CN111393365A - Preparation method of Rosxastat - Google Patents
Preparation method of Rosxastat Download PDFInfo
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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Abstract
The invention provides a preparation method of the roxasistat, which has the advantages of cheap and easily-obtained starting raw materials, short synthetic route, short reaction period, no environmental pollution, simple and convenient operation, harsh reaction conditions avoidance, simple and convenient operation and post-treatment, higher yield and product purity, solid intermediates in each step, easy purification and lower production cost, is suitable for industrial mass production and conforms to the green chemical principle.
Description
1. Field of the invention
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of a roxasistat.
2. Background of the invention
Rosesartat (Roxadustat, FG-4592) was originally developed by FibroGen (Fabry-Perot) in the United states. In 2006, 4, Astellas reached a license agreement with fibrigen, gaining the rights of development of rosxastat in europe, the solitary union, the middle east and south africa. 31/7/2013, AstraZeneca (AstraZeneca) and fibrigen entered a strategic partnership agreement, the development rights of major markets in the united states, china and outside the areas licensed by the above-mentioned Astellas.
In 2018, 12 and 18 months, rosxastat, developed by cooperation between china having fabac and china having astrikon, was first approved for marketing in china for the treatment of anemia in patients undergoing dialysis treatment due to Chronic Kidney Disease (CKD). The preparation on the market is a capsule, the specification is 20mg and 50mg, and the trade name is erethizone. The structure of the rasagiline is shown in the following formula.
Chinese patent application CN1816527A, CN102718708A, CN102977015A, CN102977016A and CN103145616A disclose a method for preparing roxasistat from 4-phenoxy phthalonitrile through 11 steps of reactions, wherein the reaction route is shown below. Reagents used in the method, such as tribromooxyphosphorus, methyl iodide, benzyl bromide and chloroformate, have high toxicity; the reaction time is longer: the reaction time of multi-step operation is more than 18h, and some reaction time is as high as 3.5 d; the reaction conditions are harsh: if the second step is a melting stirring reaction at 210 ℃, the methylation reaction is carried out at-78 ℃ and ultralow temperature, and the potential safety hazard of the final step of hydrogenation pressurization is large; the intermediate is purified by column chromatography in multiple steps, has longer steps and higher cost, and is not suitable for industrial production.
Chinese patent application CN103435546A and CN106083719A disclose a method for synthesizing roxasistat by using 5-bromophenylphthalide as a raw material through 9 steps of reaction, wherein the reaction route is shown as follows. The first step of etherification reaction in the process, 5-bromophenylphthalide is easy to open a ring to generate more impurities; the reagent acetic anhydride used in the process is easy to prepare toxin and belongs to a tube product, and in the fourth step, the tosyl glycine is used, and sulfonate genotoxic impurities are possibly introduced; heavy metals such as cuprous bromide and palladium carbon are used in the process, and element detection is added in a finished product; two pressurizing steps: the hydrogenation and pressurization have great potential safety hazard, the aminolysis reaction of the ester in the last step is difficult to carry out, special equipment is needed, the method is not suitable for industrial production, and the process cost is high.
The Chinese patent application CN107954931A discloses a method for synthesizing roxasistat by taking-hydroxy-7-phenoxyisoquinoline-3-methyl formate as a raw material through bromination, coupling hydrolysis, condensation and ester hydrolysis, wherein the reaction route is shown as follows. The reaction of each step of the process needs reflux reaction for 6 hours or overnight reaction, the reaction time of the whole process is longer, and the energy consumption is larger; in the first bromination reaction, methanol is used as a solvent, and methoxy substituted impurities are easily generated; hydrolysis impurities are easily generated in the second step of reaction, the reaction system is relatively complex and difficult to refine, the purity of an intermediate is relatively difficult to control, and the yield is relatively low.
