CN112592294B - Synthetic method of shakubatu drug intermediate - Google Patents
Synthetic method of shakubatu drug intermediate Download PDFInfo
- Publication number
- CN112592294B CN112592294B CN202011526203.6A CN202011526203A CN112592294B CN 112592294 B CN112592294 B CN 112592294B CN 202011526203 A CN202011526203 A CN 202011526203A CN 112592294 B CN112592294 B CN 112592294B
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- combined
- shakubatu
- stirring
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000003814 drug Substances 0.000 title claims abstract description 16
- 229940079593 drug Drugs 0.000 title claims abstract description 13
- 238000010189 synthetic method Methods 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000000243 solution Substances 0.000 claims abstract description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012074 organic phase Substances 0.000 claims abstract description 12
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 6
- 239000008346 aqueous phase Substances 0.000 claims abstract description 6
- 239000007864 aqueous solution Substances 0.000 claims abstract description 6
- 235000019439 ethyl acetate Nutrition 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 238000012544 monitoring process Methods 0.000 claims abstract description 3
- 238000010791 quenching Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims 2
- 239000000543 intermediate Substances 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- -1 lithium aluminum hydride Chemical compound 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000012280 lithium aluminium hydride Substances 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 3
- 206010019280 Heart failures Diseases 0.000 description 7
- PYNXFZCZUAOOQC-UTKZUKDTSA-N sacubitril Chemical compound C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 PYNXFZCZUAOOQC-UTKZUKDTSA-N 0.000 description 6
- 229960003953 sacubitril Drugs 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 3
- OWIZSBUSCSIZSA-GOSISDBHSA-N tert-butyl n-[(2r)-1-oxo-3-(4-phenylphenyl)propan-2-yl]carbamate Chemical compound C1=CC(C[C@@H](NC(=O)OC(C)(C)C)C=O)=CC=C1C1=CC=CC=C1 OWIZSBUSCSIZSA-GOSISDBHSA-N 0.000 description 3
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 229940122586 Enkephalinase inhibitor Drugs 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 239000002792 enkephalinase inhibitor Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229940100334 sacubitril / valsartan Drugs 0.000 description 2
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 2
- 229960004699 valsartan Drugs 0.000 description 2
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102000003729 Neprilysin Human genes 0.000 description 1
- 108090000028 Neprilysin Proteins 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940100321 entresto Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- ZASXKEGREHRXDL-CAWNUZPDSA-H hexasodium;4-[[(2s,4r)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate;(2s)-3-methyl-2-[pentanoyl-[[4-[2-(1,2,3-triaza-4-azanidacyclopenta-2,5-dien-5-yl)phenyl]phenyl]methyl]amino]butanoate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1 ZASXKEGREHRXDL-CAWNUZPDSA-H 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of synthesis of medical intermediates, in particular to a synthetic method of a shakubaqu drug intermediate, which comprises the following synthetic route:
adding a compound II and a solvent into a reaction bottle under the protection of nitrogen, stirring to dissolve, and then adding diisobutylaluminum hydride, wherein the feeding molar ratio of the compound II to the diisobutylaluminum hydride (DIBAH) is 1: 1-2, controlling the temperature, stirring for reaction, and monitoring the reaction by TLC; after the reaction is finished, KHSO is added4Quenching reaction with aqueous solution; the resulting solution was combined with 1N HCl solution, stirred for 5 minutes and the organic phase separated; the aqueous phase was extracted with EtOAc and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness to give compound I. The invention adopts diisobutyl aluminum hydride to replace lithium aluminum hydride which is easy to be explosively decomposed when meeting water. The reaction is simple to operate, has high yield and is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the technical field of synthesis of medical intermediates, in particular to a synthesis method of a Sacubitril drug intermediate [ (1R) -2- (biphenyl-4-yl) -1-formylethyl ] tert-butyl carbamate.
Background
Heart failure is an extremely important global public health problem which endangers human health, is the terminal stage of occurrence and development of cardiovascular diseases, and the morbidity, the rehospitalization rate and the mortality of the cardiovascular diseases are continuously increased year by year, so that more effective novel heart failure treatment medicines are urgently developed, and the marketing of the Sacubitril/valsartan with the dual action mechanism of an angiotensin receptor enkephalinase inhibitor brings new revolution for treating heart failure patients.
Sacubitril/valsartan (Entresto) is a dual-effect angiotensin receptor-enkephalinase inhibitor developed by Nowa company, and can be clinically used for treating hypertension and heart failure. The medicine consists of the Sacubitril acting on enkephalinase and the valsartan acting on a renin-angiotensin-aldosterone system, can effectively improve heart failure symptoms, reduce blood pressure and positively improve renal function, and is an ideal heart failure treatment medicine.
Because the synthesis process of the valsartan part is relatively mature, the synthesis focus falls on the Sacubitril fragment. Sacubitril (Sacubitril), chemically known as 4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopropan-2-yl) amino) -4-oxobutanoic acid, having the following structure:
the [ (1R) -2- (biphenyl-4-yl) -1-formylethyl ] carbamic acid tert-butyl ester shown in the compound I is an important intermediate for preparing the Shakubaqu medicament. The original patent US5217996 used the following method for the synthesis of compound I:
the compound I is obtained by reducing the lithium aluminum hydride in the route, but the lithium aluminum hydride in the method is easy to be explosively decomposed when meeting water, so that the danger is brought to large-scale production. In view of the importance of the drug of Sacubitril in the treatment of heart failure, it is necessary to develop a more economical and industrially advantageous process for the preparation of intermediate I.
Disclosure of Invention
The invention aims to provide a preparation method of a Sacaba drug intermediate [ (1R) -2- (biphenyl-4-yl) -1-formylethyl ] carbamic acid tert-butyl ester, which has the advantages of mild reaction, low cost and high yield and is suitable for industrial production, so as to solve the problems of expensive reagent, high risk and the like in the preparation process of the Sacaba drug intermediate in the prior art.
In order to achieve the purpose, the invention provides the following technical scheme:
a synthetic method of a shakubatu drug intermediate comprises the following synthetic route:
the method specifically comprises the following steps:
adding a compound II and a solvent into a reaction bottle under the protection of nitrogen, stirring to dissolve, and then adding diisobutylaluminum hydride, wherein the feeding molar ratio of the compound II to the diisobutylaluminum hydride (DIBAH) is 1: 1-2, controlling the temperature, stirring for reaction, and monitoring the reaction by TLC; after the reaction is finished, KHSO is added4Quenching reaction with aqueous solution; the resulting solution was combined with 1N HCl solution, stirred for 5 minutes and the organic phase separated; the aqueous phase was extracted with EtOAc and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness to give compound I.
Wherein the solvent is one of tetrahydrofuran, diethyl ether, toluene or dichloromethane.
Wherein the reaction temperature is-20-0 ℃.
Compared with the prior art, the invention has the beneficial effects that:
the synthetic method of the invention is to improve the existing synthetic route of the intermediate [ (1R) -2- (biphenyl-4-yl) -1-formylethyl ] carbamic acid tert-butyl ester of the Shakubaqu drug, and diisobutyl aluminum hydride is selected to replace lithium aluminum hydride which is easy to be explosively decomposed when meeting water.
The method has the advantages of simple experimental operation and high yield, and is suitable for industrial large-scale production.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Under the protection of nitrogen, compound II (10g, 26mmol) and 100mL tetrahydrofuran were added to a reaction flask, stirred to dissolve, and then diisobutylaluminum hydride (5.5g, 39mmol) was added, the temperature was controlled at-10 deg.C, the reaction was stirred, and the reaction was monitored by TLC. After the reaction was complete, 6.6g KHSO was added4The reaction was quenched with 35mL of aqueous solution. The resulting solution was combined with 1N HCl (75mL) solution, stirred for 5 minutes and the organic phase separated. The aqueous phase was extracted with EtOAc (3X 100mL) and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness to give compound I (8g, 24.7mmol) in 95% yield and 99.6% purity.
Example 2
Under the protection of nitrogen, compound II (10g, 26mmol) and 100mL of diethyl ether were added to a reaction flask, stirred to dissolve, then diisobutylaluminum hydride (7.3g, 51mmol) was added, the temperature was controlled at 0 ℃, the reaction was stirred, and the reaction was monitored by TLC. After the reaction was complete, 6.6g KHSO was added4The reaction was quenched with 35mL of aqueous solution. The resulting solution was combined with 1N HCl (75mL) solution, stirred for 5 minutes and the organic phase separated. The aqueous phase was extracted with EtOAc (3X 100mL) and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness to give the title compound I (7.9g, 24.3mmol) which was collectedThe rate was 93.5% and the purity was 99.4%.
Example 3
Under the protection of nitrogen, compound II (10g, 26mmol) and 100mL of toluene were added to a reaction flask, stirred to dissolve, and then diisobutylaluminum hydride (4.1g, 29mmol) was added, the temperature was controlled at-20 ℃, the reaction was stirred, and the reaction was monitored by TLC. After the reaction was complete, 6.6g KHSO was added4The reaction was quenched with 35mL of aqueous solution. The resulting solution was combined with 1N HCl (75mL) solution, stirred for 5 minutes and the organic phase separated. The aqueous phase was extracted with EtOAc (3X 100mL) and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness to give compound I (7.8g, 24mmol) in 92.3% yield and 99.3% purity.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (3)
1. A synthetic method of a shakubatu drug intermediate is characterized by comprising the following steps: the synthetic route is as follows:
adding a compound II and a solvent into a reaction bottle under the protection of nitrogen, stirring to dissolve, and then adding diisobutylaluminum hydride, wherein the feeding molar ratio of the compound II to the diisobutylaluminum hydride (DIBAH) is 1: 1-2, controlling the temperature, stirring for reaction, and monitoring the reaction by TLC; after the reaction is finished, KHSO is added4Quenching reaction with aqueous solution; the resulting solution was combined with 1N HCl solution, stirred for 5 minutes and the organic phase separated; the aqueous phase was extracted with EtOAc and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness to give compound I.
2. The method for synthesizing the intermediate of the shakubatu drug according to claim 1, wherein the method comprises the following steps: the solvent is one of tetrahydrofuran, diethyl ether, toluene or dichloromethane.
3. The method for synthesizing the intermediate of the shakubatu drug according to claim 1, wherein the method comprises the following steps: the reaction temperature is-20 to 0 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011526203.6A CN112592294B (en) | 2020-12-22 | 2020-12-22 | Synthetic method of shakubatu drug intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011526203.6A CN112592294B (en) | 2020-12-22 | 2020-12-22 | Synthetic method of shakubatu drug intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112592294A CN112592294A (en) | 2021-04-02 |
| CN112592294B true CN112592294B (en) | 2022-05-13 |
Family
ID=75200071
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011526203.6A Active CN112592294B (en) | 2020-12-22 | 2020-12-22 | Synthetic method of shakubatu drug intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112592294B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103261164A (en) * | 2010-12-15 | 2013-08-21 | 施万制药 | Neprilysin inhibitors |
| CN106467471A (en) * | 2015-08-18 | 2017-03-01 | 上海翰森生物医药科技有限公司 | A kind of high-optical-purity biphenyl alanine and its preparation method and application of derivant |
| CN107011203A (en) * | 2017-04-28 | 2017-08-04 | 江苏阿尔法药业有限公司 | A kind of LCZ696 intermediate As HU 377 preparation method |
| WO2017152755A1 (en) * | 2016-03-10 | 2017-09-14 | 深圳市塔吉瑞生物医药有限公司 | Substituted biphenyl compound and pharmaceutical composition thereof |
-
2020
- 2020-12-22 CN CN202011526203.6A patent/CN112592294B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103261164A (en) * | 2010-12-15 | 2013-08-21 | 施万制药 | Neprilysin inhibitors |
| CN106467471A (en) * | 2015-08-18 | 2017-03-01 | 上海翰森生物医药科技有限公司 | A kind of high-optical-purity biphenyl alanine and its preparation method and application of derivant |
| WO2017152755A1 (en) * | 2016-03-10 | 2017-09-14 | 深圳市塔吉瑞生物医药有限公司 | Substituted biphenyl compound and pharmaceutical composition thereof |
| CN107011203A (en) * | 2017-04-28 | 2017-08-04 | 江苏阿尔法药业有限公司 | A kind of LCZ696 intermediate As HU 377 preparation method |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis of New (-)-Bestatin-Based Inhibitor Libraries Reveals a Novel Binding Mode in the S1 Pocket of the Essential Malaria M1 Metalloaminopeptidase;Geetha Velmourougane等;《J. Med. Chem.》;20110324;第54卷(第6期);1655-1666页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112592294A (en) | 2021-04-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101607955B (en) | Preparation method for low-residue lipoic acid | |
| NO312893B1 (en) | <beta> -sulfonylhydroxamic acids as matrix metalloproteinase inhibitors, and pharmaceutical preparations containing these | |
| CN106431993B (en) | A kind of preparation method of LCZ-696 key intermediates | |
| CN112174798B (en) | Synthesis method of Sakuba/valsartan sodium LCZ696 | |
| CN100522926C (en) | Preparation method of memantine salt | |
| WO2019019795A1 (en) | Method for preparing sacubitril intermediate | |
| CN105085360A (en) | Preparation method of high-purity vildagliptin | |
| CN112592294B (en) | Synthetic method of shakubatu drug intermediate | |
| CN104892444B (en) | A kind of method of synthesizing D-p-hydroxyphenylglycine methyl ester | |
| CN112661671B (en) | Preparation method of Sacubitril intermediate | |
| CN106431911B (en) | Preparation and purification method of 4-felbinac | |
| CN107056685A (en) | A kind of synthetic method of doxylamine succinate | |
| CN109776624A (en) | A kind of preparation method of tribenoside | |
| CN106518840A (en) | Synthetic method of 5-chloro-2-thiophenecarboxylic acid | |
| CN102241663B (en) | Preparation method of strontium ranelate octohydrate | |
| CN111875666B (en) | Method for synthesizing Edwarden sweet | |
| CN104292098A (en) | Preparation method of 2-phenylpropionic acid | |
| CN107652215A (en) | A kind of preparation method of captopril | |
| CN116655498B (en) | A method for preparing a sacubitril intermediate | |
| CN112574132B (en) | Preparation method of sarcandra/valsartan sodium | |
| CN102381995A (en) | Preparation method of metoprolol | |
| CN103755577B (en) | A kind of method reclaiming Transbroncho alkali from Ambroxol HCl refinement mother liquor | |
| CN117736117A (en) | Synthesis method of sabatier starter drug intermediate | |
| CN107011203A (en) | A kind of LCZ696 intermediate As HU 377 preparation method | |
| CN1715275A (en) | Simple process for preparing trimetazidine and its medicinal salts |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: 223800 No.5 Yanshan Road, eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Applicant after: Jiangsu alpha Pharmaceutical Co.,Ltd. Address before: 223800 No.5 Yanshan Road, eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Applicant before: JIANGSU ALPHA PHARMACEUTICAL Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |