CN108840895A - The preparation method of Etonogestrel and Desogestrel important intermediate - Google Patents
The preparation method of Etonogestrel and Desogestrel important intermediate Download PDFInfo
- Publication number
- CN108840895A CN108840895A CN201810369554.7A CN201810369554A CN108840895A CN 108840895 A CN108840895 A CN 108840895A CN 201810369554 A CN201810369554 A CN 201810369554A CN 108840895 A CN108840895 A CN 108840895A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- formula
- solvent
- product
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of Etonogestrel and the preparation methods of Desogestrel important intermediate, it is characterized in that, it is to be prepared using formula (2) compound represented as starting material, the present invention obtains target product by the reaction of 5 steps in high yield, reaction condition is mild in whole process simultaneously, risk is extremely low, easy to operate.The problems such as no matter being all significantly better than from atom economy angle, safety perspective and Costco Wholesale angle or from storage transport angles using known references process, while avoiding used reagent and big, unstable, by-product environmental pollution is serious intermediate product toxicity.The Desogestrel and Etonogestrel important intermediate (1) being prepared in method of the present invention react more complete since its reaction condition is mild, and chemo-selective is high, and reaction yield is high, and solvent can recycle, thus is convenient for industrializing implementation.Reaction formula is as follows：
Description
Technical field
The present invention relates to a kind of new processes for preparing Desogestrel and Etonogestrel important intermediate.
Background technique
Desogestrel and Etonogestrel are the potent progestational hormone of a new generation, they are after human body metabolism to progesterone receptor
Affinity is strong, there is reliable inhibition Effect of Ovulation, low to androgen receptor affinity, therefore only slight androgen and albumen is same
Change metabolic activity, no androgenic activity but has stronger antiestrogenic, has no adverse effects to lipid metaboli, to Human Physiology
Metabolic effect is small.Desogestrel and Etonogestrel are third generation novel contraceptive drugs, and structural formula is as follows：
Currently, in existing technology, committed step be key compound (1) (its chemical name is：13 β-ethyl -11- is sub-
Female alkene -3- the ketone of methyl-17 beta-hydroxy -4-, alias are：13 β-ethyl -11- methylene-female steroid -4 (5)--17 β -ol of alkene -3- ketone)
Thioketal protection is carried out to 3 carbonyls, removing thioketal is then passed through and obtains 3 deoxidation methylene products, to 17 hydroxyls
It carries out oxidation and obtains 17 carbonyl products, 1,2 additions finally are carried out to 17 hydroxyls using metal reagent and obtain Desogestrel.Also
17 hydroxyls then can be subjected to oxidation and obtain 17 carbonyls by key compound (1) by carrying out ketal protection to 3 carbonyls
Based products carry out 1,2 additions to 17 carbonyls followed by metal reagent, remove 3 ketal protections finally by acidic hydrolysis
Obtain Etonogestrel.Its reaction equation is as follows：
In conclusion compound (1) is all essential pass during preparing Desogestrel and Etonogestrel
Key intermediate.Such as J.Amer.Chem.Soc., 1998,121:710-714 reports a kind of preparation method of compound (1),
It is chemically reacted by 12 steps, total recovery 36% obtains target product, simultaneously because it uses a large amount of valuableness, the examination that should not be obtained
Agent and process route is cumbersome, cannot achieve the industrialization of real meaning in a short time in this way.CN102675392A is with 13 β-
Ethyl -3- methoxyl group -1,3,5 (10), 8 (9)--17 β -ol of female steroid tetraene -11- ketone are that raw material first passes through and trimethyl silicane methyl
1,2 addition reactions occur for lithium, restore after through Birch and handle acquisition target product compound (1) with concentrated hydrochloric acid.This method is deposited
It is not easy to obtain and unstable in raw material, while largely using very expensive trimethyl silicane methyl lithium reagent, and use ultralow temperature
Reaction condition.Actual industrial application value in this way it is little.Verifying discovery this method by experimental study, there are 1,2
The problems such as a large amount of configuration reversals of raw material and raw material enolization can not obtain target product during addition reaction.So developing
A kind of preparation of the compound (1) with actual industrial application value just becomes have unusual meaning！
Summary of the invention
The object of the present invention is to provide a kind of preparation methods of Desogestrel important intermediate compound, to overcome existing skill
Drawbacks described above existing for art.
Method of the present invention is prepared using formula (2) compound represented as starting material, and reaction formula is such as
Under：
Specifically, including the following steps：
It is in a solvent, anti-with methyl acid phosphate dialkyl ester in the presence of the anhydrous carbonate of alkali metal by formula (6) compound
It answers, -20~60 DEG C of reactions, react 0.5~12.0h by preferably 50~60 DEG C, then preferably 2~3h adds water to reaction
In system, continue to be stirred to react 0.5-3h, from reaction system be collect product formula (1) compound, as prepare Desogestrel with
And Etonogestrel important intermediate；
The method of described collection type (1) compound, including pH is adjusted to neutral, layering, extraction, washing, filtering, filtrate
Concentration, re-crystallization step, yield can reach 90.0~95.0%；
Wherein：Alkali metal is Li, Na, K；
The anhydrous carbonate of the alkali metal is Carbon Dioxide lithium, natrium carbonicum calcinatum or Anhydrous potassium carbonate；
The anhydrous carbonate of the alkali metal is preferably Anhydrous potassium carbonate；
The methyl acid phosphate dialkyl ester is methyl-phosphoric acid dimethyl ester or methyl acid phosphate diethylester；
The solvent is anhydrous aprotic solvent, including methylene chloride, 1,2- dichloroethanes, pentane, n-hexane, second
One of nitrile, dimethyl sulfoxide, tetrahydrofuran, glycol dimethyl ether, toluene or dimethylbenzene or more；
The anhydrous carbonate of alkali metal and the molar ratio of formula (6) compound are 1~3:1；
The molar ratio of methyl acid phosphate dialkyl ester and formula (6) compound is 1~2:1；
The additional amount of water is that the weight ratio of formula (6) compound is 2~4:1；
Reaction equation is as follows：
The preparation method of described formula (6) compound, includes the following steps：
In a solvent by formula (5) compound, in inert atmosphere, chiral catalyst [Rh (R-Binap)2]+Y-Presence, fill
Enter hydrogen reaction, reaction pressure is 0.5~3.0MPa, and 60~100 DEG C of reactions are reacted 3~6h, then collected from reaction product
Product (6) compound；
The method of the collection compound (6), including be concentrated, crystallize, yield can reach 97.0~99.0%；
[the Rh (R-Binap)2]+Y-, wherein R-Binap is (+) -2,2'- is bis--(diphenyl phosphine) -1,1'- dinaphthalene；
Wherein Y-For fluoro boron acid ion, perchlorate, hexafluorophosphoricacid acid ions, it is preferred that the chiral catalyst is selected from
[Rh(R-Binap)2]+BF4 -、[Rh(R-Binap)2]+PF6-Or [Rh (R-Binap)2]+ClO4 -, structure is as follows:
US4605750A method preparation reported in the literature can be used in the catalyst；
The solvent is anhydrous aprotic solvent, preferably methylene chloride, tetrahydrofuran, glycol dimethyl ether, acetone
One or more of；
Used [Rh (R-Binap)2]+Y-It is in the reaction 1 with the mole ratio of formula (5) compound:8000~
10000；
Reaction equation is as follows：
The preparation method of described formula (5) compound, includes the following steps：
In a solvent by formula (4) compound, with nafoxidine, 30~60 DEG C are reacted, and are reacted 2.0~4.0h, are then added
Hydrobromic acid aqueous solution continues to stir 0.5-1.0h, -20~0 DEG C of reaction, then collects product (5) compound from reaction product；
The method of the collection compound (5), including elutriation, filtering, drying steps, yield can reach 90.0~
95.0%；
The solvent is proton solvent, preferably one or more of methanol or ethyl alcohol；
The weight concentration of the hydrobromic acid aqueous solution is 48% aqueous solution；
The molar ratio of the nafoxidine and formula (4) compound is 1~1.2:1；
The molar ratio of the hydrobromic acid and compound (4) is 1~2:1；
Reaction formula is as follows：
The preparation method of described formula (4) compound, includes the following steps：
In a solvent by formula (3) compound, the hydrochloric acid for being 30~36% with weight concentration, 10~20 DEG C of reactions, reaction 1.0
Then~3.0h collects product (4) compound from reaction product；
The method of the collection compound (4), including pH is adjusted to neutrality, elutriation, filtering, drying steps, yield can
Reach 85.0~90.0%；
The proton solvent is one or more of methanol, ethyl alcohol；
The weight ratio of the hydrochloric acid and formula (3) compound is 2~3:1；
Reaction equation is as follows：
The preparation method of described formula (3) compound, includes the following steps：
Formula (2) compound is dissolved in the in the mixed solvent of aprotic solvent Yu a kind of alcohol, the mixed of liquefied ammonia and metal is added
It closes in object, -78~40 DEG C of reactions react 1.0~3.0h, formula (3) compound described in product is then collected from reaction system；
The method of the collection compound (3), including quenching reaction, liquefied ammonia volatilize, adjusting pH to neutrality, extraction, divide
Layer, washing, dry, concentration, yield can reach 85.0~90.0%；
The metal is Li, Na, K；
The alcohol is one of methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol or more；
The aprotic solvent be tetrahydrofuran, glycol dimethyl ether, ether it is one or more of；
Used metal is in the reaction 8~10 with the molar ratio of formula (2) compound:1；
Used aprotic solvent is in the reaction 5 with the volume ratio of alcohol:1；
Described formula (2) compound, can according to Tetrahedron Letter 1967 (37) 3603-3606 or
Method provided by US3491089 obtains.
Method used in the present invention has no any report for Desogestrel and Etonogestrel important intermediate (1) preparation
Road is reacted by 5 steps and obtains target product in high yield, while reaction condition is mild in whole process, risk is extremely low, operation letter
It is single.No matter make from atom economy angle, safety perspective and Costco Wholesale angle or from storing transport angles and being all significantly better than
With known references process.
Product (1) is prepared with we are bright, greatly reduces production cost.Used reagent and centre are avoided simultaneously
The problems such as product toxicity is big, unstable, by-product environmental pollution is serious." three wastes " discharge is significantly dropped in its production technology
It is low.This is that other methods are unable to reach.With it is of the present invention and the method Desogestrel and Etonogestrel that are prepared
Important intermediate (1) reacts more complete since its reaction condition is mild, and chemo-selective is high, and reaction yield is high, and solvent can return
It receives and utilizes, thus be convenient for industrializing implementation.
Specific embodiment
It will be helpful to understand the present invention by implementation method in detail below, but be not intended to limit the contents of the present invention.
Embodiment 1
The preparation of compound (3)：
One dry thermometer, constant pressure funnel, reflux condensing tube, magnetic agitation are equipped with full of nitrogen
System temperature is cooled to -50 DEG C in advance in 500mL four-hole boiling flask, the dry ammonia of barium monoxide is subsequently passed, after collecting about 200mL liquefied ammonia
Lithium metal grain (1.04g is gradually added portionwise；Fw:6.94；150.00mmol), navy blue is presented in system during the addition process.With
Afterwards by formula (2) compound (5.0g；Fw:330.42；15.13mmol) it is dissolved in the in the mixed solvent of tetrahydrofuran and the tert-butyl alcohol
(50 milliliters of tetrahydrofuran, 10 milliliters of the tert-butyl alcohol), then the solution is slowly added dropwise into system, system temperature during dropwise addition
Degree maintains -40 DEG C, and after being added dropwise, system continues after stirring 0.5h.
System is added solid ammonium chloride to system blue and takes off after completion of the reaction, and ammonia is slowly then volatilized system,
2M salt acid for adjusting pH is added to neutrality, separates organic phase, water phase is extracted with methylene chloride, and then merging organic phase obtains faint yellow clear
Liquid, it is dry with anhydrous magnesium sulfate.Removing solvent is concentrated under reduced pressure and obtains thick yellow liquid, then obtains off-white color with isopropyl ether crystallization
4.53 grams of solid, molar yield：90%.
Embodiment 2
The preparation of compound (4)：
One it is dry full of nitrogen be equipped with thermometer, reflux condensing tube, magnetic agitation 250mL there-necked flask in successively
It is added 100 ml methanols, compound (3) 10.00g, 5 milliliters of concentrated hydrochloric acid, 20-25 DEG C of stirring 1.5h in subsequent system；
After end of reaction, saturated sodium bicarbonate solution is added in reaction system, adjusts pH to neutrality, is then added 100
Milliliter water continues stirring after crystal is precipitated completely by filtering, washing, vacuum drying, acquisition off-white powder
9.04 grams, molar yield：90%, HPLC content are greater than 98.0%.
Embodiment 3
The preparation of compound (5)：
One it is dry full of nitrogen be equipped with thermometer, reflux condensing tube, magnetic agitation 250mL there-necked flask in successively
100 milliliters of methanol, compound (4) (10.00g is added；Fw:300.39；33.30mmol), nafoxidine (2.37g；Fw:
71.12；33.30mmol), 50 DEG C are then raised temperature to and is stirred to react 1.0h, there are a large amount of Precipitations；
System is then cooled to -20 DEG C, by hydrobromic acid aqueous solution (5.61g, 48%, Fw:80.91,33.30mmol) molten
It is slowly added dropwise into reaction system；
After being added dropwise, 100 milliliters of water are then added in -20 DEG C of reaction 0.5h, continue stirring after crystal is precipitated completely
By filtering, washing, vacuum drying, 13.67 grams of faint yellow solid are obtained, molar yield：94.5%, HPLC content are big
In 97.0%.
Embodiment 4
The preparation of compound (6)：：
Compound (5) (20.00g is sequentially added in a 500mL high-pressure reactor；Fw434.41；46.04mmol),
Anhydrous tetrahydro furan 200mL, then by [Rh (R-Binap)2]+BF4 -(8.3mg；Fw:1435.05；It is 0.0058mmol) disposable
In addition system, for subsequent system with nitrogen vacuum displacement 3 times, subsequent system is warming up to 60 DEG C, with pressurized with hydrogen to 0.10MPa,
React 6h；Then after system temperature is down to 20 DEG C of reactor pressure releases, reaction solution is turned to be transferred to single port burning after silica gel absorption
It being concentrated under reduced pressure in bottle and removes solvent, filtered after normal heptane crystallization after, filter cake is vacuum dried to obtain off-white powder 19.50g,
Yield：97.0%, HPLC content are greater than 99.0%.
Embodiment 5
The preparation of compound (1)：
One it is dry full of nitrogen be equipped with thermometer, reflux condensing tube, magnetic agitation 1.0L there-necked flask in according to
Secondary addition compound (6) (50.00g；Fw436.43；114.57mmol), anhydrous tetrahydro furan 500mL, then by Carbon Dioxide
Potassium (47.50g；Fw:138.21；It 343.71mmol) is added at one time in system, finally by methyl-phosphoric acid dimethyl ester (21.32g；
Fw:124.08；It 171.86mmol) is added at one time in system, subsequent system is warming up to 60 DEG C, reacts 12h；Then by deionization
200 milliliters of water are added in system, continue to be stirred to react 3h at 60 DEG C；
After completion of the reaction, system temperature is down to room temperature, and reaction solution is transferred in separatory funnel, and water phase is extracted to nothing with ether
Product is abandoned, and is merged organic phase, is dried, filtered after organic phase deionized water, saturated common salt water washing by anhydrous magnesium sulfate
Obtain faint yellow clear solution.Reduced pressure, ethyl alcohol and water mixed solution recrystallization are then passed through, white crystalline powder is filtered to obtain
End, filter cake is vacuum dried to obtain white powder 32.70g, yield：95.0%, fusing point is：182~183 DEG C, HPLC content is greater than
99.50%.
Claims (11)
1. the preparation method of Etonogestrel and Desogestrel important intermediate, which is characterized in that be with chemical combination shown in formula (2)
Object is what starting material prepared, and reaction formula is as follows：
2. the preparation method of Etonogestrel and Desogestrel important intermediate, which is characterized in that include the following steps：By formula
(6) compound in the presence of the anhydrous carbonate of alkali metal, reacts with methyl acid phosphate dialkyl ester in a solvent, then adds water
Enter into reaction system, react, then from reaction system be collect product formula (1) compound, as prepare Desogestrel and
Etonogestrel important intermediate.
3. according to the method described in claim 2, it is characterized in that, the preparation method of described formula (6) compound, including it is as follows
Step：In a solvent by formula (5) compound, in inert atmosphere, chiral catalyst [Rh (R-Binap)2]+Y-Presence, be filled with hydrogen
Then solid/liquid/gas reactions collect product (6) compound from reaction product.
4. according to the method described in claim 3, it is characterized in that, the preparation method of described formula (5) compound, including it is as follows
Step：Formula (4) compound in a solvent, is reacted with nafoxidine, hydrobromic acid aqueous solution is then added, the reaction was continued, then from
Product (5) compound is collected in reaction product.
5. according to the method described in claim 4, it is characterized in that, the preparation method of described formula (4) compound, including it is as follows
Step：Formula (3) compound in a solvent, is reacted with hydrochloric acid, product (4) compound is then collected from reaction product.
6. according to the method described in claim 5, it is characterized in that, the preparation method of described formula (3) compound, including it is as follows
Step：Formula (2) compound is dissolved in the in the mixed solvent of aprotic solvent Yu a kind of alcohol, the mixture of liquefied ammonia and metal is added
In, then formula (3) compound described in product is collected in reaction from reaction system.
7. according to the method described in claim 2, the reaction time is it is characterized in that, reaction temperature is -20~60 DEG C of reactions
0.5~12.0h is added water in reaction system, reacts 0.5-3h, alkali metal Li, Na, K；The methyl acid phosphate dioxane
Base ester is methyl-phosphoric acid dimethyl ester or methyl acid phosphate diethylester.
8. according to the method described in claim 3, it is characterized in that, reaction pressure be 0.5~3.0MPa, 60~100 DEG C reaction,
Reaction 3~6, used [Rh (R-Binap)2]+Y-It is in the reaction 1 with the mole ratio of formula (5) compound:8000~
10000。
9. according to the method described in claim 4, it is characterized in that, the solvent is one or more of methanol or ethyl alcohol；
The weight concentration of the hydrobromic acid aqueous solution is 48% aqueous solution；The molar ratio of the nafoxidine and formula (4) compound
It is 1~1.2:1；The molar ratio of the hydrobromic acid and compound (4) is 1~2:1.
10. according to the method described in claim 5, it is characterized in that, in a solvent, being with weight concentration by formula (3) compound
30~36% hydrochloric acid, 10~20 DEG C of reactions, reacts 1.0~3.0h, and product (4) compound is then collected from reaction product；
The proton solvent is one or more of methanol, ethyl alcohol；
The weight ratio of the hydrochloric acid and formula (3) compound is 2~3:1.
11. according to the method described in claim 6, the reaction time is it is characterized in that, reaction temperature is -78~40 DEG C of reactions
1.0~3.0h, the metal are Li, Na, K；The alcohol be one of methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol or with
On；The aprotic solvent be tetrahydrofuran, glycol dimethyl ether, ether it is one or more of；The metal is reacting
In with the molar ratio of formula (2) compound be 8~10:1；The aprotic solvent is in the reaction 5 with the volume ratio of alcohol:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810369554.7A CN108840895B (en) | 2018-04-24 | 2018-04-24 | Preparation method of etonogestrel and desogestrel intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810369554.7A CN108840895B (en) | 2018-04-24 | 2018-04-24 | Preparation method of etonogestrel and desogestrel intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108840895A true CN108840895A (en) | 2018-11-20 |
| CN108840895B CN108840895B (en) | 2020-09-04 |
Family
ID=64212165
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810369554.7A Active CN108840895B (en) | 2018-04-24 | 2018-04-24 | Preparation method of etonogestrel and desogestrel intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108840895B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115215916A (en) * | 2022-08-15 | 2022-10-21 | 湖南原野医药有限公司 | Method for preparing key intermediate of alphaxalone |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3962291A (en) * | 1974-09-05 | 1976-06-08 | G. D. Searle & Co. | Total synthesis of 11-alkyl steroids |
| CN1865276A (en) * | 2005-05-20 | 2006-11-22 | 上海迪赛诺化学制药有限公司 | Method for synthesizing steroid progestogen |
| WO2009033499A1 (en) * | 2007-09-13 | 2009-03-19 | Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts | Total synthesis of enantiopure desogestrel |
| CN101857624A (en) * | 2010-06-25 | 2010-10-13 | 北京紫竹药业有限公司 | Preparation process of desogestrel and novel intermediate compound thereof |
| CN102675392A (en) * | 2011-03-18 | 2012-09-19 | 上海柯林斯堡医药科技有限公司 | Preparation method of progestogen and intermediate thereof |
| WO2017149091A1 (en) * | 2016-03-03 | 2017-09-08 | Bionice, S.L.U | Process and new intermediates for the preparation of 11-methylene steroids |
-
2018
- 2018-04-24 CN CN201810369554.7A patent/CN108840895B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3962291A (en) * | 1974-09-05 | 1976-06-08 | G. D. Searle & Co. | Total synthesis of 11-alkyl steroids |
| CN1865276A (en) * | 2005-05-20 | 2006-11-22 | 上海迪赛诺化学制药有限公司 | Method for synthesizing steroid progestogen |
| WO2009033499A1 (en) * | 2007-09-13 | 2009-03-19 | Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts | Total synthesis of enantiopure desogestrel |
| CN101857624A (en) * | 2010-06-25 | 2010-10-13 | 北京紫竹药业有限公司 | Preparation process of desogestrel and novel intermediate compound thereof |
| CN102675392A (en) * | 2011-03-18 | 2012-09-19 | 上海柯林斯堡医药科技有限公司 | Preparation method of progestogen and intermediate thereof |
| WO2017149091A1 (en) * | 2016-03-03 | 2017-09-08 | Bionice, S.L.U | Process and new intermediates for the preparation of 11-methylene steroids |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115215916A (en) * | 2022-08-15 | 2022-10-21 | 湖南原野医药有限公司 | Method for preparing key intermediate of alphaxalone |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108840895B (en) | 2020-09-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103502203A (en) | Methods of making L-ornithine phenyl acetate | |
| CN108217622A (en) | A kind of preparation method of sodium hexafluoro phosphate | |
| CN103880596B (en) | A kind of preparation method of Nitric acid butoconazole intermediate of applicable suitability for industrialized production | |
| EP0628052A1 (en) | Alkali metal 8,9-dehydroestrone sulfate esters | |
| CN106883133A (en) | A kind of preparation method of dapoxetine hydrochloride | |
| CN106458857A (en) | Crystalline free acid, hemicalcium salt and alfa-phenylethylamine salt of ahu-377 as well as preparation method therefor and application thereof | |
| CN108840895A (en) | The preparation method of Etonogestrel and Desogestrel important intermediate | |
| CN106749361A (en) | A kind of high efficiency preparation method of high-purity difluorine oxalic acid boracic acid lithium | |
| CN106928260B (en) | A kind of double-core caged rare earth samarium (III) organic coordination compound and its preparation method and application | |
| CN102924474B (en) | Preparation method of crystal form I of clopidogrel hydrogen sulfate | |
| CN104557975A (en) | Methods for preparing everolimus intermediates and everolimus degradation impurities | |
| CN102225938A (en) | Novel synthesis process of entecavir monohydrate | |
| CN102050825B (en) | Method for preparing pemetrexed disodium 2.5 water crystal | |
| CN108264529A (en) | A kind of synthetic method of bis- piperidines -5-O- mycamino syl-tylono lides of 20,23- | |
| CN101418029A (en) | Method for synthesizing methylprednisolone | |
| Zhao et al. | Synthesis, structure and gas adsorption properties of coordination polymers based on mixed imidazole-containing ligands and carboxylate ligands | |
| CN110950920A (en) | Preparation method of tetraeestrone | |
| CN114181272B (en) | Synthesis method of levonorgestrel | |
| CN113149946B (en) | Dimethylamine michelia lactone-m-hydroxybenzoate, and preparation method and application thereof | |
| CA2032850C (en) | Crystalline magnesium valproate and a method for the preparation thereof | |
| CN107488156A (en) | A kind of synthetic method of unformed glucitol | |
| CN108148061B (en) | The industrialized process for preparing of Entecavir | |
| CN103724250B (en) | A kind of preparation method of (S)-Olaxiracetam | |
| WO2023000636A1 (en) | Method for synthesis of (3-fluorooxetan-3-yl)methyl 4-methylbenzenesulfonate | |
| CN104844604B (en) | A kind of preparation method of allopurinol sodium |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |