CN110818661B - Preparation method of key intermediate 4-amino-5-halogenobenzofuran-7-carboxylic acid of 5-HT4 receptor agonist - Google Patents
Preparation method of key intermediate 4-amino-5-halogenobenzofuran-7-carboxylic acid of 5-HT4 receptor agonist Download PDFInfo
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Abstract
A process for the preparation of 4-amino-5-halobenzofuran-7-carboxylic acid, a key intermediate of 5-HT4 receptor agonists. The invention discloses a preparation method of 4-amino-5-halogenated benzofuran-7-carboxylic acid, belonging to the field of organic synthesis. The 4-amino-5-halogenated benzofuran-7-carboxylic acid is obtained by three-step reaction by taking para-protected amino-o-hydroxybenzoic acid/ester, a halogenated reagent and triethylacetylene silicon as main raw materials. The method has the advantages of simple and convenient process operation, short reaction steps, easy separation of intermediates, total yield of more than 51 percent, cheap and easily obtained raw materials, great reduction of production cost and obvious competitive advantage.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 4-amino-5-halogenobenzofuran-7-carboxylic acid.
Background
The 5-HT4 receptor is one of seven subtypes of the 5-hydroxytryptamine receptor and studies have shown potential utility in the treatment of disorders such as alzheimer's disease, schizophrenia, depression, attention deficit hyperactivity disorder, huntington's disease, parkinson's disease, and several other psychiatric disorders (curr. top. med. chem.,2010,10, 527-553). At the same time, the receptor agonists improve memory in different behavioral experiments in rodents (Nauyn-Schmiedeberg's Archives of PharmacoLogy,2003,367: 621-.
However, no drug is available on the market that specifically targets the cellular mechanism of alzheimer's disease, i.e. the production of neurotoxic amyloid protein (β -protein) from amyloid precursor protein. Alzheimer's disease is a progressive neurodegenerative disorder characterized by the appearance of senile plaques in the brain of patients, composed mainly of amyloid β -protein, and the occurrence of neurofibrillary tangles. Such patients also have cognitive deficits, impaired long-term enhancement, deficits in learning and memory, and a consistent deficit in cholinergic neurotransmission.
Several patents (e.g. WO2005049608, WO2006090224, WO2011099305, WO2011101774, WO2007048643, WO2007068739, WO2007096352, US20080207690 and US20080269211) disclose 5-HT4 receptor compounds. However, no compounds targeting the 5-HT4 receptor, either agonists or partial agonists, have been identified on the market to date for the treatment of dementia-related disorders. Therefore, there is a great need to develop novel 5-HT4 receptor agonists/partial agonists for treatment of diseases with a novel chemical structure.
Key intermediates of 5-HT4 receptor agonists are published in CN 107406434A: 4-amino-5-chlorobenzofuran-7-carboxylic acid. 4-amino-5-halobenzofuran-7-carboxylic acid is a colorless oil, having the name: 4-amino-5-halobenzofuran-7-carboxyIic acid, the chemical structural formula is as follows:
among the existing synthetic methods, WO 2016128990A1 reports the use of 4-amino-2-hydroxybenzoic acid to obtain 4-amino-5-chlorobenzofuran-7-carboxylic acid through saponification, acetyl protection, chlorination, iodination, Sonogashira coupling, ring closure and other reactions. The reaction equation is expressed as:
the process has the advantages of complex operation, expensive raw materials, more reaction sites and more generated byproducts, and the external standard yield is only 24 percent when the process is repeated in gram-scale in a laboratory, and is only 22 percent when the process is amplified in kilogram-scale. The existing synthesis process has low yield, difficult purification and poor economic benefit.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of 4-amino-5-halogenobenzofuran-7-carboxylic acid, which is simple, convenient and stable to operate, easy to separate products in each step, high in yield, environment-friendly, low in production cost and suitable for industrial mass production.
In making improvements to the patented route mentioned in the background, it was found experimentally that: when the 3-position is chlorine or bromine, the ring closing reaction can be completed, so that from the point of simplifying the reaction, two halogen atoms of chlorine or bromine with the same 3-position and 5-position are generated at one time by reacting with a halogenating reagent in the process, thereby simplifying the process operation steps.
