CN113336761B - Preparation method of JAK inhibitor key intermediate - Google Patents
Preparation method of JAK inhibitor key intermediate Download PDFInfo
- Publication number
- CN113336761B CN113336761B CN202110627757.3A CN202110627757A CN113336761B CN 113336761 B CN113336761 B CN 113336761B CN 202110627757 A CN202110627757 A CN 202110627757A CN 113336761 B CN113336761 B CN 113336761B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- reaction
- compound shown
- pyrimidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a JAK inhibitor key intermediate, which comprises the following steps: step a, protecting amino of 4-chloro-7H-pyrrole- [2.3-d ] -pyrimidine serving as a raw material to synthesize 4-chloro-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine; step b, reacting 4-chloro-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine with a methylating agent to synthesize 4-methyl-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine; and c, deprotecting the 4-methyl-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine to synthesize 4-methyl-7H-pyrrole- [2.3-d ] -pyrimidine. According to the preparation method of the JAK inhibitor key intermediate, the raw materials are low in price and easy to obtain in the market, the production cost is low, each step of the synthesis method is a conventional reaction, a high-risk reagent is not used, the operation is simple, the dosage of a format reagent is reduced and the generation of C-N bimolecular coupling impurities is avoided due to protection, the product purity is improved, and the aftertreatment is easier.
Description
Technical Field
The invention relates to the technical field of organic matter synthesis, in particular to a preparation method of a JAK inhibitor key intermediate.
Background
4-methyl-7H-pyrrolo [2,3-d ] pyrimidine is an important medical intermediate, and is mainly used for synthesis of JAK1/JAK2 tyrosine kinase inhibitor (CN108699063), Fms kinase small molecule inhibitor and Kit, Flt3, TrkA/TrkB/TrkC enzyme inhibitor (Joc,2019), wherein the ruxolitinib phosphate (other name: ruxolitinib phosphate) is a JAK1/JAK2 tyrosine kinase inhibitor, and is mainly used for treating high-risk bone fibrosis (PMF) in (1), including primary myelofibrosis (2) myelofibrosis (PPV-MF) secondary to polycythemia vera, approved by the European Union in 8 months in 2012, approved in Japan in 7 months in 2014, and approved as the first bone fibrosis drug by FDA in U.S. 12 months in 2014. 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine is used as a key intermediate, few synthesis routes are reported at present, and the following methods are mainly adopted.
The method comprises the following steps: US2019/23712/WO2020/142557/CN108699063 respectively discloses a synthesis method of the intermediate, 4-chloro-7H-Pyrrolo [2,3-d ] s ]Pyrimidine as a starting material, Pd (dppf) Cl 2 The process uses expensive palladium metal and has larger catalyst consumption, so the cost is high and the industrial production amplification is not facilitated; the second method comprises the following steps: in the synthesis method disclosed in US2007/191293, iron acetylacetonate is used to replace palladium catalysts, although the cost is reduced, the reaction time is long, the yield is low, the post-treatment is difficult, column purification is required, and the method is not suitable for industrial amplification; the third method comprises the following steps: WO2018/55097/Bioorganic and Medicinal Chemistry Letters,2012, vol.22, #24p.7742-7747 discloses another synthesis method, uses combustible trimethylaluminum in the air as a methylating agent, has harsh reaction conditions and higher operation requirements, and in addition, a large amount of commercial products of the trimethylaluminum are not provided with stable manufacturers at home and need to be imported, and the amplification production has greater difficulty. At present, the three synthetic methods also have the defects of large solvent consumption and more dangerous wastes.
Because the starting material 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine has imino in the raw material, if the protection is not carried out, the Buchwald-Hartwig C-N coupling reaction can be carried out simultaneously when the Kumada C-C coupling reaction is carried out by a one-step method; in addition, a typical side reaction of the coupling reaction is dechlorination reaction, so that 3 impurities are generated together, the properties of the 3 impurities are very close to those of the product, TLC is only a very regular round dot, the impurities are separated by HPLC after a large amount of experiments, and the product quality is difficult to meet the requirement of API production due to the fact that refining and removing are extremely difficult. Moreover, multiple refinements lead to a considerable reduction in the yield and to an increase in the cost.
Based on the above, in order to solve the disadvantages in the above synthesis process, the present application aims to provide a preparation method of a key intermediate 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine, which has the advantages of low cost, safety, environmental protection, easy operation and industrial production prospect.
