CN115819347A - Preparation method of 1-alkyl-3-bromopyrazole - Google Patents
Preparation method of 1-alkyl-3-bromopyrazole Download PDFInfo
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Abstract
The invention provides a preparation method of 1-alkyl-3-bromopyrazole, and relates to the technical field of pharmaceutical chemistry preparation. The preparation method comprises the following steps: 3, 5-dibromo-pyrazole is reacted to prepare the raw material 1-alkyl-3, 5-dibromo-pyrazole. Removing bromine at the 5-position of the 1-alkyl-3, 5-dibromopyrazole in an alcohol solvent under the action of a catalyst to obtain the 1-alkyl-3-bromopyrazole. The method has the advantages of simple reaction system, low cost, convenient preparation of raw materials, no dangerous operation steps and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry preparation, and particularly relates to a preparation method of 1-alkyl-3-bromopyrazole.
Background
1-alkylpyrazoles appear as building blocks in many active molecules, such as the ALK5 inhibitor 1, 5-naphthyridine class developed by Schwann biopharmaceutical company (WO 2021102468), the hepatitis C virus inhibitor class developed by Nanjing Sheng and the pharmaceuticals (WO 2016015638), and the protein kinase inhibitor class developed by Moshadong (WO 2016161572).
The fragment is mainly introduced by the coupling reaction of 1-alkyl-3-bromopyrazole and the docking of a core fragment. The synthesis methods of 1-alkyl-3-bromopyrazoles reported in the literature are all relatively complicated. Such as those prepared by alkylation of 3-bromopyrazoles, are generally obtained as mixtures which are alkylated in the 1,5 position and are difficult to separate.
The specific structure of the 1-alkyl-3-bromopyrazole is as follows:
in the prior literature, the compound has two main preparation routes:
the method comprises the following steps: and reacting alkyl hydrazine with acrylate to obtain pyrazolone containing isomers, purifying the intermediate, carrying out bromination reaction on the intermediate and tribromooxyphosphorus, and oxidizing the purified bromopyrazoline to obtain the 1-alkyl-3-bromopyrazole. (Journal of Organic Chemistry,2018,83, 2830-2839) the method has more problems, one is that the preparation route mainly comprises three steps of reaction, the route is long, the reagent is complex and expensive, and the condition is harsh. Secondly, the mixture containing isomers is obtained by the reaction, and complex purification operations are required for many times, so that the whole process generates more waste acid and waste gas.
The specific preparation route is as follows:
the second method comprises the following steps: 1-methyl-3-aminopyrazole as a starting material was subjected to diazotization to prepare bromide (Synthesis, 47 (5), 679-691,2015, WO 2013125543, journal of Organic chemistry,56 (22), 6313-20, 1991. The method has a plurality of problems, one is that diazotization-halogenation reaction is carried out by using an amino compound, the preparation of raw materials is complex, and the price is very high. Secondly, the production operation of the diazotization reaction has certain potential safety hazard and cannot carry out large-scale production.
The specific route is as follows:
therefore, it is necessary to develop a method for preparing 1-alkyl-3-bromopyrazole, which has the advantages of simple reaction system, low cost, no dangerous operation steps and suitability for industrial production.
Disclosure of Invention
The invention provides a preparation method of 1-alkyl-3-bromopyrazole, which aims at solving the problems of complex route and high raw material price in the preparation process and provides a preparation method of 1-alkyl-3-bromopyrazole, which has the advantages of simple reaction system, low cost, convenient preparation of raw materials, no dangerous operation steps and suitability for industrial production.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides a preparation method of 1-alkyl-3-bromopyrazole, which is characterized by comprising the following steps:
mixing 1-alkyl-3, 5-dibromopyrazole, an alcohol solvent and a catalyst, and reacting to obtain 1-alkyl-3-bromopyrazole;
wherein R is selected from substituted or unsubstituted C 1-8 An alkyl group.
Preferably, the substituted substituent is selected from at least one of aryl, cycloalkyl, alkoxy, cyano, amido and halogen.
Further preferably, R is selected from substituted or unsubstituted C 1-5 Alkyl, said substituted substituent being selected from C 1-5 Alkyl, phenyl, C 3-6 At least one of cycloalkyl and halogen.
Further preferably, R is selected from substituted or unsubstituted C 1-3 Alkyl, said substituted substituent being selected from C 1-5 At least one of alkyl and phenyl.
Most preferably, R is selected from substituted or unsubstituted C 1-2 Alkyl, said substituted substituent being phenyl.
Preferably, the alcoholic solvent is selected from at least one of methanol, ethanol, ethylene glycol, n-propanol, isopropanol, propylene glycol, butanol, isobutanol.
Further preferably, the alcohol solvent is at least one selected from methanol, ethanol, ethylene glycol, n-propanol, isopropanol and propylene glycol.
Still more preferably, the alcohol solvent is at least one selected from methanol, ethanol, and isopropanol.
Most preferably, the alcoholic solvent is isopropanol.
Preferably, the catalyst is selected from one or more of cuprous iodide, cuprous chloride, cuprous bromide and diamine;
further preferred is a combination of cuprous iodide and diamine.
Preferably, the molar ratio of the cuprous iodide to the diamine is 1 (1-5).
Further preferably, the molar ratio of cuprous iodide to diamine is 1.
Preferably, the molar ratio of the 1-alkyl-3, 5-dibromopyrazole to the catalyst is 1: (0.1-0.3);
further preferably, the molar ratio of the 1-alkyl-3, 5-dibromopyrazole to the catalyst is 1: (0.15-0.25);
most preferably, the molar ratio of the 1-alkyl-3, 5-dibromopyrazole to the catalyst is 1:0.18.
preferably, the molar ratio of the 1-alkyl-3, 5-dibromopyrazole to the catalyst cuprous iodide is 1: (0.02-0.2);
more preferably, the molar ratio of the 1-alkyl-3, 5-dibromopyrazole to the catalyst cuprous iodide is 1: (0.05-0.1);
most preferably, the molar ratio of the 1-alkyl-3, 5-dibromopyrazole to the catalytic cuprous iodide is 1:0.06.
preferably, the mass-volume ratio of the 1-alkyl-3, 5-dibromopyrazole to the alcohol solvent is 1: (10-20);
more preferably, the mass-volume ratio of the 1-alkyl-3, 5-dibromopyrazole to the alcohol solvent is 1: (10-15);
most preferably, the mass-volume ratio of the 1-alkyl-3, 5-dibromopyrazole to the alcohol solvent is 1: (11-11.5).
Preferably, the 1-alkyl-3, 5-dibromopyrazole is prepared by the following method: adding potassium carbonate and halide into the 3, 5-dibromopyrazole in a DMF solution to prepare a crude product of the 1-alkyl-3, 5-dibromopyrazole, extracting by a solvent, drying, concentrating under reduced pressure, and drying in vacuum to obtain the 1-alkyl-3, 5-dibromopyrazole.
Further preferably, the reaction temperature for preparing the 1-alkyl-3, 5-dibromopyrazole is 20-60 ℃ and the reaction time is 10-20h.
Still more preferably, the reaction temperature for preparing the 1-alkyl-3, 5-dibromopyrazole is 30-50 ℃ and the reaction time is 14-16h.
Most preferably, the reaction temperature for preparing the 1-alkyl-3, 5-dibromopyrazole is 30 ℃ and the reaction time is 15h.
Further preferably, the extraction solvent is at least one of methyl acetate, ethyl acetate, isopropyl acetate, methyl tert-butyl ether and dichloromethane; most preferred is ethyl acetate.
Further preferably, the drying agent is one or more of anhydrous sodium sulfate and anhydrous magnesium sulfate; most preferred is anhydrous sodium sulfate.
Further preferably, the reduced pressure temperature is 30-50 ℃, most preferably 40 ℃.
Interpretation of terms:
unless otherwise indicated, the term "alkyl" as used herein includes both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, including all isomers. Common abbreviations for alkyl groups, such as methyl, may be used as "Me" or CH 3 The ethyl group can be represented by "Et" or CH 2 CH 3 The propyl group can be represented by "Pr" or CH 2 CH 2 CH 3 The butyl group may be represented by "Bu" or CH 2 CH 2 CH 2 CH 3 Indicate, etc. E.g. "C 1-10 Alkyl "(or" C) 1 -C 10 Alkyl ") refers to a straight or branched chain alkyl group having the specified number of carbon atoms, including all isomers. C 1-10 Alkyl groups include n-, iso-, sec-and tert-butyl, n-and iso-propyl, ethyl and methyl. The term "C 1-5 Alkyl group "," C 1-3 Alkyl "and the like have similar meanings.
The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro (F), chloro (Cl), bromo (Br) and iodo (I)).
The term "aryl" refers to aromatic mono-and polycarbocyclic systems in which the individual carbocyclic rings are fused or connected to each other by single bonds in a polycyclic ring system. Typical aryl groups include phenyl, naphthyl, and biphenylene.
The aryl group in the term "substituted aryl" is as previously defined and, when a substituent for a substituted aryl group is not specified, the substituent may be selected from the following groups, including but not limited to: halogen, C 1 -C 20 Alkyl, CF 3 、NH 2 、N(C 1 -C 6 Alkyl radical) 2 、NO 2 Oxo, CN, N 3 、-OH、-O(C 1 -C 6 Alkyl), C 3 -C 10 Cycloalkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, (C) 0 -C 6 Alkyl) S (O) 0-2 -, aryl-S (O) 0-2 -、(C 0 -C 6 Alkyl) S (O) 0-2 (C 0 -C 6 Alkyl) -, (C) 0 -C 6 Alkyl) C (O) NH-, H 2 N-C(NH)-、-O(C 1 -C 6 Alkyl) CF 3 、(C 0 -C 6 Alkyl) C (O) -, (C) 0 -C 6 Alkyl) OC (O) -, (C) 0 -C 6 Alkyl radical) 2 NC(O)-(C 0 -C 6 Alkyl) O (C) 1 -C 6 Alkyl) -, (C) 0 -C 6 Alkyl) C (O) 1-2 (C 0 -C 6 Alkyl) -, (C) 0 -C 6 Alkyl) OC (O) NH-, aryl, aralkyl, heteroaryl, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle, and cyano-heterocyclylalkyl. The term "substituted phenyl" has similar definitions.
The term "alkoxy" denotes straight and branched chain alkyl groups of the indicated number of carbon atoms connected by an oxygen bridge.
The term "cyano" denotes a group in which a carbon atom and a nitrogen atom are linked by a triple bond.
The term "amido" refers to a group resulting from the nucleophilic substitution reaction of a fatty acid acyl group with ammonia or an amine group.
All ranges set forth herein are inclusive, unless explicitly stated otherwise. For example, "1-10" refers to all real numbers between 1-10, including 1, 10, including but not limited to 1,2, 2.1, 2.2, 2.25, 8, 9, 10, etc.
Compared with the prior art, the invention has at least the following advantages:
the 1-alkyl-3-bromopyrazole provided by the invention has an isomer ratio of more than 300, a simple reaction system, low cost and no dangerous operation steps. Meanwhile, reaction raw materials are convenient and easy to obtain, and the obtained product has high 1-alkyl-3-bromopyrazole content and meets the requirement of large-scale industrial production.
Detailed Description
The following describes embodiments of the present invention in further detail with reference to examples.
Example 1A method for preparing 1-methyl-3-bromopyrazole
(1) Preparation of 1-methyl-3, 5-dibromopyrazole:
67.8g of 3, 5-dibromopyrazole (0.3 mol) was added to 680mL of DMF, 0.5mol of potassium carbonate (69g) and 0.36mol of methyl iodide (51.1 g) were added thereto, and the reaction was carried out at 50 ℃ for 15 hours to complete the conversion. The mixture is cooled to room temperature, poured into 2L of water, extracted for 2 times by 500mL of ethyl acetate, and the organic phase is washed by 300mL of saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 40 ℃ and dried in vacuum to obtain 1-methyl-3, 5-dibromopyrazole, 63.4g,99 percent purity and 88 percent yield. 1 H NMR(300MHz,CDCl 3 )δ6.29(s,1H),3.84(s,3H)，LC-MS(m/z):239[M+H] + 。
(2) Preparation of 1-methyl-3-bromopyrazole:
adding 2.4g of 10mmol of 1-methyl-3, 5-dibromopyrazole into 36mL of ethanol, adding 0.6mmol of CuI 0.11g and 0.11g of 1.2mmol of N, N' -dimethylethylenediamine, carrying out reflux reaction for 18 hours, and controlling by HPLC to show that the raw material is remained for 2.1 percent, the retention time is 4.39min, the purity of the product 1-methyl-3-bromopyrazole is 95.5 percent, the retention time is 3.04min, the purity of the isomer 1-methyl-5-bromopyrazole is 0.2 percent, and the retention time is 3.36min.
Example 2A method for preparing 1-methyl-3-bromopyrazole
The difference from example 1 lies in step (2), 10mmol of 1-methyl-3, 5-dibromopyrazole 2.4g is added into 36mL of isopropanol, 0.6mmol of CuI 0.11g and 1.2mmol of N, N' -dimethylethylenediamine 0.11g are added, reflux reaction is carried out for 15 hours, and HPLC control shows that 1.1% of raw material remains, retention time is 4.39min, product 1-methyl-3-bromopyrazole purity is 96.6%, retention time is 3.04min, isomer 1-methyl-5-bromopyrazole purity is 0.2%, and retention time is 3.36min.
Example 3A method for preparing 1-methyl-3-bromopyrazole
The difference from example 1 lies in step (2), 2.4g of 10mmol of 1-methyl-3, 5-dibromopyrazole was added to 36mL of methanol, 0.6mmol of CuI 0.11g and 1.2mmol of N, N' -dimethylethylenediamine 0.11g were added, and the reaction was refluxed for 24 hours, and HPLC control showed that 22.1% of the starting material remained, retention time was 4.39min, purity of product 1-methyl-3-bromopyrazole was 74.8%, retention time was 3.04min, purity of isomer 1-methyl-5-bromopyrazole was 0.1%, and retention time was 3.36min.
Example 4A preparation method of 1-methyl-3-bromopyrazole
The difference from example 1 is in step (2), 100mmol of 1-methyl-3, 5-dibromopyrazole (24 g) was added to 36mL of isopropanol, 6mmol of CuI (1.1 g) and 1.1g of N, N' -dimethylethylenediamine (12mmol) were added, reflux reaction was carried out for 16 hours, and HPLC control showed that 0.9% of starting material remained, retention time was 4.39min, purity of product 1-methyl-3-bromopyrazole was 96.8%, retention time was 3.04min, purity of isomer 1-methyl-5-bromopyrazole was 0.2%, and retention time was 3.36min. Cooling to room temperature, concentrating under reduced pressure at 40 deg.C to remove solvent, adding 500mL dichloromethane, washing with 5% diluted ammonia water for one time (200 mL), washing with water for one time (200 mL), drying organic phase with anhydrous sodium sulfate, concentrating under reduced pressure at 40 deg.C to remove solvent, and performing silica gel column chromatography to obtain 15g product, 93% yield, and 99.2% purity. 1 H NMR(400MHz,CDCl 3 )δ7.24(d,J＝2.2Hz，1H)，6.22(d,J＝2.2Hz，1H),3.86(s，3H),LC-MS(m/z):161[M+H] + 。
Example 5A preparation method of 1-ethyl-3-bromopyrazole
(1) Preparation of 1-ethyl-3, 5-dibromopyrazole:
67.8g of 3, 5-dibromopyrazole (0.3 mol) was added to 680mL of DMF, 0.5mol of potassium carbonate (69g) and 0.36mol of iodoethane (56.2 g) were added thereto, and the reaction was carried out at 50 ℃ for 15 hours to complete the conversion. Cooled to room temperature, poured into 2L of water, extracted 2 times with 500mL of ethyl acetate, the organic phase washed with 300mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 40 ℃, and dried in vacuum to obtain 1-ethyl-3, 5-dibromopyrazole, 65.3g,99% purity, yield 86%. 1 H NMR(300MHz,CDCl 3 )δ6.31(s,1H),4.08(q，J＝7.2Hz，2H)，1.48(t，J＝7.2Hz，3H)，LC-MS(m/z):253[M+H] + 。
(2) Preparation of 1-ethyl-3-bromopyrazole:
10mmol of 1-ethyl-3, 5-dibromopyrazole (2.54 g) is added into 36mL of isopropanol, 0.6mmol of CuI,0.11g and 1.2mmol of N, N' -dimethylethylenediamine (0.11 g) are added, reflux reaction is carried out for 24 hours, and HPLC control shows that 1.3% of raw materials remain, retention time is 4.45min, purity of the product 1-ethyl-3-bromopyrazole is 96.0%, retention time is 3.14min, purity of the isomer 1-ethyl-5-bromopyrazole is 0.2%, and retention time is 3.49min. Cooling to room temperature, concentrating under reduced pressure at 40 deg.C to remove solvent, adding 100mL dichloromethane, washing with 5% diluted ammonia water for 50mL once, washing with water for 50mL once, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure at 40 deg.C to remove solvent, and performing silica gel column chromatography to obtain 1.58g,91% yield and 99.1% purity product. 1 H NMR(300MHz,CDCl 3 )δ7.25(d,J＝2.1Hz，1H)，6.30(d,J＝2.1Hz，1H),4.02(q，J＝7.2Hz，2H)，1.45(t，J＝7.2Hz，3H)，LC-MS(m/z):175[M+H] + 。
Example 6 preparation of 1-benzyl-3-bromopyrazole
(1) Preparation of 1-benzyl-3, 5-dibromopyrazole:
67.8g of 3, 5-dibromopyrazole (0.3 mol) was added to 680mL of DMF, and 0.5mol of potassium carbonate (69g) and 61.6g of benzyl bromide (0.36mol) were added thereto, followed by reaction at 30 ℃ for 15 hours to complete the conversion. Cooling to room temperature, pouring into 2L of water, extracting 2 times with 500mL of ethyl acetate, washing the organic phase with 300mL of saturated sodium chloride solution, drying with anhydrous sodium sulfateDrying, filtering, decompressing and concentrating at 40 ℃, and drying in vacuum to obtain the 1-benzyl-3, 5-dibromopyrazole, 87.2g,99 percent purity and 92 percent yield. 1 H NMR(300MHz,CDCl 3 )δ7.41-7.52(m，5H)，6.38(s,1H),5.51(s，2H)，LC-MS(m/z):315[M+H] + 。
(2) Preparation of 1-benzyl-3-bromopyrazole
10mmol of 1-benzyl-3, 5-dibromopyrazole 3.16g is added into 36mL of isopropanol, 0.6mmol of CuI,0.11g of N, N' -dimethylethylenediamine 0.11g of 1.2mmol are added, reflux reaction is carried out for 24 hours, and HPLC control shows that 0.8% of raw material remains, retention time is 4.55min, product 1-benzyl-3-bromopyrazole is 97.2%, retention time is 3.26min, isomer 1-benzyl-5-bromopyrazole is 0.1%, and retention time is 3.65min. Cooling to room temperature, concentrating under reduced pressure at 40 deg.C to remove solvent, adding 100mL dichloromethane, washing with 5% diluted ammonia water for 50mL once, washing with water for 50mL once, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure at 40 deg.C to remove solvent, and performing silica gel column chromatography to obtain 2.91g, with 92% yield and 99.1% purity. 1 H NMR(300MHz,CDCl 3 )δ7.43-7.52(m，5H)，7.24(d,J＝2.1Hz，1H)，6.33(d,J＝2.1Hz，1H),5.48(s，2H)，LC-MS(m/z):237[M+H] + 。
Comparative example 1
Comparative example 1 is different from example 4 (best mode) in that cuprous iodide was used in an amount of 6%, diamine was used in an amount of 6%, the ratio was 1.
Comparative example 2
Comparative example 2 is different from example 4 (best mode) in that cuprous iodide alone is used as a catalyst in an amount of 6% and the rest is the same, and the reaction is refluxed for 16 hours without converting the raw material.
Comparative example 3
Comparative example 3 differs from example 4 (best mode) in that 6% cuprous bromide, 12% diamine and the rest being the same, are used, the reflux reaction is carried out for 16 hours, and HPLC control shows that 32.0% of the starting material remains, the retention time is 4.39min, the purity of the product 1-methyl-3-bromopyrazole is 63.8%, the retention time is 3.04min, the purity of the isomer 1-methyl-5-bromopyrazole is 4.2%, and the retention time is 3.36min.
Comparative example 4
Comparative example 4 is different from example 4 (best mode) in that toluene was used as a solvent and the rest were the same, and the reaction was refluxed for 16 hours without converting the raw material.
Comparative example 5
Comparative example 5 differs from example 4 (best mode) in that the 50 degree reaction was 16 hours, the rest was the same, and HPLC control showed 55.2% starting material remaining, 4.39min retention time, 44.6% purity of product 1-methyl-3-bromopyrazole, 3.04min retention time, 0.2% purity of isomer 1-methyl-5-bromopyrazole, and 3.36min retention time.
Comparative example 6
Comparative example 6 differs from example 4 (best mode) in that the reflux reaction was 12 hours, the rest was the same, and HPLC control showed 10.3% of starting material remaining, retention time was 4.39min, purity of product 1-methyl-3-bromopyrazole was 89.5%, retention time was 3.04min, purity of isomer 1-methyl-5-bromopyrazole was 0.2%, retention time was 3.36min.
Comparative example 7
Comparative example 6 differs from example 4 (best mode) in that 2% cuprous bromide, 4% diamine and the rest being the same, are used, the reflux reaction is 16 hours, and HPLC control shows that 56.6% of the starting material remains, the retention time is 4.39min, the purity of the product 1-methyl-3-bromopyrazole is 43.3%, the retention time is 3.04min, the purity of the isomer 1-methyl-5-bromopyrazole is 0.1%, and the retention time is 3.36min.
Claims (10)
1. A method for preparing 1-alkyl-3-bromopyrazole, which is characterized by comprising the following steps:
mixing 1-alkyl-3, 5-dibromopyrazole, an alcohol solvent and a catalyst, and reacting to obtain 1-alkyl-3-bromopyrazole;
wherein R is selected from substituted or unsubstituted C 1-8 An alkyl group.
2. The method of claim 1, wherein R is selected from substituted or unsubstituted C 1-5 Alkyl, said substituted substituent being selected from C 1-5 Alkyl, phenyl, C 3-6 At least one of cycloalkyl and halogen.
3. The method of claim 2, wherein R is selected from substituted or unsubstituted C 1-2 Alkyl, said substituted substituent being phenyl.
4. The method according to claim 1, wherein the alcoholic solvent is at least one selected from methanol, ethanol, ethylene glycol, n-propanol, isopropanol, propylene glycol, butanol, and isobutanol.
5. The method according to claim 4, wherein the alcoholic solvent is isopropyl alcohol.
6. The production method according to claim 1, wherein the molar ratio of the 1-alkyl-3, 5-dibromopyrazole to the catalyst is 1: (0.1-0.3).
7. The method of claim 6, wherein the molar ratio of 1-alkyl-3, 5-dibromopyrazole to catalyst is 1:0.18.
8. the method according to claim 1, wherein the catalyst is at least one selected from the group consisting of cuprous iodide, cuprous chloride, cuprous oxide, cupric sulfate, cupric acetate, cupric trichloroacetate, and diamine.
9. The method of claim 8, wherein the catalyst is a combination of cuprous iodide and a diamine.
10. The method according to claim 9, wherein the molar ratio of cuprous iodide to diamine is 1 (1-5).
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