CN106866560A - A kind of synthetic method of Lesinurad - Google Patents
A kind of synthetic method of Lesinurad Download PDFInfo
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- CN106866560A CN106866560A CN201710201933.0A CN201710201933A CN106866560A CN 106866560 A CN106866560 A CN 106866560A CN 201710201933 A CN201710201933 A CN 201710201933A CN 106866560 A CN106866560 A CN 106866560A
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- Prior art keywords
- compound
- lesinurad
- reaction
- formula
- synthetic method
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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
- 238000010189 synthetic method Methods 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 24
- 238000005893 bromination reaction Methods 0.000 claims abstract description 5
- 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
- 230000031709 bromination Effects 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- 239000012670 alkaline solution Substances 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Chemical group 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 3
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 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
- 239000012141 concentrate Substances 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
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 239000000284 extract Substances 0.000 claims 1
- 229940126214 compound 3 Drugs 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 6
- 229940125898 compound 5 Drugs 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 3
- 239000002585 base Substances 0.000 abstract description 2
- 125000001246 bromo group Chemical group Br* 0.000 abstract description 2
- GUPWNYUKYICHQX-UHFFFAOYSA-N carbonobromidic acid Chemical compound OC(Br)=O GUPWNYUKYICHQX-UHFFFAOYSA-N 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000000034 method Methods 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
- 150000002540 isothiocyanates Chemical class 0.000 abstract 2
- VZZBXOLWBXJHEK-UHFFFAOYSA-N 1-cyclopropylnaphthalene Chemical compound C1CC1C1=CC=CC2=CC=CC=C12 VZZBXOLWBXJHEK-UHFFFAOYSA-N 0.000 abstract 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 239000003513 alkali Substances 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 150000004820 halides Chemical class 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 230000000977 initiatory effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000005935 nucleophilic addition reaction Methods 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 201000005569 Gout Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 0 *OC(CSC(CC(*1)c2ccc(C3CC3)c3c2cccc3)=NN=C1O)=O Chemical compound *OC(CSC(CC(*1)c2ccc(C3CC3)c3c2cccc3)=NN=C1O)=O 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 2
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 125000005909 ethyl alcohol group Chemical group 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 238000000643 oven drying Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229940116269 uric acid Drugs 0.000 description 2
- 238000010792 warming Methods 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
- 241001415342 Ardea Species 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- 108010078791 Carrier Proteins Proteins 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
- 206010054949 Metaplasia Diseases 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- 102100021495 Solute carrier family 22 member 12 Human genes 0.000 description 1
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-N bromoacetic acid Chemical class OC(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- -1 dichloromethane Alkane Chemical class 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical group COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- NAFSTSRULRIERK-UHFFFAOYSA-M monosodium urate Chemical class [Na+].N1C([O-])=NC(=O)C2=C1NC(=O)N2 NAFSTSRULRIERK-UHFFFAOYSA-M 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical class BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- ZVIWEYTXPYNLGB-UHFFFAOYSA-M potassium;4-[[2-[[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-1,2,4-triazol-3-yl]sulfanyl]acetyl]amino]-3-chlorobenzoate Chemical compound [K+].ClC1=CC(C(=O)[O-])=CC=C1NC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 ZVIWEYTXPYNLGB-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- VODRWDBLLGYRJT-UHFFFAOYSA-N propan-2-yl 2-chloroacetate Chemical class CC(C)OC(=O)CCl VODRWDBLLGYRJT-UHFFFAOYSA-N 0.000 description 1
- 230000004144 purine metabolism Effects 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- FWQHRZXEQNUCSY-UHFFFAOYSA-N tert-butyl N-[2-(ethoxycarbonylamino)-5-[(4-fluorophenyl)methyl-prop-2-ynylamino]phenyl]carbamate Chemical compound CCOC(=O)NC1=C(C=C(C=C1)N(CC#C)CC2=CC=C(C=C2)F)NC(=O)OC(C)(C)C FWQHRZXEQNUCSY-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 230000003424 uricosuric effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
-
- 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
Landscapes
- 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 present invention relates to a kind of synthetic method of Lesinurad, the method is initiation material with the base isothiocyanates (compound 7) of 1 cyclopropyl naphthalene 4, nucleophilic addition generation compound 6 is carried out with methyl hydrazinocarboxylate, compound 6 is cyclized generation compound 5 in the presence of NaOH, compound 5 generates compound 3 with the condensation one molecular halides hydrogen of removing of compound 4 again, compound 3 generates compound 2 after bromination, and finally hydrolysis obtains target product Lesinurad in the presence of alkali.Preparation method of the invention is simple and easy to apply, prepare compound 2 carries out nucleophilic substitution and carry out when introducing bromine atoms by the hydroxyl of compound 3, it is to avoid the generation of α bromo carboxylic acid impurities in target product；The application product purity is high, can reach more than 99.5%；Side reaction is few, and gained target product yield is higher, can reach 96%；Meanwhile, the raw materials for using non-toxic more in whole preparation process, is easy to implement industrialized production.
Description
Technical field
The present invention relates to technical field of medicine preparation, a kind of novel synthesis of Lesinurad are referred specifically to.
Background technology
Gout is with the crystal correlation arthropathy caused by monosodium urate salt precipitation, with purine metabolism wadding unrest and uric acid excretion
Hyperuricemia caused by reducing is directly related.Lesinured is a kind of uricosuric excretion oral medicine, can be closely bent by suppressing kidney
The sub- URAT1 of uric acid transporter of tubule and treat the patient with gout of hyperuricemia.Chemical entitled the 2- [[5- of Lesinurad
Bromo- 4- (4- cyclopropyl -1- naphthalenes) -4H-1,2,4- triazole -3- bases] thio] acetic acid, No. CAS is 878672-00-5, the medicine
Chemical structural formula is as follows：
The initial compound is that the compound 5 (RDEA806) synthesize by Valeant in 2006 is developed, and it synthesizes road
Line is as follows：
In the near future, Ardea Bio are found that the Lesinurad to treating the more effective fruit of gout.Existing Lesinurad's
General synthetic routes are：
In the route when compound 3 synthesizes compound 4, because amino does not have to protect meeting and methyl chloroacetate
Substitution reaction and be inevitably generated disubstituted impurity, the quality on Lesinurad makes a significant impact, and compound 4
Yield to compound is relatively costly less than 50%.
A kind of synthetic method of Lesinurad of CN201310482334.2 patent reports, its synthetic route is as follows：
The route has used violent in toxicity bromine in bromination, is unfavorable for realizing industrialization.
Therefore, for the synthetic method of current Lesinurad, await being further improved.
The content of the invention
The technical problems to be solved by the invention are directed to the present situation of prior art, there is provided a kind of simple and easy to do, high income,
Quality is good, be easy to industrialized production Lesinurad synthetic method.
The present invention solve the technical scheme that is used of above-mentioned technical problem for：A kind of synthetic method of Lesinurad, it is special
Levy is to comprise the following steps：
(1) to following formula: compound 7 is added in organic solvent, methyl hydrazinocarboxylate is subsequently adding, heating response, reaction terminates
Adding water stirring afterwards separates out product, filters, dry the compound of following formula 6；
(2) make the compound of formula 6 that generation ring-closure reaction is heated in alkaline solution, then the pH of reaction solution adjusted to acidity with acid,
Product is separated out, filtered, be dried to obtain the compound of following formula 5；
(3) compound of formula 5 is dissolved in organic solvent, adds acid binding agent, dropping type 4 is changed after being cooled to 0~10 DEG C
Compound reacts 0.5~2 hour, and after reaction terminates, extraction, concentration, weight are brilliant successively, obtain the compound of following formula 3；
Wherein, X is chlorine or bromine, and R is methyl, ethyl or isopropyl；
(4) make the compound of formula 3 that bromination reaction occurs in the presence of bromide reagent, product obtains following formula 2 after recrystallization
Compound；
(5) compound 2 is hydrolyzed in alkaline solution, and reaction end obtains the compound of following formula 1, and the compound of formula 1 is
Target product Lesinurad,
In such scheme, the reaction temperature in step (1) is 50~60 DEG C.
Preferably, the alkaline solution in step (2) is sodium hydroxide solution；Reaction temperature is 80~90 DEG C.
Preferably, the organic solvent described in step (3) is ethyl acetate；Described acid binding agent is potassium carbonate.
Preferably, the compound of formula 4 described in step (3) and the mol ratio of the compound of formula 5 are 1~2:1.
Preferably, the bromide reagent described in step (4) is tribromo oxygen phosphorus.
Preferably, the alkaline solution described in step (5) is the one kind in NaOH, potassium hydroxide, lithium hydroxide.
Compared with prior art, the advantage of the invention is that：Preparation method of the invention is simple and easy to apply, in preparation process
By the preparation for preparing new compound 3 so as to further complete target product.It is former that the application introduces bromine in prepare compound 2
The period of the day from 11 p.m. to 1 a.m carries out nucleophilic substitution by the hydroxyl of compound 3 to be carried out, and bromine is introduced rather than radical reaction is carried out by NBS,
So as to avoid the generation of α bromo carboxylic acid impurities in target product；With Sandmeyer reactions are carried out by amino in the prior art
The method for introducing bromine atoms is compared, and the application product purity is high, can reach more than 99.5%；Side reaction is few, gained target
Product yield is higher, can reach 96%；Meanwhile, the raw materials for using non-toxic more in whole preparation process, is easy to implement industry
Metaplasia is produced.
Brief description of the drawings
Fig. 1 is compound 3 in the embodiment of the present invention 11H-NMR collection of illustrative plates；
Fig. 2 is compound 3 in the embodiment of the present invention 113C-NMR collection of illustrative plates；
Fig. 3 is the HPLC collection of illustrative plates of Lesinurad in the embodiment of the present invention 1；
Fig. 4 is the ESI-MS collection of illustrative plates of Lesinurad in the embodiment of the present invention 1；
Fig. 5 is the infared spectrum of Lesinurad in the embodiment of the present invention 1；
Fig. 6 is Lesinurad in the embodiment of the present invention 11H-NMR collection of illustrative plates；
Fig. 7 is Lesinurad in the embodiment of the present invention 113C-NMR collection of illustrative plates.
Specific embodiment
The present invention is described in further detail below in conjunction with accompanying drawing embodiment.
Embodiment 1：
The synthetic method of Lesinurad is comprised the following steps in the present embodiment：
(1) at room temperature, the compound of 100g formulas 7,500mL DMF, 48g methyl hydrazinocarboxylates are mixed and is added to reaction bulb
In, heating makes reactant mixture be warming up to 50~60 DEG C, and insulated and stirred 5~8 hours；Be cooled to for reaction solution after terminating by reaction
Room temperature, adds 4000mL water to separate out product, filters and dry the compound dry product 125g of formula 6, and yield is 89%；
(2) compound of 100g formulas 6 is added in the sodium hydroxide solution of 1500mL 1M at room temperature, is heated to 80~90 DEG C
Insulation 1 hour is molten clear, and TLC detection reactions are cooled to room temperature after terminating, and the hydrochloric acid solutions of 3500mL 5% are added dropwise and separate out solid, filtering
Wet product is obtained afterwards, and 55 DEG C of hot-air oven dryings obtain the compound dry product 85g of formula 5 to constant weight, and yield is 95.5%；
(3) at room temperature, the compound of 0.3mol formulas 5 and potassium carbonate, DMF are mixed in reaction bulb, mixed liquor is cooled to 0
~5 DEG C, 0.33mol bromoacetates are added dropwise, drip off within 10 minutes, reaction solution is heated into 15~25 DEG C after dripping off reacts 1 hour,
TLC monitoring reactions add 1000mL water after receiving, and are then extracted with ethyl acetate 3 times, then are washed with saturated common salt, then with nothing
