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Boron-containing intermediate and application of same to medical industry

A technology for intermediates and boron compounds, which is applied to boron-containing intermediates and its application in the pharmaceutical industry, can solve the problems of compound V that is difficult to purify, cannot be purified, and does not reveal transformation, and achieves cheap and easy-to-obtain raw materials and purification Reduced difficulty and high product purity

Inactive Publication Date: 2017-03-15
CHENGDU BESTCHIRALBIO LIMITED LIABILITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Intermediate VI is an oily compound, which cannot be purified by recrystallization or "normal temperature beating" process
[0016] 2. Compound V is difficult to purify, and the reaction by-product impurities are extremely difficult to remove
Patent CN102066386 does not disclose the purification method of compound V, only the method of converting compound V from an oily product to a crystalline product, which cannot remove the impurities introduced in the preparation process of compound V
[0017] 3. The quality of the final product IV is determined by the quality of compound V, but compound V cannot remove many impurities
[0018] Patent WO2012177835 discloses that compound II is more stable than compound V, but this patent document does not disclose how stable compound II can be transformed into compound I
[0019] In summary, in the existing public literature, the purification strategy of the product MLN9708 cannot remove process impurities. Therefore, developing and finding a preparation process and purification scheme for the preparation of MLN9708 has always been a scientific problem that the pharmaceutical industry needs to overcome

Method used

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  • Boron-containing intermediate and application of same to medical industry
  • Boron-containing intermediate and application of same to medical industry
  • Boron-containing intermediate and application of same to medical industry

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1 4-(R,S)-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl base)-6-oxo-1,3,2-dioxaborolane-4-carboxylic acid

[0044]

[0045] Step 1: N-2,5-dichlorobenzoyl-L-glycine methyl ester

[0046]

[0047] A mixture of 2,5-dichlorobenzoic acid (9.1 g, 47.6 mmol), L-glycine methyl ester hydrochloride (6.0 g, 47.5 mmol), TBTU (18.4 g, 57.3 mmol) and tetrahydrofuran (250 mL) was cooled to 0°C, stirred for 30min, and started to add diisopropylethylamine (23.6mL, 143.2mmol) dropwise. After the dropwise addition was completed, it was slowly raised to room temperature and reacted overnight. The complete reaction was monitored by TLC, the reaction solution was concentrated, and ethyl acetate was added, washed with saturated aqueous sodium bicarbonate solution, citric acid aqueous solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain N-2,5 -The crude product of dichlorobenzoyl-L-glycine m...

Embodiment 2

[0064]

[0065] A total of 5 g (11.3 mmol) of compound 1-6 obtained in Example 1 was dissolved in methanol (100 ml), and 4M KHF was added under room temperature 2 Aqueous solution (15ml), then stirred and reacted at room temperature for 2 hours, and TLC detected the reaction progress. After the reaction was completed, the solid was filtered and washed with methanol to obtain the solid compound I-b, which was dried under reduced pressure at 50°C to obtain the target solid compound I-a , the target product was recrystallized in methanol to obtain 3.9 g of the product (yield 84.7%).

[0066]A total of 3g (7.3mmol) of the compound I-b obtained above was dispersed and dissolved in acetonitrile (25ml) to form a suspension, then triethylamine (5ml) was added, and an ethyl acetate solution of citric acid (1.4g, 7.3mmol) was added , the above mixed solution was stirred and reacted at room temperature for 30 minutes. At room temperature, 5.3 g of silicon tetrachloride was added, and ...

Embodiment 3

[0068]

[0069] Compound 1-6 was prepared according to Example 1 to obtain a total of 10 g (22.5 mmol), ethyl acetate (100 ml) and N-methyliminodiacetic acid (compound 3-1, 3.31 g, 22.5 mmol) were added, and stirred overnight at room temperature, Filter, wash with ethyl acetate, and dry to obtain 9.5 g of the target product with a yield of 89.4%.

[0070] A total of 9 g (19.0 mmol) of compound 3-2 obtained above was dissolved in methanol (100 ml), and 4M KHF was added at room temperature 2 Aqueous solution (15ml), then stirred and reacted at room temperature for 2 hours, TLC detected the reaction progress, after the reaction was completed, filtered the solid, washed with methanol to obtain solid compound I-a, and dried under reduced pressure at 50°C to obtain the target solid product compound I-a , the target product was recrystallized in methanol to obtain 6.9 g of the product (yield 85.9%).

[0071] A total of 6g (14.2mmol) of the compound I-a obtained above was disperse...

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Abstract

The invention discloses a preparation method for novel boron-containing intermediate I and a boron-containing drug MLN9708. The novel boron-containing intermediate I prepared by using a fluorination reagent is applied to preparation of the antitumor drug MLN9708; the intermediate has stable chemical properties in normal-temperature air, is easy to recrystallize and purify; and the intermediate and citric acid undergo a one-step reaction under the action of an alkaline reagent and a silicon reagent so as to prepare the antitumor drug MLN9708. The preparation method provided by the invention has no special requirements on production equipment, is mild in reaction conditions, uses commercially available raw materials and is suitable for industrial production.

Description

[0001] Technical field: [0002] The invention specifically relates to a preparation process of a boron-containing drug, and discloses a novel boron-containing intermediate and the application of the preparation process in the industrial production of the boron-containing product. [0003] Background technique: [0004] The proteasome is an important part of the ubiquitin-proteasome system, responsible for the regulation and degradation of most intracellular proteins. Proteins are first marked by ubiquitin (polypeptide), and then recognized and degraded by the proteasome. The proteasome plays a central role in regulating the cell cycle, cell proliferation and apoptosis. The first-generation proteasome inhibitor Bortezomib has been used in the clinical treatment of multiple myeloma, which can inhibit the growth of various tumor cells and enhance radiosensitization. Ixazomib citrate (MLN9708) is a second-generation proteasome inhibitor based on bortezomib. It is a nitrogen-cappe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02C07F5/04
Inventor 李德群
Owner CHENGDU BESTCHIRALBIO LIMITED LIABILITY
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