ethyl 2-methylpropanoate；ethyl isobutyrate -Drug Synthesis Database

【结构式】

【分子编号】28650

【品名】ethyl 2-methylpropanoate；ethyl isobutyrate

【CA登记号】97-62-1

【分子式】C₆H₁₂O₂

【分子量】116.16008

【元素组成】C 62.04% H 10.41% O 27.55%

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：(XXII)

Benzylic bromination of 3-bromo-o-xylene (IX) with NBS in the presence of benzoyl peroxide in refluxing CCl4 or chlorobenzene at 80 °C gives 1-bromo-2,3-bis(bromomethyl)benzene (X), which then cyclizes with benzylamine in the presence of KHCO3 in acetonitrile to yield 2-benzyl-4-bromoisoindoline (XI). Alkenylation of compound (XI) with tributyl(vinyl)tin (XII) by means of Pd(PPh3)4 in toluene provides the isoindoline (XIII), which is then deprotected by means of 1-chloroethyl chloroformate (ACE-Cl) in refluxing 1,2-dichloroethane to afford 4-vinylisoindoline (XIV). Finally, coupling of 4-vinylisoindoline (XIV) with N-Boc-trans-4-hydroxyproline methyl ester (XV), previously activated with CDI, in DMF at 60 °C results in carbamate (XVI) .
Alternatively, debenzylation of 2-benzyl-4-bromoisoindoline (XI) by means of ACE-Cl in chlorobenzene at 90 °C, followed by condensation of the deprotected isoindoline (XVII) with N-Boc-trans-4-hydroxyproline methyl ester (XV), previously treated with CDI, by means of DIEA in DMF at 50 °C furnishes carbamate (XVIII). Then, alkenylation of the aryl bromide (XVIII) with potassium vinyltrifluoroborate (XIX) and Et3N in refluxing EtOH affords the vinyl isoindoline derivative (XVI) .
Finally, Boc-deprotection of proline derivative (XVI) by means of HCl in dioxane gives the corresponding amine (XX), which is then coupled with the L-tert-leucine carbamate derivative (XXI) in the presence of EDC, DIEA and HOAt or HOBt in DMF to yield the building block diene (I) .
The L-tert-leucine carbamate (XXI) is prepared by alkylation of ethyl isobutyrate (XXII) with 4-bromo-1-butene (XXIII) and LDA in HMPA, followed by ester group reduction with LiAlH4 in Et2O, affording 2,2-dimethyl-5-hexen-1-ol (XXIV) . After treatment of hexenol (XXIV) with triphosgene by means of DIEA and NaOH in 1,4-dioxane, the resulting chloroformate is condensed with L-tert-leucine (XXV) to give carbamate (XXI) .

参考文献中间体

合成目标

【1】 Holloway, M.K., Liverton, N.J., Ludmerer, S.W. et al. (Merck & Co., Inc.). HCV NS3 protease inhibitors. EP 1910404, EP 924593, JP 2009502793, US 2007027071, WO 2007015787, WO 2007015855.
【2】 McCauley, J.A., McIntyre, C.J., Rudd, M.T. et al. Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor. J Med Chem 2010, 53(6): 2443-63.

