(2R,5R)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one -Drug Synthesis Database

【结构式】

【分子编号】31681

【品名】(2R,5R)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one

【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 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VII)

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：(I)

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

Extended Information