CN109704961A - A kind of synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate - Google Patents
A kind of synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate Download PDFInfo
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Abstract
The invention discloses the synthetic method of a kind of bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, synthetic route is as follows:
Description
Technical field
The present invention relates to machine synthesis and medicine intermediate technical field, the particularly bromo- 2- of a kind of 2- (the fluoro- 3- methoxies of 2-
Base phenyl) ethyl acetate synthetic method synthetic method.
Background technique
Pain caused by Eagolix conduct is treated because of endometriosis, is authenticated by U.S. FDA, and at
For such idicatio the first oral drugs during the last ten years.
There is larger demand in good therapeutic effect based on eagolix, market to elagolix bulk pharmaceutical chemicals and intermediate,
The structure of elagolix is as follows:
Key intermediate of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of the 2-) ethyl acetate as synthesis elagolix, structure
As shown in formula I:
Patent No.: WO2009062087 discloses the synthetic method about the compound, and reaction process is as follows:
In the technical solution of the patent literature report, with the fluoro- 2- methoxybenzene (II) of 1- for starting material, closed by four steps
At the compound, reaction route is tediously long, causes overall yield of reaction low.
Therefore, the synthesis technology for improving the above-mentioned type I compound as synthesis Eagolix, can not only significantly improve
The industrialization production application of Eagolix, meanwhile, it is capable to reduce the process costs of industrialized production Eagolix.
Summary of the invention
Technical problem to be solved by the present invention lies in provide a kind of bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) acetic acid second
The synthetic method of the synthetic method of ester.
The present invention is to solve above-mentioned technical problem by the following technical programs:
A kind of synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, synthetic route are as follows:
The synthetic method of the above-mentioned bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate the following steps are included:
(1) by 0.5-1.5g, the Formula II compound of 1equiv. is leaked using the ether dissolution of 2.5-7.5mL in constant pressure addition
In bucket, the diethyl ether solution of preparation formula II compound is spare；
In terms of Formula II compound, the ethyl chloroacetate of 1.1-1.4equiv. is dripped using the ether dissolution of 1-3mL in constant pressure
In liquid funnel, the diethyl ether solution of ethyl chloroacetate is prepared, it is spare；
(2) in terms of Formula II compound, the diethyl ether solution of the n-BuLi of 1.1-1.4equiv. is added in reactor, it is cold
But to after -85~-75 DEG C, the TMEDA of 1.1-1.4equiv. is added, after being dispersed with stirring, by the Formula II compound in step (1)
Diethyl ether solution is added dropwise in reaction system, and drop finishes, and reaction system is warming up to -55~-45 DEG C, cold after insulated and stirred 0.5-1.5h
But to -85~-75 DEG C；
(3) diethyl ether solution of the ethyl chloroacetate in step (1) is added dropwise in reaction system, drop finishes, and reaction system is slow
Slowly after being warmed to room temperature, after post-treated operation, VI compound of formula is obtained；
(4) by 0.5-1.5g, reactor is added in VI compound of formula of 1.0equiv., and the carbon tetrachloride that 5-15mL is added is molten
After solution dispersion, in terms of VI compound of formula, the bromating agent and 0.1- of 1.2-1.4equiv. are sequentially added into reaction system
The initiator of 0.15equiv., is dispersed with stirring, and is warming up to reflux, after back flow reaction 4.5-5.5h, is cooled to room temperature, is recovered under reduced pressure
For solvent to doing, residue obtains the bromo- 2- of type I compound 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate after column chromatography for separation.
Preferably, by 1.0g in the step (1), the Formula II compound of 1equiv. is using the ether dissolution of 5mL in constant pressure
In dropping funel, the diethyl ether solution of preparation formula II compound is spare；
The ethyl chloroacetate of 1equiv. is prepared into monoxone in constant pressure funnel using the ether dissolution of ether 3mL
The diethyl ether solution of ethyl ester, it is spare.
Preferably, the diethyl ether solution of the n-BuLi of 1.2equiv. is added in reactor in the step (2), it is cooling
After to -78 DEG C, the TMEDA of 1.2equiv. is added, after being dispersed with stirring, the II compound diethyl ether solution in step (1) is added dropwise to
In reaction system, drop finishes, and reaction system is warming up to -50 DEG C, after insulated and stirred 1h, is cooled to -78 DEG C.
Preferably, the processing operation in the step (3) is as follows:
After reaction system is slowly increased to room temperature, reaction solution is divided in the aqueous hydrochloric acid solution of ethyl acetate and 1.2-1.5N
Match, separates organic phase, it is dry with sodium sulphate again after being washed with brine, it is finally spin-dried for solvent, will be obtained after residue column chromatography for separation
To VI compound of formula.
Preferably, room temperature is warming up to after 5h in the control slow temperature-rise period of reaction system in the step (3).
Preferably, by 1.0g in the step (4), VI compound of formula of 1.0equiv. is added reactor, is added 10mL's
After carbon tetrachloride dissolution dispersion, the bromating agent of 1.2equiv. and the initiator of 0.1equiv. are sequentially added into reaction system,
It is dispersed with stirring, is warming up to reflux, back flow reaction 5h.
Preferably, the bromating agent is NBS.
Preferably, the initiator includes benzoyl peroxide.
Preferably, the initiator further includes azodiisobutyronitrile.
Referring now to prior art the utility model has the advantages that
The invention discloses the synthetic methods of a kind of bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, compared to existing
There is synthetic method disclosed in technology, the present invention discloses process route, and reaction step is few, can synthesize target product using two steps.
And synthesized in the prior art using four steps, not only reaction time is long, and total recovery is low, and cost is also high.
Meanwhile the present invention is prepared using two-step method, not only energy consumption of reaction it is low, " three wastes " less, short preparation period.
Specific embodiment
It elaborates below to the embodiment of the present invention, the present embodiment carries out under the premise of the technical scheme of the present invention
Implement, the detailed implementation method and specific operation process are given, but protection scope of the present invention is not limited to following implementation
Example.
Embodiment 1
A kind of synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, synthetic route are as follows:
The synthetic method of the above-mentioned bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate the following steps are included:
One, the preparation of VI compound of formula:
(1) by 1.0g, the Formula II compound of 1equiv. uses the ether dissolution of 5mL in constant pressure funnel, preparation formula
The diethyl ether solution of II compound, it is spare；
In terms of Formula II compound, the ethyl chloroacetate of 1equiv. is leaked using the ether dissolution of ether 3mL in constant pressure addition
In bucket, the diethyl ether solution of ethyl chloroacetate is prepared, it is spare；
(2) in terms of Formula II compound, the diethyl ether solution of the n-BuLi of 1.2equiv. is added in reactor, be cooled to-
After 78 DEG C, the TMEDA of 1.2equiv. is added, after being dispersed with stirring, the II compound diethyl ether solution in step (1) is added dropwise to instead
It answers in system, drop finishes, and reaction system is warming up to -50 DEG C, after insulated and stirred 1h, is cooled to -78 DEG C；
(3) diethyl ether solution of the ethyl chloroacetate in step (1) is added dropwise in reaction system, drop finishes, and reaction system is slow
Slowly after being warmed to room temperature, after being warmed to room temperature after 5h, reaction solution is divided in the aqueous hydrochloric acid solution of ethyl acetate and 1N for temperature-rise period
Match, separates organic phase, it is dry with sodium sulphate again after being washed with brine, it is finally spin-dried for solvent, will be obtained after residue column chromatography for separation
To VI compound of formula, yield 52.2%, high resolution mass spectrum (ESI+): C11H14FO3 +, 230.0927.
Two, the preparation of type I compound:
(4) by 1.0g, reactor is added in VI compound of formula of 1.0equiv., and the carbon tetrachloride dissolution dispersion of 10mL is added
Afterwards, in terms of VI compound of formula, the benzoyl peroxide first of the NBS and 0.1equiv. of 1.2equiv. are sequentially added into reaction system
Acyl is dispersed with stirring, and is warming up to reflux, back flow reaction 5h, and after back flow reaction, to dry, residue chromatographs concentrated solvent through column
Afterwards, the bromo- 2- of type I compound 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, yield 62.3%, high resolution mass spectrum (ESI are obtained
+): C11H13BrFO3 +, 291.0035.
