CN111499572B - Preparation method of intermediate of roxasistat - Google Patents
Preparation method of intermediate of roxasistat Download PDFInfo
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- CN111499572B CN111499572B CN201910097807.4A CN201910097807A CN111499572B CN 111499572 B CN111499572 B CN 111499572B CN 201910097807 A CN201910097807 A CN 201910097807A CN 111499572 B CN111499572 B CN 111499572B
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- 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 discloses a preparation method of a rosinestat intermediate, which relates to the technical field of medicine preparation, and is characterized in that 3-oxo-3- (4-phenoxyphenyl) propionate is taken as a raw material to prepare 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate, and then 4-hydroxy-1-methyl-7-phenoxyl-3-isoquinoline formate is obtained through cyclization reaction. The method has the advantages of novel line, short synthesis line, easy acquisition or preparation of all raw material reagents, no use of reagents with high risk and high pollution, safety, environmental protection, mild reaction conditions, convenient and controllable operation, good purity and high yield of the prepared intermediate of the roxasistat, obvious cost advantage and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a preparation method of a rosixastat intermediate.
Background
Anemia is a disease very common to Chronic Kidney Disease (CKD) patients, and morbidity and mortality are very high in both dialysis and non-dialysis CKD patients. CKD can develop in any age, more common in the elderly, with about 1.2 million CKD patients in china. The number of CKD people receiving dialysis in china exceeds 40 million and rapidly increases in two-digit increments, so that there is an increasing demand for anti-anemia therapy. Current anti-anemic therapy for CKD patients is primarily injection of erythropoietin, and roxadistat (roxydustat) is a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor that provides a more convenient (oral) and safer treatment option.
Rasagiltat (roxadustat), chemically known as [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino ] acetic acid, trade name erethipine, was developed by febuxogen (FibroGen) of the united states and is now licensed as a novel oral hypoxia inducible factor prolyl hydroxylase inhibitor, astralals (Astellas) of japan and AstraZeneca (AstraZeneca) of the uk, to induce erythropoiesis and treat renal anemia. In 2018, 12 months and 18 days, the first oral hypoxia inducible factor prolyl hydroxylase inhibitor (HIF-PHI) in China, which is a domestic type 1 original drug developed by cooperation between China Adobe and Asricon, is approved by the State drug administration (NMPA) on the market. The roxasistat is approved for the treatment of anemia in CKD dialysis patients, including hemodialysis and peritoneal dialysis patients. Currently, there are several routes for the synthesis of roxasistat:
the world patent WO2004108681 is a patent of original research company, 3, 4-dicyan nitrobenzene is taken as a starting raw material, and is subjected to 11 steps of phenol etherification, potassium hydroxide hydrolysis, glycine cyclization, methanol esterification, metallic sodium and tert-butyl alcohol cyclization, phosphorus tribromide bromination, sodium hydroxide hydrolysis, n-butyl lithium and methyl iodide methylation, sodium hydroxide hydrolysis, glycine benzyl ester amidation, palladium-carbon debenzylation and the like to obtain the roxasistat.
Synthetic route 1
The second synthetic route is that the world patent WO2013013609 in Beida pharmaceutical industry in Zhejiang province optimizes the process route of the original medicine, and the route also uses 3, 4-dicyano nitrobenzene as a starting material to obtain the roxastatin by phenol etherification, potassium hydroxide hydrolysis, acetic anhydride dehydration, methyl cyanoacetate oxazoline, hydrochloric acid cyclization, phosphorus oxychloride chlorination, palladium catalytic methylation, hydrolysis and amidation in sequence. Compared with the original route, the route has the advantages that one step of reaction is omitted, the reaction steps are still more, the starting material 2-cyano-4-nitrobenzonitrile needs to be prepared through multi-step reaction, the cost is high, and no commercial product is supplied; in particular, expensive palladium is used for catalyzing methylation, and the yield of the methylation reaction is only 33%, so that the route cost is greatly increased, and large-scale industrial production is difficult to realize.
Synthetic route two
Synthetic route three is a re-optimization and improvement of the synthetic route of the original research company world patent WO 2014014834. The method uses 2-bromophenphthalide as an initial raw material, and obtains the rosinestotal through phenol etherification, thionyl chloride ring opening chlorination, substituted amino acid butt joint, cyclization, hydroxyl alkylation, acetic anhydride acylation and palladium-carbon deprotection in sequence. The route has multiple steps, the entering of methyl is complex, and the methyl is protected and deprotected for multiple times, especially palladium-carbon catalytic deprotection needs special pressurizing equipment, which is not beneficial to industrial production, so that the route is difficult to realize industrial production and has high cost.
Synthetic route III
The fourth synthetic route is a new route disclosed in Shanghai gazan of China patent CN106478504A and the pharmaceutical industry, the route takes m-bromoacetophenone as an initial raw material, and the intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline formate is obtained by phenol etherification, hydroxylamine hydrochloride and sodium borohydride reduction amination, 2-carbonyl malonate formation Schiff base and cyclization in sequence.
Synthetic route four
The fifth synthetic route is a novel route of the Ming Jian company of Suzhou in Chinese patent CN104892509, and tyrosine is taken as a starting raw material, and is subjected to alcohol esterification, halogenated benzene etherification, acetaldehyde cyclization, alkali catalytic dehydrogenation, hydrogen peroxide catalytic hydroxylation and amidation in sequence to obtain the roxasistat. Compared with the prior route, the method has the advantages that the steps are greatly shortened, the etherification reaction and the amino group are easy to generate side reaction, the product is difficult to purify, and the yield of the hydrogen peroxide hydroxylation reaction is low, so the industrial production of the route needs to be improved and optimized.
Synthetic route five
The synthesis route is six of the route of European patent EP3305769A1, 2-bromo-4-fluorobenzoic acid methyl ester is taken as a starting material, and the roxasistat is obtained by phenol etherification reaction, oxazoline reaction with participation of CDI, palladium-catalyzed coupling reaction, acid-catalyzed cyclization and DBU-catalyzed amidation in sequence.
Synthetic route six
The seventh synthetic route is a very short synthetic route of J.org.chem.2018, 83, 15415-containing material 15425, and the Rosesata can be obtained only by four-step reaction, wherein 4' -phenoxybenzaldehyde is used as a starting material, and the Rosesata is obtained by methyl cyanoacetate condensation, phosphorus oxychloride dehydration, DBU catalytic cyclization and glycine amidation in sequence, but the route is short, the yield of the condensation and dehydrogenation reaction is low, the yield of the cyclization reaction is only 70%, and meanwhile, diacetyloxyiodobenzene with high price and large dosage is used as an oxidant, so that the product cost is high, and the industrial production still needs further process optimization.
Synthetic route seven
In summary, most of the existing methods for synthesizing the rasagiline are that the intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline formate (formula I) is synthesized first, and then the intermediate is subjected to cyclization and other reactions to prepare the rasagiline. In the preparation route of the intermediate, the yield is low due to the long synthesis route, the route is difficult to be industrially produced on a large scale due to the use of expensive catalysts, the use of dangerous reagents, the difficulty in purifying due to more side reactions and the like, so the process route for developing the rosisastat intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline formate (formula I) which is green, environment-friendly, high in yield, low in cost and good in selectivity has urgent needs and broad prospects.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides a preparation method of a roxasistat intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline formate, which has the advantages of easily obtained raw materials, environmental protection, novel route, short synthesis route, good purity of the prepared roxasistat intermediate, high yield and low cost.
The invention provides a preparation method of a roxasistat intermediate, which comprises the following synthetic route:
wherein R in the formula II, the formula IV and the formula I are the same and are selected from chain alkyl, cyclic alkyl or aryl;
the method comprises the following steps:
s1, preparing 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate (formula IV) by taking 3-oxo-3- (4-phenoxyphenyl) propionate (formula II) as a raw material;
s2, 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate (formula IV) to obtain 4-hydroxy-1-methyl-7-phenoxyl-3-isoquinoline formate (formula I).
In the preparation method, the 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate (formula IV) can be separated, or can be directly reacted by a one-pot method without separation.
Preferably, the chain alkyl group is an unsubstituted chain alkyl group or a substituted chain alkyl group, the unsubstituted chain alkyl group is a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, preferably a C1-C6 alkyl group, more preferably a C1-C4 alkyl group, and the substituted chain alkyl group is a fluorine-substituted alkyl group, preferably a trifluoromethyl group, a nonafluorobutyl group, a tridecafluorohexyl group, a heptadecafluorooctyl group; the cyclic alkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; the aryl is unsubstituted aryl or substituted aryl, the unsubstituted aryl is phenyl, benzyl and naphthyl, and the substituted aryl is tolyl, xylyl, trimethylphenyl, triisopropylphenyl, phenylethyl, phenylpropyl, methoxyphenyl, chlorophenyl and nitrophenyl.
Preferably, in S1, the synthetic route is as follows:
the method comprises the following steps: taking 3-oxo-3- (4-phenoxyphenyl) propionate (formula II) as a raw material, carrying out sodium nitrite hydroxylamination reaction to obtain 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III), and carrying out acetylation reaction to obtain 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate (formula IV).
Preferably, in S1, the synthetic route is as follows:
the method comprises the following steps: taking 3-oxo-3- (4-phenoxyphenyl) propionate (formula II) as a raw material, carrying out sodium nitrite hydroxylamination reaction to obtain 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III), carrying out catalytic reduction to obtain 2-amino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III-0), and carrying out acetylation reaction to obtain 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate (formula IV).
Preferably, in S1, the solvent for the hydroxylamination reaction is glacial acetic acid and water, and the volume ratio of the glacial acetic acid to the water is preferably 2-4: 3; preferably, the temperature of the hydroxylamination reaction is-10 to 30 ℃, preferably 0 ℃.
Preferably, in S1, the solvent for acetylation is acetic anhydride, and the reagent is acetic acid; preferably, the catalyst for acetylation reaction is one or any combination of zinc powder, iron powder and magnesium powder, preferably zinc powder; preferably, the temperature of the acetylation reaction is-10 to 30 ℃, preferably 0 ℃.
Preferably, in S1, the acetylation reagent is any one of acetyl chloride, acetic anhydride and acetic acid, preferably acetyl chloride; preferably, the catalyst for the catalytic reduction reaction is a palladium on carbon catalyst.
Preferably, in S2, the solvent for the cyclization reaction is one or any combination of toluene, xylene, acetonitrile, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide, preferably toluene; preferably, the catalyst for the cyclization reaction is one or any combination of phosphorus oxychloride, phosphorus pentachloride, phosphorus pentoxide and acetyl chloride, and is preferably phosphorus oxychloride.
Preferably, the molar ratio of 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate to phosphorus oxychloride is 1: 2-10, preferably 1: 5.
the invention also provides 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate prepared by the method, and the structural formula is as follows:
wherein R is selected from chain alkyl, cyclic alkyl or aryl; preferably, the chain alkyl group is an unsubstituted chain alkyl group or a substituted chain alkyl group, the unsubstituted chain alkyl group is a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, preferably a C1-C6 alkyl group, more preferably a C1-C4 alkyl group, and the substituted chain alkyl group is a fluorine-substituted alkyl group, preferably a trifluoromethyl group, a nonafluorobutyl group, a tridecafluorohexyl group, a heptadecafluorooctyl group; the cyclic alkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; the aryl is unsubstituted aryl or substituted aryl, the unsubstituted aryl is phenyl, benzyl and naphthyl, and the substituted aryl is tolyl, xylyl, trimethylphenyl, triisopropylphenyl, phenylethyl, phenylpropyl, methoxyphenyl, chlorophenyl and nitrophenyl.
Has the advantages that: the invention provides a preparation method of a Rosemastat intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline formate, which takes 3-oxo-3- (4-phenoxyphenyl) propionate as a starting raw material to prepare an intermediate 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate, and then the intermediate is prepared through cyclization reaction. The method has the advantages of novel line, short synthesis line, easy acquisition or preparation of all raw material reagents, no use of reagents with high risk and high pollution, safety, environmental protection, mild reaction conditions, convenient and controllable operation, good purity and high yield of the prepared intermediate of the roxasistat, obvious cost advantage and suitability for industrial production.
Detailed Description
The technical solution of the present invention will be described in detail below with reference to specific examples. Including but not limited to the following examples.
Example 1
A preparation method of a roxasistat intermediate comprises the following synthetic route:
the method comprises the following steps:
synthesis of methyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III)
135g (0.5mol, 1.0eq) of methyl 3-oxo-3- (4-phenoxyphenyl) propionate, 160mL of glacial acetic acid and 240mL of water are sequentially added into a round bottom flask with mechanical stirring, the temperature of a reaction system is reduced to about 0 ℃, 41g (0.6mol, 1.2eq) of sodium nitrite is added in batches, the reaction system is stirred and reacted for 3 hours at 0 ℃, and the completion of the conversion of the raw materials is detected by TLC. 1000mL of water and 1000mL of methylene chloride were added to the reaction system, and the mixture was stirred for 15 minutes and then allowed to stand for separation. The aqueous phase was extracted twice more with 1000mL x 2 of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated pale yellow oil was filtered for 138g of methyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate in 92.0% yield and 97.5% HPLC purity.
Synthesis of methyl 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate (formula VI)
Under a ice salt bath, 120g (0.4mol, 1.0eq) of methyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate and 1200mL of acetic anhydride which participate in the reaction are sequentially added into a round bottom flask with mechanical stirring, 38.4g (1.6mol, 4.0eq) of magnesium powder are added into 10 batches and stirred for 15 minutes, 192g (3.2mol, 8.0eq) of glacial acetic acid is slowly added dropwise, the temperature of the reaction system is controlled at minus 10 ℃ and is continuously stirred for 20 hours, sampling TLC detection is carried out, 300mL of water is added into the reaction system after the raw materials are completely converted, insoluble substances are removed by filtration, a filter cake is washed by dichloromethane, filtrate is extracted by dichloromethane, organic layers are combined, washed by 2000mL of saturated sodium bicarbonate, anhydrous sodium sulfate is dried, and 121g of methyl 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate is obtained by filtration and concentration, yield 92.4% and HPLC purity 97.5%.
Synthesis of methyl 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate (formula I)
120g (0.36mol, 1.0eq) of methyl 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate, 1000mL of N, N-dimethylformamide and 112g (0.72mol, 2.0eq) of phosphorus oxychloride are added into a round-bottomed flask with mechanical stirring, the mixture is heated to reflux reaction for 6 hours, the mixture is cooled to room temperature, the solvent is removed under reduced pressure, a filter cake is collected, 500mL of 2.0M sodium hydroxide is added into the filter cake, the mixture is stirred for 15 minutes and filtered, the filter cake is washed twice by 1000mL of 2 water to obtain a wet product, and the wet product is dried by air blowing at 40 ℃ to obtain 105g of white-like 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline methyl formate solid, the yield is 92.9 percent and the purity is 98.8 percent.
Example 2
A preparation method of a roxasistat intermediate comprises the following synthetic route:
the method comprises the following steps:
synthesis of methyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III)
135g (0.5mol, 1.0eq) of methyl 3-oxo-3- (4-phenoxyphenyl) propionate, 200mL of glacial acetic acid and 200mL of water are sequentially added into a round-bottomed flask with mechanical stirring, the temperature of a reaction system is reduced to about 0 ℃, 52g (0.75mol, 1.5eq) of sodium nitrite is added in batches, the reaction system is stirred and reacted for 3 hours at 0 ℃, and the completion of the conversion of the raw material is detected by TLC. 1000mL of water and 1000mL of methylene chloride were added to the reaction system, and the mixture was stirred for 15 minutes and then allowed to stand for separation. The aqueous phase was extracted twice more with 1000mL x 2 of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated pale yellow oil was filtered for 144g of methyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate, yield 96.0%, HPLC purity 98.6%.
Synthesis of methyl 2-amino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III-0)
120g (0.4mol) of methyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III), 1.2g of 5% palladium carbon and 1200mL of methanol are sequentially added into a round bottom flask with mechanical stirring to participate in the reaction, the mixture is stirred for 24 hours at room temperature in a hydrogen atmosphere, HPLC (high performance liquid chromatography) detects that the raw materials are completely converted, the palladium carbon is removed by filtration, the solvent methanol is removed by concentration under reduced pressure to obtain a light yellow liquid, 500mL of ethanol hydrogen chloride solution is poured into the mixture and stirred for 3 hours at room temperature, a large amount of white solid is separated out, the mixture is filtered, the mixture is washed by 300mL of cold ethanol with 3, the solid is dissolved in 1000mL of deionized water, the pH value is adjusted to 8-9 by 10% of sodium hydroxide, the mixture is extracted by 500mL of toluene with 3 and concentrated to obtain 97g of light yellow oily matter with the purity of HPLC (high performance liquid chromatography, high performance liquid chromatography and High Performance Liquid Chromatography (HPLC) yield is 85%.
Synthesis of methyl 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate (formula I)
Adding 80g (0.28mol, 1.0eq) of methyl 2-amino-3-oxo-3- (4-phenoxyphenyl) propionate participating in the reaction, 43g (0.42mol, 1.5eq) of triethylamine and 800mL of toluene in turn into a round bottom flask with mechanical stirring, reducing the temperature of a reaction system to 0 ℃, slowly dropwise adding 200mL of toluene solution dissolved with 23g of acetyl chloride, controlling the reaction temperature to be not more than 10 ℃, heating to 50 ℃ after dropwise adding, refluxing for 3 hours, filtering to remove triethylamine hydrochloride, slowly adding 218g (1.4mol, 5.0eq) of phosphorus oxychloride, heating to reflux reaction for 6 hours, cooling to room temperature, decompressing to remove a solvent, collecting a filter cake, adding 500mL of 2.0M sodium hydroxide into the filter cake, stirring for 15 minutes, filtering, washing the filter cake twice with 500mL of water to 2 to obtain a wet product, and performing forced air drying at 40 ℃ to obtain a white-like product, namely 4-hydroxy-1-methyl-7-phenoxy-3-iso-phenoxy 61g of quinolinecarboxylic acid methyl ester solid, 71% yield, 99.6% purity,
example 3
A preparation method of a roxasistat intermediate comprises the following synthetic route:
the method comprises the following steps:
synthesis of trifluoromethyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III)
In a round bottom flask equipped with mechanical stirring, 162g (0.5mol, 1.0eq) of trifluoromethyl 3-oxo-3- (4-phenoxyphenyl) propionate, 160mL of glacial acetic acid, and 240mL of water were added in this order, the temperature of the reaction system was lowered to about 0 ℃, 52g (0.6mol, 1.5eq) of sodium nitrite was added in portions, the reaction system was stirred at 30 ℃ for 3 hours, and the completion of conversion of the starting material was detected by TLC. 1000mL of water and 1000mL of methylene chloride were added to the reaction system, and the mixture was stirred for 15 minutes and then allowed to stand for separation. The aqueous phase was extracted twice more with 1000mL x 2 of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated pale yellow oil was filtered 166g of trifluoromethyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate in 94.0% yield with 98.5% HPLC purity.
Synthesis of 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionic acid trifluoromethyl ester (formula VI)
141g (0.4mol, 1.0eq) of trifluoromethyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate and 1200mL of acetic anhydride which participate in the reaction are sequentially added into a round-bottomed flask with mechanical stirring under ice salt bath, 130.0g (2.0mol, 5eq) of zinc powder is added into 10 batches and stirred for 15 minutes, 240g (4mol, 10.0eq) of glacial acetic acid is slowly added dropwise, the temperature of the reaction system is controlled at-10 ℃ and continuously stirred for 20 hours, sampling TLC detection is carried out, 300mL of water is added into the reaction system after the raw materials are completely converted, insoluble substances are removed by filtration, a filter cake is washed by dichloromethane, a filtrate is extracted by dichloromethane again, an organic layer is combined, washed by 2000mL of saturated sodium bicarbonate, dried by anhydrous sodium sulfate, filtered and concentrated to obtain 143g of trifluoromethyl 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate, the yield was 94.0.4%, with an HPLC purity of 98.2%.
Synthesis of 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylic acid trifluoromethyl ester (formula I)
Adding 141g (0.37mol, 1.0eq) of trifluoromethyl 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate, 1000mL of toluene and 211g (1.85mol, 5.0eq) of phosphorus oxychloride into a round bottom flask with mechanical stirring, heating to reflux reaction for 6 hours, cooling to room temperature, removing the solvent under reduced pressure, collecting a filter cake, adding 500mL of 2.0M sodium hydroxide into the filter cake, stirring for 15 minutes, filtering, washing the filter cake twice with 1000mL of water to obtain a wet product, and drying by air blast at 40 ℃ to obtain 114g of 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline methyl formate solid with yield of 85.9 percent and purity of 98.8 percent,
example 4
A preparation method of a roxasistat intermediate comprises the following synthetic route:
the method comprises the following steps:
synthesis of cyclopropyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III)
In a round bottom flask equipped with mechanical stirring, 118g (0.4mol, 1.0eq) of cyclopropyl 3-oxo-3- (4-phenoxyphenyl) propionate, 200mL of glacial acetic acid, and 150mL of water were added in this order, the temperature of the reaction system was lowered to about 0 ℃, 55g (0.8mol, 1.5eq) of sodium nitrite was added in portions, the reaction system was stirred at 30 ℃ for 3 hours, and the completion of conversion of the starting material was detected by TLC. 1000mL of water and 1000mL of methylene chloride were added to the reaction system, and the mixture was stirred for 15 minutes and then allowed to stand for separation. The aqueous phase was extracted twice more with 1000mL x 2 of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated pale yellow oil was filtered, methyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate 123g, yield 94.0%, 98.2% purity by HPLC.
Synthesis of cyclopropyl 2-amino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III-0)
130g (0.4mol) of cyclopropyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III), 1.2g of 5% palladium carbon and 1300mL of methanol are sequentially added into a round bottom flask with mechanical stirring to participate in the reaction, the mixture is stirred for 24 hours at room temperature in a hydrogen atmosphere, HPLC (high performance liquid chromatography) detects that the raw materials are completely converted, the palladium carbon is removed by filtration, the solvent methanol is removed by concentration under reduced pressure, a light yellow liquid is obtained, 500mL of ethanol hydrogen chloride solution is poured into the mixture and stirred for 3 hours at room temperature, a large amount of white solid is separated out, the mixture is filtered, the mixture is washed by 300mL of cold ethanol with 3, the solid is dissolved in 1000mL of deionized water, the pH value is adjusted to be between 8 and 9 by 10% of sodium hydroxide, the mixture is extracted by 500mL of toluene with 3 and concentrated to obtain 101g of light yellow oily matter, the purity of HPLC is 99.4%, and the yield is 88%.
Synthesis of cyclopropyl 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate (formula I)
Adding 80g (0.28mol, 1.0eq) of cyclopropyl 2-amino-3-oxo-3- (4-phenoxyphenyl) propionate participating in the reaction, 43g (0.42mol, 1.5eq) and 800mL of toluene into a round-bottomed flask with mechanical stirring in sequence, reducing the temperature of a reaction system to 0 ℃, slowly dropwise adding 200mL of toluene solution dissolved with 23g of acetyl chloride, controlling the reaction temperature to be not more than 10 ℃, heating to 50 ℃ after dropwise adding, refluxing for 3 hours, filtering to remove triethylamine hydrochloride, slowly adding 218g (1.4mol, 5.0eq) of phosphorus oxychloride, heating to reflux reaction for 6 hours, cooling to room temperature, decompressing to remove the solvent, collecting a filter cake, adding 500mL of 2.0M sodium hydroxide into the filter cake, stirring for 15 minutes, filtering, washing the filter cake twice with 500mL of water to obtain a wet product, and drying by blowing at 40 ℃ to obtain the white-like 4-hydroxy-1-methyl-7-phenoxy-3-one-hydroxy-type compound 61g of isoquinoline formic acid cyclopropyl ester solid, 79 percent of yield and 99.6 percent of purity,
example 5
A preparation method of a roxasistat intermediate comprises the following synthetic route:
the method comprises the following steps:
synthesis of benzyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III)
In a round bottom flask equipped with mechanical stirring, 116g (0.35mol, 1.0eq) of benzyl 3-oxo-3- (4-phenoxyphenyl) propionate, 200mL of glacial acetic acid and 150mL of water were added in sequence, the temperature of the reaction system was lowered to about 0 ℃, 48g (0.7mol, 2eq) of sodium nitrite was added in portions, the reaction system was stirred at 0 ℃ for 3 hours, and the completion of conversion of the starting material was detected by TLC. 1000mL of water and 1000mL of methylene chloride were added to the reaction system, and the mixture was stirred for 15 minutes and then allowed to stand for separation. The aqueous phase was extracted twice more with 1000mL x 2 of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated pale yellow oil was filtered for benzyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate 117g in 92.9% yield and 97.7% HPLC purity.
Synthesis of benzyl 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate (formula VI)
Under a ice salt bath, 117g (0.35mol, 1.0eq) of methyl 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate and 1200mL of acetic anhydride which participate in the reaction are sequentially added into a round bottom flask with mechanical stirring, 99g (1.5mol, 5.0eq) of zinc powder is added into 10 batches, the mixture is stirred for 15 minutes, 182g (3.4mol, 10.0eq) of glacial acetic acid is slowly added dropwise, the temperature of the reaction system is controlled at minus 10 ℃ and is continuously stirred for 20 hours, sampling TLC detection is carried out, 300mL of water is added into the reaction system after the raw materials are completely converted, insoluble substances are removed by filtration, a filter cake is washed by dichloromethane, a filtrate is extracted by dichloromethane, organic layers are combined, the organic layers are washed by 2000mL of saturated sodium bicarbonate, anhydrous sodium sulfate is dried, and filtered and concentrated to obtain 112g of benzyl 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate, the yield was 94.4% and the HPLC purity was 97.5%.
