CN106866560B - Lesinurad synthesis method - Google Patents
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- CN106866560B CN106866560B CN201710201933.0A CN201710201933A CN106866560B CN 106866560 B CN106866560 B CN 106866560B CN 201710201933 A CN201710201933 A CN 201710201933A CN 106866560 B CN106866560 B CN 106866560B
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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 title claims abstract description 32
- 229960003838 lesinurad Drugs 0.000 title claims abstract description 31
- 238000001308 synthesis method Methods 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 9
- 229940125782 compound 2 Drugs 0.000 claims abstract description 5
- WFJRIDQGVSJLLH-UHFFFAOYSA-N methyl n-aminocarbamate Chemical compound COC(=O)NN WFJRIDQGVSJLLH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000002194 synthesizing effect Effects 0.000 claims abstract 7
- 238000006243 chemical reaction Methods 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 239000012670 alkaline solution Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Chemical group 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 16
- 238000002360 preparation method Methods 0.000 abstract description 9
- 229940126214 compound 3 Drugs 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 6
- 125000001246 bromo group Chemical group Br* 0.000 abstract description 3
- 229940125898 compound 5 Drugs 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- GUPWNYUKYICHQX-UHFFFAOYSA-N carbonobromidic acid Chemical compound OC(Br)=O GUPWNYUKYICHQX-UHFFFAOYSA-N 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- CCPTWMNSFHCZPB-UHFFFAOYSA-N 1-cyclopropyl-4-isothiocyanatonaphthalene Chemical compound C12=CC=CC=C2C(N=C=S)=CC=C1C1CC1 CCPTWMNSFHCZPB-UHFFFAOYSA-N 0.000 abstract 2
- 239000003513 alkali Substances 0.000 abstract 1
- 229910000039 hydrogen halide Inorganic materials 0.000 abstract 1
- 239000012433 hydrogen halide Substances 0.000 abstract 1
- 238000005935 nucleophilic addition reaction Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 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
- 201000005569 Gout Diseases 0.000 description 3
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-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
- 238000000605 extraction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000126 substance Substances 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 201000001431 Hyperuricemia Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RNEACARJKXYVND-KQGZCTBQSA-N (2r)-2-[[(5z)-5-[(5-ethylfuran-2-yl)methylidene]-4-oxo-1,3-thiazol-2-yl]amino]-2-(4-fluorophenyl)acetic acid Chemical compound O1C(CC)=CC=C1\C=C/1C(=O)N=C(N[C@@H](C(O)=O)C=2C=CC(F)=CC=2)S\1 RNEACARJKXYVND-KQGZCTBQSA-N 0.000 description 1
- MPNGLQDRSJNLPL-UHFFFAOYSA-N 4-[[2-[[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-1,2,4-triazol-3-yl]sulfanyl]acetyl]amino]-3-chlorobenzoic acid Chemical compound ClC1=CC(C(=O)O)=CC=C1NC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 MPNGLQDRSJNLPL-UHFFFAOYSA-N 0.000 description 1
- 241001415342 Ardea Species 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- 101000821903 Homo sapiens Solute carrier family 22 member 12 Proteins 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 239000013078 crystal Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- NAFSTSRULRIERK-UHFFFAOYSA-M monosodium urate Chemical compound [Na+].N1C([O-])=NC(=O)C2=C1NC(=O)N2 NAFSTSRULRIERK-UHFFFAOYSA-M 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- VODRWDBLLGYRJT-UHFFFAOYSA-N propan-2-yl 2-chloroacetate Chemical compound CC(C)OC(=O)CCl VODRWDBLLGYRJT-UHFFFAOYSA-N 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a method for synthesizing Lesinurad, which takes 1-cyclopropyl naphthalene-4-yl-isothiocyanate (compound 7) as a starting material, carries out nucleophilic addition reaction with methyl hydrazinoformate to generate a compound 6, cyclizes the compound 6 under the action of sodium hydroxide to generate a compound 5, then condenses the compound 5 with the compound 4 to remove one molecule of hydrogen halide to generate a compound 3, bromizes the compound 3 to generate a compound 2, and finally hydrolyzes under the action of alkali to obtain a target product Lesinurad. The preparation method is simple and easy to implement, nucleophilic substitution reaction is carried out through the hydroxyl of the compound 3 when bromine atoms are introduced into the preparation of the compound 2, and the generation of alpha bromocarboxylic acid impurities in the target product is avoided; the purity of the reaction product is high and can reach more than 99.5 percent; the side reaction is less, the yield of the obtained target product is higher and can reach 96%; meanwhile, the raw materials used in the whole preparation process are nontoxic, so that the industrial production is convenient to realize.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a novel synthesis method of Lesinurad.
Background
Gout is a crystal-related arthropathy caused by precipitation of monosodium urate, and is directly related to hyperuricemia caused by purine metabolic disorder and reduced uric acid excretion. Lesinuried is an oral drug for promoting uric acid excretion, and can be used for treating gout patients with hyperuricemia by inhibiting uric acid transporter URAT1 of renal proximal tubular. Lesinurad has the chemical name of 2- [ [ 5-bromo-4- (4-cyclopropyl-1-naphthalene) -4H-1,2, 4-triazol-3-yl ] thio ] acetic acid and CAS number 878672-00-5, and the chemical structural formula of the drug is shown as follows:
originally, this compound was developed from Valeant synthesized compound 5 (RDEA 806) in 2006, and its synthetic route is as follows:
shortly thereafter, ardea Bio found Lesinurad to be more effective in treating gout. The conventional synthetic route of the existing Lesinurad is as follows:
in the process, when the compound 3 synthesizes the compound 4, the amino is not protected and can carry out substitution reaction with methyl chloroacetate to inevitably generate double-substituted impurities, so that the quality of Lesinurad is obviously influenced, the yield of the compound 4 to the compound is less than 50 percent, and the cost is high.
The CN201310482334.2 patent reports a synthesis method of Lesinurad, and the synthesis route is as follows:
the route uses the highly toxic liquid bromine during bromination, which is not beneficial to realizing industrialization.
Therefore, there is a need for further improvements in the current synthesis of Lesinurad.
Disclosure of Invention
Aiming at the current state of the art, the invention provides a simple and easy synthesis method of Lesinurad, which has high yield and quality and is convenient for industrial production.
The technical scheme adopted for solving the technical problems is as follows: the synthesis method of Lesinurad is characterized by comprising the following steps of:
(1) Adding a compound 7 shown in the following formula into an organic solvent, then adding methyl hydrazinoformate, heating for reaction, adding water after the reaction is finished, stirring to separate out a product, filtering, and drying to obtain a compound 6 shown in the following formula;
(2) Heating a compound of formula 6 in an alkaline solution to perform cyclization reaction, regulating the pH of the reaction solution to be acidic by using acid, separating out a product, filtering and drying to obtain a compound of formula 5;
(3) Dissolving a compound of formula 5 in an organic solvent, adding an acid binding agent, cooling to 0-10 ℃, dripping a compound of formula 4 for reacting for 0.5-2 hours, and sequentially extracting, concentrating and recrystallizing after the reaction is finished to obtain a compound of formula 3;
wherein X is chlorine or bromine, and R is methyl, ethyl or isopropyl;
(4) Brominating the compound shown in the formula 3 under the action of a brominating reagent, and recrystallizing the product to obtain a compound shown in the formula 2;
(5) The compound 2 is hydrolyzed in alkaline solution, the compound of the following formula 1 is obtained after the reaction is finished, the compound of the formula 1 is the target product Lesinurad,
in the above scheme, the reaction temperature in step (1) is 50 to 60 ℃.
Preferably, the alkaline solution in step (2) is sodium hydroxide solution; the reaction temperature is 80-90 ℃.
Preferably, the organic solvent in step (3) is ethyl acetate; the acid binding agent is potassium carbonate.
Preferably, the molar ratio of the compound of formula 4 to the compound of formula 5 in step (3) is 1-2:1.
Preferably, the brominating reagent in step (4) is phosphorus oxybromide.
Preferably, the alkaline solution in the step (5) is one of sodium hydroxide, potassium hydroxide and lithium hydroxide.
