Synthesis method of Pexidartinib intermediate

A synthesis method and intermediate technology, which is applied in the field of synthesis of the anticancer drug pecidatinib intermediate, can solve the problems of lack of market competitiveness in large-scale production and expensive raw materials, and achieve easy scale production promotion and low cost. Low cost, easy to achieve the effect of process conditions

Inactive Publication Date: 2021-09-24
武汉格迪泰健康科技有限公司
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  • Description
  • Claims
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Problems solved by technology

[0009] The raw material price of the reaction of the above-mentioned one-step reaction is expensive, and lacks market competitiveness for large-scale production

Method used

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  • Synthesis method of Pexidartinib intermediate
  • Synthesis method of Pexidartinib intermediate
  • Synthesis method of Pexidartinib intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0048] In a 100ml single-necked flask, add 10ml of acetonitrile, 86.9mg of 6-aminonicotinic acid methyl ester, stir for 10min until completely dissolved, then add 100mg of 6-trifluoromethylnicotinaldehyde, continue stirring for 20min, add sodium borohydride 108mg, glacial acetic acid 172mg, heated to 50°C, kept for 36h, then poured the reaction liquid into 50ml of 10% potassium carbonate aqueous solution, added 50ml of ethyl acetate to stir and extract, collected the organic phase after layering, concentrated and dried to obtain 168mg of yellow solidified product, Calculated yield is 94.51%, proton nuclear magnetic resonance spectrum detects as figure 1 Shown: The specific analysis results are as follows:

[0049] 1 H NMR (400MHz, dmso): δ8.73(s, 1H), 8.56(d, J=2.2Hz, 1H), 8.07(t, J=5.8Hz, 1H), 7.98(d, J=6.8Hz, 1H), 7.87(d, J=1.8Hz, 1H), 7.85(d, J=2.6Hz, 1H), 6.61(d, J=8.8Hz, 1H), 4.69(d, J=5.8Hz, 2H) ,3.76(s,3H).

[0050] It can be known that the obtained compound is 6-({...

Embodiment 2

[0058] In a 100ml single-necked flask, add 10ml of acetonitrile and 78.7mg of 6-aminonicotinic acid, stir for 10min until they are completely dissolved, then add 110mg of 6-trifluoromethylnicotinaldehyde, continue stirring for 20min, then add 107mg of sodium cyanoborohydride, 10% 100 mg of ferric chloride solution, heated to 25°C, and kept for 10 hours, then poured the reaction solution into 50 ml of 10% potassium carbonate aqueous solution, added 50 ml of ethyl acetate to stir and extract, collected the organic phase after layering, concentrated and dried, and obtained yellow The solid was 157 mg, and the calculated yield was 92.68%. The yellow solid was detected as 6-({[6-(trifluoromethyl)pyridin-3-yl]methyl}amino)pyridine-3-carboxylic acid.

[0059] In a 100ml three-necked flask, add 100mg of 6-({[6-(trifluoromethyl)pyridin-3-yl]methyl}amino)pyridine-3-carboxylic acid, then add 10ml of anhydrous tetrahydrofuran, stir for 30min, and slowly drop Add 45mg of diisobutyl aluminu...

Embodiment 3

[0062] In a 100ml single-necked flask, add 10ml of acetonitrile and 94.7mg of ethyl 6-aminonicotinate, stir for 10min until they are all dissolved, then add 130mg of 6-trifluoromethylnicotinaldehyde, continue stirring for 20min, and then add triacetoxy borohydrogenate Sodium 724.7mg, hydrochloric acid-magnesium chloride mixed solution 100mg, heated to 80°C, heat preservation reaction for 48h, then pour the reaction solution into 50ml of 10% potassium carbonate aqueous solution, add 50ml of ethyl acetate, stir and extract, collect the organic phase after layering, concentrate Dried to obtain 176.5 mg of yellow solid, the calculated yield was 95.26%, and the yellow solid was detected as 6-({[6-(trifluoromethyl)pyridin-3-yl]methyl}amino)pyridine-3- Ethyl formate.

[0063] In a 100ml three-necked flask, add 100mg of ethyl 6-({[6-(trifluoromethyl)pyridin-3-yl]methyl}amino)pyridine-3-carboxylate, then add 10ml of anhydrous tetrahydrofuran, and stir for 30min , slowly add 1.23ml of ...

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Abstract

The invention provides a synthesis method of a Pexidartinib intermediate, which specifically comprises the steps of synthesizing a compound I by taking a 6-aminonicotinate compound and 6-trifluoromethyl nicotinaldehyde as raw materials, and generating [6-({[6-(trifluoromethyl) pyridine-3-yl] methyl} amino) pyridine-3-yl] methanol by taking the compound I as a raw material and performing reduction reaction through a reducing agent; and taking [6-({[6-(trifluoromethyl) pyridine-3-yl] methyl} amino) pyridine-3-yl] methanol as a raw material, and generating 6-({[6-(trifluoromethyl) pyridine-3-yl] methyl} amino) pyridine-3-formaldehyde through an oxidizing reaction of an oxidizing agent. The synthesis method disclosed by the invention has the advantages of cheap and easily available raw materials, simplicity and convenience in operation, mild reaction conditions, high yield (the total yield is greater than 58.62%) and the like, large-scale production can be realized, and the production cost of Pexidartinib is reduced, so that the market competitiveness of the product is improved.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for synthesizing an intermediate of an anticancer drug, pecidatinib. Background technique [0002] Pexidartinib, also known as pexitinib, its chemical name is 5-((5-chloro-1H-pyrrolo[2,3-B]pyridin-3-yl)methyl)-N -((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine, CAS No.: 1029044-16-3. As a KIT, CSF-1R and FLT3 inhibitor, the drug was approved by the US FDA on August 2, 2019, and is suitable for the treatment of patients with severe morbidity or functional limitations who are ineffective for bundle therapy Adult patients with symptomatic tenosynovial giant cell tumor (TGCT). At present, the drug is the only drug used to treat TGCT and has been granted an orphan drug designation. Its chemical structure is as follows: [0003] [0004] Since the launch of pecidatinib, its market share has gradually increased, and it has attracted extensive attention from the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/74
CPCC07D213/74
Inventor 刘明星童航詹一丰
Owner 武汉格迪泰健康科技有限公司
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