CN109704981A - Replace the method for synthesis (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl - Google Patents
Replace the method for synthesis (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl Download PDFInfo
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- CN109704981A CN109704981A CN201910118478.7A CN201910118478A CN109704981A CN 109704981 A CN109704981 A CN 109704981A CN 201910118478 A CN201910118478 A CN 201910118478A CN 109704981 A CN109704981 A CN 109704981A
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Abstract
The invention discloses the methods for replacing synthesis (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl, the following steps are included: substitution reaction occurs for (1) 2- as shown in Formula II (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate and methane sulfonyl chloride, 2- chlorine shown as a formula V (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate is obtained；(2) 2- chlorine shown as a formula V (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate reacts to obtain (Z) -3- amino -2- shown in formula I (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl through Blaise；
Description
Technical field
The invention belongs to organic syntheses and medicine intermediate technical field, and in particular to replace synthesis (Z) -3- amino -2-
The method of (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl.
Background technique
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:
According to the record of United States Patent (USP) WO2009062087, which can synthesize to obtain via following routes:
From said synthesis route it is found that the route of the prior art is four step rule 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: the regular course for synthesizing title intermediate is longer.
The present invention solves above-mentioned technical problem using following technical scheme:
Replace the method for synthesis (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl, including following
Step:
(1) (the fluoro- 3- methoxyphenyl of the 2-) -2- hydroxyl ethyl acetate of the 2- as shown in Formula II and methane sulfonyl chloride occur
Substitution reaction obtains 2- chlorine shown as a formula V (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate；
(2) 2- chlorine shown as a formula V (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate reacts to obtain such as Formulas I institute through Blaise
(Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of the 2-) -2- butenoic acid ethyl shown；
Preferably, substitution of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The concrete operations of the method for ethyl ester, the step (1) are as follows: the 2- as shown in Formula II (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl
Ethyl is dissolved in solvent, and substitution reaction occurs after methane sulfonyl chloride, alkali is added thereto；It after reaction will mixing
Object is concentrated to dryness, and to concentrate washing, is dried to obtain 2- chlorine shown as a formula V (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate.
Preferably, substitution of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The concrete operations of the method for ethyl ester, the step (2) are as follows: by 2- chlorine (the fluoro- 3- methoxyphenyl of 2-) acetic acid shown as a formula V
Ethyl ester is dissolved in organic solvent, and Blaise reaction occurs after zinc powder is added thereto；After reaction, mixture is concentrated to dryness,
Washed, dry, purifying obtains (Z) -3- amino -2- shown in formula I (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl.
Preferably, substitution of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The method of ethyl ester further includes having catalyst in the reactant of the step (2).
Preferably, substitution of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The method of ethyl ester, solvent described in step (1) are selected from methylene chloride, 1,2- dichloroethanes, chloroform, THF, DMF, diethylene glycol
Any one of dimethyl ether；And/or
Alkali described in step (1) is selected from the mixture of triethylamine, DIPEA, pyridine, DMAP or triethylamine and pyridine.
Preferably, substitution of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The concrete operations of the method for ethyl ester, washing described in step (1) are as follows: first using the mixture of methylene chloride and aqueous hydrochloric acid solution
Concentrate is washed as detergent, is divided after taking organic phase, saturated sodium bicarbonate aqueous solution, saturated salt solution are successively used
Wash organic phase.
Preferably, substitution of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The method of ethyl ester, organic solvent described in step (2) are mixed solvent, and the mixed solvent is by acetonitrile and toluene, diformazan
Any one of benzene, 1,2- dichloroethanes, THF, DMF mix；And/or
The catalyst is TBAB, TBACl, TBAOTf or TBAI.
Preferably, substitution of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The concrete operations of the method for ethyl ester, washing described in step (2) are as follows: using the mixed of methylene chloride and saturated aqueous ammonium chloride
Object is closed as detergent washing concentrate, divides and takes organic phase, then successively practical saturated sodium bicarbonate aqueous solution, saturated common salt washing
Wash organic phase.
