CN102718821B - Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent - Google Patents
Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent Download PDFInfo
- Publication number
- CN102718821B CN102718821B CN201210214998.6A CN201210214998A CN102718821B CN 102718821 B CN102718821 B CN 102718821B CN 201210214998 A CN201210214998 A CN 201210214998A CN 102718821 B CN102718821 B CN 102718821B
- Authority
- CN
- China
- Prior art keywords
- methyl
- methylation reaction
- reaction
- methylation
- compound
- 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.)
- Active
Links
Classifications
-
- 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
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention mainly discloses methylation reaction in a clarithromycin synthesis process and a recycling method of a methylation reagent. In the methylation reaction, methyl benzenesulfonate is used as the methylation reagent, potassium hydroxide is used as a catalyst, and methyl tertbutyl ether and dimethyl sulfoxide are used as solvents. After the methylation reaction, water is added for stratification, the dimethylsulfoxide (DMSO) layer is recycled and dried to obtain P-methyl benzene potassium sulfonate, dimethylsulfoxide is added for reaction to obtain P-methyl benzene sulfonyl chloride, and P-methyl benzene methyl sulfonate is regenerated via reaction with methanol. The generation of bismethyl impurities can be avoided effectively. Meanwhile, P-methyl benzene methyl sulfonate is regenerated via reaction of the dimethylsulfoxide and the methanol, and thus the recycling of the methylation reagent is realized.
Description
Technical field
The present invention relates to the recovery of methylation reaction in clarithromycin building-up process and methylating reagent, belong to the preparing technical field of Macrocyclolactone lactone kind medicine intermediate and other compound.
Background technology
(2 '; 4 " )-O two trimethyl silicon based-CAMA A-9[O-(1-oxyethyl group-1-the first and second bases)] oxime (formula 1) is the intermediate in synthetic clarithromycin technological process, it is generally by the two trimethyl silicon based Erythromycin A-9[O-(1-oxyethyl group-1-the first and second bases) of (2 ', 4 ")-O] oxime (formula 2) makes through methylating of 6 hydroxyls.Its reaction formula is as follows:
Formula 2 formulas 1
1, patent US4331803 has introduced the method for 6 HMs of erythromycin derivatives first, and its anti-microbial activity and acid acceptance are studied, it adopts methyl iodide is methylating reagent, with alkali as a catalyst, polar aprotic solvent and tetrahydrofuran (THF) are mixed into solvent and carry out methylation reaction.
2,6 hydroxy alkylated methods introducing in patent EP0272110A2 are under the condition existing at alkali,-15 DEG C to the condition of room temperature, taking monobromethane, methyl iodide, methyl-sulfate, p-methyl benzenesulfonic acid methyl esters etc. as alkylating reagent, carry out alkylated reaction taking polar aprotic solvent and other solvent as solvent.In embodiment, be mainly with methyl iodide and methyl-sulfate be alkylating reagent, there is no the introduction of alkylating reagent recovery.
3, a kind of introduced Three-phase solvent in patent WO2007029265 6 HM methods, the alkylating reagent of employing is methyl iodide.
4, Chinese pharmaceutical chemistry magazine the 16th volume fourth phase P218 in 2006, the people such as Liang Jianhua are at paper " 2 '; 4 " two (trimethyl silicane) Erythromycin A 9-O-(1-isopropyl oxygen cyclohexyl of-O-) the by product research of isonitrosomethylization reaction " in to adopt methyl iodide be methylating reagent, tetrahydrofuran (THF) and dimethyl sulfoxide (DMSO) are solvent, and potassium hydroxide is that catalyzer carries out methylation reaction.
From reported paper and patent, do not introduce the report of the recycling of alkylating reagent.
Summary of the invention
The object of the invention is in clarithromycin building-up process, adopting p-methyl benzenesulfonic acid methyl esters is methylating reagent, and has studied the recycle utilization of p-methyl benzenesulfonic acid methyl esters after methylation reaction.
