Ro-64-6198, -Drug Synthesis Database

【结构式】

【药物名称】Ro-64-6198

【化学名称】8-[(1S,3aS)-2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one

【CA登记号】228246-60-4 (undefined isomer)

【分子式】C₂₆H₃₁N₃O

【分子量】401.55647

【开发单位】CeNeS (Originator), Roche (Originator)

【药理作用】Anxiolytics, PSYCHOPHARMACOLOGIC DRUGS, ORL1 (OP4) Agonists

合成路线1 合成路线2

合成路线1

The nitrosation of hexahydrophenalenone oxime (I) by means of NaNO2 and H2SO4 produced the N-nitroimine (II). Condensation of this intermediate with 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (III) in acetonitrile in the presence of molecular sieves gave rise to enamine (IV), which was finally reduced to the title amine using NaBH3CN.

参考文献中间体

【1】 Adam, G.; Monsma, F.; Wichmann, J.; Jenck, F.; Galley, G.; Cesura, A.; Rover, S. (F. Hoffmann-La Roche AG); 8-Substd.-1,3,8-triazaspiro[4.5]decan-4-on derivs.. EP 0856514; US 6071925 .

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)	39762	2,3,3a,4,5,6-hexahydro-1H-phenalen-1-one oxime		C₁₃H₁₅NO	详情	详情
(II)	39763			C₁₃H₁₄N₂O₂	详情	详情
(III)	18116	1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one	1021-25-6	C₁₃H₁₇N₃O	详情	详情
(IV)	39764	8-(7,8,9,9a-tetrahydro-1H-phenalen-3-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one		C₂₆H₂₉N₃O	详情	详情

合成路线2

The Stobbe-type condensation of tetralone (I) with diethyl succinate (II) by means of potassium tert-butoxide in tert butanol and subsequent hydrolysis/decarboxylation in HOAc/HCl gives the propionic acid (III), which is asymmetrically reduced with H2 over a chiral ruthenium catalyst in methanol to afford (S)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)propionic acid (S)-(IV). The cyclization of (IV) by means of PPA at 130 C provides the hexahydrophenalen-1-one (V), which by reaction with hydroxylamine is converted into the oxime (VI). The reduction of (VI) with H2 over Raney Ni in methanol yields the corresponding amine (VII), which is condensed with the piperidinium iodide (VIII) by means of K2CO3 in refluxing ethanol to afford a diastereomeric mixture from which the desired enantiomer (IX) is separated by column chromatography. A Strecker reaction of (IX) with aniline and Tms-CN in HOAc gives the anilino nitrile (X), which is finally cyclized by reaction with formic acid, Ac2O and formamide at 200 C to yield the target spiro compound. Alternatively, the anilino nitrile (X) is hydrolyzed with formic acid/Ac2O to give the formylated carboxamide (XI), which is finally cyclized with refluxing triethyl orthoformate, followed by reduction with NaBH4 in methanol.

参考文献中间体

【1】 Hennig, M.; Adam, G.; Wichmann, J.; Cesura, A.M.; Dautzenberg, F.M.; Scalone, M.; Jenck, F.; Rover, S.; Synthesis of (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, a potent and selective orphanin FQ (OFQ) receptor agonist with anxiolytic properties. Eur J Med Chem 2000, 35, 9, 839.

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)	20720	3,4-dihydro-1(2H)-naphthalenone	529-34-0	C₁₀H₁₀O	详情	详情
(II)	12313	diethyl succinate	123-25-1	C₈H₁₄O₄	详情	详情
(III)	51989	3-(3,4-Dihydronaphthalen-1-yl)propionic acid		C₁₃H₁₄O₂	详情	详情
(IV)	51990	3-[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]propionic acid		C₁₃H₁₆O₂	详情	详情
(V)	51991	(3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-one		C₁₃H₁₄O	详情	详情
(VI)	51992	(3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-one oxime		C₁₃H₁₅NO	详情	详情
(VII)	51993	(3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-amine; (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-ylamine		C₁₃H₁₇N	详情	详情
(VIII)	51994	1-ethyl-1-methyl-4-oxopiperidinium iodide		C₈H₁₆INO	详情	详情
(IX)	51995	1-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-4-piperidinone		C₁₈H₂₃NO	详情	详情
(X)	51996	1-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-4-anilino-4-piperidinecarbonitrile		C₂₅H₂₉N₃	详情	详情
(XI)	51997	1-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-4-(formylanilino)-4-piperidinecarboxamide		C₂₆H₃₁N₃O₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)