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A kind of preparation method of bortezomib

A technology of bortezomib and borate ester, which is applied in the field of bortezomib synthesis, can solve the problems of increasing post-processing time and difficulty, increasing the risk of reaction, and complicated equipment, so as to save separation and purification time and reduce pollution of three wastes , the effect of simple operation

Inactive Publication Date: 2020-06-12
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the existing liquid phase synthesis method, the equipment is complex and the operation is cumbersome
Such as hydrogenation, high pressure and other operations increase the risk of reaction
In addition, in the post-processing process, operations such as two-phase extraction and silica gel column purification will inevitably cause more loss of products during the transfer extraction process, affecting the improvement of product purity, increasing post-processing time and difficulty, and the three wastes are serious

Method used

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  • A kind of preparation method of bortezomib
  • A kind of preparation method of bortezomib
  • A kind of preparation method of bortezomib

Examples

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preparation example Construction

[0027] The invention provides a kind of preparation method of bortezomib, comprises the steps:

[0028] a. With pinacol-1-amino-3-methylbutane-1-boronate (compound II) and 5-(4-formyl-3,5-dimethoxyphenoxy)pentane The acid (compound I) was used as the starting material, and the intermediate product 3 was obtained through condensation, reduction, and Fmoc-protection reactions. The structural formula is as follows:

[0029]

[0030] b. Using a resin as a solid phase carrier, sequentially couple the intermediate product 3 of step a, Fmoc-L-phenylalanine (compound III) and pyrazine-2-carboxylic acid (compound IV) to obtain resin compound 6 ;

[0031] c. Cutting the resin compound 6 of step b to obtain boronate 7 of bortezomib,

[0032] d. The product obtained in step c is hydrolyzed to obtain the final product.

[0033] step 1)

[0034] The intermediate product 3 can be prepared as follows:

[0035] a. Add pinacol-1-amino-3-methylbutane-1-boronate, 5-(4-formyl-3,5-dimethoxy...

Embodiment 1

[0069] The synthesis of embodiment 1 intermediate product 3

[0070] Weigh compound Ⅰ (14.2g, 50mmol), compound Ⅱ (10.6g, 50mmol) and NaBH3CN (0.3g, 50mmol) into a 500ml glass flask, add MeOH (500ml), dissolve and react at room temperature for 60 minutes. After the reaction, the above reaction solution was concentrated and vacuum-dried to obtain an oily compound. Afterwards the oily compound was dissolved with dioxane and water (1:1, 400ml) and solid NaHCO was added 3 (13g, 150mmol), stirring was continued for 30 minutes. Fmoc-Cl (16.2g, 60mmol) was dissolved in 100ml of dioxane, added to the above solution under ice-cooling conditions, kept stirring under ice-cooling for 90 minutes, and then continued stirring at room temperature for 90 minutes until the reaction was completed. The above reaction solution was solid NaHCO 3 Adjust to pH=9, add water (2000ml) to dilute, and use Et 2 O was extracted twice, the aqueous phase was collected, and the aqueous phase was acidified ...

Embodiment 2

[0071] The synthesis of embodiment two resin compound 4

[0072] Rink amide resin (40 g, substitution degree 0.5 mmol / g) was weighed and added to a solid-phase reaction column (purchased from Sichuan Shuniu), swelled with DMF for 30 minutes, and drained of DMF. Weigh HATU (15.5g, 40mmol), HOAT (6.0g, 40mmol) and the intermediate product 3 (28g, 40mmol) in Example 1 and dissolve it with DMF (120ml), add DIPEA (14ml, 80mmol) under ice bath conditions After activating for 5 minutes, it was added to the reaction column, detected by ninhydrin until the resin was colorless, the reaction was completed for 2 hours, and the resin was washed 5 times with DMF to obtain resin compound 4, which was directly carried out in the next step.

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Abstract

The invention provides a preparation method of bortezomib. The preparation method comprises the following steps: step a, taking pinacol-1-amino-3-methylbutane-1-borate and 5-(4-formyl-3,5-dimethoxylphenoxyl)pentanoic acid as the primary raw materials, subjecting the raw materials to condensation reactions, reduction reactions, and Fmoc-protection reactions so as to obtain an intermediate, which is represented in the description; step b, taking a resin as the solid carrier, sequentially coupling the intermediate obtained in the step a, Fmoc-L-phenylalanine, and pyrazine-2-carboxylic acid so as to obtain a resin compound, which is represented in the description; step c, cutting the resin compound obtained in the step b so as to obtain bortezomib borate; and step d, hydrolyzing bortezomib borate obtained in the step c so as to obtain the finished product. The preparation method of bortezomib has the advantages of simple procedure and equipment, easy operation, and greatly-improved yield.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and relates to a synthesis method of bortezomib, more specifically to [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl- Synthesis of 2-[(pyrazinyl)amino]propyl]amino]butyl]-boronic acid (common name: Bortezomib). Background technique [0002] Bortezomib, foreign name (or) common name: Bortezomib, chemical formula: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazine Formyl)amino]propyl]amino]butyl]-boronic acid, molecular formula: C 19 h 25 BN 4 o 4 , has the following structure: [0003] [0004] Bortezomib (trade name: Velcade) is the first-choice drug for new anti-multiple myeloma (MM) developed and launched by American Millennium Pharmaceutical Company (now owned by Japanese Takeda Pharmaceutical Company) in 2003. A revolution in cancer treatment, a major advance in the treatment of multiple myeloma. Studies in recent decades have shown that bortezomib, as a synthetic highly selective 2...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/078C07K1/06C07K1/04
Inventor 肖庆潘俊锋马亚平袁建成
Owner HYBIO PHARMA
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