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【结 构 式】 
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【分子编号】26650 【品名】ethyl 7-[(3S,4S)-3-[(tert-butoxycarbonyl)(methyl)amino]-4-methoxypyrrolidinyl]-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate 【CA登记号】 |
【 分 子 式 】C25H31N5O6S 【 分 子 量 】529.61724 【元素组成】C 56.7% H 5.9% N 13.22% O 18.13% S 6.05% |
合成路线1
该中间体在本合成路线中的序号：(IX)The reaction of 2,6-dichloropyridine (I) with BuLi and CO2 in THF gives 2,6-dichloropyridine-3-carboxylic acid (II) (1), which by reaction with refluxing SOCl2 yields the acyl chloride (III). The reaction of (III) with malonic ester by means of magnesium ethoxide in ethyl ether affords the nicotinoylacetic ester (IV), which is condensed with thiazol-2-amine (V) and triethylorthoformate by means of acetic anhydride providing the nicotinoyl acrylate (VI). The cyclization of (VI) by means of K2CO3 in hot dioxane gives the 7-chloro-4-oxo-1-(2-thiazolyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (VII), which is condensed with the chiral pyrrolidine (VIII) by means of triethylamine yielding the proteted intermediate (IX). Finally, this compound is deprotected and hydrolyzed with hot aqueous HCl.
| 【1】 Tomita, K.; et al.; Synthesis and antitumor activity of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 249. |
| 【2】 Tomita, K.; Chiba, K.; Kashimoto, S.; Shibamori, K.; Tsuzuki, Y. (Dainippon Pharmaceutical Co., Ltd.); Novel cpd., process for producing the same, and antitumor agent. EP 0787726; US 5817669; WO 9534559 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 | |
| (I) | 13573 | 2,6-Dichloropyridine | 2402-78-0 | C5H3Cl2N | 详情 | 详情 |
| (II) | 26644 | 2,6-dichloronicotinic acid | 38496-18-3 | C6H3Cl2NO2 | 详情 | 详情 |
| (III) | 26645 | 2,6-dichloronicotinoyl chloride | C6H2Cl3NO | 详情 | 详情 | |
| (IV) | 26646 | ethyl 3-(2,6-dichloro-3-pyridinyl)-3-oxopropanoate | C10H9Cl2NO3 | 详情 | 详情 | |
| (V) | 19795 | 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine | 96-50-4 | C3H4N2S | 详情 | 详情 |
| (VI) | 26647 | ethyl (Z)-2-[(2,6-dichloro-3-pyridinyl)carbonyl]-3-(1,3-thiazol-2-ylamino)-2-propenoate | C14H11Cl2N3O3S | 详情 | 详情 | |
| (VII) | 26648 | ethyl 7-chloro-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C14H10ClN3O3S | 详情 | 详情 | |
| (VIII) | 26649 | tert-butyl (3S,4S)-4-methoxypyrrolidinyl(methyl)carbamate | C11H22N2O3 | 详情 | 详情 | |
| (IX) | 26650 | ethyl 7-[(3S,4S)-3-[(tert-butoxycarbonyl)(methyl)amino]-4-methoxypyrrolidinyl]-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C25H31N5O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)Treatment of 2,6-dichloropyridine (I) with butyllithium in THF followed by quenching with CO2 affords 2,6-dichloronicotinic acid (II) . After chlorination with boiling SOCl2, the resulting acid chloride (IIIa) is condensed with diethyl malonate by means of magnesium ethoxide in Et2O to give the nicotinoyl acetate (IV) . Alternatively, activation of 2,6-dichloronicotinic acid (II) with CDI provides imidazolide (IIIb) which, without isolation, is condensed with the potassium salt of diethyl malonate in the presence of MgCl2 and Et3N to yield the keto ester (IV) . Treatment of compound (IV) with triethylorthoformate and acetic anhydride followed by reaction with 2-aminothiazole (V) gives the enamino ester (VI), which is cyclized to the 1,8-naphthyridine derivative (VII) upon heating with K2CO3 in dioxane . Condensation of chloronaphthyridine (VII) with the chiral pyrrolidine (VIII) by means of triethylamine in acetonitrile yields the protected voreloxin (IX), which is finally hydrolyzed with hot aqueous HCl . In a related method, chloronaphthyridine (VII) is coupled with the unprotected pyrrolidine (X) to afford voreloxin ethyl ester (XI), which is finally hydrolyzed with NaOH in H2O/EtOH .
| 【1】 Tomita, K. et al. Synthesis and antitumor activity of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids. 217th ACS Natl Meet (March 21-25, Anaheim) 1999, Abst MEDI 249. |
| 【2】 Tomita, K., Chiba, K., Kashimoto, S., Shibamori, K., Tsuzuki, Y. (Dainippon Sumitomo Pharma Co., Ltd.). Novel compound, process for producing the same, and antitumor agent. EP 0787726, US 5817669, WO 1995034559. |
| 【3】 Tsuzuki, Y., Tomita, K., Shibamori, K.-I., Sato, Y., Kashimoto, S., Chiba, K. Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents. Part 2. J Med Chem 2004, 47(8): 2097-109. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 26645 | 2,6-dichloronicotinoyl chloride | C6H2Cl3NO | 详情 | 详情 | |
| (I) | 13573 | 2,6-Dichloropyridine | 2402-78-0 | C5H3Cl2N | 详情 | 详情 |
| (II) | 26644 | 2,6-dichloronicotinic acid | 38496-18-3 | C6H3Cl2NO2 | 详情 | 详情 |
| (IV) | 26646 | ethyl 3-(2,6-dichloro-3-pyridinyl)-3-oxopropanoate | C10H9Cl2NO3 | 详情 | 详情 | |
| (V) | 19795 | 2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine | 96-50-4 | C3H4N2S | 详情 | 详情 |
| (VI) | 26647 | ethyl (Z)-2-[(2,6-dichloro-3-pyridinyl)carbonyl]-3-(1,3-thiazol-2-ylamino)-2-propenoate | C14H11Cl2N3O3S | 详情 | 详情 | |
| (VII) | 26648 | ethyl 7-chloro-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C14H10ClN3O3S | 详情 | 详情 | |
| (VIII) | 26649 | tert-butyl (3S,4S)-4-methoxypyrrolidinyl(methyl)carbamate | C11H22N2O3 | 详情 | 详情 | |
| (IX) | 26650 | ethyl 7-[(3S,4S)-3-[(tert-butoxycarbonyl)(methyl)amino]-4-methoxypyrrolidinyl]-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C25H31N5O6S | 详情 | 详情 | |
| (X) | 69211 | (3S,4S)-4-methoxy-N-methylpyrrolidin-3-amine compound with 1-methyl-4-(methylsulfonyl)benzene (1:2) | C6H14N2O.2C8H10O2S | 详情 | 详情 | |
| (XI) | 69210 | ethyl 7-((3S,4S)-3-methoxy-4-(methylamino)pyrrolidin-1-yl)-4-oxo-1-(thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate | C20H23N5O4S | 详情 | 详情 |