3-bromo-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one -Drug Synthesis Database

【结构式】

【分子编号】31554

【品名】3-bromo-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one

【CA登记号】

【分子式】C₁₁H₁₁BrO

【分子量】239.11174

【元素组成】C 55.25% H 4.64% Br 33.42% O 6.69%

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：(XIII)

In an alternative synthesis, 2,4,6-triaminopyrimidine (VI) was condensed with bromomalonaldehyde (VII) under acidic conditions to give pyridopyrimidine (VIII), which was protected with pivaloyl anhydride in pyridine, yielding the bispivaloylamide (IX). Palladium-catalyzed Heck coupling of (IX) with styrene (X) afforded (XI). Subsequent ozonolysis of the styryl derivative (XI), followed by reductive workup with dimethyl sulfide gave aldehyde (XII). Reduction of (XII) to the corresponding alcohol with NaBH4, followed by bromination with PPh3 and Br2 provided bromide (XIII). The N-methyl aniline (XIV) was synthesized by direct alkylation of 3,4,5-trimethoxyaniline (IV) with methyl iodide. Nucleophilic displacement of the bromide (XIII) with aniline (XIV) afforded the tertiary amine (XV). The pivaloyl protecting groups of (XV) were finally removed by treatment with methanolic NaOMe.

参考文献中间体

合成目标

【1】 Gangjee, A.; et al.; Synthesis and dihydrofolate reductase inhibitory activities of 2,4-diamino-5-deaza and 2,4-diamino-5, 10-dideaza lipophilic antifolates. J Med Chem 1997, 40, 4, 470.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	31545	3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine；3,4,5-Trimethoxybenzenamine；[3,4,5-Tris(methyloxy)phenyl]amine	24313-88-0	C₉H₁₃NO₃	详情	详情
(VI)	28977	2,6-diamino-4-pyrimidinylamine	1004-38-2	C₄H₇N₅	详情	详情
(VII)	14278	2-Bromomalonaldehyde		C₃H₃BrO₂	详情	详情
(VIII)	31547	6-bromopyrido[2,3-d]pyrimidine-2,4-diamine; 2-amino-6-bromopyrido[2,3-d]pyrimidin-4-ylamine		C₇H₆BrN₅	详情	详情
(IX)	31548	N-[6-bromo-2-[(2,2-dimethylpropanoyl)amino]pyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide		C₁₇H₂₂BrN₅O₂	详情	详情
(X)	19649	1-vinylbenzene	100-42-5	C₈H₈	详情	详情
(XI)	31549	N-[2-[(2,2-dimethylpropanoyl)amino]-6-[(E)-2-phenylethenyl]pyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide		C₂₅H₂₉N₅O₂	详情	详情
(XII)	31550	N-[2-[(2,2-dimethylpropanoyl)amino]-6-formylpyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide		C₁₈H₂₃N₅O₃	详情	详情
(XIII)	31554	3-bromo-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one		C₁₁H₁₁BrO	详情	详情
(XIV)	31552	3,4,5-trimethoxy-N-methylaniline; N-methyl-N-(3,4,5-trimethoxyphenyl)amine		C₁₀H₁₅NO₃	详情	详情
(XV)	31553	N-(2-[(2,2-dimethylpropanoyl)amino]-6-[[3,4,5-trimethoxy(methyl)anilino]methyl]pyrido[2,3-d]pyrimidin-4-yl)-2,2-dimethylpropanamide		C₂₈H₃₈N₆O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Suzuki coupling of 3-bromo-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (I) with 4-methylphenylboronic acid (II) by means of palladium tetrakis(triphenylphosphine) gave (III). Subsequent refluxing of (III) with dimethyl carbonate in the presence of NaOMe afforded ketoester (IV). This was reduced with NaBH4 to give hydroxy ester (V), which was then dehydrated and hydrolyzed to the unsaturated acid (VI) with HCl in diglyme at 100 C. Alternatively, ketone (III) was carboxylated under CO2 atmosphere in the presence of either potassium carbonate or potassium tert-butoxide. The resulting ketoacid (VII) was reduced to hydroxyacid (VIII) with NaBH4, and then dehydrated to (VI) using 80% formic acid at 100 C. Carboxylic acid (VI) was then converted to the corresponding acid chloride (IX) by means of oxalyl chloride in CH2Cl2.

参考文献中间体

合成目标

【1】 Shiraishi, M.; Aramaki, Y.; Seto, M.; et al.; Discovery of small molecule CCR5 antagonists. 19th Symp Med Chem and 8th Annu Meet Div Med Chem Jpn (Nov 17-19, Tokyo) 1999, Abst 2P-06.
【2】 Kitayoshi, T.; Aramaki, Y.; Oda, T.; Honda, S.; Shiraishi, M. (Takeda Chemical Industries, Ltd.); Anilide deriv., production and use thereof. JP 1999263764; WO 9932468 .

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)	31554	3-bromo-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one		C₁₁H₁₁BrO	详情	详情
(II)	15540	4-methylphenylboronic acid; p-Tolylboronic acid	5720-05-8	C₇H₉BO₂	详情	详情
(III)	31555	3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one		C₁₈H₁₈O	详情	详情
(IV)	31556	ethyl 3-(4-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate		C₂₁H₂₂O₃	详情	详情
(V)	31557	ethyl 5-hydroxy-3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate		C₂₁H₂₄O₃	详情	详情
(VI)	31560	2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxylic acid		C₁₉H₁₈O₂	详情	详情
(VII)	31558	3-(4-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylic acid		C₁₉H₁₈O₃	详情	详情
(VIII)	31559	5-hydroxy-3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylic acid		C₁₉H₂₀O₃	详情	详情
(IX)	31561	2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carbonyl chloride		C₁₉H₁₇ClO	详情	详情

Extended Information