1-(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)-2-chloro-1-ethanone -Drug Synthesis Database

【结构式】

【分子编号】54870

【品名】1-(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)-2-chloro-1-ethanone

【CA登记号】

【分子式】C₁₀H₁₀ClNO₃

【分子量】227.64704

【元素组成】C 52.76% H 4.43% Cl 15.57% N 6.15% O 21.08%

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：(V)

Benzodioxan-6-amine (I) was protected as the corresponding acetanilide (II), which was subsequently subjected to Friedel-Crafts condensation with chloroacetyl chloride (III) in the presence of ZnCl2, yielding the chloro ketone (IV). Acidic hydrolysis of the acetamide function of (IV) provided amino ketone (V). Alternatively, intermediate (V) was prepared by direct acylation of aniline (I) employing chloroacetonitrile (VI) in the presence of BCl3. The 7-(chloromethyl)camptothecin derivative (VIII) was synthesized through a Friedlander condensation between amino ketone (V) and the known keto lactone (VII). Finally, displacement of the chloride of (VIII) with N-methylpiperazine (IX) gave rise to the title piperazinylmethyl camptothecin.

参考文献中间体

合成目标

【1】 Luzzio, M.J.; et al.; Synthesis and antitumor activity of novel water soluble derivatives of camptothecin as specific inhibitors of topoisomerase I. J Med Chem 1995, 38, 3, 395.
【2】 Luzzio, M.J.; Besterman, J.M.; Evans, M.G.; Myers, P.L. (GlaxoSmithKline plc); Water soluble camptothecin derivs.. EP 0540099; JP 1993222048; JP 2000109475; US 5559235 .
【3】 Sternbach, D.D.; Lackey, K. (GlaxoSmithKline Inc.); Preparation of water soluble camptothecin derivs.. US 5342947 .

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)	54867	1,4-Benzodioxan-6-amine; 3,4-Ethylenedioxyaniline; 6-Amino-1,4-benzodioxane	22013-33-8	C₈H₉NO₂	详情	详情
(II)	54868	N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide		C₁₀H₁₁NO₃	详情	详情
(III)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情
(IV)	54869	N-[7-(2-chloroacetyl)-2,3-dihydro-1,4-benzodioxin-6-yl]acetamide		C₁₂H₁₂ClNO₄	详情	详情
(V)	54870	1-(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)-2-chloro-1-ethanone		C₁₀H₁₀ClNO₃	详情	详情
(VI)	14443	2-chloroacetonitrile; chloroacetonitrile	107-14-2	C₂H₂ClN	详情	详情
(VII)	10841	(4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione		C₁₃H₁₃NO₅	详情	详情
(VIII)	54871	(8S)-15-(chloromethyl)-8-ethyl-8-hydroxy-2,3-dihydro-11H-[1,4]dioxino[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H,14H)-dione		C₂₃H₁₉ClN₂O₆	详情	详情
(IX)	10061	1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine	109-01-3	C₅H₁₂N₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

In a different strategy, the dioxinoquinoline system (XII) was prepared by acylation of amino ketone (X) with methyl malonyl chloride (XI), followed by intramolecular Knoevenagel condensation of the intermediate keto malonamide. Chlorination of (XII) with POCl3 afforded the dichloro derivative (XIII), which was subsequently condensed with N-methylpiperazine (IX) to give (XIV). Reduction of the ester group of (XIV) by means of DIBAL provided alcohol (XV). Replacement of the 7-chloro of (XV) by an iodide group required previous oxidation of (XV) to the more reactive aldehyde (XVI). Treatment of (XVI) with NaI and HCl led to the corresponding iodo aldehyde, which was further reduced to alcohol (XVII) using NaBH4.

参考文献中间体

合成目标

【1】 Fang, F.G.; Xie, S.; Lowery, M.W. (GlaxoSmithKline Inc.); Intermediates in pharmaceutical camptothecin preparation. WO 9529917 .
【2】 Huie, E.M.; Fang, F.G.; Xie, S.; Comins, D.L. (GlaxoSmithKline Inc.; North Carolina State University); Preparation of a camptothecin deriv. by intramolecular cyclisation. WO 9529919 .

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)	10061	1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine	109-01-3	C₅H₁₂N₂	详情	详情
(X)	54870	1-(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)-2-chloro-1-ethanone		C₁₀H₁₀ClNO₃	详情	详情
(XI)	50272	Malonic acid monomethyl ester chloride; Methyl (chloroformyl)acetate; Methyl malonyl chloride ;Methyl 3-chloro-3-oxopropionate	37517-81-0	C₄H₅ClO₃	详情	详情
(XII)	54872	methyl 9-(chloromethyl)-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylate		C₁₄H₁₂ClNO₅	详情	详情
(XIII)	54873	methyl 7-chloro-9-(chloromethyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylate		C₁₄H₁₁Cl₂NO₄	详情	详情
(XIV)	54874	methyl 7-chloro-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylate		C₁₉H₂₂ClN₃O₄	详情	详情
(XV)	54875	{7-chloro-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methanol		C₁₈H₂₂ClN₃O₃	详情	详情
(XVI)	54876	7-chloro-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbaldehyde		C₁₈H₂₀ClN₃O₃	详情	详情
(XVII)	54877	{7-iodo-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methanol		C₁₈H₂₂IN₃O₃	详情	详情

Extended Information