CN101619064A - Synthesis and process method for novel polynitrogen heterocycle pharmaceutical intermediates - Google Patents
Synthesis and process method for novel polynitrogen heterocycle pharmaceutical intermediates Download PDFInfo
- Publication number
- CN101619064A CN101619064A CN200810043577A CN200810043577A CN101619064A CN 101619064 A CN101619064 A CN 101619064A CN 200810043577 A CN200810043577 A CN 200810043577A CN 200810043577 A CN200810043577 A CN 200810043577A CN 101619064 A CN101619064 A CN 101619064A
- Authority
- CN
- China
- Prior art keywords
- methyl
- hydrogen
- phenyl
- substituted
- lactan
- 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
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a synthesis and process method for pharmaceutical intermediates, namely polynitrogen heterocycles. Various cheap and easily-obtained maleic acid esters and nitrogen-substituted glycin or dipicolinic acid are taken as raw materials to obtain a dicyclic polynitrogen compound through a four-step or five-step reaction. The method has the advantages of easily-obtained raw materials, low cost, simple reaction, easy control, simple processing, and high yield, is easy for scale-up production, and comprises, but is not limited to aliphatic, aromatic and heterocyclic polynitrogen heterocycles. The invention provides the feasible synthesis and process method for the pharmaceutical intermediates, namely the polynitrogen heterocycles for the green chemical industry.
Description
I. background is summarized
Polynitrogen heterocycle becomes numerous new drugs (US5202337, US5071999, US20050234031 in recent years, US5179090, US5468742, US 20050101602, US20050197333, US6114531, US5298629, US2004242641, TL46 (42), 2005,7179-7200, US5654318, JMC36 (16), 1993,2311-2320, W02004/832) important intermediate, this type of compound is synthetic to cause extensive interest, general synthetic route is longer, the loaded down with trivial details difficulty of aftertreatment, the raw materials cost height, the three wastes are many, pollute big.Therefore the scientific research personnel is still constantly seeking more easy synthetic method.
The purpose of this invention is to provide one begins through synthetic, processing method than short-circuit line synthesizing new polynitrogen heterocycle pharmaceutical intermediate from the raw material that simply is easy to get.Present method can be synthesized multi-series polynitrogen heterocycle pharmaceutical intermediate; And raw material is easy to get, and cost is lower, and the three wastes are few, handle simple, yield height, and be easy to suitability for industrialized production.
II. main contents of the present invention
The present invention relates to the synthetic and processing method of a class medicine intermediate polynitrogen heterocycle, its molecular formula is shown in figure (I).Method synthetic route of the present invention is short, and raw material is easy to get, and is easy to purifying, and cost is low, is easy to industrialization.
R wherein
1Be methyl, hydrogen, phenyl, be preferably hydrogen, methyl; R
2Be methyl, hydrogen, phenyl, be preferably hydrogen, methyl; R
3Be hydrogen, alkyl, aryl, heterocyclic radical, be preferably hydrogen, methyl, ethyl, sec.-propyl, cyclopropyl, isobutyl-, benzyl, phenyl, substituted-phenyl, pyridyl, substituted pyridinyl, thienyl; R
4Be hydrogen, alkyl, aryl, heterocyclic radical, be preferably hydrogen, methyl, ethyl, sec.-propyl, benzyl, phenyl, pyridyl, thienyl; M=1-3 is preferably 1 and 2; N=1,2; P=0,1.
For helping further to understand the present invention, the structural formula of this compounds can further be expressed as structural formula (II) [m=n=p=1], (III) [m=2, n=p=1] and (IV) [m=n=2, p=0].
R wherein
1Be methyl, hydrogen, phenyl, be preferably hydrogen, methyl; R
2Be methyl, hydrogen, phenyl, be preferably hydrogen, methyl; R
3Be hydrogen, alkyl, aryl, heterocyclic radical, be preferably hydrogen, methyl, ethyl, sec.-propyl, cyclopropyl, isobutyl-, benzyl, phenyl, substituted-phenyl, pyridyl, substituted pyridinyl, thienyl.
Typical synthetic method reaction formula of the present invention is as follows, but does not limit content of the present invention.
Synthetic route 1
Synthetic route 2
Synthetic route 3
The synthetic method can further describe as follows:
Synthetic route 1
The first step replaces maleic acid ester and N-substituted glycinic acid is dissolved in the appropriate solvent, makes two acid esters.Maleic acid ester and N-substituted glycinic acid mol ratio are 3: 1-1: 1, recommending used replacement maleic acid ester molar weight is 1.5-1, the recommendation solvent for use is low polarity or polar solvents such as toluene, benzene, dimethylbenzene, DMF, DMSO, DMA, the recommendation response temperature is the 80-150 degree, and the second step diester and benzylamine are dissolved in the appropriate solvent, make dicyclo, the mol ratio of diester and benzylamine 1: 1.5, recommending the benzylamine molar weight is 1, recommends etoh solvent, methyl alcohol or the like, recommendation response temperature 50-90 degree.The 3rd step reducing carbonyl, carbonyl compound and lithium aluminium hydride mol ratio 1: 6, recommending mol ratio is 1: 3, the final step hydrogenation makes product, useful catalyst Pd/C, Pd (OH) 2/C or the like.
Synthetic route 2
The first step pyridine dicarboxylic acid and benzylamine reaction make lactan, second step lactan and the haloalkane react pyridinium salt, lactan and haloalkane mol ratio 1: 3, recommended mol ratio 1: 1.2, recommending solvent for use is little polar solvents such as benzene,toluene,xylene, the 3rd step reduction pyridine ring, the recommendation catalyzer is Pd/C, Pd (OH)
2/ C, Rh/C or the like, recommended pressure 1-50kg/cm
2, temperature of reaction 20-100 degree, the 4th step was reduced into amine with lithium aluminium hydride with lactan, carbonyl compound and lithium aluminium hydride mol ratio 1: 6, recommending mol ratio is 1: 3.
Synthetic route 3
The first step is that amino propylal dimethanol of alkali and Vinyl chloroformate reaction make acid amides with sodium hydroxide; second step acid amides and haloalkane under phase-transfer catalyst catalysis reacts and makes tertiary amine; recommending used phase-transfer catalyst is benzyltriethylammoinium chloride; benzyl triethyl ammonium bromide; tetrabutylammonium chloride etc.; the 3rd step made aldehyde with sour deprotection; recommending used acid is formic acid; acetate; tosic acid or the like; the 4th step was closed ring with N-substituted glycinic acid in appropriate solvent; recommending solvent is benzene; toluene; little polar solvent such as dimethylbenzene; the 5th step piptonychia acetoacetic ester in acid gets product, and recommending acid is concentrated hydrochloric acid; 50% sulfuric acid etc.
Synthetic route method reaction temperature of the present invention and, be easy to control, be easy to amplify to produce, raw material is easy to get, the productive rate height, purifying products is simple.
III. invention example
To help further to understand the present invention by following example; They are not only limited by example for the practical ranges of giving an example.
Example 1 structural formula (II) compounds 3-methyl-3,7-diazabicyclo[3.3.0] octanes synthetic
The first step
With 10.3g (0.1mol, 1.5eq) sarcosine, 8.35g (0.067mol, 1eq) dimethyl maleate and 6g (0.2mol, 3eq) be added in the toluene of 100ml, reflux stirs about 2h, TLC detects, and reacts completely, and is spin-dried for, in residual night, add the 100mL ethyl acetate, with saturated common salt water washing (3*50mL), dried over mgso, be spin-dried for pure product (17g, 80%) MS (M+H),
+=202.2
Second step
With 2.01g (10mmol, 1eq) the first step product and 1.07g (10mmol, 1eq) benzylamine joins in the 30mL dehydrated alcohol, reflux is spent the night, the TLC endpoint detection, be spin-dried for the pure product of 1.9g, yield 80%, MS (M+H)
+=245
The 3rd step
Under the nitrogen protection, in three bottles of 500mL, add the 13.3g Li-Al hydrogen (0.35mol, 3eq) and the anhydrous THF of 350mL; be cooled to 0 degree; the 28g second step product (0.115mo1) is dissolved among the anhydrous THF of 120mL, is added drop-wise in the reaction flask, after dropwising; naturally rise to room temperature; stir 30min, the 3h that refluxes then is cooled to 0 degree; drip 13.3g water successively; 26.6g15% aqueous sodium hydroxide solution and 13.3g water; filter, filter cake is used extracted with diethyl ether (3*200mL) with ether washing (3*200mL), filtrate; merge organic phase; use dried over mgso, filtration is spin-dried for, and underpressure distillation gets pure product (15g; 60%) MS (M+H),
+=217
The 4th step
In the single port bottle of 100mL 10g the 3rd step product is dissolved in the 100mL methyl alcohol, 1gPd/C (10%w/w) joins in the reaction solution, uses hydrogen exchange three times, stirred overnight at room temperature, and the TLC detection reaction finishes, and filters, and concentrates, and gets pure product (5.5g, 95%).MS (M+H)
+=127, purity GC＞98.0%.
Example 2 structural formulas (III) compounds 3-methyl-3,8-diazabicyclo[4.3.0] nonanes synthetic
The first step
At room temperature, with the acetic anhydride of 170mL be added to 100g (0.6mol, 1eq) 3, in the 4-pyridine dicarboxylic acid, after dropwising, be heated to 110 degree, stirred 4 hours, be cooled to room temperature, it is dense dried to reduce pressure, and the ether of 200mL joined in residual night, filtered, filter cake washs (4*100) with ether, gets the acid anhydrides of 86g.Under cooling, acid anhydrides is joined 76mL (0.7mol in batches, 1.17eq) benzylamine in, be heated to 180 degree and stirred 30 minutes, the mixture with this reaction is cooled to 0 degree again, drip the 170mL acetic anhydride, stirred 2 hours at 110 degree, the TLC detection reaction finishes, and naturally cools to room temperature, in reaction mixture, add the 500mL dehydrated alcohol, filter, get 89g product (62%), MS (M+H)
+=239
Second step
With example 5 products of 10g (0.042mol), 7.2g (0.0504mol, 1.2eq) methyl iodide and 90mL toluene add in the tube sealing, are heated to 110 degree reactions and spend the night, and are cooled to room temperature, filter, the pure product of 15g (94%), MS (M+H)
+=253
The 3rd step
The second step product of 10g (26.3mmol) is dissolved in the methyl alcohol of 10mL, adds 0.2gPd/C, 15atm hydrogenation is spent the night under the room temperature, TLC controls reaction end, filter, be spin-dried for, add the sodium hydroxide solution of 20mL2M residual night, at room temperature stir 30min, with ethyl acetate extraction (3*50mL), dried over mgso is filtered, be spin-dried for the pure product of 4.2g (95%), MS (M+H)
+=169
The 4th step
Under the nitrogen protection; (54mmol 3eq) and the anhydrous THF of 30mL, is cooled to 0 degree to add the 2.05g Li-Al hydrogen in three bottles of 200mL; the product in the 3rd step of 3g (18mmol) is dissolved among the anhydrous THF of 50mL; be added drop-wise in the reaction flask, after dropwising, rise to room temperature naturally; stir 30min; the 6h that refluxes then is cooled to 0 degree, drips 2.05g water successively; 4.1g15% aqueous sodium hydroxide solution and 2.5g water; filter; filter cake merges organic phase with ether washing (3*200mL), filtrate with extracted with diethyl ether (3*200mL); use dried over mgso; filtration is spin-dried for, and underpressure distillation gets the pure product of 2.24g (89%), MS (M+H)
+=141.
Example 3 structural formulas (III) compounds 7-methyl-3,7-diazabicyclo[4.3.0] nonanes synthetic
The first step
The dissolution of sodium hydroxide of 90g in the water of 500mL, is added the toluene of 1L, and the amino propylal dimethanol of 214g (2mol) drips in the mixed solvent, be cooled to 10 degree, drip 214g (2mol) Vinyl chloroformate, stirred 2 hours, divide water-yielding stratum, saturated with salt, with toluene (2*500mL) extraction, merge organic phase, dried over mgso, filter, be spin-dried for, reduce pressure the pure product of 338g (95.4%).
Second step
The first step product with 500g (2.82mol), the potassium hydroxide of 625g and 10g triethyl benzyl ammonia chloride are dissolved in the toluene of 2.7L, at room temperature drip the allyl bromide 98 of 385g (2.85mol), stirring is spent the night, filter, organic phase is washed with saturated sodium-chloride water solution, dried over mgso, filtration is spin-dried for, and underpressure distillation gets the pure product of 657g (95%)
The 3rd step
The second step product of 76g (0.313mol) is dissolved in the formic acid of 150mL, be heated to 100 degree reactions 1 hour, reaction solution is poured in the frozen water, extract with methylene dichloride (3*300mL), organic phase is washed once with saturated sodium bicarbonate, and dried over mgso is filtered, be spin-dried for, underpressure distillation gets the pure product of 54g (87%)
The 4th step
The 3rd step product and 4.5g (50mmol) sarcosine of 9.96g (50mmol) are dissolved in the 200mL toluene, and reflux is spent the night, and concentrates, and underpressure distillation gets the pure product of 7.43g (70%)
The 5th step
8.5g (40mmol) the 4th step product is dissolved in the 50mL concentrated hydrochloric acid, and reflux is spent the night, and is cooled to room temperature, in ice bath, transfer to alkalescence, with methylene dichloride (4*200mL) extraction, dried over mgso with the 2MKOH aqueous solution, filter, concentrate, reduce pressure the pure product of 3.9g (70%).
IV. claims
1. a class has structural formula (II) 3,7-diazabicyclo[3.3.0] the synthetic and processing method of the medicine intermediate polynitrogen heterocycle of octanes, it is characterized in that this method comprises the following step:
Wherein R1 is methyl, hydrogen, phenyl, is preferably hydrogen, methyl; R2 is methyl, hydrogen, phenyl, is preferably hydrogen, methyl; R3 is hydrogen, alkyl, aryl, heterocyclic radical, is preferably hydrogen, methyl, ethyl, sec.-propyl, cyclopropyl, isobutyl-, benzyl, phenyl, substituted-phenyl, pyridyl, substituted pyridinyl, thienyl.
(1) cyclization: the N-substituted amino acid carries out cyclization with replacement maleic acid ester and Paraformaldehyde 96 and obtains substituted pyrrolidin;
(2) reaction of tetramethyleneimine diester and organic amine makes bridged ring tetramethyleneimine lactan; (3) lactan generates the two tetramethyleneimine of bridged ring through the LAH reduction; (4) make object construction (II) 3,7-diazabicyclo[3.3.0 through the hydrogenation deprotection] octanes.
2. a class has structural formula (III) 3,8-diazabicyclo[4.3.0] the synthetic and processing method of the medicine intermediate polynitrogen heterocycle of nonanes, it is characterized in that this method comprises the following step:
Wherein R3 is hydrogen, alkyl, aryl, heterocyclic radical, is preferably hydrogen, methyl, ethyl, sec.-propyl, cyclopropyl, isobutyl-, benzyl.
(1) reaction of pyridine dicarboxylic acid and benzylamine makes lactan; (2) lactan and haloalkane react pyridinium salt; (3) the hydro-reduction pyridinium salt prepares the endocyclic compound of lactan; (4) with lithium aluminium hydride lactan is reduced into amine (III) 3,8-diazabicyclo[4.3.0] nonanes.
3. a class has structural formula (IV) 3,7-diazabicyclo[4.3.0] the synthetic and processing method of the medicine intermediate polynitrogen heterocycle of nonanes, it is characterized in that this method comprises the following step:
Wherein R3 is hydrogen, alkyl, aryl, heterocyclic radical, is preferably hydrogen, methyl, ethyl, sec.-propyl, cyclopropyl, isobutyl-, benzyl, phenyl, substituted-phenyl, pyridyl, substituted pyridinyl, thienyl.
(1) reaction of amino propylal dimethanol and Vinyl chloroformate makes acid amides; (2) reaction of acid amides and haloalkane makes tertiary amine under phase-transfer catalyst catalysis; (3) make aldehyde with sour deprotection; (4) aldehyde and N-substituted glycinic acid close encircle the endocyclic compound of protection; (5) the piptonychia acetoacetic ester gets product (IV) 3,7-diazabicyclo[4.3.0 in acid] nonanes.
V. brief summary/Abstract
The invention provides the synthetic and processing method of a class medicine intermediate polynitrogen heterocycle.Utilize glycine or pyridine dicarboxylic acid cheap and be easy to get all kinds of maleic acid esters and nitrogen replacement to be raw material,, obtain the dicyclo polyazin through 4 steps or the reaction of 5 steps.Present method raw material is easy to get, cost is low, reaction is simple, be easy to control, handle simply the yield height, and be easy to amplify and produce, include but not limited to aliphatics, aromatic series and heterocyclic polynitrogen heterocycle, the present invention provides the synthetic and processing method of a practicable class medicine intermediate polynitrogen heterocycle for green chemical industry.
Claims (3)
1. a class has structural formula (II) 3,7-diazabicyclo[3.3.0] the synthetic and processing method of the medicine intermediate polynitrogen heterocycle of octanes, it is characterized in that this method comprises the following step:
Wherein R1 is methyl, hydrogen, phenyl, is preferably hydrogen, methyl; R2 is methyl, hydrogen, phenyl, is preferably hydrogen, methyl; R3 is hydrogen, alkyl, aryl, heterocyclic radical, is preferably hydrogen, methyl, ethyl, sec.-propyl, cyclopropyl, isobutyl-, benzyl, phenyl, substituted-phenyl, pyridyl, substituted pyridinyl, thienyl.
(1) cyclization: the N-substituted amino acid carries out cyclization with replacement maleic acid ester and Paraformaldehyde 96 and obtains substituted pyrrolidin; (2) reaction of tetramethyleneimine diester and organic amine makes bridged ring tetramethyleneimine lactan; (3) lactan generates the two tetramethyleneimine of bridged ring through the LAH reduction; (4) make object construction (II) 3,7-diazabicyclo[3.3.0 through the hydrogenation deprotection] octanes.
2. a class has structural formula (III) 3,8-diazabicyclo[4.3.0] the synthetic and processing method of the medicine intermediate polynitrogen heterocycle of nonanes, it is characterized in that this method comprises the following step:
Wherein R3 is hydrogen, alkyl, aryl, heterocyclic radical, is preferably hydrogen, methyl, ethyl, sec.-propyl, cyclopropyl, isobutyl-, benzyl.
(1) reaction of pyridine dicarboxylic acid and benzylamine makes lactan; (2) lactan and haloalkane react pyridinium salt; (3) the hydro-reduction pyridinium salt prepares the endocyclic compound of lactan; (4) with lithium aluminium hydride lactan is reduced into amine (III) 3,8-diazabicyclo[4.3.0] nonanes.
3. a class has structural formula (IV) 3,7-diazabicyclo[4.3.0] the synthetic and processing method of the medicine intermediate polynitrogen heterocycle of nonanes, it is characterized in that this method comprises the following step:
Wherein R3 is hydrogen, alkyl, aryl, heterocyclic radical, is preferably hydrogen, methyl, ethyl, sec.-propyl, cyclopropyl, isobutyl-, benzyl, phenyl, substituted-phenyl, pyridyl, substituted pyridinyl, thienyl.
(1) reaction of amino propylal dimethanol and Vinyl chloroformate makes acid amides; (2) reaction of acid amides and haloalkane makes tertiary amine under phase-transfer catalyst catalysis; (3) make aldehyde with sour deprotection; (4) aldehyde and N-substituted glycinic acid close encircle the endocyclic compound of protection; (5) the piptonychia acetoacetic ester gets product (IV) 3,7-diazabicyclo[4.3.0 in acid] nonanes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100435775A CN101619064B (en) | 2008-07-01 | 2008-07-01 | Synthesis and process method for novel polynitrogen heterocycle pharmaceutical intermediates |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100435775A CN101619064B (en) | 2008-07-01 | 2008-07-01 | Synthesis and process method for novel polynitrogen heterocycle pharmaceutical intermediates |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110066023A Division CN102180874B (en) | 2008-07-01 | 2008-07-01 | Synthetic process method for azabicyclo medicinal intermediates |
| CN2011100660224A Division CN102101861B (en) | 2008-07-01 | 2008-07-01 | Synthesis and process method of nitrogen-containing bis-heterocyclic medicine intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101619064A true CN101619064A (en) | 2010-01-06 |
| CN101619064B CN101619064B (en) | 2011-05-11 |
Family
ID=41512481
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008100435775A Active CN101619064B (en) | 2008-07-01 | 2008-07-01 | Synthesis and process method for novel polynitrogen heterocycle pharmaceutical intermediates |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101619064B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011109232A1 (en) * | 2010-03-01 | 2011-09-09 | Novadrug, Llc | Compositions and methods for treating viral diseases |
| WO2014061031A1 (en) | 2012-10-17 | 2014-04-24 | Cadila Healthcare Limited | 2-phenyl-5-heterocyclyl-tetrahydro-2h-pyran-3-amine compounds for use in the treatment of diabetes and its associated disorders |
| CN104402891A (en) * | 2014-11-19 | 2015-03-11 | 苏州乔纳森新材料科技有限公司 | Synthetic method of drug intermediate 3-methyl-3,7-diazabicyclo(3.3.0)octane |
| US9241930B2 (en) | 2011-08-24 | 2016-01-26 | Novadrug, Llc | Compositions and methods for treating viral diseases |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1122257B1 (en) * | 2000-01-05 | 2005-10-12 | Pfizer Inc. | Benzimidazole compounds as ORL1-receptor agonists |
-
2008
- 2008-07-01 CN CN2008100435775A patent/CN101619064B/en active Active
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011109232A1 (en) * | 2010-03-01 | 2011-09-09 | Novadrug, Llc | Compositions and methods for treating viral diseases |
| CN102781448A (en) * | 2010-03-01 | 2012-11-14 | 诺瓦药品公司 | Compositions and methods for treating viral diseases |
| CN102781448B (en) * | 2010-03-01 | 2015-01-21 | 诺瓦药品公司 | Compositions and methods for treating viral diseases |
| US9056099B2 (en) | 2010-03-01 | 2015-06-16 | Novadrug, Llc | Compositions and methods for treating viral diseases |
| US9241930B2 (en) | 2011-08-24 | 2016-01-26 | Novadrug, Llc | Compositions and methods for treating viral diseases |
| WO2014061031A1 (en) | 2012-10-17 | 2014-04-24 | Cadila Healthcare Limited | 2-phenyl-5-heterocyclyl-tetrahydro-2h-pyran-3-amine compounds for use in the treatment of diabetes and its associated disorders |
| CN104402891A (en) * | 2014-11-19 | 2015-03-11 | 苏州乔纳森新材料科技有限公司 | Synthetic method of drug intermediate 3-methyl-3,7-diazabicyclo(3.3.0)octane |
| WO2016078108A1 (en) * | 2014-11-19 | 2016-05-26 | 苏州乔纳森新材料科技有限公司 | Method for synthesizing 3-methyl-3,7-diazabicyclo[3.3.0]octane pharmaceutical intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101619064B (en) | 2011-05-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105732622B (en) | A kind of preparation method of Eliquis | |
| CN101619064B (en) | Synthesis and process method for novel polynitrogen heterocycle pharmaceutical intermediates | |
| CN106588897A (en) | New preparation method of Pranlukast | |
| CN101486753A (en) | Novel method for synthesizing finasteroid | |
| CN102367260A (en) | Synthesis method of 2-aminopyrimidine-5-boric acid | |
| CN106279175A (en) | A kind of preparation method of Ertapenem Sodium | |
| CN103709086A (en) | Preparation method for ezetimibe optical isomers and intermediate applied in preparation method | |
| CN108864084B (en) | Apixaban related substances and preparation method thereof | |
| CN104557663A (en) | Synthetic method of dicarbonyl substituted indole pharmaceutical intermediate compound | |
| CN111004205A (en) | Synthetic method for preparing piperonyl butoxide under catalysis of composite alkali | |
| CN103435610B (en) | A kind of preparation method of imidazo [1,2-a] pyridine compounds and their | |
| CN101531634B (en) | High-purity blonanserin and preparation method thereof | |
| CN102101861B (en) | Synthesis and process method of nitrogen-containing bis-heterocyclic medicine intermediate | |
| CN106220617A (en) | A kind of new synthetic method of his Wei of Dacca | |
| CN101747343B (en) | Sulbactam pivoxil preparation method | |
| CN104592222A (en) | Preparation method for antiplatelet medicine AZD6482 | |
| CN102093354B (en) | Indolizine Mannich base compound and preparation method thereof | |
| CN103833660A (en) | Preparation method of lamotrigine and intermediate thereof | |
| CN110922402B (en) | C-3 iodo-indolizine compound and preparation method thereof | |
| CN113754630B (en) | Synthetic method of alpha-lipoic acid | |
| CN107033090A (en) | A kind of preparation method of 1,2,3,4 tetrahydrochysene cinnolines | |
| CN102180874B (en) | Synthetic process method for azabicyclo medicinal intermediates | |
| CN102408353A (en) | Preparation method of candesartan intermediate | |
| CN105130987B (en) | A kind of synthetic method of medicine intermediate pyrrolopyridines | |
| CN104974160B (en) | The simultaneously carboxylic acid derivates of [1,5 a] pyrimidine 6 and its application of 2 methylpyrazoles |
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 | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: The splendid chemical Science and Technology Ltd. far away in Qidong Assignor: Accela ChemBio Inc. Contract record no.: 2011310000105 Denomination of invention: Synthesis and process method for novel polynitrogen heterocycle pharmaceutical intermediates Granted publication date: 20110511 License type: Common License Open date: 20100106 Record date: 20110718 |
|
| C56 | Change in the name or address of the patentee | ||
| CP02 | Change in the address of a patent holder |
Address after: 201318 Shanghai city wide 222 Lane 21 Pudong New Area Road Patentee after: Accela ChemBio Inc. Address before: 201210 Shanghai Zhangjiang High Tech Park of Pudong New Area Cailun Road No. 88 Building 2 Room 301 Patentee before: Accela ChemBio Inc. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Synthesis and process method for novel polynitrogen heterocycle pharmaceutical intermediates Effective date of registration: 20140520 Granted publication date: 20110511 Pledgee: Pudong Shanghai technology financing Company limited by guarantee Pledgor: Accela ChemBio Inc. Registration number: 2014310000026 |
|
| PLDC | Enforcement, change and cancellation of contracts on pledge of patent right or utility model | ||
| C56 | Change in the name or address of the patentee |
Owner name: ACCELA CHEMBIO CO., LTD. Free format text: FORMER NAME: ACCELA CHEMBIO INC. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 201318 Shanghai city wide 222 Lane 21 Pudong New Area Road Patentee after: ACCELA CHEMBIO CO., LTD. Address before: 201318 Shanghai city wide 222 Lane 21 Pudong New Area Road Patentee before: Accela ChemBio Inc. |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20160328 Granted publication date: 20110511 Pledgee: Pudong Shanghai technology financing Company limited by guarantee Pledgor: Accela ChemBio Inc. Registration number: 2014310000026 |
|
| PLDC | Enforcement, change and cancellation of contracts on pledge of patent right or utility model |