Brasofensine sulfate, BMS-204756, NS-2214, -Drug Synthesis Database

【结构式】

【药物名称】Brasofensine sulfate, BMS-204756, NS-2214

【化学名称】(E)-(1R,2R,3S,5S)-3-(3,4-Dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carbaldehyde O-methyloxime sulfate (1:1) salt

【CA登记号】171655-92-8, 173830-15-4 (citrate (1:1)), 171655-91-7 (free base), 173830-10-9 (free base, undefined isomer), 173830-14-3 (malea

【分子式】C₁₆H₂₂Cl₂N₂O₅S

【分子量】425.33414

【开发单位】NeuroSearch (Originator)

【药理作用】Antiparkinsonian Drugs, Extrapyramidal Disorders, Treatment of, NEUROLOGIC DRUGS, Dopamine Reuptake Inhibitors

合成路线1 合成路线2

合成路线1

The hydrolysis of (1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester (I) with refluxing 1M HCl gives the corresponding hydroxy acid (II), which is dehydrated with refluxing POCl3 and treated with methanol to the unsaturated methyl ester (III). The reaction of (III) with 3,4-dichlorophenylmagnesium bromide in ether yields a mixture of (1R,2S,3S,5S)- and (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl esters (V) and (VI), respectively. Enantiomer (V) is isomerized to (VI) by treating the mixture with sodium methoxide in refluxing methanol. The reduction of (VI) with LiAlH4 in ethyl ether gives (1R,2R,3S,5S)-[3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]methanol (VII), which is oxidized with oxalyl chloride in dichloromethane, affording aldehyde (VIII). Finally, this compound is treated with methoxyammonium chloride and Na2CO3 in methanol, giving brasofensine as an oil. Several salts of brasofensine were obtained by addition of the acid to a solution of brasofensine in ethanol and recrystallization from either water or isopropanol.

参考文献中间体

【1】 Castañer, J.; Graul, A.; Brasofensine Sulfate . Drugs Fut 1999, 24, 2, 128.
【2】 Moldt, P.; Watjen, F.; Scheel-Kruger, J. (NeuroSearch A/S); Tropane-2-aldoxine derivs. as neurotransmitter reuptake inhibitors. EP 0756596; JP 1997505607; US 5736556; WO 9528401 .

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)	21116	methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate		C₁₇H₂₁NO₄	详情	详情
(II)	21117	(1R,2R,3S,5S)-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid		C₉H₁₅NO₃	详情	详情
(III)	21118	methyl (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate		C₁₀H₁₅NO₂	详情	详情
(IV)	10069	Bromo(3,4-dichlorophenyl)magnesium	79175-35-2	C₆H₃BrCl₂Mg	详情	详情
(V)	21120	methyl (1R,2S,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate		C₁₆H₁₉Cl₂NO₂	详情	详情
(VI)	21121	methyl (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate		C₁₆H₁₉Cl₂NO₂	详情	详情
(VII)	21122	[(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methanol		C₁₅H₁₉Cl₂NO	详情	详情
(VIII)	21123	(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carbaldehyde		C₁₅H₁₇Cl₂NO	详情	详情

合成路线2

Synthesis of 8-[11C-methyl]-brasofensine: The demethylation of the previously described intermediate (VI) by means of 2,2,2-trichloroethyl chloroformate in refluxing toluene gives the expected ester (IX), which is protected with di-tert-butyl dicarbonate in THF, affording (1R,2R,3S,5S)-8-(tert-butoxycarbonyl)-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester (X). The reduction of (X) with LiAlH4 in ethyl ether gives (1R,2R,3S,5S)-8-(tert-butoxycarbonyl)-[3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]methanol (XI), which is oxidized with oxalyl chloride in dichloromethane, affording the aldehyde (XII). The reaction of (XII) with methoxyammonium chloride and Na2CO3 in methanol gives the O-methyloxime (XIII), which is deprotected with trifluoroacetic acid in dichloromethane, yielding (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane-2-carbadehyde O-methyloxime (XIV). Finally, this compound is methylated with [11C]-methyl iodide in DMSO at 130 C.

参考文献中间体

【1】 Gjedde, A.; Moldt, P.; Gee, A.D.; The labelling of a novel tropane derivative [C-11]NS 2214 (BMS-204756) - An inhibitor of the dopamine transporter. J Label Compd Radiopharm 1997, 39, 12, 959.
【2】 Castañer, J.; Graul, A.; Brasofensine Sulfate . Drugs Fut 1999, 24, 2, 128.
【3】 Moldt, P.; Watjen, F.; Scheel-Kruger, J. (NeuroSearch A/S); Tropane-2-aldoxine derivs. as neurotransmitter reuptake inhibitors. EP 0756596; JP 1997505607; US 5736556; WO 9528401 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	21121	methyl (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate	C₁₆H₁₉Cl₂NO₂	详情	详情
(IX)	21124	methyl (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate	C₁₅H₁₇Cl₂NO₂	详情	详情
(X)	21125	8-(tert-butyl) 2-methyl (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate	C₂₀H₂₅Cl₂NO₄	详情	详情
(XI)	21126	tert-butyl (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate	C₁₉H₂₅Cl₂NO₃	详情	详情
(XII)	21127	tert-butyl (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate	C₁₉H₂₃Cl₂NO₃	详情	详情
(XIII)	21128	tert-butyl (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-[(methoxyimino)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate	C₂₀H₂₆Cl₂N₂O₃	详情	详情
(XIV)	21129	(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane-2-carbaldehyde O-methyloxime	C₁₅H₁₈Cl₂N₂O	详情	详情

Extended Information