CN110128457B - Preparation method of heterocyclic small molecule compound - Google Patents
Preparation method of heterocyclic small molecule compound Download PDFInfo
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- CN110128457B CN110128457B CN201910439486.1A CN201910439486A CN110128457B CN 110128457 B CN110128457 B CN 110128457B CN 201910439486 A CN201910439486 A CN 201910439486A CN 110128457 B CN110128457 B CN 110128457B
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Abstract
The invention belongs to the field of medicinal chemistry, particularly belongs to the field of organic synthesis in medicinal chemistry, and more particularly relates to a preparation method of a heterocyclic small molecular compound. Therefore, the method provides guarantee for subsequent deep research and development for important building blocks in drug research and development and synthesis and facilitates the research and development of related drug synthesis.
Description
Technical Field
The invention belongs to the field of medical chemistry, particularly belongs to the field of organic synthesis in medical chemistry, and more particularly relates to a preparation method of a heterocyclic small molecular compound.
Background
Heterocyclic compounds are a large class of cyclic compounds containing heteroatoms, accounting for one third of the known organic compounds. Heterocyclic compounds are widely distributed in nature and have many functions. For example, the effective components of Chinese herbs, alkaloid, are mostly heterocyclic compounds; the basic groups of heme, chlorophyll and nucleic acid playing important physiological roles in animals and plants are nitrogen-containing heterocycles; some vitamins, antibiotics; some plant pigments, plant dyes, synthetic dyes all contain heterocycles. The high temperature resistant polymers such as polybenzoxazole and polyimidazolone in recent years also contain heterocyclic structures. Therefore, the heterocyclic compound has very important significance in theoretical research or practical application.
Heterocyclic small molecules refer to small molecule compounds having a heterocyclic structure. Mainly comprises small molecular compounds such as indoles, thiazoles, spirocyclic rings, bridged rings, pyridines, pyrimidines, quinolines, borate, chiral amines and the like. These small molecule compounds generally have high biological activity and are therefore also referred to as bioactive small molecules.
These small molecule compounds are small molecule fragments, and through various chemical reactions, reaction sites are linked to synthesize complex target compounds. These small molecule compounds are also referred to as "heterocyclic small molecule building blocks".
The heterocyclic micromolecules referred to in the invention refer to one of numerous heterocyclic micromolecules, in particular to trifluoromethyl pyrazole borate micromolecule compounds. The compounds have the following structure:
its CAS is 1218790-53-4, and its physical properties are off-white solids.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel preparation method of the trifluoromethyl pyrazole borate micromolecule compound, so that the production process can be simplified, the requirements and the limitations on reaction conditions in the production process are reduced, and a foundation is provided for realizing the industrial production of the product.
In order to solve the technical problem, the invention discloses a preparation method of a heterocyclic micromolecule compound, wherein the heterocyclic micromolecule is a trifluoromethyl pyrazole boric acid ester micromolecule compound (compound E), and the reaction is as follows:
further preferably, the synthesis reaction of the compound D is as follows:
further preferably, the synthesis reaction of the compound C is as follows:
further preferably, the synthesis reaction of the compound B is as follows:
further, the complete synthesis steps of the heterocyclic small molecule compound are as follows:
meanwhile, the invention further discloses that the specific steps for preparing the compound E from the compound D are as follows:
dissolving a compound D in anhydrous Tetrahydrofuran (THF), cooling to-80 ℃ under the protection of nitrogen, dropwise adding n-butyllithium, uniformly stirring, detecting the temperature, dropwise adding isopropanol pinacol borate under the condition of ensuring the temperature to be-80 ℃, reacting at-80 ℃, detecting by TLC, determining that the reaction end point is reached when no compound D exists in the detection result, quenching by using a saturated ammonium chloride aqueous solution, removing the THF, adding methyl tert-butyl ether, filtering by using kieselguhr, separating an organic phase, drying and concentrating to obtain a compound E.
