CN111153862B - A kind of refining method of Recinade - Google Patents
A kind of refining method of Recinade Download PDFInfo
- Publication number
- CN111153862B CN111153862B CN202010059448.6A CN202010059448A CN111153862B CN 111153862 B CN111153862 B CN 111153862B CN 202010059448 A CN202010059448 A CN 202010059448A CN 111153862 B CN111153862 B CN 111153862B
- Authority
- CN
- China
- Prior art keywords
- hexane
- ethyl acetate
- mixed solvent
- stirring
- crude
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000007670 refining Methods 0.000 title claims abstract description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 86
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 40
- 238000002425 crystallisation Methods 0.000 claims abstract description 7
- 230000008025 crystallization Effects 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 87
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 47
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 25
- 239000000047 product Substances 0.000 claims description 23
- 239000012046 mixed solvent Substances 0.000 claims description 18
- 239000012043 crude product Substances 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims 1
- 238000001816 cooling Methods 0.000 abstract description 20
- 238000001914 filtration Methods 0.000 abstract description 18
- 238000010438 heat treatment Methods 0.000 abstract description 17
- 239000002904 solvent Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000009835 boiling Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 46
- 239000012535 impurity Substances 0.000 description 24
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- 238000000967 suction filtration Methods 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CCPTWMNSFHCZPB-UHFFFAOYSA-N 1-cyclopropyl-4-isothiocyanatonaphthalene Chemical compound C12=CC=CC=C2C(N=C=S)=CC=C1C1CC1 CCPTWMNSFHCZPB-UHFFFAOYSA-N 0.000 description 4
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 229940116269 uric acid Drugs 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 201000001431 Hyperuricemia Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 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 2
- 238000000746 purification Methods 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UFYFJMMSOUURSF-UHFFFAOYSA-N 4-(4-cyclopropylnaphthalen-1-yl)-1h-1,2,4-triazole-5-thione Chemical compound S=C1NN=CN1C(C1=CC=CC=C11)=CC=C1C1CC1 UFYFJMMSOUURSF-UHFFFAOYSA-N 0.000 description 1
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960005101 febuxostat Drugs 0.000 description 1
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 1
- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 229940032415 zurampic Drugs 0.000 description 1
Images
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明涉及一种雷西纳德的精制方法，包括以下步骤：将雷西纳德粗品加入到加热至沸的溶剂中，加热至溶解，加入活性炭，过滤，滴加正己烷，缓慢降温至35～45℃析晶1～2h，再缓慢降温至0～10℃析晶2～3h，过滤，减压干燥，得到高纯度的成品。与现有方法相比，本发明所述方法精制效果好，精制过程所用到的溶剂较普通，工业化操作简单，精制目标产物收率和纯度高，适合工业化大生产。
The invention relates to a method for purifying resinard, which comprises the following steps: adding crude resinad into a solvent heated to boiling, heating to dissolving, adding activated carbon, filtering, adding n-hexane dropwise, and slowly cooling to 35 ℃ Crystallize at ~45 °C for 1 ~ 2 hours, then slowly cool down to 0 ~ 10 °C for crystallization for 2 ~ 3 hours, filter, and dry under reduced pressure to obtain high-purity finished products. Compared with the existing method, the method of the invention has good refining effect, common solvent used in the refining process, simple industrial operation, high yield and high purity of the refining target product, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to a refining method of Resinard, belonging to the technical field of medicines.
Background
Gout is a crystal-related arthropathy caused by precipitation of mono-sodiuurate, and is directly related to hyperuricemia caused by purine metabolic disturbance and reduced uric acid excretion. Rassinard (Lesinured) is an oral drug for promoting uric acid excretion, which can treat gout patients with hyperuricemia by inhibiting uric acid transporter URAT of renal proximal convoluted tubule, and the drug has a trade name of Zurampic in the United states, Rassinard is the first approved inhibitor of urate reabsorption transporter (URAT1) in the world, and the dosage form is an oral tablet, and the specification is 200 mg. The recommended dose is 200mg once a day in combination with allopurinol or febuxostat. Chemical name of Ravinard: 2- [ [ 5-bromo-4- (4-cyclopropyl-1-naphthalenyl) -4H-1,2, 4-triazol-3-yl ] thio ] acetic acid of the formula:
the original patent CN104736522A discloses that 1-cyclopropyl naphthalene-4-yl isothiocyanate (2) is used as a starting material, cyclizing with formyl hydrazine to obtain 4- (1-cyclopropyl naphthalene-4-yl) -4H-1,2, 4-triazole-thiol (3), and then nucleophilic substitution is carried out on the methyl bromoacetate to obtain 2- (4- (1-cyclopropyl naphthalene-4-yl) -4H-1,2, 4-triazole-3-yl sulfenyl) methyl acetate (4), NBS bromination is carried out to obtain 2- (5-bromine-4- (1-cyclopropyl naphthalene-4-yl) -4H-1,2, 4-triazole-3-yl sulfenyl) methyl acetate (5), and then hydrolysis is carried out to obtain the Raschindyle (1).
The synthetic route is as follows:
through a plurality of tests, the crude product compound (1) of the Racinidde synthesized by the method has low purity, and the impurities are mainly two: respectively as impurity A and impurity B
Impurity A: the residual compound 4 is hydrolyzed.
Impurity B: the chloride contained in NBS reacts with compound 4, and the generated chloride impurity is further hydrolyzed.
According to patent CN104736522A example 2A, compound 5 is synthesized, tetrahydrofuran is used as a solvent, NBS is used as a brominating agent, compound 4 has large residue, the content is about 3-10%, and the content of chlorinated impurities is 0.1-1.0%.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a method for refining a crude product of Raschild, which removes or controls impurities in the crude product within a certain range and improves the product quality.
The technical scheme adopted by the invention is as follows:
a method for refining Raschindde comprises the following steps:
adding the crude product of Racinidde into an organic solvent, heating to dissolve, adding activated carbon, filtering, dropwise adding n-hexane, cooling to 35-45 ℃ for crystallization for 1-2 h, cooling to 0-10 ℃ for crystallization for 2-3 h, filtering, and drying under reduced pressure to obtain a high-purity finished product.
Preferably, the organic solvent is one or more of ethyl acetate, isopropanol, n-hexane and dichloromethane.
Preferably, the organic solvent is a mixed solvent of ethyl acetate and n-hexane, a mixed solvent of ethyl acetate and isopropanol, and a mixed solvent of dichloromethane and n-hexane.
Preferably, the volume ratio of the ethyl acetate to the n-hexane in the mixed solvent of the ethyl acetate and the n-hexane is 1.0: (0.1 to 1.0); the volume ratio of ethyl acetate to isopropanol in the mixed solvent of ethyl acetate and isopropanol is 1.0 (0.1-0.5); the volume ratio of the dichloromethane to the n-hexane in the mixed solvent of the dichloromethane and the n-hexane is 1.0: (1-5).
More preferably, the volume ratio of ethyl acetate to n-hexane in the mixed solvent of ethyl acetate and n-hexane is 1.0: 0.2; the volume ratio of ethyl acetate to isopropanol in the mixed solvent of ethyl acetate and isopropanol is 1.0: 0.3; the volume ratio of the dichloromethane to the n-hexane in the mixed solvent of the dichloromethane and the n-hexane is 1.0: 1.5.
preferably, the feeding ratio of the crude Raxinard product to the organic solvent is 1 g: (10-60) ml.
Preferably, the feeding ratio of the crude Raxinard product to the n-hexane is 1 g: (5-20) ml.
Preferably, the dissolving temperature is 35-80 ℃.
Preferably, the feed ratio of the activated carbon to the crude product of Racinade is that of the crude product of Racinade: activated carbon 1 g: 0.1 g.
Compared with the prior art, the invention has the beneficial effects that:
the refining effect is good, the target product is refined, the yield and the purity are high, and the impurities A and B in the refined product are obviously reduced compared with the impurities A and B before refining, so that the quality of the finished product Racinidde is ensured; the refining process is simple, and the used solvent is common. Easy recovery, greatly simplifies the industrial operation, and is suitable for industrial production.