The Chinese patent application CN107602466A discloses a method for synthesizing roxasistat by taking 3-nitrobenzylamine as a raw material through 10-step reaction, and the reaction route is shown as follows. The initial raw materials of the process are not easy to obtain and the cost is high; the adopted chloroacetic acid is of moderate toxicity, chloromethane carcinogenesis has genotoxicity, potassium permanganate is strong in oxidability, hydrochloric acid, sulfuric acid, liquid bromine and chloroacetic acid are tube products, and the reagents have certain potential safety hazards; the reaction temperature of the first step is up to 150 ℃, and the reaction temperature of the ninth step is up to 220 ℃; the chloromethane and ammonia gas steel cylinders have larger potential safety hazard during storage, and are not suitable for industrial production.
Therefore, the research on a preparation method of the roxasistat, which has the advantages of readily available reaction raw materials, low toxicity of the reaction raw materials, simple synthetic route, short reaction time, simple and convenient operation, low cost, no environmental pollution and suitability for industrial mass production, is a problem to be solved in the field.
3. Summary of the invention
The invention aims to solve the problems in the prior art, and provides a novel preparation method of the roxasistat, which has the advantages of cheap and easily-obtained starting raw materials, low toxicity of reaction raw materials, short synthetic route, short reaction period, no environmental pollution, simple and convenient operation, harsh reaction conditions avoidance, simple and convenient operation and post-treatment, high yield and product purity, solid intermediates in each step, easy purification, low production cost, suitability for industrial mass production and accordance with the green chemical principle, so as to overcome the problems in the prior art.
In order to achieve the above object, the present invention provides a method for preparing a rasagiline comprising the steps of:
(1) carrying out substitution reaction on the compound shown in the formula I and a halogenating reagent to generate a compound shown in a formula II;
(2) carrying out hydrolysis reaction on the compound of the formula II in the presence of an organic solvent and alkali to generate a compound of a formula III;
(3) carrying out condensation reaction on the compound shown in the formula III and glycine ester hydrochloride in the presence of a condensing agent to generate a compound shown in the formula V;
(4) under the catalysis of a catalyst, carrying out methylation reaction on the compound shown in the formula V and a methylation reagent in a mixed solution of an organic solvent and an aqueous solution of an inorganic base, and simultaneously carrying out hydrolysis reaction to obtain the rosixostat;
wherein X is halogen; r1And R2Is C1-6An alkyl group.
In the step (1), the halogenating reagent is selected from one or more of 1, 3-dichloro-5, 5-dimethylhydantoin, 1, 3-dibromo-5, 5-dimethylhydantoin, 1, 3-diiodo-5, 5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine and elementary iodine; preferably, it is N-bromosuccinimide.
In the step (1), the reaction temperature is 10-70 ℃; preferably 25 deg.c.
In the step (1), the reaction time is 0-5 h.
In step (1), the reaction molar ratio of the compound of formula I to the halogenating agent is 1: (1-2).
In the step (2), the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and cesium carbonate; preferably sodium hydroxide.
In the step (2), the reaction temperature is 50-120 ℃.
In the step (2), the reaction time is 0-5 h.
In the step (3), the reaction temperature is 0-50 ℃.
In the step (3), the reaction time is 1-5 h.
In the step (4), the methylating agent is selected from one or more of methyl boric acid, isopropyl methylborate, trimethyl boron, tetramethyl tin, methyl magnesium bromide and methyl magnesium chloride; preferably methyl boronic acid.
In the step (4), the organic solvent is one or more selected from methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol methyl ether, ethylene glycol diethyl ether, ethylene glycol ethyl ether, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane and acetonitrile; ethylene glycol methyl ether is preferred.
In the step (4), the catalyst is palladium catalyst selected from PdCl2、Pd2(dba)3、Pd(OAc)2、Pd(dppf)Cl2、 Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(PPh3)2(OAc)2One or more of (a); preferably, Pd (PPh)3)4。
In the step (4), the aqueous solution of the inorganic base is one or more aqueous solutions of sodium bicarbonate, potassium acetate, potassium carbonate, sodium acetate, potassium bicarbonate, cesium carbonate, sodium ethoxide, sodium methoxide, potassium phosphate and sodium phosphate; preferably, it is an aqueous solution of potassium phosphate.