Synthesis of benzyl 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate (formula I)
Adding 112g (0.28mol, 1.0eq) of benzyl 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate, 1000mL of toluene and 440g (2.8mol, 10.0eq) of phosphorus oxychloride into a round bottom flask with mechanical stirring, heating to reflux reaction for 6 hours, cooling to room temperature, removing the solvent under reduced pressure, collecting a filter cake, adding 500mL of 2.0M sodium hydroxide into the filter cake, stirring for 15 minutes, filtering, washing the filter cake twice with 1000mL of water to obtain a wet product, and drying by air blast at 40 ℃ to obtain 98g of benzyl 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate solid with yield of 91.7 percent and purity of 98.8 percent,
it should be noted that, in each step, other auxiliary steps for collecting the product, increasing the yield, increasing the product purity, removing impurities, etc. may be adopted, such as common auxiliary means of filtration, washing, extraction, purification, drying, etc.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (7)
1. The preparation method of the intermediate of the roxasistat is characterized in that the synthetic route is as follows:
wherein R in the formula II, the formula IV and the formula I are the same and are selected from chain alkyl, cyclic alkyl or aryl; the chain alkyl is unsubstituted chain alkyl or substituted chain alkyl, and the unsubstituted chain alkyl is methyl, ethyl or propyl; the substituted chain alkyl is trifluoromethyl; the cyclic alkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; the aryl is unsubstituted aryl or substituted aryl, the unsubstituted aryl is phenyl and naphthyl, and the substituted aryl is tolyl, xylyl and trimethylphenyl;
the method comprises the following steps:
s1, preparing 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate (formula IV) by taking 3-oxo-3- (4-phenoxyphenyl) propionate (formula II) as a raw material;
s2, 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate (formula IV) to obtain 4-hydroxy-1-methyl-7-phenoxyl-3-isoquinoline formate (formula I);
in S1, the synthetic route is as follows:
the method comprises the following steps: taking 3-oxo-3- (4-phenoxyphenyl) propionate (formula II) as a raw material, carrying out sodium nitrite hydroxylamination reaction to obtain 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III), and carrying out acetylation reaction to obtain 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate (formula IV).
2. A process for the preparation of the intermediate of rosxastat as claimed in claim 1, characterized in that the synthetic route of S1 is replaced by:
the method comprises the following steps: taking 3-oxo-3- (4-phenoxyphenyl) propionate (formula II) as a raw material, carrying out sodium nitrite hydroxylamination reaction to obtain 2-hydroxylamino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III), carrying out catalytic reduction to obtain 2-amino-3-oxo-3- (4-phenoxyphenyl) propionate (formula III-0), and carrying out acetylation reaction to obtain 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate (formula IV).
3. The method for preparing the intermediate of rosmarinic acid as claimed in claim 1 or 2, wherein in S1, the solvent of the hydroxylamination reaction is glacial acetic acid and water, the volume ratio of glacial acetic acid to water is 2-4: 3; the temperature of the hydroxylamination reaction is-10 to 30 ℃.
4. The process for the preparation of the intermediate of rosmarinic acid as claimed in claim 1, wherein in S1, the solvent for acetylation is acetic anhydride and the reagent is acetic acid; the catalyst for acetylation reaction is one or any combination of zinc powder, iron powder and magnesium powder; the temperature of the acetylation reaction is-10 to 30 ℃.
5. The process for preparing a rosisastat intermediate as claimed in claim 2, wherein in S1, the acetylation reagent is any one of acetyl chloride, acetic anhydride and acetic acid; the catalyst for catalytic reduction reaction is palladium carbon catalyst.
6. The process for preparing the intermediate of rosxastat according to claim 1 or 2, wherein in S2, the solvent for the cyclization reaction is one or any combination of toluene, xylene, acetonitrile, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide; the catalyst for the cyclization reaction is phosphorus oxychloride.
7. The process for the preparation of the intermediate of Rosxastat of claim 6 wherein the molar ratio of 2-acetamido-3-oxo-3- (4-phenoxyphenyl) propionate to phosphorus oxychloride is 1: 2 to 10.
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| 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 |
| CN108424388A (en) * | 2018-04-19 | 2018-08-21 | 杭州科巢生物科技有限公司 | A kind of preparation method of chronic anaemia drug |
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| 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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