(2S)-2-cyclohexyl-2-hydroxy-2-phenylethanoic acid -Drug Synthesis Database

【结构式】

【分子编号】51215

【品名】(2S)-2-cyclohexyl-2-hydroxy-2-phenylethanoic acid

【CA登记号】

【分子式】C₁₄H₁₈O₃

【分子量】234.29512

【元素组成】C 71.77% H 7.74% O 20.49%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(Ib),(IV)

Racemic cyclohexylphenyl glycolic acid (CHPGA) (I) is dissolved with (L)-tyrosine methyl ester (II) in refluxing acetonitrile/water to yield a mixture of diastereomeric salts, which is resolved by crystallization to afford the desired diastereomeric salt [(S)-CHPGA-(L)-TME] (III). Finally, the hydrolysis of salt (III) with HCl or H2SO4 at 40-50ºC in toluene yields the enantiomer (IV). Alternatively intermediate (IV) can be obtained as follows: acetalization of (S)-mandelic acid (V) with pivaldehyde (VI) in pentane and catalytic TfOH provides derivative (VII), which is then treated with LHMDS and then condensed with cyclohexanone (VIII) in THF to furnish aldol adduct (IX). Elimination of tertiary alcohol in (IX) with SOCl2 and pyridine in THF gives derivative (X), which is then converted into intermediate (IV) either by first hydrolysis of lactone (X) with KOH in MeOH and subsequent hydrogenation of the obtained derivative (XI) over Pd/C in MeOH, or by first hydrogenation of (X) over Pd/C in MeOH to give (XII), followed by hydrolysis with KOH in MeOH. On turn, derivative (XII) can alternatively be synthesized by treatment of derivative (VII) with LHMDS, followed by reaction with 3-bromocyclohexene (XIII) in THF to provide derivative (XIV), which is then hydrogenated over Pd/C.

参考文献中间体

合成目标

【1】 Grover, P.T.; et al.; Chiral mandelic acid template provides a highly practical solution for (S)-oxybutynin synthesis. J Org Chem 2000, 65, 19, 6283.
【2】 Senanayake, C.H.; Bakale, R.P.; Vandenbossche, C.P.; McConville, F.X.; Lopez, J.L. (Sepracor Inc.); Synthesis of optically active cyclohexylphenylglycolic acid and its esters. US 5973182; US 6140529; WO 0023414 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Ia)	51214	(2R)-2-cyclohexyl-2-hydroxy-2-phenylethanoic acid		C₁₄H₁₈O₃	详情	详情
(Ib),(IV)	51215	(2S)-2-cyclohexyl-2-hydroxy-2-phenylethanoic acid		C₁₄H₁₈O₃	详情	详情
(II)	21431	methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate	1080-06-4	C₁₀H₁₃NO₃	详情	详情
(III)	51216		n/a	C₂₄H₃₁NO₆	详情	详情
(V)	12563	(2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid	17199-29-0	C₈H₈O₃	详情	详情
(VI)	19797	Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal	630-19-3	C₅H₁₀O	详情	详情
(VII)	31681	(2R,5R)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one		C₁₃H₁₆O₃	详情	详情
(VIII)	11059	Cyclohexanone	108-94-1	C₆H₁₀O	详情	详情
(IX)	51217	(2S,5R)-2-(tert-butyl)-5-(1-hydroxycyclohexyl)-5-phenyl-1,3-dioxolan-4-one		C₁₉H₂₆O₄	详情	详情
(X)	51218	(2S,5S)-2-(tert-butyl)-5-(1-cyclohexen-1-yl)-5-phenyl-1,3-dioxolan-4-one		C₁₉H₂₄O₃	详情	详情
(XI)	51219	(2S)-2-(1-cyclohexen-1-yl)-2-hydroxy-2-phenylethanoic acid		C₁₄H₁₆O₃	详情	详情
(XII)	51220	(2S,5S)-2-(tert-butyl)-5-cyclohexyl-5-phenyl-1,3-dioxolan-4-one		C₁₉H₂₆O₃	详情	详情
(XIII)	30800	3-bromo-1-cyclohexene	1521-51-3	C₆H₉Br	详情	详情
(XIV)	51221	(2S,5S)-2-(tert-butyl)-5-[(1R)-2-cyclohexen-1-yl]-5-phenyl-1,3-dioxolan-4-one		C₁₉H₂₄O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The desired product is finally obtained by first formation of a mixed anhydride (XVI) by reaction of the cyclohexylphenyl glycolic acid (IV) with isobutylchloroformate (XV) in cyclohexane in the presence of Et3N, followed by treatment with 4-N,N-diethylamino butynol (XVII) (obtained on turn from reaction of propargyl alcohol (XVIII) with diethylamine (XIX) in the presence of paraformaldehyde and CuCl.

参考文献中间体

合成目标

【1】 Senanayake, C.H.; Bakale, R.P.; Vandenbossche, C.P.; McConville, F.X.; Lopez, J.L. (Sepracor Inc.); Synthesis of optically active cyclohexylphenylglycolic acid and its esters. US 5973182; US 6140529; WO 0023414 .

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)	51215	(2S)-2-cyclohexyl-2-hydroxy-2-phenylethanoic acid		C₁₄H₁₈O₃	详情	详情
(XV)	13423	1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate	543-27-1	C₅H₉ClO₂	详情	详情
(XVI)	51222			C₁₉H₂₆O₅	详情	详情
(XVII)	51223	4-(diethylamino)-2-butyn-1-ol		C₈H₁₅NO	详情	详情
(XVIII)	16664	Propargyl Alcohol; 2-propyn-1-ol	107-19-7	C₃H₄O	详情	详情
(XIX)	24486	Diethylamine; N,N-Diethylamine	109-89-7	C₄H₁₁N	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

The catalytic enantioselective cyanosilylation of the ketone (I) by means of Tms-CN catalyzed by gadolinium isopropoxide and the chiral ligand (II) in THF/propionitrile gives the silylated cyanohydrin (III), which is reduced by means of DIBAL in toluene to yield the carbaldehyde (IV). The desilylation of (IV) by means of HCl in aqueous THF affords the hydroxyaldehyde (V), which is finally oxidized by means of NaClO2 in tert-butanol/water to provide the target (S)-2-cyclohexyl-2-hydroxy-2-phenylacetic acid intermediate (VI) (see Scheme no. 23604001a, intermediate (IV)).

参考文献中间体

合成目标

【1】 Masumoto, S.; et al.; A practical synthesis of (S)-oxybutynin. Tetrahedron Lett 2002, 43, 48, 8647.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	60659	cyclohexyl(phenyl)methanone	C₁₃H₁₆O	详情	详情
(II)	60660	(2S,3R,4R)-2-[(diphenylphosphoryl)methyl]-4-(2-hydroxyphenoxy)tetrahydro-2H-pyran-3-ol	C₂₄H₂₅O₅P	详情	详情
(III)	60661	(2S)-2-cyclohexyl-2-phenyl-2-[(trimethylsilyl)oxy]ethanenitrile	C₁₇H₂₅NOSi	详情	详情
(IV)	60662	(2S)-2-cyclohexyl-2-phenyl-2-[(trimethylsilyl)oxy]ethanal	C₁₇H₂₆O₂Si	详情	详情
(V)	60663	(2S)-2-cyclohexyl-2-hydroxy-2-phenylethanal	C₁₄H₁₈O₂	详情	详情
(VI)	51215	(2S)-2-cyclohexyl-2-hydroxy-2-phenylethanoic acid	C₁₄H₁₈O₃	详情	详情

Extended Information