In the step (4), the reaction temperature is 70-130 ℃; preferably 80 ℃ to 110 ℃.
In the step (4), the reaction time is 6-36 h; preferably 12-24 h.
Further, step (3) of the present invention may optionally further comprise the following reaction steps:
(a) carrying out substitution reaction on the compound shown in the formula III and thionyl chloride to generate a compound shown in a formula IV;
(b) carrying out substitution reaction on the compound shown in the formula IV and glycine ester hydrochloride in the presence of an acid-binding agent to generate a compound shown in the formula V;
wherein X is halogen, R2Is C1-6An alkyl group.
In the step (a), the reaction temperature is 25-80 ℃.
In the step (a), the reaction time is 0-5 h.
In step (a), the reaction molar ratio of the compound of formula III to thionyl chloride is 1: (1-5).
In step (b), the condensation reagent is selected from the group consisting of N, N-carbonyldiimidazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP), 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, preferably 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP).
In the step (b), the reaction temperature is 15-50 ℃.
In the step (b), the reaction time is 1-5 h.
The halogen is selected from fluorine, chlorine, bromine and iodine; preferably, chlorine, bromine, iodine; most preferably bromine.
C according to the invention1-6Alkyl means from C containing 1 to 6 carbon atoms1-6A monovalent group derived from a hydrocarbon compound by removal of one hydrogen atom, which hydrocarbon compound may be aliphatic or alicyclic or a combination thereof, and which may be saturated, partially saturated or fully saturated. Saturated straight chain C1-6Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, and n-pentyl. Saturated branched chain C1-6Examples of alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, and neopentyl. Saturated alicyclic (carbocyclic) C1-6Examples of alkyl groups include, but are not limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl, and cyclopropylmethyl. Preferably methyl, tert-butyl.
The invention has the beneficial effects that:
(1) the present invention provides a new process for the preparation of a rasagiline base.
(2) According to the method for preparing the roxasistat, the initial reaction raw material 4-hydroxy-7-phenoxyisoquinoline-3-methyl formate is easy to obtain, can be directly purchased and obtained, and is low in toxicity and non-controlled substances.
(3) The method for preparing the roxasistat has short synthetic route and 4 reaction steps.
(4) The method for preparing the roxasistat has short reaction time of about 20-22 h.
(5) The method for preparing the roxasistat has high yield, the yield of each step of reaction is more than 83.20%, the total yield is more than 71.51% and is as high as 80.82%.
(6) The method for preparing the roxasistat adopts a recrystallization method for post-treatment, does not need column purification, and is simple to operate.
(7) Compared with the comparative example 1, the intermediate 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-methyl formate prepared by the method has less impurities, an L C-MS spectrogram has no methoxy substituted impurity peak, and the intermediate is easy to control.
(8) Compared with the comparative example 2, the 1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid prepared by the method has less impurities, namely the roxasistat, the purity is higher than 98 percent, and an L C-MS spectrogram does not have an impurity peak of hydrolysis of the 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester.
(9) The preparation method provided by the invention has the advantages of mild reaction conditions, simple and convenient operation, no pressurization reaction and potential safety hazard because all adopted solvents are conventional solvents, easy control and low process cost, and is suitable for industrial production.
4. Description of the drawings
FIG. 1 is a L C-MS spectrum of methyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate prepared in example 1.
FIG. 2 is a L C-MS spectrum of (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) glycine prepared in example 8.
FIG. 3 is a L C-MS spectrum of methyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate prepared in comparative example 1.
FIG. 4 is a L C-MS spectrum of 1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid prepared in comparative example 2.
5. Detailed description of the preferred embodiments
The following detailed description of specific embodiments of the present invention is provided for illustrative purposes only and is not intended to limit the scope of the present invention.
Example 1: 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester
Adding 4-hydroxy-7-phenoxyisoquinoline-3-methyl formate (50.00g, 169.45mmol) into 500ml tetrahydrofuran, then adding NBS (31.67g,177.93mmol) and AIBN (1.39g, 8.47mmol), reacting at 25 ℃ for 1h, T L C analyzing (petroleum ether-ethyl acetate is 3:2), completely reacting, post-treating, concentrating under reduced pressure to remove most of the solvent, then adding 500ml methanol, heating to reflux and beating for 0.5h, cooling, filtering, washing the filter cake with about 50ml methanol, and drying to obtain 60.60g of white solid, wherein the yield is 95.64%, and the spectrum of L C-MS is shown in figure 1, and the spectrum shows no obvious impurity peak.
1H-NMR(600MHz，DMSO-d6)：3.00(3H，s)，7.27(2H，dd，J＝7.2,1.2Hz)，7.34 (1H，t，J＝7.2Hz)，7.41(1H，d，J＝2.4Hz)，7.54(2H，td，J＝7.2,1.2Hz)，7.69(1H，dd， J＝9.0,2.4Hz)，8.37(1H，d，J＝9.0Hz)，11.54(1H，s)。
Example 2: 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid
Adding 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-methyl formate (71.00g, 189.74mmol) into 300ml of ethanol, then adding a mixed solution of sodium hydroxide (22.71g, 569.22mmol) and 300ml of water, after the addition is finished, heating to reflux reaction about 1 h.T L C for analysis (petroleum ether-ethyl acetate is 5:1), after the reaction is completed, cooling, concentrating under reduced pressure to remove part of the solvent, then adding 500ml of water, adjusting pH to 2-3 with 2M hydrochloric acid, stirring for crystallization for 0.5h, filtering, and drying to obtain 67.70g of light red solid, 99.31% of related substances, and 99.06% of yield.
1H-NMR(600MHz，DMSO-d6): 7.27(2H, dd, J ═ 7.2,1.2Hz), 7.34(1H, t, J ═ 7.2Hz), 7.42(1H, d, J ═ 2.4Hz), 7.54(2H, td, J ═ 7.2,1.2Hz), 7.68(1H, dd, J ═ 9.0,2.4Hz), 8.36(1H, d, J ═ 9.0Hz), 13.08 (about 2H, brs).
Example 3: (1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) glycine methyl ester
1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid (20.00g, 55.53mmol) is added to 250ml dichloromethane, followed by glycine methyl ester hydrochloride (10.46g, 83.30mmol) and PyBOP (43.35g, 83.30mmol), and finally triethylamine (22.48g, 222.12mmol) is added, after addition, reaction is carried out at 25 ℃ for about 2 h.T L C analysis (DCM-MeOH (10:1) +3dHAc), reaction is substantially complete, post-treatment, 120ml water is added to the reaction system, separation is carried out, dichloromethane is extracted for 2 times (200ml × 2), the organic phases are combined, anhydrous magnesium sulfate is dried, activated carbon is decolored, filtration is carried out, and concentration under reduced pressure is carried out to obtain 75.02g of an off-white solid.
Refining: adding 400ml of isopropanol into the crude product, heating up, refluxing and pulping for 0.5h, cooling, filtering, washing a filter cake by using about 30ml of isopropanol, and drying to obtain 24.00g of off-white solid with the yield of about 100%.
1H-NMR(600MHz，DMSO-d6): 3.69(3H, s), 4.13(2H, d, J ═ 6.6Hz), 7.27(2H, dd, J ═ 7.2,1.2Hz), 7.34(1H, tt, J ═ 7.2,1.2Hz), 7.46(1H, d, J ═ 2.4Hz), 7.54(2H, td, J ═ 7.2,1.2Hz), 7.69(1H, dd, J ═ 9.0,2.4Hz), 8.36(1H, d, J ═ 9.0Hz), 9.30(1H, brs), 13.47 (about 1H, brs).
Example 4: (1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) glycine tert-butyl ester
1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid (10.00g, 27.77mmol) is added to 150ml dichloromethane, followed by glycine tert-butyl ester hydrochloride (6.98g, 41.66mmol) and PyBOP (21.68g, 41.66mmol), and finally triethylamine (11.24g, 111.08mmol) is added, after addition, reaction is carried out at 25 ℃ for about 2 h.T L C analysis (DCM-MeOH (10:1) +3dHAc), reaction is substantially complete, work-up is carried out by adding 120ml water and 150ml dichloromethane to the reaction system, separating, extracting with dichloromethane for 2 times (100ml × 2), combining the organic phases, drying over anhydrous magnesium sulfate, decolorizing with activated carbon, filtering, and concentrating under reduced pressure to obtain 38.01g off-white solid.
Refining: adding 200ml of isopropanol into the crude product, heating up, refluxing and pulping for 0.5h, cooling, filtering, washing a filter cake by using about 15ml of isopropanol, and drying to obtain 12.53g of off-white solid with the yield of about 95.35%.
1H-NMR(600MHz，DMSO-d6)：1.44(9H，s)，4.00(2H，d，J＝6.0Hz)，7.27(2H， dd，J＝7.2,1.2Hz)，7.34(1H，tt，J＝7.2,1.2Hz)，7.47(1H，d，J＝2.4Hz)，7.54(2H，td， J＝7.2,1.2Hz)，7.70(1H，dd，J＝9.0,2.4Hz)，8.36(1H，d，J＝9.0Hz)，9.16(1H，t，J＝6.0Hz)，13.61(1H，s)。
Example 5: 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl chloride
1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid (5.0g, 13.88mmol) is added to 50ml dichloromethane, then thionyl chloride (4.13g, 34.70mmol) is added dropwise, after addition, the reflux reaction is carried out for about 2 h.T L C analysis (DCM-MeOH (10:1) +3dHAc), reaction is complete, post-treatment, solvent is removed by concentration under reduced pressure to give 5.26g of a pale yellow solid, with about 100% yield, which is reserved for use directly in the next reaction.
Example 6: (1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) glycine methyl ester
Glycine methyl ester hydrochloride (2.61g, 20.82mmol) is added into 26m L dichloromethane, then triethylamine (5.62g, 55.52mmol) is added, the temperature is reduced, the temperature is controlled below 25 ℃, a mixed solution of 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-formyl chloride (5.26g, 13.88mmol) and 50m L dichloromethane is added dropwise, after the addition is finished, the temperature is slowly raised to room temperature, the reaction is about 2 h.T L C analysis (DCM-MeOH (10:1), the reaction is almost complete, post-treatment is carried out, 40m L water and 40m L dichloromethane are added into the reaction system, liquid separation is carried out, dichloromethane is extracted for 1 time (50ml × 1), organic phases are combined, anhydrous magnesium sulfate is dried, filtering is carried out, and vacuum concentration is carried out to obtain a crude product.
Refining: adding the crude product into 33ml of isopropanol, heating to reflux for about 0.5h, cooling for crystallization, filtering, washing a filter cake by using about 5ml of isopropanol, and drying to obtain 5.51g of off-white solid with the yield of about 92.06%.
1H-NMR(600MHz，DMSO-d6): 3.69(3H, s), 4.13(2H, d, J ═ 6.6Hz), 7.27(2H, dd, J ═ 7.2,1.2Hz), 7.34(1H, tt, J ═ 7.2,1.2Hz), 7.46(1H, d, J ═ 2.4Hz), 7.54(2H, td, J ═ 7.2,1.2Hz), 7.69(1H, dd, J ═ 9.0,2.4Hz), 8.36(1H, d, J ═ 9.0Hz), 9.30(1H, brs), 13.47 (about 1H, brs).
Example 7: (1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) glycine tert-butyl ester
Glycine tert-butyl ester hydrochloride (3.49g, 20.82mmol) is added into 35m L dichloromethane, triethylamine (5.62g, 55.52mmol) is added, the temperature is reduced, the temperature is controlled below 25 ℃, 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-formyl chloride (5.26g, 13.88mmol) and 50m L dichloromethane are added to form a mixed solution, after the addition is finished, the temperature is slowly raised to room temperature, the mixed solution reacts for about 2 h.T L C analysis (DCM-MeOH (10:1), the reaction is basically completed, post-treatment is carried out, 50m L water and 50m L dichloromethane are added into the reaction system, liquid separation is carried out, dichloromethane is extracted for 1 time (50ml × 1), organic phases are combined, anhydrous magnesium sulfate is dried, filtering is carried out, and vacuum concentration is carried out to obtain a crude product.
