CN109734616A - 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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- CN109734616A CN109734616A CN201910118481.9A CN201910118481A CN109734616A CN 109734616 A CN109734616 A CN 109734616A CN 201910118481 A CN201910118481 A CN 201910118481A CN 109734616 A CN109734616 A CN 109734616A
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- Prior art keywords
- fluoro
- methoxyphenyl
- butenoic acid
- amino
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- -1 fluoro- 3- methoxyphenyl Chemical group 0.000 title claims abstract description 57
- 238000003786 synthesis reaction Methods 0.000 title abstract description 7
- 230000015572 biosynthetic process Effects 0.000 title abstract description 6
- 230000002194 synthesizing Effects 0.000 title abstract description 6
- XYIBRDXRRQCHLP-UHFFFAOYSA-N Ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- RSHBAGGASAJQCH-UHFFFAOYSA-N 1-iodo-3-methoxybenzene Chemical compound COC1=CC=CC(I)=C1 RSHBAGGASAJQCH-UHFFFAOYSA-N 0.000 claims abstract description 12
- 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
- 125000004494 ethyl ester group Chemical group 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 11
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 9
- 239000000908 ammonium hydroxide Substances 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-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
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 239000003054 catalyst Substances 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
- ZPWVASYFFYYZEW-UHFFFAOYSA-L Dipotassium phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 4
- 239000003599 detergent 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
- NKNDPYCGAZPOFS-UHFFFAOYSA-M Copper(I) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 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
- 229940113088 dimethylacetamide Drugs 0.000 claims description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000001184 potassium carbonate Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000001119 stannous chloride Substances 0.000 claims description 3
- 229940013123 stannous chloride Drugs 0.000 claims description 3
- 235000011150 stannous chloride Nutrition 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin dichloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 claims description 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N Anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N Trifluoromethanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 230000005587 bubbling Effects 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims 1
- 238000005039 chemical industry Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000007039 two-step reaction Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 description 16
- 238000001819 mass spectrum Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 10
- 238000011017 operating method Methods 0.000 description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 5
- 150000001336 alkenes Chemical class 0.000 description 5
- 238000000746 purification 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
- 238000010792 warming Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 4
- MFJNOXOAIFNSBX-UHFFFAOYSA-N 1-fluoro-3-methoxybenzene Chemical compound COC1=CC=CC(F)=C1 MFJNOXOAIFNSBX-UHFFFAOYSA-N 0.000 description 3
- 201000009273 endometriosis Diseases 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-Methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 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 2
- 229950004823 Elagolix Drugs 0.000 description 2
- 108010084340 Gonadotropin-Releasing Hormone Proteins 0.000 description 2
- 208000000450 Pelvic Pain Diseases 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 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
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000000509 Infertility Diseases 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 206010028334 Muscle spasms Diseases 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003042 antagnostic Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 239000003814 drug Substances 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
- 210000004914 menses Anatomy 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- HGJLYMGBCAKBLK-UHFFFAOYSA-N sodium;trifluoromethanesulfonic acid Chemical compound [Na].OS(=O)(=O)C(F)(F)F HGJLYMGBCAKBLK-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 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 organic syntheses and medicine intermediate technical field, and in particular to a kind of two-step method synthesis (Z) -3- ammonia
The method of base -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl.
Background technique
A kind of women that endometriosis (EMs) refers to that endo cell is planted in abnormal position and is formed is common
Gynecological disease.The disease incidence of the disease reaches 10.0%, and is in obvious ascendant trend.It is mainly with dysmenorrhea, pelvic pain and infertile
Infertility is main feature.According to statistics, in the world, puzzlement of much 1.76 hundred million women by endometriosis.
Elagolix is a kind of oral antagonists of gonadotropin-releasing hormone (GnRHA), for mullerianosis
Cramp caused by disease and non-menstruation pelvic pain have a good effect and previous well known GnRH agonist
(GnRHa) it compares, oral administration biaavailability with higher, avoids feeling of pain caused by injection and allergic reaction, increase
Patient compliance.
It will use intermediate (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid second in synthesis
Ester, structural formula are as follows:
The substance can usually be synthesized by following routes:
From said synthesis route it is found that the route of the prior art is five-step approach synthesis, there are synthetic route length, technique are multiple
Deficiency miscellaneous, equipment cost investment is high and reaction process is not easy to control, yield is low.
Summary of the invention
Technical problem to be solved by the present invention lies in: elagolix intermediate (Z) -3- amino -2- (the fluoro- 3- methoxy of 2-
Base phenyl) -2- butenoic acid ethyl general synthetic routes it is long and yield is low.
The present invention solves above-mentioned technical problem using following technical scheme:
The method that two-step method synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl, including with
Lower step:
(1) the iodo- 3- methoxybenzene of the fluoro- 1- of 2- and ethyl acetoacetate as shown in formula (II) are obtained through coupling reaction
(Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl；
(2) (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl is through aminating reaction
Obtain (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl；
Preferably, two-step method of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butylene
The concrete operations of the method for acetoacetic ester, shown step (1) are as follows: it is iodo- that the fluoro- 1- of 2- as shown in formula (II) being added into reactor
3- methoxybenzene, ethyl alcohol, catalyst, alkali and organic solvent are passed through nitrogen bubbling, then to addition acetoacetate second in reactor
Ester, heating carry out coupling reaction；After reaction, detergent is added into mixture, point takes organic phase and purifies and obtain such as formula
(III) (Z) -2- shown in (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl.
Preferably, two-step method of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butylene
The concrete operations of the method for acetoacetic ester, the step (2) are as follows: (the fluoro- 3- methoxyl group of 2- of (Z) -2- as shown in formula (III)
Phenyl) -2- butenoic acid ethyl is dissolved in organic solvent, and ammonium hydroxide is added thereto, and aminating reaction occurs for stirring；After reaction,
Isolated (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl.
Preferably, two-step method of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butylene
The method of acetoacetic ester, the catalyst are selected from cuprous iodide, cuprous bromide, stannous chloride, copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid
Any one of cuprous, cuprous bromide-methyl sulfide complex.
Preferably, two-step method of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butylene
The method of acetoacetic ester, alkali described in step (2) are selected from any one of potassium phosphate, dipotassium hydrogen phosphate, potassium carbonate, saleratus.
Preferably, two-step method of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butylene
The method of acetoacetic ester, organic solvent described in step (2) are selected from dimethyl sulfoxide, n,N-Dimethylformamide, dimethyl second
Any one of amide, sulfolane；And/or
The detergent is formed by ethyl acetate and combined.
Preferably, two-step method of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butylene
The method of acetoacetic ester, the reaction temperature of the coupling reaction are 50-150 DEG C.
Preferably, two-step method of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butylene
The method of acetoacetic ester, organic solvent described in step (3) are selected from methyl tertiary butyl ether(MTBE), Isosorbide-5-Nitrae-dioxane, 2- methyl tetrahydro furan
It mutters, any one of n,N dimethylformamide, dimethyl acetamide, diethylene glycol dimethyl ether.
Preferably, two-step method of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butylene
The method of acetoacetic ester, in the step (1), every 1.0g, the 1.0equiv. iodo- 3- methoxybenzene of the fluoro- 1- of 2- as shown in formula (II)
With the ethyl acetoacetate of 1-6equiv., the alkali of 2-4equiv., the catalyst of 0.2-0.3equiv., 2-5equiv. ethyl alcohol
After mixing, it is dissolved in 5-10mL organic solvent.
Preferably, two-step method of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butylene
The method of acetoacetic ester, in the step (2), every 0.81g, 1equiv. (the fluoro- 3- methoxyl group of 2- of (Z) -2- as shown in formula (III)
Phenyl) -2- butenoic acid ethyl is dissolved in 5-10mL organic solvent；And/or
The mass fraction of the ammonium hydroxide is 25%, volume 5-10mL；And/or
The temperature of the aminating reaction is 0-50 DEG C.
The technology of the present invention the utility model has the advantages that
The technology of the present invention side by the iodo- 3- methoxybenzene of the fluoro- 1- of commercialized basic chemical industry raw material 2- as starting material,
Target product can be obtained through two-step reaction, simplify the synthetic route of target product, have and purify simple, high-efficient, yield
Advantage high, at low cost is suitble to industrial mass production to use.
Specific embodiment
For convenient for those skilled in the art understand that technical solution of the present invention, now in conjunction with specification specific embodiment to the present invention
Technical solution is described further.
(Z) -3- amino -2- shown in institute's formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl in the present invention
Preparation route is as follows:
Embodiment 1
(1) preparation of (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl prepares road
Line is as follows:
Operating procedure: by 1.0g, the 1.0equiv. iodo- 3- methoxybenzene of the fluoro- 1- of 2- and 3equiv. as shown in formula (II)
Potassium phosphate, the cuprous iodide of 0.2equiv., 3equiv. ethyl alcohol reactor is added, the dimethyl sulfoxide of 5mL is added thereto.
