Preparation of compound (1s,2s,3r,5s)-pinanediol-l-phenylalanine-l-leucine boronate

A technology of leucine borate and pinanediol, which is applied in the field of preparation of bortezomib intermediates, can solve the problems of unsuitability for industrial production, excessive three wastes, and large environmental pollution, and achieve low cost, reduction of three wastes, The effect of high yield

Active Publication Date: 2011-12-07
SUZHOU ERYE PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And the condensing agent TBTU is used in the synthesis, which produces a lot of three wastes, which pollutes the environment greatly and is not suitable for industrial production

Method used

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  • Preparation of compound (1s,2s,3r,5s)-pinanediol-l-phenylalanine-l-leucine boronate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] At room temperature, triphosgene (3.6g, 12.1mmol) in tetrahydrofuran (50ml) was added dropwise to a solution of L-phenylalanine (2.0g, 12.1mmol) in tetrahydrofuran (50ml). After the addition was complete, heat to reflux for 4h.

[0016] After the reaction was completed, the reaction solution was concentrated and cooled to obtain 2.2 g of 4-benzyl-oxazolidine-2,5-dione as a solid, with a yield of 96%.

[0017] Add (1R)-(S)-pinanediol-1-trifluoroacetate-3-methylbutane-1-boronate (4.3g, 11.3mmol) and 30ml of dichloromethane into the reaction flask , cooled to -5°C. A mixture of N,N-diisopropylethylamine (6ml, 34.5mmol) and 20ml of dichloromethane was added dropwise to the above dichloromethane solution, and stirred at -5°C for 2h. 50ml of tetrahydrofuran in 4-benzyl-oxazolidine-2,5-dione was added dropwise to the above dichloromethane solution. After the addition was complete, the mixture was reacted at room temperature for 4 hours. The organic layer was washed with wate...

Embodiment 2

[0019] Add triphosgene (3.6g, 12.1mmol) in 50ml of diethyl ether dropwise to L-phenylalanine (2.0g, 12.1mmol) in tetrahydrofuran (50ml) at room temperature. After the dropwise addition, heat to reflux for 4 hours.

[0020] After the reaction was completed, the reaction solution was concentrated and cooled to obtain 1.8 g of 4-benzyl-oxazolidine-2,5-dione as a solid, with a yield of 78%.

[0021] Add (1R)-(S)-pinanediol-1-trifluoroacetate-3-methylbutane-1-boronate (3.6g, 9.5mmol) and 20ml of dichloromethane into the reaction flask , cooled to -5°C. A mixture of N,N-diisopropylethylamine (4.5ml, 28.2mmol) and 20ml of dichloromethane was added dropwise to the above dichloromethane solution, and stirred at -5°C for 2h. 40ml of 4-benzyl-oxazolidine-2,5-dione in tetrahydrofuran was added dropwise to the above dichloromethane solution, and after the addition was complete, the mixture was reacted at room temperature for 4h. The organic layer was washed with water, and the organic la...

Embodiment 3

[0023] At room temperature, triphosgene (7.2g, 24.2mmol) in tetrahydrofuran (50ml) was added dropwise into a solution of L-phenylalanine (4.0g, 24.2mmol) in tetrahydrofuran (50ml). After the addition was complete, it was heated to reflux for 4h.

[0024] After the reaction was completed, the reaction solution was concentrated and cooled to obtain 3.7 g of 4-benzyl-oxazolidine-2,5-dione as a solid, with a yield of 85%.

[0025] Add (1R)-(S)-pinanediol-1-trifluoroacetate-3-methylbutane-1-boronate (7.4g, 19.4mmol) and 60ml of dichloromethane into the reaction flask , cooled to -5°C. A mixture of N,N-diisopropylethylamine (9.6ml, 58.2mmol) and 40ml of dichloromethane was added dropwise to the above dichloromethane solution, and stirred at -5°C for 2h. 50ml of tetrahydrofuran in 4-benzyl-oxazolidine-2,5-dione was added dropwise to the above dichloromethane solution. After the addition was complete, the mixture was reacted at room temperature for 4h. The organic layer was washed w...

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Abstract

The invention discloses a preparation method of a compound (1S, 2S, 3R, 5S)-pinanediol-L-phenylalanine-L-leucine boric acid ester (shown in the structural formula 1). The preparation method comprises the following steps that L-phenylalanine and triphosgene undergo a reaction to produce a compound shown in the structural formula 8; the compound shown in the structural formula 8 and a compound shown in the structural formula 7 undergo a condensation reaction to produce a compound which has a single configuration and is shown in the structural formula 1; the compound shown in the structural formula 1 and pyrazinecarboxylic acid undergo a condensation reaction to produce a compound shown in the formula 10; and the compound shown in the formula 10 is hydrolyzed to form bortezomib which is an anticancer drug. The preparation method has the advantages of simple operation, high yield, easy acquirement of raw materials, and low pollution on the environment. The preparation method is suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of a bortezomib intermediate, in particular to a preparation method of a bortezomib intermediate which is high in yield, easy to operate and suitable for industrial production. Background technique [0002] Bortezomib (bortezomib) was developed by Millennium Pharmaceuticals in Cambridge, Massachusetts, USA. Bortezomib is the first dipeptide boronic acid proteasome inhibitor that reversibly binds to the 26S proteasome and blocks Protein degradation, prevent malignant proliferation of tumor cells. Mainly used in the treatment of multiple myeloma. Its chemical name is [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarbonyl)amino]propyl]amino]butyl]- boric acid. It was launched in the United States in May 2003 and in China in September 2005. [0003] Bortezomib is composed of (1S,2S,3R,5S)-pinanediol-L-phenylalanine-L-leucine boronate (compound of structural formula 1) and pyrazine-2-carboxylic acid (st...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/04
Inventor 毛化钟静芬陈学文韩强时惠麟
Owner SUZHOU ERYE PHARMA CO LTD
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