WO2023035718A1 - 一种棘白菌素药物杂质及其制备、纯化方法和应用 - Google Patents
一种棘白菌素药物杂质及其制备、纯化方法和应用 Download PDFInfo
- Publication number
- WO2023035718A1 WO2023035718A1 PCT/CN2022/099564 CN2022099564W WO2023035718A1 WO 2023035718 A1 WO2023035718 A1 WO 2023035718A1 CN 2022099564 W CN2022099564 W CN 2022099564W WO 2023035718 A1 WO2023035718 A1 WO 2023035718A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- echinocandin
- purifying
- drug
- impurity
- impurities
- Prior art date
Links
- 239000012535 impurity Substances 0.000 title claims abstract description 106
- 108010049047 Echinocandins Proteins 0.000 title claims abstract description 82
- 239000003814 drug Substances 0.000 title claims abstract description 80
- 229940079593 drug Drugs 0.000 title claims abstract description 78
- 238000000034 method Methods 0.000 title claims abstract description 56
- 238000000746 purification Methods 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 108010021062 Micafungin Proteins 0.000 claims abstract description 28
- KOOAFHGJVIVFMZ-WZPXRXMFSA-M micafungin sodium Chemical compound [Na+].C1=CC(OCCCCC)=CC=C1C1=CC(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@H](O)CC(N)=O)[C@H](O)[C@@H](O)C=2C=C(OS([O-])(=O)=O)C(O)=CC=2)[C@@H](C)O)=O)=NO1 KOOAFHGJVIVFMZ-WZPXRXMFSA-M 0.000 claims abstract description 28
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 26
- 229960004806 micafungin sodium Drugs 0.000 claims abstract description 25
- 239000007864 aqueous solution Substances 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 13
- 238000004458 analytical method Methods 0.000 claims abstract description 8
- 239000013558 reference substance Substances 0.000 claims abstract description 6
- 238000003908 quality control method Methods 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 23
- 239000003960 organic solvent Substances 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 23
- 239000011347 resin Substances 0.000 claims description 19
- 229920005989 resin Polymers 0.000 claims description 19
- 238000001179 sorption measurement Methods 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000000741 silica gel Substances 0.000 claims description 17
- 229910002027 silica gel Inorganic materials 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- 238000010828 elution Methods 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 8
- 239000003929 acidic solution Substances 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 238000013375 chromatographic separation Methods 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- 238000002013 hydrophilic interaction chromatography Methods 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- CHRJZRDFSQHIFI-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;styrene Chemical compound C=CC1=CC=CC=C1.C=CC1=CC=CC=C1C=C CHRJZRDFSQHIFI-UHFFFAOYSA-N 0.000 claims description 2
- 101100313763 Arabidopsis thaliana TIM22-2 gene Proteins 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 238000006731 degradation reaction Methods 0.000 abstract description 2
- 230000015556 catabolic process Effects 0.000 abstract 1
- 238000011097 chromatography purification Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 18
- 239000007787 solid Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 206010017533 Fungal infection Diseases 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 241000228212 Aspergillus Species 0.000 description 3
- 108010062877 Bacteriocins Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000000843 anti-fungal effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229960002159 micafungin Drugs 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 2
- 241000244160 Echinococcus Species 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 208000024386 fungal infectious disease Diseases 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229920002498 Beta-glucan Polymers 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000028399 Critical Illness Diseases 0.000 description 1
- 206010017523 Fungaemia Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 239000012612 commercial material Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000012362 drug development process Methods 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- -1 micafungin compound Chemical class 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/16—Extraction; Separation; Purification by chromatography
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/16—Extraction; Separation; Purification by chromatography
- C07K1/22—Affinity chromatography or related techniques based upon selective absorption processes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
Definitions
- the invention relates to the technical field of medicine, and provides an echinocandin drug impurity and its preparation, purification method and application.
- Micafungin sodium as one of the echinocandins, has good antifungal activity and is the first choice for the treatment of infections caused by Candida or Aspergillus. It has a good therapeutic effect, has little effect on human cells, and has clinical effects of low toxicity and high efficiency.
- the echinocandin drug impurity (shown in formula 1) is a by-product in the degradation process of micafungin. Through in-depth research on the impurity, it is found that the impurity is similar in structure to micafungin sodium and has multiple chirality. center, and functional groups such as multiple peptide bonds are extremely unstable to acid, alkali, heat, and light, and there is no literature report on the preparation method of this impurity.
- the inventor has conducted in-depth research on the preparation process of echinocandin drug impurities, referring to the literature [Journal of Synthetic Organic Chemistry 2006,64,12] and patents [US 6107458, US 7199248] for the preparation process of micafungin sodium
- the impurity cannot be effectively removed, and a certain proportion of the unknown compound still exists.
- the impurity content of the unknown compound tended to increase when the micafungin sodium sample was placed in an acidic aqueous solution. Therefore conceive the present invention, design synthesis experiment is about to react micafungin sodium with acid, prepare this impurity.
- the inventor used micafungin sodium as a raw material and reacted it with hydrochloric acid aqueous solution at room temperature, and the obtained RRT 1.1 unknown impurity had a purity of only 3%.
- the inventor optimized the reaction conditions through a large number of experiments, and finally determined the optimal process for synthesizing the unknown impurity of RRT 1.1.
- the impurity is easily degraded during the purification process, and the purification is very difficult.
- the best purification process was determined, and the unknown impurity of RRT1.1 with a HPLC purity of more than 90% was obtained.
- the object of the present invention is to provide an echinocandin drug impurity and its preparation, purification method and application.
- the echinocandin pharmaceutical impurity provided by the present invention has a chemical name of: 5-[(1S,2S)-2-[(3S,6S,9S,11R,15S,18S,20R,21S,24S,25S,26S )-3-[(R)-2-carbamoyl-1-hydroxyethyl]-11,20,21,25-tetrahydroxy-15-[(R)-1-hydroxyethyl]-26-methyl Base-2,5,8,14,17,23-hexaoxo-18-[4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzamido]-1 ,4,7,13,16,22-Hexaazatricyclo[22.3.0.09,13]heptac-6-yl]-1,2-dihydroxyethyl]-2-hydroxyphenyl sodium sulfate, Its structure is shown in formula I.
- the protonic acid in step (a) is a molecule or ion that can donate a proton (H + ).
- the protonic acid aqueous solution in step (a) is selected from acetic acid; the pH of the solution is adjusted to 2.0-3.0.
- reaction temperature in step (b) is 10-80°C.
- reaction temperature in step (b) is 20-50°C.
- reaction time in step (b) is 1-48h.
- reaction time in step (b) is 10-24h.
- the HPLC purity of the reaction product is greater than 20%.
- the invention also provides a further purification method to obtain high-purity echinocandin drug impurities through column chromatography purification.
- the column chromatography purification adopted includes macroporous adsorption resin purification and silica gel purification.
- Macroporous adsorption resin purification specifically comprises the following steps:
- the macroporous adsorption resin used in step (a) has styrene-divinylbenzene as the skeleton.
- the macroporous adsorption resin used in step (a) includes HP20, HP20SS, HP21, SP70, SP700, SP825L, SP850, CHP20, CHP55 or their mixtures, and the present invention is preferably HP20SS macroporous adsorption resin.
- the organic solvent in step (b) is selected from methanol, ethanol, propanol, butanol, acetone, acetonitrile or mixtures thereof.
- the volume percentage of the organic solvent in step (b) is 0%-50% relative to the total volume of the eluent.
- the volume percentage of the organic solvent in step (b) is 0%-40% relative to the total volume of the eluent.
- the volume percentage of the organic solvent in step (c) is preferably 70%-100%.
- the volume percentage of the organic solvent in step (c) is preferably 70%-95%.
- the flow rate is 0.1-10 column bed volumes per hour.
- the flow rate is 0.5-2 column bed volumes per hour.
- the low-temperature concentration temperature in step (c) is 5-25° C. to obtain a concentrated solution containing the impurity components of the echinocandin drug.
- the silica gel is silica gel with a hydrophilic interaction chromatography mode (HILIC).
- the proportion of the organic solvent in the sample solution in step (a) is no more than 5%
- the silica gel is selected from One or a mixture of Chromatorex ARG Silica, Click XIon, Inertsil.
- the organic solvent is selected from one or a combination of methanol, ethanol, acetone, and acetonitrile.
- the volume percentage of the organic solvent and water used is 20%-100%.
- the volume percentage of the organic solvent and water used is 50%-100%.
- the acidic solution is selected from aqueous solutions of formic acid, acetic acid, hydrochloric acid, phosphoric acid, trifluoroacetic acid or mixtures thereof.
- the pH of the acidic solution is 2.0-7.0.
- the pH of the acidic solution is 3.0-5.0.
- the HPLC purity of the obtained echinocandin drug impurity is more than 90%.
- a high-purity echinocandin drug impurity with the structure of formula I can be applied to the quality control of echinocandin drugs and used as a reference substance for establishing an analysis method.
- the high-purity echinocandin drug impurity means that the HPLC purity is above 90%.
- Fig. 1 is the hydrogen nuclear magnetic resonance spectrum ( 1 H NMR) of the echinocandin drug impurity in Example 5.
- Fig. 2 is the carbon nuclear magnetic resonance spectrum ( 13 C NMR) of the echinocandin drug impurity in Example 5.
- Fig. 3 is the high-resolution mass spectrogram (HRMS) of the echinocandin drug impurity in Example 5.
