1,2,4,9-Tetrahydro-3H-carbazol-3-one -Drug Synthesis Database

【结构式】

【分子编号】12288

【品名】1,2,4,9-Tetrahydro-3H-carbazol-3-one

【CA登记号】

【分子式】C₁₂H₁₁NO

【分子量】185.22548

【元素组成】C 77.81% H 5.99% N 7.56% O 8.64%

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：(I)

The synthesis of Bay u 3405 was carried out as follows: Reductive amination of 3-oxo-1,2,3,4-tetrahydrocarbazole (I) with S-phenethylamine (II) afforded a mixture of diastereomeric amines, of which the desired isomer (III) crystallized in high diastereomeric purity as the hydrogensulfate. Cleavage of the phenethyl group by transfer hydrogenolysis with amminium formate and palladium on charcoal yielded the enantiomerically pure (3R)-3-amino-1,2,3,4-tetrahydrocarbazole (IV). Sulfonylation of (IV) with 4-fluorobenzenesulfonyl chloride (V) to the sulfonamide (VI) followed by addition of acrylonitrile and subsequent hydrolysis gave Bay u 3405.

参考文献中间体

合成目标

【1】 Raz, A.; Needleman, P.; Minkes, M.; Thromboxanes: Selective biosynthesis and distinct biological properties. Science 1976, 193, 163-5.
【2】 Svensson, J.; Hamberg, M.; Samuelsson, B.; Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 1975, 72, 8, 2994-8.
【3】 Gardiner, P.J.; Boberg, M.; Fiedler, V.B.; Perzborn, E.; Boshagen, H.; Buhner, K.; Muller, U.; Rosentreter, U.; Seuter, F.; Weber, H.; Norman, P.; Ritter, W.; Bay u 3405. Drugs Fut 1991, 16, 8, 701.

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)	12288	1,2,4,9-Tetrahydro-3H-carbazol-3-one		C₁₂H₁₁NO	详情	详情
(II)	20042	(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine		C₈H₁₁N	详情	详情
(III)	12290	N-[(1S)-1-Phenylethyl]-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amine; (3R)-N-[(1S)-1-Phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine		C₂₀H₂₂N₂	详情	详情
(IV)	12291	(3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-ylamine; (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-amine		C₁₂H₁₄N₂	详情	详情
(V)	12292	4-Fluorobenzenesulfonyl chloride	349-88-2	C₆H₄ClFO₂S	详情	详情
(VI)	12293	4-Fluoro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]benzenesulfonamide		C₁₈H₁₇FN₂O₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The synthesis of [14C]-labeled Bay-u-3405 by two closely related ways has been described: 1) [14C]-Labeled aniline (I) is diazotized and reduced with sodium sulfite, yielding the labeled hydrazine (II), which is condensed with the monoketal of cyclohexane-1,4-dione (III) under Fisher's indole synthesis (ZnCl2) to afford the tetrahydrocarbazole (IV). The hydrolysis of (IV) with HCl in THF/water yields 1,2,3,4-tetrahydrocarbazol-3-one (V), which is submitted to a reductive condensation with (S)-1-phenylethylamine (VI) by means of tetrabutylammonium borohydride, yielding preferentially the secondary amine (VII), which, after purification, is dealkylated with ammonium formate and Pd/C to afford 1,2,3,4-tetrahydrocarbazole-3(R)-amine (VIII). The acylation of (VIII) with 4-fluorophenylsulfonyl chloride (IX) gives the corresponding sulfonamide (X), which is condensed with acrylonitrile by means of NaH, yielding 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]pro pionitrile (XI). Finally, this compound is hydrolyzed in the usual way. 2) The condensation of the sulfonamide (X) with methyl acrylate by means of NaH as before gives 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]propionic acid methyl ester (XII), which is finally hydrolyzed in the usual way.

参考文献中间体

合成目标

【1】 Pleiss, U.; Radtke, M.; Rosentreter, U.; Boberg, M.; Synthesis of (+)-(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-[5,6,7,8,12,13-u-C-14]carbazolepropanoic acid, [C-14]BAY u 3405. J Label Compd Radiopharm 1994, 34, 12, 1207.

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)	12294	Aniline; Phenylamine	62-53-3	C₆H₇N	详情	详情
(I)	45117			C₆H₇N	详情	详情
(II)	11818	Phenyl hydrazine; 1-Phenylhydrazine	100-63-0	C₆H₈N₂	详情	详情
(II)	45118			C₆H₈N₂	详情	详情
(III)	11377	1,4-Dioxaspiro[4.5]decan-8-one	4746-97-8	C₈H₁₂O₃	详情	详情
(IV)	12297	1,2,3,4-Tetrahydrospiro[9H-carbazole-3,2'-1,3-dioxolane]		C₁₄H₁₅NO₂	详情	详情
(IV)	45119			C₁₄H₁₅NO₂	详情	详情
(V)	12288	1,2,4,9-Tetrahydro-3H-carbazol-3-one		C₁₂H₁₁NO	详情	详情
(V)	45120			C₁₂H₁₁NO	详情	详情
(VI)	20042	(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine		C₈H₁₁N	详情	详情
(VII)	12290	N-[(1S)-1-Phenylethyl]-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amine; (3R)-N-[(1S)-1-Phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine		C₂₀H₂₂N₂	详情	详情
(VII)	45121			C₂₀H₂₂N₂	详情	详情
(VIII)	12291	(3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-ylamine; (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-amine		C₁₂H₁₄N₂	详情	详情
(VIII)	45122			C₁₂H₁₄N₂	详情	详情
(IX)	12292	4-Fluorobenzenesulfonyl chloride	349-88-2	C₆H₄ClFO₂S	详情	详情
(X)	12293	4-Fluoro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]benzenesulfonamide		C₁₈H₁₇FN₂O₂S	详情	详情
(X)	45123			C₁₈H₁₇FN₂O₂S	详情	详情
(XI)	12304	N-[(3R)-9-(2-cyanoethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-4-fluorobenzenesulfonamide		C₂₁H₂₀FN₃O₂S	详情	详情
(XI)	45124			C₂₁H₂₀FN₃O₂S	详情	详情
(XII)	12305	methyl 3-((3R)-3-[[(4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl)propanoate		C₂₂H₂₃FN₂O₄S	详情	详情
(XII)	45125			C₂₂H₂₃FN₂O₄S	详情	详情

Extended Information