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The synthetic method of [1-methyl-2-(7'-heptyl hydroxamic acid group)-5-n,n-bis(2'-chloroethyl)]-1h-benzimidazole

A -5-N, benzimidazole technology, applied in the field of antitumor drug synthesis, can solve the problems of long reaction route, unsafe production environment, unfavorable temperature control, etc., and achieve the effect of easy operation

Active Publication Date: 2016-08-24
HANGZHOU TINO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The invention provides a method for synthesizing [1-methyl-2-(7'-heptylhydroxamic acid)-5-N,N-bis(2'-chloroethyl)]-1H-benzimidazole The new method uses chloroacetic acid as the raw material to replace ethylene oxide, which is safe, non-toxic, and easy to operate, and solves the technical defects of the prior art that the synthesis of NL-101 has a long reaction route, is not conducive to temperature control, and the production environment is unsafe

Method used

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  • The synthetic method of [1-methyl-2-(7'-heptyl hydroxamic acid group)-5-n,n-bis(2'-chloroethyl)]-1h-benzimidazole
  • The synthetic method of [1-methyl-2-(7'-heptyl hydroxamic acid group)-5-n,n-bis(2'-chloroethyl)]-1h-benzimidazole
  • The synthetic method of [1-methyl-2-(7'-heptyl hydroxamic acid group)-5-n,n-bis(2'-chloroethyl)]-1h-benzimidazole

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Experimental program
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Effect test

Embodiment 1

[0072] step 1)

[0073] First, add 2,4-dinitroaniline (10.0g, 54.6mmol) and toluene (100mL) in a 250mL reaction flask, nitrogen protection, stirring at room temperature, then dropwise add monomethyl suberate monoacyl chloride (13.5g, 65.5 mmol). After dropping, the temperature was raised to reflux, followed by TLC to the end of the reaction, and after about 24 hours, the temperature was lowered to 60°C. Add water (100mL), remove toluene by rotary evaporation under reduced pressure, precipitate a yellow solid, and dry at low temperature to obtain 8-(2,4-dinitrophenyl)amino-8-oxooctanoic acid methyl ester: 18.6g, 96.4% .

[0074]The 8-(2,4-dinitrophenyl)amino-8-oxooctanoic acid methyl ester (18.6g, 52.6mmol) obtained above was added to acetonitrile (50mL) to react at room temperature, and dimethyl sulfate ( 8.0g, 63.1mmol) and potassium carbonate (14.5g, 105.2mmol), TLC followed the reaction to the end point, about 24h. Remove the filter cake by suction filtration, rinse wit...

Embodiment 2

[0082] step 1)

[0083] Add N-methyl-2,4-dinitroaniline (10.8g, 54.6mmol) and xylene (100mL) into a 250mL reaction flask, under nitrogen protection, reflux and stir, then add dropwise monomethyl suberic acid monoacyl chloride (13.5 g, 65.5 mmol). After dropping, the temperature was raised to reflux, followed by TLC to the end of the reaction, and after about 24 hours, the temperature was lowered to 60°C. Add water (100mL), remove xylene by rotary evaporation under reduced pressure, precipitate a yellow solid, and dry at low temperature to obtain the product 8-(2,4-dinitrophenyl)methylamino-8-oxooctanoic acid methyl ester: 18.3g , 91.2%.

[0084] step (2)

[0085] 8-(2,4-dinitrophenyl)methylamino-8-oxo-octanoic acid methyl ester (18.3g, 50.0mmol), 10% palladium carbon (1.0g) were placed in methanol (150mL), in 3 Under 1 atmospheric pressure, hydrogen was passed through for about 8 hours. After suction filtration, concentrated hydrochloric acid (4.5 mL) was added to the mot...

Embodiment 3

[0091] step 1)

[0092] First, in a 250mL reaction flask, add 2,4-dinitroaniline (10.0g, 54.6mmol), monomethyl suberate (12.3g, 65.5mmol) and dimethylformamide (60mL), nitrogen protection, After stirring at room temperature, DMAP (8.0 g, 65.5 mmol) was added. The temperature was raised to reflux, followed by TLC to the end of the reaction. After about 36 hours, the reaction solution was added to ice water (800mL), and a yellow sticky substance was precipitated, left to stand, filtered with suction to obtain a sticky substance, rinsed with ether, and solidified. Dry at low temperature to obtain methyl 8-(2,4-dinitrophenyl)amino-8-oxoctanoate: 15.1 g, 78.3%.

[0093] Add the 8-(2,4-dinitrophenyl)amino-8-oxooctanoic acid methyl ester (15.1g, 42.7mmol) obtained above into dimethylformamide (50mL) to react at room temperature, add iodine dropwise Methane (7.3g, 51.2mmol) and potassium carbonate (11.8g, 85.4mmol), TLC followed the reaction to the end point, about 6h. Remove the f...

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Abstract

The invention discloses a synthetic method of [1-methyl-2-(8'-octyl hydroxamic acid group)-5-N,N-bi(2'-chloroethyl)]-1H-benzimidazole. NL-101, namely [1-methyl-2-(8'-octyl hydroxamic acid group)-5-N,N-bi(2'-chloroethyl)]-1H-benzimidazole is prepared from chloroacetic acid replacing hypertoxic low-boiling ethylene oxide as a raw material by multi-reactions in one pot. The separating and purifying step is cancelled, the synthetic route is short, and the reaction environment in particular including temperature, pressure and the like can be safely controlled and the method is green and environment-friendly. The invention also discloses a series of intermediate compounds obtained in the reaction of synthesizing NL-101. The purity of NL-101 prepared by the synthetic route through analysis and characterization reaches 95%, and the purity after recrystallization and refining is greater than 99%. The method is high in product yield, easy to operate, and beneficial for industrialized production in a large scale.

Description

technical field [0001] The present invention relates to a method for synthesizing antitumor drugs of histone deacetylase inhibitors, in particular to a [1-methyl-2-(7'-heptyl hydroxamic acid group)-5-N,N -Synthetic method of two (2'-chloroethyl)]-1H-benzimidazoles. Background technique [0002] At present, the design of histone deacetylase inhibitors presents a multi-target trend, that is, often a single drug molecule can inhibit both the activity of histone deacetylase and the inhibitory activity of a certain other enzyme or target. This single-molecule multi-target drug has many advantages compared with combined administration, including the ability to effectively overcome the problems of different solubility and different pharmacokinetic parameters of each drug component (Meunier, B.Acc.Chem. Res. 2008, 41, 69.; Tsogoeva, S.B. Mini-Rev. Med. Chem. 2010, 10, 773.). [0003] Vorinostat (SAHA) is the world's first new anticancer drug that inhibits histone deacetylase (HDAC...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D235/16C07D405/12C07C233/15C07C231/02
Inventor 葛求富张世杰吴春霞沈锡明王树龙郭殿武
Owner HANGZHOU TINO PHARMA CO LTD
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