Abaperidone hydrochloride, FI-8602.HCl, -Drug Synthesis Database

【结构式】

【药物名称】Abaperidone hydrochloride, FI-8602.HCl

【化学名称】7-[3-[4-(6-Fluorobenz-1,2-isoxazol-3-yl)piperidin-1-yl]propoxy]-3-(hydroxymethyl)-4H-1-benzopyran-4-one hydrochloride

【CA登记号】183849-45-8, 183849-43-6 (free base)

【分子式】C₂₅H₂₆ClFN₂O₅

【分子量】488.94777

【开发单位】Ferrer (Originator)

【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, 5-HT2A Antagonists, Dopamine D2 Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

2',4'-Dihydroxyacetophenone (I) was selectively alkylated at position 4' with 1-bromo-3-chloropropane (II) in the presence of K2CO3 in refluxing acetone to yield the 4'-(3-chloropropyl)ether (III). Further condensation of (III) with Vilsmeier reagent, followed by aqueous work up, provided the 3-formylchromenone (IV), which was subsequently reduced with sodium borohydride in CHCl3-EtOH at 0 C to give the (hydroxymethyl)chromenone (V). Finally, alkylation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (VI) with chloride (V) in the presence of K2CO3 and KI in refluxing acetonitrile yielded the title compound, which was isolated as the hydrochloride salt from methanol.

参考文献中间体

【1】 Princep, M.; Guglietta, A.; Bolos, J.; Abaperidone Hydrochloride. Drugs Fut 2001, 26, 4, 335.
【2】 Bolos, J.; et al.; 7-[3-(1-Piperidinyl)propoxy]chromenones as potential atypical antipsychotics. J Med Chem 1996, 39, 15, 2962.
【3】 Bolós, J.; Anglada, L.; Gubert, S.; Planas, J.M.; Agut, J.; Princep, M.; De la Fuente, N.; Sacristan, A.; Ortiz, J.A.; 7-[3-(1-Piperidinyl)propoxy]chromenones as potential atypical antipsychotics. 2. Pharmacological profile of 7-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidin-1-yl]propoxy]-3-(hydroxymethyl)chromen-4-one (abaperidone, FI-8602). J Med Chem 1998, 41, 27, 5402.
【4】 Foguet, R.; Anglada, L.; Bolós, J.; Ortiz, J.; Sacristán, A.; Castellò, J.M. (Ferrer Internacional SA); 4-(6-Fluoro-1, 2-benzisoxazolyl)-1-piperidinyl-propoxy-chromen-4-one derivs., their preparation and their use in the treatment of psychosis, schizophrenia and anxiety. EP 0765323; ES 2101646; ES 2103237; JP 1998501557; US 5736558; WO 9632389 .

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)	13961	Resacetophenone; 1-(2,4-Dihydroxyphenyl)-1-ethanone	89-84-9	C₈H₈O₃	详情	详情
(II)	10358	1-Bromo-3-chloropropane	109-70-6	C₃H₆BrCl	详情	详情
(III)	26820	1-[4-(3-chloropropoxy)-2-hydroxyphenyl]-1-ethanone		C₁₁H₁₃ClO₃	详情	详情
(IV)	26821	7-(3-chloropropoxy)-4-oxo-4H-chromene-3-carbaldehyde		C₁₃H₁₁ClO₄	详情	详情
(V)	26822	7-(3-chloropropoxy)-3-(hydroxymethyl)-4H-chromen-4-one		C₁₃H₁₃ClO₄	详情	详情
(VI)	17910	6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole		C₁₂H₁₃FN₂O	详情	详情

合成路线2

Methyl 2,4-dihydroxybenzoate (VII) was selectively protected as the 4-benzyl ether (VIII) with benzyl bromide in the presence of potassium carbonate. Condensation with sodium (methylsulfinyl)methyde provided the corresponding methylsulfinyl ketone (IX). This was condensed with two equivalents of formaldehyde to yield (X). Subsequent pyrolysis of the sulfoxide group furnished chromenone (XI). Deprotection of the benzyl ether was achieved by treatment with boron trichloride, and the resulting 7-hydroxychromenone (XII) was then alkylated with 1-bromo-3-chloropropane (II) to give 7-(3-chloropropoxy)-3-(hydroxymethyl)-4H-chromen-4-one (V).

参考文献中间体

【1】 Nieto, J.; Bolos, J.; Unpublished results .
【2】 Princep, M.; Guglietta, A.; Bolos, J.; Abaperidone Hydrochloride. Drugs Fut 2001, 26, 4, 335.

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)	10358	1-Bromo-3-chloropropane	109-70-6	C₃H₆BrCl	详情	详情
(V)	26822	7-(3-chloropropoxy)-3-(hydroxymethyl)-4H-chromen-4-one		C₁₃H₁₃ClO₄	详情	详情
(VII)	16623	methyl 2,4-dihydroxybenzoate	2150-47-2	C₈H₈O₄	详情	详情
(VIII)	46606	methyl 4-(benzyloxy)-2-hydroxybenzoate		C₁₅H₁₄O₄	详情	详情
(IX)	46607	1-[4-(benzyloxy)-2-hydroxyphenyl]-2-(methylsulfinyl)-1-ethanone		C₁₆H₁₆O₄S	详情	详情
(X)	46608	7-(benzyloxy)-3-(hydroxymethyl)-3-(methylsulfinyl)-2,3-dihydro-4H-chromen-4-one		C₁₈H₁₈O₅S	详情	详情
(XI)	46609	7-(benzyloxy)-3-(hydroxymethyl)-4H-chromen-4-one		C₁₇H₁₄O₄	详情	详情
(XII)	46610	7-hydroxy-3-(hydroxymethyl)-4H-chromen-4-one		C₁₀H₈O₄	详情	详情

合成路线3

Since this synthetic method did not allow the scale-up preparation, mainly due to safety concerns regarding the use of sodium (methylsulfinyl)methyde, an improved and scalable procedure was further developed. Claisen condensation of acetophenone (III) with ethyl formate in the presence of sodium methoxide produced the 2-hydroxychromanone (XIII). This was condensed with formaldehyde, employing sodium acetate as the catalyst, and the intermediate 3-(hydroxymethyl)-2-hydroxychromanone (XIV) was subsequently dehydrated by treatment with HCl to give (V).

参考文献中间体

【1】 Bolos, J.; et al.; A new and efficient synthesis of 3-(hydroxymethyl)-4H-chromen-4-ones. J Heterocycl Chem 2000, 37, 5, 1203.
【2】 Princep, M.; Guglietta, A.; Bolos, J.; Abaperidone Hydrochloride. Drugs Fut 2001, 26, 4, 335.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(III)	26820	1-[4-(3-chloropropoxy)-2-hydroxyphenyl]-1-ethanone	C₁₁H₁₃ClO₃	详情	详情
(V)	26822	7-(3-chloropropoxy)-3-(hydroxymethyl)-4H-chromen-4-one	C₁₃H₁₃ClO₄	详情	详情
(XIII)	46611	7-(3-chloropropoxy)-2-hydroxy-2,3-dihydro-4H-chromen-4-one	C₁₂H₁₃ClO₄	详情	详情
(XIV)	46612	7-(3-chloropropoxy)-2-hydroxy-3-(hydroxymethyl)-2,3-dihydro-4H-chromen-4-one	C₁₃H₁₅ClO₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)