CN103694146B - The preparation method of 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate - Google Patents
The preparation method of 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate Download PDFInfo
- Publication number
- CN103694146B CN103694146B CN201310638440.5A CN201310638440A CN103694146B CN 103694146 B CN103694146 B CN 103694146B CN 201310638440 A CN201310638440 A CN 201310638440A CN 103694146 B CN103694146 B CN 103694146B
- Authority
- CN
- China
- Prior art keywords
- acetone
- reaction solution
- methyl
- formiate
- ethylidene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The preparation method of a kind of Aprepitant intermediate 2-provided by the invention (the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, the method adopt chloromethyl cyanide in methyl alcohol/sodium methylate reaction solution after glacial acetic acid catalysis with methyl hydrazinocarboxylate condensation reaction, reaction solution adopts acetone to carry out aftertreatment purifying, simple to operate, the product purity obtained reaches more than 99%, and yield is high, be applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to the synthetic method of antiemetic Aprepitant intermediate 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate.
Background technology
Aprepitant (English name aprepitant), chemistry 5-[[(2R by name, 3S)-2-[(1R)-1-[3,5-bis-(trifluoromethyl) phenyl] oxyethyl group]-3-(4-fluorophenyl)-4-morpholinyl] methyl]-1,2-dihydro-3H-1,2,4-triazole-3-ketone, first neurokinin 1 (NK-1) receptor-blocking agent that U.S. FDA goes on the market in approval in 2003, by combining the effect of blocking Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 with nk 1 receptor (being mainly present in central nervous system and periphery thereof).This product can pass through hemato encephalic barrier, captures the nk 1 receptor in brain, has selectivity and high-affinity, and very low to NK-2 and NK-3 receptor affinity.Simultaneously this product target spot (as Dopamine Receptors, 5HT acceptor) affinity interaction of being used for the treatment of the medicine of the nausea and vomiting symptom of chemotherapy induction to other is also very low, and its effect reducing Nausea and vomiting is better than other drug.Its structural formula is:
Chinese Journal of Pharmaceuticals (Chinese Journal of Pharmaceuticals 2009, 40 (12), 951-953) disclose Aprepitant graphical Synthetic Routes, from this diagram, key intermediate 2 i.e. (2R is prepared by number of ways, 3S)-2-[(1R)-1-[3, 5-bis-(trifluoromethyl) phenyl] oxyethyl group] after-3-(4-fluorophenyl) morpholine, need react with 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate and obtain Aprepitant to continue synthesis, therefore 2-(2-chloro-1-ethylidene) hydrazides methyl-formiate is very important intermediate in the process of synthesis Aprepitant.
The synthetic method disclosing 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate (type I compound) in patent (CN1261882A) is, the method adopts chloromethyl cyanide after glacial acetic acid catalysis, to obtain the methanol solution of target product with methyl hydrazinocarboxylate condensation in methyl alcohol/sodium methylate reaction solution, and concentration of reaction solution is decompressed to and dryly obtains yellow powder product.Reaction formula is as follows:
Actual experiment result shows, the product characteristics that this method obtains are bad, purity is on the low side, easily residual highly toxic chloromethyl cyanide and other unreacted raw material completely, affect the purity of subsequent product, aftertreatment concentrating under reduced pressure spends the night, length consuming time, energy consumption is high, is not suitable for suitability for industrialized production.
Summary of the invention
The invention provides the preparation method of a kind of Aprepitant intermediate 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, the method purification process is simple to operate, and the product purity obtained reaches more than 99.9%, and yield is high, is applicable to suitability for industrialized production.
The preparation method of Aprepitant intermediate 2-provided by the invention (the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, adopt chloromethyl cyanide in methyl alcohol/sodium methylate reaction solution after glacial acetic acid catalysis with methyl hydrazinocarboxylate condensation reaction, it is characterized in that, adopt acetone to carry out aftertreatment purifying to reaction solution.
Contriver, in order to avoid long concentrating under reduced pressure, has carried out the effects to other aftertreatment purification process of reaction solution after completion of the reaction.A kind of method reduces the time of concentrating under reduced pressure, after reaction solution concentrating under reduced pressure is removed lower boiling methyl alcohol, just adding solvent making beating, expecting to filter high boiling solvent and other impurity by crossing, select the solvent of indissoluble solution reaction product, comprise sherwood oil, isopropyl ether, acetonitrile, ethyl acetate or their mixed solvent, under room temperature, fully making beating is rear filters, and dry, the product purity obtained sees the following form:
| Making beating solvent | HPLC |
| Sherwood oil | 96.2% |
| Isopropyl ether | 96.2% |
| Acetonitrile | 98.3% |
| Ethyl acetate | 97.0% |
| Methylene dichloride | 96.3% |
| Acetonitrile/sherwood oil | 97.1% |
| Acetonitrile/isopropyl ether | 96.9% |
| Acetone | 99.5% |
From upper table result, the method purifying that making beating is filtered adopts most solvent still can remain a small amount of impurity, through tlc analysis of control, finds methyl hydrazinocarboxylate complete containing unreacted in product, only has acetone making beating product purity higher, reaches more than 99%.