Preferably, substitution of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The method of ethyl ester, every 1.0g, the 1.0equiv. 2- as shown in Formula II (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate with
The alkali reaction of the methylsufonyl chloride, 1-4equiv. of 0.9-2.4equiv.；And/or
The process of substitution reaction described in step (1) is to be heated to 50 DEG C of reaction 18h；Or it is heated to back flow reaction 4-32h.
Preferably, substitution of the present invention synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
The method of ethyl ester, 2- chlorine (the fluoro- 3- methoxyphenyl of the 2-) ethyl acetate and 1- shown as a formula V of every 1.0g, 1.0equiv
The catalyst reaction of the zinc powder of 5equiv., 0.1-0.2equiv.；And/or
The process of the reaction of Blaise described in step (2) is to be heated to 50 DEG C of reaction 10h, or be heated to back flow reaction 6-
32h。
The technology of the present invention is achieved with target product the utility model has the advantages that technical solution of the present invention only passes through two-step reaction, synthesis
Route is short, easy to operate；By selecting reasonable reagent, solvent, reaction condition to obtain higher yield, economic effect is improved
Benefit；By the way that catalyst is added in second step reaction, promotes the generation of main reaction, reduce side reaction, avoid introducing unnecessary
Impurity, so that reactant is easy to purify, to obtain the higher product of purity.
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- (the 2- fluoro- 3- methoxybenzene shown in formula I by the synthesis of following route of the embodiment of the present invention
Base) -2- butenoic acid ethyl:
Embodiment 1
(1) synthetic route of 2- chlorine shown as a formula V (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate:
Concrete operations: in the reactor, by 1.0g, (the fluoro- 3- methoxybenzene of 2- of the 2- as shown in Formula II of 1.0equiv.
Base) -2- hydroxyl ethyl acetate is dissolved in 10mL methylene chloride, be added thereto 1.2equiv. methylsufonyl chloride (MsCl),
The DMAP of 2.0equiv. is heated to back flow reaction 18h；After reaction, mixture is concentrated to dryness, using methylene chloride and
The mixed liquor of 1N aqueous hydrochloric acid solution divides as detergent washing concentrate and takes organic phase, then successively molten with saturated sodium bicarbonate water
Then liquid, saturated common salt water washing organic phase use sodium sulphate dry and are spin-dried for, most chromatographs to obtain 0.86equiv.'s through column afterwards
2- chlorine (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate shown as a formula V, yield 86%.Using high resolution mass spectrum (ESI+)
Detection, detected value 247.0539；M+H+High resolution mass spectrum calculating value be 247.0532, through compare can confirm product knot
Structure.
(2) the synthesis road of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl shown in formula I
Line:
Concrete operations: in the reactor, by 1.0g, (2- is fluoro- by (Z) -3- amino -2- shown as a formula V of 1.0equiv.
3- methoxyphenyl) -2- butenoic acid ethyl be dissolved in 10mL acetonitrile and 10mL toluene composition in the mixed solvent, be added thereto
The TBAI of the zinc powder of 2.0equiv., 0.1equiv., system is heated to flowing back, and is stirred and lower is reacted 18h；After reaction, will
Mixture is concentrated to dryness；Using the mixture of methylene chloride and saturated aqueous ammonium chloride as detergent washing concentrate, divide
Take organic phase；Saturated sodium bicarbonate, saturated common salt water washing organic phase are successively used again, then use sodium sulphate dry and are revolved
It is dry, obtain 0.52equiv. colorless oil, i.e., (Z) -3- amino -2- shown in formula I (the fluoro- 3- methoxyphenyl of 2-) -2-
Butenoic acid ethyl, yield 52%.It is detected using high resolution mass spectrum (ESI+), detected value 254.1195；M+H+High score
It distinguishes that mass spectrum calculated value is 254.1187, can confirm product structure through comparing.
Embodiment 2
(1) synthetic route of 2- chlorine shown as a formula V (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate:
Concrete operations: in the reactor, by 1.0g, (the fluoro- 3- methoxybenzene of 2- of the 2- as shown in Formula II of 1.0equiv.
Base) -2- hydroxyl ethyl acetate is dissolved in 15mL 1, and the methylsufonyl chloride of 0.9equiv. is added in 2- dichloroethanes thereto
(MsCl), the triethylamine of 1.0equiv. is heated to back flow reaction 4h；After reaction, mixture is concentrated to dryness, using two
The mixed liquor of chloromethanes and 1N aqueous hydrochloric acid solution divides as detergent washing concentrate and takes organic phase, then successively uses unsaturated carbonate
Then hydrogen sodium water solution, saturated common salt water washing organic phase use sodium sulphate dry and are spin-dried for, most chromatograph to obtain through column afterwards
2- chlorine (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate shown as a formula V of 0.77equiv., yield 77%.Using high score
Distinguish that mass spectrum (ESI+) is detected, detected value 247.0534.
(2) the synthesis road of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl shown in formula I
Line:
Concrete operations: in the reactor, by 1.0g, (2- is fluoro- by (Z) -3- amino -2- shown as a formula V of 1.0equiv.
3- methoxyphenyl) -2- butenoic acid ethyl is dissolved in 3mL acetonitrile and 15mL1, the in the mixed solvent of 2- dichloroethanes composition, Xiang Qi
The TBAB of the middle zinc powder that 1.0equiv. is added, 0.2equiv., system is heated to flowing back, and stirs lower reaction 18h；Reaction terminates
Afterwards, mixture is concentrated to dryness；Using the mixture of methylene chloride and saturated aqueous ammonium chloride as detergent washing concentrating
Object divides and takes organic phase；Saturated sodium bicarbonate, saturated common salt water washing organic phase are successively used again, it is then dry using sodium sulphate
And be spin-dried for, obtain 0.45equiv. colorless oil, i.e., (Z) -3- amino -2- (fluoro- 3- methoxybenzene of 2- shown in formula I
Base) -2- butenoic acid ethyl, yield 45%.It is detected using high resolution mass spectrum (ESI+), detected value 254.1192.
Embodiment 3
(1) synthetic route of 2- chlorine shown as a formula V (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate:
Concrete operations: in the reactor, by 1.0g, (the fluoro- 3- methoxybenzene of 2- of the 2- as shown in Formula II of 1.0equiv.
Base) -2- hydroxyl ethyl acetate is dissolved in 12mL DMF, be added thereto 2.4equiv. methylsufonyl chloride (MsCl),
The pyridine of 2.0equiv. is heated to back flow reaction 18h；After reaction, mixture is concentrated to dryness, using methylene chloride and
The mixed liquor of 1N aqueous hydrochloric acid solution divides as detergent washing concentrate and takes organic phase, then successively molten with saturated sodium bicarbonate water
Then liquid, saturated common salt water washing organic phase use sodium sulphate dry and are spin-dried for, most chromatographs to obtain 0.90equiv.'s through column afterwards
2- chlorine (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate shown as a formula V, yield 90%.Using high resolution mass spectrum (ESI+)
Detection, detected value 247.0536.
(2) the synthesis road of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl shown in formula I
Line:
Concrete operations: in the reactor, by 1.0g, (2- is fluoro- by (Z) -3- amino -2- shown as a formula V of 1.0equiv.
3- methoxyphenyl) -2- butenoic acid ethyl be dissolved in 15mL acetonitrile and 3mL dimethylbenzene composition in the mixed solvent, be added thereto
The TBAI of the zinc powder of 2.0equiv., 0.1equiv., system is heated to flowing back, and is stirred and lower is reacted 32h；After reaction, will
Mixture is concentrated to dryness；Using the mixture of methylene chloride and saturated aqueous ammonium chloride as detergent washing concentrate, divide
Take organic phase；Saturated sodium bicarbonate, saturated common salt water washing organic phase are successively used again, then use sodium sulphate dry and are revolved
It is dry, obtain 0.41equiv. colorless oil, i.e., (Z) -3- amino -2- shown in formula I (the fluoro- 3- methoxyphenyl of 2-) -2-
Butenoic acid ethyl, yield 41%.It is detected using high resolution mass spectrum (ESI+), detected value 254.1194.
Embodiment 4
(1) synthetic route of 2- chlorine shown as a formula V (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate:
Concrete operations: in the reactor, by 1.0g, (the fluoro- 3- methoxybenzene of 2- of the 2- as shown in Formula II of 1.0equiv.
Base) -2- hydroxyl ethyl acetate is dissolved in 10mL chloroform, be added thereto 1.2equiv. methylsufonyl chloride (MsCl),
The DIPEA of 4.0equiv. is stirred, is heated to 50 DEG C of reaction 18h；After reaction, mixture is concentrated to dryness, using dichloro
The mixed liquor of methane and 1N aqueous hydrochloric acid solution divides as detergent washing concentrate and takes organic phase, then successively uses unsaturated carbonate hydrogen
Then sodium water solution, saturated common salt water washing organic phase use sodium sulphate dry and are spin-dried for, most chromatograph to obtain through column afterwards
2- chlorine (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate shown as a formula V of 0.85equiv., yield 85%.Using high score
Distinguish that mass spectrum (ESI+) is detected, detected value 247.0534.
(2) the synthesis road of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl shown in formula I
Line:
Concrete operations: in the reactor, by 1.0g, (2- is fluoro- by (Z) -3- amino -2- shown as a formula V of 1.0equiv.
3- methoxyphenyl) -2- butenoic acid ethyl be dissolved in 10mL acetonitrile and 10mL THF composition in the mixed solvent, be added thereto
The TBACl of the zinc powder of 2.0equiv., 0.2equiv., stirring, heating systems stir to 50 DEG C and lower react 6h；After reaction,
Mixture is concentrated to dryness；Using the mixture of methylene chloride and saturated aqueous ammonium chloride as detergent washing concentrate,
Divide and takes organic phase；Saturated sodium bicarbonate, saturated common salt water washing organic phase are successively used again, then use sodium sulphate dry and are revolved
It is dry, obtain 0.31equiv. colorless oil, i.e., (Z) -3- amino -2- shown in formula I (the fluoro- 3- methoxyphenyl of 2-) -2-
Butenoic acid ethyl, yield 31%.It is detected using high resolution mass spectrum (ESI+), detected value 254.1194.
Embodiment 5
(1) synthetic route of 2- chlorine shown as a formula V (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate:
Concrete operations: in the reactor, by 1.0g, (the fluoro- 3- methoxybenzene of 2- of the 2- as shown in Formula II of 1.0equiv.
Base) -2- hydroxyl ethyl acetate is dissolved in 15mL diethylene glycol dimethyl ether, the methylsufonyl chloride of 1.2equiv. is added thereto
(MsCl), the pyridine of the triethylamine of 1.1equiv., 0.1equiv. is heated to back flow reaction 32h；After reaction, it will mix
Object is concentrated to dryness, and using the mixed liquor of methylene chloride and 1N aqueous hydrochloric acid solution as detergent washing concentrate, is divided and is taken organic phase,
Saturated sodium bicarbonate aqueous solution, saturated common salt water washing organic phase are successively used again, and then just sodium sulphate is dry and is spin-dried for, and most passes through afterwards
Column chromatographs to obtain 2- chlorine (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate shown as a formula V of 0.85equiv., and yield is
85%.It is detected using high resolution mass spectrum (ESI+), detected value 247.0539.
(2) the synthesis road of (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl shown in formula I
Line:
Concrete operations: in the reactor, by 1.0g, (2- is fluoro- by (Z) -3- amino -2- shown as a formula V of 1.0equiv.
3- methoxyphenyl) -2- butenoic acid ethyl be dissolved in 10mL acetonitrile and 10mL toluene composition in the mixed solvent, be added thereto
System is heated to flowing back by the zinc powder of 5.0equiv., stirs lower reaction 20h；After reaction, mixture is concentrated to dryness；It adopts
It uses the mixture of methylene chloride and saturated aqueous ammonium chloride as detergent washing concentrate, divides and take organic phase；Successively make again
It is then dry using sodium sulphate and be spin-dried for saturated sodium bicarbonate, saturated common salt water washing organic phase, obtain 0.52equiv. without
Color grease, i.e., (Z) -3- amino -2- shown in formula I (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl, yield are
52%.It is detected using high resolution mass spectrum (ESI+), detected value 254.1189.
