CN115057822A - Novel synthesis method of pratinib intermediate 2097133-31-6 - Google Patents
Novel synthesis method of pratinib intermediate 2097133-31-6 Download PDFInfo
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Abstract
The invention relates to the technical field of organic synthesis of medical intermediates, in particular to a novel synthesis method of a pratinib intermediate 2097133-31-6. The invention provides a new synthetic route of a pratinib intermediate 2097133-31-6. The method has the advantages of simple operation, mild conditions, easily available raw materials, high safety, environmental protection, good purity of the prepared product and high yield.
Description
Technical Field
The invention relates to the field of synthesis of medical intermediates, in particular to a new synthesis method of a pratinib intermediate 2097133-31-6.
Background
Praatinib (trade name is Pujihua), is a receptor tyrosine kinase RET (reacted reduced transfection) inhibitor, is the selective RET inhibitor which is approved to be on the market in China first, can inhibit RET and downstream molecule phosphorylation thereof, and effectively inhibits cell proliferation expressing RET gene variation. The selectivity for RET is significantly improved compared to the effects of approved multi-kinase inhibitors. By inhibiting primary and secondary variation, pratinib is expected to prevent the occurrence of clinical drug resistance. It was developed by Blueprint medicins and the foundational pharmaceutical industry received exclusive development and commercial authorization of this drug in the major and central areas.
Praatinib is an oral, once-a-day, potent and highly selective RET inhibitor, approved by the chinese national drug administration for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have previously received platinum-containing chemotherapy positive for transfection-Rearrangement (RET) gene fusion; for the treatment of advanced or metastatic RET-mutated Medullary Thyroid Carcinoma (MTC) adults and children 12 years and older in need of systemic treatment, and advanced or metastatic RET fusion-positive thyroid carcinoma adults and children 12 years and older in need of systemic treatment and radioiodine refractory (if radioiodine is applicable).
The existing original research on the synthesis of the pratinib key intermediate 2097133-31-6 adopts a metal coupling mode to synthesize the intermediate 2097133-31-6, and has high cost and difficult synthesis.
2, 4-dichloro-6-methylpyrimidine is used as a raw material to prepare an intermediate compound 2097133-31-6 through multi-step reaction, wherein the iodine-containing compound needs to be catalytically coupled by noble metal, and the iodine-containing compound has higher price and iodine-containing wastewater is difficult to treat. (WO2017/79140,2017, A1)
Disclosure of Invention
The technical problem to be solved by the invention is as follows: through extensive research on a method for solving the defects of the prior art, the inventor finds a more economic synthetic route, provides a new synthetic route of the pratinib intermediate 2097133-31-6, and has the characteristics of high purity of a target compound, high yield, simple operation, low cost, environment-friendly process and the like.
In order to solve the above problems, the technical solution provided by the present invention is as follows:
a novel synthesis method of pratinib intermediate 2097133-31-6 comprises the following steps:
the specific reaction formula is as follows:
further, step 1: reacting a compound SM01 with p-toluenesulfonylmethylisocyanamide in a solvent under an alkaline condition, and carrying out rearrangement isomerization to obtain a compound 01, wherein the compound SM 01: p-toluenesulfonylmethyl isonitrile: alkali: the molar ratio of the solvent is as follows: 1: 1-3: 1-5: 8-40; the preferred molar ratio is 1:1.3:1.3:20, with preference: the base is potassium tert-butoxide or sodium tert-butoxide, and the solvent is selected from tetrahydrofuran, methyl tert-butylether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether or dioxane; the reaction temperature is-30 to 30 ℃, and the reaction time is 5 to 15 hours;
in the step 2, the compound 01 reacts with hydroxylamine salt in a solvent under the action of alkali, and a compound 02 is obtained through addition, wherein the reaction ratio of the compound 01: hydroxylamine salts: alkali: the molar ratio of the solvent is 1: 1-3: 1-5: 8-40, preferably in a molar ratio of 1:2:3.6:30, preferably hydroxylamine sulfate, hydrochloride, acetate or p-toluenesulfonate; the alkali 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 ℃ to 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 ratio of the compound 02: catalyst: reducing agent: the molar ratio of the solvent is 1: 0.1-0.5: 1-10: 8-40, preferably in a molar ratio of 1:0.3: 8: 20, the preferred 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 and ethyl acetoacetate are subjected to ring closure in a solvent under the action of alkali to obtain a compound 04, wherein the compound 03, the alkali and the ethyl acetoacetate: the molar ratio of the solvent is 1: 1-5: 1-3: 8-40, and the preferable molar ratio is: 1:1.5:1.5:30, preferably selecting sodium ethoxide as alkali, ethanol as solvent, reaction temperature of 70-80 ℃ and reaction time of 8-10 hours;
deprotection of compound 04 under acidic conditions in step 5 affords compound 05, wherein compound 04: acid: the molar ratio of the solvent is 1: 1-20: : 8-40, and the preferable molar ratio is: 1:10:15, preferably the acid is 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;
in the step 6, the compound 05 is prepared into a compound 06 in a solvent under the alkaline condition and bromoform in one step, wherein the ratio of 05: bromoform: alkali: the molar ratio of the solvent is 1: 1-10: 1-20: 8-40, preferably in a molar ratio of 1:7:2:30, and 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 a solvent in the presence of an acid-binding agent to prepare a compound 00, namely a pratinib intermediate 2097133-31-6. The compound 06, the chlorination reagent, the acid-binding agent and the solvent are in a molar ratio of 1: 1-5: 1-8: 8-40, the preferred molar ratio is 1:4:4:26, and the preferred chlorination reagent is selected from thionyl chloride, phosphorus oxychloride, oxalyl chloride or solid phosgene; the acid-binding agent is selected from diisopropylethylamine, DBU, 2, 6-dimethylpyridine; the solvent is selected from dichloromethane, dichloroethane or toluene; the reaction temperature is reflux, and the reaction time is 20-24 hours.
Compared with the prior art, the invention has the advantages of simple operation, mild condition, easily obtained raw materials, avoidance of use of expensive reagents, high safety, convenient post-treatment, reduction of environmental protection pressure, good purity of the prepared product, high yield and wide application prospect.
The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; the structural formula is subject to obvious errors.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of Compound 01 1 H-NMR；
FIG. 2 is the NMR spectrum of Compound 04 1 H-NMR；
FIG. 3 is a NMR hydrogen spectrum of Compound 06 1 H-NMR；
FIG. 4 is the NMR hydrogen spectrum of Compound 00 1 H-NMR。
Detailed Description
The invention is illustrated but not limited by the following examples. In the technical scheme, the invention is protected by simple replacement or improvement of the invention by a person skilled in the art.
Example 1: synthesis of Compound 01
Placing 1000g of starting material SM01 (monoethylene glycol protected 1, 4-cyclohexanedione), 1.3 times of molar equivalent of p-toluenesulfonylmethylisocyanogen and 20 times of molar equivalent of solvent tetrahydrofuran into a 20L four-mouth bottle equipped with a mechanical stirrer, replacing nitrogen in the reaction system, cooling the reaction material to-30 ℃, slowly adding 1.3 times of molar equivalent of potassium tert-butoxide solid into the reaction system under the protection of heat preservation nitrogen, stirring for 2 hours under heat preservation after the addition is finished, slowly raising the mixture to room temperature within 2 hours, reacting for 3 hours under heat preservation, and detecting by HPLC, wherein the reaction is finished. And (3) reducing the temperature of the mixture to-30 ℃ again, slowly adding 2kg of distilled water into the system at a temperature not higher than-10 ℃, raising the temperature to room temperature within 2 hours after the addition is finished, stirring for 4 hours, transferring the mixture to a reaction kettle, concentrating to a small volume, adding 5kg of distilled water and 10 kg of ethyl acetate into the mixture, stirring, standing, separating, extracting the water phase for 2 times by using the same amount of ethyl acetate, combining the organic phases, and concentrating under reduced pressure to be dry for later use, wherein the crude 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 last step according to the quantitative yield, stirring for 15 minutes at room temperature, sequentially adding 2 molar equivalent of hydroxylamine sulfate and 3.6 equivalent of sodium hydroxide flake caustic soda under the condition of not more than 50 ℃, directly raising the reaction system to reflux for 8 hours after the addition, and finishing the HPLC detection reaction. 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, extracting the water phase for 2 times by using the same amount of ethyl acetate, combining the ethyl acetate phases, concentrating, and using methanol as a product: crystallizing with water at a ratio of 1:3, filtering, drying in a vacuum oven at a temperature of not more than 50 ℃ under reduced pressure, weighing, and obtaining a yield of 68% in two steps.
