CN109761764A - A kind of method of the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate - Google Patents
A kind of method of the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate Download PDFInfo
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- CN109761764A CN109761764A CN201910118493.1A CN201910118493A CN109761764A CN 109761764 A CN109761764 A CN 109761764A CN 201910118493 A CN201910118493 A CN 201910118493A CN 109761764 A CN109761764 A CN 109761764A
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Abstract
The invention discloses a kind of method of four step rule synthesis 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 fields, and particularly a kind of four step rule synthesizes the bromo- 2- (2- of 2-
Fluoro- 3- methoxyphenyl) ethyl acetate method synthetic method.
Background technique
Eagolix is clinically used for the treatment of uterus pain, and structure is as follows:
Key intermediate of the bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of the 2-) ethyl acetate as synthesis elagolix, industrialization
Production has been used widely.
In the prior art, about the synthesis of the compound, mostly using compound as follows as starting material, through excessive
The bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate is prepared in step reaction, and reaction step is not only tediously long, and operating process
Many and diverse, overall yield is not high, and process costs are excessively high.
Meanwhile using process route disclosed in the prior art, the bromo- 2- of above-mentioned 2- (the fluoro- 3- methoxyphenyl of 2-) second is prepared
" three wastes " of acetoacetic ester, industrialized production are higher,
Therefore, a kind of process route of the completely new bromo- 2- of synthesis 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate is designed,
Drawbacks described above in the prior art is solved, the industrialization production application of elagolix bulk pharmaceutical chemicals can be significantly improved.
Summary of the invention
Technical problem to be solved by the present invention lies in: a kind of four step rule synthesis bromo- 2- of 2- (fluoro- 3- methoxyl group of 2- is provided
Phenyl) ethyl acetate method.
The present invention is to solve above-mentioned technical problem by the following technical programs:
A kind of method of the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, the following institute of synthetic route
Show:
The method of the above-mentioned four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate the following steps are included:
The preparation of S1, VI compound of formula: by 0.5-1.5g, the Formula II compound of 1.0equiv. is with the THF solution of 2-8mL
It dissolves spare, in terms of Formula II compound, the THF solution of the lithium diisopropyl amido of 1.2-1.4equiv. is added to reactor
Afterwards, it and cools down, be cooled to -85~-75 DEG C, the THF solution of Formula II compound is added drop-wise in reaction system dropwise, drop finishes, instead
After answering liquid to be warming up to -55~-45 DEG C, during insulation reaction, epoxy second is passed through into reaction system by insulation reaction 0.5-1.5h
Alkane is until TLC detects fully reacting；
After fully reacting, reaction solution is distributed in the aqueous hydrochloric acid solution of ethyl acetate and 0.5-1.5N, separates organic phase,
Organic phase is dry with sodium sulphate again after being washed with brine, and residue column chromatography for separation is obtained formula VI to doing by last concentrated solvent
Compound；
The preparation of S2, VII compound of formula:
The preparation method of VII compound of formula includes method A1, the method A1 are as follows: by 0.5-1.5g, 1.0equiv.
Formula IV compound be added into reactor, dissolved with the acetonitrile solution of 5-15mL, under room temperature, in terms of Formula IV compound, according to
The secondary pyridine chlorochromate salting liquid by the periodic acid of 1.5-2.5equiv., 0.025-0.075equiv. is added into reactor,
Addition finishes, and after 2.5-3.5h is stirred at room temperature, reaction terminates, and after reaction distributes reaction solution in water and ethyl acetate,
Organic phase is separated, is successively finished with saturation aqueous solution of sodium bisulfite and saturated common salt water washing, washing, is obtained after solvent concentration
Residue, residue obtain VII compound of formula after column chromatography for separation；
The preparation of S3, VIII compound of formula: 0.5-1.5g is weighed, VII compound of formula of 1.0equiv. is in reactor, 5-
After the ethyl alcohol dissolution of 15mL, in terms of VII compound of formula, the inorganic acid of 1.2-1.5equiv. is added into reaction solution, is warming up to back
It flows, after back flow reaction 15-20h, after reaction, reaction solution is distributed in water and ethyl acetate, separate organic phase and be simultaneously concentrated
For solvent to doing, the residue after concentration obtains VIII compound of formula through column chromatography for separation；
The preparation of S4, type I compound:
0.5-1.5g is weighed, VIII compound of formula of 1.0equiv. is in reactor, after the carbon tetrachloride dissolution of 5-15mL,
In terms of VIII compound of formula, the bromating agent and 0.1-0.15equiv. that 1.2-1.4equiv. is successively added into reaction system cause
Agent, after temperature rising reflux 4.5-5.5h, reaction solution is concentrated to dryness, the residue being concentrated to get, and the change of formula I is obtained after column chromatography for separation
Close object.
Preferably, by 1.0g in the step S1, the Formula II compound of 1.0equiv. is standby with the THF solution dissolution of 5mL
With, the THF solution of the lithium diisopropyl amido of 1.2equiv. is added to reactor, and it is cooling, be cooled to -78 DEG C after, will
The THF solution of Formula II compound is added drop-wise in reaction system dropwise, and drop finishes, after reaction solution is warming up to -50 DEG C, insulation reaction 1h,
During insulation reaction, ethylene oxide is passed through into reaction system until TLC detection fully reacting, after fully reacting, will react
Liquid distributes in the aqueous hydrochloric acid solution of ethyl acetate and 1N, separates organic phase.
Preferably, by 1.0g in the method A1, the Formula IV compound of 1.0equiv. is added into reactor, with 10mL
Acetonitrile solution dissolution, under room temperature, successively the pyridine chlorochromate salting liquid of the periodic acid of 2equiv., 0.05equiv. are added
Enter into reactor, addition finishes, and 3h reaction, which is stirred at room temperature, to be terminated.
Preferably, the pyridine chlorochromate salting liquid the preparation method is as follows: pyridinium chloro-chromate will be adopted according to the proportion
Up to pyridine chlorochromate salting liquid after being dispersed with the acetonitrile dissolution of 1-4mL.
Preferably, the pyridine chlorochromate salting liquid the preparation method is as follows: pyridinium chloro-chromate will be adopted according to the proportion
Up to pyridine chlorochromate salting liquid after being dispersed with the acetonitrile dissolution of 2mL.
Preferably, the preparation method of VII compound of formula further includes method A2, the method A2 are as follows: weigh 0.5-
The Formula IV compound of 1.5g, 1.0equiv. after the tert-butyl alcohol dissolution of 5-15mL, successively add into reaction solution in reactor
Enter the sodium tungstate dihydrate of 0.025-0.075equiv. and the 4-butyl ammonium hydrogen sulfate of 0.025-0.075equiv., heats up
To reflux, by 1.0-2.0equiv., the hydrogen peroxide that mass fraction is 30% is added into reaction system, and it is anti-to continue reflux
After answering 0.5-1.5h, reaction terminates, and reaction solution is distributed in water and ethyl acetate, separates organic phase, successively with saturation sulfurous
After sour hydrogen sodium water solution and saturated common salt water washing, after organic phase is concentrated to dryness, residue column chromatography for separation is obtained into formula VII and is changed
Close object.
Preferably, 1.0g is weighed in the method A2, the Formula IV compound of 1.0equiv. is in reactor, with 10mL's
After tert-butyl alcohol dissolution, the sodium tungstate dihydrate of 0.05equiv. and four fourths of 0.05equiv. are successively added into reaction solution
Base ammonium hydrogen sulfate, after being warming up to reflux, by 1.5equiv., the hydrogen peroxide that mass fraction is 30% is added into reaction system,
After continuing back flow reaction 1h, reaction terminates.
Preferably, 1.0g is weighed in the step S3, VII compound of formula of 1.0equiv. is in reactor, the second of 10mL
After alcohol dissolution, the inorganic acid of 1.0equiv. is added into reaction solution, is warming up to reflux, after back flow reaction 18h, after reaction,
Reaction solution is distributed in water and ethyl acetate, simultaneously to doing, the residue after concentration chromatographs concentrated solvent separation organic phase through column
Isolated VIII compound of formula.
Preferably, the inorganic acid selects concentrated hydrochloric acid or the concentrated sulfuric acid.
Preferably, 1.0g is weighed in the step S4, VIII compound of formula of 1.0equiv. in reactor, 5-15mL's
After carbon tetrachloride dissolution, the bromating agent and 0.1equiv. initiator of 1.2equiv. are successively added into reaction system, heats up back
Flow 5h；
The bromating agent is NBS, and the initiator is benzoyl peroxide.
The present invention has the advantage that compared with prior art
The present invention discloses a kind of synthesis of the four step rule as shown in the formula I bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate
Method, compare with traditional synthetic route, process route disclosed by the invention is not only cheap and easy to get on synthesis material, and
Synthetic route is environmentally protective, such as avoids using mesyl chloride, easy to operate, has industrialized production and application prospect.
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 method of the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, the following institute of synthetic route
Show:
The method of the above-mentioned four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate the following steps are included:
The preparation of S1, VI compound of formula:
The Formula II compound of 1.0g, 1.0equiv. is spare with the THF solution dissolution of 5mL, it, will in terms of Formula II compound
The THF solution of the lithium diisopropyl amido of 1.2equiv. is added to reactor, and it is cooling, be cooled to -78 DEG C after, by Formula II
The THF solution of compound is added drop-wise in reaction system dropwise, and drop finishes, after reaction solution is warming up to -50 DEG C, insulation reaction 1h, and heat preservation
In reaction process, ethylene oxide is passed through into reaction system until TLC detection fully reacting, after fully reacting, reaction solution is existed
It is distributed in the aqueous hydrochloric acid solution of ethyl acetate and 1N, separates organic phase, organic phase is dry with sodium sulphate again after being washed with brine, most
Concentrated solvent is to dry afterwards, and residue column chromatography for separation is obtained VI compound of formula, yield 88.5%, high resolution mass spectrum (ESI+):
C9H12FO2 +, 171.0823；
The preparation of S2, VII compound of formula:
The Formula IV compound of 1.0g, 1.0equiv. are added into reactor, dissolved with the acetonitrile solution of 10mL, with formula
VI compound meter, under room temperature, successively by the periodic acid of 2equiv., the pyridine chlorochromate salting liquid (chloro-chromic acid of 0.05equiv.
Pyridine salt solution is configured using the pyridinium chloro-chromate of 0.05equiv. and the acetonitrile of 2mL) it is added into reactor, it is added
It finishing, 3h reaction, which is stirred at room temperature, to be terminated, and reaction solution is distributed in water and ethyl acetate after reaction, separates organic phase, according to
It is secondary to be finished with saturation aqueous solution of sodium bisulfite and saturated common salt water washing, washing, residue, residue are obtained after solvent concentration
VII compound of formula, yield 98.3%, high resolution mass spectrum (ESI-): C are obtained after column chromatography for separation9H8FO3 -, 183.0471；
The preparation of S3, VIII compound of formula:
1.0g is weighed, VII compound of formula of 1.0equiv. is in reactor, after the ethyl alcohol dissolution of 10mL, with VII chemical combination of formula
The concentrated sulfuric acid of 1.0equiv. is added into reaction solution, is warming up to reflux for object meter, after reaction, will be anti-after back flow reaction 18h
Liquid is answered to distribute in water and ethyl acetate, simultaneously concentrated solvent is to doing for separation organic phase, and the residue after concentration is through column chromatography for separation
Obtain VIII compound of formula, yield 98.5%, high resolution mass spectrum (ESI+): C11H14FO3 +, 213.0927；
The preparation of S4, type I compound:
1.0g is weighed, VIII compound of formula of 1.0equiv. is in reactor, after the carbon tetrachloride dissolution of 10mL, with formula VIII
NBS the and 0.1equiv. benzoyl peroxide of 1.2equiv., temperature rising reflux 5h is successively added in compound meter into reaction system
Afterwards, reaction solution is concentrated to dryness, the residue being concentrated to get, and after column chromatography for separation, obtains type I compound, yield 62.1% is high
Resolution Mass Spectrometry (ESI+): C11H13BrFO3+, 291.0031.
Embodiment 2
A kind of method of the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, the following institute of synthetic route
Show:
The method of the above-mentioned four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate the following steps are included:
The preparation of S1, VI compound of formula:
The Formula II compound of 0.5g, 1.0equiv. is spare with the THF solution dissolution of 2mL, it, will in terms of Formula II compound
The THF solution of the lithium diisopropyl amido of 1.2equiv. is added to reactor, and it is cooling, be cooled to -75 DEG C after, by Formula II
The THF solution of compound is added drop-wise in reaction system dropwise, and drop finishes, and after reaction solution is warming up to -45 DEG C, insulation reaction 0.5h is protected
In warm reaction process, ethylene oxide is passed through into reaction system until TLC detects fully reacting；After fully reacting, by reaction solution
It is distributed in the aqueous hydrochloric acid solution of ethyl acetate and 1.5N, separates organic phase, organic phase is dry with sodium sulphate again after being washed with brine
Dry, last concentrated solvent obtains VI compound of formula to dry, by residue column chromatography for separation, yield 88.4%, (ESI+):
C9H12FO2 +, 171.0823；
The preparation of S2, VII compound of formula:
VII compound of formula is prepared using method A2, specifically: 1.0g is weighed, the Formula IV compound of 1.0equiv. is in reaction
In device, after the tert-butyl alcohol dissolution of 10mL, in terms of Formula IV compound, the sodium tungstate of 0.05equiv. is successively added into reaction solution
The 4-butyl ammonium hydrogen sulfate of dihydrate and 0.05equiv., after being warming up to reflux, by 1.5equiv., mass fraction is
30% hydrogen peroxide is added into reaction system, and after continuing back flow reaction 1h, reaction terminates, and reaction solution exists after reaction
It is distributed in water and ethyl acetate, separates organic phase, successively with saturation aqueous solution of sodium bisulfite and saturated common salt water washing, washing
It finishes, residue is obtained after solvent concentration, residue obtains VII compound of formula, yield 75%, high-resolution after column chromatography for separation
Mass spectrum (ESI-): C9H8FO3 -, 183.0471；
The preparation of S3, VIII compound of formula: weighing 1.5g, VII compound of formula of 1.0equiv. in reactor, 5-15mL's
After ethyl alcohol dissolution, in terms of VII compound of formula, the concentrated hydrochloric acid of 1.5equiv. is added into reaction solution, is warming up to reflux, back flow reaction
After 18h, after reaction, reaction solution is distributed in water and ethyl acetate, separation organic phase and concentrated solvent are to dry, after concentration
Residue obtain VIII compound of formula, yield 98.2%, high resolution mass spectrum (ESI+): C through column chromatography for separation11H14FO3 +,
213.0928；
The preparation of S4, type I compound:
0.5g is weighed, VIII compound of formula of 1.0equiv. is in reactor, after the carbon tetrachloride dissolution of 5mL, with the change of formula VIII
Object meter is closed, the benzoyl peroxide of the NBS and 0.15equiv. of 1.2equiv., temperature rising reflux are successively added into reaction system
After 4.5h, reaction solution is concentrated to dryness, and the residue being concentrated to get obtains type I compound, yield after column chromatography for separation
62.4%, high resolution mass spectrum (ESI+): C11H13BrFO3+, 291.0030.
Embodiment 3
A kind of method of the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, the following institute of synthetic route
Show:
The method of the above-mentioned four step rule synthesis bromo- 2-- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate the following steps are included:
The preparation of S1, VI compound of formula:
The Formula II compound of 1.5g, 1.0equiv. is spare with the THF solution dissolution of 8mL, it, will in terms of Formula II compound
The THF solution of the lithium diisopropyl amido of 1.4equiv. is added to reactor, and it is cooling, be cooled to -85 DEG C after, by Formula II
The THF solution of compound is added drop-wise in reaction system dropwise, and drop finishes, and after reaction solution is warming up to -55 DEG C, insulation reaction 1.5h is protected
In warm reaction process, ethylene oxide is passed through into reaction system until TLC detects fully reacting；
After fully reacting, reaction solution is distributed in the aqueous hydrochloric acid solution of ethyl acetate and 0.5N, separates organic phase, it is organic
Dry with sodium sulphate again after being mutually washed with brine, residue column chromatography for separation is obtained VI chemical combination of formula to doing by last concentrated solvent
Object, yield 88.6%, high resolution mass spectrum (ESI+): C9H12FO2 +, 171.0823；
The preparation of S2, VII compound of formula:
VII compound of formula uses method A1, specifically: the Formula IV compound of 0.5g, 1.0equiv. are added to reactor
In, dissolved with the acetonitrile solution of 5mL, in terms of Formula IV compound, under room temperature, successively by the periodic acid of 1.5equiv.,
0.075equiv. pyridine chlorochromate salting liquid (pyridine chlorochromate salting liquid using 0.05equiv. pyridinium chloro-chromate with
The acetonitrile of 4mL configures) it is added into reactor, addition finishes, and 2.5h reaction, which is stirred at room temperature, to be terminated, after reaction will be anti-
It answers liquid to distribute in water and ethyl acetate, separates organic phase, successively with saturation aqueous solution of sodium bisulfite and saturated common salt washing
It washs, washing finishes, and residue is obtained after solvent concentration, and residue obtains VII compound of formula, yield after column chromatography for separation
98.1%, high resolution mass spectrum (ESI-): C9H8FO3 -, 183.0471；
The preparation of S3, VIII compound of formula:
0.5g is weighed, VII compound of formula of 1.0equiv. is in reactor, after the ethyl alcohol dissolution of 5mL, with VII compound of formula
The inorganic acid of 1.2equiv. is added into reaction solution, is warming up to reflux for meter, after back flow reaction 15h, after reaction, will react
Liquid distributes in water and ethyl acetate, and simultaneously to doing, the residue after concentration obtains concentrated solvent separation organic phase through column chromatography for separation
To VIII compound of formula, yield 97.9%, high resolution mass spectrum (ESI+): C11H14FO3 +, 213.0929；
The preparation of S4, type I compound:
1.5g is weighed, VIII compound of formula of 1.0equiv. is in reactor, after the carbon tetrachloride dissolution of 8mL, with the change of formula VIII
Object meter is closed, NBS the and 0.15equiv. benzoyl peroxide of 1.4equiv., temperature rising reflux are successively added into reaction system
After 5.5h, reaction solution is concentrated to dryness, and the residue being concentrated to get obtains type I compound, yield after column chromatography for separation
62.5%, high resolution mass spectrum (ESI+): C11H13BrFO3+, 291.0035.
Embodiment 4
A kind of method of the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, the following institute of synthetic route
Show:
The method of the above-mentioned four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate the following steps are included:
The preparation of S1, VI compound of formula: the Formula II compound of 1.2g, 1.0equiv. is standby with the THF solution dissolution of 4mL
With, in terms of Formula II compound, the THF solution of the lithium diisopropyl amido of 1.3equiv. is added to reactor, and cooling,
After being cooled to -78 DEG C, the THF solution of Formula II compound is added drop-wise in reaction system dropwise, drop finishes, and reaction solution is warming up to -50
After DEG C, during insulation reaction, ethylene oxide is passed through into reaction system until TLC detects fully reacting by insulation reaction 1.2h；
After fully reacting, reaction solution is distributed in the aqueous hydrochloric acid solution of ethyl acetate and 1N, separates organic phase, organic phase
Dry with sodium sulphate again after being washed with brine, residue column chromatography for separation is obtained VI compound of formula to doing by last concentrated solvent,
Yield 88.1%, high resolution mass spectrum (ESI+): C9H12FO2 +, 171.0823；
The preparation of S2, VII compound of formula:
VII compound of formula uses method A1, specifically: the Formula IV compound of 1.5g, 1.0equiv. are added to reactor
In, dissolved with the acetonitrile solution of 15mL, in terms of Formula IV compound, under room temperature, successively by the periodic acid of 2equiv.,
0.05equiv. pyridine chlorochromate salting liquid (pyridine chlorochromate salting liquid using 0.05equiv. pyridinium chloro-chromate with
The acetonitrile of 1mL configures) it is added into reactor, addition finishes, and 2.5h reaction, which is stirred at room temperature, to be terminated, after reaction will be anti-
It answers liquid to distribute in water and ethyl acetate, separates organic phase, successively with saturation aqueous solution of sodium bisulfite and saturated common salt washing
It washs, washing finishes, and residue is obtained after solvent concentration, and residue obtains VII compound of formula, yield after column chromatography for separation
98.4%, high resolution mass spectrum (ESI-): C9H8FO3 -, 183.0471；
The preparation of S3, VIII compound of formula: weighing 1.2g, VII compound of formula of 1.0equiv. in reactor, 5-15mL's
After ethyl alcohol dissolution, in terms of VIII compound of formula, the inorganic acid of 1.2equiv. is added into reaction solution, is warming up to reflux, back flow reaction
After 16h, after reaction, reaction solution is distributed in water and ethyl acetate, separation organic phase and concentrated solvent are to dry, after concentration
Residue obtain VIII compound of formula, yield 97.9%, high resolution mass spectrum (ESI+): C through column chromatography for separation11H14FO3 +,
213.0927；
The preparation of S4, type I compound:
1.2g is weighed, VIII compound of formula of 1.0equiv. is in reactor, after the carbon tetrachloride dissolution of 12mL, with formula VIII
The bromating agent and 0.14equiv. initiator of 1.4equiv., temperature rising reflux 5h is successively added in compound meter into reaction system
Afterwards, reaction solution is concentrated to dryness, the residue being concentrated to get, and type I compound is obtained after column chromatography for separation, and yield 66.4% is high
Resolution Mass Spectrometry (ESI+): C11H13BrFO3+, 291.0034.
Embodiment 5
In the preparation process of Formula VII compound, reaction condition is especially sour, is affected for reaction yield, therefore, this
To in organic synthesis, common organic acid and inorganic acid are screened for invention.
Using the preparation method of Formula VII compound disclosed in 1 step S3 of embodiment (reaction condition as test variable), examination
Test that the results are shown in Table 1:
Table 1
| Acid | The equivalents of acid | Reaction temperature | Reaction time | Yield |
| The concentrated sulfuric acid | 1.0 | Reflux | 18h | 98% |
| Concentrated hydrochloric acid | 1.0 | Reflux | 18h | 94% |
| Concentrated phosphoric acid | 1.0 | Reflux | 18h | 51% |
| Thionyl chloride | 1.0 | Reflux | 18h | 97% |
| Sodium bisulfate | 1.0 | Reflux | 18h | 32% |
| P-methyl benzenesulfonic acid | 1.0 | Reflux | 18h | 99% |
| Methanesulfonic acid | 1.0 | Reflux | 18h | 96% |
| The concentrated sulfuric acid | 0.5 | Reflux | 18h | 90% |
| The concentrated sulfuric acid | 2.0 | Reflux | 18h | 95% |
| The concentrated sulfuric acid | 1.0 | 30℃ | 18h | 10% |
| The concentrated sulfuric acid | 1.0 | 60℃ | 18h | 86% |
| The concentrated sulfuric acid | 1.0 | Reflux | 6h | 51% |
| The concentrated sulfuric acid | 1.0 | Reflux | 32h | 97% |
The data disclosed in table 1: the concentrated sulfuric acid and concentrated hydrochloric acid are preferable to reaction effect as reaction acid reagent.
Embodiment 6
In the preparation process of 1 compound of formula, the reaction conditions such as bromating agent, initiator and solvent influence reaction effect
It is larger, in order to filter out preferable reaction condition, according to technical solution disclosed in embodiment 1 (bromating agent, initiator, solvent etc.
For variable), finally screen preferable experiment parameter as shown in Table 2:
Table 2
The data disclosed in table 2: NBS is as bromating agent, and benzoyl peroxide is as initiator and carbon tetrachloride
As solvent, 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 (10)
1. a kind of method of the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate, which is characterized in that synthesis
Route is as follows:
2. the method for the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 1,
It is characterized in that, the method for the described four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate includes following step
It is rapid:
The preparation of S1, VI compound of formula: the Formula II compound of 0.5-1.5g, 1.0equiv. are dissolved with the THF solution of 2-8mL
It is spare, in terms of Formula II compound, the THF solution of the lithium diisopropyl amido of 1.2-1.4equiv. is added to reactor, and
Cooling is cooled to -85~-75 DEG C, and the THF solution of Formula II compound is added drop-wise to dropwise in reaction system, and drop finishes, reaction solution liter
Temperature is to after -55~-45 DEG C, insulation reaction 0.5-1.5h, during insulation reaction, be passed through into reaction system ethylene oxide up to
TLC detects fully reacting；
After fully reacting, reaction solution is distributed in the aqueous hydrochloric acid solution of ethyl acetate and 0.5-1.5N, separates organic phase, it is organic
Dry with sodium sulphate again after being mutually washed with brine, residue column chromatography for separation is obtained VI chemical combination of formula to doing by last concentrated solvent
Object；
The preparation of S2, VII compound of formula:
The preparation method of VII compound of formula includes method A1, the method A1 are as follows: by 0.5-1.5g, the formula of 1.0equiv.
VI compound is added into reactor, is dissolved with the acetonitrile solution of 5-15mL, under room temperature, in terms of Formula IV compound, successively will
The periodic acid of 1.5-2.5equiv., the pyridine chlorochromate salting liquid of 0.025-0.075equiv. are added into reactor, are added
It finishes, after 2.5-3.5h is stirred at room temperature, reaction terminates, and after reaction distributes reaction solution in water and ethyl acetate, separates
Organic phase is successively finished with saturation aqueous solution of sodium bisulfite and saturated common salt water washing, washing, remnants is obtained after solvent concentration
Object, residue obtain VII compound of formula after column chromatography for separation；
The preparation of S3, VIII compound of formula: weighing 0.5-1.5g, VII compound of formula of 1.0equiv. in reactor, 5-15mL's
After ethyl alcohol dissolution, in terms of VII compound of formula, the inorganic acid of 1.2-1.5equiv. is added into reaction solution, is warming up to reflux, flow back
After reacting 15-20h, after reaction, reaction solution is distributed in water and ethyl acetate, separates organic phase and concentrated solvent extremely
Dry, the residue after concentration obtains VIII compound of formula through column chromatography for separation；
The preparation of S4, type I compound:
0.5-1.5g is weighed, VIII compound of formula of 1.0equiv. is in reactor, after the carbon tetrachloride dissolution of 5-15mL, with formula
The bromating agent and 0.1-0.15equiv. initiator of 1.2-1.4equiv. is successively added in VIII compound meter into reaction system, rises
After temperature reflux 4.5-5.5h, reaction solution is concentrated to dryness, and the residue being concentrated to get obtains type I compound after column chromatography for separation.
3. the method for the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 2,
It is characterized in that, the Formula II compound of 1.0equiv. is spare with the THF solution dissolution of 5mL by 1.0g in the step S1, it will
The THF solution of the lithium diisopropyl amido of 1.2equiv. is added to reactor, and it is cooling, be cooled to -78 DEG C after, by Formula II
The THF solution of compound is added drop-wise in reaction system dropwise, and drop finishes, after reaction solution is warming up to -50 DEG C, insulation reaction 1h, and heat preservation
In reaction process, ethylene oxide is passed through into reaction system until TLC detection fully reacting, after fully reacting, reaction solution is existed
It is distributed in the aqueous hydrochloric acid solution of ethyl acetate and 1N, separates organic phase.
4. the method for the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 3,
It is characterized in that, the Formula IV compound of 1.0equiv. is added into reactor, by 1.0g in the method A1 with the second of 10mL
Nitrile solution dissolution, under room temperature, successively by the pyridine chlorochromate salting liquid of the periodic acid of 2equiv., 0.05equiv. be added to
In reactor, addition is finished, and 3h reaction, which is stirred at room temperature, to be terminated.
5. the method for the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 4,
It is characterized in that, the pyridine chlorochromate salting liquid the preparation method is as follows: will according to the proportion by pyridinium chloro-chromate use 1-
Up to pyridine chlorochromate salting liquid after the acetonitrile dissolution dispersion of 4mL.
6. the method for the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 5,
It is characterized in that, the pyridine chlorochromate salting liquid the preparation method is as follows: will according to the proportion by pyridinium chloro-chromate use 2mL
Acetonitrile dissolution dispersion after up to pyridine chlorochromate salting liquid.
7. the method for the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 2,
It is characterized in that, the preparation method of VII compound of formula further includes method A2, the method A2 are as follows: 0.5-1.5g is weighed,
The Formula IV compound of 1.0equiv. after the tert-butyl alcohol dissolution of 5-15mL, is successively added into reaction solution in reactor
The sodium tungstate dihydrate of 0.025-0.075equiv. and the 4-butyl ammonium hydrogen sulfate of 0.025-0.075equiv., are warming up to
After reflux, by 1.0-2.0equiv., the hydrogen peroxide that mass fraction is 30% is added into reaction system, continues back flow reaction
After 0.5-1.5h, reaction terminates, and reaction solution is distributed in water and ethyl acetate, separates organic phase, successively with saturation sulfurous acid
After hydrogen sodium water solution and saturated common salt water washing, after organic phase is concentrated to dryness, residue column chromatography for separation is obtained into VII chemical combination of formula
Object.
8. the method for the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 7,
It is characterized in that, weighing 1.0g in the method A2, the Formula IV compound of 1.0equiv. is in reactor, with the tertiary fourth of 10mL
After alcohol dissolution, the sodium tungstate dihydrate of 0.05equiv. and the tetrabutyl sulphur of 0.05equiv. are successively added into reaction solution
Sour hydrogen ammonium, after being warming up to reflux, by 1.5equiv., the hydrogen peroxide that mass fraction is 30% is added into reaction system, is continued
After back flow reaction 1h, reaction terminates.
9. the method for the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 2,
It is characterized in that, weighing 1.0g in the step S3, for VII compound of formula of 1.0equiv. in reactor, the ethyl alcohol of 10mL is molten
The inorganic acid of 1.0equiv. is added into reaction solution, is warming up to reflux by Xie Hou, after reaction, will be anti-after back flow reaction 18h
Liquid is answered to distribute in water and ethyl acetate, simultaneously concentrated solvent is to doing for separation organic phase, and the residue after concentration is through column chromatography for separation
Obtain VIII compound of formula.
10. the method for the four step rule synthesis bromo- 2- of 2- (the fluoro- 3- methoxyphenyl of 2-) ethyl acetate according to claim 2,
It is characterized in that, weighing 1.0g in the step S4, VIII compound of formula of 1.0equiv. is in reactor, the tetrachloro of 5-15mL
After changing carbon dissolution, the bromating agent and 0.1equiv. initiator of 1.2equiv., temperature rising reflux 5h are successively added into reaction system；
The bromating agent is NBS, and the initiator is benzoyl peroxide.
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| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| CN108752218A (en) * | 2018-07-18 | 2018-11-06 | 浙江沙星科技有限公司 | A kind of variation route prepared by Du Lutewei key intermediates 2,4- difluorobenzylamines |
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| 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 |
| CN108752218A (en) * | 2018-07-18 | 2018-11-06 | 浙江沙星科技有限公司 | A kind of variation route prepared by Du Lutewei key intermediates 2,4- difluorobenzylamines |
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| DALJIT S. DHANOA等: "Non-Peptide Angiotensin I1 Receptor Antagonists. 2.’ Design, Synthesis, and Biological Activity of N-Substituted (Pheny1amino)phenylacetic Acids and Acyl S ulfonamides", 《J. MED. CHEM》 * |
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