Refining: and adding the crude product into 33ml of isopropanol, heating to reflux for about 0.5h, cooling, crystallizing, filtering, washing a filter cake by using about 5ml of isopropanol, and drying to obtain 5.96g of off-white solid with the yield of about 90.72%.
1H-NMR(600MHz，DMSO-d6)：1.44(9H，s)，4.00(2H，d，J＝6.0Hz)，7.27(2H， dd，J＝7.2,1.2Hz)，7.34(1H，tt，J＝7.2,1.2Hz)，7.47(1H，d，J＝2.4Hz)，7.54(2H，td， J＝7.2,1.2Hz)，7.70(1H，dd，J＝9.0,2.4Hz)，8.36(1H，d，J＝9.0Hz)，9.16(1H，t，J＝6.0Hz)，13.61(1H，s)。
Example 8: (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) glycine
After (1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) glycine methyl ester (10.00g, 23.19mmol) was added to 100ml of ethylene glycol monomethyl ether, followed by methyl boronic acid (8.33g, 139.14mmol), potassium phosphate (18.21g, 85.80mmol), 25ml of water and tetrakis (triphenylphosphine) palladium (1.61g, 1.39mmol) added, nitrogen displacement was performed 3 times, the temperature was raised to 100 ℃ to react for about 16 h.T L C assay (DCM-MeOH (10:1) +2d HAc), the reaction was completed, the temperature was lowered, 48ml of ethylene glycol monomethyl ether and 25ml of water were added to the reaction system, filtration was performed, the filtrate PH was adjusted to 2-3 with 2M hydrochloric acid, stirred for crystallization for about 0.5h, filtered, the filter cake was washed with about 25ml of water, and air dried to obtain 8.20g of a pale yellow solid with a yield of about 100%.
Refining, adding the crude product into 82ml ethanol, heating to 80 deg.C, refluxing and stirring for about 10min, cooling, filtering, washing the filter cake with about 5ml ethanol, and air drying to obtain 6.97g light yellow solid with related substance 98.73%, yield 85.31%, L C-MS spectrogram as shown in figure 2, which shows no obvious impurity peak.
1H-NMR(600MHz，DMSO-d6): 2.71(3H, s), 4.05(2H, d, J ═ 6.0Hz), 7.19(2H, d, J ═ 7.2Hz), 7.26(1H, t, J ═ 7.2Hz), 7.49(2H, t, J ═ 7.2Hz), 7.54(1H, td, J ═ 9.0,2.4Hz), 7.62(1H, d, J ═ 2.4Hz), 8.30(1H, d, J ═ 9.0Hz), 9.10(1H, t, J ═ 6.0Hz), 12.68 (about 1H, brs), 14.33(1H, brs).
Example 9: (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) glycine
(1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) glycine tert-butyl ester (10.00g, 21.13mmol) was added to 100ml of ethylene glycol monomethyl ether, followed by addition of methylboronic acid (7.59g, 126.78mmol), potassium phosphate (16.60g, 78.18mmol), 25ml of water and tetrakis (triphenylphosphine) palladium (1.47g, 1.27 mmol). after addition, nitrogen substitution 3 times, heating to 100 ℃ for reaction analysis at about 16 h.T L C (DCM-MeOH (10:1) +2d HAc), completion of the reaction, workup, cooling, addition of 80ml of ethylene glycol monomethyl ether and 25ml of water to the reaction system, filtration, adjustment of the pH of the filtrate to 2-3 with 2M hydrochloric acid, stirred crystallization for about 0.5h, filtration, washing of the filter cake with about 25ml of water, and air-drying to obtain 7.50g of a pale yellow solid with a yield of about 100%.
