A method for preparing 2-(hydroxymethyl)spiropropanes

Abstract

The application provides a preparation method of 2-(hydroxymethyl) spirocyclopropane compounds, wherein a starting substrate 1A is reacted with an epoxy bromopropane under the action of an inorganic base to prepare a hydroxymethyl spirocyclopropane compound formula 3A and derivatives thereof. The preparation method provided by the application does not need to use noble metals and ligands, nor does it need to use dangerous diazo compounds, and has the advantages of safe route process, simple reaction condition, easy operation and potential for industrial production application.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing 2-(hydroxymethyl)spirocyclopropane compounds. Background Technology

[0002] Spirocyclopropane-oxyindole, due to its rigid cyclopropane ring structure, possesses a variety of significant pharmacological activities and has attracted much attention in drug development, serving as the core framework of many bioactive molecules. Compound 1, as a non-nucleoside reverse transcriptase inhibitor of HIV-1, exhibits nanomolar activity, effectively inhibiting drug-resistant HIV-1 variants and offering greater safety and cost-effectiveness. Compounds 2 and 3 possess antitumor activity; compound 2 effectively inhibits the proliferation of various breast, colon, and ovarian cancer cells with good tolerability. Compound 3 demonstrates significant anticancer activity against prostate cancer cells, arresting the cell cycle at the G0 / G1 phase and inducing apoptosis, leading to cell death.

[0003] .

[0004] Spirocyclopropane-oxyindole is a highly challenging class of target molecules to synthesize due to the presence of a heavily strained three-membered ring in its structure. Currently, the main synthetic routes for these compounds are based on two types of reactions: one utilizes alkylene-oxyindole as a substrate; the other involves an addition reaction of a 3-substituted oxyindole derivative followed by ring closure. Both methods suffer from significant drawbacks, as described below, that limit their industrial applications.

[0005] In 2011, Ramendra K. Singh's research group used substituted indigo as a starting material, first reacting it with p-toluenesulfonyl hydrazine in anhydrous methanol, and then preparing a diazonium indolone intermediate using sodium hydroxide as a base. Finally, under rhodium catalysis, the diazonium indolone reacted with an allyl compound to generate the corresponding spiro[cyclopropane-1,3'-indoline]-2'-one derivative. The drawbacks of this reaction are the use of the precious metal rhodium as a catalyst and the formation of a flammable and explosive diazonium compound intermediate, which rapidly releases nitrogen gas during the reaction, making it unsuitable for industrial production.

[0006] .

[0007] In 2015, Ahmed Kamal's group also reacted substituted indigo with acetophenone to generate a 3-methyleneindoline-2-one derivative, which was then co-refluxed with ethyl diazonium in tetrahydrofuran and ethylenediamine to generate the final diastereomeric pure spiro[cyclopropane-1,3'-indoline]-2'-one derivative. This method is complex and uses expensive rhodium acetate as a catalyst and diazo compound, making it less economical.

[0008] .

[0009] In 2012, Yixin Lu reported the first direct asymmetric cyclopropanation reaction of hydroxyindole. In this cyclopropanation strategy, the authors utilized hydroxyindole with an amphiphilic nucleophilic center as the C1 synthon and employed a brominated nitro alkene containing an amphiphilic electrophilic center as a unique C2 synthon, achieving highly enantioselective synthesis of 3-spirocyclopropane-2-hydroxyindole. Although this method yields the product in one step, the tertiary amine-thiourea catalyst used is expensive, and the substrates are limited to hydroxyindole and nitro-substituted alkenes.

[0010] .

[0011] In 2013, Tonis Kanger's group synthesized spiro[cyclopropane-1,3'-indoline]-2'-one derivatives using methylene indolone and α,β-unsaturated aldehydes as starting materials under hydrogen-bonding catalysis. When methylene indolone is used instead of α,β-unsaturated aldehydes, a series of bispirocyclic products can be synthesized in high yields through a series of cascade reactions. The drawback of this method is the complexity of the catalyst used, requiring multiple reaction steps, and the limitation of the substrate scope to α,β-unsaturated aldehydes or ketones.

[0012] .

[0013] In summary, although there are many publications on the preparation of spirocyclopropane-oxyindole, most of them require the use of expensive transition metal catalysts and generate flammable and explosive diazo compound intermediates, or use expensive or cumbersome ligands and have a narrow substrate range. Summary of the Invention

[0014] In order to overcome some of the shortcomings of existing technologies, it is essential to develop simple and efficient synthetic methods to prepare the corresponding 2-(hydroxymethyl)spiro[cyclopropane-1,3'-indoline]-2'-one and its derivatives.

[0015] This invention provides a method for preparing 2-(hydroxymethyl)spirocyclopropane compounds, wherein a starting substrate of formula 1A is reacted with epibromopropane in the presence of an inorganic base and an organic solvent to prepare hydroxymethylspirocyclopropane product of formula 3A.

[0016] The initial substrate 1A structure is as follows: or ;

[0017] The structure of the hydroxymethylspirocyclopropane product 3A is as follows: or ;

[0018] B is an aryl group or its derivative, and EWG is CO2Me.

[0019] More preferably, the present invention provides a method for preparing 2-(hydroxymethyl)spirocyclopropane compounds, wherein a starting substrate of formula 1A1 reacts with epibromopropane in the presence of an inorganic base and an organic solvent, and an epibromopropane intermediate of formula 2A1 is prepared by nucleophilic substitution reaction. Subsequently, a hydroxymethylspirocyclopropane product of formula 3A1 is prepared by nucleophilic substitution ring-opening reaction of lithium hexamethyldisilamide (LiHMDS).

[0020] ,

[0021] Where EWG stands for CO2Me; B stands for... , or .

[0022] Most preferably, the specific structure of the hydroxymethylspirocyclopropane product of formula 3A1 is as follows:

[0023] ;

[0024] The group structures defined in the compounds of formula 1A1 and 2A1 are determined with reference to the specific structure of the compound of formula 3A1 and the corresponding reactions described above.

[0025] In the process of preparing the hydroxymethylspirocyclopropane product 3A1-1, the two steps described above will further react to generate the cyclic byproduct 3A1-1', the specific structure of which is as follows: .

[0026] The inorganic base is cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert-butoxide, or potassium hydroxide; more preferably, the inorganic base is cesium carbonate.

[0027] The organic solvent is acetonitrile (ACN), acetone, tetrahydrofuran (THF), toluene, dioxane, or dichloromethane (DCM); preferably, the organic solvent is ACN.

[0028] The nucleophilic substitution epoxy ring-opening reaction was carried out in the presence of anhydrous tetrahydrofuran.

[0029] The molar equivalent ratio of the starting substrate of formula 1A1, the inorganic base, and the epichlorohydrin is 1:3:1.1.

[0030] The nucleophilic substitution reaction is carried out at a temperature of 25~100℃; more preferably, the nucleophilic substitution reaction is carried out at a temperature of 50℃.

[0031] The nucleophilic substitution reaction takes 12 to 48 hours; more preferably, the nucleophilic substitution reaction takes 24 hours.

[0032] The reaction temperature of the nucleophilic substitution epoxy ring-opening reaction is 0~30℃; more preferably, the reaction temperature of the nucleophilic substitution epoxy ring-opening reaction is 0℃.

[0033] The reaction time for the nucleophilic substitution epoxy ring-opening reaction is 1 to 4 hours; more preferably, the reaction time for the nucleophilic substitution epoxy ring-opening reaction is 2 hours.

[0034] More preferably, the present invention also provides a method for preparing 2-(hydroxymethyl)spirocyclopropane compounds, characterized in that the hydroxymethyl spirocyclopropane product 3A1 or 3A2 is prepared by reacting a starting substrate of formula 1A1 or 1A2 with epoxybromopropane in the presence of an inorganic base and an organic solvent via a one-step tandem nucleophilic substitution-nucleophilic substitution epoxide ring-opening reaction:

[0035] ,

[0036] B is an aryl group or a derivative thereof;

[0037] The starting substrates, formulas 1A1 and 1A2, have the same reaction site and can undergo the same type of nucleophilic substitution epoxide ring-opening reaction with epoxide bromide to achieve the same inventive purpose.

[0038] More preferably, the hydroxymethylspirocyclopropane products of formula 3A1 and 3A2 have the following structures: ;

[0039] Where EWG stands for CO2Me; R1 stands for CN, Cl, or H;

[0040] X1 is either C or N;

[0041] X2 is 0 or N. When X2 is 0, R2 does not exist. When X2 is N, R2 is Boc, Ph, or Me. n = 0 or 1.

[0042] Most preferably, the specific structures of the hydroxymethylspirocyclopropane products of formula 3A1 and 3A2 are as follows:

[0043] .

[0044] The group structure defined by the compound of formula 1A1 or 1A2 is determined by referring to the specific structure of the compound of formula 3A1 or 3A2 and the corresponding reaction described above.

[0045] In the above-mentioned nucleophilic substitution epoxy ring-opening reaction, when preparing hydroxymethylspirocyclopropane products of formula 3A1-4, 3A1-5, 3A1-6, and 3A2-3, another configuration will undergo further reaction to generate cyclocyclic byproducts of formula 3A1-4', 3A1-5', 3A1-6', and 3A2-3'. Among them, byproduct formula 3A2-3' is unstable and easily decomposes.

[0046] The specific structures of these cyclic byproducts are as follows:

[0047] .

[0048] The inorganic base is cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert-butoxide, or potassium hydroxide; more preferably, the inorganic base is cesium carbonate or potassium carbonate.

[0049] The organic solvent is acetonitrile (ACN), acetone, tetrahydrofuran, toluene, dioxane, or dichloromethane; more preferably, the organic solvent is ACN.

[0050] The molar equivalent ratio of the starting substrate of formula 1A1 or 1A2, the inorganic base, and the epoxide propane is 1:3:1.1.

[0051] The reaction temperature of the one-step tandem nucleophilic substitution-nucleophilic substitution epoxy ring-opening reaction is 25~100℃; more preferably, the reaction temperature of the one-step tandem nucleophilic substitution-nucleophilic substitution epoxy ring-opening reaction is 80℃.

[0052] The reaction time for the one-step tandem nucleophilic substitution-nucleophilic substitution epoxy ring-opening reaction is 12-36 hours; more preferably, the reaction time for the one-step tandem nucleophilic substitution-nucleophilic substitution epoxy ring-opening reaction is 24 hours.

[0053] The synthetic route provided by this invention allows for the one- or two-step synthesis of hydroxymethylspirocyclopropane compound 3A and its derivatives. Starting substrate 1A1 reacts with epibromopropane in the presence of an inorganic base and an organic solvent to generate an epibromopropane intermediate 2A1, which then further reacts in the presence of LiHMDS to generate the hydroxymethylspirocyclopropane product 3A1. Alternatively, starting substrates 1A1 or 1A2 can react directly with epibromopropane in a one-step tandem reaction in the presence of an inorganic base and an organic solvent to obtain the corresponding hydroxymethylspirocyclopropane product 3A1 or 3A2. Substrates with electron-withdrawing groups on the hydroxyindole and aromatic rings exhibit stronger reactivity and are more readily synthesized in a one-pot, two-step tandem reaction to obtain the desired product 3A. The preparation method provided by this invention does not require the use of precious metals and ligands, nor does it require the use of hazardous diazo compounds. The reaction conditions are simple, easy to operate, and have potential for industrial production applications. Detailed Implementation

[0054] To further understand the present invention, a method for preparing a 2-(hydroxymethyl)spirocyclopropane compound provided by the present invention will be described in detail below with reference to embodiments. It should be understood that these embodiments are described only to further illustrate the features of the present invention, and are not intended to limit the scope of the present invention or the scope of the claims.

[0055] Example 1: Preparation of 2A1-1

[0056]

[0057] At 25°C (room temperature), methyl 2-nitrobenzeneacetate 1A1-1 (1.95 g, 10 mmol, 1.0 equivalent) and cesium carbonate (9.77 g, 30 mmol, 3.0 equivalent) were added to a 250 mL three-necked round-bottom flask. Under nitrogen (N2) protection, an acetonitrile solution (40 mL) of epibromopropane (1.51 g, 11 mmol, 1.1 equivalent) was added, and the system was stirred overnight at 50°C. After 24 h of reaction, a TLC sample (n-hexane:ethyl acetate = 4:1) showed that most of the starting material 1A1-1 had reacted. The reaction mixture was removed from the oil bath and brought to room temperature. Cesium carbonate was removed by filtration, and the filtrate was collected. The filter cake was washed three times with ethyl acetate (25 mL * 3), and crude 2A1-1 was obtained by vacuum distillation. The crude product was purified by column chromatography (eluent: n-hexane:ethyl acetate = ... (100 / 0~80 / 20) A pale yellow oily substance 2A1-1 was obtained, pure product. It was dried by vacuum pump and weighed to obtain 1.53 g. The molar yield was 61% and the dr value was 1:1. 1 ¹H NMR (400MHz, deuterated chloroform (CDCl₃)) δ 8.00 – 7.93 (m, 1H), 7.65 – 7.59 (m, 1H), 7.55 – 7.43 (m, 2H), 4.46 – 4.33 (m, 1H), 3.69 (d, J = 2.1 Hz, 3H), 3.09 – 2.85 (m, 1H), 2.79 – 2.72 (m, 1H), 2.61 – 2.50 (m, 1H), 2.49 – 2.36 (m, 1H), 2.17 – 1.95 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 172.39, 172.28, 149.00, 148.94, 133.40,133.36, 133.22, 132.98, 130.83, 130.31, 128.56, 128.48, 125.19, 125.07,52.51, 52.49, 50.39, 49.98, 47.46, 47.18, 44.67, 44.12, 35.76, 35.67.

[0058] Example 2: Preparation of 3Al-1 and 3Al-1'

[0059]

[0060] At 25°C (room temperature), 2A1-1 (1.535 g, 6.1 mmol, 1.0 equivalent) was added to a 100 ml three-necked round-bottom flask; under N2 protection, 20 ml of anhydrous tetrahydrofuran was added, and the system was stirred at 0°C for 10 min; at 0°C, bis(trimethylsilyl)aminolithium (LiHMDS) (6.7 mL, 6.7 mmol, 1.1 equivalent) was added dropwise, and the reaction was stirred at 0°C. The reaction was monitored by TLC; after 2 h of reaction, a sample was spotted on the TLC (n-hexane:ethyl acetate = 2:1), showing that the starting material 2A1-1 had reacted completely. The reaction mixture was then removed from the ice bath and brought to room temperature; the reaction system was quenched with ammonium chloride aqueous solution (2 ml), and then the reaction solution was extracted 5 times (10 ml * 5) with an ethyl acetate / saturated brine system. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain crude 3A1-1, which was purified by column chromatography (eluent: n-hexane:ethyl acetate = (100 / 0~65 / 35) A pale yellow oily substance 3A1-1 and a pale yellow solid cyclic byproduct 3A1-1' were obtained, both of which were pure. The product was dried under vacuum, and 3A1-1 was weighed to obtain 843 mg, with a molar yield of 55%. 1 H NMR (400 MHz, CDCl3) δ 7.65 – 7.60 (m, 1H), 7.52 – 7.40 (m,2H), 3.59 (s, 3H), 3.34 (s, 1H), 3.05 (t, J = 9.7 Hz, 1H), 2.46 (s, 1H), 2.20– 2.12 (m, 1H), 1.82 – 1.71 (m, 1H), 1.52 – 1.39 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 172.96, 150.12, 133.55, 133.24, 131.41, 128.78, 125.39, 61.96, 52.59, 33.08, 29.79, 19.92. 3A1-1' weighed to obtain 163 mg, molar yield: 12%. 1 H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 8.2, 1.4 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.60 – 7.52 (m,2H), 4.64 (dd, J = 9.1, 4.5 Hz, 1H), 4.34 (d, J = 9.1 Hz, 1H), 2.39 – 2.34(m, 1H), 1.75 – 1.71 (m, 1H), 1.47 (t, J = 4.9 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 175.14, 149.25, 134.09, 133.84, 129.95, 129.64, 125.34, 69.17, 32.07, 25.03, 17.53.

[0061] Example 3: Preparation of 2A1-2

[0062]

[0063] At 25°C (room temperature), methyl 2-(quinoline-6-yl)acetate 1A1-2 (2.01 g, 10 mmol, 1.0 equivalent) and cesium carbonate (9.77 g, 30 mmol, 3.0 equivalent) were added to a 250 mL three-necked round-bottom flask. Under N2 protection, an acetonitrile solution (40 mL) of epibromopropane (1.51 g, 10 mmol, 1.1 equivalent) was added, and the system was stirred overnight at 50°C. After 24 h of reaction, a TLC sample (n-hexane:ethyl acetate = 4:1) showed that most of the starting material 1A1-2 had reacted. The reaction mixture was removed from the oil bath and brought to room temperature. Cesium carbonate was removed by filtration, and the filtrate was collected. The filter cake was washed three times with ethyl acetate (25 mL * 3), and crude 2A1-2 was obtained by vacuum distillation. The crude product was purified by column chromatography (eluent: n-hexane:ethyl acetate = ... (100 / 0~70 / 30) A pale yellow oily substance 2A1-2 was obtained, pure product. It was dried by vacuum pump and weighed to obtain 1.53 g, with a molar yield of 59% and a dr value of 1:1. 1H NMR (400MHz, CDCl3) δ 8.96 – 8.84 (m, 1H), 8.21 – 8.03 (m, 2H), 7.76 (dd, J = 17.0,2.0 Hz, 1H), 7.72 – 7.62 (m, 1H), 7.46 – 7.36 (m, 1H), 4.09 – 3.93 (m, 1H), 3.69 (d, J = 4.6 Hz, 3H), 3.08 – 2.94 (m, 1H), 2.88 – 2.73 (m, 1H), 2.73 –2.62 (m, 1H), 2.62 – 2.50 (m, 1H), 2.50 – 2.41 (m, 1H), 2.35 – 2.14 (m, 1H),1.97 – 1.81 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 173.61, 173.51, 150.67, 150.63,147.76, 147.70, 137.01, 136.47, 136.17, 130.25, 130.19, 129.53, 129.49,128.38, 127.18, 126.55, 121.61, 121.59, 52.50, 52.48, 50.50, 50.03, 48.63,48.54, 47.59, 47.45, 36.63, 36.28.

[0064] Example 4: Preparation of 3A1-2

[0065]

[0066] At 25°C (room temperature), 2A1-2 (1.29 g, 5 mmol, 1.0 equivalent) was added to a 100 ml three-necked round-bottom flask; under N2 protection, 20 ml of anhydrous tetrahydrofuran was added, and the system was stirred at 0°C for 10 min; at 0°C, LiHMDS (5.5 mL, 5.5 mmol, 1.1 equivalent) was added dropwise, and the reaction was stirred at 0°C. The reaction was monitored by TLC; after 2 h of reaction, a sample was taken and TLC (n-hexane:ethyl acetate = 1:1) showed that the starting material 2A1-2 had reacted completely. The reaction mixture was removed from the ice bath and brought to room temperature; the reaction system was quenched with ammonium chloride aqueous solution (2 ml), and then the reaction solution was extracted 5 times (10 ml * 5) with an ethyl acetate / saturated brine system. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain crude 3A1-2, which was purified by column chromatography (eluent: n-hexane:ethyl acetate = (100 / 0~0 / 100) A pale yellow oily substance 3A1-2 was obtained, pure product, dried by vacuum pump, and weighed to obtain 643 mg, molar yield: 50%. 1 H NMR (400 MHz, CDCl3) δ 8.83 – 8.62 (m, 1H), 8.04 (dd, J = 8.4, 1.8 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.79 – 7.65 (m,2H), 7.35 – 7.27 (m, 1H), 4.12 (s, 1H), 3.56 (s, 3H), 3.49 – 3.34 (m, 1H), 3.24 – 3.03 (m, 1H), 2.38 – 2.02 (m, 1H), 1.88 – 1.68 (m, 1H), 1.38 – 1.24(m, 1H); 13 C NMR (101 MHz, CDCl3) δ 174.16, 149.99, 147.11, 136.22, 134.38,133.45, 129.70, 128.42, 127.87, 121.08, 61.58, 52.41, 33.80, 30.15, 18.81.

[0067] Example 5: Preparation of 2A1-3

[0068]

[0069] At 25°C (room temperature), tert-butyl 3-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxylic acid ester 1A1-3 (2.89 g, 10 mmol, 1.0 equivalent) and cesium carbonate (9.77 g, 30 mmol, 3.0 equivalent) were added to a 250 mL three-necked round-bottom flask; under N2 protection, an acetonitrile solution (40 mL) of epichlorohydrin (1.51 g, 11 mmol, 1.1 equivalent) was added, and the system was stirred overnight at 50°C; after 24 h of reaction, a TLC sample (n-hexane:ethyl acetate = 4:1) showed that most of the starting material 1A1-3 had reacted. The reaction vessel was removed from the oil bath and brought to room temperature; the cesium carbonate was removed by filtration, the filtrate was collected, and the filter cake was washed three times with ethyl acetate (25 mL * 3) Crude product 2A1-3 was obtained by vacuum distillation, and purified by column chromatography (eluent: hexane: ethyl acetate = 100 / 0~70 / 30) to obtain a pale yellow oily substance 2A1-3, which was pure. The product was dried under vacuum and weighed to obtain 1.62 g, with a molar yield of 47% and a dr value of 1:1. 1 H NMR (400 MHz, CDCl3) δ 8.22 – 8.05 (m, 1H), 7.69 – 7.51 (m, 2H), 7.41 – 7.29 (m, 1H), 7.27 – 7.23 (m, 1H), 4.12 – 4.02 (m, 1H), 3.70 (d, J =5.2 Hz, 3H), 3.11 – 2.85 (m, 1H), 2.84 – 2.69 (m, 1H), 2.61 – 2.30 (m, 2H), 2.24 – 1.94 (m, 1H), 1.67 (d, J = 2.0 Hz, 9H); 13 C NMR (101 MHz, CDCl3) δ173.53, 173.44, 149.55, 129.16, 129.11, 124.70, 123.89, 123.39, 122.76,122.72, 119.35, 119.21, 117.92, 117.28, 115.41, 115.39, 83.91, 83.88, 52.34,52.30, 50.42, 50.19, 47.40, 47.38, 39.97, 39.62, 35.15, 35.01, 28.21.

[0070] Example 6: Preparation of 3A1-3

[0071]

[0072] At 25℃ (room temperature), 2A1-3 (1.62 g, 4.7 mmol, 1.0 equivalent) was added to a 100 ml three-necked round-bottom flask; under N2 protection, 20 ml of anhydrous tetrahydrofuran was added, and the system was stirred at 0℃ for 10 min; at 0℃, LiHMDS (5.5 mL, 5.5 mmol, 1.1 equivalent) was added dropwise, and the reaction was stirred at 0℃. The reaction was monitored by TLC; after 2 h of reaction, a sample was taken and TLC (n-hexane:ethyl acetate = 1:1) showed that the starting material 2A1-3 had reacted completely. The reaction mixture was removed from the ice bath and brought to room temperature; the reaction system was quenched with ammonium chloride aqueous solution (2 ml), and then the reaction solution was extracted 5 times (10 ml * 5) with an ethyl acetate / saturated saline system. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain crude 3A1-3, which was purified by column chromatography (eluent: n-hexane:ethyl acetate = (100 / 0~0 / 100) A pale yellow oily substance 3A1-3 was obtained, pure product, dried by vacuum pump, and weighed to obtain 811 mg, molar yield: 50%. 1 H NMR (400 MHz, CDCl3) δ 8.18 – 8.08 (m, 1H), 7.55 – 7.45 (m, 2H), 7.37 – 7.29 (m, 1H), 7.27 (d, J = 1.1 Hz, 1H), 7.25 – 7.23(m, 1H), 3.61 (s, 3H), 3.50 – 3.48 (m, 1H), 3.22 – 3.08 (m, 1H), 2.40 – 2.23(m, 1H), 1.81 – 1.72 (m, 1H), 1.67 (s, 9H), 1.28 – 1.23 (m, 1H); 13 C NMR (101MHz, CDCl3) δ 173.93, 149.55, 135.58, 130.80, 126.13, 124.75, 122.98, 119.49,116.17, 115.59, 83.97, 62.27, 52.48, 29.76, 28.21, 24.85, 18.67.

[0073] Example 7: Preparation of 3Al-4 and 3Al-4'

[0074]

[0075] At 25°C (room temperature), methyl 2-(4-cyanophenyl)acetate 1A1-4 (1.75 g, 10 mmol, 1.0 equivalent) and cesium carbonate (9.77 g, 30 mmol, 3.0 equivalent) were added to a 250 mL three-necked round-bottom flask. Under N2 protection, an acetonitrile solution (40 mL) of epibromopropane (1.51 g, 11 mmol, 1.1 equivalent) was added, and the system was stirred overnight at 80°C. After 24 h of reaction, a TLC sample (n-hexane:ethyl acetate = 4:1) showed that most of the starting material 1A1-4 had reacted. The reaction mixture was removed from the oil bath and brought to room temperature. Cesium carbonate was removed by filtration, and the filtrate was collected. The filter cake was washed three times with ethyl acetate (25 mL * 3), and crude 3A1-4 was obtained by vacuum distillation. The crude product was purified by column chromatography (eluent: n-hexane:ethyl acetate = ... (100 / 0~70 / 30) A pale yellow oily substance 3A1-4 and a pale yellow oily cyclic byproduct 3A1-4' were obtained, both of which were pure. The product was dried under vacuum, and 3A1-4 was weighed to obtain 532 mg. The molar yield was 23%. 1 H NMR (400 MHz, CDCl3) δ 7.67 – 7.60 (m, 2H), 7.54 – 7.45(m, 2H), 3.64 (s, 3H), 3.55 – 3.46 (m, 1H), 3.13 – 3.02 (m, 1H), 2.30 – 2.17(m, 1H), 1.84 – 1.74 (m, 2H), 1.29 – 1.21 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 173.33, 141.12, 132.24, 131.95, 118.70, 111.33, 111.32, 62.01, 52.69, 33.94, 30.11, 18.46. 3A1-4' weighed to obtain 677 mg, molar yield: 34%. 1 H NMR (400 MHz, CDCl3) δ 7.69 –7.63 (m, 2H), 7.62 – 7.55 (m, 2H), 4.56 – 4.46 (m, 1H), 4.34 (d, J = 9.4 Hz,1H), 2.74 – 2.65 (m, 1H), 1.73 – 1.66 (m, 1H), 1.51 (t, J = 4.9 Hz, 1H); 13CNMR (101 MHz, CDCl3) δ 174.68, 139.70, 132.35, 128.51, 118.51, 111.40, 67.90, 31.24, 25.82, 21.44.

[0076] Example 8: Preparation of 3A1-5 and 3A1-5'

[0077]

[0078] At 25°C (room temperature), methyl 3-chlorophenylacetate 1A1-5 (1.99 g, 10 mmol, 1.0 equivalent) and cesium carbonate (9.77 g, 30 mmol, 3.0 equivalent) were added to a 250 mL three-necked round-bottom flask. Under N2 protection, an acetonitrile solution (40 mL) of epibromopropane (1.51 g, 11 mmol, 1.1 equivalent) was added, and the system was stirred overnight at 80°C. After 24 h of reaction, a TLC sample (n-hexane:ethyl acetate = 4:1) showed that most of the starting material 1A1-5 had reacted. The reaction mixture was removed from the oil bath and brought to room temperature. Cesium carbonate was removed by filtration, and the filtrate was collected. The filter cake was washed three times with ethyl acetate (25 mL * 3), and crude 3A1-5 was obtained by vacuum distillation. The crude product was purified by column chromatography (eluent: n-hexane:ethyl acetate = ... (100 / 0~70 / 30) A pale yellow oily substance 3A1-5 and a pale yellow oily cyclic byproduct 3A1-5' were obtained, both of which were pure. The product was dried under vacuum, and 3A1-5 was weighed to obtain 560 mg. The molar yield was 34%. 1 H NMR (400 MHz, CDCl3) δ 7.36 – 7.31 (q, J = 1.4 Hz, 1H), 7.29 –7.21 (m, 3H), 4.17 – 4.00 (m, 2H), 3.42 – 3.33 (m, 1H), 3.23 – 3.11 (m, 1H), 2.23 – 2.11 (m, 1H), 1.78 – 1.66 (m, 1H), 1.25 – 1.20 (m, 1H), 1.17 (t, J =7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 173.38, 137.69, 133.87, 131.26, 129.53, 129.37, 127.65, 62.28, 61.38, 33.70, 29.63, 18.36, 14.07. 3A1-5' weighed to obtain 626 mg, molar yield: 30%, dr > 20:1. 1H NMR (400 MHz, CDCl3) δ 7.46 – 7.42 (m, 1H), 7.35 –7.23 (m, 3H), 4.45 (dd, J = 9.3, 4.6 Hz, 1H), 4.27 (d, J = 9.3 Hz, 1H), 2.64– 2.55 (m, 1H ), 1.66 – 1.58 (m, 1H), 1.37 (t, J = 4.8 Hz, 1H); 13 C NMR (101MHz, CDCl3) δ 175.47, 136.29, 134.36, 129.90, 128.43, 127.83, 126.49, 68.10,31.29, 25.27, 20.53.

[0079] Example 9: Preparation of 3A1-6 and 3A1-6'

[0080]

[0081] At 25°C (room temperature), methyl 2-pyridine acetate 1A1-6 (1.51 g, 10 mmol, 1.0 equivalent) and cesium carbonate (9.77 g, 30 mmol, 3.0 equivalent) were added to a 250 mL three-necked round-bottom flask. Under N2 protection, an acetonitrile solution (40 mL) of epibromopropane (1.51 g, 11 mmol, 1.1 equivalent) was added, and the system was stirred overnight at 80°C. After 24 h of reaction, a TLC sample (n-hexane:ethyl acetate = 4:1) showed that most of the starting material 1A1-6 had reacted. The reaction mixture was removed from the oil bath and brought to room temperature. Cesium carbonate was removed by filtration, and the filtrate was collected. The filter cake was washed three times with ethyl acetate (25 mL * 3), and crude 3A1-6 was obtained by vacuum distillation. The crude product was purified by column chromatography (eluent: n-hexane:ethyl acetate = ... (100 / 0~70 / 30) A pale yellow oily substance 3A1-6 and a pale yellow oily cyclic byproduct 3A1-6' were obtained, both of which were pure. The product was dried under vacuum, and 3A1-6 was weighed to obtain 394 mg, with a molar yield of 19%. 1H NMR (400 MHz, CDCl3) δ 8.56 – 8.49 (m, 1H), 7.75 (td, J = 7.7,1.8 Hz, 1H), 7.43 (dt, J = 7.9, 1.1 Hz, 1H), 7.31 – 7.24 (m, 1H), 4.04 – 3.92(m, 1H), 3.61 (s, 3H), 2.77 – 2.64 (m, 1H), 2.42 – 2.27 (m, 1H), 1.90 – 1.77(m, 1H), 1.22 – 1.11 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 173.69, 156.39, 148.42, 137.24, 127.09, 122.84, 63.03, 52.43, 35.50, 31.14, 20.18. 3A1-6' weighed to obtain 491 mg, molar yield: 28%. 1 H NMR (400 MHz, CDCl3) δ 8.50 – 8.40 (m, 1H), 8.16 –8.05 (m, 1H), 7.73 – 7.62 (m, 1H), 7.21 – 7.09 (m, 1H), 4.42 (dd, J = 9.2,4.7 Hz, 1H), 4.29 (d, J = 9.2 Hz, 1H), 2.96 – 2.85 (m, 1H), 2.15 – 2.08 (m,1H), 1.50 – 1.41 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 175.10, 153.64, 149.14, 136.28, 122.43, 121.83, 67.91, 32.00, 27.53, 22.76.

[0082] Example 10: Preparation of 3A2-1

[0083]

[0084] At 25°C (room temperature), 1.48 g (10 mmol, 1.0 equivalent) of 3-isochromone 1A2-1 and cesium carbonate (9.77 g, 30 mmol, 3.0 equivalent) were added to a 250 mL three-necked round-bottom flask. Under N2 protection, a solution of acetonitrile (1.51 g, 11 mmol, 1.1 equivalent) of epichlorohydrin was added (40 mL), and the system was stirred overnight at 80°C. After 24 h of reaction, a TLC sample (n-hexane:ethyl acetate = 4:1) showed that most of the starting material 1A2-1 had reacted. The reaction mixture was removed from the oil bath and brought to room temperature. Cesium carbonate was removed by filtration, and the filtrate was collected. The filter cake was washed three times with ethyl acetate (25 mL * 3), and crude 3A2-1 was obtained by vacuum distillation. The crude product was purified by column chromatography (eluent: n-hexane:ethyl acetate = ... (100 / 0~30 / 70) A pale yellow oily substance 3A2-1 was obtained, pure product, dried by vacuum pump, weighed to obtain 840 mg, molar yield: 41%, dr value 1.2:1. 1 H NMR (400 MHz, CDCl3) δ 7.36 – 7.23 (m, 3H), 7.05 – 7.95 (m, 1H), 5.54 – 5.48 (m, 1H), 5.20 (d, J = 13.2 Hz, 1H), 3.79 – 3.72 (m, 1H), 3.06 – 2.98 (m, 1H), 2.11 – 1.97 (m, 2H), 1.70 (s, 1H), 1.61 – 1.56 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 173.73,134.44, 131.27, 128.27, 127.11, 124.85, 124.84, 69.23, 60.39, 33.52, 29.59,12.52.

[0085] Example 11: Preparation of 3A2-2

[0086]

[0087] At 25°C (room temperature), N-Boc-2-oxoindole 1A2-2 (2.33 g, 10 mmol, 1.0 equivalent) and potassium carbonate (4.15 g, 30 mmol, 3.0 equivalent) were added to a 250 mL three-necked round-bottom flask. Under N2 protection, an acetonitrile solution (40 mL) of epichlorohydrin (1.51 g, 11 mmol, 1.1 equivalent) was added, and the system was stirred overnight at 80°C. After 24 h of reaction, a TLC sample (n-hexane:ethyl acetate = 4:1) showed that most of the starting material 1A2-2 had reacted. The reaction mixture was removed from the oil bath and brought to room temperature. The potassium carbonate was removed by filtration, and the filtrate was collected. The filter cake was washed three times with ethyl acetate (25 mL * 3), and the crude product 3A2-2 was obtained by vacuum distillation. The crude product was purified by column chromatography (eluent: n-hexane:ethyl acetate = ... (100 / 0~30 / 70) A pale yellow oily substance 3A2-2 was obtained, pure product. It was dried under vacuum and weighed to obtain 1.88 g, molar yield: 65%. 1 H NMR (400 MHz, CDCl3) δ7.92 (d, J = 8.2 Hz, 1H), 7.33 – 7.26 (m, 1H), 7.16 – 7.11 (m, 1H), 7.00 (d,J = 7.5 Hz, 1H), 4.00 (s, 1H), 3.79 (s, 1H), 2.38 – 2.21 (m, 1H), 2.03 – 1.93 (m, 1H), 1.79 (s, 1H), 1.63 (s, 9H), 1.57 – 1.54 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 175.22, 149.39, 140.01, 127.41, 126.66, 124.24, 120.32, 115.38,84.58, 60.25, 36.55, 31.68, 28.17, 23.44.

[0088] Example 12: Preparation of 3A2-3 and 3A2-3'

[0089]

[0090] At 25°C (room temperature), N-phenylindolone 1A2-3 (2.09 g, 10 mmol, 1.0 equivalent) and potassium carbonate (4.15 g, 30 mmol, 3.0 equivalent) were added to a 250 mL three-necked round-bottom flask. Under N2 protection, an acetonitrile solution (40 mL) of epibromopropane (1.51 g, 11 mmol, 1.1 equivalent) was added, and the system was stirred overnight at 80°C. After 24 h of reaction, a TLC sample (n-hexane:ethyl acetate = 4:1) showed that most of the starting material 1A2-3 had reacted. The reaction mixture was removed from the oil bath and brought to room temperature. The potassium carbonate was removed by filtration, and the filtrate was collected. The filter cake was washed three times with ethyl acetate (25 mL * 3), and the crude product 3A2-3 was obtained by vacuum distillation. The crude product was purified by column chromatography (eluent: n-hexane:ethyl acetate = ... (100 / 0~30 / 70) A pale yellow oily substance 3A2-3 and a pale yellow oily byproduct 3A2-3' were obtained, both of which were pure. The product was dried by vacuum pump, and 3A2-3 was weighed to obtain 1.14 g, with a molar yield of 43%. 1 H NMR (400 MHz, CDCl3) δ 7.55 – 7.49 (m, 2H), 7.46 – 7.38 (m, 3H), 7.24 –7.18 (m, 1H), 7.13 – 7.04 (m, 2H), 6.93 (d, J = 7.9 Hz, 1H), 4.14 – 4.04 (m,1H), 3.94 – 3.84 (m, 1H), 2.42 – 2.33 (m, 1H), 2.06 – 1.99 (m, 1H), 1.75 (s,1H), 1.65 – 1.59 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 175.90, 144.11, 134.85, 129.68, 128.07, 127.58, 127.11, 126.77, 122.63, 120.80, 109.78, 60.90, 34.90, 31.35, 22.90. 3A2-3' weighed to obtain 132 mg, molar yield: 5%. 1H NMR (400 MHz, CDCl3) δ 7.57 –7.47 (m, 4H), 7.43 – 7.36 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.19 – 7.13 (m,1H), 7.12 – 7.07 (m, 1H), 4.37 (s, 1H), 4.33 – 4.22 (m, 2H), 3.21 – 3.08 (m,1H), 2.90 – 2.80 (m, 1H), 2.26 – 2.13 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ147.14, 135.83, 132.48, 129.38, 127.17, 127.07, 126.41, 120.70, 120.31,116.72, 109.74, 84.95, 72.45, 64.10, 27.65.

[0091] Example 13: Preparation of 3A2-4

[0092]

[0093] At 25°C (room temperature), 1.47 g (10 mmol, 1.0 equivalent) of 1-methylindolin-2-one 1A2-4 and cesium carbonate (9.77 g, 30 mmol, 3.0 equivalent) were added to a 250 mL three-necked round-bottom flask. Under N2 protection, a solution of acetonitrile (1.51 g, 11 mmol, 1.1 equivalent) of epichlorohydrin was added (40 mL), and the system was stirred overnight at 80°C. After 24 h of reaction, a TLC sample (n-hexane:ethyl acetate = 4:1) showed that most of the starting material 1A2-4 had reacted. The reaction mixture was removed from the oil bath and brought to room temperature. Cesium carbonate was removed by filtration, and the filtrate was collected. The filter cake was washed three times with ethyl acetate (25 mL * 3), and crude 3A2-4 was obtained by vacuum distillation. The crude product was purified by column chromatography (eluent: n-hexane:ethyl acetate = ... (100 / 0~30 / 70) A pale yellow oily substance 3A2-4 was obtained, pure product, dried by vacuum pump, weighed to obtain 853 mg, molar yield: 42%. 1H NMR (400 MHz, CDCl3)δ 7.32 – 7.26 (m, 1H), 7.07 – 7.01 (m, 2H), 6.96 – 6.87 (m, 1H), 4.13 – 4.00(m, 1H), 3.92 – 3.74 (m, 1H), 3.27 (s, 3H), 2.38 – 2.19 (m, 1H), 1.99 –1.86(m, 1H), 1.66 (s, 1H), 1.59 – 1.47 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 176.47,144.28, 127.72, 127.25, 122.13, 120.51, 108.47, 61.09, 34.24, 31.16, 26.74,22.14。

Claims

1. A method for preparing a 2-(hydroxymethyl)spirocyclopropane compound, characterized in that, The product 3A of hydroxymethylspirocyclopropane was prepared by reacting starting substrate 1A with epibromopropane in the presence of an inorganic base and an organic solvent. The initial substrate 1A structure is as follows: or ; The structure of the hydroxymethylspirocyclopropane product 3A is as follows: or ; B is an aryl group or its derivative, and EWG is CO2Me.

2. The preparation method according to claim 1, characterized in that, Starting with substrate 1A1, an epoxide bromide intermediate of formula 2A1 was prepared via a nucleophilic substitution reaction with epoxide bromide in the presence of an inorganic base and an organic solvent. This intermediate was then further prepared via a nucleophilic substitution ring-opening reaction with lithium hexamethyldisilamide to yield hydroxymethylspirocyclopropane product formula 3A1. ， Where EWG stands for CO2Me; B stands for... , or .

3. The preparation method according to claim 1, characterized in that, Hydroxymethylspirocyclopropane product 3A1 or 3A2 is prepared from a starting substrate of formula 1A1 or 1A2 in the presence of an inorganic base and an organic solvent via a one-step tandem nucleophilic substitution-nucleophilic substitution epoxide ring-opening reaction. ， B is an aryl group or a derivative thereof; The structures of the hydroxymethylspirocyclopropane products, formula 3A1 and 3A2, are as follows: ， Where EWG stands for CO2Me; R1 stands for CN, Cl, or H; X1 is either C or N; X2 is 0 or N. When X2 is 0, R2 does not exist. When X2 is N, R2 is Boc, Ph, or Me. n = 0 or 1.

4. The preparation method according to claim 2, characterized in that, The specific structure of the hydroxymethylspirocyclopropane product 3A1 is as follows: 。 5. The preparation method according to claim 3, characterized in that, The specific structure of the hydroxymethylspirocyclopropane product, formula 3A1 or 3A2, is as follows: 。 6. The preparation method according to claim 1, 2 or 3, characterized in that, The inorganic base is cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert-butoxide, or potassium hydroxide.

7. The preparation method according to claim 1, 2 or 3, characterized in that, The organic solvent is acetonitrile, acetone, tetrahydrofuran, toluene, dioxane, or dichloromethane.

8. The preparation method according to claim 2, characterized in that, The nucleophilic substitution epoxy ring-opening reaction was carried out in the presence of anhydrous tetrahydrofuran.

9. The preparation method according to claim 2 or 3, characterized in that, The starting substrate of formula 1A1 or 1A2, the inorganic base, and the molar equivalent ratio of epoxide bromopropane are 1:3:1.

1.

10. The preparation method according to claim 3, characterized in that, The reaction temperature for the one-step tandem nucleophilic substitution-nucleophilic substitution epoxy ring-opening reaction is 25~100℃.

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