CN115650977A

CN115650977A - Synthesis method of tocaintinib

Info

Publication number: CN115650977A
Application number: CN202211224971.5A
Authority: CN
Inventors: 张定初
Original assignee: Guangdong Runxing Biotechnology Co ltd
Current assignee: Guangdong Runxing Biotechnology Co ltd
Priority date: 2022-10-09
Filing date: 2022-10-09
Publication date: 2023-01-31

Abstract

The invention discloses a synthesis method of tocaintinib, which is characterized by comprising the following steps: s1, mixing the raw material R-NH ₂ Adding the mixture into a reaction vessel, adding a solvent, a thionizing reagent and alkali, mixing and reacting to obtain dithiocarbamate, adding a cyanating reagent into the dithiocarbamate, and reacting to obtain isothiocyanate; s2, adding isothiocyanate into a new reaction vessel, then respectively adding a solvent and AMP, and reacting to obtain an intermediate compound; and S3, adding the intermediate compound into a new reaction vessel, and then respectively adding a solvent, alkali and p-toluenesulfonyl chloride to react to obtain the tacatinib. The synthesis method of the tocaininib can effectively improve the reaction yield and is beneficial to product purification.

Description

Synthesis method of tocaintinib

Technical Field

The invention relates to the technical field of pharmacy, in particular to a synthetic method of tocaintinib.

Background

Tukysa (Tucatenib) Tukatinib/Tukatinib (ONT-380) is an oral TKI (tyrosine kinase) inhibitor with high specificity for HER 2. Tocaininib, in combination with trastuzumab and capecitabine, is useful in treating adult patients with advanced unresectable or metastatic HER2 positive breast cancer, including patients with brain metastases. The chemical name of tocaintinib is:

chinese name: n6- (4, 5-dihydro-4, 4-dimethyl-2-oxazole) -N4- [ 3-methyl-4- ([ 1,2,4] thiazolo [1,5-a ] pyridin-7-yloxy) phenyl ] -4, 6-quinazolinediamine

English name:

N6-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-n4-[3-methyl-4-([1,2,4]triazolo[1,5-a]p yridin-7-yloxy)phenyl]-4,6-quinazolinediamine

CAS number: 937263-43-9

The molecular formula is as follows: C26H24N8O2

Molecular weight: 480.20

The chemical structural formula is as follows:

the synthesis of the tatarinib is reported in patents and literatures to be few, and the currently known synthetic route is to take 2-methyl-4-nitrophenol and 2-amino-4-chloropyridine as starting materials, obtain a key intermediate compound 15 through a seven-step reaction path, and then obtain the tatarinib by coupling the compound 15 and oxazole trifluoromethanesulfonate (as shown in the following route).

The synthetic method has long route, expensive starting materials and difficult self-made synthesis, and the total yield is only 19 percent; and the last step of coupling has low repetition rate and difficult scale-up production, and is not suitable for industrial production.

Disclosure of Invention

In order to make up for the defects in the prior art, the invention provides a synthesis method of tocaintinib, which can effectively improve the reaction yield and is beneficial to product purification.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

a synthesis method of tocaintinib is characterized by comprising the following steps:

s1, mixing raw material R-NH ₂ (namely the intermediate compound marked with the number 15 in the background technical route) is added into a reaction vessel, then a solvent, a thioreagent and alkali are added, the mixture is mixed and reacted at the temperature of 25-50 ℃ for 3-20 h to obtain dithiocarbamate, then a cyaniding reagent is added into the dithiocarbamate, the reaction temperature is 0-25 ℃ for 0.5-2 h, and the PH is adjusted by alkali after the reaction to obtain isothiocyanate;

s2, adding isothiocyanate into a new reaction vessel, then adding a solvent and AMP into the new reaction vessel respectively, and reacting at the temperature of 5-25 ℃ for 0.5-4 h to obtain an intermediate compound;

and S3, adding the intermediate compound into a new reaction vessel, and then respectively adding a solvent, alkali and p-toluenesulfonyl chloride, wherein the reaction temperature is 0-40 ℃, the reaction time is 0.5-2 h, and reacting to obtain the tocaintinib.

The reaction route of the synthesis method is as follows:

further, in step S1, the alkali is selected from one or a combination of potassium hydroxide, sodium hydroxide, ammonium hydroxide, sodium carbonate, sodium bicarbonate and potassium carbonate.