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)	69055	(3S,5R)-1-(2-((((2,2-dimethylhex-5-en-1-yl)oxy)carbonyl)amino)-3,3-dimethylbutanoyl)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-vinylisoindoline-2-carboxylate		C₃₂H₄₅N₃O₇	详情	详情
(IX)	69063	3-bromo-o-xylene;2,3-Dimethylbromobenzene;3-Bromo-1,2-dimethylbenzene	576-23-8	C₈H₉Br	详情	详情
(X)	69064	1-bromo-2,3-bis(bromomethyl)benzene		C₈H₇Br₃	详情	详情
(XI)	69065	2-benzyl-4-bromoisoindoline		C₁₅H₁₄BrN	详情	详情
(XII)	24920	tributyl(vinyl)stannane；Tributylvinylstannane;Vinyltributylstannane	7486-35-3	C₁₄H₃₀Sn	详情	详情
(XIII)	69066	2-benzyl-4-vinylisoindoline		C₁₇H₁₇N	详情	详情
(XIV)	69067	4-vinylisoindoline		C₁₀H₁₁N	详情	详情
(XV)	15780	1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate		C₁₁H₁₉NO₅	详情	详情
(XVI)	69070	(2S,4S)-1-tert-butyl 2-methyl 4-((4-vinylisoindoline-2-carbonyl)oxy)pyrrolidine-1,2-dicarboxylate		C₂₂H₂₈N₂O₆	详情	详情
(XVII)	69068	4-bromoisoindoline hydrochloride;3-Bromo-1H-isoindoline Hydrochloride;4-Bromo-1H-isoindoline hydrochloride;4-Bromo-2,3-dihydro-1H-isoindole hydrochloride	923590-95-8	C₈H₈BrN.HCl	详情	详情
(XVIII)	69071	(2S,4S)-1-tert-butyl 2-methyl 4-((4-bromoisoindoline-2-carbonyl)oxy)pyrrolidine-1,2-dicarboxylate		C₂₀H₂₅BrN₂O₆	详情	详情
(XIX)	69072	potassium vinyltrifluoroborate;potassium trifluoro(vinyl)borate		C₂H₃BF₃K	详情	详情
(XX)	69069	(3S,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-vinylisoindoline-2-carboxylate hydrochloride		C₁₇H₂₀N₂O₄.HCl	详情	详情
(XXI)	69073	2-((((2,2-dimethylhex-5-en-1-yl)oxy)carbonyl)amino)-3,3-dimethylbutanoic acid		C₁₅H₂₇NO₄	详情	详情
(XXII)	28650	ethyl 2-methylpropanoate；ethyl isobutyrate	97-62-1	C₆H₁₂O₂	详情	详情
(XXIII)	11720	4-Bromo-1-butene	5162-44-7	C₄H₇Br	详情	详情
(XXIV)	69074	2,2-dimethyl-5-hexen-1-ol		C₈H₁₆O	详情	详情
(XXV)	69075	(S)-2-amino-3,3-dimethylbutanoic acid;L-tert-leucine;L-2-Amino-3,3-dimethylbutanoic acid	20859-02-3	C₆H₁₃NO₂	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 ethyl isobutyrate (I) with ethanal and trimethylsilylamine in THF gives the azetidinone (III), which is treated with 4-cyanobenzoic acid succinimidyl ester (IV) in DMF yielding 3-(4-cyanobenzamido)-2,2-dimethylnonanoic acid (V). Finally, this compound is condensed with L-phenylalanine ethyl ester (VI) by means of DEC and HOBT in dichloromethane.

参考文献中间体

合成目标

【1】 Iijima, K.; Katada, J.; Yasuda, E.; Uno, I.; Hayashi, Y.; N-[2,2-Dimethyl-3-(N-(4-cyanobenzoyl)amino)nonanoyl]-L-phenylalanine ethyl ester as a stable ester-type inhibitor of chymotrypsin-like serine proteases: Structural requirements for potent inhibition of alpha-chymotrypsin. J Med Chem 1999, 42, 2, 312.

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)	28650	ethyl 2-methylpropanoate；ethyl isobutyrate	97-62-1	C₆H₁₂O₂	详情	详情
(II)	28655	Enanthic aldehyde; 1-Heptanal; Heptaldehyde; Oenanthol; Oenanthaldehyde; Enanthal; Oenanthal; Heptyl aldehyde; n-Heptaldehyde; Enanthaldehyde; Enanthole; 1-Heptaldehyde; Heptanaldehyde; n-Heptanal; Oenanthic aldehyde; n-Heptylaldehyde; Heptanal	111-71-7	C₇H₁₄O	详情	详情
(III)	28651	4-hexyl-3,3-dimethyl-2-azetidinone		C₁₁H₂₁NO	详情	详情
(IV)	28652	4-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]benzonitrile		C₁₂H₈N₂O₄	详情	详情
(V)	28653	3-[(4-cyanobenzoyl)amino]-2,2-dimethylnonanoic acid		C₁₉H₂₆N₂O₃	详情	详情
(VI)	28654	(2S)-3-ethoxy-1-phenyl-3-buten-2-amine		C₁₂H₁₇NO	详情	详情

Extended Information