CN109704980B - Preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate - Google Patents
Preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate Download PDFInfo
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Abstract
The invention discloses a preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate, which comprises the following steps: (1) carrying out substitution reaction on 1, 2-difluoro-3-methoxybenzene shown in a formula (II) and ethyl acetoacetate to obtain (Z) -2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown in a formula (III);
(2) carrying out amination reaction on (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in a formula (III) to obtain (Z) -ethyl 3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in a formula (I);
Description
Technical Field
The invention belongs to the technical field of organic synthesis and medical intermediates, and particularly relates to a preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate.
Background
Endometriosis (EMs) refers to a common gynecological disease in women with intimal cells planted in abnormal locations. The incidence rate of the disease reaches 10.0 percent and is in a remarkably rising trend. It is mainly characterized by dysmenorrhea, pelvic pain and infertility. Statistically, about 1.76 million women suffer from endometriosis worldwide.
elagolix is an oral GnRH antagonist that has received approval from the U.S. food and drug administration for the treatment of pain due to endometriosis. The intermediate (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate used in the synthesis has the following structural formula:
this material can be synthesized generally by the following route:
however, the route is long and the yield is low.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the conventional synthesis route of ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate is long and the yield is low.
The invention adopts the following technical scheme to solve the technical problems:
a preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester comprises the following steps:
(1) carrying out substitution reaction on 1, 2-difluoro-3-methoxybenzene shown in a formula (II) and ethyl acetoacetate to obtain (Z) -2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown in a formula (III);
(2) carrying out amination reaction on (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in a formula (III) to obtain (Z) -ethyl 3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in a formula (I);
preferably, in the preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester according to the present invention, the operation of step (1) is as follows: dissolving 1, 2-difluoro-3-methoxybenzene shown in a formula (II) and ethyl acetoacetate in an organic solvent, adding alkali in an ice bath, and then carrying out substitution reaction; after the reaction is finished, spin-drying the solvent, adding a detergent into the residue for washing, separating the organic phase, spin-drying the solvent, and purifying the residue by using a silica gel column to obtain the (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester shown in the formula (III).
Preferably, in the preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester according to the present invention, the operation of step (II) is as follows: dissolving (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in the formula (3) in an organic solvent, adding ammonia water, stirring to carry out amination reaction, then separating the organic phase and spin-drying the solvent to obtain (Z) -ethyl 3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in the formula (I).
Preferably, in the preparation method of ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate, the organic solvent in the step (1) is any one selected from 1, 4-dioxane, THF, DMF, DMAc and diethylene glycol dimethyl ether.
Preferably, in the preparation method of ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate, the base in the step (1) is selected from any one of sodium hydride, lithium hexamethyldisilazide, potassium tert-butoxide and sodium tert-butoxide.
Preferably, in the preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester according to the present invention, the detergent in the step (1) is a mixture of ethyl acetate and hydrochloric acid solution.
Preferably, in the preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate, the process of the substitution reaction is heating to reflux reaction for 16-20 h; or heating to 90-160 ℃ for reacting for 18-20 h.
Preferably, in the preparation method of ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate, the organic solvent in the step (3) is one or a mixture of two or more of water, ethanol, methanol, THF, DMF, DMAc, methyl tert-butyl ether and diethylene glycol dimethyl ether.
Preferably, in the preparation method of the ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate, 1.0g of 1equiv of 1, 2-difluoro-3-methoxybenzene shown in the formula (II) is mixed with 5-20equiv of ethyl acetoacetate and dissolved by 8-14mL of organic solvent.
Preferably, in the preparation method of the (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester, every 0.81g of 1equiv of the (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester shown in the formula (I) is dissolved by 2-10mL of an organic solvent; and/or
The mass fraction of the ammonia water is 25%, and the volume of the ammonia water is 5-10 ml; and/or
The temperature of the amination reaction is 0-50 ℃.
The invention has the following beneficial effects:
according to the technical scheme, the target product can be obtained through two-step reaction by using the commercialized basic chemical raw material 1, 2-difluoro-3-methoxybenzene as the starting raw material, so that the synthetic route of the target product is simplified, and the method has the advantages of simplicity in purification, high efficiency, high yield and low cost, and is very suitable for industrial mass production.
Detailed Description
In order to facilitate the understanding of the technical solutions of the present invention for those skilled in the art, the technical solutions of the present invention will now be further described with reference to specific embodiments.
The preparation route of the (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as the formula (I) in the invention is as follows:
example 1
(1) The preparation method of the (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in the formula (III) comprises the following steps:
the method comprises the following operation steps: adding 1.0g, 1equiv. 1, 2-difluoro-3-methoxybenzene shown in formula (II), 10equiv. ethyl acetoacetate and 10mL1, 4-dioxane into a reaction bottle, dissolving, adding 60 percent and 1.1equiv. NaH into the reaction bottle under the condition of ice bath, heating to reflux, reacting for 18h, and cooling. After the TLC detection reaction was completed, the solvent was spin-dried, ethyl acetate and 2N aqueous hydrochloric acid were added to the residue, the organic phase was separated and the solvent was spin-dried, and the residue was purified by a silica gel column to obtain a colorless oil of (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate 0.72equiv., which is represented by formula (III), and the yield thereof was 72%. M + H+The calculated high resolution mass spectrum of (a) is 255.1027, the found value is 255.1027, and the structure can be confirmed by comparison.
(2) The preparation of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester shown in the formula (I) comprises the following steps:
the method comprises the following operation steps: 0.81g, 1equiv. (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate represented by the formula (III), 5mL of methyl tert-butyl ether and 5mL of 25% by mass aqueous ammonia were added to a reaction flask, and the mixture was stirred at 35 ℃ for reaction for 3 hours. After the reaction is finished, the organic phase is separated and the solvent is spin-dried, so that colorless oily substance (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as the formula (I) is obtained, wherein the yield is 99 percent. 254.1193 is obtained after the detection of high-resolution mass spectrum; m + H+The calculated high resolution mass spectrum of (a) is 254.1187, and the comparison confirms the structure of the product.
Example 2
(1) The preparation method of the (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in the formula (III) comprises the following steps:
the method comprises the following operation steps: 1.0g, 1equiv. 1, 2-difluoro-3-methoxybenzene represented by the formula (II), 5equiv. ethyl acetoacetate and 8mL THF are added into a reaction bottle, and after dissolution, 60% and 1.1equiv.LiHMDS are added into the reaction bottle under the condition of ice bath, heated to reflux, reacted for 18h and cooled. After the TLC detection reaction was completed, the solvent was spin-dried, ethyl acetate and 2N aqueous hydrochloric acid were added to the residue, the organic phase was separated and the solvent was spin-dried, and the residue was purified by a silica gel column to obtain a colorless oil of (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate 0.69equiv., as shown in formula (III), with a yield of 69%. The result of detection by high resolution mass spectrometry (ESI +) was 255.1032.
(2) The preparation of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester shown in the formula (I) comprises the following steps:
the method comprises the following operation steps: 0.81g, 1equiv. (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate represented by the formula (III), 5mL of 1, 4-dioxane, 5mL of 25% by mass aqueous ammonia were added to a reaction flask, and the mixture was stirred at 25 ℃ for reaction for 3 hours. After the reaction is finished, the organic phase is separated and the solvent is dried in a spinning mode, and colorless oily matter (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as a formula (I) is obtained, wherein the yield is 99%. The result of high resolution mass spectrometry detection was 254.1195.
Example 3
(1) The preparation method of the (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in the formula (III) comprises the following steps:
the method comprises the following operation steps: adding 1.0g, 1equiv. 1, 2-difluoro-3-methoxybenzene shown in formula (II), 15equiv. ethyl acetoacetate and 14mL of diethylene glycol dimethyl ether into a reaction bottle, dissolving, adding 60 percent and 1.1equiv. sodium tert-butoxide under the condition of ice bath, heating to 120 ℃, reacting for 18h, and cooling. After the TLC detection reaction was completed, the solvent was spin-dried, ethyl acetate and 2N aqueous hydrochloric acid were added to the residue, the organic phase was separated and the solvent was spin-dried, and the residue was purified by a silica gel column to obtain a colorless oil of (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate 0.70equiv., as shown in formula (III), with a yield of 70%. The result of detection by high resolution mass spectrometry (ESI +) was 255.1037.
(2) The preparation of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester shown in the formula (I) comprises the following steps:
the method comprises the following operation steps: adding 0.81g, 1equiv. ethyl (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoate as shown in the formula (III), 8mL of methyl tert-butyl ether and 2mL of ammonia water with the mass fraction of 25%, stirring and reacting at 0 ℃ for 24h, detecting by TLC (thin layer chromatography) to obtain an organic phase, and spin-drying the solvent to obtain a colorless oily substance, namely ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate as shown in the formula (I). The result of high resolution mass spectrometry detection was 254.1195.
Example 4
(1) The preparation method of the (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in the formula (III) comprises the following steps:
the method comprises the following operation steps: adding 1.0g, 1equiv. 1, 2-difluoro-3-methoxybenzene shown in formula (II), 20equiv. ethyl acetoacetate and 14mL DMAc into a reaction bottle, dissolving, adding 60 percent and 1.1equiv. potassium tert-butoxide under the condition of ice bath, heating to reflux, reacting for 18h, and cooling. After the TLC detection reaction was completed, the solvent was spin-dried, ethyl acetate and 2N aqueous hydrochloric acid were added to the residue, the organic phase was separated and the solvent was spin-dried, and the residue was purified by a silica gel column to obtain a colorless oil of (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate 0.73equiv., which is represented by formula (III), with a yield of 73%. The result of detection by high resolution mass spectrometry (ESI +) was 255.1033.
(2) The preparation of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester shown in the formula (I) comprises the following steps:
the method comprises the following operation steps: 0.81g, 1equiv. (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate represented by the formula (III), 10mL of diethylene glycol dimethyl ether and 5mL of 25% by mass aqueous ammonia were added to a reaction flask, and the mixture was stirred at 50 ℃ for reaction for 3 hours. After the reaction is finished, the organic phase is separated and the solvent is dried in a spinning mode, and colorless oily matter (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as a formula (I) is obtained, wherein the yield is 95%. The result of high resolution mass spectrometry detection was 254.1191.
Technical solution of the present invention, the present invention is described above by way of example with reference to the specific embodiments, and it is obvious that the specific implementation of the present invention is not limited by the above-described manner, and it is within the scope of the present invention to employ various insubstantial modifications of the method concept and technical solution of the present invention, or to directly apply the concept and technical solution of the present invention to other occasions without modification.
Claims (10)
1. A preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate is characterized by comprising the following steps:
(1) carrying out substitution reaction on 1, 2-difluoro-3-methoxybenzene shown in a formula (II) and ethyl acetoacetate to obtain (Z) -2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown in a formula (III);
(2) carrying out amination reaction on (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in a formula (III) to obtain (Z) -ethyl 3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in a formula (I);
2. the method for preparing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester according to claim 1, wherein the step (1) is carried out by: dissolving 1, 2-difluoro-3-methoxybenzene shown in a formula (II) and ethyl acetoacetate in an organic solvent, adding alkali in an ice bath, and then carrying out substitution reaction; after the reaction is finished, spin-drying the solvent, adding a detergent into the residue for washing, separating the organic phase, spin-drying the solvent, and purifying the residue by using a silica gel column to obtain the (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester shown in the formula (III).
3. The method for preparing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 1, wherein the step (II) is performed as follows: dissolving (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in the formula (3) in an organic solvent, adding ammonia water, stirring to carry out amination reaction, then separating the organic phase and spin-drying the solvent to obtain (Z) -ethyl 3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in the formula (I).
4. The method for preparing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 2, wherein the organic solvent used in the step (1) is any one selected from the group consisting of 1, 4-dioxane, THF, DMF, DMAc and diethylene glycol dimethyl ether.
5. The method for synthesizing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 2, wherein the base in the step (1) is selected from any one of sodium hydride, lithium hexamethyldisilazide, potassium tert-butoxide and sodium tert-butoxide.
6. The method for preparing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester according to claim 2, wherein the washing agent in the step (1) is a mixture of ethyl acetate and hydrochloric acid solution.
7. The preparation method of ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 1 or 2, wherein the substitution reaction is carried out by heating to reflux for 16-20 h; or heating to 90-160 ℃ for reaction for 18-20 h.
8. The process according to claim 3, wherein the organic solvent used in step (3) is selected from the group consisting of water, ethanol, methanol, THF, DMF, DMAc, methyl tert-butyl ether, and diethylene glycol dimethyl ether.
9. The process for producing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 2, wherein 1.0g of 1equiv of 1, 2-difluoro-3-methoxybenzene represented by the formula (II) is mixed with 5 to 20equiv of ethyl acetoacetate and dissolved in 8 to 14mL of an organic solvent.
10. The method for preparing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 3, wherein ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate represented by the formula (I) is dissolved in 2 to 10mL of an organic solvent per 0.81g, 1 equiv; and/or
The mass fraction of the ammonia water is 25%, and the volume of the ammonia water is 5-10 ml; and/or
The temperature of the amination reaction is 0-50 ℃.
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