CN104761461A - Preparation method of novel gadoxetate disodium intermediate - Google Patents
Preparation method of novel gadoxetate disodium intermediate Download PDFInfo
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- CN104761461A CN104761461A CN201410281984.5A CN201410281984A CN104761461A CN 104761461 A CN104761461 A CN 104761461A CN 201410281984 A CN201410281984 A CN 201410281984A CN 104761461 A CN104761461 A CN 104761461A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- SLYTULCOCGSBBJ-UHFFFAOYSA-I disodium;2-[[2-[bis(carboxylatomethyl)amino]-3-(4-ethoxyphenyl)propyl]-[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate;gadolinium(3+) Chemical compound [Na+].[Na+].[Gd+3].CCOC1=CC=C(CC(CN(CCN(CC([O-])=O)CC([O-])=O)CC([O-])=O)N(CC([O-])=O)CC([O-])=O)C=C1 SLYTULCOCGSBBJ-UHFFFAOYSA-I 0.000 title abstract 3
- 229940075342 gadoxetate disodium Drugs 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000010992 reflux Methods 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 230000000630 rising effect Effects 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 2
- AQOXEJNYXXLRQQ-KRWDZBQOSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-(4-ethoxyphenyl)propyl]-[2-[bis(carboxymethyl)amino]ethyl]amino]acetic acid Chemical compound CCOC1=CC=C(C[C@@H](CN(CCN(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 AQOXEJNYXXLRQQ-KRWDZBQOSA-N 0.000 abstract 1
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 16
- 230000021523 carboxylation Effects 0.000 description 8
- 238000006473 carboxylation reaction Methods 0.000 description 8
- SLYTULCOCGSBBJ-FCQHKQNSSA-I disodium;2-[[(2s)-2-[bis(carboxylatomethyl)amino]-3-(4-ethoxyphenyl)propyl]-[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate;gadolinium(3+) Chemical compound [Na+].[Na+].[Gd+3].CCOC1=CC=C(C[C@@H](CN(CCN(CC([O-])=O)CC([O-])=O)CC([O-])=O)N(CC([O-])=O)CC([O-])=O)C=C1 SLYTULCOCGSBBJ-FCQHKQNSSA-I 0.000 description 6
- 150000004985 diamines Chemical class 0.000 description 5
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- QKRAOTCLMXZGQF-UHFFFAOYSA-N [Na].BrCC(=O)O Chemical compound [Na].BrCC(=O)O QKRAOTCLMXZGQF-UHFFFAOYSA-N 0.000 description 1
- IEQAHTMXGZUOGN-UHFFFAOYSA-N acetic acid N'-[2-[benzyl(ethoxy)amino]ethyl]ethane-1,2-diamine Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.NCCNCCN(OCC)CC1=CC=CC=C1 IEQAHTMXGZUOGN-UHFFFAOYSA-N 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000005408 paramagnetism Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009919 sequestration Effects 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a novel gadoxetate disodium intermediate (4S)-4-(4-ethoxy benzyl)-3,6,9-tri(carboxyl methyl)-3,6,9-triazaundecanedioic acid (formula I compound). The preparation method of the gadoxetate disodium intermediate shown as a formula I provided by the invention solves the problems of complex process, impurities and unsuitability for industrial production in the prior art. The invention ha the advantages of simple preparation method, mild reaction system, less side effects, green, environment-friendliness, and applicability to large-scale industrial production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to a kind of preparation method of Primovist intermediate compound (4S)-4-(4-ethoxy benzyl)-3,6,9-tri-(carboxylation methyl)-3,6,9-tri-azepine undecane diacid.
Background technology
Gadoxetic acid disodium (Gadoxetic acid disodium, Gd-EOB-DTPA), it is the New Liver specificity mr angiography agent of German Schering Corp exploitation, T1 weighting MR can be significantly improved to the recall rate of liver inner disease foci, in conjunction with reflecting that the strengthening initial stage dynamic T1 weighting MR of focus blood for feature shows, the etiologic diagnosis accuracy to liver inner disease foci more can be significantly improved.In July, 2008, U.S. FDA approval was used for clinical.It is by paramagnetism gadolinium ion and lipophilicly forms ethoxy benzyl diethylenetriamine pentaacetic acid ligand sequestration, normal liver cell optionally absorbs Gd-EOB-DTPA molecule, significantly improve the T1 relaxivity of tissue, contribute to detecting of liver lesion, the special recall rate that can improve little liver neoplasm, thus contribute to the early diagnosis and therapy of hepatic disease.
(4S)-4-(4-ethoxy benzyl)-3,6,9-tri-(carboxylation methyl)-3,6,9-tri-azepine undecane diacid (formula I) is the key intermediate (being the chemical formula of formula I see Figure of description 1, Fig. 1) of Gadoxetic acid disodium.
Current bibliographical information (4S)-4-(4-ethoxy benzyl)-3,6,9-tri-(carboxylation methyl)-3,6,9-tri-azepine undecane diacid synthetic method have several:
Patent US5695739 discloses and adopts S-1-(4-ethoxy benzyl)-3-aza-pentane-1,5 diamines (formula VII compound) and bromo-acetic acid tert-butyl are obtained by reacting formula II compound, then (4S)-4-(4-ethoxy benzyl)-3 is obtained by hydrolysis, 6,9-tri-(carboxylation methyl)-3,6,9-tri-azepine undecane diacid (formula I) is (see Figure of description 2, Fig. 2 is that formula VII compound and bromo-acetic acid tert-butyl are obtained by reacting formula II compound, is then obtained the accompanying drawing of formula I by hydrolysis);
Patent US6039931 discloses and adopts S-1-(4-hydroxy phenyl)-3-aza-pentane-1, 5 diamines (formula V compound) and bromo-acetic acid tert-butyl are obtained by reacting formula IV compound, formula IV compound carries out alkylation with iodoethane again and obtains formula II compound, then (4S)-4-(4-ethoxy benzyl)-3 is obtained by hydrolysis, 6, 9-tri-(carboxylation methyl)-3, 6, 9-tri-azepine undecane diacid (formula I) is (see Figure of description 3, Fig. 3 is that formula V compound and bromo-acetic acid tert-butyl are obtained by reacting formula IV compound, formula IV compound carries out alkylation with iodoethane again and obtains formula II compound, then the accompanying drawing of formula I is obtained by hydrolysis),
Aforesaid method connects 5 tert.-butyl acetates due to needs on three nitrogen; and bromo-acetic acid tert-butyl structure is comparatively large, steric hindrance of having living space, therefore easily reaction does not thoroughly cause impurity in products more; formula II compound is purified to be needed to adopt preparation liquid phase, and therefore prior art is unsuitable for large-scale production.
Summary of the invention
For the deficiency that prior art exists, the invention provides a kind of method preparing Primovist intermediate formula I newly, can be used for Gadoxetic acid disodium suitability for industrialized production.
Technical scheme of the present invention is as follows:
(1) a kind of method (see Figure of description 1) preparing Primovist intermediate formula I newly
According to the present invention, the preparation method of formula I, adopt S-1-(4-hydroxy phenyl)-3-aza-pentane-1,5 diamines (formula III compound) and formula VI compound react a step and obtain Primovist intermediate formula I (see Figure of description 4, Fig. 4 is the accompanying drawing that formula III compound and formula VI compound react that a step obtains formula I), wherein S-1-(4-hydroxy phenyl)-3-aza-pentane-1,5 diamines (formula III compound) can prepare according to the method for patent CN200710019379.0 report.
X in formula VI compound is halides, is specially Cl, Br.
Formula I its preparation method comprises the steps:
By soluble in water for formula III compound, add sodium hydroxide, then add formula VI compound, temperature rising reflux reaction 20-40 hour, be 2-3 with inorganic acid for adjusting pH after being down to room temperature, filter, drying obtains formula I.
The invention is characterized in, adopt formula III compound and formula VI compound to react preparation I compound first.
According to the present invention, the mass ratio of formula III compound and sodium hydroxide is 1:1 ~ 2;
According to the present invention, the mol ratio of formula III compound and formula VI compound is 1:6 ~ 10;
According to the present invention, reflux time is 20-40 hour, preferably 30 hours;
According to the present invention, described mineral acid is sulfuric acid, hydrochloric acid;
Compared to the prior art, the present invention has following advantage and beneficial effect:
The invention provides a kind of method preparing Primovist intermediate formula I newly, the present invention avoid or eliminates the aforementioned drawback of prior art.Excellent results of the present invention is as follows:
1. process contaminants is few, and product purity is high;
2. green reaction, does not adopt organic solvent, does not produce organic reaction by product, environmental friendliness;
3. present invention process is succinct, and raw material is easy to get, and cost is lower, and suitability for mass industrializedization is produced.
Embodiment
Below by way of concrete embodiment, foregoing of the present invention is described in further detail, but this should be interpreted as any restriction the present invention being protected to theme.All technical schemes realized based on foregoing of the present invention all belong to scope of the present invention.
The present invention carries out generality or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.
Embodiment 1:(4S) preparation of-4-(4-ethoxy benzyl)-3,6,9-tri-(carboxylation methyl)-3,6,9-tri-azepine undecane diacid (formula I).
By S-1-(4-hydroxy phenyl)-3-aza-pentane-1,5 diamines (formula III compound) (1kg, 4.21mol) are soluble in water, add sodium hydroxide (1kg), add sodium chloroacetate (2.94kg again, 25.3mol), temperature rising reflux reacts 30 hours, regulates pH to be 2-3 after being down to room temperature with concentrated hydrochloric acid, filter, drying obtains formula I 1.67kg, yield: 75.1%, purity 98.2%.
Embodiment 2:(4S) preparation of-4-(4-ethoxy benzyl)-3,6,9-tri-(carboxylation methyl)-3,6,9-tri-azepine undecane diacid (formula I).
By formula III compound (1kg, 4.21mol) soluble in water, add sodium hydroxide (2kg), then add bromoacetic acid sodium (4.75kg, 29.5mol), temperature rising reflux reacts 20 hours, be 2-3 with sulphur acid for adjusting pH after being down to room temperature, filter, drying obtains formula I 1.64kg, yield: 73.8%, purity 98.0%.
Embodiment 3:(4S) preparation of-4-(4-ethoxy benzyl)-3,6,9-tri-(carboxylation methyl)-3,6,9-tri-azepine undecane diacid (formula I).
By formula III compound (1kg, 4.21mol) soluble in water, add sodium hydroxide (2kg), then add sodium chloroacetate (4.91kg, 42.1mol), temperature rising reflux reacts 40 hours, be 2-3 with sulphur acid for adjusting pH after being down to room temperature, filter, drying obtains formula I 1.72, yield: 77.4%, purity 98.7%.
Claims (2)
1. prepare the method for Primovist intermediate formula I for one kind, described method is: by soluble in water for formula III compound, add sodium hydroxide, add formula VI compound again, temperature rising reflux reaction 20-40 hour, be 2-3 with inorganic acid for adjusting pH after being down to room temperature, filter, drying obtains formula I.
2. its reaction formula is as follows:
Wherein, X is halides, is specially Cl, Br;
The preparation method of formula I as claimed in claim 1, is characterized in that, the mass ratio of formula III compound and sodium hydroxide is 1:1 ~ 2;
The preparation method of formula I as claimed in claim 1, is characterized in that, the mol ratio of formula III compound and formula VI compound is 1:6 ~ 10;
The preparation method of formula I as claimed in claim 1, is characterized in that, reflux time is 20-40 hour, preferably 30 hours;
The preparation method of formula I as claimed in claim 1, is characterized in that, described mineral acid is sulfuric acid, hydrochloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201410281984.5A CN104761461A (en) | 2014-09-09 | 2014-09-09 | Preparation method of novel gadoxetate disodium intermediate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410281984.5A CN104761461A (en) | 2014-09-09 | 2014-09-09 | Preparation method of novel gadoxetate disodium intermediate |
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| CN104761461A true CN104761461A (en) | 2015-07-08 |
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| CN201410281984.5A Pending CN104761461A (en) | 2014-09-09 | 2014-09-09 | Preparation method of novel gadoxetate disodium intermediate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017208258A1 (en) * | 2016-05-30 | 2017-12-07 | Biophore India Pharmaceuticals Pvt. Ltd. | Novel process for the preparation of gadolinium complex of (4s)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9- triazaundecanedioic acid disodium (gadoxetate disodium) |
| CN107573291A (en) * | 2017-10-27 | 2018-01-12 | 上海司太立制药有限公司 | A kind of preparation method and purposes of Gadoxetic acid disodium part impurity |
| WO2018084625A1 (en) | 2016-11-04 | 2018-05-11 | St Pharm Co., Ltd. | Method for preparation of (s)-n1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0405704A2 (en) * | 1989-06-30 | 1991-01-02 | Schering Aktiengesellschaft | DTPA-complexes derivatives, pharmaceutical compositions containing them, their use and process for their preparation |
| DE102010023890A1 (en) * | 2010-06-11 | 2011-12-15 | Bayer Schering Pharma Aktiengesellschaft | Preparing crystalline 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(ethoxybenzyl)-undecanedioic acid comprises hydrolyzing 3,6,9-triaza-3,6,9-tris(tert-butoxy-carbonylmethyl)-4-(ethoxybenzyl)-undecanedioic acid-ditert-butylester and acidifying |
| CN102603550A (en) * | 2012-02-16 | 2012-07-25 | 佛山普正医药科技有限公司 | Preparation method of intermediate BOPTA (4-hydroxy-5,8,11-tricarboxymethyl-1-phenyl-2-oxa-5,8,11-triazanaphthalenetridecane-13-acid) |
| CN104672099A (en) * | 2013-11-27 | 2015-06-03 | 山东富创医药科技有限公司 | New preparation method of gadoxetic acid disodium intermediate |
-
2014
- 2014-09-09 CN CN201410281984.5A patent/CN104761461A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0405704A2 (en) * | 1989-06-30 | 1991-01-02 | Schering Aktiengesellschaft | DTPA-complexes derivatives, pharmaceutical compositions containing them, their use and process for their preparation |
| DE102010023890A1 (en) * | 2010-06-11 | 2011-12-15 | Bayer Schering Pharma Aktiengesellschaft | Preparing crystalline 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(ethoxybenzyl)-undecanedioic acid comprises hydrolyzing 3,6,9-triaza-3,6,9-tris(tert-butoxy-carbonylmethyl)-4-(ethoxybenzyl)-undecanedioic acid-ditert-butylester and acidifying |
| CN102603550A (en) * | 2012-02-16 | 2012-07-25 | 佛山普正医药科技有限公司 | Preparation method of intermediate BOPTA (4-hydroxy-5,8,11-tricarboxymethyl-1-phenyl-2-oxa-5,8,11-triazanaphthalenetridecane-13-acid) |
| CN104672099A (en) * | 2013-11-27 | 2015-06-03 | 山东富创医药科技有限公司 | New preparation method of gadoxetic acid disodium intermediate |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017208258A1 (en) * | 2016-05-30 | 2017-12-07 | Biophore India Pharmaceuticals Pvt. Ltd. | Novel process for the preparation of gadolinium complex of (4s)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9- triazaundecanedioic acid disodium (gadoxetate disodium) |
| US11149041B2 (en) | 2016-05-30 | 2021-10-19 | Biophore India Pharmaceuticals Pvt. Ltd. | Process for the preparation of gadolinium complex of (4S)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid disodium (Gadoxetate disodium) |
| WO2018084625A1 (en) | 2016-11-04 | 2018-05-11 | St Pharm Co., Ltd. | Method for preparation of (s)-n1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride |
| US10501403B2 (en) | 2016-11-04 | 2019-12-10 | St Pharm Co., Ltd. | Method for preparation of (S)-N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride |
| CN107573291A (en) * | 2017-10-27 | 2018-01-12 | 上海司太立制药有限公司 | A kind of preparation method and purposes of Gadoxetic acid disodium part impurity |
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Application publication date: 20150708 |