CN113336703B - Synthesis of 1,3,4, 5-tetrasubstituted 1H-pyrazole derivatives - Google Patents

Synthesis of 1,3,4, 5-tetrasubstituted 1H-pyrazole derivatives Download PDF

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CN113336703B
CN113336703B CN202110532229.XA CN202110532229A CN113336703B CN 113336703 B CN113336703 B CN 113336703B CN 202110532229 A CN202110532229 A CN 202110532229A CN 113336703 B CN113336703 B CN 113336703B
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张园园
雍灿
陈元元
杨维清
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Xihua University
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Abstract

The invention relates to an important intermediate of an antitumor drug Laratinib (PF-06463922)N-synthesis of Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole. Bromoacetone and diethyl oxalate are used as starting materials, and are condensed and closed7-step reactions such as cyclization, bromination, ammonolysis, methylation, dehydration, N-H protection and the like, and finally synthesizingN-Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole; compared with the prior art, the method has the advantages that the reaction selectivity is better, and the designed route is more environment-friendly and economical.

Description

Synthesis of 1,3,4, 5-tetrasubstituted 1H-pyrazole derivatives
Technical Field
The invention relates to 1,3,4, 5-tetrasubstituted 1H-pyrazinesSynthesis of azole derivatives, in particular by condensation, ring closure, bromination, ammonolysis, methylation, dehydration, N-H protection, etc. using bromoacetone as the initial starting materialN-Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole synthesis method.
Background
Latifinib (Lorlatinib, PF-06463922), english is named: (R) -26-amino-55-fluoro-11,4,7-trimethyl-6-oxo-11H-3-oxa-7-za-2 (3, 5) -pyridina-1 (4, 3) -pyrazola-5 (1, 2) -benzocyclicotaphane-15-carbonifle, CAS number: 14548 46-35-5, molecular formula: c (C) 21 H 19 FN 6 O 2 Molecular weight: 406.4.lorlatinib is a third generation ALK (anaplastic lymphoma kinase) inhibitor. The first generation of ALK inhibitor Crizotinib (Crizotinib) is an ATP-competitive multi-target protein kinase inhibitor, and its approval by the U.S. FDA was in 2016 for the treatment of patients with advanced (metastatic) non-small cell lung cancer (NSCLC) carrying a mutation in the ROS-1 gene. Unfortunately, most patients develop resistance to Crizotinib within 12 months after treatment and acquired resistance mutations occur. In recent years, a number of second generation ALK inhibitors have been developed that are therapeutically effective and have low toxicity: ceritinib, alectinib, brigatinib. However, refractory tumors soon develop resistance to these new inhibitors. In the face of resistance to Crizotinib and second generation ALK inhibitors, scientists began to develop third generation ALK inhibitors, i.e., drugs that are useful for NSCLC patients resistant to Crizotinib and second generation ALK inhibitors and that develop central nervous system metastases, yet still have therapeutic effects. The third generation of ALK inhibitors is lorelatinib developed by the company pyroxene. 27, 2017, FDA granted the designation of the new generation ALK/ROS1 tyrosine kinase inhibitor lorelatinib "breakthrough drug" for the second line treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC).
Figure 811906DEST_PATH_IMAGE001
Structural formula of Lalatinib
As regards LatifinibThe synthesis of (a) and its intermediates have been reported in many literature, but the most industrially applicable route among the synthetic routes (ref. JohnsonTW, richardsonPF, bailey S, et al Journal of Medicinal Chemistry, 2014, 57 (11): 4720-4744) is shown in reaction scheme 1, and compound 1 (4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole derivative) and compound 2 are coupled by Suzuki-Miyaura to give compound 3, followed by hydrolysis of the ester to give a carboxylic acid, followed by deprotection of the Boc to give an intermediate compound, and finally by formation of a molecular lactam bond, a macrocyclic compound, namely loretinib, is formed. Furthermore, the publication CN109232607 a, EP 3415518 A1,WO 2018137679 A1, etc. discloses a synthesis method of loratidine successively. But in almost all publications reporting the synthesis of loratidine,N-Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole derivatives are all necessary intermediates for loratidine, and thus, the theoretical and practical application values of synthesis thereof are studied.
Figure 132029DEST_PATH_IMAGE002
Reaction 1
With respect to the synthesis of 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole derivatives, few literature reports are currently focused mainly on two documents (Elleraas J, ewanicki J, johnson T W, et al, conformational Studies and Atrop-isomerism Kinetics of the ALK Clinical Candidate Lorlatinib (PF-06463922) and Desmethyl Cong-mers [ J ]. Angewandte Chemie, 2016, 128 (11): 3654-3659; huang D, huang M, liu W, et al Design, synthesis and biological evaluation of H-pyrazole-5-carboxamide derivatives as potential fungici-deal and insecticidal agents [ J ]. Chemical Papers, 2017, 71 (6): 2053-2061.).
Diethyl oxalate is taken as an initial raw material (as shown in a reaction formula 2), and is subjected to condensation reaction with acetone in an ethanol-sodium ethoxide reaction system to synthesize ethyl acetylacetonate (compound C1); the compound C1 and methyl hydrazine are subjected to ring closure reaction 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); carrying out ammonolysis reaction on the compound C3 in ammonia water solution to obtain 4-bromo-1, 3-dimethyl-1H-pyrazole-5-formamide (compound C4); heating the compound C4 under strong dehydrating agents such as phosphorus pentoxide, phosphorus oxychloride and the like to generate 4-bromo-5-cyano-1, 3-dimethyl-1H-pyrazole (compound C5), carrying out secondary bromination reaction on the compound C5 to obtain 4-bromo-3-bromomethyl-5-cyano-1-methyl-1H-pyrazole (compound C6), carrying out substitution reaction on the compound C6 and methylamine to obtain 4-bromo-3-methylaminomethyl-5-cyano-1-methyl-1H-pyrazole (compound C7), and carrying out N-H protection reaction on the compound C7 by using BOC anhydride to obtain the compound 1.
The reaction route is longer, and more importantly, in the process of obtaining the compound C6 by carrying out secondary bromination reaction on the compound C5, because two methyl groups exist in the compound C5, the problem of regioselectivity exists, so that the reaction selectivity is poor in the step, and the purification and separation after synthesis are difficult. Therefore, there is a need to develop a more compact and highly selective processN-synthetic route to Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (compound 1).
Figure 561873DEST_PATH_IMAGE003
Reaction 2
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel Laratinib intermediate with shorter synthetic route and high selectivityN-Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole.
Figure 131394DEST_PATH_IMAGE004
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Reaction 3
The present invention is achieved as follows (equation 3): using bromoacetone and diethyl oxalate as starting materialsThrough 7 steps of condensation, ring closure, bromination, ammonolysis, methylation, dehydration, N-H protection and the like, the final synthesis is realizedN-Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole. More detailed description follows:
first, condensation reaction step (reaction formula 4), synthesis of ethyl bromoacetylacetonate (compound D1):
under the protection of nitrogen, sequentially adding anhydrous lower fatty alcohol as a solvent and sodium alkoxide into a three-necked bottle, and uniformly stirring in an ice salt bath. Then slowly dripping a mixture of bromoacetone and diethyl oxalate into a sodium alkoxide-alcohol reaction system, keeping the reaction temperature between-10 ℃ and-5 ℃, keeping the temperature for reaction for a certain time after dripping, detecting the reaction progress degree by gas chromatography, pouring the reaction liquid into ice water after the reaction is finished, adjusting the pH value to be=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, with anhydrous Na 2 SO 4 Drying, filtering, concentrating ethyl acetate under reduced pressure to obtain bromoacetyl ethyl acetate crude product, rectifying and purifying under reduced pressure to obtain yellow viscous liquid with yield of 42-48%, and gas chromatography normalized content of 92-96% (without further purification, and can be directly used for the next reaction).
Figure 468835DEST_PATH_IMAGE005
Reaction 4
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 may be one of sodium ethoxide, sodium methoxide, sodium n-propoxide, and the like;
in the condensation reaction step, the mol 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 sodium alkoxide to bromoacetone is 3:1-0.9:1, and the optimal ratio is 2:1-1.5:1.
Second step, ring closure reaction step (equation 5), synthesis of 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D2):
Figure 112306DEST_PATH_IMAGE006
reaction 5
Under the protection of nitrogen, sequentially adding solvent lower aliphatic alcohol, bromoacetyl ethyl acetonate (compound D1) prepared by the reaction, dicyclohexylcarbodiimide (DCC) and a small amount of glacial acetic acid into a three-necked bottle with mechanical stirring, dropwise adding methyl hydrazine under the condition of heating reflux, continuing to vigorously stir and react for a certain time after dropwise adding, performing Gas Chromatography (GC) central control monitoring reaction, removing the solvent under reduced pressure after the reaction is finished, stirring and dispersing the obtained solid by using a mixed solvent of toluene and water, and regulating pH=5 by using 1 equivalent of hydrochloric acid. Separating, washing the organic phase with saturated sodium bicarbonate solution and distilled water sequentially, and washing with anhydrous Na 2 SO 4 Drying, filtering, concentrating the solvent toluene under reduced pressure to obtain a crude product of 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester, and obtaining a gray solid with the yield of 88-92%, wherein the normalized content of liquid chromatography is 90-97% (which can be directly used for the next reaction without further purification).
In the ring closure reaction step, the lower aliphatic alcohol can be one of ethanol, methanol, n-propanol, isopropanol, n-butanol, tertiary butanol and the like;
in the ring closure reaction step, the mol ratio of bromoacetyl ethyl pyruvate (compound D1) to methyl hydrazine materials is 1:3-1:0.9, and the optimal ratio is 1:1.5-1:1.05;
in the ring closure reaction step, the reaction is performed under an acidic condition provided by glacial acetic acid and in the presence of Dicyclohexylcarbodiimide (DCC), a dehydrating agent.
Third step, bromination reaction step (equation 6), synthesis of 4-bromo-3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D3):
Figure 447472DEST_PATH_IMAGE007
reaction 6
Dissolving 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D2) in a solvent, adding a brominating reagent in batches, and reacting at 20-25 ℃. TLC detection reaction, quenching reaction with water, separating, extracting water layer with solvent, mixing organic phases, and adding anhydrous Na 2 SO 4 Drying, filtering, 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 pale yellow solid, wherein the yield is 76-83%, and the normalized content of liquid chromatography is 93-98%.
In the bromination reaction step, a bromination reaction solvent can be one of chloroform, dichloromethane, cyclohexane, n-hexane and the like;
in the bromination reaction step, a brominating reagent can be one of NBS, dibromohydantoin, liquid bromine and the like;
in the bromination reaction step, the molar ratio of 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D2) to a brominating reagent material is 1:0.9-1:3, and the optimal ratio is 1:1-1:1.4.
Fourth step, ammonolysis reaction step (equation 7), synthesis of 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D4):
Figure 235781DEST_PATH_IMAGE008
reaction 7
And cooling a certain amount of ethanol solution containing ammonia by using an ice salt bath to 0-2 ℃, slowly dropwise adding the 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 ℃, and then heating to 25 ℃ and stirring for 10-20 hours. TLC monitoring, after the reaction, recovering excessive ammonia under reduced pressure, then distilling off most ethanol under reduced pressure, cooling, adding proper amount of water and chloroform into the residue, stirring for dissolving,separating, extracting the water layer with small amount of chloroform, mixing chloroform organic layers, and extracting with anhydrous Na 2 SO 4 Drying, filtering, 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, wherein the yield is 72-80%, and the normalized content of liquid chromatography is 94-97%.
Fifth, methylation step (equation 8), synthesis of 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D5):
Figure 314595DEST_PATH_IMAGE009
reaction 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 inorganic base, controlling the temperature to be 0-5 ℃, dropwise adding a methylation reagent, heating to 25 ℃ after the dropwise addition, reacting for 6 hours, pouring the reaction solution into proper water after the reaction is finished, extracting 3 times by using ethyl acetate, washing the combined ethyl acetate organic layer twice by using a certain amount of water, and using anhydrous Na 2 SO 4 Drying, filtering, concentrating ethyl acetate under reduced pressure, and vacuum drying to remove residual solvent to obtain crude 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D5), wherein the yield is 78-88% and the normalized content of liquid chromatography is 93-95% (without further purification, and 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), dimethylsulfoxide (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 material molar ratio of the 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D4) to the methylating agent 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):
Figure 812573DEST_PATH_IMAGE010
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reaction 9
Under the protection of nitrogen, acetonitrile and 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D5) are sequentially added into a three-necked flask equipped with an acid gas absorption device and mechanically stirred, the temperature is raised to 65-70 ℃, a dehydration reagent is slowly added, and the temperature is raised to 80 ℃ after the addition is completed, and the reaction is carried out for 6-12 hours. After TLC monitoring reaction is completed, cooling to room temperature, slowly dropwise adding the reaction mixture into a certain amount of ice-water mixture, keeping the internal temperature at not more than 35 ℃ in the dropwise adding process, adding a certain amount of water into the obtained mixture after dropwise adding, cooling the mixture to 5 ℃, stirring for 1 hour, standing, filtering to obtain a crude product of 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (compound D6), 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 POCl 3 、P 2 O 5 One of them;
in the dehydration reaction step, the material molar ratio of the 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D5) to the dehydration reagent is 1:0.9-1:30, and the optimal ratio is 1:2-1:10.
Seventh, the N-H protection reaction step (equation 10),N-synthesis of Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (compound 1):
Figure 646537DEST_PATH_IMAGE011
reaction type 10
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 to be 20-25 ℃, and the mixture is added dropwise (Boc) 2 O, after the dripping is finished, heating to 30-35 ℃ for reaction, and recovering dichloromethane and excessive (Boc) by reduced pressure distillation after the reaction is finished 2 O and newly produced tertiary butanol 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 a white solid with the yield of 92-96% and the normalized content of 97-99% by liquid chromatography.
Compared with the original literature synthesis method (reaction formula 2), the invention has the following remarkable technical characteristics:
1. the adopted starting material bromoacetone is used for replacing acetone, one bromine atom exists in bromoacetone, bromomethyl is directly generated after ring closure, and the primary bromination reaction (the primary synthetic route needs to carry out twice bromination reaction) is reduced by synthesizing a target compound 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (compound D6);
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-carboxamide (compound D4), ammonia is adopted as a reaction material, so that ammonolysis reaction and substitution reaction of bromoalkane occur simultaneously, and the two reactions can be performed under the same reaction conditions.
3. In the process of synthesizing 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D5) by methylation of 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D4), the selectivity is very high because the two amino groups differ greatly in nature (one belonging to the amidylamino group and one belonging to the paraffinic amino group).
Therefore, the invention has good economic benefit and social benefit.
Drawings
FIG. 1 shows a target compound synthesized according to 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 according to 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 ethyl bromoacetylacetonate (Compound D1) (reaction scheme 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 well in an ice-salt bath. Then, a mixture of bromoacetone (8.2 g,0.06 mol) and diethyl oxalate (8.8 g,0.060 mol) is slowly dripped into a sodium ethoxide-ethanol reaction system, the reaction temperature is kept between-10 ℃ and-5 ℃, and after the dripping is finished, the temperature is kept for reaction for 3 hours. The reaction solution 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 water, with anhydrous Na 2 SO 4 Drying, filtering, concentrating ethyl acetate under reduced pressure to obtain a bromoacetyl ethyl acetate crude product, rectifying and purifying under reduced pressure to obtain 6.5 g of yellow liquid, wherein the yield is 46%, and the gas chromatography normalized content is 95%.
Example 2: synthesis of 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (Compound D2) (reaction scheme 5):
under the protection of nitrogen, n-butanol (45 mL), the compound D1 (7.5 g, 95% purity, 0.030mol in a reduced form), 1 mL glacial acetic acid and dicyclohexylcarbodiimide (6.2 g, 0.030 mol) prepared by the above reaction, are sequentially added into a three-necked flask equipped with mechanical stirring, heating to reflux, dropwise adding methylhydrazine (1.8 g, 0.038 mol), rapidly stirring the solution after the dropwise adding is finished, reacting for 8 hours (monitoring the residual amount of the compound D1 as a reaction raw material by gas chromatography), removing the solvent n-butanol under reduced pressure after the raw material is completely reacted, stirring and dispersing the obtained solid by using a mixed solvent of toluene and water (volume ratio of 1:1) and using dilute hydrochloric acid(1 moL/L) ph=5. Separating, washing the organic phase with saturated sodium bicarbonate solution and distilled water sequentially, and washing with anhydrous Na 2 SO 4 Drying, filtering and concentrating the solvent toluene under reduced pressure to obtain a crude product of 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester, wherein the yield is 91% and the normalized content of liquid chromatography is 95% (the crude product is directly used for the next reaction without further purification) of 6.7 g of gray solid.
Example 3: synthesis of 4-bromo-3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D3) (reaction scheme 6):
3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D2) (5.2 g, 95% purity, 0.020mol in total) was dissolved in 40mL 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 water to quench the reaction, separating the solution, extracting the water layer with 30mL chloroform, combining the organic phases, and using anhydrous Na 2 SO 4 Drying, filtering, concentrating chloroform under reduced pressure to obtain 4-bromo-3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (compound D3) crude product, and separating and purifying by column chromatography (eluent: ethyl acetate: petroleum ether=1:2) to obtain compound D3 as pale yellow solid 5.3g, with yield of 82%, and liquid chromatography normalized content of 98%. 1 H NMR (400 MHz, CDCl 3 ) 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) (equation 7):
cooling 100 mL ammonia-containing 4% ethanol solution to 0-2 ℃ by using an ice salt bath, mechanically stirring, slowly dropwise adding a 30mL 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), stirring at 0-2 ℃ for 5 hours, and then heating to 25 ℃ and stirring for 12 hours. After the reaction was completed, excess ammonia was recovered under reduced pressure, most of the ethanol was distilled off under reduced pressure, and after cooling, 40mL of water and 40mL of chloroform were added to the residue, and the mixture was dissolved with stirring, separated, the aqueous layer was extracted once with 30mL of chloroform, and the combined chloroform organic layer was extracted with anhydrous Na 2 SO 4 Drying, filtering, concentrating chloroform under reduced pressure to obtain crude 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 about 1.82 g of white solid, wherein the yield is 78%, and the normalized content of liquid chromatography is 96%. 1 H 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) (equation 8):
under the protection of nitrogen, 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D4) (1.5 g, 96% purity, 6.4 mmol) is added into 30mL DMF, 2.8 g anhydrous powdered potassium carbonate is added, the temperature is controlled to be 0-5 ℃, methyl iodide (1.8 g, 12.8 mmol) is added dropwise, the temperature is raised to 25 ℃ after the dropwise addition, the reaction is carried out for 6 hours, after the reaction is finished, the reaction solution is poured into 120 mL water, 50 x 3 mL ethyl acetate is used for extraction for 3 times, the combined ethyl acetate organic layer is washed twice with 50 x 2 mL water, and anhydrous Na is used for washing twice 2 SO 4 Drying, filtering, concentrating ethyl acetate under reduced pressure, and vacuum drying to remove residual DMF to obtain crude 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D5), 1.3 g of gray solid, 86% yield, and 95% normalized content by liquid chromatography (which is used in the next reaction without further purification).
Example 6: synthesis of 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (Compound D6) (scheme 9):
under the protection of nitrogen, acetonitrile (60 mL), 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide (compound D5) (5.3 g, 95% purity, reduced to 20 mmol, pretreated into fine powder) and then heated to 65-70 ℃ are sequentially added into a three-necked flask equipped with an acid gas absorber and mechanically stirred, and freshly distilled POCl is slowly added dropwise 3 (15 g,0.10 mol) and after the completion of the dropwise addition, the temperature was raised to 80℃for 10 hours. After cooling to room temperature, the reaction mixture was slowly added dropwise to an ice-water mixture (150 g) while keeping the internal temperature at not more than 35℃during the addition, and after the addition, 5 was added to the resulting mixture0mL water, the mixture was cooled to 5 ℃ and stirred for 1 hour, and left to stand and filtered to give a crude 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (compound D6), a pale yellow solid, and purified by column chromatography (eluent: ethyl acetate: petroleum ether=1:2) to give 3.3 g of a white solid in a yield of 72%, with a normalized content of 99% by liquid chromatography. 1 H NMR (400 MHz, DMSO-d6) 4.01 (s, 3H), 3.60 (s, 2H), 2.26 (s, 3H),2.08 (br s, 1H)。
Example 7:N-Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (Compound 1, english name of which is tert-Butyl [ (4-bromoo-5-cyanoo-1-methyl-1H-pyrazol-3-yl) methyl)]methyl carbamate) synthesis (equation 10):
4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole (Compound D6) (4.6 g, 20 mmol, prepared according to the method of example 6) was added to 50mL of DCM under nitrogen, the temperature was controlled at 20deg.C, and the mixture was added dropwise (Boc) 2 O (5.3 g,24 mmol), after the completion of the dropwise addition, the temperature was raised to 30℃and the reaction was completed for 3 hours, and DCM and excess (Boc) were recovered by distillation under reduced pressure 2 O, newly produced tert-butanol, and then washing the resulting solid with a small amount of petroleum ether to give [ (4-bromo-5-cyano-1-methyl-1H-pyrazol-3-yl) methyl]The crude product of tert-butyl methylcarbamate (compound 1) is separated and purified by column chromatography (eluent: ethyl acetate/n-hexane=1/4), and the white solid is obtained in an amount of 6.3 g, the yield is 96%, and the normalized content of liquid chromatography is 98%. 1 H NMR (400 MHz, CDCl 3 ) 4.47 (d, J = 19.1 Hz, 2H), 4.04 (s, 3H), 2.86 (d, J = 10.0 Hz, 3H), 1.49 (s, 9H). 13 C NMR (101 MHz, CDCl 3 ) 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 experiments: synthetic methods of reference Huang D, huang M, liu W, et al Design, synthesis and biological evaluation of H-pyrazole-5-carboxamide derivatives as potential fungicidal and insecticidal agents [ J ]. Chemical Papers, 2017): synthesis of 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (Compound D2):
Figure 597175DEST_PATH_IMAGE012
reaction 11
Absolute ethanol (35 mL) and compound D1 (7.5, g, 95% purity, 0.030mol in a reduced form) prepared by the above reaction were added in sequence to a three-necked flask equipped with mechanical stirring under nitrogen protection, and stirred well in an ice salt bath (maintaining the temperature between-2 ℃ and 0 ℃). Methyl hydrazine (1.8 g, 0.038 mol) is added dropwise, the reaction temperature is controlled to be between-2 ℃ and 0 ℃, after the dropwise addition is finished, the solution is stirred rapidly for 2 hours, the solvent ethanol is removed under reduced pressure, and the solution is extracted for 2 times by 30 x 2 mL ethyl acetate. The combined ethyl acetate organic layers were washed twice with 30 x 2 mL water, with anhydrous Na 2 SO 4 Drying, filtering, concentrating ethyl acetate under reduced pressure to mainly produce a byproduct D7 (reaction formula 11), and obtaining a target product 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (D2) (namely, the yield of the target product D2 is 0).

Claims (7)

1. The method comprises the following steps ofNThe synthesis method of (E) -Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole is characterized by using bromoacetone and diethyl oxalate as starting materials, and adopting 7 steps of reactions of condensation, ring closure, bromination, ammonolysis, methylation, dehydration and N-H protection to finally synthesizeN-Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole, mainly of the formula:
Figure DEST_PATH_IMAGE002
the specific experimental operation steps are as follows:
first, condensation reaction, namely synthesizing bromoacetyl ethyl pyruvate:
under the protection of nitrogen, sequentially adding anhydrous lower fatty alcohol serving as a solvent and sodium alkoxide into a three-necked bottle, and uniformly stirring in an ice salt bath;
bromoacetone and grass are then addedSlowly dropwise adding the mixture of diethyl acetate into a sodium alkoxide-alcohol reaction system, keeping the reaction temperature between-10 ℃ and-5 ℃, keeping the temperature for reacting for a certain time after dropwise adding, performing gas chromatography central control detection on the reaction progress, determining that the reaction is finished, pouring the reaction solution into ice water, adjusting the pH to be=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, with anhydrous Na 2 SO 4 Drying, filtering, concentrating ethyl acetate under reduced pressure to obtain bromoacetyl ethyl acetate crude product, rectifying and purifying under reduced pressure to obtain 42-48% yield, and gas chromatography normalized content is 92-96%;
second, the ring closure reaction step, namely, the synthesis of 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester: under the protection of nitrogen, sequentially adding solvent lower aliphatic alcohol, bromoacetyl ethyl pyruvate, dicyclohexylcarbodiimide and a small amount of glacial acetic acid prepared by the reaction into a three-necked bottle with mechanical stirring, dropwise adding methyl hydrazine under the condition of heating reflux, continuing to vigorously stir and react for a certain time after dropwise adding, monitoring and reacting in a gas chromatograph, removing the solvent under reduced pressure after the reaction is finished, stirring and dispersing the obtained solid by using a mixed solvent of toluene and water, and regulating pH=5 by using 1 equivalent of hydrochloric acid; separating, washing the organic phase with saturated sodium bicarbonate solution and distilled water sequentially, and washing with anhydrous Na 2 SO 4 Drying, filtering, concentrating solvent toluene under reduced pressure to obtain 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester crude product, gray solid with yield of 88-92%, liquid chromatography normalized content of 90-97%, and directly using for the next reaction without further purification;
thirdly, a bromination reaction step, namely, synthesizing 4-bromo-3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester: dissolving 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester in a solvent, adding a brominating reagent in batches, and reacting at 20-25 ℃; TLC detection reaction, quenching reaction with water, separating, extracting water layer with solvent, mixing organic phases, and adding anhydrous Na 2 SO 4 Drying, filtering, concentrating the solvent under reduced pressure to obtain crude product of 4-bromo-3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester, and separating and purifying by column chromatographyObtaining pale yellow solid with the yield of 76-83% and the normalized content of liquid chromatography of 93-98%;
fourthly, synthesizing 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-carboxamide in an ammonolysis reaction step: cooling a certain amount of ethanol solution containing ammonia by using an ice salt bath to 0-2 ℃, slowly dropwise adding the ethanol solution containing 4-bromo-3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester under mechanical stirring, stirring for 5 hours at 0-2 ℃, and then heating to 25 ℃ and stirring for 10-20 hours; TLC monitoring, reaction completion, recovery of excess ammonia under reduced pressure, then distilling off most of ethanol under reduced pressure, cooling, adding appropriate amount of water and chloroform to the residue, stirring for dissolution, separating the liquid, extracting the water layer once with small amount of chloroform, combining chloroform organic layers, and using anhydrous Na 2 SO 4 Drying, filtering, concentrating chloroform under reduced pressure to obtain a crude product of 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-carboxamide, and separating and purifying by column chromatography to obtain an almost white solid with a yield of 72-80% and a liquid chromatography normalized content of 94-97%;
fifth, methylation reaction step, synthesis of 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide: under the protection of nitrogen, adding 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-carboxamide into aprotic polar solvent, adding inorganic base, controlling the temperature to be 0-5 ℃, dropwise adding methylating agent, heating to 25 ℃ after dropwise adding, reacting for 6 hours, pouring reaction solution into proper water after the reaction is finished, extracting with ethyl acetate for 3 times, washing the combined ethyl acetate organic layer twice with a certain amount of water, and using anhydrous Na 2 SO 4 Drying, filtering, concentrating ethyl acetate under reduced pressure, and vacuum drying to remove residual solvent to obtain a crude product of 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide, wherein the yield is 78-88%, the normalized content of liquid chromatography is 93-95%, and the crude product is directly used for the next reaction without further purification;
sixth, dehydration reaction step, synthesis of 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole: under the protection of nitrogen, acetonitrile and 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-formamide are sequentially added into a three-necked flask equipped with an acid gas absorption device and mechanically stirred, the temperature is raised to 65-70 ℃, a dehydration reagent is slowly added, and the temperature is raised to 80 ℃ after the addition is completed for reaction for 6-12 hours; after TLC monitoring reaction is completed, cooling to room temperature, slowly dropwise adding the reaction mixture into a certain amount of ice-water mixture, keeping the internal temperature at not more than 35 ℃ in the dropwise adding process, adding a certain amount of water into the obtained mixture after dropwise adding, cooling the mixture to 5 ℃, stirring for 1 hour, standing, filtering to obtain a crude product of 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole, separating and purifying by column chromatography to obtain a white solid, wherein the yield is 68-75%, and the normalized content of liquid chromatography is 96-99%;
seventh, N-H protection reaction step,N-synthesis of Boc-4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole: under the protection of nitrogen, 4-bromo-1-methyl-3-methylaminomethyl-5-cyano-1H-pyrazole is added into a certain volume of dichloromethane, the temperature is controlled to be 20-25 ℃, and the mixture is added dropwise (Boc) 2 O, after the dripping, heating to 30-35 ℃ for reaction, and after the reaction is finished, distilling under reduced pressure to recover dichloromethane and excessive (Boc) 2 O and newly produced tertiary butanol to obtain a crude product of the compound 1, and further separating and purifying by column chromatography to obtain white solid with the yield of 92-96% and the normalized content of 97-99% by liquid chromatography.
2. The synthesis method of claim 1, wherein: synthesis of 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester: the synthesis of 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester is carried out by taking bromoacetyl ethyl pyruvate and methyl hydrazine as main raw materials in the presence of dicyclohexylcarbodiimide and a small amount of glacial acetic acid.
3. The synthesis method according to claim 1, wherein in the condensation reaction step, the anhydrous lower aliphatic alcohol is one of ethanol, methanol, n-propanol, isopropanol, and n-butanol; the sodium alkoxide is one of sodium ethoxide, sodium methoxide and sodium n-propoxide; the mol ratio of bromoacetone to diethyl oxalate is 1:1.05-1.05:1; the molar ratio of the sodium alkoxide to the bromoacetone is 2:1-1.5:1.
4. The synthesis method according to claim 1, wherein in the ring closure reaction step, the lower aliphatic alcohol is one of ethanol, methanol, n-propanol, isopropanol, n-butanol and tert-butanol; the mol ratio of bromoacetyl ethyl pyruvate to methyl hydrazine is 1:1.5-1:1.05; the reaction is under the acidic condition provided by glacial acetic acid; the reaction is carried out in the presence of a dehydrating agent dicyclohexylcarbodiimide.
5. The synthesis method according to claim 1, wherein in the bromination reaction step, the bromination reaction solvent is one of chloroform, methylene dichloride, cyclohexane and n-hexane; the brominating reagent is one of NBS, dibromohydantoin and liquid bromine; the molar ratio of the 3-bromomethyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester to the brominating reagent material is 1:1-1:1.4.
6. The synthesis method according to claim 1, wherein in the methylation step, the aprotic polar solvent is one of N, N-dimethylformamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidone, N-dimethylacetamide aprotic polar solvent; the inorganic base is one of potassium carbonate, sodium hydroxide and potassium hydroxide; the methylation reagent is one of methyl iodide, dimethyl sulfate and dimethyl carbonate; the molar ratio of the 4-bromo-3-aminomethyl-1-methyl-1H-pyrazole-5-carboxamide to the methylating agent is 1:1.1-1:1.5.
7. The synthesis method according to claim 1, wherein in the dehydration step, the dehydration reagent is POCl 3 、P 2 O 5 One of them; in the dehydration reaction step, the material molar ratio of 4-bromo-3-methylaminomethyl-1-methyl-1H-pyrazole-5-carboxamide to the dehydration reagent is 1:2-1:10.
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