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【结 构 式】 
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【药物名称】KF-31327 【化学名称】3-Ethyl-8-[2-[4-(hydroxymethyl)piperidin-1-yl]benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]quinazoline-2-thione dihydrochloride 【CA登记号】204077-66-7 【 分 子 式 】C24H30Cl2N6OS 【 分 子 量 】521.5163 |
【开发单位】Kyowa Hakko (Originator) 【药理作用】Antiplatelet Therapy, CARDIOVASCULAR DRUGS, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Hypertension, Treatment of, Phosphodiesterase V (PDE5A) Inhibitors |
合成路线1
The condensation between 2-fluorobenzonitrile (I) and ethyl isonipecotate (II) produced the piperidino benzonitrile (III). Reduction of nitrile and ester functions of (III) to afford the intermediate amino alcohol (IV) was accomplished using either LiAlH4 or, in a more practical, scalable procedure, using NaBH4/ZnCl2.
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 41199 | 2-fluorobenzonitrile | 394-47-8 | C7H4FN | 详情 | 详情 |
| (II) | 17410 | Ethyl isonipecotate; ethyl 4-piperidinecarboxylate | 1126-09-6 | C8H15NO2 | 详情 | 详情 |
| (III) | 54824 | ethyl 1-(2-cyanophenyl)-4-piperidinecarboxylate | C15H18N2O2 | 详情 | 详情 | |
| (IV) | 54825 | {1-[2-(aminomethyl)phenyl]-4-piperidinyl}methanol | C13H20N2O | 详情 | 详情 |
合成路线2
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3
In an improved procedure, commercial 7-chloroquinazolinedione (XII) was nitrated to (XIII) using 60% HNO3 in the presence of H2SO4. Subsequent chloro displacement in (XIII) with ethylamine in hot DMSO furnished nitro amine (XIV). Chlorination of quinazolinedione (XIV) to the dichloro derivative (XV) was carried out by means of POCl3 in the presence of diisopropylethylamine in hot toluene. The 4-chloro group of (XV) was regioselectively displaced by the intermediate benzylamine (IV) yielding (XVI). Simultaneous reduction of the nitro and chloro groups of (XVI) by transfer hydrogenation provided the phenylenediamine (XI). The imidazothione ring was finally constructed by condensation of (XI) with phenyl isothiocyanate.
| 【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. |
| 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 | |
| (XI) | 54829 | {1-[2-({[6-amino-7-(ethylamino)-4-quinazolinyl]amino}methyl)phenyl]-4-piperidinyl}methanol | C23H30N6O | 详情 | 详情 | |
| (XII) | 54830 | 7-chloro-2,4(1H,3H)-quinazolinedione | C8H5ClN2O2 | 详情 | 详情 | |
| (XIII) | 54831 | 7-chloro-6-nitro-2,4(1H,3H)-quinazolinedione | C8H4ClN3O4 | 详情 | 详情 | |
| (XIV) | 54832 | 7-(ethylamino)-6-nitro-2,4(1H,3H)-quinazolinedione | C10H10N4O4 | 详情 | 详情 | |
| (XV) | 54833 | N-(2,4-dichloro-6-nitro-7-quinazolinyl)-N-ethylamine; 2,4-dichloro-N-ethyl-6-nitro-7-quinazolinamine | C10H8Cl2N4O2 | 详情 | 详情 | |
| (XVI) | 54834 | {1-[2-({[2-chloro-7-(ethylamino)-6-nitro-4-quinazolinyl]amino}methyl)phenyl]-4-piperidinyl}methanol | C23H27ClN6O3 | 详情 | 详情 |