WO2016142902A1 - Cefixime with reduced surface area and high stability - Google Patents
Cefixime with reduced surface area and high stability Download PDFInfo
- Publication number
- WO2016142902A1 WO2016142902A1 PCT/IB2016/051372 IB2016051372W WO2016142902A1 WO 2016142902 A1 WO2016142902 A1 WO 2016142902A1 IB 2016051372 W IB2016051372 W IB 2016051372W WO 2016142902 A1 WO2016142902 A1 WO 2016142902A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- less
- process according
- surface area
- cefixime
- mixture
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
Definitions
- the present invention provides cefixime trihydrate (I) with reduced surface area and high stability. BACKGROUND OF THE INVENTION
- Cefixime is an orally active third generation broad spectrum cephalosporin antibiotic and is more potent against gram negative bacteria. Cefixime is commonly used to treat various infections caused by susceptible isolates of the designated bacteria. Cefixime and cefixime trihydrate (I) are disclosed in patent US 4,409,214; the patent discloses process for preparation of cefixime and isolation of cefixime trihydrate (I) from a mixture of ethanol and water. Various processes for preparation as well as purification of cefixime and cefixime trihydrate (I) are available in the literature.
- the present invention provides cefixime trihydrate (I) with reduced surface area and high stability with respect to content of impurity Al.
- the present invention provides a detailed study of surface area of cefixime trihydrate (I) and the content of impurity Al of cefixime trihydrate (I).
- the impurity Al is one of the stereoisomer of impurity A which is provided in the British pharmacopeia monograph of cefixime and is as depicted below.
- Impurity A in the present invention it was surprisingly found that cefixime trihydrate (I) with a surface area of less than 1.2 m /gm is highly stable with respect to impurity Al which is less than 0.5% by area percentage of HPLC.
- the present invention provides cefixime trihydrate (I) with surface area of less than 1.2 m /gm containing impurity Al less than 0.5% by area percentage of HPLC.
- the present invention provides cefixime trihydrate (I) with surface area of less than 1.2 m /gm.
- the surface area is measured by Brunauer-Emmett- Teller (BET) method.
- BET Brunauer-Emmett- Teller
- the present invention provides cefixime trihydrate (I) with surface area of less than 1.2 m /gm and the content of impurity Al of less than 0.5% by area percentage of HPLC.
- the present invention provides process for preparation of cefixime trihydrate (I) with surface area of less than 1.2 m /gm.
- cefixime trihydrate (I) Various process for purification of cefixime trihydrate (I) were carried out in our endeavor to obtain stable cefixime trihydrate (I). Physical and chemical parameters of the Cefixime trihydrate (I) samples were determined. All the experimental parameters which could alter the physical and chemical properties of cefixime trihydrate (I) were thoroughly studied. After a detailed study it was observed that there was a correlation between experimental parameters and the surface area of cefixime trihydrate (I) obtained and stability of cefixime trihydrate (I).
- cefixime trihydrate (I) with surface area of less than 1.2 m /gm is stable (entries 2 and 3 of Table 1). As the surface area of cefixime trihydrate (I) increases impurity Al formation also increases (entry 1 of Table 1). The impurity Al appeared at RRT 0.75 in the HPLC chromatogram. Correlation between RPM of the experiment, surface area of cefixime trihydrate (I) and content of impurity Al during stability was studied and the results obtained are depicted below in Table 1. Table 1: Stability study of cefixime trihydrate (I).
- Table 1 shows that stability of cefixime trihydrate (I) depends on the surface area, which in turn depends on the RPM employed in the purification of cefixime trihydrate (I). Stability of cefixime trihydrate (I) was studied at 40 ⁇ 2°C RH 75 ⁇ 5% RH.
- the present invention provides process for preparation of cefixime trihydrate (I) with surface area of less than 1.2 m /gm comprising the steps of: i) adjusting pH of cooled aqueous solution of cefixime trihydrate (I) to 5.8-6 using base, ii) optionally treating with EDTA and carbon, iii) stirring the mixture at low RPM, iv) adjusting pH of the mixture to 4.8-5.0 using acid, v) adding ketone solvent, vi) heating the mixture to 34-38°C, vii) adjusting pH to 2.4-2.5 slowly using acid, viii) cooling the mixture, and ix) isolating the solid.
- Cefixime trihydrate (I) is prepared by methods known in the literature.
- the process for preparation of cefixime trihydrate (I) is carried out at low RPM.
- low RPM means RPM less than 400, preferably less than 100, more preferably less than 60.
- the pH of 5.8 to 6 is achieved by using base selected from alkaline solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and the like, preferably sodium hydroxide.
- the pH of 4.8 to 2.4 is achieved by using acid selected from inorganic acids like hydrochloric acid, sulfuric acid and the like, preferably hydrochloric acid.
- the pH is adjusted to 2.4-2.5 slowly using acid. "Slowly” means over a period of 60-300 minutes.
- the ketone solvent is selected form acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, acetophenone; preferably acetone.
- the mixture is cooled to 0-10°C, preferably 0-5°C.
- UV detector UV detector
- Instrument Smart Srob 93, based on dynamic BET principal.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The present invention provides cefixime trihydrate (I) with surface area of less than 1.2 m2/gm containing impurity A1 less than 0.5% by area percentage of HPLC. The impurity A1 is one of the stereoisomers of impurity A as depicted below.
Description
CEFIXIME WITH REDUCED SURFACE AREA AND HIGH STABILITY
FIELD OF INVENTION
The present invention provides cefixime trihydrate (I) with reduced surface area and high stability. BACKGROUND OF THE INVENTION
Cefixime is an orally active third generation broad spectrum cephalosporin antibiotic and is more potent against gram negative bacteria. Cefixime is commonly used to treat various infections caused by susceptible isolates of the designated bacteria. Cefixime and cefixime trihydrate (I) are disclosed in patent US 4,409,214; the patent discloses process for preparation of cefixime and isolation of cefixime trihydrate (I) from a mixture of ethanol and water. Various processes for preparation as well as purification of cefixime and cefixime trihydrate (I) are available in the literature.
The present invention provides cefixime trihydrate (I) with reduced surface area and high stability with respect to content of impurity Al. The present invention provides a detailed study of surface area of cefixime trihydrate (I) and the content of impurity Al of cefixime trihydrate (I).
The impurity Al is one of the stereoisomer of impurity A which is provided in the British pharmacopeia monograph of cefixime and is as depicted below.
Impurity A In the present invention it was surprisingly found that cefixime trihydrate (I) with a surface area of less than 1.2 m /gm is highly stable with respect to impurity Al which is less than 0.5% by area percentage of HPLC.
Stability and control of impurity content in a pharmaceutical product is very desirable, in order to reduce adverse side effect and improve the shelf life. SUMMARY OF THE INVENTION
The present invention provides cefixime trihydrate (I) with surface area of less than 1.2 m /gm containing impurity Al less than 0.5% by area percentage of HPLC.
DETAILED DESCRIPTION OF THE INVENTION
In the preferred embodiment, the present invention provides cefixime trihydrate (I) with surface area of less than 1.2 m /gm. The surface area is measured by Brunauer-Emmett- Teller (BET) method.
In another embodiment, the present invention provides cefixime trihydrate (I) with surface area of less than 1.2 m /gm and the content of impurity Al of less than 0.5% by area percentage of HPLC.
In yet another embodiment, the present invention provides process for preparation of cefixime trihydrate (I) with surface area of less than 1.2 m /gm.
Various process for purification of cefixime trihydrate (I) were carried out in our endeavor to obtain stable cefixime trihydrate (I). Physical and chemical parameters of the Cefixime trihydrate (I) samples were determined. All the experimental parameters which could alter the physical and chemical properties of cefixime trihydrate (I) were thoroughly studied. After a detailed study it was observed that there was a correlation between experimental parameters and the surface area of cefixime trihydrate (I) obtained and stability of cefixime trihydrate (I).
It was observed that different experimental parameters utilized in the purification step altered the surface area of cefixime trihydrate (I) obtained. Further studies revealed that the purification procedure carried out at a certain RPM (Rotation per minute of the stirrer) played a pivotal role in obtaining cefixime trihydrate (I) with the required surface area.
From the studies carried out in the present invention it is revealed that cefixime trihydrate (I) with surface area of less than 1.2 m /gm is stable (entries 2 and 3 of Table 1). As the surface area of cefixime trihydrate (I) increases impurity Al formation also increases (entry 1 of Table 1). The impurity Al appeared at RRT 0.75 in the HPLC chromatogram. Correlation between RPM of the experiment, surface area of cefixime trihydrate (I) and content of impurity Al during stability was studied and the results obtained are depicted below in Table 1.
Table 1: Stability study of cefixime trihydrate (I).
*RH= Relative humidity.
Table 1 shows that stability of cefixime trihydrate (I) depends on the surface area, which in turn depends on the RPM employed in the purification of cefixime trihydrate (I). Stability of cefixime trihydrate (I) was studied at 40 ± 2°C RH 75±5% RH.
The present invention provides process for preparation of cefixime trihydrate (I) with surface area of less than 1.2 m /gm comprising the steps of: i) adjusting pH of cooled aqueous solution of cefixime trihydrate (I) to 5.8-6 using base, ii) optionally treating with EDTA and carbon, iii) stirring the mixture at low RPM, iv) adjusting pH of the mixture to 4.8-5.0 using acid, v) adding ketone solvent, vi) heating the mixture to 34-38°C, vii) adjusting pH to 2.4-2.5 slowly using acid, viii) cooling the mixture, and ix) isolating the solid.
Cefixime trihydrate (I) is prepared by methods known in the literature.
The process for preparation of cefixime trihydrate (I) is carried out at low RPM. The term "low RPM" means RPM less than 400, preferably less than 100, more preferably less than 60.
In the process for preparation of cefixime trihydrate (I) use of ethylenediaminetetraacetic acid (EDTA) and carbon treatment is optional so as to improve colour quality of the product.
The pH of 5.8 to 6 is achieved by using base selected from alkaline solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and the like, preferably sodium hydroxide.
The pH of 4.8 to 2.4 is achieved by using acid selected from inorganic acids like hydrochloric acid, sulfuric acid and the like, preferably hydrochloric acid. In operation (vii) the pH is adjusted to 2.4-2.5 slowly using acid. "Slowly" means over a period of 60-300 minutes. The ketone solvent is selected form acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, acetophenone; preferably acetone.
The mixture is cooled to 0-10°C, preferably 0-5°C.
The solid can be isolated by common techniques known in the art like filtration, concentration etc. The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.
EXAMPLES
I. Details of HPLC methods for analysis are provided below:
Variables Details
HPLC model Shimadzu LC-2010 equipped with pump,
injector, UV detector and recorder
Column: Inertsil ODS 3V (250mm x 4.6mm) 5μπι
Detector: UV at 254 nm.
Column temp.: 40°C
Buffer: 0.05M Ammonium in HPLC grade water
Mobile phase A: buffer and methanol (95:05) pH-4.2
Mobile phase B: buffer and methanol (50:50) pH-4.2
Sample preparation: 1000 ppm in Diluent (pH-7.0 phosphate
buffer)
Injection volume: 20 ml
Mode of elution: Gradient
Flow: 1.5 mL/minute.
Run time: 70 minutes
Impurity Al RRT 0.75
Cefixime trihydrate (I) RRT 1
II. Details for surface area analyser are provided below: Instrument: Smart Srob 93, based on dynamic BET principal.
System: 30% nitrogen and 70% Helium gas mixture is passed over the sample, the absorbed nitrogen is used to calculate surface area.
Operating temperature: -15°C to 40°C
Experiment 1:
A mixture of cefixime trihydrate (I) (5.0 kg) and water (55 liters) was cooled to 4-8°C. The pH was adjusted to 5.8 to 6°C with 5% sodium hydroxide solution (18.5 liters). EDTA (0.05 kg) and activated carbon (0.5 kg) was added and the mixture stirred for 30 minutes. The mixture was filtered. The filtrate was collected in the reactor and the RPM of the stirrer was maintained to 36.0±2. The pH of the filtrate was adjusted to 4.8 to 5 with 10% HCl solution (0.25 liters) at 4-8°C. A mixture of water (30.0 liter) and acetone (30.0 liter) was added to it and heated at 34-38°C. The pH was adjusted to 2.4 to 2.5 with 10% HCl solution (5.5 liters) in 275 minutes. The mixture was cooled to 0 to 5°C and filtered, washed with water (50 liter) and dried. Surface area: 0.55 m /gm; content of impurity Al by HPLC: 0.04 % (initial), 0.17% (15 days) and 0.22% (1 month).
Claims
1. Cefixime trihydrate (I) with surface area of less than 1.2 m /gm.
2
2. Cefixime trihydrate (I) with surface area of less than 1.2 m /gm and the content of impurity Al of less than 0.5% by area percentage of HPLC.
3. Process for preparation of cefixime trihydrate (I) with surface area of less than 1.2 m /gm comprising the steps of:
i) adjusting pH of cooled aqueous solution of cefixime trihydrate (I) to 5.8-6 using base,
ii) optionally treating with EDTA and carbon,
iii) stirring the mixture at low RPM,
iv) adjusting pH of the mixture to 4.8-5.0 using acid,
v) adding ketone solvent,
vi) heating the mixture to 34-38°C,
vii) adjusting pH to 2.4-2.5 slowly using acid,
viii) cooling the mixture, and
ix) isolating the solid.
4. A process according to claim 3, wherein RPM is less than 400.
5. A process according to claim 3, wherein RPM is less than 100.
6. A process according to claim 3, wherein RPM is less than 60.
7. A process according to claim 3, wherein base is selected from alkaline solutions of sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate preferably sodium hydroxide.
8. A process according to claim 3, wherein acid is selected from inorganic acids like hydrochloric acid and sulfuric acid.
9. A process according to claim 3, wherein pH is adjusted to 2.4-2.5 over a period of 60- 300 minutes.
A process according to claim 3, wherein ketone solvent is selected form acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, acetophenone; preferably acetone.
11. A process according to claim 3, wherein mixture is cooled to 0-10°C, preferably 0- 5°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN796/MUM/2015 | 2015-03-11 | ||
| IN796MU2015 | 2015-03-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2016142902A1 true WO2016142902A1 (en) | 2016-09-15 |
Family
ID=55911004
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2016/051372 WO2016142902A1 (en) | 2015-03-11 | 2016-03-10 | Cefixime with reduced surface area and high stability |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2016142902A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109490440A (en) * | 2018-11-21 | 2019-03-19 | 成都倍特药业有限公司 | A method of detection Cefixime related impurities |
| CN111487354A (en) * | 2020-04-27 | 2020-08-04 | 广州白云山医药集团股份有限公司白云山制药总厂 | Method for detecting cefixime related impurities |
| CN111551654A (en) * | 2020-05-07 | 2020-08-18 | 广州白云山医药集团股份有限公司白云山制药总厂 | Method for detecting cefixime polymer impurities |
| WO2021202481A1 (en) * | 2020-03-30 | 2021-10-07 | Florida State University Research Foundation, Inc. | Compositions and methods for inhibiting type 1 collagen production |
| CN115326950A (en) * | 2022-07-27 | 2022-11-11 | 广州白云山医药集团股份有限公司白云山制药总厂 | Method for detecting dissolution rate of cefixime |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4409214A (en) | 1979-11-19 | 1983-10-11 | Fujisawa Pharmaceutical, Co., Ltd. | 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof |
| WO1995033753A1 (en) * | 1994-06-03 | 1995-12-14 | Marcham Trading & Investment Ltd. | Process for the preparation of trihydrated cefixime |
| WO1998006723A1 (en) * | 1996-08-14 | 1998-02-19 | Biochemie Gesellschaft Mbh | Amine salts |
| WO1999051607A2 (en) * | 1998-04-02 | 1999-10-14 | Biochemie Gesellschaft Mbh | Process for purification of a cephalosporin derivative |
| WO2001070749A1 (en) * | 2000-03-20 | 2001-09-27 | Hanmi Fine Chemicals Co. Ltd. | A process for preparing cephalosporin derivatives using new thiazole compound |
| WO2006067806A1 (en) * | 2004-12-21 | 2006-06-29 | Lupin Limited | Process for the preparation of cefixime |
| WO2006103686A1 (en) * | 2005-03-29 | 2006-10-05 | Hetero Drugs Limited | An improved process for the preparation of cefixime |
-
2016
- 2016-03-10 WO PCT/IB2016/051372 patent/WO2016142902A1/en active Application Filing
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4409214A (en) | 1979-11-19 | 1983-10-11 | Fujisawa Pharmaceutical, Co., Ltd. | 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof |
| WO1995033753A1 (en) * | 1994-06-03 | 1995-12-14 | Marcham Trading & Investment Ltd. | Process for the preparation of trihydrated cefixime |
| WO1998006723A1 (en) * | 1996-08-14 | 1998-02-19 | Biochemie Gesellschaft Mbh | Amine salts |
| WO1999051607A2 (en) * | 1998-04-02 | 1999-10-14 | Biochemie Gesellschaft Mbh | Process for purification of a cephalosporin derivative |
| WO2001070749A1 (en) * | 2000-03-20 | 2001-09-27 | Hanmi Fine Chemicals Co. Ltd. | A process for preparing cephalosporin derivatives using new thiazole compound |
| WO2006067806A1 (en) * | 2004-12-21 | 2006-06-29 | Lupin Limited | Process for the preparation of cefixime |
| WO2006103686A1 (en) * | 2005-03-29 | 2006-10-05 | Hetero Drugs Limited | An improved process for the preparation of cefixime |
Non-Patent Citations (1)
| Title |
|---|
| KITAMURA S ET AL: "Dehydration effect on the stability of cefixime trihydrate", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER BV, NL, vol. 59, no. 3, 30 March 1990 (1990-03-30), pages 217 - 224, XP025554429, ISSN: 0378-5173, [retrieved on 19900330], DOI: 10.1016/0378-5173(90)90112-H * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109490440A (en) * | 2018-11-21 | 2019-03-19 | 成都倍特药业有限公司 | A method of detection Cefixime related impurities |
| CN109490440B (en) * | 2018-11-21 | 2021-09-07 | 成都倍特药业股份有限公司 | Method for detecting cefixime related impurities |
| WO2021202481A1 (en) * | 2020-03-30 | 2021-10-07 | Florida State University Research Foundation, Inc. | Compositions and methods for inhibiting type 1 collagen production |
| US11554121B2 (en) | 2020-03-30 | 2023-01-17 | Florida State University Research Foundation, Inc. | Compositions and methods for inhibiting type 1 collagen production |
| CN111487354A (en) * | 2020-04-27 | 2020-08-04 | 广州白云山医药集团股份有限公司白云山制药总厂 | Method for detecting cefixime related impurities |
| CN111551654A (en) * | 2020-05-07 | 2020-08-18 | 广州白云山医药集团股份有限公司白云山制药总厂 | Method for detecting cefixime polymer impurities |
| CN111551654B (en) * | 2020-05-07 | 2022-04-22 | 广州白云山医药集团股份有限公司白云山制药总厂 | Method for detecting cefixime polymer impurities |
| CN115326950A (en) * | 2022-07-27 | 2022-11-11 | 广州白云山医药集团股份有限公司白云山制药总厂 | Method for detecting dissolution rate of cefixime |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2016142902A1 (en) | Cefixime with reduced surface area and high stability | |
| US10882813B2 (en) | Method for the synthesis of ferric oraganic compounds | |
| EP1927586B1 (en) | Process for producing 5-aminolevulinic acid hydrochloride | |
| CN115505051A (en) | Method for refining sugammadex sodium | |
| DE60201498T2 (en) | IMPROVED PROCESS FOR THE PREPARATION OF CARBAPENEMEN | |
| US20080021210A1 (en) | Compositions and methods of making a photoactive agent | |
| EP0247436B1 (en) | Process for recovery of amino acid from aqueous mixtures | |
| US6552191B1 (en) | Method of extracting tetrodotoxin | |
| CA2678165A1 (en) | Crystalline forms of (6r)-l-erythro-tetrahydrobiopterin dihydrochloride | |
| CN106256830B (en) | A kind of deuterated IDO inhibitor and its preparation method and application | |
| UA41902C2 (en) | process for producing asitromycin dihydrochloride | |
| CN109134556B (en) | Hydrochloric acid crystallization separation and purification method of lincomycin | |
| JP4954421B2 (en) | Purification method of clavulanate | |
| WO2014178013A1 (en) | Vilazodone impurities, process for their preparation, and their use as reference standards | |
| CN115417819B (en) | Preparation method of phentolamine mesylate | |
| CN108147988B (en) | Preparation method of lactam compound with high chiral purity | |
| CN111662246A (en) | Mirabegron impurity compound and preparation method and application thereof | |
| KR102441251B1 (en) | Method for removing residual solvents from vancomycin | |
| EP2982759B1 (en) | Method for purifying quinolinic acid | |
| CN104892637B (en) | A kind of infant industry crystallization method of Sodium O-formylcefamole and preparation thereof | |
| CN114057727B (en) | Synthesis method of zolpidem intermediate | |
| CN110903346B (en) | Method for preparing vancomycin hydrochloride impurity impC | |
| CN115991637B (en) | Method for extracting quebrachitol and quebrachitol | |
| CN113004184A (en) | Efficient crystallization process for preparing ultrapure treprostinil and crystals made therefrom | |
| CN109503426A (en) | α-(o-chloraniline base) methine-β-formamido propionitrile method of purification |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 16720553 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 16720553 Country of ref document: EP Kind code of ref document: A1 |