CN111233981A - Preparation method of caspofungin - Google Patents
Preparation method of caspofungin Download PDFInfo
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- CN111233981A CN111233981A CN202010186312.1A CN202010186312A CN111233981A CN 111233981 A CN111233981 A CN 111233981A CN 202010186312 A CN202010186312 A CN 202010186312A CN 111233981 A CN111233981 A CN 111233981A
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- caspofungin
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- pneumocandin
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- 108010020326 Caspofungin Proteins 0.000 title claims abstract description 41
- JYIKNQVWKBUSNH-WVDDFWQHSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-WVDDFWQHSA-N 0.000 title claims abstract description 41
- 229960003034 caspofungin Drugs 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 20
- 108010016309 pneumocandin B(0) Proteins 0.000 claims abstract description 19
- DQXPFAADCTZLNL-FXDJFZINSA-N pneumocandin B0 Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CC(N)=O)=CC=C(O)C=C1 DQXPFAADCTZLNL-FXDJFZINSA-N 0.000 claims abstract description 18
- 238000006467 substitution reaction Methods 0.000 claims abstract description 15
- 238000006722 reduction reaction Methods 0.000 claims abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 17
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- -1 mercapto-substituted pyridine Chemical class 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- XCOBLONWWXQEBS-KPKJPENVSA-N N,O-bis(trimethylsilyl)trifluoroacetamide Chemical group C[Si](C)(C)O\C(C(F)(F)F)=N\[Si](C)(C)C XCOBLONWWXQEBS-KPKJPENVSA-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
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 4
- 238000006884 silylation reaction Methods 0.000 claims description 4
- FHTDDANQIMVWKZ-UHFFFAOYSA-N 1h-pyridine-4-thione Chemical compound SC1=CC=NC=C1 FHTDDANQIMVWKZ-UHFFFAOYSA-N 0.000 claims description 3
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 claims description 3
- FFWJHVGUAKWTKW-UHFFFAOYSA-N pyridine-3-thiol Chemical compound SC1=CC=CN=C1 FFWJHVGUAKWTKW-UHFFFAOYSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 3
- 238000002444 silanisation Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 abstract description 10
- 238000009776 industrial production Methods 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 abstract 1
- 229960002528 ticagrelor Drugs 0.000 abstract 1
- 238000001816 cooling Methods 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 238000002390 rotary evaporation Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 125000003368 amide group Chemical group 0.000 description 5
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000003916 ethylene diamine group Chemical group 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- RCFTWKOEDDCHBF-WXJVFSNFSA-N (2s)-2,5-diamino-4,5-dihydroxypentanoic acid Chemical compound NC(O)C(O)C[C@H](N)C(O)=O RCFTWKOEDDCHBF-WXJVFSNFSA-N 0.000 description 2
- GGZHVNZHFYCSEV-UHFFFAOYSA-N 1-Phenyl-5-mercaptotetrazole Chemical compound SC1=NN=NN1C1=CC=CC=C1 GGZHVNZHFYCSEV-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 2
- 229960003942 amphotericin b Drugs 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000003032 molecular docking Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- MDCWDBMBZLORER-UHFFFAOYSA-N triphenyl borate Chemical compound C=1C=CC=CC=1OB(OC=1C=CC=CC=1)OC1=CC=CC=C1 MDCWDBMBZLORER-UHFFFAOYSA-N 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 206010030154 Oesophageal candidiasis Diseases 0.000 description 1
- 206010042938 Systemic candida Diseases 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 208000017773 candidemia Diseases 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 201000005655 esophageal candidiasis Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000009085 invasive aspergillosis Diseases 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- DKTXXUNXVCHYDO-UHFFFAOYSA-N phenoxyborinic acid Chemical compound OBOC1=CC=CC=C1 DKTXXUNXVCHYDO-UHFFFAOYSA-N 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of caspofungin, which takes pneumocandin B0 as a raw material and prepares the caspofungin through a sulfydryl substitution reaction, an amino substitution reaction and a reduction reaction. The method has the advantages of simple process, less side reaction impurities and high yield, and is suitable for the process amplification preparation to meet the industrial production of the ticagrelor crude drug.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of caspofungin.
Background
Caspofungin (Caspofungin) is a semi-synthetic derivative of pneumocandin B0, the acetate of which was first marketed in the united states in 2001. Caspofungin has broad-spectrum antifungal activity, and is suitable for treating fungal infection, candidemia, esophageal candidiasis, and other drugs such as amphotericin B, amphotericin B liposome, and itraconazole which are ineffective or intolerant for invasive aspergillosis. The chemical structural formula of caspofungin is:
the caspofungin preparation method has different process routes reported in various documents and patents, and is mainly realized by using Pneumocandin B0(Pneumocandin B0) as a raw material, reducing an amido group of the raw material by a reducing agent, and substituting 5-hydroxyl on 4, 5-dihydroxyornithine by ethylenediamine, wherein the following reaction transformations are shown:
the reduction of the amide group can be achieved directly or by dehydration to the nitrile and then reduction of the nitrile to the primary amine; the 5-hydroxyl group on 4, 5-dihydroxyornithine is generally protected by phenylboronate, then reacts with thiol-substituted compounds such as thiophenols and the like serving as stereospecificity selectors to generate thiol-substituted intermediates with easy-to-leave groups, and finally ethylenediamine replaces the thiophenyl group to obtain caspofungin, or the obtained thiol-intermediate is oxidized to generate a sulfone intermediate, and then ethylenediamine is substituted.
Patent WO9747645 and the Journal of Organic Chemistry 2007, vol.72, p.2335-2343 report a stereoselective method for preparing caspofungin starting from pneumocandin B0, by first reacting pneumocandin B0 with thiophenol under the protection of phenylboronate, then continuing the protection of phenylboronate, reducing the amide group to the corresponding amine group, and finally reacting with ethylenediamine, to obtain caspofungin. The thiophenol has the characteristics of strong toxicity, foul smell and pungent smell, and is not suitable for industrial production. Patent CN102219833A uses 2-mercaptobenzothiazole or 1-phenyl-5-mercapto-tetrazole as a stereo characteristic selector, and the same preparation method is performed to obtain caspofungin, however, 2-mercaptobenzothiazole or 1-phenyl-5-mercapto-tetrazole is expensive, and post-treatment purification is not easy and difficult to remove, so new impurities are introduced, and the total yield is reduced. In recent years several patents such as WO02083713a2, WO2012062213a1, WO2012077853a1, CN105440109A, CN105481952A, CN106349337A, CN106478781A and CN107778360A disclose different steric selectors and perform the same docking mode to prepare caspofungin. The methods disclosed in patents WO9624613a1, WO2009151341a1 and US5936062 also use pneumocandin B0 as a raw material to prepare caspofungin, under the protection of phenyl borate, an amide group is reduced to a corresponding amine group, then the corresponding amine group reacts with thiophenol to obtain a mercapto-substituted intermediate, and finally, ethylenediamine is subjected to a substitution reaction to obtain caspofungin. The process has short steps, but the reduction selectivity is poor, the number of byproducts is large, the separation and purification difficulty is high, and therefore, the yield is low.
The methods disclosed in patents WO2010008493a2, WO2012062212a1, WO2012146099a1, CN101648994A, CN101792486A and CN102367269A, etc. report that under the protection of phenyl borate, pneumocandin B0 is firstly reacted with various mercapto-substituted derivative reagents with different structures to obtain mercapto-substituted intermediates, then ethylenediamine is substituted, and finally the amide group is reduced to the corresponding amine group to obtain caspofungin.
In the route disclosed in patent WO2007057141a1, the pneumocandin B0 cyano compound intermediate is first prepared by dehydration, then mercapto substitution and ethylenediamine substitution are carried out under phenyl boronate protection, and finally the nitrile is reduced by hydrogenation to amine to obtain caspofungin. Patents US20100168415a1 and WO2010064219a1 adjusted the docking sequence, after dehydration to give pneumocandin B0 cyano, the nitrile is reduced by hydrogenation to the corresponding amine, followed by sulfhydryl substitution and ethylenediamine substitution to afford caspofungin. The process has long reaction time, so that isomers are changed into new impurities, the difficulty of the refining and purifying process is increased, and the industrial production is not facilitated.
