J-106366, -Drug Synthesis Database

【结构式】

【药物名称】J-106366

【化学名称】2(R)-Cyclopentyl-2-hydroxy-N-[1-[4(S)-methylhexyl]piperidin-4-yl]-2-phenylacetamide

【CA登记号】

【分子式】C₂₅H₄₀N₂O₂

【分子量】400.60975

【开发单位】Banyu (Originator)

【药理作用】Asthma Therapy, Bronchodilators, GASTROINTESTINAL DRUGS, Irritable Bowel Syndrome, Agents for, RENAL-UROLOGIC DRUGS, RESPIRATORY DRUGS, Urinary Incontinence Therapy, Muscarinic M3 Antagonists

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

The chiral precursor (IV) was obtained by two alternative procedures. Addition of cyclopentylmagnesium bromide (II) to ethyl phenylglyoxylate (I) afforded the racemic hydroxyester (III). Basic hydrolysis of the ethyl ester group of (III) gave the corresponding carboxylic acid, which was resolved using cinchonidine.

参考文献中间体

【1】 Yamakawa, T.; et al.; Synthesis and structure-activity-relationships of 4-acetamidopiperidines as M3 selective antagonists. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.294.
【2】 Tsuchiya, Y.; Nomoto, T.; Ohsawa, H.; Kawakami, K.; Ohwaki, K.; Nishikibe, M. (Banyu Pharmaceutical Co., Ltd.); 1,4-Disubstd. piperidine derivs.. EP 0823423; US 5750540; WO 9633973 .

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)	41596	ethyl 2-oxo-2-phenylacetate	1603-79-8	C₁₀H₁₀O₃	详情	详情
(II)	41597	chloro(cyclopentyl)magnesium	32916-51-1	C₅H₉ClMg	详情	详情
(III)	41598	ethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate		C₁₅H₂₀O₃	详情	详情
(IV)	31466	(2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoic acid		C₁₃H₁₆O₃	详情	详情

合成路线2

An alternative asymmetric procedure consisted in the LDA-promoted addition of cyclopentenone (VI) to the chiral dioxolanone (V), followed by catalytic hydrogenation to furnish (VII). The dioxolane group of (VII) was then cleaved by basic hydrolysis yielding the target (R)-hydroxyacid (IV).

参考文献中间体

【1】 Tsuchiya, Y.; Nomoto, T.; Ohsawa, H.; Kawakami, K.; Ohwaki, K.; Nishikibe, M. (Banyu Pharmaceutical Co., Ltd.); 1,4-Disubstd. piperidine derivs.. EP 0823423; US 5750540; WO 9633973 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	31466	(2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoic acid		C₁₃H₁₆O₃	详情	详情
(V)	41599	(2S,5R)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one		C₁₃H₁₆O₃	详情	详情
(VI)	25950	2-cyclopenten-1-one	930-30-3	C₅H₆O	详情	详情
(VII)	41600	(2S,5R)-2-(tert-butyl)-5-cyclopentyl-5-phenyl-1,3-dioxolan-4-one		C₁₈H₂₄O₃	详情	详情

合成路线3

The alkylation of 4-(tert-butoxycarbonylamino)piperidine (VIII) with (S)-4- methylhexyl methanesulfonate (IX) provided the tertiary amine (X). Cleavage of the Boc protecting group of (X) gave aminopiperidine (XI), which was finally coupled with the chiral hydroxyacid (IV) by means of carbonyl diimidazole.

参考文献中间体

【1】 Tsuchiya, Y.; Nomoto, T.; Ohsawa, H.; Kawakami, K.; Ohwaki, K.; Nishikibe, M. (Banyu Pharmaceutical Co., Ltd.); 1,4-Disubstd. piperidine derivs.. EP 0823423; US 5750540; WO 9633973 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	41601	tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine	73874-95-0	C₁₀H₂₀N₂O₂	详情	详情
(IX)	41602	(4S)-4-methylhexyl methanesulfonate		C₈H₁₈O₃S	详情	详情
(X)	41603	tert-butyl 1-[(4S)-4-methylhexyl]-4-piperidinylcarbamate		C₁₇H₃₄N₂O₂	详情	详情
(XI)	41604	1-[(4S)-4-methylhexyl]-4-piperidinylamine; 1-[(4S)-4-methylhexyl]-4-piperidinamine		C₁₂H₂₆N₂	详情	详情
(XII)	31466	(2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoic acid		C₁₃H₁₆O₃	详情	详情

合成路线4

In a related procedure, hydroxyacid (IV) was coupled with 1-Boc-4-aminopiperidine (XII) employing EDC and HOBt to give amide (XIII). Acid cleavage of the Boc group of (XIII) yielded amine (XIV), that was finally alkylated with mesylate (IX).

参考文献中间体

【1】 Yamakawa, T.; et al.; Synthesis and structure-activity-relationships of 4-acetamidopiperidines as M3 selective antagonists. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.294.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	31466	(2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoic acid		C₁₃H₁₆O₃	详情	详情
(IX)	41602	(4S)-4-methylhexyl methanesulfonate		C₈H₁₈O₃S	详情	详情
(XII)	28414	4-Amino-1-N-Boc-piperidine; tert-butyl 4-amino-1-piperidinecarboxylate; N-Boc-4-aminopiperidine	87120-72-7	C₁₀H₂₀N₂O₂	详情	详情
(XIII)	41605	tert-butyl 4-[[(2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoyl]amino]-1-piperidinecarboxylate		C₂₃H₃₄N₂O₄	详情	详情
(XIV)	41606	(2R)-2-cyclopentyl-2-hydroxy-2-phenyl-N-(4-piperidinyl)ethanamide		C₁₈H₂₆N₂O₂	详情	详情

Extended Information