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【结 构 式】

【药物名称】J-104129

【化学名称】2(R)-Cyclopentyl-2-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]-2-phenylacetamide

【CA登记号】185029-36-1 (fumarate (1:1)), 185029-08-7 (undefined isomer)

【 分 子 式 】C24H36N2O2

【 分 子 量 】384.56672

【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5合成路线6合成路线7

合成路线1

The alkylation of 4-piperidone monohydrate hydrochloride (I) with 5-bromo-2-methyl-2-pentene (II) in the presence of KI and K2CO3 afforded the tertiary amine (III). Subsequent reductive amination using ammonium acetate and sodium cyanoborohydride provided aminopiperidine (IV).

参考文献 中间体
【1】 Mase, T.; Mitsuya, M.; Tsuchiya, Y.; et al.; J-104129, a novel muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors. Bioorg Med Chem 1999, 7, 11, 2555.
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) 27115 4-piperidinone 40064-34-4 C5H9NO 详情 详情
(II) 31462 5-bromo-2-methyl-2-pentene C6H11Br 详情 详情
(III) 31464 1-(4-methyl-3-pentenyl)-4-piperidinone C11H19NO 详情 详情
(IV) 31463 1-(4-methyl-3-pentenyl)-4-piperidinamine; 1-(4-methyl-3-pentenyl)-4-piperidinylamine C11H22N2 详情 详情

合成路线2

Racemic 2-cyclopentyl-2-hydroxy-2-phenylacetic acid (V) was resolved by recrystallization of its cinchonidine salt from toluene to furnish the (-)-(R)-enantiomer (VI). Coupling with amine (IV) by means of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) then gave the target amide.

参考文献 中间体
【1】 Mase, T.; Mitsuya, M.; Tsuchiya, Y.; et al.; J-104129, a novel muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors. Bioorg Med Chem 1999, 7, 11, 2555.
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) 31463 1-(4-methyl-3-pentenyl)-4-piperidinamine; 1-(4-methyl-3-pentenyl)-4-piperidinylamine C11H22N2 详情 详情
(V) 31465 2-cyclopentyl-2-hydroxy-2-phenylacetic acid; alpha-Cyclopentylmandelic acid 427-49-6 C13H16O3 详情 详情
(VI) 31466 (2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoic acid C13H16O3 详情 详情

合成路线3

The condensation of chiral dioxolane (I) with 2-cyclopentenone (II) by means of lithium diisopropylamide (LDA) in THF, followed by reaction with N-phenyl-trifluoromethanesulfonylimide gives the enol triflate (III), which is reduced with H2 over Pd/C in methanol yielding the chiral dioxolane (IV)(as major isomer (93:7)). The hydrolysis of (IV) with NaOH in methanol affords impure acid (V), which was purified through crystallization of its (-)-cinchonidine salt. Pure (V) is finally condensed with piperidine-4-amine (VI) by means of CDI and DIEA in DMF to afford the target amide.

参考文献 中间体
【1】 Mitsuya, M.; et al.; Stereoselective synthesis of a new muscarinic M3 receptor antagonist, J-104129. Bioorg Med Chem Lett 1999, 9, 14, 2037.
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) 31681 (2R,5R)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one C13H16O3 详情 详情
(II) 25950 2-cyclopenten-1-one 930-30-3 C5H6O 详情 详情
(III) 31682 (3S)-3-[(2R,4R)-2-(tert-butyl)-5-oxo-4-phenyl-1,3-dioxolan-4-yl]-1-cyclopenten-1-yl trifluoromethanesulfonate C19H21F3O6S 详情 详情
(IV) 31683 (2R,5R)-2-(tert-butyl)-5-cyclopentyl-5-phenyl-1,3-dioxolan-4-one C18H24O3 详情 详情
(V) 31466 (2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoic acid C13H16O3 详情 详情
(VI) 31463 1-(4-methyl-3-pentenyl)-4-piperidinamine; 1-(4-methyl-3-pentenyl)-4-piperidinylamine C11H22N2 详情 详情

合成路线4

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5

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6

The alkylation of 4-(tert-butoxycarbonylamino)piperidine (VIII) with 5-bromo-2-methyl-2-pentene (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
(IV) 31466 (2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoic acid C13H16O3 详情 详情
(VIII) 41601 tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine 73874-95-0 C10H20N2O2 详情 详情
(IX) 31462 5-bromo-2-methyl-2-pentene C6H11Br 详情 详情
(X) 41607 tert-butyl 1-(4-methyl-3-pentenyl)-4-piperidinylcarbamate C16H30N2O2 详情 详情
(XII) 31463 1-(4-methyl-3-pentenyl)-4-piperidinamine; 1-(4-methyl-3-pentenyl)-4-piperidinylamine C11H22N2 详情 详情

合成路线7

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 bromide (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) 31462 5-bromo-2-methyl-2-pentene C6H11Br 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
Drug NewChemical Entity Original Patent(1)