Preparation method of paclitaxel or docetaxel octreotide conjugate

A technology for docetaxel and mono-docetaxel, which is applied in the field of drug synthesis and can solve the problems of unavailability of octreotide resin complexes, expensive catalysts and the like

Active Publication Date: 2013-10-16
SOUTHEAST UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Technical problem: The object of the present invention is to provide a method for preparing octreotide conjugates of paclitaxel or docetaxel, which overcomes the problems of not being able to buy octreotide resin complexes and using expensive catalysts on the market, so that the above-mentioned conjugates can be used in the market. Large-scale synthesis of diphenyl N-succinimidyl phosphate (SDPP) from commercially available starting materials and inexpensive reagents

Method used

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  • Preparation method of paclitaxel or docetaxel octreotide conjugate
  • Preparation method of paclitaxel or docetaxel octreotide conjugate
  • Preparation method of paclitaxel or docetaxel octreotide conjugate

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Vacuum-dry paclitaxel 200mg (0.234mmol) and succinic anhydride 300mg (3mmol) for 5 hours, dissolve in 5ml of dry pyridine, stir and react at 30°C for 24h, recover the solvent under reduced pressure to dryness, stir the residue with 10ml of ice water, filter The residue was dissolved in 10ml of acetone, 10ml of water was added dropwise under stirring, the solid was filtered out, and dried under reduced pressure to obtain paclitaxel succinate with a yield of 65%, a purity of 96%, ESI-MS (m / z): 976 [M+Na ] + ;992[M+K] + .

Embodiment 2

[0040]Docetaxel 200mg (0.248mmol) and diglycolic anhydride 348mg (3mmol) were vacuum-dried for 5 hours, dissolved in 5ml of dry pyridine, stirred and reacted at 30°C for 24h, the solvent was recovered under reduced pressure to dryness, and the residue was stirred with 10ml of ice water , the residue after filtration was dissolved in 10ml of acetone, and 10ml of water was added dropwise under stirring, the solid was precipitated by filtration, and dried under reduced pressure to obtain docetaxel diglycolate, with a yield of 63%, a purity of 93%, ESI-MS (m / z) : 946[M+Na] + .

Embodiment 3

[0042] Dissolve 25 mg (0.025 mmol) of paclitaxel succinate, 30 mg (0.086 mmol) of SDPP and 30 mg (0.296 mmol) of triethylamine in 0.5 ml of anhydrous acetonitrile, stir at room temperature overnight, and after the reaction is detected by TLC, concentrate in vacuo, and the crude product The mixed solution was dissolved in ethyl acetate, washed with saturated brine, dried and recovered from the solvent to obtain the target product, ESI-MS (m / z): 1052.15 [M+H] + , directly used in the next reaction without further purification.

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Abstract

The invention relates to a preparation method of a paclitaxel or docetaxel octreotide conjugate. The method comprises the steps that: 1, in an aprotic solvent, paclitaxel-2'-linker sequence acid or docetaxel-2'-acid linker sequence and diphenyl N-succinimidyl phosphate (SDPP) are subjected to the catalysis of tertiary amine, such that N-hydroxysuccinimide paclitaxel-2'-linker sequence ester or N-hydroxysuccinimide docetaxel-2'-linker sequence ester is obtained; 2, in an aprotic solvent, N-hydroxysuccinimide paclitaxel-2'-linker sequence ester or N-hydroxysuccinimide docetaxel-2'-linker sequence ester and octreotide are conjugated under the catalysis of tertiary amine, such that paclitaxel or docetaxel octreotide conjugate is obtained. The invention assists in solving problems of impossibility of purchasing octreotide resin compositions and expensive catalysts. The conjugate provided by the invention can be synthesized in large batches by using raw materials in the market and a cheap reagent diphenyl N-succinimidyl phosphate (SDPP).

Description

technical field [0001] The invention provides a method for synthesizing an octreotide conjugate of paclitaxel or docetaxel. It belongs to the technical field of drug synthesis. Background technique [0002] Somatostatin (SST) is a neuropeptide hormone present in the gastric mucosa, pancreatic islets, gastrointestinal nerves, posterior pituitary gland, and central nervous system, and it has been recognized as a regulator of factors such as secretion, cell division, proliferation, and apoptosis. basic process of death. Octreotide is a synthetic octapeptide derivative of somatostatin. It has a similar spectrum of action to somatostatin but a longer biological half-life, and it has stronger, longer-lasting effects and stronger selectivity. Since 1983, many literatures have reported the therapeutic effect and systematic evaluation of octreotide on some diseases, and it has been confirmed that it has inhibitory effects on neuroendocrine tumors, digestive tract tumors, breast can...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/107
Inventor 沈杨吴永平任慕兰蔡云朗张啸宇王琦卢定强
Owner SOUTHEAST UNIV
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