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【结 构 式】 
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【分子编号】52504 【品名】4-Chloro-2-aminobenzoic acid; 2-Amino-4-chlorobenzoic acid; 2-Carboxy-5-chloroaniline; 3-Amino-4-carboxy-1-chlorobenzene; 4-Chloroanthranilic acid 【CA登记号】89-77-0 |
【 分 子 式 】C7H6ClNO2 【 分 子 量 】171.58288 【元素组成】C 49% H 3.52% Cl 20.66% N 8.16% O 18.65% |
合成路线1
该中间体在本合成路线中的序号：(IX)The condensation of the chiral oxazolidinone (I) with 2,4-difluorophenacyl bromide (II) by means of NaHMDS in THF/Et2 O gives the chiral oxirane (III), which is treated with LiOH and H2O2 to eliminate the chiral auxiliary, yielding the carboxylic acid (IV). The cleavage of the oxirane ring of (IV) with 1,2,4-triazole (V) and NaH in hot DMF affords the chiral hydroxyacid (VI), which is submitted to Curtius rearrangement by means of DPPA in hot pyridine to provide the chiral oxazolidinone (VII). The cleavage of the oxazolidinone ring of (VII) by means of refluxing aq. HCl gives the chiral aminoalcohol (VIII), which is condensed with 2-amino-4-chlorobenzoic acid (IX) by means of DCC and HOBt to yield the corresponding amide (X). Finally, this compound is cyclized to the target quinazolinone by reaction with triethyl orthoformate in hot dioxane/NMP.
| 【1】 Bartroli, J.; et al.; Aldol condensation of Evans chiral enolates with acetophenones. Its application to the stereoselective synthesis of homochiral antifungal agents. J Org Chem 1995, 60, 10, 3000. |
| 【2】 Bartroli, J.; et al.; New azole antigungals. 3. Synthesis and antifungal activity of 3-substituted-4(3H)-quinazolinones. J Med Chem 1998, 41, 11, 1869. |
| 【3】 Bartrolí, J.; Turmo, E.; Anguita, M. (J. Uriach & Cía., SA); New pyrimidone derivs. with antifungal activity. EP 0783501; ES 2107376; ES 2120885; JP 1998508317; US 5807854; WO 9705130 . |
| 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) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (II) | 47646 | 2-bromo-1-(2,4-difluorophenyl)-1-ethanone | C8H5BrF2O | 详情 | 详情 | |
| (III) | 56711 | (4S)-4-benzyl-3-{(2R)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propanoyl}-1,3-oxazolidin-2-one | C21H19F2NO4 | 详情 | 详情 | |
| (IV) | 56712 | (2R)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propanoic acid | C11H10F2O3 | 详情 | 详情 | |
| (V) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (VI) | 56713 | (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoic acid | C13H13F2N3O3 | 详情 | 详情 | |
| (VII) | 56714 | (4R,5R)-5-(2,4-difluorophenyl)-4-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-oxazolidin-2-one | C13H12F2N4O2 | 详情 | 详情 | |
| (VIII) | 56715 | (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C12H14F2N4O | 详情 | 详情 | |
| (IX) | 52504 | 4-Chloro-2-aminobenzoic acid; 2-Amino-4-chlorobenzoic acid; 2-Carboxy-5-chloroaniline; 3-Amino-4-carboxy-1-chlorobenzene; 4-Chloroanthranilic acid | 89-77-0 | C7H6ClNO2 | 详情 | 详情 |
| (X) | 56716 | 2-amino-4-chloro-N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]benzamide | C19H18ClF2N5O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The Ullmann condensation between 2-chloro-5-nitrobenzoic acid (I) and 2-amino-4-chlorobenzoic acid (II) afforded the diaryl amine (III). Cyclization of (III) by treatment with POCl3 in refluxing xylene yielded a mixture of the desired acridine (IV) and minor amounts of its regioisomer (V). The isomeric mixture of acids (IV) and (V) was activated as the respective mixed anhydrides with ethyl chloroformate and subsequently condensed with N,N-dimethylethylenediamine (VI) to produce the corresponding amides. The required isomer (VII) was easily isolated from the mixture owing to its insolubility in the reaction solvent. Finally, the title pyrazoloacridine compound was prepared by condensation of (VII) with 2-(dimethylamino)ethyl hydrazine in 2-ethoxyethanol at 120 C.