More preferably, the method further comprises a refining step, specifically, after the compound E is obtained, Petroleum Ether (PE) is added, the mixture is stirred uniformly to be in a slurry state, and the slurry is filtered to obtain a refined compound E. The purity of the compound is 99% and the yield is 76% through detection.
The hydrogen nuclear magnetic data of compound E is:1h NMR (400MHz, CDCl3) delta 7.71(s,1H),3.95(s,3H),1.33(s, 12H). This compound was confirmed to be the target compound.
In addition, the invention also discloses a concrete step for preparing the compound D by the compound C, which is as follows:
firstly, respectively dissolving a compound C and reduced Fe powder in water, then controlling the temperature of a reaction system at 30 ℃, dropwise adding bromine, after the system is stable, heating to 100 ℃ until the reaction is complete, cooling to room temperature, adding a reaction product into a sodium thiosulfate aqueous solution, extracting with dichloromethane, taking an organic phase, drying, concentrating, distilling under reduced pressure, and obtaining a colorless liquid which is an azeotrope, wherein the external temperature is 55 ℃, the internal temperature is 32 ℃, and the internal temperature is 0.5 Torr; the product is cooled and received by an ice salt bath, the external temperature is 65 ℃, the internal temperature is 58 ℃, and 0.5Torr is used for obtaining yellow solid, namely the compound D.
The purity of compound D was determined to be 99% and the nuclear magnetic identification data was 1H NMR (400MHz, CDCl3) delta 7.47(s,1H),3.95(s, 3H).
The order of adding the compound C and the reduced Fe powder into the water is not required, and the compound C can be added firstly, or the reduced Fe powder can be added firstly. It is noteworthy, however, that both compounds must be soluble in water. Since the reagent bromine, a highly corrosive compound and a dangerous chemical, must be added during the reaction, if a large amount of bromine is accumulated in a non-solvent state, resulting in a large local reaction concentration, it causes a safety problem. In the invention, water is used as a reaction solvent, so that the safety problem caused by a non-solvent state can be avoided, and the water solvent is economic and environment-friendly and is a solvent capable of industrial large-scale production.
Meanwhile, the invention also discloses a specific step for preparing the compound C from the compound B, which is as follows:
firstly, dissolving methylhydrazine sulfate in water, then dripping compound B into the solution under the stirring state, and after finishing dripping, heating to 100 ℃ to completely react. Cooling to room temperature, taking the aqueous phase, extracting with Dichloromethane (DCM), drying the extract, concentrating, distilling under reduced pressure, cooling the product with ice salt bath, and collecting the product at an external temperature of 50 ℃ and an internal temperature of 38 ℃ and 0.5Torr to obtain a colorless liquid, which is the compound C.
The nuclear magnetic data are identified as follows:1H NMR(400MHz,CDCl3)δ7.42(s,1H),6.53(d,J＝2.0Hz,1H),3.98(s,3H)。
in the reaction process, water is selected as a reaction solvent, so that the method is more economical and environment-friendly compared with other organic solvents such as methanol, and is suitable for industrial application. Meanwhile, the unexpected discovery that the product after reaction can be automatically layered with water after water is used as a solvent, so that the subsequent purification and refining processes can be simplified. It is noted that, in the prior art, 40% methylhydrazine aqueous solution is usually used for methylhydrazine, but methylhydrazine sulfate is used in the present invention, so that the reaction yield can be greatly improved, and after methylhydrazine sulfate is used, the subsequent treatment of the product is easy, and the method is suitable for industrial production and popularization.
In addition, the invention also discloses a specific step of preparing the compound B by the compound A, which is as follows:
firstly, anhydrous Dichloromethane (DCM), trifluoroacetic anhydride (TFAA) and 4-Dimethylaminopyridine (DMAP) are mixed, then the temperature of a reaction system is reduced to-10 ℃, vinyl ethyl ether is dropwise added at the temperature, then the temperature of the system is recovered to room temperature (25 +/-5 ℃) under the condition of natural temperature rise (namely, no heating), when no compound A exists, the reaction is complete, at the moment, a reaction product is added into an ice-water mixture (namely, water with the temperature of 0 ℃ containing ice blocks) for quenching, an organic phase is taken, the pH value of the solution is adjusted to 8 by saturated sodium bicarbonate, the organic phase is separated out, drying, concentration and reduced pressure distillation are carried out, the product is cooled and received by an ice salt bath, the external temperature is 60 ℃, the internal temperature is 40 ℃, and the internal temperature is 10Torr, and a light yellow liquid, namely, the compound B is obtained.
Finally, the invention also discloses a preparation method for preparing the compound E from the compound A, which comprises the following steps:
(1) firstly, mixing anhydrous Dichloromethane (DCM), trifluoroacetic anhydride (TFAA) and 4-Dimethylaminopyridine (DMAP), then reducing the temperature of a reaction system to-10 ℃, dropwise adding vinyl ethyl ether at the temperature, naturally heating (namely, not heating) to restore the system temperature to room temperature (25 +/-5 ℃), completely reacting when detecting no compound A by TLC, adding a reaction product into an ice-water mixture (namely, water at 0 ℃ containing ice blocks) for quenching, taking an organic phase, adjusting the pH of the solution to 8 by using saturated sodium bicarbonate, separating the organic phase, drying, concentrating, distilling under reduced pressure, cooling and receiving a product by using an ice salt bath, wherein the external temperature is 60 ℃, the internal temperature is 40 ℃, and the internal temperature is 10Torr to obtain a light yellow liquid, namely a compound B;
(2) dissolving methylhydrazine sulfate in water, then dropwise adding a compound B into the solution under the stirring state, and after dropwise adding, heating to 100 ℃ to completely react; cooling to room temperature, taking the water phase, extracting with Dichloromethane (DCM), drying the extract, concentrating, distilling under reduced pressure, cooling the product with ice salt bath, and collecting the product at 50 deg.C, 38 deg.C and 0.5Torr to obtain colorless liquid as compound C;
(3) respectively dissolving a compound C and reduced Fe powder in water, controlling the temperature of a reaction system at 30 ℃, dropwise adding bromine, heating to 100 ℃ after the system is stable until the reaction is completed, cooling to room temperature, adding a reaction product into a sodium thiosulfate aqueous solution, extracting with dichloromethane, taking an organic phase, drying, concentrating, distilling under reduced pressure, and obtaining a colorless liquid which is an azeotrope, wherein the external temperature is 55 ℃, the internal temperature is 32 ℃ and the internal temperature is 0.5 Torr; cooling and receiving the product by using an ice salt bath, wherein the external temperature is 65 ℃, the internal temperature is 58 ℃ and the Torr is 0.5to obtain yellow solid, namely the compound D;
(4) dissolving a compound D in anhydrous Tetrahydrofuran (THF), cooling to-80 ℃ under the protection of nitrogen, dropwise adding n-butyl lithium, uniformly stirring, detecting the temperature, dropwise adding isopropanol pinacol borate under the condition of ensuring the temperature to be-80 ℃, reacting at-80 ℃, detecting by TLC, determining that the reaction end point is reached when no compound D exists in the detection result, quenching by using a saturated ammonium chloride aqueous solution, removing the THF, adding methyl tert-butyl ether, filtering by using kieselguhr, separating an organic phase, drying, concentrating, and pulping by using petroleum ether PE to obtain a compound E.
Wherein in the above step, the drying involved is preferably drying over anhydrous sodium sulfate.
