CN105399732A - Preparation method of topiroxostat - Google Patents
Preparation method of topiroxostat Download PDFInfo
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- CN105399732A CN105399732A CN201510886955.6A CN201510886955A CN105399732A CN 105399732 A CN105399732 A CN 105399732A CN 201510886955 A CN201510886955 A CN 201510886955A CN 105399732 A CN105399732 A CN 105399732A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
The invention discloses a preparation method of topiroxostat, and belongs to the technical field of medicine synthesis and organic compound synthesis and preparation. N2-Boc-isonicotinic acid hydrazide-(compound 1)oxide and 4-cyanopyridine(compound 2) serve as the initial raw materials, and a compound 1 is subjected to cyanation, protect base removal and salifying to form a compound 4; the compound 4 and a compound 2 are subjected to a ring closing reaction and salifying to form a compound 5, and the compound 5 is subjected to salifying and refining, impurity removing achieved through activated carbon, alkali regulating and drying to form a high-purity product. By means of the method, the defects of the prior art are overcome, and the method has the advantages that raw materials are stable and easy to obtain, reaction conditions are mild, the technological process is simple, convenient and easy to control and the yield is high; the method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of holder his preparation method of department, belong to pharmaceutical synthesis and organic compound synthesis preparing technical field.
Background technology
Holder takes charge of him, chinesization formal name used at school: 4-[5-(pyridin-4-yl)-1
h-1,2,4-triazole-3-base] pyridine-2-formonitrile HCN, structural formula is as follows:
Molecular formula: C
13h
8n
6
Molecular weight: 248.24
It is the XOR inhibitor developed by Fuji of Amada Co., Ltd. pharmaceutical research that holder takes charge of him, is used for the treatment of gout, hyperuricemia, goes on the market in June, 2013 in Japan, and this product is not in China's registration list marketing at present.
Gout is the crystal dependency joint disease caused by monosodium urate salt sedimentation, directly related with the hyperuricemia caused by purine metabolic disturbance and (or) underexcretion, refer in particular to acute characteristic sacroiliitis and chronic gout stone disease, mainly comprising acute attack sacroiliitis, uratoma formation, tophaceous chronic arthritis, urate nephropathy and uric acid lithangiuria, can there is joint deformity and renal insufficiency in severe one.Gout often accompanies the performances such as abdominal obesity, hyperlipidaemia, hypertension, diabetes B and cardiovascular diseases.The final therapeutic goal of gout and hyperuricemia is improve the hyperuricemia/gout prognosis with cardiovascular disorder high risk, narrow sense therapeutic goal is suppress the urate deposition in body tissue, the many symptoms (as urarthritis etc.) avoiding urate deposition to cause.
It is by the non-purine type selectivity xanthine oxidoreductase inhibitors of a kind of selectivity of Japanese fuji medicine Co., Ltd. research and development, reversible inhibition xanthine oxidoreductase enzyme, reduction serum uric acid value that holder takes charge of him.Holder takes charge of him to the competitive inhibition of xanthine oxidoreductase enzyme, thus suppresses uricogenesis.Inhibition is not had to other pyrimidine purine metabolic enzymes, selectivity inhibition is shown as to xanthine oxidoreductase enzyme.Holder takes charge of him all has significant restraining effect to the XOR of oxidized form and reduced form, and thus its effect reducing uric acid is more powerful, lasting, and therefore this product can be used for the chronic hyperuricemia for the treatment of gout.Have two advantages compared with Zyloric: 1) Zyloric only has restraining effect to the XOR of reduced form, and he all has significant restraining effect to the XOR of oxidized form and reduced form to hold in the palm a department, thus its effect reducing uric acid is more powerful, lasting; 2) because Zyloric is purine analogue, inevitably cause the impact relating to purine and other enzymic activitys of pyridine metabolism, therefore in allopurinol treatment, need to repeat heavy dose of administration to maintain higher levels of drugs.Also the serious even fatal untoward reaction caused by drug accumulation is brought thus.And he is non-purines XOR inhibitor to hold in the palm a department, therefore there is better security.
Mention a kind of holder his synthetic method of department in patent EP1471056A1, but synthetic route is longer; The synthetic method route related in " Bioorganic & MedicinalChemistryLetters19 (2009) 6225-6229 " is shorter, but the starting raw material of synthesis is more difficult to get, and is difficult to suitability for industrialized production; His synthetic method working condition of a holder department in " TetrahedronLetters49 (2008) 4369-4371 " is harsh, need High Temperature High Pressure, and starting raw material is rare, is difficult to suitability for industrialized production equally; Patent CN104230891A and CN104151297A uses copper catalysis.
In sum, existing method all has some limitations, and make to yield poorly, purity is low, and the cycle is long.A kind of technique of current urgent need is simple, purity is high, be applicable to the synthetic method of industrial amplification production.
Summary of the invention
The object of the invention is to make up prior art deficiency, provide a kind of synthesis technique simple, stable yield and product purity is high, be suitable for his synthetic method of a holder department of suitability for industrialized production.
For achieving the above object, the present invention is with N
2-Boc-isoniazid-1 oxygen (compound 1) and 4-cyanopyridine (compound 2) are starting raw material, compound 1 through cyanalation, deprotection base, salify obtains compound 4; Compound 4 and compound 2 ring closure reaction, salify obtains compound 5, passes through into salt refining, remove impurity with active carbon, alkali tune, dry, obtains high purity finished product.
The compound 1 that the present invention relates to is N
2-Boc-isoniazid-1 oxygen; Compound 2 is 4-cyanopyridine; Compound 3 is N
2-Boc-2-cyano-isonicotinic acid hydrazine; Compound 4 is 2-cyano group isoniazid tosilate; Compound 5 is 4-[5-(4-pyridyl)-1H-1,2,4-triazole-3-base] pyridine-2-cyano group tosilate.
Concrete preparation process of the present invention is:
1, under room temperature, compound 1 and dimethylaminoethyl chloride are added in acetonitrile, under nitrogen protection, add trimethylsilyl cyanide; Be warming up to 60 DEG C of reaction 3h; Question response is complete, reaction solution is down to room temperature and falls back middle stirring and crystallizing, and adjust pH is to 6-8; Treat that crystallization is complete, filter, filter cake washes with water, and solid obtains off-white powder after drying, and is compound 3.
2, compound 3 and tosic acid are added in ethyl acetate react 24h; TLC detects, and having reacted rear solution is white suspended matter, and by solid filtering, filter cake ethyl acetate is washed, and dry white solid is compound 4.
3, compound 2 is added in ethanol dissolve, then sodium methylate is added, room temperature reaction 2h; Then compound 4 added and be warming up to reflux temperature reaction 20h; Be down to room temperature, be poured into water by solution, stirring and crystallizing, filter, filter cake washes with water, drains to obtain flaxen wet product; Wet product is added methyl alcohol together with tosic acid: water: in the mixed solvent of ethyl acetate (5:1:1), stirring at room temperature, end reaction solution is white suspension, filters to obtain faint yellow solid; Reduced vacuum 80 DEG C of dryings; Faint yellow solid is added methyl alcohol: in the mixed solvent of water (6:1), nitrogen protection, temperature rising reflux reacts, until solid molten clear after, add gac back flow reaction, heat filtering, be cooled to room temperature crystallization, dry white solid is compound 5.
In the mixed solvent of the acetone/water (volume ratio is 1:1) 4, compound 5 and sodium carbonate added, stirring at room temperature, filter, the solids washed with water obtained, drying, obtain off-white color solid, for his bulk drug is taken charge of in holder.
The chemical equation that the present invention relates to is:
Compared with prior art, method choice is reasonable, and operational path is simple in the present invention, and his high purity 99.9% is taken charge of in separating obtained holder, overcomes prior art problem, is applicable to industrialized production.
Specific embodiment
Below in conjunction with embodiment, the present invention is elaborated further.
Embodiment:
Identical with summary of the invention of the technique main procedure that the present embodiment relates to, wherein the specific embodiment of compound 3, compound 5 is as follows:
1, the preparation of compound 3:
Under room temperature, 3.1Kg compound 1 and 3.95Kg dimethylaminoethyl chloride are added in the acetonitrile of 20L, under nitrogen protection, adds 1.822Kg trimethylsilyl cyanide; Be warming up to 60 DEG C of reaction 3h; Question response is complete, pour stirring and crystallizing 3h in 200L water into, and adjust pH is to 6-8 after reaction solution being down to room temperature; Treat that crystallization is complete, filter, filter cake 500mL water washing, obtain off-white powder 1.55Kg after 45 DEG C of dryings, be compound 3, productive rate is 48%.
2, the preparation of compound 3:
Under room temperature, 4Kg compound 1 and 5.1Kg dimethylaminoethyl chloride are added in the acetonitrile of 20L, under nitrogen protection, adds 2.35Kg trimethylsilyl cyanide; Be warming up to 60 DEG C of reaction 3h; Question response is complete, pour stirring and crystallizing 3h in 200L water into, and adjust pH is to 6-8 after reaction solution being down to room temperature; Treat that crystallization is complete, filter, filter cake 500mL water washing, obtain off-white powder 1.8Kg after 45 DEG C of dryings, be compound 3, productive rate is 45%.
3, the preparation of compound 5:
572g compound 2 is added in 25.0L ethanol and dissolves, then 405g sodium methylate is added, room temperature reaction 2h; Then 2100g compound 4 added and be warming up to reflux temperature reaction 20h; Be down to room temperature, poured into by solution in 90L, stirring and crystallizing 4h, filter, filter cake use water 1.0L washs, and drains to obtain flaxen wet product; Wet product is added 12.0L methyl alcohol together with 1290g tosic acid: water: in the mixed solvent of ethyl acetate (5:1:1), stirring at room temperature 24h, end reaction solution is white suspension, filters to obtain faint yellow solid; Reduced vacuum 80 DEG C of dry 24h, obtain 1290g faint yellow solid; Faint yellow solid is added 20.0L methyl alcohol: in the mixed solvent of water (6:1); nitrogen protection; temperature rising reflux reacts; until solid molten clear after, add 400g gac back flow reaction 2.0h, heat filtering; be cooled to room temperature crystallization; 45 DEG C of forced air drying 24.0h obtain white solid 880g, and be compound 5, productive rate is 42%.
4, the preparation of compound 5:
858g compound 2 is added in 25.0L ethanol and dissolves, then 608g sodium methylate is added, room temperature reaction 2h; Then 3150g compound 4 added and be warming up to reflux temperature reaction 20h; Be down to room temperature, poured into by solution in 90L, stirring and crystallizing 4h, filter, filter cake use water 2.0L washs, and drains to obtain flaxen wet product; Wet product is added 18.0L methyl alcohol together with 1935g tosic acid: water: in the mixed solvent of ethyl acetate (5:1:1), stirring at room temperature 24h, end reaction solution is white suspension, filters to obtain faint yellow solid; Reduced vacuum 80 DEG C of dry 24h, obtain 1935g faint yellow solid; Faint yellow solid is added 30.0L methyl alcohol: in the mixed solvent of water (6:1); nitrogen protection; temperature rising reflux reacts; until solid molten clear after, add 500g gac back flow reaction 2.0h, heat filtering; be cooled to room temperature crystallization; 45 DEG C of forced air drying 24.0h obtain white solid 1190g, and be compound 5, productive rate is 38%.
His sample survey result is taken charge of in holder
Claims (2)
1. holder his preparation method of department, is characterized in that technological process is:
Under a, room temperature, compound 1 and dimethylaminoethyl chloride are added in acetonitrile, under nitrogen protection, add trimethylsilyl cyanide; Be warming up to 60 DEG C of reaction 3h; Question response is complete, reaction solution is down to room temperature and falls back middle stirring and crystallizing, and adjust pH is to 6-8; Treat that crystallization is complete, filter, filter cake washes with water, and solid obtains off-white powder after drying, and is compound 3;
B, compound 3 and tosic acid added in ethyl acetate and reacts 24h; TLC detects, and having reacted rear solution is white suspended matter, and by solid filtering, filter cake ethyl acetate is washed, and dry white solid is compound 4;
C, compound 2 added in ethanol and dissolves, then sodium methylate is added, room temperature reaction 2h; Then compound 4 added and be warming up to reflux temperature reaction 20h; Be down to room temperature, be poured into water by solution, stirring and crystallizing, filter, filter cake washes with water, drains to obtain flaxen wet product; Wet product is added methyl alcohol together with tosic acid: water: in the mixed solvent of ethyl acetate (5:1:1), stirring at room temperature, end reaction solution is white suspension, filters to obtain faint yellow solid; Reduced vacuum 80 DEG C of dryings; Faint yellow solid is added methyl alcohol: in the mixed solvent of water (6:1), nitrogen protection, temperature rising reflux reacts, until solid molten clear after, add gac back flow reaction, heat filtering, be cooled to room temperature crystallization, dry white solid is compound 5;
In d, the mixed solvent of acetone/water (volume ratio is 1:1) that compound 5 and sodium carbonate added, stirring at room temperature, filter, the solids washed with water obtained, drying, obtain off-white color solid, is his bulk drug of a holder department.
2. holder according to claim 1 his preparation method of department, is characterized in that the chemical equation related to is:
。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510886955.6A CN105399732A (en) | 2015-12-07 | 2015-12-07 | Preparation method of topiroxostat |
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|---|---|---|---|
| CN201510886955.6A CN105399732A (en) | 2015-12-07 | 2015-12-07 | Preparation method of topiroxostat |
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| CN105399732A true CN105399732A (en) | 2016-03-16 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632265A (en) * | 2016-12-15 | 2017-05-10 | 北京满格医药科技有限公司 | Preparation method of high-purity topiroxostat |
| CN115572747A (en) * | 2022-09-23 | 2023-01-06 | 湖南一格制药有限公司 | Preparation method of topiroxostat |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003064410A1 (en) * | 2002-01-28 | 2003-08-07 | Fuji Yakuhin Co., Ltd. | Novel 1,2,4-triazole compound |
| CN104151297A (en) * | 2014-08-27 | 2014-11-19 | 庄妍 | Preparation of 4-[5-(pyridine-4-yl)-1H-[1,2,4]triazole-3-yl]pyridine-2-formonitrile |
-
2015
- 2015-12-07 CN CN201510886955.6A patent/CN105399732A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003064410A1 (en) * | 2002-01-28 | 2003-08-07 | Fuji Yakuhin Co., Ltd. | Novel 1,2,4-triazole compound |
| CN104151297A (en) * | 2014-08-27 | 2014-11-19 | 庄妍 | Preparation of 4-[5-(pyridine-4-yl)-1H-[1,2,4]triazole-3-yl]pyridine-2-formonitrile |
Non-Patent Citations (2)
| Title |
|---|
| 崔福德: "《药剂学（第二版）》", 31 January 2011 * |
| 王福来: "《有机化学实验（第1版）》", 28 February 2001 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632265A (en) * | 2016-12-15 | 2017-05-10 | 北京满格医药科技有限公司 | Preparation method of high-purity topiroxostat |
| CN115572747A (en) * | 2022-09-23 | 2023-01-06 | 湖南一格制药有限公司 | Preparation method of topiroxostat |
| CN115572747B (en) * | 2022-09-23 | 2023-05-05 | 湖南一格制药有限公司 | Topiroxostat preparation method |
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