto acid ester III and its racemic benzylidene derivative IV were prepared from L-tyrosine

V. Thaller

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AR HIV Z A KEM I JU 27 (1955) Some Derivatives of Tyrosine. Amino Acids. XXX* . V. Thaller Chemical I nstitllte, Faculty of Science, University of Zagreb, Strossmayerov trg 14, Zagreb and 193 Department of Biochemistry, I nstitute »Ruder Boskovic«, Zagreb, Croatia, Yugoslavia Received November 25, 1955 A new synthesis of DL-l-(p-hydroxyphenyl) - 2- aminobutan-3-one (la) is given. The oipticaJly active ~-,keto acid esiter III and its r acemic benzylidene derivative IV were prepared from L-tyrosine. It has been shown. that replacement of -COOR by -COCH3 in a-amino acids gi1ves compounds showing interesting biol.ogica1l activities1- 3. The m ethyl-a -armi1n:o ketones thus obtaine d can be r egarded as isnsters of a-amino acids1• The preparation o.f the ophcally active m eth ylaminoketone Ib starting from L-ty.ros ine was recently described by Ba1lenovi1c and Tha1ler4• One of the ~ey in:termediates in this synthesis, L-l-(p-,methoxyphenyl)-2-:phthalimidobutan-3-one (II), was hydrnlyzed with hydriodic acid in gfaciail acetic acid . with simultaneous racemisation to DL-1-(:p-hydiroxyphenyl)-2-arminoibutan-3-one (la). Thus a new pa:th for the synthesis of methyl-a-aminoketones, :p'I'oceeding from N-phthaloyl-:x-amino acids via their acid chlorides5, diaizoiketones5, and methyl ke1:o nes4 has been found. The compound Ia was firs1t prepare d by Levene and Steiger6 from tyrosine, UJSing the Dakin-West reactiOIIl7• R-CHCOCHs a, R = p-hydroxybenzyl I H 3N] + x- b , R = p-methoxybenzyl I p-CH30 . C6H4CH2CHCOCH3 I CH6H4(C0)2N II p-CHsO . C6H4CH2CHCOCH2COOC2H0 I C6H 4(C0)2N III p -CHsO . C6H4CH2CHC OCCOOC2H 5 I II CGH 4(C0)2N CHC6H5 IV * Contribution No. 46 from t he Chemical Institute; paper XXIX, K. Balenovic, N . Bregant, T . Galijan, Z. Stefanac and V. Skaric, J. Org. Chem., in press; XXVIII, K. BalenoviC and D . Cerar, J. Chem. Soc. 1955, 1631. 194 V. THALLER The preparation of compound II by p<ill'tial hydrolysis of the condensation product obtained £mm 0-methyl-N-phthaloyl-L-tyrosinyl chloride5 and sod.ium · diethylmal1onate accrn:-ding to , Ga!briel8 wa1s also attempted. As condensation product, L-l-{rp-methoxyiphenyl)-2-phthaiimido-4-carhoethoxybutan-3-one (III) was obtained. This compound was treated with hydro:br:omic acid in glacial acetic acid iat 70°. EvoiLution of caribon dioxide was observed. As. the reaction mixture showed no optical activity, the isolation of oompound II was not a tt.emrpted. The om:J1densation of compound III with ben:zaldehyde and t<r~aces of pirpe-ridine as catalyst proceeded also with racem~sation. The resulting ben:zyldene derivart:ive IV could not be hydrolysed and decarboxylated by heating with propionic and surlrphuric acids according 1Jo Bowman's p .rocedure9• EXPERIMENT AL All melting points are corrected. DL-1-(p-Hydroxyphenyl)-2-aminobutan-3-one hydriodide (la; X = I) A solution of L-1-(p-methoxyphenyl)-2-phthalimidobutan-3-one4 (2 g.) in glacial acetic acid (6 ml.) and hydriodic acid (sp. g. 1.7 ; 12 ml.) was reifluxed for three hours. The phthalic acid was then filtered off (0.7 g., 670/o) and the brown mother liquor evaporated under reduced pressure. The dark syrupy residue was dissolved in water, treated with charcoal and shaken several times with ether. The nearly colourless aqueous layer was then evaporated in vacuo under an atmosphere nf nitrogen. The residue was dissolved at room temperature in ethanol (8 ml.) and absolute ether (120 ml.) added. DL-l-(p-Hydroxyphenyl)-2-aminobutan-3-one hydriodide separated in long colourless needles, yield 0.5 g. (260/o) , m. p. 197-1990 (decomp.). From the mother liquor an additional crop of crystals was obtained ; total yield 0.95 g. (50°/o). Anal. 10.86 mg. subst.: 15.49 mg. C02, 4.69 mg. H20 C10H14IN02 (~.07.14) calc'd.: C 39.12; H 4•.590/o found: C 38.94; H 4.840/o I>L-1-(p-Hydroxyphenyl)-2-aminobutan-3-one hydrcchloride (la, X = Cl) The hydriodide la (<0.25 g.) was shaken for ten hours with a freshly prepared silver chloride suspension (orbtained from 0.8 g. of silver nitrate) in 0.30/o hydrochLiric acid (90 ml.). After standing for 12 hours the .supernatant liquid was poured off, and the precipitate washed with dilute hydrochloric acid. The combined supernatant and washings were evaporated under reduced pressure, and DL-l-(p-hydrophenyl)-2-aminobutan-3-one hydrochloride was obtained from the residue by recrystall-ization from ethanolic hydrochloric acid (50/o gaseous hydrochloric acid in ethanol), as colourless needles, yield 0.11 g. (630/o), m . p . 