CN113336703A - Synthesis of 1,3,4, 5-tetrasubstituted 1H-pyrazole derivatives - Google Patents
Synthesis of 1,3,4, 5-tetrasubstituted 1H-pyrazole derivatives Download PDFInfo
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Abstract
The invention relates to an important intermediate of antitumor drug Laolatinib (Lorlatinib, PF-06463922)N-synthesis of Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole. Bromoacetone and diethyl oxalate are used as initial raw materials, and the final synthesis is carried out by 7-step reactions of condensation, ring closing, bromination, ammonolysis, methylation, dehydration, N-H protection and the likeN-Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole; compared with the prior art, the method has better reaction selectivity, and the designed route is more environment-friendly and economical.
Description
Technical Field
The invention relates to the synthesis of 1,3,4, 5-tetra-substituted 1H-pyrazole derivatives, in particular to a method for carrying out condensation, ring closing, bromination, ammonolysis, methylation, dehydration, N-H protection and other reaction steps by using bromoacetone as an initial starting materialN-Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole.
Background
Laolatinib (Lorlatinib, PF-06463922), named in English: (R) -26-amino-55-fluoro-11, 4, 7-trimethy-6-oxo-11H-3-oxa-7-aza-2 (3,5) -pyridina-1(4,3) -pyrazoli-5 (1,2) -benzacycloctyphane-15-carbonitrile, CAS number: 1454846-35-5, formula: c21H19FN6O2Molecular weight: 406.4. lorlatinib is a third-generation inhibitor of ALK (anaplastic lymphoma kinase). The first generation ALK inhibitor, Crizotinib (Crizotinib), is an ATP-competitive, multi-target protein kinase inhibitor that was approved by the us FDA in 2016 for the treatment of advanced (metastatic) non-small cell lung cancer (NSCLC) patients carrying mutations in the ROS-1 gene. Unfortunately, most patients are 12 months after treatmentInternally develop resistance to the Crizotinib and develop acquired resistance mutation. In recent years, a plurality of second-generation ALK inhibitors with good curative effect and low toxicity have been continuously emerged: ceritinib, Alectonib, Brigatinib. Refractory tumors, however, quickly develop resistance to these new inhibitors. In the face of drug resistance of the criptotiib and second generation ALK inhibitors, scientists began to develop third generation ALK inhibitors, i.e., drugs that are still therapeutically effective in patients with NSCLC who develop central nervous system metastases and are resistant to criptotiib and second generation ALK inhibitors. The third generation ALK inhibitors were lorelatinib, developed by the company pyroxene. 27 Rizeri, 4.4.2017, the FDA awards the name of Lorlatinib 'breakthrough drug' as a new generation ALK/ROS1 tyrosine kinase inhibitor for the second-line treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC).
Structural formula of Laolatinib
The synthesis of Laolatinib and the synthesis method of its intermediate are reported in many documents, but the most industrialized application potential route (reference: Johnson TW, Richardson PF, Bailey S, et al. Journal of Medicinal Chemistry, 2014, 57(11): 4720-4744) in the synthesis route is shown in reaction formula 1, wherein compound 1 (4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole derivative) and compound 2 are coupled by Suzuki-Miyaura to obtain compound 3, carboxylic acid is obtained by hydrolysis of ester, then Boc protection is performed to obtain intermediate compound, and finally macrocyclic compound, namely Lorlatinib, is formed by forming intramolecular amide bond. Furthermore, documents CN 109232607A, EP 3415518 a1, WO 2018137679 a1 and the like also successively disclose methods for synthesizing loratinib. But in almost all publications reporting the synthesis of loratinib,Nthe (Boc) -4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole derivatives are all necessary intermediates of Lauratinib, so the research on the theoretical and practical application value of the synthesis of the (Boc) -4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole derivatives is realized.
Reaction scheme 1
With respect to the synthesis of 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole derivatives, there are few reports in the literature and two major contributions are currently being made (Elleraas J, Ewanicki J, Johnson T W, et al. structural Studies and atomic-isometrics Kinetics of the ALK Clinical laboratory Lorlationb (PF-06463922) and Desmethyl Cong-olefins [ J ]. Angewandte Chemie, 2016, 128(11): 3654. 3659; Huang D, Huang M, Liu W, Design, synthesis and biological evaluation of 1H-pyrazoie-5-carboxamide derivatives as potential Chemical intermediates J. (2057. 20671)).
Taking diethyl oxalate as a starting material (shown as a reaction formula 2), carrying out condensation reaction with acetone in an ethanol-sodium ethoxide reaction system, and synthesizing to obtain ethyl acetylacetonate (a compound C1); performing a ring closure reaction on the compound C1 and methylhydrazine to obtain 1, 3-dimethylpyrazole-5-ethyl formate (compound C2); carrying out bromination reaction on the compound C2 and NBS to obtain 4-bromo-1, 3-dimethyl-1H-pyrazole-5-ethyl formate (compound C3); aminolysis reaction of the compound C3 in ammonia water solution to obtain 4-bromo-1, 3-dimethyl-1H-pyrazole-5-formamide (compound C4); heating a compound C4 under a strong dehydrating agent such as phosphorus pentoxide and phosphorus oxychloride to generate 4-bromo-5-cyano-1, 3-dimethyl-1H-pyrazole (a compound C5), carrying out a second bromination reaction on the compound C5 to obtain 4-bromo-3-bromomethyl-5-cyano-1-methyl-1H-pyrazole (a compound C6), carrying out a substitution reaction on the compound C6 and methylamine to obtain 4-bromo-3-methylaminomethyl-5-cyano-1-methyl-1H-pyrazole (a compound C7), and carrying out an N-H protection reaction on the compound C7 by using BOC anhydride to obtain a compound 1.
The reaction route is long, and more importantly, in the process of obtaining the compound C6 by carrying out the second bromination reaction on the compound C5, because the compound C5 has two methyl groups, the problem of regioselectivity exists, so that the reaction selectivity of the step is poor, and the purification and separation after the synthesis are difficult. Therefore, there is a need to develop a more compact and highly selective methodN-Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (Compound 1).
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel Laratinib intermediate with short synthetic route and high selectivityN-Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole.
Reaction formula 3
The present invention is thus achieved (reaction formula 3): bromoacetone and diethyl oxalate are used as initial raw materials, and the final synthesis is carried out by 7-step reactions of condensation, ring closing, bromination, ammonolysis, methylation, dehydration, N-H protection and the likeN-Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole. More detailed description is as follows:
first, condensation reaction step (reaction formula 4), synthesis of ethyl bromoacetyl pyruvate (compound D1):
under the protection of nitrogen, anhydrous lower aliphatic alcohol as a solvent and sodium alkoxide are sequentially added into a three-necked bottle, and the mixture is uniformly stirred in a ice salt bath. And then slowly dropwise adding a mixture of bromoacetone and diethyl oxalate into a sodium alkoxide-alcohol reaction system, keeping the reaction temperature between minus 10 ℃ and minus 5 ℃, keeping the temperature for reacting for a certain time after dropwise adding, carrying out gas chromatography to control and detect the reaction progress, pouring the reaction liquid into ice water after the reaction is finished, adjusting the pH to =5 by using 1mol/L hydrochloric acid, and extracting the water phase for 2 times by using a certain amount of ethyl acetate. The combined ethyl acetate organic layers were washed twice with appropriate amount of water and dried over anhydrous Na2SO4Drying, filtering, and concentrating ethyl acetate under reduced pressure to obtain bromoacetylThe crude ethyl pyruvate product is yellow viscous liquid, and is purified by rectification under reduced pressure, the yield is 42-48%, and the normalized content of gas chromatography is 92-96% (no further purification is needed, the ethyl pyruvate product can be directly used for the next reaction).
In the condensation reaction step, the anhydrous lower aliphatic alcohol can be one of ethanol, methanol, n-propanol, isopropanol, n-butanol and the like;
in the condensation reaction step, the sodium alkoxide can be one of sodium ethoxide, sodium methoxide, sodium n-propoxide and the like;
in the condensation reaction step, the molar ratio of bromoacetone to diethyl oxalate is 1: 1.5-1.5: 1, and the optimal ratio is 1: 1.05-1.05: 1;
in the condensation reaction step, the molar ratio of the sodium alkoxide to the bromoacetone is 3: 1-0.9: 1, and the optimal ratio is 2: 1-1.5: 1.