Embodiment 2
A kind of synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, synthetic route are as follows:
The synthetic method of the above-mentioned bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate the following steps are included:
One, the preparation of VI compound of formula:
(1) by 0.5g, the Formula II compound of 1equiv. in constant pressure funnel, is prepared using the ether dissolution of 2.5mL
The diethyl ether solution of Formula II compound, it is spare；
In terms of Formula II compound, by the ethyl chloroacetate of 1.1equiv. using the ether dissolution of ether 1mL in constant pressure addition
In funnel, the diethyl ether solution of ethyl chloroacetate is prepared, it is spare；
(2) in terms of Formula II compound, the diethyl ether solution of the n-BuLi of 1.1equiv. is added in reactor, be cooled to-
After 85 DEG C, the TMEDA of 1.1equiv. is added, after being dispersed with stirring, the II compound diethyl ether solution in step (1) is added dropwise to instead
It answers in system, drop finishes, and reaction system is warming up to -55 DEG C, after insulated and stirred 1.5h, is cooled to -75 DEG C；
(3) diethyl ether solution of the ethyl chloroacetate in step (1) is added dropwise in reaction system, drop finishes, and reaction system is slow
Slowly after being warmed to room temperature, after being warmed to room temperature after 5h, reaction solution is divided in the aqueous hydrochloric acid solution of ethyl acetate and 1N for temperature-rise period
Match, separates organic phase, it is dry with sodium sulphate again after being washed with brine, it is finally spin-dried for solvent, will be obtained after residue column chromatography for separation
To VI compound of formula, yield 51.8%, high resolution mass spectrum (ESI+): C11H14FO3 +, 230.0927.
Two, the preparation of type I compound:
(4) by 1.5g, reactor is added in VI compound of formula of 1.0equiv., and the carbon tetrachloride dissolution dispersion of 15mL is added
Afterwards, in terms of VI compound of formula, the benzoyl peroxide first of the NBS and 0.15equiv. of 1.2equiv. are sequentially added into reaction system
Acyl is dispersed with stirring, and is warming up to reflux, back flow reaction 4.5h, and after back flow reaction, concentrated solvent is to dry, and residue is through column layer
After analysis, the bromo- 2- of type I compound 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, yield 63.3%, high resolution mass spectrum are obtained
(ESI+): C11H13BrFO3 +, 291.0035.
Embodiment 3
A kind of synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, synthetic route are as follows:
The synthetic method of the above-mentioned bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate the following steps are included:
One, the preparation of VI compound of formula:
(1) by 1.5g, the Formula II compound of 1equiv. in constant pressure funnel, is prepared using the ether dissolution of 15mL
The diethyl ether solution of Formula II compound, it is spare；
In terms of Formula II compound, by the ethyl chloroacetate of 1.4equiv. using the ether dissolution of ether 3mL in constant pressure addition
In funnel, the diethyl ether solution of ethyl chloroacetate is prepared, it is spare；
(2) in terms of Formula II compound, the diethyl ether solution of the n-BuLi of 1.4equiv. is added in reactor, be cooled to-
After 75 DEG C, the TMEDA of 1.4equiv. is added, after being dispersed with stirring, the II compound diethyl ether solution in step (1) is added dropwise to instead
It answers in system, drop finishes, and reaction system is warming up to -45 DEG C, after insulated and stirred 0.5h, is cooled to -78 DEG C；
(3) diethyl ether solution of the ethyl chloroacetate in step (1) is added dropwise in reaction system, drop finishes, and reaction system is slow
Slowly after being warmed to room temperature, after being warmed to room temperature after 5h, reaction solution is divided in the aqueous hydrochloric acid solution of ethyl acetate and 1N for temperature-rise period
Match, separates organic phase, it is dry with sodium sulphate again after being washed with brine, it is finally spin-dried for solvent, will be obtained after residue column chromatography for separation
To VI compound of formula, yield 51.8%, high resolution mass spectrum (ESI+): C11H14FO3 +, 230.0927.
Two, the preparation of type I compound:
(4) by 1.0g, reactor is added in VI compound of formula of 1.0equiv., and the carbon tetrachloride dissolution dispersion of 10mL is added
Afterwards, in terms of VI compound of formula, the benzoyl peroxide first of the NBS and 0.15equiv. of 1.4equiv. are sequentially added into reaction system
Acyl is dispersed with stirring, and is warming up to reflux, back flow reaction 5.5h, and after back flow reaction, concentrated solvent is to dry, and residue is through column layer
After analysis, the bromo- 2- of type I compound 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate is obtained, 61.5%, high resolution mass spectrum (ESI+):
C11H13BrFO3 +, 291.0035.
Embodiment 4
A kind of synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, synthetic route are as follows:
The synthetic method of the above-mentioned bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate the following steps are included:
One, the preparation of VI compound of formula:
(1) by 1.3g, the Formula II compound of 1equiv. in constant pressure funnel, is prepared using the ether dissolution of 12mL
The diethyl ether solution of Formula II compound, it is spare；
In terms of Formula II compound, by the ethyl chloroacetate of 1.2equiv. using the ether dissolution of ether 3mL in constant pressure addition
In funnel, the diethyl ether solution of ethyl chloroacetate is prepared, it is spare；
(2) in terms of Formula II compound, the diethyl ether solution of the n-BuLi of 1.2equiv. is added in reactor, be cooled to-
After 80 DEG C, the TMEDA of 1.2equiv. is added, after being dispersed with stirring, the II compound diethyl ether solution in step (1) is added dropwise to instead
It answers in system, drop finishes, and reaction system is warming up to -48 DEG C, after insulated and stirred 1.2h, is cooled to -80 DEG C；
(3) diethyl ether solution of the ethyl chloroacetate in step (1) is added dropwise in reaction system, drop finishes, and reaction system is slow
Slowly after being warmed to room temperature, after being warmed to room temperature after 5h, reaction solution is divided in the aqueous hydrochloric acid solution of ethyl acetate and 1N for temperature-rise period
Match, separates organic phase, it is dry with sodium sulphate again after being washed with brine, it is finally spin-dried for solvent, will be obtained after residue column chromatography for separation
To VI compound of formula, yield 51.7%, high resolution mass spectrum (ESI+): C11H14FO3 +, 230.0927.
Two, the preparation of type I compound:
(4) by 1.2g, reactor is added in VI compound of formula of 1.0equiv., and the carbon tetrachloride dissolution dispersion of 12mL is added
Afterwards, in terms of VI compound of formula, two isobutyl of azo of the NBS and 0.12equiv. of 1.2equiv. is sequentially added into reaction system
Nitrile is dispersed with stirring, and is warming up to reflux, back flow reaction 4.8h, and after back flow reaction, concentrated solvent is to dry, and residue is through column layer
After analysis, the bromo- 2- of type I compound 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, yield 60.5%, high resolution mass spectrum are obtained
(ESI+): C11H13BrFO3 +, 291.0035.
Embodiment 5
In the preparation process of VI compound of formula, the selection of base reagent is affected to the yield of compound shown in VI, in order to
Preferable base reagent is filtered out, according to technical solution disclosed in embodiment 1 (base reagent is variable), finally screens structure such as table 1
It is shown:
Table 1
The data as disclosed in table 1 are it is found that use the TMEDA of n-BuLi and equivalent for preferable base reagent.
In the preparation process of type I compound, bromating agent, initiator and solvent are affected to reaction effect, in order to sieve
Preferable reaction condition is selected, according to technical solution disclosed in embodiment 1 (bromating agent, initiator and solvent are variable), most
Whole the selection result is as shown in table 2:
Table 2
The data disclosed in table 2: NBS as bromating agent, benzoyl peroxide or AIBN as initiator, and
Carbon tetrachloride is preferable as solvent reaction effect.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (10)
1. a kind of synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, which is characterized in that synthetic route is such as
Shown in lower:
2. the synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 1, feature
Be, the synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of the 2-) ethyl acetate the following steps are included:
(1) by 0.5-1.5g, the Formula II compound of 1equiv. uses the ether dissolution of 2.5-7.5mL in constant pressure funnel,
The diethyl ether solution of preparation formula II compound, it is spare；
In terms of Formula II compound, the ethyl chloroacetate of 1.1-1.4equiv. is leaked using the ether dissolution of 1-3mL in constant pressure addition
In bucket, the diethyl ether solution of ethyl chloroacetate is prepared, it is spare；
(2) in terms of Formula II compound, the diethyl ether solution of the n-BuLi of 1.1-1.4equiv. is added in reactor, be cooled to-
After 85~-75 DEG C, the TMEDA of 1.1-1.4equiv. is added, it is after being dispersed with stirring, the Formula II compound ether in step (1) is molten
Drop adds in reaction system, and drop finishes, and reaction system is warming up to -55~-45 DEG C, after insulated and stirred 0.5-1.5h, is cooled to -85
~-75 DEG C；
(3) diethyl ether solution of the ethyl chloroacetate in step (1) is added dropwise in reaction system, drop finishes, and reaction system slowly rises
To room temperature, after post-treated operation, VI compound of formula is obtained；
(4) by 0.5-1.5g, reactor is added in VI compound of formula of 1.0equiv., and the carbon tetrachloride dissolution point of 5-15mL is added
After dissipating, in terms of VI compound of formula, the bromating agent and 0.1-0.15equiv. of 1.2-1.4equiv. are sequentially added into reaction system
Initiator, be dispersed with stirring, be warming up to reflux, after back flow reaction 4.5-5.5h, be cooled to room temperature, solvent is recovered under reduced pressure to dry,
Residue obtains the bromo- 2- of type I compound 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate after column chromatography for separation.
3. the synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 2, feature
It is, by 1.0g in the step (1), the Formula II compound of 1equiv. is using the ether dissolution of 5mL in constant pressure funnel
In, the diethyl ether solution of preparation formula II compound is spare；
The ethyl chloroacetate of 1equiv. is prepared into ethyl chloroacetate in constant pressure funnel using the ether dissolution of ether 3mL
Diethyl ether solution, it is spare.
4. the synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 2, feature
It is, the diethyl ether solution of the n-BuLi of 1.2equiv. is added in reactor in the step (2), after being cooled to -78 DEG C,
The TMEDA of 1.2equiv. is added, after being dispersed with stirring, the II compound diethyl ether solution in step (1) is added dropwise to reaction system
In, drop finishes, and reaction system is warming up to -50 DEG C, after insulated and stirred 1h, is cooled to -78 DEG C.
5. the synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 2, feature
It is, the processing operation in the step (3) is as follows:
After reaction system is slowly increased to room temperature, reaction solution is distributed in the aqueous hydrochloric acid solution of ethyl acetate and 1.2-1.5N, point
Organic phase out, it is dry with sodium sulphate again after being washed with brine, it is finally spin-dried for solvent, formula VI will be obtained after residue column chromatography for separation
Compound.
6. the synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 2, feature
It is, in the step (3) in the control slow temperature-rise period of reaction system, is warming up to room temperature after 5h.
7. the synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 2, feature
It is, by 1.0g in the step (4), reactor is added in VI compound of formula of 1.0equiv., and the carbon tetrachloride that 10mL is added is molten
After solution dispersion, the bromating agent of 1.2equiv. and the initiator of 0.1equiv. are sequentially added into reaction system, is dispersed with stirring, rise
Temperature extremely flows back, back flow reaction 5h.
8. the synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 7, feature
It is, the bromating agent is NBS.
9. the synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 8, feature
It is, the initiator includes benzoyl peroxide.
10. the synthetic method of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 9, feature
It is, the initiator further includes azodiisobutyronitrile.
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2019
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| CN1572782A (en) * | 2003-05-28 | 2005-02-02 | 大日本油墨化学工业株式会社 | Process for the preparation of fluorophenylalkylene acid derivatives |
| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| CN105208859A (en) * | 2013-03-15 | 2015-12-30 | 美国陶氏益农公司 | Novel 4-aminopyridine and 6-aminopyrimidine carboxylates as herbicides |
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Application publication date: 20190503 |