Water magnesium sulfate is dried, and is concentrated under reduced pressure to give solid, is added 500mL ethyl acetate and is beaten 30 minutes, is filtered and dry that formula 3 is changed
Compound 78g, yield is 91%.1H NMR (400MHz, CDCl3):δ 8.53 (d, J=8Hz, 1H), 7.66 (m, 1H), 7.59 (m,
1H), 7.37 (s, 2H), 7.25 (m, 2H), 4.17 (q, J=7.14Hz, 2H), 4.03 (dd, J=16Hz, J=22.5Hz, 2H),
2.41 (m, 1H), 1.25 (t, J=7.14Hz, 3H), 1.18 (m, 2H), 0.87 (m, 2H) (Fig. 1).13C NMR (401MHz,
DMSO-d6):δ166.9,153.5,143.1,133.4,131.3,128.6,128.1,127.2,126.8,126.5,125.1,
122.6,121.7,34.1,12.9,7.3,7.2 (Fig. 1).13C NMR (401MHz, CDCl3):δ167.8,153.8,143.5,
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) compound of 30g formulas 3 is dissolved in 100mL acetonitriles, adds 0.5g imidazoles and 0.5mL DMF, be cooled to 0 DEG C,
40g tribromo oxygen phosphorus is added dropwise, 85~90 DEG C of reactions is heated to after dripping off complete to consumption of raw materials；Reaction solution is cooled to room temperature and is inclined
Enter in 50mL water, add 100mL ethyl acetate to extract 3 times, add anhydrous magnesium sulfate to dry after saturated common salt washing, concentration is dry
It is dry, brownish red grease is obtained, add 120mL absolute ethyl alcohols to recrystallize 3 times, white solid powder is obtained, the chemical combination of formula 3 is obtained after drying
Thing 26g, yield 75%；
(5) compound of 70g formulas 2 is dissolved in 300mL tetrahydrofurans, adds the sodium hydroxide solution of 30ml 10%, 10~
15 DEG C of reactions to raw material is disappeared, and reaction solution adjusts pH to 1 with 5% hydrochloric acid solution, adds ethyl acetate extraction, and anhydrous magnesium sulfate is dried
It is concentrated under reduced pressure afterwards dry, adds acetone recrystallization, obtain Lesinurad 60g, yield is 96%.As shown in figure 3, in the present embodiment
The purity of gained Lesinurad is 99.79%；ESI-MS：M/z=404,406 (M+H)+(Fig. 4)；IR(KBr)(cm-1):
3420,2878,1723,1467,1440,768 (Fig. 5)；1H NMR (400MHz, DMSO-d6):δ 8.60 (d, J=8Hz, 1H),
7.75 (m, 1H), 7.66 (m, 1H), 7.44 (s, 2H), 7.16 (d, J=8.4Hz, 2H), 4.01 (dd, J=16Hz, 25.6Hz
2H), 2.55 (m, 1H), 1.15 (m, 2H), 0.87 (m, 2H) (Fig. 6).13C NMR (401MHz, DMSO-d6):δ166.9,
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).
Embodiment 2：
(1) at room temperature, the compound of 50g formulas 7,300mL DMF, 24g methyl hydrazinocarboxylates are mixed and are added in reaction bulb,
Heating makes reactant mixture be warming up to 50~60 DEG C, and insulated and stirred 7 hours；Reaction solution is cooled to room temperature by reaction after terminating,
Adding 2500mL water separates out product, filters and dry the compound dry product 60g of formula 6, and yield is 88%；
(2) compound of 50g formulas 6 is added in the sodium hydroxide solution of 700mL 1M at room temperature, is heated to 80~90 DEG C of guarantors
Warm 1 hour molten clear, and TLC detection reactions are cooled to room temperature after terminating, and the hydrochloric acid solutions of 1750mL 5% are added dropwise and separate out solid, after filtering
Wet product is obtained, 55 DEG C of hot-air oven dryings obtain the compound dry product 42g of formula 5 to constant weight, and yield is 95%；
(3) at room temperature, the compound of 0.1mol formulas 5 and potassium carbonate, DMF are mixed in reaction bulb, mixed liquor is cooled to 0
~5 DEG C, 0.12mol isopropyl chloracetates are added dropwise, drip off within 10 minutes, reaction solution is heated into 35 DEG C after dripping off reacts 1 hour,
TLC monitoring reactions add 400mL water after terminating, and are then extracted with ethyl acetate 3 times, then are washed with saturated common salt, then with nothing
Water magnesium sulfate is dried, and is concentrated under reduced pressure to give solid, is added 150mL ethyl acetate and is beaten 30 minutes, is filtered and dry that formula 3 is changed
Compound 24g, yield is 90%；
(4) compound of 10g formulas 3 is dissolved in 50mL dichloromethane, addition is cooled to 0 DEG C, 11g phosphorus tribromides is added dropwise,
Drip off rear room temperature reaction complete to consumption of raw materials；Reaction solution is cooled to room temperature and is poured into 50mL water, branch vibration layer, dichloromethane
Alkane layer adds anhydrous magnesium sulfate to dry after being washed with 1% sodium bicarbonate solution and saturated common salt, concentrate drying, obtains brownish red oil
Shape thing, adds 120mL absolute ethyl alcohols to recrystallize 3 times, obtains white solid powder, and the compound 10g of formula 3, yield 85% are obtained after drying；
(5) compound of 5g formulas 2 is dissolved in 50mL tetrahydrofurans, adds the lithium hydroxide solution of 5ml 5%, 10~15 DEG C
Reaction to raw material disappears, and reaction solution adjusts pH to 1 with 5% hydrochloric acid solution, adds ethyl acetate extraction, and anhydrous magnesium sulfate subtracts after drying
Pressure concentration is dry, adds acetone recrystallization, obtains Lesinurad 8.6g, and yield is 96%.
Claims (7)
1. a kind of synthetic method of Lesinurad, it is characterised in that comprise the following steps：
(1) to following formula: compound 7 is added in organic solvent, methyl hydrazinocarboxylate, heating response are subsequently adding, reaction adds after terminating
Entering water stirring separates out product, filters, dry the compound of following formula 6；
(2) make the compound of formula 6 that generation ring-closure reaction is heated in alkaline solution, then adjust the pH of reaction solution to acidity with acid, separate out
Product, filters, is dried to obtain the compound of following formula 5；
(3) compound of formula 5 is dissolved in organic solvent, adds acid binding agent, the compound of dropping type 4 after being cooled to 0~10 DEG C
Reaction 0.5~2 hour, after reaction terminates, extracts, concentrates, recrystallizes successively, obtains the compound of following formula 3；
Wherein, X is chlorine or bromine, and R is methyl, ethyl or isopropyl；
(4) make the compound of formula 3 that bromination reaction occurs in the presence of bromide reagent, product obtains the chemical combination of following formula 2 after recrystallization
Thing；
(5) compound 2 is hydrolyzed in alkaline solution, and reaction end obtains the compound of following formula 1, and the compound of formula 1 is target
Product Lesinurad,
2. the synthetic method of Lesinurad according to claim 1, it is characterised in that：Reaction temperature in step (1) is
50~60 DEG C.
3. the synthetic method of Lesinurad according to claim 1, it is characterised in that：Alkaline solution in step (2) is
Sodium hydroxide solution；Reaction temperature is 80~90 DEG C.
4. the synthetic method of Lesinurad according to claim 1, it is characterised in that：It is organic molten described in step (3)
Agent is ethyl acetate；Described acid binding agent is potassium carbonate.
5. the synthetic method of Lesinurad according to claim 1, it is characterised in that：Formula 4 described in step (3) is changed
Compound is 1~2 with the mol ratio of the compound of formula 5:1.
6. the synthetic method of Lesinurad according to claim 1, it is characterised in that：Bromination examination described in step (4)
Agent is tribromo oxygen phosphorus.
7. the synthetic method of Lesinurad according to claim 1, it is characterised in that：Alkaline solution described in step (5)
It is the one kind in NaOH, potassium hydroxide, lithium hydroxide.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109970668A (en) * | 2017-12-28 | 2019-07-05 | 普济生物科技（台州）有限公司 | A method of preparing the thio -1,2,4- triazole compound of 3- |
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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- 2017-03-30 CN CN201710201933.0A patent/CN106866560B/en active Active
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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109970668A (en) * | 2017-12-28 | 2019-07-05 | 普济生物科技（台州）有限公司 | A method of preparing the thio -1,2,4- triazole compound of 3- |
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