CN109704980A - Preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate - Google Patents
Preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate Download PDFInfo
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- CN109704980A CN109704980A CN201910118487.6A CN201910118487A CN109704980A CN 109704980 A CN109704980 A CN 109704980A CN 201910118487 A CN201910118487 A CN 201910118487A CN 109704980 A CN109704980 A CN 109704980A
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- butenoic acid
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Abstract
The invention discloses a preparation method of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate, which comprises the following steps: (1) carrying out substitution reaction on 1, 2-difluoro-3-methoxybenzene shown in a formula (II) and ethyl acetoacetate to obtain (Z) -2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown in a formula (III);(2) carrying out amination reaction on (Z) -ethyl 2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in a formula (III) to obtain (Z) -ethyl 3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate shown in a formula (I);
Description
Technical field
The invention belongs to organic syntheses and medicine intermediate technical field, and in particular to one kind (Z) -3- amino -2- (2-
Fluoro- 3- methoxyphenyl) -2- butenoic acid ethyl preparation method.
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 GnRH antagonist, the approval of food and drug administration is obtained, to control
Pain caused by treating because of endometriosis.It will use intermediate (Z) -3- amino -2- (the fluoro- 3- first of 2- in synthesis
Phenyl) -2- butenoic acid ethyl, structural formula is as follows:
The substance can usually be synthesized by following routes:
But the route is longer, and yield is low.
Summary of the invention
Technical problem to be solved by the present invention lies in: (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butylene
The general synthetic routes of acetoacetic ester are long and yield is low.
The present invention solves above-mentioned technical problem using following technical scheme:
A kind of preparation method of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl, including it is as follows
Step:
(1) the fluoro- 3- methoxybenzene of 1,2- bis- as shown in formula (II) is substituted with ethyl acetoacetate reacts, obtain as
(Z) -2- 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 through aminating reaction, obtains
To (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl；
Preferably, a kind of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl of the present invention
Preparation method, the operation of the step (1) is as follows: the fluoro- 3- methoxybenzene of 1,2- bis- as shown in formula (II) and acetyl second
Acetoacetic ester is dissolved in organic solvent, and alkali is added under ice bath, then carries out substitution reaction；After reaction, it is spin-dried for solvent, to residual
Detergent washing is added in excess, divides and takes organic phase and be spin-dried for solvent, residue is obtained as shown in formula (III) with silica gel column purification
(Z) -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl.
Preferably, a kind of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl of the present invention
Preparation method, the operation of the step (II) is as follows: (Z) -2- as shown in formula (3) (the fluoro- 3- methoxyphenyl of 2-) -2-
After butenoic acid ethyl is dissolved in organic solvent, ammonium hydroxide is added thereto, stirring occurs aminating reaction, then divides and take organic phase and be spin-dried for
Solvent obtains (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl.
Preferably, a kind of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl of the present invention
Preparation method, the organic solvent in the step (1) is selected from Isosorbide-5-Nitrae-dioxane, THF, DMF, DMAc, diethylene glycol diformazan
Any one of ether.
Preferably, a kind of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl of the present invention
Preparation method, the alkali in the step (1) is in sodium hydride, hexamethyldisilazide lithium, potassium tert-butoxide, sodium tert-butoxide
It is any.
Preferably, a kind of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl of the present invention
Preparation method, the detergent in the step (1) is the mixture of ethyl acetate and hydrochloric acid solution.
Preferably, a kind of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl of the present invention
Preparation method, the process of the substitution reaction is to be warming up to back flow reaction 16-20h；Or it is warming up to 90-160 DEG C of reaction 18-
20h。
Preferably, a kind of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl of the present invention
Preparation method, the organic solvent in the step (3) be selected from water, ethyl alcohol, methanol, THF, DMF, DMAc, methyl tertiary butyl ether(MTBE),
The mixture of one or more of diethylene glycol dimethyl ether.
Preferably, a kind of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl of the present invention
Preparation method, the second of 1, the 2- as shown in formula (II) bis- fluoro- the 3- methoxybenzene and 5-20equiv. of every 1.0g, 1equiv.
The mixing of ethyl acetoacetic acid ethyl ester, and dissolved with the organic solvent of 8-14mL.
Preferably, a kind of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl of the present invention
Preparation method, (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- of every 0.81g, 1equiv.
The butenoic acid ethyl organic solvent of 2-10mL dissolves；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
For technical solution of the present invention by commercialized basic chemical industry raw material 1, the fluoro- 3- methoxybenzene of 2- bis- is former as starting
Material, can be obtained target product through two-step reaction, simplifies the synthetic route of target product, has and purifies simple, high-efficient, receipts
Rate height, advantage at low cost are extremely suitable for industrial mass production 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.