Example 3: synthesis of Compound 03
Adding 300g of compound 02, 0.2 time molar equivalent of Pd/C catalyst and 20 times molar equivalent of methanol into a 2L hydrogenation kettle, reducing the mixture to below 35 ℃ under the hydrogen pressure of 2MPa, reducing the pressure after HPLC detection reaction, filtering, recovering the catalyst, concentrating the filtrate under reduced pressure till the filtrate is nearly dry, removing methanol and water for 2 times by using 2 volumes of absolute ethyl alcohol, and adding 20 times molar equivalent of ethyl alcohol to prepare a solution for later use.
Example 4: synthesis of Compound 04
Transferring the prepared ethanol solution of the compound 03 to a 10L four-mouth bottle equipped with a mechanical stirring device, a reflux device and a gas displacement device, adding 2 times of molar equivalent of sodium ethoxide, starting stirring, performing nitrogen displacement, slowly dropwise adding an ethyl acetoacetate solution dissolved by using 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 HPLC detection reaction is finished, slowly dropwise adding 5 times of distilled water into the system to quench the reaction, performing reduced pressure concentration on the mixture to reduce the volume, adding 30 times of molar equivalent of water to dilute the product, extracting by using dichloromethane to remove impurities, adjusting the pH of the mixture to be neutral by hydrochloric acid, separating out solids, extracting by using ethyl acetate for 4 times, combining organic phases, concentrating to be nearly dry, adding methyl tert-butyl ether and pulping, filtration gave the solid product in 74% yield over two steps.
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
Adding 100g of compound 04 and 15 times of molar equivalent of methanol into a 2000ml four-mouth bottle, slowly dropwise adding 10 times of molar equivalent of concentrated hydrochloric acid into the mixture under the condition of not exceeding 25 ℃, after the dropwise adding is finished, heating the mixture to 25 ℃ within 2 hours, preserving heat for reaction for 14 hours, after the HPLC shows that the reaction is complete, slowly dropwise adding 15 times of molar equivalent of saturated sodium bicarbonate solution into the mixture, carrying out reduced pressure concentration to remove the methanol, supplementing 10 times of molar equivalent of water, extracting for 3 times by using 15 times of molar equivalent of ethyl acetate, combining organic phases, and carrying out reduced pressure concentration to dryness to obtain a white solid with the yield of 89%.
Example 6: synthesis of Compound 06
Adding 60g of compound 05, 7 times of molar equivalent of tribromomethane and 15 times of molar equivalent of methanol into a 1000ml four-mouth bottle, slowly dropwise adding a 2 times of molar equivalent of potassium hydroxide solution dissolved in 15 times of molar equivalent of methanol into the system under the condition of not more than 0 ℃, preserving heat for reaction for 2 hours after dropwise adding, then slowly raising the temperature of the mixture to 35 ℃ within 2 hours, preserving heat for reaction for 14 hours, after HPLC shows that the reaction is finished, slowly dropwise adding the mixture into 5 times of molar equivalent of 3N hydrochloric acid under the condition of not more than 10 ℃, extracting for three times by using 15 times of molar quantitative ethyl acetate, combining organic phases, carrying out reduced pressure concentration, and then using silica gel column chromatography, dichloromethane: methanol 50: 1, collecting eluent, and concentrating the eluent under reduced pressure until the eluent is dried to obtain a white solid with the yield of 83 percent.
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
Adding 50g of compound 06, 4 times of molar equivalent of DIPEA and 20 times of molar equivalent of dichloromethane into a 1000ml four-necked bottle, slowly dropwise adding 4 times of molar equivalent of thionyl chloride diluted by 6 times of molar equivalent of dichloromethane under the condition of not more than 5 ℃, after dropwise adding, preserving heat for reaction for 1 hour, then heating to reflux reaction for 20 hours, after HPLC detection reaction is completed, cooling the mixture to 25 ℃, immersing the mixture into ice water, extracting for 3 times by using 20 times of molar equivalent of dichloromethane, combining organic phases, concentrating under reduced pressure to be dry, performing chromatography, using n-hexane: eluting with ethyl acetate 4: 1-2: 1, collecting the eluent, and concentrating to obtain colorless oil, which is a white solid after freezing, wherein the yield is 86% and the HPLC purity is 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 above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, it is possible to make various changes and modifications without departing from the inventive concept, and these changes and modifications are all within the scope of the present invention.
Claims (8)
1. A novel synthesis method of a pratinib intermediate 2097133-31-6 is characterized by comprising the following steps:
step 1, carrying out rearrangement and cyanation on a compound SM01 and p-toluenesulfonylmethylisocyanamide to obtain a 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, deprotecting the compound 04 under an acidic condition to obtain a compound 05;
step 6, reacting the compound 05 with bromoform under an alkaline condition to obtain a compound 06;
step 7, chloridizing the compound 06 to obtain a compound 00, namely a praatinib intermediate 2097133-31-6;
the specific reaction formula is as follows:
2. the novel synthesis of pratinib intermediate 2097133-31-6 according to claim 1, wherein in step 1, compound SM01 and p-toluenesulfonylmethylitrile are reacted under basic conditions in a solvent, and rearrangement isomerization is carried out to obtain compound 01, wherein the compound SM 01: p-toluenesulfonylmethyl isonitrile: alkali: the molar ratio of the solvent is as follows: 1: 1-3: 1-5: 8-40, wherein the base 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 to 30 ℃ and the reaction time is 5 to 15 hours.
3. A novel synthesis of pratinib intermediate 2097133-31-6 according to claim 1, wherein in step 2, compound 01 is reacted with hydroxylamine salt in a solvent under the action of a base to obtain compound 02, wherein the ratio of compound 01: hydroxylamine salts: alkali: the molar ratio of the solvent is 1: 1-3: 1-5: 8-40, wherein the hydroxylamine salt is hydroxylamine sulfate, hydrochloride, acetate or p-toluenesulfonate; the alkali 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 ℃ to reflux, and the reaction time is 8-10 hours.
4. The novel synthesis of pratinib intermediate 2097133-31-6 according to claim 1, wherein in step 3, compound 02 is reduced in a solvent under the action of a catalyst to obtain compound 03, wherein the ratio of compound 02: catalyst: reducing agent: the molar ratio of the solvent is 1: 0.1-0.5: 1-10: 8-40, wherein 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.
5. The novel synthesis of pratinib intermediate 2097133-31-6 according to claim 1, wherein in step 4, compound 03 is cyclized with ethyl acetoacetate in a solvent under the action of a base to obtain compound 04, wherein the ratio of compound 03: alkali: ethyl acetoacetate: the molar ratio of the solvent is 1: 1-5: 1-3: 8-40, wherein the alkali is sodium ethoxide, the solvent is ethanol, the reaction temperature is 70-80 ℃, and the reaction time is 8-10 hours.
6. A novel synthesis of pratinib intermediate 2097133-31-6 according to claim 1, wherein deprotection of compound 04 in step 5 under acidic conditions provides compound 05, wherein compound 04: acid: the molar ratio of the solvent is 1: 1-20: 8-40, wherein the acid is 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.
7. A novel synthesis of pratinib intermediate 2097133-31-6 according to claim 1, wherein in step 6 compound 05 is prepared in one step with bromoform in a solvent under basic conditions to compound 06, wherein compound 05: bromoform: alkali: the molar ratio of the solvent is 1: 1-10: 1-20: 8-40, wherein the alkali 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.
8. A novel synthesis of praatinib intermediate 2097133-31-6 as claimed in claim 1, wherein in step 7 compound 06 is chlorinated in solvent in the presence of acid-binding agent to obtain compound 00 i.e. praatinib intermediate 2097133-31-6; the molar ratio of the compound 06 to the chlorination reagent to the acid-binding agent to the solvent is 1: 1-5: 1-8: 8-40, wherein the chlorination reagent is selected from thionyl chloride, phosphorus oxychloride, oxalyl chloride or solid phosgene; the acid-binding agent is selected from diisopropylethylamine, DBU, 2, 6-dimethylpyridine; the solvent is selected from dichloromethane, dichloroethane or toluene; the reaction temperature is reflux, and the reaction time is 20-24 hours.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108473468A (en) * | 2015-11-02 | 2018-08-31 | 蓝图药品公司 | The inhibitor of RET |
| CN111362923A (en) * | 2020-03-25 | 2020-07-03 | 魏威 | Method for preparing RET inhibitor pracetib, intermediate of pracetib and preparation method of pracetib |
| CN113072541A (en) * | 2021-04-02 | 2021-07-06 | 山东四环药业股份有限公司 | Preparation method of targeted drug BLU-667 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108473468A (en) * | 2015-11-02 | 2018-08-31 | 蓝图药品公司 | The inhibitor of RET |
| CN111362923A (en) * | 2020-03-25 | 2020-07-03 | 魏威 | Method for preparing RET inhibitor pracetib, intermediate of pracetib and preparation method of pracetib |
| CN113072541A (en) * | 2021-04-02 | 2021-07-06 | 山东四环药业股份有限公司 | Preparation method of targeted drug BLU-667 |
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