CN106432212B - A method of synthesis piribedil - Google Patents
A method of synthesis piribedil Download PDFInfo
- Publication number
- CN106432212B CN106432212B CN201610837127.8A CN201610837127A CN106432212B CN 106432212 B CN106432212 B CN 106432212B CN 201610837127 A CN201610837127 A CN 201610837127A CN 106432212 B CN106432212 B CN 106432212B
- Authority
- CN
- China
- Prior art keywords
- added dropwise
- piribedil
- room temperature
- piperonylpiperazine
- cooled
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to a kind of methods for synthesizing piribedil, synthesis piperonylpiperazine in next step is acted in hydrochloric acid using piperonyl cyclonene, piperazine pyrimidine, paraformaldehyde, the completely new technique for reacting synthesis piribedil with dichloro pyrimidine again there are no the report that piperonylpiperazine uses the synthetic method before this.Compared to the synthesis technology of traditional piribedil, synthesis step is simplified, three wastes generation is reduced, significantly improves the utilization rate of piperonyl cyclonene, post-process more environmentally protective.
Description
Technical field
The present invention relates to the field of chemical synthesis, and in particular to a method of synthesis piribedil.
Background technique
Entitled 2-[4-(3, the 4 methylene-dioxy benzyl)] piperazine-1- yl pyrimidines of piribedil chemistry, be by
A kind of slow-release dopamine agonist of French Les Laboratoires servier exploitation.D2, D3 receptor are acted on, by improving DOPA
The emerging property of amine receptor and restore the balance between acetylcholine and dopamine system, clinically be used for Parkinson's disease (PD) treatment.
Piribedil medicine and joint levodopa application can not only improve early PD patient motion function well, and can substantially reduce
Unusual fluctuation disease caused by levodopa treatment.Compared with levodopa, there is motor complication using dopamine body agonist is less.
L ebrun etc. is hidden to bromine to stop, Luoping Buddhist nun sieve, pergolide, Pramipexole and pyrrole Bell compare, it is believed that pyrrole
Shellfish you are alternative strong, each stage of Parkinson's disease can be used for.Its safety is good, and dosage regimen is simple, is to treat at present
The drug of first choice of Parkinson's disease.
The synthetic method of current document introduction there are several types of:
1 using piperonal as raw material, carries out reduction amination with Piperazine anhydrous and obtains piperonylpiperazine, then with 2- chlorine pyrimidine into
Row ammonia hydrocarbyl reaction synthesizes piribedil, total recovery 34.3%, and reduction amination and needs progress of pressurizeing, and is unfavorable for production operation.
2 using 2- chlorine pyrimidine as raw material, carries out the single hydrocarbonylation of selectivity with Piperazine anhydrous and obtains piperazine pyrimidine, then with piperonal
Reduction amination is carried out, reduction amination can be carried out with formic acid, total recovery 31.8%.Using cyanoborohydride reduction, yield is reachable
60%, but it is cumbersome, and purification difficult needs ion exchange chromatography, is unfavorable for industrializing.
3 using piperazine pyrimidine as raw material, and under ruthenium catalyst effect and the direct alkylation reaction of piperitol prepares piribedil,
But cost of material is too high, it is difficult to industrialize.
4 piperazine pyrimidines and piperonyl chlorine carry out alkylation reaction in dimethylbenzene under potassium carbonate catalysis and synthesize piribedil
Preparation, total recovery 32.4%, and dimethylbenzene toxicity is big, boiling point is high.
5 piperazine pyrimidines and piperonyl chlorine carry out alkylation reaction in triethylamine, isopropanol and prepare piribedil, total recovery
44 ~ 63.9% or so are calculated with 2- chlorine pyrimidine, purity 99.8%.The experiment of document second step yield repeats to be difficult to reach, and document the
Three step yields only have 68%.
Summary of the invention
This patent is acted in hydrochloric acid using piperonyl cyclonene, piperazine pyrimidine, paraformaldehyde and synthesizes piperonylpiperazine in next step, then and
The completely new technique of dichloro pyrimidine reaction synthesis piribedil, there are no the report that piperonylpiperazine uses the synthetic method before this.
Final total recovery is calculated as 80%, product purity 92%.The present invention is to utilize piperazine hydrochloride using the synthetic method of " treating different things alike "
Under water phase and the piperonyl chlorine of side border ring generation carries out N alkylated reaction, obtains the synthesis thinking of piperonylpiperazine, unlimited
Example cited by the present invention, all other improvements technique using the one-step method thinking, all falls within the protection scope of this patent.
Old synthetic route:
New technology route 1:
Technical scheme is as follows: a method of synthesis piribedil, the method is specially following steps:
Hydrochloric acid is added dropwise at room temperature, drips off and is warming up to 50 DEG C by piperazine, paraformaldehyde, water investment reaction flask for step 1,
Piperonyl cyclonene is slowly added dropwise, drips off heat preservation, is then cooled to 5 ~ 10 DEG C, starts that sodium hydrate aqueous solution is added dropwise, control temperature does not surpass
30 DEG C are crossed, until PH >=12, are extracted with dichloromethane, merge organic phase, is washed twice with saturated salt solution, separate organic phase, often
Pressure-off removes methylene chloride phase, obtains thick object intermediate piperonylpiperazine;
Piperonylpiperazine, dehydrated alcohol and triethylamine are put into reaction flask, 95 DEG C ~ 100 are heated under stirring by step 2
DEG C, the mixed solution of dichloro pyrimidine and dehydrated alcohol is added dropwise, is kept the temperature at 95 DEG C ~ 100 DEG C, is evaporated under reduced pressure, is then cooled to room
Temperature, filtering;Air-distillation removes ethyl alcohol and triethylamine, is cooled to room temperature, crosses filter solid, water is added to be beaten, and filters, obtain pyrrole
Ground that crude product.
Further, 210g piperazine, 25g paraformaldehyde, water 200ml are put into three mouthfuls of reaction flasks, salt is added dropwise at room temperature
Sour 600ml is dripped off and is warming up to 50 DEG C, starts the piperonyl cyclonene that 75g is slowly added dropwise, and is added dropwise 2 hours, is dripped off heat preservation 5 hours, is cooled to
5 ~ 10 DEG C, start that 20% sodium hydrate aqueous solution is added dropwise, control temperature is no more than 30 DEG C, until PH >=12, use methylene chloride
80ml is extracted 3 times, is merged organic phase, is washed twice with saturated salt solution, and organic phase is separated, and normal pressure removes methylene chloride phase, obtains
To thick object intermediate piperonylpiperazine.
Further, previous step intermediate piperonylpiperazine, 360ml dehydrated alcohol and 120ml triethylamine are put into
In tri- mouthfuls of reaction flasks of 1000ml, it is heated to 95 DEG C ~ 100 DEG C under stirring, the mixed of 70g dichloro pyrimidine and 360ml dehydrated alcohol is added dropwise
Solution is closed, was dripped off at 3 hours or so, keeps the temperature 1 hour at 95 DEG C ~ 100 DEG C, is evaporated under reduced pressure, about 400ml volume ethanol and three is removed
It after ethylamine solution, is then cooled to room temperature, filters.Air-distillation removes ethyl alcohol and triethylamine about 250ml, is cooled to room temperature, mistake
Filter solid adds water to be beaten, and filters, and obtains pyrrole that crude product.
The beneficial effects of the present invention are: the present invention is next in hydrochloric acid effect using piperonyl cyclonene, piperazine pyrimidine, paraformaldehyde
Step synthesis piperonylpiperazine, then the completely new technique for synthesizing piribedil is reacted with dichloro pyrimidine, it there are no piperonylpiperazine before this
Using the report of the synthetic method.Method of the present invention compares traditional pyrrole your synthesis technology, simplifies synthesis and walks
Suddenly, three wastes generation is reduced, the utilization rate of piperonyl cyclonene is significantly improved, is post-processed more environmentally protective.
Specific embodiment
React example 1(Chinese patent 1884280)
The preparation of 1 piperonylpiperazine
39.2g piperonal, 34.4g piperazine, 400ml methyl tertiary butyl ether(MTBE) and 7g10% palladium are added in high-pressure hydrogenation kettle
Pd/carbon catalyst is used hydrogen displaced air 3 times after nitrogen displaced air 3 times again, under 10kg Hydrogen Vapor Pressure, is protected at 50 ~ 60 DEG C
Temperature reaction 15 ~ 20 hours, cooling, filtration catalytic agent, cooling filtrate filter the piperazine of precipitation, filtrate adds water to 13 ~ 18 DEG C
150ml keeps the temperature 13 ~ 18 DEG C, with 7N hydrochloric acid tune ph to 7.9 ~ 8.0.Liquid separation, water phase are extracted 3 times with toluene, merge water phase, ice bath
It is lower to use 20g sodium hydroxide tune ph to 12, it is extracted again with toluene 3 times, merges organic phase, anhydrous magnesium sulfate dry filter is concentrated,
Obtain the faint yellow dope of 45g, yield 78%.
Prepared by your crude product for 2 pyrroles
50g piperonylpiperazine, 26g dichloro pyrimidine, 330ml tetrahydrofuran and 65g potassium carbonate are added in 250ml there-necked flask,
It is heated to reflux 2 hours, cooling down, 1600ml distilled water is added, extracted with 800ml*3 times, saturated salt solution 400ml washing,
Anhydrous sodium sulfate dries, filters, and filtrate is concentrated to dryness to obtain peony thick liquid 56.3g.The heating of 560ml dehydrated alcohol is added,
Dissolution, it is slightly cold, active carbon 40g is added, flows back 30 minutes, heat filtering is cooling, and white solid, filtering, 40 DEG C of vacuum drying are precipitated
Obtain 30.2g off-white color crystalline powder, yield 44%.
It reacts example 2 (US3299067)
16.4g piperazine pyrimidine is dissolved in the dimethylbenzene of 300ml, and 28g potassium carbonate and 18g piperonyl chlorine, suspension is added
Keep the temperature 9 hours for (130 DEG C) at a reflux temperature, cooling, several times with 10% salt acid extraction, the hydrochloric acid solution separated is washed with ether, acid
Liquid recalls to alkalinity with potassium carbonate again, separates organic phase, and water phase is extracted with chloroform, merges organic phase and is dried, filtered with potassium carbonate, is steamed
Removing solvent is evaporated, residual oil organic matter 20g is obtained, is recrystallized with ethyl alcohol, obtains 15g product pyrrole that, yield
52%。
React example 3:
1. prepared by piperonyl chlorine
By 100g1, in the Asia 2- methoxybenzene, 40g paraformaldehyde investment tri- mouthfuls of reaction flasks of 500ml, at room temperature (20 to 25
Degree) stirring, hydrochloric acid 266ml is added dropwise, is added dropwise about 50 minutes, drips off and stirs 2 hours at room temperature, methylene chloride extraction is added, every time
100ml merges, and 20g calcium chloride is added and is dried overnight, filters, and 40 degree of lower vacuum rotary steams remove methylene chloride, changes oil and pumps high vacuum
Distillation, obtains product 73.7g, GC purity 92.6%, main peak rear impurity content 0.45%.Yield 64.8%.
2. prepared by piperazine pyrimidine
100g Piperazine anhydrous, 360ml water and 32ml ammonium hydroxide are put into tri- mouthfuls of reaction flasks of 1000ml, are heated to 95 under stirring
DEG C ~ 100 DEG C, the mixed solution of 44g dichloro pyrimidine and 360ml water is added dropwise, was dripped off at 3 hours or so, keeps the temperature 1 at 95 DEG C ~ 100 DEG C
Hour.It carries out revolving to evaporate, removes the water of about 480ml or so, be cooled to room temperature, be extracted with dichloromethane 3 times, each 120m.It closes
And methylene chloride, 16g anhydrous calcium chloride drying 1 hour is added, filtering is boiled off in 40 DEG C of backspins except methylene chloride, obtains 57g production
Product, liquid phase purity 89.74%, two replace by-product (two pyrimidylpiperazines) 10%.GC analyzes piperazine residual 0.19%, yield
80.7%。
3. pyrrole younger brother that crude product preparation
By in 50g piperazine pyrimidine, 60g triethylamine, 170ml isopropanol investment tri- mouthfuls of reaction flasks of 100ml, lower drop is stirred at room temperature
Add 58g piperonyl chlorine, dripped off in 30 minutes, be heated to 50 DEG C, keep the temperature 5 hours, room temperature is cooled under stirring, filters, recycling
The mashing of 100ml water is added in filter cake, filters, then plus 50ml water washing filter cake for mother liquor.50 DEG C of drying, obtain piribedil crude product
71.5g, HPLC analyze content 99.1%.Yield 92%
React example 4:
The preparation of 1 piperonylpiperazine
210g piperazine, 25g paraformaldehyde, water 200ml are put into three mouthfuls of reaction flasks, hydrochloric acid 600ml, drop are added dropwise at room temperature
It is complete to be warming up to 50 DEG C, start the piperonyl cyclonene that 75g is slowly added dropwise, be added dropwise 2 hours, drips off heat preservation 5 hours, be cooled to 5 ~ 10 DEG C, open
20% sodium hydrate aqueous solution is added dropwise in beginning, and control temperature is no more than 30 DEG C, until PH >=12, are extracted 3 times with methylene chloride 80ml,
Merge organic phase, washed twice with saturated salt solution, separate organic phase, normal pressure removes methylene chloride phase, obtains in thick object
Mesosome piperonylpiperazine.It is directly entered in next step.
2. prepared by your crude product for pyrrole
Previous step intermediate piperonylpiperazine, 360ml dehydrated alcohol and 120ml triethylamine are put into tri- mouthfuls of 1000ml reactions
In bottle, it is heated to 95 DEG C ~ 100 DEG C under stirring, the mixed solution of 70g dichloro pyrimidine and 360ml dehydrated alcohol is added dropwise, at 3 hours
Left and right drips off, and keeps the temperature 1 hour at 95 DEG C ~ 100 DEG C, is evaporated under reduced pressure, cold after removing about 400ml volume ethanol and triethylamine solution
But room temperature is arrived, is filtered.Air-distillation removes ethyl alcohol and triethylamine about 250ml, is cooled to room temperature, crosses filter solid, water is added to be beaten,
It filters, obtains pyrrole that crude product 160g, content 92%, total recovery 80%.
Compared to original three step process, new process is reduced to two steps, greatly improves the trans-utilization rate of piperonyl cyclonene, while
Corresponding reduction three waste discharge, it is more environmentally protective.Compared to other process routes, synthesis under normal pressure is anti-without using special high pressure
Device and hydrogen are answered, safer, yield is also higher.
Claims (3)
1. a kind of method for synthesizing piribedil, which is characterized in that using piperonyl cyclonene, piperazine, paraformaldehyde under hydrochloric acid effect
One-step synthesis piperonylpiperazine, then synthesis piribedil is reacted with 2- chlorine pyrimidine;The process is specially following steps:
Hydrochloric acid is added dropwise at room temperature, drips off and is warming up to 50 DEG C, slowly by piperazine, paraformaldehyde, water investment reaction flask for step 1
Piperonyl cyclonene is added dropwise, drips off heat preservation, is then cooled to 5 ~ 10 DEG C, starts that sodium hydrate aqueous solution is added dropwise, control temperature is no more than 30
DEG C, until PH >=12, are extracted with dichloromethane, merge organic phase, washed twice with saturated salt solution, separate organic phase, normal pressure is de-
Except methylene chloride phase, thick object intermediate piperonylpiperazine is obtained;
Piperonylpiperazine, dehydrated alcohol and triethylamine are put into reaction flask, 95 DEG C ~ 100 DEG C are heated under stirring by step 2,
The mixed solution of 2- chlorine pyrimidine and dehydrated alcohol is added dropwise, is kept the temperature at 95 DEG C ~ 100 DEG C, vacuum distillation removal part ethyl alcohol and three second
Amine is then cooled to room temperature, filtering;Air-distillation removes ethyl alcohol and triethylamine, is cooled to room temperature, crosses filter solid, water is added to beat
Slurry filters, obtains piribedil crude product.
2. a kind of method for synthesizing piribedil according to claim 1, which is characterized in that, will in the step 1
210g piperazine, 25g paraformaldehyde, water 200ml are put into three mouthfuls of reaction flasks, and hydrochloric acid 600ml is added dropwise at room temperature, drips off and is warming up to 50
DEG C, start the piperonyl cyclonene that 75g is slowly added dropwise, be added dropwise 2 hours, drips off heat preservation 5 hours, be cooled to 5 ~ 10 DEG C, start dropwise addition 20%
Sodium hydrate aqueous solution, control temperature is no more than 30 DEG C, until PH >=12, is extracted 3 times, is merged organic with methylene chloride 80ml
Phase is washed twice with saturated salt solution, separates organic phase, and normal pressure removes methylene chloride phase, obtains thick object intermediate pepper
Base piperazine.
3. a kind of method for synthesizing piribedil according to claim 1, which is characterized in that in the step 2, will walk
In piperonylpiperazine made from rapid one, 360ml dehydrated alcohol and 120ml triethylamine investment tri- mouthfuls of reaction flasks of 1000ml, under stirring
95 DEG C ~ 100 DEG C are heated to, the mixed solution of 70g2- chlorine pyrimidine and 360ml dehydrated alcohol is added dropwise, was dripped off at 3 hours or so, 95
DEG C ~ 100 DEG C at keep the temperature 1 hour, be evaporated under reduced pressure, after removing 400ml volume ethanol and triethylamine solution, be then cooled to room temperature,
Filtering;Air-distillation removes ethyl alcohol and triethylamine 250ml, is cooled to room temperature, crosses filter solid, water is added to be beaten, and filters, obtains pyrrole
Your crude product of shellfish ground.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610837127.8A CN106432212B (en) | 2016-09-21 | 2016-09-21 | A method of synthesis piribedil |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610837127.8A CN106432212B (en) | 2016-09-21 | 2016-09-21 | A method of synthesis piribedil |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106432212A CN106432212A (en) | 2017-02-22 |
CN106432212B true CN106432212B (en) | 2019-01-11 |
Family
ID=58166851
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610837127.8A Active CN106432212B (en) | 2016-09-21 | 2016-09-21 | A method of synthesis piribedil |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106432212B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2737721C2 (en) * | 2017-12-15 | 2020-12-02 | Алексей Георгиевич Александров | Method for preparing pharmaceutical substance based on piribedil |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3299067A (en) * | 1963-11-19 | 1967-01-17 | Science Union & Cie | 2-[1'-(benzyl and phenyl)-4'-piperazinyl]-pyrimidine derivatives |
US5340811A (en) * | 1990-03-08 | 1994-08-23 | Asahi Kasei Kogyo Kabushiki Kaisha | Isoquinoline-or quinoline-sulfonamide derivative and a pharmaceutical composition comprising the same |
FR2799464B1 (en) * | 1999-10-12 | 2001-12-28 | Norchim | PROCESS FOR THE MANUFACTURE OF PIPERONYL PIPERAZINE BY REDUCTIVE ANIMATION |
CN101830891A (en) * | 2010-05-18 | 2010-09-15 | 沈阳药科大学 | Synthesizing method of piribedil |
CN103373991A (en) * | 2013-07-12 | 2013-10-30 | 安徽安腾药业有限责任公司 | Method for preparing piribedil in high-purity high-yield manner |
CN104926799A (en) * | 2015-04-16 | 2015-09-23 | 中国科学技术大学 | Method for synthesizing piribedil |
-
2016
- 2016-09-21 CN CN201610837127.8A patent/CN106432212B/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3299067A (en) * | 1963-11-19 | 1967-01-17 | Science Union & Cie | 2-[1'-(benzyl and phenyl)-4'-piperazinyl]-pyrimidine derivatives |
US5340811A (en) * | 1990-03-08 | 1994-08-23 | Asahi Kasei Kogyo Kabushiki Kaisha | Isoquinoline-or quinoline-sulfonamide derivative and a pharmaceutical composition comprising the same |
FR2799464B1 (en) * | 1999-10-12 | 2001-12-28 | Norchim | PROCESS FOR THE MANUFACTURE OF PIPERONYL PIPERAZINE BY REDUCTIVE ANIMATION |
CN101830891A (en) * | 2010-05-18 | 2010-09-15 | 沈阳药科大学 | Synthesizing method of piribedil |
CN103373991A (en) * | 2013-07-12 | 2013-10-30 | 安徽安腾药业有限责任公司 | Method for preparing piribedil in high-purity high-yield manner |
CN104926799A (en) * | 2015-04-16 | 2015-09-23 | 中国科学技术大学 | Method for synthesizing piribedil |
Non-Patent Citations (2)
Title |
---|
"Synthesis and antimalarial activity of hydroxyethylpiperazine derivatives";Wilson Cunico,et al.;《European Journal of Medicinal Chemistry》;20080429;第44卷;1363-1368 * |
"SYNTHESIS, CHARACTERIZATION AND EVALUATION OF MANNICH BASES AS POTENT ANTIFUNGAL AND HYDROGEN PEROXIDE SCAVENGING AGENTS";MANAV MALHOTRA,et al.;《Acta Poloniae Pharmaceutica - Drug Research》;20121231;第69卷(第2期);355-361 * |
Also Published As
Publication number | Publication date |
---|---|
CN106432212A (en) | 2017-02-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102040606B (en) | Synthetic method of vinpocetine | |
CN103435538B (en) | (R) preparation method of-3-amido piperidine hydrochlorate | |
CN104987339A (en) | Synthesis method of tofacitinib citrate | |
CN101735201B (en) | Preparation method of piribedil | |
CN106432212B (en) | A method of synthesis piribedil | |
EP2285799A2 (en) | Method for preparing argatroban monohydrate | |
CN101544603A (en) | Preparation method of 3,4-dihydropapaverine and hydrochloride thereof | |
CN101704755A (en) | Method for preparing p-tert-butylbenzylamine | |
WO2022252789A1 (en) | Method for preparing jak inhibitor key intermediate | |
CN104016954B (en) | The preparation of Nebivolol Intermediates and purification process | |
CN110590587A (en) | Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride | |
CN106397227A (en) | Preparation method of dapoxetine hydrochloride | |
CN104803883A (en) | Synthesis method of cyhalofop-butyl | |
CN105884625B (en) | A kind of synthetic method of R- salmeterols | |
CN100443466C (en) | Cycloalkylaminoacid compounds, processes for making and uses thereof | |
CN107501316A (en) | LUMEFANTRINE isomers and preparation method thereof | |
CN103214434A (en) | Improved method of 1-diphenylmethyl-4-(2-hydroxyethyl) piperazine synthesis technology | |
CN111170847A (en) | Novel method for preparing drotaverine hydrochloride intermediate | |
CN101337903A (en) | Method for preparing ethyl levodopa | |
CN109776300A (en) | The synthetic method of loxoprofen sodium | |
KR100256866B1 (en) | Process for the preparation of l-muscone and d-muscone from d,l-muscone | |
CN107216318A (en) | A kind of piribedil preparation method | |
US20060004230A1 (en) | Process for the preparation of terbinafine and salts thereof | |
CN109942571B (en) | Preparation method of drug terliptin for treating diabetes | |
CN106831652B (en) | A kind of preparation method of Wo Saiting |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |