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【结 构 式】 
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【药物名称】BI-6727;Volasertib 【化学名称】trans-N-[4-[4-(Cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-4-[7(R)-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino]-3-methoxybenzamide 【CA登记号】755038-65-4；946161-17-7 (as trihydrochloride) 【 分 子 式 】C34H50N8O3 【 分 子 量 】618.8126 |
【开发单位】Boehringer Ingelheim (DE) 【药理作用】Serine/Threonine-Protein Kinase PLK1 Inhibitor；Oncolytic |
合成路线1
3-Methoxy-4-nitrobenzoic acid (I) is chlorinated using SOCl2 in the presence of DMF or pyridine in refluxing toluene to yield the benzoyl chloride (II) , which is then coupled with trans-4-aminocyclohexanol (III) by means of K2CO3 in THF to provide amide (IV). Subsequent oxidation of the secondary alcohol group in compound (IV) by means of RuCl3 and NMMO in refluxing acetonitrite leads to the cyclohexanone (V), which, after condensation with N-(cyclopropylmethyl)piperazine (VI) in the presence of MsOH in refluxing toluene, is reduced to the cyclohexyl piperazine (VII) using NaBH4 in EtOH (1, 2). Reduction of the nitro group in compound (VII) by catalytic hydrogenation over Raney-Ni results in amine (VIII) ,which is finally condensed with 2-chloro-7-ethyl-7,8-dihydro-8-isopropyl-5-methylpteridin-6-one (IX) in the presence of p-TsOH·H2O in refluxing i-AmOH .
| 【1】 Grauert, M., Linz, G., Schmid, R., Sieger, P. (Boehringer Ingelheim Pharma GmbH & Co. KG). Trihydrochloride forms of a dihydropteridinone derivative and process for preparation. WO 2007090844. |
| 【2】 Linz, G., Kraemer, G.F., Gutschera, L., Asche, G. (Boehringer Ingelheim International GmbH). Method for the production of dihydropteridinones. WO 2006018220. |
| 【3】 Schnaubelt, J., Herter, R. (Boehringer Ingelheim International GmbH). Process for manufacturing dihydropteridinones and intermediates thereof. WO 2012049153. |
| 【4】 Linz, G., Sieger, P., Schmid, R., Goepper, S. (Boehringer International GmbH). Crystalline form of a dihydropteridinone derivative. WO 2009019205. |
| 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) | 21085 | 3-methoxy-4-nitrobenzoic acid；4-Nitro-3-methoxybenzoic acid | 5081-36-7 | C8H7NO5 | 详情 | 详情 |
| (II) | 21086 | 3-methoxy-4-nitrobenzoyl chloride | C8H6ClNO4 | 详情 | 详情 | |
| (III) | 68529 | trans-4-aminocyclohexanol；trans-4-Hydroxycyclohexylamine；trans-4-Amino-1-cyclohexanol;trans-1-Amino-4-cyclohexanol;4-trans-Hydroxycyclohexylamine;trans-1,4-Cyclohexanolamine | 27489-62-9 | C6H13NO | 详情 | 详情 |
| (IV) | 68530 | C14H18N2O5 | 详情 | 详情 | ||
| (V) | 68531 | 3-methoxy-4-nitro-N-(4-oxocyclohexyl)benzamide | C14H16N2O5 | 详情 | 详情 | |
| (VI) | 68532 | N-(cyclopropylmethyl)piperazine；1-(Cyclopropylmethyl)piperazine | 57184-25-5 | C8H16N2 | 详情 | 详情 |
| (VII) | 68533 | N-((1r,4r)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxy-4-nitrobenzamide | C22H32N4O4 | 详情 | 详情 | |
| (VIII) | 68534 | 4-amino-N-(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide | C22H34N4O2 | 详情 | 详情 | |
| (IX) | 68535 | (R)-2-chloro-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one | C12H17ClN4O | 详情 | 详情 |
合成路线2
Esterification of (R)-2-aminobutyric acid (X) with MeOH by means of SOCl2 and trimethyl orthoformate, followed by reductive alkylation of the resulting amino ester (XI) with acetone (XII) and NaBH(OAc)3, and treatment with HCl, gives methyl (R)-2-isopropylamino)butyrate hydrochloride (XIII). Basification of amino ester hydrochloride (XIII) with NaOH in cyclohexane/H2O, and subsequent condensation of the obtained free base with 2,4-dichloro-5-nitropyrimidine (XIV) in the presence of NaHCO3 in refluxing cyclohexane, yields the Npyrimidinyl amino ester (XV). Reductive cyclization of compound (XV) by catalytic hydrogenation in the presence of Pt/C and VO(acac)2 in THF gives pteridinone (XVI), which is finally methylated by heating with Me2CO3 in an autoclave in the presence of K2CO3 .
