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A kind of method for preparing micafungin

A technology of micafungin and protecting group, which is applied in the field of preparing micafungin, can solve problems such as needs, and achieve the effects of high yield and convenient post-treatment

Inactive Publication Date: 2016-02-17
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that it relies on the echinocandin antibiotic Coleophomaempetri as the raw material basis and requires the support of microbial culture technology
So far, there is no report on the total synthesis of micafungin

Method used

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  • A kind of method for preparing micafungin
  • A kind of method for preparing micafungin
  • A kind of method for preparing micafungin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1: Fmoc-P-OH unnatural amino acid is synthesized through the following three steps:

[0043] (1) Synthesis of ortho-dihydroxyl groups by Sharpless asymmetric dihydroxylation reaction. 70g (217mmol) K 3 Fe(CN) 6 , 29.3g (217mmol) K 2 CO 3 , 53.2 mg (0.14 mmol) K 2 OSo 2 (OH) 4 And 0.56g (0.7mmol) hydroquinidine 1,4-(2,3-naphthyridine) diether ((DHQD) 2 -PHAL) was dissolved in 350ml tert-butanol and 350ml water, and stirred at room temperature for 10 minutes. Add 6.7g (70mmol) amine mesylate, at 0°C, Boc-4-ene-L-ornithinolactam (JournalofOrganometallicChemistry691 (2006), 5487-5496, experimental part) prepared according to the method of known literature 4.3.3, Compound 24) 14.9g (70mmol) was added to the system, and kept at 0°C for 40h. Subsequently, 105 g (833 mmol) of sodium sulfite was added, the reaction was naturally raised to room temperature and stirred for 1 hour, and 700 ml of ethyl acetate was added. The aqueous layer was extracted with ethyl a...

Embodiment 2

[0046] Embodiment 2: the synthesis of Fmoc-P-CTC resin

[0047] Weigh 20.0 g of 2-CTC resin with a substitution degree of 0.7 mmol / g, add it to a solid-phase reaction column, and wash it twice with DMF. After swelling the resin with DMF for 30 minutes, take 24.0g of Fmoc-P-OH and dissolve it in DMF, add 14.6mL of DIPEA in an ice-water bath to activate for 3 minutes, then add it to the above-mentioned reaction column filled with resin, react for 2 hours, add 20mL of anhydrous Methanol blocked for 1 hour. Wash 3 times with DMF and 3 times with DCM, seal with anhydrous methanol for 30 minutes, shrink and dry with methanol to obtain Fmoc-P-CTC resin, the detection degree of substitution is 0.56mmol / g.

Embodiment 3

[0048] Example 3: Synthesis of (4S)-N-Fmoc-4-acetoxy-4-(3'-sodium sulfonate-4'-acetoxy)phenyl-L-threonine:

[0049] Dissolve 50 g (185 mmol) of 3'-acetoxy-4'-benzyloxy-benzaldehyde (Org. Biomol. Chem., 2010, 8, 5199–5211 experimental part compound 29) in 250 ml of freshly distilled DCM, add 101.4 g (185 mmol) of phosphine ylides were reacted with stirring at room temperature for 4 hours, and the reaction liquid was purified by silica gel flash column chromatography to obtain 80.1 g of white solid. Dissolve this solid in 300ml of freshly distilled DCM, add a solution of 15g (277mmol) sodium methoxide in 2300ml of anhydrous methanol, stir and react at room temperature for 30 minutes, add 1500ml of 1mol / L hydrochloric acid solution to acidify, spin off the organic solvent, and use the remaining liquid DCM extraction (3 x 600ml). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate for 2 h, and then concentrated under reduced pr...

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Abstract

The invention relates to a solid phase-liquid phase full synthetic method for preparing micafungin. The method comprises that Fmoc-P-CTC resin serves as a carrier, a solid phase polypeptide synthetic method is adopted to gradually couple amino acid with an Fmoc protecting group from the C end to the N end, and then the protecting group is deprived through splitting, intramolecular reaction and liquid phase condensation to obtain the micafungin. The method is high in yield, brings convenience to aftertreatment and provides a new thinking way for industrial scale production of the micafungin.

Description

technical field [0001] The invention relates to a method for preparing echinocandin antifungal drugs, in particular to a method for preparing micafungin. Background technique [0002] Echinocandins are new semi-synthetic antifungal drugs, which inhibit the synthesis of fungal cell walls by inhibiting the activity of β-1,3-glucan synthase, and have low toxicity and good kinetic properties. Micafungin (Micafungin) is one of the echinocandin antifungal drugs with good performance. It was developed by Fujisawa Co., Ltd. in Japan and was launched in Japan in December 2002 under the trade name Fungusrd. FDA certification, currently approved for the treatment of esophageal candida infection, prevention and treatment of neutropenia in patients with bone marrow transplantation and ADS. [0003] The structure of micafungin is shown below: [0004] [0005] At present, micafungin is mainly prepared by a semi-synthetic method: the acyl group of the exocyclic amide in the structure ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/56C07K1/20C07K1/06C07K1/04
CPCY02P20/55
Inventor 姚志军刘建马亚平袁建成
Owner HYBIO PHARMA
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