CN111116500B - A kind of purification method of key intermediate of Recinade - Google Patents
A kind of purification method of key intermediate of Recinade Download PDFInfo
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- CN111116500B CN111116500B CN201911388222.4A CN201911388222A CN111116500B CN 111116500 B CN111116500 B CN 111116500B CN 201911388222 A CN201911388222 A CN 201911388222A CN 111116500 B CN111116500 B CN 111116500B
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- 238000000746 purification Methods 0.000 title claims description 16
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- CCPTWMNSFHCZPB-UHFFFAOYSA-N 1-cyclopropyl-4-isothiocyanatonaphthalene Chemical compound C12=CC=CC=C2C(N=C=S)=CC=C1C1CC1 CCPTWMNSFHCZPB-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
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- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 3
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- NAFSTSRULRIERK-UHFFFAOYSA-M monosodium urate Chemical group [Na+].N1C([O-])=NC(=O)C2=C1NC(=O)N2 NAFSTSRULRIERK-UHFFFAOYSA-M 0.000 description 2
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- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
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- FGQFOYHRJSUHMR-UHFFFAOYSA-N lesinurad Chemical compound OC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 FGQFOYHRJSUHMR-UHFFFAOYSA-N 0.000 description 1
- 229960003838 lesinurad Drugs 0.000 description 1
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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 ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for purifying a key intermediate of Reisinad, which comprises the following steps: and stirring and dissolving the key intermediate crude product in a mixed solvent of alcohols and esters, adding activated carbon, filtering, cooling and crystallizing, filtering, and drying under reduced pressure to obtain a high-purity intermediate compound. The method has good refining effect, high yield and purity of the refined target product, and better ensures the stability of the next process; the refining process is simple, the used solvent is common and easy to recover, and the industrial operation is greatly simplified, so that the method is suitable for industrial mass production.
Description
Technical Field
The invention relates to the technical field of preparation of Raschindde medicaments, in particular to a purification method of a Raschindde key intermediate.
Background
Hyperuricemia (HUA) is one of the important components of metabolic syndrome, is closely related to gout, and is also a risk factor of hypertension, chronic kidney disease, dyslipidemia, diabetes, cardiovascular disease and the like. The prevalence rate of the HUA in developed western countries is 15-20%, and in recent years, with the improvement of the living standard of China, the change of the dietary structure and the prolonging of the average life span, the prevalence rate of the HUA is increased year by year. It is estimated that the number of patients with the present HUA in China is nearly 1.2 million, and about 1700 million patients with gout are. Gout is a chronic metabolic disease mainly characterized by hyperuricemia and pain caused by deposition of monosodium urate (MSU) on joints and other parts, and is mainly caused by purine metabolic disorder and/or uric acid excretion disorder.
Rexinard (Lesinurad), chemical name 2- [ [ 5-bromo-4- (4-cyclopropyl-1-naphthalen) -4H-1,2, 4-triazol-3-yl ] thio ] acetic acid, was approved by the Food and Drug Administration (FDA) on the market at 12/22 of 2015, and by the european drug administration (EMA) on 18 of 12/18 of the year, recommended approval for the drug to market in the european union. Racinadine is the first approved urate reabsorption transporter (URAT1) inhibitor worldwide, in combination with xanthine oxidase inhibitors for the treatment of hyperuricemia-associated gout.
The key intermediate disclosed in the original patent CN104736522A is prepared by taking 4-cyclopropyl-1-naphthyl isothiocyanate as a starting material through cyclization and then carrying out substitution reaction with methyl bromoacetate. The obtained methyl 2- (4- (1-cyclopropyl-naphthalene-4-yl) -4H-1,2, 4-triazole-3-yl-sulfenyl) acetate (compound (4) synthesized by the method has low purity, and the system has dark color when the compound is dissolved by a reaction solvent in the next step.
A large number of experiments show that impurities can seriously affect the bromination free radical reaction because the bromination reaction is the free radical reaction, so that the reaction of the intermediate (4) is incomplete, and the quality of Raschild is affected.
The synthesis route of the Racinade mainly comprises the following steps:
compound (4) was synthesized according to the method reported in patent CN104736522A, followed by synthesis of Ravinard. However, it is difficult to obtain acceptable rasidone products according to the above method. Therefore, a purification method for purifying the compound (4) is urgently required.
Disclosure of Invention
The invention aims to provide a refining method of 2- (4- (1-cyclopropyl naphthalene-4-yl) -4H-1,2, 4-triazole-3-yl sulfenyl) methyl acetate which is a key intermediate of Reisinad aiming at the defects in the prior art, so that the color and impurities in the compound (4) are reduced, and the product quality is improved.
The technical scheme of the invention is realized as follows: the crude product of the compound (4) can be synthesized by the prior art, namely, the synthesis is carried out according to the route disclosed in the original patent CN104736522A, namely, 4-cyclopropyl-1-naphthyl isothiocyanate is taken as a starting material, and the crude product is obtained by cyclization and substitution reaction with methyl bromoacetate, and has dark color, more impurities and no purification step. The synthetic route is as follows:
a method for purifying a key Leishard intermediate comprises the following steps: stirring and dissolving the key intermediate crude product in a mixed solvent of alcohols and esters, adding activated carbon, filtering, cooling and crystallizing, filtering, and drying under reduced pressure to obtain a high-purity intermediate compound (2- (4- (1-cyclopropyl naphthalene-4-yl) -4H-1,2, 4-triazole-3-yl sulfenyl) methyl acetate), wherein the structural formula of the compound is shown as the formula (4):
further, the mixed solvent is prepared by mixing an alcohol organic solvent and an ester organic solvent, wherein the alcohol organic solvent is at least one of methanol, ethanol and isopropanol, and the ester organic solvent is at least one of ethyl acetate, butyl acetate and isopropyl acetate.
Further, the mixed solvent is a mixed solvent of ethyl acetate and isopropanol.
Further, in the mixed solvent, the volume ratio of the alcohol organic solvent to the ester organic solvent is 10-5: 1.
furthermore, the volume usage of the mixed solvent is 5-15 times of the mass ml/g of the crude intermediate product.
Furthermore, the volume consumption of the mixed solvent is 8-10 times of the mass ml/g of the crude intermediate product.
Further, the dissolving temperature is 50-75 ℃.
Further, the dissolving temperature is 60-65 ℃.
Further, the crystallization temperature is-10-30 ℃.
Further, the crystallization temperature is 0-10 ℃.
Further, the method for purifying the key intermediate of the Raschild sodium comprises the following steps: adding an 8:1 alcohol and ester mixed solvent into the crude product of the compound (4), and controlling the mass-volume ratio within 8-10 times; heating to 60-65 ℃, stirring for dissolving, adding activated carbon, stirring for 10-15 min, filtering while hot, slowly cooling to 0-10 ℃, crystallizing for 3-5 h, performing suction filtration to obtain a filter cake, and performing vacuum reduced pressure drying on the filter cake at 50 ℃ for 6-8 h to obtain a white solid, namely the high-purity compound.
The high performance liquid analysis method used was as follows:
a chromatographic column: kromasil C184.6X 150mm, 5 μm
Mobile phase: a: 0.02mol/L potassium dihydrogen phosphate (adjusted to pH 3.0 with phosphoric acid) B: methanol
The gradient elution procedure was as follows:
| time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 5 | 90 | 10 |
| 15 | 70 | 30 |
| 35 | 45 | 55 |
| 80 | 15 | 85 |
| 95 | 15 | 85 |
| 97 | 90 | 10 |
| 107 | 90 | 10 |
Column temperature: 35 deg.C
Detection wavelength: 226nm
Diluent agent: acetonitrile
Sample concentration: 0.5mg/ml
Flow rate: 1.0ml/min
Sample introduction amount: 5 μ l
Compared with the prior art, the invention has the beneficial effects that:
(1) according to the invention, after refining the key intermediate of Racinidide, the impurity content is effectively reduced, the purity of the obtained target compound 2- (4- (1-cyclopropyl naphthalene-4-yl) -4H-1,2, 4-triazole-3-yl sulfenyl) methyl acetate is high, the adverse effect of incomplete reaction in the next step caused by impurities is reduced, the process stability in the next step is better ensured, the quality of Racinidide is improved, and a high-purity product is obtained.
(2) The method has the advantages of good refining effect, high yield and purity of the refined target product, simple refining process, common used solvent and easy recovery, greatly simplifies the industrial operation, and is suitable for industrial mass production.
Drawings
FIG. 1 is an HPLC chromatogram of the crude product of reference example 1.
FIG. 2 is an HPLC chromatogram of bromide in reference example 2.
FIG. 3 is an HPLC chromatogram of the purification of example 2.
FIG. 4 is an HPLC chromatogram of test example 1.
Detailed Description
In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.
The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified.
The materials, reagents and the like used in the examples of the present invention can be obtained commercially without specific description.
Reference example 1
The crude product of the compound (4) is synthesized into the crude product of the intermediate compound (4) according to the synthesis method of the patent publication CN104736522A, namely 4-cyclopropyl-1-naphthyl isothiocyanate is used as a starting material, and is obtained by cyclization and substitution reaction with methyl bromoacetate, so that the crude product is dark in color and more in impurities, and the purity of the crude product is 84.876%. The synthetic route is as follows:
reference example 2: synthesis of methyl 2- (5-bromo-4- (1-cyclopropylnaphthalen-4-yl) -4H-1,2, 4-triazol-3-ylthio) acetate
Taking 8.0g of the crude compound (4) obtained in the reference example 1 and 64ml of tetrahydrofuran, starting stirring, heating to a temperature T of 30-35 ℃, and stirring until the compound is dissolved; adding 6.4g of NBS, stirring and reacting for 3-4 h, after the reaction is finished, cooling to 0-5 ℃ of T, adding 40ml of toluene, dropwise adding 40ml of purified water, controlling the temperature to be not more than 7 ℃, stirring for 10min after dropwise adding, and standing for liquid separation; cooling the organic phase to 0-5 ℃, dropwise adding 40ml of 3% sodium bisulfite solution, keeping the temperature below 10 ℃, stirring for 20min after dropwise adding, standing for liquid separation, and collecting the organic phase; heating to 18-25 ℃ by using an organic camera, adding 40ml of 7% sodium bicarbonate solution, stirring for 10min, standing for liquid separation, collecting an organic phase, concentrating, and drying to obtain the Raschild product, wherein the purity of the Raschild product is detected to be 96.443%.
Example 1
Taking 10.0g of the crude compound (4) obtained in reference example 1, adding a 6-time mixed solvent of ethanol and ethyl acetate (ethanol: ethyl acetate: 10: 1), heating to 60-65 ℃, stirring for dissolving, adding 3.0g of activated carbon, keeping the temperature, stirring for 10-15 min, filtering, slowly cooling to 0-10 ℃, stirring for 3-5 h, performing suction filtration, and performing vacuum drying at 50 ℃ under reduced pressure for 6-8 h to obtain 8.51g of a white solid, namely the high-purity compound (I), wherein the yield is 85.1%.
Example 2
Taking 10.0g of the crude compound (4) obtained in reference example 1, adding 9 times (90ml) of isopropanol and ethyl acetate mixed solvent (isopropanol: ethyl acetate: 8: 1), heating to 60-65 ℃, stirring for dissolving, adding 3.0g of activated carbon, keeping the temperature and stirring for 10-15 min, filtering, slowly cooling to 0-10 ℃, stirring for 3-5 h, performing suction filtration, and performing vacuum drying at 50 ℃ for 6-8 h under reduced pressure to obtain 8.45g of white solid, namely the high-purity compound (4), wherein the yield is 84.5%.
Example 3
Taking 10.0g of the crude compound (4) obtained in reference example 1, adding 9 times (90ml) of a mixed solvent of ethanol and butyl acetate (ethanol: butyl acetate: 9: 1), heating to 60-65 ℃, stirring for dissolving, adding 3.0g of activated carbon, keeping the temperature, stirring for 10-15 min, filtering, slowly cooling to 0-10 ℃, stirring for 3-5 h, performing suction filtration, and performing vacuum drying at 50 ℃ for 6-8 h under reduced pressure to obtain 8.65g of a white solid, namely the high-purity compound (4), wherein the yield is 86.5%.
Example 4
Taking 10.0g of the crude compound (4) obtained in reference example 1, adding 9 times (90ml) of isopropanol-butyl acetate mixed solvent (isopropanol: butyl acetate: 7: 1), heating to 60-65 ℃, stirring for dissolving, adding 3.0g of activated carbon, keeping the temperature and stirring for 10-15 min, filtering, slowly cooling to 0-10 ℃, stirring for 3-5 h, performing suction filtration, and performing vacuum drying at 50 ℃ for 6-8 h under reduced pressure to obtain 8.57g of white solid, namely the high-purity compound (4), wherein the yield is 85.7%.
Example 5
Taking 10.0g of the crude compound (4) obtained in reference example 1, adding 10 times (100ml) of a mixed solvent of isopropanol and isopropyl acetate (isopropanol: isopropyl acetate: 7: 1), heating to 60-65 ℃, stirring for dissolving, adding 3.0g of activated carbon, keeping the temperature and stirring for 10-15 min, filtering, slowly cooling to 0-10 ℃, stirring for 3-5 h, performing suction filtration, and performing vacuum drying at 50 ℃ for 6-8 h under reduced pressure to obtain 8.53g of a white solid, namely the high-purity compound (4), wherein the yield is 85.3%.
Example 6
Taking 10.0g of the crude compound (4) obtained in reference example 1, adding a 7-fold (70ml) amount of a mixed solvent of methanol and isopropyl acetate (methanol: isopropyl acetate: 10: 1), heating to 60-65 ℃, stirring for dissolving, adding 3.0g of activated carbon, keeping the temperature, stirring for 10-15 min, filtering, slowly cooling to 0-10 ℃, stirring for 3-5 h, performing suction filtration, and performing vacuum drying at 50 ℃ for 6-8 h under reduced pressure to obtain 8.46g of a white solid, namely the high-purity compound (4), wherein the purity is 99.2%, and the yield is 84.6%.
Test example 1: synthesis of methyl 2- (5-bromo-4- (1-cyclopropylnaphthalen-4-yl) -4H-1,2, 4-triazol-3-ylthio) acetate
Taking 8.0g of the purified product of the compound (4) obtained in example 3 and 64ml of tetrahydrofuran, starting stirring, heating to the temperature of between 30 and 35 ℃, and stirring until the mixture is dissolved; adding 6.4g of NBS, stirring and reacting for 3-4 h, after the reaction is finished, cooling to 0-5 ℃ of T, adding 40ml of toluene, dropwise adding 40ml of purified water, controlling the temperature to be not more than 7 ℃, stirring for 10min after dropwise adding, and standing for liquid separation; cooling the organic phase to 0-5 ℃, dropwise adding 40ml of 3% sodium bisulfite solution, keeping the temperature below 10 ℃, stirring for 20min after dropwise adding, standing for liquid separation, and collecting the organic phase; heating to 18-25 ℃ by using an organic camera, adding 40ml of 7% sodium bicarbonate solution, stirring for 10min, standing for liquid separation, collecting an organic phase, concentrating and drying to obtain the Raschild product, wherein the purity of the Raschild product is detected to be 99.940%.
The intermediate compounds before and after purification of reference example and examples 1 to 6 and reference example 2 and test example 1 were weighed and tested for purity, wherein,
yield of fine product is 100% of weight of fine product after purification/weight of intermediate coarse body;
percent reduction of impurities (pre-purification impurity content-post-purification impurity content)/pre-purification impurity content 100%.
The results show that the purification method provided by the invention, examples 1-6, can be used for refining the crude product of the key intermediate of Ravinard, and can effectively reduce the impurity content and obtain the target product with high purity on the premise of high yield of the refined product.
Furthermore, experimental example 1 the purity of the product of rasidone obtained from the preparation of the purified product of the present invention (99.940%) was much higher than that of the product of rasidone prepared without purification in reference example 2 (96.443%), and the content of impurities was reduced by 98.31%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (6)
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Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103524440A (en) * | 2013-10-15 | 2014-01-22 | 苏州鹏旭医药科技有限公司 | Preparation method of gout curative medicine Lesinurad and midbody of Lesinurad |
| CN104736522A (en) * | 2012-07-03 | 2015-06-24 | 阿迪亚生命科学公司 | Manufacture of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetic acid |
| CN105017168A (en) * | 2015-07-01 | 2015-11-04 | 安徽万邦医药科技有限公司 | New preparation method of [5-bromo-4-(4-cyclopropyl-naphthalene-1-yl)-4H-[1, 2, 4]triazole-3-ylsulfanyl]-methyl acetate |
| CN105175348A (en) * | 2015-10-16 | 2015-12-23 | 北京康立生医药技术开发有限公司 | Preparation method for lesinurad |
| CN105263913A (en) * | 2013-06-14 | 2016-01-20 | 广东东阳光药业有限公司 | Thio-1,2,4-triazole derivatives and method for preparing the same |
| CN105294585A (en) * | 2014-07-02 | 2016-02-03 | 成都海创药业有限公司 | Compound for treating gout |
| CN105399694A (en) * | 2015-12-11 | 2016-03-16 | 浙江京新药业股份有限公司 | Axially chiral enantiomers of drug Lesinurad |
| CN105906576A (en) * | 2016-06-12 | 2016-08-31 | 成都百裕制药股份有限公司 | Method for preparing lesinurad intermediate |
| EP3281941A1 (en) * | 2016-08-11 | 2018-02-14 | Zentiva K.S. | Process for preparing 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4h-1,2,4-triazol-3-ylthio)acetic acid |
| CN109970667A (en) * | 2017-12-27 | 2019-07-05 | 徐州万邦金桥制药有限公司 | A kind of refining methd of the western Nader of thunder |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10351537B2 (en) * | 2017-03-10 | 2019-07-16 | Apotex Inc. | Processes for the preparation of lesinurad and intermediates thereof |
-
2019
- 2019-12-30 CN CN201911388222.4A patent/CN111116500B/en not_active Expired - Fee Related
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104736522A (en) * | 2012-07-03 | 2015-06-24 | 阿迪亚生命科学公司 | Manufacture of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetic acid |
| CN105263913A (en) * | 2013-06-14 | 2016-01-20 | 广东东阳光药业有限公司 | Thio-1,2,4-triazole derivatives and method for preparing the same |
| CN103524440A (en) * | 2013-10-15 | 2014-01-22 | 苏州鹏旭医药科技有限公司 | Preparation method of gout curative medicine Lesinurad and midbody of Lesinurad |
| CN105294585A (en) * | 2014-07-02 | 2016-02-03 | 成都海创药业有限公司 | Compound for treating gout |
| CN105017168A (en) * | 2015-07-01 | 2015-11-04 | 安徽万邦医药科技有限公司 | New preparation method of [5-bromo-4-(4-cyclopropyl-naphthalene-1-yl)-4H-[1, 2, 4]triazole-3-ylsulfanyl]-methyl acetate |
| CN105175348A (en) * | 2015-10-16 | 2015-12-23 | 北京康立生医药技术开发有限公司 | Preparation method for lesinurad |
| CN105399694A (en) * | 2015-12-11 | 2016-03-16 | 浙江京新药业股份有限公司 | Axially chiral enantiomers of drug Lesinurad |
| CN105906576A (en) * | 2016-06-12 | 2016-08-31 | 成都百裕制药股份有限公司 | Method for preparing lesinurad intermediate |
| EP3281941A1 (en) * | 2016-08-11 | 2018-02-14 | Zentiva K.S. | Process for preparing 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4h-1,2,4-triazol-3-ylthio)acetic acid |
| CN109970667A (en) * | 2017-12-27 | 2019-07-05 | 徐州万邦金桥制药有限公司 | A kind of refining methd of the western Nader of thunder |
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Denomination of invention: A Purification Method of the Key Intermediate of Racenard Effective date of registration: 20220929 Granted publication date: 20210608 Pledgee: Haikou Xiuying Sub branch of Bank of China Ltd. Pledgor: Beijing Xin Kai Yuan Pharmaceutical Technology Co.,Ltd. Hainan branch Registration number: Y2022980017059 |
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