Second, ring closure reaction step (reaction formula 5), synthesis of ethyl 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylate (compound D2):
reaction formula 5
Under the protection of nitrogen, sequentially adding a solvent of lower aliphatic alcohol, ethyl bromoacetyl pyruvate (compound D1) prepared by the reaction, Dicyclohexylcarbodiimide (DCC) and a small amount of glacial acetic acid into a three-necked flask with mechanical stirring, heating and refluxing, dropwise adding methylhydrazine, after dropwise adding, continuing to stir vigorously for a certain time, monitoring the reaction by Gas Chromatography (GC), after the reaction is finished, removing the solvent under reduced pressure, stirring and dispersing the obtained solid by using a mixed solvent of toluene and water, and adjusting the pH =5 by using 1 equivalent of hydrochloric acid. Separating, washing the organic phase with saturated solution of sodium bicarbonate and distilled water, and washing with anhydrous Na2SO4Drying, filtering, and concentrating the solvent toluene under reduced pressure to obtainThe crude 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester is a gray solid with a yield of 88-92% and a normalized content of 90-97% by liquid chromatography (which can be used directly in the next reaction without further purification).
In the step of ring closing reaction, the lower aliphatic alcohol can be one of ethanol, methanol, n-propanol, isopropanol, n-butanol, tert-butanol and the like;
in the step of ring closing reaction, the molar ratio of ethyl bromoacetyl pyruvate (compound D1) to methylhydrazine is 1: 3-1: 0.9, and the optimal ratio is 1: 1.5-1: 1.05;
in the ring-closing reaction step, the reaction is carried out under the acidic condition provided by glacial acetic acid and in the presence of a dehydrating agent Dicyclohexylcarbodiimide (DCC).
The third step, bromination reaction step (reaction formula 6), synthesis of ethyl 4-bromo-3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylate (compound D3):
reaction formula 6
Dissolving 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D2) in a solvent, adding a bromination reagent in batches, and reacting at 20-25 ℃. TLC detecting reaction, adding appropriate amount of water to quench reaction after reaction, separating liquid, extracting water layer with certain amount of solvent, mixing organic phases, and extracting with anhydrous Na2SO4Drying, filtering, and concentrating the solvent under reduced pressure to obtain a crude product of 4-bromo-3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D3), and separating and purifying by column chromatography (eluent: ethyl acetate: petroleum ether =1: 2) to obtain a light yellow solid, wherein the yield is 76-83%, and the normalized content of liquid chromatography is 93-98%.
In the bromination reaction step, the bromination reaction solvent can be one of trichloromethane, dichloromethane, cyclohexane, normal hexane and the like;
in the bromination reaction step, the bromination reagent can be one of NBS, dibromohydantoin, liquid bromine and the like;
in the bromination reaction step, the molar ratio of the 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D2) to the bromination reagent material is 1: 0.9-1: 3, and the optimal ratio is 1: 1-1: 1.4.
The fourth step, ammonolysis step (equation 7), synthesis of 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D4):
reaction formula 7
Cooling a certain amount of ethanol solution containing 4% of ammonia to 0-2 ℃ by using a ice salt bath, slowly dropwise adding ethanol solution containing 4-bromo-3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D3) under mechanical stirring, stirring for 5 hours at 0-2 ℃, then heating to 25 ℃, and stirring for 10-20 hours. TLC monitoring, reacting, recovering excessive ammonia under reduced pressure, distilling off most ethanol under reduced pressure, cooling, adding appropriate amount of water and chloroform to the residue, stirring to dissolve, separating, extracting the water layer with small amount of chloroform, mixing the chloroform organic layers, and adding anhydrous Na2SO4Drying, filtering, and concentrating chloroform under reduced pressure to obtain a crude product of 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D4), and separating and purifying by column chromatography (eluent: ethyl acetate: petroleum ether =1: 3) to obtain an off-white solid with a yield of 72-80% and a normalized content of 94-97% by liquid chromatography.
Fifth step, methylation reaction step (reaction formula 8), synthesis of 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D5):
reaction formula 8
Under the protection of nitrogen, adding 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-formamide (compound D4) into an aprotic polar solvent, adding an inorganic base, controlling the temperature to be 0-5 ℃, dropwise adding a methylating agent, heating to 25 ℃ after dropwise adding, reacting for 6 hours, pouring a reaction solution into a proper amount of water after the reaction is finished,extracting with ethyl acetate for 3 times, mixing the organic layers, washing with water twice, and adding anhydrous Na2SO4Drying, filtering, concentrating ethyl acetate under reduced pressure, and drying in vacuum to remove residual solvent to obtain a crude product of 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-formamide (compound D5), wherein the crude product is a gray solid, the yield is 78-88%, and the normalized content of liquid chromatography is 93-95% (no further purification is needed, and the product can be directly used for the next reaction).
In the methylation reaction step, the aprotic polar solvent may be one of aprotic polar solvents such as N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), sulfolane, N-methylpyrrolidone (NMP), N-Dimethylacetamide (DMA), and the like;
in the methylation reaction step, the inorganic base can be one of potassium carbonate, sodium hydroxide, potassium hydroxide and the like;
in the methylation reaction step, the methylation reagent can be one of methyl iodide, dimethyl sulfate, dimethyl carbonate and the like;
in the methylation reaction step, the molar ratio of the 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-formamide (compound D4) to the methylation reagent material is 1: 0.9-1: 3, and the optimal ratio is 1: 1.1-1: 1.5.
Sixth step, dehydration reaction step (reaction formula 9), synthesis of 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (compound D6):
reaction formula 9
Under the protection of nitrogen, acetonitrile and 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-formamide (compound D5) are sequentially added into a mechanically-stirred three-necked bottle equipped with an acid gas absorption device, the temperature is raised to 65-70 ℃, a dehydration reagent is slowly added, and the temperature is raised to 80 ℃ after the addition for reaction for 6-12 hours. After TLC monitoring reaction is completed, cooling to room temperature, slowly dropping the reaction mixture into a certain amount of ice-water mixture, keeping the internal temperature not higher than 35 ℃ in the dropping process, adding a certain amount of water into the obtained mixture after dropping is completed, cooling the mixture to 5 ℃, stirring for 1 hour, standing, and filtering to obtain a crude product of 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (compound D6), a near-white solid, and separating and purifying by column chromatography (eluent: ethyl acetate: petroleum ether =1: 2) to obtain a white solid, wherein the yield is 68-75%, and the normalized content of liquid chromatography is 96-99%.
In the dehydration reaction step, the dehydration reagent may be POCl3、P2O5One of the above two methods;
in the dehydration reaction step, the molar ratio of the 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D5) to the dehydration reagent material is 1: 0.9-1: 30, and the optimal ratio is 1: 2-1: 10.
The seventh step, the N-H protection reaction step (reaction formula 10),N-synthesis of Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (compound 1):
Under the protection of nitrogen, 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (compound D6) is added into a certain volume of dichloromethane, the temperature is controlled at 20-25 ℃, and (Boc) is dropwise added2Heating to 30-35 ℃ after the dropwise addition, reacting, recovering dichloromethane and excessive (Boc) by reduced pressure distillation after the reaction is finished2And O, newly generated tert-butyl alcohol to obtain a crude product of the compound 1, and further separating and purifying by column chromatography (eluent: ethyl acetate/n-hexane = 1/4) to obtain the white solid with the yield of 92-96% and the normalized content of 97-99% by liquid chromatography.
Compared with the synthetic method (reaction formula 2) of the original document, the method has the following remarkable technical characteristics:
1. the starting material bromoacetone is adopted to replace acetone, one bromine atom in the bromoacetone directly generates bromomethyl after ring closing, and the synthesis of the target compound 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (compound D6) reduces one bromination reaction (two bromination reactions are needed in the original synthetic route);
2. in the process of synthesizing 4-bromo-3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D3) into 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-formamide (compound D4), ammonia is used as a reaction material, so that not only ammonolysis reaction but also substitution reaction of bromoalkane is carried out, and the two reactions can be carried out under the same reaction conditions.
3. In the process of synthesizing 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D4) by methylation reaction of 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D5), selectivity is very high because of the great difference between the two amino properties (one belongs to amido and the other to alkane amino).
Therefore, the invention has good economic benefit and social benefit.
Drawings
FIG. 1 shows the target compound synthesized by the present inventionN-nuclear magnetic resonance hydrogen spectrum of Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole;
FIG. 2 shows the target compound synthesized by the present inventionN-nuclear magnetic resonance carbon spectrum of Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole.
Detailed Description
Example 1: synthesis of Ethylbromoacetyl pyruvate (Compound D1) (reaction formula 4)
Absolute ethanol (60 mL) and sodium ethoxide (6.0 g, 0.090 mol) were added sequentially to a three-necked flask under nitrogen protection, and stirred uniformly in an ice salt bath. Then, slowly dropwise adding a mixture of bromoacetone (8.2 g, 0.06 mol) and diethyl oxalate (8.8 g, 0.060 mol) into a sodium ethoxide-ethanol reaction system, keeping the reaction temperature between minus 10 ℃ and minus 5 ℃, and keeping the temperature for reaction for 3 hours after dropwise adding. The reaction was poured into ice water, adjusted to pH =5 using hydrochloric acid (1 mol/L), and the aqueous phase was extracted 2 times with 60 x 2 mL ethyl acetate. The combined ethyl acetate organic layers were washed twice with 50 x 2 mL of water and with anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressureEthyl acetate is condensed to obtain a crude product of ethyl bromoacetyl pyruvate, and the crude product is rectified and purified under reduced pressure to obtain 6.5 g of yellow liquid, wherein the yield is 46 percent, and the normalized content of gas chromatography is 95 percent.
Example 2: synthesis of ethyl 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylate (Compound D2) (reaction formula 5):
under the protection of nitrogen, n-butanol (45 mL), compound D1 (7.5 g, 95% purity, 0.030 moL) prepared by the above reaction, 1 mL of glacial acetic acid, and dicyclohexylcarbodiimide (6.2 g, 0.030 moL) were sequentially added to a three-necked flask equipped with a mechanical stirrer, stirred, heated to reflux, methylhydrazine (1.8 g, 0.038 moL) was added dropwise, the solution was stirred rapidly for reaction for 8 hours after the addition of the dropwise addition (the remaining amount of the reaction starting compound D1 was monitored in gas chromatography), after the completion of the reaction of the starting material, the solvent n-butanol was removed under reduced pressure, the obtained solid was dissolved in a mixed solvent of toluene and water (volume ratio 1: 1), stirred and dispersed, and pH =5 was adjusted using dilute hydrochloric acid (1 moL/L). Separating, washing the organic phase with saturated solution of sodium bicarbonate and distilled water, and washing with anhydrous Na2SO4Drying, filtering, and concentrating the solvent toluene under reduced pressure to obtain crude 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester, 6.7 g of gray solid, 91% yield, and 95% normalized content by liquid chromatography (used in the next reaction without further purification).
Example 3: synthesis of ethyl 4-bromo-3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylate (Compound D3) (reaction formula 6):
3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D2) (5.2 g, 95% purity, 0.020 mol) was dissolved in 40mL of chloroform, NBS (5.0 g, 0.028 mol) was added in portions, and the mixture was reacted at 20 to 25 ℃ for 2 hours. After the reaction is finished, adding 50mL of water to quench the reaction, separating the liquid, extracting the water layer with 30mL of trichloromethane, combining the organic phases, and using anhydrous Na2SO4Drying, filtering, and concentrating chloroform under reduced pressure to obtain crude 4-bromo-3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D3), separating and purifying by column chromatography (eluent: ethyl acetate: petroleum ether =1: 2) to obtain compound D3 as pale yellow solid 5.3g, yield 82%, and normalized content of liquid chromatography is 98%。1H NMR (400 MHz, CDCl3) 4.76 (s, 2H),4.42 (qd, J= 7.0, 2.8 Hz, 2H), 4.15 (s, 3H), 1.44 (dd, J = 7.0, 2.8 Hz, 3H)。
Example 4: synthesis of 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D4) (reaction formula 7):
cooling 100 mL of ammonia-containing 4% ethanol solution by using a ice salt bath to 0-2 ℃, slowly dropwise adding 30mL of ethanol solution containing 4-bromo-3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D3) (3.3 g, 98% purity, 0.01 mol) under mechanical stirring, stirring at 0-2 ℃ for 5 hours, then heating to 25 ℃, and stirring for 12 hours. After the reaction is finished, recovering excessive ammonia under reduced pressure, then distilling most ethanol under reduced pressure, cooling, adding 40mL of water and 40mL of chloroform into the residue, stirring for dissolving, separating liquid, extracting the water layer once with 30mL of chloroform, combining the chloroform organic layers, and using anhydrous Na2SO4Drying, filtering, and concentrating chloroform under reduced pressure to obtain crude 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D4), which is separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether =1: 3) to obtain 1.82 g of an off-white solid with a yield of 78% and a normalized content of 96% by liquid chromatography.1H NMR (400 MHz, CDCl3) 8.03 (s, 2H),4.21 (s, 3H), 3.8 (br s, 2H)。
Example 5: synthesis of 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide (Compound D5) (reaction formula 8):
under the protection of nitrogen, adding 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-formamide (compound D4) (1.5 g, 96% purity, 6.4 mmol) into 30mL of DMF, adding 2.8 g of anhydrous powdered potassium carbonate, controlling the temperature to be 0-5 ℃, dropwise adding methyl iodide (1.8 g, 12.8 mmol), heating to 25 ℃ after dropwise adding, reacting for 6 hours, pouring the reaction solution into 120 mL of water after the reaction is finished, extracting 3 times with 50X 3 mL of ethyl acetate, combining the organic layers of ethyl acetate, washing twice with 50X 2 mL of water, and washing with anhydrous Na2SO4Drying, filtering, concentrating ethyl acetate under reduced pressure, vacuum drying to remove residual DMF to obtain crude product of 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-formamide (compound D5), and collecting ash1.3 g of a colored solid, 86% yield and 95% normalized content by liquid chromatography (used directly in the next reaction without further purification).
Example 6: synthesis of 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (Compound D6) (reaction formula 9):
under the protection of nitrogen, acetonitrile (60 mL) and 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-formamide (compound D5) (5.3 g, 95% purity, reduced to 20 mmol) are sequentially added into a mechanically-stirred three-necked bottle equipped with an acid gas absorption device to be pretreated into fine powder, the temperature is raised to 65-70 ℃, and newly-distilled POCl is slowly added dropwise3(15 g, 0.10 mol), after the addition, the temperature was raised to 80 ℃ for 10 hours. After cooling to room temperature, the reaction mixture was slowly dropped into an ice-water mixture (150 g), the internal temperature was kept at not more than 35 ℃ during the dropping, after the dropping was completed, 50mL of water was added to the obtained mixture, the mixture was cooled to 5 ℃, stirred for 1 hour, allowed to stand, and filtered to obtain a crude product of 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (compound D6) as a pale yellow solid, which was separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether =1: 2) to obtain 3.3 g of a white solid, the yield was 72%, and the normalized content of liquid chromatography was 99%.1H NMR (400 MHz, DMSO-d6) 4.01 (s, 3H), 3.60 (s, 2H), 2.26 (s, 3H),2.08 (br s, 1H)。
Example 7:NBoc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (Compound 1, England name: tert-Butyl [ (4-bromo-5-cyanoo-1-methyl-1H-pyrazol-3-yl) methyl]Synthesis of methyl carbamate) (equation 10):
4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (Compound D6) (4.6 g, 20 mmol, prepared as in example 6) was added to 50mL of DCM under nitrogen, the temperature was controlled at 20 deg.C, and (Boc)2O (5.3 g, 24 mmol), after dropwise addition, the temperature was raised to 30 ℃ to effect reaction for 3 hours, after completion of the reaction, DCM and excess (Boc) were recovered by distillation under reduced pressure2O, freshly produced tert-butanol, and washing the resulting solid with a small amount of petroleum ether to give [ (4-bromo-5-cyano-1-methyl-1H-pyrazol-3-yl)Methyl radical]The crude t-butyl methylcarbamate (compound 1) was separated and purified by column chromatography (eluent: ethyl acetate/n-hexane = 1/4) to give 6.3 g of a white solid with a yield of 96% and a normalized content of 98% by liquid chromatography.1H NMR (400 MHz, CDCl3) 4.47 (d, J = 19.1 Hz, 2H), 4.04 (s, 3H), 2.86 (d, J = 10.0 Hz, 3H), 1.49 (s, 9H). 13C NMR (101 MHz, CDCl3) 147.94, 117.36, 109.21, 101.43, 80.03, 43.96, 39.36, 34.02, 28.42. LCMS ES m/z M += 229/230 (-Boc)。
Example 8 (comparative experiment: Synthesis of references Huang D, Huang M, Liu W, et al. Design, Synthesis and biological evaluation of 1H-pyrazole-5-carboxamide derivatives as potential Chemical and inductive agents [ J ]. Chemical Papers, 2017): synthesis of ethyl 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylate (Compound D2):
reaction formula 11
Anhydrous ethanol (35 mL) and the compound D1 (7.5 g, 95% purity, 0.030 mol) prepared by the above reaction were sequentially added to a three-necked flask equipped with mechanical stirring under nitrogen protection, and stirred uniformly in an ice salt bath (keeping the temperature between-2 ℃ and 0 ℃). Dropwise adding methylhydrazine (1.8 g, 0.038 mol), controlling the reaction temperature between-2 ℃ and 0 ℃, after dropwise adding, sharply stirring the solution for 2 hours, removing the solvent ethanol under reduced pressure, and extracting with 30 x 2 mL ethyl acetate for 2 times. The combined ethyl acetate organic layers were washed twice with 30 x 2 mL of water and with anhydrous Na2SO4Drying, filtering and concentrating ethyl acetate under reduced pressure to mainly generate a by-product D7 (reaction formula 11), and a target product, namely 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (D2) is not obtained (namely, the yield of the target product D2 is 0).
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