CN109809992A - A kind of fluoro- 3- methoxyphenyl of 2-(2-) -2- hydroxyl ethyl acetate synthetic method - Google Patents
A kind of fluoro- 3- methoxyphenyl of 2-(2-) -2- hydroxyl ethyl acetate synthetic method Download PDFInfo
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- CN109809992A CN109809992A CN201910121539.5A CN201910121539A CN109809992A CN 109809992 A CN109809992 A CN 109809992A CN 201910121539 A CN201910121539 A CN 201910121539A CN 109809992 A CN109809992 A CN 109809992A
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Abstract
The invention discloses a kind of synthetic method of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, synthetic route is as follows:
Description
Technical field
The present invention relates to machine synthesis and medicine intermediate technical field, particularly a kind of 2- (fluoro- 3- methoxybenzenes of 2-
Base) -2- hydroxyl ethyl acetate 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.Good therapeutic effect based on eagolix, market is to elagolix original
Material medicine and intermediate have larger demand, and the structure of elagolix is as follows:
Key intermediate of 2- (the fluoro- 3- methoxyphenyl of the 2-) -2- hydroxyl ethyl acetate as synthesis elagolix, knot
Structure is as shown in formula I:
The prior art, about the synthetic method of the compound, usually using the fluoro- 2- methoxybenzene of 1- as starting material, through lithium
Change, addition, three big steps of reduction are prepared, as disclosed 2- (the fluoro- 3- methoxybenzene of 2- in Patent No. WO2009062087
Base) -2- hydroxyl ethyl acetate, reaction process is as follows:
By the technical solution of the patent literature report, need to be prepared 2- (the fluoro- 3- methoxybenzene of 2- by two steps
Base) -2- hydroxyl ethyl acetate, and need to use sodium borohydride as reproducibility reagent in second step.Using sodium borohydride
Reduction, not only reaction step is tediously long, and reaction yield bottom is readily incorporated impurity, and post-reaction treatment is relatively complicated.
Therefore, develop that a kind of short reaction step, high income, impurity content be low, synthetic route of Environmental Safety, for supporting
The meaning of the production of elagolix bulk pharmaceutical chemicals is larger.
Summary of the invention
Technical problem to be solved by the present invention lies in: a kind of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyacetic acid is provided
The synthetic method of ethyl ester, using fluoro- 2 methoxybenzene of 1- as starting material, target product is can be obtained after a step in reaction.
The present invention is to solve above-mentioned technical problem by the following technical programs:
A kind of synthetic method of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, synthetic route are as follows:
The synthetic method of above-mentioned 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, comprising the following steps:
(1) by 0.5-1.5g, the Formula II compound of 1equiv. is dissolved in constant pressure funnel using the THF of 2.5-7.5mL
In it is spare, in terms of Formula II compound, the THF solution of the lithium diisopropyl amido of 1.2-1.6equiv. is added in reactor, is stirred
It mixes after being cooled to -80~-70 DEG C, the THF solution of Formula II compound is added dropwise in reactor, drop finishes, and reaction system is warming up to -
60 DEG C~-50 DEG C, insulated and stirred 0.5-1.5h；
(2) glyoxylic acid ethyl ester is dissolved using the toluene of 2.5-9mL, is added into reactor, insulated and stirred 1.5-2.5h,
Reaction system is cooled to room temperature；
(3) hydrochloric acid solution of ethyl acetate and 0.5-1.5N are added separately in reactor, after extraction, are isolated organic
Layer, it is dry using anhydrous sodium sulfate after organic layer salt water washing, solvent is recovered under reduced pressure to doing, concentrate is after column chromatography for separation
Obtain type I compound 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate.
Preferably, by 1.0g in the step (1), 1equiv. Formula II compound is dissolved in constant pressure drop using the THF of 5mL
It is spare in liquid funnel, the THF solution of the lithium diisopropyl amido of 1.2equiv. is added in reactor, stirring is cooled to -78 DEG C
Afterwards, the THF solution of Formula II compound is added dropwise in reactor, drop finishes, and reaction system is warming up to -50 DEG C, insulated and stirred 1h.
Preferably, glyoxylic acid ethyl ester is dissolved in the step (2) using the toluene of 7mL, is added into reactor, heat preservation
2h is stirred, reaction system is cooled to room temperature.
Preferably, in the step (2) in terms of Formula II compound, the glyoxylic acid ethyl ester of 1.2-1.4equiv. is used into first
Benzene dissolution.
Preferably, the glyoxylic acid ethyl ester of 1.2equiv. is dissolved using toluene in the step (3).
Preferably, the hydrochloric acid solution of ethyl acetate and 1N is added separately to extract in reactor in the step (3).
The present invention has the advantage that compared with prior art
The invention discloses a kind of synthetic method of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, compared to
Synthetic method disclosed in the prior art, not only reaction step is few by the present invention, can be obtained target product using one-step synthesis.And it closes
It is environmentally friendly at route, in synthetic route, do not need using reproducibility reagent such as sodium borohydride etc., thus not only industrial production cost
It is low, it is with short production cycle, and convenient post-treatment, sewage quantity are few.Therefore, which is suitable as industrialized producing technology road
Line.