Another kind method, add solvent crystallization directly in reaction solution after reaction terminates, crystallization mode is stirred at ambient temperature crystallization, and the selection result of crystallization solvent sees the following form:
| Solvent | Crystallization state | HPLC |
| Sherwood oil | Wall built-up, precipitation solid are clamminess | 94.0% |
| Isopropyl ether | Wall built-up, precipitation solid are clamminess | 95.3% |
| Ether | Wall built-up, precipitation solid are clamminess | 95.5% |
| Normal hexane | Wall built-up, precipitation solid are clamminess | 93.9% |
| Normal heptane | Wall built-up, precipitation solid are clamminess | 93.5% |
| Methyl tertiary butyl ether | Wall built-up, precipitation solid are clamminess | 95.0% |
| Acetone | Light yellow crystalline powder | 99.8% |
Surprisingly found by above-mentioned experiment screening, the product purity that other reaction solvent crystallization except acetone obtains is on the low side, through thin-layer chromatographic analysis contrast, finds in product containing chloromethyl cyanide and methyl hydrazinocarboxylate, because chloromethyl cyanide is liquid, so the product of separating out is clamminess.And adopt the method adding acetone crystallization, find adopting thin-layer chromatographic analysis contrast to product, chloromethyl cyanide and methyl hydrazinocarboxylate is not had in product, thin-layer chromatographic analysis discovery is carried out to filtrate, containing chloromethyl cyanide in filtrate, but there is no methyl hydrazinocarboxylate, and produce another one impurity, from above-mentioned phenomenon, methyl hydrazinocarboxylate in acetone and reaction solution there occurs reaction, consider to generate schiff bases, and this product is dissolved in acetone, thus reaches the effect removing methyl hydrazinocarboxylate in reaction solution.In addition, chloromethyl cyanide is easily molten in acetone, but target product 2-(2-chloro-1-ethylidene) hydrazides methyl-formiate is insoluble, thus separation eliminates chloromethyl cyanide.
Based on the result of above-mentioned two kinds of methods, contriver has surprisingly found that acetone can carry out purifying fast and effectively to the reaction solution that chloromethyl cyanide obtains with methyl hydrazinocarboxylate condensation reaction in methyl alcohol/sodium methylate reaction solution after glacial acetic acid catalysis, the purification effect of further other ketones solvents of research, the results are shown in following table:
| Solvent | Volume | Temperature | Result |
| Acetone | 50ml | Room temperature | Separate out a large amount of |
| Butanone | 50ml | 15℃ | Separate out a small amount of |
| Pentanone | 50ml | 10℃ | Separate out minute quantity |
| Octanone | 50ml | -5-0℃ | Separate out minute quantity |
| Methylacetone | 50ml | -5-0℃ | Separate out minute quantity |
| 4-methyl-2 pentanone | 100ml | Room temperature | Do not separate out |
| Dimethyl diketone | 100ml | Room temperature | Do not separate out |
| Diacetylmethane | 100ml | Room temperature | Do not separate out |
| Cyclopropanone | 100ml | Room temperature | Do not separate out |
| Cyclopentanone | 100ml | Room temperature | Do not separate out |
As seen from the above table, target product 2-(the chloro-1-ethylidene of 2-) the solvability difference of hydrazides methyl-formiate in ketones solvent is comparatively large, and only have solvability in acetone minimum, therefore acetone is used to the optimum solvent of purification of target product.
Adopt acetone that the method that reaction solution carries out aftertreatment purifying for after reaction solution is concentrated, can be added to acetone making beating and filter, or add acetone crystallization in reaction solution.Further optimization, temperature when adopting acetone aftertreatment is-10 ~ 30 DEG C, preferably 20 ~ 30 DEG C, 20 ~ 30 DEG C is room temperature range, after experiment, find that this temperature range purity and yield reach maximum value, and without the need to cooling or heating operation, save energy, is applicable to suitability for industrialized production.Acetone used is 10 ~ 50:1, preferably 20 ~ 30:1 with the volume mass ratio of chloromethyl cyanide, and in addition, when adopting the method adding acetone crystallization in reaction solution, the consumption of acetone and the volume ratio of methyl alcohol are 1 ~ 3:1.
When adding the method for acetone making beating after adopting reaction solution to concentrate, beating time preferably 0.5 ~ 4 hour; When employing adds the method for acetone crystallization in reaction solution, crystallization mode is stirring and crystallizing, and churning time is 0.5 ~ 4 hour.
The preparation method of a kind of Aprepitant intermediate 2-provided by the invention (the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, the method adopt chloromethyl cyanide in methyl alcohol/sodium methylate reaction solution after glacial acetic acid catalysis with methyl hydrazinocarboxylate condensation reaction, reaction solution adopts acetone to carry out aftertreatment purifying, simple to operate, the product purity obtained reaches 99 more than %, and yield is high, be applicable to suitability for industrialized production.
Below in conjunction with the embodiment of embodiment, the present invention will be further described.
Embodiment
embodiment one
in 1000ml there-necked flask, chloromethyl cyanide 50g(0.67mol is added successively under nitrogen protection), 200ml methyl alcohol, is cooled to 0 DEG C.1g sodium methylate is dissolved in 50ml methyl alcohol, slowly drops in reaction flask.Dropwise, rise to stirring at room temperature 30 minutes.Add 1.06ml Glacial acetic acid, in gained mixture, then drip the 250ml methanol solution of 39g (0.43mol) methyl hydrazinocarboxylate.Dropwise, continue stirring 30 minutes.
Concentrating under reduced pressure reaction solution, near dry, adds 1000ml acetone, stirring at room temperature making beating 30min, filter, obtain faint yellow solid, solid 50 DEG C of forced air dryings, obtain 70.1g2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, yield: 93.1%, HPLC purity 99.8%.
embodiment two
in 1000ml there-necked flask, chloromethyl cyanide 50g(0.67mol is added successively under nitrogen protection), 200ml methyl alcohol, is cooled to 0 DEG C.1g sodium methylate is dissolved in 50ml methyl alcohol, slowly drops in reaction flask.Dropwise, rise to stirring at room temperature 30 minutes.Add 1.06ml Glacial acetic acid, in gained mixture, then drip the 250ml methanol solution of 39g (0.43mol) methyl hydrazinocarboxylate.Dropwise, continue stirring 30 minutes.
Concentrating under reduced pressure reaction solution, near dry, adds 500ml acetone, stirring at room temperature making beating 2min, filter, obtain faint yellow solid, solid 50 DEG C of forced air dryings, obtain 69.5g 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, yield: 93.0%, HPLC purity 99.5%.
embodiment three
In 1000ml there-necked flask, chloromethyl cyanide 50g(0.67mol is added successively under nitrogen protection), 200ml methyl alcohol, is cooled to 0 DEG C.1g sodium methylate is dissolved in 50ml methyl alcohol, slowly drops in reaction flask.Dropwise, rise to stirring at room temperature 30 minutes.Add 1.06ml Glacial acetic acid, in gained mixture, then drip the 250ml methanol solution of 39g (0.43mol) methyl hydrazinocarboxylate.Dropwise, continue stirring 30 minutes.
500ml acetone is dripped in above-mentioned reaction solution, dropping limit, limit is stirred, after dripping ,-10 ~ 0 DEG C is continued stirring and crystallizing, starts crystallization, insulated and stirred 40 ~ 60min after 1h, filter, obtain faint yellow solid, solid 50 DEG C of forced air dryings, obtain 38.1g 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, yield: 50.6%, HPLC purity 99.93%.
embodiment four
In 1000ml there-necked flask, chloromethyl cyanide 50g(0.67mol is added successively under nitrogen protection), 200ml methyl alcohol, is cooled to 0 DEG C.1g sodium methylate is dissolved in 50ml methyl alcohol, slowly drops in reaction flask.Dropwise, rise to stirring at room temperature 30 minutes.Add 1.06ml Glacial acetic acid, in gained mixture, then drip the 250ml methanol solution of 39g (0.43mol) methyl hydrazinocarboxylate.Dropwise, continue stirring 30 minutes.
In above-mentioned reaction solution, drip 1000ml acetone, dropping limit, limit is stirred, and-10 ~ 0 DEG C of stirring and crystallizing after dripping, starts crystallization after 0.5h, insulated and stirred 40 ~ 60min, filters, obtains faint yellow solid, solid 50 DEG C of forced air dryings.Obtain 72.0g2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, yield: 95.6%, HPLC purity 99.85%.
embodiment five
In 1000ml there-necked flask, chloromethyl cyanide 50g(0.67mol is added successively under nitrogen protection), 200ml methyl alcohol, is cooled to 0 DEG C.1g sodium methylate is dissolved in 50ml methyl alcohol, slowly drops in reaction flask.Dropwise, rise to stirring at room temperature 30 minutes.Add 1.06ml Glacial acetic acid, in gained mixture, then drip the 250ml methanol solution of 39g (0.43mol) methyl hydrazinocarboxylate.Dropwise, continue stirring 30 minutes.
In above-mentioned reaction solution, drip 2000ml acetone, dropping limit, limit is stirred, and after dropwising, 20 ~ 30 DEG C are continued stirring and crystallizing, start crystallization after 0.5h, continues insulated and stirred 40 ~ 60min and filters, obtain faint yellow solid, solid 50 DEG C of forced air dryings.Obtain 71.8g 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, yield: 95.3%, HPLC purity 99.97%.
embodiment six
In 1000ml there-necked flask, chloromethyl cyanide 50g(0.67mol is added successively under nitrogen protection), 200ml methyl alcohol, is cooled to 0 DEG C.1g sodium methylate is dissolved in 50ml methyl alcohol, slowly drops in reaction flask.Dropwise, rise to stirring at room temperature 30 minutes.Add 1.06ml Glacial acetic acid, in gained mixture, then drip the 250ml methanol solution of 39g (0.43mol) methyl hydrazinocarboxylate.Dropwise, continue stirring 30 minutes.
In reaction solution, drip 1500ml acetone, dropping limit, limit is stirred, and 20 ~ 30 DEG C of stirring and crystallizing after dripping, start crystallization after 1h, and 20 ~ 30 DEG C of insulation 40 ~ 60min, filter, obtain faint yellow solid, solid 50 DEG C of forced air dryings.Obtain 72.4g2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, yield: 96.1%, HPLC purity 99.80%.
embodiment seven
In 1000ml there-necked flask, chloromethyl cyanide 50g(0.67mol is added successively under nitrogen protection), 200ml methyl alcohol, is cooled to 0 DEG C.1g sodium methylate is dissolved in 50ml methyl alcohol, slowly drops in reaction flask.Dropwise, rise to stirring at room temperature 30 minutes.Add 1.06ml Glacial acetic acid, in gained mixture, then drip the 250ml methanol solution of 39g (0.43mol) methyl hydrazinocarboxylate.Dropwise, continue stirring 30 minutes.
In reaction solution, drip 1000ml acetone, dropping limit, limit is stirred, and 20 ~ 30 DEG C of stirring and crystallizing after dripping, start crystallization after 1h, and 20 ~ 30 DEG C of insulation 40 ~ 60min, filter, obtain faint yellow solid, solid 50 DEG C of forced air dryings.Obtain 71.5g2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, yield: 95.0%, HPLC purity 99.96%.
Claims (7)
1. the preparation method of Aprepitant intermediate 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate, adopt chloromethyl cyanide in methyl alcohol/sodium methylate reaction solution after glacial acetic acid catalysis with methyl hydrazinocarboxylate condensation reaction, it is characterized in that, acetone is adopted to carry out aftertreatment purifying to reaction solution, the method of described aftertreatment purifying can be after being concentrated by reaction solution, add acetone making beating to filter, or acetone crystallization is added in reaction solution, wherein acetone is 10 ~ 50:1 with the volume mass ratio of chloromethyl cyanide, and temperature during aftertreatment is-10 ~ 30 DEG C.
2. method according to claim 1, is characterized in that, the method for described aftertreatment purifying for add acetone crystallization in reaction solution.
3. method according to claim 1, is characterized in that, temperature when adopting acetone aftertreatment is 20 ~ 30 DEG C.
4. method according to claim 1, is characterized in that, acetone is 20 ~ 30:1 with the volume mass ratio of chloromethyl cyanide.
5. method according to claim 2, is characterized in that, the volume ratio of acetone and methyl alcohol is 1 ~ 3:1.
6. method according to claim 1, is characterized in that, when described aftertreatment purification process is the method adding acetone making beating after reaction solution concentrates, beating time is 0.5 ~ 4 hour.
7. method according to claim 1, is characterized in that, when described aftertreatment purification process is the method adding acetone crystallization in reaction solution, crystallization mode is stirring and crystallizing, and churning time is 0.5 ~ 4 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310638440.5A CN103694146B (en) | 2013-12-04 | 2013-12-04 | The preparation method of 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310638440.5A CN103694146B (en) | 2013-12-04 | 2013-12-04 | The preparation method of 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103694146A CN103694146A (en) | 2014-04-02 |
| CN103694146B true CN103694146B (en) | 2015-10-28 |
Family
ID=50355839
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310638440.5A Expired - Fee Related CN103694146B (en) | 2013-12-04 | 2013-12-04 | The preparation method of 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103694146B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112684028B (en) * | 2020-12-04 | 2022-05-17 | 中山奕安泰医药科技有限公司 | Method for detecting purity of 2- (2-chloro-1-ethylene) hydrazide methyl formate |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1142819A (en) * | 1993-12-17 | 1997-02-12 | 麦克公司 | Morpholine and thiomorpholine tachykinin receptor antagonists |
| CN1147254A (en) * | 1994-03-04 | 1997-04-09 | 麦克公司 | Prodrugs of morpholine tachykinin receptor antagonists |
| WO2009001203A2 (en) * | 2007-06-27 | 2008-12-31 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of aprepitant |
| CN102295611A (en) * | 2010-05-24 | 2011-12-28 | 成都地奥制药集团有限公司 | Synthetic method for medicines of neurokinin 1 receptor antagonists |
| CN103030668A (en) * | 2011-10-09 | 2013-04-10 | 江苏豪森药业股份有限公司 | Method for preparing fosaprepitant |
| WO2013124823A1 (en) * | 2012-02-23 | 2013-08-29 | Piramal Enterprises Limited | An improved process for the preparation of aprepitant |
-
2013
- 2013-12-04 CN CN201310638440.5A patent/CN103694146B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1142819A (en) * | 1993-12-17 | 1997-02-12 | 麦克公司 | Morpholine and thiomorpholine tachykinin receptor antagonists |
| CN1147254A (en) * | 1994-03-04 | 1997-04-09 | 麦克公司 | Prodrugs of morpholine tachykinin receptor antagonists |
| WO2009001203A2 (en) * | 2007-06-27 | 2008-12-31 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of aprepitant |
| CN102295611A (en) * | 2010-05-24 | 2011-12-28 | 成都地奥制药集团有限公司 | Synthetic method for medicines of neurokinin 1 receptor antagonists |
| CN103030668A (en) * | 2011-10-09 | 2013-04-10 | 江苏豪森药业股份有限公司 | Method for preparing fosaprepitant |
| WO2013124823A1 (en) * | 2012-02-23 | 2013-08-29 | Piramal Enterprises Limited | An improved process for the preparation of aprepitant |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103694146A (en) | 2014-04-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102276611B (en) | Method for purifying tebipenem by recrystallizing | |
| EP3241837A1 (en) | Method for preparing sofosbuvir crystal form-6 | |
| CN102746289B (en) | The preparation method of a kind of lurasidone hydrochloride | |
| CN104356111B (en) | A kind of method for preparing dabigatran etcxilate mesylate hydrolysis impurity | |
| CN103694146B (en) | The preparation method of 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate | |
| CN105503638A (en) | Sacubitril dicyclohexylamine salt, crystal form and preparation method of crystal form | |
| CN104781245A (en) | Process for producing dihydro-2H-pyran derivatives | |
| CN107814802A (en) | A kind of new method for preparing citric acid tropsch imatinib medicinal crystal-form | |
| CN104402973A (en) | Method for preparing carfilzomib amorphous crystal | |
| CN105503854A (en) | New crystal form substance of Dasatinib anhydrous substance and preparation method thereof | |
| CN102643255A (en) | Andrographolide compound | |
| CN104311485A (en) | Preparation method of medicine bosutinib for treating leukemia | |
| CN103113408B (en) | A kind of novel method preparing phosphonomycin fosfomycin phenylethylamine calt | |
| CN105820174A (en) | Polysubstituted thienoindole derivative and preparation method thereof | |
| CN102718797A (en) | Purifying method of antioxidant 168 | |
| CN104402895A (en) | Method for purifying homoharringtonine | |
| CN110668922B (en) | Refining method of musk camphor | |
| CN107033114A (en) | A kind of isolation and purification method of dihydromyricetin | |
| CN103382179A (en) | Ingavirin polymorph and its preparation method | |
| CN104844681B (en) | The process for purification of the brilliant type eplerenone of a kind of L | |
| CN104710373A (en) | Preparation method for high-purity cyproconazole isomer | |
| CN101885727A (en) | Method for preparing penipenem | |
| CN105001232A (en) | Purification method for moxidectin | |
| CN114133356B (en) | Pyridazine compound and application thereof | |
| CN105085499A (en) | Crystal separation method for nebivolol hydrochloride intermediate mixture |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20151028 Termination date: 20191204 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |