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Preparation methods of 2-(amino)ethyl methyl sulfone salt and intermediate of 2-(amino)ethyl methyl sulfone salts

A technology of ethyl methyl sulfone salt and amino group, which is applied in the field of preparation of 2-ethyl methyl sulfone salt and its intermediates, which can solve the problems of large environmental pollution and unfavorable industrial production

Inactive Publication Date: 2013-09-25
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The technical problem to be solved by the present invention is, in order to overcome the large environmental pollution in the method for preparing 2-(amino) ethyl methyl sulfone salt in the prior art, be unfavorable for the defective of industrialized production, and provide a kind of 2-(amino) ethyl methyl sulfone salt ) Preparation method of ethyl methyl sulfone salt and intermediate thereof

Method used

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  • Preparation methods of 2-(amino)ethyl methyl sulfone salt and intermediate of 2-(amino)ethyl methyl sulfone salts
  • Preparation methods of 2-(amino)ethyl methyl sulfone salt and intermediate of 2-(amino)ethyl methyl sulfone salts
  • Preparation methods of 2-(amino)ethyl methyl sulfone salt and intermediate of 2-(amino)ethyl methyl sulfone salts

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Embodiment 1

[0034] The synthesis of embodiment 1 lapatinib

[0035] Add 5-[4-[[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]amino]-6-quinazoline]-2-furancarbaldehyde (4.73 g, 10mmol), 2-(amino)ethylmethylsulfone hydrochloride (2.56g, 16mmol), diisopropylethylamine (5.17g, 40mmol), acetic acid (2.4g, 40mmol) and 50ml tetrahydrofuran, Stir the reaction at room temperature for 3 h, add sodium triacetoxyborohydride (8.48 g, 40 mmol) in batches, and react at room temperature for 12 h. Add 30ml of 20% aqueous sodium hydroxide solution and stir to separate the layers, and extract the inorganic phase with ethyl acetate. Combine the organic phases, concentrate, add 50ml of THF to the residue to dissolve, add p-toluenesulfonic acid aqueous solution (7.6g, 40mmol / 15ml), stir at room temperature for 12h, filter, and dry the filter cake to obtain 7.58g of light yellow solid, melting point 244-246°C , yield 82.8%, HPLC purity: 99.6%.

[0036] The structural identification data are as follows: HNMR (DM...

Embodiment 2

[0037] The synthesis of embodiment 22-chloroethyl methyl sulfone

[0038] Add 2-hydroxyethyl sulfone (6.21g, 50mmol), pyridine (3.9g, 50mmol) and 50ml toluene into a 250ml reaction flask, slowly add thionyl chloride (17.8g, 0.15mol) dropwise, and heat to reflux after dropping 2h, cooling. Add 50 ml of ice water and stir, separate the liquids, extract the aqueous phase with dichloromethane, combine the organic phases, dry and concentrate to obtain 5.9 g of brown oil, which can be directly used in the next step reaction with a yield of 83.1%.

Embodiment 3

[0039] Synthesis of Example 32-(2-thiamphenicol ethyl)isoindole-1,3-dione

[0040] Add potassium phthalimide (5.56g, 30mmol), sodium iodide (0.42g, 2.8mmol) and 30ml of DMF in a 250ml reaction flask, raise the temperature to 100°C, and add 2-chloroethylmethyl sulfone ( 4.2g, 30mmol), keep warm at 100°C for 2.5h, and cool. Add 50ml of water and stir for 1 hour, filter, and dry the filter cake to obtain 6.75g of white solid with a melting point of 172-174°C and a yield of 88.8%.

[0041] The structural identification data are as follows: H-NMR (CDCl 3 ): δ7.88(m, 2H), 7.75(m, 2H), 4.20(t, 2H), 3.43(2, 1H), 3.03(s, 3H)

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Abstract

The invention discloses a preparation method of a 2-(amino)ethyl methyl sulfone salt represented by formula 1. The preparation method comprises: (1) in an organic solvent and under the action of a substitution reaction catalyst, a compound 3 is reacted with a compound 4; and X is a halogen, and M is an alkali metal or an alkaline earth metal; and (2) a compound 2 prepared by the step (1) is reacted with an acidic aqueous solution to obtain a compound 1; n is equal to 1 or 2; m is equal to 1 or 2; and HmA is an organic acid or an inorganic acid. The invention also discloses a preparation method of the compound 2. The preparation method of the compound 2 comprises: 1) in an organic solvent and under the action of an alkali, a compound 5 is reacted with a halogenation reagent; and 2) in the organic solvent, under the action of the substitution reaction catalyst, the compound 4 is reacted with the compound 3 prepared by the step 1), X is a halogen, and M is an alkali metal or an alkaline earth metal. The preparation methods have low cost and easy availability of raw materials, have no environmental pollution factors, and are suitable for industrial mass production.

Description

technical field [0001] The invention relates to a preparation method of 2-(amino)ethyl methyl sulfone salt and its intermediate. Background technique [0002] [0003] Lapatinib, chemical name N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[[[2-(methylsulfonyl)ethyl ]amino]methyl]-2-furyl]-4-quinazolinamine di(p-toluenesulfonate) monohydrate is a new type of tyrosine kinase inhibitor developed by GlaxoSmithKline for For the treatment of patients with advanced or metastatic breast cancer with overexpression of HER-2, it was approved for marketing by the US FDA in March 2007. [0004] 2-(amino)ethyl methyl sulfone salt is an important intermediate for the preparation of lapatinib, which is combined with 5-[4-[[3-chloro-4-[(3-fluorophenyl) The reductive amination of methoxy]phenyl]amino]-6-quinazoline]-2-furancarbaldehyde can obtain lapatinib, and the synthetic route reported in literature is as follows: [0005] [0006] Among them, 2-(amino)ethyl methyl sulfide ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C317/28C07C315/04
Inventor 史娇阳吴雪松岑均达
Owner SHANGHAI INST OF PHARMA IND CO LTD
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