EP3226885A2 - Zwischenprodukte und verfahren zur herstellung von micafungin - Google Patents
Zwischenprodukte und verfahren zur herstellung von micafunginInfo
- Publication number
- EP3226885A2 EP3226885A2 EP15849490.6A EP15849490A EP3226885A2 EP 3226885 A2 EP3226885 A2 EP 3226885A2 EP 15849490 A EP15849490 A EP 15849490A EP 3226885 A2 EP3226885 A2 EP 3226885A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- compound
- micafungin
- preparation
- chloro
- 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.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
Definitions
- the present invention relates to active esters of compound of Formula I which are used as key intermediates in the synthesis of Micafungin, an antifungal agent and process of preparation of said active esters.
- the invention also relates to process of preparing Micafungin from said active esters.
- mice with CAS Registry Number: 2351 14-32-6 and IUPAC name as ⁇ 5-[(l S,2S)-2-[(3S,6S,9S,l 1R,15S,18S,20R,21R,24S,25S,26S)- 3 [( 1 R)-2-carbamoyl- 1 -hydroxyethyl]- 1 1 ,20,21 ,25-tetrahydroxy- 15-[( 1 R)- 1 - hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-18-[(4- ⁇ 5-[4- (pentyloxy)phenyl]-l ,2-oxazol-3-yl ⁇ benzene)amido]-l, 4,7, 13,16,22- hexaazatricyclo[22.3.0.09,13]heptacosan-6-yl]- 1 , 2-dihydroxyethy
- the peptide compounds are prepared by reaction wherein the amino compounds are treated with R'-OH compounds by elimination reaction of amino protective group in R 1 .
- Micafungin is obtained from reaction of CMICA/FR- 179642 with the benzotriazole- active ester of PPIB in the presence of 4-dimethylaminopyridine (DMAP).
- WO2004014879 describes process for preparation of intermediate compound used for producing an antifungal agent and a process for preparing antifungal agent from the said intermediate compound.
- This patent application discloses reaction of CMICA/FR- 179642 with the benzotriazole active ester of compound of Formula III, wherein R 2 is lower alkoxy or higher alkoxy, R 4 is carboxy, A 1 is an aromatic bivalent group, heterocyclic bivalent 5 group or cyclo(lower)alkane bivalent group, and A is an aromatic bivalent group, heterocyclic bivalent group or cyclo(lower)alkane bivalent group to provide
- WO2013034670 describes various active esters of PPIB, more particularly those which allow a one-pot synthesis from PPIB to give an antifungal agent preferably MICA, or a salt thereof, preferably without the need to isolate and/or purify the active ester of PPIB before the conversion with another key intermediate, preferably CMICA.
- active esters represented therein are as follows:
- the present invention relates to active esters of PPIB, novel key intermediates, the process for their preparation and preparation of MICA from these active esters.
- the active esters are used either in situ form or they are isolated and purified and used in the preparation of Micafungin in isolated form.
- One such active ester has been isolated, is shelf stable and can be stored in a dry condition for several months after its preparation.
- the first object of the present invention is to provide novel active esters of 4-(5-(4-(pentyloxy)phenyl)isoxazol-3-yl)benzoic acid (PPIB), in particular novel key intermediate of Micafungin, which is an antifungal agent.
- the novel active esters are esters of 4-(5-(4-(pentyloxy)phenyl)isoxazol-3-yl)benzoic acid (PPIB).
- the active ester is prepared "in situ " and reacted further to produce Micafungin or is isolated and stored before use. One such isolated active ester is shelf stable and can be stored for further synthesis of Micafungin.
- Second object of the present invention is to provide process to prepare novel active esters of PPIB, which is simple and economical.
- Third object of the present invention is to provide a process to prepare Micafungin (MICA) from novel active esters of PPIB with another key intermediate, preferably CMICA/FR- 179642 or a salt thereof in good yield.
- MICA Micafungin
- the present invention provides novel key intermediates, in particular novel active esters of PPIB represented by Formula I as below:
- the active esters of PPIB are formed "in situ" or it is isolated compound.
- the active ester of Formula I wherein R' and R" both are methoxy is successfully isolated, purified and characterized. This ester is found storage stable.
- the isolated ester is further characterized for physicochemical and spectroscopic methods.
- the active ester purity was confirmed by RP-HPLC and it is further characterized by MS, ⁇ NMR.
- This active ester is shelf stable and can be stored in a dry condition for months after its preparation. This would enable to prepare and store the active ester and use it when needed for synthesis of Micafungin.
- the active ester of Formula I of the present invention is selected from
- the process for preparation of active esters of Formula I comprises reaction of the compound of formula III with a triazine salt selected from 2-chloro-4,6- dimethoxy-l,3,5-triazine (CDMT) or 2-chloro-4,6-diphenyloxy-l,3,5-triazine (CDPT) in presence of base and solvent.
- a triazine salt selected from 2-chloro-4,6- dimethoxy-l,3,5-triazine (CDMT) or 2-chloro-4,6-diphenyloxy-l,3,5-triazine (CDPT) in presence of base and solvent.
- the solvent is aprotic solvent selected from the group consisting of tetrahydrofuran (THF), dimethyl formamide (DMF), dimethylacetamide, toluene, 2-methyltetrahydrofuran, N-methyl-2-pyrrolidone (NMP), and mixtures thereof.
- THF tetrahydrofuran
- DMF dimethyl formamide
- NMP N-methyl-2-pyrrolidone
- the base is selected from the group consisting of N-methylmorpholine, ⁇ , ⁇ , ⁇ , ⁇ - tetramethylguanidine, pyridine, JV-methyl-2-pyrrolidone (NMP), triethylamine, 4- picoline, 4-dimethylaminopyridine (DMAP), toluene, N-methylpiperidine and N,N, N,N-tetramethylethylenediamine, and combination thereof.
- the preferred base is vV-methylmorpholine and the preferred solvent is DMF.
- the process for preparation of active esters of Formula I A comprises reaction of PPIB of Formula III with CDMT in presence of base in DMF as solvent is as follows:
- This step viz. isolation is optional
- the first step involves reacting, the triazine compound of formula (A) with a compound of formula (B) to generate a triazine salt of formula (C).
- Ri, R 2 , R 3 independently is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, heterocyclic groups or alternatively Ri, R 2 and R 3 together with Nitrogen or any two of the Ri, R 2 and R 3 together with Nitrogen form a ring which can be heterocycloalkyl, or heterocyclic and any such ring is optionally substituted by alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, heterocyclic groups, nitro, halo, amino or substituted amino groups or alternatively Ri, R 2 and R 3 together with Nitrogen form guanidine or substituted guanidine.
- the compound of formula (B) is a base and preferably the base is N- methylmorpholine.
- the N-methylmorpholine reacts with triazine compound of formula (A) and generates "in situ " the compound of formula (C).
- N-methylmorpholine is reacted with 2-chloro-4,6-dimethoxy- 1 ,3,5-triazine (CDMT) [or 2-chloro-4,6-diphenyloxy-l,3,5-triazine (CDPT)] to produce 4-(4,6-dimethoxy-l ,3,5-triazin-2-yl)-4-methylmorpholin-4-iumchloride, DMTMM [or 4-(4,6-diphenoxy-l ,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride, DPTMM] as represented in below scheme.
- CDMT 2-chloro-4,6-dimethoxy- 1 ,3,5-triazine
- CDPT 2-chloro-4,6-diphenyloxy-l,3,5-triazine
- the triazine salt, DMTMM or DPTMM generated by reaction of a base with CDMT or CDPT can be isolated or reacted "in situ" [(DMTMM) or (DPTMM)] further with PPIB compound of Formula III to produce the corresponding active ester.
- the active ester which is compound of Formula IA can be further isolated optionally.
- any salt generated by reaction of a base with CDMT or CDPT can be isolated. Such isolated salt is reacted with the compound of Formula III to produce active ester of Formula I. In this process DMTMM or DPTMM or any such salt is used as a coupling agent for preparation of an active ester.
- Further aspect of the invention is to provide process of preparation of an antifungal agent, Micafungin represented by the compound of Formula II from the novel active ester either "In situ" or in isolated form as follows:
- isolated novel active ester of Formula IA is reacted with FR-179642 to produce Micafungin.
- novel active esters of the present invention which are the active forms of the acid are generated in situ using CDMT or CDPT as a coupling agents and Micafungin is prepared from the active esters prepared from CDPT or any salt of CDMT / CDPT and a base.
- Fig. 1 represents 1H-NMR of Formula IA in CDC1 3
- Fig. 2 represents ⁇ -NMR of Formula IA in CDC1 3 (Expanded region from 6.3 to 8.5 5 region of Fig.1).
- Fig. 3 represents 1H-NMR of Formula IA in CDCI3 (Expanded region from 0.5 to 4.5 ⁇ region of Fig.1 ).
- Fig. 4 represents RP-HPLC profile of Formula IA
- Fig. 5 represents MS spectra of Formula IA
- Fig. 6 represents stability of Formula IA by HPLC profile.
- CDMT 2-chloro-4,6-dimethoxy-l ,3,5-triazine
- CDPT 2-chloro-4,6-diphenyloxy-l,3,5-triazine
- PPIB 4-(5-[4-(pentyloxy)phenyl]-isooxazol-3-yl)benzoic acid
- Micafungin is an echinocandin antifungal agent, is used to treat a variety of fungal infections (such as candidemia, esophageal candidiasis). It is also used to prevent fungal infections in people who have undergone bone marrow or stem cell transplant, since these people have weak immune systems and hence at the higher risk of fungal infections. It works by way of concentration-dependent inhibition of 1,3-beta-D-glucan synthase resulting in reduced formation of 1 ,3- beta-D-glucan, which is an essential polysaccharide comprising one-third of the majority of Candida spp. cell walls. This decreased glucan production leads to osmotic instability and thus cellular lysis.
- the first aspect of the present invention relates to novel active esters represented by a compound of Formula I.
- the active ester of compound of formula I are used to prepare Micafungin of Formula II.
- the active esters of Formula I are prepared "in situ " and reacted further as they are or the active esters of Formula I are isolated and further reacted.
- This active ester is shelf stable and can be stored for several months after its preparation. This would enable one to prepare and store the active ester and use it when needed for synthesis of Micafungin. This would also enable one to transport active ester from one lab to another for further scale up of Micafungin from development scale to commercial level or one commercial scale to higher commercial scale. This would also enable one to obtain ready key intermediate of Micafungin from market for further synthesis. Further this ester provides means for one pot synthesis of Micafungin.
- the active ester of Formula I is subjected to acylation reaction with FR- 179642 of Formula IV to produce Micafungin, preferably in presence of a base selected from diisopropylethyl amine, N-methyl morpholine (NMM), pyridines, lutidines, picolines, dimethylaminopyridine, triethylamine and collidines, and any combination thereof.
- a base selected from diisopropylethyl amine, N-methyl morpholine (NMM), pyridines, lutidines, picolines, dimethylaminopyridine, triethylamine and collidines, and any combination thereof.
- the preferred base is diisopropylethyl amine.
- the active ester of Formula 1A is characterized as follows:
- An active ester of Formula I A is characterized by studying 1 H-NMR spectra, mass spectra, and RP-HPLC profile; the details of which are provided in figures.
- the gradient is provided under table 2.
- A is mobile phase containing 0.01 % trifluroacetic acid in Milli Q water and B is 0.01 % trifluroacetic acid in acetonitrile.
- the novel active ester elutes at the retention time of 22.5.
- the invention provides a process for in situ preparation of novel active ester.
- Process for "in situ" preparation of active ester is as follows and involves preparation of active ester followed by isolation.
- An active ester in accordance with the present invention is prepared by process in which compound of the Formula III viz. PPIB is reacted with 2-chloro-4,6- dimethoxy-l ,3,5-triazine (CDMT) or 2-chloro-4,6-diphenoxy-l,3,5-triazine (CDPT).
- the step is carried out in a solvent, preferably in an aprotic solvent, selected from tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide, toluene, 2-methyltetrahydrofuran, N-methyl-2-pyrrolidone (NMP), and any combination thereof, and is preferably tetrahydrofuran.
- the step is carried out in presence of base.
- the base is selected from N-methylmorpholine (NMM), N,N,N,N-tetramethylguanidine, pyridine, 4-picoline, 4- dimethylaminopyridine (DMAP), N-methylpiperidine and ⁇ , ⁇ , ⁇ , ⁇ - tetramethylethylenediamine, trimethylamine and any combination thereof, and is preferably N-methylmorpholine (NMM).
- NMM N-methylmorpholine
- DMAP dimethylaminopyridine
- NMM N-methylmorpholine
- the novel active ester of the present invention which is an active form of the acid is generated in situ using CDMT or CDPT as a coupling agent. Further the novel ester prepared "in situ" can be isolated by evaporating the reaction mixture to dryness. The crude mixtures were dissolved in aprotic solvent such as ethyl acetate and solution is filtered to remove unreacted reagents and salts generated. The filtrate was evaporated to dryness and the solid obtained was stored in cold and anhydrous condition for prolonged usage.
- aprotic solvent such as ethyl acetate
- the active ester of Formula IA when CDMT or its derivative is used as a coupling agent as follows:
- CDPT and its derivative DPTMM can also be used as coupling agents.
- various other salts made by reaction of CDMT and CDPT with other bases can be used as coupling agents. The reaction is preferably carried out in aprotic solvents, most preferred are THF or DMF.
- DMTMM salt can be further reacted “in situ” (DMTMM) or isolated for further reaction.
- DMTMM salt in situ or isolated form is reacted with compound of Formula III which yields the formation of active ester of Formula I.
- the active ester which is compound of Formula I can be further isolated.
- CDPT in place of CDMT, 2-chloro-4,6-diphenyloxy- 1,3,5 - triazine, CDPT can be used to produce 4-(4,6-diphenyloxy-l,3,5-triazin-2-yl)-4- methylmorpholin-4-ium chloride, DPTMM, which further can be used to prepare following active ester.
- This active ester of formula IB is either isolated or prepared insitu and further converted into Micafungin.
- the compound of Formula IB is used for preparation of Micafungin without isolation.
- each of R[, R 2 , R 3 independently is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, heterocyclic groups or alternatively R
- the isolation and purification process of active esters would depend upon the solvents in which such active ester is prepared.
- the solvent is preferably aprotic and can be one selected from the group consisting of tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide, toluene, 2- methyltetrahydrofuran, N-methyl-2-pyrrolidone (NMP), and any combination thereof.
- solvent is dimethylformamide or tetrahydrofuran.
- the active ester prepared can be obtained by evaporating the solvent to obtain residue.
- the residue is further dissolved in another solvent, preferably aprotic such as ethyl acetate and purified to obtain pure active ester.
- aprotic such as ethyl acetate
- dimethylformamide used as a solvent
- the active ester dissolved therein is precipitated by adding water.
- the precipitated active ester is dissolved in a solvent, preferably aprotic such as ethyl acetate and purified to obtain pure active ester.
- Washings can be given before purification to remove unreacted materials.
- Purity of active ester is usually about or greater than 95 %, preferably greater than
- the most desired properties of active esters of Formula I include i) purity of esters without subjecting to purification step and ii) storage stability for at least 1 month, preferably greater than 3 months and most preferably greater than 6 months.
- the invention relates to the process for preparation of an antifungal agent (MICA) from novel active ester, compound of Formula I.
- MICA antifungal agent
- Micafungin (MICA) of Formula II is prepared from the novel active ester (compound of Formula IA) by reacting with FR-179642 compound of Formula IV as follows:
- Isolated novel active ester can be similarly reacted with Formula IV compound (FR -179642) to produce Micafungin.
- invention relates to process of preparing Micafungin of Formula II from the active ester of Formula IA of the present invention.
- the process can be described in details as follows:
- the process for the preparation of an antifungal agent comprises reacting the active ester of Formula IA with compound of Formula IV (FR- 179642) preferably in presence of a base selected from diisopropylethyl amine, N- methylmorpholine (NMM), pyridines, lutidines, picolines, dimethylaminopyridine, and collidines, and any combination thereof.
- a base selected from diisopropylethyl amine, N- methylmorpholine (NMM), pyridines, lutidines, picolines, dimethylaminopyridine, and collidines, and any combination thereof.
- NMM N- methylmorpholine
- pyridines lutidines
- picolines dimethylaminopyridine
- collidines and any combination thereof.
- the most preferred base diisopropylethyl amine.
- an active ester of Formula IB is prepared from CDPT can produce DPTMM which is further reacted with PPIB or compound of Formula III to produce active ester which is acylated using compound of Formula IV (FR- 179642) to produce Micafungin as follows:
- N-methylmorpholine other bases can be used to prepare several equivalents of DMTMM or DPTMM and these equivalents are further reacted with the FR 179642 or compound of Formula IV to produce Micafungin.
- the DMTMM or DPTMM or their equivalents produced by using bases other than N-methylmorpholine can be isolated or reacted "in situ " with the FR 179642 or compound of Formula IV to produce Micafungin.
- the present invention provides processes to prepare Micafungin using active esters of Formula IA and Formula IB.
- the active esters are reacted either
- Micafungin can be converted into its sodium salt by following methods.
- micellafungin the compound of Formula II is dissolved in solvent such as DMF and sodium 2-ethylhexanoate is added in one portion and stirred at temperature below 25°C for 2-3 h. The mixture is diluted with solvent such as ethyl acetate. The sodium salt of Micafungin compound is precipitated out. The precipitated solid is filtered and washed with ethyl acetate to remove excess reactants and dried. The dried compound is further dissolved in water and lyophilized.
- solvent such as DMF
- sodium 2-ethylhexanoate is added in one portion and stirred at temperature below 25°C for 2-3 h.
- solvent such as ethyl acetate
- the sodium salt of Micafungin compound is precipitated out.
- the precipitated solid is filtered and washed with ethyl acetate to remove excess reactants and dried.
- the dried compound is further dissolved in water and lyophilized.
- compound of the Formula II is reacted or titrated against sodium salts and/ or hydroxides.
- the present invention also provides process for preparation of Micafungin comprising the steps of
- the solvent used in this process of preparing Micafungin is selected from the group consisting of tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide, toluene, 2-methyltetrahydrofuran, N-methyl-2-pyrrolidone (NMP), and mixtures thereof and base is selected from the group consisting of N- methylmorpholine, N,N,N, N-tetramethylguanidine, pyridine, N-methyl-2- pyrrolidone (NMP), triethylamine, 4-picoline, 4-dimethylaminopyridine (DMAP), toluene, JV-methylpiperidine and N, N,N, N-tetramethyl ethyl enediamine, and combination thereof.
- the reaction is carried out overnight at room temperature.
- the present invention provides a process for preparation of Micafungin comprising reacting 4-(5-(4-(pentyloxy)phenyl)isoxazol-3-yl)benzoic acid (PPIB), 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT) or 2-chloro-4,6- diphenyloxy-l,3,5-triazine (CDPT), the compound of Formula IV in presence of a base and isolating Micafungin which is optionally purified.
- PPIB 4-(5-(4-(pentyloxy)phenyl)isoxazol-3-yl)benzoic acid
- CDMT 2-chloro-4,6-dimethoxy-l,3,5-triazine
- CDPT 2-chloro-4,6- diphenyloxy-l,3,5-triazine
- Micafungin prepared according to the present invention is converted into its pharmaceutically acceptable salt.
- the sodium salt of Micafungin is prepared by stirring a solution of Micafungin in alcohol such as methanol and charging with, aqueous solution of sodium 2-ethylhexanoate at 0-5 °C and stirring the mixture for 16 hrs at room temperature.
- THF method Solvent was evaporated and residue dissolved in dichloromethane /chloroform/ethyl acetate (30 volumes) and or other aprotic solvents. The mixture was filtered and the filtrate was washed with water and brine, dried over anhydrous sodium sulfate and evaporated to dryness by rotary evaporator.
- the crude product was further purified by flash column chromatography using dichloromefhane as eluent.
- Method-II To a stirred solution of PPIB in THF/DMF (40 vol.) under N 2 atmosphere, was charged 4-(4,6-Dimefhoxy-l ,3,5-triazin-2-yl)-4- methylmorpholin-4-ium chloride (DMTMM) (1.5 eq.) and stir for 15 min at room temperature. Reaction mixture was cooled to 10-15°C and DIPEA charged slowly. Reaction mixture was allowed to stir for overnight at room temperature and workup and purification was carried as described in method I.
- DTMM 4-(4,6-Dimefhoxy-l ,3,5-triazin-2-yl)-4- methylmorpholin-4-ium chloride
- reaction is carried out in an analogous manner as in example 2 using NMM as base.
- reaction is carried out in an analogous manner as in example 4 for 3-12hrs at 40°C.
- reaction is carried out in an analogous manner as in example 4 for 3-12hrs at 60°C.
- reaction is carried out in an analogous manner as in example 4 for overnight at RT.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN3174MU2014 | 2014-10-07 | ||
PCT/IN2015/000379 WO2016056023A2 (en) | 2014-10-07 | 2015-10-07 | Intermediates and processes to prepare micafungin |
Publications (2)
Publication Number | Publication Date |
---|---|
EP3226885A2 true EP3226885A2 (de) | 2017-10-11 |
EP3226885A4 EP3226885A4 (de) | 2018-07-18 |
Family
ID=55653918
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP15849490.6A Withdrawn EP3226885A4 (de) | 2014-10-07 | 2015-10-07 | Zwischenprodukte und verfahren zur herstellung von micafungin |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP3226885A4 (de) |
WO (1) | WO2016056023A2 (de) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106866650A (zh) * | 2017-01-09 | 2017-06-20 | 博瑞生物医药泰兴市有限公司 | 一种米卡芬净的合成与提纯方法 |
WO2019138299A1 (en) * | 2018-01-09 | 2019-07-18 | Aurozymes | An improved process for the preparation of micafungin sodium |
CN113087775B (zh) * | 2018-05-31 | 2022-07-08 | 杭州中美华东制药有限公司 | 米卡芬净钠新晶型ii及其制备方法 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE229541T1 (de) * | 1994-10-07 | 2002-12-15 | Fujisawa Pharmaceutical Co | Zyklische hexapeptide mit antibiotischer aktivität |
FR2794747B1 (fr) * | 1999-06-09 | 2004-04-16 | Hoechst Marion Roussel Inc | Nouveaux derives de l'echinocandine, leur procede de preparation et leur application comme anti-fongiques |
JP4784093B2 (ja) * | 2002-08-08 | 2011-09-28 | アステラス製薬株式会社 | イソオキサゾリル安息香酸の製造法 |
KR20140069097A (ko) * | 2011-09-09 | 2014-06-09 | 산도즈 아게 | 미카펀진 중간체의 제조 |
-
2015
- 2015-10-07 WO PCT/IN2015/000379 patent/WO2016056023A2/en active Application Filing
- 2015-10-07 EP EP15849490.6A patent/EP3226885A4/de not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
WO2016056023A3 (en) | 2016-07-07 |
WO2016056023A2 (en) | 2016-04-14 |
EP3226885A4 (de) | 2018-07-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Shi et al. | Synthesis and evaluation of a class of new coumarin triazole derivatives as potential antimicrobial agents | |
DK162647B (da) | Fremgangsmaade til fremstilling af pyrido-imidazorifamyciner | |
AU2012233667C1 (en) | Regioselective acylation of Rapamycin at the C-42 position | |
EP3170812A1 (de) | Imidazolverbindung und liposom damit | |
NO329020B1 (no) | Difluorpyridiner | |
AU2015341779B2 (en) | Synthesis of copanlisib and its dihydrochloride salt | |
MX2008008447A (es) | Proceso para la preparacion de imatinib. | |
EP3018127A1 (de) | Synthese von Copanlisib sowie dessen Dihydrochloridsalz | |
WO2016056023A2 (en) | Intermediates and processes to prepare micafungin | |
JP5781432B2 (ja) | ピリピロペン誘導体の製造法 | |
KR20150042847A (ko) | 피라졸 카르복시산 유도체의 제조 방법 | |
EP3802515B1 (de) | Verfahren zur herstellung von apalutamid | |
EP3464319A2 (de) | Zwischenprodukte und verfahren zur herstellung von anidulafungin | |
CN106083807B (zh) | 4-氨基-5-联苯-4-基-2-羟甲基-2-甲基-戊酸化合物及其制备方法 | |
US20230018429A1 (en) | Process for synthesis of (3-chloro-2-pyridyl)hydrazine | |
US5639877A (en) | Intermediates in the synthesis of cephalosporins | |
DK160829B (da) | Fremgangsmaade til fremstilling af pyrido-imidazorifamyciner | |
CA3208625A1 (en) | Synthesis method for aminopyrimidine fak inhibitor compound | |
WO2007038452A1 (en) | Process for synthesizing 1,2,4-triazoles | |
EP2571854B1 (de) | Verfahren zum herstellen von 1-alkyl-3-difluormethyl-5-hydroxypyrazolen | |
KR101529963B1 (ko) | 에베로리무스의 제조방법 및 이의 중간체 | |
KR20140128998A (ko) | 2-페닐-[1,2,4]트라이아졸로[1,5-a]피리딘 유도체의 제조 방법 | |
Ryazanov et al. | Chemoselective cyclocondensation of α-acylacetamidines with 2-methylsulfanyl-4, 6-dichloropyrimidine-5-carbaldehyde | |
CN115960014A (zh) | N-oh谷氨酰胺衍生物及其制备方法与应用 | |
CN111655670A (zh) | 制备2-氯-4-硝基咪唑衍生物的方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20170814 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
A4 | Supplementary search report drawn up and despatched |
Effective date: 20180619 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C07D 261/08 20060101AFI20180613BHEP Ipc: C07D 413/12 20060101ALI20180613BHEP Ipc: A61K 38/12 20060101ALI20180613BHEP |
|
17Q | First examination report despatched |
Effective date: 20190924 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20200205 |