Further, in step S1, the thionating agent is selected from one of carbon disulfide, sulfur dioxide and hydrogen sulfide.

Further, in step S1, the solvent is selected from one or a combination of water, methanol, ethanol, acetonitrile, DMF, and DMAC.

Further, in step S1, the ratio of the raw material, the thionating agent, and the base is selected from one of 1.

Furthermore, in step S1, the cyaniding agent is cyanuric chloride, and the equivalent is 0.35-0.5.

Further, in step S2, the solvent is one or a combination of THF, DMF and DMAC, and the AMP is added in an equivalent of 1-2 equivalents.

Further, in step S3, the solvent is selected from one or a combination of THF, DMF, and DMAC.

Further, in step S3, the base is selected from one or a combination of potassium tert-butoxide, sodium hydroxide, sodium hydride and triethylamine, and the added equivalent is 1 to 5 equivalents.

Further, in step S3, the equivalent of the added p-toluenesulfonyl chloride is 1 to 2 equivalents.

Compared with the prior art, the invention has the following beneficial technical effects:

the invention prolongs the synthesis route and uses the raw material R-NH ₂ Making a stable intermediate, and then combining the heterocyclic ring to obtain the tacanib, fromThereby making full use of the raw material R-NH ₂ The reaction yield of the last steps is improved, and the purification of the final product is facilitated.

Detailed Description

In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

A synthetic method of tocaintinib comprises the following synthetic route:

with reference to the above route, the synthesis method specifically comprises the following steps:

s1, preparing isothiocyanate (the parallel scheme is shown below, and the scheme can be freely selected and implemented)

The first scheme is as follows: preparing a three-mouth bottle, erecting a thermometer, and adding the raw material R-NH into the three-mouth bottle ₂ Then, a mixture of DMF and water is added, 2 times equivalent of carbon sulfide and 2 times equivalent of potassium carbonate are added, the mixed reaction liquid is heated to 40 ℃, and sampling monitoring is carried out after 6 hours of reaction, so that the raw materials are completely reacted. The mixture was then cooled to 0 ℃ and a solution of dichloromethane in TCT was added dropwise. Stirring the mixture for reaction for 0.5h after the dropwise addition is finished, and then adjusting the pH value of the mixture by using 6N sodium hydroxide>11. Extracting with dichloromethane for 3 times, mixing organic phases, and concentrating to dryness to obtain isothiocyanate 19.

Scheme II: preparing a three-mouth bottle, erecting a thermometer, and adding the raw material R-NH into the three-mouth bottle ₂ And then a mixture of DMF and water (1. The mixture was cooled to 0 ℃ and a solution of dichloromethane in TCT was added dropwise. Stirring the mixture for reaction for 0.5h after the dropwise addition is finished, and then adjusting the pH value of the mixture by using 6N sodium hydroxide>11. Extracting with dichloromethane for 3 times, mixing organic phase, and concentrating to dryness to obtain isothiocyanate 19。

The third scheme is as follows: preparing a three-mouth bottle, erecting a thermometer, and adding the raw material R-NH into the three-mouth bottle ₂ Then, a mixture of DMF and water (1. The mixture was cooled to 0 ℃ and a solution of dichloromethane in TCT was added dropwise. After the dropwise addition, the mixture was stirred for 0.5 hour, and then the pH was adjusted with 6N sodium hydroxide>11. Extracting with dichloromethane for 3 times, mixing organic phase, and concentrating to dryness to obtain isothiocyanate 19.

S2, preparation of intermediate 20 of isothiocyanate 19 Butt-Linked with AMP (parallel scheme, optional implementation hereinafter)

The first scheme is as follows: preparing a three-necked bottle, erecting a thermometer, adding isothiocyanate, adding DMF (dimethyl formamide), stirring for dissolving, adding AMP, stirring for reacting for 2 hours at room temperature, sampling to monitor the reaction completion of the raw materials, pouring the reaction liquid into water, stirring fully for 1 hour, precipitating solids, filtering, and drying the solids to obtain the intermediate compound 20.

Scheme II: preparing a three-necked bottle, erecting a thermometer, adding isothiocyanate, adding THF, stirring for dissolving, adding AMP, stirring at room temperature for reacting for 2h, sampling to monitor the reaction completion of the raw materials, pouring the reaction liquid into water, stirring fully for 1 h, precipitating a solid, filtering, and drying the solid to obtain the intermediate compound 20.

S3, the intermediate compound 20 and p-toluenesulfonyl chloride are combined to form an oxazole heterocyclic ring to obtain the Tukatinib (the parallel scheme is shown below, can be freely selected and implemented)

The first scheme comprises the following steps: preparing a three-mouth bottle, erecting a thermometer, adding the intermediate compound, adding DMF (dimethyl formamide), stirring and dissolving the mixed reaction solution, adding sodium hydroxide and paratoluensulfonyl chloride, heating the mixed reaction solution to 60 ℃, and reacting for 3 hours. The reaction solution was poured into stirred water, stirred well for 2 hours, solid was precipitated, and filtered. The solid was recrystallized from methanol to give a white solid. The content of HPLC is more than or equal to 98 percent.

Scheme II: preparing a three-mouth bottle, erecting a thermometer, adding the intermediate compound, adding THF (tetrahydrofuran), stirring and dissolving the mixed reaction solution, adding sodium hydroxide and paratoluensulfonyl chloride, heating the mixed reaction solution to 60 ℃, and reacting for 3 hours. The reaction solution was poured into stirred water, stirred sufficiently for 2 hours, solid was precipitated, and filtered. The solid was recrystallized from methanol to give a white solid. The content of HPLC is detected to be more than or equal to 98 percent.

And a third scheme is as follows: a three-necked flask was set up, and a thermometer was mounted, and then the compound 20 and THF were added thereto, and the mixed reaction solution was stirred and dissolved, and then sodium hydroxide and p-toluenesulfonyl chloride were added thereto, and the mixed reaction solution was reacted at room temperature for 16 hours. The reaction solution was poured into stirred water, stirred well for 2 hours, solid was precipitated, and filtered. The solid was recrystallized from methanol to give a white solid. The content of HPLC is more than or equal to 98 percent.

Although the present invention has been described in detail with reference to the embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments or portions thereof without departing from the spirit and scope of the invention.

Claims

1. A synthetic method of tocaintinib is characterized by comprising the following steps:

s1, mixing the raw material R-NH ₂ Adding the mixture into a reaction vessel, adding a solvent, a thioreagent and alkali, mixing and reacting to obtain dithiocarbamate, adding a cyaniding reagent into the dithiocarbamate, and reacting to obtain isothiocyanate;

s2, adding isothiocyanate into a new reaction vessel, then respectively adding a solvent and AMP, and reacting to obtain an intermediate compound;

and S3, adding the intermediate compound into a new reaction vessel, and then respectively adding a solvent, alkali and p-toluenesulfonyl chloride to react to obtain the tacaninib.

2. The method of synthesizing tocaintinib according to claim 1, wherein: in step S1, the alkali is selected from one or a combination of potassium hydroxide, sodium hydroxide, ammonium hydroxide, sodium carbonate, sodium bicarbonate, and potassium carbonate.

3. The method of synthesizing tacanib according to claim 2, wherein: in step S1, the thionating agent is selected from one of carbon disulfide, sulfur dioxide, and hydrogen sulfide.

4. The method of synthesizing tacanib according to claim 3, wherein: in step S1, the solvent is selected from one or a combination of water, methanol, ethanol, acetonitrile, DMF, and DMAC.

5. The method of synthesizing tacalcinib according to claim 4, characterized in that: in step S1, the ratio of the starting material, thionating agent, base is selected from one of 1.

6. The method of synthesizing tacalcinib according to claim 5, characterized in that: in the step S1, the cyaniding reagent is cyanuric chloride, and the equivalent is 0.35-0.5.

7. The method for the synthesis of tocaintinib according to any one of claims 1 to 6, characterized in that: in step S2, the solvent is one or a combination of THF, DMF and DMAC, and the added equivalent of AMP is 1-2 equivalents.

8. The method for the synthesis of tocaintinib according to any one of claims 1 to 6, characterized in that: in step S3, the solvent is selected from one or a combination of THF, DMF, DMAC.

9. The method of synthesizing tocaintinib according to claim 8, wherein: in step S3, the alkali is selected from one or a combination of potassium tert-butoxide, sodium hydroxide, sodium hydride and triethylamine, and the added equivalent is 1 to 5 equivalents.

10. The method of synthesizing tocaintinib according to claim 9, wherein: in step S3, the equivalent of the added p-toluenesulfonyl chloride is 1 to 2 equivalents.