CN105418401A - Preparation method of (S)-2-benzylsuccinic acid - Google Patents
Preparation method of (S)-2-benzylsuccinic acid Download PDFInfo
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- CN105418401A CN105418401A CN201510749477.4A CN201510749477A CN105418401A CN 105418401 A CN105418401 A CN 105418401A CN 201510749477 A CN201510749477 A CN 201510749477A CN 105418401 A CN105418401 A CN 105418401A
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- Prior art keywords
- succsinic acid
- benzyl
- benzyl succsinic
- acid
- preparation
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- Granted
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- GTOFKXZQQDSVFH-VIFPVBQESA-N (r)-2-benzylsuccinate Chemical compound OC(=O)C[C@@H](C(O)=O)CC1=CC=CC=C1 GTOFKXZQQDSVFH-VIFPVBQESA-N 0.000 title abstract 4
- 238000000034 method Methods 0.000 claims abstract description 16
- 230000006340 racemization Effects 0.000 claims abstract description 12
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- GTOFKXZQQDSVFH-SECBINFHSA-N (R)-2-benzylsuccinic acid Chemical compound OC(=O)C[C@H](C(O)=O)CC1=CC=CC=C1 GTOFKXZQQDSVFH-SECBINFHSA-N 0.000 claims abstract description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 235000010755 mineral Nutrition 0.000 claims description 2
- 229940093916 potassium phosphate Drugs 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- PMRVFZXOCRHXFE-FMEJWYFOSA-L Kad 1229 Chemical compound [Ca+2].C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1.C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1 PMRVFZXOCRHXFE-FMEJWYFOSA-L 0.000 abstract description 6
- 229960003365 mitiglinide Drugs 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- GTOFKXZQQDSVFH-UHFFFAOYSA-N 2-benzylsuccinic acid Chemical compound OC(=O)CC(C(O)=O)CC1=CC=CC=C1 GTOFKXZQQDSVFH-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 9
- 238000011084 recovery Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- 239000012452 mother liquor Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000006002 Pepper Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000005194 fractionation Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000009413 insulation Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of (S)-2-benzylsuccinic acid, and relates to a method for preparing (S)-2-benzylsuccinic acid from (R)-2-benzylsuccinic acid. After EDTA is added in an alkaline aqueous solution containing the (R)-2-benzylsuccinic acid, racemization can be implemented effectively. By the method provided by the invention, the (S)-2-benzylsuccinic acid can be prepared from a solution of 2-benzylsuccinic acid (R)-alpha-phenylethanammonium generated in a production process of mitiglinide calcium, and economic benefit is improved further.
Description
Technical field
The present invention relates to a kind of by (
r) preparation of-2-benzyl succsinic acid (
s) method of-2-benzyl succsinic acid, belong to medical art.
Background technology
S 21403 is synthesized by Japanese Kissei Pharmaceutical Co., Ltd., and in December, 2002 application is used for patients with NIDDM and controls postprandial blood sugar, and in April, 2004 goes on the market in Japan.Compared with repaglinide, Na Gelie a kind of apple and traditional sulfonylureas, have following advantage: (1) mechanism of action is novel, onset is faster, and acting duration is shorter; (2) curative effect is stronger; (3) administration is flexible; (4) security is high, better tolerance.
(
s)-2-benzyl succsinic acid be synthesis S 21403 key intermediate.The height of its cost of manufacture, directly has influence on the cost of manufacture of S 21403.The synthetic route that patent US6133454, WO9901430, WO9832727 report the preparation method of S 21403 main is as follows:
The synthetic route of one of critical materials of this preparation method (S)-2-benzyl succsinic acid is as follows:
This route needs to split, (
s) yield about 80% of-2-benzyl succsinic acid, have 20% (
s)-2-benzyl succsinic acid and 100% (
r)-2-benzyl succsinic acid is lost in and splits in mother liquor, causes serious waste and pollution.
Summary of the invention
The object of this invention is to provide a kind of utilize recovery (
r) preparation of-2-benzyl succsinic acid (
s) method of-2-benzyl succsinic acid.
Technical scheme of the present invention be a kind of (
s) preparation method of-2-benzyl succsinic acid, it is characterized in that,
(1) to containing (
r)-2-benzyl succinate alkaline aqueous solution in add EDTA, impel under heating condition (
r) racemization of-2-benzyl succsinic acid, treat (
r) ratio of-2-benzyl succsinic acid and (S)-2-benzyl succsinic acid close to 1:1 time, adjust pH to acid, obtain solid 2-benzyl succsinic acid;
(2) the 2-benzyl succsinic acid upper step obtained with
r-α-phenylethylamine is salify in ethanol, and gained solid is free through acid, crystallization, filtration, dry
s-benzyl succsinic acid.
According to the present invention, the alkaline aqueous solution described in step (1), alkali used is selected from mineral alkali or organic bases, preferred sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, cesium carbonate, potassiumphosphate, triethylamine, more preferably sodium hydroxide or potassium hydroxide.
According to the present invention, the heating condition described in step (1), Heating temperature is 20-60
oc, preferred 30-40
oC.
According to the present invention, step (2) is carried out operation according to published splitting condition and can be realized, such as Chinese patent 200610011970.7.
According to the present invention, with the 2-benzyl succsinic acid produced in S 21403 production process
rthe ethanolic soln of-α-phenylethylamine salt is starting material, also can carry out above-mentioned reaction.Concrete:
The first step is by 2-benzyl succsinic acid
rthe ethanolic soln concentrating under reduced pressure of-α-phenylethylamine salt, reclaims ethanol, then in residue system, adds water, potassium hydroxide stirring and dissolving.By aqueous phase organic solvent extraction, separate and reclaim organic solvent, obtain (
r)-α-phenylethylamine;
Second step upwards walks in the aqueous phase separated and adds EDTA, is then heated to 50-60
oc is incubated 4h, in high performance liquid phase detection system (
r)-2-benzyl succsinic acid with (
s) ratio of-2-benzyl succsinic acid close to 1:1 time, stop heating, lower the temperature and adjust pH to acidity, obtaining solid 2-benzyl succsinic acid;
3rd step by gained 2-benzyl succsinic acid with
r-α-phenylethylamine carries out into salt-pepper noise according to resolution process disclosed in document in ethanol, can obtain
s-benzyl succsinic acid.
The invention has the beneficial effects as follows and can improve to greatest extent (
s) yield of-2-benzyl succsinic acid, racemization total recovery 41.0%, ee value is not less than 99.5%, and purity is not less than 99.8%, both improves economic benefit, additionally reduces the generation of solvent slop and other pollutents, is conducive to protection of the environment.
embodiment:
Content for a better understanding of the present invention, is described further below in conjunction with specific embodiment, but the present invention is not only confined to this.
The blank test of embodiment 1 catalyzer
Will containing 100g2-benzyl succsinic acid
r-α-phenylethylamine salt (
r/
s=83/17) ethanolic soln concentrating under reduced pressure reclaims ethanol, then in residue system, adds 500ml water, 24g sodium hydroxide stirring and dissolving.By aqueous phase dichloromethane extraction twice, combined dichloromethane phase, reclaim methylene dichloride and (
r)-α-phenylethylamine.
By heated aqueous to 80-90
oCinsulation 12h, in high performance liquid phase detection system (
r)-2-benzyl succsinic acid with (
s) ratio of-2-benzyl succsinic acid is 1:1, stop heating, be cooled to 0-10
oC, in system, add hydrochloric acid to pH ≈ 1-2, in 0-10
oc is incubated 2h, system is filtered, and solid is dried.Yield 95%.
By gained 2-benzyl succsinic acid with
r-α-phenylethylamine is heated to backflow at ethanol and dissolves, then decrease temperature crystalline, 20-25
oCinsulation 1h, filters.Gained solid adjusts pH=1-2 with hydrochloric acid in water, is then cooled to 0-10
oc is incubated 2h, filtration, drying,
s-benzyl succsinic acid 18.5g, racemization total recovery 40.1%, ee value 99.5%, purity 99.9%.
Mother liquor after fractionation can split by above-mentioned technique again racemization, salify, free, crystallization.
Embodiment 2
Will containing 100g2-benzyl succsinic acid
r-α-phenylethylamine salt (
r/
s=85/15) ethanolic soln concentrating under reduced pressure reclaims ethanol, then in residue system, adds 500ml water, 35g potassium hydroxide stirring and dissolving.By aqueous phase dichloromethane extraction twice, combined dichloromethane phase, reclaim methylene dichloride and (
r)-α-phenylethylamine.
In aqueous phase, add 0.2gEDTA, be then heated to 50-60
oc is incubated 4h, in high performance liquid phase detection system (
r) ratio of-2-benzyl succsinic acid and (S)-2-benzyl succsinic acid is 1:1, stop heating, be cooled to 0-10
oC, in system, add hydrochloric acid to pH=1-2, in 0-10
oc is incubated 2h, system is filtered, and solid is dried.Yield 96%.
By gained 2-benzyl succsinic acid with
r-α-phenylethylamine becomes salt-pepper noise in ethanol.By the method process of embodiment 1,
s-benzyl succsinic acid 18.9g, racemization total recovery 41.0%, ee value 99.6%, purity 99.8%.
Mother liquor after fractionation can split by above-mentioned technique again racemization, salify, free, crystallization.
Embodiment 3
Will containing 100g2-benzyl succsinic acid
r-α-phenylethylamine salt (
r/
s=85/15) ethanolic soln concentrating under reduced pressure reclaims ethanol, then in residue system, adds 500ml water, 80g salt of wormwood stirring and dissolving.By aqueous phase dichloromethane extraction twice, combined dichloromethane phase, reclaim methylene dichloride and (
r)-α-phenylethylamine.
In aqueous phase, add 0.4gEDTA, be then heated to 30-40
oc is incubated 3h, in high performance liquid phase detection system (
r)-2-benzyl succsinic acid with (
s) ratio of-2-benzyl succsinic acid is 1:1, stop heating, be cooled to 0-10
oC, in system, add hydrochloric acid to pH=1-2, in 0-10
oc is incubated 2h, system is filtered, and solid is dried.Yield 94.6%.
Gained 2-benzyl succsinic acid is become salt-pepper noise in ethanol with R-α-phenylethylamine.By the method process of embodiment 1,
s-benzyl succsinic acid 18.3g, racemization total recovery 39.5%, ee value 99.4%, purity 99.8%.
Mother liquor after fractionation can split by above-mentioned technique again racemization, salify, free, crystallization.
Embodiment 4
Will containing 100g2-benzyl succsinic acid
r-α-phenylethylamine salt (
r/
s=85/15) ethanolic soln concentrating under reduced pressure reclaims ethanol, then in residue system, adds 500ml water, 61g sodium carbonate stirring and dissolving.By aqueous phase dichloromethane extraction twice, combined dichloromethane phase, reclaim methylene dichloride and (
r)-α-phenylethylamine.
In aqueous phase, add 0.4gEDTA, be then heated to 20-25
oc is incubated 5h, in high performance liquid phase detection system (
r)-2-benzyl succsinic acid with (
s) ratio of-2-benzyl succsinic acid is 1:1, stop heating, be cooled to 0-10
oC, in system, add hydrochloric acid to pH=1-2, in 0-10
oc is incubated 2h, system is filtered, and solid is dried.Yield 95.4%.
By gained 2-benzyl succsinic acid with
r-α-phenylethylamine becomes salt-pepper noise in ethanol.By the method process of embodiment 1,
s-benzyl succsinic acid 17.9g, racemization total recovery 38.8%, ee value 99.5%, purity 99.9%.
Mother liquor after fractionation can split by above-mentioned technique again racemization, salify, free, crystallization.
Claims (3)
- A 1. utilization ( r) preparation of-2-benzyl succsinic acid ( s) method of-2-benzyl succsinic acid, it is characterized in that:(1) to containing ( r)-2-benzyl succinate alkaline aqueous solution in add EDTA, impel under heating condition ( r) racemization of-2-benzyl succsinic acid, treat ( r) ratio of-2-benzyl succsinic acid and (S)-2-benzyl succsinic acid close to 1:1 time, adjust pH to acid, obtain solid 2-benzyl succsinic acid;(2) by the 2-benzyl succsinic acid that obtains with r-α-phenylethylamine is salify in ethanol, and gained solid is free through acid, crystallization, filtration, dry s-benzyl succsinic acid.
- 2. preparation method according to claim 1, it is characterized in that, the alkaline aqueous solution described in (1), alkali used is selected from mineral alkali, preferred sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, cesium carbonate, potassiumphosphate, more preferably sodium hydroxide or potassium hydroxide.
- 3. preparation method according to claim 1, is characterized in that, the heating condition described in (1), and Heating temperature is 20-60 oc, preferred 30-40 oC.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510749477.4A CN105418401B (en) | 2015-11-09 | 2015-11-09 | The preparation method of one kind (S) -2- benzyl succinic acid |
Applications Claiming Priority (1)
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|---|---|---|---|
| CN201510749477.4A CN105418401B (en) | 2015-11-09 | 2015-11-09 | The preparation method of one kind (S) -2- benzyl succinic acid |
Publications (2)
| Publication Number | Publication Date |
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| CN105418401A true CN105418401A (en) | 2016-03-23 |
| CN105418401B CN105418401B (en) | 2019-03-05 |
Family
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Family Applications (1)
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109580821A (en) * | 2018-12-21 | 2019-04-05 | 山东铂源药业有限公司 | The detection method of impurity succinic acid in a kind of S- benzyl succinic acid |
| CN111253244A (en) * | 2020-03-10 | 2020-06-09 | 山东铂源药业有限公司 | Recycling method of (S) -2-benzylsuccinic acid resolution mother liquor |
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| CN101880695A (en) * | 2010-02-26 | 2010-11-10 | 华东理工大学 | Method for preparing (S)-naproxen by enzyme resolution of racemic naproxen ester |
| CN101973926A (en) * | 2010-11-05 | 2011-02-16 | 威海迪素制药有限公司 | Method for preparing R-mitiglinide calcium |
-
2015
- 2015-11-09 CN CN201510749477.4A patent/CN105418401B/en active Active
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| CN101560132A (en) * | 2009-05-14 | 2009-10-21 | 浙江普洛医药科技有限公司 | Method for racemizing chiral amino acid or derivatives of chiral amino acid |
| CN101880695A (en) * | 2010-02-26 | 2010-11-10 | 华东理工大学 | Method for preparing (S)-naproxen by enzyme resolution of racemic naproxen ester |
| CN101973926A (en) * | 2010-11-05 | 2011-02-16 | 威海迪素制药有限公司 | Method for preparing R-mitiglinide calcium |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109580821A (en) * | 2018-12-21 | 2019-04-05 | 山东铂源药业有限公司 | The detection method of impurity succinic acid in a kind of S- benzyl succinic acid |
| CN109580821B (en) * | 2018-12-21 | 2021-03-19 | 山东铂源药业有限公司 | Method for detecting impurity succinic acid in S-benzylsuccinic acid |
| CN111253244A (en) * | 2020-03-10 | 2020-06-09 | 山东铂源药业有限公司 | Recycling method of (S) -2-benzylsuccinic acid resolution mother liquor |
| CN111253244B (en) * | 2020-03-10 | 2020-10-16 | 山东铂源药业有限公司 | Recycling method of (S) -2-benzylsuccinic acid resolution mother liquor |
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Effective date of registration: 20160623 Address after: 264205 Shandong city of Weihai province by the district Gushan Town No. 18 South Road, No. 19 North Road, No. 3 East Road, the west five Applicant after: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. Applicant after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: 264205 Shandong city of Weihai province by the district Gushan Town No. 18 South Road, No. 19 North Road, No. 3 East Road, the west five Applicant before: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. Applicant before: WEIHAI DIJIA PHARMACEUTICAL Co.,Ltd. |
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Effective date of registration: 20191106 Address after: 264205 Guangzhou East Road South and an East Road East, Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Co-patentee after: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Co-patentee after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: 264205 Shandong city of Weihai province by the district Gushan Town No. 18 South Road, No. 19 North Road, No. 3 East Road, the west five Co-patentee before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Patentee before: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. |
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Effective date of registration: 20210615 Address after: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Patentee before: Dijia Pharmaceutical Group Co.,Ltd. Patentee before: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. Patentee before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. |
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Address after: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |
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| CP03 | Change of name, title or address | ||
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Address after: No. 268, Tianrun Road, Wendeng Economic and Technological Development Zone, Weihai City, Shandong Province, 264200 Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |