A method for preparing 5-bromobenzo[D][1,3]dioxo-4-amine

Abstract

The invention provides a method for preparing 5-bromobenzo[D][1,3]dioxy-4-amine, and belongs to the field of chemical synthesis. Compared with the method for preparing 5-bromobenzo[D][1,3]dioxy-4-amine in the prior art, on the one hand, the method for preparing 5-bromobenzo[D][1,3]dioxy-4-amine in the present invention is safe to operate, avoids the use of expensive DPPA reagent, and the raw material price used in the present invention is low, which reduces production cost; on the other hand, the 5-bromobenzo[D][1,3]dioxy-4-amine prepared by the inventive method has high purity and high yield, and is suitable for large-scale synthesis of 5-bromobenzo[D][1,3]dioxy-4-amine.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and specifically relates to a method for preparing 5-bromobenzo[D][1,3]dioxo-4-amine. Background Art

[0002] 5-Bromobenzo[D][1,3]dioxo-4-amine is an important pharmaceutical intermediate. Patent application with publication number CN1471527A reports that it can be used to synthesize quinazoline derivatives for treating solid tumors.

[0003]

[0004] Patent application number W202140469A discloses a method for preparing 5-bromobenzo[D][1,3]dioxo-4-amine (synthesis route is shown below), which is divided into two steps: (1) n-butyl lithium (1.6M hexane solution, 5.7mL, 9.1mmol) was added dropwise to a THF solution (40mL) of diisopropylamine (1.3mL, 9.2mmol) at -80°C and stirred for 20 minutes. A THF solution (10mL) of 4-bromo-1,2-(methylenedioxy)benzene (1.0mL, 8.4mmol) was added dropwise to the solution and stirred for 40 minutes. After stirring for 45 minutes while blowing carbon dioxide into the solution, the solution was further stirred at room temperature for 19 hours. 2M hydrochloric acid was added to the reaction solution for neutralization, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the precipitated solid was filtered out, washed with hexane and dried to obtain 4-bromo-3-carboxy-1,2-methylenedioxybenzene (yield: 1.1 g). (2) At room temperature, 4-bromo-3-carboxy-1,2-methylenedioxybenzene (1.0 g, 4.1 mmol) was added to the distilled water. To the oxane solution (15 mL) was added TEA (0.63 mL, 4.5 mmol), tert-butyl alcohol (3.2 mL, 34 mmol) and diphenylphosphoryl azide (DPPA, 0.97 mL, 4.5 mmol), and the mixture was heated under reflux for 3 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution, water, and saturated saline in sequence, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and dried. Under ice cooling, 4M hydrochloric acid-ethyl acetate solution (10 mL, 40 mmol) was added to the ethyl acetate solution (6.0 mL) of the intermediate, and the mixture was stirred at room temperature for 16 hours. A 2M sodium hydroxide aqueous solution was added to the reaction solution for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain 3-amino-4-bromo-1,2-methylenedioxybenzene (i.e., 5-bromobenzo[D][1,3]dioxy-4-amine, yield 0.80 g).

[0005]

[0006] However, on the one hand, the DPPA reagent used in the second step of the above method is expensive, which increases the production cost, and DPPA is a azido compound, which is relatively dangerous and not suitable for large-scale synthesis of 5-bromobenzo[D][1,3]dioxo-4-amine. On the other hand, the total yield of the above method is low and needs to be further improved. Summary of the invention

[0007] In order to overcome the above problems, the purpose of the present invention is to provide a method for preparing 5-bromobenzo[D][1,3]dioxo-4-amine with low raw material price, low production cost, safe operation and high yield.

[0008] The present invention provides a method for preparing 5-bromobenzo[D][1,3]dioxo-4-amine, which comprises the following steps:

[0009]

[0010] (1) Using compound 2 as a raw material to prepare compound 3;

[0011] (2) Compound 4 was prepared using compound 3 as raw material.

[0012] Furthermore, the operation of step (1) is as shown in step (1.1): compound 2, an amine source, an organic base and an amino protecting agent react, and deprotection is performed to obtain compound 3;

[0013] Alternatively, the operation of step (1) is as shown in step (1.2): first, an acyl chloride reagent is added to compound 2 to react to obtain an intermediate product, and then ammonia water is added to continue the reaction to obtain compound 3.

[0014] Furthermore, in step (1.1), the amine source is ammonium bicarbonate, the organic base is pyridine, and the amino protecting agent is di-tert-butyl dicarbonate;

[0015] Alternatively, in step (1.2), the acyl chloride reagent is oxalyl chloride.

