CN115057822B

CN115057822B - New synthesis method of platinib intermediate 2097133-31-6

Info

Publication number: CN115057822B
Application number: CN202210834192.0A
Authority: CN
Inventors: 王甜甜; 刘�文
Original assignee: Shanghai Youhebeide Pharmaceutical Technology Co ltd
Current assignee: Shanghai Youhebeide Pharmaceutical Technology Co ltd
Priority date: 2022-07-14
Filing date: 2022-07-14
Publication date: 2023-05-02
Anticipated expiration: 2042-07-14
Also published as: CN115057822A

Abstract

The invention relates to the technical field of organic synthesis of medical intermediates, in particular to a novel synthesis method of a platinib intermediate 2097133-31-6. The invention provides a new synthetic route of a platinib intermediate 2097133-31-6. The method has the advantages of simple operation, mild conditions, easily obtained raw materials, high safety, environmental protection, and high purity and yield of the prepared product.

Description

New synthesis method of platinib intermediate 2097133-31-6

Technical Field

The invention relates to the field of synthesis of medical intermediates, in particular to a novel synthesis method of a platinib intermediate 2097133-31-6.

Background

Platinib (trade name is Prague), which is a receptor tyrosine kinase RET (Rearranged during Transfection) inhibitor, is a selective RET inhibitor on the market in the first lot in China, can inhibit RET and downstream molecular phosphorylation thereof, and effectively inhibit proliferation of cells expressing RET gene variation. The selectivity for RET is significantly improved compared to the effect of an approved multi-kinase inhibitor. By inhibiting both primary and secondary variations, platinib is expected to prevent the occurrence of clinical resistance. It was developed by Blueprint Medicines and the kerbstone pharmaceutical industry obtained exclusive development and commercial authorization of the drug in the Dazhong province.

Pratinib is an oral, once-a-day, potent and highly selective RET inhibitor, approved by the national drug administration, for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) adult patients who had undergone transfection Rearrangement (RET) gene fusion positive prior to receiving platinum-containing chemotherapy; treatment for advanced or metastatic RET mutant thyroid medullary cancer (MTC) adults and children 12 years old and older in need of systemic treatment, and treatment for advanced or metastatic RET fusion-positive thyroid cancer adults and children 12 years old and older in need of systemic treatment and refractory to radioiodination if radioiodinated is applicable.

The prior original research relates to the synthesis of a platinib key intermediate 2097133-31-6, namely the synthesis of the intermediate 2097133-31-6 is carried out in a metal coupling mode, and the cost is high and the synthesis is difficult.

The intermediate compound 2097133-31-6 is prepared from 2, 4-dichloro-6-methylpyrimidine serving as a raw material through multi-step reaction, wherein noble metal catalytic coupling is needed for neutralizing the iodine-containing compound, the iodine-containing compound is high in price, and iodine-containing wastewater is difficult to treat. (WO 2017/79140,2017, A1)

Disclosure of Invention

The invention aims to solve the technical problems that: through widely researching the solution to the defects of the prior art, the inventor finds a more economic synthesis route, provides a new synthesis route of the platinib intermediate 2097133-31-6, and has the characteristics of high purity of target compounds, good yield, simplicity in operation, low cost, environment-friendly process and the like.

In order to solve the problems, the technical scheme provided by the invention is as follows:

a novel synthesis method of a platinib intermediate 2097133-31-6 comprises the following steps:

step 1, compound SM01 and p-toluenesulfonylmethyl isonitrile are rearranged and cyanated to obtain compound 01;

step 2, adding the compound 01 and hydroxylamine salt, and reacting to obtain a compound 02;

step 3, reducing the compound 02 under the action of a catalyst to obtain a compound 03;

step 4, carrying out reflux reaction on the compound 03 and ethyl acetoacetate under the action of alkali to close the ring to obtain a compound 04;

step 5, deprotection of compound 04 under acidic conditions gives compound 05;

step 6, reacting the compound 05 with bromoform under alkaline conditions to obtain a compound 06;

step 7, chloridizing the compound 06 to obtain a compound 00 namely a platinib intermediate 2097133-31-6;

the specific reaction formula is as follows:

further, step 1: reacting a compound SM01 with p-toluenesulfonyl methyl isonitrile under alkaline conditions in a solvent, and carrying out rearrangement isomerization to obtain a compound 01, wherein the compound SM01 is as follows: p-toluenesulfonylmethyl isonitrile: alkali: the molar ratio of the solvent is as follows: 1:1-3: 1 to 5: 8-40; preferred molar ratios are 1:1.3:1.3:20, preferred: the alkali is potassium tert-butoxide or sodium tert-butoxide, and the solvent is selected from tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether or dioxane; the reaction temperature is between 30 ℃ below zero and 30 ℃ and the reaction time is between 5 and 15 hours;

in the step 2, the compound 01 reacts with hydroxylamine salt in a solvent under the action of alkali, and the compound 02 is obtained by addition, wherein the compound 01: hydroxylamine salt: alkali: the mol ratio of the solvent is 1:1-3:1-5: 8 to 40, preferably a molar ratio of 1:2:3.6:30, preferably hydroxylamine sulphate, hydrochloride, acetate or p-toluene sulphonate; the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or triethylamine; the solvent is selected from ethanol, methanol, n-propanol, isopropanol or n-butanol; the temperature is 20-reflux, and the reaction time is 8-10 hours;

in the step 3, the compound 02 is reduced in a solvent under the action of a catalyst to obtain a compound 03, wherein the compound 02: catalyst: reducing agent: the mol ratio of the solvent is 1:0.1-0.5:1-10: 8 to 40, preferably a molar ratio of 1:0.3:8: 20, preferably the reducing agent is hydrogen; the catalyst is palladium/carbon, pt/C or Raney nickel; the solvent is selected from methanol, ethanol or isopropanol; the reaction temperature is not more than 35 ℃ and the reaction time is 12-24 hours;

in the step 4, the compound 03 is cyclized with acetoacetic acid ethyl ester in a solvent under the action of alkali to obtain a compound 04, wherein the compound 03, the alkali and the acetoacetic acid ethyl ester are: the mol ratio of the solvent is 1:1-5:1-3: 8 to 40, the preferable mole ratio is: 1:1.5:1.5:30, sodium ethoxide as a preferred base, ethanol as a solvent, a reaction temperature of 70-80 ℃ and a reaction time of 8-10 hours;

deprotection of compound 04 in step 5 under acidic conditions gives compound 05, wherein compound 04: acid: the mol ratio of the solvent is 1:1-20: :8 to 40, the preferable mole ratio is: 1:10:15, preferred acids are selected from hydrochloric acid, sulfuric acid or acetic acid; the solvent is selected from methanol, ethanol, dioxane or water; the temperature is 25-35 ℃; the reaction time is 12-14 hours;

compound 05 in step 6 was prepared in one step under basic conditions with bromoform in a solvent to afford compound 06, wherein 05: bromine simulation: alkali: the mol ratio of the solvent is 1:1-10: 1-20: 8-40, preferably in a molar ratio of 1:7:2:30, preferably the base is selected from potassium hydroxide or sodium hydroxide; the solvent is methanol, the temperature is 0-25 ℃, and the reaction time is 17-20 hours;

in the step 7, the compound 06 is chlorinated in the presence of an acid-binding agent in a solvent to prepare the compound 00, namely the platinib intermediate 2097133-31-6. The mol ratio of the compound 06 to the chlorinating agent to the acid binding agent to the solvent is 1:1-5:1-8:8-40, the preferable mol ratio is 1:4:4:26, and the preferable chlorinating agent is selected from thionyl chloride, phosphorus oxychloride, oxalyl chloride or solid phosgene; the acid binding agent is selected from diisopropylethylamine, DBU, 2, 6-lutidine; the solvent is selected from dichloromethane, dichloroethane or toluene; the reaction temperature is reflux, and the reaction time is 20-24 hours.

The inventor newly develops a route and a new synthesis method of the platinib intermediate 2097133-31-6, compared with the prior art, the invention has the advantages of simple operation, mild condition, easily obtained raw materials, no use of expensive reagents, high safety, convenient post-treatment, reduced environmental protection pressure, good purity of the prepared product, high yield and wide application prospect.

The Chinese naming of the compound in the invention conflicts with the structural formula, and the structural formula is taken as the reference; except that the structural formula is obviously wrong.

Drawings

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of Compound 01 ¹ H-NMR；

FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of Compound 04 ¹ H-NMR；

FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of Compound 06 ¹ H-NMR；

FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of Compound 00 ¹ H-NMR。

Detailed Description

The invention is illustrated but not limited by the following examples. Simple alternatives and modifications to the invention will be within the scope of the invention as defined by the appended claims.

