ethyl 2-bromo-2-methylpropanoate -Drug Synthesis Database

【结构式】

【分子编号】39799

【品名】ethyl 2-bromo-2-methylpropanoate

【CA登记号】600-00-0

【分子式】C₆H₁₁BrO₂

【分子量】195.05614

【元素组成】C 36.95% H 5.68% Br 40.96% O 16.4%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(VIII)

Protected piperidone (I) is condensed with methoxybromobenzene (II) via Grignard reaction by means of Mg and catalytic iodine in refluxing THF, and the resulting alcohol is then dehydrated with refluxing HCl in dioxane to afford compound (III). Hydrogenation of tetrahydropyridine (III) over Pd/C in EtOH yields piperidine derivative (IV), which is then demethylated with aqueous HBr to provide phenol (V). Condensation of (V) with 4-fluorobenzoyl chloride (VI) by means of NaOH in iPrOH/MeOH/H2O furnishes N-benzoylpiperidine derivative (VII), which is converted into the desired product by reaction with ethyl 2-bromo-2-methylpropanoate (VIII) by means of K2CO3 followed by hydrolysis with NaOH in H2O/MeOH/dioxane.

参考文献中间体

合成目标

【1】 Komoto, T.; et al.; Preparation of new fibrates with piperidine ring and the pharmacological activity. 20th Symp Med Chem (Dec 6 2000, Tokyo) 2000, Abst 2P-06.
【2】 Komoto, T.; et al.; New strong fibrates with piperidine moiety. Chem Pharm Bull 2000, 48, 12, 1978.
【3】 Komoto, T.; Hirota, H.; Sato, S.; Othsuka, M.; Koya, H.; Mizuno, H.; Kuraishi, T. (SSP Co., Ltd.); Arylamide derivs.. EP 0607536; JP 1995053517; US 5411972 .

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)	15720	1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one	3612-20-2	C₁₂H₁₅NO	详情	详情
(II)	35983	m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether	2398-37-0	C₇H₇BrO	详情	详情
(III)	47137	1-benzyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine; 3-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)phenyl methyl ether		C₁₉H₂₁NO	详情	详情
(IV)	47138	4-(3-methoxyphenyl)piperidine; methyl 3-(4-piperidinyl)phenyl ether		C₁₂H₁₇NO	详情	详情
(V)	47139	3-(4-piperidinyl)phenol		C₁₁H₁₅NO	详情	详情
(VI)	17263	4-fluorobenzoyl chloride	403-43-0	C₇H₄ClFO	详情	详情
(VII)	47140	(4-fluorophenyl)[4-(3-hydroxyphenyl)-1-piperidinyl]methanone		C₁₈H₁₈FNO₂	详情	详情
(VIII)	39799	ethyl 2-bromo-2-methylpropanoate	600-00-0	C₆H₁₁BrO₂	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 benzoylation of tyramine (2-(p-hydroxyphenyl)ethylamine) (I) with 4-chlorobenzoyl chloride (II) in pyridine gives 4-(4-chlorobenzoylaminoethyl)phenol (III), which by condensation with ethyl alpha-bromoisobutyrate (IV) by means of K2CO3 in refluxing butanone affords ethyl alpha-[4-(4-chlorobenzoylaminoethyl)phenoxy]isobutyrate (V). Finally, this compound is hydrolyzed with KOH in dioxane - water.

参考文献中间体

合成目标

【1】 Castañer, J.; Thorpe. P.; Bezafibrate. Drugs Fut 1978, 3, 4, 258.
【2】 Witte, E.C.; et al. (Boehringer Ingelheim GmbH); Phenoxyalkylcarbosaurederivate und Verfahren zur Herstellung derselben. DE 2149070; ZA 7206638 .

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)	10295	p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride	122-01-0	C₇H₄Cl₂O	详情	详情
(II)	19988	4-(2-Aminoethyl)phenol; Tyramine	51-67-2	C₈H₁₁NO	详情	详情
(III)	39798	4-chloro-N-(4-hydroxyphenethyl)benzamide	41859-57-8	C₁₅H₁₄ClNO₂	详情	详情
(IV)	39799	ethyl 2-bromo-2-methylpropanoate	600-00-0	C₆H₁₁BrO₂	详情	详情
(V)	39800	ethyl 2-(4-[2-[(4-chlorobenzoyl)amino]ethyl]phenoxy)-2-methylpropanoate		C₂₁H₂₄ClNO₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Alkylation of 2,4-dinitrothiophenol (I) with 2-bromoisobutyrate (II) and K2CO3 in DMF yields thioether (III), which is then subjected to reduction with Fe/HCl in EtOH/H2O, followed by ring closure with refluxing NaOH, to give benzothiazine derivative (IV). Conversion of amino compound (IV) into nitro derivative (V) is then performed via Sandmeyer reaction by first treatment with NaNO2/H2SO4 in H2O, followed by reaction with NaHCO3, NaNO2, CuSO4 and Cu2O in H2O. N-Alkylation of (V) with chloroacetone (VI) and K2CO3 in DMF provides (VII), which is finally converted into the target compound by reduction with BH3-THF complex in THF, followed by Swern oxidation with DMSO and oxalyl chloride in CH2Cl2.

参考文献中间体

合成目标

【1】 Yoden, T.; Matsuhisa, A.; Yamagiwa, Y.; Nohira, H.; Tsuzuki, R.; Yanagisawa, I.; Matsumoto, Y.; Shibanuma, T.; Novel potassium channel openers. Part 4: Transformation of the 1,4-benzoxazine skeleton into 1,4-benzothiazine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroquinoxaline, indoline, and 1,5-benzoxazepine. Bioorg Med Chem 2000, 8, 2, 393.