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 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, synthetic route are as follows:
The synthetic method of above-mentioned 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, comprising the following steps:
(1) by 0.5g, it is spare in constant pressure funnel that 1equiv. Formula II compound uses the THF of 2.5mL to be dissolved in, with
The THF solution of the lithium diisopropyl amido of 1.2equiv. is added in reactor Formula II compound meter, and stirring is cooled to -70 DEG C
Afterwards, the THF solution of Formula II compound is added dropwise in reactor, drop finishes, and reaction system is warming up to -50 DEG C, insulated and stirred 1.5h；
(2) glyoxylic acid ethyl ester is dissolved using the toluene of 2.5mL, is added into reactor, insulated and stirred 1.5h, reactant
System is cooled to room temperature；
(3) hydrochloric acid solution of ethyl acetate and 0.5N are added separately in reactor, after extraction, isolate organic layer,
It is dry using anhydrous sodium sulfate after organic layer salt water washing, solvent is recovered under reduced pressure to doing, concentrate obtains after column chromatography for separation
Type I compound 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, yield 83%, high resolution mass spectrum (ESI+):
C11H14FO4 +, 229.0874.
Embodiment 2
A kind of synthetic method of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, synthetic route are as follows:
The synthetic method of above-mentioned 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, comprising the following steps:
(1) by 1.0g, it is spare in constant pressure funnel that 1equiv. Formula II compound uses the THF of 5mL to be dissolved in, with formula
The THF solution of the lithium diisopropyl amido of 1.6equiv. is added in reactor II compound meter, and stirring is cooled to -78 DEG C
Afterwards, the THF solution of Formula II compound is added dropwise in reactor, drop finishes, and reaction system is warming up to -50 DEG C, insulated and stirred 1h；
(2) glyoxylic acid ethyl ester is dissolved using the toluene of 7mL, is added into reactor, insulated and stirred 2h, reaction system drop
It warms to room temperature；
(3) hydrochloric acid solution of the ethyl acetate of 10mL and 1N is added separately in reactor, after extraction, is isolated organic
Layer, it is dry using anhydrous sodium sulfate after organic layer salt water washing, solvent is recovered under reduced pressure to doing, concentrate is after column chromatography for separation
Obtain type I compound 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, yield 85%, high resolution mass spectrum (ESI+):
C11H14FO4 +, 229.0874.
Embodiment 3
A kind of synthetic method of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, synthetic route are as follows:
The synthetic method of above-mentioned 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, comprising the following steps:
(1) by 1.5g, it is spare in constant pressure funnel that the Formula II compound of 1equiv. uses the THF of 7.5mL to be dissolved in,
In terms of Formula II compound, the THF solution of the lithium diisopropyl amido of 1.4equiv. is added in reactor, stirring is cooled to -80
After DEG C, the THF solution of Formula II compound is added dropwise in reactor, drop finishes, and reaction system is warming up to -50 DEG C, insulated and stirred
0.5h；
(2) glyoxylic acid ethyl ester is dissolved using the toluene of 9mL, is added into reactor, insulated and stirred 2.5h, reaction system
It is cooled to room temperature；
(3) hydrochloric acid solution of ethyl acetate and 0.5N are added separately in reactor, after extraction, isolate organic layer,
It is dry using anhydrous sodium sulfate after organic layer salt water washing, solvent is recovered under reduced pressure to doing, concentrate obtains after column chromatography for separation
Type I compound 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, yield 82.7%, high resolution mass spectrum (ESI+):
C11H14FO4 +, 229.0874.
Embodiment 4
A kind of synthetic method of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, synthetic route are as follows:
The synthetic method of above-mentioned 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, comprising the following steps:
(1) by 0.9g, the Formula II compound of 1equiv. is dissolved in standby in constant pressure funnel using the THF of 2.5-7.5mL
With in terms of Formula II compound, by the THF solution addition reactor of the lithium diisopropyl amido of 1.3equiv., stirring cools down
After to -80~-70 DEG C, the THF solution of Formula II compound is added dropwise in reactor, drop finishes, and reaction system is warming up to -60 DEG C
~-50 DEG C, insulated and stirred 0.5-1.5h；
(2) glyoxylic acid ethyl ester is dissolved using the toluene of 8mL, is added into reactor, insulated and stirred 1.5-2.5h, reaction
System is cooled to room temperature；
(3) hydrochloric acid solution of ethyl acetate and 0.8N are added separately in reactor, after extraction, isolate organic layer,
It is dry using anhydrous sodium sulfate after organic layer salt water washing, solvent is recovered under reduced pressure to doing, concentrate obtains after column chromatography for separation
Type I compound 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, yield 84.6%, high resolution mass spectrum (ESI+):
C11H14FO4 +, 229.0874.
Embodiment 5
Reaction condition especially alkali (is used to form) selection, reaction temperature etc., for reaction result
Be affected, therefore, screened for alkali, experimental method is same as Example 1, and the results are shown in Table 1:
Table 1
| Alkali | Yielda |
| Lithium diisopropyl amido | 85% |
| N-BuLi | 82% |
| N-BuLi+equivalent TMEDA | 83% |
| Li hMDS | 56% |
| Lithium diisopropyl amido | 73% |
| Lithium diisopropyl amido | 61% |
| Lithium diisopropyl amido | 71% |
| Lithium diisopropyl amido | 86% |
A: yield is in terms of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate.
The data disclosed in table 1: higher using lithium diisopropyl amido reaction yield, reaction effect is preferable.
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 (7)
1. a kind of synthetic method of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate, which is characterized in that synthetic route
It is as follows:
2. the synthetic method of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate according to claim 1, special
Sign is, comprising the following steps:
(1) by 0.5-1.5g, the Formula II compound of 1equiv. is dissolved in standby in constant pressure funnel using the THF of 2.5-7.5mL
With in terms of Formula II compound, by the THF solution addition reactor of the lithium diisopropyl amido of 1.2-1.6equiv., stirring is dropped
After extremely -80~-70 DEG C of temperature, the THF solution of Formula II compound is added dropwise in reactor, drop finishes, and reaction system is warming up to -60 DEG C
~-50 DEG C, insulated and stirred 0.5-1.5h；
(2) glyoxylic acid ethyl ester is dissolved using the toluene of 2.5-9mL, is added into reactor, insulated and stirred 1.5-2.5h, reaction
System is cooled to room temperature；
(3) hydrochloric acid solution of ethyl acetate and 0.5-1.5N are added separately in reactor, after extraction, isolate organic layer,
It is dry using anhydrous sodium sulfate after organic layer salt water washing, solvent is recovered under reduced pressure to doing, concentrate obtains after column chromatography for separation
Type I compound 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate.
3. the synthetic method of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate according to claim 2, special
Sign is that, by 1.0g in the step (1), the Formula II compound of 1equiv. is dissolved in constant pressure funnel using the THF of 5mL
In it is spare, the THF solution of the lithium diisopropyl amido of 1.2equiv. is added in reactor, will after stirring is cooled to -78 DEG C
The THF solution of Formula II compound is added dropwise in reactor, and drop finishes, and reaction system is warming up to -50 DEG C, insulated and stirred 1h.
4. the synthetic method of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate according to claim 2, special
Sign is, dissolves glyoxylic acid ethyl ester using the toluene of 7mL in the step (2), is added into reactor, insulated and stirred 2h,
Reaction system is cooled to room temperature.
5. the synthetic method of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate according to claim 4, special
Sign is, in the step (2) in terms of Formula II compound, the glyoxylic acid ethyl ester of 1.2-1.4equiv. is dissolved using toluene.
6. the synthetic method of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate according to claim 2, special
Sign is, dissolves the glyoxylic acid ethyl ester of 1.2equiv. using toluene in the step (3).
7. the synthetic method of 2- (the fluoro- 3- methoxyphenyl of 2-) -2- hydroxyl ethyl acetate according to claim 2, special
Sign is that the hydrochloric acid solution of ethyl acetate and 1.0N are added separately in reactor by the step (3).
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| CN101541809A (en) * | 2006-11-29 | 2009-09-23 | 辉瑞产品公司 | Spiroketone acetyl-CoA carboxylase inhibitors |
| JP2010248144A (en) * | 2009-04-17 | 2010-11-04 | Sagami Chemical Research Institute | 2-(2,3-difluoro-6-vinylphenyl)acetic acid derivative, and method of producing the same |
| JP2010280629A (en) * | 2009-06-05 | 2010-12-16 | Asahi Glass Co Ltd | Compound, polymerizable liquid crystal composition, optically anisotropic material, optical element and optical information recording reproducing apparatus |
| JP5419075B2 (en) * | 2009-04-17 | 2014-02-19 | 公益財団法人相模中央化学研究所 | 2-Acyloxy-1,7,8-trifluoronaphthalene derivative and method for producing the same |
-
2019
- 2019-02-16 CN CN201910121539.5A patent/CN109809992A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101541809A (en) * | 2006-11-29 | 2009-09-23 | 辉瑞产品公司 | Spiroketone acetyl-CoA carboxylase inhibitors |
| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| JP2010248144A (en) * | 2009-04-17 | 2010-11-04 | Sagami Chemical Research Institute | 2-(2,3-difluoro-6-vinylphenyl)acetic acid derivative, and method of producing the same |
| JP5419075B2 (en) * | 2009-04-17 | 2014-02-19 | 公益財団法人相模中央化学研究所 | 2-Acyloxy-1,7,8-trifluoronaphthalene derivative and method for producing the same |
| JP2010280629A (en) * | 2009-06-05 | 2010-12-16 | Asahi Glass Co Ltd | Compound, polymerizable liquid crystal composition, optically anisotropic material, optical element and optical information recording reproducing apparatus |
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