CN101270096A - Method for synthesizing diovan - Google Patents
Method for synthesizing diovan Download PDFInfo
- Publication number
- CN101270096A CN101270096A CN 200710038346 CN200710038346A CN101270096A CN 101270096 A CN101270096 A CN 101270096A CN 200710038346 CN200710038346 CN 200710038346 CN 200710038346 A CN200710038346 A CN 200710038346A CN 101270096 A CN101270096 A CN 101270096A
- Authority
- CN
- China
- Prior art keywords
- salt
- solvent
- compound
- benzyl
- acid
- 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
Abstract
The present invention provides an improved method used for synthesizing valsartan. No tin compounds are required in the reaction. In the method, the condensate of N-[(2'-cyano-1, 1'- biphenyl-4-group)-alkyl]-L-valine ester is used as raw material. And the method comprises valerylation and synthesis of the valsartan. The method has the advantages of easily available raw materials, simple operation, no environmental pollution, high yield, low cost, and suitability for large-scale industrial production.
Description
Technical field
The invention belongs to technical field of pharmaceuticals.Be specifically related to improving one's methods of a kind of synthesizing Xieshatan that participates in reaction without tin compound.
Background technology:
Valsartan is the hypertensive chemical synthetic drug of a kind of effective treatment, its chemical name: (S) .N-(1-oxo amyl group)-N-[4-[2-(1H-tetrazole-5-yl) phenyl] benzyl]-the L-Xie Ansuan, English name (S)-N-pentanoyl-N-[[2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl] methyl]-L-valine (valsartan), its synthetic method mainly be divided into condenses (N-[(2 '-cyano group-1,1 '-biphenyl-4-yl) alkyl]-the L-L-valine ester) synthetic (containing the ester protection) of (hydrochloride), synthetic (containing valerylization) two parts of valsartan; The synthetic main route of condenses mainly contains: the one, with 2-cyano group-4 '-bromomethylbiphenyl is a raw material, get with carboxyl protected L-Xie Ansuan condensation, the 2nd, with 2-cyano group-4 '-formyl biphenyl is that raw material and the protected L-Xie Ansuan of carboxyl condensating reductive get; The synthetic of valsartan is raw material with condenses and sodium azide substantially all, in reaction under the catalysis that haloalkyl tin is arranged more than 40 hours and get.Owing to adopted stanniferous reagent, residual tin can take in the final product always, and organo-tin compound is the very strong compound of a kind of toxicity.According to medicine ICH requirement, organo-tin compound should be very difficult to control in 1ppmm in finished product.The relevant patent and the document of concrete reference, as US5399578, J.Med.Chem.1991, Vol.34, No.8,2525-2547 etc.
Summary of the invention:
Technical problem to be solved by this invention is to overcome the shortcoming of above-mentioned valsartan synthesis step, cancellation uses the haloalkyl tin compound to participate in reaction, the improved valsartan new synthetic method of research and design, the total recovery of raising valsartan, reduce and produce and raw materials cost, reduce environmental pollution.
The invention provides a kind of improvement synthetic method of synthesizing Xieshatan, to achieve the object of the present invention, it is raw material that the present invention adopts with the condenses, after the valeryl reaction, finishes the synthetic of valsartan without tin compound participates in reaction.
1; N-(1-pentanoyl)-N-[4-[2-(1H-tetrazole-5-yl) phenyl] benzyl]-L-Xie Ansuan (R is acceptable substituting groups such as hydrogen, methyl, ethyl, sec.-propyl or benzyl)
2:N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-L-Xie Ansuan alkyl ester (R is acceptable substituting groups such as hydrogen, methyl, ethyl, sec.-propyl or benzyl)
3:N-[(2 '-cyano group-1,1 '-biphenyl-4-yl) alkyl]-L-L-valine ester hydrochloride (R is acceptable substituting groups such as hydrogen, methyl, ethyl, sec.-propyl or benzyl)
Concrete grammar of the present invention is: (1) is with N-[(2 '-cyano group-1,1 '-biphenyl-4-yl) alkyl]-aromatic solvents of L-L-valine ester (abbreviation condenses) (hydrochloride) and 0.5～10 times of weight and the aqueous solution of carbonate are even, controlled temperature is at 0～30 ℃ of mixture that begins to drip 0.4～0.8 times of weight valeryl chloride and 1～10 times of weight aromatic solvents, 0.5 dripped and finish in～4 hours, keeping 10～40 ℃ stirred 1～3 hour, branch vibration layer, organic layer saturated common salt water washing, penta acylate solution is directly used in follow-up syntheticly or boil off partial solvent, it is standby to separate out penta acylate solid; (2) use penta acylate solution of step preparation or the solution that penta acylate solid is dissolved in the solvent of identical with step (1) solvent for use (also can be different); 0.5 the amine salt of the metal-salt of～4.0 times of amount of substance hydrazoic acid and 0.5～2.0 times of amount of substance or other Lewis acids; stir; be heated to 70～150 ℃; back flow reaction 10～50 hours; reaction finishes postcooling to room temperature; add the saturated common salt water washing, organic layer adds the aqueous solution of 10%～30% alkali again, and controlled temperature was 0～40 ℃ of reaction 4～10 hours; divide and remove organic layer; add an amount of aromatic solvents washing to the alkali layer, be cooled to below 0 ℃, regulate pH value 1～2 with hydrochloride aqueous solution; use ethyl acetate extraction; organic layer saturated common salt water washing boils off the part ethyl acetate, the cooling precipitation and crystallization; filter, get valsartan.
In the method for the invention, described condenses N-[(2 '-cyano group-1,1 '-biphenyl-4-yl) alkyl]-alkyl in the L-L-valine ester is acceptable substituting groups such as methyl, ethyl, sec.-propyl or benzyl, aromatic solvents is a toluene, acceptable all kinds of SOLVENTS such as parachlorotoluene or dimethylbenzene, preferred toluene or parachlorotoluene; The usage quantity of solvent is 1.5～20 times of condenses (hydrochloride) weight, preferred 10 times; Carbonate is yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus etc.; The metal-salt of hydrazoic acid comprises sodium azide, nitrine potassium, nitrine lithium etc., amine salt or other Lewis acids are triethylamine salt, methylamine salt, organic salt and ammonium chlorides such as ethylenediamine salt or tert-butylamine salt, zinc chloride, inorganic salt such as ferrous sulfate, amine salt or other lewis acidic acid groups are the salt acid group, sulfate radical, inorganic acid radical and oxalic acid roots such as nitrate radical, oxalate, organic acids such as tosic acid root, the best is a triethylamine hydrochloride.Two steps of synthesizing Xieshatan that relate to the valerylization of step and the step (2) of above-mentioned steps (1) among the present invention; reaction solvent all can be selected toluene for use; acceptable all kinds of SOLVENTS such as parachlorotoluene or dimethylbenzene; two steps can be selected identical or different solvent for use; be preferably and select for use with a kind of solvent, the best is a toluene.
Method yield height of the present invention, calculating total recovery with condenses can be greater than 75%, and has following remarkable advantage:
1) valsartan improved need not cost an arm and a leg in synthetic and also corrodibility extremely strong, easily environment is caused the organotin halogenide of bigger harm, avoided fundamentally that residual heavy metal tin exceeds standard in the product.
2) two-step reaction selects for use price relatively cheap and reclaim easy solvent, and can be with the one kettle way synthesizing Xieshatan, can not switch solvent midway, indivedual in addition solvents have good promoter action for reaction, make solvent such as adopting parachlorotoluene, reaction times was shortened in 10 hours, improved working efficiency greatly.Help large-scale production
Embodiment:
Example 1
Add the 50L tap water, add 25kg salt of wormwood again and be stirred to molten clearly, add 20kg condenses hydrochloride and 150L toluene again, be stirred to molten clear.Controlled temperature begins to drip 9kg valeryl chloride and 25L toluene mixture liquid at 20～30 ℃, dropwises in about 2 hours, and holding temperature was 20～30 ℃ of stirring reactions 1 hour again, and standing demix divides the sub-cloud water layer, and organic layer adds the saturated common salt water washing again.Divide and remove the salt water layer, organic layer (penta acylate solution) is stand-by.Use penta acylate solution of step preparation, add sodium azide 7.3Kg again, triethylamine hydrochloride 17.8kg stirs, and is heated to backflow, react 20 hours, and the end postcooling to 30 ℃ of refluxing adds saturated aqueous common salt 50L, standing demix again.Dividing goes salt water layer, organic layer to use an amount of saturated common salt water washing again.Organic layer adds 13%KOH solution 180L again, and controlled temperature divides and removes organic layer 40 ℃ of reactions 4 hours.The alkali layer adds an amount of toluene wash again, divides and removes toluene layer.Be cooled to 0 ℃, drip the hydrochloric acid of 6N again, regulate pH value 1～2.Add ethyl acetate 400ml again and extract branch vibration layer.Organic layer adds saturated common salt water washing, layering again.Holding temperature is at 40 ℃, and decompression steams the part ethyl acetate, is cooled to precipitation and crystallization below-5 ℃ 12 hours, filters, and oven dry gets the product valsartan,, yield 78%.
Example 2
Replace outside the salt of wormwood in the example 1 with yellow soda ash, all the other are with example 1, yield 75%.
Example 3
Outside the salt of wormwood in the sodium bicarbonate replacement example 1, all the other are with example 1.
Example 4
Outside the salt of wormwood in the saleratus replacement example 1, all the other are with example 1.
Example 5
Aromatic solvents toluene in the example 1 is changed into outside the parachlorotoluene, and all the other are with example 1.
Example 6
Aromatic solvents toluene in the example 1 is changed into outside the dimethylbenzene, and all the other are with example 1.
Example 7
Except that sodium azide changed nitrine potassium into, all the other were with example 1.
Example 8
Except that sodium azide changed the nitrine lithium into, all the other were with example 1.
Example 9
Change triethylamine hydrochloride into triethylamine vitriol, all the other are with example 1.
Example 10
Change triethylamine hydrochloride into ethylenediamine-hydrochloride, all the other are with example 1.
Example 11
Change triethylamine hydrochloride into the tert-butylamine salt hydrochlorate, all the other are with example 1.
Example 12
Change triethylamine hydrochloride into ammonium chloride, all the other are with example 1.
Example 13
Change triethylamine hydrochloride into zinc chloride, all the other are with example 1.
Example 14
Aromatic solvents toluene in the example 2 is changed into outside the parachlorotoluene, and all the other are with example 2.
Example 15
Aromatic solvents toluene in the example 2 is changed into outside the dimethylbenzene, and all the other are with example 2.
Example 16
Except that sodium azide changed nitrine potassium into, all the other were with example 2.
Example 17
Except that sodium azide changed the nitrine lithium into, all the other were with example 2.
Example 18
Change triethylamine hydrochloride into zinc chloride, all the other are with example 2.
Example 19
Aromatic solvents toluene in the example 3 is changed into outside the parachlorotoluene, and all the other are with example 3.
Example 20
Aromatic solvents toluene in the example 3 is changed into outside the dimethylbenzene, and all the other are with example 3.
Example 21
Except that sodium azide changed nitrine potassium into, all the other were with example 3.
Example 22
Change triethylamine hydrochloride into ammonium chloride, all the other are with example 3.
Example 23
Change triethylamine hydrochloride into zinc chloride, all the other are with example 3.
Example 24
Aromatic solvents toluene in the example 4 is changed into outside the parachlorotoluene, and all the other are with example 4.
Example 25
Aromatic solvents toluene in the example 4 is changed into outside the dimethylbenzene, and all the other are with example 4.
Example 26
Except that sodium azide changed nitrine potassium into, all the other were with example 4.
Example 27
Except that sodium azide changed the nitrine lithium into, all the other were with example 4.。
Example 28
Change triethylamine hydrochloride into ammonium chloride, all the other are with example 4.
Example 29
Change triethylamine hydrochloride into zinc chloride, all the other are with example 4.
Example 30
Except that sodium azide changed nitrine potassium into, all the other were with example 5.
Example 31
Except that sodium azide changed the nitrine lithium into, all the other were with example 5.
Example 32
Change triethylamine hydrochloride into ammonium chloride, all the other are with example 5.
Example 33
Change triethylamine hydrochloride into zinc chloride, all the other are with example 5.
Example 34
Change triethylamine hydrochloride into iron protochloride, all the other are with example 5.
Example 35
Except that sodium azide changed nitrine potassium into, all the other were with example 6.
Example 36
Except that sodium azide changed the nitrine lithium into, all the other were with example 6.
Example 37
Change triethylamine hydrochloride into triethylamine vitriol, all the other are with example 6.
Example 38
Change triethylamine hydrochloride into ammonium chloride, all the other are with example 6.
Example 39
Change triethylamine hydrochloride into zinc chloride, all the other are with example 6.
Example 40
Change triethylamine hydrochloride into iron protochloride, all the other are with example 6.
Example 41
Change triethylamine hydrochloride into ammonium chloride, all the other are with example 7.
Example 42
Change triethylamine hydrochloride into zinc chloride, all the other are with example 7.
Example 43
Change triethylamine hydrochloride into iron protochloride, all the other are with example 7.
Example 44
Except that sodium azide changed nitrine potassium into, all the other were with example 37.
Example 45
Except that sodium azide changed the nitrine lithium into, all the other were with example 37.
Claims (10)
1. the method for a synthesizing Xieshatan is characterized in that this method comprises the following steps:
(1) with compound 3 (N-[(2 '-cyano group-1,1 '-biphenyl-4-yl) alkyl]-L-L-valine ester hydrochloride) even with the aqueous solution of the aromatic solvents of 0.5～10 times of weight and carbonate, controlled temperature is at 0～30 ℃ of mixture that begins to drip 0.4～0.8 times of weight valeryl chloride and 1～10 times of weight aromatic solvents, 0.5 dripped and finish in～4 hours, keeping 10～40 ℃ stirred 1～3 hour, branch vibration layer, organic layer saturated common salt water washing, penta acylate solution be directly used in follow-up synthetic or boil off partial solvent, separate out compound thing 2 (N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-L-Xie Ansuan alkyl ester is standby;
(2) use step preparation compound thing 2 (N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-L-Xie Ansuan alkyl ester solution or compound 2 (N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-L-Xie Ansuan alkyl ester solid is dissolved in solvent, this solvent and step (1) solvent for use is identical or different; To the metal-salt of the hydrazoic acid that wherein adds 0.5～4.0 times of penta acylate weight and the amine salt or the Lewis acid of 0.5～2.0 times of weight; stir; be heated to 70～150 ℃; back flow reaction 10～50 hours, reaction finish postcooling to room temperature, add the saturated common salt water washing; organic layer adds the aqueous solution of 10%～30% alkali again; controlled temperature divides and removes organic layer 0～40 ℃ of reaction 4～10 hours, adds an amount of aromatic solvents washing to the alkali layer; be cooled to below 0 ℃; regulate pH value 1～2 with hydrochloride aqueous solution, use ethyl acetate extraction, organic layer saturated common salt water washing; boil off the part ethyl acetate; the cooling precipitation and crystallization filters, and gets compound 1:
In the following formula:
Compound 1 is N-(1-pentanoyl)-N-[4-[2-(1H-tetrazole-5-yl) phenyl] benzyl]-the L-Xie Ansuan, wherein R is hydrogen, methyl, ethyl, sec.-propyl or benzyl; When R is H, be valsartan;
Compound 2 is N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-L-Xie Ansuan alkyl ester, wherein R is hydrogen, methyl, ethyl, sec.-propyl or benzyl;
Compound 3N-[(2 '-cyano group-1,1 '-biphenyl-4-yl) alkyl]-L-L-valine ester hydrochloride, wherein R is hydrogen, methyl, ethyl, sec.-propyl or benzyl.
2. by the method for the described a kind of synthesizing Xieshatan of claim 1, it is characterized in that step (2) amine salt is triethylamine, methylamine, quadrol or TERTIARY BUTYL AMINE.
3. by the method for the described a kind of synthesizing Xieshatan of claim 1, it is characterized in that step (2) Lewis acid is the organic salt of triethylamine salt, methylamine salt, ethylenediamine salt or tert-butylamine salt or is the inorganic salt of ammonium chloride, zinc chloride or ferrous sulfate; Described amine salt or lewis acidic acid group are the inorganic acid radical of salt acid group, sulfate radical or nitrate radical or are the organic acid of oxalic acid root, oxalate or tosic acid root.
4. by the method for the described a kind of synthesizing Xieshatan of claim 1, the metal-salt that it is characterized in that step (2) hydrazoic acid is sodium azide, nitrine potassium or nitrine lithium.
5. by the method for the described a kind of synthesizing Xieshatan of claim 1, it is characterized in that described solvent is toluene, parachlorotoluene or dimethylbenzene, preferred toluene.
6. by the method for the described a kind of synthesizing Xieshatan of claim 1, it is characterized in that step (2) reaction is to carry out in 70～150 ℃ temperature range.
7. by the method for the described a kind of synthesizing Xieshatan of claim 1, formula 1 compound that it is characterized in that step (2) preparation can carry out ester hydrolysis reaction without separation and obtain valsartan.
8. press the method for the described a kind of synthesizing Xieshatan of claim 1, it is characterized in that this method comprises that reaction obtains formula 2 compounds in the presence of the alkali having in solvent by formula 3 compounds and valeryl chloride, after separating alkali and acid salt thereof, formula 2 compounds do not need to separate from solvent, are directly used in preparation formula 1 compound.
9. by the described method of claim 8, described solvent is that aromatic hydrocarbon solvent is toluene, parachlorotoluene or dimethylbenzene.
10. by the described method of claim 8, alkali is the carbonate or the supercarbonate of basic metal or alkaline-earth metal, and they are salt of wormwood, yellow soda ash, magnesiumcarbonate, saleratus, sodium bicarbonate or Magnesium hydrogen carbonate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100383460A CN101270096B (en) | 2007-03-22 | 2007-03-22 | Method for synthesizing diovan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100383460A CN101270096B (en) | 2007-03-22 | 2007-03-22 | Method for synthesizing diovan |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101270096A true CN101270096A (en) | 2008-09-24 |
| CN101270096B CN101270096B (en) | 2011-08-03 |
Family
ID=40004349
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007100383460A Active CN101270096B (en) | 2007-03-22 | 2007-03-22 | Method for synthesizing diovan |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101270096B (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102060797A (en) * | 2010-12-31 | 2011-05-18 | 江苏江神药物化学有限公司 | High-purity valsartanmethyl ester crystal production process |
| CN102321038A (en) * | 2011-07-11 | 2012-01-18 | 安徽省虹升生物科技有限公司 | Improved valsartan preparation method |
| CN102649780A (en) * | 2011-02-28 | 2012-08-29 | 广东东阳光药业有限公司 | Improved process for synthesizing valsartan |
| CN102822151A (en) * | 2010-04-07 | 2012-12-12 | 新梅斯托克公司 | Improved process for preparing valsartan |
| CN101817795B (en) * | 2010-05-13 | 2013-03-27 | 浙江美诺华药物化学有限公司 | Improved method for synthesizing valsartan |
| CN103052630A (en) * | 2010-08-03 | 2013-04-17 | 诺华有限公司 | Highly crystalline valsartan |
| CN103613558A (en) * | 2013-11-08 | 2014-03-05 | 浙江新赛科药业有限公司 | Preparation method of valsartan |
| CN103922528A (en) * | 2014-03-21 | 2014-07-16 | 浙江华海药业股份有限公司 | Method for processing valsartan waste water |
| CN103923028A (en) * | 2014-05-04 | 2014-07-16 | 青岛雪洁助剂有限公司 | Preparation method of valsartan |
| US11655220B2 (en) | 2020-10-22 | 2023-05-23 | Hetero Labs Limited | Process for the preparation of angiotensin II receptor blockers |
-
2007
- 2007-03-22 CN CN2007100383460A patent/CN101270096B/en active Active
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102822151B (en) * | 2010-04-07 | 2015-03-18 | 新梅斯托克公司 | Improved process for preparing valsartan |
| CN102822151A (en) * | 2010-04-07 | 2012-12-12 | 新梅斯托克公司 | Improved process for preparing valsartan |
| CN101817795B (en) * | 2010-05-13 | 2013-03-27 | 浙江美诺华药物化学有限公司 | Improved method for synthesizing valsartan |
| CN103052630A (en) * | 2010-08-03 | 2013-04-17 | 诺华有限公司 | Highly crystalline valsartan |
| CN102060797A (en) * | 2010-12-31 | 2011-05-18 | 江苏江神药物化学有限公司 | High-purity valsartanmethyl ester crystal production process |
| CN102649780A (en) * | 2011-02-28 | 2012-08-29 | 广东东阳光药业有限公司 | Improved process for synthesizing valsartan |
| CN102321038A (en) * | 2011-07-11 | 2012-01-18 | 安徽省虹升生物科技有限公司 | Improved valsartan preparation method |
| CN102321038B (en) * | 2011-07-11 | 2014-03-26 | 安徽省虹升生物科技有限公司 | Improved valsartan preparation method |
| CN103613558A (en) * | 2013-11-08 | 2014-03-05 | 浙江新赛科药业有限公司 | Preparation method of valsartan |
| CN103613558B (en) * | 2013-11-08 | 2015-10-21 | 浙江新赛科药业有限公司 | A kind of preparation method of valsartan |
| CN103922528A (en) * | 2014-03-21 | 2014-07-16 | 浙江华海药业股份有限公司 | Method for processing valsartan waste water |
| CN103922528B (en) * | 2014-03-21 | 2019-07-02 | 浙江华海药业股份有限公司 | A kind of method of Valsartan wastewater treatment |
| CN103923028A (en) * | 2014-05-04 | 2014-07-16 | 青岛雪洁助剂有限公司 | Preparation method of valsartan |
| CN103923028B (en) * | 2014-05-04 | 2017-05-24 | 青岛雪洁助剂有限公司 | Preparation method of valsartan methyl ester |
| US11655220B2 (en) | 2020-10-22 | 2023-05-23 | Hetero Labs Limited | Process for the preparation of angiotensin II receptor blockers |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101270096B (en) | 2011-08-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101270096B (en) | Method for synthesizing diovan | |
| CN103524440B (en) | The preparation method of gout therapertics Lesinurad and Lesinurad intermediate | |
| CN105418460B (en) | Intermediate of pimavanserin and similar compound thereof, and preparation method thereof, and method for preparing pimavanserin and similar compound thereof | |
| CN103588657A (en) | Method for producing phenylacetamide compound | |
| CN105017082B (en) | A kind of preparation method of heart failure medicine Entresto key intermediates (R) tert-butyl group (base of 1 ([1,1` biphenyl] 4 bases) 3 hydroxy propane 2) carbamate | |
| CN101817795B (en) | Improved method for synthesizing valsartan | |
| CN100575338C (en) | Compound of optically pure sulfenamides and application thereof | |
| CN102964313B (en) | Synthetic method of febuxostat | |
| CN104829493A (en) | Synthetic method for romatic carbamic acid ester | |
| AU2003248280A1 (en) | New process for the industrial synthesis of tetraesters of 5-[bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid, and application to the synthesis of bivalent salts of ranelic acid and their hydrates | |
| CN101563312A (en) | Process for producing intermediate of asenapine synthesis | |
| CN106749259A (en) | A kind of synthetic method of cyclopenta pyrimido azoles | |
| CN103467445B (en) | Preparation method of alogliptin benzoate | |
| CN103804267A (en) | Simple environment-friendly synthesis process of vildagliptin | |
| CN106631823A (en) | Preparation method of lorcaserin intermediate | |
| CN103922528B (en) | A kind of method of Valsartan wastewater treatment | |
| CN110156721A (en) | Utilize diazotate, cyclic ethers, amine and CO2The method of synthesis of carbamates | |
| CN105669651A (en) | Preparation technique of dabigatran methanesulfonate | |
| CN107513048B (en) | Synthesis method of deuterated vortioxetine hydrobromide | |
| CN102757390B (en) | Method for preparing 2-methoxy-4-diazanyl-5-fluoropyrimidine | |
| CN104725292A (en) | Preparation method of (S)(-)-amisulpride | |
| CN102002012A (en) | Method for synthesizing 1,3-oxazole-2,4-diketone compounds | |
| MX2012005025A (en) | Process for the manufacture of organic compounds. | |
| CN105254611B (en) | The preparation method of the carboxylic acid of benzothiophene 2 | |
| CN106946724A (en) | The synthetic method of the benzyl malonic acid mono ethyl ester of 2 acetylamino of monoamine base inhibitor class intermediate 2 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY Effective date: 20131125 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| C53 | Correction of patent for invention or patent application | ||
| CB03 | Change of inventor or designer information |
Inventor after: Shi Huilin Inventor after: Wang Liquan Inventor after: Chen Wei Inventor after: Liu Dapeng Inventor after: Zhou Hu Inventor after: Tu Guoliang Inventor before: Wang Liquan Inventor before: Chen Wei Inventor before: Liu Dapeng |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: WANG LIQUAN CHEN WEI LIU DAPENG TO: SHI HUILIN WANG LIQUAN CHEN WEI LIU DAPENG ZHOU HU TU GUOLIANG |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20131125 Address after: 317024 flood bridge, Linhai City, Zhejiang Patentee after: Zhejiang Huahai Pharmaceutical Co., Ltd. Patentee after: Shanghai Institute of pharmaceutical industry Address before: 317024, Zhejiang province Linhai City Xun Town Li Zhuang Patentee before: Zhejiang Huahai Pharmaceutical Co., Ltd. |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| CB03 | Change of inventor or designer information |
Inventor after: Wang Liquan Inventor after: Chen Wei Inventor after: Liu Dapeng Inventor before: Shi Huilin Inventor before: Wang Liquan Inventor before: Chen Wei Inventor before: Liu Dapeng Inventor before: Zhou Hu Inventor before: Tu Guoliang |
|
| COR | Change of bibliographic data | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20151117 Address after: 317024 flood bridge, Linhai City, Zhejiang Patentee after: Zhejiang Huahai Pharmaceutical Co., Ltd. Address before: 317024 flood bridge, Linhai City, Zhejiang Patentee before: Zhejiang Huahai Pharmaceutical Co., Ltd. Patentee before: Shanghai Institute of pharmaceutical industry |