Synthetic method of proteasome inhibitor bortezomib and analogs

A technology of bortezomib and its analogues, applied in the field of new chemical synthesis, can solve the problems of high cost, limited use, difficult synthesis, etc., and achieve the effect of reducing the cost of synthesis

Active Publication Date: 2013-04-10
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

ICy reported in the literature is usually in the form of its boron tetrafluoride salt ICy·HB

Method used

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  • Synthetic method of proteasome inhibitor bortezomib and analogs
  • Synthetic method of proteasome inhibitor bortezomib and analogs
  • Synthetic method of proteasome inhibitor bortezomib and analogs

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Experimental program
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preparation example Construction

[0072] 2. Preparation of catalyst

[0073]

[0074] First complete ICy·HCl synthesis according to other documents (CN1216536A);

[0075]

[0076] In the existing literature, the synthesis of the target product (ICy)CuOt-Bu is completed in two steps, that is, the first step is to convert ICy·HCl into (ICy)CuCl, and then convert it into the desired product under the action of sodium tert-butoxide catalyst. In the present invention, the target product is obtained by directly using 2 times the amount of sodium tert-butoxide in one step, and the catalyst (ICy)CuOt-Bu can still be obtained well, which not only shortens the reaction time, but also simplifies the reaction steps.

[0077] 3. Catalytic addition and deprotection of boric acid pinacol ester

[0078]

[0079] The catalyst obtained in the previous step is directly dropped into the addition reaction system for catalysis after being dissolved in toluene, benzene, tetrahydrofuran, dioxane, etc. (preferably toluene) ...

Embodiment 1

[0093] (R)-N-tert-butylsulfinyl-3-methyl-1-butylimine

[0094]

[0095]Add 40mL of toluene to a 100ml flask, add 1.2ml (11mmol) of isovaleraldehyde, 1.2g (10mmol) of tert-butylsulfinamide and 4g (27mmol) of anhydrous sodium sulfate at room temperature, and stir for more than 48h. The post-treatment is to filter the excess content through diatomaceous earth, spin the organic phase to dryness and direct column chromatography (PE200ml for PE: EA = 20: 1 to complete) to obtain the product as 1.77g of colorless oily substance with special The sweet smell of hair, yield 95%. 1 H NMR (400MHz, CDCl 3 )δ8.06(t, J=5.1Hz, IH), 2.42(t, J=5.9Hz, 2H), 2.07(dp, J=13.6, 6.8Hz, IH), 1.21(d, J=7.8Hz, 9H), 1.00(d, J=6.5Hz, 6H).

Embodiment 2

[0097] 2-Chloro-1,3-dicyclohexyl-2,3-dihydro-1H-imidazole (ICy·HCl)

[0098]

[0099] Inject 100 ml of toluene into a 500 ml round bottom flask, add 9.92 g (100 mmol) of cyclohexylamine and 3 g (100 mmol) of paraformaldehyde while vigorously stirring. After reacting at room temperature for 30 minutes, cool it down to 0° C., further add 9.92 g (100 mmol) of cyclohexylamine, and slowly add 30 ml of 3.3 mol / L HCl aqueous solution (100 mmol) dropwise under cooling and vigorous stirring. Then remove the cooling device, slowly add 14.5 milliliters of 40% glyoxal aqueous solution (100mmol), and stir overnight at 50°C to obtain the desired compound, yield: 60-80%, melting point: 256-257°C . 1 H NMR (400MHz, CDCl 3 )δ10.98(s, IH), 7.46(s, 2H), 4.57(tt, J=11.8, 3.6Hz, 2H), 2.22(d, J=11.0Hz, 4H), 2.03-1.65(m, 10H ), 1.57-1.17(m, 6H).

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Abstract

The invention provides a synthetic method of proteasome inhibitor bortezomib and analogs.

Description

technical field [0001] The invention relates to a new chemical synthesis method, in particular to a synthesis method of proteasome inhibitor bortezomib and its analogs. Background technique [0002] Bortezomib (PS-341), trade name Velcade TM . In 2003, the U.S. Food and Drug Administration (FDA) quickly approved Velcade for the clinical treatment of multiple myeloma (MM); in 2005, the U.S. FDA and the European Medicines Agency approved Velcade for the first relapse of MM. Treatment. Currently, NCCN (National Comprehensive Cancer Network) diagnosis and treatment guidelines recommend Velcade as a second-line treatment for MCL (mantle cell lymphoma). [0003] The chemical name of bortezomib is: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarboxy)amino]propyl]amino] Butyl] boronic acid, the specific structure is as follows: [0004] [0005] Currently, there are two relatively representative synthetic routes reported, the difference mainly lies in the synthetic me...

Claims

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Application Information

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IPC IPC(8): C07F5/02
Inventor 李润涛葛泽梅孙崎韩利强程铁明
Owner PEKING UNIV
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