CN111018789A - Synthetic method of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole - Google Patents
Synthetic method of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole Download PDFInfo
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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Abstract
The invention discloses a method for synthesizing 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole, which comprises the following steps: (1) adding sodium hydride into a reaction bottle, adding an aprotic solvent into the reaction bottle, and stirring at constant temperature for reaction; (2) dissolving N- (4-bromo-2, 6-difluorophenyl) -N' -isopropylacetamidine in an aprotic solvent, slowly dropwise adding the clear solution into a reaction bottle, heating the reaction system to 40-100 ℃, and then stirring for reaction for 4-10 hours; (3) cooling to room temperature after the reaction is completed, adding water to prepare a solution, extracting for three times, combining organic phases, washing the organic phases once by using saturated saline solution, drying by using anhydrous sodium sulfate, and filtering; (4) concentrating the filtrate, adding n-hexane for dissolving, adding deionized water into the reaction system solution, standing overnight, filtering and drying after white crystals are separated out to obtain 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole. The synthetic method has the advantages of short reaction time, simple treatment, labor cost saving and environmental pollution reduction.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and relates to a synthetic method of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole.
Background
Abetimib is a cyclin-dependent kinase inhibitor and is mainly used for adult late-stage patients with advanced or metastatic breast cancer after endocrine treatment at present, while 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole is an important intermediate compound for synthesizing Abetimib, but the intermediate compound is mainly synthesized by using sodium/potassium tert-butoxide as a base to extract free hydrogen protons on imine and then performing intramolecular nucleophilic substitution to form ring. Because the 4-position fluorine on the benzene ring is substituted due to the nucleophilicity of the sodium/potassium tert-butoxide, a byproduct that the 4-position fluorine group is substituted by a tert-butoxy group is generated; if the using amount of the sodium/potassium tert-butoxide is adjusted, the reaction raw materials can not react completely, so that the reaction is obtained by column chromatography purification by using a large amount of manpower and a large amount of eluent, and the consumption of the eluent is increased, so that the amount of waste liquid and solid waste is increased, and more environmental pollution and treatment cost are caused. Therefore, a new method for synthesizing 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole is needed to solve the technical problems of substituted by-products or incomplete reaction of raw materials.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects and provide a method for synthesizing 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole, the method is adopted to synthesize 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole, no substituted by-product or incomplete reaction of raw materials occurs, the reaction time is correspondingly shortened, and after the reaction is finished, the required compound intermediate is directly obtained by a crystallization mode.
In order to solve the technical problems, the technical scheme of the invention is as follows:
a synthetic method of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole comprises the following steps:
(1) adding sodium hydride into a reaction bottle at the temperature of-10-25 ℃, pumping air and changing nitrogen for three times, then adding an aprotic solvent into the reaction bottle, and stirring at constant temperature for reaction;
(2) dissolving a compound N- (4-bromo-2, 6-difluorophenyl) -N' -isopropyl acetamidine in an aprotic solvent until the compound is dissolved and clarified; slowly dropwise adding the clarified solution into the reaction bottle in the step (1), heating the reaction system to 40-100 ℃ after dropwise adding, and then stirring for reaction for 4-10 hours;
(3) cooling the reaction system to room temperature after the reaction is completed, slowly pouring the reaction liquid into water to prepare a solution, extracting with ethyl acetate for three times, combining organic phases, washing the organic phases with saturated saline solution once, drying with anhydrous sodium sulfate, and filtering;
(4) and (4) concentrating the filtrate obtained in the step (3), adding n-hexane into the concentrated solution for dissolving, adding deionized water into the solution of the reaction system, standing overnight, separating out white crystals, filtering, and drying in vacuum to obtain 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole.
Preferably, the aprotic solvent is one or more of tetrahydrofuran, 1, 4-dioxane, acetonitrile, dimethyl sulfoxide and N, N-dimethylformamide.
Preferably, the amount of ethyl acetate added in step (3) is 5 to 8 times of the total volume of the solution.
Preferably, the adding amount of the n-hexane in the step (4) is 10-12 times of the total volume of the concentrated solution.
Preferably, the deionized water is added in the step (4) in an amount of 5-8 times of the total volume of the solution.
The chemical reaction equation of the reaction is as follows:
compared with the prior art, the invention has the beneficial effects that:
according to the synthetic method, sodium hydride is used as alkali, the problem of substituted byproducts or incomplete reaction of raw materials is avoided, meanwhile, the reaction time is shortened to 4-10 h from the original 10-16 h, the required compound intermediate is obtained directly through a crystallization mode after reaction, a large amount of manpower and eluant are not needed for column chromatography purification, the consumption of the eluant is reduced, the labor cost is saved, the yield of waste liquid and solid waste residue is reduced, and the pollution to the environment and the treatment cost are reduced.
Detailed Description
The following further describes the embodiments of the present invention. It should be noted that the description of the embodiments is provided to help understanding of the present invention, but the present invention is not limited thereto. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1
A synthetic method of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole comprises the following steps:
(1) at-10 ℃, adding 20.61g of sodium hydride into a reaction bottle, pumping air and changing nitrogen for three times, then adding 500ml of 1, 4-dioxane solvent into the reaction bottle, and stirring at constant temperature for reaction;
(2) dissolving 100g of compound N- (4-bromo-2, 6-difluorophenyl) -N' -isopropylacetamidine in 500ml of 1, 4-dioxane solvent until the solution is clear; then slowly dropwise adding the clear solution into the reaction bottle in the step (1), controlling the temperature not to exceed 30 ℃, after dropwise adding, heating the reaction system to 40 ℃, and then stirring for reaction for 10 hours;
(3) after HPLC detection shows that the compound completely disappears, cooling the reaction system to room temperature, slowly pouring the reaction liquid into water to prepare a solution, extracting with ethyl acetate for three times, each time 800ml, combining organic phases, washing the organic phases with saturated salt solution once, drying with anhydrous sodium sulfate, and filtering;
(4) and (3) concentrating the filtrate obtained in the step (3), adding 1200ml of n-hexane into the concentrated solution for dissolving, adding 800ml of deionized water into the solution of the reaction system, standing overnight, separating out white crystals, filtering, and drying at 40 ℃ in vacuum to obtain 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole.
The above preparation gave 55.52g of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole in 60% yield.
Example 2
A synthetic method of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole comprises the following steps:
(1) at the temperature of 0 ℃, adding 20.61g of sodium hydride into a reaction bottle, pumping air and changing nitrogen for three times, then adding 500ml of tetrahydrofuran solvent into the reaction bottle, and stirring at constant temperature for reaction;
(2) dissolving 100g of compound N- (4-bromo-2, 6-difluorophenyl) -N' -isopropyl acetamidine in 500ml of tetrahydrofuran solvent until the solution is clear; then slowly dropwise adding the clear solution into the reaction bottle in the step (1), controlling the temperature not to exceed 30 ℃, after dropwise adding, heating the reaction system to 85 ℃, and then stirring for reacting for 6 hours;
(3) after HPLC detection shows that the compound completely disappears, cooling the reaction system to room temperature, slowly pouring the reaction liquid into water to prepare a solution, extracting with ethyl acetate for three times (500 ml each time), combining organic phases, washing the organic phases with saturated saline solution once, drying with anhydrous sodium sulfate, and filtering;
(4) and (3) concentrating the filtrate obtained in the step (3), adding 1000ml of n-hexane into the concentrated solution for dissolving, adding 500ml of deionized water into the solution of the reaction system, standing overnight, separating out white crystals, filtering, and drying at 40 ℃ in vacuum to obtain 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole.
The above preparation gave 55.52g of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole in 60% yield.
Example 3
A synthetic method of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole comprises the following steps:
(1) at 10 ℃, adding 20.61g of sodium hydride into a reaction bottle, pumping air and changing nitrogen for three times, then adding 500ml of acetonitrile solvent into the reaction bottle, and stirring at constant temperature for reaction;
(2) dissolving 100g of compound N- (4-bromo-2, 6-difluorophenyl) -N' -isopropyl acetamidine in 500ml of acetonitrile solvent until the solution is clear; then slowly dropwise adding the clear solution into the reaction bottle in the step (1), controlling the temperature not to exceed 30 ℃, after dropwise adding, heating the reaction system to 60 ℃, and then stirring for reacting for 8 hours;
(3) after HPLC detection shows that the compound completely disappears, cooling the reaction system to room temperature, slowly pouring the reaction liquid into water to prepare a solution, extracting with ethyl acetate for three times (500 ml each time), combining organic phases, washing the organic phases with saturated saline solution once, drying with anhydrous sodium sulfate, and filtering;
(4) and (3) concentrating the filtrate obtained in the step (3), adding 1000ml of n-hexane into the concentrated solution for dissolving, adding 500ml of deionized water into the solution of the reaction system, standing overnight, separating out white crystals, filtering, and drying at 40 ℃ in vacuum to obtain 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole.
The above preparation gave 55.52g of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole in 60% yield.
Example 4
A synthetic method of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole comprises the following steps:
(1) at 15 ℃, adding 20.61g of sodium hydride into a reaction bottle, pumping air and changing nitrogen for three times, then adding 500ml of dimethyl sulfoxide solvent into the reaction bottle, and stirring at constant temperature for reaction;
(2) dissolving 100g of compound N- (4-bromo-2, 6-difluorophenyl) -N' -isopropyl acetamidine in 500ml of dimethyl sulfoxide solvent until the compound is dissolved and clarified; then slowly dropwise adding the clear solution into the reaction bottle in the step (1), controlling the temperature not to exceed 30 ℃, after dropwise adding, heating the reaction system to 100 ℃, and then stirring for reaction for 4 hours;
(3) after HPLC detection shows that the compound completely disappears, cooling the reaction system to room temperature, slowly pouring the reaction liquid into water to prepare a solution, extracting with ethyl acetate for three times (500 ml each time), combining organic phases, washing the organic phases with saturated saline solution once, drying with anhydrous sodium sulfate, and filtering;
(4) and (3) concentrating the filtrate obtained in the step (3), adding 1000ml of n-hexane into the concentrated solution for dissolving, adding 500ml of deionized water into the solution of the reaction system, standing overnight, separating out white crystals, filtering, and drying at 40 ℃ in vacuum to obtain 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole.
The above preparation gave 55.52g of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole in 60% yield.
Example 5
A synthetic method of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole comprises the following steps:
(1) at 25 ℃, adding 20.61g of sodium hydride into a reaction bottle, pumping air and changing nitrogen for three times, then adding 500ml of N, N-dimethylformamide solvent into the reaction bottle, and stirring at constant temperature for reaction;
(2) dissolving 100g of compound N- (4-bromo-2, 6-difluorophenyl) -N' -isopropylacetamidine in 500ml of N, N-dimethylformamide solvent until the solution is clear; then slowly dropwise adding the clear solution into the reaction bottle in the step (1), controlling the temperature not to exceed 30 ℃, after dropwise adding, heating the reaction system to 50 ℃, and then stirring for reaction for 9 hours;
(3) after HPLC detection shows that the compound completely disappears, cooling the reaction system to room temperature, slowly pouring the reaction liquid into water to prepare a solution, extracting with ethyl acetate for three times (500 ml each time), combining organic phases, washing the organic phases with saturated saline solution once, drying with anhydrous sodium sulfate, and filtering;
(4) and (3) concentrating the filtrate obtained in the step (3), adding 1000ml of n-hexane into the concentrated solution for dissolving, adding 500ml of deionized water into the solution of the reaction system, standing overnight, separating out white crystals, filtering, and drying at 40 ℃ in vacuum to obtain 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole.
The above preparation gave 55.52g of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole in 60% yield.
The foregoing is considered as illustrative of the preferred embodiments of the invention, but is made merely for the purpose of providing an understanding of the principles of the embodiments; meanwhile, for a person skilled in the art, according to the present embodiment, there may be a change in the specific implementation and application scope, and in summary, the present disclosure should not be construed as a limitation to the present invention.
Claims (5)
1. A synthetic method of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole is characterized in that: the method comprises the following steps:
(1) adding sodium hydride into a reaction bottle at the temperature of-10-25 ℃, pumping air and changing nitrogen for three times, then adding an aprotic solvent into the reaction bottle, and stirring at constant temperature for reaction;
(2) dissolving a compound N- (4-bromo-2, 6-difluorophenyl) -N' -isopropyl acetamidine in an aprotic solvent until the compound is dissolved and clarified; slowly dropwise adding the clarified solution into the reaction bottle in the step (1), heating the reaction system to 40-100 ℃ after dropwise adding, and then stirring for reaction for 4-10 hours;
(3) cooling the reaction system to room temperature after the reaction is completed, slowly pouring the reaction liquid into water to prepare a solution, extracting with ethyl acetate for three times, combining organic phases, washing the organic phases with saturated saline solution once, drying with anhydrous sodium sulfate, and filtering;
(4) and (4) concentrating the filtrate obtained in the step (3), adding n-hexane into the concentrated solution for dissolving, adding deionized water into the solution of the reaction system, standing overnight, separating out white crystals, filtering, and drying in vacuum to obtain 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole.
2. The method of synthesizing 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole according to claim 1, wherein: the aprotic solvent is one or more of tetrahydrofuran, 1, 4-dioxane, acetonitrile, dimethyl sulfoxide and N, N-dimethylformamide.
3. The method of synthesizing 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole according to claim 1, wherein: and (4) adding the ethyl acetate in the step (3) in an amount which is 5-8 times of the total volume of the solution.
4. The method of synthesizing 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole according to claim 1, wherein: and (4) adding the n-hexane in the step (4) in an amount which is 10-12 times of the total volume of the concentrated solution.
5. The method of synthesizing 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole according to claim 1, wherein: and (4) adding the deionized water in the step (4) in an amount which is 5-8 times of the total volume of the solution.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104529904A (en) * | 2015-01-09 | 2015-04-22 | 苏州明锐医药科技有限公司 | Preparing method for bemaciclib |
| CN106467517A (en) * | 2015-08-14 | 2017-03-01 | 正大天晴药业集团股份有限公司 | The Abemaciclib derivant that deuterium is modified |
| CN108602802A (en) * | 2016-07-26 | 2018-09-28 | 深圳市塔吉瑞生物医药有限公司 | Amino-metadiazine compound for inhibiting protein tyrosine kinase activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104529904A (en) * | 2015-01-09 | 2015-04-22 | 苏州明锐医药科技有限公司 | Preparing method for bemaciclib |
| CN106467517A (en) * | 2015-08-14 | 2017-03-01 | 正大天晴药业集团股份有限公司 | The Abemaciclib derivant that deuterium is modified |
| CN108602802A (en) * | 2016-07-26 | 2018-09-28 | 深圳市塔吉瑞生物医药有限公司 | Amino-metadiazine compound for inhibiting protein tyrosine kinase activity |
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Application publication date: 20200417 |