methyl 2-(4-bromophenyl)acetate -Drug Synthesis Database

【结构式】

【分子编号】16992

【品名】methyl 2-(4-bromophenyl)acetate

【CA登记号】41841-16-1

【分子式】C₉H₉BrO₂

【分子量】229.07326

【元素组成】C 47.19% H 3.96% Br 34.88% O 13.97%

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：(XI)

Tritium-labeled RS-25259-197 can be obtained by the reaction of methyl 4-bromophenylacetate (XI) with methyl chloroformate (XII) by means of lithium diisopropylamide (LDA) in THF, giving the malonic ester (XIII), which is condensed with methyl acrylate (XIV) by means of Na in methanol to yield the tricarboxylic ester (XV). The decarboxylative hydrolysis of (XV) first with NaOH and finally in acidic medium (HCl) affords 2-(4-bromophenyl)glutaric acid (XVI), which is cyclized with hot polyphosphoric acid (PPA) to give 6-bromo-4-oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (XVII). The reduction of (XVII) with NaBH4 in isopropanol yields the corresponding hydroxy acid (XVIII), which is dehydrated with p-toluenesulfonic acid to the lactone (XIX). Isomerization of (XIX) with H3PO4 in THF affords 6-bromo-1,2-dihydronaphthalene-1-carboxylic acid (XX), which is condensed with quinuclidin-3(S)-ylamine (III) by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in acetonitrile to give the corresponding amide as a mixture of diastereomers that is resolved by chromatography and crystallization in order to obtain the (S,S)-isomer (XXI). The hydrogenation of (XXI) with tritium (3H2) and Pd/C in ethyl acetate affords (S,S)-N-(3-quinuclidinyl)-3,4,7-tri-3H-1,2,3,4-tetrahydronaphthalene-1-carboxamide (XXII), which is reduced with the complex borane.dimethylsulfide to the corresponding amine (XXIII). Finally, this compound is cyclized with trichloromethyl chloroformate (diphosgene) in refluxing toluene.

参考文献中间体

合成目标

【1】 Graul, A.; Castañer, J.; RS-25259-197. Drugs Fut 1996, 21, 9, 906.
【2】 Gong, L.; Parnes, H.; Synthesis of the 3H-labelled 5-HT3 antagonist (RS-25259-197) at high specific activity. J Label Compd Radiopharm 1996, 38, 5, 425.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	16984	(3S)-1-azabicyclo[2.2.2]octan-3-amine; 1-aza-Bicyclo[2.2.2]oct-3-ylamine; (3S)-1-azabicyclo[2.2.2]oct-3-ylamine	120570-05-0	C₇H₁₄N₂	详情	详情
(XI)	16992	methyl 2-(4-bromophenyl)acetate	41841-16-1	C₉H₉BrO₂	详情	详情
(XII)	16993	methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate	79-22-1	C₂H₃ClO₂	详情	详情
(XIII)	16994	dimethyl 2-(4-bromophenyl)malonate		C₁₁H₁₁BrO₄	详情	详情
(XIV)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(XV)	16996	trimethyl 1-(4-bromophenyl)-1,1,3-propanetricarboxylate		C₁₅H₁₇BrO₆	详情	详情
(XVI)	16997	2-(4-bromophenyl)pentanedioic acid		C₁₁H₁₁BrO₄	详情	详情
(XVII)	16998	6-bromo-4-oxo-1,2,3,4-tetrahydro-1-naphthalenecarboxylic acid		C₁₁H₉BrO₃	详情	详情
(XVIII)	16999	6-bromo-4-hydroxy-1,2,3,4-tetrahydro-1-naphthalenecarboxylic acid		C₁₁H₁₁BrO₃	详情	详情
(XIX)	17000	5-bromo-9-oxatricyclo[6.2.2.0(2,7)]dodeca-2,4,6-trien-10-one		C₁₁H₉BrO₂	详情	详情
(XX)	17001	6-bromo-1,2-dihydro-1-naphthalenecarboxylic acid		C₁₁H₉BrO₂	详情	详情
(XXI)	17002	(1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-dihydro-1-naphthalenecarboxamide		C₁₈H₂₁BrN₂O	详情	详情
(XXII)	17003	(1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2,3,4-tetrahydro-1-naphthalenecarboxamide		C₁₈H₂₄N₂O	详情	详情
(XXII)	45319	(1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2,3,4-tetrahydro-1-naphthalenecarboxamide		C₁₈H₂₄N₂O	详情	详情
(XXIII)	17004	(3S)-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]-1-azabicyclo[2.2.2]octan-3-amine; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]amine		C₁₈H₂₆N₂	详情	详情
(XXIII)	45320	N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]amine; (3S)-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]-1-azabicyclo[2.2.2]octan-3-amine		C₁₈H₂₆N₂	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 2-(4-bromophenyl)acetic acid methyl ester (I) with 2-(trimethylstannyl)pyridine (II) by means of Pd(PPh3)4 in refluxing toluene gives 2-[4-(2-pyridyl)phenyl]acetic acid methyl ester (III), which is hydrolyzed with KOH in THF/water to yield the corresponding acetic acid (IV). Finally, this compound is condensed with 4-methyl-2-(methylamino)thiazole-5-sulfonamide (V) by means of HOBt and DEC in DMF to afford the target phenylacetamide. The intermediate 4-methyl-2-(methylamino)thiazole-5-sulfonamide (V) is obtained as follows: the reaction of 1-chloroacetone (VI) with KSCN in water gives the corresponding thiocyanato (VII), which is cyclized by means of dry HCl in dichloromethane to yield 2-chloro-4-methylthiazole (VIII). The reaction of (VIII) with Cl-SO3H and SOCl2 affords the sulfonyl chloride (IX), which is treated with ammonia in THF/water to provide 2-chloro-4-methylthiazole-5-sulfonamide (X). Finally, this compound is treated with methylamine in acetonitrile to obtain the target sulfonamide intermediate (V).

