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【结 构 式】 
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【分子编号】31075 【品名】2-methyl-3,6,7,8-tetrahydro-4H-cyclopenta[g]quinazolin-4-one 【CA登记号】 |
【 分 子 式 】C12H12N2O 【 分 子 量 】200.24016 【元素组成】C 71.98% H 6.04% N 13.99% O 7.99% |
合成路线1
该中间体在本合成路线中的序号：(V)The reaction of indan-5-amine (I) with acetic anhydride gives the acetamide (II), which is brominated with Br2 in acetic acid yielding the 6-bromo derivative (III). The reaction of (III) with CuCN in 1-methyl-2-pyrrolidone at 125 C affords the corresponding nitrile (IV), which is cyclized by means of H2O2 and NaOH in hot ethanol/water giving the tricyclic ketone (V). The reaction of (V) with chloromethyl pivalate (A) and potassium tert-butoxide in DMSO yields the pivaloyloxymethyl derivative (VI), which is oxidized with CrO3 and tert-butyl peroxide in dichloromethane affording the diketone (VII) (after chromatographic separation of the undesired regioisomer). The condensation of (VII) with N-(4-aminobenzoyl)-Lglutamic acid diethyl ester (VIII) by means of TsOH in refluxing DME gives the imino derivative (IX), which without isolation, is reduced to the secondary amine (X) (as a diastereomeric mixture) with NaBH3CN in methanol/acetic acid. The alkylation of the secondary amine group of (X) with propargyl bromide (XI) and CaCO3 in hot DMA yields the tertiary amine (XII), which is hydrolyzed and deprotected with first with NaOH in methanol/water, and then with aqueous HCl to provide the target compound as a diastereomeric mixture. Finally, this compound is resolved by a treatment with carboxypeptidase G2 and ZnCl2 in water that hydrolyzes selectively the undesired isomer.
| 【1】 Bavetsias, V.; Matusiak, Z.; Melin, C.; Neidle, S.; Marriott, J.H.; Boyle, F.T.; Jackman, A.L.; Chemoenzymatic preparation of the novel antifolate thymidylate synthase inhibitor N-(4-{N-[(6S)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}-benzoyl)-L-glutamic acid and its glutamyl cleavage product. J Chem Soc - Perkins Trans I 1999, 11, 1495. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 16166 | chloromethyl pivalate | 18997-19-8 | C6H11ClO2 | 详情 | 详情 |
| (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) | 31077 | (2-methyl-4,6-dioxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate | C18H20N2O4 | 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) | 31079 | diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-ylidene)amino]benzoyl]amino)pentanedioate | C34H40N4O8 | 详情 | 详情 | |
| (X) | 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 | |
| (XI) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (XII) | 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 | |
| (XIII) | 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 |
合成路线2
该中间体在本合成路线中的序号：(V)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3
该中间体在本合成路线中的序号：(V)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 |