CN104497089A - Synthesis method of hydrocortisone intermediate - Google Patents
Synthesis method of hydrocortisone intermediate Download PDFInfo
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- CN104497089A CN104497089A CN201410747239.5A CN201410747239A CN104497089A CN 104497089 A CN104497089 A CN 104497089A CN 201410747239 A CN201410747239 A CN 201410747239A CN 104497089 A CN104497089 A CN 104497089A
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- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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Abstract
The invention discloses a synthesis method of a hydrocortisone intermediate. The hydrocortisone intermediate is prepared from a compound I as an initial raw material through cyanohydrintion, removal, etherification, rearrangement and replacement reaction. The hydrocortisone intermediate is available in raw materials; the adopted synthesis process is economical in technical route, low in production cost, simple and convenient to operate, high in yield, environment-friendly, and suitable for massive production.
Description
Technical field
The present invention relates to a kind of synthetic method of medicine intermediate, be specifically related to a kind of synthetic method of hydrocortisone intermediate.
Background technology
Hydrocortisone is a class high reactivity and has effect adrenin corticosteroid drugs such as affecting carbohydrate metabolism, anti-inflammatory, antitoxin, antishock and antianaphylaxis, be widely used in the treatment of the anaphylactic diseases such as adrenal cortex function deficiency, reactivity rheumatosis, similar rheumatism, lupus erythematosus, serious bronchial asthma, serious dermatitis, also can be used for the treatment of high febrile illness caused by some bacteriological infection.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of synthetic method of hydrocortisone intermediate, and it can reduce reactions steps, reduces production cost.
For solving the problems of the technologies described above, the technical solution of the synthetic method of hydrocortisone intermediate of the present invention is:
Take chemical compounds I as starting raw material, through cyanohydrination, elimination, etherificate, rearrangement, replacement(metathesis)reaction, obtained hydrocortisone intermediate, reaction scheme is as follows:
。
The step of described cyanohydrination reaction is: take chemical compounds I as substrate, first alcohol and water is solvent, and under the weak basic condition that basic catalyst is formed, add acetone cyanohydrin as cyano group addition reagent, insulation reaction, obtains compound ii;
In described cyanohydrination reaction, the mass ratio of solvent and chemical compounds I is 1 ~ 10:1; The mass ratio of acetone cyanohydrin and chemical compounds I is 1 ~ 2:1; Basic catalyst is salt of wormwood or sodium carbonate solution, and the consumption of basic catalyst is catalytic amount, and the mass ratio of basic catalyst and chemical compounds I is no more than 5%; The insulation reaction time is 18 ~ 24 hours; Insulation reaction temperature is 35 ~ 40 DEG C.
The step of described eliminative reaction is: take compound ii as substrate, and methylene dichloride or chloroform are organic solvent, add boron trifluoride acetic acid solution, insulation reaction, obtain compound III;
In described eliminative reaction, the mass ratio of organic solvent and compound ii is 10 ~ 20:1; The mass ratio of boron trifluoride acetic acid solution and compound ii is 0.5 ~ 1.5:1; The insulation reaction time is 5 ~ 8 hours; Insulation reaction temperature is 35 ~ 45 DEG C.
The step of described etherification reaction is: be substrate with compound III, take methylene dichloride as solvent, under the weak basic condition that basic catalyst is formed, adds dimethylchlorosilane and react, obtain compounds Ⅳ;
In described etherification reaction, the mass ratio of solvent and compound III is 5 ~ 10:1; Basic catalyst is triethylamine or quadrol; The pH value scope that basic catalyst is formed is 8 ~ 11; The mass ratio of dimethylchlorosilane and compound III is 0.5 ~ 1.5:1; Temperature of reaction is-5 ~ 10 DEG C.
The step of described rearrangement reaction is: take compounds Ⅳ as substrate, with tetrahydrofuran (THF) or dimethyl furan for solvent, adds lithium diisopropylamine and carries out rearrangement reaction; Add hydrochloric acid formation acidic conditions after having reacted and carry out transposition, extract as extraction solvent with chloroform or methylene dichloride, obtain compound V;
In described rearrangement reaction, solvent is tetrahydrofuran (THF); The mass ratio of solvent and compounds Ⅳ is 3 ~ 8:1; Reaction times is 5 ~ 8 hours; Temperature of reaction is-30 ~-60 DEG C; Form acidic conditions pH value scope be 1 ~ 2; Extraction solvent is chloroform.
The step of described replacement(metathesis)reaction is: with compound V for substrate, adds acetone or DMF is that solvent dissolves, and adds Potassium ethanoate, carries out replacement(metathesis)reaction, obtain compound VI under the solutions of weak acidity that an acidic catalyst is formed.
In described replacement(metathesis)reaction, solvent is acetone; The mass ratio of solvent and compound V is 15 ~ 22:1; The mass ratio of Potassium ethanoate and compound V is 0.8 ~ 1.5:1; An acidic catalyst is acetic acid; The consumption of an acidic catalyst is catalytic amount, and the mass ratio of an acidic catalyst and compound V is no more than 5%; Reaction times is 4 ~ 6 hours; Temperature of reaction is 45 ~ 60 DEG C.
The technique effect that the present invention can reach is:
Raw material of the present invention is easy to get, the synthesis technology route economy adopted, low production cost, easy and simple to handle, and yield is high, environmental protection, is applicable to large production.
Below in conjunction with embodiment, the present invention is further detailed explanation.
Embodiment
The synthetic method of hydrocortisone intermediate of the present invention take chemical compounds I as starting raw material, through cyanohydrination, elimination, etherificate, rearrangement, replacement(metathesis)reaction, and obtained hydrocortisone intermediate, reaction scheme is as follows:
The step of described cyanohydrination reaction is: take chemical compounds I as substrate, first alcohol and water is solvent, and under the weak basic condition that basic catalyst is formed, add acetone cyanohydrin as cyano group addition reagent, insulation reaction at moderate temperatures, obtains compound ii; Rear hydrochloric acid or sulfuric acid termination reaction are reacted;
Wherein, the mass ratio of solvent and chemical compounds I is 1 ~ 10:1, preferably 2 ~ 5:1;
The mass ratio of acetone cyanohydrin and chemical compounds I is 1 ~ 2:1;
Basic catalyst can be salt of wormwood or sodium carbonate solution, and the consumption of basic catalyst is catalytic amount, and the mass ratio of basic catalyst and chemical compounds I is no more than 5%;
The insulation reaction time is 18 ~ 24 hours; Insulation reaction temperature is 35 ~ 40 DEG C.
The step of described eliminative reaction is: take compound ii as substrate, and methylene dichloride or chloroform are organic solvent, add boron trifluoride acetic acid solution, at moderate temperatures insulation reaction, obtains compound III (namely 9 hydroxyls eliminate thing); Sodium carbonate or sodium hydroxide termination reaction is added, washing layering after having reacted; Be evaporated to most of material to separate out, add proper amount of methanol, remaining methylene dichloride is carried in decompression secretly;
Wherein, the mass ratio of organic solvent and compound ii is 10 ~ 20:1;
The mass ratio of boron trifluoride acetic acid solution and compound ii is 0.5 ~ 1.5:1;
The insulation reaction time is 5 ~ 8 hours; Insulation reaction temperature is 35 ~ 45 DEG C.
The step of described etherification reaction is: be substrate with compound III, take methylene dichloride as solvent, under the weak basic condition that basic catalyst is formed, adds dimethylchlorosilane and react; Add water after having reacted extracting and demixing, concentrated obtained compounds Ⅳ;
Wherein, the mass ratio of solvent and compound III is 5 ~ 10:1;
Basic catalyst can be triethylamine or quadrol, preferred triethylamine; The pH value scope that basic catalyst is formed is 8 ~ 11;
The mass ratio of dimethylchlorosilane and compound III is 0.5 ~ 1.5:1;
Insulation reaction temperature is-5 ~ 10 DEG C.
The step of described rearrangement reaction is: take compounds Ⅳ as substrate, with tetrahydrofuran (THF) or dimethyl furan for solvent, adds lithium diisopropylamine and carries out rearrangement reaction; Add hydrochloric acid formation acidic conditions after having reacted and carry out transposition, extract as extraction solvent with chloroform or methylene dichloride, carry out concentrating under reduced pressure after washing is clean, obtain compound V;
Wherein, the preferred tetrahydrofuran (THF) of solvent; The mass ratio of solvent and compounds Ⅳ is 3 ~ 8:1;
The insulation reaction time is 5 ~ 8 hours; Insulation reaction temperature is-30 ~-60 DEG C;
Form acidic conditions pH value scope be 1 ~ 2;
Extract the preferred chloroform of solvent.
The step of described replacement(metathesis)reaction is: with compound V for substrate, add acetone or DMF(dimethyl formamide) dissolve for solvent, Potassium ethanoate is added under the solutions of weak acidity that an acidic catalyst is formed, be heated to backflow, after replacement(metathesis)reaction completes, concentrate and remove most of solvent, then add water, material is separated out, and obtains compound VI;
Wherein, the preferred acetone of solvent; The mass ratio of solvent and compound V is 15 ~ 22:1;
The mass ratio of Potassium ethanoate and compound V is 0.8 ~ 1.5:1;
The preferred acetic acid of an acidic catalyst; The consumption of an acidic catalyst is catalytic amount, and the mass ratio of an acidic catalyst and compound V is no more than 5%;
The insulation reaction time is 4 ~ 6 hours; Insulation reaction temperature is 45 ~ 60 DEG C.
The present invention is with chemical compounds I (9 α-OH-4AD,) be reaction substrate, under the prerequisite not eliminating 9 hydroxyls, first carry out the cyanohydrination addition reaction of 17 ketone groups, and then carry out the eliminative reaction of 9 hydroxyls, to be different from prior art first 9 eliminate the synthetic route of carrying out the addition of 17 ketone group cyanohydrinations again, being more different from traditional take diene as the synthesis route of starting raw material.Owing to there being the reservation of 9 hydroxyls, in 17 addition reaction processes, the conversion of chemical compounds I is more thorough, and yield and quality level have obvious raising.
The present invention is in the eliminative reaction of 9 hydroxyls, with methylene dichloride or chloroform for solvent, add appropriate boron trifluoride acetic acid solution, under relatively mild reaction conditions, just can carry out the elimination of 9 hydroxyls well, be different from prior art the report adopting aceticanhydride or sulfuric acid to carry out 9 hydroxyl eliminative reaction.
The present invention is that etherifying reagent carries out etherification reaction in the introducing of 17 side chains with dimethylchlorosilane, under the effect of lithium diisopropylamine, Intramolecular core addition rearrangement reaction is carried out again after etherification reaction completes, transposition generates 17 side chains of band halogen in acid condition, then carries out replacement(metathesis)reaction with the effect of Glacial acetic acid potassium and obtain target compound VI.Advantage of the present invention is: the introducing of 17 side chains and 21 halogens settles at one go, decreases reactions steps, reduces production cost; Be different from first at 17 introducing side chains in prior art, then carry out halogenating reaction at 21 methyl, then carry out replacement(metathesis)reaction and obtain 21 bit esterified things.
Embodiment:
Cyanohydrination reacts
In 500 milliliters of three mouthfuls of reaction flasks, drop into the chemical compounds I of 50 grams, add the methyl alcohol of 100 milliliter 60% and the mixed solution of water, 65 milliliters of acetone cyanohydrins, and contain 25 ml water solution of 2.0 grams of salt of wormwood, 35 ~ 40 degree of reactions 22 hours, add 100 ml water layerings after tlc analysis reacts completely and clean, stir and be cooled to less than 5 DEG C filtrations, washing, dry 49 g of compound II, mass yield 98%, HPLC content 97.2%.
Eliminative reaction
In 500 milliliters of four mouthfuls of reaction flasks, drop into the methylene dichloride of 300 milliliters, the compound ii of 20 grams, stir molten clear after, add the boron trifluoride acetic acid solution of 25 milliliters; Be warming up to 41 DEG C of backflows 6 hours, after tlc analysis reacts completely, add water stratification and clean, be evaporated to dry, obtain 18.2 g of compound III, mass yield 91%, HPLC content 98.5%.
Etherification reaction
In 500 milliliters of four mouthfuls of reaction flasks, drop into the compound III of 20 grams, 155 milliliters of methylene dichloride, add 5 grams of triethylamines, less than 5 DEG C, drip 24 grams of dimethylchlorosilanes and control 0 ~ 5 DEG C of reaction, within about 3 hours, react completely, (thin layer control) adds the water of 120 milliliters, layering, oil reservoir less than 40 DEG C pressure reducing and steaming methylene dichloride; Add 50 ml water crystallizatioies, suction filtration, dry, obtain 21.8 g of compound IV, mass yield 109%, HPLC content 96.8%.
Rearrangement reaction
In four mouthfuls of reaction flasks of 500 milliliters, drop into the compounds Ⅳ of 20 grams, add tetrahydrofuran (THF) 115 milliliters, cool to-40 DEG C, drip lithium diisopropylamine 175 milliliters, control temperature is below-40 DEG C, be incubated 7 hours, take a sample to check, after terminating to reaction, drip hydrochloric acid 70 milliliters, slowly be warmed up to 35 DEG C, regulate pH value to 1 with hydrochloric acid, be incubated 12 hours, extract for three times with chloroform 250 milliliters, merge, washing once, neutrality is washed again with the sodium bicarbonate of 10%, dry, pressure reducing and steaming chloroform, add sherwood oil 50 milliliters, stir even after, suction filtration, dry 22 g of compound V, mass yield 110%, HPLC content 95.7%.
Replacement(metathesis)reaction
In three mouthfuls of reaction flasks of 500 milliliters, drop into the compound V of 20 grams, Potassium ethanoate 20 grams, 400 milliliters, acetone, 1 milliliter, Glacial acetic acid, is warming up to 55 DEG C, refluxes 5 hours, and thin layer controls reaction, complete, pressure reducing and steaming acetone, adds 350 milliliters of frozen water and analyses, suction filtration, after washing, dry to obtain crude product, crude product resets and add gac 4 grams of reflux decolours with 500 milliliters of chloroforms are molten, filters, pressure reducing and steaming chloroform, with 100 ml methanol crystallizations, suction filtration, dry, obtain 15 g of compound VI, mass yield 75%, HPLC content 98.7%.
Claims (7)
1. a synthetic method for hydrocortisone intermediate, is characterized in that: take chemical compounds I as starting raw material, through cyanohydrination, elimination, etherificate, rearrangement, replacement(metathesis)reaction, and obtained hydrocortisone intermediate, reaction scheme is as follows:
。
2. the synthetic method of hydrocortisone intermediate according to claim 1, it is characterized in that: the step of described cyanohydrination reaction is: take chemical compounds I as substrate, first alcohol and water is solvent, under the weak basic condition that basic catalyst is formed, add acetone cyanohydrin as cyano group addition reagent, insulation reaction, obtains compound ii;
The step of described eliminative reaction is: take compound ii as substrate, and methylene dichloride or chloroform are organic solvent, add boron trifluoride acetic acid solution, insulation reaction, obtain compound III;
The step of described etherification reaction is: be substrate with compound III, take methylene dichloride as solvent, under the weak basic condition that basic catalyst is formed, adds dimethylchlorosilane and react, obtain compounds Ⅳ;
The step of described rearrangement reaction is: take compounds Ⅳ as substrate, with tetrahydrofuran (THF) or dimethyl furan for solvent, adds lithium diisopropylamine and carries out rearrangement reaction; Add hydrochloric acid formation acidic conditions after having reacted and carry out transposition, extract as extraction solvent with chloroform or methylene dichloride, obtain compound V;
The step of described replacement(metathesis)reaction is: with compound V for substrate, adds acetone or DMF is that solvent dissolves, and adds Potassium ethanoate, carries out replacement(metathesis)reaction, obtain compound VI under the solutions of weak acidity that an acidic catalyst is formed.
3. the synthetic method of hydrocortisone intermediate according to claim 2, is characterized in that: in described cyanohydrination reaction, the mass ratio of solvent and chemical compounds I is 1 ~ 10:1;
The mass ratio of acetone cyanohydrin and chemical compounds I is 1 ~ 2:1;
Basic catalyst is salt of wormwood or sodium carbonate solution, and the consumption of basic catalyst is catalytic amount, and the mass ratio of basic catalyst and chemical compounds I is no more than 5%;
The insulation reaction time is 18 ~ 24 hours; Insulation reaction temperature is 35 ~ 40 DEG C.
4. the synthetic method of hydrocortisone intermediate according to claim 2, is characterized in that: in described eliminative reaction, and the mass ratio of organic solvent and compound ii is 10 ~ 20:1;
The mass ratio of boron trifluoride acetic acid solution and compound ii is 0.5 ~ 1.5:1;
The insulation reaction time is 5 ~ 8 hours; Insulation reaction temperature is 35 ~ 45 DEG C.
5. the synthetic method of hydrocortisone intermediate according to claim 2, is characterized in that: in described etherification reaction, and the mass ratio of solvent and compound III is 5 ~ 10:1;
Basic catalyst is triethylamine or quadrol; The pH value scope that basic catalyst is formed is 8 ~ 11;
The mass ratio of dimethylchlorosilane and compound III is 0.5 ~ 1.5:1;
Temperature of reaction is-5 ~ 10 DEG C.
6. the synthetic method of hydrocortisone intermediate according to claim 2, is characterized in that: in described rearrangement reaction, solvent is tetrahydrofuran (THF); The mass ratio of solvent and compounds Ⅳ is 3 ~ 8:1;
Reaction times is 5 ~ 8 hours; Temperature of reaction is-30 ~-60 DEG C;
Form acidic conditions pH value scope be 1 ~ 2;
Extraction solvent is chloroform.
7. the synthetic method of hydrocortisone intermediate according to claim 2, is characterized in that: in described replacement(metathesis)reaction, solvent is acetone; The mass ratio of solvent and compound V is 15 ~ 22:1;
The mass ratio of Potassium ethanoate and compound V is 0.8 ~ 1.5:1;
An acidic catalyst is acetic acid; The consumption of an acidic catalyst is catalytic amount, and the mass ratio of an acidic catalyst and compound V is no more than 5%;
Reaction times is 4 ~ 6 hours; Temperature of reaction is 45 ~ 60 DEG C.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017364A (en) * | 2015-07-06 | 2015-11-04 | 湖南新合新生物医药有限公司 | Methylprednisolone intermediate, preparation method therefor and application thereof |
| CN107619426A (en) * | 2016-07-15 | 2018-01-23 | 天津金耀集团有限公司 | A kind of preparation method of Fluocinonide |
| CN107619423A (en) * | 2016-07-15 | 2018-01-23 | 天津金耀集团有限公司 | A kind of preparation method of hydrocortisone |
| CN107619424A (en) * | 2016-07-15 | 2018-01-23 | 天津金耀集团有限公司 | A kind of preparation method of 17 hydroxyl nitrile steroid derivative |
| CN108264531A (en) * | 2016-12-30 | 2018-07-10 | 上海市农药研究所有限公司 | A kind of preparation method of NSC 24345 |
| CN115385797A (en) * | 2022-09-15 | 2022-11-25 | 山东斯瑞药业有限公司 | Resource utilization treatment method for chloride production mother liquor of anecortave acetate |
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2014
- 2014-12-10 CN CN201410747239.5A patent/CN104497089A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4921638A (en) * | 1986-11-05 | 1990-05-01 | The Upjohn Company | 17β-cyano-9α,17α-dihydroxyandrost-4-en-3-one |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017364A (en) * | 2015-07-06 | 2015-11-04 | 湖南新合新生物医药有限公司 | Methylprednisolone intermediate, preparation method therefor and application thereof |
| CN107619426A (en) * | 2016-07-15 | 2018-01-23 | 天津金耀集团有限公司 | A kind of preparation method of Fluocinonide |
| CN107619423A (en) * | 2016-07-15 | 2018-01-23 | 天津金耀集团有限公司 | A kind of preparation method of hydrocortisone |
| CN107619424A (en) * | 2016-07-15 | 2018-01-23 | 天津金耀集团有限公司 | A kind of preparation method of 17 hydroxyl nitrile steroid derivative |
| CN108264531A (en) * | 2016-12-30 | 2018-07-10 | 上海市农药研究所有限公司 | A kind of preparation method of NSC 24345 |
| CN108264531B (en) * | 2016-12-30 | 2022-08-09 | 上海市农药研究所有限公司 | Preparation method of anecortave acetate |
| CN115385797A (en) * | 2022-09-15 | 2022-11-25 | 山东斯瑞药业有限公司 | Resource utilization treatment method for chloride production mother liquor of anecortave acetate |
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