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. replacing the method for synthesis (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl, which is characterized in that
The following steps are included:
(1) 2- as shown in Formula II (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate replaces with methane sulfonyl chloride
Reaction, obtains 2- chlorine shown as a formula V (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate；
(2) 2- chlorine shown as a formula V (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate reacts to obtain shown in formula I through Blaise
(Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl；
2. substitution according to claim 1 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid second
The method of ester, which is characterized in that the concrete operations of the step (1) are as follows: (the fluoro- 3- methoxyl group of 2- of the 2- as shown in Formula II
Phenyl) -2- hydroxyl ethyl acetate is dissolved in solvent, substitution reaction occurs after methane sulfonyl chloride, alkali is added thereto；Reaction knot
Mixture is concentrated to dryness after beam, 2- chlorine shown as a formula V (the fluoro- 3- methoxyl group of 2- is obtained to concentrate washing, dry, purifying
Phenyl) ethyl acetate.
3. substitution according to claim 1 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid second
The method of ester, which is characterized in that the concrete operations of the step (2) are as follows: by 2- chlorine (the fluoro- 3- methoxyl group of 2- shown as a formula V
Phenyl) ethyl acetate is dissolved in organic solvent, Blaise reaction occurs after zinc powder is added thereto；After reaction, by mixture
It is concentrated to dryness, it is washed, be dried to obtain (Z) -3- amino -2- shown in formula I (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid
Ethyl ester.
4. substitution according to claim 3 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid second
The method of ester, which is characterized in that further include having catalyst in the reactant of the step (2).
5. substitution according to claim 2 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid second
The method of ester, which is characterized in that solvent described in step (1) be selected from methylene chloride, 1,2- dichloroethanes, chloroform, THF,
Any one of DMF, diethylene glycol dimethyl ether；And/or
Alkali described in step (1) is selected from the mixture of triethylamine, DIPEA, pyridine, DMAP or triethylamine and pyridine.
6. substitution according to claim 2 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid second
The method of ester, which is characterized in that the concrete operations of washing described in step (1) are as follows: first water-soluble using methylene chloride and hydrochloric acid
The mixture of liquid washs concentrate as detergent, after point taking organic phase, successively using saturated sodium bicarbonate aqueous solution,
Saturated common salt water washing organic phase.
7. substitution according to claim 4 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid second
The method of ester, which is characterized in that organic solvent described in step (2) be mixed solvent, the mixed solvent be by acetonitrile with
Any one of toluene, dimethylbenzene, 1,2- dichloroethanes, THF, DMF mix；And/or
The catalyst is TBAB, TBACl, TBAOTf or TBAI.
8. substitution according to claim 3 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid second
The method of ester, which is characterized in that the concrete operations of washing described in step (2) are as follows: methylene chloride and saturated ammonium chloride are used
The mixture of aqueous solution point takes organic phase as detergent washing concentrate, then successively practical saturated sodium bicarbonate aqueous solution, full
With brine It organic phase.
9. substitution according to claim 2 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid second
The method of ester, which is characterized in that every 1.0g, the 1.0equiv. 2- as shown in Formula II (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl
Ethyl acetate is reacted with the alkali of the methylsufonyl chloride of 0.9-2.4equiv., 1-4equiv.；And/or
The process of substitution reaction described in step (1) is to be heated to 50 DEG C of reaction 18h；Or it is heated to back flow reaction 4-32h.
10. substitution according to claim 4 synthesizes (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid second
The method of ester, which is characterized in that 2- chlorine (the fluoro- 3- methoxyphenyl of 2-) acetic acid second shown as a formula V of every 1.0g, 1.0equiv
The catalyst reaction of the zinc powder of ester and 1-5equiv., 0.1-0.2equiv.；And/or
The process of the reaction of Blaise described in step (2) is to be heated to 50 DEG C of reaction 10h, or be heated to back flow reaction 6-32h.
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| 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 |
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- 2019-02-16 CN CN201910118478.7A patent/CN109704981B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007103996A1 (en) * | 2006-03-09 | 2007-09-13 | Bristol-Myers Squibb Company | 2-(aryloxy)acetamide factor viia inhibitors useful as anticoagulants |
| 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 |
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