Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid

A technology of leucine boronic acid and phenylalanine, applied in chemical instruments and methods, compounds containing periodic table Group 3/13 elements, production of bulk chemicals, etc., can solve the problem of bortezomib purity decrease, yield Reduce the problems of large-scale industrial production, etc., to achieve the effect of improving product purity and recrystallization yield, simple operation, and reducing degradation loss

Active Publication Date: 2015-05-13
深圳万乐药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The recrystallization of bortezomib in Chinese patent application CN102351890A, CN102492021 uses acetone and toluene as the recrystallization solvent, and acetone is an organic solvent controlled by the state, which brings inconvenience to large-scale industrial production
Experiments have proved that when the above recrystallization method is implemented, the degradation of bortezomib will produce impurities, resulting in a decrease in the purity of bortezomib and a decrease in the yield.

Method used

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  • Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid
  • Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid
  • Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Example 1 Preparation of bortezomib pinanediol ester (compound II)

[0033] In a clean three-necked bottle, 7.7g of compound (III) and 9.3g of O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU) were added successively, 300mL of two Methyl chloride, placed in a low temperature reactor, mechanically stirred, nitrogen protection, and cooled to below 0 °C, and slowly added 10 g of compound (IV) in batches. Maintain the reaction temperature for 2h, adjust the reaction temperature to 5°C, and react for 12h. Filtration at room temperature, the filtrate was concentrated to dryness under reduced pressure and dissolved in 500 mL of ethyl acetate. The organic layer was washed three times with 100 mL of water, three times with 100 mL of 1% phosphoric acid, three times with 100 mL of 2% sodium carbonate, and 100 mL of 10% sodium chloride. Washed 3 times, then washed 3 times with 100 mL of water, separated and removed the water layer, and dried the organic layer with...

Embodiment 2

[0036] The preparation of embodiment 2 bortezomib crude product

[0037] Dissolve compound II with 100ml methanol and 100ml n-hexane, add it to a 500mL three-necked flask, place it in a low temperature reactor, stir the temperature in the system to below 0°C, add 1N HCl 50mL dropwise, after the dropwise addition, add isobutylboronic acid 4.2g, react at -5°C for 12h. After the reaction was completed, the layers were separated, the methanol layer was washed three times with 100 mL of n-hexane, the methanol layer was concentrated, adjusted to pH 11 with 2N sodium hydroxide, and washed three times with 100 mL of dichloromethane. Dichloromethane (100 mL) was added to the aqueous layer, the pH was adjusted to 6 with 1N hydrochloric acid, extracted three times with 100 mL of dichloromethane, combined and dried over anhydrous magnesium sulfate. Filtration and concentration to obtain the crude product and concentrated to obtain 8 g of white solid with a yield of 91% and a purity of 98...

Embodiment 3

[0040] The recrystallization of embodiment 3 bortezomib crude product

[0041] 140 ml of ethyl acetate was added to the round-bottomed flask, 0.6 mL of formic acid was added, heated to 70° C., 10 g of 81% was added in batches, and the purity was 99.1%.

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Abstract

The invention provides a preparation method of bortezomib, namely N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid. The method provided by the invention can enhance the productive rate and purity of the bortezomib and reduce the generation of impurities, is easy and convenient to operate and low in solvent dosage, achieves recrystallized products with high purity being more than 99% and is high in reproducibility and suitable for industrialized production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, and further relates to a method for preparing an anticancer drug bortezomib, namely N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucineboronic acid. Background technique [0002] Bortezomib is a cancer treatment drug and the world's first synthetic proteasome inhibitor, which can delay, stop and treat the progression of multiple myeloma and mantle cell lymphoma, and belongs to targeted therapy. The new anticancer drug was approved by the FDA in 2003, and was approved by the US FDA in June 2008 as a first-line treatment for multiple myeloma. Bortezomib, also known as N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucineboronic acid, has the following structural formula: [0003] [0004] Bortezomib pinanediol ester (II) is an important intermediate in the synthesis of (I). [0005] [0006] WO2009004350 discloses a method for synthesizing bortezomib, which comprises compound of formula III and c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02
CPCY02P20/55
Inventor 阳怡林王先登宝玉荣李玉艳
Owner 深圳万乐药业有限公司
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