Preparation method of 4-bromo-2-(1-methylcyclopropyl) pyridine

Abstract

The invention relates to the technical field of chemical synthesis, in particular to a preparation method of 4-bromo-2-(1-methylcyclopropyl) pyridine, which comprises the following steps: taking 2, 4-dibromopyridine as an initial raw material, and sequentially carrying out deprotonation, nucleophilic addition, Wittig reaction and cyclopropanation reaction to obtain the 4-bromo-2-(1-methylcyclopropyl) pyridine. The specific reaction route is as follows: # imgabs0. The preparation method comprises the following steps: taking 2, 4-dibromopyridine as an initial raw material, and synthesizing 4-bromo-2-(1-methyl cyclopropyl) pyridine through reaction with N-methoxy-N-methylacetamide, Wittig reaction and cyclopropanation; the preparation method disclosed by the invention has the advantages of relatively cheap raw materials, high yield and simplicity in operation, and can further promote the industrial application of the 4-bromo-2-(1-methylcyclopropyl) pyridine.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for preparing 4-bromo-2-(1-methylcyclopropyl)pyridine. Background Art

[0002] 4-Bromo-2-(1-methylcyclopropyl)pyridine is an important organic synthesis intermediate and can be used to synthesize organic drug molecules for diseases that are improved by inhibiting phosphatidylinositol 3-kinase, which is of great significance.

[0003] According to the document CN 102471332 A, the synthesis of 4-bromo-2-(1-methylcyclopropyl)pyridine mainly uses trans-4-methoxy-3-butene-2-one and 1-methyl-cyclopropanecarbonyl chloride as raw materials, and undergoes condensation, cyclization, amination, and bromination to obtain 4-bromo-2-(1-methylcyclopropyl)pyridine. The yield is low and the raw materials such as trans-4-methoxy-3-butene-2-one and 1-methyl-cyclopropanecarbonyl chloride are expensive, which is not conducive to large-scale production.

[0004]

[0005] Based on the above research status, how to provide a preparation method of 4-bromo-2-(1-methylcyclopropyl)pyridine with high yield and cheap raw materials to solve the problem of expensive raw materials in the above process has become a technical problem that the present invention urgently needs to solve. Summary of the invention

[0006] The invention aims to overcome the deficiencies in the prior art and provides a method for preparing 4-bromo-2-(1-methylcyclopropyl)pyridine. The method comprises the following steps: using 2,4-dibromopyridine as a starting material, reacting with N-methoxy-N-methylacetamide, performing a Wittig reaction and performing a cyclopropanation to synthesize 4-bromo-2-(1-methylcyclopropyl)pyridine. The method has the advantages of relatively cheap raw materials, high yield and simple operation, and can further promote the industrial application of 4-bromo-2-(1-methylcyclopropyl)pyridine.

[0007] The present invention is achieved through the following technical scheme: On the one hand, a method for preparing 4-bromo-2-(1-methylcyclopropyl)pyridine is provided, wherein 2,4-dibromopyridine is used as a starting material, and the product is obtained by sequentially undergoing deprotonation, nucleophilic addition, Wittig reaction, and cyclopropanation reaction; the specific reaction path is as follows:

[0008]

[0009] Further, the method comprises the following specific steps:

[0010] Step S1, under nitrogen, dissolving the compound of formula (I) in an organic solvent, cooling, then dropping n-butyl lithium-n-hexane solution, n-butyl lithium reacts with the compound of formula (I), lithium replaces hydrogen atoms in the compound, generating corresponding lithium salt, the system turns brown-black, keeping warm and stirring, then dropping N-methoxy-N-methylacetamide, N-methoxy-N-methylacetamide reacts with the lithium salt, and generates the compound of formula (II) through nucleophilic addition reaction;

[0011] Step S2, under nitrogen, add the phosphine reagent to the organic solvent, then add the base, the reaction solution quickly turns into yellow turbidity, then add the compound represented by formula (II) dropwise, the color of the system turns lighter after the addition, stir at room temperature for Witting reaction, and obtain the compound represented by formula (III);

[0012] Step S3, under nitrogen, trimethyl sulfoxide iodide is added to an organic solvent, and then a base is added. The solid in the system gradually dissolves and becomes a clear solution. The solution is stirred at room temperature, and the compound represented by formula (III) is added dropwise. After the addition is completed, the color of the system darkens slightly. After continued stirring, a Corey-Chaykovsky cyclopropanation reaction is carried out to obtain a compound represented by formula (IV).

[0013] Further, in step S1, 2,4-dibromopyridine is used as the starting substrate, deprotonated under the action of n-butyl lithium-n-hexane solution, and then subjected to nucleophilic addition with N-methoxy-N-methylacetamide to obtain the compound represented by formula (II). The reaction needs to be carried out under anhydrous and anaerobic conditions, with a cooling temperature in the range of -60--78°C. After the addition of the materials is completed, the temperature is slowly raised to 25°C and stirred for 10-15h. The reaction is complete with a high yield.

[0014] Furthermore, in step S1, the molar ratio of the n-butyllithium-n-hexane solution to the compound of formula (I) is 1.1-1.5:1, preferably 2.5:1.

[0015] Furthermore, in step S1, the molar ratio of the N-methoxy-N-methylacetamide to the compound represented by formula (I) is (1.1-1.5):1, preferably 2.5:1.

[0016] Further, in step S2, the Wittig reaction is applied, and the carbon anion of the phosphine ylide is used as a nucleophilic reagent to attack the carbonyl carbon to generate an intermediate, followed by conformational isomerization, and finally through a four-membered ring transition state, the phosphine oxide compound is removed to generate an olefin. The compound represented by formula (II) is used as a substrate, and a phosphine reagent and a base are added. The reaction needs to be carried out under anhydrous and oxygen-free conditions, the reaction temperature is in the range of 20-25°C, and the reaction is stirred for 10-15h. The reaction is cleaner and has a higher yield.

[0017] Furthermore, in step S2, the phosphine reagent is any one of methyltriphenylphosphine bromide and methyltriphenylphosphine iodide, preferably methyltriphenylphosphine bromide; the molar ratio of its addition amount to the compound represented by formula (II) is 1.1-1.5:1, preferably 1.5:1.

[0018] Furthermore, in step S2, the base is any one of sodium bicarbonate, sodium carbonate, and sodium bis(trimethylsilyl)amide, preferably sodium bicarbonate; and the molar ratio of the base added to the compound represented by formula (II) is 1.5-2.5:1, preferably 2.5:1.

[0019] Further, in step S3, the Corey-Chaykovsky cyclopropanation reaction is applied, and the olefin is subjected to conjugate addition through the addition reaction of sulfonium salt to obtain a cyclopropane product; trimethyl sulfoxide iodide and a strong base are selected to cooperate, and the compound represented by formula (III) is used as a substrate, and the reaction is carried out in a mixed solvent of dimethyl sulfoxide and tetrahydrofuran, the reaction temperature is in the range of 20-25°C, and the reaction is stirred for 10-15h, the reaction is cleaner, and the yield is higher.

[0020] Furthermore, in step S3, the molar ratio of trimethyl sulfoxide iodide to the compound represented by formula (III) is 1.1-1.5:1, preferably 2.5:1.

[0021] Furthermore, in step S3, the strong base is any one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, and sodium hydrogen sulfide, preferably sodium hydroxide; and the molar ratio of the added amount thereof to the compound represented by formula (III) is 1.1-2.5:1, preferably 2.5:1.

[0022] Furthermore, the solvent is one or more of toluene, tetrahydrofuran, dimethyl sulfoxide, and tetrahydrofuran; the molar ratio of the solvent to the compound represented by formula (I), the compound represented by formula (II), and the compound represented by formula (III) is 10mL:1g.

[0023] Furthermore, in step S3, the solvent is a mixture of dimethyl sulfoxide and tetrahydrofuran; the volume ratio of dimethyl sulfoxide to tetrahydrofuran in the mixture is 4-1:1, preferably 4:1.

[0024] Based on the above-mentioned preparation method of 4-bromo-2-(1-methylcyclopropyl)pyridine, the nuclear magnetic purity of the obtained 4-bromo-2-(1-methylcyclopropyl)pyridine is above 95%, and the yield is above 70%.

[0025] Beneficial Effects

[0026] The invention provides a preparation method of 4-bromo-2-(1-methylcyclopropyl)pyridine. 2,4-dibromopyridine is used as a starting material, deprotonated under the action of n-butyl lithium, and then subjected to nucleophilic addition with N-methoxy-N-methylacetamide; then Wittig reaction is applied, and the carbon anion of phosphine ylide is used as a nucleophilic reagent to attack the carbonyl carbon to generate an intermediate, followed by conformational isomerization, and finally through a four-membered ring transition state, the phosphine oxide compound is removed to generate an olefin; finally, Corey-Chaykovsky cyclopropanation reaction is applied, and through an addition reaction carried out by a sulfonium salt, the olefin is subjected to conjugate addition to obtain a cyclopropane product. The preparation method adopted by the invention is a process after screening the material equivalents of each step, the base type, the temperature and the solvent, and is a relatively complete new process route; it has the advantages of relatively cheap raw materials, high yield and simple operation, effectively solves the problems of high cost and low yield of the existing process, and can further promote the industrial application of 4-bromo-2-(1-methylcyclopropyl)pyridine. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 4-bromo-2-(1-methylcyclopropyl)pyridine 1 HNMR spectrum;

[0028] Figure 2 This is the GC-MS spectrum of 4-bromo-2-(1-methylcyclopropyl)pyridine. DETAILED DESCRIPTION

[0029] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0030] Provided is a method for preparing 4-bromo-2-(1-methylcyclopropyl)pyridine, which uses 2,4-dibromopyridine as a starting material, and sequentially undergoes deprotonation, nucleophilic addition, Wittig reaction, and cyclopropanation reaction to obtain the 4-bromo-2-(1-methylcyclopropyl)pyridine. The specific reaction path is as follows:

[0031]

[0032] The specific steps include:

[0033] S1. Under nitrogen atmosphere, the compound of formula (I) was dissolved in toluene, cooled to -78°C, and then n-butyl lithium-n-hexane solution was added dropwise, the system turned brown-black, and stirred for 0.5 h. N-methoxy-N-methylacetamide was then added dropwise. After the addition, the temperature was slowly raised to 25°C and stirred for 12 h. The reaction was complete when detected by TLC. The reaction solution was then slowly poured into water to quench, and then extracted twice with EA, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain the compound shown in (II).

[0034] S2. Under nitrogen atmosphere, add the phosphine reagent to tetrahydrofuran, then add alkali, the reaction solution suddenly turns yellow and turbid, then add the compound represented by formula (II) dropwise, the color of the system becomes lighter after addition, stir at room temperature for 12 hours, and the reaction is complete when detected by TLC. Then add water to quench, extract with EA twice, dry with anhydrous sodium sulfate, spin dry, and column chromatography to obtain the compound represented by formula (III).

[0035] S3. Under nitrogen atmosphere, trimethyl sulfoxide iodide was added to a mixed solvent of dimethyl sulfoxide and tetrahydrofuran, and then a strong base was added. The solid in the system gradually dissolved and became a clear solution. After stirring for 0.5 h at room temperature, the compound represented by formula (III) was added dropwise. After the addition was completed, the color of the system slightly deepened. Stirring was continued for 12 h. TLC detected that the reaction was complete. Then water was added to quench, and EA was used for extraction twice. The mixture was dried over anhydrous sodium sulfate, spin-dried, and column chromatographed to obtain the compound represented by formula (IV).

[0036] Preferably, in step S1, the solvent is toluene, and the ratio of the solvent to the compound represented by formula (I) is 10 mL: 1 g.

[0037] Preferably, in step S2, the solvent is tetrahydrofuran, and the ratio of the solvent to the compound represented by formula (II) is 10 mL: 1 g.

[0038] Preferably, in step S3, the mixed solvent is a mixed solution of dimethyl sulfoxide and tetrahydrofuran; the volume ratio of dimethyl sulfoxide and tetrahydrofuran in the mixed solution is (4-1):1; the dosage ratio of the mixed solvent of dimethyl sulfoxide and tetrahydrofuran to the compound represented by formula (III) is 10mL:1g.

[0039] Based on the above-mentioned preparation method of 4-bromo-2-(1-methylcyclopropyl)pyridine, the nuclear magnetic purity of the obtained 4-bromo-2-(1-methylcyclopropyl)pyridine is above 95%, and the yield is above 70%.

[0040] Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. The experimental methods without specific conditions in the following examples are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, all percentages, ratios, proportions or parts are by weight.

[0041] Unless otherwise specified, the reagents and raw materials used in the examples and comparative examples of the present invention can be obtained through commercial channels.

[0042] Example 1

[0043] S1. Under nitrogen atmosphere, 100g of the compound of formula (I) was dissolved in 1000mL of toluene, cooled to -78°C, and then 253mL of n-butyl lithium-n-hexane solution was added dropwise, the system turned brown-black, and the mixture was stirred for 0.5h at room temperature, and then 65g of N-methoxy-N-methylacetamide was added dropwise. After the addition, the temperature was slowly raised to 25°C and stirred for 12h. The reaction was detected to be complete by TLC, and then the reaction solution was slowly poured into water to quench, and then extracted with EA 2 times, dried over anhydrous sodium sulfate, and spin-dried. Column chromatography obtained 80g of the compound shown in (II), with a yield of 95%. In this embodiment, the molar ratio of the compound shown in formula (I), n-butyl lithium-n-hexane solution, and N-methoxy-N-methylacetamide was 1:1.5:1.5.

[0044] S2. Under nitrogen atmosphere, 215g of methyl triphenylphosphine bromide was added to 800mL of tetrahydrofuran, and then 84g of sodium bicarbonate was added. The reaction solution quickly turned into a yellow turbid state, and then 80g of the compound shown in formula (II) was added dropwise. After the addition, the color of the system became lighter, and the mixture was stirred at room temperature for 12h. The reaction was detected by TLC to be complete. Then water was added to quench the mixture, and the mixture was extracted with EA twice, dried over anhydrous sodium sulfate, spin-dried, and column chromatographed to obtain 67.5g of the compound shown in formula (III), with a yield of 85%. In this embodiment, the molar ratio of the compound shown in formula (II), methyl triphenylphosphine bromide, and sodium bicarbonate was 1:1.5:2.5.

[0045] S3, under nitrogen atmosphere, 113g trimethyl sulfoxide iodide was added to a mixed solvent of 540mL dimethyl sulfoxide and 135mL tetrahydrofuran, and then 34g sodium hydroxide was added. The solid in the system gradually dissolved and became a clear solution. Stirring was performed at room temperature for 0.5h, and 67.5g of the compound shown in formula (III) was added dropwise. After the addition was completed, the color of the system was slightly deepened, and stirring was continued for 12h. The reaction was detected by TLC. Then water was added to quench, extracted with EA 2 times, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain a compound shown in formula 62.2g (IV), with a yield of 86%. Wherein, in this embodiment, the molar ratio of the compound shown in formula (III), trimethyl sulfoxide iodide, and sodium hydroxide was 1:1.5:2.5.

[0046] like Figure 1 As shown, the compound represented by formula (IV): GC-MS: [M+H] + 212.9 / 226.9, TLC: R f =0.4(PE / EA=15:1); 1 H-NMR (CDCl3, 400MHz): 8.262-8.249 (d, 1H), 7.431-7.427 (d, 1H), 7.198-7.18 (dd, 1H), 1.475 (s, 3H), 1.248-1.223 (m, 2H), 0.833-0.808 (m, 2H).

[0047] Example 2

[0048] S1. Under nitrogen atmosphere, 100g of the compound of formula (I) was dissolved in 1000mL of toluene, cooled to -78°C, and then 186mL of n-butyl lithium-n-hexane solution was added dropwise, the system turned brown-black, and the mixture was stirred for 0.5h at room temperature, and then 48g of N-methoxy-N-methylacetamide was added dropwise. After the addition, the temperature was slowly raised to 25°C and stirred for 12h. The reaction was detected to be complete by TLC, and then the reaction solution was slowly poured into water to quench, and then extracted with EA 2 times, dried over anhydrous sodium sulfate, and spin-dried. Column chromatography obtained 77g of the compound shown in (II), with a yield of 91.3%. In this embodiment, the molar ratio of the compound shown in formula (I), n-butyl lithium-n-hexane solution, and N-methoxy-N-methylacetamide was 1:1.1:1.1.

[0049] S2, under nitrogen atmosphere, 151g methyl triphenyl phosphine bromide was added to 800mL tetrahydrofuran, and then 46g sodium bicarbonate was added. The reaction solution quickly became yellow and turbid, and then 77g of the compound shown in formula (II) was added dropwise. The color of the system after addition was light yellow, and it was stirred at room temperature for 12h. TLC detected that there was a small amount of raw material remaining. The stirring was extended for 6h, and the raw material remained unchanged. Then water was added to quench, extracted with EA 2 times, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain 60g of the compound shown in formula (III), with a yield of 79%. Wherein, in this embodiment, the molar ratio of the compound shown in formula (II), methyl triphenyl phosphine bromide, and sodium bicarbonate is 1:1.1:1.5.

[0050] S3, under nitrogen atmosphere, 74g trimethyl sulfoxide iodide was added to a mixed solvent of 482mL dimethyl sulfoxide and 121mL tetrahydrofuran, and then 18g sodium hydroxide was added, most of the system was dissolved, stirred at room temperature for 0.5h, 60g of the compound shown in formula (III) was added dropwise, and after the addition was complete, the color of the system was slightly deepened, and stirring was continued for 12h. TLC detected that there was a small amount of raw material remaining, and the reaction time was extended for 5h, and the raw material remained unchanged. Then water was added to quench, extracted with EA 2 times, dried over anhydrous sodium sulfate, spin-dried, column chromatography, and the compound shown in formula 51.7g (IV) was obtained, with a yield of 80%. Wherein, in this embodiment, the molar ratio of the compound shown in formula (III), trimethyl sulfoxide iodide, and sodium hydroxide is 1:1.1:1.5.

[0051] Example 3

[0052] S1. Under nitrogen atmosphere, 100g of the compound of formula (I) was dissolved in 1000mL of toluene, cooled to -78°C, and then 186mL of n-butyl lithium-n-hexane solution was added dropwise, the system turned brown-black, and the mixture was stirred for 0.5h at room temperature, and then 65g of N-methoxy-N-methylacetamide was added dropwise. After the addition, the temperature was slowly raised to 25°C and stirred for 12h. The reaction was detected to be complete by TLC, and then the reaction solution was slowly poured into water to quench, and then extracted with EA 2 times, dried over anhydrous sodium sulfate, and spin-dried. Column chromatography obtained 77.7g of the compound shown in (II), with a yield of 92%. Wherein, in this embodiment, the molar ratio of the compound shown in formula (I), n-butyl lithium-n-hexane solution, and N-methoxy-N-methylacetamide was 1:1.1:1.5.

[0053] S2. Under nitrogen atmosphere, 208g of methyl triphenylphosphine bromide was added to 800mL of tetrahydrofuran, and then 103g of sodium carbonate was added. The reaction solution quickly turned into a yellow turbid state, and then 77.7g of the compound shown in formula (II) was added dropwise. After the addition, the color of the system became lighter, and the mixture was stirred at room temperature for 12h. The reaction was detected by TLC to be complete. Then water was added to quench the mixture, and the mixture was extracted with EA twice, dried over anhydrous sodium sulfate, spin-dried, and column chromatographed to obtain 61.5g of the compound shown in formula (III), with a yield of 80%. In this embodiment, the molar ratio of the compound shown in formula (II), methyl triphenylphosphine bromide, and sodium carbonate was 1:1.5:2.5.

[0054] S3, under nitrogen atmosphere, 103g trimethyl sulfoxide iodide was added to a mixed solvent of 492mL dimethyl sulfoxide and 123mL tetrahydrofuran, and then 31g sodium hydroxide was added. The solid in the system gradually dissolved and became a clear solution. Stirring was performed at room temperature for 0.5h, and 61.5g of the compound shown in formula (III) was added dropwise. After the addition was completed, the color of the system was slightly deepened, and stirring was continued for 12h. The reaction was detected by TLC. Then water was added to quench, extracted with EA 2 times, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain a compound shown in formula 54g (IV), with a yield of 82%. Wherein, in this embodiment, the molar ratio of the compound shown in formula (III), trimethyl sulfoxide iodide, and sodium hydroxide was 1:1.5:2.5.

[0055] Example 4

[0056] S1. Under nitrogen atmosphere, 100g of the compound of formula (I) was dissolved in 1000mL of toluene, cooled to -65°C, and then 253mL of n-butyl lithium-n-hexane solution was added dropwise, the system turned black, and the mixture was stirred for 0.5h at room temperature, and then 48g of N-methoxy-N-methylacetamide was added dropwise. After the addition, the mixture was slowly heated to 25°C and stirred for 12h. The reaction was detected to be complete by TLC, and then the reaction solution was slowly poured into water to quench, and then extracted with EA twice, dried over anhydrous sodium sulfate, and spin-dried. Column chromatography was performed to obtain 79g of the compound shown in (II), with a yield of 93.5%. In this embodiment, the molar ratio of the compound shown in formula (I), n-butyl lithium-n-hexane solution, and N-methoxy-N-methylacetamide was 1:1.5:1.1.

[0057] S2, under nitrogen atmosphere, add 239g methyl triphenylphosphine iodide to 800mL tetrahydrofuran, add 181g bis(trimethylsilyl) sodium amide, the reaction solution quickly turns yellow and turbid, then add 79g compound shown in formula (II) dropwise, the color of the system becomes lighter after addition, stir at room temperature for 12h, and the reaction is complete by TLC detection. Then add water to quench, extract with EA 2 times, dry with anhydrous sodium sulfate, spin dry, column chromatography, obtain 61g compound shown in formula (III), yield 78%. Wherein, in this embodiment, the molar ratio of compound shown in formula (II), methyl triphenylphosphine iodide, and bis(trimethylsilyl) sodium amide is 1:1.5:2.5.

[0058] S3, under nitrogen atmosphere, 102g trimethyl sulfoxide iodide was added to a mixed solvent of 305mL dimethyl sulfoxide and 305mL tetrahydrofuran, and then 86g potassium tert-butoxide was added. The solid in the system gradually dissolved and became a clear solution. Stirring was performed at room temperature for 0.5h, and 61g of the compound shown in formula (III) was added dropwise. After the addition was complete, the color of the system was slightly deepened, and stirring was continued for 12h. The reaction was detected by TLC. Then water was added to quench, extracted with EA 2 times, dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain a compound shown in formula 51.2g (IV), with a yield of 83%. Wherein, in this embodiment, the molar ratio of the compound shown in formula (III), trimethyl sulfoxide iodide, and potassium tert-butoxide is 1:1.5:2.5.

[0059] Experimental example

[0060] Take the 4-bromo-2-(1-methylcyclopropyl)pyridine prepared in Examples 1 to 4 and perform nuclear magnetic resonance analysis. The obtained nuclear magnetic resonance 1HNMR spectrum is as follows: Figure 1 As shown. Figure 1 It can be seen that the present invention successfully prepared the target product 4-bromo-2-(1-methylcyclopropyl)pyridine, and the nuclear magnetic purity is greater than 95%. The results are shown in Table 1. According to the yield analysis, Example 1 is the best example.

[0061] Table 1:

[0062]

[0063]

[0064] Depend on Figure 1 , Figure 2 As can be seen from the data in Table 1, the preparation method of 4-bromo-2-(1-methylcyclopropyl)pyridine provided by the present invention uses 2,4-dibromopyridine as a starting material, reacts with N-methoxy-N-methylacetamide, performs a Wittig reaction, and synthesizes 4-bromo-2-(1-methylcyclopropyl)pyridine through cyclopropanation. The method adopted by the present invention has the advantages of relatively cheap raw materials, high yield, and simple operation, and can further promote the industrial application of 4-bromo-2-(1-methylcyclopropyl)pyridine.

[0065] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing 4-bromo-2-(1-methylcyclopropyl)pyridine, characterized in that: The method uses 2,4-dibromopyridine as a starting material, and sequentially undergoes deprotonation, nucleophilic addition, Wittig reaction, and cyclopropanation reaction to obtain the product; the specific reaction path is as follows:

2. The method for preparing 4-bromo-2-(1-methylcyclopropyl)pyridine according to claim 1, characterized in that: The specific steps include: Step S1, under nitrogen, dissolving the compound of formula (I) in an organic solvent, cooling, then dropping n-butyl lithium-n-hexane solution, n-butyl lithium reacts with the compound of formula (I), lithium replaces hydrogen atoms in the compound, generating corresponding lithium salt, the system turns brown-black, keeping warm and stirring, then dropping N-methoxy-N-methylacetamide, N-methoxy-N-methylacetamide reacts with the lithium salt, and generates the compound of formula (II) through nucleophilic addition reaction; Step S2, under nitrogen, add the phosphine reagent to the organic solvent, then add the base, the reaction solution quickly turns into yellow turbidity, then add the compound represented by formula (II) dropwise, the color of the system turns lighter after the addition, stir at room temperature for Witting reaction, and obtain the compound represented by formula (III); Step S3, under nitrogen, trimethyl sulfoxide iodide is added to an organic solvent, and then a base is added. The solid in the system gradually dissolves and becomes a clear solution. The solution is stirred at room temperature, and the compound represented by formula (III) is added dropwise. After the addition is completed, the color of the system darkens slightly. After continued stirring, a Corey-Chaykovsky cyclopropanation reaction is carried out to obtain a compound represented by formula (IV).

3. The method for preparing 4-bromo-2-(1-methylcyclopropyl)pyridine according to claim 2, characterized in that: In step S1, the molar ratio of the n-butyllithium-n-hexane solution to the compound of formula (I) is 1.1-1.5:

1.

4. The method for preparing 4-bromo-2-(1-methylcyclopropyl)pyridine according to claim 2, characterized in that: In step S1, the molar ratio of N-methoxy-N-methylacetamide to the compound represented by formula (I) is (1.1-1.5):

1.

5. The method for preparing 4-bromo-2-(1-methylcyclopropyl)pyridine according to claim 2, characterized in that: In step S2, the phosphine reagent is any one of methyltriphenylphosphine bromide and methyltriphenylphosphine iodide; the molar ratio of the added amount thereof to the compound represented by formula (II) is 1.1-1.5:

1.

6. The method for preparing 4-bromo-2-(1-methylcyclopropyl)pyridine according to claim 2, characterized in that: In step S2, the base is any one of sodium bicarbonate, sodium carbonate, sodium bis(trimethylsilyl)amide, sodium hydroxide, and potassium tert-butoxide, and the molar ratio of the base added to the compound represented by formula (II) is 1.5-2.5:

1.

7. The method for preparing 4-bromo-2-(1-methylcyclopropyl)pyridine according to claim 2, characterized in that: In step S3, the molar ratio of trimethyl sulfoxide iodide to the compound represented by formula (III) is 1.1-1.5:

1.

8. The method for preparing 4-bromo-2-(1-methylcyclopropyl)pyridine according to claim 2, characterized in that: The solvent is one or more of toluene, tetrahydrofuran, dimethyl sulfoxide, and tetrahydrofuran; the molar ratio of the solvent to the compound represented by formula (I), the compound represented by formula (II), and the compound represented by formula (III) is 10 mL: 1 g.

9. The method for preparing 4-bromo-2-(1-methylcyclopropyl)pyridine according to claim 8, characterized in that: In step S3, the solvent is a mixture of dimethyl sulfoxide and tetrahydrofuran; the volume ratio of dimethyl sulfoxide to tetrahydrofuran in the mixture is 4-1:

1.

10. A method for preparing 4-bromo-2-(1-methylcyclopropyl)pyridine according to any one of claims 1 to 9, characterized in that: The nuclear magnetic purity of the prepared 4-bromo-2-(1-methylcyclopropyl)pyridine is above 95%, and the yield is above 70%.

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