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 PDF

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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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fluoro
methoxyphenyl
butenoic acid
amino
formula
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CN109734616B (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

Two-step method synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid The method of ethyl ester
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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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DIETER HAMPRECHT 等: "5-HT2C antagonists based on fused heterotricyclic templates:Design, synthesis and biological evaluation", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
HATTORI, HARUHIKO 等: "Total Syntheses of Aurachins A and B", 《ANGEWANDTE CHEMIE, INTERNATIONAL EDITION》 *

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