methyl 2-{[(4-methylphenyl)sulfonyl]amino}acetate -Drug Synthesis Database

【结构式】

【分子编号】57744

【品名】methyl 2-{[(4-methylphenyl)sulfonyl]amino}acetate

【CA登记号】2645-02-5

【分子式】C₁₀H₁₃NO₄S

【分子量】243.28356

【元素组成】C 49.37% H 5.39% N 5.76% O 26.31% S 13.18%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

Mitsunobu coupling between isopropyl 3-(hydroxymethyl)pyridine-2-carboxylate (I) and N-tosyl glycine methyl ester (II) affords amino diester (III). Diester (III) is subsequently converted to the naphthyridine (IV) under Dieckmann cyclization conditions. Bromination of naphthyridine (IV) by means of N-bromosuccinimide provides (V). The methyl ester group of (V) is then displaced with 4-fluorobenzylamine (VI) to furnish amide (VII). Finally, copper-catalyzed displacement of the bromide (VII) with butanesultam (VIII) provides the title compound.

参考文献中间体

合成目标

【1】 Young, S.D.; Guare, J.P.; Wai, J.S.; Fisher, T.E.; Perlow, D.S.; Anthony, N.J.; Egbertson, M.; Gomez, R.P.; Kuo, M.S.; Tran, L.; Zhuang, L.; Langford, H.M.; Melamed, J.Y.; Bennett, J.J.; Embrey, M.; Jolly, S.M.; Funk, T.W. (Merck & Co., Inc.); Aza- and polyaza-naphthalenyl carboxamides useful as HIV integrase inhibitors. WO 0230930; WO 0230931 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	57743	isopropyl 3-(hydroxymethyl)-2-pyridinecarboxylate		C₁₀H₁₃NO₃	详情	详情
(II)	57744	methyl 2-{[(4-methylphenyl)sulfonyl]amino}acetate	2645-02-5	C₁₀H₁₃NO₄S	详情	详情
(III)	57745	isopropyl 3-({(2-methoxy-2-oxoethyl)[(4-methylphenyl)sulfonyl]amino}methyl)-2-pyridinecarboxylate		C₂₀H₂₄N₂O₆S	详情	详情
(IV)	57746	methyl 8-hydroxy[1,6]naphthyridine-7-carboxylate		C₁₀H₈N₂O₃	详情	详情
(V)	57747	methyl 5-bromo-8-hydroxy[1,6]naphthyridine-7-carboxylate		C₁₀H₇BrN₂O₃	详情	详情
(VI)	31095	4-fluorobenzylamine; (4-fluorophenyl)methanamine	140-75-0	C₇H₈FN	详情	详情
(VII)	57748	5-bromo-N-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-7-carboxamide		C₁₆H₁₁BrFN₃O₂	详情	详情
(VIII)	57749	1lambda~6~,2-thiazinane-1,1-dione		C₄H₉NO₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXVII)

Condensation of 5-bromophthalide (XXIII) with phenol (XIII) by means of K2CO3, CuBr and acetylacetone in DMF gives 5-phenoxyphthalide (XXIV), which is submitted to lactone ring opening using SOCl2, Ph3PCl2, B(OMe)3 and K2CO3 in refluxing toluene to yield 2-(chloro-methyl)-4-phenoxybenzoyl chloride (XXV). Esterification of acid chloride (XXV) with MeOH at 50 °C provides the methyl ester (XXVI), which is then condensed with methyl N-tosylglycinate (XXVII) in the presence of K2CO3 and NaI in DMF at 50 °C to afford the N-substituted amino ester (XXVIII). Cyclization of diester (XXVIII) with NaOMe in MeOH leads to methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XXIX), which is submitted to Mannich reaction with bis(dimethylamino)methane (XXX) by means of AcOH at 57 °C to provide the 1-(dimethylaminomethyl)isoquinoline derivative (XXXI). Treatment of compound (XXXI) with Ac2O at 103 °C, followed by selective hydrolysis of the phenolic acetate with morpholine leads to methyl 1-(acetoxymethyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XXXII). Hydrogenolysis of benzylic acetate (XXXII) in the presence of Pd/C and Na2CO3 in EtOAc yields methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboylate (XX), which is finally condensed with glycine (II) by means of NaOMe in MeOH at 110 °C .

参考文献中间体

合成目标

【1】 Thompson, M.D., Park, J.M., Arend, M.P. (FibroGen, Inc.). Process for making isoquinoline compounds. CN 103435546; WO 2014014834.
【2】 Witschi, C., Park, J.M., Thompson, M.D., Martinelli, M.J., Yeowell, D.A.,Arend, M.P. (FibroGen, Inc.). Crystalline forms of a prolyl hydroxylase inhibitor. WO 2014014835, US 2014024675.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	20436	glycine	56-40-6	C₂H₅NO₂	详情	详情
(XIII)	23540	Phenol	108-95-2	C₆H₆O	详情	详情
(XX)	67882	methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate		C₁₈H₁₅NO₄	详情	详情
(XXIII)	33229	5-bromophthalide; 5-bromo-2-benzofuran-1(3H)-one	64169-34-2	C₈H₅BrO₂	详情	详情
(XXIV)	67885	5-phenoxyphthalide	57830-14-5	C₁₄H₁₀O₃	详情	详情
(XXV)	67886	2-(chloromethyl)-4-phenoxybenzoyl chloride		C₁₄H₁₀Cl₂O₂	详情	详情
(XXVI)	67887	methyl 2-(chloromethyl)-4-phenoxybenzoate		C₁₅H₁₃ClO₃	详情	详情
(XXVII)	57744	methyl 2-{[(4-methylphenyl)sulfonyl]amino}acetate	2645-02-5	C₁₀H₁₃NO₄S	详情	详情
(XXVIII)	67888	methyl 2-((N-(2-methoxy-2-oxoethyl)-4-methylphenylsulfonamido)methyl)-4-phenoxybenzoate		C₂₅H₂₅NO₇S	详情	详情
(XXIX)	67889	methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate		C₁₇H₁₃NO₄	详情	详情
(XXX)	14349	N,N,N,N-tetramethylmethanediamine; tetramethylmethylenediamine;bis(dimethylamino)methane; N-[(dimethylamino)methyl]-N,N-dimethylamine	51-80-9	C₅H₁₄N₂	详情	详情
(XXXI)	67890	methyl 1-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate		C₂₀H₂₀N₂O₄	详情	详情
(XXXII)	67891	methyl 1-(acetoxymethyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate		C₂₀H₁₇NO₆	详情	详情

Extended Information