Disclosure of Invention
The preparation method of the key intermediate of the JAK inhibitor according to the embodiment of the invention comprises the following steps: protecting amino group of the compound of formula (IV) to convert into compound of formula (III), reacting compound of formula (III) with methylating agent to convert into compound of formula (II), and deprotecting compound of formula (II) to convert into compound of formula (I). The preparation method of the intermediate compound of the invention comprises the following steps:
in some embodiments of the present application, the specific steps are as follows:
step a, dissolving a compound shown as a formula (IV) in acetone, adding an amino protective agent, dropwise adding an alkaline reagent at the temperature of 10-30 ℃, preserving heat for reacting for 3 hours after dropwise adding, and filtering to obtain a compound shown as a formula (III);
b, dissolving the compound shown in the formula (III) in an ether solvent, adding a catalyst, dropwise adding a methyl Grignard reagent at a controlled temperature, heating to 60-70 ℃ for reacting for 2 hours after dropwise adding, cooling after the reaction is finished, dropwise adding a saturated ammonium chloride aqueous solution for quenching, extracting with ethyl acetate, drying, filtering and concentrating to obtain a compound shown in the formula (II);
And c, suspending the compound shown in the formula (II) in methanol, adding potassium hydroxide, adding water for quenching after the reaction is finished, adjusting the pH value to 6-7 by hydrochloric acid, extracting by ethyl acetate, drying, filtering, concentrating and purifying to obtain the compound shown in the formula (I).
According to the preparation method of the JAK inhibitor key intermediate provided by the embodiment of the invention, the used starting material, tofacitinib hydrochloride and rukutinib phosphate are the same intermediate, and the intermediate is cheap and easy to obtain in the market; each step of the synthesis method is a conventional reaction, a high-risk reagent is not used, and the operation is simple; compared with a one-step method, the method has the advantages that the dosage of a methylating agent is reduced, the three wastes are reduced, and the treatment cost of the three wastes is reduced due to the protection; and secondly, an expensive palladium catalyst is not used, so that high yield is ensured, the generation of impurities is reduced, the cost is reduced, and the product quality is improved. In conclusion, the preparation method of the JAK inhibitor key intermediate has a good industrial application prospect.
According to some embodiments of the invention, the method further comprisesIn step a, the amino protecting agent is selected from 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl), methoxymethyl chloride (MOM-Cl), N-pivaloyloxymethyl chloride (POM-Cl), 2-Tetrahydropyranyl (THP), p-methylbenzenesulfonyl chloride (Tos-Cl), methanesulfonyl chloride (Ms-Cl), p-nitrobenzenesulfonyl chloride (Ns-Cl), benzyloxycarbonylchloride (Cbz-Cl), di-tert-butyl dicarbonate (Boc) 2 O) one or more of; the alkaline reagent is selected from one or more of sodium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen.
According to some embodiments of the invention, in the step a, the amino protecting agent is p-methyl benzenesulfonyl chloride (Tos-Cl) or di-tert-butyl dicarbonate (Boc) 2 O); the alkaline reagent is sodium hydroxide.
According to some embodiments of the present invention, in the step b, the ether solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and diethyl ether; the catalyst is selected from (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride (Ni (dppf) Cl 2 ) 1, 2-bis (diphenylphosphino) ethane nickel (Ni) (dppe) Cl 2 ) 1, 2-bis (diphenylphosphino) propanenickel (Ni) (dppp) Cl 2 ) One or more of iron acetylacetonate and nickel acetylacetonate; the methyl Grignard reagent is selected from one or more of 3.0M methyl magnesium bromide/2-methyl tetrahydrofuran solution, 3.0M methyl magnesium chloride/tetrahydrofuran solution and 1.0M methyl magnesium bromide/tetrahydrofuran solution; the molar ratio of the compound of formula (III), the catalyst and the methyl Grignard reagent is 1: 0.01-0.1: 1.2-3.
According to some embodiments of the invention, in step b, the catalyst is selected from the group consisting of 1, 2-bis (diphenylphosphino) propanenickel chloride (ni (dppp) Cl 2 ) One or more of iron acetylacetonate; the molar ratio of the compound of formula (III), the catalyst and the methylating agent is 1: 0.05-0.07: 1.5-2.5.
According to some embodiments of the present invention, in step c, the compound of formula (ii) is subjected to deprotection on amino group under basic condition by a solvent and a catalyst to obtain the compound of formula (i), wherein the solvent is one or more selected from methanol, tetrahydrofuran and acetonitrile, and the basic agent is one or more selected from potassium hydroxide, sodium hydroxide, potassium tert-butoxide and potassium carbonate.
According to some embodiments of the present invention, in step c, the compound of formula (ii) is deprotected on amino group under acidic condition by a solvent selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile and water and a catalyst to obtain the compound of formula (i), and the acidic reagent is one or more of trifluoroacetic acid, concentrated hydrochloric acid, hydrobromic acid and boron trifluoride diethyl etherate.
According to some embodiments of the present invention, in step c, the purification process includes dissolving the compound of formula (i) in tetrahydrofuran under heating, filtering, evaporating the solvent, adding acetonitrile, heating, refluxing, and pulping, wherein the mass ratio of formula (i) to tetrahydrofuran and acetonitrile is 1: 5-10: 1-5.
According to some embodiments of the invention, in step a, the molar ratio of the compound of formula (iv) to the protecting agent is 1: 1.0-1.5; in the step b, the reaction temperature is 35-80 ℃; in the step c, the molar ratio of the compound represented by the formula (III) to potassium hydroxide is 1: 1.0-5.0.
According to some embodiments of the invention, in step a, the molar ratio of the compound of formula (iv) to the protecting agent is 1: 1.0-1.2; in the step b, the reaction temperature is 60-70 ℃; in step c, the molar ratio of the compound represented by the formula (III) to potassium hydroxide is 1: 1.5-2.5.
Drawings
In order to more clearly illustrate the embodiments of the present invention, we will briefly introduce the drawings that need to be used in the embodiments, and the drawings described below are only exemplary illustrations of the present application.
Figure 1 is a process scheme of a method for the preparation of key intermediates of JAK inhibitors according to an embodiment of the invention.
Detailed Description
Reference will now be made in detail to the embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar chemical structures represent like or similar compounds throughout. The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention.
The preparation of key intermediates of JAK inhibitors according to the embodiments of the present invention is described below with reference to fig. 1.
The preparation method of the key intermediate of the JAK inhibitor according to the embodiment of the invention comprises the following steps: protecting amino group of the compound of formula (IV) to convert into compound of formula (III), reacting compound of formula (III) with methylating agent to convert into compound of formula (II), and deprotecting compound of formula (II) to convert into compound of formula (I). The preparation method of the intermediate compound of the invention comprises the following steps:
in some embodiments of the present application, the specific steps are as follows:
step a, dissolving a compound shown as a formula (IV) in acetone, adding an amino protective agent, dropwise adding an alkaline reagent at the temperature of 10-30 ℃, preserving heat for reacting for 3 hours after dropwise adding, and filtering to obtain a compound shown as a formula (III);
b, dissolving the compound shown in the formula (III) in an ether solvent, adding a catalyst, dropwise adding a methyl Grignard reagent at a controlled temperature, heating to 60-70 ℃ for reacting for 2 hours after dropwise adding, cooling after the reaction is finished, dropwise adding a saturated ammonium chloride aqueous solution for quenching, extracting with ethyl acetate, drying, filtering and concentrating to obtain a compound shown in the formula (II);
and c, suspending the compound shown in the formula (II) in methanol, adding potassium hydroxide, adding water for quenching after the reaction is finished, adjusting the pH value to 6-7 by hydrochloric acid, extracting by ethyl acetate, drying, filtering, concentrating and purifying to obtain the compound shown in the formula (I).
According to the preparation method of the JAK inhibitor key intermediate, the used starting material, tofacitinib hydrochloride and tricinctinib phosphate are the same intermediate, and the intermediate is low in market price and easy to obtain; each step of the synthesis method is a conventional reaction, a high-risk reagent is not used, and the operation is simple; compared with a one-step method, the method has the advantages that the dosage of a methylating agent is reduced, the three wastes are reduced, and the treatment cost of the three wastes is reduced due to the protection; and secondly, an expensive palladium catalyst is not used, so that high yield is ensured, the generation of impurities is reduced, the cost is reduced, and the product quality is improved. In conclusion, the preparation method of the JAK inhibitor key intermediate has a good industrial application prospect.
According to some embodiments of the invention, in step a, the amino protecting agent is selected from the group consisting of 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl), methoxymethyl chloride (MOM-Cl), N-pivaloyloxymethyl chloride (POM-Cl), 2-Tetrahydropyranyl (THP), p-methylbenzenesulfonyl chloride (Tos-Cl), methanesulfonyl chloride (Ms-Cl), p-nitrobenzenesulfonyl chloride (Ns-Cl), benzyloxycarbonylchloride (Cbz-Cl), di-tert-butyl dicarbonate (Boc-Cl) 2 One or more of O); the alkaline reagent is selected from one or more of sodium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen.
According to some embodiments of the invention, in the step a, the amino protecting agent is p-methyl benzenesulfonyl chloride (Tos-Cl) or di-tert-butyl dicarbonate (Boc) 2 O); the alkaline reagent is sodium hydroxide.
According to some embodiments of the present invention, in the step b, the ether solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and diethyl ether; the catalyst is selected from (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride (Ni (dppf) Cl 2 ) 1, 2-bis (diphenylphosphino) ethane nickel (Ni) (dppe) Cl 2 ) 1, 2-bis (diphenylphosphino) propanenickel (Ni) (dppp) Cl 2 ) One or more of iron acetylacetonate and nickel acetylacetonate; the methyl Grignard reagent is selected from one or more of 3.0M methyl magnesium bromide/2-methyl tetrahydrofuran solution, 3.0M methyl magnesium chloride/tetrahydrofuran solution and 1.0M methyl magnesium bromide/tetrahydrofuran solution; the molar ratio of the compound of formula (III), the catalyst and the methyl Grignard reagent is 1: 0.01-0.1: 1.2-3.
According to some embodiments of the invention Example, in step b, the catalyst is selected from the group consisting of 1, 2-bis (diphenylphosphino) propanenickel chloride (Ni (dppp) Cl 2 ) One or more of iron acetylacetonate; the molar ratio of the compound of formula (III), the catalyst and the methylating agent is 1: 0.05-0.07: 1.5-2.5.
According to some embodiments of the present invention, in step c, the compound of formula (ii) is subjected to deprotection on amino group under basic condition by a solvent and a catalyst to obtain the compound of formula (i), wherein the solvent is one or more selected from methanol, tetrahydrofuran and acetonitrile, and the basic agent is one or more selected from potassium hydroxide, sodium hydroxide, potassium tert-butoxide and potassium carbonate.
According to some embodiments of the present invention, in step c, the compound of formula (ii) is deprotected on amino group under acidic condition by a solvent selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile and water and a catalyst to obtain the compound of formula (i), and the acidic reagent is one or more of trifluoroacetic acid, concentrated hydrochloric acid, hydrobromic acid and boron trifluoride diethyl etherate.
According to some embodiments of the present invention, in step c, the purification process includes dissolving the compound of formula (i) in tetrahydrofuran under heating, filtering, evaporating the solvent, adding acetonitrile, heating, refluxing, and pulping, wherein the mass ratio of formula (i) to tetrahydrofuran and acetonitrile is 1: 5-10: 1-5.
According to some embodiments of the invention, in step a, the molar ratio of the compound of formula (iv) to the protecting agent is 1: 1.0-1.5; in the step b, the reaction temperature is 35-80 ℃; in the step c, the molar ratio of the compound represented by the formula (III) to potassium hydroxide is 1: 1.0-5.0.
According to some embodiments of the invention, in step a, the molar ratio of the compound of formula (iv) to the protecting agent is 1: 1.0-1.2; in the step b, the reaction temperature is 60-70 ℃; in step c, the molar ratio of the compound represented by the formula (III) to potassium hydroxide is 1: 1.5-2.5.
The preparation of key intermediates of JAK inhibitors according to embodiments of the present invention is described below with reference to specific examples, and solvents, reagents, starting materials, etc. used in the present invention are all commercially available chemically pure or analytically pure products.
Example 1:
step a: synthesis of 4-chloro-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine
100g of 4-chloro-7H-pyrrole- [2.3-d ] -pyrimidine and 136.6g of p-toluenesulfonyl chloride were dissolved in 500mL of acetone, 300mL of 2.5N aqueous NaOH was added at room temperature, the reaction was stirred at room temperature for 3 hours, monitored by TLC (DCM: MeOH ═ 10:1), and after completion of the reaction, the mixture was filtered, and the filter cake was washed with 100mL of acetone/water ═ 1:1, and dried to obtain compound (iii) (190g, 94.81%).
Step b: synthesis of 4-methyl-7-p-toluenesulfonyl-7H-pyrrole- [2.3-d ] -pyrimidine
Weighing 30g of compound (III), dissolving 1.7g of ferric acetylacetonate in 300mL of tetrahydrofuran, cooling the reaction solution to-5-0 ℃, controlling the temperature to be less than 5 ℃ under the protection of nitrogen, slowly dropwise adding 65mL of 3.0M methyl magnesium bromide, heating to 65 ℃ after the completion of dropwise addition, reacting for 2 hours, monitoring by TLC (PE: EA is 1:1), cooling after the reaction is finished, controlling the temperature to be less than 10 ℃, dropwise adding 200mL of saturated ammonium chloride aqueous solution for quenching, stirring for 30 minutes, standing for layering, extracting the aqueous phase once by 100mL of EA, combining organic phases, drying with anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain compound (II) (23.6g, 84.26%).
Step c Synthesis of 4-methyl-7H-pyrrole- [2.3-d ] -pyrimidine
Weighing 23.6g of the compound (II) and suspending the compound (II) in 120mL of methanol, adding 9.22g of potassium hydroxide, stirring to dissolve the mixture, reacting at room temperature for 1 hour, monitoring by TLC (PE: EA 1:1), adding 200mL of purified water after the reaction is finished, dropwise adding 2MHCl to adjust the pH value to 6-7, adding EA to extract for 3 times and 100 mL/time, combining organic phases, drying by anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain a crude compound (I) (10.7g, 97.8%). Heating, refluxing and dissolving the crude product in 60mL tetrahydrofuran, performing hot filtration, concentrating the filtrate to dryness, adding 25mL acetonitrile, heating, refluxing and pulping for 1 hour, slowly cooling, stirring at room temperature for 1 hour, and performing suction filtration to obtain a compound (I) (8.86g, 80.99% of two-step yield)
Example 2:
step a: synthesis of 4-chloro-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine
100g of 4-chloro-7H-pyrrole- [2.3-d ] -pyrimidine and 136.6g of p-toluenesulfonyl chloride were dissolved in 500mL of acetone, 300mL of 2.5N aqueous NaOH was added at room temperature, the reaction was stirred at room temperature for 3 hours, monitored by TLC (DCM: MeOH ═ 10:1), and after completion of the reaction, the mixture was filtered, and the filter cake was washed with 100mL of acetone/water ═ 1:1, and dried to obtain compound (iii) (190g, 94.81%).
Step b: synthesis of 4-methyl-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine
30g of Compound (III), 2.63g of 1, 2-bis (diphenylphosphino) ethanenickel (Ni) (dppe) Cl 2 ) Dissolving in 300mL tetrahydrofuran, cooling the reaction solution to-5-0 deg.C, controlling temperature under nitrogen protection<Slowly adding 65mL of 3.0M methyl magnesium bromide dropwise at 5 ℃, heating to 65 ℃ after dropping, reacting for 2 hours, monitoring by TLC (PE: EA is 1:1), cooling after the reaction is finished, and controlling the temperature<And (3) dropwise adding 200mL of saturated ammonium chloride aqueous solution at 10 ℃ for extraction, stirring for 30 minutes, standing for layering, extracting the aqueous phase once by using 100mL of EA, combining the organic phases, drying by using anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain a compound (II) (21.1g, 75.33%).
Step c Synthesis of 4-methyl-7H-pyrrole- [2.3-d ] -pyrimidine
21.1g of the compound (II) is weighed, suspended in 110mL of methanol, added with 8.24g of potassium hydroxide, stirred to dissolve and clear, reacted at room temperature for 1 hour, monitored by TLC (PE: EA 1:1), after the reaction is finished, added with 200mL of purified water, dropwise added with 2MHCl to adjust the pH to 6-7, extracted 3 times with 100mL of EA, combined with the organic phases, dried with anhydrous sodium sulfate, filtered and evaporated to dryness to obtain a crude compound (I) (9.2g, 94.09%). Heating, refluxing and dissolving the crude product in 60mL tetrahydrofuran, performing hot filtration, concentrating the filtrate to dryness, adding 25mL acetonitrile, heating, refluxing and pulping for 1 hour, slowly cooling, stirring at room temperature for 1 hour, and performing suction filtration to obtain a compound (I) (8.0g, the two-step yield is 81.80%)
Example 3:
step a: synthesis of 4-chloro-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine
100g of 4-chloro-7H-pyrrole- [2.3-d ] -pyrimidine and 136.6g of p-toluenesulfonyl chloride were dissolved in 500mL of acetone, 320mL of a 2.5N KOH aqueous solution was added at room temperature, the reaction was stirred at room temperature for 3 hours, monitored by TLC (DCM: MeOH ═ 10:1), and after completion of the reaction, the mixture was filtered, and the filter cake was washed with 100mL of acetone/water ═ 1:1, and dried to obtain compound (iii) (195.5g, 97.55%).
Step b: synthesis of 4-methyl-7-p-toluenesulfonyl-pyrrole- [2.3-d ] -pyrimidine
Weighing 30g of compound (III), dissolving 1.7g of ferric acetylacetonate in 300mL of tetrahydrofuran, cooling the reaction solution to-5-0 ℃, controlling the temperature to be less than 5 ℃ under the protection of nitrogen, slowly dropwise adding 65mL of 3.0M methyl magnesium bromide, heating to 65 ℃ after the completion of dropwise addition, reacting for 2 hours, monitoring by TLC (PE: EA is 1:1), cooling after the reaction is finished, controlling the temperature to be less than 10 ℃, dropwise adding 200mL of saturated ammonium chloride aqueous solution for quenching, stirring for 30 minutes, standing for layering, extracting the aqueous phase once by 100mL of EA, combining organic phases, drying by anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain compound (II) (23.6g, 84.26%).
Step c Synthesis of 4-methyl-7H-pyrrole- [2.3-d ] -pyrimidine
Weighing 23.6g of compound (II) and dissolving in 100mL of dichloromethane, adding 29.45g of trifluoroacetic acid in an ice-water bath, reacting at room temperature for 6 hours after the addition is finished, monitoring by TLC (PE: EA ═ 1:1), concentrating and pouring into ice water after the reaction is finished, dropwise adding 2N NaOH aqueous solution to adjust the pH to 6-7, adding EA to extract for 3 times and 100 mL/time, combining organic phases, drying by anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain a crude product (8.4g, 76.81%) of compound (I). Heating, refluxing and dissolving the crude product in 60mL tetrahydrofuran, performing hot filtration, concentrating the filtrate to dryness, adding 25mL acetonitrile, heating, refluxing and pulping for 1 hour, slowly cooling, stirring at room temperature for 1 hour, and performing suction filtration to obtain a compound (I) (7.4g, the two-step yield is 67.64%)
Example 4:
step a: synthesis of tert-butyl 4-chloropyrrolo [2,3-d ] pyrimidine-7-carboxylate
Weighing 18.8g of sodium hydride, dissolving in 240mL of tetrahydrofuran, cooling the reaction liquid to-5-0 ℃, adding 60g of 4-chloro-7H-pyrrole- [2.3-d ] -pyrimidine in batches, stirring for 1 hour under heat preservation, adding 93.8g of di-tert-butyl dicarbonate, stirring for reaction for 2 hours at room temperature after the addition is finished, monitoring by TLC (DCM: MeOH 10:1), cooling after the reaction is finished, controlling the temperature to be less than 15 ℃, dropwise adding 150mL of water for quenching, stirring for 30 minutes, adding 100mL of EA for extraction, combining organic phases, adding 200mL of saturated sodium chloride aqueous solution for washing once, drying by anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain 4-chloropyrrolo [2,3-d ] pyrimidine-7-carboxylic acid tert-butyl ester (89.3g, 90.1%).
Step b: synthesis of tert-butyl 4-methylpyrrolo [2,3-d ] pyrimidine-7-carboxylate
Weighing 20g of 4-chloropyrrolo [2,3-d ] pyrimidine-7-carboxylic acid tert-butyl ester and 1.39g of iron acetylacetonate in 200mL of tetrahydrofuran, cooling the reaction solution to-5-0 ℃, controlling the temperature to be below 5 ℃ under the protection of nitrogen, slowly adding 52.5mL of 3.0M methyl magnesium bromide dropwise, heating to 65 ℃ after dropping, reacting for 2 hours, monitoring by TLC (PE: EA is 1:1), cooling after the reaction is finished, controlling the temperature to be below 10 ℃, adding 200mL of saturated ammonium chloride aqueous solution dropwise, quenching, stirring for 30 minutes, standing for layering, extracting the aqueous phase by 100mL of EA, combining the organic phases, drying by anhydrous sodium sulfate, filtering, and evaporating to obtain a compound (II) (15.1g, 82.10%).
Step c Synthesis of 4-methyl-7H-pyrrole- [2.3-d ] -pyrimidine
Weighing 15.1g of 4-chloropyrrolo [2,3-d ] pyrimidine-7-carboxylic acid tert-butyl ester, suspending the mixture in 80mL of methanol, adding 7.25g of potassium hydroxide, stirring to dissolve, reacting at room temperature for 1 hour, monitoring by TLC (PE: EA ═ 1:1), adding 150mL of purified water after the reaction is finished, dropwise adding 2M HCl to adjust the pH to 6-7, adding EA to extract for 3 times and 100 mL/time, combining organic phases, drying with anhydrous sodium sulfate, filtering, and evaporating to obtain a crude compound (I) (9.1g, 86.69%). Heating, refluxing and dissolving the crude product in 45mL tetrahydrofuran, performing hot filtration, concentrating the filtrate to dryness, adding 18mL acetonitrile, heating, refluxing and pulping for 1 hour, slowly cooling, stirring at room temperature for 1 hour, and performing suction filtration to obtain the compound (I) (7.8g, the two-step yield is 74.29%).
The preparation method of the key intermediate of the JAK inhibitor according to the embodiment of the invention comprises the following steps:
step a, dissolving a compound shown as a formula (IV) in acetone, adding an amino protective agent, dropwise adding an alkaline reagent at the temperature of 10-30 ℃, preserving heat for reaction for 3 hours after dropwise adding, and filtering to obtain a compound shown as a formula (III), wherein the amino protective agent is selected from 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl), methoxymethyl chloride (MOM-Cl) and N-tert-butyl chloride Valeryloxymethyl chloride (POM-Cl), 2-Tetrahydropyranyl (THP), p-methylbenzenesulfonyl chloride (Tos-Cl), methanesulfonyl chloride (Ms-Cl), p-nitrobenzenesulfonyl chloride (Ns-Cl), benzyloxycarbonylchloride (Cbz-Cl), di-tert-butyl dicarbonate (Boc-Cl) 2 O), preferably p-methylbenzenesulfonyl chloride (Tos-Cl), di-tert-butyl dicarbonate (Boc) 2 O); the alkaline agent used is selected from sodium hydroxide, potassium carbonate, sodium hydrogen, preferably sodium hydroxide, potassium hydroxide, sodium hydrogen, more preferably sodium hydroxide.