In the present invention (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl
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: being added 1.0g into reaction flask, 1equiv. fluoro- 3- methoxybenzene of 1,2- bis- as shown in formula (II),
10equiv. ethyl acetoacetate, 10mL1,4- dioxane after dissolution, are added 60% under condition of ice bath thereto,
1.1equiv.NaH is heated to flowing back, and reacts 18h, cooling.TLC is detected after completion of the reaction, is spin-dried for solvent, is added into residue
Enter ethyl acetate and 2N aqueous hydrochloric acid solution, divides and take organic phase and be spin-dried for solvent, residue silica gel column purification obtains colorless oil
Object (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl 0.72equiv., yield are
72%.M+H+High resolution mass spectrum calculating value be 255.1027, measured value 255.1027 can confirm its structure through comparing.
(2) preparation of (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl,
Route is as follows:
Operating procedure: 0.81g, 1equiv. (the fluoro- 3- methoxy of 2- of (Z) -2- as shown in formula (III) are added into reaction flask
Base phenyl) -2- butenoic acid ethyl, 5mL methyl tertiary butyl ether(MTBE), the ammonium hydroxide that 5mL mass fraction is 25% is stirred to react at 35 DEG C
3h.Divide after reaction and take organic phase and be spin-dried for solvent, obtains colorless oil (Z) -3- amino -2- (2- as shown in formula (I)
Fluoro- 3- methoxyphenyl) -2- butenoic acid ethyl 0.99equiv., yield 99%.It is detected through high resolution mass spectrum, result is
254.1193；M+H+High resolution mass spectrum calculating value be 254.1187, product structure can be confirmed by being compared.
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: being added 1.0g into reaction flask, 1equiv. fluoro- 3- methoxybenzene of 1,2- bis- as shown in formula (II),
5equiv. ethyl acetoacetate, 8mL THF after dissolution, are added 60% under condition of ice bath thereto,
1.1equiv.LiHMDS is heated to flowing back, and reacts 18h, cooling.TLC is detected after completion of the reaction, solvent is spin-dried for, into residue
Ethyl acetate and 2N aqueous hydrochloric acid solution is added, divides and takes organic phase and be spin-dried for solvent, residue silica gel column purification obtains colorless oil
Shape object (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl 0.69equiv., yield are
69%.It is detected through high resolution mass spectrum (ESI+), as a result 255.1032.
(2) preparation of (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl,
Route is as follows:
Operating procedure: 0.81g, 1equiv. (the fluoro- 3- methoxy of 2- of (Z) -2- as shown in formula (III) are added into reaction flask
Base phenyl) -2- butenoic acid ethyl, 5mL Isosorbide-5-Nitrae-dioxane, the ammonium hydroxide that 5mL mass fraction is 25% is stirred to react at 25 DEG C
3h.Divide after reaction and take organic phase and be spin-dried for solvent, obtains colorless oil (Z) -3- amino -2- (2- as shown in formula (I)
Fluoro- 3- methoxyphenyl) -2- butenoic acid ethyl 0.98equiv., yield 99%.It is detected through high resolution mass spectrum, result is
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: being added 1.0g into reaction flask, 1equiv. fluoro- 3- methoxybenzene of 1,2- bis- as shown in formula (II),
15equiv. ethyl acetoacetate, 14mL diethylene glycol dimethyl ether after dissolution, are added 60% under condition of ice bath thereto,
1.1equiv. sodium tert-butoxide is heated to 120 DEG C, reacts 18h, cooling.TLC is detected after completion of the reaction, solvent is spin-dried for, to remnants
Ethyl acetate and 2N aqueous hydrochloric acid solution are added in object, divides and takes organic phase and be spin-dried for solvent, residue silica gel column purification obtains nothing
Color grease (Z) -2- as shown in formula (III) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl 0.70equiv. is received
Rate is 70%.It is detected through high resolution mass spectrum (ESI+), as a result 255.1037.
(2) preparation of (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl,
Route is as follows:
Operating procedure: 0.81g, 1equiv. (the fluoro- 3- methoxy of 2- of (Z) -2- as shown in formula (III) are added into reaction flask
Base phenyl) -2- butenoic acid ethyl, 8mL methyl tertiary butyl ether(MTBE), the ammonium hydroxide that 2mL mass fraction is 25% is stirred to react at 0 DEG C
For 24 hours, TLC detection reaction not exclusively, divides and takes organic phase and be spin-dried for solvent, obtain colorless oil (Z) -3- as shown in formula (I)
Amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl.It is detected through high resolution mass spectrum, result 254.1195.
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: being added 1.0g into reaction flask, 1equiv. fluoro- 3- methoxybenzene of 1,2- bis- as shown in formula (II),
After dissolution, 60%, 1.1equiv. uncle is added in 20equiv. ethyl acetoacetate, 14mL DMAc thereto under condition of ice bath
Butanol potassium is heated to flowing back, and reacts 18h, cooling.TLC is detected after completion of the reaction, is spin-dried for solvent, acetic acid is added into residue
Ethyl ester and 2N aqueous hydrochloric acid solution divide and take organic phase and be spin-dried for solvent, and residue silica gel column purification obtains colorless oil such as formula
(III) (Z) -2- shown in (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl 0.73equiv., yield 73%.Through height
Resolution Mass Spectrometry (ESI+) detection, as a result 255.1033.
(2) preparation of (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl,
Route is as follows:
Operating procedure: 0.81g, 1equiv. (the fluoro- 3- methoxy of 2- of (Z) -2- as shown in formula (III) are added into reaction flask
Base phenyl) -2- butenoic acid ethyl, 10mL diethylene glycol dimethyl ether, the ammonium hydroxide that 5mL mass fraction is 25% stirs at 50 DEG C anti-
Answer 3h.Divide after reaction and take organic phase and be spin-dried for solvent, obtains colorless oil (Z) -3- amino -2- as shown in formula (I)
(the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl 0.95equiv., yield 95%.It is detected through high resolution mass spectrum, as a result
It is 254.1191.
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. a kind of preparation method of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl, which is characterized in that
Include the following steps:
(1) the fluoro- 3- methoxybenzene of 1,2- bis- as shown in formula (II) is substituted with ethyl acetoacetate reacts, and obtains 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 through aminating reaction, obtain as
(Z) -3- amino -2- shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl；
2. one kind (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl according to claim 1
Preparation method, which is characterized in that the operation of the step (1) is as follows: the fluoro- 3- methoxybenzene of 1,2- bis- as shown in formula (II)
It is dissolved in organic solvent with ethyl acetoacetate, alkali is added under ice bath, then carry out substitution reaction；After reaction, it is spin-dried for
Detergent washing is added into residue, divides and takes organic phase and be spin-dried for solvent, residue is obtained with silica gel column purification such as formula for solvent
(III) (Z) -2- shown in (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl.
3. one kind (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl according to claim 1
Preparation method, which is characterized in that the operation of the step (II) is as follows: (the fluoro- 3- methoxy of 2- of (Z) -2- as shown in formula (3)
Base phenyl) after -2- butenoic acid ethyl is dissolved in organic solvent, ammonium hydroxide is added thereto, aminating reaction occurs for stirring, then point has taken
Machine phase is simultaneously spin-dried for solvent, obtains (Z) -3- amino -2- as shown in formula (I) (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid second
Ester.
4. one kind (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl according to claim 2
Preparation method, which is characterized in that the organic solvent in the step (1) is selected from Isosorbide-5-Nitrae-dioxane, THF, DMF, DMAc, diethyl
Any one of glycol dimethyl ether.
5. one kind (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl according to claim 2
Synthetic method, which is characterized in that alkali in the step (1) be selected from sodium hydride, hexamethyldisilazide lithium, potassium tert-butoxide,
Any one of sodium tert-butoxide.
6. one kind (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl according to claim 2
Preparation method, which is characterized in that the detergent in the step (1) is the mixture of ethyl acetate and hydrochloric acid solution.
7. one kind (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl according to claim 1 or 2
Preparation method, which is characterized in that the process of the substitution reaction be warming up to back flow reaction 16-20h；Or it is warming up to 90-160
DEG C reaction 18-20h.
8. one kind (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl according to claim 3
Preparation method, which is characterized in that the organic solvent in the step (3) is selected from water, ethyl alcohol, methanol, THF, DMF, DMAc, methyl
The mixture of one or more of tertbutyl ether, diethylene glycol dimethyl ether.
9. according to the preparation of one kind described in right 2 (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl
Method, which is characterized in that the fluoro- 3- methoxybenzene of 1, the 2- as shown in formula (II) bis- and 5-20equiv. of every 1.0g, 1equiv.
Ethyl acetoacetate mixing, and with the organic solvent of 8-14mL dissolution.
10. one kind (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl according to claim 3
Preparation method, which is characterized in that (Z) -3- amino -2- (fluoro- 3- methoxyl group of 2- as shown in formula (I) of every 0.81g, 1equiv.
Phenyl) -2- butenoic acid ethyl the organic solvent of 2-10mL dissolves；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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| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
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| 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 |
| CN109311920A (en) * | 2016-05-24 | 2019-02-05 | 萨勒普塔医疗公司 | The method for preparing phosphoric acid diamides morpholino oligomers |
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2019
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| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| CN105218389A (en) * | 2014-06-30 | 2016-01-06 | 山东诚创医药技术开发有限公司 | One prepares the method for 3-amino-2-(the fluoro-3-methoxyphenyl of 2-)-2-butylene acid esters |
| 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 |
| CN109311920A (en) * | 2016-05-24 | 2019-02-05 | 萨勒普塔医疗公司 | The method for preparing phosphoric acid diamides morpholino oligomers |
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