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Preparation method of fluoromethyl ketone peptide series compounds

A technology of compound and carboxyl group, which is applied in the field of compound preparation, can solve the problems of unfavorable industrial production, strong corrosion of reaction reagents, and limited industrial production.

Inactive Publication Date: 2017-01-11
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The pure liquid phase synthesis conditions are cumbersome, and the reaction conditions require relatively low temperature (some reactions require as low as -60°C or even -78°C), and some reactions require the separation of racemates. The conditions are harsh, and post-processing is inconvenient. Industrial production
In addition, the report of pure solid-phase synthesis shows that the total synthesis yield is 29.5-32.5%, and the product purity is only 96.3-98.8%. The physical and mental health of the operators, the unfavorable environment where the waste gas and liquid are difficult to deal with, and the industrial production is limited

Method used

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  • Preparation method of fluoromethyl ketone peptide series compounds
  • Preparation method of fluoromethyl ketone peptide series compounds
  • Preparation method of fluoromethyl ketone peptide series compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Example 1 Preparation of Fmoc-Asp(OtBu)-FMK

[0094] 1.1 Fmoc-Asp(OtBu)-N 2 preparation of

[0095]

[0096] Fmoc-Asp(OtBu)-OH (1eq, 0.5mol, 206g) and nitrogen methylmorpholine (1.25eq, 0.625mol, 63.2g) were added to the reaction kettle, and dissolved in THF (2.0L), and the Hydrazine lowered the temperature of the system to about -10°C, slowly added isobutyl chloroformate (1.15eq, 0.575mol, 78.5g) dropwise, and kept at -10°C for 30 minutes. Then diazomethane-diethyl ether solution (4eq, 2.0mol, 84g) was slowly added to the above reaction system, after the addition was completed, the temperature was naturally raised to 25°C for 3 hours, and the reaction was detected by TLC spotting.

[0097] After the reaction was completed, 3.0 L of water and 0.1 L of acetic acid were slowly added to quench, and then 6.0 L of ethyl acetate was added for extraction. The separated organic phase was washed successively with 3.0 L saturated brine and 5% aqueous sodium bicarbonate solu...

Embodiment 2

[0106] The removal of tBu in the embodiment 2 Fmoc-Asp(OtBu)-FMK

[0107] 2.1 Preparation of Fmoc-Asp-FMK

[0108]

[0109] Cool 30% formic acid / DCM to 0°C, add Fmoc-Asp(OtBu)-FMK (1eq, 0.282mol, 100g) prepared according to the method of Example 1, stir to dissolve, naturally heat up to 25°C, and stir for 10 After 1 hour, TLC spot plate monitoring.

[0110] After the reaction was completed, the solvent was removed by a rotary evaporator, and 3.0 L of ethyl acetate was added for extraction. The separated organic phase was washed successively with 3.0 L saturated brine and 5% aqueous sodium bicarbonate solution, and finally dried with anhydrous magnesium sulfate. The solvent was removed by a rotary evaporator, recrystallized with absolute ethanol, and dried to obtain 94.4 g of white solid Fmoc-Asp-FMK, with a yield of 90.2%.

[0111] 2.2 Preparation of Fmoc-Asp-FMK

[0112]

[0113] Cool 50% TFA / DCM to 0°C, and add Fmoc-Asp(OtBu)-FMK (1eq, 0.282mol, 100g) prepared acco...

Embodiment 3

[0127] Example 3 Coupling of Fmoc-Asp-FMK and 2-CTC resin

[0128]

[0129] 2-CTC resin (1.1eq, 296mmol, 269g) with a degree of substitution of 1.1mmol / g was added to a solid-phase reaction column, washed twice with DMF, swelled for 1 hour, and drained. Dissolve Fmoc-Asp-FMK (1.0eq, 269mmol, 100g) prepared according to 2.4 in Example 2 in 700ml DMF and cool down to 2-5°C, add DIPEA (3.3eq, 888mmol, 115g), keep stirring for 10 minutes After that, it was added to the above-mentioned solid-phase reaction column, stirred with nitrogen gas for 1 hour, then added with 200ml of methanol and stirred for 30 minutes, then washed with DMF for 4 times, and the DMF was drained for later use to obtain Fmoc-Asp-FMK-CTC.

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Abstract

The invention relates to a preparation method of fluoromethyl ketone peptide series compounds. The preparation method comprises the following steps: (1) preparing Fmoc-Asp(OR0)-FMK from Fmoc-Asp(OR0)-OH; (2) removing the side chain protective group (R0) from Fmoc-Asp(OR0)-FMK to obtain Fmoc-Asp-FMK with a naked side chain carboxyl group; (3) taking 2-CTC resin as the solid phase carrier to synthesize Fmoc-Asp-FMK-CTC amino acid resin; (4) using Fmoc-Asp-FMK-CTC to sequentially couple the protected amino acids (An) to obtain R1-An-Asp-FMK-CTC; (5) using a TFE / DCM reagent (20%) to cut R1-An-Asp-FMK-CTC peptide resin to obtain totally protected peptide R1-An-Asp-FMK; step (6) modifying and protecting the side chain carboxyl group of carbon terminal Asp in R1-An-Asp-FMK to obtain totally protected peptide R1-An-Asp(OR2)-FMK; and (7) if in the peptide sequence, amino acids other than the carbon terminal Asp have a side chain protective group, carrying out cracking so as to remove the protective groups. The provided method has the advantages of mild synthesis conditions and simple and stable technology.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of a fluoromethyl ketone peptide series compound. Background technique [0002] Apoptosis is a major form of cell death, and it generally exists in the growth process of organisms. It is very important for the normal development of organisms and the control of certain diseases. The treatment of many diseases requires the control or modification of disease-associated apoptosis. Caspase plays a key role in the apoptosis signal transduction pathway. [0003] Caspase is a kind of cysteine ​​protease specific to aspartic acid. It contains a cysteine ​​structure in its active center and can specifically cut the site behind aspartic acid on the peptide chain. Tumor / leukemia family members have important enzymatic modifications, including Caspase1-10 and so on. [0004] Caspase zymogen includes 3 parts: prodomain, large subunit and small subunit. Zymogens the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K1/06C07K1/04C07K1/02
CPCY02P20/55
Inventor 陈学明朱日成宓鹏程陶安进袁建成
Owner HYBIO PHARMA
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