CN105153056A - New preparation method of [5-bromo-4-(4-cyclopropyl-naphthalene-1-yl)-4H-[1, 2, 4]triazole-3-ylthioalkyl]-methyl acetate - Google Patents

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

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Publication number
CN105153056A
CN105153056A CN201510375599.1A CN201510375599A CN105153056A CN 105153056 A CN105153056 A CN 105153056A CN 201510375599 A CN201510375599 A CN 201510375599A CN 105153056 A CN105153056 A CN 105153056A
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Prior art keywords
formula
compound
sodium
cyclopropyl
preparation
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CN201510375599.1A
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Inventor
易加明
陶春蕾
邵凤
陈国祥
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
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C263/00—Preparation of derivatives of isocyanic acid
    • C07C263/10—Preparation of derivatives of isocyanic acid by reaction of amines with carbonyl halides, e.g. with phosgene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C265/00—Derivatives of isocyanic acid
    • C07C265/12—Derivatives of isocyanic acid having isocyanate groups bound to carbon atoms of six-membered aromatic rings
    • 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

Abstract

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

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 5-amino-4-(4-cyclopropyl naphthalene-1-base thereof)-4H-[1,2,4] triazole-3-alcohol 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.
Summary of the invention
Accordingly, the invention provides a kind of new synthesis route and the intermediate 5-amino-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 5-amino-4-(4-cyclopropyl naphthalene-1-base of preparation Lesinurad)-4H-[1,2,4] triazole-3-alcohol and preparation method thereof.
In first case study on implementation, this patent provides a kind of preparation method of formula 2 compound; Comprise:
A (), in the first solvent and the first alkali coexisted environment, under certain temperature, formula 1 compound contacts production 2 compound with BTC;
Wherein:
The first solvent is selected from one or more in chlorobenzene, orthodichlorobenzene, nitro benzene,toluene,xylene, n-tetradecane, Pentadecane, n-hexadecane, hexane, heptane, nonane, decane and methylene dichloride;
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 of reaction is selected from: one or more in-20-150 DEG C.
In second case study on implementation, this patent provides a kind of preparation method of formula 4 compound; Comprise:
(b) under the effect of the second alkali, formula 2 compound and formula 3 compound production 4 compound;
Wherein:
In reaction (b):
The second 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.
In the 3rd case study on implementation, this patent provides a kind of preparation method of formula 5 compound, comprising:
C () instills a certain amount of sodium nitrite solution in the dilute hydrochloric acid solution of formula 4 compound;
D gained diazonium salt is slowly poured in 2-Methyl Thioglycolate solution and is obtained formula 5 compound by ();
Wherein:
In reaction (c):
Sodium Nitrite instillation temperature is selected from one or more in 0-50 DEG C.
In the 4th case study on implementation, this patent provides a kind of preparation method of formula 6 compound, comprising:
E (), under bromide reagent and tosic acid existence condition, formula 5 compound changes an accepted way of doing sth 6 compound;
Wherein:
In reaction (e):
Bromide reagent is selected from bromine, NBS, DBBA, DBI, C5H6Br2N2O2, PBr 3and one or more in TBAB;
Organic solvent is selected from one or more in chlorobenzene, orthodichlorobenzene, nitro benzene,toluene,xylene, n-tetradecane, Pentadecane, n-hexadecane, hexane, heptane, nonane, decane and methylene dichloride.
The preparation of embodiment 1:4-cyclopropyl-1-isocyanic ester
Add in 100mL dropping funnel stand-by after taking 18.5g4-cyclopropyl-naphthalidine 80mL anhydrous methylene chloride dilution, take 29.5gBTC, 30.2gTEA adds in 250mL there-necked flask, with 120mL anhydrous methylene chloride, bottleneck material is washed in bottle completely, be warming up to backflow, 4-cyclopropyl-naphthalidine dichloromethane solution in dropping funnel is slowly instilled in reaction solution, drip off, return stirring 4h, reaction solution is cooled to room temperature, filtering white solid, mother liquor 50mL1N dilute hydrochloric acid is washed once, separate organic layer, anhydrous sodium sulfate drying, removing organic solvent, 90mL hexanaphthene is added in concentrated solution, stirring at room temperature 30min, filtering insolubles, mother liquor concentrating under reduced pressure removing organic solvent, obtain oily matter 18.8g, yield 90%.
Embodiment 2:5-amino-4-(4-cyclopropyl naphthalene-1-base) preparation of-4H-[1,2,4] triazole-3-alcohol
Take 16.7g4-cyclopropyl-1-isocyanic ester, 14.1g GER-11, 19.4gTEA adds in 250mL single port bottle, with 100mLDMF, bottleneck material is washed in bottle completely, 70-75 DEG C of reaction 6h, reaction solution is cooled to 50-55 DEG C, 8.6g sodium methylate is added in reaction solution, 2h is kept under 50-55, reaction solution is down to about 0 DEG C, 100mL purified water is added in reaction solution, a large amount of white solid is had to separate out after stirring for some time, continue to stir 1h, suction filtration, filter cake with 50mL purify washing twice, 50 DEG C of dried in vacuo overnight, obtain off-white color solid 17.7g(moisture 10%), yield 75%.
Embodiment 3:[5-hydroxyl-4-(4-cyclopropyl naphthalene-1-base)-4H-[1,2,4] triazole-3-base sulfanyl] preparation of-methyl acetate
Take the above-mentioned off-white color solid of 14.8g, wherein containing 13g5-amino-4-(4-cyclopropyl naphthalene-1-base)-4H-[1,2,4] triazole-3-alcohol adds in 250mL there-necked flask, add 100mL1N dilute hydrochloric acid wherein, taking 13.5g35% sodium nitrite solution adds in 100mL dropping funnel, and interior temperature about 10 slowly instills, and drips off stirring 1h stand-by; Taking 5.3g2-Methyl Thioglycolate adds in 250mL single port bottle, with vigorous stirring, is slowly poured into wherein by the diazonium salt solution of brand-new, stirred at ambient temperature 3h, suction filtration, filter cake with 50mL purify washing twice, 85 DEG C of dried in vacuo overnight, obtain white solid 15.9g(moisture 0.1%) yield 90%.
Embodiment 4:[5-bromo-4-(4-cyclopropyl naphthalene-1-base)-4H-[1,2,4] triazole-3-base sulfanyl] preparation of-methyl acetate
Take 10.5g [5-hydroxyl-4-(4-cyclopropyl naphthalene-1-base)-4H-[1, 2, 4] triazole-3-base sulfanyl]-methyl acetate, 2.8g tosic acid adds in 250mL there-necked flask, add 100mL methylene dichloride, be warming up to backflow, slowly add 6.3gNBS, add, backflow 8h, reaction solution is cooled to room temperature, 50mL30% hypo solution is added in reaction solution, stirring at room temperature 30min, separate organic layer, with 50mL saturated common salt washing twice, anhydrous sodium sulfate drying is spin-dried for, slowly 100mL ethyl acetate is instilled in 5 DEG C of downhill reaction liquid, a large amount of off-white color solid is had to separate out, stir 2h, filter, filter cake 20mL cold ethyl acetate washes twice, vacuum-drying at 40 DEG C, obtain white solid 8.0g, yield 65%.

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 H, halogen, OR 1or NH 2, wherein R 1represent H, alkylsulfonyl, acyl group; R 2represent cyclopropyl, halogen; R 3represent H, halogen, OR 1or NH 2, wherein R 1represent H, alkylsulfonyl, acyl group.
2. Lesinurad intermediate according to claim 1, is characterized in that: R in formula I 2cyclopropyl, R is OR 1, wherein R 1for H, R 3for NH 2, 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 2for cyclopropyl, structural formula as shown in Equation 2:
。
5. the preparation method of formula 2 compound; Comprise:
In the first solvent and the first alkali coexisted environment, under certain temperature, formula 1 compound contacts production 2 compound with BTC;
Wherein:
The first solvent is selected from one or more in chlorobenzene, orthodichlorobenzene, nitro benzene,toluene,xylene, n-tetradecane, Pentadecane, n-hexadecane, hexane, heptane, nonane, decane and methylene dichloride;
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 of reaction is selected from: one or more in-20-150 DEG C.
6. the preparation method of formula 4 compound; Comprise:
(b) under the effect of the second alkali, formula 2 compound and formula 3 compound production 4 compound;
Wherein:
In reaction (b):
The second 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.
7. a preparation method for formula 5 compound, comprising:
C () instills a certain amount of sodium nitrite solution in the dilute hydrochloric acid solution of formula 4 compound;
D gained diazonium salt is slowly poured in 2-Methyl Thioglycolate solution and is obtained formula 5 compound by ();
Wherein:
In reaction (c):
Sodium Nitrite instillation temperature is selected from one or more in 0-50 DEG C.
8. a preparation method for formula 6 compound, comprising:
E (), under bromide reagent and tosic acid existence condition, formula 5 compound changes an accepted way of doing sth 6 compound;
Wherein:
In reaction (d):
Bromide reagent is selected from bromine, NBS, DBBA, DBI, C5H6Br2N2O2, PBr 3and one or more in TBAB;
Organic solvent is selected from one or more in chlorobenzene, orthodichlorobenzene, nitro benzene,toluene,xylene, n-tetradecane, Pentadecane, n-hexadecane, hexane, heptane, nonane, decane and methylene dichloride.
CN201510375599.1A 2015-07-01 2015-07-01 New preparation method of [5-bromo-4-(4-cyclopropyl-naphthalene-1-yl)-4H-[1, 2, 4]triazole-3-ylthioalkyl]-methyl acetate Pending CN105153056A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106632108A (en) * 2016-12-14 2017-05-10 湖南欧亚生物有限公司 Preparation method of lesinurad
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
CZ307277B6 (en) * 2016-09-30 2018-05-09 Zentiva, K.S. A method of producing 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3ylthio)acetic acid – lesinurade
US10351537B2 (en) 2017-03-10 2019-07-16 Apotex Inc. Processes for the preparation of lesinurad and intermediates thereof

Citations (4)

* 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
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

Patent Citations (4)

* 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
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

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CZ307277B6 (en) * 2016-09-30 2018-05-09 Zentiva, K.S. A method of producing 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3ylthio)acetic acid – lesinurade
CN106632108A (en) * 2016-12-14 2017-05-10 湖南欧亚生物有限公司 Preparation method of lesinurad
US10351537B2 (en) 2017-03-10 2019-07-16 Apotex Inc. Processes for the preparation of lesinurad and intermediates thereof

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