3-methyl-3-phenylbutyric acid -Drug Synthesis Database

【结构式】

【分子编号】38637

【品名】3-methyl-3-phenylbutyric acid

【CA登记号】

【分子式】C₁₁H₁₄O₂

【分子量】178.23096

【元素组成】C 74.13% H 7.92% O 17.95%

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：(IV)

The cyclization of pyridine-3-carbaldehyde (I) with L-cysteine (II) gives 2-(3-pyridyl)thiazolidine-4(R)-carboxylic acid (III), which is finally condensed with 1-(3-methyl-3-phenylbutyl)piperazine (IV) by means of DCC and HOBT In DMF. The intermediate 1-(3-methyl-3-phenylbutyl)piperazine (IV) has been obtained as follows: The reduction of 3-methyl-3-phenylbutyric acid (IV) with LiAlH4 in THF gives the corresponding butanol (V), which is treated with refluxing 48% HBr to yield the 3-methyl-3-phenylbutyl bromide (VI). The condensation of (VI) with piperazine-1-carboxylic acid ethyl ester (VII) by means of K2CO3 in 2-butanone gives 4-(3-methyl-3-phenylbutyl)piperazine-1-carboxylic acid ethyl ester (VIII), which is decarboxylated with NaOH in refluxing ethanol.

参考文献中间体

合成目标

【1】 Mase, T.; Hara, H.; Nagaoka, H.; Takahasi, T.; Suzuki, T.; Tomioka, K.; Yamada, T. (Yamanouchi Pharmaceutical Co., Ltd.); Saturated heterocyclic carboxamide derivs.. AU 8812080; EP 0279681; JP 1988208582; US 4987132 .

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)	12849	Nicotinaldehyde; 3-Pyridinecarboxaldehyde	500-22-1	C₆H₅NO	详情	详情
(II)	38633	(2S)-2-amino-2-(methylsulfanyl)ethanoic acid		C₃H₇NO₂S	详情	详情
(III)	38634	(4R)-2-(3-pyridinyl)-1,3-thiazolidine-4-carboxylic acid		C₉H₁₀N₂O₂S	详情	详情
(IV)	38637	3-methyl-3-phenylbutyric acid		C₁₁H₁₄O₂	详情	详情
(IV)	38641	1-(3-methyl-3-phenylbutyl)piperazine		C₁₅H₂₄N₂	详情	详情
(V)	38638	3-methyl-3-phenyl-1-butanol		C₁₁H₁₆O	详情	详情
(VI)	38639	1-(3-bromo-1,1-dimethylpropyl)benzene		C₁₁H₁₅Br	详情	详情
(VII)	24694	N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine	120-43-4	C₇H₁₄N₂O₂	详情	详情
(VIII)	38640	ethyl 4-(3-methyl-3-phenylbutyl)-1-piperazinecarboxylate		C₁₈H₂₈N₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The amino acid building block (XI) was prepared as follows. Friedel-Crafts condensation of dimethylacrylic acid (I) with benzene in the presence of AlCl3 afforded 3-methyl-3-phenylbutanoic acid (II). After activation of acid (II) as the mixed anhydride (IV) by treatment with pivaloyl chloride (III) and Et3N, coupling with the lithium salt of (S)-4-isopropyl-2-oxazolidinone (V) furnished the chiral N-acyl oxazolidinone (VI). Diastereoselective introduction of an azido group into the lithium enolate of (VI) by means of 2,4,6-triisopropylbenzenesulfonyl azide led to the (S,S)-azido compound (VII). Catalytic hydrogenation of azide (VII) in the presence of Boc2O provided the Boc-protected amine (VIII). The chiral auxiliary of (VIII) was removed by hydrolysis with lithium hydroperoxide, and the resultant carboxylic acid was further converted to the methyl ester (IX) upon treatment with an ethereal solution of diazomethane. The N-methyl derivative (X) was then prepared by alkylation of the tert-butyl carbamate (IX) with iodomethane in the presence of NaH. Basic hydrolysis of ester (X) provided the target N-Boc amino acid (XI).

参考文献中间体

合成目标

【1】 Roberge, M.; Andersen, R.; Piers, E.; Nieman, J.; Coleman, J. (University of British Columbia); Hemiasterlin analogs. WO 9932509 .

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)	34677	3-methyl-2-butenoic acid	541-47-9	C₅H₈O₂	详情	详情
(II)	38637	3-methyl-3-phenylbutyric acid		C₁₁H₁₄O₂	详情	详情
(III)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	详情	详情
(IV)	55112	1,1-dimethylpropanoic 2-methyl-2-phenylbutanoic anhydride		C₁₆H₂₂O₃	详情	详情
(V)	12867	(4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone	17016-83-0	C₆H₁₁NO₂	详情	详情
(VI)	55113	(4S)-4-isopropyl-3-(3-methyl-3-phenylbutanoyl)-1,3-oxazolidin-2-one		C₁₇H₂₃NO₃	详情	详情
(VII)	55114	(4S)-3-[(2S)-2-azido-3-methyl-3-phenylbutanoyl]-4-isopropyl-1,3-oxazolidin-2-one		C₁₇H₂₂N₄O₃	详情	详情
(VIII)	55115	tert-butyl (1S)-1-{[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-2-methyl-2-phenylpropylcarbamate		C₂₂H₃₂N₂O₅	详情	详情
(IX)	55116	methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methyl-3-phenylbutanoate		C₁₇H₂₅NO₄	详情	详情
(X)	55117	methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutanoate		C₁₈H₂₇NO₄	详情	详情
(XI)	55118	(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutanoic acid		C₁₇H₂₅NO₄	详情	详情

Extended Information