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 PDFInfo
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- 230000002194 synthesizing Effects 0.000 title claims abstract description 28
- OQDGXWPLUBDEDS-FLIBITNWSA-N ethyl (Z)-3-amino-2-(2-fluoro-3-methoxyphenyl)but-2-enoate Chemical compound CCOC(=O)C(=C(\C)N)\C1=CC=CC(OC)=C1F OQDGXWPLUBDEDS-FLIBITNWSA-N 0.000 claims abstract description 21
- FLUBKZRFDYRVBF-WTKPLQERSA-N C(C)OC(\C(=C/C)\C1=C(C(=CC=C1)OC)F)=O Chemical compound C(C)OC(\C(=C/C)\C1=C(C(=CC=C1)OC)F)=O FLUBKZRFDYRVBF-WTKPLQERSA-N 0.000 claims abstract description 20
- DNRXJYHKUIMHIO-UHFFFAOYSA-N 2-fluoro-1-iodo-3-methoxybenzene Chemical compound COC1=CC=CC(I)=C1F DNRXJYHKUIMHIO-UHFFFAOYSA-N 0.000 claims abstract description 14
- XYIBRDXRRQCHLP-UHFFFAOYSA-N Ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000005576 amination reaction Methods 0.000 claims abstract description 7
- 238000005859 coupling reaction Methods 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 12
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 11
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- ZPWVASYFFYYZEW-UHFFFAOYSA-L Dipotassium phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 239000003599 detergent Substances 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 4
- 235000019798 tripotassium phosphate Nutrition 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-Methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M Copper(I) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M Copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M Copper(I) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- SBZXBUIDTXKZTM-UHFFFAOYSA-N Diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N Sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 3
- WZZMHOBVLAEJOD-UHFFFAOYSA-M [Br-].CSC Chemical compound [Br-].CSC WZZMHOBVLAEJOD-UHFFFAOYSA-M 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- 239000001184 potassium carbonate Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 230000005587 bubbling Effects 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- HWUPLUNLNUHIQZ-UHFFFAOYSA-N copper;trifluoromethanesulfonic acid Chemical compound [Cu].OS(=O)(=O)C(F)(F)F.OS(=O)(=O)C(F)(F)F HWUPLUNLNUHIQZ-UHFFFAOYSA-N 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 238000007039 two-step reaction Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 description 11
- 238000001514 detection method Methods 0.000 description 9
- 238000004896 high resolution mass spectrometry Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000007792 addition Methods 0.000 description 4
- -1 (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate Chemical compound 0.000 description 3
- 201000009273 endometriosis Diseases 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006011 modification reaction Methods 0.000 description 2
- HEAUOKZIVMZVQL-VWLOTQADSA-N 4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]amino]butanoic acid Chemical compound COC1=CC=CC(C=2C(N(C[C@H](NCCCC(O)=O)C=3C=CC=CC=3)C(=O)N(CC=3C(=CC=CC=3F)C(F)(F)F)C=2C)=O)=C1F HEAUOKZIVMZVQL-VWLOTQADSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 208000003455 Anaphylaxis Diseases 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L Copper(II) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 229950004823 Elagolix Drugs 0.000 description 1
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 1
- 108010084340 Gonadotropin-Releasing Hormone Proteins 0.000 description 1
- 208000000509 Infertility Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000000450 Pelvic Pain Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000000630 rising Effects 0.000 description 1
- XGPOMXSYOKFBHS-UHFFFAOYSA-M sodium;trifluoromethanesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C(F)(F)F XGPOMXSYOKFBHS-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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
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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