In order to achieve the above object, the present invention is achieved through the following technical solutions:
Methylation reaction in a kind of clarithromycin building-up process, (2 '; 4 " the two trimethyl silicon based Erythromycin A-9[O-(1-oxyethyl group-1-the first and second bases) of)-O] oxime (formula 2, hereinafter referred to as compound 2) obtains through 6 HMs reactions, in its methylation reaction:
1, adopting p-methyl benzenesulfonic acid methyl esters is methylating reagent, and potassium hydroxide is catalyzer, and methyl tertiary butyl ether and dimethyl sulfoxide (DMSO) are that solvent carries out methylation reaction;
2, the mol ratio of p-methyl benzenesulfonic acid methyl esters and compound 2 is 1.5~3.5, preferably 2~2.5; The mol ratio of potassium hydroxide and compound 2 is 1.5~3.5, preferably 2~2.5.
3, the quality of methyl tertiary butyl ether is 4~10 times of consumptions of compound 2, preferably 5~7 times of consumptions; The quality of dimethyl sulfoxide (DMSO) is 4~10 times of consumptions of compound 2, preferably 5~7 times of consumptions.
4, methylation reaction temperature is controlled at 0~30 DEG C, preferably 15~20 DEG C.
5, the methylation reaction time is controlled at 20~60min, preferably 25~40min.
In above-mentioned methylation reaction, the recovery method of alkylating reagent is as follows:
After methylation reaction finishes, add water stratification, dimethyl sulfoxide (DMSO) (DMSO) layer reclaims after dry and obtains p-methyl benzenesulfonic acid potassium, adds thionyl chloride reaction, obtains p-methyl benzene sulfonic chloride, then reacts with methyl alcohol and regenerate p-methyl benzenesulfonic acid methyl esters.
Wherein, the mol ratio of thionyl chloride and p-methyl benzenesulfonic acid potassium is 3~10, preferably 5~7.
It is methylating reagent that the present invention adopts p-methyl benzenesulfonic acid methyl esters, can effectively avoid the generation of two methyl impurity; With respect to other methylating reagent, its selectivity that methylates is stronger, and along with the prolongation in reaction times, two methyl impurity also has no obvious increase, is better than other methylating reagent.After p-methyl benzenesulfonic acid methyl ester methyl, generate p-methyl benzenesulfonic acid potassium, by reacting and regenerate p-methyl benzenesulfonic acid methyl esters with thionyl chloride and methyl alcohol, realized applying mechanically of methylating reagent.Compound 2 is self-control, and synthetic method is:
In four-hole bottle, drop into 20g erythromycin oxime, 180ml methylene dichloride; Be cooled to 16~18 DEG C, drop into 5.0g pyridine hydrochloride and 7.7ml2-ethoxy propylene, at 20~25 DEG C, be incubated 15 minutes, add 6.4g imidazoles, continue to be incubated 10 minutes at 20~25 DEG C, be cooled to 16~18 DEG C, drip 8ml trimethylchlorosilane, within 2~3 minutes, dropwise, control temperature at 25~30 DEG C. be incubated 15 minutes.Add 70ml water termination reaction, and with 20%NaOH regulate pH value to 9~10.Layering, reclaims dry dichloromethane, adds the making beating of 50ml acetone, is cooled to 0 DEG C, is incubated 1 hour, filters, and oven dry can obtain 19.2g compound 2, and purity is 95%.
Embodiment
embodiment mono-:
20g(0.02mol) compound 2 drops into the dissolving of 120g methyl tertiary butyl ether, add again 120g DMSO, be cooled to 15 DEG C, drop into 7.6g(0.04mol) p-methyl benzenesulfonic acid methyl esters, stir after 5 minutes, drop into again 2.3g(0.04mol) potassium hydroxide powder, keeping temperature of reaction is 15 DEG C, reacts 25 minutes, adds 50ml water termination reaction, stratification, methyl tertiary butyl ether feed liquid directly reclaims dry, and oven dry can obtain 19.9g solid chemical compound 1, purity 85.2%, wherein the complete compound 2 of unreacted has 6.4%, two replacement impurity 2.2%.DMSO layer and water layer directly reclaim to do and can obtain solid p-methyl benzenesulfonic acid potassium 9.0g.
embodiment bis-:
20g(0.02mol) compound 2 drops into the dissolving of 120g methyl tertiary butyl ether, add again 120gDMSO, be cooled to 15 DEG C, drop into 5.58g(0.03mol) p-methyl benzenesulfonic acid methyl esters, stir after 5 minutes, drop into again 1.68g(0.03mol) potassium hydroxide powder, keeping temperature of reaction is 30 DEG C, reacts 20 minutes, adds 50ml water termination reaction, stratification, methyl tertiary butyl ether feed liquid directly reclaims dry, and oven dry can obtain 19.5g solid chemical compound 1, purity 85.8%, wherein the complete compound 2 of unreacted has 6.5%, two replacement impurity 1.5%.DMSO layer and water layer directly reclaim to do and can obtain solid p-methyl benzenesulfonic acid potassium 11.3g.
embodiment tri-:
20g(0.02mol) compound 2 drops into the dissolving of 120g methyl tertiary butyl ether, add again 120gDMSO, be cooled to 0-5 DEG C, drop into 13.0g(0.07mol) p-methyl benzenesulfonic acid methyl esters, stir after 5 minutes, drop into again 3.9g(0.07mol) potassium hydroxide powder, maintenance temperature of reaction is 0-5 DEG C, reacts 60 minutes, adds 50ml water termination reaction, stratification, methyl tertiary butyl ether feed liquid directly reclaims dry, and oven dry can obtain 19.8g solid chemical compound 1, purity 86.7%, wherein the complete compound 2 of unreacted has 5.4%, two replacement impurity 2.2%.DMSO layer and water layer directly reclaim to do and can obtain solid p-methyl benzenesulfonic acid potassium 9.1g.
embodiment tetra-:
20g(0.02mol) compound 2 drops into the dissolving of 200g methyl tertiary butyl ether, add again 200gDMSO, be cooled to 15 DEG C, drop into 7.6g(0.04mol) p-methyl benzenesulfonic acid methyl esters, stir after 5 minutes, drop into again 2.3g(0.04mol) potassium hydroxide powder, keeping temperature of reaction is 15 DEG C, reacts 40 minutes, adds 50ml water termination reaction, stratification, methyl tertiary butyl ether feed liquid directly reclaims dry, and oven dry can obtain 19.2g solid chemical compound 1, purity 86.8%, wherein the complete compound 2 of unreacted has 3.3%, two replacement impurity 3.2%.DMSO layer and water layer directly reclaim to do and can obtain solid p-methyl benzenesulfonic acid potassium 8.7g.
embodiment five:
20g(0.02mol) compound 2 drops into the dissolving of 80g methyl tertiary butyl ether, add again 80gDMSO, be cooled to 15 DEG C, drop into 7.6g(0.04mol) p-methyl benzenesulfonic acid methyl esters, stir after 5 minutes, drop into again 2.3g(0.04mol) potassium hydroxide powder, keeping temperature of reaction is 15 DEG C, reacts 40 minutes, adds 50ml water termination reaction, stratification, methyl tertiary butyl ether feed liquid directly reclaims dry, and oven dry can obtain 19.8g solid chemical compound 1, purity 84.8%, wherein the complete compound 2 of unreacted has 5.3%, two replacement impurity 2.8%.DMSO layer and water layer directly reclaim to do and can obtain solid p-methyl benzenesulfonic acid potassium 8.9g.
embodiment six:
20g(0.095mol) p-methyl benzenesulfonic acid potassium, drops in 100ml methylene dichloride, adds 56g(0.47mol) thionyl chloride, be warming up at 30 DEG C and react 5 hours, rear recovery dry dichloromethane and thionyl chloride, add the making beating of 50ml water, filter, obtain p-methyl benzene sulfonic chloride wet product, drop in 50ml methyl alcohol, drip 25% aqueous sodium hydroxide solution, regulating pH value is 9.0, controlling temperature of reaction is 25 DEG C, stirs 2h, layering.Take off a layer reactant, upper strata 50ml methylbenzene extraction, extracting solution merges with lower floor after reclaiming toluene, water and the washing of 5% solution of potassium carbonate successively, the dry toluene of reclaim under reduced pressure, obtains p-methyl benzenesulfonic acid methyl esters 16.5g.
embodiment seven:
20g(0.095mol) p-methyl benzenesulfonic acid potassium, drops in 100ml methylene dichloride, adds 113g(0.95mol) thionyl chloride, be warming up at 30 DEG C and react 5 hours, rear recovery dry dichloromethane and thionyl chloride, add the making beating of 50ml water, filter, obtain p-methyl benzene sulfonic chloride wet product, drop in 50ml methyl alcohol, drip 25% aqueous sodium hydroxide solution, regulating pH value is 9.0, controlling temperature of reaction is 25 DEG C, stirs 2h, layering.Take off a layer reactant, upper strata 50ml methylbenzene extraction, extracting solution merges with lower floor after reclaiming toluene, water and the washing of 5% solution of potassium carbonate successively, the dry toluene of reclaim under reduced pressure, obtains p-methyl benzenesulfonic acid methyl esters 17.3g.
embodiment eight:
20g(0.095mol) p-methyl benzenesulfonic acid potassium, drops in 100ml methylene dichloride, adds 33.9g(0.285mol) thionyl chloride, be warming up at 30 DEG C and react 5 hours, rear recovery dry dichloromethane and thionyl chloride, add the making beating of 50ml water, filter, obtain p-methyl benzene sulfonic chloride wet product, drop in 50ml methyl alcohol, drip 25% aqueous sodium hydroxide solution, regulating pH value is 9.0, controlling temperature of reaction is 25 DEG C, stirs 2h, layering.Take off a layer reactant, upper strata 50ml methylbenzene extraction, extracting solution merges with lower floor after reclaiming toluene, water and the washing of 5% solution of potassium carbonate successively, the dry toluene of reclaim under reduced pressure, obtains p-methyl benzenesulfonic acid methyl esters 15.8g.
Above-described embodiment is only for the inventive concept of the present invention of explaining, but not restriction to rights protection of the present invention, allly utilizes this design to carry out the change of unsubstantiality to the present invention, all should fall into protection scope of the present invention.
Claims (5)
1. methylation reaction in a clarithromycin building-up process, its intermediate is by compound 2, (2 ', 4 ") the two trimethyl silicon based Erythromycin A-9[O-(1-oxyethyl group-1-the first and second bases) of-O] oxime; obtain through 6 HMs reactions, it is characterized in that:
In this methylation reaction:
Adopting p-methyl benzenesulfonic acid methyl esters is methylating reagent, and potassium hydroxide is catalyzer, and methyl tertiary butyl ether and dimethyl sulfoxide (DMSO) are that solvent carries out methylation reaction; Wherein, the mol ratio of p-methyl benzenesulfonic acid methyl esters and compound 2 is 1.5~3.5; The mol ratio of potassium hydroxide and compound 2 is 1.5~3.5; The quality of methyl tertiary butyl ether is 4~10 times of consumptions of compound 2; The quality of dimethyl sulfoxide (DMSO) is 4~10 times of consumptions of compound 2; Methylation reaction temperature is controlled at 0~30 DEG C, and the reaction times is controlled at 20~60min;
Methylating reagent in methylation reaction carries out recovery, the mode adopting:
After methylation reaction finishes, add water stratification, dimethyl sulfoxide (DMSO) layer reclaims after dry and obtains p-methyl benzenesulfonic acid potassium, adds thionyl chloride reaction, obtains p-methyl benzene sulfonic chloride, then reacts with methyl alcohol and regenerate p-methyl benzenesulfonic acid methyl esters; Wherein, the mol ratio of thionyl chloride and p-methyl benzenesulfonic acid potassium is 3~10.
2. methylation reaction in a kind of clarithromycin building-up process as claimed in claim 1, is characterized in that: the quality of methyl tertiary butyl ether is 5~7 times of consumptions of compound 2; The quality of dimethyl sulfoxide (DMSO) is 5~7 times of consumptions of compound 2.
3. methylation reaction in a kind of clarithromycin building-up process as claimed in claim 1, is characterized in that: methylation reaction temperature is controlled at 15~20 DEG C.
4. methylation reaction in a kind of clarithromycin building-up process as claimed in claim 1, is characterized in that: the methylation reaction time is controlled at 25~40min.
5. methylation reaction in a kind of clarithromycin building-up process as claimed in claim 1, is characterized in that: wherein methylating reagent recovery method, wherein, the mol ratio of thionyl chloride and p-methyl benzenesulfonic acid potassium is 5~7.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210214998.6A CN102718821B (en) | 2012-06-27 | 2012-06-27 | Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210214998.6A CN102718821B (en) | 2012-06-27 | 2012-06-27 | Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102718821A CN102718821A (en) | 2012-10-10 |
CN102718821B true CN102718821B (en) | 2014-12-03 |
Family
ID=46944713
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201210214998.6A Active CN102718821B (en) | 2012-06-27 | 2012-06-27 | Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102718821B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103880901A (en) * | 2012-12-23 | 2014-06-25 | 菏泽市方明制药有限公司 | Preparation method of clarithromycin intermediate methide |
CN103232506B (en) * | 2013-04-11 | 2016-02-03 | 宜昌东阳光药业股份有限公司 | The preparation technology of clarithromycin impurity O and similar compound thereof |
CN105801642B (en) * | 2016-03-11 | 2019-03-26 | 北京理工大学 | A method of preparing the bis--O- erythromycin A of 6,11- |
CN106905204B (en) * | 2017-02-24 | 2018-07-20 | 杭州新桂实业有限公司 | A kind of recovery method of methylation reaction solvent in clarithromycin building-up process |
CN116239644A (en) * | 2023-01-09 | 2023-06-09 | 浙江国邦药业有限公司 | Recycling method of protective reaction auxiliary materials on clarithromycin |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001064224A1 (en) * | 2000-02-29 | 2001-09-07 | Teva Pharmaceutical Industries Ltd. | Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same |
WO2004011009A1 (en) * | 2002-07-25 | 2004-02-05 | Enanta Pharmaceuticals, Inc. | 6, 11-4-carbon bridged erythromycin derivatives |
WO2009007988A1 (en) * | 2007-07-11 | 2009-01-15 | Alembic Limited | Process for the preparation of 6-o-methylerythromycin a 9-oxime |
CN101362783A (en) * | 2008-10-06 | 2009-02-11 | 浙江国邦药业有限公司 | Preparation method of erythromycin A(E) oxime |
CN102250173A (en) * | 2010-05-18 | 2011-11-23 | 上海医药工业研究院 | Preparation methods of 6-O-methylerythromycin A derivative and clarithromycin |
-
2012
- 2012-06-27 CN CN201210214998.6A patent/CN102718821B/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001064224A1 (en) * | 2000-02-29 | 2001-09-07 | Teva Pharmaceutical Industries Ltd. | Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same |
WO2004011009A1 (en) * | 2002-07-25 | 2004-02-05 | Enanta Pharmaceuticals, Inc. | 6, 11-4-carbon bridged erythromycin derivatives |
WO2009007988A1 (en) * | 2007-07-11 | 2009-01-15 | Alembic Limited | Process for the preparation of 6-o-methylerythromycin a 9-oxime |
CN101362783A (en) * | 2008-10-06 | 2009-02-11 | 浙江国邦药业有限公司 | Preparation method of erythromycin A(E) oxime |
CN102250173A (en) * | 2010-05-18 | 2011-11-23 | 上海医药工业研究院 | Preparation methods of 6-O-methylerythromycin A derivative and clarithromycin |
Non-Patent Citations (4)
Title |
---|
Ernesto Brunet,等.Preparation of clarithromycin. Selective 6-O-methylation of the novel erythromycin A 9-O-(2-pyrimidyl)oxime.《Tetrahedron Letters》.2007,第48卷(第8期),第1321-1324页. * |
R.T.莫里森,等著,复旦大学有机化学教研组译.有机化学.《有机化学》.科学出版社 第一版,1980,第434-435页. * |
孔祥文,等.有机化学.《有机化学》.第1版,2010,第204-205页. * |
邓志华,等.红霉素A肟的新合成方法.《中国药物化学杂志》.2003,第13卷(第2期),第89-92、96页. * |
Also Published As
Publication number | Publication date |
---|---|
CN102718821A (en) | 2012-10-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102718821B (en) | Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent | |
CN104876995A (en) | A preparing method of a chenodeoxycholic acid derivative | |
CN104961715A (en) | Preparation method for Dapagliflozin | |
CN107963958A (en) | The synthetic method of trans- 4- (trans- 4 '-alkyl-cyclohexyl) cyclohexyl. vinyl liquid crystal monomer | |
CN102766166B (en) | A kind of preparation method of flame retardant hexaphenoxy cyclotriphosphazene compound | |
CN102993246A (en) | Method for synthesizing isopropyl-beta-D-thiogalactoside | |
CN103864673A (en) | Preparation of chirality-1-t-butyloxycarboryl-3-hydroxy piperidine and method for chirality turning | |
CN102050705B (en) | Novel method for preparing resveratrol through decarbonylation heck reaction | |
CN103965125A (en) | Synthetic method of 3,3'-binitro-5,5'-di-1,2,4-triazole | |
CN104844525B (en) | A kind of preparation method of Rosuvastatin calcium impurities | |
CN103304550A (en) | Preparation method of Olmesartan Medoxomil | |
CN101417956A (en) | Synthesis method of methoxamine hydrochloride | |
CN101693662B (en) | Preparation method of heat-resisting stabilizing agent of bisphenolmonoacryates | |
CN103772189B (en) | Synthesis method of diethylstilbestrol compound methyl pigeon pea ketonic acid A | |
CN104628653A (en) | Method for synthesizing key intermediate of rosuvastatin calcium | |
CN109608349A (en) | A kind of environment-friendly preparation method thereof of magnesium glycinate | |
CN105294556A (en) | Method for preparing montelukast acid | |
CN104326927B (en) | A kind of preparation method of 1-[2-amino-1-(4-methoxyphenyl) ethyl] Hexalin sulfate | |
CN103044356A (en) | New method for synthesizing levocetirizine and key intermediate thereof | |
CN103804187B (en) | Synthesis method of diethylstilbestrol compound pigeon pea ketonic acid A | |
CN105175359A (en) | Lomerizine Hydrochloride isomeride and preparation method therefor | |
CN106167453B (en) | A kind of preparation method of 2,4 dichlorophenoxyacetic acid methyl esters | |
CN205368191U (en) | N - isopropyl azanol production system | |
CN111138269A (en) | Process method for preparing 2-butanone acid sodium salt | |
CN105732613B (en) | A kind of synthetic method of 9 demethyl (+) α dihydrotetrabenazineins |
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 |