A kind of preparation method of (z)-3-amino-2-(2-fluoro-3-methoxyphenyl)-2-butenoic acid ethyl ester
A technology of methoxyphenyl and ethyl crotonate, which is applied in the fields of organic synthesis and pharmaceutical intermediates, can solve the problems of long routes and low yields, and achieve the effects of simplified synthetic routes, high yields and simple purification
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Embodiment 1
[0032] (1) Preparation of (Z)-2-(2-fluoro-3-methoxyphenyl)-2-butenoic acid ethyl ester as shown in formula (III), the preparation route is as follows:
[0033]
[0034] Operation steps: add 1.0g, 1equiv. 1,2-difluoro-3-methoxybenzene as shown in formula (II), 10equiv. ethyl acetoacetate, 10mL1,4-dioxane to the reaction flask , After dissolving, add 60%, 1.1 equiv.NaH to it under the condition of ice bath, heat to reflux, react for 18h, and cool. After the reaction was detected by TLC, the solvent was spin-dried, ethyl acetate and 2N hydrochloric acid aqueous solution were added to the residue, the organic phase was separated and the solvent was spin-dried, and the residue was purified with a silica gel column to obtain a colorless oil as shown in formula (III). (Z)-2-(2-fluoro-3-methoxyphenyl)-2-butenoic acid ethyl ester 0.72 equiv., the yield is 72%. M+H + The calculated value of the high-resolution mass spectrum is 255.1027, and the measured value is 255.1027. After com...
Embodiment 2
[0039] (1) Preparation of (Z)-2-(2-fluoro-3-methoxyphenyl)-2-butenoic acid ethyl ester as shown in formula (III), the preparation route is as follows:
[0040]
[0041] Operation steps: add 1.0g, 1equiv. 1,2-difluoro-3-methoxybenzene as shown in formula (II), 5equiv. ethyl acetoacetate, 8mL THF to the reaction flask, after dissolving, place in ice Add 60%, 1.1equiv.LiHMDS to it under bath conditions, heat to reflux, react for 18h, and cool. After the reaction was detected by TLC, the solvent was spin-dried, ethyl acetate and 2N hydrochloric acid aqueous solution were added to the residue, the organic phase was separated and the solvent was spin-dried, and the residue was purified with a silica gel column to obtain a colorless oil as shown in formula (III). The indicated ethyl (Z)-2-(2-fluoro-3-methoxyphenyl)-2-butenoate was 0.69 equiv., and the yield was 69%. It was detected by high-resolution mass spectrometry (ESI+), and the result was 255.1032.
[0042] (2) Preparation...
Embodiment 3
[0046] (1) Preparation of (Z)-2-(2-fluoro-3-methoxyphenyl)-2-butenoic acid ethyl ester as shown in formula (III), the preparation route is as follows:
[0047]
[0048] Operation steps: add 1.0g to the reaction flask, 1equiv. 1,2-difluoro-3-methoxybenzene as shown in formula (II), 15equiv. ethyl acetoacetate, 14mL diethylene glycol dimethyl ether , After dissolving, add 60%, 1.1 equiv. sodium tert-butoxide to it under ice-bath conditions, heat to 120°C, react for 18h, and cool. After the reaction was detected by TLC, the solvent was spin-dried, ethyl acetate and 2N hydrochloric acid aqueous solution were added to the residue, the organic phase was separated and the solvent was spin-dried, and the residue was purified with a silica gel column to obtain a colorless oil as shown in formula (III). (Z)-2-(2-fluoro-3-methoxyphenyl)-2-butenoic acid ethyl ester 0.70 equiv., the yield is 70%. It was detected by high-resolution mass spectrometry (ESI+), and the result was 255.1037. ...
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