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Method for synthesizing sunitinib alkali

A technology of sunitinib base and synthesis method, which is applied in the directions of drug combination, organic chemistry, antitumor drugs, etc., can solve the problems of incomplete hydrolysis, and achieve the effects of reduced cost, high yield and simple post-processing

Inactive Publication Date: 2008-12-31
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Technical problem: In the methods mentioned above, there is one-step hydrolysis of esters,

Method used

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  • Method for synthesizing sunitinib alkali
  • Method for synthesizing sunitinib alkali
  • Method for synthesizing sunitinib alkali

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] 0.70 g (3.59 mmol) of ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate, 0.45 g (3 mmol) of 5-fluoroindol-2-one, 9mL of ethanol and several drops of piperidine were reacted at 80°C for 3 hours under nitrogen protection, and a large amount of solids appeared. After cooling, filter with suction, wash the filter cake with ethanol, and vacuum-dry to obtain 0.88 g of solid, with a yield of 89.3%.

[0030] Appearance: yellow solid

[0031] Melting point: 284-286°C

[0032] 1H-NMR (DMSO2-d6) δ: 1.29(t, 3H), 2.422(s, 3H), 2.442(s, 3H), 4.203(q, 2H), 6.847(q, 1H), 6.947(t, 1H ), 7.762 (s, 1H, vinylH), 7.801 (d, 1H), 10.948 (s, 1H, indoleNH), 13.921 (s, 1H, pyrroleNH).

Embodiment 2

[0034] 5-((5-fluoro-2-oxoindol-3-enyl)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 0.8g (2.5mmol), 2 -(Diethylamino)ethylenediamine 0.5ml, catalyst 0.05g, xylene 20ml, react at 100°C for 12h, cool down, add chloroform to dilute, filter, evaporate xylene under reduced pressure to obtain solid 0.81g, yield 73.2%.

[0035] Appearance; orange-yellow solid

[0036] Melting point: 214-216°C

[0037] 1H-NMR (DMSO2-d6) δ: 0.977(t, 6H), 2.420(s, 3H), 2.440(s, 3H), 2.518~2.556(m, 6H), 3.275(m, 2H), 6.837(br s, 1H), 6.923 (dd, 1H), 7.423 (m, 1H), 7.712 (s, 1H), 7.764 (dd, 1H), 10.873 (s, indole NH), 13.676 (s, pyrrole NH).

[0038] Starting from ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate, the traditional three-step reaction is combined into two, and the yield of each step is high, which greatly improves the reaction yield.

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Abstract

A Sunitinib alkali synthetic methodsynthesis method makes improvement on the synthetic route of Sunitinib alkali so as to avoid the problems in the traditional route and shorten the synthetic route by one step. From the initial synthesis idea, the following two steps are improved in the design: (1), the key intermediate 5-formyl -2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester and 5-fluoroindole-2-ketone are directly condensed in ethanol with piperidine serving as catalyst so as to obtain 5-((5-fluoro-2-oxo-indole-3-alkenyl) methyl)-2,4- dimethyl-1H-pyrrole-3-carboxylate; (2), under the effect of a specific catalyst, the 5-((5-fluoro-2-oxo-indole-3-alkenyl) methyl)-2,4- dimethyl-1H-pyrrole-3-carboxylate is further ammonolyzed with 2-(diethylamino) ethylenediamine in ethylene glycol dimethyl ether so as to directly obtain the Sunitinib alkali; the two products are confirmed through NMR spectrum. The two-step reaction has relatively high yield and shortens the reaction process so as to greatly reduce production costs.

Description

technical field [0001] The invention relates to an improved method for preparing sunitinib base, which belongs to Background technique [0002] Sunitinib malate is a small molecule compound that can inhibit a variety of tyrosine kinase receptors, some of which are related to tumor growth, pathological angiogenesis and cancer metastasis. Tyrosine kinase receptors for platelet-derived growth factor receptor, stem cell factor receptor, Fms-like tyrosine kinase-3, colony-stimulating factor receptor type I, and glial cell line-derived neurotrophic factor receptor It blocks the blood and nutrient supply for tumor cell growth, thereby producing anti-angiogenic and anti-tumor effects. [0003] Phase III clinical trial results confirmed that sunitinib malate can delay the development of tumors in patients with gastrointestinal stromal tumors who have become resistant (or intolerant) to imatinib (imatinib, Gleevec) treatment, significantly reducing patient mortality. It also has a ...

Claims

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Application Information

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IPC IPC(8): C07D403/06A61P35/00A61P43/00
Inventor 汪海波康思顺陆然哲曾海粟李海林
Owner NANJING UNIV OF TECH
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