160-1630 (decomp.) (Levene and Steigers reported m. p. 165-1660.) Anal. 11.63 mg. subst.: 23.49 mg. C02, 6.85 mg. H20 C10H14ClN02 (215.68) calc'd.: C 55.68; H 6.54°/o found: C 55,12 ; H 6.59°/o L-1 -(p-M ethoxyphenyl)-2-phthalimido-4 -carboethoxy- bntan-3 · one (III) A suspension of sodium diethylmalonate in benzene (80 ml.) was prepared from metallic sodium (l.38 g., 0.06 mole) and diethylmalonate (12.6 g., 0.08 mole), and a solution of 0-methyl-N-phthaloyl-L-tyrosinyl chloride7 (10 g., 0.03 mole) in benzene (50 ml.) added, with cooling and stirring. The clear reaction mixture was left at room temperature for five days, and then refluxed for one hour on · a steam bath. After cooling, it was poured into a mixture of ice and 250/o sulphuric acid (103 ml.). The benzene layer was washed with water, the solvent removed by evaporation, and steam distillation. The residue was extracted with benzene, the extract dried SOME DERIVATIVES OF TYROSINE 195· (CaC12) and the benzene evaporated. A yellow viscous oil remained (10.44 g.) which crystallized on addition of ethanol (20 ml.) into colourless needles of L-1-(p-methox y-phenyl)-2-phthalimido-4-carboethoxybutan-3-one, yield 7.07 g. (61.40/o), m. p . 87-910. Repeated · recrystallization from ethanol yielded the pure compound, m. p . 95-960, '" + . [aJn-2200 _ 10 (c, 1.78 m benzene). Anal. 11.71 mg. subst.: 28.73 mg. C02, 5.65 mg. H20 C22H21N06 (395.40) calc'd .: C 66.82; H 5.350/o found: C 66.95; H 5.406/o The benzylidene derivative IV of L-l-(p-methoxphenyl)-2-phthalimido-4-carbo-ethoxybutan-3-one was obtained from the compound II (0.39 g.) and benzaldehyde,. with piperidine as catalyst, at oo. The crude reaction product was steam-distilled and the undistilled residue extracted with benzene, the solvent evaporated, and the· residue heated in propionic acid with traces of sulphuric acid. The acids were removed, and the crude benzylidene derivative of L-1-(p-methoxyphenyl)-2-phthalimi-do-4-carboethoxybutan-3-one (0.22 g.) chromatographed on alumina from benzene. From the first fraction, after evaporation of the solvent, the pure compound was obtained (0.12 g.). Recrystallization from ethanol gave colourless prisms, m . p .. 142-1430. Anal. 10.61 mg. subst.: 28.01 mg. C02, 5.00 mg. H20 C29H26N06 (483.50) calc'd.: C 72.04; H 5,.210/o found: C 72.04; H 5.210/o Acknowledgment. The author thanks Professor K . Balenovic for his interest in this work, and Dr. L . Filipovic for the microanalyses. REFERENCES 1. H . Erlenmeyer and H. Kuhne, Helv. Chim. Acta 32 (1949) 370. 2. F . E. Le h m a n n , A. B r e t s c h e r, H . K il h n e, E. S o r 'k i n, M. E r n e and H. Er 1 en me ye r , Helv. Chim. Acta 33 (1950) 1217. 3. F. E. Lehmann and A. Bret s c her, Helv. Physiol. et Pharmakol. Acta 10 (1952) 20. 4. K. B a 1 en o v i c and V. Th a 11 er, J. Org. Chem. (in press). 5. K. Balenovic, V. Th all er and L. Filipovic, Helv. Chim Acta 32 (1949) 745. 6. P . A. Leven e and R. E. S t e i g er, J. Biol. Chem. 79 (1928) 95. 7. H . D. Dakin and R. West, J . Biol. Chem 78 (19·28) 91; 78 (1928) 745. 8. S. Gabri e 1 and J. Co 1 man, Ber. 35 (1902) 3805. 9. R E. B ow ma n, J . Chem. Soc. 1950, 322. IZVOD O nekim derivatima tirozina. Aminokiseline XXX V . Thaller Opisuje se nova sinteza DL-l-(p-oksifenil)-2-aminobutan-2-ona (la). Iz J.-tiro-zina prireden je opticki aktivni B-keto derivat L-l-(p-metoksifenil)-2-ftalimido-4-karboetoksibutan-3-on (III) kao i racemicki benzilidenski derivat IV spoja III. KEMIJSKI INSTITUT PRIRODOSLOVNO-MA TEMATICKOG F AKULTET A ZAGREB I INSTITUT »RUDER BOSKOVIC« BIOKEMIJSKI ODJEL ZAGREB Primljeno 25. novembra 1955. 

Some Derivatives of Tyrosine. Amino Acids. XXX

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