In addition, the invention further preferably each reaction step in the reactants in the preferred addition amount, should understand these addition amount representation is the relevant proportional relationship, specific application can be according to the need proportional scaling up or reduce specific addition value, specific preferred addition amount as follows:
in the reaction for preparing the compound B from the compound A, the addition amount of anhydrous Dichloromethane (DCM) is 2L, and the addition amount of trifluoroacetic anhydride (TFAA) is 1.46mol, namely 306 g; the addition amount of 4-Dimethylaminopyridine (DMAP) is 83.4mmol, namely 3 g; the amount of addition of vinyl ethyl ether (Compound A) was 1.39mol, i.e. 100 g;
in the reaction for preparing the compound C from the compound B, the addition amount of water is 600 mL; the addition amount of the methylhydrazine sulfate is 170 g; the addition amount of the compound B is 170 g;
in the reaction for preparing the compound D from the compound C, the addition amount of water is 400 mL; the addition amount of the compound C is 0.57mol, namely 86 g; the addition amount of the reduced Fe powder is 0.285mol, namely 15.96 g; the total addition of bromine was 1.55mol, i.e. 242 g;
in the reaction for preparing the compound E from the compound D, anhydrous Tetrahydrofuran (THF) is added in an excessive amount; the amount of compound D added was 0.218mol, i.e. 50 g; the addition amount of n-butyllithium was 2.5M, i.e., 100 mL; the addition amount of the isopropanol pinacol borate was 0.225mol, namely 41.8 g; the amount of the saturated aqueous ammonium chloride solution added was 500 mL.
The preparation method of the heterocyclic small molecular compound trifluoromethyl pyrazole disclosed by the invention is simple in preparation process and high in reaction safety, products generated in the reaction process are easy to separate from a reaction system, the purification and refining process flow is simple, the steps are few, the whole reaction yield is high, the product purity is high, and the preparation method is suitable for industrial production and popularization.
The trifluoromethyl pyrazole is used as an important building block in drug research and development and synthesis, and the disclosure of the industrial preparation method can provide guarantee for subsequent deep research and development, thereby being beneficial to the research and development of related drug synthesis.
Detailed Description
In order that the invention may be better understood, we now provide further explanation of the invention with reference to specific examples.
EXAMPLE 1 preparation of Compound A Compound B
2L of anhydrous DCM, TFAA (306g,1.46mol) and DMAP (3g,83.4mmol) were added to a 5L reaction flask, cooled to-10 deg.C, vinyl ethyl ether (100g,1.39mol) was added dropwise, and the reaction was allowed to return to room temperature naturally for 8 hours. TLC detects the reaction of raw materials completely, pouring the reaction liquid into ice water for quenching, paying attention to a large amount of bubbles, separating an organic phase, adjusting the pH of the organic phase to 8 by using saturated sodium bicarbonate, separating the organic phase, washing the organic phase for 2 times by using saturated sodium chloride aqueous solution, drying the organic phase by using anhydrous sodium sulfate, and concentrating. Vacuum distilling, cooling the product with ice salt bath, and collecting the product, wherein the external temperature is 60 ℃, the internal temperature is 40 ℃, and the temperature is 10Torr, thus obtaining 170g of light yellow liquid.
