CN104987311A - Preparing method for (4-(4-cyclopropyl-naphthalene-1-yl)-5-nitr-4H-(1, 2, 4) triazole-3-ylsulfanyl)-ethyl acetate and intermediate (5-nitr-4H-(1, 2, 4) triazole-3-sulfenyl)-ethyl acetate thereof - Google Patents
Preparing method for (4-(4-cyclopropyl-naphthalene-1-yl)-5-nitr-4H-(1, 2, 4) triazole-3-ylsulfanyl)-ethyl acetate and intermediate (5-nitr-4H-(1, 2, 4) triazole-3-sulfenyl)-ethyl acetate thereof Download PDFInfo
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- CN104987311A CN104987311A CN201510384858.7A CN201510384858A CN104987311A CN 104987311 A CN104987311 A CN 104987311A CN 201510384858 A CN201510384858 A CN 201510384858A CN 104987311 A CN104987311 A CN 104987311A
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- 0 CCCCC(CNC([C@@](CC(CC)=*)C1=CC=C(C2CC2)C2NCCCC12)=I)=C Chemical compound CCCCC(CNC([C@@](CC(CC)=*)C1=CC=C(C2CC2)C2NCCCC12)=I)=C 0.000 description 2
- VEUUMBGHMNQHGO-UHFFFAOYSA-N CCOC(CCl)=O Chemical compound CCOC(CCl)=O VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- KWRBZESLGXYFOV-UHFFFAOYSA-N CCOC(CSc1nnc[nH]1)=O Chemical compound CCOC(CSc1nnc[nH]1)=O KWRBZESLGXYFOV-UHFFFAOYSA-N 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
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Abstract
The invention provides a preparing method for (4-(4-cyclopropyl-naphthalene-1-yl)-5-nitr-4H-(1, 2, 4) triazole-3-ylsulfanyl)-ethyl acetate and an intermediate (5-nitr-4H-(1, 2, 4) triazole-3-ylsulfenyl)-ethyl acetate thereof. The intermediate is used for synthesizing an anti-gout drug Lesinurad, and has the advantages of being economical, environmentally friendly, efficient, high in yield and the like.
Description
Technical field
The present invention relates to intermediate used by synthesis antigout drug Lesinurad [4-(4-cyclopropyl naphthalene-1-base)-5-nitro-4H-[1,2,4] triazole-3-base sulfanyl]-ethyl acetate and preparation method thereof, intermediate (5-nitro-4H-[1,2,4] triazole-3-base sulfenyl)-ethyl acetate 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 synthesize Lesinurad new intermediate [4-(4-cyclopropyl naphthalene-1-base)-5-nitro-4H-[1,2,4] triazole-3-base sulfanyl]-ethyl acetate and intermediate (5-nitro-4H-[1,2,4] triazole-3-base sulfenyl)-ethyl acetate 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 new intermediate [4-(4-cyclopropyl naphthalene-1-base)-5-nitro-4H-[1,2,4] triazole-3-base sulfanyl]-ethyl acetate of preparation Lesinurad and preparation method thereof;
The present invention relates to new intermediate (5-nitro-4H-[1,2,4] triazole-3-base sulfenyl)-ethyl acetate of preparation Lesinurad and preparation method thereof.
In 1 case study on implementation, the invention provides a kind of preparation method of formula 3 compound; Comprise:
In a environment that () coexists at solvent and the first alkali, certain temperature following formula 1 compound and formula 2 compound are in conjunction with production 3 compound;
Wherein:
The first alkali is selected from K
2cO
3, Na
2cO
3, in NaOH, KOH, LiOH, TEA, triethylene diamine and diisopropylethylamine one or more;
Solvent selected from methanol, ethanol, Virahol, methylene dichloride, one or more in ethyl acetate or toluene;
Temperature of reaction is selected from one or more in 0-60 DEG C.
In 2 case study on implementation, the invention provides a kind of preparation method of formula 4 compound; Comprise:
B compound 3 is dissolved in the first acid by (), under low temperature, in the first acid, slowly instillation sodium nitrite solution obtains compound 4
Wherein:
In reaction (b): the first acid is selected from one or more in hydrochloric acid, sulfuric acid, acetic acid or diacetyl oxide; Instillation temperature is selected from one or more in-25-25 DEG C.
In 3 case study on implementation, the invention provides a kind of preparation method of formula 7 compound; Comprise:
In c environment that () exists at copper catalyst, part and alkali, certain temperature following formula 5 compound contacts production 7 compound with formula 6 compound;
Wherein:
Copper catalyst is selected from Cu(OAc)
2, CuOAc, isopropylformic acid copper, CuCl, CuBr, CuI, CuClO
4, Cu(NO
3)
2, CuFAP and CuSO
4in one or more;
Part is selected from one or more in Pyridine, TEA, TMEDA, 8-hydroxyquinoline, phenanthroline and triethylene diamine;
The second alkali is selected from K
2cO
3, K
3pO
4and Cs
2cO
3in one or more.
Embodiment 1:(4H-[1,2,4] triazole-3-base sulfenyl) preparation of-ethyl acetate
Take (10.5 g; 103 mmol) 4H-[1,2,4] triazole-3-mercaptan, (15.7 g; 129 mmol) ethyl chloroacetate adds in 500 mL there-necked flasks, adds 250 mL ethyl acetate, (31.5 g; 3 eq) triethylamine, be warming up to 50 DEG C, LC follows the tracks of reaction, and about 1.5 h raw materials transform completely, suction filtration, and by the insolubles removing in reaction solution, concentrating under reduced pressure at 50 DEG C, mother liquor, obtains faint yellow oily enriched material 18.1 g, yield 95%.
Embodiment 2:(5-nitro-4H-[1,2,4] triazole-3-base sulfenyl) preparation of-ethyl acetate
(55 mL are added in above-mentioned enriched material; 5 vol) diacetyl oxide, be cooled to 0 DEG C, slowly instillation 40 mL 20% sodium nitrite solutions, used time 8 h, drips off and rises to stirring at room temperature two hours, reaction solution is down to 0 DEG C, instill 100 mL purified water, separate out yellow solid, stir 1 h at 0 DEG C, suction filtration, filtrate is washed till neutrality by purified water, 80 DEG C of vacuum-dryings, obtain 16.5 g yellow solids, yield 75%.
Embodiment 3:[4-(4-cyclopropyl naphthalene-1-base)-5-nitro-4H-[1,2,4] triazole-3-base sulfanyl] preparation of-ethyl acetate
Take (12.5 g; 54 mmol) above-mentioned yellow solid, (15.9 g; 64.8 mmol) 4-cyclopropyl-1-bromonaphthalene, (3.4g; 20%mmol) CuI
2, (22.9 g; 2 eq) K
3pO
4, (195 mg, 20% mmol) H
2o, (1.6 g; 20%mmol) oxine; 100 mL toluene add in 250 mL there-necked flasks; nitrogen protection; be warming up to backflow; LC follows the tracks of reaction, about 16 h raw materials lower than 3%, processing reaction; reaction solution is down to 10 DEG C; under nitrogen protection, in reaction solution, add 100 mL purified water, 60 mL methyl tertiary butyl ethers, 125 mL normal heptanes, maintain the temperature at less than 10 DEG C; stir two hours; suction filtration, filter cake 30 mL methyl tertiary butyl ethers wash twice, 80 DEG C of vacuum-dryings; obtain off-white color solid 13.9 g, yield 65%.
Claims (7)
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, COR
1or C
1-3alkane, wherein R
1represent C
1-3alkane; Or R represents CH
2r
2, wherein R
2represent ester group, CN or CH
2oH;
R
3represent cyclopropyl or halogen;
R
4represent NO
2, OH, OTf, NH
2, halogen or SO
3.
2. Lesinurad intermediate according to claim 1, is characterized in that: R in formula I
3cyclopropyl, R is CH
2r
2, R
2for COOCH
2cH
3, R
4for NO
2, structural formula as shown in Equation 7:
。
3. a Lesinurad intermediate, is characterized in that: described Lesinurad intermediate is the compound that general formula I I represents,
In formula II:
R represents H, COR
1or C
1-3alkane, wherein R
1represent C
1-3alkane; Or R represents CH
2r
2, wherein R
2represent ester group, CN or CH
2oH;
R
4represent NO
2, OH, OTf, NH
2, halogen or SO
3.
4. Lesinurad intermediate according to claim 3, is characterized in that: R in formula II
3cyclopropyl, R is CH
2r
2, R
2for COOCH
2cH
3, R
4for NO
2, structural formula as shown in Equation 3:
。
5. the preparation method of formula 3 compound; Comprise:
In a environment that () coexists at solvent and the first alkali, certain temperature following formula 1 compound and formula 2 compound are in conjunction with production 3 compound;
Wherein:
The first alkali is selected from K
2cO
3, Na
2cO
3, in NaOH, KOH, LiOH, TEA, triethylene diamine and diisopropylethylamine one or more;
Solvent selected from methanol, ethanol, Virahol, methylene dichloride, one or more in ethyl acetate or toluene;
Temperature of reaction is selected from one or more in 0-60 DEG C.
6. the preparation method of formula 4 compound; Comprise:
B compound 3 is dissolved in the first acid by (), under low temperature, in the first acid, slowly instillation sodium nitrite solution obtains compound 4
Wherein:
In reaction (b): the first acid is selected from one or more in hydrochloric acid, sulfuric acid, acetic acid or diacetyl oxide; Instillation temperature is selected from one or more in-25-25 DEG C.
7. the preparation method of formula 7 compound; Comprise:
In c environment that () exists at copper catalyst, part and alkali, certain temperature following formula 5 compound contacts production 7 compound with formula 6 compound;
Wherein:
Copper catalyst is selected from Cu(OAc)
2, CuOAc, isopropylformic acid copper, CuCl, CuBr, CuI, CuClO
4, Cu(NO
3)
2, CuFAP and CuSO
4in one or more;
Part is selected from one or more in Pyridine, TEA, TMEDA, 8-hydroxyquinoline, phenanthroline and triethylene diamine;
The second alkali is selected from K
2cO
3, K
3pO
4and Cs
2cO
3in one or more.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510384858.7A CN104987311A (en) | 2015-06-30 | 2015-06-30 | Preparing method for (4-(4-cyclopropyl-naphthalene-1-yl)-5-nitr-4H-(1, 2, 4) triazole-3-ylsulfanyl)-ethyl acetate and intermediate (5-nitr-4H-(1, 2, 4) triazole-3-sulfenyl)-ethyl acetate thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510384858.7A CN104987311A (en) | 2015-06-30 | 2015-06-30 | Preparing method for (4-(4-cyclopropyl-naphthalene-1-yl)-5-nitr-4H-(1, 2, 4) triazole-3-ylsulfanyl)-ethyl acetate and intermediate (5-nitr-4H-(1, 2, 4) triazole-3-sulfenyl)-ethyl acetate thereof |
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| Publication Number | Publication Date |
|---|---|
| CN104987311A true CN104987311A (en) | 2015-10-21 |
Family
ID=54299232
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|---|---|---|---|
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105906576A (en) * | 2016-06-12 | 2016-08-31 | 成都百裕制药股份有限公司 | Method for preparing lesinurad intermediate |
| 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 |
| CN106220577A (en) * | 2016-07-26 | 2016-12-14 | 苏州明锐医药科技有限公司 | The preparation method of Li Xinluode |
| CN108164471A (en) * | 2016-12-07 | 2018-06-15 | 浙江京新药业股份有限公司 | Lesinurad derivatives and its preparation method and application |
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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 |
-
2015
- 2015-06-30 CN CN201510384858.7A patent/CN104987311A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| 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 |
| 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 (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105906576A (en) * | 2016-06-12 | 2016-08-31 | 成都百裕制药股份有限公司 | Method for preparing lesinurad intermediate |
| CN105906576B (en) * | 2016-06-12 | 2018-04-17 | 成都百裕制药股份有限公司 | It is a kind of come Si Nuolei intermediates preparation method |
| 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 |
| CN106220577A (en) * | 2016-07-26 | 2016-12-14 | 苏州明锐医药科技有限公司 | The preparation method of Li Xinluode |
| 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 |
| CN108164471A (en) * | 2016-12-07 | 2018-06-15 | 浙江京新药业股份有限公司 | Lesinurad derivatives and its preparation method and application |
| CN108164471B (en) * | 2016-12-07 | 2019-09-13 | 浙江京新药业股份有限公司 | Lesinurad derivative and its preparation method and application |
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