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【结 构 式】 
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【分子编号】41349 【品名】4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoic acid 【CA登记号】 |
【 分 子 式 】C22H19N3O3 【 分 子 量 】373.41128 【元素组成】C 70.76% H 5.13% N 11.25% O 12.85% |
合成路线1
该中间体在本合成路线中的序号：(XIII)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).
| 【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：(XIII)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.
| 【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 |
合成路线3
该中间体在本合成路线中的序号：(XIII)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).
| 【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 |
合成路线4
该中间体在本合成路线中的序号：(XIII)Benzoic acid derivative (XIII) was converted to pentafluorophenyl ester (XIV) by DCC-mediated coupling with pentafluorophenol. Then, condensation with tri-tert-butyl L-gamma-glutamyl-D-glutamate (XV) furnished the corresponding amide (XVI). The tert-butyl esters of (XVI) were finally cleaved by treatment with trifluoroacetic acid.
| 【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 |
|---|---|---|---|---|---|---|
| (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) | 41350 | 2,3,4,5,6-pentafluorophenyl 4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoate | C28H18F5N3O3 | 详情 | 详情 | |
| (XV) | 41351 | di(tert-butyl) (2R)-2-[[(4S)-4-amino-5-(tert-butoxy)-5-oxopentanoyl]amino]pentanedioate | C22H40N2O7 | 详情 | 详情 | |
| (XVI) | 41352 | di(tert-butyl) (2R)-2-[[(4S)-5-(tert-butoxy)-4-([4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)-5-oxopentanoyl]amino]pentanedioate | C44H57N5O9 | 详情 | 详情 |