| 【1】 Antonini, I.; et al.; Synthesis, antitumor cytotoxicity, and DNA-binding of novel N-5,2-Di(omega-aminoalkyl)-2,6-dihydropyrazolo[3,4,5-kl) acridine-5-carboxamides. J Med Chem 2001, 44, 20, 3329. |
| 【2】 Matelli, S.; Polucci, P.; Antonini, I. (Università degli Studi di Camerino); Pyrazolo-acridine derivs. having antitumour activity. WO 9906405 . |
| 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) | 10188 | 2-Chloro-5-nitrobenzoic acid | 2516-96-3 | C7H4ClNO4 | 详情 | 详情 |
| (II) | 52504 | 4-Chloro-2-aminobenzoic acid; 2-Amino-4-chlorobenzoic acid; 2-Carboxy-5-chloroaniline; 3-Amino-4-carboxy-1-chlorobenzene; 4-Chloroanthranilic acid | 89-77-0 | C7H6ClNO2 | 详情 | 详情 |
| (III) | 52505 | C14H9ClN2O6 | 详情 | 详情 | ||
| (IV) | 52506 | 1-chloro-7-nitro-9-oxo-9,10-dihydro-4-acridinecarboxylic acid | C14H7ClN2O5 | 详情 | 详情 | |
| (V) | 52507 | 6-chloro-2-nitro-9-oxo-9,10-dihydro-4-acridinecarboxylic acid | C14H7ClN2O5 | 详情 | 详情 | |
| (VI) | 14881 | N-(2-aminoethyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,2-ethanediamine; 2-Dimethylaminoethylamine | 108-00-9 | C4H12N2 | 详情 | 详情 |
| (VII) | 52508 | 1-chloro-N-[2-(dimethylamino)ethyl]-7-nitro-9-oxo-9,10-dihydro-4-acridinecarboxamide | C18H17ClN4O4 | 详情 | 详情 | |
| (VIII) | 41186 | N-(2-hydrazinoethyl)-N,N-dimethylamine; 2-hydrazino-N,N-dimethyl-1-ethanamine | C4H13N3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Quinazolinone (VI) was prepared by condensation of 4-chloroanthranilic acid (V) with hot formamide. Subsequent electrophilic nitration of (VI) provided the 6-nitroquinazolinone (VII) as the major regioisomer. Displacement of the 7-chloro of (VII) upon heating with ethylamine in a sealed tube gave rise to the nitro amine (VIII). The 4-chloroquinazoline derivative (IX) was then obtained by chlorination of (VIII) with phosphorus oxychloride. Condensation of (IX) with the intermediate benzylamine (IV) furnished adduct (X). The nitro group of (X) was then reduced by catalytic hydrogenation to yield the phenylenediamine derivative (XI). Finally, condensation of phenylenediamine (XI) with carbon disulfide in the presence of Et3N generated the target imidazoquinazoline, which was isolated as the dihydrochloride salt.
