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A kind of sunitinib preparation method

A molar ratio and compound technology, applied in organic chemistry and other directions, can solve the problems of long production cycle, unfavorable large-scale production, affecting the quality of sunitinib, and achieve the cost reduction of production power, suitability for industrial production, and shortening of reaction time. Effect

Active Publication Date: 2020-04-07
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The problem that this route exists: the yield of preparing compound 2 from compound 6 is only 80%; The reaction is slow when preparing compound 7, needs the reaction time of 50 hours; Compound 6 is easy to remain, and with 5-fluoroindole-2- Ketone (5) reacts to produce impurities, which seriously affects the quality of sunitinib
Problems in this route: the yield of compound 2 prepared from compound 10 is only 74%; due to the introduction of amides in advance, compounds 9, 10, and 11 are all oily, which increases the difficulty of purification and is not conducive to large-scale production; Ketene is flammable and explosive, which is not conducive to safe production
Problems in this route: compound 12 is an extremely insoluble substance, and it is extremely difficult to filter during the preparation process; thionyl chloride is a strong corrosive reagent, which will cause great damage to equipment; compound 14 has low reactivity, and large-scale production and use will easily lead to incomplete reaction. Thus affecting the quality of sunitinib
The above situation caused the reaction to generate compound 12 for too long, and the chemical purity was low
[0030] Second, compound 12 is a yellow powdery solid. According to investigations, compound 12 has the characteristics of being extremely difficult to dissolve and filter (even a few hundred grams of compound 12 often requires more than 12 hours of filtering time), which leads to long production cycle, difficulty in filtering, Difficult to clean and easy to residue and other problems affecting industrial production

Method used

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  • A kind of sunitinib preparation method
  • A kind of sunitinib preparation method
  • A kind of sunitinib preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the preparation of Sunitinib

Embodiment 2

[0058] Embodiment 2: the selection of optimum experimental condition

[0059] Step 1), 5-fluoroindol-2-one (compound 5, 13g, 1.1eq.) and 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid (compound 3, 13g, 1.0eq.) and solvent (39mL) were added to a 100L reaction flask, stirred and heated up according to the experimental requirements, and then catalyst 1 was added to the reaction flask. After the reaction was completed, intermediate compound 12 was obtained.

[0060] Step 2), compound 12 obtained in step 1 was not separated, catalyst 2 / catalyst 3 was added to the reaction solution, N,N-diethylethylenediamine (10.9g, 1.2eq) was added, and the reaction was stirred until the completion of the reaction. A poor solvent (39mL) was added to the solution for crystallization, the stirring was continued until the reaction was complete, and the sunitinib solid was obtained by suction filtration. Orthogonal table L 18 (2×3 7 ) design experiments, the specific results are shown in Table ...

Embodiment 4

[0066] Embodiment 4: Verification of optimal experimental conditions

[0067] Influence of pyrrolidine consumption and experimental temperature in step 1):

[0068] 5-fluoroindol-2-one (compound 5,13g, 1.1eq.) and 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid (compound 3,13g, 1.0eq .) and DMF (39mL) were added to a 100L reaction flask, stirred and heated up according to the requirements of the experiment, and then pyrrolidine was added to the reaction flask until the reaction was complete. Add TBTU / DIEA (1.1eq. / 1.7eq.) to the reaction solution, add N,N-diethylethylenediamine (10.9g, 1.2eq.), stir the reaction until complete, add purified water to the reaction solution (39 mL) for crystallization, continued stirring until the reaction was complete, and suction filtered to obtain sunitinib as a solid. The specific results are shown in Table 3.

[0069] The impact of different reaction conditions on the experimental results in table 3

[0070]

[0071]

[0072] It ...

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Abstract

The invention relates to a method for preparing sunitinib. According to the method, the sunitinib is prepared by adopting a one-pot method. The method comprises the steps of reacting a starting material 5-fluoroindole-2-ketone with 4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid to generate an intermediate 5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indole-3-subunit) methyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid; and directly reacting the generated intermediate with N,N-diethylethylenediamine without separating the intermediate to form the sunitinib.

Description

technical field [0001] The invention belongs to the technical field of synthesis in the field of medicinal chemistry, and in particular relates to a preparation method of sunitinib. Background technique [0002] Sunitinib malate, chemical name (Z)-N-[2-(diethylamino)ethyl-5-[(5-fluoro-2-oxo-1,2-dihydro-3H- Indole-3-ylidene)methyl]-2,4-dimethyl-3-carbamoyl-1H-pyrrole malate (Formula 1), CAS341031-54-7, structure: [0003] [0004] The structure of sunitinib is as follows: [0005] [0006] Sunitinib malate, as the malate salt of sunitinib, is a tyrosine kinase inhibitor with potential to inhibit angiogenesis and antitumor effects. Developed and marketed by Pfizer, the FDA-approved indications are: [0007] 1) Gastrointestinal stromal tumor (GIST) that failed or could not be tolerated with imatinib mesylate; [0008] 2) Inoperable advanced renal cell carcinoma (RCC); [0009] 3) Adult patients with unresectable, metastatic well-differentiated advanced pancreatic neu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/06
CPCC07D403/06
Inventor 纪德华张茜刘翠艳张豪豪郭小丰何丽娟董玉祝晓艳陈尧
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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