CN102002017A - Method for preparing febuxostat intermediate - Google Patents
Method for preparing febuxostat intermediate Download PDFInfo
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- CN102002017A CN102002017A CN 201010534098 CN201010534098A CN102002017A CN 102002017 A CN102002017 A CN 102002017A CN 201010534098 CN201010534098 CN 201010534098 CN 201010534098 A CN201010534098 A CN 201010534098A CN 102002017 A CN102002017 A CN 102002017A
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- acid
- methylthiazol
- ethyl ester
- hydroxy phenyl
- formic acid
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- 238000000034 method Methods 0.000 title claims abstract description 12
- 229960005101 febuxostat Drugs 0.000 title abstract description 12
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 title abstract description 12
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 11
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 9
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- WISQBJLUORKXNY-UHFFFAOYSA-N ethyl 4-methyl-1,3-thiazole-5-carboxylate Chemical compound CCOC(=O)C=1SC=NC=1C WISQBJLUORKXNY-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- -1 heterocyclic aldehyde Chemical class 0.000 abstract description 3
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- LOCYSKNNFCGDTR-UHFFFAOYSA-N ethyl 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate Chemical compound CC1=C(C(=O)OCC)SC(C=2C=CC(O)=CC=2)=N1 LOCYSKNNFCGDTR-UHFFFAOYSA-N 0.000 description 7
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 6
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 5
- 229940116269 uric acid Drugs 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- OGAZOYHQFBSRMC-UHFFFAOYSA-N ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate Chemical compound CC1=C(C(=O)OCC)SC(C=2C=C(C(OCC(C)C)=CC=2)C#N)=N1 OGAZOYHQFBSRMC-UHFFFAOYSA-N 0.000 description 3
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 201000001431 Hyperuricemia Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000004144 purine metabolism Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- QBNJPSHRAWSBDW-UHFFFAOYSA-N 2-methylpropane;hydrobromide Chemical compound Br.CC(C)C QBNJPSHRAWSBDW-UHFFFAOYSA-N 0.000 description 1
- FMHRQJJWJQGSDR-UHFFFAOYSA-N 3-cyano-4-(2-methylpropoxy)benzenecarbothioamide Chemical compound CC(C)COC1=CC=C(C(N)=S)C=C1C#N FMHRQJJWJQGSDR-UHFFFAOYSA-N 0.000 description 1
- ZGWGSEUMABQEMD-UHFFFAOYSA-N 4-methyl-1,3-thiazole-5-carboxylic acid Chemical compound CC=1N=CSC=1C(O)=O ZGWGSEUMABQEMD-UHFFFAOYSA-N 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960002708 antigout preparations Drugs 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- RQDZYELGFUZPQX-UHFFFAOYSA-N ethyl 2-[3-amino-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate Chemical compound CC1=C(C(=O)OCC)SC(C=2C=C(N)C(OCC(C)C)=CC=2)=N1 RQDZYELGFUZPQX-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention relates to a method for preparing a febuxostat intermediate, which comprises the following steps of: dissolving 2-[4-hydroxyphenyl]-4-methylthiazol-5-ethyl formate in a mixed acid reaction solvent, adding a certain amount of urotropine, heating to react for 1-36 h at certain temperature, and treating the reaction liquid to obtain corresponding heterocyclic aldehyde.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to febuxostat intermediate 2-[3-aldehyde radical-4-hydroxy phenyl]-preparation of 4-methylthiazol-5-formic acid ethyl ester.
Background technology
Gout has now become the especially common disease of middle-aging male of the world today, and pathogenesis is too much, the kidney removing ability drop of generation uric acid in the body, causes uric acid constantly to be put aside in vivo, forms hyperuricemia.The generation of uric acid is relevant with purine metabolism in the body, final stage at purine metabolism, xanthine generates uric acid under the effect of XOD (XO), the activity that suppresses XO can effectively reduce the generation of uric acid, and therefore the development of novel anti-gout drugs is the focus of drug research always.。
Febuxostat, chemistry 2-[3-cyano-4-isobutoxy phenyl by name]-the 4-methylthiazol-5-formic acid, be a new generation's non-purine class selectivity xanthine oxidase inhibitor, be used for the treatment of chronic hyperuricemia that urate deposition takes place (comprised once or occur now gout or urarthritis) clinically.
Synthesizing of Febuxostat, report that more route can reduce three:
(1) at document Heterocycles, 47 (2), among the 857-864 with 4-isobutoxy-1, the 3-benzene dinitrile is a raw material, obtain 3-cyano-4-isobutoxy thiobenzamide with the thioacetamide reaction, the latter again with the cyclization of 2-chloroacetyl acetacetic ester, the 2-of gained (3-cyano-4-isobutoxy phenyl)-4-methylthiazol-5-formic acid ethyl ester hydrolysis under alkaline condition obtains Febuxostat.
(2) at Chinese Journal of Pharmaceuticals 2009; 40 (10); 2-among the 726-728 (3-formyl radical-4-hydroxy phenyl)-4-methylthiazol-5-formic acid ethyl ester is used the oxammonium hydrochloride cyaniding in methyl alcohol; the 2-that obtains (3-cyano group-4-hydroxy phenyl)-4-methylthiazol-5-formic acid ethyl ester and isobutane bromide reaction make 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazol-5-formic acid ethyl ester, obtain Febuxostat after latter's hydrolysis.
(3) in the document US 5614520,2-(3-nitro-4-isobutoxy phenyl)-4-methylthiazol-5-formic acid ethyl ester hydrogenation under the catalysis of palladium carbon, the 2-that obtains (3-amino-4-isobutoxy phenyl)-4-methylthiazol-5-formic acid ethyl ester, elder generation's diazotization is reacted with cuprous cyanide again, get 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazol-5-formic acid ethyl ester, latter's hydrolysis obtains Febuxostat.
2-[3-aldehyde radical-4-hydroxy phenyl]-4-methylthiazol-5-formic acid ethyl ester is the important intermediate of synthetic Febuxostat, structure is as follows
In the existing synthetic document, the synthetic method of II formula is by the Duff-Bills reaction, uses urotropine aldehyde on three of phenyl ring, and reaction solvent has two kinds,
(1) in JP1045733, use PPA (polyphosphoric acid) as solvent, yield 70%,
(2) in CN101412699, use trifluoroacetic acid as solvent, yield 95%,
Use PPA (polyphosphoric acid) as reaction solvent, advantage is low price, but reaction generation impurity is many, difficult treatment, and product yield is low.
Use trifluoroacetic acid as reaction solvent, it is few that reaction produces impurity, and product yield height, but trifluoroacetic acid price height are difficult to reclaim, and can increase synthetic cost.
We find in synthetic Febuxostat process, if the mixing acid that uses polyphosphoric acid and other strong acid is as reaction solvent, can obtain high yield (92%), can reduce the difficulty of aftertreatment again, reducing synthetic cost, is a kind of good method of intermediate of synthetic Febuxostat, this method reaction conditions gentleness, simple to operate, be convenient to industrialization.
Summary of the invention
The invention provides compound 2-[3-aldehyde radical-4-hydroxy phenyl of a kind of structure I I]-preparation method of 4-methylthiazol-5-formic acid ethyl ester, may further comprise the steps:
2-[4-hydroxy phenyl with structure I]-4-methylthiazol-5-formic acid ethyl ester is dissolved in the mixing acid reaction solvent, adds urotropine, reacts 1-36 hour, obtains the compound of structure I I.
Wherein said mixing acid reaction solvent is selected from: the mixed solvent of polyphosphoric acid and concentrated hydrochloric acid, polyphosphoric acid and the vitriol oil, polyphosphoric acid and nitric acid or polyphosphoric acid and trifluoroacetic acid, polyphosphoric acid and other sour volume ratio are 4 in the mixing acid: 1-1: 1.
The amount that wherein adds urotropine is a substrate 2-[4-hydroxy phenyl]-0.5-10 of 4-methylthiazol-5-formic acid ethyl ester molar weight is doubly.
Temperature of reaction 40-120 ℃.
The add-on of mixing acid is a substrate 2-[4-hydroxy phenyl]-5-10 of 4-methylthiazol-5-formic acid ethyl ester charging capacity is doubly.
The advantage of the inventive method is: simple to operate, and purity height, yield height, reaction conditions gentleness.
Embodiment
Further specify the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1:
26.3g 2-[4-hydroxy phenyl]-4-methylthiazol-5-formic acid ethyl ester is dissolved in 100ml polyphosphoric acid and the 40ml concentrated hydrochloric acid, adds the 13g urotropine, is heated to 80 ℃, keeps 12 hours, and reaction solution is chilled to room temperature, and processing obtains product, yield 90%.
Embodiment 2:
26.3g 2-[4-hydroxy phenyl]-4-methylthiazol-5-formic acid ethyl ester is dissolved in the 100ml polyphosphoric acid and the 50ml vitriol oil, adds the 12g urotropine, is heated to 80 ℃, keeps 12 hours, and reaction solution is chilled to room temperature, and processing obtains product, yield 93%.
Embodiment 3:
26.3g 2-[4-hydroxy phenyl]-4-methylthiazol-5-formic acid ethyl ester is dissolved in 100ml polyphosphoric acid and the 40ml phosphoric acid, adds the 10g urotropine, is heated to 120 ℃, keeps 12 hours, and reaction solution is chilled to room temperature, and processing obtains product, yield 70%.
Embodiment 4:
26.3g 2-[4-hydroxy phenyl]-4-methylthiazol-5-formic acid ethyl ester is dissolved in 150ml polyphosphoric acid and the 25ml trifluoroacetic acid, adds the 13g urotropine, is heated to 90 ℃, keeps 6 hours, and reaction solution is chilled to room temperature, and processing obtains product, yield 93%.
Embodiment 5:
26.3g 2-[4-hydroxy phenyl]-4-methylthiazol-5-formic acid ethyl ester is dissolved in 100ml polyphosphoric acid and the 40ml concentrated hydrochloric acid, adds the 13g urotropine, is heated to 60 ℃, keeps 24 hours, and reaction solution is chilled to room temperature, and processing obtains product, yield 79%.
Embodiment 6:
26.3g 2-[4-hydroxy phenyl]-4-methylthiazol-5-formic acid ethyl ester is dissolved in 100ml polyphosphoric acid and the 40ml concentrated hydrochloric acid, adds the 13g urotropine, is heated to 100 ℃, keeps 3 hours, and reaction solution is chilled to room temperature, and processing obtains product, yield 80%.
Embodiment 7:
26.3g 2-[4-hydroxy phenyl]-4-methylthiazol-5-formic acid ethyl ester is dissolved in 100ml polyphosphoric acid and the 40ml concentrated hydrochloric acid, adds the 15g urotropine, is heated to 80 ℃, keeps 12 hours, and reaction solution is chilled to room temperature, and processing obtains product, yield 93%.
Claims (6)
1. the preparation method of a structural formula II compound, it is characterized in that, may further comprise the steps: with the compound 2-[4-hydroxy phenyl of structure I]-4-methylthiazol-5-formic acid ethyl ester is dissolved in the mixing acid reaction solvent, adds urotropine, reacted 1-36 hour, and obtained the compound of structure I I.
2. according to the method for claim 1, it is characterized in that described mixing acid reaction solvent is selected from: the mixed solvent of polyphosphoric acid and concentrated hydrochloric acid, polyphosphoric acid and the vitriol oil, polyphosphoric acid and nitric acid or polyphosphoric acid and trifluoroacetic acid.
3. according to the method for claim 1, it is characterized in that the amount that adds urotropine is a substrate 2-[4-hydroxy phenyl]-0.5-10 of 4-methylthiazol-5-formic acid ethyl ester molar weight is doubly.
4. according to the method for claim 1, it is characterized in that temperature of reaction 40-120 ℃.
5. according to the method for claim 1, it is characterized in that the add-on of mixing acid is a substrate 2-[4-hydroxy phenyl]-5-10 of 4-methylthiazol-5-formic acid ethyl ester charging capacity is doubly.
6. according to the method for claim 2, it is characterized in that polyphosphoric acid and other sour volume ratio are 4 in the mixing acid: 1-1: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010534098A CN102002017B (en) | 2010-11-02 | 2010-11-02 | Method for preparing febuxostat intermediate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010534098A CN102002017B (en) | 2010-11-02 | 2010-11-02 | Method for preparing febuxostat intermediate |
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| Publication Number | Publication Date |
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| CN102002017A true CN102002017A (en) | 2011-04-06 |
| CN102002017B CN102002017B (en) | 2012-09-26 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910695A (en) * | 2014-04-24 | 2014-07-09 | 重庆科瑞制药(集团)有限公司 | Synthetic method of febuxostat |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1045733A (en) * | 1996-08-01 | 1998-02-17 | Teijin Ltd | Method for producing 2- (4-alkoxy-3-cyanophenyl) thiazole derivative |
| CN101412699A (en) * | 2007-10-19 | 2009-04-22 | 上海医药工业研究院 | Preparation of 2-(3-carboxaldehyde-4-hydroxy phenyl)-4-methyl-5-thiazole ethyl formate |
| CN102086169A (en) * | 2009-12-04 | 2011-06-08 | 重庆医药工业研究院有限责任公司 | Preparation method of intermediates of Febuxostat |
-
2010
- 2010-11-02 CN CN201010534098A patent/CN102002017B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1045733A (en) * | 1996-08-01 | 1998-02-17 | Teijin Ltd | Method for producing 2- (4-alkoxy-3-cyanophenyl) thiazole derivative |
| CN101412699A (en) * | 2007-10-19 | 2009-04-22 | 上海医药工业研究院 | Preparation of 2-(3-carboxaldehyde-4-hydroxy phenyl)-4-methyl-5-thiazole ethyl formate |
| CN102086169A (en) * | 2009-12-04 | 2011-06-08 | 重庆医药工业研究院有限责任公司 | Preparation method of intermediates of Febuxostat |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910695A (en) * | 2014-04-24 | 2014-07-09 | 重庆科瑞制药(集团)有限公司 | Synthetic method of febuxostat |
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| Publication number | Publication date |
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| CN102002017B (en) | 2012-09-26 |
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