- Fig. 4 is the HPLC spectrogram of echinocandin drug impurity in embodiment 5.
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Analytical Chemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Cell Biology (AREA)
- Microbiology (AREA)
- Food Science & Technology (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
一种棘白菌素药物杂质及其制备、纯化方法和应用。所述棘白菌素药物杂质具有式I所示结构:将米卡芬净钠与质子酸水溶液反应得到棘白菌素药物杂质,再经层析纯化后得到高纯度棘白菌素药物杂质。克服了纯化过程中棘白菌素药物杂质极易降解,纯化难度大等问题,得到的棘白菌素药物杂质的HPLC纯度可达到90%以上。该棘白菌素药物杂质可作为建立分析方法的对照品用于棘白菌素药物质量控制。
Description
本发明涉及医药技术领域,提供一种棘白菌素药物杂质及其的制备、纯化方法和应用。
米卡芬净钠为新一代棘白菌素类抗真菌药物,主要用于治疗由曲霉菌和念珠菌的真菌血症、呼吸道真菌病、胃肠道真菌病,也用于预防造血干细胞患者曲菌霉及念珠菌感染。它是棘白菌素类抗真菌类的一种,能抑制丝状真菌和酵母菌β(1,3)-葡聚糖的合成。
近年来,真菌感染发病率致死率也上升趋势,尤其危重患者更是致命的威胁。米卡芬净钠作为棘白菌素类药物一种,以良好的抗真菌活性,是治疗由念珠菌或曲霉引起的感染药物首选。在治疗方面效果良好,且对人体细胞影响不大,具有低毒高效的临床效果。
棘白菌素药物杂质(式1所示)是米卡芬净降解过程中的副产物,通过对该杂质进行了深入研究,发现该杂质与米卡芬净钠结构类似,具有多个手性中心,以及多个肽键等官能团对酸、碱、热、光极不稳定,目前还没有关于该杂质制备方法的文献报道。
在药物研发过程中,杂质的分析是关键。杂质与药品的质量、安全和稳定性密切相关,对杂质进行制备和结构确证可以了解杂质产生的途径,为药物合成工艺路线和生产工艺的改进提供依据。杂质可应用于药品质量控制,作为建立分析方法的对照品,对于药品生产企业来说,需要对杂质有严格的控制。对棘白菌素药物杂质的相关研究可以用于米卡芬净钠生产中的杂质的定性及定量分析,从而对后续的米卡芬净钠的质量研究提供技术支持,提高米卡芬净钠的质量标准。
因此,目前急需提供一种高效便捷的棘白菌素药物杂质(式1所示)的制备方法。
发明内容
发明人对棘白菌素药物杂质的制备工艺进行了深入研究,参照文献[Journal of Synthetic Organic Chemistry 2006,64,12]及专利[US 6107458,US 7199248]对米卡芬净钠进行制备的过程中,发现HPLC谱图中RRT 1.1位置存在一个未知杂质,该杂质与米卡芬净钠的峰面积比为0.2%。且在后续的重结晶阶段,该杂质并不能有效去除,仍存在一定比例的该未知化合物。在实验过程中,意外的发现将米卡芬净钠样品放置在酸性水溶液中,该未知的化合物杂质含量有升高的趋势。因此构思了本发明,设计合成实验即将米卡芬净钠与酸反应,制备该杂质。
发明人以米卡芬净钠为原料,将其与盐酸水溶液室温下反应,得到的RRT 1.1未知杂质纯度较低仅为3%。发明人经过大量实验将反应条件进行优化,最终确定最优的合成RRT 1.1未知杂质的工艺。当采用层析柱对杂质进行纯化时,发现该杂质在纯化过程中极易降解,纯化难度非常大。通过对纯化条件优化,确定最佳纯化工艺,得到HPLC纯度90%以上的RRT1.1未知杂质。通过对该未知杂质进行结构鉴定,确定该杂质为式1所示化合物。发现其与米卡芬净钠结构区别为C-21位置羟基为S构型,而米卡芬净钠C-21位羟基为R构型。制备工艺中此杂质能够在酸性条件下产生,分析此杂质产生路径为酸性条件下的C-21位羟基消旋的产物。
本发明的目的在于提供一种棘白菌素药物杂质及其制备、纯化方法和应用。
本发明的制备方法,所使用的原辅料均为简单易得的商品化物料。以商品化的米卡芬净为起始原料,意外的发现调节PH在酸性环境下,反应液中棘白菌素药物杂质的HPLC纯度显著提高。本发明同时提供了进一步的纯化方法,纯化过 程中,依次采用大孔吸附树脂和硅胶柱纯化,使得反应液中棘白菌素药物杂质HPLC纯度进一步提高,HPLC纯度最高达到90%以上,为工业化生产提供新的思路。药物杂质对照品的纯度需达到90%以上,是本领域所公知的要求,本发明首次制备出纯度在90%以上的棘白菌素药物杂质,可作为药品质量控制对照品。
本发明提供的棘白菌素药物杂质,其化学名称为:5-[(1S,2S)-2-[(3S,6S,9S,11R,15S,18S,20R,21S,24S,25S,26S)-3-[(R)-2-氨甲酰基-1-羟乙基]-11,20,21,25-四羟基-15-[(R)-1-羟乙基]-26-甲基-2,5,8,14,17,23-六氧代-18-[4-[5-(4-戊氧基苯基)异恶唑-3-基]苯甲酰氨基]-1,4,7,13,16,22-六氮杂三环[22.3.0.09,13]二十七-6-基]-1,2-二羟乙基]-2-羟苯基硫酸钠,其结构见式I。
本发明制备方法包括如下步骤:
(a)配制质子酸水溶液,调节水溶液PH值
(b)将米卡芬净钠加入质子酸水溶液中,加热。
作为上述制备方法的进一步改进,步骤(a)中所述质子酸即能给出质子(H
+)的分子或离子。
作为上述制备方法的进一步改进,步骤(a)中所述质子酸水溶液选自甲酸、硫酸、盐酸、磷酸、醋酸,磷酸二氢钠中的任意一种或它们的组合;将溶液的pH调节为1.0-6.0。
作为上述制备方法的进一步改进,步骤(a)中所述质子酸水溶液选自醋酸; 将溶液的pH调节为2.0-3.0。
作为上述制备方法的进一步改进,步骤(b)中反应温度为10-80℃。
作为上述制备方法的进一步改进,步骤(b)中反应温度为20-50℃。
作为上述制备方法的进一步改进,步骤(b)中反应时间为1-48h。
作为上述制备方法的进一步改进,步骤(b)中反应时间为10-24h。
本发明提供的棘白菌素药物杂质的优选制备方法,反应产物中HPLC纯度大于20%。
本发明还提供了进一步的纯化方法,通过柱层析纯化得到高纯度棘白菌素药物杂质。
作为上述制备方法的进一步改进,采用的柱层析纯化包括大孔吸附树脂纯化和硅胶纯化。
大孔吸附树脂纯化具体包括如下步骤:
(a)将反应产物使用大孔吸附树脂进行吸附;
(b)采用有机溶剂进行洗脱得到收集液;
(c)再用有机溶剂进行洗脱得到收集液,并进行低温浓缩。
作为上述纯化方法的进一步改进,步骤(a)中所用大孔吸附树脂为以苯乙烯-二乙烯苯为骨架。
作为上述纯化方法的进一步改进,步骤(a)中所用大孔吸附树脂包括HP20、HP20SS、HP21、SP70、SP700、SP825L、SP850、CHP20、CHP55或它们的混合物,本发明优选的是HP20SS大孔吸附树脂。
作为上述纯化方法的进一步改进,步骤(b)中所述有机溶剂选自甲醇、乙醇、丙醇、丁醇、丙酮、乙腈或它们的混合物。
作为上述纯化方法的进一步改进,步骤(b)中有机溶剂的体积百分比相对于洗脱液的总体积为0%-50%。
作为上述纯化方法的进一步改进,步骤(b)中有机溶剂的体积百分比相对于洗脱液的总体积为0%-40%。
作为上述纯化方法的进一步改进,步骤(c)中有机溶剂的体积百分比优选为70%-100%。
作为上述纯化方法的进一步改进,步骤(c)中有机溶剂的体积百分比优选 为70%-95%。
作为上述纯化方法的进一步改进,纯化时温度控制在10-30℃。
作为上述纯化方法的进一步改进,纯化时温度控制在15-25℃。
作为上述纯化方法的进一步改进,所述的流过速度为每小时0.1-10个柱床体积。
作为上述纯化方法的进一步改进,所述的流过速度为每小时0.5-2个柱床体积。
作为上述纯化方法的进一步改进,步骤(c)中低温浓缩温度为5-25℃,得到含有棘白菌素药物杂质组分的浓缩液。
硅胶纯化具体包括如下步骤:
(a)将上述浓缩液稀释后,配制上样液,并通过硅胶柱进行吸附。
(b)采用有机溶剂的酸性水溶液进行洗脱;
作为上述纯化方法的进一步改进,所述的硅胶是具有亲水作用色谱模式(HILIC)的硅胶。
作为上述纯化方法的进一步改进,步骤(a)上样液中有机溶剂的比例不超过5%,
作为上述纯化方法的进一步改进,所述有机溶剂选自甲醇、乙醇、丙酮、乙腈中的一种或者组合溶剂。
作为上述纯化方法的进一步改进,所用有机溶剂与水的体积百分比为20%-100%。
作为上述纯化方法的进一步改进,所用有机溶剂与水的体积百分比为50%-100%。
作为上述纯化方法的进一步改进,所述酸性溶液选自甲酸、乙酸、盐酸、磷酸、三氟乙酸或它们混合物的水溶液。
作为上述纯化方法的进一步改进,所述酸性溶液的pH值为2.0-7.0。
作为上述纯化方法的进一步改进,所述酸性溶液的pH值为3.0-5.0。
作为上述纯化方法的进一步改进,通过层析柱纯化后,获得的棘白菌素药物 杂质的HPLC纯度为90%以上。
将收集液组分在20℃以下浓缩,冷冻干燥得到该棘白菌素药物杂质成品。
一种式I结构的高纯度的棘白菌素药物杂质,可应用于棘白菌素药物质量控制,作为建立分析方法的对照品。高纯度的棘白菌素药物杂质是指HPLC纯度为90%以上。
图1是实施例5中棘白菌素药物杂质的核磁共振氢谱图(
1H NMR)。
图2是实施例5中棘白菌素药物杂质的核磁共振碳谱图(
13C NMR)。
图3是实施例5中棘白菌素药物杂质高分辨质谱图(HRMS)。
图4是实施例5中棘白菌素药物杂质HPLC谱图。
下面结合具体实施例,对本发明作进一步的说明。
比较例1
参照文献[Journal of Synthetic Organic Chemistry 2006,64,12]及专利[US 6107458,US 7199248]将米卡芬净钠侧链(100g)溶解于DMF(2.0L)中,降温至0℃,加入DIPEA(22.3ml),搅拌5min后加入FR-179642(100g),保温反应1.5h。加入甲醇/丙酮(V:V=1:2)1.0L,再加入12L乙酸乙酯搅拌12h后过滤,得到米卡芬净合成物。通过UBK树脂纯化,得到含有0.2%棘白菌素药物杂质。再通过HP20SS柱层析,将收集液进行结晶得到米卡芬净钠,HPLC谱图中棘白菌素药物杂质纯度为0.1%。
实施例1
在反应瓶中加入水100mL,缓慢滴加浓盐酸,直至PH至1.0;加入1.0g米卡芬净钠搅拌至固体溶解,控制反应液温度为45℃,搅拌24小时,取样分析,其反应液中棘白菌素药物杂质的HPLC纯度为3%。
实施例2
在反应瓶中加入水100mL,缓慢滴加浓硫酸,直至PH至2.0;加入1.0g米卡芬净钠搅拌至固体溶解,控制反应液温度为50℃,搅拌24小时,取样分析,其反应液中棘白菌素药物杂质的HPLC纯度为8%。
实施例3
在反应瓶中加入水100mL,缓慢滴加磷酸,直至PH至4.0,加入1.0g米卡芬净钠搅拌至固体溶解,控制反应液温度为55℃,搅拌24小时,取样分析,其反应液中棘白菌素药物杂质的HPLC纯度为12%。
实施例4
在反应瓶中加入水100mL,缓慢滴加醋酸,直至PH至3.0;加入1.0g米卡芬净钠搅拌至固体溶解,控制反应液温度为45℃,搅拌36小时,其反应液中棘白菌素药物杂质的HPLC纯度为23%。
实施例5
在反应瓶中加入水100mL,缓慢滴加醋酸,直至PH至2.8;加入1.0g米卡芬净钠搅拌至固体溶解,控制反应液温度为50℃,搅拌24小时,其反应液中棘白菌素药物杂质的HPLC纯度为21%。反应结束后,先采用20mlHP20ss树脂进行吸附,40ml 50%甲醇进行洗涤,60ml 90%甲醇洗脱。收集、减压蒸馏,浓缩得到含有棘白菌素药物杂质组分收集液。然后再使用Click Xion硅胶进行层析分离,使用PH约为4.0的60%乙腈水溶液进行洗脱,得到棘白菌素药物杂质,HPLC纯度为92%,冻干后得到白色固体30mg。
1H NMR(DMSO-d6,400MHz)δ:0.91(t,J=8.0Hz,3H),0.99(d,J=8.0Hz,3H),1.27(d,J=4.0Hz,3H),1.29-1.45(m,4H),1.73-1.77(m,3H),1.87-1.93(m,2H),2.20-2.30(m,4H),3.22(t,J=4.0Hz,1H),3.58-3.60(m,1H),3.78(s,2H),3.94(m,1H),4.06-4.12(m,5H),4.22(m,2H),4.36-4.41(m,3H),4.59(m,2H),4.86-4.88(m,2H),4.98(s,1H),5.21-5.30(m,3H),5.33(d,J=4.0Hz,1H),5.64(d,J=4.0Hz,1H),6.76(d,J=8.0Hz,1H),6.85 (d,J=8.0Hz,1H),6.99(s,1H),7.05(s,1H),7.08-7.20(m,4H),7.45(b,1H),7.55(b,2H),7.84(d,J=8.0Hz,2H),8.00-8.04(m,4H),8.46(d,J=8.0Hz,1H),8.86(s,1H).