Example 1: synthesis of Compound 01

1000g of starting material SM01 (monoethylene glycol-protected 1, 4-cyclohexanedione), 1.3 times of molar equivalent of p-toluenesulfonyl methyl isonitrile and 20 times of molar equivalent of solvent tetrahydrofuran are placed in a 20L four-necked flask equipped with mechanical stirring, nitrogen is replaced in the reaction system, the reaction mass is cooled to-30 ℃,1.3 times of molar equivalent of potassium tert-butoxide solid is slowly added into the reaction system under the protection of heat-preserving nitrogen, after the addition is finished, the mixture is slowly raised to room temperature within 2 hours after the heat-preserving stirring is carried out for 2 hours, the reaction is carried out for 3 hours under the heat-preserving condition, and HPLC detection is carried out after the reaction is finished. The mixture is cooled to-30 ℃ again, 2kg of distilled water is slowly added into the system at the temperature of not more than-10 ℃, the temperature is raised to room temperature within 2 hours after the addition, the mixture is stirred for 4 hours, the mixture is transferred to a reaction kettle for concentration to a small volume, 5kg of distilled water and 10 kg of ethyl acetate are added into the mixture, the mixture is stirred, stood still and separated, the aqueous phase is extracted for 2 times by using the same amount of ethyl acetate, the organic phases are combined, the mixture is concentrated to dryness under reduced pressure for later use, and the gross yield is more than 100%.

¹ H-NMR(CDCl3):1.56-1.68(m,2H)、1.77-1.88(m,2H)、1.89-2.02(m,4H)、2.57-2.77(m,1H)、 3.94(br.s.,4H)；

Example 2: synthesis of Compound 02

Adding 30 times of molar equivalent of ethanol into the compound 01 concentrated in the previous step according to the quantitative yield, stirring for 15 minutes at room temperature, sequentially adding 2 mol equivalent of hydroxylamine sulfate and 3.6 equivalent of caustic soda flake sodium hydroxide at the temperature of not more than 50 ℃, directly raising the reaction system to reflux for reaction for 8 hours after the addition, and detecting the end of the reaction by HPLC. Slowly cooling the mixture to 35 ℃, slowly adding 4 equivalents of distilled water into the system, concentrating ethanol to about 3 volumes under reduced pressure at the temperature of not more than 80 ℃, adding 6 volumes of distilled water and 40 equivalents of ethyl acetate, stirring, extracting, separating liquid, extracting the water phase with the same amount of ethyl acetate for 2 times, merging ethyl acetate phases, concentrating, and using methanol as a product: water=1:3 crystallization, filtration, vacuum oven no more than 50 ℃, drying under reduced pressure, weighing, and two-step yield of 68%.

Example 3: synthesis of Compound 03

Adding 300g of compound 02, 0.2 times of mole equivalent of Pd/C catalyst and 20 times of mole equivalent of methanol into a 2L hydrogenation kettle, carrying out hydrogenation reduction on the mixture at the temperature of not more than 35 ℃ and under the pressure of 2MPa hydrogen, reducing pressure after the reaction is detected by HPLC, filtering, recovering the catalyst, concentrating the filtrate under reduced pressure until the filtrate is nearly dry, using 2 volumes of absolute ethyl alcohol to carry out stripping of methanol and water for 2 times, and adding 20 times of mole equivalent of ethanol to prepare a solution for later use.

Example 4: synthesis of Compound 04

Transferring the ethanol solution of the compound 03 prepared in the previous step into a 10L four-mouth bottle provided with a mechanical stirring device, a reflux device and a gas displacement device, adding 2 times of molar equivalent of sodium ethoxide, starting stirring, displacing nitrogen, slowly dropwise adding an acetoacetate solution dissolved by 10 times of molar equivalent of ethanol at room temperature, heating the mixture to reflux reaction for 8 hours after the addition is finished, cooling the mixture to 0-5 ℃ after the reaction is finished, slowly dropwise adding 5 times of molar equivalent of distilled water into the system for quenching reaction, concentrating the mixture under reduced pressure to a small volume, adding 30 times of molar equivalent of water for diluting the product, extracting with dichloromethane for removing impurities, regulating the pH of the mixture to neutrality with hydrochloric acid, precipitating solids, extracting 4 times with ethyl acetate, combining organic phases, concentrating to near dryness, adding methyl tertiary butyl ether, pulping, and filtering to obtain a solid product, wherein the yield of the two steps is 74%.

¹ H-NMR(CDCl ₃ ):12.49(m,1H)、6.17(S,1H)、3.98(S,4H)、2.65(m,1H)、2.29(S,3H)、 2.47(m,2H)、2.29(S,3H)、1.87-1.97(m,6H)、1.69(m,2H)；

Example 5: synthesis of Compound 05

100g of

compound

04 and 15 times molar equivalent of methanol are added into a 2000ml four-mouth bottle, 10 times molar equivalent of concentrated hydrochloric acid is slowly added into the mixture dropwise under the condition of not exceeding 25 ℃, after the dropwise addition, the mixture is heated to 25 ℃ in 2 hours, the reaction is kept for 14 hours, 15 times molar equivalent of saturated sodium bicarbonate solution is slowly added into the mixture after the reaction is complete by HPLC, the methanol is removed by decompression concentration, 10 times molar equivalent of water is added, 15 times molar equivalent of ethyl acetate is used for extraction for 3 times, the organic phases are combined, and the mixture is concentrated to dryness under reduced pressure, so that white solid is obtained, and the yield is 89%.

Example 6: synthesis of Compound 06

To a 1000ml four-necked flask, 60g of a compound of 05,7 molar equivalents of tribromomethane and 15 molar equivalents of methanol were added, a 2-fold molar equivalent potassium hydroxide solution obtained by dissolving 15-fold molar equivalents of methanol was slowly dropped into the system at not more than 0℃and reacted at a temperature of 2 hours after the completion of the dropping, then the temperature of the mixture was slowly raised to 35℃over 2 hours and reacted at a temperature of 14 hours, after which the mixture was gradually dropped into 5-fold molar equivalents of 3N hydrochloric acid at not more than 10℃after the completion of the HPLC, and the mixture was extracted three times with 15-fold molar equivalents of ethyl acetate, and the organic phase was combined and concentrated under reduced pressure, followed by column chromatography using silica gel, methylene chloride: methanol=50: 1 eluting, collecting the eluent, concentrating under reduced pressure to dryness to obtain white solid with the yield of 83%.

¹ H-NMR(CDCl3):11.91(m,1H)、6.17(S,1H)、3.83(S,3H)、3.27(S,3H)、2.69(m,1H)、 2.47(m,2H)、2.29(S,3H)、2.02(m,2H)、1.83(m,2H)、1.65(m,2H)。

Example 7: synthesis of Compound 00, 2097133-31-6

To a 1000ml four-necked flask, 50g of the

compound

06, 4 times molar equivalent of DIPEA and 20 times molar equivalent of methylene chloride were added, and under the condition of not more than 5 ℃,4 times molar equivalent of thionyl chloride diluted with 6 times molar equivalent of methylene chloride was slowly added dropwise, after the addition was completed, the reaction was kept for 1 hour, then the temperature was raised to reflux reaction for 20 hours, after the completion of the HPLC detection reaction, the mixture was cooled to 25 ℃, immersed in ice water, extracted 3 times with 20 times molar equivalent of methylene chloride, the organic phases were combined, concentrated to dryness under reduced pressure, silica gel column chromatography was performed using n-hexane: ethyl acetate=4:1 to 2:1, the eluent was collected and concentrated to give a colorless oil, which was a white solid after freezing in 86% yield with an HPLC purity of 98.0%.

¹ H-NMR(CDCl3):7.02(S,1H)、3.77(S,3H)、3.26(S,3H)、2.91(m,1H)、2.49(S,3H)、2.36(m, 2H)、2.05(m,2H)、1.87(m,2H)、1.61(m,2H)

The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and improvements could be made by those skilled in the art without departing from the inventive concept, which falls within the scope of the present invention.