Compared with the prior art, the invention has the advantages that: the preparation method is simple and feasible, and the preparation of the target product is further completed by preparing the novel compound 3 in the preparation process. When bromine atoms are introduced into the preparation of the compound 2, nucleophilic substitution reaction is carried out through hydroxyl groups of the compound 3, and bromine is not introduced through free radical reaction of NBS, so that alpha bromocarboxylic acid impurities in a target product are avoided; compared with the method for introducing bromine atoms through the Sandmeyer reaction of amino in the prior art, the purity of the reaction product is high and can reach more than 99.5 percent; the side reaction is less, the yield of the obtained target product is higher and can reach 96%; meanwhile, the raw materials used in the whole preparation process are nontoxic, so that the industrial production is convenient to realize.
Drawings
FIG. 1 shows the compound 3 of example 1 of the present invention 1 H-NMR spectrum;
FIG. 2 shows the compound 3 of example 1 of the present invention 13 C-NMR spectrum;
FIG. 3 is an HPLC chart of Lesinurad in example 1 of the present invention;
FIG. 4 is an ESI-MS spectrum of Lesinurad in example 1 of the present invention;
FIG. 5 is an infrared spectrum of Lesinurad in example 1 of the present invention;
FIG. 6 is a diagram of Lesinurad in example 1 of the present invention 1 H-NMR spectrum;
FIG. 7 is a diagram of Lesinurad in example 1 of the present invention 13 C-NMR spectrum.
Detailed Description
The invention is described in further detail below with reference to the embodiments of the drawings.
Example 1:
the synthesis method of Lesinurad in the embodiment comprises the following steps:
(1) 100g of the compound of formula 7, 500mL of DMF and 48g of methyl hydrazinoformate are mixed and added into a reaction bottle at room temperature, the reaction mixture is heated to 50-60 ℃ and stirred for 5-8 hours under heat preservation; after the reaction is finished, cooling the reaction solution to room temperature, adding 4000mL of water to precipitate a product, filtering and drying to obtain 125g of a compound of formula 6, wherein the yield is 89%;
(2) 100g of the compound of formula 6 is added into 1500ml of 1M sodium hydroxide solution at room temperature, heated to 80-90 ℃ and kept for 1 hour for dissolving, after TLC detection reaction is finished, cooled to room temperature, added with 3500ml of 5% hydrochloric acid solution dropwise for separating out solids, filtered to obtain a wet product, and dried in a hot air oven at 55 ℃ to constant weight, thus 85g of the compound of formula 5 is obtained, and the yield is 95.5%;
(3) Mixing 0.3mol of compound shown in formula 5 with potassium carbonate and DMF in a reaction bottle at room temperature, cooling the mixture to 0-5 ℃, dropwise adding 0.33mol of ethyl bromoacetate, after 10 minutes, heating the reaction liquid to 15-25 ℃ for reaction for 1 hour, adding 1000mL of water after TLC monitoring reaction, extracting 3 times with ethyl acetate, washing with saturated salt water, drying with anhydrous magnesium sulfate, concentrating under reduced pressure to obtain a solid, adding 500mL of ethyl acetate, pulping for 30 minutes, filtering and drying to obtain 78g of compound shown in formula 3, wherein the yield is 91%. 1 H NMR(400MHz，CDCl 3 ) δ8.53 (d, j=8 hz, 1H), 7.66 (m, 1H), 7.59 (m, 1H), 7.37 (s, 2H), 7.25 (m, 2H), 4.17 (q, j=7.14 hz, 2H), 4.03 (dd, j=16 hz, j=22.5 hz, 2H), 2.41 (m, 1H), 1.25 (t, j=7.14 hz, 3H), 1.18 (m, 2H), 0.87 (m, 2H) (fig. 1). 13 C NMR (401 MHz, DMSO-d 6): delta 166.9,153.5,143.1,133.4,131.3,128.6,128.1,127.2,126.8,126.5,125.1,122.6,121.7,34.1,12.9,7.3,7.2 (FIG. 1). 13 C NMR(401MHz，CDCl 3 ) Delta 167.8,153.8,143.5,134.3,131.3,129.1,127.9,127.2,126.9,126.2,125.3,123.1,122.1,62.1,24.2,14.0,13.5,7.0,6.9 (FIG. 2).
(4) 30g of the compound of formula 3 is dissolved in 100mL of acetonitrile, 0.5g of imidazole and 0.5mL of DMF are added, the mixture is cooled to 0 ℃,40 g of phosphorus tribromoxide is added dropwise, and the mixture is heated to 85-90 ℃ after the dripping is finished, and the mixture reacts until the raw material consumption is complete; cooling the reaction solution to room temperature, pouring the reaction solution into 50mL of water, adding 100mL of ethyl acetate for extraction for 3 times, adding anhydrous magnesium sulfate for drying after saturated saline washing, concentrating and drying to obtain brownish red oily matter, adding 120mL of anhydrous ethanol for recrystallization for 3 times to obtain white solid powder, and drying to obtain 26g of a compound of the formula 3, wherein the yield is 75%;
(5) 70g of the compound of formula 2 is dissolved in 300mL of tetrahydrofuran, 30mL of 10% sodium hydroxide solution is added, the reaction is carried out at the temperature of 10-15 ℃ until the raw materials disappear, the pH of the reaction solution is adjusted to 1 by 5% hydrochloric acid solution, ethyl acetate is added for extraction, anhydrous magnesium sulfate is dried, then the dried product is concentrated under reduced pressure, acetone is added for recrystallization, and 60g of Lesinurad is obtained, and the yield is 96%. As shown in fig. 3, the purity of the Lesinurad obtained in this example was 99.79%; ESI-MS: m/z=404, 406 (m+h) + (FIG. 4); IR (KBr) (cm) -1 ) 3420,2878,1723,1467,1440,768 (FIG. 5); 1 h NMR (400 mhz, dmso-d 6): δ8.60 (d, j=8 hz, 1H), 7.75 (m, 1H), 7.66 (m, 1H), 7.44 (s, 2H), 7.16 (d, j=8.4 hz, 2H), 4.01 (dd, j=16 hz,25.6hz 2H), 2.55 (m, 1H), 1.15 (m, 2H), 0.87 (m, 2H) (fig. 6). 13 C NMR (401 MHz, DMSO-d 6): delta 166.9,153.5,143.1,133.4,131.3,128.6,128.1,127.2,126.8,126.5,125.1,122.6,121.7,34.1,12.9,7.3,7.2 (FIG. 7).
Example 2:
(1) 50g of the compound of formula 7, 300mL of DMF and 24g of methyl hydrazinoformate are mixed and added into a reaction bottle at room temperature, the reaction mixture is heated to 50-60 ℃ and stirred for 7 hours under heat preservation; after the reaction is finished, cooling the reaction solution to room temperature, adding 2500mL of water to precipitate a product, filtering and drying to obtain 60g of a compound of formula 6, wherein the yield is 88%;
(2) 50g of the compound of formula 6 is added into 700mL of 1M sodium hydroxide solution at room temperature, heated to 80-90 ℃ and kept for 1 hour for dissolving, after TLC detection reaction is finished, the solution is cooled to room temperature, 1750mL of 5% hydrochloric acid solution is dripped to precipitate solid, a wet product is obtained after filtration, and a 55 ℃ hot air oven is dried to constant weight, thus 42g of the compound of formula 5 is obtained, and the yield is 95%;
(3) Mixing 0.1mol of compound shown in formula 5 with potassium carbonate and DMF in a reaction bottle at room temperature, cooling the mixture to 0-5 ℃, dropwise adding 0.12mol of isopropyl chloroacetate, after 10 minutes, heating the reaction liquid to 35 ℃ for reaction for 1 hour, adding 400mL of water after TLC monitoring reaction, extracting for 3 times with ethyl acetate, washing with saturated salt water, drying with anhydrous magnesium sulfate, concentrating under reduced pressure to obtain a solid, adding 150mL of ethyl acetate, pulping for 30 minutes, filtering and drying to obtain 24g of compound shown in formula 3, wherein the yield is 90%;
(4) 10g of the compound of formula 3 is dissolved in 50mL of dichloromethane, the mixture is added and cooled to 0 ℃, 11g of phosphorus tribromide is added dropwise, and after the dripping is finished, the mixture reacts at room temperature until the consumption of raw materials is complete; cooling the reaction solution to room temperature, pouring the reaction solution into 50mL of water, separating a water layer, washing a dichloromethane layer with 1% sodium bicarbonate solution and saturated salt water, adding anhydrous magnesium sulfate for drying, concentrating and drying to obtain a brownish red oily substance, adding 120mL of anhydrous ethanol for recrystallization for 3 times to obtain white solid powder, and drying to obtain 10g of a compound of the formula 3, wherein the yield is 85%;
(5) 5g of the compound of formula 2 is dissolved in 50mL of tetrahydrofuran, 5mL of 5% lithium hydroxide solution is added, the reaction is carried out at the temperature of 10-15 ℃ until the raw materials disappear, the pH of the reaction solution is adjusted to 1 by 5% hydrochloric acid solution, ethyl acetate is added for extraction, anhydrous magnesium sulfate is dried, then the dried product is concentrated under reduced pressure, acetone is added for recrystallization, and 8.6g of Lesinurad is obtained, and the yield is 96%.
Claims (7)
1. The synthesis method of Lesinurad is characterized by comprising the following steps of:
(1) Adding a compound 7 shown in the following formula into an organic solvent, then adding methyl hydrazinoformate, heating for reaction, adding water after the reaction is finished, stirring to separate out a product, filtering, and drying to obtain a compound 6 shown in the following formula;
(2) Heating a compound of formula 6 in an alkaline solution to perform cyclization reaction, regulating the pH of the reaction solution to be acidic by using acid, separating out a product, filtering and drying to obtain a compound of formula 5;
(3) Dissolving a compound of formula 5 in an organic solvent, adding an acid binding agent, cooling to 0-10 ℃, dripping a compound of formula 4 for reacting for 0.5-2 hours, and sequentially extracting, concentrating and recrystallizing after the reaction is finished to obtain a compound of formula 3;
wherein X is chlorine or bromine, and R is methyl, ethyl or isopropyl;
(4) Brominating the compound shown in the formula 3 under the action of a brominating reagent, and recrystallizing the product to obtain a compound shown in the formula 2;
(5) The compound 2 is hydrolyzed in alkaline solution, the compound of the following formula 1 is obtained after the reaction is finished, the compound of the formula 1 is the target product Lesinurad,
2. the method for synthesizing Lesinurad according to claim 1, wherein: the reaction temperature in the step (1) is 50-60 ℃.
3. The method for synthesizing Lesinurad according to claim 1, wherein: the alkaline solution in the step (2) is sodium hydroxide solution; the reaction temperature is 80-90 ℃.
4. The method for synthesizing Lesinurad according to claim 1, wherein: the organic solvent in the step (3) is ethyl acetate; the acid binding agent is potassium carbonate.
5. The method for synthesizing Lesinurad according to claim 1, wherein: the molar ratio of the compound of formula 4 to the compound of formula 5 in the step (3) is 1-2:1.
6. The method for synthesizing Lesinurad according to claim 1, wherein: the brominating reagent in the step (4) is phosphorus oxybromide.
7. The method for synthesizing Lesinurad according to claim 1, wherein: the alkaline solution in the step (5) is one of sodium hydroxide, potassium hydroxide and lithium hydroxide.
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|---|---|---|---|---|
| CN102002016A (en) * | 2009-09-01 | 2011-04-06 | 北京美迪康信医药科技有限公司 | Improvement method for synthesizing febuxostat |
| 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 |
| CN105315218A (en) * | 2014-07-17 | 2016-02-10 | 天津药物研究院 | Preparation method of lesinurad intermediate namely 1-naphthyltriazole thioketone |
| CN105566237A (en) * | 2016-03-01 | 2016-05-11 | 山东大学 | Preparing method of triazole thioglycolic acid compound for curing metabolic arthritis |
| CN106187927A (en) * | 2016-07-26 | 2016-12-07 | 山东川成医药股份有限公司 | A kind of preparation method of Lesinurad intermediate |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102002016A (en) * | 2009-09-01 | 2011-04-06 | 北京美迪康信医药科技有限公司 | Improvement method for synthesizing febuxostat |
| 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 |
| CN105315218A (en) * | 2014-07-17 | 2016-02-10 | 天津药物研究院 | Preparation method of lesinurad intermediate namely 1-naphthyltriazole thioketone |
| CN105566237A (en) * | 2016-03-01 | 2016-05-11 | 山东大学 | Preparing method of triazole thioglycolic acid compound for curing metabolic arthritis |
| CN106187927A (en) * | 2016-07-26 | 2016-12-07 | 山东川成医药股份有限公司 | A kind of preparation method of Lesinurad intermediate |
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