Refining: the crude product is added into 75ml ethanol, heated to 80 ℃ and stirred under reflux for about 10 min. The temperature is reduced, filtration is carried out, the filter cake is washed by about 10ml of ethanol and dried to obtain 6.19g of light yellow solid, related substances are 98.29 percent, and the yield is 83.20 percent.
1H-NMR(600MHz，DMSO-d6): 2.71(3H, s), 4.05(2H, d, J ═ 6.0Hz), 7.19(2H, d, J ═ 7.2Hz), 7.26(1H, t, J ═ 7.2Hz), 7.49(2H, t, J ═ 7.2Hz), 7.54(1H, td, J ═ 9.0,2.4Hz), 7.62(1H, d, J ═ 2.4Hz), 8.30(1H, d, J ═ 9.0Hz), 9.10(1H, t, J ═ 6.0Hz), 12.68 (about 1H, brs), 14.33(1H, brs).
Comparative example 1: 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester
Adding 4-hydroxy-7-phenoxyisoquinoline-3-methyl formate (0.50g, 1.69mmol) into 7.5ml of methanol, cooling, controlling the temperature below 10 ℃, adding 1, 3-dibromo-5, 5-dimethylhydantoin (0.27g, 0.93mmol), heating to reflux reaction to about 6 h.T L C for analysis (petroleum ether-ethyl acetate is 3:2), after reaction is almost complete, slowly cooling to about 5 ℃, filtering, washing a filter cake by 3.5ml of methanol, and airing to obtain 0.40g of white-like solid, wherein the batch number is 19111903, L C-MS shows that the methyl formate is presumed to be methoxy substituted impurities, has no bromine atom isotope peak and is a non-target product, and is shown in figure 3.
Comparative example 2: 1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid
After the addition of methyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (6.00g, 16.03mmol) to 105ml of ethylene glycol monomethyl ether, methyl boronic acid (8.33g, 139.14mmol), potassium phosphate (12.52g, 58.99mmol), 20ml of water and tetrakis (triphenylphosphine) palladium (0.56g, 0.48mmol), 3 times displacement with nitrogen, warming to 100 ℃ overnight reaction, T L C analysis (DCM-MeOH (10:1) +2d HAc), completion of the reaction, workup, cooling, washing the filter cake with 15ml of ethylene glycol monomethyl ether and 10ml of water in sequence, adjusting the pH of the filtrate to 2-3 with 2M hydrochloric acid, stirring to crystallize for about 0.5h, filtering, washing the filter cake with about 25ml of water, and air drying to give 4.20g of a pale yellow solid, with a yield of about 81.08%, L C-MS showed poor product purity, and hydrolysis of methyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate with more impurities as shown in FIG. 4.
Claims (10)
1. A preparation method of a roxarsone is characterized by comprising the following steps:
(1) carrying out substitution reaction on the compound shown in the formula I and a halogenating reagent to generate a compound shown in a formula II;
(2) carrying out hydrolysis reaction on the compound of the formula II in the presence of an organic solvent and alkali to generate a compound of a formula III;
(3) carrying out condensation reaction on the compound shown in the formula III and glycine ester hydrochloride in the presence of a condensing agent to generate a compound shown in the formula V;
(4) under the catalysis of a catalyst, carrying out methylation reaction on the compound shown in the formula V and a methylation reagent in a mixed solution of an organic solvent and an aqueous solution of an inorganic base, and simultaneously carrying out hydrolysis reaction to obtain the rosixostat;
wherein X is halogen; r1And R2Is C1-6An alkyl group.
2. A process for the preparation of a rasagiline base according to claim 1 wherein: in the step (1), the halogenating agent is selected from one or more of 1, 3-dichloro-5, 5-dimethylhydantoin, 1, 3-dibromo-5, 5-dimethylhydantoin, 1, 3-diiodo-5, 5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine and elementary iodine.
3. A process for the preparation of a rasagiline base according to claim 2 wherein: in the step (1), the halogenating agent is selected from N-bromosuccinimide.