EXAMPLE 2 preparation of Compound C from Compound B
600mL of water and 170g of methylhydrazine sulfate are added into a 2L reaction bottle, 170g of B is added dropwise with stirring, and the temperature is raised to 100 ℃ for reaction for 8 hours. Cooled to room temperature, the organic phase was separated, the aqueous phase was extracted once with DCM, washed 1 time with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated. Distilling under reduced pressure, cooling the product with ice salt bath, and collecting the product at an external temperature of 50 deg.C and an internal temperature of 38 deg.C under 0.5Torr to obtain 86g. The compound was subjected to nuclear magnetic identification, and the data were:1H NMR(400MHz,CDCl3)δ7.42(s,1H),6.53(d,J＝2.0Hz,1H),3.98(s,3H)。
EXAMPLE 3 preparation of Compound D from Compound C
Adding 400mL of water, a compound C (86g,0.57mol) and reduced iron powder (15.96g,0.285mol) into a 1L reaction bottle, dropwise adding bromine (242g,1.55mol) at 30 ℃, heating to 100 ℃ after the system is stable, reacting for 4 hours, cooling to room temperature, pouring the reaction liquid into 2L of sodium thiosulfate aqueous solution, stirring, extracting with DCM for 3 times, washing with the sodium thiosulfate aqueous solution for 2 times, drying with anhydrous sodium sulfate, concentrating, distilling under reduced pressure, keeping the external temperature at 55 ℃, keeping the internal temperature at 32 ℃ and keeping the internal temperature at 0.5Torr to obtain colorless liquid which is an azeotrope; the product was cooled in an ice-salt bath at 65 ℃ outside temperature and 58 ℃ inside temperature with 0.5Torr to obtain 98g of a yellow solid. GC 99%, and the compound was subjected to nuclear magnetic identification, and the data are: 1H NMR (400MHz in CDCl 3). delta.7.47 (s,1H),3.95(s, 3H).
EXAMPLE 4 preparation of Compound E from Compound D
In a 1L reaction flask, anhydrous THF, compound D (50g,0.218mol), under nitrogen protection, was cooled to-80 deg.C, n-butyllithium (100mL,2.5M) was added dropwise, and stirring was carried out30min, then isopropanol pinacol borate (41.8g,0.225mol) is added dropwise at-80 ℃, the temperature is kept for reaction for 30min, and the raw materials are detected by TLC. The reaction was quenched with 500mL of saturated aqueous ammonium chloride, THF was spin dried, methyl tert-butyl ether MTBE was added, celite was filtered over a pad to separate the organic phase, washed once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated, slurried with Petroleum Ether (PE), filtered to give a white solid 46g.gc 99%, and the compound was subject to nuclear magnetic characterization with the data:1H NMR(400MHz,CDCl3)δ7.71(s,1H),3.95(s,3H),1.33(s,12H)。
EXAMPLE 5 preparation of Compound A Compound E
2L of anhydrous DCM, TFAA (306g,1.46mol) and DMAP (3g,83.4mmol) were added to a 5L reaction flask, cooled to-10 deg.C, vinyl ethyl ether (100g,1.39mol) was added dropwise, and the reaction was allowed to return to room temperature naturally for 8 hours. TLC detects the reaction of raw materials completely, pouring the reaction liquid into ice water for quenching, paying attention to a large amount of bubbles, separating an organic phase, adjusting the pH of the organic phase to 8 by using saturated sodium bicarbonate, separating the organic phase, washing the organic phase for 2 times by using saturated sodium chloride aqueous solution, drying the organic phase by using anhydrous sodium sulfate, and concentrating. Vacuum distilling, cooling the product with ice salt bath, and collecting the product, wherein the external temperature is 60 ℃, the internal temperature is 40 ℃, and the temperature is 10Torr, thus obtaining 170g of light yellow liquid.
Then 600mL of water and 170g of methylhydrazine sulfate were added to a 2L reaction flask, and B170g was added dropwise with stirring, and the temperature was raised to 100 ℃ to react for 8 hours. Cooled to room temperature, the organic phase was separated, the aqueous phase was extracted once with DCM, washed 1 time with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated. Distilling under reduced pressure, cooling the product with ice salt bath, and collecting the product at an external temperature of 50 deg.C and an internal temperature of 38 deg.C under 0.5Torr to obtain 86g. The compound was subjected to nuclear magnetic identification, and the data were:1H NMR(400MHz,CDCl3)δ7.42(s,1H),6.53(d,J＝2.0Hz,1H),3.98(s,3H)。
then, 400mL of water, a compound C (86g,0.57mol), and reduced iron powder (15.96g,0.285mol) are added into a 1L reaction bottle, bromine (242g,1.55mol) is dropwise added at 30 ℃, after the system is stabilized, the temperature is raised to 100 ℃ for reaction for 4 hours, the reaction solution is cooled to room temperature, the reaction solution is poured into 2L of sodium thiosulfate aqueous solution for stirring, DCM is used for extraction for 3 times, the sodium thiosulfate aqueous solution is washed for 2 times, anhydrous sodium sulfate is dried, concentrated and distilled under reduced pressure, the external temperature is 55 ℃, the internal temperature is 32 ℃, and 0.5Torr is used to obtain colorless liquid which is an azeotrope; the product was cooled in an ice-salt bath at 65 ℃ outside temperature and 58 ℃ inside temperature with 0.5Torr to obtain 98g of a yellow solid. GC 99%, and the compound was subjected to nuclear magnetic identification, and the data are: 1H NMR (400MHz in CDCl 3). delta.7.47 (s,1H),3.95(s, 3H).