[0016] Further, in step (1.1), the equivalent ratio of the compound 2, the amine source, the organic base and the amino protecting agent is 1: (1.5-2.5): (0.5-1.0): (1.25-1.75), preferably 1: 2: 0.7: 1.5; the solvent of the reaction is an organic solvent, preferably tetrahydrofuran or dichloromethane; the reaction temperature is 20-70° C., preferably 60° C., and the reaction time is 2-16 h, preferably 3 h;

[0017] Alternatively, in step (1.2), the equivalent ratio of compound 2 to acyl chloride reagent is 1:(1.0-1.5), preferably 1:1.2, the solvent of the reaction is an organic solvent, preferably one or a mixture of dichloromethane and N,N-dimethylformamide; the reaction temperature is room temperature, and the reaction time is 16-20h; the mass volume ratio of compound 2 to ammonia water is 1:(1.5-2.5) g / mL, preferably 1:2 g / mL; the temperature of the continued reaction is room temperature, and the continued reaction time is 0.5-2h.

[0018] Furthermore, the operation of step (2) is as follows: compound 3, hypochlorite and base react to obtain compound 4.

[0019] Furthermore, the hypochlorite is sodium hypochlorite, and the alkali is sodium hydroxide.

[0020] Furthermore, the equivalent ratio of the compound 3, hypochlorite and alkali is 1:(1-3):(0.5-1.5), preferably 1:2:1; the solvent of the reaction is water, an organic solvent or a mixture of water and an organic solvent, and all organic solvents are preferably methanol, tetrahydrofuran, ethanol or dioxane; the reaction temperature is 10-70°C, preferably 20-60°C, and the reaction time is 0.5-12h, preferably 2 hours.

[0021] Furthermore, the preparation method of compound 2 comprises the following steps:

[0022]

[0023] Compound 1, a non-nucleophilic strong base reagent and carbon dioxide react to obtain compound 2.

[0024] Furthermore, the non-nucleophilic strong base reagent is lithium diisopropylamide, and the carbon dioxide is carbon dioxide gas or carbon dioxide solid.

[0025] Furthermore, the equivalent ratio of the compound 1, the non-nucleophilic strong base reagent and the carbon dioxide is 1:(1.0-1.5):(1-3), preferably 1:1.1:2;

[0026] The reaction temperature is -50°C to -90°C, preferably -78°C, and the reaction time is 0.5-24h, preferably 1-2h; the reaction solvent is an organic solvent, preferably tetrahydrofuran.

[0027] In the present invention, room temperature refers to 25±5°C.

[0028] Compared with the method for preparing 5-bromobenzo[D][1,3]dioxy-4-amine in the prior art, on the one hand, the method for preparing 5-bromobenzo[D][1,3]dioxy-4-amine of the present invention is safe to operate, avoids the use of expensive DPPA reagent, and uses low-priced raw materials, thereby reducing production costs; on the other hand, the 5-bromobenzo[D][1,3]dioxy-4-amine prepared by the method of the present invention has high purity and high yield, and is suitable for large-scale synthesis of 5-bromobenzo[D][1,3]dioxy-4-amine.

[0029] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0030] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0031] The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products.

[0032] The route for synthesizing 5-bromobenzo[D][1,3]dioxo-4-amine in the embodiment of the present invention is as follows:

[0033]

[0034] Example 1: Synthesis of 5-bromobenzo[D][1,3]dioxo-4-amine

[0035] Step 1:

[0036]

[0037] 2.5 L of tetrahydrofuran and diisopropylamine (302.0 g, 2.98 mol, 1.2 eq) were mixed and stirred, cooled to -50°C, and 2.5 mol / L of n-butyllithium (1.1 L, 2.74 mol, 1.1 eq) was dropped into the mixture. After the addition, the temperature was maintained for 1 hour to obtain a tetrahydrofuran solution of lithium diisopropylamide. In another reaction bottle, add 5-bromo-4-isothiocyanatobenzo[d][1,3]diazole (Compound 1, 500.0 g, 2.49 mol, 1 eq) and 2.5 L of tetrahydrofuran, cool to -78°C, and dropwise add the prepared tetrahydrofuran solution of lithium diisopropylamide (1.1 eq). After the addition, keep the temperature at -78°C and react for 1 hour. After the reaction is complete, maintain the temperature at -78°C and introduce CO2 gas (218.0 g, 4.97 eq, 2.0 eq). After the introduction is complete, maintain the temperature and react for 1 hour. After the reaction is complete, the reaction solution is poured into 8L of water, 5L of methyl tert-butyl ether is added to extract impurities, the aqueous phase is extracted once again with 5L of methyl tert-butyl ether, and then 10L of methyl tert-butyl ether is added to the aqueous phase, and the pH is adjusted to between 1-3 with hydrochloric acid, extracted, separated, the aqueous phase is extracted with 5L of methyl tert-butyl ether, the organic phases are combined, washed with 5L of water, and the organic phase is concentrated until a large amount of solid precipitates, 500mL of petroleum ether is added for pulping, filtered, and dried to obtain 575.0g of 5-bromobenzo[1,3]dioxole-4-carboxylic acid (Compound 2), with a yield of 94% and a purity of 98%.

[0038] H NMR (400MHz, DMSO, δ): 12.75 (s, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 6.26 (br.s., 2H).

[0039] Step2:

[0040]

[0041] 5-Bromobenzo[1,3]dioxole-4-carboxylic acid (compound 2, 530 g, 2.16 mol, 1 eq) was dissolved in 4 L of tetrahydrofuran, and ammonium bicarbonate (342 g, 4.33 mol, 2 eq) and pyridine (120 g, 1.51 mol, 0.7 eq) were added and stirred evenly. Di-tert-butyl dicarbonate (708 g, 3.24 mol, 1.5 eq) was dissolved in 1.3 L of tetrahydrofuran and slowly added dropwise to the reaction bottle. After the addition was completed, the temperature was raised to 60 °C and reacted for 3 h. After the reaction is complete, 8L of water and 8L of ethyl acetate are added, stirred and separated, the aqueous phase is extracted with 5L of ethyl acetate, the organic phases are combined, washed once with 8L of water, concentrated until a large amount of solid precipitates, 500mL of petroleum ether is added for slurrying, filtered, and dried to obtain 455g of 5-bromobenzo[d][1,3]dioxo-4-carboxamide (compound 3), with a yield of 87% and a purity of 97.2%.

[0042] H NMR (400MHz, DMSO, δ): 6.26 (br.s., 2H), 7.22 (s, 1H), 7.40 (s, 1H), 7.90 (br.s., 2H).

[0043] Step 3:

[0044]

[0045] 5-bromobenzo[d][1,3]dioxo-4-carboxamide (compound 3, 438g, 1.79mol, 1eq) was dispersed in 6.6L water, sodium hydroxide (72g, 1.79mol, 1eq) was dissolved in 12% sodium hypochlorite (2.23kg, 3.6mol, 2eq), and slowly dripped into the reaction solution, keeping the temperature at 20-50°C, reacting for 1h after the dripping, and then heating to 60°C for 1h. After the reaction was complete, the reaction solution was cooled to room temperature, adjusted to pH=6-8 with 2N hydrochloric acid, filtered, and the filter cake was rinsed with 1.5L water and dried to obtain 370g 5-bromobenzo[D][1,3]dioxo-4-amine (compound 4), with a yield of 96% and a purity of 99.1%.

[0046] HNMR(400M,DMSO): 5.32(br.s.,2H), 6.07(br.s.,2H), 6.43(s,1H), 7.07(s,1H).

[0047] Example 2: Synthesis of 5-bromobenzo[D][1,3]dioxo-4-amine

[0048] Step 1:

[0049]

[0050] Add 4.5 L of tetrahydrofuran to 5-bromo-4-isothiocyanatobenzo[d][1,3]diazole (compound 1, 910 g, 4.53 mol, 1 eq), cool to -78°C, dropwise add 2.0 mol / L tetrahydrofuran solution of lithium diisopropylamide (2.5 kg, 4.98 mol, 1.1 eq), after addition, maintain the temperature at -78°C and pass CO2 gas (218.0 g, 4.97 eq, 2.0 eq), after completion of the introduction, maintain the temperature for reaction for 1 h. After the reaction is complete, the reaction solution is poured into 8L of water, 5L of methyl tert-butyl ether is added to extract impurities, the aqueous phase is extracted once with 5L of methyl tert-butyl ether, and then 10L of methyl tert-butyl ether is added to the aqueous phase, and the pH is adjusted to between 1-3 with hydrochloric acid, extracted, separated, the aqueous phase is extracted with 5L of methyl tert-butyl ether, the organic phases are combined, washed with 5L of water, and the organic phase is concentrated until a large amount of solid precipitates, 500mL of petroleum ether is added for pulping, filtered, and dried to obtain 992g of 5-bromobenzo[1,3]dioxole-4-carboxylic acid (Compound 2), with a yield of 92% and a purity of 97.2%.

[0051] H NMR (400MHz, DMSO, δ): 12.75 (s, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 6.26 (br.s., 2H).

[0052] Step2:

[0053]

[0054] 5-Bromobenzo[1,3]dioxole-4-carboxylic acid (Compound 2, 100 g, 408 mmol, 1 eq) was dissolved in 500 mL of dichloromethane, and ammonium bicarbonate (65 g, 816 mmol, 2 eq), pyridine (23 g, 286 mmol, 0.7 eq) and di-tert-butyl dicarbonate (112 g, 510 mmol, 1.25 eq) were added and reacted at room temperature overnight. After the reaction is complete, the reaction solution is poured into 1L of water, the pH is adjusted to about 1-2 with hydrochloric acid, the dichloromethane is concentrated to dryness, 200mL of tetrahydrofuran and 700mL of ethyl acetate are added, extracted, the aqueous phase is extracted with 500mL of ethyl acetate, the organic phases are combined, washed once with 500mL of water, concentrated until a large amount of solid precipitates, 100mL of petroleum ether is added for pulping, filtered, and dried to obtain 91g of 5-bromobenzo[d][1,3]dioxo-4-carboxamide (Compound 3), with a yield of 90% and a purity of 99.1%.

[0055] H NMR (400MHz, DMSO, δ): 6.26 (br.s., 2H), 7.22 (s, 1H), 7.40 (s, 1H), 7.90 (br.s., 2H).

[0056] Step 3:

[0057]

[0058] 5-Bromobenzo[d][1,3]dioxo-4-carboxamide (compound 3, 20 g, 82 mmol, 1 eq) was dispersed in 200 mL of dioxane, and 12% sodium hypochlorite (153 g, 246 mmol, 3 eq) was slowly dripped into the reaction solution, and the temperature was maintained at 20-30°C. After the addition was completed, the reaction was allowed to proceed for 1 h (0.5-12 h). After the reaction was complete, sodium hydroxide (3.3 g, 82 mmol, 1 eq) was dissolved in 30 g of water, and dripped into the reaction solution. The temperature was raised to 60°C and the reaction was continued for 1 h. After the reaction is complete, the reaction solution is cooled to room temperature, 300 mL of methyl tert-butyl ether and 100 mL of water are added for extraction, and 200 mL of methyl tert-butyl ether is added to the aqueous phase for extraction, the organic phases are combined, washed once with 200 mL of water, and a large amount of solid is concentrated. A mixed solution of dichloromethane and n-heptane (volume ratio of 1:3) is used as an eluent to pass through a fast column, and the organic phase is collected, concentrated to dryness, and dried to obtain 15 g of 5-bromobenzo[D][1,3]dioxy-4-amine (compound 4), with a yield of 84% and a purity of 98.4%.

[0059] HNMR(400M,DMSO): 5.32(br.s.,2H), 6.07(br.s.,2H), 6.43(s,1H), 7.07(s,1H).

[0060] Example 3: Synthesis of 5-bromobenzo[D][1,3]dioxo-4-amine

[0061] Step 1:

[0062]

[0063] Mix 6.5L tetrahydrofuran and diisopropylamine (785g, 7.76mol, 1.2eq) with stirring, cool to -70°C, drop 2.5mol / L n-butyllithium (2845mL, 7.11mol, 1.1eq) into it, and after the addition, keep the temperature at -30°C to -90°C for 1 hour (0.5-4h) to obtain a tetrahydrofuran solution of lithium diisopropylamide. In another reaction bottle, add 5-bromo-4-isothiocyanatobenzo[d][1,3]diazole (Compound 1, 1300 g, 6.47 mol, 1 eq) and 6.5 L of tetrahydrofuran, cool to -78°C, and dropwise add the prepared tetrahydrofuran solution of lithium diisopropylamide (1.1 eq, 7.11 mol). After the addition, keep the temperature at -78°C for 1 h; add the reaction solution dropwise into dry ice (3 eq, 21.33 mol). After the addition, keep the temperature for 1 h. After the reaction is complete, the reaction solution is poured into 15L of water, 10L of methyl tert-butyl ether is added to extract impurities, the aqueous phase is extracted once with 8L of methyl tert-butyl ether, and then 15L of methyl tert-butyl ether is added to the aqueous phase, the pH is adjusted to between 1-3 with hydrochloric acid, extracted, separated, the aqueous phase is extracted with 10L of methyl tert-butyl ether, the organic phases are combined, washed with 10L of water, and the organic phase is concentrated until a large amount of solid precipitates, 1500mL of petroleum ether is added for pulping, filtered, and dried to obtain 1440g of 5-bromobenzo[1,3]dioxole-4-carboxylic acid (Compound 2), with a yield of 91% and a purity of 97.8%.

[0064] H NMR (400MHz, DMSO, δ): 12.75 (s, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 6.26 (br.s., 2H).

[0065] Step2:

[0066]

[0067] Dissolve 5-bromobenzo[1,3]dioxole-4-carboxylic acid (compound 2, 50g, 204mmol, 1eq) in 200mL dichloromethane, add 4mL N,N-dimethylformamide, cool to 0°C, slowly add oxalyl chloride (31g, 245mmol, 1.2eq), and after the addition is complete, warm to room temperature and stir at room temperature for 18h. After the reaction is complete, concentrate until there is no fraction, add 100mL ammonia water and stir at room temperature for 1h, filter, rinse the solid with 200mL water, and dry to obtain 44g 5-bromobenzo[d][1,3]dioxo-4-carboxamide (compound 3), with a yield of 88% and a purity of 98.5%.

[0068] H NMR (400MHz, DMSO, δ): 6.26 (br.s., 2H), 7.22 (s, 1H), 7.40 (s, 1H), 7.90 (br.s., 2H).

[0069] Step 3:

[0070]

[0071] Disperse 5-bromobenzo[d][1,3]dioxo-4-carboxamide (compound 3, 490 g, 2.01 mmol, 1 eq) in 2 L of tetrahydrofuran, dissolve sodium hydroxide (120 g, 3.02 mol, 1.5 eq) in 12% sodium hypochlorite (3.74 kg, 6.03 mol, 3 eq), and slowly drip into the reaction solution, keeping the temperature at 20-30 ° C. After the addition is completed, react for 1 hour, and then heat to 60 ° C. and react for 1 hour. After the reaction is complete, the reaction solution is cooled to room temperature, 4 L of methyl tert-butyl ether and 2 L of water are added for extraction, and the aqueous phase is extracted by adding 2 L of methyl tert-butyl ether. The organic phases are combined, washed once with 2 L of water, and a large amount of solids are concentrated. A mixed solution of dichloromethane and n-heptane (volume ratio of 1:3) is used as an eluent to pass through a fast column, and the organic phase is collected, concentrated to dryness, and dried to obtain 380 g of 5-bromobenzo[D][1,3]dioxy-4-amine (compound 4), with a yield of 83% and a purity of 98.7%.

[0072] HNMR(400M, DMSO): 5.32(br.s.,2H), 6.07(br.s.,2H), 6.43(s,1H), 7.07(s,1H).

Claims

1. A method for preparing 5-bromobenzo[D][1,3]dioxo-4-amine, characterized in that: It includes the following steps: (1) Using compound 2 as a raw material to prepare compound 3; (2) Compound 4 was prepared using compound 3 as a raw material; In step (1), compound 2, an amine source, an organic base and an amino protective agent react and deprotect to obtain compound 3; the amine source is ammonium bicarbonate; the organic base is pyridine; the amino protective agent is di-tert-butyl dicarbonate; the equivalent ratio of compound 2, amine source, organic base and amino protective agent is 1:2:0.7:1.5; the solvent of the reaction is tetrahydrofuran; the reaction temperature is 60°C and the reaction time is 3h; In step (2), compound 3, hypochlorite and base react to obtain compound 4; the hypochlorite is sodium hypochlorite; the base is sodium hydroxide; the equivalent ratio of compound 3, hypochlorite and base is 1:2:1; the solvent of the reaction is water; the reaction temperature is 20-60°C, and the reaction time is 2h.

2. The method according to claim 1, characterized in that: The preparation method of the compound 2 comprises the following steps: Compound 1, a non-nucleophilic strong base reagent and carbon dioxide react to obtain compound 2.

3. The method according to claim 2, characterized in that: The non-nucleophilic strong base reagent is lithium diisopropylamide, and the carbon dioxide is carbon dioxide gas or carbon dioxide solid.

4. The method according to claim 3, characterized in that: The equivalent ratio of the compound 1, the non-nucleophilic strong base reagent and the carbon dioxide is 1:(1.0-1.5):(1-3); The reaction temperature is -50°C to -90°C, the reaction time is 0.5-24h, and the reaction solvent is an organic solvent.

5. The method according to claim 4, characterized in that: The equivalent ratio of the compound 1, the non-nucleophilic strong base reagent and the carbon dioxide is 1:1.1:2; The reaction temperature is -78°C, the reaction time is 1-2h, and the reaction solvent is tetrahydrofuran.

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