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Process for preparing caspofungin and intermediates thereof

一种化合物、分子式的技术，应用在抗真菌剂、肽等方向，能够解决材料损耗等问题

Inactive Publication Date: 2011-06-29
CELIA PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Since the mainstream method for producing caspofungin involves multiple synthesis and purification steps, and a large amount of material is lost during the process, there is a need for an improved method for producing caspofungin
In addition, the most efficient existing process relies on extremely foul-smelling and highly toxic thiophenol as an auxiliary agent

Method used

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  • Process for preparing caspofungin and intermediates thereof
  • Process for preparing caspofungin and intermediates thereof
  • Process for preparing caspofungin and intermediates thereof

Examples

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example

[0073] The present invention will now be described in detail with reference to examples, but the examples should not be construed as limiting the scope of the present invention and the appended claims.

[0074] High performance liquid chromatography (HPLC) analysis is carried out under the following conditions: chromatographic column Waters Symmetry C18, 250x 4.6mm, 5μm; column temperature: 45°C; mobile phase: solution A: 0.1% v / v perchloric acid aqueous solution, solution B: acetonitrile, elution gradient 67 / 33A:B to 35 / 65A:B; flow rate: 1.5mL / min ; Detection: 205nm; Integration setting: peak area %; Solution: acetonitrile / water 1:1. Mass spectra were acquired under electrospray ionization conditions, with the device operating in positive ion mode. Analytes are detected in protonated form.

example 1

[0076] A compound of formula VIII, R 1 =-(CO)NH 2 ，R 2 ＝R 3 ＝H

[0077] Neomocontin B 0 (2.02 g (grams), 1.90 mmol (mmol)) and trifluoromethanesulfonic acid (3.0 mL (milliliter), 5.09 g, 33.9 mmol) were dissolved in pyridine (30 mL). The mixture was heated to 80 °C and stirred under an inert atmosphere for 12 h (hours). After cooling to 0°C, 1,2-ethylenediamine (1.00 mL, 0.90 g, 15.0 mmol) was added and the mixture was stirred overnight. The reaction was cooled by adding the reaction mixture to a mixture of water (100 mL) and acetic acid (21 mL, 22.0 g, 0.37 mol) to give a solution at pH 5.0. The solution was loaded into a chromatographic column and eluted with a gradient of 20% acetonitrile / 80% water to 25% acetonitrile / 75% water. Evaporation of the organic solvent and lyophilization of the rich cuts afforded 534 mg (22% yield) of the title compound as the triflic acid addition salt. HPLC purity: 87.8%.

[0078] 1 H NMR (nuclear magnetic resonance) (6...

example 2

[0080] A compound of formula VIII, R 1 =-(CO)NH 2 ，R 2 ＝R 3 ＝H

[0081] Neomercantin B 0 (100 mg (milligram), 0.094 mmol) was dissolved in pyridine (2 mL), and triethylsilyl triflate (107 μL (microliter), 125 mg, 0.47 mmol) was added. The mixture was stirred at 80 °C for 12 h and the progress of the reaction was monitored by HPLC. After stirring overnight, HPLC showed 72% conversion into new compounds (compound VI, R 1 =-(CO)NH 2 ). LC-MS (liquid chromatography-mass spectrometry) showed m / z 1126.4 as the major product, which confirmed the pyridine substitution. The mixture was cooled to room temperature, and 1,2-ethylenediamine (2 mL) was added. After 15 minutes HPLC showed complete conversion of the pyridine addition to another product with LC-MS mass to nucleus ratio m / z of 1107.6 Å, the predicted mass of the title compound. No separation of the product was performed.

[0082] Example 3

[0083] Compound of formula III

[0084] Neomocontin B ...

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Abstract

The present invention relates to novel intermediates of formula (VII), or an acid addition salt or a solvate thereof, wherein R1 is -(CO)NH2, -CH2NH2 or -CN; R2 = R3 = H or R2 and R3 together form a cyclic boronate or borate ester; X is a helping group selected from the group consisting of i) a five or six membered heterocyclic aromatic ring and derivatives thereof comprising at least one N-atom being a part of an imine-group, wherein said N-atom forms the point of connection to the cyclohexapeptide ring, and ii) tetrazolyl and derivatives thereof for which a nitrogen atom forms the point of connection to the cyclohexapeptide ring, and a process for the preparation of caspofungin utilizing said intermediates.

Description

technical field [0001] The present invention relates to an improved process for the preparation of caspofungin characterized by formula I. [0002] Background technique [0003] Caspofungin is a novel semi-synthetic echinocandins antifungal agent. The drug passed through pneumocontin B 0 Synthetic derivatization preparation, while pneumocantine B 0 It is produced by the fermentation of the fungus Glarea lozoyensis. Caspofungin prevents the biosynthesis of β-(1,3)-D-glucan, an essential part of the fungal cell wall, and is used to treat invasive aspergillosis in patients who are refractory to or cannot tolerate other treatments , and for the empirical treatment of febrile and neutropenic patients. Caspofungin is commercially available under the trademark Cancidas from Merck & Co. of diacetate. [0004] Caspofungin is a compound claimed in US Patent No. 5,378,804 authorized to Merck & Co. The drug consists of pneumocontin B 0 Prepared through a lengthy synthetic se...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/54
CPCC07K7/56A61P31/10
Inventor 澳顿·海格路德欧尔·海内·科佛内内斯维达尔·乔尼斯塔德
Owner CELIA PHARM
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