参考文献中间体

合成目标

【1】 Fischer, R.; Bender, W.; Henninger, K.; Eckenberg, P.; Handke, G.; Keldenich, J.; Weber, O.; Kleymann, G.; Betz, U.; Hendrix, M.; Schneider, U.; Jensen, A.; Baumeister, J. (Bayer AG); Thiazolyl amide derivs.. DE 19962532; WO 0147904 .
【2】 Fischer, R.; Bender, W.; Henninger, K.; Eckenberg, P.; Handke, G.; Keldenich, J.; Weber, O.; Kleymann, G.; Betz, U.; Hendrix, M.; Schneider, U.; Jensen, A.; Baumeister, J.; Hewlett, G.; Pevzner, V. (Bayer AG); Incompetitive inhibitors of helicase primase. DE 10044353; WO 0220014 .

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)	16992	methyl 2-(4-bromophenyl)acetate	41841-16-1	C₉H₉BrO₂	详情	详情
(II)	55389	2-Pyridyltrimethyltin; Trimethyl(2-pyridyl)tin	13737-05-8	C₈H₁₃NSn	详情	详情
(III)	55390	methyl 2-[4-(2-pyridinyl)phenyl]acetate		C₁₄H₁₃NO₂	详情	详情
(IV)	55391	2-[4-(2-pyridinyl)phenyl]acetic acid		C₁₃H₁₁NO₂	详情	详情
(V)	55392	4-methyl-2-(methylamino)-1,3-thiazole-5-sulfonamide		C₅H₉N₃O₂S₂	详情	详情
(VI)	15288	1-Chloroacetone; Chloroacetone	78-95-5	C₃H₅ClO	详情	详情
(VII)	55393	2-oxo-1-propanesulfenyl cyanide		C₄H₅NOS	详情	详情
(VIII)	55394	2-chloro-4-methyl-1,3-thiazole		C₄H₄ClNS	详情	详情
(IX)	55395	2-chloro-4-methyl-1,3-thiazole-5-sulfonyl chloride		C₄H₃Cl₂NO₂S₂	详情	详情
(X)	55396	2-chloro-4-methyl-1,3-thiazole-5-sulfonamide		C₄H₅ClN₂O₂S₂	详情	详情

Extended Information