4. A process for the preparation of a rasagiline base according to claim 1 wherein: in the step (4), the step (c),
the methylating agent is one or more selected from methylboronic acid, isopropyl methylborate, trimethylboron, tetramethyltin, methylmagnesium bromide and methylmagnesium chloride;
the organic solvent is selected from one or more of methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol methyl ether, ethylene glycol diethyl ether, ethylene glycol ethyl ether, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane and acetonitrile;
the catalyst is palladium catalyst selected from PdCl2、Pd2(dba)3、Pd(OAc)2、Pd(dppf)Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(PPh3)2(OAc)2One or more of (a);
the aqueous solution of the inorganic base is selected from one or more aqueous solutions of sodium bicarbonate, potassium acetate, potassium carbonate, sodium acetate, potassium bicarbonate, cesium carbonate, sodium ethoxide, sodium methoxide, potassium phosphate and sodium phosphate.
5. A process for the preparation of a rasagiline base according to claim 4 wherein: in the step (4), the step (c),
the methylating agent is selected from methyl boric acid;
the catalyst is palladium catalyst selected from Pd (PPh)3)4；
The aqueous solution of inorganic base is selected from the group consisting of aqueous solutions of potassium phosphate.
6. A process for the preparation of a rasagiline base according to claim 1 wherein: x is bromine, R1And R2Each independently methyl or tert-butyl.
7. The process for the preparation of Rosesarta stat according to claim 1, wherein said step (3), optionally, further comprises the steps of:
(a) carrying out substitution reaction on the compound shown in the formula III and thionyl chloride to generate a compound shown in a formula IV;
(b) carrying out substitution reaction on the compound shown in the formula IV and glycine ester hydrochloride in the presence of an acid-binding agent to generate a compound shown in the formula V;
wherein, X, R2As claimed in claim 1.
8. The process for the preparation of Rosesastat of claim 7 wherein in step (b),
the condensation reagent is selected from one or more of N, N-carbonyl diimidazole, 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride, dicyclohexylcarbodiimide, N, N ' -diisopropyl carbodiimide, 1H-benzotriazole-1-oxytripyrrolidine hexafluorophosphate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, O- (7-azabenzotriazole-1-yl) -N, N, N ', N ' -tetramethylurea hexafluorophosphate and O-benzotriazol-N, N, N ', N ' -tetramethylurea tetrafluoroborate.
9. The process for the preparation of Rosesastat of claim 8 wherein in step (b) said condensing agent is selected from the group consisting of 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate.
10. The process for the preparation of Rosesastat of claim 7 wherein X is bromine and R is bromine2Is methyl or tert-butyl.
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| CN112409258A (en) * | 2020-11-20 | 2021-02-26 | 杭州科巢生物科技有限公司 | Preparation method of Rosxastat |
| CN113956198A (en) * | 2021-06-18 | 2022-01-21 | 济川(上海)医学科技有限公司 | Impurity of roxasistat, preparation method and application thereof |
| CN114736157A (en) * | 2022-03-11 | 2022-07-12 | 海口市制药厂有限公司 | Preparation method of rosxastat, and pharmaceutical composition and application thereof |
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| WO2004108681A1 (en) * | 2003-06-06 | 2004-12-16 | Fibrogen, Inc. | Nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietin |
| CN107954931A (en) * | 2016-10-17 | 2018-04-24 | 上海医药集团股份有限公司 | A kind of preparation method of Nuo get Si Ta |
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| CN112409258A (en) * | 2020-11-20 | 2021-02-26 | 杭州科巢生物科技有限公司 | Preparation method of Rosxastat |
| CN113956198A (en) * | 2021-06-18 | 2022-01-21 | 济川(上海)医学科技有限公司 | Impurity of roxasistat, preparation method and application thereof |
| CN114736157A (en) * | 2022-03-11 | 2022-07-12 | 海口市制药厂有限公司 | Preparation method of rosxastat, and pharmaceutical composition and application thereof |
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