2-methyl-2-phenylpropyl acetate -Drug Synthesis Database

【结构式】

【分子编号】17175

【品名】2-methyl-2-phenylpropyl acetate

【CA登记号】2901-13-5

【分子式】C₁₂H₁₆O₂

【分子量】192.25784

【元素组成】C 74.97% H 8.39% O 16.64%

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：(III)

1) The reduction of 2-methyl-2-phenylpropionic acid with LiAlH4 in THF gives 2-methyl-2-phenyl-1-propanol (II), which is acetylated with acetic anhydride in pyridine yielding the acetate (III). The Friedel-Crafts condensation of (III) with 4-chlorobutyryl chloride (IV) by means of AlCl3 in dichloromethane affords the butyrophenone (V), which is condensed with alpha,alpha-diphenylipiperidine-4-methanol (VI) by means of KHCO3 and KI in refluxing toluene/water to give the butyrophenone (VII). The deacetylation of (VII) with NaOH in refluxing methanol yields the primary alcohol (VIII), which is oxidized with oxalyl chloride and DMSO in methylene chloride to the corresponding aldehyde (IX). The oxidation of (IX) with KMnO4 in acetone affords the ketoacid (X), which is finally reduced with NaBH4 in water. 2) The acetate (III) can also be obtained by Friedel-Crafts condensation of 2-methyl-2-propenyl acetate (XI) with refluxing benzene (XII) by means of AlCl3. 3) The ketoacid (X) can also be obtained by direct oxidation of the primary alcohol (VIII) with H5IO6 in chloroform/acetonitrile, or K2S2O8 in acetone/acetonitrile, both catalyzed by RuCl3.5H2O.

参考文献中间体

合成目标

【1】 Graul, A.; Castañer, J.; Fexofenadine Hydrochloride. Drugs Fut 1996, 21, 10, 1017.
【2】 King, C.-H.; Kaminski, M.A. (Merrell Pharmaceuticals, Inc.); 4-Diphenylmethyl piperidine derivs. and process for their preparation. JP 1996502022; WO 9321156 .

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)	17173	2-Methyl-2-phenylpropionic acid; 2-Methyl-2-phenyl-propionic acid	826-55-1	C₁₀H₁₂O₂	详情	详情
(II)	17174	2-methyl-2-phenyl-1-propanol		C₁₀H₁₄O	详情	详情
(III)	17175	2-methyl-2-phenylpropyl acetate	2901-13-5	C₁₂H₁₆O₂	详情	详情
(IV)	11265	4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride	4635-59-0	C₄H₆Cl₂O	详情	详情
(V)	17177	2-[4-(4-chlorobutanoyl)phenyl]-2-methylpropyl acetate		C₁₆H₂₁ClO₃	详情	详情
(VI)	17178	diphenyl(4-piperidinyl)methanol; alpha,alpha-Diphenyl-4-piperidinomethanol; Azacyclonol	115-46-8	C₁₈H₂₁NO	详情	详情
(VII)	17179	2-[4-(4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butanoyl)phenyl]-2-methylpropyl acetate	76811-96-6	C₃₄H₄₁NO₄	详情	详情
(VIII)	17180	1-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]-1-butanone		C₃₂H₃₉NO₃	详情	详情
(IX)	17181	2-[4-(4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butanoyl)phenyl]-2-methylpropanal		C₃₂H₃₇NO₃	详情	详情
(X)	17182	2-[4-(4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butanoyl)phenyl]-2-methylpropionic acid	76811-98-8	C₃₂H₃₇NO₄	详情	详情
(XI)	17183	2-methyl-2-propenyl acetate；methallyl acetate	820-71-3	C₆H₁₀O₂	详情	详情
(XII)	13364	Benzene	71-43-2	C₆H₆	详情	详情
(XIV)	17609	ethyl 2-methyl-2-phenylpropanoate		C₁₂H₁₆O₂	详情	详情
(XV)	17610	ethyl 2-[4-(cyclopropylcarbonyl)phenyl]-2-methylpropanoate		C₁₆H₂₀O₃	详情	详情
(XVI)	17611	ethyl 2-[4-(4-chlorobutanoyl)phenyl]-2-methylpropanoate		C₁₆H₂₁ClO₃	详情	详情
(XVII)	17612	ethyl 2-[4-(4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butanoyl)phenyl]-2-methylpropanoate		C₃₄H₄₁NO₄	详情	详情
(XVIII)	17613	ethyl 2-[4-(1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butyl)phenyl]-2-methylpropanoate		C₃₄H₄₃NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Ethyl phenylacetate (I) was alkylated with two equivalents of methyl iodide in the presence of potassium tert-butoxide to yield 2-methyl-2-phenylpropionic ester (II), which was reduced to alcohol (III) with LiAlH4. The alcohol function of (III) was esterified with Ac2O in pyridine, and the resulting compound (IV) was converted to sulfonyl chloride (V) by sulfonation with H2SO4, followed by treatment with SOCl2. Further reaction of (V) with ammonium hydroxide yielded sulfonamide (VI). Condensation of this sulfonamide with the dichloropyrimidine (VII) furnished, after saponification with NaOH, the N-pyrimidinylsulfonamide (VIII)). The alcohol function of (VIII) was then protected as the tetrahydropyranyl ether with dihydropyran and camphorsulfonic acid, and further treatment with the sodium salt of ethylene glycol at 100 C yielded the (2-hydroxyethoxy)pyrimidine (IX). Condensation of (IX) with 5-bromo-2-chloropyrimidine (X) in the presence of NaH gave (XI), which was finally converted to the target compound by acid deprotection of the tetrahydropyranyl acetal, followed by formation of the sodium salt with NaOMe in THF-MeOH.

