1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone -Drug Synthesis Database

【结构式】

【分子编号】48151

【品名】1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone

【CA登记号】

【分子式】C₁₀H₁₁ClFNO

【分子量】215.6545832

【元素组成】C 55.7% H 5.14% Cl 16.44% F 8.81% N 6.49% O 7.42%

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：(IX)

Nitrosation of tetrahydrobenzothiazepine (I) with NaNO2 and HOAc, followed by LiAlH4 reduction of the resulting N-nitroso derivative (II), furnished hydrazine (III). Subsequent Fischer indole cyclization of hydrazine (III) with piperidone hydrate (IV) under acidic conditions afforded the tetracyclic system (V). The pyrrole ring double bond of (V) was then reduced employing NaBH3CN and CF3COOH to provide the racemic cis-tetracycle (VI). Resolution of (VI) was carried out by preparative chiral HPLC of the corresponding N-Boc derivative. The desired N-Boc enantiomer (VII) was then deprotected by acidic treatment to give the chiral secondary amine (VIII). This was finally alkylated with 4-chloro-4'-fluorobutyrophenone (IX) to yield the title compound.

参考文献中间体

合成目标

【1】 Boyle, K.E.; Robichaud, A.J.; Lee, T.; et al.; Novel, highly potent and selective serotonin 5-HT2A/dopamine D2 receptor antagonists as potential antipsychotics. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 98.

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)	22617	2,3,4,5-tetrahydro-1,5-benzothiazepine		C₉H₁₁NS	详情	详情
(II)	48145	5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine		C₉H₁₀N₂OS	详情	详情
(III)	48146	3,4-dihydro-1,5-benzothiazepin-5(2H)-amine; 3,4-dihydro-1,5-benzothiazepin-5(2H)-ylamine		C₉H₁₂N₂S	详情	详情
(IV)	18178	4,4-piperidinediol	73390-11-1	C₅H₁₁NO₂	详情	详情
(V)	48147	6,7,9,10,11,12-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole		C₁₄H₁₆N₂S	详情	详情
(VI)	48148	6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole		C₁₄H₁₈N₂S	详情	详情
(VII)	48149	tert-butyl (8aS,12aR)-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole-11(8aH)-carboxylate		C₁₉H₂₆N₂O₂S	详情	详情
(VIII)	48150	(8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole		C₁₄H₁₈N₂S	详情	详情
(IX)	48151	1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone		C₁₀H₁₁ClFNO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

Nitrosation of dihydrobenzoxazine (I) with NaNO2 and HOAc, followed by LiAlH4 reduction of the resulting N-nitroso derivative (II), furnished hydrazine (III). Subsequent Fischer indole cyclization of hydrazine (III) with piperidone hydrate (IV) under acidic conditions afforded the tetracyclic system (V). The pyrrole ring double bond of (V) was then reduced employing NaBH3CN and CF3COOH to provide the racemic cis-tetracycle (VI). Resolution of (VI) was carried out by preparative chiral HPLC of the corresponding N-Boc derivative. The desired N-Boc enantiomer (VII) was then deprotected by acidic treatment to give the chiral secondary amine (VIII). This was finally alkylated with 2'-amino-4-chloro-4'-fluorobutyrophenone (IX) to yield the title compound.

参考文献中间体

合成目标

【1】 Boyle, K.E.; Robichaud, A.J.; Lee, T.; et al.; Novel, highly potent and selective serotonin 5-HT2A/dopamine D2 receptor antagonists as potential antipsychotics. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 98.

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)	48152	3,4-dihydro-2H-1,4-benzoxazine		C₈H₉NO	详情	详情
(II)	48153	4-nitroso-3,4-dihydro-2H-1,4-benzoxazine		C₈H₈N₂O₂	详情	详情
(III)	48154	2,3-dihydro-4H-1,4-benzoxazin-4-amine; 2,3-dihydro-4H-1,4-benzoxazin-4-ylamine		C₈H₁₀N₂O	详情	详情
(IV)	18178	4,4-piperidinediol	73390-11-1	C₅H₁₁NO₂	详情	详情
(V)	48155	1,2,7,8,9,10-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole		C₁₃H₁₄N₂O	详情	详情
(VI)	48156	1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole		C₁₃H₁₆N₂O	详情	详情
(VII)	48157	tert-butyl (6bR,10aS)-1,2,6b,9,10,10a-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate		C₁₈H₂₄N₂O₃	详情	详情
(VIII)	48158	(6bR,10aS)-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole		C₁₃H₁₆N₂O	详情	详情
(IX)	48151	1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone		C₁₀H₁₁ClFNO	详情	详情

Extended Information