CN113735744A - Synthesis method of bumetanide intermediate - Google Patents

Synthesis method of bumetanide intermediate Download PDF

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CN113735744A
CN113735744A CN202111049044.XA CN202111049044A CN113735744A CN 113735744 A CN113735744 A CN 113735744A CN 202111049044 A CN202111049044 A CN 202111049044A CN 113735744 A CN113735744 A CN 113735744A
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李强
刘华权
姚尧
沈正文
胡志恒
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Nanjing Choipharm Technology Co ltd
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Nanjing Choipharm Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a synthesis method of a bumetanide intermediate, which comprises the steps of adopting a compound containing benzyl protecting groups to protect amino in 3-amino-4-chlorobenzoic acid shown in a formula 1 to obtain a compound shown in a formula 2; reacting the compound shown in the formula 2 with thionyl chloride, and treating with ammonia water to obtain a compound shown in a formula 3; reacting the compound shown in the formula 3 with phenol to obtain a compound shown in a formula 4; after the compound shown in the formula 4 reacts with an oxidant, the intermediate of bumetanide shown in the formula 5, namely 3-amino-4-phenoxy-5-sulfamoylbenzoic acid, is obtained. Compared with the prior art, the method provided by the invention avoids the use of highly toxic chlorosulfonic acid, avoids nitration reaction, is convenient for production organization, and improves the production safety.

Description

Synthesis method of bumetanide intermediate
Technical Field
The invention belongs to the field of medicines, further belongs to the synthesis industry of raw material medicines, and particularly relates to a synthesis method of a bumetanide intermediate.
Background
Bumetanide is a potent diuretic, and is mainly used clinically for treating heart failure, liver diseases, renal disease edema including various refractory edema and acute pulmonary edema, and the structural formula is as follows:
Figure BDA0003252174390000011
in the route for synthesizing bumetanide, compound 5 (3-amino-4-phenoxy-5-sulfamoylbenzoic acid) is a key intermediate, and is alkylated by reacting with n-butanol, and then undergoes ester hydrolysis to obtain bumetanide (compound 7).
Figure BDA0003252174390000012
As a synthetic method of Compound 5, Journal of laboratory Compound and radiopharmaceuticals.21(2):173-80,1984 reports the following synthetic route.
Figure BDA0003252174390000013
In this synthetic route, chlorosulfonic acid is used and special approval is required for its purchase, which is highly toxic. In addition, in the reaction process, concentrated sulfuric acid and concentrated nitric acid are required to be used for nitration reaction, so that great challenge is brought to safe production, and higher risk is brought. Accordingly, the present invention provides a novel method for synthesizing an intermediate of bumetanide.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to solve the technical problem of providing a synthetic method of a bumetanide intermediate aiming at the defects of the prior art.
In order to solve the technical problem, the invention discloses a synthetic method of a bumetanide intermediate, which comprises the following steps:
(1) protecting amino in 3-amino-4-chlorobenzoic acid shown in the formula 1 by using a compound containing benzyl protecting groups to obtain a compound shown in the formula 2, wherein N atoms are protected by one benzyl protecting group;
(2) reacting the compound shown in the formula 2 with thionyl chloride, and treating with ammonia water to obtain a compound shown in a formula 3;
(3) reacting the compound shown in the formula 3 with phenol to obtain a compound shown in a formula 4;
(5) reacting the compound shown in the formula 4 with an oxidant to obtain a bumetanide intermediate shown in the formula 5, namely 3-amino-4-phenoxy-5-sulfamoylbenzoic acid;
Figure BDA0003252174390000021
wherein R is selected from H or methoxy.
In the step (1), the benzyl protecting group is benzyl or p-methoxybenzyl.
In the step (1), the compound containing a benzyl protecting group is any one of benzyl chloride, benzyl bromide, p-methoxybenzyl chloride and p-methoxybenzyl bromide.
In the step (1), the molar ratio of the compound containing the benzyl protecting group to the 3-amino-4-chlorobenzoic acid shown in the formula 1 is (1-1.5): 1; preferably, the molar ratio of the compound containing the benzyl protecting group to the 3-amino-4-chlorobenzoic acid shown in the formula 1 is (1.0-1.1): 1; further preferably, the molar ratio of the compound containing a benzyl protecting group to the 3-amino-4-chlorobenzoic acid represented by formula 1 is 1.1: 1.
In step (1), the solvent for the reaction is an organic solvent, including but not limited to dichloromethane.
In the step (1), the dosage ratio of the 3-amino-4-chlorobenzoic acid shown in the formula 1 to the solvent is 0.4-1.6 mmol/ml; preferably, the dosage ratio of the 3-amino-4-chlorobenzoic acid shown in the formula 1 to the solvent is 0.7-1.3 mmol/ml; preferably, the amount ratio of the 3-amino-4-chlorobenzoic acid represented by formula 1 to the solvent is 0.9 to 1.0 mmol/ml.
In step (1), the reaction further comprises a basic compound, including but not limited to triethylamine; preferably, the molar ratio of the 3-amino-4-chlorobenzoic acid shown in the formula 1 to the basic compound is 1 (1-3); further preferably, the molar ratio of the 3-amino-4-chlorobenzoic acid represented by the formula 1 to the basic compound is 1 (1.5-2.5); still more preferably, the molar ratio of the 3-amino-4-chlorobenzoic acid represented by formula 1 to the basic compound is 1: 2.
In the step (1), preferably, a basic compound is added to a solution of 3-amino-4-chlorobenzoic acid and a solvent, a compound containing a benzyl protecting group is added, the addition rate and temperature are controlled, and the reaction is monitored by TLC until the reaction is completed.
In the step (1), the reaction temperature is 35-45 ℃, preferably 40 ℃.
In the step (1), the reaction time is monitored by TLC until the reaction is completed; preferably, a GF254 silica gel plate is used, the developing solvent is dichloromethane methanol (v/v) 10:1, and observation is carried out using a 254nm uv lamp.
In the step (1), after the reaction is finished, adding a sodium hydroxide solution for extraction, separating out a water phase, adjusting the pH value to 4-5 by using dilute hydrochloric acid, performing crystallization at 0-10 ℃ to obtain a white-like solid, and drying to obtain the compound shown in the formula 2.
In the step (2), the dosage ratio of the compound shown in the formula 2 to the thionyl chloride is (0.2-0.8) mol:300 ml; preferably, the dosage ratio of the compound shown in the formula 2 to the thionyl chloride is (0.4-0.6) mol:300 ml; further preferably, the amount ratio of the compound represented by the formula 2 to thionyl chloride is (0.5-0.55) mol:300 ml.
In the step (2), the volume ratio of the ammonia water to the thionyl chloride is (1-7) to 3; preferably, the volume ratio of the ammonia water to the thionyl chloride is (3-5) to 3; further preferably, the volume ratio of the ammonia water to the thionyl chloride is 4: 3.
In the step (2), preferably, the temperature of the thionyl chloride is reduced to below 0 ℃, the compound shown in the formula 2 is added in batches, the adding speed is controlled, the temperature is kept below 10 ℃, and after the adding is finished, the temperature is raised for reaction.
In the step (2), the reaction temperature is below 35 ℃; preferably, the temperature of the reaction is 30 ℃ or less; further preferably, the temperature of the reaction is 25 ℃ or lower.
In the step (2), the reaction time is monitored by TLC until the reaction is completed; preferably, a GF254 silica gel plate is used, the developing solvent is dichloromethane methanol (v/v) 50:1, and observation is carried out using a 254nm uv lamp.
In the step (2), after the reaction is finished, adding ammonia water at the temperature of below 10 ℃; preferably, after the reaction is finished, adding ammonia water with the temperature of below 10 ℃, and continuing the reaction at 20 +/-5 ℃; further preferably, after the reaction is finished, adding ammonia water with the temperature of below 10 ℃, controlling the adding speed, controlling the temperature of a reaction system to be below 25 ℃, and continuously reacting at 20 +/-5 ℃; more preferably, after the reaction is finished, adding ammonia water with the temperature of below 10 ℃, controlling the adding speed, controlling the temperature of a reaction system to be below 25 ℃, and continuously reacting at 20 +/-5 ℃ for more than 0.5 h; still more preferably, after the reaction is finished, adding ammonia water with the temperature of below 10 ℃, controlling the adding speed, controlling the temperature of the reaction system to be below 25 ℃, continuing to react at 20 +/-5 ℃ for more than 0.5h, filtering the precipitated solid, leaching the filter cake, and drying to obtain the compound shown in the formula 3.
In the step (3), the mol ratio of the compound shown in the formula 3 to the phenol is 1 (1.5-2.9); preferably, the molar ratio of the compound shown in the formula 3 to the phenol is 1 (1.8-2.6); further preferably, the molar ratio of the compound represented by the formula 3 to phenol is 1 (2.1-2.3).
In the step (3), preferably, a solution containing phenol is added to a solution containing the compound represented by formula 3, and the reaction is carried out.
Wherein the solution containing the compound shown in the formula 3 comprises the compound shown in the formula 3, sodium bicarbonate and water; preferably, the dosage ratio of the three is 1mol, (1-3) mol, (2-3) L; preferably, the dosage ratio of the three is 1mol:2mol (2.5-2.7) L.
Wherein the phenol-containing solution comprises phenol, sodium hydroxide and water; preferably, the dosage ratio of the three is 1mol, (0.5-1.5) mol, (0.2-0.9) L; preferably, the dosage ratio of the three is 1mol:1mol (0.5-0.6) L.
In the step (3), the reaction temperature is 60-100 ℃; preferably, the temperature of the reaction is 70-80 ℃.
In the step (3), the reaction time is more than 5 hours; preferably, the reaction time is 5-15 h; further preferably, the reaction time is 10 h.
In the step (3), after the reaction is finished, cooling the reaction liquid to below 0 ℃, filtering the precipitated solid, washing the filter cake, and drying to obtain the compound shown in the formula 4.
In the step (4), the oxidant is dichloro dicyano benzoquinone (DDQ) and/or Cerium Ammonium Nitrate (CAN).
In the step (4), the molar ratio of the oxidant to the compound shown in the formula 4 is (2-6): 1.
Preferably, when the oxidizing agent is dichlorodicyanobenzoquinone, the molar ratio of the oxidizing agent to the compound represented by the formula 4 is 2.5 to 6; further preferably, when the oxidizing agent is dichlorodicyanobenzoquinone, the molar ratio of the oxidizing agent to the compound represented by formula 4 is 3.
Preferably, when the oxidizing agent is cerium ammonium nitrate, the molar ratio of the oxidizing agent to the compound represented by formula 4 is 2 to 5; further preferably, when the oxidizing agent is cerium ammonium nitrate, the molar ratio of the oxidizing agent to the compound represented by formula 4 is 2.5.
In the step (4), when the oxidant dichloro dicyano benzoquinone exists;
wherein the solvent of the reaction is acetonitrile.
Wherein the dosage ratio of the compound shown in the formula 4 to the solvent is 0.1-0.5 mmol/ml; preferably, the amount ratio of the compound represented by formula 4 to the solvent is 0.3 to 0.35 mmol/ml.
Wherein, after the compound shown in the formula 4 and a solvent are heated and dissolved, dichlorodicyano benzoquinone is added for reaction.
Wherein the heating temperature is 30-50 ℃.
Wherein the reaction temperature is 50-70 ℃; preferably, the temperature of the reaction is 55-65 ℃.
Wherein the reaction time is more than 1 h; preferably, the reaction time is 1-5 h; further preferably, the reaction time is 3 h.
After the reaction is finished, cooling the reaction liquid, adding water, extracting with ethyl acetate, washing an organic phase with a saturated sodium chloride solution, adding n-heptane into ethyl acetate, cooling to 0-10 ℃ for crystallization, filtering out solids, leaching the solids with a mixed solvent of ethyl acetate and n-heptane in a ratio of 1:1, and drying to obtain the compound shown in the formula 5.
In the step (4), when the oxidant is cerium ammonium nitrate;
wherein the solvent for the reaction is acetonitrile and water; preferably, the volume ratio of acetonitrile to water is (0.5-2) to 1; preferably, the volume ratio of acetonitrile to water is (1-1.5) to 1; further preferably, the volume ratio of acetonitrile to water is (1.2-1.4): 1.
Wherein the dosage ratio of the compound shown in the formula 4 to the solvent is 0.05-0.2 mmol/ml; preferably, the amount ratio of the compound represented by formula 4 to the solvent is 0.1 to 0.15 mmol/ml.
Preferably, cerium ammonium nitrate is added to a solution of the compound represented by formula 4 below 5 ℃ and a solvent for reaction; more preferably, ammonium cerium nitrate is added to a solution of the compound represented by formula 4 at 0 ℃ or lower and a solvent to react.
Wherein the reaction temperature is-5-10 ℃; preferably the reaction temperature is 0-5 ℃.
Wherein the reaction time is more than 5 h; preferably, the reaction time is 5-15 h; further preferably, the reaction time is 10 h.
After the reaction is finished, adding ethyl acetate for extraction, combining organic phases, washing the organic phases with a saturated sodium chloride solution for several times, dropwise adding n-heptane into the ethyl acetate, cooling the system to 0-10 ℃ for crystallization, filtering out solids, leaching the solids with a mixed solvent of ethyl acetate and n-heptane in a ratio of 1:1, and drying to obtain the compound shown in the formula 5.
Has the advantages that: compared with the prior art, the invention has the following advantages:
the invention provides a novel method for preparing 3-amino-4-phenoxy-5-sulfamoylbenzoic acid, which avoids the use of highly toxic chlorosulfonic acid, avoids nitration reaction, is convenient for production organization and improves the production safety.
Detailed Description
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the raw materials, reagents and solvents are all conventional commercial chemicals and are not purified before use.
In the following examples, similar descriptions of said temperature not higher than 40 ℃, not higher than 20 ℃ and the like refer to exotherms during the dropping, said temperature approaching the corresponding 40 ℃, or 20 ℃ and the like, which are common expressions in the field of synthesis.
The control of the dropping rate in the following examples means to control the feeding rate depending on the temperature of the reaction system, and if the temperature is close, the rate is slowed or the dropping is suspended, and the dropping is resumed or increased as the temperature is lowered.
Example 1: preparation of Compound 2a
Figure BDA0003252174390000061
Adding 3-amino-4-chlorobenzoic acid (100g, 0.583mol) into a reaction bottle, adding dichloromethane (600ml) for dissolution, adding triethylamine (162ml,1.166mol), dropwise adding benzyl chloride (81.18g,0.641mol), controlling the dropwise adding speed to be not higher than 40 ℃, controlling the dropwise adding speed to be over, monitoring the reaction by TLC until the reaction is finished, adding 0.5mol/L sodium hydroxide solution (500ml) for extraction, separating out an aqueous phase, adjusting the pH value to 4-5 by using dilute hydrochloric acid, carrying out crystallization at 0-10 ℃ to obtain a white-like solid, and carrying out forced air drying at 40-50 ℃ to obtain a compound 2a (141.9g) with the yield of 93%.
ESI-MS(+):262.2[M+H]+.1H-NMR(400MHz,DMSO-d6+D2O):7.49(d,1H,J＝7.0Hz),7.47(d,1H,J＝7.0Hz),7.31-7.27(m,6H),4.31(s,2H).
Example 2: preparation of Compound 2a
Figure BDA0003252174390000062
Adding 3-amino-4-chlorobenzoic acid (100g, 0.583mol) into a reaction bottle, adding dichloromethane (600ml) for dissolution, adding triethylamine (162ml,1.166mol), dropwise adding benzyl bromide (109.64g,0.641mol), controlling the dropwise adding speed to be not higher than 40 ℃, controlling the dropwise adding speed to be over, monitoring the reaction by TLC until the reaction is finished, adding 0.5mol/L sodium hydroxide solution (500ml) for extraction, separating out a water phase, adjusting the pH value to 4-5 by using dilute hydrochloric acid, carrying out crystallization at 0-10 ℃ to obtain a white-like solid, carrying out forced air drying at 40-50 ℃ to obtain a compound 2a (138.8g), wherein the yield is 91%.
Example 3: preparation of Compound 2a
Adding 3-amino-4-chlorobenzoic acid (100g, 0.583mol) into a reaction bottle, adding dichloromethane (600ml) for dissolution, adding triethylamine (162ml,1.166mol), dropwise adding benzyl bromide (149.66g,0.875mol), controlling the dropwise adding speed to be not higher than 40 ℃, controlling the dropwise adding speed to be over, finishing the dropwise adding, monitoring the reaction by TLC until the reaction is finished, adding 0.5mol/L sodium hydroxide solution (500ml) for extraction, separating out a water phase, adjusting the pH value to 4-5 by using dilute hydrochloric acid, carrying out crystallization at 0-10 ℃ to obtain a white-like solid, carrying out forced air drying at 40-50 ℃ to obtain a compound 2a (140.3g), wherein the yield is 92%.
Example 4: preparation of Compound 2b
Figure BDA0003252174390000071
Adding 3-amino-4-chlorobenzoic acid (100g, 0.583mol) into a reaction bottle, adding dichloromethane (600ml) for dissolution, adding triethylamine (162ml,1.166mol), dropwise adding p-methoxybenzyl chloride (100.39g,0.641mol), controlling the dropwise adding speed to be not higher than 40 ℃, monitoring the reaction by TLC until the reaction is finished, adding 0.5mol/L sodium hydroxide solution (500ml) for extraction, separating out a water phase, adjusting the pH value to 4-5 by using dilute hydrochloric acid, carrying out crystallization at 0-10 ℃ to obtain a white-like solid, and carrying out forced air drying at 40-50 ℃ to obtain a compound 2b (151.4g) with the yield of 89%.
ESI-MS(+):292.1[M+H]+.1H-NMR(400MHz,DMSO-d6+D2O):7.48(d,1H,J＝6.9Hz),7.47(d,1H,J＝7.0Hz),7.31(s,1H),7.12(d,2H,J＝6.6Hz),7.02(d,2H,J＝6.6Hz),4.31(s,2H),3.77(s,3H).
Example 5: preparation of Compound 2b
Adding 3-amino-4-chlorobenzoic acid (100g, 0.583mol) into a reaction bottle, adding dichloromethane (600ml) for dissolution, adding triethylamine (162ml,1.166mol), adding p-methoxybenzyl chloride (91.3g,0.583mol) dropwise, controlling the dropwise adding speed to be not higher than 40 ℃, monitoring the reaction by TLC until the completion of the dropwise adding, adding 0.5mol/L sodium hydroxide solution (500ml) for extraction, separating out an aqueous phase, adjusting the pH value to 4-5 by using dilute hydrochloric acid, carrying out crystallization at 0-10 ℃ to obtain a white-like solid, and carrying out forced air drying at 40-50 ℃ to obtain a compound 2b (141.2g) with the yield of 83%.
Example 6: preparation of Compound 2b
Figure BDA0003252174390000081
Adding 3-amino-4-chlorobenzoic acid (100g, 0.583mol) into a reaction bottle, adding dichloromethane (600ml) for dissolution, adding triethylamine (162ml,1.166mol), dropwise adding p-methoxybenzyl bromide (128.88g,0.641mol), controlling the dropwise adding speed to be not higher than 40 ℃, monitoring the reaction by TLC until the reaction is finished, adding 0.5mol/L sodium hydroxide solution (500ml) for extraction, separating out an aqueous phase, adjusting the pH value to 4-5 by using dilute hydrochloric acid, carrying out crystallization at 0-10 ℃ to obtain a white-like solid, and carrying out forced air drying at 40-50 ℃ to obtain a compound 2b (159.9g) with the yield of 94%.
Example 7: preparation of Compound 3a
Figure BDA0003252174390000082
Adding thionyl chloride (300ml) into a reaction bottle, cooling to below 0 ℃ by using a cold bath, adding a compound 2a (138.8g, 0.530mol) solid in batches, controlling the acceleration speed, keeping the temperature below 10 ℃, after the addition is finished, heating the reaction system to 25 +/-5 ℃, stirring for reaction, and monitoring the reaction process by TLC (thin layer chromatography) until the raw material point disappears.
Cooling ammonia water (400ml) to below 10 ℃, stirring, adding the reaction solution dropwise, controlling the dropwise adding speed, and keeping the temperature of the reaction system not higher than 25 ℃. After the addition, the mixture was stirred at 20. + -. 5 ℃ for 1 hour. The precipitated solid was filtered, and the filter cake was rinsed with purified water (100ml × 2). Drying with forced air at 50 ℃ or lower gave 125.6g in total of compound 3a in a yield of 73%.
ESI-MS(+):325.1[M+H]+.1H-NMR(400MHz,DMSO-d6+D2O):7.63(s,1H),7.48(s,1H),7.32-7.29(m,5H),4.31(s,2H).
Example 8: preparation of Compound 3a
Adding thionyl chloride (300ml) into a reaction bottle, cooling to below 0 ℃ by using a cold bath, adding a compound 2a (52.4g, 0.2mol) solid in batches, controlling the acceleration speed, keeping the temperature below 10 ℃, after the addition is finished, heating the reaction system to 25 +/-5 ℃, stirring for reaction, and monitoring the reaction process by TLC (thin layer chromatography) until the raw material point disappears.
Cooling ammonia water (400ml) to below 10 ℃, stirring, adding the reaction solution dropwise, controlling the dropwise adding speed, and keeping the temperature of the reaction system not higher than 25 ℃. After the addition, the mixture was stirred at 20. + -. 5 ℃ for 1 hour. The precipitated solid was filtered, and the filter cake was rinsed with purified water (100ml × 2). Forced air drying at 50 ℃ or lower gave 43.52g in total, 67% yield of compound 3 a.
Example 9: preparation of Compound 3b
Figure BDA0003252174390000091
Adding thionyl chloride (300ml) into a reaction bottle, cooling to below 0 ℃ by using a cold bath, adding the compound 2b (159.0g, 0.545mol) solid in batches, controlling the acceleration speed, keeping the temperature below 10 ℃, heating the reaction system to 25 +/-5 ℃ after the addition is finished, stirring for reaction, and monitoring the reaction process by TLC until the raw material point disappears.
Cooling ammonia water (400ml) to below 10 ℃, stirring, adding the reaction solution dropwise, controlling the dropwise adding speed, and keeping the temperature of the reaction system not higher than 25 ℃. After the addition, the mixture was stirred at 20. + -. 5 ℃ for 1 hour. The precipitated solid was filtered, and the filter cake was rinsed with purified water (100ml × 2). Drying with forced air at 50 ℃ or lower gave 127.6g, in total, of compound 3b in 66% yield.
ESI-MS(+):354.04[M+H]+.1H-NMR(400MHz,DMSO-d6+D2O):7.62(s,1H),7.49(s,1H),7.37(d,2H,J＝6.7Hz),7.29(d,2H,J＝6.7Hz),4.31(s,2H),3.81(s,3H).
Example 10: preparation of Compound 3b
Adding thionyl chloride (300ml) into a reaction bottle, cooling to below 0 ℃ by using a cold bath, adding the compound 2b (233.4g, 0.8mol) solid in batches, controlling the acceleration speed, keeping the temperature below 10 ℃, heating the reaction system to 25 +/-5 ℃ after the addition is finished, stirring for reaction, and monitoring the reaction process by TLC (thin layer chromatography) until the raw material point disappears.
Cooling ammonia water (400ml) to below 10 ℃, stirring, adding the reaction solution dropwise, controlling the dropwise adding speed, and keeping the temperature of the reaction system not higher than 25 ℃. After the addition, the mixture was stirred at 20. + -. 5 ℃ for 1 hour. The precipitated solid was filtered, and the filter cake was rinsed with purified water (100ml × 2). Drying with forced air at 50 ℃ or lower gave 173.1g of Compound 3b in a total yield of 61%.
Example 11: preparation of Compound 4a
Figure BDA0003252174390000101
Purified water (1000ml) was added to a reaction flask, compound 3a (123.0g,0.379mol) was added, sodium bicarbonate (63.7g,0.758mol) was added with stirring, the solid was dissolved, and the reaction system was warmed to 80-85 ℃. Phenol (78.5g,0.834mol) and sodium hydroxide (33.4g,0.834mol) were dissolved in purified water (500 ml). The solution of phenol and sodium hydroxide is added dropwise into the solution of the compound 3a, the dropping speed is controlled, the temperature is kept at 70-80 ℃, and then the reaction is stirred at 70-80 ℃ for 10 hours.
The reaction solution was cooled to below 0 ℃, the precipitated solid was filtered off, the filter cake was rinsed with purified water, and the solid was air dried at 60 ± 5 ℃ for 12 hours to give compound 4a, in total 118.9g, with a yield of 82.0%.
ESI-MS(+):405.2[M+Na]+.1H-NMR(400MHz,DMSO-d6+D2O):7.65(s,1H),7.50(s,1H),7.42-7.31(m,7H),7.18-7.10(m,3H),4.32(s,2H).
Example 12: preparation of Compound 4a
Purified water (1000ml) was added to a reaction flask, compound 3a (123.0g,0.379mol) was added, sodium bicarbonate (63.7g,0.758mol) was added with stirring, the solid was dissolved, and the reaction system was warmed to 80-85 ℃. Phenol (103.52g,1.10mol) and sodium hydroxide (44g,1.10mol) were dissolved in purified water (500 ml). The solution of phenol and sodium hydroxide is added dropwise into the solution of the compound 3a, the dropping speed is controlled, the temperature is kept at 70-80 ℃, and then the reaction is stirred at 70-80 ℃ for 10 hours.
The reaction solution was cooled to below 0 ℃, the precipitated solid was filtered off, the filter cake was rinsed with purified water, and the solid was air dried at 60 ± 5 ℃ for 12 hours to give compound 4a, in total 107.4g, with a yield of 74.1%.
Example 13: preparation of Compound 4b
Figure BDA0003252174390000102
Purified water (1000ml) was added to a reaction flask, compound 3b (125.0g,0.352mol) was added thereto, sodium hydrogencarbonate (59.1g,0.704mol) was added with stirring to dissolve the solid, and the reaction system was warmed to 80-85 ℃. Phenol (72.9g,0.774mol) and sodium hydroxide (31.0g,0.774mol) were dissolved in purified water (500 ml). And (3) dropwise adding a solution of phenol and sodium hydroxide into a solution of the compound 3b, controlling the dropwise adding speed, keeping the temperature at 90-100 ℃, and then stirring and reacting for 10 hours at 90-100 ℃.
The reaction solution was cooled to below 0 ℃, the precipitated solid was filtered off, the filter cake was rinsed with purified water, and the solid was air dried at 60 ± 5 ℃ for 12 hours to give compound 4b, in total 116.1g, with a yield of 80.0%.
ESI-MS(+):413.20[M+H]+,435.11[M+Na]+1H-NMR(400MHz,DMSO-d6+D2O):7.66(s,1H),7.50(s,1H),7.42-7.31(m,6H),7.18-7.10(m,3H),4.32(s,2H),3.86(s,3H).
Example 14: preparation of Compound 4b
Purified water (1000ml) was added to a reaction flask, compound 3b (125.0g,0.352mol) was added thereto, sodium hydrogencarbonate (59.1g,0.704mol) was added with stirring to dissolve the solid, and the reaction system was warmed to 80-85 ℃. Phenol (49.69g,0.528mol) and sodium hydroxide (21.12g,0.528mol) were dissolved in purified water (500 ml). And (3) dropwise adding a solution of phenol and sodium hydroxide into a solution of the compound 3b, controlling the dropwise adding speed, keeping the temperature at 60-70 ℃, and then stirring and reacting for 10 hours at 60-70 ℃.
The reaction solution was cooled to below 0 ℃, the precipitated solid was filtered off, the filter cake was rinsed with purified water, and the solid was air dried at 60 ± 5 ℃ for 12 hours to give compound 4b, in total 107.4g, with a yield of 74.0%.
Example 15: preparation of Compound 5 from 4a (DDQ 2.5 eq.)
Figure BDA0003252174390000111
Compound 4a (100g,0.261mol) was charged into a reaction flask, acetonitrile (800ml) was added, heated to 40 ℃ to dissolve the solid, dichlorodicyanobenzoquinone (148.39g,0.65mol,2.5 eq) was added, the reaction was heated to 60. + -. 5 ℃ and reacted for 3 hours. Cooled to below 25 ℃, purified water (480ml) was added, extraction was performed with ethyl acetate (320ml × 3), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution (160ml × 3). Adding n-heptane (960ml) dropwise into ethyl acetate solution, cooling the system to 0-10 deg.C for crystallization, filtering out solid, eluting the solid with mixed solvent of ethyl acetate and n-heptane 1:1, and drying at 45-55 deg.C under reduced pressure to obtain compound 5 with 60.46g total yield of 75%.
ESI-MS(+):309.10[M+H]+.1H-NMR(400MHz,DMSO-d6+D2O):8.02(s,1H),7.81(s,1H),7.42(d,2H,J＝6.3Hz),7.18-7.10(m,3H).
Example 16: preparation of Compound 5 from 4a (DDQ used 3 equivalents)
Figure BDA0003252174390000121
Compound 4a (200g,0.523mol) was charged to a reaction flask, acetonitrile (1600ml) was added, heated to 40 ℃ to dissolve the solid, dichlorodicyanobenzoquinone (356.14g,1.57mol,3 eq) was added, the reaction was heated to 60. + -. 5 ℃ and allowed to react for 3 hours. Cooled to below 25 ℃, purified water (960ml) was added, extraction was performed with ethyl acetate (640ml × 3), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution (320ml × 3). N-heptane (1920ml) was added dropwise to the ethyl acetate solution, the system was cooled to 0-10 ℃ for crystallization, the solid was filtered off, the solid was rinsed with a mixed solvent of ethyl acetate and n-heptane 1:1, and dried under reduced pressure at 45-55 ℃ to give compound 5 in 143.50g in total with a yield of 89%.
Example 17: preparation of Compound 5 from 4a (DDQ used 4.5 equivalents)
Figure BDA0003252174390000122
Compound 4a (100g,0.261mol) was charged into a reaction flask, acetonitrile (800ml) was added, heated to 40 ℃ to dissolve the solid, dichlorodicyanobenzoquinone (267.11g,1.18mol,4.5 eq) was added, the reaction was heated to 60. + -. 5 ℃ and reacted for 3 hours. Cooled to below 25 ℃, purified water (480ml) was added, extraction was performed with ethyl acetate (320ml × 3), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution (160ml × 3). N-heptane (960ml) was added dropwise to the ethyl acetate solution, the system was cooled to 0-10 ℃ for crystallization, the solid was filtered off, the solid was rinsed with a mixed solvent of ethyl acetate and n-heptane 1:1, and dried under reduced pressure at 45-55 ℃ to give compound 5 in 59.66g in total with a yield of 74%.
Example 18: preparation of Compound 5 from 4a (DDQ used 6 equivalents)
Figure BDA0003252174390000131
Compound 4a (150g,0.392mol) was charged to a reaction flask, acetonitrile (1200ml) was added, heated to 40 ℃ to dissolve the solid, dichlorodicyanobenzoquinone (534.22g,2.35mol,6 equivalents) was added, the reaction was heated to 60. + -. 5 ℃ and reacted for 3 hours. Cooled to below 25 ℃, purified water (720ml) was added, extraction was performed with ethyl acetate (320ml × 3), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution (240ml × 3). N-heptane (1440ml) was added dropwise to the ethyl acetate solution, the system was cooled to 0-10 ℃ for crystallization, the solid was filtered off, the solid was rinsed with a mixed solvent of ethyl acetate and n-heptane 1:1, and dried under reduced pressure at 45-55 ℃ to give compound 5 in 65.30g in 54% yield.
Example 19: preparation of Compound 5 from 4b (DDQ 2.5 eq.)
Figure BDA0003252174390000132
Compound 4b (100g,0.242mol) was charged into a reaction flask, acetonitrile (800ml) was added, heated to 40 ℃ to dissolve the solid, dichlorodicyanobenzoquinone (137.59g,0.61mol,2.5 eq) was added, the reaction was heated to 60. + -. 5 ℃ and reacted for 3 hours. Cooled to below 25 ℃, purified water (480ml) was added, extraction was performed with ethyl acetate (320ml × 3), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution (160ml × 3). N-heptane (960ml) was added dropwise to the ethyl acetate solution, the system was cooled to 0-10 ℃ for crystallization, the solid was filtered off, the solid was rinsed with a mixed solvent of ethyl acetate and n-heptane 1:1, and dried under reduced pressure at 45-55 ℃ to give compound 5 in 47.84g in total with a yield of 64%.
Example 20: preparation of Compound 5 from 4b (DDQ used 3 equivalents)
Figure BDA0003252174390000133
Compound 4b (100g,0.242mol) was charged into a reaction flask, acetonitrile (800ml) was added, heated to 40 ℃ to dissolve the solid, dichlorodicyanobenzoquinone (165.11g,0.73mol,3 equivalents) was added, and the reaction was heated to 60. + -. 5 ℃ for 3 hours. Cooled to below 25 ℃, purified water (480ml) was added, extraction was performed with ethyl acetate (320ml × 3), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution (160ml × 3). N-heptane (960ml) was added dropwise to the ethyl acetate solution, the system was cooled to 0-10 ℃ for crystallization, the solid was filtered off, the solid was rinsed with a mixed solvent of ethyl acetate and n-heptane 1:1, and dried under reduced pressure at 45-55 ℃ to give compound 5 in 53.07g in total with a yield of 71%.
Example 21: preparation of Compound 5 from 4b (DDQ used 4.5 equiv.)
Figure BDA0003252174390000141
Compound 4b (100g,0.242mol) was charged into a reaction flask, acetonitrile (800ml) was added, heated to 40 ℃ to dissolve the solid, dichlorodicyanobenzoquinone (247.66g,1.09mol,4.5 eq) was added, the reaction was heated to 60. + -. 5 ℃ and reacted for 3 hours. Cooled to below 25 ℃, purified water (480ml) was added, extraction was performed with ethyl acetate (320ml × 3), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution (160ml × 3). Adding n-heptane (960ml) dropwise into the ethyl acetate solution, cooling the system to 0-10 deg.C for crystallization, filtering out the solid, leaching the solid with a mixed solvent of ethyl acetate and n-heptane 1:1, and drying at 45-55 deg.C under reduced pressure to obtain compound 5 with a yield of 67% of 50.08 g.
Example 22: preparation of Compound 5 from 4b (DDQ used 6 equivalents)
Figure BDA0003252174390000142
Compound 4b (100g,0.242mol) was charged into a reaction flask, acetonitrile (800ml) was added, heated to 40 ℃ to dissolve the solid, dichlorodicyanobenzoquinone (330.21g,1.45mol,6 equivalents) was added, and the reaction was heated to 60. + -. 5 ℃ for 3 hours. Cooled to below 25 ℃, purified water (480ml) was added, extraction was performed with ethyl acetate (320ml × 3), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution (160ml × 3). Adding n-heptane (960ml) dropwise into the ethyl acetate solution, cooling the system to 0-10 deg.C for crystallization, filtering out the solid, leaching the solid with a mixed solvent of ethyl acetate and n-heptane 1:1, and drying at 45-55 deg.C under reduced pressure to obtain compound 5 with a yield of 45.60g and 61%.
Example 23: preparation of Compound 5 from 4a (2 equiv. for CAN)
Figure BDA0003252174390000151
Compound 4a (120g,0.314mol) was charged into a reaction flask, acetonitrile (1200ml) was added, purified water (960ml) was added, the temperature was reduced to 0 ℃ and ceric ammonium nitrate (344.04g,0.628mol,2 equivalents) was added and reacted at 0-5 ℃ for 10 hours. Adding ethyl acetate (600ml × 3) for extraction, combining organic phases, washing the organic phases with a saturated sodium chloride solution (120ml × 3), dropwise adding n-heptane (720ml) into ethyl acetate, cooling the system to 0-10 ℃ for crystallization, filtering out solids, leaching the solids with a mixed solvent of ethyl acetate and n-heptane 1:1, and drying at 45-55 ℃ under reduced pressure to obtain 67.72g of compound 5 with the yield of 70%.
Example 24: preparation of Compound 5 from 4a (CAN Using 3 equiv.)
Figure BDA0003252174390000152
Compound 4a (200g,0.523mol) was charged into a reaction flask, acetonitrile (2000ml) was added, purified water (1600ml) was added, the temperature was reduced to 0 ℃ and ceric ammonium nitrate (860.11g,1.569mol,3 equivalents) was added and the reaction was carried out at 0-5 ℃ for 10 hours. Adding ethyl acetate (1000ml multiplied by 3) for extraction, combining organic phases, washing the organic phases by a saturated sodium chloride solution (200ml multiplied by 3), dropwise adding n-heptane (1200ml) into the ethyl acetate, cooling the system to 0-10 ℃ for crystallization, filtering out solids, leaching the solids by a mixed solvent of the ethyl acetate and the n-heptane with the ratio of 1:1, and drying at 45-55 ℃ under reduced pressure to obtain the compound 5 with the yield of 104.80g in total.
Example 25: preparation of Compound 5 from 4a (2.5 equivalents for CAN)
Figure BDA0003252174390000153
Compound 4a (200g,0.523mol) was charged into a reaction flask, acetonitrile (2000ml) was added, purified water (1600ml) was added, the temperature was reduced to 0 ℃ and ceric ammonium nitrate (716.76g,1.307mol,2.5 eq) was added and the reaction was carried out at 0-5 ℃ for 10 hours. Adding ethyl acetate (1000ml × 3) for extraction, combining organic phases, washing the organic phases with a saturated sodium chloride solution (200ml × 3), dropwise adding n-heptane (1200ml) into ethyl acetate, cooling the system to 0-10 ℃ for crystallization, filtering out solids, leaching the solids with a mixed solvent of ethyl acetate and n-heptane 1:1, and drying at 45-55 ℃ under reduced pressure to obtain 130.60g of compound 5 with the yield of 81%.
Example 26: preparation of Compound 5 from 4a (5 equivalents for CAN)
Figure BDA0003252174390000161
Compound 4a (120g,0.314mol) was charged into a reaction flask, acetonitrile (1200ml) was added, purified water (960ml) was added, the temperature was reduced to 0 ℃ and ceric ammonium nitrate (860.11g,1.569mol,5 equivalents) was added and reacted at 0-5 ℃ for 10 hours. Adding ethyl acetate (600ml multiplied by 3) for extraction, combining organic phases, washing the organic phases by a saturated sodium chloride solution (120ml multiplied by 3), dropwise adding n-heptane (720ml) into the ethyl acetate, cooling the system to 0-10 ℃ for crystallization, filtering out solids, leaching the solids by a mixed solvent of the ethyl acetate and the n-heptane with the ratio of 1:1, and drying at 45-55 ℃ under reduced pressure to obtain the compound 5 with the yield of 72.56g in total.
Example 27: preparation of Compound 5 from 4b (2 equiv for CAN)
Figure BDA0003252174390000162
Compound 4b (150g,0.364mol) was charged into a reaction flask, acetonitrile (1500ml) was added, purified water (1200ml) was added, the temperature was lowered to 0 ℃ and ceric ammonium nitrate (398.74g,0.727mol,2 equivalents) was added and the reaction was carried out at 0-5 ℃ for 10 hours. Adding ethyl acetate (750ml × 3) for extraction, combining organic phases, washing the organic phases with a saturated sodium chloride solution (150ml × 3), dropwise adding n-heptane (900ml) into the ethyl acetate, cooling the system to 0-10 ℃ for crystallization, filtering out solids, leaching the solids with a mixed solvent of ethyl acetate and n-heptane 1:1, and drying at 45-55 ℃ under reduced pressure to obtain the compound 5 with 52.70g in total and 47% yield.
Example 28: preparation of Compound 5 from 4b (CAN used 3 equiv.)
Figure BDA0003252174390000171
Compound 4b (150g,0.364mol) was added to a reaction flask, acetonitrile (1500ml) was added, purified water (1200ml) was added, the temperature was reduced to 0 ℃ and ceric ammonium nitrate (598.12g,1.091mol,3 equivalents) was added and the reaction was carried out at 0-5 ℃ for 10 hours. Adding ethyl acetate (750ml × 3) for extraction, combining organic phases, washing the organic phases with a saturated sodium chloride solution (150ml × 3), dropwise adding n-heptane (900ml) into the ethyl acetate, cooling the system to 0-10 ℃ for crystallization, filtering out solids, leaching the solids with a mixed solvent of ethyl acetate and n-heptane 1:1, and drying at 45-55 ℃ under reduced pressure to obtain 79.61g of the compound 5 with a yield of 71%.
Example 29: preparation of Compound 5 from 4b (2.5 equivalents for CAN)
Figure BDA0003252174390000172
Compound 4b (150g,0.364mol) was charged into a reaction flask, acetonitrile (1500ml) was added, purified water (1200ml) was added, the temperature was reduced to 0 ℃ and ceric ammonium nitrate (498.43g,0.909mol,2.5 equivalents) was added and reacted at 0-5 ℃ for 10 hours. Adding ethyl acetate (750ml × 3) for extraction, combining organic phases, washing the organic phases with a saturated sodium chloride solution (150ml × 3), dropwise adding n-heptane (900ml) into the ethyl acetate, cooling the system to 0-10 ℃ for crystallization, filtering out solids, leaching the solids with a mixed solvent of ethyl acetate and n-heptane 1:1, and drying at 45-55 ℃ under reduced pressure to obtain the compound 5 with 87.46g in total and 78% yield.
Example 30: preparation of Compound 5 from 4b (5 equivalents for CAN)
Figure BDA0003252174390000181
Compound 4b (150g,0.364mol) was charged into a reaction flask, acetonitrile (1500ml) was added, purified water (1200ml) was added, the temperature was reduced to 0 ℃ and ceric ammonium nitrate (996.86g,1.818mol,5 equivalents) was added and the reaction was carried out at 0-5 ℃ for 10 hours. Adding ethyl acetate (750ml × 3) for extraction, combining organic phases, washing the organic phases with a saturated sodium chloride solution (150ml × 3), dropwise adding n-heptane (900ml) into ethyl acetate, cooling the system to 0-10 ℃ for crystallization, filtering out solids, leaching the solids with a mixed solvent of ethyl acetate and n-heptane 1:1, and drying at 45-55 ℃ under reduced pressure to obtain 84.09g of compound 5 with a yield of 75%.
The invention provides a method and a thought of a method for synthesizing an intermediate of bumetanide, and a method and a way for realizing the technical scheme are many, the above description is only a preferred embodiment of the invention, and it should be noted that, for a person skilled in the art, a plurality of improvements and modifications can be made without departing from the principle of the invention, and the improvements and modifications should be regarded as the protection scope of the invention. All the components not specified in the present embodiment can be realized by the prior art.

Claims (10)

1. A synthetic method of a bumetanide intermediate is characterized by comprising the following steps:
(1) protecting amino in 3-amino-4-chlorobenzoic acid shown in a formula 1 by using a compound containing a benzyl protecting group to obtain a compound shown in a formula 2;
(2) reacting the compound shown in the formula 2 with thionyl chloride, and treating with ammonia water to obtain a compound shown in a formula 3;
(3) reacting the compound shown in the formula 3 with phenol to obtain a compound shown in a formula 4;
(5) reacting the compound shown in the formula 4 with an oxidant to obtain a bumetanide intermediate shown in the formula 5, namely 3-amino-4-phenoxy-5-sulfamoylbenzoic acid;
Figure FDA0003252174380000011
wherein R is selected from H or methoxy.
2. The method according to claim 1, wherein the benzyl-type protecting group in the step (1) is benzyl or p-methoxybenzyl.
3. The method according to claim 1, wherein in the step (1), the compound containing a benzyl protecting group is any one of benzyl chloride, benzyl bromide, p-methoxybenzyl chloride and p-methoxybenzyl bromide.
4. The process according to claim 1, wherein in the step (1), the molar ratio of the compound having a benzyl-type protecting group to 3-amino-4-chlorobenzoic acid represented by the formula 1 is (1-1.5): 1.
5. The process according to claim 1, wherein in the step (1), the molar ratio of the compound containing a benzyl-type protecting group to 3-amino-4-chlorobenzoic acid represented by the formula 1 is 1.1: 1.
6. The process according to claim 1, wherein in the step (2), the compound represented by the formula 2 and thionyl chloride are used in a ratio of (0.2 to 0.8) mol:300 ml.
7. The process according to claim 1, wherein in the step (3), the molar ratio of the compound represented by the formula 3 to phenol is 1 (1.5 to 2.9).
8. The method according to claim 1, wherein the temperature of the reaction in the step (3) is 60 to 100 ℃.
9. The method according to claim 1, wherein in the step (4), the oxidizing agent is dichlorodicyanoquinone and/or ceric ammonium nitrate.
10. The method according to claim 1, wherein in the step (4), the molar ratio of the oxidizing agent to the compound represented by formula 4 is (2-6): 1.
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