(2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoic acid -Drug Synthesis Database

【结构式】

【分子编号】31466

【品名】(2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoic acid

【CA登记号】

【分子式】C₁₃H₁₆O₃

【分子量】220.26824

【元素组成】C 70.89% H 7.32% O 21.79%

与该中间体有关的原料药合成路线共 10 条

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8 合成路线9 合成路线10

合成路线1

该中间体在本合成路线中的序号：(IV)

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

合成目标

【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

该中间体在本合成路线中的序号：(IV)

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

合成目标

【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

该中间体在本合成路线中的序号：(XII)

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

合成目标

【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

该中间体在本合成路线中的序号：(IV)

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

合成目标

【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

合成路线5

该中间体在本合成路线中的序号：(VI)

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

合成目标

【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6

该中间体在本合成路线中的序号：(V)

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

合成目标

【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7

该中间体在本合成路线中的序号：(IV)

参考文献中间体

合成目标

【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8

该中间体在本合成路线中的序号：(IV)

参考文献中间体

合成目标

【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9

该中间体在本合成路线中的序号：(IV)

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

合成目标

【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10

该中间体在本合成路线中的序号：(IV)

参考文献中间体

合成目标

【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