(6-bromo-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate -Drug Synthesis Database

【结构式】

【分子编号】41348

【品名】(6-bromo-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate

【CA登记号】

【分子式】C₁₈H₂₁BrN₂O₃

【分子量】393.28042

【元素组成】C 54.97% H 5.38% Br 20.32% N 7.12% O 12.2%

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：(VII)

5-Aminoindan (I) was acetylated, and the resulting anilide (II) was brominated in HOAc to afford (III). Displacement of the bromine of (III) with CuCN in N-methylpyrrolidinone at 125 C furnished nitrile (IV), which was cyclized to the desired quinazolinone derivative (V) upon treatment with sodium hydroperoxide. Protection of the NH group of (V) was achieved by alkylation with chloromethyl pivaloate yielding (VI). Benzylic bromination of (VI) with N-bromosuccinimide in the presence of benzoyl peroxide gave bromide (VII). This was condensed with diethyl p-aminobenzoyl-L-glutamate (VIII) by means of CaCO3 to produce adduct (IX). Further alkylation of (IX) with propargyl bromide (X) using CaCO3 provided propargyl amine (XI). Hydrolysis of the ethyl esters and pivaloyloxymethyl protecting group of (XI) with NaOH afforded (XII). The glutamic acid moiety of (XII) was then removed by enzimatic hydrolysis with carboxypeptidase G2 to furnish intermediate (XIII).

参考文献中间体

合成目标

【1】 Bavetsias, V.; Boyle, F.T.; Hennequin, L.F.A.; Marriott, J.H. (AstraZeneca plc; BTG plc); Anti-cancer cpds. containing cyclopentaquinazoline ring. EP 0758328; GB 2290082; JP 1997512812; US 5747499; WO 9530673 .
【2】 Jackman, A.L.; Melin, C.; Bavetsias, V.; Matusiak, Z.S.; Marriott, J.H.; Kimbel, C.; Boyle, F.T.; Design and synthesis of cyclopenta[g]quinazoline-based antifolates as inhibitors of thymidylate synthase and potential antitumor agents. J Med Chem 2000, 43, 10, 1910.

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)	21473	5-indanamine; 2,3-dihydro-1H-inden-5-ylamine	24425-40-9	C₉H₁₁N	详情	详情
(II)	21474	N-(2,3-dihydro-1H-inden-5-yl)acetamide		C₁₁H₁₃NO	详情	详情
(III)	31073	N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide		C₁₁H₁₂BrNO	详情	详情
(IV)	31074	N-(6-cyano-2,3-dihydro-1H-inden-5-yl)acetamide		C₁₂H₁₂N₂O	详情	详情
(V)	31075	2-methyl-3,6,7,8-tetrahydro-4H-cyclopenta[g]quinazolin-4-one		C₁₂H₁₂N₂O	详情	详情
(VI)	31076	(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate		C₁₈H₂₂N₂O₃	详情	详情
(VII)	41348	(6-bromo-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate		C₁₈H₂₁BrN₂O₃	详情	详情
(VIII)	31078	diethyl (2S)-2-[(4-aminobenzoyl)amino]pentanedioate; Diethyl N-(4-aminobenzoyl)-L-glutamate	13726-52-8	C₁₆H₂₂N₂O₅	详情	详情
(IX)	31080	diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)amino]benzoyl]amino)pentanedioate		C₃₄H₄₂N₄O₈	详情	详情
(X)	11176	3-Bromopropyne; 3-Bromo-1-propyne	106-96-7	C₃H₃Br	详情	详情
(XI)	31081	diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioate		C₃₇H₄₄N₄O₈	详情	详情
(XII)	31082	(2S)-2-([4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioic acid		C₂₇H₂₆N₄O₆	详情	详情
(XIII)	41349	4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoic acid		C₂₂H₁₉N₃O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

参考文献中间体

合成目标

【1】 Boyle, F.; Crook, J.W.; Matusiak, Z.S. (AstraZeneca plc; BTG plc); Tricyclic cpds. with pharmaceutical activity. EP 0667864; GB 2272217; JP 1996505838; US 5789417; WO 9411354 .

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)	21473	5-indanamine; 2,3-dihydro-1H-inden-5-ylamine	24425-40-9	C₉H₁₁N	详情	详情
(II)	21474	N-(2,3-dihydro-1H-inden-5-yl)acetamide		C₁₁H₁₃NO	详情	详情
(III)	31073	N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide		C₁₁H₁₂BrNO	详情	详情
(IV)	31074	N-(6-cyano-2,3-dihydro-1H-inden-5-yl)acetamide		C₁₂H₁₂N₂O	详情	详情
(V)	31075	2-methyl-3,6,7,8-tetrahydro-4H-cyclopenta[g]quinazolin-4-one		C₁₂H₁₂N₂O	详情	详情
(VI)	31076	(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate		C₁₈H₂₂N₂O₃	详情	详情
(VII)	41348	(6-bromo-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate		C₁₈H₂₁BrN₂O₃	详情	详情
(VIII)	31078	diethyl (2S)-2-[(4-aminobenzoyl)amino]pentanedioate; Diethyl N-(4-aminobenzoyl)-L-glutamate	13726-52-8	C₁₆H₂₂N₂O₅	详情	详情
(IX)	31080	diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)amino]benzoyl]amino)pentanedioate		C₃₄H₄₂N₄O₈	详情	详情
(X)	11176	3-Bromopropyne; 3-Bromo-1-propyne	106-96-7	C₃H₃Br	详情	详情
(XI)	31081	diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioate		C₃₇H₄₄N₄O₈	详情	详情
(XII)	31082	(2S)-2-([4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioic acid		C₂₇H₂₆N₄O₆	详情	详情
(XIII)	41349	4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoic acid		C₂₂H₁₉N₃O₃	详情	详情

Extended Information