The invention provides a preparation method of 4-amino-5-halogenobenzofuran-7-carboxylic acid, which comprises the following synthetic route:
the method comprises the following steps: the 4-protected amino-2-hydroxybenzoic acid/ester (1) is subjected to halogenation reaction to obtain an intermediate (2), then the intermediate (2) is subjected to coupling reaction with trialkyl acetylene silicon to obtain an intermediate (3), and deprotection or deprotection/hydrolysis is carried out to obtain 4-amino-5-halogeno benzofuran-7-carboxyl (4).
The method comprises the following specific steps:
the first step is as follows: synthesis of 4-protected amino-3, 5-dihalo-2-hydroxybenzoic acid/ester (2)
Heating 4-protected amino-2-hydroxybenzoic acid/ester (1) and a halogenating reagent in an organic solvent for reaction to obtain 4-protected amino-3, 5-dihalo-2-hydroxybenzoic acid/ester (2).
The halogenating agent is selected from N-chlorosuccinimide, dichlorohydantoin, N-bromosuccinimide, dibromohydantoin, N-iodosuccinimide and the like.
The organic solvent is selected from common organic solvents such as 1, 2-dichloroethane, dichloromethane, chloroform, acetone, dioxane, acetonitrile and the like, mainly plays a role in dissolving, and has no obvious influence on reaction yield; the preferred organic solvent is 1, 2-dichloroethane.
The mol ratio of the 4-protected amino-2-hydroxybenzoic acid/ester (1) to the halogenating reagent is 1: 2-3.
The second step is that: synthesis of 2-trialkylsilyl-4-protected amino-5-halobenzofuran-7-carboxylic acid/ester (3)
Reacting 4-protected amino-3, 5-dihalo-2-hydroxybenzoic acid/ester (2) with trialkyl acetylene silicon in the presence of palladium catalyst, cuprous iodide and organic base in an organic solvent to obtain 2-trialkyl silicon-based-4-protected amino-5-halogeno benzofuran-7-carboxylic acid/ester (3).
The organic solvent is selected from 1, 2-dichloroethane, ethylene glycol dimethyl ether, 2-methyltetrahydrofuran, acetonitrile, toluene or any combination of the solvents, and the solvent has no obvious influence on the reaction yield. The preferred solvent is acetonitrile.
The trialkyl acetylene silicon is selected from trimethyl silicon acetylene or triethyl silicon acetylene. The reaction is carried out under the heating condition, and the heating reaction temperature is 45-70 ℃.
The palladium catalyst is selected from bis (triphenylphosphine) palladium dichloride or [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride. The organic base is selected from N, N-diisopropylethylamine, triethylamine, pyridine and the like.
The molar ratio of the 4-protected amino-3, 5-dihalo-2-hydroxybenzoic acid/ester (2), trialkyl acetylene silicon, palladium catalyst, cuprous iodide and organic base is 1: 1.13-2: 0.03-0.08: 0.05-0.2: 3-10.
The third step: synthesis of 4-amino-5-halogenobenzofuran-7-carboxylic acid (4)
And (3) deprotecting or deprotecting/hydrolyzing the 2-trialkylsilyl-4-protected amino-5-halogenobenzofuran-7-carboxylic acid/ester under alkaline conditions to obtain 4-amino-5-halogenobenzofuran-7-carboxylic acid (4).
Under the alkaline condition, it is preferable to perform desilylation protection (for acid) or deprotection/hydrolysis (for ester) using an inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, or the like. Preferably in dioxane with an aqueous solution of the base.
The deprotection reaction is preferably carried out under heating at a temperature of 60 to 85 ℃. The hydrolysis is completed at room temperature.
The molar ratio of the trialkyl silicon-4-protected amino-5-halogenobenzofuran-7-carboxylic acid/ester (3) to the alkali is 1: 3-15.
The invention has the beneficial effects that:
1) the comprehensive yield of the invention is more than 51 percent, and compared with the prior yield of 24 percent, the yield is obviously improved, the production cost is greatly reduced, and the market competitiveness of the product is improved.
2) The invention optimizes the preparation process, has no obvious by-product in the reaction process, has simple operation in the reaction process and the post-treatment process and good process reproducibility, and can be smoothly amplified to the kilogram-level reaction scale.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Example 1
The first step is as follows: synthesis of 4-amino-3, 5-dibromo-2-hydroxybenzoic acid
P-amino-o-hydroxybenzoic acid (146.3g, 0.956mol, 1.0eq) was dissolved in dichloroethane (4.0L), NBS (373.8g, 2.1mol, 2.2eq) was added with stirring, heated to 80-85 ℃ for 4 hours, then the temperature was controlled, HPLC showed complete consumption of the starting material, cooled to below 35 ℃, and the solvent was evaporated under reduced pressure. Pouring the system into 2.0L of ice water, stirring vigorously for half an hour, filtering, washing twice to obtain a crude product, pulping the crude product twice by using ethanol, draining, recrystallizing a filter cake by using ethyl acetate to obtain 274.5g of 4-amino-3, 5-dibromo-2-hydroxybenzoic acid, wherein the purity is 99%, and the yield is as follows: 93.0 percent. Mass spectrometric detection of m/z 311.7[ MH ]]+The solid was determined to be 4-amino-3, 5-dibromo-2-hydroxybenzoic acid.
The second step is that: synthesis of 2-trimethylsilyl-4-amino-5-bromobenzofuran-7-carboxylic acid
4-amino-3, 5-dibromo-2-hydroxybenzoic acid (475.6g, 1.54mol), 4.0L of acetonitrile, cuprous iodide (15.2g, 0.08mol), and N, N-diisopropylethylamine (1.69kg, 13mol) were sequentially added to a reaction flask, nitrogen was replaced 3 times, and trimethylethynylsilicon (172g, 1.75mol) and bistriphenylphosphine palladium dichloride (41g, 0.05mol) were added to react at 45-50 ℃ for 6 hours. After the reaction is finished, the system is filtered when the system is hot, the acetonitrile is washed twice, 4.0L of water is added after decompression and desolventization, the mixture is stirred vigorously, filtered and washed twice to obtain the 2-trimethylsilyl-4-amino-5-bromobenzofuran-7-carboxylic acid362.6g, yield: 72.0 percent. Mass spectrometric detection of m/z 329.8,327.9[ MH ]]+And determined to be 2-trimethylsilyl-4-amino-5-bromobenzofuran-7-carboxylic acid.
The third step: synthesis of 4-amino-5-bromobenzofuran-7-carboxylic acid
Cesium carbonate (855g, 5.7mol) was added portionwise to a mixed solution of 2-trimethylsilyl-4-amino-5-bromobenzofuran-7-carboxylic acid (124.2g, 0.38mol) in water (0.65L) and dioxane (0.65L). The reaction was stirred at 60-65 ℃ for 8 h, cooled to room temperature, diluted with water (2.5L), insoluble material filtered off, methyl tert-butyl ether (2 x 1L) extracted, the aqueous phase adjusted to pH 4 with 5N hydrochloric acid, and the solid filtered off was dried under vacuum to give 77.7g 4-amino-5-bromobenzofuran-7-carboxylic acid, yield: 80.2 percent. Mass spectrometric detection of m/z 256.0,258.1[ MH ]]+The solid was identified as 4-amino-5-bromobenzofuran-7-carboxylic acid.
The total yield of the three-step reaction is as follows: 53.7 percent.
Example 2
The first step is as follows: synthesis of 4-amino-3, 5-dichloro-2-hydroxybenzoic acid
P-amino-o-hydroxybenzoic acid (146.3g, 0.956mol, 1eq) was dissolved in dioxane (4.0L), NCS (333.8g, 2.5mol, 2.6eq) was added with stirring, heated to 80-85 deg.C, controlled after 4 hours, HPLC showed complete consumption of raw materials, cooled to below 35 deg.C, and the solvent was evaporated under reduced pressure. Pouring the system into 2.0L of ice water, stirring vigorously for half an hour, filtering, washing twice to obtain a crude product, pulping the crude product twice by using ethanol, draining, recrystallizing a filter cake by using ethyl acetate to obtain 198.5g of 4-amino-3, 5-dichloro-2-hydroxybenzoic acid, wherein the purity is 99%, and the yield is as follows: 94 percent. 222.2[ MH ] m/z detected by mass spectrum]+The solid was determined to be 4-amino-3, 5-dichloro-2-hydroxybenzoic acid.
The second step is that: synthesis of 2-triethylsilyl-4-amino-5-chlorobenzofuran-7-carboxylic acid
4-amino-3, 5-dichloro-2-hydroxybenzoic acid (340.3g, 1.54mol), 4.0L1, 2-dichloroethane, cuprous iodide (22.26g, 0.12mol) and triethylamine (1.55kg, 15.4mol) were added in this order to a reaction flask, nitrogen was replaced 3 times, triethylethynylsilicon (432.12g, 3.08mol) and [1,1' -bis (diphenylphosphino) ferrocene ] were added]Palladium dichloride (87.7g, 0.12mol) was reacted at 50-55 ℃ for 6 hours. After the reaction is finished, the system is filtered when the system is hot, washed twice by 1, 2-dichloroethane, decompressed and desolventized, added with 4.0L of water and stirred vigorously, filtered and washed twice to obtain 356.5g of 2-triethylsilyl-4-amino-5-chlorobenzofuran-7-carboxylic acid, and the yield is as follows: 71.2 percent. 284.1[ MH ] m/z detected by mass spectrum]+And was identified as 2-triethylsilyl-4-amino-5-chlorobenzofuran-7-carboxylic acid.
The third step: synthesis of 4-amino-5-chlorobenzofuran-7-carboxylic acid
Potassium carbonate (524.4g, 3.8mol) was added in portions to a mixed solution of 2-triethylsilyl-4-amino-5-chlorobenzofuran-7-carboxylic acid (123.5g, 0.38mol) in water (0.65L) and dioxane (0.65L). The reaction solution was stirred at 65-70 ℃ for 8 hours, cooled to room temperature, diluted with water (2.5L), insoluble material was filtered off, methyl tert-butyl ether (2 x 1.0L) was extracted, the aqueous phase was adjusted to pH 4 with 5N hydrochloric acid, and the solid after filtration was dried under vacuum to give 65.0g of 4-amino-5-chlorobenzofuran-7-carboxylic acid, yield: 81.1 percent.1H NMR(400MHz,CDCl3):δ12.45(s,1H),7.86(d，J＝2Hz，1H),7.62(s,1H),7.21(d,J＝2.4Hz,1H),6.62(s,2H)。
The total yield of the three-step reaction is as follows: 54.3 percent.
Example 3
The first step is as follows: synthesis of methyl 4-acetamido-3, 5-dichloro-2-hydroxybenzoate
Dissolving methyl p-acetamido-o-hydroxybenzoate (200g, 0.956mol, 1.0eq) in acetonitrile (4.0L), adding dichlorohydantoin (376.3g, 1.91mol, 2.0eq) under stirring, heating to 80-85 deg.C, controlling after 4 hr, HPLC shows complete consumption of raw materials, cooling to below 35 deg.C, and removing solvent under reduced pressure. Pouring the system into 2.0L of ice water, stirring vigorously for half an hour, filtering, washing twice to obtain a crude product, pulping the crude product twice by using ethanol, draining, recrystallizing a filter cake by using ethyl acetate to obtain 243.6g of 4-acetamido-3, 5-dichloro-2-hydroxybenzoic acid methyl ester, wherein the purity is 99%, and the yield is as follows: 92 percent. 278.1[ MH ] m/z detected by mass spectrometry]+And the residue was identified as methyl 4-acetylamino-3, 5-dichloro-2-hydroxybenzoate.
The second step is that: synthesis of 2-trimethylsilyl-4-acetamido-5-chlorobenzofuran-7-carboxylic acid methyl ester
Methyl 4-acetamido-3, 5-dichloro-2-hydroxybenzoate (426.5g, 1.54mol), 4.0L of ethylene glycol dimethyl ether, cuprous iodide (30.25g, 1.54mol) and pyridine (364.98g, 4.62mol) were sequentially added to a reaction flask, nitrogen was replaced 3 times, and trimethylethynylsilicon (226.89g, 2.31mol) and bistriphenylphosphine palladium dichloride (58.5g, 0.08mol) were added to react at 55-60 ℃ for 6 hours. After the reaction is finished, filtering the system while the system is hot, washing the system with ethylene glycol dimethyl ether twice, adding 4.0L of water after decompression and desolventization, stirring the mixture vigorously, filtering and washing the mixture twice, and drying the mixture to obtain 354.4g of 2-trimethylsilyl-4-acetamido-5-chlorobenzofuran-7-carboxylic acid methyl ester, wherein the yield is as follows: 70.8 percent.1H NMR(400MHz,DMSO-d6):δ10.12(s,1H),7.84(s,1H),7.05(s,1H),3.91(s,3H),2.15(s,3H),0.36(s,9H)。
The third step: synthesis of 4-amino-5-chlorobenzofuran-7-carboxylic acid
Potassium hydroxide (106.4g, 1.9mol) was added in portions to a mixed solution of methyl 2-trimethylsilyl-4-acetylamino-5-chlorobenzofuran-7-carboxylate (128.8g, 0.38mol) in water (0.65L) and dioxane (0.65L). The reaction mixture was stirred at 70-75 ℃ for 8 hours, cooled to room temperature, diluted with water (2.5L), insoluble material was filtered off, methyl tert-butyl ether (2X 1L) was extracted, the pH of the aqueous phase was adjusted to 4 with 5N hydrochloric acid, and the solid after filtration was dried under vacuum to give 64.9g of 4-amino-5-chlorobenzofuran-7-carboxylic acid, yield: 80.9 percent. HNMR (400MHz, CDCL)3):δ12.45(s,1H),7.86(d,J＝2Hz,1H),7.62(s,1H),7.21(d,J＝2.4Hz,1H,6.62(s,2H)。
The total yield of the three-step reaction is as follows: 52.6 percent
Example 4
The first step is as follows: synthesis of methyl 4-trifluoroacetylamino-3, 5-dibromo-2-hydroxybenzoate
4-trifluoroacetylamino-o-hydroxybenzoic acid methyl ester (251.5g, 0.956mol, 1.0eq) was dissolved in dichloroethane (4.0L), dibromohydantoin (574.0g, 2.1mol, 2.2eq) was added with stirring, the mixture was heated to 80-85 ℃ for 4 hours, the temperature was controlled, HPLC showed complete consumption of the starting material, the temperature was lowered to below 35 ℃, and the solvent was evaporated under reduced pressure. Pouring the system into 2L of ice water, stirring vigorously for half an hour, filtering, washing twice to obtain crude product, and purifying with waterPulping the ethanol twice, draining, recrystallizing a filter cake by using ethyl acetate to obtain 370.2g of 4-trifluoroacetylamino-3, 5-dibromo-2-hydroxybenzoic acid methyl ester with the purity of 99 percent and the yield: 92.5 percent. Mass spectrometric detection of m/z 421.9[ MH ]]+And the compound was identified as methyl 4-trifluoroacetylamino-3, 5-dibromo-2-hydroxybenzoate.
The second step is that: synthesis of methyl 2-triethylsilyl-4-trifluoroacetylamino-5-bromobenzofuran-7-carboxylate
Methyl 4-trifluoroacetylamino-3, 5-dibromo-2-hydroxybenzoate (645.3g, 1.54mol), 4.0L 2-methyltetrahydrofuran, cuprous iodide (58.68g, 0.31mol) and N, N-diisopropylethylamine (1.0kg, 7.7mol) were sequentially added to a reaction flask, nitrogen gas was substituted 3 times, triethylethynylsilicon and bistriphenylphosphine palladium dichloride (41g, 0.05mol) were added (280.6g, 2.0mol), and the mixture was reacted at 60 to 65 ℃ for 6 hours. After the reaction is finished, filtering the system while the system is hot, washing the system twice with 2-methyltetrahydrofuran, removing the solvent under reduced pressure, adding 4.0L of water, stirring the mixture vigorously, filtering the mixture, and washing the mixture twice with water to obtain 534.9g of 2-triethylsilyl-4-trifluoroacetylamino-5-bromobenzofuran-7-carboxylic acid methyl ester, wherein the yield is as follows: 71.9 percent. Mass spectrometric detection of m/z 482.1,480.1[ MH ]]+And was identified as methyl 2-triethylsilyl-4-trifluoroacetylamino-5-bromobenzofuran-7-carboxylate.
The third step: synthesis of 4-amino-5-bromobenzofuran-7-carboxylic acid
Sodium hydroxide (45.6g, 1.14mol) was added portionwise to a mixed solution of methyl 2-triethylsilyl-4-trifluoroacetylamino-5-bromobenzofuran-7-carboxylate (182.0g, 0.38mol) in water (0.65L) and dioxane (0.65L). The reaction was stirred at 75-80 ℃ for 8 h, cooled to room temperature, diluted with water (2.5L), insoluble material filtered off, methyl tert-butyl ether (2 x 1.0L) extracted, the aqueous phase adjusted to pH 4 with 5N hydrochloric acid, and the solid filtered off was dried under vacuum to give 79.3g of 4-amino-5-bromobenzofuran-7-carboxylic acid, yield: 81.9 percent. Mass spectrometric detection of m/z 256.1[ MH ]]+And identified as 4-amino-5-bromobenzofuran-7-carboxylic acid.
The total yield of the three-step reaction is as follows: 54.5 percent
Example 5
The first step is as follows: 4-acetamido-3, 5-diiodo-2-ethyl hydroxybenzoate.
Dissolving 4-acetamido-o-hydroxybenzoic acid ethyl ester (213.3g, 0.956mol, 1eq) in dichloroethane (4.0L), adding N-iodosuccinimide (645.2g, 2.87mol, 3eq) with stirring, heating to 80-85 deg.C, controlling after 4 hours, HPLC shows complete consumption of raw materials, cooling to below 35 deg.C, and removing solvent under reduced pressure. Pouring the system into 2L of ice water, stirring vigorously for half an hour, filtering, washing twice to obtain a crude product, pulping the crude product twice by using ethanol, draining, recrystallizing a filter cake by using ethyl acetate to obtain 422.7g of 4-acetamido-3, 5-diiodo-2-hydroxybenzoic acid ethyl ester, wherein the purity is 99%, and the yield is as follows: 93.1 percent. Mass spectrometric detection of m/z 475.9 MH]+And the compound was identified as ethyl 4-acetylamino-3, 5-diiodo-2-hydroxybenzoate.
The second step is that: synthesis of ethyl 2-triethylsilyl-4-acetamido-5-iodobenzofuran-7-carboxylate
Ethyl 4-acetamido-3, 5-diiodo-2-hydroxybenzoate (731.3g, 1.54mol), 4L of toluene, cuprous iodide (43.80g, 0.23mol), triethylamine (1.10kg, 10.78mol) were added in sequence to a reaction flask, nitrogen was replaced 3 times, and triethylethynyl silicon (388.9g, 2.77mol) and [1,1' -bis (diphenylphosphino) ferrocene were added]Palladium dichloride (42.1g, 0.06mol) was reacted at 65-70 ℃ for 6 hours. After the reaction is finished, filtering the system while the system is hot, washing with toluene twice, removing the solvent under reduced pressure, adding 4L of water, stirring vigorously, filtering, and washing with water twice to obtain 530.3g of 2-triethylsilyl-4-acetamido-5-iodobenzofuran-7-carboxylic acid ethyl ester, wherein the yield is as follows: 70.7 percent. Mass spectrometric detection of m/z 488.1[ MH ]]+And determined to be 2-triethylsilyl-4-acetylamino-5-iodobenzofuran-7-carboxylic acid ethyl ester.
The third step: synthesis of 4-amino-5-iodobenzofuran-7-carboxylic acid
Lithium hydroxide (54.7g, 2.28mol) was added in portions to a mixed solution of ethyl 2-triethylsilyl-4-acetylamino-5-iodobenzofuran-7-carboxylate (185.1g, 0.38mol) in water (0.65L) and dioxane (0.65L). Stirring the reaction solution at 80-85 deg.C for 8 hr, cooling to room temperature, diluting with water (2.5L), filtering off insoluble substances, extracting with methyl tert-butyl ether (2X 1.0L), adjusting pH of the aqueous phase to 4 with 5N hydrochloric acid, filtering, and vacuum drying to obtain 94.3g 4-amino-5-iodobenzofuran-7-carboxylic acidAcid, yield: 81.9 percent. Mass spectrometric detection of m/z 303.9 MH]+And was identified as 4-amino-5-iodobenzofuran-7-carboxylic acid.
The total yield of the three-step reaction is as follows: 53.9 percent.
Comparative example 1
The synthetic route reported in WO 2016128990a1 is as follows:
the first step is as follows: synthesis of o-hydroxy-p-aminobenzoic acid methyl ester
Sulfuric acid (200mL) was slowly added dropwise to a solution of 4-amino-2-hydroxybenzoic acid (100g, 0.653mol) in methanol (1500mL) at 0 ℃. The reaction mixture was slowly heated to 80 ℃ and stirred for 6 hours. The temperature was lowered to room temperature and methanol was spin-dried, the residue was dissolved in water, the pH was adjusted to 7 with an aqueous solution of sodium hydroxide, filtered, the filter cake was dissolved in methylene chloride (2000mL) and washed with brine (500mL), and the organic phase was dried to give 98.3g of methyl o-hydroxy-p-aminobenzoate (yield: 90%).
The second step is that: synthesis of p-acetamido-o-hydroxybenzoic acid methyl ester
Acetic anhydride (66.50mL,0.704mol) was slowly added dropwise to a solution of methyl o-hydroxy-p-aminobenzoate (98g,0.586mol) in dichloromethane (980mL) at 0 ℃. The reaction was warmed to 10 ℃ and allowed to react at that temperature for 4 hours, the reaction mixture was poured into 1.0L of ice water and stirred for 30 minutes, filtered, the filter cake was dissolved in ethyl acetate (1.0L) and washed with brine, and the organic phase was dried and spin-dried to give 88.8g of methyl p-acetamido-o-methoxybenzoate in 72.4% yield.
The third step: synthesis of 2-hydroxy-4-acetamido-5-chlorobenzoic acid methyl ester
N-chlorosuccinimide (69g, 0.509mol) was added to p-acetamido-methyl o-methoxybenzoate (88.8g, 0.424mol) in dichloroethane (2.0L) at room temperature, the reaction was slowly heated to 80 ℃ and stirred at that temperature for 4 hours, after TLC monitoring of the completion of the reaction, cooled to room temperature, the solvent was dried, the residue was diluted with water (1.0L), the filtered solid was dissolved in dichloromethane (2.0L) and washed with 500mL brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and dried to give 97g of methyl 2-hydroxy-4-acetamido-5-chlorobenzoate, yield: 93.9 percent.
The fourth step: 4-acetamido-5-chloro-2-hydroxy-3-iodobenzoic acid methyl ester.
Benzyltrimethylammoniumdichloroiodate (17.33g, 0.0498mol) was added portionwise to a solution of methyl 4-acetamido-5-chloro-2-hydroxybenzoate (12.13g, 0.0498mol) and sodium bicarbonate (10.46g, 0.124mol) in dichloromethane and methanol (120mL/50mL) at room temperature. The reaction was stirred at room temperature for 18 h, then the solvent was spun off, the residue was poured into 500L of cold water and stirred for 1 h, after filtration the solid was dissolved in 500mL of chloroform and washed with sodium bisulfite (3 x 250 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and dried to give 15.8g of 4-acetamido-5-chloro-2-hydroxy-3-iodobenzoic acid methyl ester, yield: 85.8 percent.
The fifth step: synthesis of 2-trimethylsilyl-4-acetamido-5-chlorobenzofuran-7-carboxylic acid methyl ester
Methyl 4-acetylamino-5-chloro-2-hydroxy-3-iodobenzoate (15.8g, 0.0427mol), trimethylethynylsilicon, cuprous iodide, and bis (triphenylphosphine) palladium dichloride were added to a mixed solution of triethylamine and dioxane (10mL/80mL) and reacted at 70 ℃ for 6 hours. After completion of the reaction, it was cooled to room temperature, and the solvent, tetramethylguanidine (10.09g, 0.0876mol) in toluene (100mL) was added to the residue. Reflux for 3 hours, cool and dilute with chloroform (400mL), filter the insoluble and spin dry the organic phase through a flash silica gel column to give 4g of methyl 2-trimethylsilyl-4-acetamido-5-chlorobenzofuran-7-carboxylate, yield: and 69 percent.
And a sixth step: synthesis of 4-amino-5-chlorobenzofuran-7-carboxylic acid
Potassium hydroxide (2.3g, 0.029mol) was added in portions to a mixed solution of methyl 2-trimethylsilyl-4-acetylamino-5-chlorobenzofuran-7-carboxylate (4g, 0.01mol) in water and dioxane (20 mL: 20 mL). The reaction was stirred at 70 ℃ for 8 h, cooled to room temperature, diluted with water (100mL), extracted with ethyl acetate (2 × 50mL), the aqueous phase was adjusted to pH 4 with 5N hydrochloric acid, the solid was filtered and dried under vacuum to give 1.65g of 4-amino-5-chlorobenzofuran-7-carboxylic acid, yield: 66.7 percent.
Six steps total yield: 24.16 percent.
Claims (7)
1. A method for preparing 4-amino-5-halogenobenzofuran-7-carboxylic acid, which is characterized by comprising the following steps of: 4-protected amino-2-hydroxybenzoic acid/ester is subjected to halogenation reaction to obtain 4-protected amino-3, 5-dihalo-2-hydroxybenzoic acid/ester, then the 4-protected amino-3, 5-dihalo-2-hydroxybenzoic acid/ester is subjected to coupling reaction with trialkyl acetylene silicon to obtain 2-trialkyl silicon base-4-protected amino-5-halogeno benzofuran-7-carboxylic acid/ester, and the 4-amino-5-halogeno benzofuran-7-carboxylic acid is obtained through deprotection or deprotection/hydrolysis; the protecting group in the protected amino is acetyl, trifluoroacetyl or hydrogen; the trialkyl silicon base is trimethyl silicon base or triethyl silicon base.
2. The process for producing 4-amino-5-halogenobenzofuran-7-carboxylic acid according to claim 1, wherein: the first step is as follows: 4-protected amino-3, 5-dihalo-2-hydroxybenzoic acid/ester synthesis, heating 4-protected amino-2-hydroxybenzoic acid/ester and a halogenating reagent in an organic solvent for reaction to obtain 4-protected amino-3, 5-dihalo-2-hydroxybenzoic acid/ester; the second step is that: synthesizing 2-trialkylsilyl-4-protected amino-5-halogenobenzofuran-7-carboxylic acid/ester by reacting 4-protected amino-3, 5-dihalogen-2-hydroxybenzoic acid/ester with trialkyloetyl silicon in the presence of palladium catalyst, cuprous iodide and organic base in an organic solvent to obtain 2-trialkylsilyl-4-protected amino-5-halogenobenzofuran-7-carboxylic acid/ester; the third step: synthesis of 4-amino-5-halogenobenzofuran-7-carboxylic acid 2-trialkylsilyl-4-protected amino-5-halogenobenzofuran-7-carboxylic acid/ester is deprotected or deprotected/hydrolyzed under alkaline conditions to obtain 4-amino-5-halogenobenzofuran-7-carboxylic acid.
3. The process for producing 4-amino-5-halogenobenzofuran-7-carboxylic acid according to claim 2, wherein: in the first step, the halogenating agent is selected from N-chlorosuccinimide, dichlorohydantoin, N-bromosuccinimide, dibromohydantoin or N-iodosuccinimide; in the second step, trialkyl acetylene silicon is selected from trimethyl silicon acetylene or triethyl silicon acetylene; the palladium catalyst is selected from bis (triphenylphosphine) palladium dichloride or [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride; the organic base is selected from N, N-diisopropylethylamine, triethylamine and pyridine; in the third step, the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate.
4. The process for producing 4-amino-5-halogenobenzofuran-7-carboxylic acid according to claim 2, wherein: in the first step, the molar ratio of the 4-protected amino-2-hydroxybenzoic acid/ester to the halogenating agent is 1: 2-3; in the second step, the molar ratio of the 4-protected amino-3, 5-dihalo-2-hydroxybenzoic acid/ester, trialkyl acetylene silicon, palladium catalyst, cuprous iodide to organic base is 1: 1.13-2: 0.03-0.08: 0.05-0.2: 3-10; in the third step, the molar ratio of 2-trialkylsilyl-4-protected amino-5-halogenobenzofuran-7-carboxylic acid/ester to alkali is 1: 3-15.
5. The process for producing 4-amino-5-halogenobenzofuran-7-carboxylic acid according to claim 2, wherein: in the first step, the organic solvent is selected from 1, 2-dichloroethane, dichloromethane, chloroform, acetone, dioxane or acetonitrile; in the second step, the organic solvent is selected from 1, 2-dichloroethane, ethylene glycol dimethyl ether, 2-methyltetrahydrofuran, acetonitrile, toluene or any combination of the above solvents; in the third step, the alkaline condition is in an alkaline aqueous solution.
6. The process for producing 4-amino-5-halogenobenzofuran-7-carboxylic acid according to claim 5, wherein: in the first step, the organic solvent is 1, 2-dichloroethane; in the second step, the organic solvent is acetonitrile; in the third step, the reaction is carried out in dioxane using an aqueous alkaline solution.
7. The process for producing 4-amino-5-halogenobenzofuran-7-carboxylic acid according to claim 2, wherein: in the first step, the heating reaction temperature is 80-85 ℃; in the second step, the reaction is carried out under the heating condition, and the heating reaction temperature is 45-70 ℃; in the third step, the reaction is carried out under the heating condition, and the heating reaction temperature is 60-85 ℃.
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