| 【1】 Grauert, M., Linz, G., Schmid, R., Sieger, P. (Boehringer Ingelheim Pharma GmbH & Co. KG). Trihydrochloride forms of a dihydropteridinone derivative and process for preparation. WO 2007090844. |
| 【2】 Linz, G., Sieger, P., Schmid, R., Goepper, S. (Boehringer International GmbH). Crystalline form of a dihydropteridinone derivative. WO 2009019205. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 68535 | (R)-2-chloro-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one | C12H17ClN4O | 详情 | 详情 | |
| (X) | 68536 | (R)-2-aminobutyric acid | C4H9NO2 | 详情 | 详情 | |
| (XI) | 68537 | (R)-methyl 2-aminobutanoate hydrochloride | C4H9NO2.HCl | 详情 | 详情 | |
| (XII) | 53313 | acetone | 67-64-1 | C3H6O | 详情 | 详情 |
| (XIII) | 68538 | (R)-methyl 2-(isopropylamino)butanoate hydrochloride;methyl (R)-2-isopropylamino)butyrate hydrochloride | C8H17NO2.HCl | 详情 | 详情 | |
| (XIV) | 68539 | 2,4-dichloro-5-nitropyrimidine | 49845-33-2 | C4HCl2N3O2 | 详情 | 详情 |
| (XV) | 68540 | (R)-methyl 2-((2-chloro-5-nitropyrimidin-4-yl)(isopropyl)amino)butanoate | C12H17ClN4O4 | 详情 | 详情 | |
| (XVI) | 68541 | (R)-2-chloro-7-ethyl-8-isopropyl-7,8-dihydropteridin-6(5H)-one | C11H15ClN4O | 详情 | 详情 |
合成路线3
Condensation of 4-acetamidocyclohexanone (XVII) with N-(cyclopropylmethyl)piperazine (VI) in refluxing toluene, optionally in the presence of MsOH , followed by reduction by means of NaBH4 or H2 over PtO2 in EtOH yields the trans-diaminocyclohexane derivative (XVIII) . Hydrolysis of acetamide (XVIII) using either boiling aqueous HCl or p-TsOH in H2O at 120 °C in a sealed reactor gives the corresponding cyclohexylamine trihydrochloride (XXa) or tritosylate salt (XXb) (1-3). Finally, compounds (XIXa) or (XIXb) are acylated with 3-methoxy-4-nitrobenzoyl chloride (II) in the presence of DIEA in THF or aqueous NaOH .
| 【1】 Grauert, M., Linz, G., Schmid, R., Sieger, P. (Boehringer Ingelheim Pharma GmbH & Co. KG). Trihydrochloride forms of a dihydropteridinone derivative and process for preparation. WO 2007090844. |
| 【2】 Linz, G., Kraemer, G.F., Gutschera, L., Asche, G. (Boehringer Ingelheim International GmbH). Method for the production of dihydropteridinones. WO 2006018220. |
| 【3】 Schnaubelt, J., Herter, R. (Boehringer Ingelheim International GmbH). Process for manufacturing dihydropteridinones and intermediates thereof. WO 2012049153. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIXa) | 68543 | 4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexanamine trihydrochloride | C14H27N3.3HCl | 详情 | 详情 | |
| (XIXb) | 68544 | 4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexanamine tris(4-methylbenzenesulfonate) | C14H27N3.3C7H8O3S | 详情 | 详情 | |
| (II) | 21086 | 3-methoxy-4-nitrobenzoyl chloride | C8H6ClNO4 | 详情 | 详情 | |
| (VI) | 68532 | N-(cyclopropylmethyl)piperazine；1-(Cyclopropylmethyl)piperazine | 57184-25-5 | C8H16N2 | 详情 | 详情 |
| (VII) | 68533 | N-((1r,4r)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxy-4-nitrobenzamide | C22H32N4O4 | 详情 | 详情 | |
| (XVII) | 11895 | N-(4-Oxocyclohexyl)acetamide | 27514-08-5 | C8H13NO2 | 详情 | 详情 |
| (XVIII) | 68542 | N-(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)acetamide | C16H29N3O | 详情 | 详情 |