S-21552-1, -Drug Synthesis Database

【结构式】

【药物名称】S-21552-1

【化学名称】(+)-(R)--8-[4-[5-Methoxyspiro[3,4-dihydro-2H-1-benzopyran-3,2'-pyrrolidin]-1'-yl]butyl]-8-azaspiro[4.5]decane-7,9-dione hydrochloride

【CA登记号】153167-20-5 ((-)-enantiomer, free base), 153167-21-6 ((-)-enantiomer, monooxalate), 153167-18-1 (free base), 153167-19-2 (monoox

【分子式】C₂₆H₃₇ClN₂O₄

【分子量】477.04879

【开发单位】Servier (Originator)

【药理作用】Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT1A Receptor Agonists

合成路线1 合成路线2

合成路线1

The condensation of 5-methoxy-3-nitro-3,4-dihydro-2H-1-benzopyran (I) with methyl acrylate (II) by means of benzyltrimethylammonium methoxide in methanol gives the propionic ester (III), which is submitted to a reductive cyclization with H2 over RaNi in methanol yielding the racemic spiro compound (IV). Optical resolution of (IV) by means of (+)-1,1'-dinaphthyl-2,2'-diyl hydrogen phosphate [(+)-BNP] in methanol/dichloromethane affords (+)(R)-(V), which is finally condensed with 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione (VI) by means of triethylamine (TEA) in hot DMF.

参考文献中间体

【1】 Comoy, C.; et al.; 3-Amino-3,4-dihydro-2H-1-benzopyran derivatives as 5-HT1A receptor ligands and potential anxiolytic agents. 2. Synthesis and quantitative structure-activity relationship studies of spiro[pyrrolidine- and piperidine-2, 3'(2'H)-benzopyrans]. J Med Chem 1996, 39, 21, 4285.
【2】 Guillaumet, G.; Podona, T.; Adam, G.; Guardiola, B.; Renard, P. (ADIR et Cie.); 3-Aminochromane spiro derivs., processes for their preparation and pharmaceutical compsns. containing them. EP 0564358; FR 2689509; JP 1994287190; JP 1995084471; US 5376661; US 5397783 .

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)	33124	methyl 3-nitro-3,4-dihydro-2H-chromen-5-yl ether; 5-methoxy-3-nitrochromane		C₁₀H₁₁NO₄	详情	详情
(II)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(III)	33125	methyl 3-(5-methoxy-3-nitro-3,4-dihydro-2H-chromen-3-yl)propanoate		C₁₄H₁₇NO₆	详情	详情
(IV)	33126	5-Methoxy-3,4-dihydro-2H-spiro[1-benzopyran-3,2'-pyrrolidine]		C₁₃H₁₇NO₂	详情	详情
(V)	33127	(R)-5-Methoxy-3,4-dihydro-2H-spiro[1-benzopyran-3,2'-pyrrolidine]		C₁₃H₁₇NO₂	详情	详情
(VI)	29455	8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione		C₁₃H₂₀BrNO₂	详情	详情

合成路线2

The chiral intermediate (V) can also be obtained as follows: The cyclization of L-proline (VII) with pivalaldehyde (VIII) by means of LDA gives the pyrrolooxazolidinone (IX), which is condensed with the benzaldehyde (X) by means of LDA in THF yielding the alcohol (XI). The reaction of (XI) with I2, PPh3 and imidazole affords the corresponding iodide (XII), which is deiodinated with SmI2 to the intermediate (XIII). The hydrolysis of the oxazolidinone ring of (XIII) with refluxing methanol/water gives the pyrrolidine-carboxylic acid (XIV), which is reduced with BH3 in THF yielding the carbinol (XV). The protection of the NH group of (XV) with Boc2O in THF affords the carbamate (XVI), which is treated with trimethylsilyl bromide in dichloromethane to provide he diol (XVII). The cyclization of (XVII) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in ether gives the chiral protected spiro-benzopyran (XVIII), which is finally deprotected with TFA in dichloromethane to afford the desired chiral intermediate (V).

参考文献中间体

【1】 Usse, S.; et al.; Synthesis of a chiral spiranic aminochroan derivative from L-proline. J Org Chem 2000, 65, 3, 914.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	33127	(R)-5-Methoxy-3,4-dihydro-2H-spiro[1-benzopyran-3,2'-pyrrolidine]		C₁₃H₁₇NO₂	详情	详情
(VII)	16731	L-proline	147-85-3	C₅H₉NO₂	详情	详情
(VIII)	19797	Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal	630-19-3	C₅H₁₀O	详情	详情
(IX)	33128	(3R,7aS)-3-(tert-butyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one		C₁₀H₁₇NO₂	详情	详情
(X)	33129	2-methoxy-6-(methoxymethoxy)benzaldehyde		C₁₀H₁₂O₄	详情	详情
(XI)	33130	(3R,7aR)-3-(tert-butyl)-7a-[(R)-hydroxy[2-methoxy-6-(methoxymethoxy)phenyl]methyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one		C₂₀H₂₉NO₆	详情	详情
(XII)	33131	(3R,7aS)-3-(tert-butyl)-7a-[(R)-iodo[2-methoxy-6-(methoxymethoxy)phenyl]methyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one		C₂₀H₂₈INO₅	详情	详情
(XIII)	33132	(3R,7aR)-3-(tert-butyl)-7a-[2-methoxy-6-(methoxymethoxy)benzyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one		C₂₀H₂₉NO₅	详情	详情
(XIV)	33133	(2R)-2-[2-methoxy-6-(methoxymethoxy)benzyl]-2-pyrrolidinecarboxylic acid		C₁₅H₂₁NO₅	详情	详情
(XV)	33134	[(2R)-2-[2-methoxy-6-(methoxymethoxy)benzyl]pyrrolidinyl]methanol		C₁₅H₂₃NO₄	详情	详情
(XVI)	33135	tert-butyl (2R)-2-(hydroxymethyl)-2-[2-methoxy-6-(methoxymethoxy)benzyl]-1-pyrrolidinecarboxylate		C₂₀H₃₁NO₆	详情	详情
(XVII)	33136	tert-butyl (2R)-2-(2-hydroxy-6-methoxybenzyl)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate		C₁₈H₂₇NO₅	详情	详情
(XVIII)	33137	(R)-5-Methoxy-3,4-dihydro-2H-spiro[1-benzopyran-3,2'-pyrrolidine]-1'-carboxylic acid tert-buytyl ester		C₁₈H₂₅NO₄	详情	详情

Extended Information