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Method for synthesizing key intermediate of antitumour medicament Romidepsi

A technology of romidistatide and anti-tumor drugs, which is applied in the field of drug synthesis, and can solve the problems of expensive reagents, low yield, and many reaction steps

Active Publication Date: 2011-11-16
NANTONG SHIMEIKANG PHARMA CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The synthetic route II of romidistatide has the disadvantage of high cost, and the reagents used in the subsequent removal of the Alloc protecting group of N-Alloc-S-Trt-D-Cys are more expensive
And the reaction step of this technology is more, and productive rate is low, and total productive rate is only 48%

Method used

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  • Method for synthesizing key intermediate of antitumour medicament Romidepsi
  • Method for synthesizing key intermediate of antitumour medicament Romidepsi
  • Method for synthesizing key intermediate of antitumour medicament Romidepsi

Examples

Experimental program
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Effect test

Embodiment 1

[0050] Example 1: Preparation I of dipeptide protected by fluorenyl moxycarbonyl group.

[0051] L-valine methyl ester hydrochloride (L-Val-OMe·HCl, 168 mg, 1 mmol) and fluorenylmethoxycarbonyl-L-threonine (N-Fmoc-L-Thr, 409 mg, 1.2 millimoles) into a 25 milliliter flask, and at room temperature, 15 milliliters of acetonitrile was added for dissolution, after which the flask was evacuated with an oil pump and flushed with nitrogen several times, so that the flask was filled with nitrogen. Turn on the magnetic stirrer and stir slowly at room temperature, and then add benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate (624.4 mg, 1.2 mmol) and basic catalyst nitrogen, nitrogen diisopropyl Diethylamine (DIEA) (0.52 ml, 3 mmol) was added into the flask, and then the magnetic stirrer was accelerated for stirring. After reacting at room temperature for 30 minutes, the stirring was stopped to end the reaction. Concentrate under reduced pressure with a rotary evaporat...

Embodiment 2

[0055] Example 2: Preparation II of fluorenylmethoxycarbonyl-protected dipeptides.

[0056] L-valine methyl ester hydrochloride (L-Val-OMe·HCl, 168 mg, 1 mmol) and fluorenylmethoxycarbonyl-L-threonine (N-Fmoc-L-Thr, 682.8 mg, 2 mmol) was added into a 25 ml flask, and 20 ml of dichloromethane was added to dissolve at room temperature, after which the flask was evacuated with an oil pump and flushed with nitrogen several times, so that the flask was filled with nitrogen. Turn on the magnetic stirrer and stir slowly at room temperature, and then add benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate (1040.6 mg, 2.0 mmol) and basic catalyst nitrogen, nitrogen diisopropyl Diethylamine (DIEA) (1.04 ml, 6 mmol) was added into the flask, and then the magnetic stirrer was accelerated for stirring. After reacting at room temperature for 120 minutes, the stirring was stopped to end the reaction. Concentrate under reduced pressure with a rotary evaporator to remove the s...

Embodiment 3

[0057] Embodiment 3: Preparation I of dipeptide.

[0058] The obtained dipeptide (obtained in Example 1, 460 mg, 0.98 mmol) protected by the fluorenyl moxycarbonyl group was added to a 50 ml flask, and 20 ml of acetonitrile was added to dissolve at room temperature, after which the flask was evacuated with an oil pump and flushed with nitrogen. Fill the flask with nitrogen several times. Turn on the magnetic stirrer to stir at room temperature, then add diethylamine (1 ml, 9.8 mmol) dropwise into the flask at 0° C., then stir at room temperature for 3 hours, then stop stirring to end the reaction. Concentrate under reduced pressure with a rotary evaporator to remove the solvent to obtain a crude dipeptide product, which can be directly used in the next reaction without further purification.

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Abstract

The invention discloses a method for synthesizing a key intermediate of an antitumour medicament Romidepsi, comprising the following steps of: with PyBop as a condenser, carrying out condensation on L-Val-OMe and Fmoc-L-Thr by dehydrating, removing a Fmoc protective group with diethylamine, carrying out condensation on the obtained dipeptide and N-Boc-D-Cys(Trt), reacting the obtained tripeptide with para-toluenesulfonic acid anhydride, then adding DABCO (1,4-Diazabicyclo[2.2.2]octane), and carrying out elimination reaction by virtue of E1 to form tripeptide containing double bonds; removing a Boc protective group with boron trifluoride etherate, and condensing Fmoc-D-Val with tripeptide the terminal of which is a free amino group to obtain the key intermediate of Romidepsi, wherein the structure of the key intermediate is shown by a formula (described in the specification). According to the method disclosed by the invention, two commercial L-type amino acids and two commercial D-typeamino acids are taken as raw materials, a classical peptide condensing agent is utilized, and the key intermediate is obtained at high total yield of 63.8% and can be directly applied to the next synthesis step of Romidepsi.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing key intermediates of the antitumor drug romidistatide. Background technique [0002] Romidepsi (Romidepsi, FK-228, FK-901228, drug trade name: ISTODAX) is a bicyclic tetrapeptide isolated from the broth medium of Chromobacterium violaceum, which has a special decondensed cyclopeptide structure , whose structural formula is shown in (1), can effectively penetrate the cell membrane, and exhibit good anti-tumor activity by inhibiting histone deacetylase. Clinical studies have shown that romidistatide can act on a variety of tumors, especially for skin T-cell lymphoma and drug-resistant tumors. In October 2004, it was included in the "fast-track approval" channel by the US Food and Drug Administration. It was officially approved in November 2009 and officially launched in January 2010. The code number approved by the US Food and Drug Administration and the Eu...

Claims

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Application Information

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IPC IPC(8): C07K5/103C07K1/06
CPCY02P20/55
Inventor 董守良刘正锟李晓莉王俊华刘一超
Owner NANTONG SHIMEIKANG PHARMA CHEM
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