Pteridine C-6 Side Chain에서 C-2 치환에 따른 Pteroic Acid 유도체 합성에 관한 연구

류성렬; 유의경; 변윤섭

Journal of the Korean Industrial and Engineering Chemistry, Vol.6, No.4, 556-561, August, 1995

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Pteridine C-6 Side Chain에서 C-2 치환에 따른 Pteroic Acid 유도체 합성에 관한 연구

Studies on the Synthesis of the C-2 Substituent Analogues of Pteroic Acid at Pteridine C-6 Side Chain

류성렬, 유의경, 변윤섭

초록

새로운 amethopterin 유도체를 합성하기 위해서 Pteridine의 C-2 탈아미노화와 C-2 methyl로 치환된 새로운 pteroic acid 유도체인 4-[[(4-amino-2-desaminopteridin-6-yl)methyl]thio]benzoic acid와 4-[[ (4-amino-2-methyl-teridin-6-yl)methyl]thio]benzoic acid 합성을 시도하였다. 즉 p-aminobenzoic acid의 amino기를 SH로 치환하고 이 화합물을 에스테르화하였다. 그리고 이것을 2-amino-3-cyano-5-chloromethylpyrazine (11)과 결합하여 benzylester 화합물인 pyrazine 유도체 (14)를 얻었다. 따라서 이 화합물 (14)를 formamidine HCI, acetamidine HCI과 각각 cyclization시켜 화합물 4-[[(4-amino-2-desaminopterindin-6-yl)methyl]thio]benzoic acid benzylester와 4-[[(4-amino-2-methylpteri-din-6-yl)methyl]thio]benzoic acid benzylester를 얻었으며, 이를 알칼리 가수분해 하여 71%, 36%의 수율로 pteroic acid유도체 인 7a와 7b를 합성하였다.

In order to produce new amethopterin derivatives, We tried to synthesized 4- [[(4-amino-2-desaminopteridin-6-yl) methyl]thio ]benzoic acid of and 4-[[(4-amino-2-methyl- pteridin-6-yl)methy1]thio]benzoic acid of new pteroic acid derivative substituted with C-2 desamino and C-2 desamino-2-methyl. That is, We substituted SH group for amino of p-aminobenzoic acid, and esterificated it. Then we coupled the compound with 2-amino-3-cyano-5-chloromethylpyrazine(11) and obtained a benzyl esther compound, pyrazine derivative(14). Consequently the compound(4) was cyclizated with formamidine HCI and acetamidine HCl respectively, and so a compound of 4-[[(4-amino-2-desaminopterindin-6-yl)methyl]thio]benzoic acid benzylester and a compound of 4-[[(4-amino-2-methylpteri-din-6-yl)methyl]thio]benzoic acid benzylester were obtained. Finally we hydrolyzed them and obtained (7a) and (7b) of pteroic acid derivative by yield 71 % and 36% respectively.

[References]

Schnitzer RJ, Hawking F, "Experimental Chemistry," Vol. IV Part I, Academic Press, N.Y. (1966)
Prinder RM, "Medical Chemistry," 3rd ed., Part I, A. Burger, Ed., 492-521, Wiley-Interscience, New York, N.Y. (1970)
Jolievet J, Cowan KH, Curt GA, Clendenium NY, Chabner BA, Engl N, J. Med., 309, 1094 (1983)
Seeger DR, Smith JM, Hulquist ME, J. Am. Chem. Soc., 69, 2567 (1947)
Piper JR, Montogomery JA, J. Het. Chem., 11, 279 (1974)
Taylor EC, "Chemistry and Biology of Pteridine," Proceeding of the Forth, International Symposium of Pteridine, Toba (1969)
Taylor EC, 79, International Academic Printing Co., Ltd., Tokyo (1970)
Taylor EC, Lenard K, Annu. Chem., 726, 100 (1979)
Taylor EC, Rortnoy RC, Hochstetler DC, Kobayashi T, J. Org. Chem., 40, 2347 (1975)
Nair MG, Edwards D, J. Med. Chem., 34, 2746 (1991)
Hughes LR, Marsham PR, Oldfield J, Jackman AL, Proc. Am. Assoc. Cancer. Res., 29, 286 (1988)
Jones TR, Calvert AH, Jackman AL, Brown SJ, Jones M, Harrap KR, Eur. J. Cancer, 17, 11 (1981)
Jackson RC, Jackman AL, Calvert AH, Biochem. Pharmacol., 32, 3783 (1983)
Synonyms: ICI 155387; CB 3717; NSC 327182; N-[4-[(2-amino-3.4-dihydro-4-oxo-6-quinazolinyl)methyl]-N-prop-2-ynylamino]benzoyl]-L-glutamic acid.
Taylor EC, "The Chemistry and Biology of Pteridine," Ed.: K. Lwai, M. Akin; M. Goto, 79, International Academic Printing Co. (1970)
Ferris JP, Sanchez RA, Mamcuso RW, Org. Syn. Collect., 5, 79 (1970)
Kim YH, Kisliuk RL, Gaumont Y, Mautner HG, J. Med. Chem., 18, 776 (1975)

[1] Schnitzer RJ, Hawking F, "Experimental Chemistry," Vol. IV Part I, Academic Press, N.Y. (1966)

[2] Prinder RM, "Medical Chemistry," 3rd ed., Part I, A. Burger, Ed., 492-521, Wiley-Interscience, New York, N.Y. (1970)

[3] Jolievet J, Cowan KH, Curt GA, Clendenium NY, Chabner BA, Engl N, J. Med., 309, 1094 (1983)

[4] Seeger DR, Smith JM, Hulquist ME, J. Am. Chem. Soc., 69, 2567 (1947)

[5] Piper JR, Montogomery JA, J. Het. Chem., 11, 279 (1974)

[6] Taylor EC, "Chemistry and Biology of Pteridine," Proceeding of the Forth, International Symposium of Pteridine, Toba (1969)

[7] Taylor EC, 79, International Academic Printing Co., Ltd., Tokyo (1970)

[8] Taylor EC, Lenard K, Annu. Chem., 726, 100 (1979)

[9] Taylor EC, Rortnoy RC, Hochstetler DC, Kobayashi T, J. Org. Chem., 40, 2347 (1975)

[10] Nair MG, Edwards D, J. Med. Chem., 34, 2746 (1991)

[11] Hughes LR, Marsham PR, Oldfield J, Jackman AL, Proc. Am. Assoc. Cancer. Res., 29, 286 (1988)

[12] Jones TR, Calvert AH, Jackman AL, Brown SJ, Jones M, Harrap KR, Eur. J. Cancer, 17, 11 (1981)

[13] Jackson RC, Jackman AL, Calvert AH, Biochem. Pharmacol., 32, 3783 (1983)

[14] Synonyms: ICI 155387; CB 3717; NSC 327182; N-[4-[(2-amino-3.4-dihydro-4-oxo-6-quinazolinyl)methyl]-N-prop-2-ynylamino]benzoyl]-L-glutamic acid.

[15] Taylor EC, "The Chemistry and Biology of Pteridine," Ed.: K. Lwai, M. Akin; M. Goto, 79, International Academic Printing Co. (1970)

[16] Ferris JP, Sanchez RA, Mamcuso RW, Org. Syn. Collect., 5, 79 (1970)

[17] Kim YH, Kisliuk RL, Gaumont Y, Mautner HG, J. Med. Chem., 18, 776 (1975)