It is passed through nitrogen into reactor and is bubbled 5min, the ethyl acetoacetate of 3equiv. is then added, is warming up to 100 DEG C, is stirred to react
18h.After reaction, ethyl acetate and 2N aqueous hydrochloric acid solution are added into reaction mixture, divides after washing and takes organic phase and revolve
Dry solvent, residue obtain colorless oil (the fluoro- 3- methoxybenzene of 2- of (Z) -2- as shown in formula (III) with silica gel column purification
Base) -2- butenoic acid ethyl 0.65equiv., yield 65%.It is detected using high resolution mass spectrum (ESI+), measured value is
255.1029；M+H+High resolution mass spectrum calculating value be 255.1027.
(2) preparation of (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl,
Preparation route is as follows:
Operating procedure: by 0.81g, 1equiv. (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- fourth
Olefin(e) acid ethyl ester is dissolved in 5mL methyl tertiary butyl ether(MTBE), and the ammonium hydroxide 5mL that mass fraction is 25% is added thereto, is stirred to react under room temperature
3h, point takes and is spin-dried for organic phase and obtain colorless oil (Z) -3- amino -2- (fluoro- 3- methoxybenzene of 2- as shown in formula (I)
Base) -2- butenoic acid ethyl 0.99equiv., yield 99%.It is detected using high resolution mass spectrum, measured value 254.1193.M
+H+High resolution mass spectrum calculating value be 254.1187, through comparing, can confirm its structure.
Embodiment 2
(1) preparation of (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl prepares road
Line is as follows:
Operating procedure: by 1.0g, the 1.0equiv. iodo- 3- methoxybenzene of the fluoro- 1- of 2- and 2equiv. as shown in formula (II)
Potassium hydrogen phosphate, the cuprous bromide of 0.3equiv., 5equiv. ethyl alcohol reactor is added, the dimethyl that 8mL is added thereto is sub-
Sulfone.It is passed through nitrogen into reactor and is bubbled 5min, the ethyl acetoacetate of 1equiv. is then added, is warming up to 100 DEG C, stirring
React 20h.After reaction, ethyl acetate and 2N aqueous hydrochloric acid solution are added into reaction mixture, divides after washing and takes organic phase
And it is spin-dried for solvent, residue obtains colorless oil (the fluoro- 3- methoxy of 2- of (Z) -2- as shown in formula (III) with silica gel column purification
Base phenyl) -2- butenoic acid ethyl 0.16equiv., yield 16%.It is detected using high resolution mass spectrum (ESI+), measured value is
255.1032。
(2) preparation of (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl,
Preparation route is as follows:
Operating procedure: by 0.81g, 1equiv. (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- fourth
Olefin(e) acid ethyl ester is dissolved in 8mL Isosorbide-5-Nitrae dioxane, and the ammonium hydroxide 10mL that mass fraction is 25% is added thereto, is stirred to react at 25 DEG C
3h, point takes and is spin-dried for organic phase and obtain colorless oil (Z) -3- amino -2- (fluoro- 3- methoxybenzene of 2- as shown in formula (I)
Base) -2- butenoic acid ethyl 0.98equiv., yield 98%.It is detected using high resolution mass spectrum, measured value 254.1195.
Embodiment 3
(1) preparation of (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl prepares road
Line is as follows:
Operating procedure: by 1.0g, the 1.0equiv. iodo- 3- methoxybenzene of the fluoro- 1- of 2- and 4equiv. as shown in formula (II)
Dipotassium hydrogen phosphate, the trifluoromethanesulfonic acid sodium of 0.3equiv., 3equiv. ethyl alcohol reactor is added, the two of 10mL is added thereto
Methylacetamide.It is passed through nitrogen into reactor and is bubbled 5min, the ethyl acetoacetate of 6equiv. is then added, is warming up to 150
DEG C, it is stirred to react 32h.After reaction, ethyl acetate and 2N aqueous hydrochloric acid solution are added into reaction mixture, divides after washing and takes
Organic phase is simultaneously spin-dried for solvent, and residue with silica gel column purification obtains colorless oil (Z) -2- as shown in formula (III), and (2- is fluoro-
3- methoxyphenyl) -2- butenoic acid ethyl 0.65equiv., yield 65%.It is detected using high resolution mass spectrum (ESI+), it is real
Measured value is 255.1030.
