Preparation method of high-optical purity bortezomib and intermediate of bortezomib

A bortezomib and optical purity technology, applied in the field of drug synthesis, can solve the problems of difficult removal of isomers and unsatisfactory chiral purity, and achieve the effect of high optical purity

Active Publication Date: 2013-09-18
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the use of the chiral ligand pinanediol is avoided, the chiral purity ob

Method used

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  • Preparation method of high-optical purity bortezomib and intermediate of bortezomib
  • Preparation method of high-optical purity bortezomib and intermediate of bortezomib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1: Synthesis of compound of formula II

[0071] Add 6.2L of tetrahydrofuran to a 10L clean and dry reactor, add 232.9g of isobutylboric acid and 600g of formula I compound in sequence, react at room temperature for 16 hours, and distill under reduced pressure to obtain a colorless and transparent liquid, and add 8L of n-hexane to it , Washed once with 3L of saturated sodium chloride, collected the organic phase, dried over anhydrous sodium sulfate, and distilled under reduced pressure until there was no dripping liquid to obtain 599 g of colorless oil with a yield of 100% and a GC content of 99.8%.

[0072]

Embodiment 2

[0073] Example 2: Synthesis of compound of formula III

[0074] Under nitrogen protection, add 6L of tetrahydrofuran, 500g of formula II compound into a 10L clean and dry reactor, cool to -65°C, add 855ml of lithium diisopropylamide (2mol / L) dropwise for 2-3 hours, after the addition is complete , Continue the reaction for 30 minutes, add 350g of anhydrous zinc chloride in batches, after the addition, continue to react for 30 minutes, place at room temperature to continue the reaction for 8 hours, the reaction is over, the reaction is concentrated to no dripping liquid, add 4L saturated chlorinated The reaction was quenched by ammonium and extracted twice by adding 8L of n-hexane, washed with 4L of saturated sodium chloride solution, combined the organic phases, dried with 2kg of anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a pale yellow oil, 524g, yield, 90 %, GC content 92%.

[0075] 1 H NMR (CDCl 3 , 400MHz) δ 0.80-0.83 (m, 6H), 0.91-1.89 (m, 25H)...

Embodiment 3

[0076] Example 3: Synthesis of formula IV compound hydrochloride

[0077] Under nitrogen protection, add 4.8L of tetrahydrofuran, 500g of compound of formula III to a 10L clean and dry reaction kettle, cool to -65℃, dropwise add 1614ml (bistrimethylsilylamino) lithium (1mol / L), 2-3 hours After the dripping is completed, place at room temperature to continue the reaction for 6 hours. After the reaction is completed, the reaction is concentrated to no dripping liquid, a large amount of yellow solid is precipitated by adding n-hexane, filtered, the filtrate is concentrated to dryness, and 2L dioxane is added 4L 2N ether hydrogen chloride was added dropwise at -5~5℃, reacted for 12 hours, filtered, the filtrate was concentrated to no dripping liquid, a large amount of white solid was precipitated by adding n-hexane, filtered and dried to obtain the hydrochloric acid of formula IV compound Salt 417.9g, the yield is 80%.

[0078] 1 H NMR (DMSO- d 6 , 400MHz) δ 0.80-0.85 (m, 6H), 0.98-1....

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Abstract

The invention discloses a preparation method of high-optical purity bortezomib and an intermediate of bortezomib, and belongs to the field of pharmaceutical synthesis. The invention discloses a synthetic method of bortezomib or boric anhydride thereof and related intermediate of bortezomib or boric anhydride. The invention firstly discloses bortezomib intermediate shown in a formula A and a preparation method thereof, and further discloses a method for preparing bortezomib by the intermediate. The bortezomib, which is obtained by introducing novel chiral ligand in the method, is high optical purity, low in material cost, easily available, simple and convenient to operate in the process, capable of greatly lowering the production cost of the process, high in product yield, high in optical purity and suitable for the industrial production of bortezomib, wherein R is Cl, Br, NH2 or FORMULA; and R1 is hydrogen or an amino protecting group.

Description

technical field [0001] The invention relates to a method for preparing bortezomib with high optical purity and an intermediate thereof, belonging to the technical field of drug synthesis, and relates to a new preparation method for synthesizing bortezomib or its boric acid anhydride and related intermediates. Background technique [0002] Bortezomib (English name: Bortezomib, trade name: Velcade) is a protease inhibitor developed by Millennium Corporation of the United States. It was approved by the FDA in 2003 and is the first drug approved for the treatment of multiple myeloma in the past ten years. It is also the first cancer drug targeting protein-degrading enzyme complexes. The research on its mechanism of action won the Nobel Prize in Chemistry in 2004. Currently, bortezomib is regarded as a breakthrough therapy for the treatment of relapsed and refractory multiple myeloma, which can slow, reverse or stop the progression of patients who have failed two or more lines of...

Claims

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Application Information

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IPC IPC(8): C07K5/078C07F5/04
CPCY02P20/55
Inventor 赵俊杜有国赵宇蔡开明吴晨晖杨建楠
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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