(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】26385

【品名】(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxylic acid

【CA登记号】

【分子式】C₁₈H₂₂FNO₃

【分子量】319.3760232

【元素组成】C 67.69% H 6.94% F 5.95% N 4.39% O 15.03%

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：(XXIV)

2) The bromination of 3(R)-amino-5-methoxy-3,4-dihydro-2H-1-benzopyran (XV) with Br2 in acetic acid gives the 8-bromo compound (XVI), which is protected with benzyl bromide and K2CO3 in acetonitrile, yielding the dibenzylamino compound (XVII). The reaction of (XVII) with N-fluorobenzenesulfonimide and BuLi in THF provides the corresponding 8-fluoro derivative (XVIII), which is deprotected with H2 over Pd/C in methanol/THF, giving 3(R)-amino-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (XIX). The alkylation of (XIX) with cyclobutanone (XII) and sodium cyanoborohydride in methanol gives the dicyclobutylamino compound (XX), which is demethylated by means of boron tribromide in dichloromethane to afford the 5-hydroxy compound (XXI). The triflation of (XXI) with trifluoromethanesulfonic anhydride and collidine in dichloromethane yields the triflate (XXII), which is treated with carbon monoxide, palladium acetate and methanol to give methyl 3(R)-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxylate (XXIII). The hydrolysis of (XXIII) with refluxing 6M aqueous HCl yields the free acid (XXIV), which by reaction with SOCl2 is converted into the acyl chloride (XXV). Finally, this compound is treated with ammonia in dichloromethane to give robalzotan (XIII).

参考文献中间体

合成目标

【1】 Leeson, P.; Castañer, J.; Sorbera, L.A.; Robalzotan Tartrate Hydrate. Drugs Fut 1999, 24, 7, 740.
【2】 Evenden, J.L.; Hammarberg, E.M.; Hansson, H.S.; Hellberg, S.E.; Johansson, L.G.; Lundkvist, J.R.M.; Ross, S.B.; Sohn, D.D.; Thorberg, S.O. (AstraZeneca plc); Novel (R)-5-carbamoyl-8-fluoro-3,-N, N-disubstd.-amino-3,4-dihydro-2H-1-benzopyranes. EP 0725779; JP 1997504287; WO 9511891 .
【3】 Hammarberg, E.M.; Johansson, L.G.; Ross, S.B.; Thorberg, S.O. (AstraZeneca plc); 3-(N-Isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman as a selective 5-hydroxytryptamine receptor stimulant. EP 0538222; EP 0607274; JP 1995500320; US 5616610; WO 9307135 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	26374	cyclobutanone	1191-95-3	C₄H₆O	详情	详情
(XIII)	26375	(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxamide		C₁₈H₂₃FN₂O₂	详情	详情
(XV)	26376	(3R)-5-methoxy-3,4-dihydro-2H-chromen-3-ylamine; (3R)-5-methoxy-3,4-dihydro-2H-chromen-3-amine		C₁₀H₁₃NO₂	详情	详情
(XVI)	26377	(3R)-8-bromo-5-methoxy-3,4-dihydro-2H-chromen-3-amine; (3R)-8-bromo-5-methoxy-3,4-dihydro-2H-chromen-3-ylamine		C₁₀H₁₂BrNO₂	详情	详情
(XVII)	26378	N,N-dibenzyl-N-[(3R)-8-bromo-5-methoxy-3,4-dihydro-2H-chromen-3-yl]amine; (3R)-N,N-dibenzyl-8-bromo-5-methoxy-3,4-dihydro-2H-chromen-3-amine		C₂₄H₂₄BrNO₂	详情	详情
(XVIII)	26379	(3R)-N,N-dibenzyl-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-amine; N,N-dibenzyl-N-[(3R)-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-yl]amine		C₂₄H₂₄FNO₂	详情	详情
(XIX)	26380	(3R)-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-amine; (3R)-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-ylamine		C₁₀H₁₂FNO₂	详情	详情
(XX)	26381	(3R)-N,N-dicyclobutyl-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-amine; N,N-dicyclobutyl-N-[(3R)-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-yl]amine		C₁₈H₂₄FNO₂	详情	详情
(XXI)	26382	(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromen-5-ol		C₁₇H₂₂FNO₂	详情	详情
(XXII)	26383	(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate		C₁₈H₂₁F₄NO₄S	详情	详情
(XXIII)	26384	methyl (3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxylate		C₁₉H₂₄FNO₃	详情	详情
(XXIV)	26385	(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxylic acid		C₁₈H₂₂FNO₃	详情	详情
(XXV)	26386	(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carbonyl chloride		C₁₈H₂₁ClFNO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The synthesis of [14C]-labeled robalzotan has been described: The treatment of 3(R)-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-benzopyran-5-ol (I), a known intermediate in the synthesis of robalzotan, with Tf2O in dichloromethane provides the triflate (II), which by reaction with [14C]-KCN and a Pd catalyst in N-methylpyrrolidine gives the labeled nitrile (III). Hydrolysis of nitrile (III) with refluxing HBr yields the carboxylic acid (IV), which by reaction with SOCl2 affords the corresponding acyl chloride (V). Finally, this acyl chloride (V) is treated with ammonia to provide [14C]-labeled robalzotan.

参考文献中间体

合成目标

【1】 Werner, T.F.; et al.; Radiosynthesis of [C-14]- and [H-3]-robalzotan a selective 5-HT1A antagonist. J Label Compd Radiopharm 2000, 43, 5, 437.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	26382	(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromen-5-ol	C₁₇H₂₂FNO₂	详情	详情
(II)	26383	(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate	C₁₈H₂₁F₄NO₄S	详情	详情
(III)	37662	(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carbonitrile	C₁₈H₂₁FN₂O	详情	详情
(III)	45321	(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carbonitrile	C₁₈H₂₁FN₂O	详情	详情
(IV)	26385	(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxylic acid	C₁₈H₂₂FNO₃	详情	详情
(IV)	45322	(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxylic acid	C₁₈H₂₂FNO₃	详情	详情
(V)	26386	(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carbonyl chloride	C₁₈H₂₁ClFNO₂	详情	详情
(V)	45323	(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carbonyl chloride	C₁₈H₂₁ClFNO₂	详情	详情

Extended Information