CN106467535A - One kind prepares the purifying process of 2,2 pairs of (2 thienyl) glycolic Rhizoma Scopoliae Japonicae esters - Google Patents
One kind prepares the purifying process of 2,2 pairs of (2 thienyl) glycolic Rhizoma Scopoliae Japonicae esters Download PDFInfo
- Publication number
- CN106467535A CN106467535A CN201610733772.5A CN201610733772A CN106467535A CN 106467535 A CN106467535 A CN 106467535A CN 201610733772 A CN201610733772 A CN 201610733772A CN 106467535 A CN106467535 A CN 106467535A
- Authority
- CN
- China
- Prior art keywords
- thienyl
- double
- glycolic
- ester
- scopoliae japonicae
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
Abstract
The present invention relates to a kind of formula（I）The purifying process of shown tiotropium bromide key intermediate 2,2 pairs (2 thienyl) glycolic Rhizoma Scopoliae Japonicae ester.Simplify purification step, improve quality and the yield of product.
Description
Technical field
The present invention relates to chemosynthesis technical field, specific design a kind of tiotropium bromide key intermediate 2, double (the 2- thiophene of 2-
Fen base) preparation of glycolic Rhizoma Scopoliae Japonicae ester and post-processing approach..
Background technology
Tiotropium bromide is the anticholinergic agent of specific selectivity, is currently the only one long-acting, high selectivity M3 receptor resistance
Stagnant dose, be that the line that the medical guide of chronic obstructive pulmonary disease is recommended maintains medicine.As current treatment chronic obstructive pulmonary disease
One of best medicine, from calendar year 2001 11 about since Holland is approved listing, tiotropium bromide is always treated as cookle, in the world
The focus that the research that it is synthesized also always is studied.
And the key intermediate as tiotropium bromide synthesis, the synthesis of 2,2- double (2- thienyl) glycolic Rhizoma Scopoliae Japonicae esters grinds
Study carefully and also gain great popularity.Find that a kind of simple to operate, reaction safety, low cost, quality be good, high income, be suitable for industrialized production
The preparation of double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of 2,2- and process for purification are extremely important.
The method preparing double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of 2,2- of existing report is typically all with the double (2- of 2,2-
Thienyl) methyl glycollate or its similar compound and scopine reaction generate.
As first reported scopine in European patent EP 0418716, double (2- thienyl) methyl glycollates exist with 2,2-
Ester exchange reaction is occurred to generate double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of 2,2- in the presence of the hazardous agents such as metallic sodium.The party
Method is dangerous big, and prepares double (2- thienyl) glycolic Rhizoma Scopoliae Japonicae ester low yield of 2,2- of gained, and HPLC purity is also only 45-
50%.
And for example in United States Patent (USP) US5610163, the synthetic method of report is, 2,2- double (2- thienyl) methyl glycollates with
Scopine reaction under toluene or solvent-free molten condition in the presence of metallic sodium or Feldalat NM generates double (the 2- thiophene of 2,2-
Fen base) glycolic Rhizoma Scopoliae Japonicae ester.This reaction yield is in 44-70%, but reaction reagent used is more dangerous, and post processing is also relatively
More bother, be not suitable for industrialized production.
Then refer to scopine and 2,2- pair of (2- thienyl) methyl glycollates in Chinese patent CN200810081019
Preparation 2 is reacted under microwave action, double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of 2-, but microwave condition is not suitable for industrial metaplasia
Produce.
In addition, Chinese patent CN201010190930 discloses scopine and double (2- thienyl) the glycolic first of 2,2-
Ester in organic solvent, under inert atmosphere, 120-150 DEG C of heating reflux reaction generate 2,2- double (2- thienyl) glycolic east Liang
Henbane ester.Though this method yield may be up to 65-81%, because its reaction temperature is too high, the later stage needs a large amount of concentration high boiling solvents,
Energy consumption is big, does not possess the realistic meaning of industrialized production.
And double (2- thienyl) methyl glycollate of 2,2- reported in United States Patent (USP) US2010305146A1 and scopine
In Na12Al12Si12O36×nH2Under O and potassium tert-butoxide collective effect, room temperature reaction obtains double (2- thienyl) second of 2,2- for 15 hours
The method of alkyd Rhizoma Scopoliae Japonicae ester, yield is only 31.5%, does not possess real industrial production value.
What WO2013/117886 was same has that yield is too low, only 25.5%, and post-treatment condition is harsh, uncomfortable
Close industrialized production.
The method reported in WO2013046138, process controllability too high with the requirement of molecular sieve to catalyst n HC
Low, and yield is not high, does not possess realistic meaning.
Additionally, the one kind reported in Chinese patent CN104557905A is with lewis acid-kieselguhr for catalyst 2,2- is double
The synthetic method of (2- thienyl) glycolic Rhizoma Scopoliae Japonicae ester, double (2- thienyl) glycolic Rhizoma Scopoliae Japonicae ester of 2,2- of the method preparation
Yield, purity are higher, but the three wastes producing in course of reaction are more, and post processing is related to multiple material transfer, and operation is more numerous
Trivial, it is unfavorable for industrialized production.
In addition, also world patent WO2011123077 and WO2011123080 reports respectively with scopine and 2,2-
Double (2- thienyl) ethanol acid derivative is Material synthesis 2, double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of 2-, but in course of reaction
The condensing agent such as DCC, DCI or EDC need to be used, and need, using high boiling solvents such as DMF, DMSO, to lead to post processing extremely loaded down with trivial details,
Also improve cost simultaneously.
The related patent report of summary is visible, the preparation side of double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of current 2,2-
The drawbacks of method all has certain substantially, or for reagent dangerous for condition harsh or for yield too low or for complex operation or
Big for ambient pressure, it is unfavorable for amplifying production.Need to develop a kind of simple to operate, reaction safety, low cost, pollution less, quality good,
The preparation of double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of 2,2- of controlled, the suitable industrialized production of high income, technique and post processing
Method.
Content of the invention
Present invention seek to address that instantly present in the preparation method of double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of 2,2- not
The drawbacks of suitable industrialized production, provide a kind of simple to operate, reaction safety, low cost, pollution less, quality is good, high income, work
The preparation of double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of 2,2- of controlled, the suitable industrialized production of skill and post-processing approach.
For solving above-mentioned technical problem, the technical solution used in the present invention is as follows：
A kind of formula（I）
Shown tiotropium bromide intermediate 2, the preparation method of double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of 2-, walk including following
Suddenly：
Step one, formula（II）
Shown compound, i.e. scopine, in toluene, in the presence of alkali compoundss, under the conditions of tiny structure, with formula
（III）
Shown compound, i.e. double (2- thienyl) methyl glycollate reacting by heating of 2,2-；
Step 2, reaction finish, and after cooling system, add retarder thinner to stir with cleaning solvent, and adjust body with acid reagent
It is pH；
Step 3, point liquid, take organic faciess, concentrating under reduced pressure, obtain off-white powder crude product or the turbid liquid of off-white color；
Recrystallization solvent is added in step 4, crude product, after heating for dissolving, crystallize of lowering the temperature；
Step 5, filtration separation, solid is dried, and obtains white or off-white powder shape solid, double (2- thienyl) second of as 2,2-
Alkyd Rhizoma Scopoliae Japonicae ester.
Method according to above-mentioned reactions steps one, wherein, the consumption of toluene is the 10-16 with respect to scopine
Times volume.
Method according to above-mentioned reactions steps one, wherein, alkali compoundss used are selected from potassium tert-butoxide and uncle
Sodium butoxide.
Method according to above-mentioned reactions steps one, wherein, the consumption of alkali compoundss is with respect to scopine
0.2-1.1 times of equivalent of consumption.
Method according to above-mentioned reactions steps one, wherein, tiny structure size is 0.05MPa -0.09MPa.
Method according to above-mentioned reactions steps one, wherein, reaction temperature is 40-80 DEG C.
Method according to above-mentioned reactions steps two, wherein, retarder thinner is dichloromethane.
Method according to above-mentioned reactions steps two, wherein, the consumption of retarder thinner is to use with respect to scopine
10-16 times of volume of amount.
Method according to above-mentioned reactions steps two, wherein, cleaning solvent is water.
Method according to above-mentioned reactions steps two, wherein, the consumption of cleaning solvent is to use with respect to scopine
10-16 times of volume of amount.
Method according to above-mentioned reactions steps two, wherein, acid reagent is hydrochloric acid.
Method according to above-mentioned reactions steps two, wherein, the concentration of acid reagent is 2%-36%.
Method according to above-mentioned reactions steps two, wherein, regulation system pH to 3-8, preferably 6-8.
Method according to above-mentioned reactions steps three, wherein, the temperature of concentrating under reduced pressure is 30-70 DEG C.
Method according to above-mentioned reactions steps three, wherein, is evaporated to solvent surpluses and uses for scopine
0-15 times of volume of amount.
Method according to above-mentioned reactions steps four, wherein, the recrystallization solvent added is toluene or acetonitrile.
Method according to above-mentioned reactions steps four, wherein, after adding recrystallization solvent, solvent is with respect to eastern Liang
8-15 times of volume of henbane alcohol quality.
Method according to above-mentioned reactions steps four, wherein, recrystallization temperature is 5-25 DEG C.
Method according to above-mentioned reactions steps four, wherein, the crystallize time is 2-8 hour.
Method according to above-mentioned reactions steps five, wherein, drying mode is electric heating forced air drying.
Method according to above-mentioned reactions steps five, wherein, baking temperature is 60-80 DEG C.
Method according to above-mentioned reactions steps five, wherein, drying time is 2-6 hour.
The present invention be used potassium tert-butoxide and sodium tert-butoxide as catalysts it is ensured that reaction safety.
In course of reaction, the interphase interaction of product and raw material will produce stickiness insoluble matter, and this situation is cold in system
But become apparent from after, in existing preparation technology, often directly use hydrochloric acid regulation system pH to 2-3 in this stage, it will lead
Cause that stickiness insoluble matter is agglomerating is attached to container, largely effect on quality and the yield of product.
Present invention regulation system pH again after adding dichloromethane and water dissolution insoluble matter, on the one hand solves stickiness not
The puzzlement of molten thing attachment, on the other hand can effectively remove miscellaneous by 2,2- double (2- thienyl) methyl glycollate hydrolysis generation
Matter, it is to avoid involved extraction repeatedly, washing procedure in similar patent literature, effectively raise the quality of product with
Yield.
The present invention, by the band water function of toluene, eliminates the step that organic faciess are dried, further simplify operation.
In addition, the present invention isolates and purifies double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae of prepared 2,2- by way of recrystallization
Ester, by contrast, product quality and process controllability are higher.
The preparation being provided by the present invention and process for refining, the tiotropium bromide intermediate 2 obtaining, double (2- thienyl) second of 2-
Alkyd Rhizoma Scopoliae Japonicae ester HPLC purity >=99.5%, yield is up to 78-89%.
For a further understanding of the present invention, to describe the technology contents of the present invention in detail with reference to embodiment, to need to manage
Solution, the description of these embodiments is simply the feature further describing the present invention, rather than to the scope of the invention or this
The restriction of invention right.Technical staff belongs to this to inventing the simple replacement done or improvement etc. in the art
Invent within protected technical scheme.
Reference example：Double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of referenced patent US5610163A synthesis 2,2-：
12.7g 2 is added in the 250ml there-necked flask being dried, double (2- thienyl) methyl glycollate of 2-, 7.7g scopine, stirs
Mix, control system negative regulation to 0.09-0.10MPa, be slowly heated to 70 DEG C, after system dissolving, add 2.7g Feldalat NM
Insulation reaction 1 hour, continues to be heated to 90 DEG C of reactions 1 hour.Reaction terminates, and cooling system, to 30 DEG C, adds 100ml dichloromethane
Alkane and 100ml water.Divide liquid, phase of fetching water.After dichloromethane layer uses 50ml water to extract 3 times repeatedly, continue with 4% dilute hydrochloric acid of 50ml
Extraction.Merge aqueous phase, add 150ml dichloromethane, with sodium carbonate regulation system pH to 7-8, point liquid, dichloromethane layer is with anhydrous
After sodium sulfate is dried, it is spin-dried for.The yellow solid obtaining filters after being washed and starched with 20ml acetone room temperature, 35 DEG C of drying under reduced pressure 2 hours, obtains
8.3g faint yellow solid, HPLC purity 82.4%, yield 44.0%.
Preparation method described in patent US5610163A, synthesizes 2,2- with Feldalat NM for catalyst double under condition of no solvent
(2- thienyl) glycolic Rhizoma Scopoliae Japonicae ester, but post-processing operation is excessively loaded down with trivial details, need to repeatedly extract a point liquid, is related to multiple material transfer
And soda acid operation, be not suitable for industrialized production.And yield advantage and product quality all low, do not possess realistic meaning.
Embodiment 1：
65ml toluene, 4.65g (30mmol) scopine, double (the 2- thiophene of 9.15g 2,2- is added in the 250ml there-necked flask being dried
Fen base) methyl glycollate (36mmol), stirring is lower to add 2.02g sodium tert-butoxide（21mmol）, control negative pressure 0.07 ±
0.005MPa, 60 DEG C of insulation reaction 5 hours.Reaction terminates, and is cooled to 25 DEG C, adds 65ml water and 65ml dichloromethane, stirring
Dissolving, the dilute hydrochloric acid of Deca 9% to pH=7-8.Divide liquid, take organic layer, 35 DEG C turn 70 DEG C of concentrate systems to dry, obtain off-white color solid
Body, plus 30ml acetonitrile, after heating for dissolving, are cooled to 20 DEG C of crystallizes 2 hours, filtration separation, 60 DEG C of forced air dryings of solid 4 hours,
Obtain 8.91g off-white powder, double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of as 2,2-, HPLC purity 99.74%, yield
78.8%.
Embodiment 2：
120ml toluene, 7.75g (50mmol) scopine, the double (2- of 16.51g 2,2- is added in the 500ml there-necked flask being dried
Thienyl) methyl glycollate (65mmol), stirring is lower to add 2.80g potassium tert-butoxide（25mmol）, control negative pressure 0.06 ±
0.005MPa, 75 DEG C of insulation reaction 2 hours.Reaction terminates, and is cooled to 30 DEG C, adds 120ml water and 120ml dichloromethane, stirs
Mix dissolving, Deca concentrated hydrochloric acid adjusts pH to 5-6.Divide liquid, take organic layer, 35 DEG C of concentrate systems, obtain the turbid liquid of off-white color, take a little
Quantitation must need to add toluene 28ml（Amount to 15V）, after heating for dissolving, it is cooled to 15 DEG C of crystallizes 4 hours, filtration separation, solid 60
DEG C forced air drying 4 hours, obtains 16.28g white powder, double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of as 2,2-, HPLC purity
99.67%, yield 86.4%.
Embodiment 3：
250ml toluene, 15.5g (0.10mol) scopine, the double (2- of 30.5g 2,2- is added in the 500ml there-necked flask being dried
Thienyl) methyl glycollate (0.12mol), stirring is lower to add 6.7g potassium tert-butoxide（0.06mol）, control negative pressure 0.07 ±
0.005MPa, 70 DEG C of insulation reaction 3 hours.Reaction terminates, and is cooled to 30 DEG C, adds 250ml water and 250ml dichloromethane, stirs
Mix dissolving, the dilute hydrochloric acid of Deca 4% adjusts pH to 6-7.Divide liquid, take organic layer, 35 DEG C turn 70 DEG C of concentrate systems to dry, obtain class white
Color solid, after adding 180ml toluene heating for dissolving, is cooled to 20 DEG C of crystallizes 4 hours, filtration separation, 60 DEG C of forced air dryings 6 of solid
Hour, obtain 33.2g off-white powder, double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of as 2,2-, HPLC purity 99.83%, yield
88.1%.
Summarize：
Contrast patent documentation that is existing and having been reported that（Comparing result see table 1）Understand, the preparation 2 of existing report, double (the 2- thiophene of 2-
Base) to be usually present post-processing operation excessively loaded down with trivial details for the method for glycolic Rhizoma Scopoliae Japonicae ester, be related to material transfer, extraction, washing and
The problems such as acid-base neutralization reaction is excessive, is unfavorable for that industrialized production is amplified.
The present invention after the completion of reaction, is directly added into dichloromethane and water stirring, after dilute hydrochloric acid regulation system pH, separates
Obtain organic faciess, after concentration, add solvent recrystallization, after the 60 DEG C of dryings of solid being filtrated to get, obtain double (2- thienyl) ethanol of 2,2-
Sour Rhizoma Scopoliae Japonicae ester product, yield is in 78%-89%, HPLC purity ＞ 99.5%.
Double (2- thienyl) glycolic Rhizoma Scopoliae Japonicae ester mass yield contrast table of 2,2- in each patent documentation of table 1
Post processing of the present invention, not through cyclic washing and phase inversion, improves product yield and purity advantage is notable.
Claims (6)
1. one kind 2, the preparation method of double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of 2-, comprise the following steps：Step one, Rhizoma Scopoliae Japonicae
Alcohol, in toluene, in the presence of alkali compoundss, under the conditions of tiny structure, double (2- thienyl) methyl glycollates add with 2,2-
Thermal response；Step 2, reaction finish, and after cooling system, add retarder thinner to stir with cleaning solvent, and are adjusted with acid reagent
System pH；Step 3, point liquid, take organic faciess, concentrating under reduced pressure, obtain off-white powder crude product or the turbid liquid of off-white color；Step 4, crude product
In add recrystallization solvent, after heating for dissolving, lower the temperature crystallize；Step 5, filtration separation, solid is dried, and obtains white or off-white color
Double (2- thienyl) the glycolic Rhizoma Scopoliae Japonicae ester of pulverulent solids, as 2,2-.
2. the method according to step 2 in claims 1, wherein, alkali compoundss are selected from sodium tert-butoxide or the tert-butyl alcohol
One of potassium.
3. the method according to step 2 in claims 1, wherein, retarder thinner is dichloromethane, and cleaning solvent is
The consumption of water, retarder thinner and cleaning solvent is the 10-16 times of volume with respect to scopine quality.
4. the method according to step 2 in claims 1, wherein, acid reagent is hydrochloric acid, and concentration is 2%-36%.
5. the method according to step 2 in claims 1, wherein, regulation system pH to 3-8, preferably 6-8.
6. the method according to step 4 in claims 1, wherein, the recrystallization solvent added is toluene or acetonitrile,
After adding recrystallization solvent, solvent is the 8-15 times of volume with respect to scopine quality.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610733772.5A CN106467535A (en) | 2016-08-28 | 2016-08-28 | One kind prepares the purifying process of 2,2 pairs of (2 thienyl) glycolic Rhizoma Scopoliae Japonicae esters |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610733772.5A CN106467535A (en) | 2016-08-28 | 2016-08-28 | One kind prepares the purifying process of 2,2 pairs of (2 thienyl) glycolic Rhizoma Scopoliae Japonicae esters |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106467535A true CN106467535A (en) | 2017-03-01 |
Family
ID=58230651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610733772.5A Pending CN106467535A (en) | 2016-08-28 | 2016-08-28 | One kind prepares the purifying process of 2,2 pairs of (2 thienyl) glycolic Rhizoma Scopoliae Japonicae esters |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106467535A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0418716A1 (en) * | 1989-09-16 | 1991-03-27 | Boehringer Ingelheim Kg | Thienylcarboxylic acid ester of aminoalcohols, their quaternary products, their preparation and use of the compounds |
| CN101768158A (en) * | 2010-01-04 | 2010-07-07 | 南昌弘益科技有限公司 | Tiotropium bromide anhydride and preparation method thereof |
| CN101979391A (en) * | 2010-11-16 | 2011-02-23 | 济南德信佳生物科技有限公司 | Method for preparing tiotropium bromide |
| WO2013143510A1 (en) * | 2012-03-30 | 2013-10-03 | Zentiva, K.S. | A method of preparing the scopine ester of di-(2-thienyl)glycolic acid, an intermediate in the synthesis of tiotropium bromide |
-
2016
- 2016-08-28 CN CN201610733772.5A patent/CN106467535A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0418716A1 (en) * | 1989-09-16 | 1991-03-27 | Boehringer Ingelheim Kg | Thienylcarboxylic acid ester of aminoalcohols, their quaternary products, their preparation and use of the compounds |
| CN101768158A (en) * | 2010-01-04 | 2010-07-07 | 南昌弘益科技有限公司 | Tiotropium bromide anhydride and preparation method thereof |
| CN101979391A (en) * | 2010-11-16 | 2011-02-23 | 济南德信佳生物科技有限公司 | Method for preparing tiotropium bromide |
| WO2013143510A1 (en) * | 2012-03-30 | 2013-10-03 | Zentiva, K.S. | A method of preparing the scopine ester of di-(2-thienyl)glycolic acid, an intermediate in the synthesis of tiotropium bromide |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103980263B (en) | The synthesis technique of canagliflozin | |
| CN102584752A (en) | Preparation method of andrographolide bulk pharmaceutical | |
| CN103724261A (en) | Novel industrial production method for hydroxychloroquine sulfate | |
| CN103073438A (en) | Ambroxol hydrochloride compound refining method | |
| CN102395591B (en) | Method for preparing prasugrel | |
| CN101486753A (en) | Novel method for synthesizing finasteroid | |
| CN105294534A (en) | Industrial method for preparing apremilast and intermediate thereof | |
| CN102702232A (en) | Method for preparation of fine cefamandole nafate | |
| CN109988132B (en) | Preparation method of amiodarone hydrochloride | |
| CN102718829A (en) | Method for preparing sodium tauroursodeoxycholate | |
| CN102399200B (en) | Suspension crystallization method for preparing crystal form I of linezolid | |
| CN106831576B (en) | Preparation method of 2-methyl-1-oxo-1, 2-dihydroisoquinoline-6-formic acid | |
| CN103145636B (en) | 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof | |
| CN104844593A (en) | Synthetic method for Apixaban drug intermediate | |
| CN102351790A (en) | Method for synthesizing 7-bromo-6-chloro-4-quinazolinone | |
| CN102675267B (en) | Preparation method of dronedarone hydrochloride and intermediate of dronedarone hydrochloride | |
| CN102174007A (en) | Industrial preparation method of [2-(2-cyano-pyrrolidine-1-yl)-2-oxo-ethyl]-tert-butyl carbamate | |
| CN111943937A (en) | Synthesis method of triphenyl candesartan | |
| CN106467535A (en) | One kind prepares the purifying process of 2,2 pairs of (2 thienyl) glycolic Rhizoma Scopoliae Japonicae esters | |
| CN101759740B (en) | Method for synthesizing 3-alpha-acetoxy-deoxidized androstane-5-17-ketone | |
| CN105732547B (en) | A kind of preparation method of Dehydro and drographolide diacid half esters | |
| CN102633801A (en) | Method for preparing tebipenem ester | |
| CN110041214A (en) | A kind of Melphalan intermediate and preparation method thereof | |
| CN104311518A (en) | Preparation method for 6-methoxyscutellarin | |
| CN107200763A (en) | A kind of method using chenodeoxycholic acid as Material synthesis lithocholic acid |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170301 |