(2) preparation of (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl,
Preparation route is as follows:
Operating procedure: by 0.81g, 1equiv. (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- fourth
Olefin(e) acid ethyl ester is dissolved in 10mL diethylene glycol dimethyl ether, and the ammonium hydroxide 5mL that mass fraction is 25% is added thereto, stirs at 50 DEG C anti-
3h is answered, point organic phase is taken and is spin-dried for solvent and obtain colorless oil (Z) -3- amino -2- (fluoro- 3- methoxy of 2- as shown in formula (I)
Base phenyl) -2- butenoic acid ethyl 0.95equiv., yield 95%.It is detected using high resolution mass spectrum, measured value is
254.1191。
Embodiment 4
(1) preparation of (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl prepares road
Line is as follows:
Operating procedure: by 1.0g, the 1.0equiv. iodo- 3- methoxybenzene of the fluoro- 1- of 2- and 3equiv. as shown in formula (II)
Potassium phosphate, cuprous bromide-methyl sulfide complex of 0.3equiv., 2equiv. ethyl alcohol reactor is added, be added thereto
The sulfolane of 5mL.It is passed through nitrogen into reactor and is bubbled 5min, the ethyl acetoacetate of 5equiv. is then added, is warming up to 80
DEG C, it is stirred to react 18h.After reaction, ethyl acetate and 2N aqueous hydrochloric acid solution are added into reaction mixture, divides after washing and takes
Organic phase is simultaneously spin-dried for solvent, and residue with silica gel column purification obtains colorless oil (Z) -2- as shown in formula (III), and (2- is fluoro-
3- methoxyphenyl) -2- butenoic acid ethyl 0.32equiv., yield 32%.It is detected using high resolution mass spectrum (ESI+), it is real
Measured value is 255.1030.
(2) preparation of (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl,
Preparation route is as follows:
Operating procedure: by 0.81g, 1equiv. (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- fourth
Olefin(e) acid ethyl ester is dissolved in 5mL methyl tertiary butyl ether(MTBE), and the ammonium hydroxide 10mL that mass fraction is 25% is added thereto, is stirred to react at 0 DEG C
3h divides and takes organic phase and be spin-dried for solvent, obtains colorless oil (Z) -3- amino -2- (fluoro- 3- methoxy of 2- as shown in formula (I)
Base phenyl) -2- butenoic acid ethyl 0.97equiv., yield 97%.It is detected using high resolution mass spectrum, measured value is
254.1191。
Embodiment 5
(1) preparation of (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl prepares road
Line is as follows:
Operating procedure: by 1.0g, the 1.0equiv. iodo- 3- methoxybenzene of the fluoro- 1- of 2- and 2equiv. as shown in formula (II)
Potassium carbonate, the stannous chloride of 0.2equiv., 3equiv. ethyl alcohol reactor is added, the N of 6mL, N- dimethyl are added thereto
Formamide.It is passed through nitrogen into reactor and is bubbled 5min, the ethyl acetoacetate of 3equiv. is then added, is warming up to 50 DEG C, stirs
Mix reaction 18h.After reaction, ethyl acetate and 2N aqueous hydrochloric acid solution are added into reaction mixture, point is taken after washing organic
Mutually and it is spin-dried for solvent, residue obtains colorless oil (the fluoro- 3- first of 2- of (Z) -2- as shown in formula (III) with silica gel column purification
Phenyl) -2- butenoic acid ethyl 0.18equiv., yield 18%.It is detected using high resolution mass spectrum (ESI+), measured value
It is 255.1038.
(2) preparation of (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl,
Preparation route is as follows:
Operating procedure: by 0.81g, 1equiv. (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- fourth
Olefin(e) acid ethyl ester is dissolved in 5mL 2- methyltetrahydrofuran, and the ammonium hydroxide 5mL that mass fraction is 25% is added thereto, stirs at 25 DEG C anti-
3h is answered, divides and takes organic phase and be spin-dried for solvent, obtain colorless oil (Z) -3- amino -2- (fluoro- 3- first of 2- as shown in formula (I)
Phenyl) -2- butenoic acid ethyl 0.97equiv., yield 97%.It is detected using high resolution mass spectrum, measured value is
254.1194。
Technical solution of the present invention is exemplarily described invention above in conjunction with specific embodiment, it is clear that present invention tool
Body realization is not subject to the restrictions described above, as long as using the various non-realities that the inventive concept and technical scheme of the present invention carry out
Matter improve, or it is not improved the conception and technical scheme of invention are directly applied into other occasions, in guarantor of the invention
Within the scope of shield.
Claims (10)
1. the method that two-step method synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl, feature exist
In, comprising the following steps:
(1) the iodo- 3- methoxybenzene of the fluoro- 1- of 2- and ethyl acetoacetate as shown in formula (II) are obtained through coupling reaction such as formula
(III) (Z) -2- shown in (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl；
(2) (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl is obtained through aminating reaction
(Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl；
2. two-step method according to claim 1 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The method of ethyl ester, which is characterized in that the concrete operations of the step (1) are as follows: it is added as shown in formula (II) into reactor
The iodo- 3- methoxybenzene of the fluoro- 1- of 2-, ethyl alcohol, catalyst, alkali and organic solvent are passed through nitrogen bubbling, then to being added in reactor
Ethyl acetoacetate, heating carry out coupling reaction；After reaction, detergent is added into mixture, point takes organic phase and pure
Change obtains (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl.
3. two-step method according to claim 1 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The method of ethyl ester, which is characterized in that the concrete operations of the step (2) are as follows: (2- is fluoro- by (Z) -2- as shown in formula (III)
3- methoxyphenyl) -2- butenoic acid ethyl is dissolved in organic solvent, and ammonium hydroxide is added thereto, and aminating reaction occurs for stirring；Reaction
After, isolated (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl.
4. two-step method according to claim 2 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The method of ethyl ester, which is characterized in that the catalyst be selected from cuprous iodide, cuprous bromide, stannous chloride, copper trifluoromethanesulfcomposite,
Trifluoromethanesulfonic acid is cuprous, any one of cuprous bromide-methyl sulfide complex.
5. two-step method according to claim 2 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The method of ethyl ester, which is characterized in that alkali described in step (2) is in potassium phosphate, dipotassium hydrogen phosphate, potassium carbonate, saleratus
It is any.
6. two-step method according to claim 2 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The method of ethyl ester, which is characterized in that organic solvent described in step (2) be selected from dimethyl sulfoxide, n,N-Dimethylformamide,
Any one of dimethyl acetamide, sulfolane；And/or
The detergent is formed by ethyl acetate and combined.
7. two-step method according to claim 2 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The method of ethyl ester, which is characterized in that the reaction temperature of the coupling reaction is 50-150 DEG C.
8. two-step method according to claim 3 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The method of ethyl ester, which is characterized in that organic solvent described in step (3) is selected from methyl tertiary butyl ether(MTBE), Isosorbide-5-Nitrae-dioxane, 2- first
Any one of base tetrahydrofuran, n,N dimethylformamide, dimethyl acetamide, diethylene glycol dimethyl ether.
9. two-step method according to claim 2 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The method of ethyl ester, which is characterized in that in the step (1), every 1.0g, the 1.0equiv. fluoro- 1- of 2- as shown in formula (II) are iodo-
The ethyl acetoacetate of 3- methoxybenzene and 1-6equiv., the alkali of 2-4equiv., the catalyst of 0.2-0.3equiv., 2-
After the ethyl alcohol mixing of 5equiv., it is dissolved in 5-10mL organic solvent.
10. two-step method according to claim 3 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The method of ethyl ester, which is characterized in that in the step (2), every 0.81g, 1equiv. (Z) -2- (2- as shown in formula (III)
Fluoro- 3- methoxyphenyl) -2- butenoic acid ethyl is dissolved in 5-10mL organic solvent；And/or
The mass fraction of the ammonium hydroxide is 25%, volume 5-10mL；And/or
The temperature of the aminating reaction is 0-50 DEG C.
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| CN1646522A (en) * | 2002-04-01 | 2005-07-27 | 日产化学工业株式会社 | Processes for producing indole compound |
| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
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| CN1646522A (en) * | 2002-04-01 | 2005-07-27 | 日产化学工业株式会社 | Processes for producing indole compound |
| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| CN102351778A (en) * | 2011-08-17 | 2012-02-15 | 湖北华龙生物制药有限公司 | Preparation method of arbidol hydrochloride |
| CN107922401A (en) * | 2015-06-03 | 2018-04-17 | 百时美施贵宝公司 | For treating 4 hydroxyl 3 (heteroaryl) pyridine, the 2 ketone APJ activators of cardiovascular disorder |
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