CN109734616B - Method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by two-step method - Google Patents

Method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by two-step method Download PDF

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CN109734616B
CN109734616B CN201910118481.9A CN201910118481A CN109734616B CN 109734616 B CN109734616 B CN 109734616B CN 201910118481 A CN201910118481 A CN 201910118481A CN 109734616 B CN109734616 B CN 109734616B
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methoxyphenyl
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CN109734616A (en
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柳海杰
胡志刚
许良志
何大荣
杜小鹏
钱祝进
何勇
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Anhui Nature Pharmaceutical Co ltd
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Abstract

The invention discloses a method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by a two-step method, which comprises the following steps: (1) coupling reaction is carried out on 2-fluoro-1-iodo-3-methoxybenzene shown as a formula (II) and ethyl acetoacetate to obtain (Z) -2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as 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

Method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by two-step method
Technical Field
The invention belongs to the technical field of organic synthesis and medical intermediates, and particularly relates to a method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by a two-step method.
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.
Compared with the previously known GnRH agonist (GnRHA), the oral administration bioavailability is higher, the pain feeling and anaphylactic reaction caused by injection are avoided, and the compliance of patients is increased.
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:
the synthesis route in the prior art is synthesized by a five-step method, and has the defects of long synthesis route, complex process, high equipment cost investment, difficult control of the reaction process and low yield.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the conventional synthesis route of elagolix intermediate (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester is long and the yield is low.
The invention adopts the following technical scheme to solve the technical problems:
the method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by a two-step method comprises the following steps:
(1) coupling reaction is carried out on 2-fluoro-1-iodo-3-methoxybenzene shown as a formula (II) and ethyl acetoacetate to obtain (Z) -2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as 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, the method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by the two-step method disclosed by the invention comprises the following specific operations in the step (1): adding 2-fluoro-1-iodo-3-methoxybenzene shown in formula (II), ethanol, a catalyst, alkali and an organic solvent into a reactor, introducing nitrogen for bubbling, then adding ethyl acetoacetate into the reactor, and heating for coupling reaction; after the reaction is finished, adding a detergent into the mixture, separating and purifying an organic phase to obtain (Z) -2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as the formula (III).
Preferably, in the method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by using the two-step method, the specific operation of the step (2) is as follows: dissolving (Z) -2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as a formula (III) in an organic solvent, adding ammonia water into the organic solvent, and stirring the mixture to perform amination reaction; after the reaction is finished, (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown in the formula (I) is obtained by separation.
Preferably, in the two-step method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester, the catalyst is any one of cuprous iodide, cuprous bromide, cuprous chloride, copper trifluoromethanesulfonate, cuprous trifluoromethanesulfonate and cuprous bromide-dimethyl sulfide complex.
Preferably, in the two-step method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester according to the present invention, the base in step (2) is any one selected from potassium phosphate, dipotassium hydrogen phosphate, potassium carbonate and potassium hydrogen carbonate.
Preferably, in the two-step method for synthesizing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate, the organic solvent in the step (2) is selected from any one of dimethyl sulfoxide, N-dimethylformamide, dimethylacetamide and sulfolane; and/or
The detergent is formed by mixing ethyl acetate and a hydrochloric acid aqueous solution.
Preferably, in the method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by the two-step method, the reaction temperature of the coupling reaction is 50-150 ℃.
Preferably, in the two-step method for synthesizing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to the present invention, the organic solvent in step (3) is selected from any one of methyl tert-butyl ether, 1, 4-dioxane, 2-methyltetrahydrofuran, N-dimethylformamide, dimethylacetamide, and diethylene glycol dimethyl ether.
Preferably, in the two-step method for synthesizing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate, in the step (1), 1.0g and 1.0equiv of 2-fluoro-1-iodo-3-methoxybenzene represented by the formula (II) is mixed with 1-6equiv of ethyl acetoacetate, 2-4equiv of base, 0.2-0.3equiv of catalyst and 2-5equiv of ethanol, and then dissolved in 5-10mL of organic solvent.
Preferably, in the two-step method for synthesizing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate, in the step (2), every 0.81g of ethyl (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoate represented by the formula (III) is dissolved in 5-10mL of an organic solvent by 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 ℃.
The invention has the following beneficial effects:
the technical method of the invention uses commercial basic chemical raw material 2-fluoro-1-iodo-3-methoxybenzene as the starting material, and the target product can be obtained through two-step reaction, so that the synthesis route of the target product is simplified, and the method has the advantages of simple purification, high efficiency, high yield and low cost, and is 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: 1.0g, 1.0equiv. of 2-fluoro-1-iodo-3-methoxybenzene represented by the formula (II), 3equiv. of potassium phosphate, 0.2equiv. of cuprous iodide, 3equiv. of ethanol were added to a reactor, and 5mL of dimethyl sulfoxide was added thereto. Nitrogen was bubbled through the reactor for 5min, followed by addition of 3equiv. ethyl acetoacetate, heating to 100 ℃ and stirring for reaction for 18 h. After the reaction, ethyl acetate and a 2N aqueous solution of hydrochloric acid were added to the reaction mixture, the organic phase was separated after washing and the solvent was spin-dried, and the residue was purified by a silica gel column to obtain a colorless oily substance of ethyl (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoate 0.65equiv., which was represented by the formula (III), and the yield thereof was 65%. Detecting by using a high resolution mass spectrum (ESI +), wherein the actual measurement value is 255.1029; m + H+Calculated high resolution mass spectrum of 255.1027.
(2) The preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown in the formula (I) comprises the following steps:
the method comprises the following operation steps: dissolving 0.81g, 1equiv. ethyl (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoate as shown in the formula (III) in 5mL of methyl tert-butyl ether, adding 5mL of 25% ammonia water, stirring and reacting for 3h at normal temperature, separating and spin-drying an organic phase to obtain a colorless oily substance (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate as shown in the formula (I) of 0.99equiv., wherein the yield is 99%. The detection was carried out by high-resolution mass spectrometry, and the measured value was 254.1193. M + H+The calculated high-resolution mass spectrum of (a) was 254.1187, and the structure was confirmed by comparison.
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, 1.0equiv. of 2-fluoro-1-iodo-3-methoxybenzene represented by the formula (II), 2equiv. of potassium hydrogenphosphate, 0.3equiv. of cuprous bromide, and 5equiv. of ethanol were added to a reactor, and 8mL of dimethyl sulfoxide was added thereto. Nitrogen was bubbled through the reactor for 5min, followed by addition of 1equiv. ethyl acetoacetate, heating to 100 ℃ and stirring for reaction for 20 h. After the reaction, ethyl acetate and a 2N aqueous solution of hydrochloric acid were added to the reaction mixture, the organic phase was separated after washing and the solvent was spin-dried, and the residue was purified by a silica gel column to obtain a colorless oily substance of ethyl (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoate 0.16equiv., which was represented by the formula (III), and the yield thereof was 16%. Detection was by high resolution mass spectrometry (ESI +) and found 255.1032.
(2) The preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown in the formula (I) comprises the following steps:
the method comprises the following operation steps: dissolving 0.81g, 1equiv. ethyl (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoate as shown in the formula (III) in 8mL of 1, 4 dioxane, adding 10mL of 25% ammonia water, stirring and reacting for 3h at 25 ℃, fractionally taking and spin-drying an organic phase to obtain a colorless oily substance, namely ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate as shown in the formula (I), wherein the yield is 98%. The detection was carried out by high-resolution mass spectrometry, and the measured value 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: 1.0g, 1.0equiv. 2-fluoro-1-iodo-3-methoxybenzene represented by the formula (II), 4equiv. dipotassium hydrogenphosphate, 0.3equiv. sodium trifluoromethanesulfonate, and 3equiv. ethanol were added to a reactor, and 10mL of dimethylacetamide was added thereto. Nitrogen was bubbled through the reactor for 5min, followed by addition of 6equiv. ethyl acetoacetate, heating to 150 ℃ and stirring for reaction for 32 h. After the reaction, ethyl acetate and a 2N aqueous solution of hydrochloric acid were added to the reaction mixture, the organic phase was separated after washing and the solvent was spin-dried, and the residue was purified by a silica gel column to obtain a colorless oily substance of ethyl (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoate 0.65equiv., which was represented by the formula (III), and the yield thereof was 65%. Detection was by high resolution mass spectrometry (ESI +) and found 255.1030.
(2) The preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown in the formula (I) comprises the following steps:
the method comprises the following operation steps: dissolving 0.81g, 1equiv. ethyl (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoate as shown in the formula (III) in 10mL of diethylene glycol dimethyl ether, adding 5mL of 25% ammonia water by mass, stirring and reacting at 50 ℃ for 3h, separating the organic phase, and spin-drying the solvent to obtain a colorless oily substance (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate as shown in the formula (I) with the yield of 95%. The detection was carried out by high-resolution mass spectrometry, and the measured value was 254.1191.
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: 1.0g, 1.0equiv. of 2-fluoro-1-iodo-3-methoxybenzene represented by the formula (II), 3equiv. of potassium phosphate, 0.3equiv. of cuprous bromide-dimethyl sulfide complex, and 2equiv. of ethanol were added to a reactor, and 5mL of sulfolane was added thereto. Nitrogen was bubbled through the reactor for 5min, then 5equiv. ethyl acetoacetate was added, the temperature was raised to 80 ℃ and the reaction was stirred for 18 h. After the reaction, ethyl acetate and a 2N aqueous solution of hydrochloric acid were added to the reaction mixture, the organic phase was separated after washing and the solvent was spin-dried, and the residue was purified by a silica gel column to obtain a colorless oily substance of ethyl (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoate 0.32equiv., which was represented by the formula (III), and the yield thereof was 32%. Detection was by high resolution mass spectrometry (ESI +) and found 255.1030.
(2) The preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown in the formula (I) comprises the following steps:
the method comprises the following operation steps: dissolving 0.81g, 1equiv. ethyl (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoate as shown in the formula (III) in 5mL of methyl tert-butyl ether, adding 10mL of 25% ammonia water by mass, stirring and reacting at 0 ℃ for 3h, separating the organic phase, and spin-drying the solvent to obtain a colorless oily substance, namely 0.97equiv. ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate as shown in the formula (I), wherein the yield is 97%. The detection was carried out by high-resolution mass spectrometry, and the measured value was 254.1191.
Example 5
(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, 1.0equiv. of 2-fluoro-1-iodo-3-methoxybenzene represented by the formula (II), 2equiv. of potassium carbonate, 0.2equiv. of cuprous chloride, and 3equiv. of ethanol were added to a reactor, and 6mL of N, N-dimethylformamide was added thereto. Nitrogen was bubbled through the reactor for 5min, followed by addition of 3equiv. ethyl acetoacetate, warming to 50 ℃ and stirring for reaction for 18 h. After the reaction was completed, ethyl acetate and 2N aqueous hydrochloric acid were added to the reaction mixture, the organic phase was separated after washing and the solvent was spin-dried, and the residue was purified by a silica gel column to obtain a colorless oily substance of ethyl (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoate 0.18equiv., which was represented by the formula (III), and the yield thereof was 18%. Detection was by high resolution mass spectrometry (ESI +) and found 255.1038.
(2) The preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown in the formula (I) comprises the following steps:
the method comprises the following operation steps: dissolving 0.81g, 1equiv. ethyl (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoate as shown in the formula (III) in 5mL of 2-methyltetrahydrofuran, adding 5mL of 25% by mass of ammonia water, stirring and reacting at 25 ℃ for 3h, separating the organic phase, and spin-drying the solvent to obtain a colorless oily substance (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate as shown in the formula (I) with the yield of 97%. The detection was carried out by high-resolution mass spectrometry, and the measured value was 254.1194.
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. The method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by a two-step method is characterized by comprising the following steps of:
(1) coupling reaction is carried out on 2-fluoro-1-iodo-3-methoxybenzene shown as a formula (II) and ethyl acetoacetate to obtain (Z) -2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as 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 two-step method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester according to claim 1, wherein the specific operation of the step (1) is as follows: adding 2-fluoro-1-iodo-3-methoxybenzene shown in formula (II), ethanol, a catalyst, alkali and an organic solvent into a reactor, introducing nitrogen for bubbling, then adding ethyl acetoacetate into the reactor, and heating for coupling reaction; after the reaction is finished, adding a detergent into the mixture, separating and purifying an organic phase to obtain (Z) -2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as the formula (III).
3. The two-step synthesis method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester according to claim 1, wherein the specific operation of the step (2) is as follows: dissolving (Z) -2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as a formula (III) in an organic solvent, adding ammonia water into the organic solvent, and stirring the mixture to perform amination reaction; after the reaction is finished, (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown in the formula (I) is obtained by separation.
4. The two-step process for the synthesis of ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 2, wherein the catalyst is any one selected from cuprous iodide, cuprous bromide, cuprous chloride, cupric trifluoromethanesulfonate, cuprous trifluoromethanesulfonate, and cuprous bromide-dimethylsulfide complex.
5. The two-step process for synthesizing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 2, wherein the base in the step (2) is any one selected from potassium phosphate, dipotassium hydrogen phosphate, potassium carbonate and potassium hydrogen carbonate.
6. The two-step method for synthesizing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 2, wherein the organic solvent used in the step (2) is selected from any one of dimethyl sulfoxide, N-dimethylformamide, dimethylacetamide and sulfolane; and/or
The detergent is formed by mixing ethyl acetate and a hydrochloric acid aqueous solution.
7. The two-step process for the synthesis of ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 2, wherein the reaction temperature of the coupling reaction is 50-150 ℃.
8. The two-step method for synthesizing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 3, wherein the organic solvent used in the step (3) is selected from the group consisting of methyl tert-butyl ether, 1, 4-dioxane, 2-methyltetrahydrofuran, N dimethylformamide, dimethylacetamide and diethylene glycol dimethyl ether.
9. The two-step process for synthesizing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 2, wherein in the step (1), 1.0equiv. of 2-fluoro-1-iodo-3-methoxybenzene represented by the formula (II) is mixed with 1-6equiv. of ethyl acetoacetate, 2-4equiv. of base, 0.2-0.3equiv. of catalyst, and 2-5equiv. of ethanol, and then dissolved in 5-10mL of organic solvent.
10. The two-step process for synthesizing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 3, wherein in the step (2), ethyl (Z) -2- (2-fluoro-3-methoxyphenyl) -2-butenoate represented by the formula (III) is dissolved in 5 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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