A process for the preparation of a key intermediate of vornolafexib

Abstract

The application relates to the field of pharmaceutical chemistry and provides a preparation method of a key intermediate of fumaric acid vorolanib. The method is to prepare the key intermediate 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde from 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde through two-step procedures, the key intermediate of fumaric acid vorolanib is prepared through an economic, green and safe method, the operation is simple, the condition is mild, and the product can be obtained at a high yield and high purity.

Description

TECHNICAL FIELD

[0001] The present application provides a method for preparing a key intermediate of vonoprazan fumarate. BACKGROUND

[0002] vonoprazan fumarate, commercially known as vonoprazan ® , is a monofumarate salt of 1-[5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, and its structural information is as follows:

[0003]

[0004] Vonoprazan fumarate is a new mechanism of action of an acid inhibitor developed by Takeda Pharmaceutical Co., Ltd. of Japan. Vonoprazan fumarate tablets were launched in Japan in February 2015, and were officially approved for marketing by the NMPA in December 2019, with the approved indication of reflux esophagitis (RE). As the first potassium ion competitive acid blocker (P-CAB) approved for entry into the Chinese market, it can block the K + channel of H + -K + ATPase, competitively block the binding of K + to the enzyme, and stay in the gastric wall cells for a long time, thereby rapidly inhibiting the secretion of gastric acid. It has the significant pharmaceutical characteristics of "fast, strong, long, and stable".

[0005] Reflux esophagitis is a common disease of the digestive system, and its characteristic symptoms include heartburn and acid reflux caused by gastric contents, which can be accompanied by extraesophageal symptoms, and there is an erosion of the esophageal mucosa, which seriously affects the quality of life and sleep of patients.

[0006] According to Newport data, as of March 2021, the global sales of vonoprazan fumarate were 8.9 tons, up 15.4% from the previous year, and the global sales were 80.4 billion yuan, up 20% from the same period last year, indicating that the market demand for this product will continue to increase in the future. Therefore, it is particularly urgent to develop a green, economic, and cost-controllable production process for vonoprazan fumarate to meet the increasing market demand and the challenge of the core competitiveness of the enterprise.

[0007] After searching the literature related to the preparation of vonoprazan fumarate, there are the following several preparation routes:

[0008] 1. The preparation process of vonoprazan fumarate disclosed in the compound patent CN101300229B example is as follows:

[0009]

[0010] The preparation of formula III in the process uses palladium-carbon catalytic hydrogenation process, and the reaction temperature for preparing formula I compound from formula IV compound is -78°C. The industrial production has higher requirements for equipment and high energy consumption.

[0011] 2. Another preparation process of vofratafibra is disclosed in the preparation method patent CN102421753B published by Takeda Pharmaceutical, which is an optimization based on the method disclosed in the compound patent, as follows:

[0012] On the basis of the compound patent, the preparation process of formula I compound is optimized to avoid the deep cold reaction, but the catalytic hydrogenation process is still used for preparing formula II compound from formula III compound and preparing formula I compound from formula II compound. The catalytic hydrogenation method also has higher requirements for reaction equipment, reaction workshop, etc., and the catalytic hydrogenation method introduces certain safety risks for large-scale production of vofratafibra.

[0013] 3. The patent CN201510786974.1 discloses the following route:

[0014]

[0015] This route avoids hydrogenation reaction, but uses relatively expensive reagents in the synthesis route, and there are many active intermediates in the reaction process, which can easily introduce process impurities, cause separation and purification difficulties, and have low yield and other risk points. Moreover, this process is only at the laboratory level, and it is not suitable to be used as the preparation process of industrialized vofratafibra.

[0016] The current mature preparation method of vofratafibra on the market is route 2, but in this route, the preparation of the key intermediate (formula I) involves two hydrogenation reactions. Hydrogenation reaction is a national key regulated dangerous process (national key regulated dangerous process directory 2013 edition). The hydrogenation process has the following dangerous characteristics: 1) the reaction material has flammable and explosive danger, the explosion limit of hydrogen is 4%~75%, which has high flammable and explosive danger characteristics; 2) hydrogenation is a strong exothermic reaction, hydrogen gas contacts with steel at high temperature, carbon molecules in steel are easy to react with hydrogen to form hydrocarbons, which reduces the strength of steel equipment and forms hydrogen embrittlement; 3) the catalyst regeneration and activation process is easy to cause explosion; (4) the exhaust gas of hydrogenation reaction contains unreacted hydrogen and other impurities, which is easy to cause fire and explosion when discharged.