| 【1】 Fujino, K.; et al.; Development of a practical synthetic route of a PDE V inhibitor KF31327. Org Process Res Dev 2001, 5, 4, 426. |
| 【2】 Fujino, K.; et al.; Process development of a PDE V inhibitor KF31327. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst ORGN 612. |
| 【3】 Onoda, Y.; Nomoto, Y.; Ohno, T.; Yamada, K.; Ichimura, M. (Kyowa Hakko Kogyo Co., Ltd.); Imidazoquinazoline derivs.. EP 0863144; WO 9808848 . |
| 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) | 54825 | {1-[2-(aminomethyl)phenyl]-4-piperidinyl}methanol | C13H20N2O | 详情 | 详情 | |
| (V) | 52504 | 4-Chloro-2-aminobenzoic acid; 2-Amino-4-chlorobenzoic acid; 2-Carboxy-5-chloroaniline; 3-Amino-4-carboxy-1-chlorobenzene; 4-Chloroanthranilic acid | 89-77-0 | C7H6ClNO2 | 详情 | 详情 |
| (VI) | 50077 | 7-chloro-4(3H)-quinazolinone | C8H5ClN2O | 详情 | 详情 | |
| (VII) | 50078 | 7-chloro-6-nitro-4(3H)-quinazolinone | C8H4ClN3O3 | 详情 | 详情 | |
| (VIII) | 54826 | 7-(ethylamino)-6-nitro-4(3H)-quinazolinone | C10H10N4O3 | 详情 | 详情 | |
| (IX) | 54827 | 4-chloro-N-ethyl-6-nitro-7-quinazolinamine; N-(4-chloro-6-nitro-7-quinazolinyl)-N-ethylamine | C10H9ClN4O2 | 详情 | 详情 | |
| (X) | 54828 | {1-[2-({[7-(ethylamino)-6-nitro-4-quinazolinyl]amino}methyl)phenyl]-4-piperidinyl}methanol | C23H28N6O3 | 详情 | 详情 | |
| (XI) | 54829 | {1-[2-({[6-amino-7-(ethylamino)-4-quinazolinyl]amino}methyl)phenyl]-4-piperidinyl}methanol | C23H30N6O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)4-Chloroanthranilic acid (I) is acylated by butyryl chloride (II) in DMF to produce amide (III). This is then cyclized to the benzoxazinone (IV) upon heating with acetic anhydride. Condensation of (IV) with benzylamine (V) in refluxing chloroform, followed by treatment with NaOH in hot ethyleneglycol, gives rise to the quinazolinone (VI). Subsequent benzylic bromination of (VI) at the propyl side chain produces (VII). The bromide group of (VII) is then displaced with N,N-dimethyl-1,3-propanediamine (VIII) to furnish (IX). Finally, amine (IX) is acylated by 4-bromobenzoyl chloride (X) to afford the corresponding benzamide.
| 【1】 Chabala, J.C.; Morgans, D.J. Jr.; Feng, B.; Finer, J.T.; Bergnes, G.; Smith, W.W. (Cytokinetics, Inc.); Methods and compsns. utilizing quinazolinones. WO 0198278 . |
| 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) | 52504 | 4-Chloro-2-aminobenzoic acid; 2-Amino-4-chlorobenzoic acid; 2-Carboxy-5-chloroaniline; 3-Amino-4-carboxy-1-chlorobenzene; 4-Chloroanthranilic acid | 89-77-0 | C7H6ClNO2 | 详情 | 详情 |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 58445 | 2-(butyrylamino)-4-chlorobenzoic acid | C11H12ClNO3 | 详情 | 详情 | |
| (IV) | 58446 | 7-chloro-2-propyl-4H-3,1-benzoxazin-4-one | C11H10ClNO2 | 详情 | 详情 | |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 58447 | 3-benzyl-7-chloro-2-propyl-4(3H)-quinazolinone | C18H17ClN2O | 详情 | 详情 | |
| (VII) | 58448 | 3-benzyl-2-(1-bromopropyl)-7-chloro-4(3H)-quinazolinone | C18H16BrClN2O | 详情 | 详情 | |
| (VIII) | 25248 | N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine | 109-55-7 | C5H14N2 | 详情 | 详情 |
| (IX) | 58449 | 3-benzyl-7-chloro-2-(1-{[3-(dimethylamino)propyl]amino}propyl)-4(3H)-quinazolinone | C23H29ClN4O | 详情 | 详情 | |
| (X) | 45960 | 4-bromobenzoyl chloride | 586-75-4 | C7H4BrClO | 详情 | 详情 |