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Preparation method of elexacaftor intermediate and application thereof

A technology of intermediates and reactions, applied in the field of synthesis of pharmaceutical intermediates, can solve problems such as unfavorable scale-up production and harsh reaction conditions

Active Publication Date: 2020-11-17
SUZHOU VIGONVITA LIFE SCIENCES CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In addition, the patent JP2016-104702A describes the preparation of 3,3,3-trifluoro-2,3-trifluoro-2, Methyl 2-dimethylpropionate, sulfur tetrafluoride is a fuming toxic gas with a strong pungent smell, hydrofluoric acid is a corrosive strong acid with a strong pungent smell, and the reaction needs to be carried out in special stainless steel equipment , the reaction conditions are harsh, and the yield is only 20%, which is not conducive to large-scale production. The reaction equation is as follows:

Method used

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  • Preparation method of elexacaftor intermediate and application thereof
  • Preparation method of elexacaftor intermediate and application thereof
  • Preparation method of elexacaftor intermediate and application thereof

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preparation example Construction

[0084] The present invention also provides a method for preparing 3,3,3-trifluoro-2,2-dimethylpropan-1-ol, the method comprising the following steps:

[0085] (1) Add 3,3,3-trifluoropropionic acid and protective reagent to the solvent, continue to add condensation reagent to obtain intermediate A, the reaction equation is as follows:

[0086]

[0087] Wherein, G is selected from -OR 3 and-NR 4 R 5 ,in,

[0088] R 3 selected from substituted or unsubstituted C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0089] R 4 and R 5 are independently selected from substituted or unsubstituted C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, or R 4 and R 5 Linked to form a substituted or unsubstituted 3-7 membered heterocyclic group;

[0090] (2) The above-mentioned intermediate A, methylating reagent and alkali are added in the solvent, and the reaction obtains the ...

Embodiment 1

[0109] Add 3,3,3-trifluoropropionic acid (500.0g), dichloromethane (5L), cyclohexanol (585g), and DMAP (95.3g) into the reaction flask, stir and dissolve, then cool down to -5~15°C, Add DCC (844g) in batches to it, and rise to room temperature to react for 3h, the raw material is completely converted, then add 1N hydrochloric acid aqueous solution (0.8L), 5% sodium bicarbonate aqueous solution (1L), and saturated brine (500mL) to wash , the organic phase was dried and concentrated to obtain 857g of crude product, which was distilled under reduced pressure to obtain 803g of 3,3,3,-cyclohexyl trifluoropropionate, with a molar yield of 98%.

[0110] Add 3,3,3,-cyclohexyl trifluoropropionate (150.0g), acetone (900mL), potassium carbonate (295g) and methyl iodide (253g) into a 2L three-necked flask, stir well and heat up to reflux for 6h. The reaction solution was filtered, the filter cake was rinsed with a small amount of acetone, the filtrates were combined, and purified by disti...

Embodiment 2

[0113] Add 3,3,3-trifluoropropionic acid (50.0g), tetrahydrofuran (500mL), 4-methoxyphenol (48.5g), DMAP (9.5g) into the reaction flask, stir to dissolve and cool down to -5~15 ℃, added EDCI (36g) in batches, raised to room temperature and reacted for 3h, the raw material was completely converted, then added 1N aqueous hydrochloric acid (0.2L), washed with 5% aqueous sodium bicarbonate (0.2L), and dried the organic phase , concentrated, and purified by distillation under reduced pressure to obtain 88 g of 3,3,3,-p-methoxyphenyl trifluoropropionate, with a molar yield of 97%.

[0114] Add 3,3,3,-p-methoxyphenyl trifluoropropionate (30.0g), acetonitrile (200mL), cesium carbonate (84g), dimethyl sulfate (48.4g) into the reaction flask, stir well and then heat up After reflux for 4 hours, the reaction liquid was filtered, and the filtrate was purified by distillation to obtain 31.2 g of 3,3,3,-trifluoropropionic acid-2,2-dimethyl-p-methoxyphenyl ester, with a molar yield of 92%. ...

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Abstract

The invention relates to a preparation method and application of an elexacaftor intermediate shown as a formula I shown in the specification, and particularly relates to a preparation method of 3,3,3-trifluoro-2,2-dimethylpropan-1-ol. The method comprises the following steps: (1) adding 3,3,3-trifluoropropionic acid and a protective reagent into a solvent, and adding a condensation reagent to obtain an intermediate A; (2) adding the intermediate A, a methylation reagent and alkali into a solvent, and reacting to obtain an intermediate B; and (3) dissolving the intermediate B into a solvent, adding a reduction reagent, and reacting to obtain the 3,3,3-trifluoro-2,2-dimethylpropan-1-ol.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, in particular to intermediates for the preparation of 3,3,3-trifluoro-2,2-dimethylpropan-1-ol and 3,3,3-trifluoro-2 , The synthetic method of 2-dimethylpropan-1-ol. Background technique [0002] Elexacaftor (VX-445) is a new generation of cystic fibrosis transmembrane conductance regulator (CFTR) protein correction agent, it is used to restore the function of CFTR protein carrying F508del mutation, composed of Elexacaftor (VX-445), tezacaftor and ivacaftor three A new drug for combination therapy consisting of two drugs, which can be used to treat cystic fibrosis (CF) patients carrying a F508del gene mutation and a function-minimizing gene mutation. [0003] The prior art patent CN110267948A describes the preparation of 3,3,3-trifluoro-2,2- The preparation of dimethylpropan-1-ol and 3,3,3-trifluoro-2,2-dimethylpropionic acid currently has great difficulties. ...

Claims

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Application Information

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IPC IPC(8): C07C69/63C07C67/343C07C67/08C07D263/26C07C29/147C07C31/38
CPCC07C69/63C07D263/26C07C29/147C07C67/343C07C67/08C07C2601/14C07C31/38Y02P20/55
Inventor 李志强赵晓磊石松安龚明杨春田广辉
Owner SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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