[0017] In summary, whether the preparation process of intermediate I can be safely and controllably produced in larger batches directly affects the industrialization scale of vofratafibra. Therefore, it is particularly urgent to find a cheap and low-risk preparation method for formula I compound. SUMMARY

[0018] OBJECTIVE

[0019] The present application aims to prepare the key intermediate of vinorelbine fumarate by an economic, green and safe method, which is simple in operation, mild in conditions and high in product purity.

[0020] TECHNICAL SCHEME

[0021] The preparation method of the intermediate of formula I comprises: reacting the compound of formula III in the presence of triethylsilane, a palladium catalyst, an alkaline reagent and a solvent at a certain temperature to obtain the compound of formula II, and reacting the compound of formula II in the presence of triethylsilane, Raney nickel, an acidic reagent and a solvent at a certain temperature to obtain the compound of formula I, as shown below:

[0022]

[0023] The compound of formula III is used as a substrate, a certain proportion of base and a certain proportion of palladium catalyst are added in a mixed solvent of organic solvent and a certain proportion of purified water, and a certain proportion of triethylsilane is added at a certain temperature to react, and after post-treatment, the target intermediate of formula II is obtained; the compound of formula II is added in a mixed solvent of organic solvent and a certain proportion of purified water, a certain proportion of acid and a certain proportion of Raney nickel are added, and a certain proportion of triethylsilane is added at a certain temperature to react, and after post-treatment, the target intermediate of formula I is obtained.

[0024] Further, the preparation method of the compound of formula I and formula II comprises the following steps:

[0025] The preparation method of the compound of formula I and formula II is characterized in that the use of triethylsilane is 0.5-10.0 equivalents of the molar number of the substrate, and preferably 1.2-4.0;

[0026] The preparation method of the compound of formula I and formula II is characterized in that the palladium catalyst comprises palladium on carbon, palladium chloride, palladium acetate, tetraphenylphosphine palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tris(dibenzylideneacetone)dipalladium, 1,2-bis(diphenylphosphino)ethane and 1,3-bis(diphenylphosphino)propane, and preferably 10% palladium on carbon.

[0027] The organic solvent is an alcohol, an ether and water with a carbon number of 1-12, and preferably a mixed solvent of water or methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran and water in any proportion;

[0028] The preparation method of the compound of formula I and formula II according to claim 1 is characterized in that the reaction temperature is -10-50°C, and preferably 10-50°C, and more preferably 20-30°C.

[0029] The preparation method of the compound of formula I and formula II is characterized in that the basic reagent for preparing the compound of formula II includes inorganic bases including sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, bicarbonate amine, magnesium carbonate, barium carbonate, rubidium carbonate, cesium carbonate, wherein sodium bicarbonate is preferred; organic bases including triethylamine, N,N-diisopropyl ethylamine, pyridine, dimethyl pyridine, trimethylamine, tripropylamine, triethylene diamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 4-dimethylamino pyridine (DMAP), N-methyl morpholine, tetramethyl ethylene diamine, tetramethyl guanidine, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, n-butyllithium, phenyllithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), wherein triethylamine, N,N-diisopropyl ethylamine are preferred, and triethylamine is more preferred;

[0030] The preparation method of the compound of formula I and formula II is characterized in that the acid reagent for preparing the compound of formula I includes inorganic acids including hydrochloric acid, sulfuric acid, phosphoric acid, manganic acid, wherein hydrochloric acid is preferred; organic acids including formic acid, acetic acid, propionic acid, oxalic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, wherein formic acid and acetic acid are preferred, and formic acid is more preferred;

[0031] The preparation method of the compound of formula I and formula II is characterized in that triethylsilane is used as the H2 source, and the number of moles of triethylsilane is 0.5-10.0 equivalents of the number of moles of the substrate, wherein 1.2-4.0 is preferred;

[0032] Innovative points:

[0033] In the present application, triethylsilane reacts with water to generate hydrogen gas in situ and reacts with the substrate. This method avoids the use of a large amount of hydrogen gas, and by adding triethylsilane quantitatively, hydrogen gas is generated quantitatively for the reduction reaction of the target compound. The reaction can be completed at normal temperature and pressure without special equipment. The compound of formula I is obtained with high yield and high purity, almost no waste gas is discharged, the safety of producing the product is improved, and the supervision cost is reduced.

[0034] The preparation process route of the compound of formula II in the present application is as follows:

[0035]

[0036] The methods for reducing the structure similar to formula II (halogen reduction) reported in the literature at the present stage are searched and summarized, and all of them reduce the halogen on the pyrrole ring by catalytic hydrogenation, only the reaction pressure is different. As follows:

[0037]

[0038] The preparation process route of the compound of formula I in the application is as follows:

[0039]

[0040] The methods for the structures similar to formula I (cyano is reduced to aldehyde) reported in the literature at the present stage are searched and summarized, there are catalytic hydrogenation reduction using Raney nickel, and chemical reduction using DIBAL-H, as follows:

[0041]

[0042] According to the above literature, the reduction of chlorine on the pyrrole ring is mostly catalytic hydrogenation using palladium-carbon, and there is a certain difference in reaction pressure for different structures. In addition to hydrogenation reaction, the reaction temperature required for chemical method using DIBAL-H is harsh, the reaction temperature is-60~20℃, the reagent has poor stability and is sensitive to air and humidity. Therefore, the current catalytic hydrogenation method and chemical method both have special requirements for reaction equipment, which causes certain challenges to the control of production cost.

[0043] Based on the safety of industrial production, the controllability of supervision, we developed a green, low-cost process condition for reducing halogen and reducing cyano to aldehyde, which can reduce halogen and cyano at room temperature and normal pressure, the equipment has no special requirements, the operation is simple and can be executed, and the target intermediate compound of formula I can be obtained with high yield and high purity.

[0044] At the same time, we studied the potential impurities in the preparation process of formula II compound and formula I compound, as shown in the following table:

[0045]

[0046] For the reduction of halogen and aldehyde group using triethylsilane, we studied the potential impurities in the formula II compound and formula I compound, as shown in the above table, and formulated the control limit, which can ensure that the related substances of fumarate volorasen raw material meet the requirements.

[0047] Advantages

[0048] Innovations of the application:

[0049] 1. There is no literature report on the use of triethylsilane for halogen reduction and cyano reduction to aldehyde, and this process operation is first proposed in the application.

[0050] 2. The use of triethylsilane for halogen and cyano reduction can avoid the hydrogenation reaction, deep cooling reaction and other operations involved in the current reported process.

[0051] 3. Using triethylsilane for the reduction of halogens and cyano groups to aldehydes has low requirements for reaction temperature and pressure. The reaction can be completed at room temperature and pressure, which can greatly avoid the regulatory pressure and production safety risks caused by hydrogenation and cryogenic processes, and the power cost can also be significantly controlled.

[0052] 4. Using triethylsilane to reduce halogens and cyanides to aldehydes eliminates the need to avoid the influence of factors such as air and moisture, making it highly tolerant to operation and easy to control in industrial production.

[0053] 5. Using triethylsilane for the reduction of halogens and cyano groups to aldehydes yields and produces better results than the catalytic hydrogenation process, significantly reducing production costs.

[0054] 6. Triethylsilane is used to reduce halogens and cyano groups to aldehydes. The use of triethylsilane can be quantitative, avoiding the potential large amount of waste gas emissions and safety hazards associated with the use of hydrogen. Attached Figure Description

[0055] Appendix Figure 1 The image shows the HPLC chromatogram of the intermediate compound of formula II obtained in Example 1.

[0056] Appendix Figure 2 The image shows the HPLC chromatogram of the intermediate compound of formula I obtained in Example 1.

[0057] Appendix Figure 3 The image shows the HPLC chromatogram of the intermediate compound of formula II obtained in Comparative Example 1.

[0058] Appendix Figure 4 The image shows the HPLC chromatogram of the intermediate compound of formula I obtained in Comparative Example 1. Specific Implementation

[0059] Example 1

[0060] Preparation of compound II: At 20-30℃, 13.2L of ethanol, 1512g of triethylamine, 2200g of purified water, 2200g of compound III, and 250g of 5% palladium on carbon were added to a 20L reactor. 1380g of triethylsilane was added with stirring. After the addition was complete, the mixture was stirred for 30 minutes. The palladium on carbon was filtered off, the solvent was concentrated and evaporated, ethanol was added to dissolve the residue, purified water was added, the mixture was cooled to crystallize, filtered, and the filter cake was dried to constant weight to obtain 1650g of compound II, with a yield of 88.6% and an HPLC purity of 98.15%.

[0061] Preparation of the compound of formula I: 20~30℃, 8.7L tetrahydrofuran, 1180ml formic acid, 2700g purified water and 1300g compound of formula II, 160g Raney nickel, a mixture solution of 1254g triethylsilane and 450mL tetrahydrofuran was added under stirring, after addition, stirring for 1 hour, the Raney nickel was filtered out, the organic phase was added into ethyl acetate and water, extraction and separation, the organic phase was washed with sodium bicarbonate solution, saturated brine, concentrated to remove the organic phase, added into ethyl acetate to make a slurry, suction filtration, the filter cake was dried to constant weight, 1099g of the compound of formula I was obtained, the yield was 83.2%, the HPLC purity was 99.08%;

[0062] Example 2

[0063] Preparation of the compound of formula II: 20~30℃, 132mL methanol, 13.12g N,N-diisopropylethylamine, 22.00g purified water and 22.00g compound of formula III were added into a 250mL reaction bottle, 5.00g 10% palladium on carbon, a mixture solution of 13.80g triethylsilane and 20ml dichloromethane was added under stirring, after addition, stirring for 30 minutes, the palladium on carbon was filtered out, the solvent was evaporated by concentration, methanol was added, after stirring to dissolve, purified water was added, the temperature was lowered to crystallize, suction filtration, the filter cake was dried to constant weight, 15.27g of the compound of formula II was obtained, the yield was 82.1%;

[0064] Preparation of the compound of formula I: 20~30℃, 240mL tetrahydrofuran, 26g hydrochloric acid, 27ml purified water and 26g compound of formula II were added into a 500ml reaction kettle, 3g Raney nickel, 12.54g triethylsilane was added under stirring, after addition, stirring for 0.5 hour, the Raney nickel was filtered out, the filtrate was concentrated to remove the solvent, sodium bicarbonate aqueous solution and ethyl acetate were added, extraction and separation, the organic phase was washed with purified water again, separation, the organic phase was concentrated to evaporate ethyl acetate, methyl tert-butyl ether was added into the residue to make a slurry, suction filtration, the filter cake was dried to constant weight, 21.8g of the compound of formula I was obtained, the yield was 82.6%;

[0065] Example 3

[0066] Preparation of the compound of formula II: 20~30℃, 132mL tetrahydrofuran, 16.50g pyridine, 22.00g purified water and 40.00g compound of formula III were added into a 250mL reaction bottle, 5.30g palladium on carbon (5%), a mixture solution of 17.20g triethylsilane and 40ml tetrahydrofuran was added under stirring, after addition, stirring for 30 minutes, the palladium on carbon was filtered out, the solvent was evaporated by concentration, methanol was added, after stirring to dissolve, purified water was added, the temperature was lowered to crystallize, suction filtration, drying to constant weight, 15.27g of the compound of formula II was obtained, the yield was 82.1%;

[0067] Preparation of the compound of formula I: 20~30℃, 500ml reaction reactor was added 260mL tetrahydrofuran, 26.00g acetic acid, 54ml purified water and 26.00g compound of formula II, 6.00g Raney nickel, 16.23g triethylsilane was added under stirring, after completion of addition, stirring was continued for 0.5h, Raney nickel was filtered off, the filtrate was concentrated to remove the solvent, ethyl acetate and purified water were added to extract and separate, the organic phase was washed with sodium carbonate solution, separated, the organic phase was concentrated to remove ethyl acetate, methyl tert-butyl ether was added to the residue to dissolve and crystallize, the temperature was lowered to room temperature, filtration was carried out, and the filter cake was dried to constant weight to obtain 21.95g of the compound of formula I, with a yield of 83.1%;

[0068] Comparative example 1

[0069] Preparation of the compound of formula II and formula I by catalytic hydrogenation method

[0070] Preparation of the compound of formula II: 20~30℃, 250ml reaction bottle was added 160ml methanol, 13.79g triethylamine, 20.00g compound of formula III and 1.00g palladium-carbon, stirring was carried out, nitrogen replacement was carried out, hydrogen replacement was carried out, the pressure in the reaction bottle was maintained at 0.3Mpa, reaction was carried out for 15h, palladium-carbon was filtered off, the organic phase was concentrated to remove, 100ml purified water was added to the residue to make a slurry, filtration was carried out, and the filter cake was dried to constant weight to obtain 15.37g of the compound of formula II, with a yield of 90.8% and a purity of 89.28%.

[0071] Preparation of the compound of formula I: 20~30℃, 250ml reaction bottle was added 90ml tetrahydrofuran, 30ml water, 6ml acetic acid, 15.00g compound of formula II and 12.00g Raney nickel, stirring was carried out, nitrogen replacement was carried out three times, hydrogen replacement was carried out three times, the pressure in the reaction bottle was maintained at 0.3MPa, reaction was carried out for 9h, Raney nickel was filtered off, ethyl acetate and purified water were added to separate, the organic phase was washed with sodium bicarbonate solution, separated, the organic phase was concentrated to remove, n-heptane was added to the residue to stir and crystallize, filtration was carried out, and the filter cake was dried to constant weight to obtain 11.37g of the compound of formula II, with a yield of 74.6% and a purity of 97.60%.

[0072] Comparative example 2

[0073] Reduction of cyano group to aldehyde by DiBAL-H chemical method

[0074] Preparation of compound of formula I: 20~30℃, in 250ml reaction bottle, add 70ml dichloromethane (control moisture <0.05%), add 3g compound of formula II, cool to-40℃, add DiBAL-H dichloromethane solution under nitrogen protection, temperature not higher than-35℃, reaction for 5 hours, after reaction, warm to room temperature, wash the organic phase with 5% citric acid aqueous solution, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, column chromatography to obtain the target intermediate, yield 52.3%.

[0075] Comparative example 3

[0076] Effect of reduction temperature on the reaction

[0077] Preparation of compound of formula II: in 50ml reaction bottle, add 14ml tetrahydrofuran, 1.5g pyridine, 2.2g purified water and 4.0g compound of formula III, 0.5g palladium carbon (5%), stir and warm to reflux (60~66℃), add 2.0g triethylsilane and 4ml tetrahydrofuran mixed solution, after adding, stir for 30 minutes, TLC detection reaction, more remaining compound of formula III. When the temperature is higher, the solubility of generated hydrogen gas in the solution is significantly reduced, which leads to insufficient hydrogen gas participating in the reaction. Therefore, the reaction temperature should not be too high.

[0078] Preparation of compound of formula II: in 50ml reaction bottle, add 14ml tetrahydrofuran, 1.5g pyridine, 2.2g purified water and 4.0g compound of formula III, 0.5g palladium carbon (5%), stir and cool to-15℃, add 2.0g triethylsilane and 4ml tetrahydrofuran mixed solution, after adding, stir for 30 minutes, TLC detection reaction, more remaining compound of formula III, continue to monitor the reaction, 9 hours later, part of the material is still not completely reacted. It is judged that the reaction temperature should not be lower than-10℃, otherwise the production efficiency will be reduced.

Claims

1. A method for preparing a key intermediate I of vonoprazan fumarate, characterized in that: The reaction is carried out as follows: Compound III reacts with triethylsilane, a palladium catalyst, a basic reagent, and a solvent to give compound II; compound II reacts with triethylsilane, Raney nickel, an acidic reagent, and a solvent to give compound I, as shown in the following reaction formulas: The reaction temperature is -10 to 50°C. The solvent is selected from aqueous alcohol solvents with 1 to 12 carbon atoms and / or aqueous ether solvents; The alkaline reagent is selected from any one of triethylamine, N,N-diisopropylethylamine, and pyridine.

2. The method as described in claim 1, characterized in that, The molar number of triethylsilane is 1.0 to 10.0 times the molar number of the substrate.

3. The method as described in claim 1, characterized in that, The palladium catalyst is selected from any one of palladium on carbon, palladium chloride, palladium acetate, tetra(triphenylphosphine palladium), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, and tris(dibenzylideneacetone)palladium.

4. The method as described in claim 1, characterized in that, The solvent is a mixture of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, and water in any proportion.

5. The method as described in claim 1, characterized in that, The acidic reagent used in the preparation of compound I is selected from inorganic acids and organic acids; wherein the inorganic acid is selected from any one of hydrochloric acid, sulfuric acid, and phosphoric acid; and the organic acid is selected from any one of formic acid, acetic acid, propionic acid, oxalic acid, citric acid, trichloroacetic acid, and trifluoroacetic acid.

Images