Preparation method of maytenin-like ester and composition used in method

A compound and alkyl technology, applied in the field of preparation of maytansinoid esters, can solve the problem of not giving the reaction yield and so on

Active Publication Date: 2015-02-25
BIO THERA SOLUTIONS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although U.S. Patent US20060167245 claims that epimerization of chiral centers does not occur, no reaction yield is given

Method used

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  • Preparation method of maytenin-like ester and composition used in method
  • Preparation method of maytenin-like ester and composition used in method
  • Preparation method of maytenin-like ester and composition used in method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0765] Esterification of maytansinol with acetic acid

[0766]

[0767] Weigh maytansinol (6.0mg, 0.01062mmol), acetic acid (12.75mg, 0.2124mmol), scandium triflate (3.14mg, 0.00637mmol) and DMAP (3.89mg, 0.03186mmol) into a 5ml Schlenck bottle , added dichloromethane (1 mL) under nitrogen protection, and stirred at -8°C for 0.5 hours. Add DIC (29.49mg, 0.2337mmol) dropwise, continue to stir the reaction until the reaction is complete, quench with dilute hydrochloric acid, extract with dichloromethane, wash with saturated sodium bicarbonate and saturated brine successively, dry over anhydrous sodium sulfate, spin dry solvent. Column chromatography (silica gel, CH 2 Cl 2 / MeOH30:1) to obtain the desired product ansamitocin (ansamitocin) P1. LC-MS (M+Na + ) calculated value: 629.2, measured value: 629.3.

Embodiment 2

[0769] Esterification of maytansinol with isobutyric acid

[0770]

[0771] Weigh maytansinol (6.0mg, 0.01062mmol), isobutyric acid (23.60mg, 0.2124mmol), scandium trifluoromethanesulfonate (3.14mg, 0.00637mmol) and DMAP (3.89mg, 0.03186mmol) into 5ml Schlenck bottle, add dichloromethane (1 mL) under nitrogen protection, and stir at -8oC for 0.5 hours. Add DIC (29.49mg, 0.2337mmol) dropwise, continue to stir the reaction until the reaction is complete, quench with dilute hydrochloric acid, extract with dichloromethane, wash with saturated sodium bicarbonate and saturated brine successively, dry over anhydrous sodium sulfate, spin dry solvent. Column chromatography (silica gel, CH 2 Cl 2 / MeOH30:1) to obtain the desired product ansamitocin (ansamitocin) P3. LC-MS (M+Na+) calculated: 657.3, found: 657.4.

Embodiment 3

[0773] Esterification of maytansinol with mono(2-trimethylsilylethyl) adipate

[0774]

[0775] Weigh maytansinol (6.0mg, 0.01062mmol), adipate mono(2-trimethylsilylethyl) (52.27mg, 0.2124mmol), scandium trifluoromethanesulfonate (3.14mg, 0.00637mmol) and DMAP (3.89 mg, 0.03186mmol) was placed in a 5ml Schlenck bottle, dichloromethane (1mL) was added under nitrogen protection, and stirred at -8°C for 0.5 hours. Add DIC (29.49mg, 0.2337mmol) dropwise, continue to stir the reaction until the reaction is complete, quench with dilute hydrochloric acid, extract with dichloromethane, wash with saturated sodium bicarbonate and saturated brine successively, dry over anhydrous sodium sulfate, spin dry solvent. Column chromatography (silica gel, CH 2 Cl 2 / MeOH30:1) to obtain the desired product. LC-MS (M+Na + ) calculated value: 815.3, measured value: 815.4.

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Abstract

Provided are efficient methods for direct coupling of a maytansinoid with a carboxylic acid to prepare a maytansinoid C-3 ester in high yield using a rare earth metal-based or trifluoromethanesulfonate-based Lewis acid catalyst and a base together with a coupling reagent. Also provided are compositions used in such methods.

Description

technical field [0001] The invention relates to a method for preparing maytansinoid esters, in particular, the invention relates to a method for preparing maytansinoid C-3 esters. Furthermore, the invention relates to a composition for use in said method. Background technique [0002] Currently maytansinol and carboxylic acid in DCC / ZnCl 2 The direct coupling method has the disadvantages of low yield and poor reproducibility. When using chiral amino acids such as N-methyl-L-alanine derivatives coupled with maytansinol, the chiral centers of the side chains are completely epimerized to give 1:1 L- and D-aminocarboxylates, which is extremely Reduces the yield of the expected product in the overall coupled product and requires lengthy chromatographic purification (column chromatography and HPLC) to separate the expected product from the undesired diastereomer (US Pat. Nos. 4,137,230; 4,260,608 ; 5208020; 5416064; 6333410; Kawai et al. (1984) Chem. Pharm. Bull. 32: 3441-3451;...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/18C07D498/08
CPCC07D498/08C07D498/18
Inventor 邓小斌
Owner BIO THERA SOLUTIONS LTD
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