13C NMR(DMSO-d6,400MHz)δ:11.30,14.39,19.74,22.35,28.13,28.74,33.37,37.62,37.62,38.61,49.07,51.60,54.78,56.80,57.11,57.66,60.54,66.30,68.23,69.20,69.20,69.79,72.92,73.86,74.01,74.77,75.71,97.73,115.67,115.67,117.25,119.76,122.20,123.87,126.85,126.85,127.79,127.79,128.60,128.60,131.59,134.11,136.05,140.91,148.96,160.91,162.43,165.47,169.23,169.34,170.56,170.56,171.70,171.90,171.90,172.95.
HRMS(ESI):calcd.For C
56H
70O
23N
9Na
2S(M+Na
+):1314.41089,Found:1314.4095.
表1 实施例5中棘白菌素药物杂质HPLC谱图组成结果部分
实施例6
在反应瓶中依次加入水100mL,缓慢滴加甲酸,直至PH至3.0;加入1.0g米卡芬净钠搅拌至固体溶解,控制反应液温度为45℃,搅拌48小时,其反应液 中棘白菌素药物杂质的HPLC纯度为20%。反应结束后,先采用20mlHP20ss树脂进行吸附,40ml 30%甲醇进行洗涤,60ml 85%甲醇洗脱。收集、减压蒸馏,浓缩得到含有棘白菌素药物杂质组分收集液。然后再使用Chromatorex ARG Silica硅胶进行层析分离,使用PH约为6.0的70%乙腈水溶液进行洗脱,得到棘白菌素药物杂质,HPLC纯度为90%,冻干后得到白色固体60mg。
实施例7
在反应瓶中依次加入水100mL,缓慢滴加醋酸,直至PH至3.0;加入1.0g米卡芬净钠搅拌至固体溶解,控制反应液温度为45℃,搅拌24小时,其反应液中棘白菌素药物杂质的HPLC纯度为8%。反应结束后,先采用20ml SP207树脂进行吸附,40ml 1%乙醇进行洗涤,60ml 95%丙醇洗脱。收集、减压蒸馏,浓缩得到含有棘白菌素药物杂质组分收集液。然后再使用Inertsil硅胶进行层析分离,使用PH约为3.0的60%乙腈水溶液进行洗脱,得到棘白菌素药物杂质,HPLC纯度为91%,冻干后得到白色固体30mg。
实施例8
Claims (28)
- 一种式I结构的棘白菌素药物杂质的制备方法,其特征在于:将米卡芬净钠与质子酸水溶液反应,得到如式I所示化合物。
- 如权利要求2所述的棘白菌素药物杂质的制备方法,其特征在于:所述质子酸即能给出质子的分子或离子,加入质子酸调节反应液pH至酸性。
- 如权利要求2所述的棘白菌素药物杂质的制备方法,其特征在于:所述质子酸水溶液选自甲酸、硫酸、盐酸、磷酸、醋酸,磷酸二氢钠中的任意一种或它们的组合;将反应液pH调节为1.0-6.0。
- 如权利要求2所述的棘白菌素药物杂质的制备方法,其特征在于:所述质子酸水溶液为醋酸;将反应液pH调节为2.0-3.0;其反应产物式I所示化合物中HPLC纯度大于20%。
- 一种式I结构的棘白菌素药物杂质的纯化方法,其特征在于:通过柱层析纯化得到高纯度棘白菌素药物杂质。
- 如权利要求6所述的棘白菌素药物杂质的纯化方法,其特征在于:所述的柱层析纯化包括大孔吸附树脂纯化和硅胶纯化。
- 如权利要求7所述的棘白菌素药物杂质的纯化方法,其特征在于:所述的大孔吸附树脂纯化步骤包括:a)将反应产物使用大孔吸附树脂进行吸附;b)采用有机溶剂进行洗脱得到收集液;c)再用有机溶剂进行洗脱得到收集液。
- 如权利要求8所述的棘白菌素药物杂质的纯化方法,其特征在于:所述的大孔吸附树脂为以苯乙烯-二乙烯苯为基本骨架。
- 如权利要求9所述的棘白菌素药物杂质的纯化方法,其特征在于:所述的大孔吸附树脂选自:HP20、HP20SS、HP21、SP70、SP700、SP825L、SP850、CHP20、CHP55或它们的混合物。
- 如权利要求8所述的棘白菌素药物杂质的纯化方法,其特征在于:所述有机溶剂选自甲醇、乙醇、丙醇、丁醇、丙酮、乙腈或它们的混合物。
- 如权利要求8所述的棘白菌素药物杂质的纯化方法,其特征在于:在步骤b)中有机溶剂的体积百分比相对于洗脱液的总体积为0%-50%。
- 如权利要求12所述的棘白菌素药物杂质的纯化方法,其特征在于:在步骤b)中有机溶剂的体积百分比相对于洗脱液的总体积为0%-40%。
- 如权利要求8所述的棘白菌素药物杂质的纯化方法,其特征在于:步骤c)中有机溶剂的体积百分比为70%-100%。
- 如权利要求14所述的棘白菌素药物杂质的纯化方法,其特征在于:步骤c)中有机溶剂的体积百分比为70%-95%。
- 如权利要求8所述的棘白菌素药物杂质的纯化方法,其特征在于:纯化时温度控制在10-30℃。
- 如权利要求16所述的棘白菌素药物杂质的纯化方法,其特征在于:纯化时温度控制在15-25℃。
- 如权利要求7所述的棘白菌素药物杂质的纯化方法,其特征在于:所述的硅胶纯化步骤包括:将大孔吸附树脂纯化后含药物杂质组分的收集液通过硅胶柱进行吸附,再通过有机溶剂的酸性水溶液进行洗脱。
- 如权利要求18所述的棘白菌素药物杂质的纯化方法,其特征在于:所述的硅胶是具有亲水作用色谱模式的硅胶。
- 如权利要求18所述的棘白菌素药物杂质的纯化方法,其特征在于:所述有机溶剂选自甲醇、乙醇、丙酮、乙腈或它们的混合物。
- 如权利要求21所述的棘白菌素药物杂质的纯化方法,其特征在于:有机溶剂的体积百分比为20%-100%。
- 如权利要求22所述的棘白菌素药物杂质的纯化方法,其特征在于:有机溶剂的体积百分比为50%-100%。
- 如权利要求18所述的棘白菌素药物杂质的纯化方法,其特征在于:所述酸性溶液选自甲酸、乙酸、盐酸、磷酸、三氟乙酸或它们混合物的水溶液。
- 如权利要求24所述的棘白菌素药物杂质的纯化方法,其特征在于:所述酸性溶液的pH值为2.0-7.0。
- 如权利要求25所述的棘白菌素药物杂质的纯化方法,其特征在于:所述酸性溶液的pH值为3.0-5.0。
- 如权利要求7所述的棘白菌素药物杂质的纯化方法,其特征在于:使用HP20ss树脂进行吸附,50%甲醇进行洗涤,90%甲醇洗脱;收集、减压蒸馏,浓缩得到含有棘白菌素药物杂质组分收集液;使用Click Xion硅胶进行层析分离,使用PH4.0的60%乙腈水溶液进行洗脱,得到棘白菌素药物杂质。
- 式I结构的高纯度的棘白菌素药物杂质在棘白菌素药物质量控制中的应用,其特征在于式I结构的高纯度的棘白菌素药物杂质作为建立分析方法的对照品。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111057760.2A CN115785226A (zh) | 2021-09-09 | 2021-09-09 | 一种棘白菌素药物杂质及其制备、纯化方法和应用 |
CN202111057760.2 | 2021-09-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023035718A1 true WO2023035718A1 (zh) | 2023-03-16 |
Family
ID=85473507
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/099564 WO2023035718A1 (zh) | 2021-09-09 | 2022-06-17 | 一种棘白菌素药物杂质及其制备、纯化方法和应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN115785226A (zh) |
WO (1) | WO2023035718A1 (zh) |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1604908A (zh) * | 2001-12-14 | 2005-04-06 | 安万特医药股份有限公司 | 制备棘白菌素衍生物的方法 |
US20050227914A1 (en) * | 2002-08-08 | 2005-10-13 | Fujisawa Pharmaceutical Co., Ltd. | New process |
CN102219832A (zh) * | 2010-04-15 | 2011-10-19 | 上海天伟生物制药有限公司 | 一种氮杂环六肽或其盐的纯化方法 |
CN102627688A (zh) * | 2012-03-30 | 2012-08-08 | 上海天伟生物制药有限公司 | 一种高纯度环肽化合物及其制备方法和用途 |
CN104861044A (zh) * | 2014-05-29 | 2015-08-26 | 上海天伟生物制药有限公司 | 一种环肽类化合物的溶剂合物及其制备方法和用途 |
CN105524144A (zh) * | 2016-01-14 | 2016-04-27 | 山东鲁北药业有限公司 | 棘白菌素b的提取纯化方法 |
CN109734760A (zh) * | 2018-11-01 | 2019-05-10 | 丽珠集团新北江制药股份有限公司 | 一种多拉菌素杂质的制备方法 |
CN113087774A (zh) * | 2020-01-09 | 2021-07-09 | 鲁南制药集团股份有限公司 | 棘白菌素b母核降解杂质的去除方法 |
-
2021
- 2021-09-09 CN CN202111057760.2A patent/CN115785226A/zh active Pending
-
2022
- 2022-06-17 WO PCT/CN2022/099564 patent/WO2023035718A1/zh active Application Filing
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1604908A (zh) * | 2001-12-14 | 2005-04-06 | 安万特医药股份有限公司 | 制备棘白菌素衍生物的方法 |
US20050227914A1 (en) * | 2002-08-08 | 2005-10-13 | Fujisawa Pharmaceutical Co., Ltd. | New process |
CN102219832A (zh) * | 2010-04-15 | 2011-10-19 | 上海天伟生物制药有限公司 | 一种氮杂环六肽或其盐的纯化方法 |
CN102627688A (zh) * | 2012-03-30 | 2012-08-08 | 上海天伟生物制药有限公司 | 一种高纯度环肽化合物及其制备方法和用途 |
CN104861044A (zh) * | 2014-05-29 | 2015-08-26 | 上海天伟生物制药有限公司 | 一种环肽类化合物的溶剂合物及其制备方法和用途 |
CN105524144A (zh) * | 2016-01-14 | 2016-04-27 | 山东鲁北药业有限公司 | 棘白菌素b的提取纯化方法 |
CN109734760A (zh) * | 2018-11-01 | 2019-05-10 | 丽珠集团新北江制药股份有限公司 | 一种多拉菌素杂质的制备方法 |
CN113087774A (zh) * | 2020-01-09 | 2021-07-09 | 鲁南制药集团股份有限公司 | 棘白菌素b母核降解杂质的去除方法 |
Non-Patent Citations (1)
Title |
---|
OHIGASHI, A. ET AL.: "Process Development of Micafungin, a Novel Lipopeptide Antifungal Agent.", JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY., vol. 64, no. 12, 31 December 2006 (2006-12-31), XP007920568, DOI: 10.5059/yukigoseikyokaishi.64.1294 * |
Also Published As
Publication number | Publication date |
---|---|
CN115785226A (zh) | 2023-03-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9233318B2 (en) | Purification method of azacyclohexapeptide or its salt | |
KR20110011704A (ko) | 카스포펀진 불순물 a를 함유하지 않는 카스포펀진 | |
EP2623511B1 (en) | Process for purifying cyclic lipopeptide compounds or salts thereof | |
KR20140139122A (ko) | 고순도 고리형 펩티드 화합물 및 그 제조방법과 용도 | |
US9056897B2 (en) | Method for isolating a cyclohexapeptide | |
TWI488862B (zh) | Separation and Purification of Cyclohexyl Compounds and Their Salts | |
WO2023035718A1 (zh) | 一种棘白菌素药物杂质及其制备、纯化方法和应用 | |
US20130303753A1 (en) | Preparation method of rocuronium | |
EP3239162A1 (en) | Crystallization water-free calcium dibutyryladenosine cyclophosphate crystal form, and preparation method and use thereof | |
CN106946907A (zh) | 从菌丝体中分离纯化他克莫司的方法及应用 | |
US20170275335A1 (en) | Improved process for preparation of amorphous linaclotide | |
KR20130060267A (ko) | 펩타이드계 물질의 결정체 및 그의 제조방법과 용도 | |
CN113624898B (zh) | 一种手性镇痛类多肽药物的纯化方法 | |
CN107778360B (zh) | 一种制备醋酸卡泊芬净的方法 | |
EP3202772B1 (en) | Crystal of a complex of l-proline/sodium-glucose cotransporter 2 inhibitor | |
US8586545B2 (en) | Solid materials of {[(2S, 5R,8S,11S)-5-benzyl-11-(3-guanidino-propyl)-8-isopropyl-7-methyl-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acid} and methods for obtaining them | |
WO2021017793A1 (zh) | 一种化学合成酸性多肽的制备方法 | |
EP3915993A1 (en) | Crystal form of 1,2,3-triazolo[1,5-a]pyrazines derivative and preparation method for crystal form | |
CN114405065B (zh) | 一种利用动态热力学平衡纯化制备手性多肽型药物的方法 | |
CN110903334A (zh) | 一种1,3-n-乙基加洛糖胺的合成方法 | |
CN110903346B (zh) | 一种制备盐酸万古霉素杂质ImpC的方法 | |
CN108383841B (zh) | 一种替比培南酯中间体及其原料的制备方法 | |
CN104725470B (zh) | 一种他替瑞林新晶型及其制备方法与应用 | |
CN110066304B (zh) | 1-n-乙基小诺霉素的合成方法 | |
CN110845598A (zh) | 一种乌拉立肽杂质 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 18006110 Country of ref document: US |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22866193 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |