CN108424418A - A kind of Flomoxef sodium impurity - Google Patents
A kind of Flomoxef sodium impurity Download PDFInfo
- Publication number
- CN108424418A CN108424418A CN201710081548.7A CN201710081548A CN108424418A CN 108424418 A CN108424418 A CN 108424418A CN 201710081548 A CN201710081548 A CN 201710081548A CN 108424418 A CN108424418 A CN 108424418A
- Authority
- CN
- China
- Prior art keywords
- impurity
- flomoxef
- acid
- sodium
- flomoxef sodium
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
- C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
- C07D505/16—Nitrogen atoms
- C07D505/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
- C07D505/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D505/02—Preparation
- C07D505/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D505/08—Modification of a carboxyl group directly attached in position 2, e.g. esterification
Abstract
Present invention finds a kind of Flomoxef sodium impurities, it deduces the chemical structural formula of the impurity and designs synthetic route and prepare the impurity, belong to technical field of pharmaceuticals, is applied to registration, quality research, technical study, impurity preparation and the purposes as impurity reference substance of Flomoxef Sodium bulk pharmaceutical chemicals and preparation.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, more particularly to a kind of major impurity of oxygen cephalosporin analog antibiotic Flomoxef Sodium
And its structure and preparation method.
Background technology
Flomoxef Sodium, chemical name (6R, 7R) -7- [2- (difluoro methyl mercapto) acetamido] -7- methoxyl group -3- { [1-
(2- ethoxys) -1H-TETRAZOLE -5- bases] sulphomethyl } -8- oxos -5- oxa- -1- azabicyclos [4.2.0] oct-2-ene -2- first
Acid sodium-salt is oxacephems new antibiotic, is developed by Japanese Yan Yeyi Co., Ltd., has a broad antifungal spectrum, antimicrbial power are strong, right
Beta-lactamase has good inhibiting effect, more preferably to clinically intractable, multiple infections therapeutic effect.Its chemical structural formula
It is as follows：
Flomoxef Sodium
Due to the oxygen atom structure in the compound mother nucleus structure, processing step is more, and synthesis difficulty is big, intermediate product stability
Difference, easy tos produce impurity, and impurity separation differentiates difficulty bigger.The research of its impurity of previous document announcement and market sale known impurities
Have following several：
1. State Food and Drug Administration's import drugs registered standard（Standard No. JX20110027）Specified in impurity,
Chemical structural formula is as follows：
1- (2- hydroxyls) -1H-TETRAZOLE -5- mercaptan（Impurity 2）
2. the Flomoxef metabolism impurity mentioned in Yan Yeyi Co., Ltd. of Japan Flomoxef Sodium product description, chemistry knot
Structure formula is as follows：
Flomoxef Sodium sulfoxide（Impurity 3）
3. market sale known impurities, chemical structural formula are as follows：
（Impurity 4）（Impurity 5）
（Impurity 6）（Impurity 7）
（Impurity 8）（Impurity 9）
（Impurity 10）（Impurity 11）
To meet human drugs registration technology international coordination meeting according to internationally recognized drug registration（ICH）And European Pharmacopoeia（EP）
In requirement, stringent regulation has been carried out to the impurity in drug.ICH requires declarer's reply bulk pharmaceutical chemicals in synthesis, refines
It is summarized with those of most probable generation physical presence and potential impurity during storage, if not being subject to sternly to these impurity
Lattice control, and may generate serious toxic side effect to human body.Visible foreign is studied to the control of product quality and the use of people
Medicine all has very great significance safely.
As we for many years go deep into Flomoxef Sodium product preparation process and product quality research, the present invention is sent out again
The new impurity of Flomoxef Sodium is showed.Currently, having no the report in other documents about the impurity.
Invention content
It is an object of the invention to use LC-MS technology（HPLC-MS）, react machine in conjunction with the preparation of Flomoxef Sodium
Reason, to unknown impuritie existing for Flomoxef Sodium：Impurity 1 has carried out structure prediction, and structure by inference, and design passes through chemistry
Synthetic method synthesizes the impurity, further carries out confirming that impurity 1 is (6R, 7R) -7- [2- (formyl sulfenyl) acetamido] -7-
Methoxyl group -3- { [1- (2- ethoxys) -1H-TETRAZOLE -5- bases] sulphomethyl } -8- oxo -5- oxa- -1- azabicyclos
[4.2.0] oct-2-ene -2- formic acid, chemical structural formula are as follows：
（Impurity 1）
Wherein M is hydrogen or metal ion, such as sodium ion, potassium ion；Or ammonium ion, as triethylamine radical ion, cyclohexylamine root from
Son.
The present invention is achieved through the following technical solutions：
Step 1: with reference to State Food and Drug Administration's import drugs registered standard（Standard No. JX20110027）Fluorine oxygen head
The Related substances separation chromatographic condition of spore sodium detects HPLC purity, it is found that always there are one miscellaneous to making Flomoxef sodium sample by oneself
Mass peak, relative retention time 0.44, purity of 50 percent .1% or so are named as impurity 1, and molecular weight is reported with above-mentioned data searching and city
Impurity molecule amount is sold neither to be consistent, in order to improve preparation process, quality research and register declaration work needs, to the impurity into
Further investigation is gone.
Step 2: the mass spectrometric data of each component obtained according to HPLC-MS joint technology, association reaction mechanism, presumption
Go out the chemical structural formula of the impurity.
During HPLC-MS is measured, MS has [M+H] in main peak Flomoxef acid+For 496.9 and [M+Na]+For 518.9 molecule
Quasi-molecular ions, Flomoxef acid molecule amount are 496；Have in the MS of impurity 1 [M+H]+For 474.9 and [M+Na]+For 496.9 molecule
Quasi-molecular ions, the molecular weight for estimating the impurity are 474.
The molecular weight of the impurity is smaller by 22 than the molecular weight of major product Flomoxef acid, thus it is speculated that is to have the group of small molecule to slough
Or the change of functional group has occurred.This impurity generated in Flomoxef acid building-up process, thus it is speculated that reacting formation mechanism is：
Sulphur atom on sour 7 branches of excessive lewis acid and Flomoxef is complexed, by electronics transfer, on Flomoxef acid molecule with
The connected carbon atom of two fluorine atoms forms carbonium ion, and carbonium ion is attacked by hydroxyl group anion, and fluorine ion is left away, shape
At two alcoholic extract hydroxyl groups.Two hydroxyls are connected on the same carbon, and such compound is thermodynamically very unstable, is held very much
A molecular water easily is lost, is transformed into aldehyde.Specific transition process is as follows（Lewis acid is by taking alchlor as an example）：
Step 3: the chemical structural formula of the presumptive impurity, designs the chemical synthesis process of the impurity.
The synthetic route of design is as follows：
Specific synthetic method is as follows：
Flomoxef acid is added in solvent, solvent can suitably select chlorohydrocarbon（Dichloromethane, chloroform, dichloroethanes, trichlorine
Ethane, chlorobenzene etc.）, ether（Ether, tetrahydrofuran, methyl phenyl ethers anisole etc.）, ketone（Acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), hexamethylene
Ketone, acetophenone etc.）, ester（Ethyl acetate, butyl acetate, methyl benzoate etc.）, nitro hydrocarbon, nitrile（Acetonitrile, benzonitrile etc.）, amide
（Formamide, acetamide, dimethylformamide, dimethylacetylamide, hexamethyl phosphoramide etc.）, sulfoxide etc. and its mixed solvent,
It is preferred that dichloromethane；Then acid, the optional inorganic acid of acid, organic acid or lewis acid etc., preferred Lewis acids such as three are added
Aluminium chloride is reacted at -20 DEG C~100 DEG C, preferably -10 DEG C~20 DEG C.
Reaction terminates, and product can be by common method, and such as the methods of concentration, extraction, absorption, elution are by solvent, unreacted
After the removals such as object, by-product, precipitation, chromatography, recrystallization and other common methods is recycled to be purified and obtained.
Step 4: preparing the impurity finished product, purity 80% or so according to synthetic method.
Step 5: further confirming to the impurity.
（1）The impurity finished product for being about 80% by obtained purity, measure HPLC, go out peak position relative retention time 0.44 with it is miscellaneous
1 appearance time of matter is identical；
（2）Mass spectroscopy is directly carried out ,+being 474.9 and [the M+Na]+molecular ion peak for being 496.9 that has [M+H] in MS, accordingly
Molecular weight is 474, identical as 1 molecular weight of impurity in HPLC-MS；
（3）The impurity is added in Flomoxef sodium sample and is measured, the impurity peaks are significantly reinforced in Flomoxef Sodium, card
Impurity in the contaminant monomers and sample of bright acquisition is same substance.
The present invention parses a single contaminant of Flomoxef Sodium, is derived to its forming process, and set
Meter synthetic method obtains the contaminant monomers, and the registration, quality research, technique that can be used for Flomoxef Sodium bulk pharmaceutical chemicals and preparation are ground
Study carefully, prepared by impurity and as impurity reference substance, the quality standard to formulating and improving Flomoxef Sodium provides effective data branch
It holds, effective guarantee is provided for the clinical safety use of Flomoxef Sodium.
Using technical solutions according to the invention or those skilled in the art under the inspiration of technical solution of the present invention,
Similar technical solution is designed, and reaches similar technique effect, is to fall into protection scope of the present invention.
Specific implementation mode
Following example does not lie in the limitation present invention to illustrate the present invention.
Embodiment 1
7.5g Flomoxef acid is added in 50ml tetrahydrofurans and 50ml dichloromethane, -15 DEG C~-10 DEG C is cooled to, adds
Enter alchlor 10.0g, is to slowly warm up to 15 DEG C, is stirred to react 3h.
Reaction solution is added in the mixed liquor of 50ml dilute hydrochloric acid and 100ml ethyl acetate, extracting and demixing, water phase is used again
50ml ethyl acetate extracts, and merges organic phase, with 50ml water washing organic phases, water phase abandons it.Organic addition anhydrous sodium sulfate 3g
After drying, light yellow solid is concentrated under reduced pressure to obtain（Impurity 1）4.8g, purity 81.2%.MS shows component m/z: [M+H]+For
475, [M+Na]+It is 497, corresponding molecular weight is the HPLC-MS numbers of the impurity in 474, with the chromatogram of Flomoxef sodium sample
According to consistent.
Embodiment 2
With reference to State Food and Drug Administration's import drugs registered standard（Standard No. JX20110027）Flomoxef Sodium
Related substances separation chromatographic condition, it is a small amount of to obtain impurity solid in Example 1, is added to Flomoxef sodium sample and is surveyed
Fixed, the impurity peaks are significantly reinforced in sample chromatogram figure, it was demonstrated that the impurity in the contaminant monomers and sample of acquisition is same substance.
Embodiment 3
7.5g Flomoxef acid is added in 100ml tetrahydrofurans, butter of tin is added to -10 DEG C in dissolving postcooling
16.0ml, water 0.75g, -5~0 DEG C of reaction 1h, reacts and finishes addition dichloromethane and each 100ml of water, extraction washing is organic relevant
It after dry, concentrates, crystallization obtains off-white powder（Impurity 1）2.0g, purity 80.2%.MS：m/z: [M+H]+It is 475, [M+Na]+For
497, corresponding molecular weight is 474, consistent with the HPLC-MS data of the impurity in the chromatogram of Flomoxef sodium sample.
Embodiment 4
With reference to State Food and Drug Administration's import drugs registered standard（Standard No. JX20110027）Flomoxef Sodium
Related substances separation chromatographic condition, it is a small amount of to obtain impurity solid in Example 3, is added to Flomoxef sodium sample and is surveyed
Fixed, the impurity peaks are significantly reinforced in sample chromatogram figure, it was demonstrated that the impurity in the contaminant monomers and sample of acquisition is same substance.
Claims (7)
1. a kind of Flomoxef sodium impurity, it is characterised in that the general structure of the compound is（Impurity 1）：
（Impurity 1）
Wherein M is hydrogen or metal ion, such as sodium ion, potassium ion；Or ammonium ion, as triethylamine radical ion, cyclohexylamine root from
Son.
2. a kind of Flomoxef sodium impurity described in claim 1, it is characterised in that：Including its acid and its salt, such as sodium salt, potassium
Salt or ammonium salt, preferably acid.
Can also be mixture 3. Flomoxef sodium impurity described in claim 1, claim 2, can be sterling, such as chlorine
Change sodium mixture, mannitol mixture etc..
4. a kind of Flomoxef sodium impurity described in claim 1, from the preparation process of Flomoxef Sodium, decomposable process with
And chemical synthesis.
5. Flomoxef sodium impurity described in claim 1, claim 2, it is applied to Flomoxef Sodium bulk pharmaceutical chemicals and preparation
Registration, quality research, technical study, impurity are prepared and as impurity reference substance.
6. Flomoxef sodium impurity described in claim 1, claim 2 is prepared by the following method：
（1）Flomoxef acid is added in solvent, solvent can suitably select chlorohydrocarbon（Dichloromethane, chloroform, dichloroethanes,
Trichloroethanes, chlorobenzene etc.）, ether（Ether, tetrahydrofuran, methyl phenyl ethers anisole etc.）, ketone（Acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK),
Cyclohexanone, acetophenone etc.）, ester（Ethyl acetate, butyl acetate, methyl benzoate etc.）, nitro hydrocarbon, nitrile（Acetonitrile, benzonitrile etc.）、
Amide（Formamide, acetamide, dimethylformamide, dimethylacetylamide, hexamethyl phosphoramide etc.）, sulfoxide etc. and its mixing it is molten
Agent, preferably dichloromethane；Then acid, acid optional inorganic acid, organic acid, lewis acid etc., preferred Lewis acids such as three are added
Aluminium chloride is reacted at -20 DEG C ~ 100 DEG C, preferably -10 DEG C ~ 20 DEG C；
（2）Reaction terminates, and product can be by common method, and such as the methods of concentration, extraction, absorption, elution are by solvent, unreacted
After the removals such as object, by-product, precipitation, chromatography, recrystallization and other common methods is recycled to be purified and obtained.
7. the structural formula of the acid of Flomoxef described in claim 6 is：
Flomoxef acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710081548.7A CN108424418A (en) | 2017-02-15 | 2017-02-15 | A kind of Flomoxef sodium impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710081548.7A CN108424418A (en) | 2017-02-15 | 2017-02-15 | A kind of Flomoxef sodium impurity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108424418A true CN108424418A (en) | 2018-08-21 |
Family
ID=63155418
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710081548.7A Pending CN108424418A (en) | 2017-02-15 | 2017-02-15 | A kind of Flomoxef sodium impurity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108424418A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110003242A (en) * | 2019-04-23 | 2019-07-12 | 山西千岫制药有限公司 | A kind of preparation method of Flomoxef acid contamination levels product |
Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4532233A (en) * | 1982-12-23 | 1985-07-30 | Shionogi & Co., Ltd. | Fluoromethylthiooxacephalosporins |
| GB2300856A (en) * | 1995-05-16 | 1996-11-20 | Pfizer Ltd | Beta-lactam preparation |
| JPH11302176A (en) * | 1998-04-15 | 1999-11-02 | Shionogi & Co Ltd | Anti-helicobacter agent containing cephem derivative |
| CN1922191A (en) * | 2004-02-20 | 2007-02-28 | 盐野义制药株式会社 | Crystal of oxacephem |
| CN102875577A (en) * | 2011-07-14 | 2013-01-16 | 山东睿鹰先锋制药有限公司 | Cefminox impurity D and preparation method thereof |
| CN102952149A (en) * | 2012-11-09 | 2013-03-06 | 浙江新和成股份有限公司 | One-pot synthesis method of flomoxef intermediate |
| CN103709179A (en) * | 2013-12-17 | 2014-04-09 | 福建省福抗药业股份有限公司 | Synthesis and purification method of cefmetazole sodium |
| CN104327100A (en) * | 2014-09-30 | 2015-02-04 | 华北制药河北华民药业有限责任公司 | Preparation technology of high-purity flomoxef sodium |
| CN105037393A (en) * | 2015-06-24 | 2015-11-11 | 浙江永宁药业股份有限公司 | Preparation method of flomoxef sodium |
| CN105801601A (en) * | 2016-04-02 | 2016-07-27 | 丽珠医药集团股份有限公司 | Synthesis method of flomoxef sodium |
| CN106188097A (en) * | 2016-07-08 | 2016-12-07 | 郑州大学 | A kind of preparation method of 3 chloromethyl oxacephems antibiotic parent nucleus |
-
2017
- 2017-02-15 CN CN201710081548.7A patent/CN108424418A/en active Pending
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4532233A (en) * | 1982-12-23 | 1985-07-30 | Shionogi & Co., Ltd. | Fluoromethylthiooxacephalosporins |
| GB2300856A (en) * | 1995-05-16 | 1996-11-20 | Pfizer Ltd | Beta-lactam preparation |
| JPH11302176A (en) * | 1998-04-15 | 1999-11-02 | Shionogi & Co Ltd | Anti-helicobacter agent containing cephem derivative |
| CN1922191A (en) * | 2004-02-20 | 2007-02-28 | 盐野义制药株式会社 | Crystal of oxacephem |
| CN102875577A (en) * | 2011-07-14 | 2013-01-16 | 山东睿鹰先锋制药有限公司 | Cefminox impurity D and preparation method thereof |
| CN102952149A (en) * | 2012-11-09 | 2013-03-06 | 浙江新和成股份有限公司 | One-pot synthesis method of flomoxef intermediate |
| CN103709179A (en) * | 2013-12-17 | 2014-04-09 | 福建省福抗药业股份有限公司 | Synthesis and purification method of cefmetazole sodium |
| CN104327100A (en) * | 2014-09-30 | 2015-02-04 | 华北制药河北华民药业有限责任公司 | Preparation technology of high-purity flomoxef sodium |
| CN105037393A (en) * | 2015-06-24 | 2015-11-11 | 浙江永宁药业股份有限公司 | Preparation method of flomoxef sodium |
| CN105801601A (en) * | 2016-04-02 | 2016-07-27 | 丽珠医药集团股份有限公司 | Synthesis method of flomoxef sodium |
| CN106188097A (en) * | 2016-07-08 | 2016-12-07 | 郑州大学 | A kind of preparation method of 3 chloromethyl oxacephems antibiotic parent nucleus |
Non-Patent Citations (5)
| Title |
|---|
| MINORU HARADA,ET AL.: "IMMUNOLOGICAL PROPERTIES OF 6315-S (FLOMOXEF) AND ITS METABOLITE, 6315-S OXIDE", 《CHEMOTHERAPY》 * |
| SERGEY P. IVONIN，ET AL: "An approach to (4-fluoroalkyl-1-alkyl-1H-pyrazol-3-yl) methylamines", 《JOURNAL OF FLUORINE CHEMISTRY》 * |
| XU YU，ET AL.: "Separation and characterization of unknown impurities and isomersin flomoxef sodium by LC-IT-TOF MS and study of their negative-ionfragmentation regularities", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
| 戴海燕 等: "头孢米诺有关物质的合成及结构鉴定", 《中国医药工业杂志》 * |
| 胡建权 等: "氟氧头孢钠氧化产物FMOX~oxide定向合成及确证", 《化工管理》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110003242A (en) * | 2019-04-23 | 2019-07-12 | 山西千岫制药有限公司 | A kind of preparation method of Flomoxef acid contamination levels product |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11398645B2 (en) | Organic synthesis applications of non-aqueous fluoride salt solutions | |
| US9649315B2 (en) | Composition useful for treating disorders related to TRPA1 | |
| US8598352B2 (en) | Preparation of nalmefene hydrochloride from naltrexone | |
| US8754217B2 (en) | Nalmefene hydrochloride dihydrate | |
| JP2016199566A (en) | Method for the manufacturing of naltrexone | |
| CN108424418A (en) | A kind of Flomoxef sodium impurity | |
| EP2385054A1 (en) | Cefdinir acid double salt and its preparation | |
| US11891379B2 (en) | Deuterated Defactinib compound and use thereof | |
| CN108530468A (en) | A kind of Cefpodoxime Proxetil impurity and its preparation method and application | |
| EP2788357B1 (en) | Process for recovery of nalmefene hydrochloride | |
| US7002009B2 (en) | Crystalline tricyclic triazolobenzazepine derivative | |
| Butora et al. | The elusive 8-fluoroadenosine: a simple non-enzymatic synthesis and characterization | |
| US20140155608A1 (en) | Method for the manufacturing of naltrexone | |
| US20100125050A1 (en) | Process for the Manufacture of Eptifibatide | |
| US4391817A (en) | Pyrrolo-diazepine derivatives and their pharmaceutical compositions | |
| US20140128359A1 (en) | N-Heterocyclic Substituent-Containing Antibiotic, Preparation and Use Thereof | |
| US20210147330A1 (en) | Method for producing 3-hydroxy-3-methylbutyrate or salt thereof | |
| KR101837795B1 (en) | Method for the manufacturing of naltrexone | |
| EP0135207A1 (en) | A process for the preparation of (8S)-8-fluoroerythromycins | |
| US20190224185A1 (en) | Preparation of (-)-cocaine hydrochloride | |
| US8580963B2 (en) | Method for the manufacturing of naltrexone | |
| JP2003530382A (en) | Process for producing oxime ether | |
| CN103467483B (en) | Method for preparing hydrobromic acid prasugrel acetic acid compound | |
| WO2012076735A1 (en) | Deuterated 5-trideuteromethyl-6-methyl-2-thioxo-2,3-dihydropyridin -4(1h)-one compounds and method for the preparation thereof | |
| Unnisa et al. | A simple process for the preparation of pralidoxime chloride |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180821 |