A method for preparing 3-amino-5-ethoxy-benzoic acid

Abstract

The invention provides a method for preparing 3-amino-5-ethoxy-benzoic acid, wherein an intermediate compound is prepared from a low-cost starting raw material, and then Hofmann degradation and esterification are further performed to prepare 3-amino-5-ethoxy-benzoic acid. The method of the invention has low cost, mild reaction conditions, and simple steps; the prepared 3-amino-5-ethoxy-benzoic acid has high purity and high yield, and the whole reaction does not need column purification, and is easy to realize industrial production, and has broad application prospects.

Description

Technical Field

[0001] The invention belongs to the field of compound synthesis, and specifically relates to a method for preparing 3-amino-5-ethoxy-benzoic acid. Background Art

[0002] Alzheimer's disease (AD) is a progressive neurodegenerative disease with an insidious onset. Clinically, it is characterized by global dementia manifestations such as memory impairment, aphasia, apraxia, agnosia, visual-spatial skill impairment, executive dysfunction, and personality and behavioral changes. The cause is still unknown. Those who develop the disease before the age of 65 are called precocious dementia; those who develop the disease after the age of 65 are called senile dementia. The international patent application with publication number WO2004050619A1 discloses a hydroxyethylamine derivative for Alzheimer's disease, and 3-amino-5-ethoxy-benzoic acid is the key intermediate of this series of derivatives;

[0003] The currently reported routes for preparing 3-amino-5-ethoxy-benzoic acid (compound 7 below) are mainly:

[0004]

[0005] However, this method has the following problems: (1) the main raw materials of this method are relatively expensive and difficult to purchase, making commercialization difficult; (2) the catalyst Pd / C is required in the synthesis process, which is expensive and the production cost is relatively high.

[0006] Therefore, in order to further promote the research and development and production of drugs for treating Alzheimer's disease, it is of great significance to develop a new method for preparing 3-amino-5-ethoxy-benzoic acid that is lower in cost and more suitable for industrial production. Summary of the invention

[0007] The object of the present invention is to provide a method for preparing 3-amino-5-ethoxy-benzoic acid with low cost, simple steps, high yield and high purity.

[0008] The present invention provides an intermediate for preparing 3-amino-5-ethoxy-benzoic acid, which has the following structure:

[0009]

[0010] The present invention also provides a method for preparing the above intermediate, comprising the following steps:

[0011] (1) Compound 2 reacts with CH in an organic solvent under the action of a base and a catalyst. 2 CH 2 X undergoes ethyl substitution reaction to obtain compound 3; wherein X is halogen;

[0012] (2) Compound 3 is subjected to a monohydrolysis reaction in an organic solvent under the action of a base to obtain compound 4;

[0013] (3) Compound 4 is subjected to an aminolysis reaction with an acyl chloride and an aminolysis reagent in an organic solvent to obtain Compound 5, which is the intermediate;

[0014] The reaction formula is as follows:

[0015]

[0016] Furthermore, in step (1), the compound 2, CH 2 CH 2 The molar ratio of X, base and catalyst is 1:(1.5-2.5):(1.5-2.5):(0.03-0.07); the temperature of the ethyl substitution reaction is 0-30°C and the time is 12-16 hours;

[0017] and / or the molar ratio of the compound 3 to the base in step (2) is 1:(1.0-1.2); the temperature of the monohydrolysis reaction is 10-30° C. and the time is 12-16 hours;

[0018] And / or the molar ratio of compound 4, acyl chloride and ammonolysis reagent in step (3) is 1:(1.0-2.0):(10-20); the temperature of the ammonolysis reaction is 0-5°C and the time is 1-16 hours.

[0019] Furthermore, in step (1), the compound 2, CH 2 CH 2 The molar ratio of X, base and catalyst is 1:2.0:2.0:0.05; the temperature of the ethyl substitution reaction is 20-25°C and the time is 12 hours;

[0020] and / or the molar ratio of the compound 3 to the base in step (2) is 1:1.1; the temperature of the monohydrolysis reaction is 20-25° C. and the time is 12 hours;

[0021] And / or in step (3), the molar ratio of compound 4, acyl chloride and ammonolysis reagent is 1:2.0:15; the temperature of the ammonolysis reaction is 0-5°C and the time is 1 hour.

[0022] Furthermore, in step (1), X is bromine, the organic solvent is N,N-dimethylformamide, tetrahydrofuran or dichloromethane; preferably N,N-dimethylformamide; the base is potassium carbonate or sodium carbonate, preferably potassium carbonate; the catalyst is potassium iodide, sodium iodide, copper iodide or cuprous iodide, preferably potassium iodide;

[0023] and / or in step (2), the base is sodium hydroxide, lithium hydroxide or potassium hydroxide, preferably sodium hydroxide; the organic solvent is acetone, tetrahydrofuran or acetonitrile, preferably acetone;

[0024] And / or the organic solvent in step (3) is dichloromethane, dichloroethane or carbon tetrachloride; preferably dichloromethane; the acyl chloride is thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride, preferably thionyl chloride; the ammonolysis reagent is aqueous ammonia or liquid ammonia, preferably aqueous ammonia.

[0025] Furthermore, the above compound 2 is prepared according to a method comprising the following steps:

[0026] Compound 1 and anhydrous methanol undergo dimethyl esterification reaction in the presence of a catalyst to obtain compound 2;

[0027] The reaction formula is as follows:

[0028]

[0029] Furthermore, the catalyst is concentrated sulfuric acid, the mass volume ratio of the compound 1 to anhydrous methanol is 1 g: (8-10) mL; the mass volume ratio of the compound 1 to concentrated sulfuric acid is 1 g: (0.1-0.2) mL, the temperature of the double esterification reaction is 60-70° C., and the time is 12-24 hours;

[0030] Preferably, the mass volume ratio of the compound 1 to anhydrous methanol is 1 g:10 mL; the mass volume ratio of the compound 1 to concentrated sulfuric acid is 1 g:0.1 mL; the temperature of the double esterification reaction is 65° C., and the time is 12 hours.

[0031] The present invention also provides a method for preparing 3-amino-5-ethoxy-benzoic acid, comprising the following steps:

[0032] (a) Compound 5 undergoes Hofmann degradation under the action of a halogenating agent and an organic base to obtain compound 6;

[0033] (b) Compound 6 is subjected to an esterification reaction with an acyl chloride in an organic solvent to obtain 3-amino-5-ethoxy-benzoic acid;

[0034] The reaction formula is as follows:

[0035]

[0036] Preferably, the compound 5 in step (a) is prepared according to the method according to any one of claims 2 to 7.

[0037] Furthermore, in step (a), the molar ratio of the compound 5 to the halogenating agent and the organic base is 1:(1.0-2.0):(1.0-2.0); the temperature of the Hofmann degradation reaction is 0-65° C., and the time is 1-16 hours;

[0038] And / or, the molar ratio of the compound 6 to thionyl chloride in step (b) is 1:(1.0-2.0); the temperature of the esterification reaction is 55-65° C., and the time is 5-12 hours.

[0039] Furthermore, in step (a), the molar ratio of the compound 5 to the halogenating agent and the organic base is 1:1.2:1.5; the temperature of the Hofmann degradation reaction is 0-65°C, and the time is 1-3 hours; preferably, the halogenating agent is NBS, the organic base is DBU, the organic solvent is methanol, and the Hofmann degradation reaction is 0-10°C for 0.5 hour, then heated to 25-30°C for 0.5 hour, then heated to 60-65°C for 0.5 hour;

[0040] And / or the molar ratio of the compound 6 to the acyl chloride in step (b) is 1:2.0; the temperature of the esterification reaction is 60° C. and the time is 5 hours; preferably, the acyl chloride is thionyl chloride and the organic solvent is methanol.

[0041] Beneficial effects of the invention: 1. The starting raw materials, compound 1 and compound 2, used in the present invention are both cheap and readily available, with low cost, mild reaction conditions and simple steps;

[0042] 2. The purity of 3-amino-5-ethoxy-benzoic acid prepared by the method of the present invention is as high as 99%. The Hofmann degradation step of the present invention uses NBS as a halogen source to better improve the yield. The entire reaction does not require column purification, and industrial production is easy to achieve;

[0043] In summary, the method for preparing 3-amino-5-ethoxy-benzoic acid of the present invention has readily available raw materials, mild reaction conditions, low cost, safety and non-toxicity, is easy for large-scale production, can significantly improve the yield and purity of the target product 3-amino-5-ethoxy-benzoic acid, and has broad application prospects.

[0044] 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.

[0045] 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

[0046] The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products.

[0047] The synthetic route of the method for preparing 3-amino-5-ethoxy-benzoic acid of the present invention mainly comprises the following 6 steps:

[0048]

[0049] Example 1, Synthesis of 3-amino-5-ethoxy-benzoic acid

[0050] Step 1:

[0051] 10g of 5-hydroxyisophthalic acid (Compound 1) was dissolved in 100ml of methanol and dissolved. The temperature was controlled at 45℃~55℃, and 1ml of concentrated sulfuric acid was added to the system. After the addition was completed, the temperature was raised to 65℃ and refluxed for 12h. After the reaction was complete, the system was concentrated under reduced pressure, then quenched into ice water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate until neutral, dried, and concentrated to obtain 11g of 5-hydroxyisophthalic acid dimethyl ester (Compound 2), a white solid, with a yield of 95%. HNMR (400M, CDCl3): δ=3.96(S,6H),7.77(S,2H),8.26(S,1H).

[0052] Step 2:

[0053] 10g of dimethyl hydroxyisophthalate (Compound 2) was dissolved in 100ml of DMF, and potassium carbonate (13.15g, 2eq) and potassium iodide (0.4g, 0.05eq) were added at a temperature of 0-10℃, and ethyl bromide (10.27g, 2eq) was added dropwise at a temperature of 0-10℃. After the addition, the reaction was carried out at room temperature of 20-25℃ for 12h. The reaction was controlled to be complete in HPLC, filtered, and the filter cake was rinsed with methyl tert-butyl ether (MTBE). The filter cake was confirmed to have no product discarded, and the filtrate was slowly added to water, and then 400ml of MTBE was added, stirred and separated, and the aqueous phase was extracted with MTBE again. The aqueous phase was confirmed to have no product discarded, and the organic phases were combined, and the organic phases were washed with saturated brine, and the organic phases were dried, filtered, and the filtrate was concentrated under reduced pressure until no product was found, to obtain 10.7g of 1,3-phthalic acid-5-ethoxy-1,3-dimethyl ester (Compound 3), with a purity of 98% and a yield of 95%. HNMR (400M, CDCl 3 ): δ8.24(s,1H),7.72(s,2H),4.1(q,2H,J=6.6Hz),3.9(s,6H),1.44(t,3H,J=6.9Hz).

[0054] Step 3:

[0055] 10g of 5-ethoxy-1,3-dimethyl 1,3-phthalate (Compound 3) was dissolved in 100ml of acetone, and 1.76g of a methanol solution of sodium hydroxide was added dropwise at a temperature of 10-15 degrees. After addition, the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure until no product was produced. Water was added to the concentrated reaction system for dilution, and the aqueous phase was extracted with MTBE. The organic phase was separated and the raw material was recovered. The aqueous phase was controlled at a temperature of 0-10 degrees and the pH was adjusted to 2-3 with hydrochloric acid. The mixture was filtered and dried to obtain 7.5g of 3-ethoxy-5-(methyl)benzoic acid (Compound 4) with a purity of 85% and a yield of 80%. HNMR (400M, CDCl 3 ): δ=8.38(s,1H),7.84(s,2H),4.18(q,2H),3.98(s,3H),1.37(t,3H).

[0056] Step 4:

[0057] 10 g of 3-ethoxy-5-(methyl)benzoic acid (Compound 4) was dissolved in 80 ml of dichloromethane, 0.65 g of DMF was added, 10.6 g of thionyl chloride was added dropwise at a temperature of 20-30 degrees, and refluxed at 35-40 degrees for 8 hours after the addition, and then the reaction system was slowly added to 60 ml of ammonia water at a temperature of 0-5 degrees. After the addition, the temperature was controlled at 0-5 degrees and reacted for one hour, filtered, and the filter cake was rinsed with water and dichloromethane respectively, and dried to obtain 9.45 g of 3-carbamoyl-5-ethoxybenzoic acid methyl ester (Compound 5) as a white solid with a yield of 95%. HNMR (400M, DMSO): δ = 8.16 (s, 1H), 8.06 (s, 1H), 7.69 (s, 1H), 7.52-7.55 (d, 2H), 4.11-4.16 (m, 2H), 3.88 (s, 3H), 1.34-1.38 (t, 3H).

[0058] Step 5:

[0059] 10g of methyl 3-carbamoyl-5-ethoxybenzoate (Compound 5) was dissolved in 150ml of methanol, and the temperature was controlled at 0-10 degrees. NBS 7.97g (1eq) was added in batches, and DBU 10.23g was added dropwise at 0-10 degrees. After the addition, the temperature was kept at 0-10 degrees for half an hour, and then the temperature was raised to 25-30 degrees for half an hour, and then the temperature was raised to 60-65 degrees for half an hour, filtered, and the filtrate was concentrated under reduced pressure until no product was obtained. The concentrated system was poured into water for pulping, filtered, and then the filtered solid was dissolved in 55ml of methanol, and 52g of 10% sodium hydroxide aqueous solution was added, and the temperature was raised to 60 degrees. The reaction was reacted for 12 hours, and the reaction solution was concentrated under reduced pressure until no product was obtained. MTBE was added to the concentrated system for extraction and impurity removal, and the aqueous phase was adjusted to pH 1-2 with hydrochloric acid, and then extracted and impurities were removed with MTBE, and the aqueous phase was adjusted to pH 4 with sodium hydroxide aqueous solution, and then the product was extracted with ethyl acetate, concentrated, and dried to obtain 3.65g 3-Amino-5-ethoxy-benzoic acid (Compound 6), yield 45%. HNMR (400M, methanol): δ = 7.53 (m, 2H), 7.09 (m, 1H), 4.13 (q, 2H), 1.43 (t, 3H).

[0060] Step 6:

[0061] 10g of 3-amino-5-ethoxy-benzoic acid (Compound 6) was dissolved in 100ml of methanol, and then 13.13g of dichlorothionyl was added dropwise. After the addition was completed, the mixture was refluxed at 60 degrees for 5 hours, and the mixture was concentrated under reduced pressure until a small amount of methanol was present in the system. MTBE was added for pulping, and the mixture was filtered. Then, the filter cake was added into a mixed system of saturated sodium bicarbonate aqueous solution and MTBE, and the pH was kept at 8-9. The organic phase was separated, and the organic phase was washed with saturated brine, dried, and concentrated to obtain 8.6g of methyl 3-amino-5-ethoxybenzoate, with a yield of 83%. HNMR (400M, DMSO): δ = 6.81-6.82 (t, 1H), 6.61-6.62 (m, 1H), 6.35-6.36 (t, 1H), 5.38 (s, 2H), 3.93-3.98 (m, 2H), 3.79 (s, 3H), 1.28-1.32 (t, 3H).

[0062] Example 2, Synthesis of 3-amino-5-ethoxy-benzoic acid

[0063] Step 1:

[0064] 10g of 5-hydroxyisophthalic acid (Compound 1) was dissolved in 80ml of methanol and dissolved. The temperature was controlled at 45℃~55℃, and 1ml of concentrated sulfuric acid was added to the system. After the addition was completed, the temperature was raised to 60℃ and refluxed for 12h. After the reaction was complete, the system was concentrated under reduced pressure, then quenched into ice water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate until neutral, dried, and concentrated to obtain 11g of 5-hydroxyisophthalic acid dimethyl ester (Compound 2), a white solid, with a yield of 95%. HNMR (400M, CDCl3): δ=3.96(S,6H),7.77(S,2H),8.26(S,1H).

[0065] Step 2:

[0066] 10g of dimethyl hydroxyisophthalate (Compound 2) was dissolved in 100ml of DMF, and potassium carbonate (1.5eq) and potassium iodide (0.03eq) were added at a temperature of 0-10℃, and ethyl bromide (1.5eq) was added dropwise at a temperature of 0-10℃. After the addition, the mixture was reacted at room temperature of 20-25℃ for 12h. The reaction was controlled to be complete by HPLC, and the mixture was filtered. The filter cake was rinsed with methyl tert-butyl ether (MTBE). The filter cake was confirmed to have no product discarded. The filtrate was slowly added to water, and then 400ml of MTBE was added. The mixture was stirred and separated, and the aqueous phase was extracted with MTBE again. The aqueous phase was confirmed to have no product discarded. The organic phases were combined, and the organic phases were washed with saturated brine. The organic phases were dried, filtered, and the filtrate was concentrated under reduced pressure until no product was found to be present, thereby obtaining 1,3-benzenedicarboxylic acid-5-ethoxy-1,3-dimethyl ester (Compound 3).

[0067] Step 3:

[0068] 10 g of 5-ethoxy-1,3-dimethyl 1,3-phthalate (Compound 3) was dissolved in 100 ml of acetone, and a methanol solution of sodium hydroxide (1 eq) was added dropwise at a temperature of 10-15 degrees. The reaction was allowed to react at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure until no product was produced. Water was added to the concentrated reaction system to dilute it, and the aqueous phase was extracted with MTBE. The liquids were separated, and the raw materials were recovered from the organic phase. The aqueous phase was temperature controlled at 0-10 degrees and the pH was adjusted to 2-3 with hydrochloric acid. The mixture was filtered and dried to obtain 3-ethoxy-5-(methyl)benzoic acid (Compound 4).

[0069] Step 4:

[0070] 10 g of 3-ethoxy-5-(methyl)benzoic acid (Compound 4) was dissolved in 80 ml of dichloromethane, 0.65 g of DMF was added, and dichlorothionyl (1 eq) was added dropwise at a temperature of 20-30 degrees. After the addition, the mixture was refluxed at 35-40 degrees for 8 hours. Then, the reaction system was slowly added to ammonia water (10 eq) at a temperature of 0-5 degrees. After the addition, the mixture was reacted at a temperature of 0-5 degrees for 1 hour, filtered, and the filter cake was rinsed with water and dichloromethane respectively, and dried to obtain 3-carbamoyl-5-ethoxybenzoic acid methyl ester (Compound 5) as a white solid.

[0071] Step 5:

[0072] 10g of methyl 3-carbamoyl-5-ethoxybenzoate (Compound 5) was dissolved in 150ml of methanol, and the temperature was controlled at 0-10 degrees. NBS (1eq) was added in batches, and DBU (1eq) was added dropwise at 0-10 degrees. After the addition, the temperature was kept at 0-10 degrees for half an hour, and then the temperature was raised to 25-30 degrees for half an hour, and then the temperature was raised to 60-65 degrees for half an hour, filtered, and the filtrate was concentrated under reduced pressure until no more was produced. The concentrated system was poured into water for pulping, filtered, and then the filtered solid was dissolved in 55ml of methanol, and 52g of 10% sodium hydroxide aqueous solution was added, and the temperature was raised to 60 degrees. The reaction was reacted for 12 hours, and the reaction solution was concentrated under reduced pressure until no more was produced. MTBE was added to the concentrated system for extraction and impurity removal, and the aqueous phase was adjusted to pH 1-2 with hydrochloric acid, and then extracted and impurities were removed with MTBE, and the aqueous phase was adjusted to pH 4 with sodium hydroxide aqueous solution, and then the product was extracted with ethyl acetate, concentrated, and dried to obtain 3-amino-5-ethoxy-benzoic acid (Compound 6).

[0073] Step 6:

[0074] 10 g of 3-amino-5-ethoxy-benzoic acid (Compound 6) was dissolved in 100 ml of methanol, and then dichlorothionyl (1 eq) was added dropwise. After the addition was completed, the mixture was refluxed at 55 degrees for 5 hours, and the mixture was concentrated under reduced pressure until a small amount of methanol was present in the system. MTBE was added for pulping, and the mixture was filtered. The filter cake was then added to a mixed system of saturated sodium bicarbonate aqueous solution and MTBE, and the pH was maintained at 8-9. The organic phase was separated, and the organic phase was washed with saturated brine, dried, and concentrated to obtain methyl 3-amino-5-ethoxybenzoate.

[0075] Example 3, Synthesis of 3-amino-5-ethoxy-benzoic acid

[0076] Step 1:

[0077] 10g of 5-hydroxyisophthalic acid (Compound 1) was dissolved in 100ml of methanol and dissolved. The temperature was controlled at 45℃~55℃, and 2ml of concentrated sulfuric acid was added to the system. After the addition was completed, the temperature was raised to 70℃ and refluxed for 24h. After the reaction was complete, the system was concentrated under reduced pressure, then quenched into ice water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate until neutral, dried, and concentrated to obtain 11g of 5-hydroxyisophthalic acid dimethyl ester (Compound 2), a white solid, with a yield of 95%. HNMR (400M, CDCl3): δ=3.96(S,6H),7.77(S,2H),8.26(S,1H).

[0078] Step 2:

[0079] 10g of dimethyl hydroxyisophthalate (Compound 2) was dissolved in 100ml of DMF, potassium carbonate (2.5eq) and potassium iodide (0.07eq) were added at a temperature of 0-10℃, and ethyl bromide (2.5eq) was added dropwise at a temperature of 0-10℃. After the addition, the mixture was reacted at room temperature of 20-25℃ for 16h. The reaction was controlled to be complete by HPLC, and the mixture was filtered. The filter cake was rinsed with methyl tert-butyl ether (MTBE). The filter cake was confirmed to have no product discarded. The filtrate was slowly added to water, and then 400ml of MTBE was added. The mixture was stirred and separated, and the aqueous phase was extracted with MTBE again. The aqueous phase was confirmed to have no product discarded. The organic phases were combined, and the organic phases were washed with saturated brine. The organic phases were dried, filtered, and the filtrate was concentrated under reduced pressure until no product was found to be present, thereby obtaining 1,3-benzenedicarboxylic acid-5-ethoxy-1,3-dimethyl ester (Compound 3).

[0080] Step 3:

[0081] 10 g of 5-ethoxy-1,3-dimethyl 1,3-phthalate (Compound 3) was dissolved in 100 ml of acetone, and a methanol solution of sodium hydroxide (1.2 eq) was added dropwise at a temperature of 10-15 degrees. The reaction was allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure until no more product was obtained. Water was added to the concentrated reaction system to dilute it, and the aqueous phase was extracted with MTBE. The liquids were separated, and the raw materials were recovered from the organic phase. The aqueous phase was temperature-controlled at 0-10 degrees and the pH was adjusted to 2-3 with hydrochloric acid. The mixture was filtered and dried to obtain 3-ethoxy-5-(methyl)benzoic acid (Compound 4).

[0082] Step 4:

[0083] 10 g of 3-ethoxy-5-(methyl)benzoic acid (Compound 4) was dissolved in 80 ml of dichloromethane, 0.65 g of DMF was added, and dichlorothionyl (2 eq) was added dropwise at a temperature of 20-30 degrees. After the addition, the mixture was refluxed at 35-40 degrees for 8 hours. Then, the reaction system was slowly added to ammonia water (20 eq) at a temperature of 0-5 degrees. After the addition, the mixture was reacted at a temperature of 0-5 degrees for 16 hours, filtered, and the filter cake was rinsed with water and dichloromethane respectively, and dried to obtain 3-carbamoyl-5-ethoxybenzoic acid methyl ester (Compound 5) as a white solid.

[0084] Step 5:

[0085] 10g of methyl 3-carbamoyl-5-ethoxybenzoate (Compound 5) was dissolved in 150ml of methanol, and the temperature was controlled at 0-10 degrees. NBS (2eq) was added in batches, and DBU (2eq) was added dropwise at 0-10 degrees. After the addition, the temperature was kept at 0-10 degrees for half an hour, and then the temperature was raised to 25-30 degrees for half an hour, and then the temperature was raised to 60-65 degrees for half an hour, filtered, and the filtrate was concentrated under reduced pressure until no more was produced. The concentrated system was poured into water for pulping, filtered, and then the filtered solid was dissolved in 55ml of methanol, and 52g of 10% sodium hydroxide aqueous solution was added, and the temperature was raised to 60 degrees. The reaction was reacted for 12 hours, and the reaction solution was concentrated under reduced pressure until no more was produced. MTBE was added to the concentrated system for extraction and impurity removal, and the aqueous phase was adjusted to pH 1-2 with hydrochloric acid, and then extracted and impurities were removed with MTBE, and the aqueous phase was adjusted to pH 4 with sodium hydroxide aqueous solution, and then the product was extracted with ethyl acetate, concentrated, and dried to obtain 3-amino-5-ethoxy-benzoic acid (Compound 6).

[0086] Step 6:

[0087] 10 g of 3-amino-5-ethoxy-benzoic acid (Compound 6) was dissolved in 100 ml of methanol, and then dichlorothionyl (2 eq) was added dropwise. After the addition was completed, the mixture was refluxed at 65 degrees for 12 hours, and concentrated under reduced pressure until a small amount of methanol was present in the system. MTBE was added for pulping, and the mixture was filtered. The filter cake was then added to a mixed system of saturated sodium bicarbonate aqueous solution and MTBE, and the pH was maintained at 8-9. The organic phase was separated, washed with saturated brine, dried, and concentrated to obtain methyl 3-amino-5-ethoxybenzoate.

[0088] In summary, the present invention provides a method for preparing 3-amino-5-ethoxy-benzoic acid, wherein the starting raw materials are cheap and readily available, the cost is low, the reaction conditions are mild, and the steps are simple; the prepared 3-amino-5-ethoxy-benzoic acid has high purity and high yield, the entire reaction does not require column purification, and industrial production is easily realized, and the application prospects are broad.

Claims

1. An intermediate for preparing 3-amino-5-ethoxy-benzoic acid, characterized in that: It has the following structure:

2. A method for preparing the intermediate according to claim 1, characterized in that: The steps include: (1) Compound 2 undergoes ethyl substitution reaction with CH3CH2X in an organic solvent under the action of a base and a catalyst to obtain compound 3; wherein X is a halogen; (2) Compound 3 is subjected to a monohydrolysis reaction in an organic solvent under the action of a base to obtain compound 4; (3) Compound 4 reacts with an acyl chloride and an ammonolysis reagent in an organic solvent to obtain compound 5, which is the intermediate; The reaction formula is as follows:

3. The method according to claim 2, characterized in that In step (1), the molar ratio of compound 2, CH3CH2X, base and catalyst is 1:(1.5-2.5):(1.5-2.5):(0.03-0.07); the temperature of the ethyl substitution reaction is 0-30°C and the time is 12-16 hours; and / or the molar ratio of the compound 3 to the base in step (2) is 1:(1.0-1.2); the temperature of the monohydrolysis reaction is 10-30° C. and the time is 12-16 hours; And / or the molar ratio of compound 4, acyl chloride and ammonolysis reagent in step (3) is 1:(1.0-2.0):(10-20); the temperature of the ammonolysis reaction is 0-5°C and the time is 1-16 hours.

4. The method according to claim 3, characterized in that In step (1), the molar ratio of compound 2, CH3CH2X, base and catalyst is 1:2.0:2.0:0.05; the temperature of the ethyl substitution reaction is 20-25°C and the time is 12 hours; and / or the molar ratio of the compound 3 to the base in step (2) is 1:1.1; the temperature of the monohydrolysis reaction is 20-25° C. and the time is 12 hours; And / or in step (3), the molar ratio of compound 4, acyl chloride and ammonolysis reagent is 1:2.0:15; the temperature of the ammonolysis reaction is 0-5°C and the time is 1 hour.

5. The method according to claim 4, characterized in that In step (1), X is bromine, the organic solvent is N,N-dimethylformamide, tetrahydrofuran or dichloromethane; the base is potassium carbonate or sodium carbonate; the catalyst is potassium iodide, sodium iodide, copper iodide or cuprous iodide; And / or the base in step (2) is sodium hydroxide, lithium hydroxide or potassium hydroxide; the organic solvent is acetone, tetrahydrofuran or acetonitrile; And / or in step (3), the organic solvent is dichloromethane, dichloroethane or carbon tetrachloride; the acyl chloride is thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus oxychloride; and the ammonolysis reagent is aqueous ammonia or liquid ammonia.

6. The method according to claim 5, characterized in that In step (1), the organic solvent is N,N-dimethylformamide; the base is potassium carbonate; and the catalyst is potassium iodide; And / or in step (2), the base is sodium hydroxide; the organic solvent is acetone; And / or in step (3), the organic solvent is dichloromethane; the acyl chloride is dichlorothionyl; and the ammonolysis reagent is aqueous ammonia.

7. The method according to claim 2, characterized in that The compound 2 is prepared according to a method comprising the following steps: Compound 1 and anhydrous methanol undergo dimethyl esterification reaction in the presence of a catalyst to obtain compound 2; The reaction formula is as follows:

8. The method according to claim 7, characterized in that The catalyst is concentrated sulfuric acid, the mass volume ratio of the compound 1 to anhydrous methanol is 1g:(8-10)mL; the mass volume ratio of the compound 1 to concentrated sulfuric acid is 1g:(0.1-0.2)mL, the temperature of the dimethyl esterification reaction is 60-70°C, and the time is 12-24 hours.

9. The method according to claim 8, characterized in that The mass volume ratio of the compound 1 to anhydrous methanol is 1 g:10 mL; the mass volume ratio of the compound 1 to concentrated sulfuric acid is 1 g:0.1 mL; the temperature of the dimethyl esterification reaction is 65° C., and the time is 12 hours.

10. A method for preparing 3-amino-5-ethoxy-benzoic acid methyl ester, characterized in that: The steps include: (a) Compound 5 undergoes Hofmann degradation under the action of a halogenating agent and an organic base to obtain compound 6; (b) Compound 6 undergoes an esterification reaction with an acyl chloride in an organic solvent to obtain 3-amino-5-ethoxy-benzoic acid methyl ester; The reaction formula is as follows:

11. The method according to claim 10, characterized in that The compound 5 in step (a) is prepared according to the method described in any one of claims 2 to 8.

12. The method according to claim 10, characterized in that The molar ratio of the compound 5 to the halogenating agent and the organic base in step (a) is 1:(1.0-2.0):(1.0-2.0); the temperature of the Hofmann degradation reaction is 0-65° C., and the time is 1-16 hours; And / or, the acyl chloride in step (b) is thionyl chloride, and the molar ratio of compound 6 to thionyl chloride is 1:(1.0-2.0); the temperature of the esterification reaction is 55-65° C., and the time is 5-12 hours.

13. The method according to claim 12, characterized in that In step (a), the molar ratio of the compound 5 to the halogenating agent and the organic base is 1:1.2:1.5; the temperature of the Hofmann degradation reaction is 0 to 65° C., and the time is 1 to 3 hours; And / or the molar ratio of the compound 6 to the acyl chloride in step (b) is 1:2.0; the temperature of the esterification reaction is 60° C. and the time is 5 hours.

14. The method according to claim 13, characterized in that In step (a), the halogenating agent is NBS, the organic base is DBU, and the Hofmann degradation reaction is carried out by reacting at 0-10° C. for 0.5 hour, then heating to 25-30° C. for 0.5 hour, and then heating to 60-65° C. for 0.5 hour; And / or the organic solvent in step (b) is methanol.

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