CN111116501A - Synthesis method of Ravinard intermediate capable of effectively reducing impurity content - Google Patents
Synthesis method of Ravinard intermediate capable of effectively reducing impurity content Download PDFInfo
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- 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
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Abstract
The invention provides a method for synthesizing a Raschild intermediate capable of effectively reducing impurity content, which comprises the following steps: reacting the reactant intermediate (4) in a mixed solvent A under the action of a catalyst, carrying out post-treatment to obtain a crude product of the product intermediate (5), and recrystallizing with a mixed solvent B to obtain a refined product of the high-purity intermediate (5); the catalyst is at least one of BPO, AIBN and TEMPO. Compared with the prior art, the method for synthesizing the Raschild intermediate methyl 2- (5-bromo-4- (1-cyclopropyl naphthalene-4-yl) -4H-1,2, 4-triazole-3-yl sulfenyl) acetate obviously improves the purity of the Raschild intermediate methyl, effectively controls the impurity content, obviously reduces the residues of chloride and the intermediate in the previous step, greatly reduces the pressure burden for refining the Raschild finished product in the next step, and is favorable for improving the medication safety of Raschild.
Description
Technical Field
The invention relates to the technical field of Ravinard preparation, in particular to a synthetic method of a Ravinard intermediate for effectively reducing impurity content.
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. Racinard is a tablet for oral administration, and the specification is 200 mg. The recommended dosage is 200ml once a day, and the dosage is combined with allopurinol or febuxostat, and the specific structural formula is as follows:
the synthesis route of the Racinade mainly comprises the following steps:
the operation process is as follows: taking 1-cyclopropylnaphthalene-4-yl isothiocyanate as a starting material, cyclizing the starting material with formylhydrazine to obtain 4- (1-cyclopropylnaphthalene-4-yl) -4H-1,2, 4-triazole-thiol (3), nucleophilic substituting the 4- (1-cyclopropylnaphthalene-4-yl) -4H-1,2, 4-triazole-3-ylthio) methyl acetate (4) with methyl bromoacetate to obtain methyl 2- (5-bromo-4- (1-cyclopropylnaphthalene-4-yl) -4H-1,2, 4-triazole-3-ylthio) acetate (5), and hydrolyzing to obtain the Racinade (1).
The synthesis difficulty of the intermediate (5) is high, a chlorinated impurity exists in the synthesis of the intermediate (5) by taking NBS as a bromination reagent, and the structure of the chlorinated impurity is as follows:
if the impurities exist, the 2- [ [ 5-chloro-4- (4-cyclopropyl-1-naphthalene) -4H-1,2, 4-triazol-3-yl ] thio ] acetic acid can be further hydrolyzed in subsequent reaction, the polarity difference between the 2- [ [ 5-chloro-4- (4-cyclopropyl-1-naphthalene) -4H-1,2, 4-triazol-3-yl ] thio ] acetic acid and the Racinade is small, the acetic acid is often included in a main peak and is difficult to purify and remove, and therefore, the control of chloro-substituted impurities in the preparation process of the intermediate (5) is particularly.
The use of other brominating agents, such as liquid bromine, phenyltrimethylammonium tribromide, dibromohydantoin, etc., can reduce the generation of chlorinated impurities, but the reaction is not good or the impurities are more.
According to patent CN104736522A, example 2A, an intermediate (5) is synthesized by taking tetrahydrofuran as a solvent and NBS as a brominating agent, and by adopting different charge ratios and reaction temperatures, the intermediate (4) has large residue with the content of about 5 percent and the chlorinated impurities are 0.1-1.0 percent, and the impurities obtained by the intermediate (4) in the subsequent hydrolysis step are also important impurities in the API, and the structure of the impurities is as follows:
for the research and development of chemical drugs, not only high-quality raw material drugs and efficient and environment-friendly processes need to be obtained, but also the sources, removal and conversion of impurities in the raw material drugs and control measures need to be researched, so that the quality control of starting materials and intermediates, including process research and quality research, is particularly important for improving the medication safety of Raschild.
Disclosure of Invention
In view of this, the invention provides a method for synthesizing a rasinamide intermediate with effectively reduced impurity content, and the technical scheme of the invention is realized as follows:
a synthetic method of a Resicnide intermediate methyl 2- (5-bromo-4- (1-cyclopropylnaphthalene-4-yl) -4H-1,2, 4-triazol-3-ylthio) acetate comprises the following steps: reacting the reactant intermediate (4) in a mixed solvent A under the action of a catalyst, carrying out post-treatment to obtain a crude product of the product intermediate (5), and recrystallizing with a mixed solvent B to obtain a refined product of the high-purity intermediate (5); the catalyst is at least one of BPO, AIBN and TEMPO; the reaction formula is as follows:
further, the mixed solvent A is prepared by mixing tetrahydrofuran and at least one of dichloromethane, methanol and chloroform.
Further, the volume percentage of tetrahydrofuran in the mixed solvent A is 80-90%.
Further, the volume-to-mass ratio ml/g of the mixed solvent A to the intermediate (4) is 0.4-8: 1.
further, the molar ratio of the intermediate (4) to NBS is 1.0: 1.5 to 2.0.
Further, the reaction temperature is 30-40 ℃.
Further, the reaction time is 50-90 min.
Further, the mixed solvent B is prepared by mixing at least one of isopropanol, ethyl acetate and butyl acetate with n-hexane.
Further, the crystallization temperature is 0-5 ℃.
Further, the catalyst is TEMPO; the mixed solvent A is tetrahydrofuran and methanol according to a volume ratio of 8: 2, mixing to obtain the product; the molar ratio of the intermediate (4) to NBS is 1.0: 1.5; the reaction temperature is 30-40 ℃; the crystallization temperature is 0-5 ℃.
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) compared with the prior art, the method for synthesizing the Raschild intermediate methyl 2- (5-bromo-4- (1-cyclopropyl naphthalene-4-yl) -4H-1,2, 4-triazole-3-yl sulfenyl) acetate obviously improves the purity of the Raschild intermediate methyl 2- (5-bromo-4- (1-cyclopropyl naphthalene-4-yl) -4H-1,2, 4-triazole-3-yl sulfenyl) acetate, can control the size of the residues of the chloride and the intermediate in the previous step through reaction, enables the residues of the chloride and the intermediate to be obviously reduced, and is beneficial to improving the medication safety.
(2) The synthesis method of the invention effectively controls the content of impurities, is simple and convenient to operate, obtains a sample with high purity, and greatly reduces the pressure burden for the refining of the finished Raschindyle product in the following steps.
Drawings
FIG. 1 is an HPLC chromatogram of comparative example 1.
FIG. 2 is a spectrum of the purification of example 2.
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.
The chemical name of the intermediate (4) in the invention is 2- (4- (1-cyclopropyl-naphthalene-4-yl) -4H-1,2, 4-triazole-3-yl-sulfenyl) methyl acetate.
The chemical name of the intermediate (5) in the invention is 2- (5-bromo-4- (1-cyclopropylnaphthalene-4-yl) -4H-1,2, 4-triazol-3-ylthio) methyl acetate.
Comparative example 1
Reference CN104736522A example 2A Synthesis of intermediate (5)
Adding 20.0g of intermediate (4) and 160ml of tetrahydrofuran into a 1L three-neck flask, starting stirring, heating to 35-42.0 ℃, and stirring until the intermediate (4) and the tetrahydrofuran are dissolved; cooling to 27-32 ℃, adding 18.5g of NBS, and reacting for 3.0-4.0 h; the temperature is reduced to 5 ℃, 100ml of toluene and 100ml of purified water are added, liquid separation is carried out by stirring, the organic phase is washed by 100ml of 3% sodium bisulfite solution and 100ml of 5% sodium bicarbonate solution respectively, 10.0g of anhydrous sodium sulfate is dried, filtration is carried out, mother liquor is concentrated to dryness, and 25.2g of intermediate (5) yellow oily matter is obtained.
Example 1
Adding 20.0g of the intermediate (4), 80ml of tetrahydrofuran and 20ml of methanol into a 1L three-neck flask, starting stirring, heating to 38.0 ℃, and stirring until the intermediate (4) is dissolved; adding 0.2g of TEMPO, adding 18.0g of NBS in portions, and reacting for 60 min; cooling to 5 ℃, adding 100ml of ethyl acetate and 120ml of purified water, washing an organic phase by using 100ml of 3% sodium bisulfite solution and 100ml of 5% sodium bicarbonate solution respectively, drying 50.0g of anhydrous sodium sulfate, filtering, rinsing 50ml of ethyl acetate, concentrating a mother solution to be dry, adding 60ml of ethyl acetate into a residue, heating until the solid is dissolved, adding 240ml of n-hexane, slowly cooling to 0-5 ℃, filtering, washing and drying to obtain 21.3g of similar white solid with the yield of 86.6%.
Example 2
Adding 20.0g of intermediate (4), 90ml of tetrahydrofuran and 10ml of dichloromethane into a 1L three-neck flask, starting stirring, heating to 40.0 ℃, and stirring until the intermediate (4) is dissolved; adding 18.0g of NBS and 0.2g of TEMPO, and reacting for 60 min; cooling to 5 ℃, adding 100ml of dichloromethane and 120ml of purified water, washing an organic phase by using 120ml of 3% sodium bisulfite solution and 100ml of 5% sodium bicarbonate solution respectively, drying 50.0g of anhydrous sodium sulfate, filtering, rinsing 50ml of dichloromethane, concentrating a mother solution to be dry, adding 60ml of ethyl acetate into a residue, heating until the solid is dissolved, adding 240ml of n-hexane, slowly cooling to 0-5 ℃, filtering, washing and drying to obtain 20.6g of off-white solid with the yield of 83.7%.
Example 3
Adding 20.0g of the intermediate (4), 80ml of tetrahydrofuran and 20ml of trichloromethane into a 1L three-neck flask, starting stirring, heating to 35.0 ℃, and stirring until the intermediate (4) is dissolved; adding 19.0g of NBS and 0.2g of TEMPO, and reacting for 60 min; cooling to 5 ℃, adding 100ml of trichloromethane and 120ml of purified water, washing an organic phase by using 100ml of 3% sodium bisulfite solution and 100ml of 5% sodium bicarbonate solution respectively, drying 50.0g of anhydrous sodium sulfate, filtering, leaching 50ml of trichloromethane, concentrating a mother solution to be dry, adding 60ml of isopropanol into a residue, heating until the solid is dissolved, adding 240ml of n-hexane, slowly cooling to 0-5 ℃, filtering, washing and drying to obtain 21.5g of similar white solid with the yield of 87.4%.
Example 4
Adding 20.0g of the intermediate (4), 80ml of tetrahydrofuran and 20ml of methanol into a 1L three-neck flask, starting stirring, heating to 40.0 ℃, and stirring until the intermediate (4) is dissolved; adding 20.0g of NBS and 0.2g of TEMPO, and reacting for 60 min; cooling to 5 ℃, adding 100ml of ethyl acetate and 120ml of purified water, washing an organic phase by using 120ml of 3% sodium bisulfite solution and 100ml of 5% sodium bicarbonate solution respectively, drying 50.0g of anhydrous sodium sulfate, filtering, leaching 50ml of ethyl acetate, concentrating a mother solution to be dry, adding 60ml of isopropanol into a residue, heating until the solid is dissolved, adding 240ml of n-hexane, slowly cooling to 0-5 ℃, filtering, washing and drying to obtain 21.0g of similar white solid with the yield of 85.4%.
Example 5
Adding 20.0g of the intermediate (4), 80ml of tetrahydrofuran and 20ml of methanol into a 1L three-neck flask, starting stirring, heating to 40.0 ℃, and stirring until the intermediate (4) is dissolved; adding 20.0g of NBS and 0.2g of TEMPO, and reacting for 60 min; cooling to 5 ℃, adding 100ml of ethyl acetate and 120ml of purified water, washing an organic phase by using 120ml of 3% sodium bisulfite solution and 100ml of 5% sodium bicarbonate solution respectively, drying 50.0g of anhydrous sodium sulfate, filtering, rinsing 50ml of ethyl acetate, concentrating a mother solution to be dry, adding 60ml of ethyl acetate into a residue, heating until the solid is dissolved, adding 240ml of n-hexane, slowly cooling to 0-5 ℃, filtering, washing and drying to obtain 22.0g of off-white solid with the yield of 89.4%.
Example 6
Adding 20.0g of the intermediate (4), 80ml of tetrahydrofuran and 20ml of methanol into a 1L three-neck flask, starting stirring, heating to 39.0 ℃, and stirring until the intermediate (4) is dissolved; adding 0.3g of BPO, adding 18.0g of NBS in portions, and reacting for 60 min; cooling to 5 ℃, adding 100ml of ethyl acetate and 120ml of purified water, washing an organic phase by using 100ml of 3% sodium bisulfite solution and 100ml of 5% sodium bicarbonate solution respectively, drying 50.0g of anhydrous sodium sulfate, filtering, rinsing 50ml of ethyl acetate, concentrating a mother solution to be dry, adding 60ml of ethyl acetate into a residue, heating until the solid is dissolved, adding 240ml of n-hexane, slowly cooling to 0-5 ℃, filtering, washing and drying to obtain 20.8g of white-like solid with the yield of 84.5%.
Example 7
Adding 20.0g of the intermediate (4), 80ml of tetrahydrofuran and 20ml of methanol into a 1L three-neck flask, starting stirring, heating to 37.0 ℃, and stirring until the intermediate is dissolved; adding 0.3g of AIBN, adding 18.0g of NBS in portions, and reacting for 60 min; cooling to 5 ℃, adding 100ml of ethyl acetate and 120ml of purified water, washing an organic phase by using 100ml of 3% sodium bisulfite solution and 100ml of 5% sodium bicarbonate solution respectively, drying 50.0g of anhydrous sodium sulfate, filtering, rinsing 50ml of ethyl acetate, concentrating a mother solution to be dry, adding 60ml of ethyl acetate into a residue, heating until the solid is dissolved, adding 240ml of n-hexane, slowly cooling to 0-5 ℃, filtering, washing and drying to obtain 20.3g of off-white solid with the yield of 82.5%.
The reactants and products of examples 1-7 and comparative example 1 were weighed and the yield was calculated, while the chloro-compound and intermediate (4) residues were detected and the relative percentage reduction was calculated, wherein,
(1) percent chloride reduction (control chloride mass-example chloride mass)/control chloride mass 100%;
(2) the percentage reduction in residual amount of intermediate (4) ═ control intermediate (4) residual mass — example intermediate (4) residual mass)/control intermediate (4) residual mass 100%.
The results are as follows:
the above results show that the intermediate (5) obtained in examples 1 to 7 of the present invention has an improved purity of the intermediate (5) and significantly reduced chlorine compounds and residues of the intermediate (4) as compared to the comparative example 1.
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 (10)
1. A method for synthesizing a Raschild intermediate capable of effectively reducing the content of impurities is characterized by comprising the following steps: reacting the reactant intermediate (4) in a mixed solvent A under the action of a catalyst, carrying out post-treatment to obtain a crude product of the product intermediate (5), and recrystallizing with a mixed solvent B to obtain a refined product of the high-purity intermediate (5); the catalyst is at least one of BPO, AIBN and TEMPO; the reaction formula is as follows:
2. the method of claim 1, wherein the solvent mixture A is prepared by mixing tetrahydrofuran and at least one of dichloromethane, methanol and chloroform.
3. The method of claim 1, wherein the volume percentage of tetrahydrofuran in the mixed solvent A is 80-90%.
4. The method for synthesizing the raschide intermediate capable of effectively reducing the impurity content according to claim 1 or 3, wherein the volume-to-mass ratio ml/g of the mixed solvent A to the intermediate (4) is 0.4-8: 1.
5. the method of claim 1, wherein the molar ratio of intermediate (4) to NBS is 1.0: 1.5 to 2.0.
6. The method of claim 1, wherein the reaction temperature is 30-40 ℃.
7. The method of claim 1 or 6, wherein the reaction time is 50-90 min.
8. The method for synthesizing a raschide intermediate effective in reducing the impurity content of claim 1, wherein the mixed solvent B is prepared by mixing at least one of isopropanol, ethyl acetate, and butyl acetate with n-hexane.
9. The method for synthesizing the rasidone intermediate with effectively reduced impurity content of claim 1, wherein the crystallization temperature is 0-5 ℃.
10. The method of claim 1, wherein the catalyst is TEMPO; the mixed solvent A is tetrahydrofuran and methanol according to a volume ratio of 8: 2, mixing to obtain the product; the molar ratio of the intermediate (4) to NBS is 1.0: 1.5; the reaction temperature is 30-40 ℃; the crystallization temperature is 0-5 ℃.
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| CN107955029A (en) * | 2017-12-07 | 2018-04-24 | 成都美域高制药有限公司 | A kind of preparation method of the western Nader of thunder |
| 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 |
| CN110467580A (en) * | 2018-05-10 | 2019-11-19 | 华润赛科药业有限责任公司 | The method for splitting of the western Nader's axial chirality enantiomer of thunder |
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