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

A technology of leucine boric acid and phenylalanine, which is applied in the direction of chemical instruments and methods, compounds containing elements of group 3/13 of the periodic table, bulk chemical production, etc., can solve the inconvenience of large-scale industrial production, bortezomib Purity reduction, yield reduction and other problems, to achieve the effect of improving product purity and recrystallization yield, reducing degradation loss, and simple operation

Active Publication Date: 2013-04-17
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

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Embodiment 1

[0032] The preparation of embodiment 1 bortezomib pinanediol ester (compound II)

[0033] Add 7.7g of compound (III) and 9.3g of O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) successively into a clean three-necked flask, 300mL di Chloromethane was placed in a low-temperature reactor, mechanically stirred, protected by nitrogen, and cooled to below 0°C, and 10 g of compound (IV) was slowly added in batches. Maintain the reaction temperature for 2h, adjust the reaction temperature to 5°C, and react for 12h. Filtrate at room temperature, concentrate the filtrate to dryness under reduced pressure, add 500 mL of ethyl acetate to dissolve, wash the organic layer 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. Wash 3 times, then wash 3 times with 100 mL of water, separate and remove the water layer, and dry the organic layer with anhydrous magne...

Embodiment 2

[0036] The preparation of embodiment 2 bortezomib crude product

[0037] Dissolve compound II with 100ml of methanol and 100ml of 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 50mL of 1N HCl dropwise, after the dropwise addition, add isobutylboronic acid 4.2g, reacted at -5°C for 12h. After the reaction was completed, the liquid was separated, the methanol layer was washed three times with 100 mL of n-hexane, the methanol layer was concentrated, the pH was adjusted to 11 with 2N sodium hydroxide, and the methanol layer was 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 with anhydrous magnesium sulfate and dried. After filtration and concentration, the crude product was concentrated to obtain 8 g of white solid ...

Embodiment 3

[0040] Embodiment 3 The recrystallization of bortezomib crude product

[0041] Add 140ml of ethyl acetate into the round bottom flask, then add 0.6mL of formic acid, heat to 70°C, add 10g of 81% in batches, the purity is 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 preparation method of N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic acid, which is an anticancer drug bortezomib. Background technique [0002] Bortezomib is a cancer treatment drug and the first synthetic proteasome inhibitor in the world. It can delay, stop and treat the progression of multiple myeloma and mantle cell lymphoma. It belongs to the category of targeted therapy. It is a new type of anticancer drug that 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-leucine boronic 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 synthetic method of bortezomib, in which t...

Claims

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Application Information

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Patent Type & Authority Applications(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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