2,6-dichloronicotinoyl chloride -Drug Synthesis Database

【结构式】

【分子编号】26645

【品名】2,6-dichloronicotinoyl chloride

【CA登记号】

【分子式】C₆H₂Cl₃NO

【分子量】210.44612

【元素组成】C 34.24% H 0.96% Cl 50.54% N 6.66% O 7.6%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(III)

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.

参考文献中间体

合成目标

【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：(IIIa)

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 .

参考文献中间体

合成目标

【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

Extended Information