参考文献中间体

合成目标

【1】 Yamada, K.; et al.; Syntheses and structure-activity relationships of sulfonamide derivatives as endothelin antagonists: A potent and selective ET-A antagonist, TA-0201 and related compounds. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 057.
【2】 Yamada, K.; Yasuda, K.; Kikkawa, K.; Kohno, R. (Tanabe Seiyaku Co., Ltd.); Benzenesulfonamide deriv. and process for preparing thereof. CA 2137953; EP 0658548; JP 1996099961; US 5589478; US 5728706 .

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)	21045	ethyl 2-phenylacetate	101-97-3	C₁₀H₁₂O₂	详情	详情
(II)	17609	ethyl 2-methyl-2-phenylpropanoate		C₁₂H₁₆O₂	详情	详情
(III)	17174	2-methyl-2-phenyl-1-propanol		C₁₀H₁₄O	详情	详情
(IV)	17175	2-methyl-2-phenylpropyl acetate	2901-13-5	C₁₂H₁₆O₂	详情	详情
(V)	21049	2-[4-(chlorosulfonyl)phenyl]-2-methylpropyl acetate		C₁₂H₁₅ClO₄S	详情	详情
(VI)	21050	2-[4-(aminosulfonyl)phenyl]-2-methylpropyl acetate		C₁₂H₁₇NO₄S	详情	详情
(VII)	21051	4,6-dichloro-5-(4-methylphenyl)pyrimidine		C₁₁H₈Cl₂N₂	详情	详情
(VIII)	21052	N-[6-chloro-5-(4-methylphenyl)-4-pyrimidinyl]-4-(2-hydroxy-1,1-dimethylethyl)benzenesulfonamide		C₂₁H₂₂ClN₃O₃S	详情	详情
(IX)	21053	4-[1,1-dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-N-[6-(2-hydroxyethoxy)-5-(4-methylphenyl)-4-pyrimidinyl]benzenesulfonamide		C₂₈H₃₅N₃O₆S	详情	详情
(X)	21054	5-bromo-2-chloropyrimidine		C₄H₂BrClN₂	详情	详情
(XI)	21055	N-[6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-5-(4-methylphenyl)-4-pyrimidinyl]-4-[1,1-dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]benzenesulfonamide		C₃₂H₃₆BrN₅O₆S	详情	详情

Extended Information