Step b, dissolving the compound shown in the formula (III) in tetrahydrofuran, adding a catalyst, controlling the temperature, dropwise adding a methyl Grignard reagent, heating to 60-70 ℃ for reacting for 2 hours after dropwise adding, cooling after the reaction is finished, dropwise adding a saturated ammonium chloride aqueous solution for quenching, extracting with ethyl acetate, drying, filtering and concentrating to obtain the compound shown in the formula (II), wherein the used solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran and diethyl ether, preferably tetrahydrofuran, and the used catalyst is selected from (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride (Ni (dppf) Cl) 2 ) 1, 2-bis (diphenylphosphino) ethane nickel (Ni) (dppe) Cl 2 ) 1, 2-bis (diphenylphosphino) propanenickel (Ni) (dppp) Cl 2 ) Iron acetylacetonate, nickel acetylacetonate, preferably nickel 1, 2-bis (diphenylphosphino) propane chloride (Ni (dppp) Cl) 2 ) Ferric acetylacetonate, the methylating agent used being selected from the group consisting of 3.0M methylmagnesium bromide/2-methyltetrahydrofuran solution, 3.0M methylmagnesium chloride/tetrahydrofuran solution, 1.0M methylmagnesium bromide/tetrahydrofuran solution, preferably 3.0M methylmagnesium bromide/2-methyltetrahydrofuran solution; the molar ratio of the compound of formula (iii) to the catalyst and methylating agent is 1: 0.01-0.1: 1.2-3, preferably 1: 0.05-0.07: 1.5-2.5.
Suspending the compound shown in the formula (II) in methanol, adding potassium hydroxide, adding water for quenching after the reaction is finished, adjusting the pH value to 6-7 by using dilute hydrochloric acid, extracting by using ethyl acetate, drying, filtering, concentrating and purifying to obtain the compound shown in the formula (I), wherein the compound shown in the formula (II) can be obtained by removing a protecting group on an amino group by selecting a proper solvent and a proper catalyst under an alkaline or acidic condition. In alkaline conditions, the solvent used is selected from methanol, tetrahydrofuran, acetonitrile, preferably methanol, and the alkaline agent used is selected from potassium hydroxide, sodium hydroxide, potassium tert-butoxide, potassium carbonate, preferably potassium hydroxide. In acidic conditions, the solvent used is selected from dichloromethane, tetrahydrofuran, acetonitrile, water, preferably dichloromethane, and the acidic reagent used is selected from trifluoroacetic acid, concentrated hydrochloric acid, hydrobromic acid, boron trifluoride diethyl etherate, preferably trifluoroacetic acid. And the agricultural purification process in the step c comprises the steps of mixing, heating and dissolving the compound shown in the formula (I) and tetrahydrofuran, carrying out heat filtration, evaporating the solvent to dryness, adding acetonitrile, heating, refluxing and pulping, wherein the mass ratio of the compound shown in the formula (I) to the tetrahydrofuran to the acetonitrile is 1: 5-10: 1-5, preferably 1: 5-7: 2.
According to the preparation method of the JAK inhibitor key intermediate, the used starting material, tofacitinib hydrochloride and tricinctinib phosphate are the same intermediate, and the starting material is low in market price and easy to obtain; each step of the synthesis method is a conventional reaction, a high-risk reagent is not used, and the operation is simple; compared with a one-step method, the method has the advantages that the dosage of a methylating agent is reduced, three wastes are reduced, and the treatment cost of intermediate waste is reduced due to the protection; and secondly, an expensive palladium catalyst is not used, so that high yield is ensured, the generation of impurities is reduced, the cost is reduced, and the product quality is improved. In conclusion, the preparation method of the JAK inhibitor key intermediate has a good industrial application prospect.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, a specific operation, a chemical name, a process control parameter, etc., described in connection with the embodiment or example, is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, particular operations, chemical names, or process control parameters described, etc. may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
While embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.
Claims (1)
1. A preparation method of a key intermediate of a JAK inhibitor is characterized by comprising the following steps:
step a, weighing 100g of a compound shown in the formula IV, dissolving 136.6g of p-toluenesulfonyl chloride in 500mL of acetone, adding 300mL2.5N NaOH aqueous solution at room temperature, stirring and reacting for 3 hours at room temperature, filtering after the reaction is finished, washing a filter cake with 100mL of acetone/water of 1:1, and drying to obtain a compound shown in the formula III;
b, weighing 30g of a compound shown in the formula III, dissolving 1.7g of ferric acetylacetonate in 300mL of tetrahydrofuran, cooling the reaction solution to-5-0 ℃, controlling the temperature to be less than 5 ℃ under the protection of nitrogen, slowly dropwise adding 65mL of 3.0M methyl magnesium bromide, heating to 65 ℃ after dropwise adding, reacting for 2 hours, cooling after the reaction is finished, controlling the temperature to be less than 10 ℃, dropwise adding 200mL of saturated ammonium chloride aqueous solution, quenching, stirring for 30 minutes, standing for layering, extracting the aqueous phase once by using 100mL of LEA, combining the organic phases, drying with anhydrous sodium sulfate, filtering, and evaporating to obtain a compound shown in the formula II;
Step c, weighing 23.6g of the compound shown in the formula II, suspending the compound in 120mL of methanol, adding 9.22g of potassium hydroxide, stirring to dissolve the compound clearly, reacting at room temperature for 1 hour, adding 200mL of purified water after the reaction is finished, dropwise adding 2MHCl to adjust the pH value to 6-7, adding EA to extract for 3 times and 100 mL/time, combining organic phases, drying with anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain the compound shown in the formula I; heating, refluxing and dissolving the crude product in 60mL tetrahydrofuran, performing heat filtration, concentrating the filtrate to dryness, adding 25mL acetonitrile, heating, refluxing and pulping for 1 hour, slowly cooling, stirring at room temperature for 1 hour, and performing suction filtration to obtain a compound shown in the formula I;
the synthesis process is as follows:
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110627757.3A CN113336761B (en) | 2021-06-05 | 2021-06-05 | Preparation method of JAK inhibitor key intermediate |
| PCT/CN2022/084233 WO2022252789A1 (en) | 2021-06-05 | 2022-03-31 | Method for preparing jak inhibitor key intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110627757.3A CN113336761B (en) | 2021-06-05 | 2021-06-05 | Preparation method of JAK inhibitor key intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113336761A CN113336761A (en) | 2021-09-03 |
| CN113336761B true CN113336761B (en) | 2022-07-29 |
Family
ID=77474212
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110627757.3A Active CN113336761B (en) | 2021-06-05 | 2021-06-05 | Preparation method of JAK inhibitor key intermediate |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN113336761B (en) |
| WO (1) | WO2022252789A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113336761B (en) * | 2021-06-05 | 2022-07-29 | 山东莱福科技发展有限公司 | Preparation method of JAK inhibitor key intermediate |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015018534A1 (en) * | 2013-08-09 | 2015-02-12 | Grünenthal GmbH | Novel substituted condensed pyrimidine compounds |
| ES2882118T3 (en) * | 2015-12-31 | 2021-12-01 | Chia Tai Tianqing Pharmaceutical Group Co Ltd | Ruxolitinib Synthesis Procedure |
| JP7536767B2 (en) * | 2018-12-31 | 2024-08-20 | バイオメア フュージョン，インコーポレイテッド | Irreversible inhibitors of menin-mll interaction |
| CN113336761B (en) * | 2021-06-05 | 2022-07-29 | 山东莱福科技发展有限公司 | Preparation method of JAK inhibitor key intermediate |
-
2021
- 2021-06-05 CN CN202110627757.3A patent/CN113336761B/en active Active
-
2022
- 2022-03-31 WO PCT/CN2022/084233 patent/WO2022252789A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2022252789A1 (en) | 2022-12-08 |
| CN113336761A (en) | 2021-09-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112321602A (en) | Preparation method of Ruogeli drug intermediate | |
| JP6719527B2 (en) | Method for preparing azoxystrobin intermediate | |
| CN112062767B (en) | Preparation method and intermediate of rumepilone | |
| CN113336761B (en) | Preparation method of JAK inhibitor key intermediate | |
| CN109608468B (en) | Tofacitinib citrate impurity, and synthesis method and application thereof | |
| CN114989103B (en) | Preparation method of 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline | |
| CN111574384B (en) | Preparation method of chiral 1-amino-2-propanol | |
| CN105175316B (en) | A kind of method for preparing laxative picosulfate sodium | |
| CN104016954A (en) | Method for preparing and purifying nebivolol intermediate | |
| CN108164423A (en) | A kind of preparation method of naftifine hydrochloride | |
| CN110724098A (en) | Synthetic method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid hydrochloride | |
| CN113024454B (en) | Synthesis method of brigatinib intermediate | |
| CN113072514A (en) | Preparation method of cycleanine and intermediate thereof | |
| CN115477653B (en) | Preparation method of trehalfline key intermediate and trehalfline | |
| CN114195684B (en) | Synthesis method of amino protecting group N-substituted chiral amino acid | |
| CN103288742A (en) | Preparation method for high-purity ingavirin raw material | |
| CN115947675B (en) | Rasagiline intermediate and preparation method and application thereof | |
| CN111302997B (en) | Method for preparing Raatinib intermediate by one-pot method | |
| CN111574540B (en) | Preparation method of Degatinib | |
| CN107089928A (en) | The synthetic method of N Boc L propargylglycines | |
| CN110668951B (en) | Synthesis process of selegiline hydrochloride | |
| CN112300059B (en) | Preparation method of PF-06651600 intermediate | |
| CN118239952A (en) | Preparation method of ticagrelor | |
| CN108530390B (en) | Alkylation method of 4-hydroxybenzophenone | |
| CN108341821B (en) | Synthesis method of epinastine hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Zhao Hongshuang Inventor after: Zhao Weijian Inventor after: Song Sujun Inventor after: Sang Yunfu Inventor before: Zhao Hongshuang Inventor before: Zhao Weijian Inventor before: Song Sujun Inventor before: Sang Yunfu |
|
| CB03 | Change of inventor or designer information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |