CB-300907, -Drug Synthesis Database

【结构式】

【药物名称】CB-300907

【化学名称】4(R)-[N-[4-[N-(2-Methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)-N-(2-propynyl)amino]benzoyl]-L-gamma-glutamylamino]-4-(1H-tetrazol-5-yl)butyric acid
　　　　　　N5-[3-Carboxy-1(R)-(1H-tetrazol-5-yl)propyl]-N2-[4-[N-(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)-N-(2-propynyl)amino]benzoyl]-L-glutamine

【CA登记号】174488-18-7

【分子式】C₃₂H₃₃N₉O₇

【分子量】655.67591

【开发单位】AstraZeneca (Originator), BTG (Originator)

【药理作用】Oncolytic Drugs, Antimetabolites, Thymidylate Synthase Inhibitors

合成路线1 合成路线2

合成路线1

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

【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

N-(Benzyloxycarbonyl)-D-glutamic acid (XIV) was converted to the mixed anhydride (XV) with isobutyl chloroformate and then treated with ammonia to give amide (XVI). Dehydration of the amide with POCl3/pyridine produced nitrile (XVII) and further dipolar cycloaddition of NaN3 produced the tetrazole (XVIII). After hydrogenolysis of the benzyloxycarbonyl protecting group of (XVIII), the resulting amine (XIX) was coupled with N-(benzyloxycarbonyl)-L-glutamic acid (XX) via activation as the mixed anhydride with isobutyl chloroformate to give (XXI). The benzyloxycarbonyl group of (XXI) was then deprotected by catalytic hydrogenolysis over Pd/C as above, yielding amine (XXII). This was coupled with the intermediate benzoic acid derivative (XIII) employing benzotriazolyloxy-tris(pyrrolidino)phosphonium hexafluorophosphate to furnish amide (XXIII). The tert-butyl esters of (XXIII) were finally cleaved by treatment with trifluoroacetic acid.

参考文献中间体

【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
(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
(XIV)	41353	(2R)-2-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoic acid	3886-08-6	C₁₇H₂₃NO₆	详情	详情
(XV)	41354			C₂₂H₃₁NO₈	详情	详情
(XVI)	41355	tert-butyl (4R)-5-amino-4-[[(benzyloxy)carbonyl]amino]-5-oxopentanoate		C₁₇H₂₄N₂O₅	详情	详情
(XVII)	41356	tert-butyl (4R)-4-[[(benzyloxy)carbonyl]amino]-4-cyanobutanoate		C₁₇H₂₂N₂O₄	详情	详情
(XVIII)	41357	tert-butyl (4R)-4-[[(benzyloxy)carbonyl]amino]-4-(1H-1,2,3,4-tetraazol-5-yl)butanoate		C₁₇H₂₃N₅O₄	详情	详情
(XIX)	41358	tert-butyl (4R)-4-amino-4-(1H-1,2,3,4-tetraazol-5-yl)butanoate		C₉H₁₇N₅O₂	详情	详情
(XX)	41359	(4S)-4-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoic acid		C₁₇H₂₃NO₆	详情	详情
(XXI)	41360	tert-butyl (2S)-2-[[(benzyloxy)carbonyl]amino]-5-[[(1R)-4-(tert-butoxy)-4-oxo-1-(1H-1,2,3,4-tetraazol-5-yl)butyl]amino]-5-oxopentanoate		C₂₆H₃₈N₆O₇	详情	详情
(XXII)	41361	tert-butyl (2S)-2-amino-5-[[(1R)-4-(tert-butoxy)-4-oxo-1-(1H-1,2,3,4-tetraazol-5-yl)butyl]amino]-5-oxopentanoate		C₁₈H₃₂N₆O₅	详情	详情
(XXIII)	41362	tert-butyl (2S)-5-[[(1R)-4-(tert-butoxy)-4-oxo-1-(1H-1,2,3,4-tetraazol-5-yl)butyl]amino]-2-([4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)-5-oxopentanoate		C₄₀H₄₉N₉O₇	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)