CN108250183A - A kind of preparation method of the Topiroxostat of high-purity - Google Patents
A kind of preparation method of the Topiroxostat of high-purity Download PDFInfo
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- CN108250183A CN108250183A CN201611240942.2A CN201611240942A CN108250183A CN 108250183 A CN108250183 A CN 108250183A CN 201611240942 A CN201611240942 A CN 201611240942A CN 108250183 A CN108250183 A CN 108250183A
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- topiroxostat
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/10—Process efficiency
Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a kind of effective removal Topiroxostat hydrolysis amide impurities, purity can reach 99.9% after refining, and amide impurities content is less than 0.05% preparation method.The preparation method be dissipated with Topiroxostat crude product through moisture, the extraction of alkali soluble solution, organic solvent, acid crystal, water mashing, filtration drying and etc. the Topiroxostat of high-purity is prepared.Hydrolysis amide impurities height is prepared present invention efficiently solves Topiroxostat and purity is low waits technical barriers, and there are simple for process, favorable reproducibility, at low cost, environmental protection and energy saving, so as to have higher industrial value and significant economic results in society.Preparation method provided by the invention is used to prepare the Topiroxostat of high-purity.
Description
Technical field
The invention belongs to medical manufacture fields, are related to a kind of preparation method of the Topiroxostat of high-purity, and in particular to one
The effective removal Topiroxostat hydrolysis amide impurities of kind, refined rear purity can reach 99.9%, and amide impurities content is less than
0.05% preparation method.
Background technology
Topiroxostat (Topiroxostat) by Japanese fuji pharmaceutical development, be it is novel it is highly selective, invertibity is yellow fast
Purine oxidase inhibitor.Topiroxostat is on June 28th, 2013 in Japan's approval listing for gout and hyperuricemia, commodity
Name：Topiroxostat has the XOR of oxidized form and reduced form significant inhibiting effect, thus it reduces blood
The effect of uric acid is more powerful, lasting, and has no adverse effects to cardiovascular system, has better safety, clinical efficacy performance
Significantly, serum uric acid level can be greatly lowered, tolerance is good and adverse reaction is small, has in treatment hyperuricemia and gout
Very big application prospect, the kind not yet list at home.
Structural formula is：
Topiroxostat synthesis route is specific as follows：
Chinese patent CN1561340 reports following synthetic route：
Begin using isonicotinic acid nitrogen oxides as raw material is played, under the catalysis of 1- carbethoxyl group -2- ethyoxyl -1,2- dihydroquinoline
Oxidation generation iso methyl nicotinate nitrogen oxides, iso methyl nicotinate nitrogen oxides are anti-with third level natural division alkane under the catalysis of triethylamine
It should obtain 2- cyano iso methyl nicotinates, 2- cyano iso methyl nicotinate and hydrazine hydrate condensation generation 2- cyano isonicotinic acid formylhydrazines, 2-
Cyano isonicotinic acid formylhydrazine obtains target compound Topiroxostat under the catalysis of sodium methoxide with the condensation of 4- cyanopyridines, cyclization,
Reaction equation is as follows：
Chinese patent CN1826355, which is reported, following is collectively referred to as method：First using 4- cyanopyridines nitrogen oxides and different cigarette
Sour formylhydrazine is condensed to yield 3- (4- pyridyl groups) -5- (1- oxygen -4- pyridyl groups) -1,2,4- triazoles, then amido protecting is increased it
It is fat-soluble, third level natural division alkane is finally used to carry out cyaniding for cyanating reagent, Topiroxostat is prepared.
R can be：Benzyloxymethyl, methoxy, metoxyethoxymethyl, trimethylsilylethoxymethyl, hexichol
Ylmethyl, to methoxy-benzyl
Patent WO2014017516 is reported using 4- cyanopyridines nitrogen oxides as starting material, first with isonicotinic acid hydrazide
Condensation, obtained product carry out cyaniding with Cymag, and finally cyclization obtains Topiroxostat under the catalysis of phosphoric acid, and reaction equation is such as
Under：
No matter using that route, even if with the presence of micro water under alkaline reaction reaction condition, the cyanogen on pyridine ring
Base can also be hydrolyzed into amide, this impurity is more difficult to be removed, and can influence the purity of finished product, the Topiroxostat side of refining of open report
Method is mainly seen in the method reported in patent CN02819276.1.But this method is poor to the removal effect of impurity amide, and
And the yield of this method products obtained therefrom is low.It is therefore desirable to find a kind of preparation method of the Topiroxostat of high-purity.
Invention content：
In order to solve the above technical problem, the present invention provides a kind of preparation methods of the Topiroxostat of high-purity：
1) Topiroxostat is added in the water of 3-6 times of quality, stirring is allowed to be uniformly dispersed；
2) reaction solution is cooled to 10-15 DEG C；
3) alkali is added in into reaction solution, stirring is completely dissolved Topiroxostat：
Alkali used is inorganic base, preferred potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide etc..
The equivalent of alkali used be 0.4-1.0 times of mass equivalent, preferably 0.5-0.8 times of mass equivalent.
4) organic solvent aqueous phase extracted is added in into aqueous solution, water phase is collected in liquid separation：
Solvent for use includes dichloromethane, chloroform, ethyl acetate, n-hexane, hexamethylene, petroleum ether or toluene etc., preferably
Dichloromethane and toluene, aqueous phase extracted is primary respectively；
2-8 times mass volume ratio of the dosage of extractant for Topiroxostat, preferably 3-5 times of mass volume ratio.
5) hydrochloric acid of 3-6mol/L is added in into water phase, lower adjusting pH=6-8, preferably pH=7-8 are stirred, during dropwise addition
10-15 DEG C of temperature control.
6) after solid is precipitated, temperature control stirring 30min, 10-15 DEG C of temperature control.
7) obtained solid being added to the water and be beaten 2 times, the dosage of water is 10-50 times of mass volume ratio of Topiroxostat,
It is preferred that 15-25 times of mass volume ratio.
8) solid is added to vacuum drying chamber after filtering, and 85 DEG C are dried under reduced pressure the Topiroxostat fine work for for 24 hours, obtaining I crystal.
The present invention provides a kind of preparation method of the Topiroxostat of high-purity, it is advantageous that：
Topiroxostat hydrolysis amide impurities can be effectively removed, refined rear purity can reach 99.9%, amide impurities
Content is less than 0.05%.It is I crystal by the crystal form of Topiroxostat that the present invention prepares, the solubility of I crystal is higher, is conducive to
Prepare the higher solid orally ingestible of bioavilability.
Description of the drawings
The hydrogen nuclear magnetic resonance spectrogram of Fig. 1 Topiroxostats
The mass spectrogram of Fig. 2 Topiroxostats
The related substance liquid phase figure of Fig. 3 Topiroxostats
The XRD powder diagrams of Fig. 4 Topiroxostats
Specific embodiment：
Embodiment 1
Topiroxostat crude product 100g is added in the aqueous solution 400ml containing 40g potassium carbonate, 10-15 DEG C is cooled to, stirs
It mixes to solution and clarifies, filtering obtains clear solution.
Dichloromethane 100ml, extraction are added in into solution, water phase is gone in liquid separation, adds in toluene 100ml thereto, is extracted,
Water phase is collected in liquid separation.
The hydrochloric acid 96ml of 6mol/L is added in into water phase, as the addition of acid is slowly precipitated solid, mixing control pH=8,
10-15 DEG C of temperature control during dropwise addition stirs 30min, filtering
Obtained solid is added in 1000mL water and is beaten 2h, is filtered.It is repeated once.
Last obtained solid is added to vacuum drying chamber, 85 DEG C are dried under reduced pressure (drier P for 24 hours2O5) product 69g is obtained, it receives
Rate 69%.Final products purity >=99.0%, crystal form I.
Embodiment 2
Topiroxostat crude product 100g is added in the aqueous solution 400ml containing 100g sodium carbonate, cools to 10-15 DEG C,
Stirring to solution is clarified, and filtering obtains clear solution.
Dichloromethane 400ml, extraction are added in into solution, water phase is gone in liquid separation, adds in toluene 400ml thereto, is extracted,
Water phase is collected in liquid separation.
The hydrochloric acid 96ml of 6mol/L is added in into water phase, as solid is slowly precipitated in the addition of acid, stirring is surveyed pH=6, stirred
30min is mixed, is filtered.
Obtained solid is added in 5000mL water and is beaten 2h, is filtered.It is repeated once.
Last obtained solid is added to vacuum drying chamber, 85 DEG C are dried under reduced pressure (drier P for 24 hours2O5) product 66g is obtained, it receives
Rate 66%.Final products purity >=99.0%, crystal form I.
Embodiment 3
Topiroxostat crude product 100g is added in the aqueous solution 400ml containing 50g sodium hydroxides, cools to 10-15 DEG C,
Stirring to solution is clarified, and filtering obtains clear solution.
Dichloromethane 150ml, extraction are added in into solution, water phase is gone in liquid separation, adds in toluene 150ml thereto, is extracted,
Water phase is collected in liquid separation.
The hydrochloric acid 41ml of 6mol/L is added in into water phase, as solid is slowly precipitated in the addition of acid, pH=6.5 is surveyed in stirring,
Stir 30min, filtering.
Obtained solid is added in 1500mL water and is beaten 2h, is filtered.It is repeated once.
Last obtained solid is added to vacuum drying chamber, 85 DEG C are dried under reduced pressure (drier P for 24 hours2O5) product 80g is obtained, it receives
Rate 80%.Final products purity >=99.9%, crystal form I.
Embodiment 4
Topiroxostat crude product 100g is added to the aqueous solution 400ml containing 80g potassium hydroxide, 10-15 DEG C is cooled to, stirs
It mixes to solution and clarifies, filtering obtains clear solution.
Dichloromethane 250ml, extraction are added in into solution, water phase is gone in liquid separation, adds in toluene 250ml thereto, is extracted,
Water phase is collected in liquid separation.
The hydrochloric acid 40ml of 6mol/L is added in into water phase, as solid is slowly precipitated in the addition of acid, pH=7.5 is surveyed in stirring,
Stir 30min, filtering.
Obtained solid is added in 2500mL water and is beaten 2h, is filtered.It repeats to be beaten primary.
Last obtained solid is added to vacuum drying chamber, 85 DEG C are dried under reduced pressure (drier P for 24 hours2O5) product 78g is obtained, it receives
Rate 78%.Final products purity >=99.9%, crystal form I.
Claims (5)
1. a kind of preparation method of the Topiroxostat of high-purity, it is characterised in that include the following steps：
1) Topiroxostat is added in the water of 3-6 times of quality, stirring is allowed to be uniformly dispersed；
2) reaction solution is cooled to 10-15 DEG C；
3) alkali is added in into reaction solution, stirring is completely dissolved Topiroxostat；
4) organic solvent aqueous phase extracted is added in into aqueous solution, water phase is collected in liquid separation；
5) hydrochloric acid of 3-6mol/L is added in into water phase, stirs lower adjusting pH, 10-15 DEG C of temperature control during dropwise addition；
6) after solid is precipitated, temperature control stirring 30min, 10-15 DEG C of temperature control；
7) obtained solid is added to the water and be beaten 2 times；
8) solid is added to vacuum drying chamber after filtering, and 85 DEG C are dried under reduced pressure the Topiroxostat fine work for for 24 hours, obtaining I crystal.
2. according to the preparation method in claim 1, it is characterised in that alkali used is inorganic base, preferably potassium carbonate, sodium carbonate,
Potassium hydroxide or sodium hydroxide etc., the equivalent of alkali used are 0.4-1.0 times of mass equivalent, preferably 0.5-0.8 times of mass equivalent.
3. according to the preparation method in claim 1, it is characterised in that organic solvent used includes dichloromethane, chloroform, acetic acid
Ethyl ester, n-hexane, hexamethylene, petroleum ether or toluene etc., preferably dichloromethane and toluene, aqueous phase extracted is primary respectively；It extracts molten
2-8 times mass volume ratio of the dosage of agent for Topiroxostat, preferably 3-5 times of mass volume ratio.
4. according to the preparation method in claim 1, it is characterised in that hydrochloric acid is added in into water phase, pH=6-8 is lowered in stirring, excellent
Select pH=7-8.
5. according to the preparation method in claim 1, it is characterised in that the dosage for being beaten water is 10-50 times of quality of Topiroxostat
Volume ratio, preferably 15-25 times of mass volume ratio.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611240942.2A CN108250183A (en) | 2016-12-29 | 2016-12-29 | A kind of preparation method of the Topiroxostat of high-purity |
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| CN201611240942.2A CN108250183A (en) | 2016-12-29 | 2016-12-29 | A kind of preparation method of the Topiroxostat of high-purity |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110372668A (en) * | 2019-09-04 | 2019-10-25 | 浙江天顺药业有限公司 | A kind of preparation method of benzene sulfonic acid 4-[(S)-(4-chlorophenyl)-2-pyridinylmethoxy |
| CN113121503A (en) * | 2021-03-31 | 2021-07-16 | 翟洪 | Topiroxostat synthesis method |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1561340A (en) * | 2002-01-28 | 2005-01-05 | 株式会社富士药品 | Novel 1,2,4-triazole compound |
| WO2014017515A1 (en) * | 2012-07-25 | 2014-01-30 | 株式会社富士薬品 | 4-[5-(pyridine-4-yl)-1h-1,2,4-triazole-3-yl]pyridine-2-carbonitrile crystalline polymorph and production method therefor |
| CN104961730A (en) * | 2015-06-18 | 2015-10-07 | 山东金城医药化工股份有限公司 | Novel topiroxostat crystal form and method for preparing same |
| CN105315260A (en) * | 2014-07-29 | 2016-02-10 | 北京海步医药科技股份有限公司 | Topiroxostat monohydrate crystal form and preparation method thereof |
| WO2016134854A1 (en) * | 2015-02-25 | 2016-09-01 | Pharmathen S.A. | Methods for the preparation of topiroxostat and intermediates thereof |
-
2016
- 2016-12-29 CN CN201611240942.2A patent/CN108250183A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1561340A (en) * | 2002-01-28 | 2005-01-05 | 株式会社富士药品 | Novel 1,2,4-triazole compound |
| WO2014017515A1 (en) * | 2012-07-25 | 2014-01-30 | 株式会社富士薬品 | 4-[5-(pyridine-4-yl)-1h-1,2,4-triazole-3-yl]pyridine-2-carbonitrile crystalline polymorph and production method therefor |
| CN105315260A (en) * | 2014-07-29 | 2016-02-10 | 北京海步医药科技股份有限公司 | Topiroxostat monohydrate crystal form and preparation method thereof |
| WO2016134854A1 (en) * | 2015-02-25 | 2016-09-01 | Pharmathen S.A. | Methods for the preparation of topiroxostat and intermediates thereof |
| CN104961730A (en) * | 2015-06-18 | 2015-10-07 | 山东金城医药化工股份有限公司 | Novel topiroxostat crystal form and method for preparing same |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110372668A (en) * | 2019-09-04 | 2019-10-25 | 浙江天顺药业有限公司 | A kind of preparation method of benzene sulfonic acid 4-[(S)-(4-chlorophenyl)-2-pyridinylmethoxy |
| CN113121503A (en) * | 2021-03-31 | 2021-07-16 | 翟洪 | Topiroxostat synthesis method |
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