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Synthetic method of eribulin intermediate ER806047

A synthesis method and intermediate technology, which are applied in the synthesis field of Eribulin intermediate ER806047, can solve the problems of difficult to completely remove sulfur-containing by-products, increase the usage of Pd/C, and be difficult to realize industrialization, etc., so as to avoid catalysts. Poisoning risk, low production cost, and the effect of reducing the generation of three wastes

Inactive Publication Date: 2020-07-28
SHANGHAI MAOSHENG KAIHUI TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The method adopts a two-step reaction with longer reaction steps, and the sulfonyl chloride used in the first step reaction has obvious and unavoidable defects: 1. toxic waste gas sulfur dioxide will be produced in the reaction; A large amount of waste water; 3. In addition, post-treatment is difficult to completely remove sulfur-containing by-products, resulting in catalyst poisoning in the Pd / C dechlorination process, so that the reaction is difficult to carry out or requires a significant increase in the use of Pd / C, increasing the risk of the reaction, Lead to high cost or even difficult to realize industrialization

Method used

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Experimental program
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Effect test

Embodiment 1

[0035] Synthesis of compound b:

[0036] plan 1:

[0037] Under the protection of nitrogen, add 1,2-dichloroethane (72L, 12V), pyridine (2.19kg, 27.75mol), triphenylphosphine (10.92kg, 42.63mol) into a 100L reactor, heat up and reflux to distill off the solvent 12L, then cooled to 25°C, then added 1,2-O-isopropylidene-α-D-glucuronic acid-6,3-lactone (6kg, 27.75mol), I 2 (3.52kg, 13.88mol), heated and refluxed for 11 hours, detected by HPLC or TLC, and the reaction ended. Cool down to 25°C, add saturated aqueous sodium thiosulfate solution (18L, 3V), let stand for liquid separation, extract the aqueous phase with 1,2-dichloroethane (6L, 1V) twice, combine the organic phases, and depressurize Concentrate to 2V (12L), perform flash column chromatography, and the eluent is petroleum ether / ethyl acetate to obtain the compound of formula b (4.44kg, 22.2mol).

[0038] 1 H-NMR (400MHz, CHLOROFORM-d 6 )δppm 1.36(s,3H)1.52(s,3H)2.66-2.80(m,2H)4.84(dd,J=10.39,3.55Hz,2H)4.96-5.06(m,1...

specific Embodiment

[0077] Synthesis of compound a1:

[0078] Under nitrogen protection, compound a 1,2-O-isopropylidene-α-D-glucurono-6,3-lactone (50g, 0.231mol) was dissolved in dichloromethane (150ml, 15v), Pyridine (73.08g, 0.925mol) was added, the temperature of the system was cooled to -10~-5°C, and a solution of sulfonyl chloride (38.5g, 0.324mol) in DCM (100ml, 2V) was added dropwise. After the dropwise addition, firstly keep it warm at -10-5°C for 1 hour, then keep it at 0-5°C for 1 hour, and finally raise it to about 25°C and keep it warm for 1 hour. HPLC / TLC detects that the reaction of raw materials is complete. Then the reaction system was cooled to 0-15°C, and the reaction system was slowly added to a saturated aqueous solution of sodium bicarbonate (500ml, 10V), separated, the organic phase was washed with saturated brine (100ml, 2V), and concentrated to dryness at 30°C to obtain Compound a1 (50 g, 0.21 mol), the yield was 92.1%, and it was directly submitted to the next step.

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Abstract

The invention discloses a synthetic method of an eribulin intermediate ER806047 shown as a formula (b), comprising the following steps of: using 1, 2-O-isopropylidene-alpha-D-glucuronic acid-6, 3-lactone as a raw material, and carrying out one-step oxidation-reduction reaction for dehydroxylation synthesis of the eribulin intermediate ER806047. The synthetic method has the advantages of short reaction route, high yield, simplicity and convenience in operation, low cost, suitability for industrial production and the like. The structure of the eribulin intermediate ER806047 disclosed by the invention is as shown in the specification.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a synthesis method of eribulin intermediate ER806047. Background technique [0002] As an anticancer drug, Eribulin can be assembled from three fragments through a series of chemical reactions, and the key fragment is ER806067 (CAS: 871348-24-2). A leading compound synthesized from this fragment is ER806047. [0003] Currently existing patents or documents (WO2005 / 118565A1) in the process of synthesizing ER806067: there are disadvantages such as cumbersome operation, low yield, more wastes, poor reaction stability, etc., so that the production risk is high and the cost is high, so it is not applicable in industrial production. [0004] Among them, the method described in the patent document (WO2005 / 118565 A1) uses compound a as a raw material to first synthesize intermediate compound a1, and then synthesize compound b. The synthesis process is shown in ro...

Claims

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Application Information

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IPC IPC(8): C07D493/14
CPCC07D493/14
Inventor 王甜甜刘文应永铖
Owner SHANGHAI MAOSHENG KAIHUI TECH CO LTD
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