CN112409258A - Preparation method of Rosxastat - Google Patents
Preparation method of Rosxastat Download PDFInfo
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- CN112409258A CN112409258A CN202011306811.6A CN202011306811A CN112409258A CN 112409258 A CN112409258 A CN 112409258A CN 202011306811 A CN202011306811 A CN 202011306811A CN 112409258 A CN112409258 A CN 112409258A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention discloses a preparation method of a roxasistat, which comprises the steps of firstly condensing a compound 1 with a condensing agent under the action of organic alkali to obtain a hydroxyl acylation intermediate state, and then directly coupling the hydroxyl acylation intermediate state with methyl boric acid under the catalytic action of a catalyst to obtain a key intermediate compound 2. In the condensation step with glycine fragments, sodium glycinate is used for replacing glycine, and the amidation reaction of the sodium glycinate and an intermediate compound 2 is studied to obtain the finished product of the roxasistat 3. This improvement also greatly reduces the alkaline hydrolysis by-products of intermediate compound 2, increasing the reaction yield and purity of the finished product.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a preparation method of a roxarsone.
Background
The chemical name of the Rosxastat (Roxadustat, FG-4592) Tata is as follows: n- [ (4-hydroxy-1-methyl-7-phenoxy-3-isoquinolin) carbonyl ] glycine, the structural formula is as follows:
rosemastat is a small molecule inhibitor of the Hypoxia Inducible Factor (HIF) prolyl hydroxylase developed by non-Brougen, Ansitagland Asricon, USA for oral administration. The medicine has remarkable effect of treating anemia related to chronic nephropathy and end-stage nephropathy, has been approved by FDA and is marketed in Europe and America, has good effect of treating renal anemia of non-dialysis patients, and has good market prospect.
PCT patent WO2004108681 reports a synthesis route for preparing a roxasistat intermediate and a roxasistat, wherein key intermediate 1, 4-dihydroxy-7-phenoxyisoquinoline-3-carboxylic ester is subjected to bromination and hydrolysis, then is subjected to alkylation after reaction of butyl lithium, methyl iodide and benzyl bromide, then is subjected to hydrolysis reaction to obtain a key intermediate 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid, and finally is subjected to condensation and debenzylation with glycine tert-benzyl ester to obtain the finished product of the roxasistat.
PCT patent WO2014014834 also reports an improved synthetic route for roxasistat, which utilizes the reaction of intermediate 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate with tetramethylmethanediamine, then completes substitution reaction with acetic anhydride, then completes methylation reaction of isoquinoline ring by palladium carbon hydrogenation to obtain key intermediate 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate of roxasistat, and finally performs ammonolysis reaction with glycine to obtain the product, the route is shown as follows:
generally speaking, the method for introducing methyl into isoquinoline in the steps of the two methods is complicated, the steps are long, the yield of the route of the method 1 is low, the method II needs palladium carbon hydrogenation, the atom economy of the two methods is not good, the post-treatment three wastes are more, and the route cost is high. In addition, from the strategy of docking key intermediates and glycine fragments in the subsequent reaction, in the patent route 1, additional deprotection reaction is needed by docking glycine benzyl ester, palladium carbon hydrogenation is needed for debenzylation reaction, and in the patent route 2, although the reaction is directly performed in one step, side reactions such as strong alkalinity of sodium alkoxide are more, alkaline hydrolysis impurities are easily generated, and the purification difficulty of the final product is increased. Generally speaking, the methods for synthesizing the roxasistat have overlong general routes, low total yield, high route cost and difficult process amplification, and a method which has simple process route and low cost and is suitable for industrial production still needs to be found.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method for preparing the sauce for the roxburgh, which has the advantages of simple preparation process route, low cost and suitability for industrial production.
The invention adopts the following technical scheme for realizing the aim of the invention:
a preparation method of the Rosesastat comprises the steps of reacting an intermediate compound 2 with sodium glycinate to obtain Rosesastat 3;
wherein, R in the compound 2 is selected from methyl, ethyl, isopropyl, n-butyl or benzyl.
Further, the reaction solvent is selected from methanol, ethanol, isopropanol, N-butanol, t-butanol, tetrahydrofuran, toluene, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, DMSO or acetonitrile; the reaction temperature is-10 to 130 ℃.
Further, cooling to room temperature after the reaction is finished, adding acid to adjust the pH value to weak acidity, pulping, filtering, and recrystallizing the crude product by using an organic mixed solvent, wherein the solvent can be selected from benign solvents or uniform mixed solvents of inert solvents and benign solvents: wherein the inert solvent is selected from n-heptane, n-hexane, petroleum ether or water, and the benign solvent is selected from acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or toluene.
Preferably, for the synthesis method of the compound 2, the compound 1 and a condensing agent are condensed under the action of organic base to obtain an intermediate state, and then the intermediate state and methylboronic acid are subjected to coupling reaction under the combined action of catalyst catalysis and alkali metal salt by a one-pot method to obtain the compound 2;
wherein R in the compound 1 and the compound 2 is selected from methyl, ethyl, isopropyl, n-butyl or benzyl.
Further, the organic base is selected from triethylamine, DIPEA, N-dimethylaniline, DBU or DABCO; the catalyst is selected from palladium carbon, palladium hydroxide, sodium palladate, palladium acetate, palladium chloride, bis (triphenylphosphine) palladium dichloride or Pd (dppf) Cl2(ii) a No ligand or ligand selected from triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, S-Phos, X-Phos, Xantphos or di-tert-butylphosphine; the alkali metal salt is selected from sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide or sodium tert-butoxide; the condensing agent is selected from p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, EDCI, DIC, BOP, BrOP or PyBroP; the reaction solvent is selected from 1, 4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or DMSO; the reaction temperature is 40-130 ℃.
Further, cooling to room temperature after the reaction is finished, adding water to quench the reaction, extracting and separating liquid, washing an organic phase with water, and concentrating to obtain a crude product, wherein the crude product is crystallized by using a uniform mixed solvent of an inert solvent and a benign solvent: wherein the inert solvent is selected from n-heptane, n-hexane, petroleum ether or water, and the benign solvent is selected from acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or toluene.
More specifically, the preparation method of the Rosemary sauce comprises the following steps:
(1) under the action of a catalyst, firstly, condensing the compound 1 and a condensing agent under the action of an organic base to obtain an intermediate state, and then, carrying out a coupling reaction with methylboronic acid under the combined action of the catalytic action of the catalyst and an alkali metal salt by a one-pot method to obtain a compound 2;
(2) reacting the compound 2 obtained in the step (1) with sodium glycinate to obtain the roxasistat 3;
wherein R in the compound is selected from methyl, ethyl, isopropyl, n-butyl or benzyl.
Wherein, in the step (1), the organic base is selected from triethylamine, DIPEA, N-dimethylaniline, DBU or DABCO; the catalyst is selected from palladium carbon, palladium hydroxide, sodium palladate, palladium acetate, palladium chloride, bis (triphenylphosphine) palladium dichloride or Pd (dppf) Cl2(ii) a No ligand or ligand selected from triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, S-Phos, X-Phos, Xantphos or di-tert-butylphosphine; the alkali metal salt is selected from sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide or sodium tert-butoxide; the condensing agent is selected from p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, EDCI, DIC, BOP, BrOP or PyBroP; the reaction solvent is selected from 1, 4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or DMSO; the reaction temperature is 40-130 ℃.
In the step (2), the reaction solvent is selected from methanol, ethanol, isopropanol, N-butanol, tert-butanol, tetrahydrofuran, toluene, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, DMSO or acetonitrile; the reaction temperature is-10 to 130 ℃. The product crystallization solvent is selected from the following homogeneous mixed solvents of an inert solvent and a benign solvent: wherein the inert solvent is selected from n-heptane, n-hexane, petroleum ether or water, and the benign solvent is selected from acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or toluene.
The invention relates to a preparation method of a roxasistat, which comprises the steps of condensing a 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic ester compound 1 with a condensing agent under the action of organic base to obtain a hydroxyl acylation intermediate state, directly coupling the hydroxyl acylation intermediate state with methylboronic acid under the catalytic action of a catalyst in a one-pot manner to obtain a key intermediate 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic ester compound 2, wherein the improvement avoids the use of phosphorus oxychloride or phosphorus oxybromide, effectively reduces the generation of three wastes, shortens the reaction steps and improves the reaction yield. In the condensation step with glycine fragments, sodium glycinate is used for replacing glycine, and the amidation reaction of the sodium glycinate and an intermediate compound 2 is studied to obtain the finished product of the roxasistat 3. This improvement also greatly reduces the alkaline hydrolysis by-products of intermediate compound 2, increasing the reaction yield and purity of the finished product. Generally speaking, the method reduces the reaction steps, greatly improves the route efficiency, reduces the process cost, reduces the generation of byproducts and is beneficial to improving the purity of the final finished product. The route is simple to operate, the total yield is high, the purity of the obtained product is high, and the route is suitable for large-scale production.
The specific implementation mode is as follows:
the following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
A three-neck flask was charged with compound 1a (31.13g,100mmol), 150mL DMAC was added, triethylamine (25.30g,250mmol) was added, and after stirring and dissolution, BrOP (42.69g,110mmol) was added and reacted at room temperature for 2 to 3 hours. Adding methyl boric acid (8.98g,150mmol), adding palladium chloride (177mg,1mmol) and ligand tricyclohexylphosphine (560mg,2mmol) under the protection of nitrogen, switching nitrogen for 3 times under vacuum, adding potassium carbonate (41.46g,300mmol) and injecting deionized water for 15mL, heating to 100-105 ℃, reacting for 6-8 hours, cooling after the reaction is finished, adding water (150mL) to quench the reaction, adding ethyl acetate (150mL) into the mixed solution, extracting for 3 times, combining organic phases, washing for 2 times (150mL), drying with sodium sulfate, filtering with kieselguhr, concentrating, and recrystallizing with ethyl acetate and n-heptane to obtain a compound 2a (23.92g, 77.3%)
In example 1, the solvent DMAC N, N-dimethylacetamide may be replaced by 1, 4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide, N-methylpyrrolidone or DMSO; the organic base triethylamine can be replaced by DIPEA, N-dimethylaniline, DBU or DABCO; the condensing agent BrOP can be replaced by paratoluensulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, EDCI, DIC, BOP or PyBroP; the catalyst palladium chloride can be palladium carbon, palladium hydroxide, sodium palladate, palladium acetate, bis (triphenylphosphine) palladium dichloride or Pd (dppf) Cl2Replacing; the ligand tricyclohexylphosphine can be not added, or can be replaced by triphenylphosphine, tri-tert-butylphosphine, S-Phos, X-Phos, Xantphos or di-tert-butylphosphine; the potassium carbonate may be replaced by sodium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide or sodium tert-butoxide.
The n-heptane in the recrystallization solvent can be replaced by n-hexane, petroleum ether or water, and the ethyl acetate can be replaced by acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or toluene.
Example 2
A three-necked flask was charged with compound 1b (32.53g,100mmol), 160mL of 1, 4-dioxane was added, triethylamine (25.30g,250mmol) was added, and after stirring and dissolution, PyBrOP (51.28g,110mmol) was added and the reaction was carried out at room temperature for 2 to 3 hours. Adding methyl boric acid (8.98g,150mmol), adding palladium acetate (0.225g,1mmol) and ligand di-tert-butyl phenyl phosphine (445mg,2mmol) under the protection of nitrogen, switching nitrogen for 3 times in vacuum, adding potassium carbonate (41.46g,300mmol) and injecting deionized water for 16mL, heating to 100-105 ℃, reacting for 6-8 hours, cooling after reaction, adding water (160mL), adding ethyl acetate (160mL) into the mixed solution, extracting for 3 times, combining organic phases, washing for 2 times (160mL), drying with sodium sulfate, filtering with kieselguhr, concentrating, and recrystallizing with ethyl acetate and n-heptane to obtain compound 2a (27.52g, 85.1%)
In example 2, the solvent 1, 4-dioxane can be replaced by N, N-dimethylacetamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide, N-methylpyrrolidone or DMSO; the organic base triethylamine can be replaced by DIPEA, N-dimethylaniline, DBU or DABCO; the condensing agent PyBroP can be replaced by BrOP, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, EDCI, DIC or BOP; the catalyst palladium acetate can be palladium chloride, palladium carbon, palladium hydroxide, sodium palladate, bis (triphenylphosphine) palladium dichloride or Pd (dppf) Cl2Replacing; the ligand di-tert-butyl phenyl phosphine can be not added, or can be replaced by tricyclohexyl phosphine, triphenylphosphine, tri-tert-butyl phosphine, S-Phos, X-Phos or Xantphos; the potassium carbonate may be replaced by sodium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide or sodium tert-butoxide.
The n-heptane in the recrystallization solvent can be replaced by n-hexane, petroleum ether or water, and the ethyl acetate can be replaced by acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or toluene.
Example 3
Compound 1c (33.93g,100mmol) was charged into a three-necked flask, 170mL of 1, 4-dioxane was added, diisopropylethylamine (32.31g,250mmol) was added, and after stirring and dissolution, BrOP (42.69g,110mmol) was added and the reaction was carried out at room temperature for 2 to 3 hours. Adding methyl boric acid (8.98g,150mmol), adding bis (triphenylphosphine) palladium dichloride (0.702g,1mmol) under the protection of nitrogen, switching nitrogen for 3 times in vacuum, adding potassium phosphate (63.68g,300mmol) and injecting 17mL of deionized water, heating to 100-105 ℃, reacting for 6-8 hours, cooling after the reaction is finished, adding water (170mL), adding ethyl acetate (170mL) into the mixed solution, extracting for 3 times, combining organic phases, washing for 2 times (170mL), drying with sodium sulfate, filtering with kieselguhr, concentrating, and recrystallizing with isopropanol and water to obtain a compound 2c (28.17g, 83.5%)
In example 3, the solvent 1, 4-dioxane can be N, N-dimethylacetamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N-dioxaneMethyl formamide, N-methyl pyrrolidone or DMSO; organic base diisopropylethylamine DIPEA can be replaced by triethylamine, N-dimethylaniline, DBU or DABCO; the condensing agent BrOP can be replaced by PyBroP, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, EDCI, DIC or BOP; the catalyst palladium acetate can be palladium chloride, palladium carbon, palladium hydroxide, sodium palladate, bis (triphenylphosphine) palladium dichloride or Pd (dppf) Cl2Replacing; the ligand di-tert-butyl phenyl phosphine can be not added, or can be replaced by tricyclohexyl phosphine, triphenylphosphine, tri-tert-butyl phosphine, S-Phos, X-Phos or Xantphos; the potassium phosphate may be replaced by potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide or sodium tert-butoxide.
The water in the recrystallization solvent can be replaced by n-heptane, n-hexane or petroleum ether, and the ethyl acetate can be replaced by acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or toluene.
Example 4
A three-necked flask was charged with compound 1d (35.34g,100mmol), 176mL of 1, 4-dioxane was added, triethylamine (25.30g,250mmol) was added, and after stirring and dissolution, PyBrOP (51.28g,110mmol) was added and reacted at room temperature for 2 to 3 hours. Adding methyl boric acid (8.98g,150mmol), adding palladium acetate (0.225g,1mmol) and ligand di-tert-butyl phenyl phosphine (445mg,2mmol) under the protection of nitrogen, switching nitrogen for 3 times in vacuum, adding potassium carbonate (41.46g,300mmol) and injecting deionized water of 18mL, heating to 100-105 ℃, reacting for 6-8 hours, cooling after reaction, adding water (176mL), adding ethyl acetate (176mL) into the mixed solution, extracting for 3 times, combining organic phases, washing for 2 times (176mL), drying with sodium sulfate, filtering with kieselguhr, concentrating, and recrystallizing with ethyl acetate and n-heptane to obtain compound 2d (30.68g, 87.3%)
In example 4, the solvent 1, 4-dioxane can be replaced by N, N-dimethylacetamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide, N-methylpyrrolidone or DMSO; organic base triethylamine can be usedPropyl ethylamine DIPEA, N-dimethylaniline, DBU or DABCO; the condensing agent PyBroP can be replaced by BrOP, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, EDCI, DIC or BOP; the catalyst palladium acetate can be palladium chloride, palladium carbon, palladium hydroxide, sodium palladate, bis (triphenylphosphine) palladium dichloride or Pd (dppf) Cl2Replacing; the ligand di-tert-butyl phenyl phosphine can be not added, or can be replaced by tricyclohexyl phosphine, triphenylphosphine, tri-tert-butyl phosphine, S-Phos, X-Phos or Xantphos; the potassium phosphate may be replaced by potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide or sodium tert-butoxide.
The n-heptane in the recrystallization solvent may be replaced by water, n-hexane or petroleum ether, and the ethyl acetate may be replaced by acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or toluene.
Example 5
Compound 1e (38.74g,100mmol) was charged into a three-necked flask, 194mL of toluene was added, triethylamine (25.30g,250mmol) was added, and after stirring and dissolution, BOP (48.68g,110mmol) was added and the reaction was carried out at room temperature for 2 to 3 hours. Methylboronic acid (8.98g,150mmol) was added and Pd (dppf) Cl was added under nitrogen2(0.732g,1mmol) and ligand Xantphos (0.578g,1mmol), switching nitrogen in vacuum for 3 times, adding potassium phosphate (63.68g,300mmol) and injecting deionized water for 19mL, heating to 100-105 ℃, reacting for 6-8 hours, cooling after reaction, adding water (194mL), adding ethyl acetate (194mL) into the mixed solution for extraction for 3 times, combining organic phases, washing for 2 times (194mL), drying with sodium sulfate, filtering with kieselguhr, concentrating, and recrystallizing with ethyl acetate and n-heptane to obtain compound 2e (32.90g, 85.4%)
In example 5, the solvent toluene can be replaced by 1, 4-dioxane, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide, N-methylpyrrolidone or DMSO; the organic base triethylamine can be replaced by diisopropylethylamine DIPEA, N-dimethylaniline, DBU or DABCO; the condensing agent PyBroP can be BrOP, para-formazanBenzenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, EDCI, DIC or BOP; catalyst Pd (dppf) Cl2Can be replaced by palladium acetate, palladium chloride, palladium carbon, palladium hydroxide, sodium palladate or bis (triphenylphosphine) palladium dichloride; the ligand XantPhos can be not added, or can be replaced by di-tert-butyl phenyl phosphine, tricyclohexyl phosphine, triphenylphosphine, tri-tert-butyl phosphine, S-Phos or X-Phos; the potassium phosphate may be replaced by potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide or sodium tert-butoxide.
The n-heptane in the recrystallization solvent may be replaced by water, n-hexane or petroleum ether, and the ethyl acetate may be replaced by acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or toluene.
Example 6
Adding the compound 2a (30.93g,100mmol) and DMF (155mL) into a three-neck flask, uniformly stirring, adding sodium glycinate (14.56g,150mmol), heating to 90-95 ℃, reacting for 18-24 hours, cooling to room temperature after the reaction is finished, slowly adding dilute hydrochloric acid (5%, 309mL), slowly cooling, pulping, filtering, and recrystallizing the crude product with ethyl acetate and n-heptane to obtain the Rosemastat product 3(32.55g, 92.1%, 99.7% purity).
In example 6, the solvent N, N-dimethylacetamide may be replaced by methanol, ethanol, isopropanol, N-butanol, t-butanol, tetrahydrofuran, toluene, N-dimethylformamide, N-methylpyrrolidone, DMSO or acetonitrile; the recrystallization solvent n-heptane may be replaced by n-hexane, petroleum ether or water, and ethyl acetate may be replaced by acetone, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or toluene.
Example 7
Adding the compound 2b (32.33g,100mmol) and DMSO (160mL) into a three-neck flask, uniformly stirring, adding sodium glycinate (14.56g,150mmol), heating to 90-95 ℃, reacting for 18-24 hours, cooling to room temperature after the reaction is finished, slowly dropping dilute hydrochloric acid (5%, 323mL), slowly cooling, pulping, filtering, and recrystallizing the crude product with MTBE and n-heptane to obtain the Rosemastat product 3(33.79g, 95.8%, purity 99.9%).
In example 7, the solvent DMSO may be replaced by methanol, ethanol, isopropanol, N-butanol, t-butanol, tetrahydrofuran, toluene, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or acetonitrile. The recrystallization solvent n-heptane may be replaced by n-hexane, petroleum ether or water, and MTBE may be replaced by ethyl acetate, acetone, isopropyl acetate, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or toluene.
Example 8
Adding a compound 2c (33.64g,100mmol) and N-methylpyrrolidone (168mL) into a three-neck flask, uniformly stirring, adding sodium glycinate (14.56g,150mmol), heating to 90-95 ℃, reacting for 18-24 hours, cooling to room temperature after the reaction is finished, slowly dropping dilute hydrochloric acid (5%, 336mL), slowly cooling, pulping, filtering, and recrystallizing a crude product by using isopropanol and N-heptane to obtain a rosinestetale product 3(32.61g, 92.4%, and 99.8% in purity).
In example 8, the solvent N-methylpyrrolidone may be replaced by methanol, ethanol, isopropanol, N-butanol, t-butanol, tetrahydrofuran, toluene, N-dimethylformamide, N-dimethylacetamide, DMSO or acetonitrile. The recrystallization solvent n-heptane may be replaced by n-hexane, petroleum ether or water, and the isopropanol may be replaced by ethyl acetate, acetone, isopropyl acetate, MTBE, methanol, ethanol, tetrahydrofuran, acetonitrile or toluene.
Example 9
Adding a compound 2d (35.14g,100mmol) and n-butanol (175mL) into a three-neck flask, uniformly stirring, adding sodium glycinate (14.56g,150mmol), heating to 90-95 ℃, reacting for 16-18 hours, cooling to room temperature after the reaction is finished, slowly dropping dilute hydrochloric acid (5%, 351mL), slowly cooling, pulping, filtering, and recrystallizing a crude product by using tetrahydrofuran and n-heptane to obtain a rosisase product 3(30.63g, 86.6%, purity 99.6%).
In example 9, the solvent N-butanol may be replaced by methanol, ethanol, isopropanol, t-butanol, tetrahydrofuran, toluene, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, DMSO or acetonitrile. The recrystallization solvent n-heptane may be replaced by n-hexane, petroleum ether or water, and tetrahydrofuran may be replaced by ethyl acetate, acetone, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, acetonitrile or toluene.
Example 10
Adding the compound 2e (38.54g,100mmol) and toluene (192mL) into a three-neck flask, uniformly stirring, adding sodium glycinate (14.56g,150mmol), heating to 90-95 ℃, reacting for 18-24 hours, cooling to room temperature after the reaction is finished, slowly dropping dilute hydrochloric acid (5%, 385mL), removing most of solvent, slowly cooling, pulping, filtering, and recrystallizing the crude product with toluene and n-heptane to obtain the Rosemastat product 3(29.42g, 83.2%, 99.6% purity).
In example 10, the solvent toluene can be replaced by methanol, ethanol, isopropanol, N-butanol, t-butanol, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, DMSO or acetonitrile. The recrystallization solvent n-heptane may be replaced by n-hexane, petroleum ether or water, and toluene may be replaced by ethyl acetate, acetone, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran or acetonitrile.
Claims (7)
1. A preparation method of the Rosesastat is characterized by comprising the steps of reacting an intermediate compound 2 with sodium glycinate to obtain Rosesastat 3;
wherein, R in the compound 2 is selected from methyl, ethyl, isopropyl, n-butyl or benzyl.
2. Process for the preparation of rasagiline according to claim 1 characterized in that the reaction solvent is selected from methanol, ethanol, isopropanol, N-butanol, tert-butanol, tetrahydrofuran, toluene, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, DMSO or acetonitrile.
3. The process for the preparation of Rosesastat according to claim 1, wherein the reaction is followed by cooling to room temperature, adding acid to adjust the pH to a weakly acidic pH, pulping, filtering, and recrystallizing the crude product from an organic solvent mixture selected from a benign solvent or a homogeneous mixture of an inert solvent and a benign solvent, wherein the inert solvent is selected from n-heptane, n-hexane, petroleum ether or water, and the benign solvent is selected from acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or toluene.
4. A process for the preparation of Rosesastat according to any one of claims 1 to 3 characterized in that the synthesis of compound 2 comprises condensing compound 1 with a condensing agent under the action of an organic base to obtain an intermediate state, and then coupling reacting with methylboronic acid under the combined action of a catalyst and an alkali metal salt to obtain compound 2;
wherein R in the compound 1 and the compound 2 is selected from methyl, ethyl, isopropyl, n-butyl or benzyl.
5. The process for the preparation of Rosesastat according to claim 4 wherein said organic base is selected from triethylamine, DIPEA, N-dimethylaniline, DBU or DABCO; the catalyst is selected from palladium carbon, palladium hydroxide, sodium palladate, palladium acetate, palladium chloride, bis (triphenylphosphine) palladium dichloride or Pd (dppf) Cl2(ii) a No ligand or ligand selected from triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, S-Phos, X-Phos, Xantphos or di-tert-butylphosphine; the alkali metal salt is selected from sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide or sodium tert-butoxide; the condensing agent is selected from p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, EDCI, DIC, BOP, BrOP or PyBroP; the reaction solvent is selected from 1, 4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or DMSO.
6. The process for the preparation of Rosesastat according to claim 4 wherein the reaction is cooled to room temperature after completion, water is added to quench the reaction, extraction and separation are performed, the organic phase is washed with water and concentrated to obtain a crude product which is crystallized from a homogeneous mixed solvent of an inert solvent and a benign solvent: wherein the inert solvent is selected from n-heptane, n-hexane, petroleum ether or water, and the benign solvent is selected from acetone, ethyl acetate, isopropyl acetate, MTBE, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile or toluene.
7. A preparation method of a roxarsone sauce is characterized by comprising the following steps:
(1) firstly, condensing the compound 1 with a condensing agent under the action of organic base to obtain an intermediate state, and then carrying out coupling reaction with methylboronic acid under the combined action of catalyst catalysis and alkali metal salt by a one-pot method to obtain a compound 2;
(2) reacting the compound 2 obtained in the step (1) with sodium glycinate to obtain the roxasistat 3;
wherein R in the compound is selected from methyl, ethyl, isopropyl, n-butyl or benzyl;
in the step (1), the organic base is selected from triethylamine, DIPEA, N-dimethylaniline, DBU or DABCO; the catalyst is selected from palladium carbon, palladium hydroxide, sodium palladate, palladium acetate, palladium chloride, bis (triphenylphosphine) palladium dichloride or Pd (dppf) Cl2(ii) a No ligand or ligand selected from triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, S-Phos, X-Phos, Xantphos or di-tert-butylphosphine; the alkali metal salt is selected from sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide or sodium tert-butoxide; the condensing agent is selected from p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, DCC, EDCI, DIC, BOP, BrOP or PyBroP; the reaction solvent is selected from 1, 4-dioxane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or DMSO; in the step (2), the reaction solvent is selected from methanol, ethanol, isopropanol, N-butanol, t-butanol, tetrahydrofuran, toluene, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, DMSO or acetonitrile.
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| CN113956200A (en) * | 2021-12-16 | 2022-01-21 | 南京威凯尔生物医药科技有限公司 | Crystallization process of roxasistat bulk drug with controlled particle size |
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| CN103435546A (en) * | 2012-07-16 | 2013-12-11 | 菲布罗根有限公司 | Method for preparing isoquinoline compounds |
| CN110305143A (en) * | 2019-07-19 | 2019-10-08 | 济南新科医药科技有限公司 | A kind of furans [2,3-c] and pyridine derivate and its preparation method and application |
| CN111393365A (en) * | 2020-03-24 | 2020-07-10 | 山东百诺医药股份有限公司 | Preparation method of Rosxastat |
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