The technological process of WO9421677A1 and WO2012093293A1 is that pneumocandin B0 as material is reacted with alkyl mercaptan or aryl mercaptan to prepare mercapto substituted intermediate, and the mercapto substituted intermediate is oxidized to obtain sulfone intermediate and finally substituted with ethylenediamine to obtain caspofungin. The process has the advantages of long route, complex reaction and low yield.
The disclosed method for preparing caspofungin is not suitable for industrial production in the aspects of yield, stability, purity, time efficiency, three-waste treatment and the like. Most methods require the use of highly toxic, malodorous, irritating, thiol or thiophenol compounds as the stereotypical compound, which can cause serious environmental pollution and risks affecting the health and safety of personnel; in the existing part of preparation methods, a cyano intermediate is introduced, so that more isomer impurities are generated, the yield and the stereoselectivity are not high, expensive metal is required to be used as a hydrogenation catalyst, the industrial cost is high, and a large amount of three wastes are generated by using preparation chromatography for purification for many times. The existing caspofungin preparation technology has various defects and difficulties, so that a caspofungin preparation method which is short in process flow, simple, efficient and low in cost and is suitable for industrial production needs to be explored.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a novel preparation method of caspofungin, which adopts the following technical scheme:
the preparation method of caspofungin comprises the following steps:
(1) pneumocandin B0(Pneumocandin B0) and mercapto-substituted pyridine and phenylboronic acid are subjected to mercapto-substitution reaction in an acid and solvent system to obtain a compound shown in formula 1;
(2) performing amino substitution reaction on the compound shown in the formula 1 and ethylenediamine in a solvent system to obtain a compound shown in the formula 2;
(3) the compound shown in the formula 2 and a reducing agent are subjected to reduction reaction in a silanization reagent and a solvent system to obtain Caspofungin.
The preparation process route of caspofungin comprises the following steps:
preferably, the mercapto-substituted pyridine in the step (1) is 2-mercaptopyridine, 3-mercaptopyridine or 4-mercaptopyridine; the acid is trifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or trifluoroacetic acid; the solvent is acetonitrile, chloroform or methyl tert-butyl ether; the molar ratio of the pneumocandin B0, the mercapto-substituted pyridine, the phenylboronic acid and the acid is 1.0: 2.0-4.0.
Preferably, the solvent in step (2) is methanol, ethanol, tetrahydrofuran, isopropanol, acetonitrile, methyl tert-butyl ether or toluene; the molar ratio of the compound shown in the formula 1 to the ethylenediamine is 1.0: 2.0-4.0.
Preferably, the reducing agent in the step (3) is borane tetrahydrofuran complex or borane dimethyl sulfide complex; the silylation reagent is N, O-bis (trimethylsilyl) trifluoroacetamide or trimethylchlorosilane; the solvent is tetrahydrofuran, acetonitrile or methyl tert-butyl ether; the molar ratio of the compound formula 2, the reducing agent and the silylation reagent is 1.0: 1.5-2.2: 1.5-3.0.
Preferably, the temperature of the sulfydryl substitution reaction in the step (1) is-20 to-10 ℃, and the reaction time is 6 to 12 hours; the temperature of the amino substitution reaction in the step (2) is 20-30 ℃, and the reaction time is 24-36 h; the temperature of the reduction reaction in the step (3) is 20-50 ℃, and the reaction time is 6-12 h; the temperature of the reduction reaction in the step (3) is 20-50 ℃, and the reaction time is 6-12 h.
The technical scheme of the invention adopts mild reaction types and reaction conditions, reduces the generation of side reactions in each step of reaction, and has simple operation, thereby having the following beneficial effects: firstly, reaction steps are simplified and optimized, the reaction in each step has less and controllable impurities, no pollutant is generated, the yield is high, and the green and environment-friendly effect is reflected; secondly, the initial raw materials and the used reagents are safe, environment-friendly, easy to obtain and low in cost, and are suitable for process amplification preparation so as to meet the requirement of industrial production of caspofungin bulk drugs.
Detailed Description
The following non-limiting detailed description of the present invention is provided in connection with several preferred embodiments.
Example 1
A) Preparing a compound of formula 1:
mixing and stirring pneumocandin B0(500g,0.47mol) and acetonitrile (9L), cooling to-20 ℃, slowly adding phenylboronic acid (115g,0.94mol) and 2-mercaptopyridine (105g,0.94mol), reacting at-20 ℃ for 1h, slowly dropwise adding trifluoromethanesulfonic acid (145g,0.97mol), reacting at-20 ℃ for 12h, adding sodium acetate solution, heating to 20 ℃, stirring for 1h, cooling to-5-0 ℃, crystallizing, filtering, purifying a crude product by chromatography, concentrating and drying to obtain a compound formula 1, namely a white solid (510g), wherein the yield is 94%.
B) Preparing a compound of formula 2:
dissolving ethylenediamine (52g,0.87mol) in methanol (500mL), cooling in an ice bath, slowly adding a methanol (8L) solution of the compound of formula 1(500g,0.43mol) dropwise, slowly heating, reacting at 20 ℃ for 36h, adding glacial acetic acid dropwise to adjust to neutrality, carrying out reduced pressure rotary evaporation to dryness, extracting with dichloromethane, washing with saline water and water in sequence, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, and purifying by chromatography to obtain the compound of formula 2, namely a white solid (430g), wherein the yield is 90%.
C) Preparation of caspofungin:
the compound of formula 2(420g,0.38mol) was dissolved in tetrahydrofuran (8L), cooled in an ice bath, borane tetrahydrofuran complex solution (600mL,0.60mol,1M) and N, O-bis (trimethylsilyl) trifluoroacetamide (150g,0.58mol) were slowly added, reacted at 20 ℃ for 12h, rotary evaporated to dryness under reduced pressure, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, rotary evaporated to dryness under reduced pressure, and purified by recrystallization from ethyl acetate-petroleum ether mixed solvent to give caspofungin as white as a solid (400g) in 96% yield.
Example 2
A) Preparing a compound of formula 1:
mixing and stirring pneumocandin B0(800g,0.75mol) and chloroform (12L), cooling to-15 ℃, slowly adding phenylboronic acid (280g,2.3mol) and 3-mercaptopyridine (250g,2.3mol) to react at-15 ℃ for 1h, slowly adding p-toluenesulfonic acid (400g,2.3mol) in batches to react at-15 ℃ for 9h, adding sodium acetate solution, heating to 20 ℃, stirring for 1h, cooling to-5-0 ℃, crystallizing, filtering, purifying a crude product by chromatography, concentrating and drying to obtain a compound shown in formula 1, a white solid (795g) with a yield of 91%.
B) Preparing a compound of formula 2:
dissolving ethylenediamine (120g,2.0mol) in ethanol (1600mL), cooling in an ice bath, slowly adding ethanol (12L) solution of a compound shown in formula 1(790g,0.68mol) dropwise, slowly heating, reacting at 25 ℃ for 30 hours, adding glacial acetic acid dropwise to adjust to neutrality, carrying out reduced pressure rotary evaporation to dryness, extracting with dichloromethane, sequentially washing with saline solution and water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, and purifying by chromatography to obtain a compound shown in formula 2, namely a white solid (665g), wherein the yield is 88%.
C) Preparation of caspofungin:
dissolving the compound shown in the formula 2(660g,0.60mol) in acetonitrile (9L), cooling in an ice bath, slowly adding borane dimethyl sulfide complex solution (600mL,1.2mol,2M) and trimethylchlorosilane (130g,1.2mol), reacting at 40 ℃ for 9h, decompressing and rotary-steaming to dryness, extracting with ethyl acetate, washing with salt water, drying with anhydrous sodium sulfate, decompressing and rotary-steaming to dryness, recrystallizing and purifying by using an ethyl acetate-petroleum ether mixed solvent to obtain caspofungin which is white to solid (625g) and has the yield of 96%.
Example 3
A) Preparing a compound of formula 1:
mixing and stirring pneumocandin B0(1kg,0.94mol) and methyl tert-butyl ether (10L), cooling to-10 ℃, slowly adding phenylboronic acid (450g,3.7mol) and 4-mercaptopyridine (410g,3.7mol), reacting at-10 ℃ for 1h, slowly dropwise adding methanesulfonic acid (360g,3.7mol), reacting at-10 ℃ for 6h, adding sodium acetate solution, heating to 20 ℃, stirring for 1h, cooling to-5-0 ℃, crystallizing, filtering, purifying a crude product by chromatography, concentrating and drying to obtain a compound formula 1, namely a white solid (980g), wherein the yield is 90%.
B) Preparing a compound of formula 2:
dissolving ethylenediamine (200g,3.9mol) in tetrahydrofuran (3L), cooling in ice bath, slowly adding a tetrahydrofuran (12L) solution of a compound formula 1(980g,0.85mol) dropwise, slowly heating, reacting at 30 ℃ for 24h, adding glacial acetic acid dropwise to adjust to neutrality, carrying out reduced pressure rotary evaporation to dryness, extracting with dichloromethane, washing with saline water and water sequentially, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, and purifying by chromatography to obtain a compound formula 2, namely a white solid (830g), wherein the yield is 89%.
C) Preparation of caspofungin:
the compound of formula 2(830g,0.75mol) was dissolved in methyl tert-butyl ether (13L), cooled in an ice bath, borane-tetrahydrofuran complex solution (1600mL,1.6mol,1M) and N, O-bis (trimethylsilyl) trifluoroacetamide (570g,2.2mol) were slowly added, reacted at 50 ℃ for 6h, rotary evaporated to dryness under reduced pressure, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, rotary evaporated to dryness under reduced pressure, and purified by recrystallization from an ethyl acetate-petroleum ether mixed solvent to give caspofungin as white as a solid (772g) in 94% yield.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (5)
1. A preparation method of caspofungin comprises the following steps:
(1) pneumocandin B0(Pneumocandin B0) and mercapto-substituted pyridine and phenylboronic acid are subjected to mercapto-substitution reaction in an acid and solvent system to obtain a compound shown as a formula 1, wherein the reaction formula is as follows:
(2) performing an amino substitution reaction between the compound shown in the formula 1 and ethylenediamine in a solvent system to obtain a compound shown in the formula 2, wherein the reaction formula is as follows:
(3) the compound shown in the formula 2 and a reducing agent are subjected to reduction reaction in a silanization reagent and a solvent system to obtain Caspofungin (Caspofungin), and the reaction formula is as follows:
2. the method for preparing caspofungin according to claim 1, wherein the mercapto-substituted pyridine of step (1) is 2-mercaptopyridine, 3-mercaptopyridine or 4-mercaptopyridine; the acid is trifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or trifluoroacetic acid; the solvent is acetonitrile, chloroform or methyl tert-butyl ether; the molar ratio of the pneumocandin B0, the mercapto-substituted pyridine, the phenylboronic acid and the acid is 1.0: 2.0-4.0.
3. The method according to claim 1, wherein the solvent in step (2) is methanol, ethanol, tetrahydrofuran, isopropanol, acetonitrile, methyl tert-butyl ether or toluene; the molar ratio of the compound shown in the formula 1 to the ethylenediamine is 1.0: 2.0-4.0.
4. The method for preparing caspofungin according to claim 1 wherein the reducing agent in step (3) is borane tetrahydrofuran complex or borane dimethylsulfide complex; the silylation reagent is N, O-bis (trimethylsilyl) trifluoroacetamide or trimethylchlorosilane; the solvent is tetrahydrofuran, acetonitrile or methyl tert-butyl ether; the molar ratio of the compound formula 2, the reducing agent and the silylation reagent is 1.0: 1.5-2.2: 1.5-3.0.
5. The method for preparing caspofungin according to claim 1, wherein the temperature of the sulfhydryl substitution reaction in step (1) is-20 to-10 ℃, and the reaction time is 6 to 12 hours; the temperature of the amino substitution reaction in the step (2) is 20-30 ℃, and the reaction time is 24-36 h; the temperature of the reduction reaction in the step (3) is 20-50 ℃, and the reaction time is 6-12 h; the temperature of the reduction reaction in the step (3) is 20-50 ℃, and the reaction time is 6-12 h.
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| CN106349337A (en) * | 2016-08-30 | 2017-01-25 | 成都摩尔生物医药有限公司 | Caspofungin preparing method |
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