CN105017168A - New preparation method of [5-bromo-4-(4-cyclopropyl-naphthalene-1-yl)-4H-[1, 2, 4]triazole-3-ylsulfanyl]-methyl acetate - Google Patents

New preparation method of [5-bromo-4-(4-cyclopropyl-naphthalene-1-yl)-4H-[1, 2, 4]triazole-3-ylsulfanyl]-methyl acetate Download PDF

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Publication number
CN105017168A
CN105017168A CN201510375929.7A CN201510375929A CN105017168A CN 105017168 A CN105017168 A CN 105017168A CN 201510375929 A CN201510375929 A CN 201510375929A CN 105017168 A CN105017168 A CN 105017168A
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formula
compound
cyclopropyl
preparation
dmf
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Inventor
易加明
陶春蕾
邵凤
束超
徐怀友
王慧
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ANHUI WANBANG MEDICAL TECHNOLOGY Co Ltd
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ANHUI WANBANG MEDICAL TECHNOLOGY Co Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/06—Compounds containing any of the groups, e.g. semicarbazides

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a new preparation method of [5-bromo-4-(4-cyclopropyl-naphthalene-1-yl)-4H-[1, 2, 4]triazole-3-ylsulfanyl]-methyl acetate and an intermediate 4-(4-cyclopropyl-naphthalene-1-yl)-2, 4-dihydro-[1, 2, 4]triazole-3-one. The intermediate is used for synthesis of the anti-gout drug Lesinurad, has the advantages of economical efficiency, environmental protection property, high efficiency and high yield, etc., and can realize industrial production on a large scale.