Drawings
FIG. 1 is an HPLC chromatogram of crude product
FIG. 2 is an HPLC chromatogram of the purification of example 2
FIG. 3 is an HPLC chromatogram of example 3
Detailed Description
The present invention will be described in further detail with reference to the following detailed description and accompanying drawings.
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 crude product of Raxinard in the embodiment of the invention is synthesized by the method of reference CN 104736522A. The method comprises the following specific steps:
adding 160.0g of intermediate 4 and 1.28L of tetrahydrofuran into a 5L 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 148.0g of NBS, and reacting for 3.0-4.0 h; cooling to 5 ℃, adding 800ml of toluene and 800ml of purified water, stirring and separating liquid, washing an organic phase with 800ml of 3% sodium bisulfite solution and 800ml of 5% sodium bicarbonate solution respectively, standing and separating liquid, collecting the organic phase, adding 580ml of 1mol/L sodium hydroxide into the organic phase, reacting for 2 hours, separating liquid, collecting a water phase, concentrating, cooling and crystallizing, filtering, and washing with water to obtain a wet product; adding 720ml of purified water into the wet product, heating to 35 ℃, stirring for dissolving, adding 1.6L of ethyl acetate, adjusting the pH value of the system to be 2-4 by using 24% hydrobromic acid, stirring for 30min, separating liquid, washing the organic phase once by using 320ml of purified water, concentrating the organic phase until solid is separated out, keeping the temperature at 38-42 ℃, continuously stirring for crystallization for 3-4 h, slowly cooling to 5-10 ℃, stirring for 2h, filtering, washing, and drying under reduced pressure and vacuum to obtain 123.0g of crude product of Ravinard. Purity 95.12%, impurity a: 4.22 percent; impurity B: 0.24 percent.
In the embodiment of the invention, the method for measuring the Ravinard purity and the content of each impurity adopts an HPLC method, and the main test conditions are 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
Example 1
Taking 10.0g of crude Raxinard product, adding300ml of ethyl acetateHeating to dissolve at 35-80 deg.C, adding 1.0g of activated carbon, stirring for 10-15 min, filtering,150ml of n-hexane was added dropwise to the filtrateStirring and crystallizing for 1-2 h at the temperature of 35-45 ℃, slowly cooling to 0-10 ℃, stirring for 2-3 h, performing suction filtration, and drying under vacuum at 50 ℃ for 6-8 h to obtain 8.1g of a white solid, namely high-purity Ravinard, wherein the yield is 81.0% (weight after purification/Ravinard crude product multiplied by 100%), the purity (in terms of peak area) is 99.95%, and the impurity A: not detected; impurity B:0.05 percent.
Example 2
Taking 10.0g of crude Raxinard product, adding250ml of ethyl acetateHeating to dissolve at 35-80 deg.C, adding 1.0g of activated carbon, stirring for 10-15 min, filtering,50ml of n-hexane was added dropwise to the filtrateStirring and crystallizing for 1-2 h at the temperature of 35-45 ℃, slowly cooling to 0-10 ℃, stirring for 2-3 h, performing suction filtration, and drying under vacuum at 50 ℃ for 6-8 h under reduced pressure to obtain 8.6g of white solid, namely high-purity Ravinard, wherein the yield is 86.0%, the purity is 99.96%, and the impurity A: not detected; 0.04 percent of impurity B
Example 3
Taking 10.0g of crude Raxinard product, adding200ml of ethyl acetate and 60ml of isopropanolHeating to dissolve at 35-80 deg.C, adding 1.0g of activated carbon, stirring for 10-15 min, filtering,50ml of n-hexane was added dropwise to the filtrateStirring and crystallizing for 1-2 h at the temperature of 35-45 ℃, slowly cooling to 0-10 ℃, stirring for 2-3 h, performing suction filtration, and performing vacuum reduced pressure drying for 6-8 h at the temperature of 50 ℃ to obtain 8.4g of white solid, namely high-purity Ravinard, wherein the yield is 84.0%, and the purity is 99.94%; impurity A: not detected; 0.06 percent of impurity B.
Example 4
Taking 10.0g of crude Raxinard product, adding200ml of methylene chlorideHeating to dissolve at 35-80 deg.C, adding 1.0g of activated carbon, stirring for 10-15 min, filtering,filter with filter element200ml of n-hexane was added dropwise to the solutionStirring and crystallizing for 1-2 h at the temperature of 35-45 ℃, slowly cooling to 0-10 ℃, stirring for 2-3 h, performing suction filtration, and performing vacuum reduced pressure drying for 6-8 h at the temperature of 50 ℃ to obtain 8.3g of white solid, namely high-purity Ravinard, wherein the yield is 83.0%, and the purity is 99.98%; impurity A: not detected; 0.02 percent of impurity B.
Example 5
Taking 10.0g of crude Raxinard product, adding250ml of ethyl acetateHeating to dissolve at 35-80 deg.C, adding 1.0g of activated carbon, stirring for 10-15 min, filtering,75ml of n-hexane was added dropwise to the filtrate,maintaining the temperature at 35-45 ℃, stirring for crystallization for 1-2 h, slowly cooling to 0-10 ℃, stirring for 2-3 h, performing suction filtration, and performing vacuum reduced pressure drying at 50 ℃ for 6-8 h to obtain 8.6g of white solid, namely high-purity Ravinard, wherein the yield is 86.0%, and the purity is 99.95%; impurity A: not detected; 0.05 percent of impurity B.
Example 6
Taking 10.0g of crude Raxinard product, adding200ml of ethyl acetate and 20ml of isopropanolHeating to dissolve at 35-80 deg.C, adding 1.0g of activated carbon, stirring for 10-15 min, filtering,50ml of n-hexane was added dropwise to the filtrateStirring and crystallizing for 1-2 h at the temperature of 35-45 ℃, slowly cooling to 0-10 ℃, stirring for 2-3 h, performing suction filtration, and performing vacuum reduced pressure drying for 6-8 h at the temperature of 50 ℃ to obtain 8.4g of white solid, namely high-purity Ravinard, wherein the yield is 84.0%, and the purity is 99.97%; impurity A: not detected; 0.03 percent of impurity B.
Example 7
Taking 10.0g of crude Raxinard product, adding200ml of ethyl acetate and 100ml of isopropanolHeating to dissolve at 35-80 deg.C, adding 1.0g of activated carbon, stirring for 10-15 min, filtering,50ml of n-hexane was added dropwise to the filtrateStirring and crystallizing for 1-2 h at the temperature of 35-45 ℃, slowly cooling to 0-10 ℃, stirring for 2-3 h, performing suction filtration, and performing vacuum reduced pressure drying for 6-8 h at the temperature of 50 ℃ to obtain 8.2g of white solid, namely high-purity Ravinard, wherein the yield is 82.0%, and the purity is 99.95%; impurity A: not detected; 0.05 percent of impurity B.
Example 8
Taking 10.0g of crude Raxinard product, adding200ml of ethyl acetateAnd 20ml of n-hexaneHeating to dissolve at 35-80 deg.C, adding 1.0g of activated carbon, stirring for 10-15 min, filtering,50ml of n-hexane was added dropwise to the filtrateStirring and crystallizing for 1-2 h at the temperature of 35-45 ℃, slowly cooling to 0-10 ℃, stirring for 2-3 h, performing suction filtration, and performing vacuum reduced pressure drying for 6-8 h at the temperature of 50 ℃ to obtain 8.4g of white solid, namely high-purity Ravinard, wherein the yield is 84.0%, and the purity is 99.97%; impurity A: not detected; 0.03 percent of impurity B.
Example 9
Taking 10.0g of crude Raxinard product, adding200ml of ethyl acetate and 100ml of n-hexaneHeating to dissolve at 35-80 deg.C, adding 1.0g of activated carbon, stirring for 10-15 min, filtering,50ml of n-hexane was added dropwise to the filtrateStirring and crystallizing for 1-2 h at the temperature of 35-45 ℃, slowly cooling to 0-10 ℃, stirring for 2-3 h, performing suction filtration, and performing vacuum reduced pressure drying for 6-8 h at the temperature of 50 ℃ to obtain 8.3g of white solid, namely high-purity Ravinard, wherein the yield is 83.0%, and the purity is 99.93%; impurity A: not detected; 0.07 percent of impurity B.
Example 10
Taking 10.0g of crude Raxinard product, adding200ml of ethyl acetate and 40ml of n-hexaneHeating to dissolve at 35-80 deg.C, adding 1.0g of activated carbon, stirring for 10-15 min, filtering,50ml of n-hexane was added dropwise to the filtrateStirring and crystallizing for 1-2 h at the temperature of 35-45 ℃, slowly cooling to 0-10 ℃, stirring for 2-3 h, performing suction filtration, and performing vacuum reduced pressure drying for 6-8 h at the temperature of 50 ℃ to obtain 8.7g of white solid, namely high-purity Ravinard, wherein the yield is 87.0%, and the purity is 99.93%; impurity A: not detected; 0.07 percent of impurity B.
Example 11
Taking 10.0g of crude Raxinard product, adding100ml of methylene chloride and 100ml of n-hexaneHeating to dissolve at 35-80 deg.C, adding 1.0g of activated carbon, stirring for 10-15 min, filtering,50ml of n-hexane was added dropwise to the filtrateStirring and crystallizing for 1-2 h at the temperature of 35-45 ℃, slowly cooling to 0-10 ℃, stirring for 2-3 h, performing suction filtration, and performing vacuum reduced pressure drying for 6-8 h at the temperature of 50 ℃ to obtain 8.2g of white solid, namely high-purity Ravinard, wherein the yield is 82.0%, and the purity is 99.94%; impurity A: not detected; 0.0 part of impurity B6％。
Example 12
Taking 10.0g of crude Raxinard product, adding100ml of methylene chloride and 150ml of n-hexaneHeating to dissolve at 35-80 deg.C, adding 1.0g of activated carbon, stirring for 10-15 min, filtering,50ml of n-hexane was added dropwise to the filtrateStirring and crystallizing for 1-2 h at the temperature of 35-45 ℃, slowly cooling to 0-10 ℃, stirring for 2-3 h, performing suction filtration, and performing vacuum reduced pressure drying for 6-8 h at the temperature of 50 ℃ to obtain 8.9g of white solid, namely high-purity Ravinard, wherein the yield is 89.0%, and the purity is 99.97%; impurity A: not detected; 0.03 percent of impurity B.
Example 13
Taking 10.0g of crude Raxinard product, adding100ml of methylene chloride and 500ml of n-hexaneHeating to dissolve at 35-80 deg.C, adding 1.0g of activated carbon, stirring for 10-15 min, filtering,50ml of n-hexane was added dropwise to the filtrateStirring and crystallizing for 1-2 h at the temperature of 35-45 ℃, slowly cooling to 0-10 ℃, stirring for 2-3 h, performing suction filtration, and performing vacuum reduced pressure drying for 6-8 h at the temperature of 50 ℃ to obtain 8.3g of white solid, namely high-purity Ravinard, wherein the yield is 83.0%, and the purity is 99.93%; impurity A: not detected; 0.07 percent of impurity B.
The foregoing is a more detailed description of the present invention that is presented in conjunction with specific embodiments, and the practice of the invention is not to be considered limited to those descriptions. It will be apparent to those skilled in the art that a number of simple derivations or substitutions can be made without departing from the inventive concept.
Claims (9)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010059448.6A CN111153862B (en) | 2020-01-19 | 2020-01-19 | A kind of refining method of Recinade |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010059448.6A CN111153862B (en) | 2020-01-19 | 2020-01-19 | A kind of refining method of Recinade |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111153862A CN111153862A (en) | 2020-05-15 |
| CN111153862B true CN111153862B (en) | 2021-07-06 |
Family
ID=70564326
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010059448.6A Expired - Fee Related CN111153862B (en) | 2020-01-19 | 2020-01-19 | A kind of refining method of Recinade |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111153862B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112778223A (en) * | 2021-01-25 | 2021-05-11 | 海南鑫开源医药科技有限公司 | Preparation method of Raschindde oxidation impurities |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103298796A (en) * | 2010-12-30 | 2013-09-11 | 阿迪亚生命科学公司 | Polymorphic forms of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio) acetic acid and uses thereof |
| CN104447590A (en) * | 2013-11-22 | 2015-03-25 | 苏州晶云药物科技有限公司 | Crystal forms of 2-(5-bromo-4-(4-cyclopropyl-naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid and preparation method of crystal form |
| CN104557748A (en) * | 2014-01-25 | 2015-04-29 | 广东东阳光药业有限公司 | New Solid Forms of Thio-1,2,4-Triazole Derivatives |
| 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 |
| WO2016203436A1 (en) * | 2015-06-19 | 2016-12-22 | Dr. Reddy's Laboratories Limited | Amorphous and amorphous solid dispersion of lesinurad and their preparation |
-
2020
- 2020-01-19 CN CN202010059448.6A patent/CN111153862B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103298796A (en) * | 2010-12-30 | 2013-09-11 | 阿迪亚生命科学公司 | Polymorphic forms of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio) acetic acid and uses thereof |
| CN104447590A (en) * | 2013-11-22 | 2015-03-25 | 苏州晶云药物科技有限公司 | Crystal forms of 2-(5-bromo-4-(4-cyclopropyl-naphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid and preparation method of crystal form |
| CN104557748A (en) * | 2014-01-25 | 2015-04-29 | 广东东阳光药业有限公司 | New Solid Forms of Thio-1,2,4-Triazole Derivatives |
| WO2016203436A1 (en) * | 2015-06-19 | 2016-12-22 | Dr. Reddy's Laboratories Limited | Amorphous and amorphous solid dispersion of lesinurad and their preparation |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| AlešHalama等."Identification of an Unexpected Impurity in a New Improved Synthesis of Lesinurad".《Org. Process Res. Dev.》.2018,第22卷第1861−1867页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111153862A (en) | 2020-05-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101781270B (en) | High-purity Febuxostat and preparation method thereof | |
| CN105330609B (en) | A kind of method for preparing LCZ696 | |
| CN106256824B (en) | Preparation method of high-purity delafloxacin meglumine salt | |
| CN105085373B (en) | Purification method of apremilast product | |
| CN113045505A (en) | Favipiravir intermediate and synthesis method of favipiravir | |
| CN103664912B (en) | A kind of synthesis technique of prucalopride | |
| CN111153862B (en) | A kind of refining method of Recinade | |
| KR101275092B1 (en) | Manufacturing Method Of Azilsartan | |
| CN114213285B (en) | Formoterol related substance, preparation method and application thereof | |
| CN109912531A (en) | The preparation method of high-purity Febustat | |
| CN111646971B (en) | Method for synthesizing 4- (hydroxymethyl) -5-methyl- [1,3] dioxol-2-one | |
| CN116284018B (en) | A preparation method and application of furano[2,3-b]quinoline derivative | |
| KR101316653B1 (en) | Manufacturing Method Of Hetero Cyclic Compound | |
| CN116514841A (en) | The preparation method of fluoxetal acid impurity | |
| CN111116500B (en) | A kind of purification method of key intermediate of Recinade | |
| CN106632003B (en) | A kind of preparation method of Etoricoxib | |
| JP4892821B2 (en) | Epalrestat manufacturing method | |
| CN111606898B (en) | A kind of posaconazole related substance and its preparation method and use | |
| CN111116501B (en) | Synthesis method of Ravinard intermediate capable of effectively reducing impurity content | |
| JP6275596B2 (en) | Method for producing ammonium salt of telmisartan | |
| CN109836425B (en) | Preparation process of synthetic pemetrexed | |
| CN114773266B (en) | Improved synthesis method of montelukast sodium | |
| JP6210599B2 (en) | Process for producing 4-methyl-6 (1-methylbenzimidazol-2-yl) -2-n-propyl-1H-benzimidazole | |
| JP6147546B2 (en) | Method for producing telmisartan A-type crystals with reduced acetic acid | |
| CN111320588A (en) | Method for purifying Lesinurad impurities |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A refining method of Reynard Effective date of registration: 20220929 Granted publication date: 20210706 Pledgee: Haikou Xiuying Sub branch of Bank of China Ltd. Pledgor: Beijing Xin Kai Yuan Pharmaceutical Technology Co.,Ltd. Hainan branch Registration number: Y2022980017059 |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20210706 |