CN112625030A - Synthetic method for synthesizing N-protected 3-bromopyrazole by one-pot method - Google Patents
Synthetic method for synthesizing N-protected 3-bromopyrazole by one-pot method Download PDFInfo
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- CN112625030A CN112625030A CN202011564824.3A CN202011564824A CN112625030A CN 112625030 A CN112625030 A CN 112625030A CN 202011564824 A CN202011564824 A CN 202011564824A CN 112625030 A CN112625030 A CN 112625030A
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides a synthetic method for synthesizing N-protected 3-bromopyrazole by a one-pot method, which comprises the following steps: pyrazole reacts with a bromization reagent to obtain 3-bromopyrazole, and then reacts with vinyl ether through a one-pot reaction to obtain the N-protected 3-bromopyrazole. The preparation method of the invention omits the post-treatment step required by the first step of the two-step process, and greatly improves the industrial production efficiency.
Description
Technical Field
The invention relates to the technical field of organic matter synthesis, in particular to a synthesis method for synthesizing N-protected 3-bromopyrazole by a one-pot method.
Background
N-protected 3-bromopyrazole is an important pharmaceutical intermediate and can be used for JAK enzyme inhibitors (INCB018424, BMS-91543 and the like). However, for the preparation of N-protected 3-bromopyrazole, the two-step synthesis of bromination and up-protection is reported to date in domestic and foreign documents. In view of the above, a synthetic method for synthesizing N-protected 3-bromopyrazole by a one-pot method is necessary for accelerating the production efficiency.
Disclosure of Invention
The invention provides a synthesis method for synthesizing N-protected 3-bromopyrazole by a one-pot method, and the preparation method omits the post-treatment step required by the first-step reaction in the two-step process, thereby greatly improving the industrial production efficiency.
In order to achieve the purpose, the invention adopts the following technical scheme:
a synthesis method for synthesizing N-protected 3-bromopyrazole by a one-pot method is developed by generating partial hydrogen bromide to promote the reaction of the second step when the pyrazole reacts with the brominated product, and comprises the following steps:
(a) reacting pyrazole with a bromization reagent to generate 3-bromopyrazole reaction liquid;
(b) and (b) adding the vinyl ether into the reaction liquid obtained in the step (a), reacting by a one-pot method, and carrying out aftertreatment to obtain the N-protected 3-bromopyrazole.
As a preferred technical scheme, the specific steps are as follows:
dissolving pyrazole in dichloromethane, adding a bromization reagent in batches at the temperature of-10 ℃, and reacting to obtain 3-bromopyrazole;
dripping vinyl ether into the reaction solution, reacting by a one-pot method at 15-35 ℃ to obtain N-protected 3-bromopyrazole, and carrying out heat preservation reaction and post-treatment to obtain the N-protected 3-bromopyrazole.
The post-treatment process of the step (b) comprises the following steps: and (3) centrifuging, washing, drying and desolventizing the N-protected 3-bromopyrazole obtained by the reaction to obtain the N-protected pyrazole.
As a preferred technical scheme, the brominating agent comprises one of NBS, bromine and dibromohydantoin.
As a preferable technical scheme, the molar ratio of the pyrazole, the brominating agent and the vinyl ether is 1.0: 1.0-1.5: 1.0 to 2.0.
According to a preferable technical scheme, 100-350 g of pyrazole is added into every 1000mL of dichloromethane.
As a preferred technical scheme, the vinyl ether is vinyl ethyl ether or 3, 4-dihydro-2H-pyran.
The present invention has the following advantageous effects
The synthesis method of the invention omits the post-treatment step required by the first step reaction in the two-step process, and greatly improves the industrial production efficiency.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without inventive exercise.
FIG. 1 is a process scheme of the present invention;
FIG. 2 is a scheme showing the preparation of N-protected 3-bromopyrazole according to example 11HNMR atlas.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Referring to FIG. 1, pyrazole (30.0g,441.2mmol) was dissolved in dichloromethane (150mL) under nitrogen protection, and the reaction solution was cooled to-10 to 10 ℃. NBS (79.9g, 441.2mmol) was added slowly in portions to the reaction. After the addition, the reaction was continued for 1 hour with heat preservation. After the reaction is finished, the temperature is raised to 15-35 ℃, and vinyl ethyl ether (38.1g,529.4mmol) is slowly dripped into the reaction liquid. After the dripping is finished, the reaction is kept warm for 2 hours.
After completion of the reaction, the mixture was filtered, and a saturated aqueous sodium hydrogencarbonate solution (30mL) was added to the filtrate, followed by stirring for 30 minutes, followed by standing and separation. The organic phase was separated and washed with saturated aqueous sodium chloride (30 mL). Separating out an organic phase, sequentially adding anhydrous sodium sulfate, drying, filtering, and distilling under reduced pressure to obtain the product.
Process for preparing N-protected 3-bromopyrazoles1The HNMR map is shown in FIG. 2.
Example 2
Referring to FIG. 1, pyrazole (30.0g,441.2mmol) was dissolved in dichloromethane (300mL) under nitrogen protection, and the reaction solution was cooled to-10 to 10 ℃. Dibromohydantoin (63.1g, 220.6mmol) was slowly added to the reaction solution in portions. After the addition, the reaction was continued for 1 hour with heat preservation. After the reaction is finished, the temperature is raised to 15-35 ℃, and vinyl ethyl ether (38.1g,529.4mmol) is slowly dripped into the reaction liquid. After the dripping is finished, the reaction is kept warm for 2 hours.
After completion of the reaction, the mixture was filtered, and a saturated aqueous sodium hydrogencarbonate solution (30mL) was added to the filtrate, followed by stirring for 30 minutes, followed by standing and separation. The organic phase was separated and washed with saturated aqueous sodium chloride (30 mL). Separating out an organic phase, sequentially adding anhydrous sodium sulfate, drying, filtering, and distilling under reduced pressure to obtain the product.
Example 3
Referring to FIG. 1, pyrazole (30.0g,441.2mmol) was dissolved in dichloromethane (300mL) under nitrogen protection, and the reaction solution was cooled to-10 to 10 ℃. Dibromohydantoin (94.6g, 330.9mmol) was slowly added to the reaction solution in portions. After the addition, the reaction was continued for 1 hour with heat preservation. After the reaction, the temperature was raised to 15 to 35 ℃ and vinyl ethyl ether (63.5g,882.4mmol) was slowly added dropwise to the reaction solution. After the dripping is finished, the reaction is kept warm for 2 hours.
After completion of the reaction, the mixture was filtered, and a saturated aqueous sodium hydrogencarbonate solution (30mL) was added to the filtrate, followed by stirring for 30 minutes, followed by standing and separation. The organic phase was separated and washed with saturated aqueous sodium chloride (30 mL). Separating out an organic phase, sequentially adding anhydrous sodium sulfate, drying, filtering, and distilling under reduced pressure to obtain the product.
Example 4
Referring to FIG. 1, pyrazole (30.0g,441.2mmol) was dissolved in dichloromethane (300mL) under nitrogen protection, and the reaction solution was cooled to-10 to 10 ℃. Bromine (52.9g, 330.9mmol) was slowly added to the reaction solution in portions. After the addition, the reaction was continued for 1 hour with heat preservation. After the reaction, the temperature was raised to 15 to 35 ℃ and vinyl ethyl ether (63.5g,882.4mmol) was slowly added dropwise to the reaction solution. After the dripping is finished, the reaction is kept warm for 2 hours.
After completion of the reaction, the mixture was filtered, and a saturated aqueous sodium hydrogencarbonate solution (30mL) was added to the filtrate, followed by stirring for 30 minutes, followed by standing and separation. The organic phase was separated and washed with saturated aqueous sodium chloride (30 mL). Separating out an organic phase, sequentially adding anhydrous sodium sulfate, drying, filtering, and distilling under reduced pressure to obtain the product.
Example 5
Referring to FIG. 1, pyrazole (30.0g,441.2mmol) was dissolved in dichloromethane (300mL) under nitrogen protection, and the reaction solution was cooled to-10 to 10 ℃. NBS (79.9g, 441.2mmol) was added slowly in portions to the reaction. After the addition, the reaction was continued for 1 hour with heat preservation. After the reaction is finished, the temperature is raised to 15-35 ℃, and 3, 4-dihydro-2H-pyran (38.1g,529.4mmol) is slowly dripped into the reaction liquid. After the dripping is finished, the reaction is kept warm for 2 hours.
After completion of the reaction, the mixture was filtered, and a saturated aqueous sodium hydrogencarbonate solution (30mL) was added to the filtrate, followed by stirring for 30 minutes, followed by standing and separation. The organic phase was separated and washed with saturated aqueous sodium chloride (30 mL). Separating out an organic phase, sequentially adding anhydrous sodium sulfate, drying, filtering, and distilling under reduced pressure to obtain the product.
While the invention has been described with respect to a preferred embodiment, it will be understood by those skilled in the art that the foregoing and other changes, omissions and deviations in the form and detail thereof may be made without departing from the scope of this invention. Those skilled in the art can make various changes, modifications and equivalent arrangements, which are equivalent to the embodiments of the present invention, without departing from the spirit and scope of the present invention, and which may be made by utilizing the techniques disclosed above; meanwhile, any changes, modifications and variations of the above-described embodiments, which are equivalent to those of the technical spirit of the present invention, are within the scope of the technical solution of the present invention.
Claims (10)
1. A synthetic method for synthesizing N-protected 3-bromopyrazole by a one-pot method is characterized by comprising the following steps:
(a) reacting pyrazole with a bromization reagent to generate 3-bromopyrazole reaction liquid;
(b) and (b) adding the vinyl ether into the reaction liquid obtained in the step (a), reacting by a one-pot method, and carrying out aftertreatment to obtain the N-protected 3-bromopyrazole.
2. The synthesis method of N-protected 3-bromopyrazole by the one-pot method according to claim 1, wherein the brominating agent in step a) comprises one of NBS, bromine and dibromohydantoin.
3. The synthesis method for synthesizing the N-protected 3-bromopyrazole by the one-pot method according to claim 1, wherein the reaction temperature in the step a) is-10 ℃ to 10 ℃.
4. The synthesis method for synthesizing the N-protected 3-bromopyrazole by the one-pot method according to claim 1, wherein the reaction temperature in the step b) is 15-35 ℃.
5. The synthesis method for synthesizing N-protected 3-bromopyrazole by the one-pot method according to claim 1, wherein in the step b), the post-treatment process comprises the following steps: and (3) centrifuging, washing, drying and desolventizing the N-protected 3-bromopyrazole obtained by the reaction to obtain the N-protected pyrazole.
6. The synthesis method for synthesizing the N-protected 3-bromopyrazole by the one-pot method according to claim 1, wherein the step a) is as follows: dissolving pyrazole in dichloromethane, adding a bromization reagent in batches at the temperature of-10 ℃, and reacting to obtain the 3-bromopyrazole.
7. The synthesis method of N-protected 3-bromopyrazole by the one-pot method according to claim 6, wherein 100-350 g of pyrazole is added to 1000mL of dichloromethane.
8. The synthesis method of N-protected 3-bromopyrazole by the one-pot method according to claim 4, wherein in the step b), the vinyl ether is added and then is kept for 2 hours.
9. The synthesis method for synthesizing the N-protected 3-bromopyrazole by the one-pot method according to claim 1, wherein the molar ratio of the pyrazole, the brominating agent and the alkenyl ether is 1.0: 1.0-1.5: 1.0 to 2.0.
10. The synthesis method for synthesizing the N-protected 3-bromopyrazole by the one-pot method according to claim 1, wherein the alkenyl ether is vinyl ethyl ether or 3, 4-dihydro-2H-pyran.
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Application publication date: 20210409 |