Description

A kind of new preparation process of [the bromo-4-of 5-(4-cyclopropyl naphthalene-1-base)-4H-[1,2,4] triazole-3-base sulfanyl]-methyl acetate
Technical field
The present invention relates to synthesis antigout drug Lesinurad new synthesis route and used intermediate 4-(4-cyclopropyl naphthalene-1-base thereof)-2,4-dihydros-[1,2,4] triazole-3-ketone and preparation method thereof.
Background technology
Gout is with the crystal dependency joint disease caused by monosodium urate salt (MSU) precipitation, directly related with the hyperuricemia caused by purine metabolic disturbance and underexcretion.Be the oral medicine of a kind of promotion uric acid excretion, the sub-URAT1 of renal proximal tubules uric acid transporter can be suppressed; Lesinurad(RDEA594) be also a kind of xanthine oxidase inhibitor, be approved for the high lithemia treatment of gout, the tolerance of Lesinurad and Febuxostat combination therapy is good, and obviously can reduce uric acid.
Foreign patent WO2009070740A2, US2010056464A1, WO2011085009A2 and Patents report the synthetic route of Lesinurad, but these methods employ thiophosgene mostly, not easily scale operation.Chinese patent CN102040546A is from 4-cyclopropyl-1-naphthaldehyde through three step synthesis Lesinurad inter-mediate isocyanate, and this method synthetic route is longer, and total recovery is on the low side.Chinese patent is with 4-cyclopropyl-naphthalidine for starting raw material synthesizes Lesinurad, and this " naphthylamines method " operation is very inconvenient, and large to Environment impact, labour protection cost is higher.
Summary of the invention
Accordingly, the invention provides a kind of new synthesis route and the intermediate 4-(4-cyclopropyl naphthalene-1-base that synthesize Lesinurad)-4H-[1,2,4] triazole-3-alcohol and preparation method thereof.This intermediate and the surging force of preparation process to environment little, be applicable to large-scale production.
The present invention relates to the new synthesis route of preparation Lesinurad;
The present invention relates to the new intermediate 4-(4-cyclopropyl naphthalene-1-base of preparation Lesinurad)-2,4-dihydros-[1,2,4] triazole-3-ketone and preparation method thereof.
In 1 case study on implementation, the invention provides a kind of preparation method of formula 3 compound; Comprise:
A () at a certain temperature, in the first solvent and the first alkali coexisted environment, formula 1 compound and formula 2 compound are in conjunction with production 3 compound;
Wherein:
The first solvent be selected from DMF, methyl alcohol, ethanol, acetonitrile, ethyl acetate, methylene dichloride and toluene one or more;
The first alkali is selected from one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methylate, sodium ethylate, sodium tert-butoxide, NaH, triethylamine, triethylene diamine, DIPEA;
Temperature is selected from: one or more in-20-100 DEG C.
In 2 case study on implementation, the invention provides a kind of preparation method of formula 4 compound; Comprise:
(b) formula 3 compound in the second solvent, under certain temperature, formula 3 compound and DMF dimethylacetal production 4 compound;
Wherein:
In reaction (b): the second solvent is selected from one or more in DMF, toluene, Isosorbide-5-Nitrae-dioxane, ethyl acetate, methylene dichloride, DMF and DMSO.
In 3 case study on implementation, the invention provides a kind of preparation method of formula 6 compound, comprising:
C (), under the third alkali effect, formula 4 compound contacts production 6 compound with formula 5 compound;
Wherein:
In reaction (c), the third alkali is selected from one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, NaH, triethylamine, triethylene diamine, DIPEA.
In 4 case study on implementation, the invention provides a kind of preparation method of formula 7 compound, comprising:
D (), under bromide reagent existence condition, formula 6 compound changes an accepted way of doing sth 7 compound;
Wherein:
In reaction (d), bromide reagent is selected from bromine, NBS, DBBA, DBI, C5H6Br2N2O2, PBr 3and one or more in TBAB.
Embodiment 1:N-(4-cyclopropyl naphthalene-1-base) preparation of Hydrazinecarboxamidederivatives
Take 18.5 g 4-cyclopropyl-naphthalidines, 22.5 g triethylene diamines add in 250 mL single port bottles, at the bottom of bottleneck material all being washed bottle with 100 mL DMF, take 13.5 g methyl carbazates clearly molten with 67 mL DMF, add in 100 mL dropping funnels, reacting liquid temperature is risen to 45-50 DEG C, methyl carbazate DMF solution is slowly instilled, used time 1.5 h, drip off, reaction solution is warming up to 60 DEG C of TLC and follows the tracks of reaction, about 2 h, raw material transforms completely, reaction solution is down to less than 10 DEG C, be transferred in 500 mL there-necked flasks, 150 mL methyl alcohol and 50 mL purified water are instilled with 250 mL dropping funnels, a large amount of white solid is had to separate out, stir two hours at 10 DEG C, suction filtration, vacuum-drying 24 h at 45 DEG C, obtain 19.5 g white solids, yield 85 %, HPLC purity 98%.
Embodiment 2:4-(4-cyclopropyl naphthalene-1-base) preparation of-4H-[1,2,4]-triazole-3-alcohol
Take 15.7 g N-(4-cyclopropyl naphthalene-1-bases) Hydrazinecarboxamidederivatives, 9.3 g DMFDMA add in 250 mL single port bottles, with 78 mL DMF, bottleneck material is washed in bottle completely, reaction solution is kept 12 h at 50 DEG C, HPLC shows raw material and transforms completely, at reaction solution being down to 10 DEG C, 150 mL purified water are instilled in reaction solution, 2 h are stirred at 10 DEG C, suction filtration, filter cake with (50 × 2) mL purify washing twice, 45 DEG C of forced air dryings are spent the night, next day proceeds to vacuum drying oven, inside put Vanadium Pentoxide in FLAKES, 60 DEG C of vacuum-drying 24 h, obtain faint yellow solid 14.7 g, yield 90 %.
Embodiment 3:[4-(4-cyclopropyl naphthalene-1-base)-4H-[1,2,4] triazole-3-base sulfanyl] preparation of-methyl acetate
Take 12.3 g 4-(4-cyclopropyl naphthalene-1-bases)-4H-[1, 2, 4]-triazole-3-alcohol, 6.2 g ethyl thioglycolates, 11.2 g triethylene diamines add in 250 mL single port bottles, with 65 mL toluene, bottleneck material is all washed in bottle, be warming up to 60 DEG C, TLC follows the tracks of reaction, about 2 h raw materials transform completely, reaction solution is cooled to 5-10, order 5 g purified water in reaction solution, 15 mL methyl tertiary butyl ethers, 25 mL normal heptanes, a large amount of white solid is had to separate out after stirring for some time, 5-10 DEG C is stirred 2 h, suction filtration, filter cake (10 × 2) mL methyl tertiary butyl ether washes twice, at 45 DEG C, forced air drying is spent the night.
Embodiment 4:[5-bromo-4-(4-cyclopropyl naphthalene-1-base)-4H-[1,2,4] triazole-3-base sulfanyl] preparation of-methyl acetate
Take 6.7 g [4-(4-cyclopropyl naphthalene-1-base)-4H-[1, 2, 4] triazole-3-base sulfanyl]-methyl acetate, 1.8 g are to this methylsulfonic acid, 4.2 g NBS add in 250 mL single port bottles, with 120 mL acetonitriles, bottleneck material is washed in bottle completely, be warming up to backflow, about 4 h raw materials transform completely, acetonitrile is spin-dried for, reaction solution is cooled to less than 10 DEG C, 120 mL ethyl acetate are added in reaction solution, 30 mL 30% hypo solutions, stir 10 min, separatory, organic layer with 30 mL purify washing twice, anhydrous sodium sulfate drying, be threaded to 50 mL left/right rotations and move to less than 10 DEG C stirrings, separate out a large amount of off-white color solid, suction filtration, filter cake 20 mL cold ethyl acetates wash twice, filtrate is reclaimed, filter cake is put into 50 DEG C of air dry ovens and is spent the night, obtain off-white color solid 4.9 g, yield 60%.

