CN105218464B - The synthesis technique of Acipimox - Google Patents
The synthesis technique of Acipimox Download PDFInfo
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- CN105218464B CN105218464B CN201410226009.4A CN201410226009A CN105218464B CN 105218464 B CN105218464 B CN 105218464B CN 201410226009 A CN201410226009 A CN 201410226009A CN 105218464 B CN105218464 B CN 105218464B
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Abstract
The invention provides a kind of synthesis technique of Acipimox, it includes：1) in aqueous, under catalyst action, the carboxylic acid of 5 methylpyrazine 2 is made to be reacted with hydrogen peroxide；2) auxiliary agent is added in the solution obtained to step 1), wherein, the one kind of described auxiliary agent in sulphite, bisulfites, oxalic acid and oxalates；3) activated carbon is added in the solution obtained to step 2), filtered；And 4) solution obtained step 3) carries out decrease temperature crystalline, dries, so as to obtain Acipimox finished product.The synthesis technique of the present invention can efficiently reduce crystallisation times, avoid recrystallization operation, improve yield, reduce production cost.
Description
Technical field
The invention belongs to pharmaceutical field, in particular to a kind of synthesis technique of Acipimox.
Background technology
Acipimox (Acipimox) is in exploitation listing in 1985 by Italian Farmitalia Carol Erba companies
A kind of hypolipidemic, its can suppress adipose tissue release free fatty, reduce blood in VLDL and low-density
Lipoprotein, so that triglyceride and cholesterol concentration decline in blood, HDL increase is may additionally facilitate, therefore mainly
For treating II A, II R, III, IV and V-type hyperlipoprotememia.It has effect for reducing fat strong, and adverse reaction is few, tolerance
Well, suitable for long-term prescription the features such as.In addition Acipimox can also promote the glucose of adult-onset diabetes patient
Metabolism, it is relevant with reducing blood glucose；And it can effectively reduce the danger of coronary heart disease.It is not combined with plasma protein in vivo, not by
Metabolism, is excreted in prototype, so will not increase the danger of blood uric acid and cholelith.Therefore, Acipimox is treatment hyperlipemia
Disease, especially with the more satisfied medicine of diabetes, gout, coronary heart disease.
In the prior art, the synthesis technique of Acipimox can be found in (such as) following scientific and technical literature：Chinese Medicine industry
Magazine Chinese Journal of Pharmaceuticals 2009,40 (10), wherein using pyroracemic aldehyde and adjacent benzene two
Amine elder generation synthesizing methyl quinoxaline, then potassium permanganate oxidation, sulfuric acid catalysis decarboxylation obtain 5- methyl -2- pyrazine carboxylic acids, then
Acipimox crude product, obtained Acipimox crude product are obtained with hydrogen peroxide oxidation under the catalysis of sodium tungstate, then is taken off through activated carbon
Color, recrystallization form Acipimox finished product.But above-mentioned technique of the prior art do not only exist technique it is extremely unstable lack
Point, and generated crude product impurity content height, it is necessary to carry out recrystallization purifying after, can obtain meeting States Pharmacopoeia specifications purity
Acipimox finished product.But at present in actual production process, because the operating condition requirement of recrystallization is strict, technique is cumbersome,
And time-consuming, production efficiency is greatly reduced, therefore in actual industrial production there is the defects of obvious in above-mentioned technique, it is applied
It is limited by very large.
The content of the invention
To solve above-mentioned problems of the prior art, the invention provides a kind of synthesis technique of Acipimox.
Specifically, the present invention provides：
(1) a kind of synthesis technique of Acipimox, it includes：
1) in aqueous, under catalyst action, make 5-Methylpyrazine-2-carboxylic acid that such as Formula Il occur with hydrogen peroxide
Shown reaction,
2) auxiliary agent is added in the solution obtained to step 1), wherein, described auxiliary agent is selected from sulphite, bisulfite
One kind in salt, oxalic acid and oxalates；
3) activated carbon is added in the solution obtained to step 2), filtered；And
4) solution for obtaining step 3) carries out decrease temperature crystalline, dries, so as to obtain Acipimox finished product.
(2) synthesis technique according to (1), wherein, in step 1), described hydrogen peroxide and described 5- methyl
The mol ratio of pyrazine -2- carboxylic acids is (1.0-1.8): 1, be preferably (1.1-1.6): 1.
(3) synthesis technique according to (1), wherein, the catalyst described in step 1) is sodium tungstate；Described sodium tungstate
Mol ratio with described 5-Methylpyrazine-2-carboxylic acid is preferably (0.01-0.1): 1.
(4) synthesis technique according to (3), wherein, the reaction temperature of the step 1) reaction is 40-90 DEG C, preferably
For 50-80 DEG C.
(5) synthesis technique according to (1), wherein, the reaction time of the step 1) reaction is 1-12 hours, preferably
For 2-8 hours.
(6) synthesis technique according to (1), wherein, the sulphite described in step 2) is inorganic sulfite, preferably
For sodium sulfite or potassium sulfite.
(7) synthesis technique according to (1), wherein, the bisulfites described in step 2) is inorganic bisulfites,
Preferably sodium hydrogensulfite or potassium bisulfite.
(8) synthesis technique according to (1), wherein, the oxalates described in step 2) is inorganic oxalates, is preferably grass
Sour sodium or potassium oxalate.
(9) synthesis technique according to (1), wherein, auxiliary agent and described 5- methylpyrazine -2- carboxylics described in step 2)
The mol ratio of acid is not higher than 0.8: 1.
(10) synthesis technique according to (1), wherein, in step 2), solution and described that step 1) obtains help
The reaction time of agent is 0.5-3 hours.
(11) synthesis technique according to (1), wherein, in step 4), the solution that step 3) is obtained cools to -5
~20 DEG C, crystallize, dry, so as to obtain Acipimox finished product.
The present invention has the advantages that compared with prior art：
The present invention provides a kind of new synthesis process of Acipimox, wherein particularly by spy of the reaction mother liquor by the present invention
Fixed auxiliary agent is handled and then added activated carbon and carries out decolorization, so that it may obtains qualified finished product by decrease temperature crystalline.
Above-mentioned steps can efficiently reduce crystallisation times, avoid recrystallization operation, can be from reaction mother liquor by primary crystallization
The Acipimox finished product for meeting States Pharmacopoeia specifications purity is obtained, therefore enormously simplify production technology, shortens post-processing step
Time, and yield is improved, reduce production cost.Completed in addition, above-mentioned technique can also once stop processing in reactor,
Therefore it is simple and easy to do, particularly suitable in industrialized production.
Embodiment
Below by way of the description of embodiment, the invention will be further described, but this is not the limit to the present invention
System, those skilled in the art according to the present invention basic thought, various modifications may be made or improve, but without departing from this
The basic thought of invention, within the scope of the present invention.
Unless otherwise indicated, the chemical name of " Acipimox " as described herein is 5- methyl -4- oxidation -2- pyrazine first
Acid, its structural formula are as follows：
The present inventor passes through substantial amounts of screening test in the preparation technology of research Acipimox, it was thus unexpectedly found that：
The reaction mother liquor that existing synthesis process of Acipimox is obtained, handled and then added by some specific auxiliary agents
Activated carbon carries out decolorization, so that it may obtains qualified finished product by a decrease temperature crystalline.Said process can efficiently reduce
Crystallisation times, recrystallization operation is avoided, therefore enormously simplify production technology, improve synthesis yield, integrated cost is able to
Reduce.
Specifically, the invention provides：
A kind of synthesis technique of Acipimox, it includes：
1) in aqueous, under catalyst action, make 5-Methylpyrazine-2-carboxylic acid that such as Formula Il occur with hydrogen peroxide
Shown reaction,
2) auxiliary agent is added in the solution obtained to step 1), wherein, described auxiliary agent is selected from sulphite, bisulfite
One kind in salt, oxalic acid and oxalates；
3) activated carbon is added in the solution obtained to step 2), filtered；And
4) solution for obtaining step 3) carries out decrease temperature crystalline, dries, so as to obtain Acipimox finished product.
Preferably, in step 1), the mol ratio of described hydrogen peroxide and described 5-Methylpyrazine-2-carboxylic acid is
(1.0-1.8)∶1.If mol ratio is less than 1.0: 1, the conversion ratio deficiency of 5-Methylpyrazine-2-carboxylic acid, yield reduces；Add
Amount is higher than 1.8: 1, can not significantly improve Acipimox yield, cause the waste of raw material on the contrary, and may cause side reaction
Increase.It is highly preferred that the mol ratio of described hydrogen peroxide and described 5-Methylpyrazine-2-carboxylic acid is (1.1-1.6): 1.
Preferably, the catalyst described in step 1) is sodium tungstate.It is highly preferred that described sodium tungstate and described 5- methyl
The mol ratio of pyrazine -2- carboxylic acids is (0.01-0.1): 1.If mol ratio is less than 0.01, catalytic effect is weakened, so as to lead
The reaction time is caused significantly to extend；If mol ratio more than 0.1, can not significantly improve reaction speed, cause raw material on the contrary
Waste.
Preferably, the step 1) reaction is carried out in the presence of acid.It is highly preferred that described acid is sulfuric acid.More
Preferably, the mol ratio of described sodium tungstate and described sulfuric acid is 1: 1.
Preferably, the reaction temperature of the step 1) reaction is 40-90 DEG C.If reaction temperature is less than 40 DEG C, reaction speed
Degree is slow, and the reaction time extends；If reaction is higher than 90 DEG C, hydrogen peroxide can be caused to decompose, result in the waste of raw material, Yi Jike
Unnecessary side reaction can be introduced.Reaction temperature is more preferably 50-80 DEG C.
Preferably, the reaction time of the step 1) reaction is 1-12 hours.The selection of time of reaction has with reaction temperature
Close, generally 1-12 hours, preferably 2-8 hours.
Preferably, the sulphite described in step 2) is inorganic sulfite, preferably sodium sulfite or potassium sulfite.
Preferably, the bisulfites described in step 2) is inorganic bisulfites, preferably sodium hydrogensulfite or sulfurous
Potassium hydrogen phthalate.
Preferably, the oxalates described in step 2) is inorganic oxalates, preferably sodium oxalate or potassium oxalate.
Preferably, the auxiliary agent described in step 2) is selected from sodium sulfite, sodium hydrogensulfite, potassium sulfite, potassium bisulfite, grass
One kind in acid, sodium oxalate, potassium oxalate.
Preferably, the mol ratio of the auxiliary agent described in step 2) and described 5-Methylpyrazine-2-carboxylic acid is not higher than 0.8: 1.
The present inventor is found through experiments that, if mol ratio more than 0.8: 1, can not significantly improve the purity and receipts of Acipimox finished product
Rate, the waste of raw material is caused on the contrary.
Preferably, in step 2), the reaction time of solution and described auxiliary agent that step 1) obtains is 0.5-3 hours.
Preferably, in step 3), the weight of the activated carbon added is the 5- methylpyrazines -2- according to step 1)
0.01-0.2 times of the Acipimox theoretical weight that carboxylic acid is calculated.
Preferably, in step 4), the solution that step 3) is obtained cools to -5~20 DEG C, crystallizes, and dries, so as to obtain
Acipimox finished product.It is highly preferred that described drying temperature is 80-110 DEG C.
In a preferred embodiment of the invention, described synthesis technique comprises the following steps：
A) Disodium tungstate (Na2WO4) dihydrate is added in a kettle, is added water dissolving, is then added and Disodium tungstate (Na2WO4) dihydrate equimolar
Dilute sulfuric acid, add aqueous hydrogen peroxide solution, add 5-Methylpyrazine-2-carboxylic acid, be warming up to 40-80 DEG C reaction 1-12 it is small
When；
B) after reaction terminates, auxiliary agent sodium sulfite is added, continues to react 0.5-3 hours；
C) add and calculate theoretical 0.01-0.2 times of activated carbon of yield Acipimox according to 5-Methylpyrazine-2-carboxylic acid, continue
0.5-3 hours are stirred, are filtered while hot.
D) filtrate is cooled to -5~20 DEG C, continues to stir 0.5-3 hours, filtering, filter cake is dried between 80-110 DEG C, i.e.,
It can obtain Acipimox finished product.
Present invention is further explained and described in mode by the following examples, but these embodiments are not understood that
For limiting the scope of the invention.
In the examples below, other unless otherwise specified, each reagent is commercially available, for example, Nanning chemistry system
Medicine Co., Ltd.
Embodiment 1
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction bulbs, adds 400ml water, stirring and dissolving, under stirring
1.9g (19mmol) concentrated sulfuric acid is added, 204g (1.8mol) hydrogen peroxide (30%) is continuously added, stirs, adds 5- methyl
Pyrazine -2- carboxylic acids 207.2g (1.5mol), heating water bath insulated and stirred 8 hours, add sodium hydrogensulfite 31.2g to 60 DEG C
(0.3mol), continue stirring 1 hour, add activated carbon 12g, continue stirring 1 hour, filter while hot, filtrate is cooled to 4 DEG C, protects
To hold 3 hours, filter, filter cake is dried 3 hours at 100 DEG C, obtains off-white color crystalline powder 196.2g, HPLC purity 99.35%,
Yield 84.9%.
Embodiment 2
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction bulbs, adds 400ml water, stirring and dissolving, under stirring
1.9g (19mmol) concentrated sulfuric acid is added, 306g (2.7mol) hydrogen peroxide (30%) is continuously added, stirs, adds 5- methyl
Pyrazine -2- carboxylic acids 207.2g (1.5mol), heating water bath insulated and stirred 4 hours, add sodium sulfite 151.2g to 80 DEG C
(1.2mol), to continue stirring 0.5 hour, add activated carbon 20g, continue stirring 1 hour, filter while hot, filtrate is cooled to -4 DEG C,
Being kept for 3 hours, filtering, filter cake is dried 3 hours at 80 DEG C, obtains off-white color crystalline powder 192.2g, HPLC purity 99.1%,
Yield 83.1%.
Embodiment 3
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction bulbs, adds 400ml water, stirring and dissolving, under stirring
1.9g (19mmol) concentrated sulfuric acid is added, 204g (1.8mol) hydrogen peroxide (30%) is continuously added, stirs, adds 5- methyl
Pyrazine -2- carboxylic acids 207.2g (l.5mol), heating water bath insulated and stirred 8 hours, add potassium sulfite 47.4g to 60 DEG C
(0.3mol), continue stirring 1 hour, add activated carbon 12g, continue stirring 1 hour, filter while hot, filtrate is cooled to 4 DEG C, protects
To hold 3 hours, filter, filter cake is dried 3 hours at 100 DEG C, obtains off-white color crystalline powder 195.7g, HPLC purity 99.37%,
Yield 84.6%.
Embodiment 4
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction bulbs, adds 400ml water, stirring and dissolving, under stirring
1.9g (19mmol) concentrated sulfuric acid is added, 272g (2.4mol) hydrogen peroxide (30%) is continuously added, stirs, adds 5- methyl
Pyrazine -2- carboxylic acids 207.2g (1.5mol), heating water bath insulated and stirred 6 hours, add potassium bisulfite 108g to 70 DEG C
(0.9mol), continue stirring 1 hour, add activated carbon 15g, continue stirring 1 hour, filter while hot, filtrate is cooled to 4 DEG C, protects
To hold 3 hours, filter, filter cake is dried 3 hours at 100 DEG C, obtains off-white color crystalline powder 189.5g, HPLC purity 98.9%,
Yield 82.0%.
Embodiment 5
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction bulbs, adds 400ml water, stirring and dissolving, under stirring
1.9g (19mmol) concentrated sulfuric acid is added, 204g (1.8mol) hydrogen peroxide (30%) is continuously added, stirs, adds 5- methyl
Pyrazine -2- carboxylic acids 207.2g (1.5mol), heating water bath insulated and stirred 8 hours, add oxalic acid 27g (0.3mol) to 60 DEG C, after
Continuous stirring 1 hour, adds activated carbon 12g, continues stirring 1 hour, filters while hot, and filtrate is cooled to 4 DEG C, is kept for 3 hours, mistake
Filter, filter cake are dried 3 hours at 100 DEG C, obtain off-white color crystalline powder 196.0g, HPLC purity 99.3%, yield 84.7%.
Embodiment 6
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction bulbs, adds 400ml water, stirring and dissolving, under stirring
1.9g (19mmol) concentrated sulfuric acid is added, 204g (1.8mol) hydrogen peroxide (30%) is continuously added, stirs, adds 5- methyl
Pyrazine -2- carboxylic acids 207.2g (1.5mol), heating water bath insulated and stirred 8 hours, add sodium oxalate 40.2g to 60 DEG C
(0.3mol), continue stirring 1 hour, add activated carbon 12g, continue stirring 1 hour, filter while hot, filtrate is cooled to 4 DEG C, protects
To hold 3 hours, filter, filter cake is dried 3 hours at 100 DEG C, obtains off-white color crystalline powder 195.3g, HPLC purity 99.21%,
Yield 84.5%.
Embodiment 7
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction bulbs, adds 400ml water, stirring and dissolving, under stirring
1.9g (19mmol) concentrated sulfuric acid is added, 204g (1.8mol) hydrogen peroxide (30%) is continuously added, stirs, adds 5- methyl
Pyrazine -2- carboxylic acids 207.2g (1.5mol), heating water bath insulated and stirred 8 hours, add potassium oxalate 55.2g to 60 DEG C
(0.3mol), continue stirring 1 hour, add activated carbon 12g, continue stirring 1 hour, filter while hot, filtrate is cooled to 4 DEG C, protects
To hold 3 hours, filter, filter cake is dried 3 hours at 100 DEG C, obtains off-white color crystalline powder 195.1g, HPLC purity 99.24%,
Yield 84.4%.
Comparative example 1
Disodium tungstate (Na2WO4) dihydrate 6.2g (19mmol) is added in 1L reaction bulbs, adds 400ml water, stirring and dissolving, under stirring
1.9g (19mmol) concentrated sulfuric acid is added, 204g (1.8mol) hydrogen peroxide (30%) is continuously added, stirs, adds 5- methyl
Pyrazine -2- carboxylic acids 207.2g (1.5mol), heating water bath insulated and stirred 8 hours, are cooled to 4 DEG C to 60 DEG C, kept for 3 hours, mistake
Filter, dried 3 hours at 100 DEG C, obtain Light yellow crystals powder 202.44g, HPLC purity 93.21%, crude yield
87.6%.
Products obtained therefrom is added into 600g deionized waters, 12g activated carbons is added, is heated to 90 DEG C, insulated and stirred 1 hour, takes advantage of
Heat filtering, filtrate are cooled to 4 DEG C, are kept for 3 hours, and filtering, filter cake is dried 3 hours at 100 DEG C, obtains off-white color crystalline powder
164.4g, HPLC purity 99.68%, total recovery 71.1%.
Claims (17)
1. a kind of synthesis technique of Acipimox, it includes：
1) in aqueous, under catalyst action, 5-Methylpyrazine-2-carboxylic acid is made to occur with hydrogen peroxide as shown in Formula Il
Reaction,
2) auxiliary agent is added in the solution obtained to step 1), wherein, described auxiliary agent is selected from sulphite, bisulfites, grass
One kind in acid and oxalates, wherein the mol ratio of described auxiliary agent and described 5-Methylpyrazine-2-carboxylic acid is not higher than 0.8
∶1；
3) activated carbon is added in the solution obtained to step 2), filtered；And
4) solution for obtaining step 3) carries out decrease temperature crystalline, dries, so as to obtain Acipimox finished product.
2. synthesis technique according to claim 1, wherein, in step 1), described hydrogen peroxide and described 5- first
The mol ratio of base pyrazine -2- carboxylic acids is (1.0-1.8): 1.
3. synthesis technique according to claim 1, wherein, in step 1), described hydrogen peroxide and described 5- first
The mol ratio of base pyrazine -2- carboxylic acids is (1.1-1.6): 1.
4. synthesis technique according to claim 1, wherein, the catalyst described in step 1) is sodium tungstate.
5. synthesis technique according to claim 4, wherein, described sodium tungstate and described 5-Methylpyrazine-2-carboxylic acid
Mol ratio be (0.01-0.1): 1.
6. synthesis technique according to claim 4, wherein, the reaction temperature of the step 1) reaction is 40-90 DEG C.
7. synthesis technique according to claim 4, wherein, the reaction temperature of the step 1) reaction is 50-80 DEG C.
8. synthesis technique according to claim 1, wherein, the reaction time of the step 1) reaction is 1-12 hours.
9. synthesis technique according to claim 1, wherein, the reaction time of the step 1) reaction is 2-8 hours.
10. synthesis technique according to claim 1, wherein, the sulphite described in step 2) is inorganic sulfite.
11. synthesis technique according to claim 1, wherein, the sulphite described in step 2) is sodium sulfite or sulfurous
Sour potassium.
12. synthesis technique according to claim 1, wherein, the bisulfites described in step 2) is inorganic bisulfite
Salt.
13. synthesis technique according to claim 1, wherein, bisulfites described in step 2) for sodium hydrogensulfite or
Potassium bisulfite.
14. synthesis technique according to claim 1, wherein, the oxalates described in step 2) is inorganic oxalates.
15. synthesis technique according to claim 1, wherein, the oxalates described in step 2) is sodium oxalate or potassium oxalate.
16. synthesis technique according to claim 1, wherein, in step 2), solution and described that step 1) obtains help
The reaction time of agent is 0.5-3 hours.
17. synthesis technique according to claim 1, wherein, in step 4), the solution that step 3) is obtained cools to -5
~20 DEG C, crystallize, dry, so as to obtain Acipimox finished product.
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| CN109438369A (en) * | 2018-11-04 | 2019-03-08 | 鲁南制药集团股份有限公司 | A kind of preparation method of Acipimox |
| CN109438372B (en) * | 2018-12-30 | 2022-02-22 | 鲁南制药集团股份有限公司 | Methyl pyrazine derivative methanol compound |
| CN109438370B (en) * | 2018-12-30 | 2022-02-22 | 鲁南制药集团股份有限公司 | Methylpyrazine derivative anhydrous crystal form |
| CN109400539A (en) * | 2018-12-30 | 2019-03-01 | 山东新时代药业有限公司 | A kind of methylpyrazine derivative semihydrate |
| CN110156682A (en) * | 2019-06-05 | 2019-08-23 | 南京焕然生物科技有限公司 | A kind of preparation method of azacyclo- N- oxide |
| CN112125857A (en) * | 2019-06-25 | 2020-12-25 | 鲁南制药集团股份有限公司 | Preparation method of acipimox |
| CN113929631B (en) * | 2020-07-13 | 2024-04-12 | 鲁南制药集团股份有限公司 | Purification method of acipimox |
| CN115073384B (en) * | 2021-12-29 | 2023-03-24 | 山东新时代药业有限公司 | Acipimox crystal form and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0254259A2 (en) * | 1986-07-21 | 1988-01-27 | Otsuka Pharmaceutical Factory, Inc. | p-Aminophenol derivatives |
| CN1651417A (en) * | 2004-12-15 | 2005-08-10 | 鲁南制药股份有限公司 | Preparation method of acymose |
| WO2008031566A2 (en) * | 2006-09-13 | 2008-03-20 | Syngenta Participations Ag | Novel pyridopyrazine n-oxides |
| CN103664805A (en) * | 2013-12-05 | 2014-03-26 | 华北水利水电大学 | Method for preparing acipimox |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012512868A (en) * | 2008-12-18 | 2012-06-07 | アストラゼネカ・アクチエボラーグ | 3- {4-Methyl-5-[(1R) -1- (2- (3-methylphenyl-2H-tetrazol-5-yl) -ethoxy] -4H- [1,2,4] triazole-3- Yl} -pyridine, 4-methyl-3-methylthio-5- (3-pyridyl) -1,2,4-triazole, and (1R) -1- [2- (3-methylphenyl) -2H-tetrazole- 5-yl] ethanol production method |
| WO2013147092A1 (en) * | 2012-03-30 | 2013-10-03 | 三菱化学株式会社 | Method for manufacturing epoxy compound, and catalyst composition for epoxylating reaction |
-
2014
- 2014-05-26 CN CN201410226009.4A patent/CN105218464B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0254259A2 (en) * | 1986-07-21 | 1988-01-27 | Otsuka Pharmaceutical Factory, Inc. | p-Aminophenol derivatives |
| CN1651417A (en) * | 2004-12-15 | 2005-08-10 | 鲁南制药股份有限公司 | Preparation method of acymose |
| WO2008031566A2 (en) * | 2006-09-13 | 2008-03-20 | Syngenta Participations Ag | Novel pyridopyrazine n-oxides |
| CN103664805A (en) * | 2013-12-05 | 2014-03-26 | 华北水利水电大学 | Method for preparing acipimox |
Non-Patent Citations (1)
| Title |
|---|
| 阿昔莫司的合成;张贵民，等;《中国医药工业杂志》;20091031;第40卷(第10期);第724-725页 * |
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