Claims

1. A novel synthesis method of a platinib intermediate 2097133-31-6, which is characterized by comprising the following steps:

step 2, adding the compound 01 and hydroxylamine salt, and reacting to obtain a compound 02; the hydroxylamine salt is hydroxylamine sulfate, hydrochloride, acetate or p-toluenesulfonate;

step 3, reducing the compound 02 under the action of a catalyst to obtain a compound 03; the catalyst is palladium/carbon, pt/C or Raney nickel;

step 4, carrying out reflux reaction on the compound 03 and ethyl acetoacetate under the action of alkali to close the ring to obtain a compound 04; the alkali is sodium ethoxide;

step 5, deprotection of compound 04 under acidic conditions gives compound 05; the acid is selected from hydrochloric acid, sulfuric acid or acetic acid;

step 6, reacting the compound 05 with bromoform under alkaline conditions to obtain a compound 06; the base is selected from potassium hydroxide or sodium hydroxide; the solvent is methanol;

step 7, chloridizing the compound 06 to obtain a compound 00 namely a platinib intermediate 2097133-31-6; the chlorinating agent is selected from thionyl chloride, phosphorus oxychloride, oxalyl chloride or solid phosgene;

the specific reaction formula is as follows:

2. the novel synthesis method of platinib intermediate 2097133-31-6 according to claim 1, wherein compound SM01 and p-toluenesulfonylmethyl isonitrile in step 1 are reacted under alkaline conditions in a solvent, and the rearrangement isomerization is performed to obtain compound 01, wherein compound SM01: p-toluenesulfonylmethyl isonitrile: alkali: the molar ratio of the solvent is as follows: 1:1-3: 1 to 5: 8-40, wherein the alkali is sodium tert-butoxide or potassium tert-butoxide, and the solvent is selected from tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether or dioxane; the reaction temperature is-30 ℃ and the reaction time is 5-15 hours.

3. The novel synthesis method of platinib intermediate 2097133-31-6 according to claim 1, wherein in step 2, compound 01 is reacted with hydroxylamine salt in solvent under the action of alkali, and compound 02 is obtained by addition, wherein compound 01: hydroxylamine salt: alkali: the mol ratio of the solvent is 1:1-3:1-5: 8-40; the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or triethylamine; the solvent is selected from ethanol, methanol, n-propanol, isopropanol or n-butanol; the temperature is 20-reflux, and the reaction time is 8-10 hours.

4. The novel synthesis method of platinib intermediate 2097133-31-6 according to claim 1, wherein compound 02 is reduced in a solvent under the action of a catalyst to obtain compound 03, wherein compound 02: catalyst: reducing agent: the mol ratio of the solvent is 1:0.1-0.5:1-10: 8-40, wherein the reducing agent is hydrogen; the solvent is selected from methanol, ethanol or isopropanol; the reaction temperature is not more than 35 ℃ and the reaction time is 12-24 hours.

5. The novel synthesis method of platinib intermediate 2097133-31-6 according to claim 1, wherein compound 03 in step 4 is cyclized with ethyl acetoacetate in a solvent under the action of a base to obtain compound 04, wherein compound 03: alkali: ethyl acetoacetate: the mol ratio of the solvent is 1:1-5:1-3: 8-40, ethanol as solvent, 70-80 deg.c and 8-10 hr.

6. The novel synthesis of platinib intermediate 2097133-31-6 according to claim 1, wherein compound 04 in step 5 is deprotected under acidic conditions to afford compound 05, wherein compound 04: acid: the mol ratio of the solvent is 1:1-20: 8-40, wherein the solvent is selected from methanol, ethanol, dioxane or water; the temperature is 25-35 ℃; the reaction time is 12-14 hours.

7. The novel synthesis of platinib intermediate 2097133-31-6 according to claim 1, wherein compound 05 is prepared in one step in a solvent under basic conditions and bromoform in step 6 to provide compound 06, wherein compound 05: bromine simulation: alkali: the mol ratio of the solvent is 1:1-10: 1-20: 8-40, the temperature is 0-25 ℃, and the reaction time is 17-20 hours.

8. The novel synthesis method of the platinib intermediate 2097133-31-6 according to claim 1, wherein in the step 7, the compound 06 is chlorinated in a solvent in the presence of an acid-binding agent to obtain the compound 00, namely the platinib intermediate 2097133-31-6; the mol ratio of the compound 06 to the chloridizing reagent to the acid-binding agent to the solvent is 1:1-5:1-8:8-40, and the acid-binding agent is selected from diisopropylethylamine, DBU and 2, 6-lutidine; the solvent is selected from dichloromethane, dichloroethane or toluene; the reaction temperature is reflux, and the reaction time is 20-24 hours.