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)	45972	2,4-dinitrobenzenethiol; 2,4-dinitrophenylhydrosulfide		C₆H₄N₂O₄S	详情	详情
(II)	39799	ethyl 2-bromo-2-methylpropanoate	600-00-0	C₆H₁₁BrO₂	详情	详情
(III)	45973	ethyl 2-[(2,4-dinitrophenyl)sulfanyl]-2-methylpropanoate		C₁₂H₁₄N₂O₆S	详情	详情
(IV)	45974	6-amino-2,2-dimethyl-2H-1,4-benzothiazin-3(4H)-one		C₁₀H₁₂N₂OS	详情	详情
(V)	45975	2,2-dimethyl-6-nitro-2H-1,4-benzothiazin-3(4H)-one		C₁₀H₁₀N₂O₃S	详情	详情
(VI)	15288	1-Chloroacetone; Chloroacetone	78-95-5	C₃H₅ClO	详情	详情
(VII)	45976	2,2-dimethyl-6-nitro-4-(2-oxopropyl)-2H-1,4-benzothiazin-3(4H)-one		C₁₃H₁₄N₂O₄S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(III)

In an alternative method, 4-(4-methoxyphenyl)butyric acid (I) is demethylated to phenol (II) by heating at 190 C with pyridine hydrochloride. Alkylation of phenol (II) with ethyl 2-bromoisobutyrate (III) gives ether (IV). The carboxyl group of (IV) is then activated as the corresponding acid chloride (V) by treatment with oxalyl chloride in the presence of DMF.

参考文献中间体

合成目标

【1】 Braden, T.; et al.; Novel acid-catalyzed synthesis of triazolones from acyl semicarbazides. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 381.
【2】 Perixosome proliferator activated receptor alpha agonists. WO 0238553 .

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)	57587	4-(4-Methoxyphenyl)butyric acid		C₁₁H₁₄O₃	详情	详情
(II)	57588	4-(4-hydroxyphenyl)butanoic acid		C₁₀H₁₂O₃	详情	详情
(III)	39799	ethyl 2-bromo-2-methylpropanoate	600-00-0	C₆H₁₁BrO₂	详情	详情
(IV)	57589	4-[4-(2-ethoxy-1,1-dimethyl-2-oxoethoxy)phenyl]butanoic acid		C₁₆H₂₂O₅	详情	详情
(V)	57590	ethyl 2-[4-(4-chloro-4-oxobutyl)phenoxy]-2-methylpropanoate		C₁₆H₂₁ClO₄	详情	详情

合成路线5

该中间体在本合成路线中的序号：(XXVIII)

Two procedures have been reported for the synthesis of the intermediate 2-methyl-2-[5-(trifluoromethyl)pyridin-2-yloxy]propionic acid (I). 2-Chloro-5-(trifluoromethyl)pyridine (XXIII) is coupled with lithium lactate (XXIV) employing NaH in hot DMF to produce the 2-(pyridyloxy)propionic acid (XXV). After esterification of acid (XXV) with trimethylsilyldiazomethane in MeOH/CH2Cl2, the resulting methyl ester is alkylated with iodomethane and sodium hexamethyldisilazide to furnish the (pyridyloxy)isobutyrate (XXVI). Subsequent hydrolysis of methyl ester (XXVI) with NaOH in H2O/MeOH/THF provides the target carboxylic acid intermediate (I) (1). Alternatively, the condensation of 2-hydroxy-5-(trifluoromethyl)pyridine (XXVII) with ethyl 2-bromoisobutyrate (XXVIII) in the presence of cesium carbonate provides the 2-(pyridyloxy)isobutyrate ester (XXIX), which is hydrolyzed to the corresponding carboxylic acid (I) by means of NaOH in acetonitrile/water (2, 3). Scheme 3.

参考文献中间体

合成目标

【1】 Hagmann, W.K., Lin, L.S., Shah, S.K. et al. (Merck & Co., Inc.). Substituted amides. CA 2478183, EP 1496838, JP 2005519958, JP 2006257090, US 2004058820, US 6972295, WO 03077847.
【2】 Hagmann, W.K., Lin, L.S., Shah, S.K. et al. (Merck & Co., Inc.). Substituted amides active at the cannabinoid-1 receptor. WO 2004048317.
【3】 Lin, L.S., Lanza, T.J. Jr., Jewell, J.P. et al. Discovery of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. J Med Chem 2006, 49(26): 7584-7.

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)	65585	2-Methyl-2-[[5-(Trifluoromethyl)-2-Pyridinyl]Oxy]Propanoic Acid	605680-62-4	C₁₀H₁₀F₃NO₃	详情	详情
(XXIII)	59113	2-Chloro-5-(trifluoromethyl)pyridine; 5-Trifluoromethyl-2-chloropyridine	52334-81-3	C₆H₃ClF₃N	详情	详情
(XXIV)	65604	Lithium Lactate	16891-53-5	C₃H₅LiO₃	详情	详情
(XXV)	65605			C₉H₈F₃NO₃	详情	详情
(XXVI)	65606			C₁₁H₁₂F₃NO₃	详情	详情
(XXVII)	65607	2-Hydroxy-5-trifluoromethylpyridine; 5-(Trifluoromethyl)pyridin-2-ol	33252-63-0	C₆H₄F₃NO	详情	详情
(XXVIII)	39799	ethyl 2-bromo-2-methylpropanoate	600-00-0	C₆H₁₁BrO₂	详情	详情
(XXIX)	65608	2-Methyl-2-[[5-(Trifluoromethyl)-2-Pyridinyl]Oxy]-Propanoic Acid Ethyl Ester	913849-17-9	C₁₂H₁₄F₃NO₃	详情	详情

Extended Information