Finally, anhydrous THF and compound D (50g,0.218mol) were added to a 1L reaction flask, the temperature was reduced to-80 ℃ under nitrogen protection, n-butyllithium (100mL,2.5M) was added dropwise, stirring was carried out for 30min, isopropanol pinacol borate (41.8g,0.225mol) was added dropwise at-80 ℃, the temperature was maintained, the reaction was carried out for 30min, and the starting material was detected by TLC. The reaction was quenched with 500mL of saturated aqueous ammonium chloride, THF was spin dried, methyl tert-butyl ether MTBE was added, celite was filtered over a pad to separate the organic phase, washed once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated, slurried with Petroleum Ether (PE), filtered to give a white solid 46g.gc 99%, and the compound was subject to nuclear magnetic characterization with the data:1H NMR(400MHz,CDCl3)δ7.71(s,1H),3.95(s,3H),1.33(s,12H)。
what has been described above is a specific embodiment of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and such improvements and modifications are also considered to be within the scope of the present invention.
Claims (9)
1. A preparation method of a heterocyclic micromolecule compound is characterized in that the heterocyclic micromolecule compound is a trifluoromethyl pyrazole borate micromolecule compound, and the preparation method comprises the following steps:
the method comprises the following specific steps:
dissolving a compound D in anhydrous tetrahydrofuran, cooling to-80 ℃ under the protection of nitrogen, dropwise adding n-butyl lithium, uniformly stirring, detecting the temperature, dropwise adding isopropanol pinacol borate under the condition that the temperature is-80 ℃, reacting at-80 ℃, detecting by TLC (thin layer chromatography), determining that the reaction end point is reached when the detection result is free of the compound D, quenching by using a saturated ammonium chloride aqueous solution, removing THF (tetrahydrofuran), adding methyl tert-butyl ether, filtering by using diatomite, separating an organic phase, drying and concentrating to obtain a compound E;
wherein the addition amount of the anhydrous tetrahydrofuran is excessive; the amount of compound D added was 0.218mol, i.e. 50 g; the addition amount of n-butyllithium was 2.5M, i.e., 100 mL; the addition amount of the isopropanol pinacol borate was 0.225mol, namely 41.8 g; the addition amount of the saturated ammonium chloride aqueous solution is 500 mL;
and a refining step, specifically, after the compound E is obtained, adding petroleum ether, uniformly stirring to form a slurry, and filtering to obtain a refined compound E, wherein the purity of the compound E is 99% by detection.
2. The method for preparing a heterocyclic small molecule compound according to claim 1, characterized in that: the preparation method of the compound D comprises the following steps:
the method comprises the following specific steps:
firstly, respectively dissolving a compound C and reduced Fe powder in water, then controlling the temperature of a reaction system at 30 ℃, dropwise adding bromine, after the system is stable, heating to 100 ℃ until the reaction is complete, cooling to room temperature, adding a reaction product into a sodium thiosulfate aqueous solution, extracting with dichloromethane, taking an organic phase, drying, concentrating, distilling under reduced pressure, and obtaining a colorless liquid which is an azeotrope, wherein the external temperature is 55 ℃, the internal temperature is 32 ℃, and the internal temperature is 0.5 Torr; the product is cooled and received by an ice salt bath, the external temperature is 65 ℃, the internal temperature is 58 ℃, and 0.5Torr is used for obtaining yellow solid, namely the compound D.
3. The method for producing the heterocyclic small molecule compound according to claim 2, characterized in that: the preparation method of compound C is as follows:
the method comprises the following specific steps:
dissolving methyl hydrazine sulfate in water, dropwise adding a compound B into the mixture under the stirring state, heating to 100 ℃ after dropwise adding, completely reacting, cooling to room temperature, taking a water phase, extracting with dichloromethane, drying an extract, concentrating, distilling under reduced pressure, cooling a product by using an ice salt bath, receiving the product at an external temperature of 50 ℃, an internal temperature of 38 ℃ and 0.5Torr to obtain a colorless liquid which is a compound C.
4. The method for preparing a heterocyclic small molecule compound according to claim 3, characterized in that: the preparation method of the compound B comprises the following steps:
the method comprises the following specific steps:
firstly, mixing anhydrous dichloromethane, trifluoroacetic anhydride and 4-dimethylaminopyridine, then reducing the temperature of a reaction system to-10 ℃, dropwise adding vinyl ethyl ether at the temperature, naturally heating to restore the system temperature to room temperature, completely reacting when detecting no compound A by TLC, adding a reaction product into an ice-water mixture for quenching, taking an organic phase, adjusting the pH of the solution to 8 by using saturated sodium bicarbonate, separating the organic phase, drying, concentrating, distilling under reduced pressure, cooling and receiving the product by using an ice salt bath, wherein the external temperature is 60 ℃, the internal temperature is 40 ℃, and the internal temperature is 10Torr to obtain a light yellow liquid, namely a compound B.
5. The preparation method of the heterocyclic micromolecule compound is characterized in that the heterocyclic micromolecule compound is a trifluoromethyl pyrazole borate micromolecule compound, and the preparation method comprises the following steps:
the method comprises the following steps:
(1) firstly, mixing anhydrous dichloromethane, trifluoroacetic anhydride and 4-dimethylaminopyridine, then reducing the temperature of a reaction system to-10 ℃, dropwise adding vinyl ethyl ether at the temperature, naturally heating to restore the system temperature to room temperature, completely reacting when detecting no compound A by TLC, adding a reaction product into an ice-water mixture for quenching, taking an organic phase, adjusting the pH of the solution to 8 by using saturated sodium bicarbonate, separating the organic phase, drying, concentrating, distilling under reduced pressure, cooling and receiving the product by using an ice salt bath, wherein the external temperature is 60 ℃, the internal temperature is 40 ℃, and the internal temperature is 10Torr to obtain a light yellow liquid, namely a compound B;
(2) dissolving methylhydrazine sulfate in water, then dropwise adding a compound B into the solution under the stirring state, and after dropwise adding, heating to 100 ℃ to completely react; cooling to room temperature, taking the aqueous phase, extracting with dichloromethane, drying the extract, concentrating, distilling under reduced pressure, cooling the product with ice salt bath, and collecting the product at 50 deg.C, 38 deg.C and 0.5Torr to obtain colorless liquid as compound C;
(3) respectively dissolving a compound C and reduced Fe powder in water, controlling the temperature of a reaction system at 30 ℃, dropwise adding bromine, heating to 100 ℃ after the system is stable until the reaction is completed, cooling to room temperature, adding a reaction product into a sodium thiosulfate aqueous solution, extracting with dichloromethane, taking an organic phase, drying, concentrating, distilling under reduced pressure, and obtaining a colorless liquid which is an azeotrope, wherein the external temperature is 55 ℃, the internal temperature is 32 ℃ and the internal temperature is 0.5 Torr; cooling and receiving the product by using an ice salt bath, wherein the external temperature is 65 ℃, the internal temperature is 58 ℃ and the Torr is 0.5to obtain yellow solid, namely the compound D;
(4) dissolving a compound D in anhydrous tetrahydrofuran, cooling to-80 ℃ under the protection of nitrogen, dropwise adding n-butyllithium, uniformly stirring, detecting the temperature, dropwise adding isopropanol pinacol borate under the condition that the temperature is-80 ℃, reacting at-80 ℃, detecting by TLC (thin layer chromatography), determining that the reaction end point is reached when the detection result is free of the compound D, quenching by using a saturated ammonium chloride aqueous solution, removing THF (tetrahydrofuran), adding methyl tert-butyl ether, filtering by using diatomite, separating an organic phase, drying and concentrating to obtain a compound E;
and a refining step, specifically, after the compound E is obtained, adding petroleum ether, uniformly stirring to form a slurry, and filtering to obtain a refined compound E, wherein the purity of the compound E is 99% by detection.
6. The method for preparing a heterocyclic small molecule compound according to claim 5, characterized in that the drying is performed with anhydrous sodium sulfate.
7. The method for preparing heterocyclic small molecule compound according to claim 5, characterized in that in the reaction of compound A to compound B, the addition amount of anhydrous dichloromethane is 2L, and the addition amount of trifluoroacetic anhydride is 1.46mol, i.e. 306 g; the addition amount of 4-dimethylaminopyridine was 83.4mmol, i.e. 3 g; the amount of vinyl ethyl ether added was 1.39mol, namely 100 g.
8. The method for producing a heterocyclic small molecule compound according to claim 5, characterized in that in the reaction for producing the compound C from the compound B, the amount of water added is 600 mL; the addition amount of the methylhydrazine sulfate is 170 g; the amount of Compound B added was 170 g.
9. The method for producing a heterocyclic small molecule compound according to claim 5, characterized in that in the reaction for producing the compound D from the compound C, the amount of water added is 400 mL; the addition amount of the compound C is 0.57mol, namely 86 g; the addition amount of the reduced Fe powder is 0.285mol, namely 15.96 g; the total amount of bromine added was 1.55mol, i.e., 242 g.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011017389A1 (en) * | 2009-08-05 | 2011-02-10 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors useful against viral infections, particularly hcv |
| CN104478911A (en) * | 2014-12-19 | 2015-04-01 | 成都安斯利生物医药有限公司 | Method for preparing 3-trifluoromethyl pyrrole boric acid |
| CN108699037A (en) * | 2016-03-04 | 2018-10-23 | 加拉帕戈斯股份有限公司 | Noval chemical compound for treating fibrosis and its pharmaceutical composition |
| WO2019036407A1 (en) * | 2017-08-14 | 2019-02-21 | Merial, Inc. | Pesticidal and parasiticidal pyrazole-isoxazoline compounds |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011017389A1 (en) * | 2009-08-05 | 2011-02-10 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors useful against viral infections, particularly hcv |
| CN104478911A (en) * | 2014-12-19 | 2015-04-01 | 成都安斯利生物医药有限公司 | Method for preparing 3-trifluoromethyl pyrrole boric acid |
| CN108699037A (en) * | 2016-03-04 | 2018-10-23 | 加拉帕戈斯股份有限公司 | Noval chemical compound for treating fibrosis and its pharmaceutical composition |
| WO2019036407A1 (en) * | 2017-08-14 | 2019-02-21 | Merial, Inc. | Pesticidal and parasiticidal pyrazole-isoxazoline compounds |
Non-Patent Citations (1)
| Title |
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| Switchable Reactivity: The Site-Selective Functionalization of Trifluoromethyl-Substituted Pyrazoles;M. Schlosser et al.;《Eur. J. Org. Chem.》;20021231;第2913-2920页 * |
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