Preparation method of CSF-IR inhibitor

A reagent and catalyst technology, applied in the field of preparation of CSF-IR inhibitors, can solve the problems of unsuitability for industrial scale-up production, high preparation cycle and cost, insufficient substitution reaction yield, etc., to improve atom economy and reduce reaction difficulty. , the effect of shortening the synthesis cycle

Pending Publication Date: 2022-01-04
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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AI Technical Summary

Problems solved by technology

[0004] Patent WO2014145025A2 discloses the synthesis of Vimseltinib. According to the disclosed technical scheme (as shown in the following formula), eight steps of reaction are required to prepare Vimseltinib. The yield of iodination reaction in step d is only 48%, and the substitution reaction in step e, due to the poor activity of the substrate , when the inventor repeated the prior art, the yield of this step substitution reaction was less than 20%
In summary, the preparation methods disclosed in the prior art have very poor atomic economy, high preparation cycle and cost, poor reproducibility, and high equipment requirements, which are obviously not suitable for industrial scale-up production

Method used

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  • Preparation method of CSF-IR inhibitor
  • Preparation method of CSF-IR inhibitor
  • Preparation method of CSF-IR inhibitor

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preparation example Construction

[0047] In order to solve the above-mentioned technical problems, the first aspect of the present invention provides a preparation method of compound VII, which is characterized in that, comprising the following steps:

[0048] Step 3: Compound I is reacted with an organic amine under the action of a base to obtain Compound II;

[0049] Step 4: Compound II is demethylated and dearomatized to obtain Compound III;

[0050] Step 5: Compound III reacts with a methylating reagent under alkaline conditions to obtain Compound IV;

[0051] Step 6: Compound IV is reacted with a borate ester compound in the presence of a lithium reagent to obtain Compound V;

[0052] Step 7: Coupling reaction between compound V and compound VI to obtain VII;

[0053]

[0054] Among them, R 1 and R 2 identically or differently selected from hydrogen, C 1～6 saturated or unsaturated alkyl groups.

[0055] In some preferred embodiments, the R 1 and R 2 Respectively selected from hydrogen, isopropy...

Embodiment 1

[0120] Example 1, Preparation of Compound VI

[0121]

[0122] Compound VIII (100g, 760mmol), compound IX (174g, 836mmol), K 2 CO 3 (316g, 2280mmol) mixed with dioxane / water (1.2L) at a volume ratio of 5:1, replaced by argon, and added 3 ) 4 (10g), replaced by inert gas, and heated overnight at 90°C; after the reaction, filter, add water to the filtrate, extract with EA (2L×3), add anhydrous sodium sulfate to the combined organic phase to dry, filter, and concentrate the filtrate , the resulting crude product was purified by flash column chromatography (PE / EA=2:1) ​​to obtain pure compound X (122 g, 90%).

[0123] Compound XI (99g, 423mmol) and K 2 CO 3 (39g, 282.2mmol) was dispersed in DMA (500mL), stirred at room temperature for 30min, compound X (50g, 282.2mmol) was added, and heated at 115°C overnight; after the reaction, cooled to room temperature, added H 2 O (1.5L), extracted with EA (3L×3), the organic phases were combined, washed with brine (3L), separated, ...

Embodiment 2

[0125] Example 2, Preparation of Compound VI

[0126]

[0127] Compound VIII (100g, 760mmol), compound IX (126.5g, 608mmol), K 2 CO 3 (210g, 1520mmol) mixed with dioxane / water (1L) with a volume ratio of 5:1, replaced with argon, and added Pd(PPh 3 ) 4 (8.2g), replaced by inert gas, and heated overnight at 90°C; after the reaction, filter, add water to the filtrate, extract with EA (2L×3), add anhydrous sodium sulfate to the combined organic phase, filter, concentrate The filtrate was purified by flash column chromatography (PE / EA=2:1) ​​to obtain pure compound X (117 g, 87%).

[0128] Compound XI (66.3g, 282.2mmol) and K 2 CO 3 (31.2g, 225.76mmol) was dispersed in DMA (450mL), stirred at room temperature for 30min, compound X (50g, 282.2mmol) was added, and heated at 115°C overnight; after the reaction, cooled to room temperature, added H 2 O (1L), extracted with EA (3L×3), combined the organic phases, washed with brine (2.5L), separated the layers, added anhydrous...

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Abstract

The invention relates to a preparation method of a CSF-IR inhibitor. According to the invention, a compound I is used as a raw material, reaction conditions are further optimized according to the characteristics of reactants and intermediate products, side reactions are reduced, post-treatment difficulty can be reduced, post-treatment experimental operation steps are reduced, the defects of long route (eight steps), low yield and poor atom economy in the prior art are overcome, and the target product can be prepared by using easily available and cheap starting raw materials. The synthesis method is mild in reaction condition, simple and convenient to operate, suitable for small-amount preparation in a laboratory and suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to a preparation method of a CSF-IR inhibitor, which belongs to the technical field of organic synthesis. Background technique [0002] Vimseltinib (DCC-3014, the Chinese name is 2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazole-4- yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, the CAS number is 1628606-05-2, the structure is shown in the following formula, it is a kind of c-FMS (CSF- IR) and c-Kit dual inhibitors with anticancer and antiproliferative activities with IC50 values ​​of <0.01μM and 0.1-1μM, respectively. [0003] [0004] Patent WO2014145025A2 discloses the synthesis of Vimseltinib. According to the disclosed technical scheme (as shown in the following formula), eight steps of reaction are required to prepare Vimseltinib. The yield of iodination reaction in step d is only 48%, and the substitution reaction in step e, due to the poor activity of the substrate When the inventor repeated...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 宗新杰颜晓晨李承铎周治国高强郑保富
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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