A preparation and purification method of dehydrophenylahistine compounds

A technology of phenylahistine and purification method, applied in the direction of organic chemistry, etc., can solve the problems of complex preparation and purification methods and restrictions on the industrial production of drugs, and achieve the effects of good reproducibility, increased yield, and high yield

Active Publication Date: 2020-02-18
SHENZHEN HUAHONG MARINE BIOMEDICINE CO LTD
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AI Technical Summary

Problems solved by technology

However, there will also be a certain amount of ((3E,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl) deuterated methylene in the preparation method provided by it ) piperazine-2,5-dione isomers produced
[0007] Meanwhile, the current report on (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)methylene)piperazine-2,5-dione The preparation and purification methods of the drug are relatively complicated, and the column chromatography purification of some intermediates restricts the industrial production of the drug. Therefore, it is of great significance to establish a process suitable for industrial production.

Method used

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  • A preparation and purification method of dehydrophenylahistine compounds
  • A preparation and purification method of dehydrophenylahistine compounds
  • A preparation and purification method of dehydrophenylahistine compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Preparation of crude (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)deuteromethylene)piperazine-2,5-dione

[0037] Its specific preparation process comprises the following steps:

[0038] 1) Preparation of (Z)-1-acetyl-3-((5-(tert-butyl)-1H-imidazol-4-yl)deuterated methylene)piperazine-2,5-dione

[0039] Add 10.00g (65.29mmol) 5-(tert-butyl)-1H-imidazole-4-deuteroformaldehyde to 50mL DMF, then add 25.88g (130.59mmol) N, N-diacetylpiperazine-2,5- The diketone was exhausted three times under nitrogen protection, 31.91g (97.94mmol) cesium carbonate was added, nitrogen protection was exhausted three times, and the reaction was stirred at room temperature for 20h in the dark. Pour the reaction solution into ice water (400mL), filter with suction, wash the filter cake with water (200mL*2), petroleum ether: ethyl acetate = 8:1 (200mL) successively, and ultrasonically disperse the filter cake with ethanol and dichloromethane , filtered off the insoluble matter, conce...

Embodiment 2

[0043] (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)deuteromethylene)piperazine-2,5-dione monohydrate preparation

[0044]

[0045] Put 2.0 g of the crude product described in Example 1 in a brown bottle, add 125 mL of isopropanol under heating conditions until completely dissolved, then add 50 mL of water without crystallization, place at room temperature, stir, cool and crystallize, and filter with suction. Virahol: water=1: 1 washes filter cake, dries, obtains yellow powdery solid 1.642g, and yield is 78.13%, and the purity of product under 254nm is 99.94%, wherein isomer ((3E, 6Z)- 3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)deuteromethylene)piperazine-2,5-dione 0.06%, see figure 1 . 1 H NMR (500MHz, dmso) δ 12.22 (brs, 2H), 10.00 (brs, 1H), 7.82 (d, J = 12.7Hz, 1H), 7.51 (d, J = 7.6Hz, 2H), 7.40 (t , J=7.7Hz, 2H), 7.30(t, J=7.4Hz, 1H), 6.73(s, 1H), 1.37(s, 9H). MS(ESI)m / z 338.1715(M+H) + (calcd for C 19 h 20 DN 4 o 2 ).

[0046] The resulting p...

Embodiment 3

[0050] (3Z, 6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)methylene)piperazine-2,5-dione crude product preparation method

[0051] Its specific preparation process technology includes the following steps:

[0052] 1) Preparation of ethyl 5-(tert-butyl)oxazole-4-carboxylate

[0053] Add 90g (796mmol) ethyl isocyanoacetate to 1000mL tetrahydrofuran, slowly dropwise add 145g (955mmol) DBU, then dropwise add 178g (955mmol) trimethylacetic anhydride, and stir the reaction at room temperature for 48h after dropping. After the reaction was completed, it was concentrated under reduced pressure. For extraction, add an appropriate amount of 1500mL of dichloromethane, wash with 800mL of 10% sodium carbonate, 800mL of 10% citric acid, and 800mL of saturated brine, and back-extract the aqueous phase twice with 1000mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction after half an hour, and concentrated under reduced pre...

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Abstract

The invention provides a preparation and purification method of high-purity Plinabulin compound, which aims at mainly removing a trans-isomer. The preparation and purification method has the advantages that (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazole-4-yl)methylene)piperazine-2,5-diketone monohydrate and (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazole-4-yl)deuterated methylene)piperazine-2,5-diketone monohydrate are prepared; the purity of the prepared product is higher than 99.5%, and the content of the trans-isomer is smaller than 0.1%. The invention also relates to the preparation and purification of important intermediates, such as 5-(tert-butyl)-1H-imidazole-4-ethyl formate and 1,4-diacetylpiperazine-2,5-diketone. The preparation and purification method has the advantages that the production cost is reduced, the pos-treatment difficulty is decreased, and the technology more meets the requirements of industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to a method for preparing and purifying dehydrophenylahistine compounds. Background technique [0002] Dehydrophenylahistinoids (3Z, 6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)methylene)piperazine-2, The structural formula of 5-diketone is: [0003] [0004] The compound, also known as Plinabulin (KPU-2, NPI-2358), is a tubulin-binding agent, a synthetic derivative of the low-molecular-weight cyclic dipeptide phenylahistin or halimide derived from marine Aspergillus. It can bind to the vicinity of the colchicine binding point of tubulin, and has good anti-tumor activity, especially in non-small cell lung cancer. The drug has been launched in the third phase of clinical trials in the United States in the second half of 2015. Nabulin is also applying for clinical application in China as a concentrated solution of Plinabulin for injection, which is currently und...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/06
CPCC07D401/06
Inventor 李文保丁忠鹏王世潇孙天文侯英伟管华诗
Owner SHENZHEN HUAHONG MARINE BIOMEDICINE CO LTD
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