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: 2013-06-12
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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  • Method for preparing micafungin
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  • Method for preparing micafungin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0043] (1) Synthesis of ortho-dihydroxyl groups by Sharpless asymmetric dihydroxylation. 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-naphthalene) diether ((DHQD) 2 -PHAL) was dissolved in 350 ml of t-butanol and 350 ml of water and stirred at room temperature for 10 minutes. Add 6.7 g (70 mmol) of amine methanesulfonate, and at 0 °C, Boc-4-ene-L-ornithine lactam prepared according to the method of the known literature (Journal of Organometallic Chemistry 691 (2006), 5487-5496 , experimental part 4.3.3, compound 24) 14.9 g (70 mmol) was added to the system, and the reaction was kept at 0° C. for 40 h. Subsequently, 105 g (833 mmol) of sodium sulfite was added, and the reaction was stirred at room temperature for 1 hour, and 700 ml of ethyl acetate was added. The aqueous layer was ext...

Embodiment 2

[0046] Example 2: Synthesis of Fmoc-P-CTC resin

[0047] 20.0 g of 2-CTC resin with a substitution degree of 0.7 mmol / g was weighed, added to the solid-phase reaction column, and washed twice with DMF. After the resin was swollen with DMF for 30 minutes, 24.0 g of Fmoc-P-OH was dissolved in DMF, 14.6 mL of DIPEA was added under an ice-water bath for activation for 3 minutes, and then added to the above-mentioned reaction column containing the resin. After 2 hours of reaction, 20 mL of DIPEA was added. Water methanol blocked for 1 hour. Washed 3 times with DMF, washed 3 times with DCM, blocked with anhydrous methanol for 30 minutes, shrunk with methanol and drained to obtain Fmoc-P-CTC resin, and the detected substitution degree was 0.56 mmol / g.

Embodiment 3

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

[0049] 50 g (185 mmol) of 3'-acetoxy-4'-benzyloxy-benzaldehyde (Org. Biomol. Chem., 2010, 8, 5199-5211 experimental part compound 29) was dissolved in 250 ml of freshly distilled DCM, added 101.4 g (185 mmol) of phosphine ylide was stirred at room temperature for 4 hours, and the reaction solution was purified by silica gel flash column chromatography to obtain 80.1 g of a white solid. This solid was dissolved in 300ml of freshly distilled DCM, a solution of 15g (277mmol) of sodium methoxide in 2300ml of anhydrous methanol was added, and after stirring at room temperature for 30 minutes, 1500ml of 1mol / L hydrochloric acid solution was added to acidify, and the organic solvent was removed, and the remaining liquid was Extract with DCM (3x600ml). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate for 2 h, and concentr...

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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 fungal cell wall synthesis by inhibiting the activity of β-1,3-glucan synthase, with low toxicity and good kinetic properties. Micafungin (Micafungin) is one of the well-performing echinocandin antifungal drugs, developed by Japan's Fujisawa Company, launched in Japan in December 2002 under the trade name Fungusrd, and passed the United States in March 2005 FDA-approved and currently approved for the prevention and treatment of neutropenia in patients with esophageal candida infection, 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 echinocandin anti...

Claims

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Application Information

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Patent Type & Authority Applications(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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