Claims (8)

1. a Lesinurad intermediate, is characterized in that: described Lesinurad intermediate is the compound that general formula I represents,
In formula I:
R represents halogen, OR 1or NH 2, wherein R 1represent H, alkylsulfonyl, acyl group; R 2represent cyclopropyl, halogen.
2. Lesinurad intermediate according to claim 1, is characterized in that: R in formula I 2cyclopropyl, R is OR 1, wherein R 1for H, structural formula as shown in Equation 4:
。
3. a Lesinurad intermediate, is characterized in that: described Lesinurad intermediate is the compound that general formula I I represents,
In formula II:
R 2represent cyclopropyl, halogen.
4. Lesinurad intermediate according to claim 3, is characterized in that: R in formula II 2 arecyclopropyl, structural formula as shown in Equation 3:
。
5. the preparation method of formula 3 compound; Comprise:
A () at a certain temperature, in the first solvent and the first alkali coexisted environment, formula 1 compound and formula 2 compound are in conjunction with production 3 compound;
Wherein:
The first solvent be selected from DMF, methyl alcohol, ethanol, acetonitrile, ethyl acetate, methylene dichloride and toluene one or more;
The first alkali is selected from one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methylate, sodium ethylate, sodium tert-butoxide, NaH, triethylamine, triethylene diamine, DIPEA
Temperature is selected from: one or more in-20-100 DEG C.
6. the preparation method of formula 4 compound; Comprise:
(b) formula 3 compound in the second solvent, under certain temperature, formula 3 compound and DMF dimethylacetal production 4 compound;
Wherein:
In reaction (b): the second solvent is selected from one or more in DMF, toluene, Isosorbide-5-Nitrae-dioxane, ethyl acetate, methylene dichloride, DMF and DMSO.
7. a preparation method for formula 6 compound, comprising:
C (), under the third alkali effect, formula 4 compound contacts production 6 compound with formula 5 compound;
Wherein:
In reaction (c), the third alkali is selected from one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, NaH, triethylamine, triethylene diamine, DIPEA.
8. a preparation method for formula 7 compound, comprising:
D (), under bromide reagent existence condition, formula 6 compound changes an accepted way of doing sth 7 compound;
Wherein:
In reaction (d), bromide reagent is selected from bromine, NBS, DBBA, DBI, C5H6Br2N2O2, PBr 3and one or more in TBAB.
CN201510375929.7A 2015-07-01 2015-07-01 New preparation method of [5-bromo-4-(4-cyclopropyl-naphthalene-1-yl)-4H-[1, 2, 4]triazole-3-ylsulfanyl]-methyl acetate Pending CN105017168A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN106478531A (en) * 2015-08-25 2017-03-08 南京华威医药科技开发有限公司 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- base) -4H-1,2,4- triazole -3- base sulfenyls) acid intermediates
CN107325060A (en) * 2016-04-29 2017-11-07 石药集团中奇制药技术（石家庄）有限公司 A kind of Lesinurad intermediates of crystal habit and preparation method thereof
US10351537B2 (en) 2017-03-10 2019-07-16 Apotex Inc. Processes for the preparation of lesinurad and intermediates thereof
CN111116501A (en) * 2019-12-30 2020-05-08 北京鑫开元医药科技有限公司海南分公司 Synthesis method of Ravinard intermediate capable of effectively reducing impurity content
CN111116500A (en) * 2019-12-30 2020-05-08 北京鑫开元医药科技有限公司海南分公司 Purification method of Resinard key intermediate

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WO2006026356A2 (en) * 2004-08-25 2006-03-09 Ardea Biosciences, Inc. S-TRIAZOLYL α-MERCAPTOACETANILDES AS INHIBITORS OF HIV REVERSE TRANSCRIPTASE
WO2009070740A2 (en) * 2007-11-27 2009-06-04 Ardea Biosciences Inc. Novel compounds and compositions and methods of use
WO2011085009A2 (en) * 2010-01-08 2011-07-14 Ardea Biosciences, Inc. Polymorphic, crystalline and mesophase forms of sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio)acetate, and uses thereof
CN103524440A (en) * 2013-10-15 2014-01-22 苏州鹏旭医药科技有限公司 Preparation method of gout curative medicine Lesinurad and midbody of Lesinurad
CN104736522A (en) * 2012-07-03 2015-06-24 阿迪亚生命科学公司 Manufacture of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetic acid

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006026356A2 (en) * 2004-08-25 2006-03-09 Ardea Biosciences, Inc. S-TRIAZOLYL α-MERCAPTOACETANILDES AS INHIBITORS OF HIV REVERSE TRANSCRIPTASE
WO2009070740A2 (en) * 2007-11-27 2009-06-04 Ardea Biosciences Inc. Novel compounds and compositions and methods of use
WO2011085009A2 (en) * 2010-01-08 2011-07-14 Ardea Biosciences, Inc. Polymorphic, crystalline and mesophase forms of sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio)acetate, and uses thereof
CN104736522A (en) * 2012-07-03 2015-06-24 阿迪亚生命科学公司 Manufacture of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetic acid
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106478531A (en) * 2015-08-25 2017-03-08 南京华威医药科技开发有限公司 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- base) -4H-1,2,4- triazole -3- base sulfenyls) acid intermediates
CN106478531B (en) * 2015-08-25 2019-06-28 南京华威医药科技集团有限公司 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- base) -4H-1,2,4- triazole -3- base sulfenyls) acid intermediates
CN107325060A (en) * 2016-04-29 2017-11-07 石药集团中奇制药技术（石家庄）有限公司 A kind of Lesinurad intermediates of crystal habit and preparation method thereof
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
CN106187927B (en) * 2016-07-26 2020-02-04 山东川成医药股份有限公司 Preparation method of Lesinurad intermediate
US10351537B2 (en) 2017-03-10 2019-07-16 Apotex Inc. Processes for the preparation of lesinurad and intermediates thereof
CN111116501A (en) * 2019-12-30 2020-05-08 北京鑫开元医药科技有限公司海南分公司 Synthesis method of Ravinard intermediate capable of effectively reducing impurity content
CN111116500A (en) * 2019-12-30 2020-05-08 北京鑫开元医药科技有限公司海南分公司 Purification method of Resinard key intermediate
CN111116501B (en) * 2019-12-30 2021-03-12 北京鑫开元医药科技有限公司海南分公司 Synthesis method of Ravinard intermediate capable of effectively reducing impurity content
CN111116500B (en) * 2019-12-30 2021-06-08 北京鑫开元医药科技有限公司海南分公司 Purification method of Resinard key intermediate

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