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Bortezomib intermediate, and preparation method and application thereof

A technology of bortezomib and intermediates, applied in the field of drug synthesis, can solve the problems of long synthesis route, not suitable for industrialized production and the like, and achieves the effects of high recovery rate, meeting the needs of large-scale industrial production, and cheap and easy-to-obtain raw materials

Active Publication Date: 2013-12-04
SHANGHAI ACEBRIGHT PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthetic route is relatively long, and the multi-step reaction needs to be carried out at a lower temperature, which is not suitable for industrial production requirements.

Method used

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  • Bortezomib intermediate, and preparation method and application thereof
  • Bortezomib intermediate, and preparation method and application thereof
  • Bortezomib intermediate, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1: preparation formula 3 compound

[0041]

[0042] Add (+)-pinanediol (17.0g, 0.10mol) and 2-methylpropylboronic acid (11.2g, 0.11mol) to 200mL diethyl ether in sequence, heat the mixture to 40°C, and stir for 8 hours; end Reaction, the mixture was dried with anhydrous magnesium sulfate; filtered; the filtrate was concentrated under reduced pressure to dryness; slurried with 200mL isopropyl ether for 2 hours; then filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain 22.4g (0.095mol, molar yield) of the compound of formula 3 rate 95%).

[0043] 1 H NMR(300MHz,DMSO-d6):4.28(1H,dd,J=8.8Hz,2.0);2.30(1H,m);2.18(1H,m);1.96(1H,t,J=5.3);1.86 (1H,m);1.78(1H,set,J=6.8);1.68(1H,m);1.30(3H,s);1.25(3H,s);1.01(1H,d);0.9(6H,d ,J=6.6); 0.81(3H,s); 0.69(2H,m).

Embodiment 2

[0044] Embodiment 2: preparation formula 1 compound

[0045]

[0046] Under the protection of argon, the ZnCl 2 Add 32.7g (0.24mol) into the reaction flask, then add 200mL of tetrahydrofuran, raise the temperature to 40°C and stir for 8 hours for later use.

[0047] Under the protection of argon, add 20.2g (0.2mol) of diisopropylamine into the reaction flask, and then add 60mL of methyl tert-butyl ether, cool to -10°C under stirring, and add dropwise at a concentration of 2.5 within 0.5 to 1 hour. Add 80 mL (0.2 mol) of mol / L n-butyllithium n-hexane solution to the above diisopropylamine solution, and stir the reaction at -10°C to -5°C for 1 hour under temperature control to prepare lithium diisopropylamide (LDA) The solution is ready for use.

[0048] Under the protection of argon, add 37.8g (0.16mol) of the compound of formula 3 into the reaction flask, then add 200mL of toluene and 27.2g (0.32mol) of dichloromethane, cool the mixture to -60°C, and control the temperatu...

Embodiment 3

[0050] Embodiment 3: preparation formula 1 compound

[0051]

[0052] Under the protection of argon, the anhydrous FeCl 3 Add 48.7g (0.3mol) into the reaction flask, then add 200mL of tetrahydrofuran, raise the temperature to 40°C and stir for 8 hours for later use.

[0053] Under the protection of argon, add 20.2g (0.2mol) of diisopropylamine into the reaction flask, and then add 60mL of methyl tert-butyl ether, cool to -10°C under stirring, and add dropwise at a concentration of 2.5 within 0.5 to 1 hour. Add 80 mL (0.2 mol) of mol / L n-butyllithium n-hexane solution to the above diisopropylamine solution, and stir the reaction at -10°C to -5°C for 1 hour under temperature control to prepare lithium diisopropylamide (LDA) The solution is ready for use.

[0054] Under the protection of argon, add 35.4g (0.15mol) of the compound of formula 3 into the reaction flask, then add 200mL of toluene and 51g (0.60mol) of dibromomethane, cool the mixture to -60°C, and control the tem...

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Abstract

The invention discloses a bortezomib intermediate, and a preparation method and an application thereof. The intermediate has a chemical structural formula shown as formula I shown in the description, the preparation of the intermediate comprises a condensation reaction of the formula I compound and a phthalimide metal salt, and the condensation reaction is shown in the description, wherein X in the formula represents halogen and M represents an alkali metal. The application of the intermediate means that a known formula II intermediate of bortezomib is prepared by removing the protective group of the amine group of the formula I intermediate under an alkali condition, and the reaction is shown in the description. According to the technical scheme, high-purity bortezomib can be synthesized by utilizing cheap and easily-available raw materials and with a low cost, large-scale industrialized production requirement on bortezomib is satisfied, and the technical scheme has practical value.

Description

technical field [0001] The invention relates to a bortezomib intermediate and its preparation method and application, belonging to the technical field of drug synthesis. Background technique [0002] In recent years, boron acid and ester compounds have shown a variety of medicinal biological activities as proteasome inhibitors and have special prospects. Boronic acid peptide compounds are the most important protease inhibitors at present. Some studies have clearly shown that it has good proteasome inhibitory activity and selectivity, mainly inhibiting the activity of chymotrypsin in the core protease 20S, among which bortezomib is the most important boronic acid peptide compound. [0003] Bortezomib, trade name: Velcade, chemical name: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[ (Pyrazine carboxyl) amino] propyl group] amino] butyl] boronic acid, has following structural formula: Bortezomib (Bortezomib) has shown significant anticancer activity in human tumor xenograft mo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02
CPCY02P20/55
Inventor 郭茂君余利兵杨勤刚孙猛
Owner SHANGHAI ACEBRIGHT PHARMA CO LTD
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