CN115368278B - Method for preparing benzenesulfonic acid compound by hydrolyzing benzenesulfonamide compound - Google Patents

Method for preparing benzenesulfonic acid compound by hydrolyzing benzenesulfonamide compound Download PDF

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CN115368278B
CN115368278B CN202211306657.1A CN202211306657A CN115368278B CN 115368278 B CN115368278 B CN 115368278B CN 202211306657 A CN202211306657 A CN 202211306657A CN 115368278 B CN115368278 B CN 115368278B
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benzenesulfonic acid
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CN115368278A (en
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孙学涛
贾冰洁
于凯
昝广友
戴信敏
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Beijing Xinkaiyuan Pharmaceuticals Co Ltd
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    • 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
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
    • 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
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • 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
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Abstract

The invention belongs to the field of medicines, and particularly relates to a method for preparing benzenesulfonic acid compounds by hydrolyzing benzenesulfonamide compounds, which comprises the following steps: carrying out secondary amine group protection reaction on the compound II and a secondary amine group protective agent in a first reaction solvent in the presence of an acid-binding agent to obtain an intermediate III; carrying out diazotization reaction on the intermediate III and a diazotization reagent in a second reaction solvent to obtain a solution containing a diazonium salt of the intermediate III, and carrying out hydrolysis reaction on the diazonium salt of the intermediate III to obtain an intermediate IV; and carrying out a secondary amino protecting group removing reaction on the intermediate IV to obtain a compound I. The preparation method has the advantages of simple process, easily-controlled reaction conditions, no configuration inversion of the chirality of the benzenesulfonamide compounds with chiral centers, high yield and high purity of the prepared benzenesulfonic acid compounds with chiral centers, and great significance in synthesis of the benzenesulfonic acid compounds with chiral centers.

Description

Method for preparing benzenesulfonic acid compound by hydrolyzing benzenesulfonamide compound
Technical Field
The invention belongs to the field of medicines, and particularly relates to a method for preparing benzenesulfonic acid compounds by hydrolyzing benzenesulfonamide compounds.
Background
Many methods for preparing benzenesulfonic acid compounds by hydrolyzing benzenesulfonamide compounds are performed under strong alkali and high temperature conditions, but the use of strong alkali and high temperature conditions for benzenesulfonamide compounds with chiral centers can cause the chirality of the chiral centers to undergo configuration inversion or racemization, so that a new method for preparing benzenesulfonic acid compounds by hydrolyzing benzenesulfonamide compounds without configuration inversion is urgently needed.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the method for preparing the benzenesulfonic acid compound by hydrolyzing the benzenesulfonamide compound, the preparation method has the advantages of simple process and easily controlled reaction conditions, the chirality of the benzenesulfonamide compound with the chiral center is not subjected to configuration inversion, and the prepared benzenesulfonic acid compound with the chiral center has high yield and high purity and has important significance for synthesizing the benzenesulfonic acid compound with the chiral center.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a method for preparing benzenesulfonic acid compounds by hydrolyzing benzenesulfonamide compounds, which comprises the following steps:
Figure 800737DEST_PATH_IMAGE002
in the formula, R 1 Represents methyl, ethyl, methyl ether, anisole, phenethyl ether or aryl; r 2 Is hydrogen, methoxy, halogen, methyl, ethyl or ethoxy;
s1, synthesis of an intermediate III:
carrying out secondary amine group protection reaction on the compound II and a secondary amine group protective agent in a first reaction solvent in the presence of an acid-binding agent to obtain an intermediate III;
s2, synthesis of an intermediate IV:
carrying out diazotization reaction on the intermediate III and a diazotization reagent in a second reaction solvent to obtain a solution containing a diazonium salt of the intermediate III, and carrying out hydrolysis reaction on the diazonium salt of the intermediate III to obtain an intermediate IV;
s3, synthesis of a compound I:
and carrying out a secondary amine protecting group removing reaction on the intermediate IV to obtain a compound I.
In any of the above schemes, preferably, in step S1, the secondary amine group protecting agent is at least one of benzyl bromide, benzyl chloride, p-methoxybenzyl chloride and p-methoxybenzyl bromide; the acid-binding agent is at least one of potassium carbonate, sodium bicarbonate, triethylamine and N, N-diisopropylethylamine; the first reaction solvent is at least one of N, N-dimethylformamide, tetrahydrofuran, acetone and acetonitrile; the molar ratio of the compound II to the acid-binding agent to the secondary amino protective agent is 1 (2.0-10.0) to 1.0-5.0.
In any of the above embodiments, preferably, in step S2, the diazotizing agent is at least one of sodium nitrite and isoamyl nitrite; the second reaction solvent is at least one of trifluoroacetic acid and acetic acid; the temperature of the hydrolysis reaction is 10 to 30 ℃; the molar ratio of the intermediate III to the diazotization reagent is 1: (1 to 2); the ratio of the volume of the second reaction solvent to the mass of the intermediate III is 5-10 mL/g.
In any of the above schemes, preferably, in step S2, the second reaction solvent is added to the intermediate iii, the temperature is reduced to 10 to 15 ℃, then the diazotization reagent is added, the temperature is controlled to 10 to 15 ℃, after the diazotization reagent is added, the temperature is raised to 24 to 28 ℃ to perform the diazotization reaction, so as to obtain a solution containing the diazonium salt of the intermediate iii, water is added to the solution containing the diazonium salt of the intermediate iii, the temperature is controlled to 10 to 30 ℃, and the hydrolysis reaction of the diazonium salt is performed, so as to obtain the intermediate iv.
In any of the above schemes, it is preferable that in step S3, the secondary amine group protecting group is removed by hydrogenation reduction, by oxidation or under acidic conditions.
Preferably in any of the above schemes, the hydrogenation reduction removal of the secondary amine protecting group comprises the steps of: and in the presence of hydrogen or a hydrogen transfer reagent, carrying out a secondary amine protecting group removing reaction on the intermediate IV in a third reaction solvent in the presence of a catalyst to obtain the compound I.
In any of the above embodiments, preferably, the hydrogen transfer agent is at least one of formic acid and ammonium formate; the catalyst is at least one of palladium carbon and Raney nickel; the third reaction solvent is at least one of methanol, ethanol, dichloromethane, ethyl acetate and tetrahydrofuran; the mass ratio of the intermediate IV to the catalyst is 1: (0.1 to 0.5).
Preferably in any of the above schemes, the step of hydrogenation-reduction to remove the secondary amine protecting group comprises the steps of: and in the presence of hydrogen or a hydrogen transfer reagent, carrying out a secondary amine protecting group removing reaction on the intermediate IV in a third reaction solvent in the presence of palladium-carbon and a palladium-carbon activating agent to obtain the compound I.
In any of the above embodiments, preferably, the palladium carbon activator is at least one of acetic acid, formic acid, and hydrochloric acid.
The preparation method provided by the invention has the advantages of simple process and easily-controlled reaction conditions, the chirality of the benzenesulfonamide compound with the chiral center is not subjected to configuration inversion, and the obtained benzenesulfonic acid compound with the chiral center has high yield and high purity by optimizing the synthesis route, and has important significance for synthesis of the benzenesulfonic acid compound with the chiral center.
Drawings
FIG. 1 is an isomer liquid chromatogram of Compound I of example 1 of the present invention.
FIG. 2 is a table of peaks in a liquid chromatogram of isomers of Compound I of example 1 according to the present invention.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. The experimental reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the dosage of the experimental reagent is the dosage of the reagent in the conventional experimental operation if no special description exists; the experimental methods are conventional methods unless otherwise specified.
In a first aspect, an embodiment of the present invention provides a method for preparing a benzenesulfonic acid compound by hydrolyzing a benzenesulfonylamine compound, including the following steps:
Figure 667061DEST_PATH_IMAGE003
in the formula, R 1 Represents methyl, ethyl, methyl ether, anisole, phenethyl ether or an aromatic group; r 2 Is hydrogen, methoxy, halogen, methyl, ethyl or ethoxy;
s1, synthesis of an intermediate III:
carrying out secondary amine group protection reaction on the compound II and a secondary amine group protective agent in a first reaction solvent in the presence of an acid-binding agent to obtain an intermediate III;
s2, synthesis of an intermediate IV:
carrying out diazotization reaction on the intermediate III and a diazotization reagent in a second reaction solvent to obtain a solution containing a diazonium salt of the intermediate III, and carrying out hydrolysis reaction on the diazonium salt of the intermediate III to obtain an intermediate IV;
s3, synthesis of a compound I:
and carrying out a secondary amino protecting group removing reaction on the intermediate IV to obtain a compound I.
The structure of the secondary amine protecting group is shown as follows:
Figure 802508DEST_PATH_IMAGE004
。
the embodiment of the invention adopts benzyl to protect secondary amino, and has the advantages that: (1) The secondary amine group is prevented from being oxidized in the diazotization reaction process of the step S2, so that the yield of the product is reduced; (2) Protecting the configuration of the compound II and preventing the configuration from being overturned in the subsequent reaction process; (3) The benzyl protecting group is stable under acidic conditions, is not easy to remove in the subsequent diazotization reaction process, and the operation of removing the benzyl protecting group is simple, the product is single, and the post-treatment is simple.
The preparation method provided by the invention has the advantages of simple process and easily-controlled reaction conditions, the chirality of the benzenesulfonyl amine compound with the chiral center is not subjected to configuration inversion, and the obtained benzenesulfonic acid compound with the chiral center has high yield and high purity by optimizing a synthesis route, and has important significance for synthesis of the benzenesulfonic acid compound with the chiral center.
Further, in the formula, R 1 Represents methyl, ethyl, methyl ether, anisole, phenethyl ether or an aromatic group; r 2 Is hydrogen, methoxy, halogen, methyl, ethyl or ethoxy.
Further, the air conditioner is provided with a fan,
Figure 678060DEST_PATH_IMAGE005
selected from one of the following structures:
Figure 582562DEST_PATH_IMAGE006
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Figure 885367DEST_PATH_IMAGE007
。
further, in step S1, the secondary amino group protecting agent is at least one of benzyl bromide, benzyl chloride, p-methoxybenzyl chloride and p-methoxybenzyl bromide.
Further, in step S1, the acid-binding agent is at least one of potassium carbonate, sodium bicarbonate, triethylamine, and N, N-diisopropylethylamine.
Further, in step S1, the first reaction solvent is at least one of N, N-dimethylformamide, tetrahydrofuran, acetone, and acetonitrile, preferably N, N-dimethylformamide, and when N, N-dimethylformamide is used as the first reaction solvent, the yield of the intermediate iii is highest.
Further, in step S1, the molar ratio of the compound ii, the acid scavenger and the secondary amine group protecting agent is 1 (2.0 to 10.0) (1.0 to 5.0), for example, the molar ratio may be 1.
Further, in step S2, the diazotizing agent is at least one of sodium nitrite and isoamyl nitrite.
Further, in step S2, the second reaction solvent is at least one of trifluoroacetic acid and acetic acid, preferably trifluoroacetic acid.
Further, in the step S2, the temperature of the hydrolysis reaction is 10 ℃ to 30 ℃, for example, the temperature may be 10 ℃, 15 ℃,20 ℃, 25 ℃ or 30 ℃, when the temperature of the hydrolysis reaction is too low, the reaction rate is slow, and when the temperature of the hydrolysis reaction is too high, the reaction rate is too fast, the material is easily flushed, and a large potential safety hazard exists.
Further, in step S2, the molar ratio of the intermediate iii to the diazotizing agent is 1: (1 to 2), for example, the molar ratio may be 1:1. 1:1.5 or 1: and 2, when the dosage of the diazotization reagent is low, the reaction of the intermediate III is incomplete, and when the dosage of the diazotization reagent is high, the coupling reaction is initiated, so that more impurities are generated, the yield of the intermediate IV is low, the difficulty of post-treatment is increased, and the material waste is caused, preferably, the molar ratio of the intermediate III to the diazotization reagent is 1:1.2.
further, in step S2, the ratio of the volume of the second reaction solvent to the mass of the intermediate iii is 5mL/g to 10mL/g, for example, the mass ratio may be 5mL/g, 6mL/g, 7mL/g, 8mL/g, 9mL/g, or 10mL/g, preferably 5mL/g, if the amount of the second reaction solvent is too small, the coupling reaction is likely to occur in the reaction system, which leads to a decrease in yield of the target product, and if the amount is too large, the solvent is likely to be wasted.
Further, in step S2, adding the second reaction solvent to the intermediate iii, cooling to 10 to 15 ℃, then adding the diazotization reagent, controlling the temperature to be 10 to 15 ℃, after the diazotization reagent is added, heating to 24 to 28 ℃ to perform the diazotization reaction to obtain a solution containing the diazonium salt of the intermediate iii, adding water to the solution containing the diazonium salt of the intermediate iii, controlling the temperature to be 10 to 30 ℃, and performing a hydrolysis reaction of the diazonium salt to obtain the intermediate iv. The embodiment of the invention adopts a one-pot method, synthesizes the intermediate IV through two steps of diazotization of the intermediate III and hydrolysis of diazonium salt, strictly controls the reaction temperature, improves the reaction speed and ensures the safety at the same time.
According to the embodiment of the invention, the temperature in the reaction process is controlled to obtain the intermediate IV with high yield, and if the temperature is too low, the reaction is incomplete, the temperature is too high, the reaction is violent, coupling impurities are more, and the yield of the intermediate IV is lower.
And (3) heating to room temperature at 24 to 28 ℃, namely heating to room temperature to carry out the diazotization reaction.
Further, in step S3, the secondary amine protecting group is removed by hydrogenation reduction, the secondary amine protecting group is removed under oxidation conditions, or the secondary amine protecting group is removed under acidic conditions, preferably, the secondary amine protecting group is removed by hydrogenation reduction, and the product obtained by removing the secondary amine protecting group by hydrogenation reduction is single, and the post-treatment is simple.
Further, the hydrogenation reduction removal of the secondary amine protecting group comprises the following steps:
and in the presence of hydrogen or a hydrogen transfer reagent, carrying out a secondary amine protecting group removing reaction on the intermediate IV in a third reaction solvent in the presence of a catalyst to obtain the compound I.
Further, the hydrogen transfer reagent is at least one of formic acid and ammonium formate.
Further, the catalyst is at least one of palladium carbon and Raney nickel.
Further, the third reaction solvent is at least one of methanol, ethanol, dichloromethane, ethyl acetate, and tetrahydrofuran, preferably methanol, and the reaction can be rapidly performed with a small amount of catalyst in methanol.
Further, the mass ratio of the intermediate IV to the catalyst is 1: (0.1 to 0.5), for example, the mass ratio may be 1:0.1, 1:0.2, 1:0.3, 1:0.4 or 1:0.5, and if the amount of the catalyst is too small, the reaction time is too long, and if the amount of the catalyst is too large, the adsorption of the catalyst to the raw materials or the products is severe, so that the yield of the compound I is reduced, and preferably, the mass ratio of the intermediate IV to the catalyst is 1:0.2.
further, the hydrogenation reduction removal of the secondary amine protecting group comprises the following steps:
and in the presence of hydrogen or a hydrogen transfer reagent, carrying out a secondary amine protecting group removing reaction on the intermediate IV in a third reaction solvent in the presence of palladium-carbon and a palladium-carbon activating agent to obtain the compound I.
The addition of the palladium-carbon activator can accelerate the reaction rate and shorten the reaction time.
Further, the palladium carbon activator is at least one of acetic acid, formic acid and hydrochloric acid, the concentration of the hydrochloric acid is 1 mol/L-12 mol/L, for example, the concentration of the hydrochloric acid can be 1mol/L, 2mol/L, 4mol/L, 6mol/L or 10 mol/L.
The invention is described in further detail by taking a part of the test results as reference, and the following detailed description is given by combining with specific examples.
Example 1
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S1, synthesis of an intermediate 3:
compound 2 (0.073mol, 16.65g), N-dimethylformamide (150 mL), potassium carbonate (0.174mol, 24.05g) and benzyl bromide (0.095mol, 16.23g) were charged into a reaction flask, respectively, and the reaction was stirred at room temperature for 10 hours. The reaction was monitored by TLC, after completion of the reaction, the reaction was quenched with water (500 mL), extracted with ethyl acetate (300 mL) to give an organic phase, washed with saturated brine (200 mL) and water (200 mL) in this order, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/methanol =10/1 (vol.)) to give 19.82g of off-white intermediate 3 in a yield of 85.4%
S2, synthesis of an intermediate 4:
adding the intermediate 3 (0.060mol, 19.08g) into trifluoroacetic acid (95.4 mL), stirring to dissolve, cooling to 10-15 ℃, adding sodium nitrite (0.072mol, 4.97g) in three batches, finishing adding within half an hour, controlling the temperature to 10-15 ℃, and after the adding is finished, heating to room temperature for reacting for 3 hours. And (3) dropwise adding water (400 mL) into the reaction solution after the reaction is finished, controlling the temperature to be 25-30 ℃, carrying out diazonium salt hydrolysis reaction, wherein the heat release of the reaction system is obvious, and monitoring the reaction by TLC. After the diazonium salt hydrolysis reaction was completed, methylene chloride (200 mL) was added, extraction was performed with stirring, liquid separation was performed, the aqueous phase was extracted once with methylene chloride (200 mL), the organic phases were combined, and the organic phase was concentrated under reduced pressure and subjected to column chromatography separation and purification (eluent: methylene chloride/methanol =5/1 (volume ratio)) to obtain 16.84g of pale yellow solid intermediate 4 with a yield of 88.0%.
S3, synthesis of a compound 1:
the intermediate 4 (0.026mol, 8.29g) and methanol (130 mL) were added to a reaction flask, and stirred to dissolve, 10% palladium on carbon (50% wet basis) (1.66 g) and acetic acid (0.5 mL) were added, hydrogen was introduced, the pressure was increased to 0.1MPa, and the reaction was stirred at 20 to 25 ℃ for 2 hours. After the reaction is finished, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, purifying the crude product by a preparation liquid phase, collecting a main peak component, and concentrating the main peak component under reduced pressure to obtain 3.58g of a white solid compound 1, wherein the yield is 60.1%, and the chiral purity of the compound 1 (the retention time is 11.322 min) is 99.846% (according to the detection results in the figures 1 and 2). The retention time of the isomer was 19.845min.
Preparative liquid purification the chromatographic conditions were as follows:
a chromatographic column: polysaccharide derivative-coated chiral chromatography columns (CHIRALCEL OX-H,4.6mm x 250mm,5 μm or equivalent performance columns); the mobile phase was n-hexane-ethanol-trifluoroacetic acid (90; the flow rate is 1mL per minute; the column temperature is 30 ℃; detection wavelength: 225nm.
Example 2
The synthetic route is the same as that of example 1.
S1, synthesis of an intermediate 3:
compound 2 (0.073mol, 16.65g), tetrahydrofuran (150 mL), potassium carbonate (0.174mol, 24.05g) and benzyl bromide (0.095mol, 16.23g) were each charged into a reaction flask, and the reaction was stirred at room temperature for 10 hours. The reaction was monitored by TLC, and after completion of the reaction, the reaction was quenched with water (500 mL), extracted with ethyl acetate (300 mL) to give an organic phase, which was washed with saturated brine (200 mL) and water (200 mL) in that order, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/methanol =10/1 (volume ratio)) to give 14.49g of off-white intermediate 3 in 62.5% yield.
S2, synthesis of an intermediate 4:
adding the intermediate 3 (0.044 mol, 13.99g) into trifluoroacetic acid (98 mL), stirring for dissolving, cooling to 10-15 ℃, adding sodium nitrite (0.088mol, 6.07g) in three batches, finishing adding within half an hour, controlling the temperature to 10-15 ℃, and after adding, heating to room temperature for reacting for 2 hours. After the reaction is finished, dropwise adding water (300 mL) into the reaction solution, controlling the temperature to be 10-15 ℃, carrying out diazonium salt hydrolysis reaction, wherein the heat release of the reaction system is obvious, and monitoring the reaction by TLC. After completion of the diazonium salt hydrolysis reaction, methylene chloride (200 mL) was added, extraction was performed with stirring, liquid separation was performed, the aqueous phase was extracted once with methylene chloride (200 mL), the organic phases were combined, the organic phase was concentrated under reduced pressure, and column chromatography separation and purification (eluent: methylene chloride/methanol =5/1 (volume ratio)) was performed to obtain 11.73g of intermediate 4 as a pale yellow solid in a yield of 83.6%.
S3, synthesis of a compound 1:
the intermediate 4 (0.026mol, 8.29g) and methanol (130 mL) were added to a reaction flask, and the mixture was dissolved with stirring, 10% palladium on carbon (wet basis 50%) (4.15 g) and acetic acid (1.25 mL) were added thereto, hydrogen gas was introduced thereinto, the pressure was increased to 0.1MPa, and the reaction was stirred at 20 to 25 ℃ for 2 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative liquid phase, and the main peak fraction was collected and concentrated under reduced pressure to obtain 2.58g of white solid compound 1 with a yield of 43.3%. Preparative liquid phase purification process the chromatographic conditions were the same as in example 1, and the chiral purity of compound 1 was 99.694%.
Example 3
The synthetic route is the same as that of example 1.
S1, synthesis of an intermediate 3:
compound 2 (0.073mol, 16.65g), N-dimethylformamide (150 mL), potassium carbonate (0.174mol, 24.05g) and benzyl bromide (0.219mol, 37.46g) were added to each flask, and the reaction was stirred at room temperature for 10 hours. The reaction was monitored by TLC, and after completion of the reaction, the reaction was quenched with water (500 mL), extracted with ethyl acetate (300 mL) to give an organic phase, which was washed with saturated brine (200 mL) and water (200 mL) in that order, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/methanol =10/1 (volume ratio)) to give 19.70g of off-white intermediate 3 in 84.9% yield.
S2, synthesis of an intermediate 4:
adding the intermediate 3 (0.060mol, 19.08g) into trifluoroacetic acid (95.4 mL), stirring to dissolve, cooling to 10-15 ℃, adding sodium nitrite (0.072mol, 4.97g) in three batches, finishing adding within half an hour, controlling the temperature to 10-15 ℃, and after the adding is finished, heating to room temperature for reacting for 3 hours. After the reaction is finished, dropwise adding water (400 mL) into the reaction solution, controlling the temperature to be 15-20 ℃, carrying out the diazonium salt hydrolysis reaction, wherein the heat release of the reaction system is obvious, monitoring the reaction by TLC, adding dichloromethane (200 mL) after the diazonium salt hydrolysis reaction is finished, stirring, extracting, separating, extracting the water phase once by using dichloromethane (200 mL), combining organic phases, carrying out pressure concentration on the organic phases, and carrying out column chromatography separation and purification (eluent: dichloromethane/methanol =5/1 (volume ratio)) to obtain 16.65g of pale yellow solid intermediate 4, wherein the yield is 86.9%.
S3, synthesis of a compound 1:
intermediate 4 (0.026mol, 8.29g) and methylene chloride (130 mL) were added to a reaction flask, and the mixture was dissolved with stirring, 10% palladium on carbon (wet basis 50%) (1.66 g) and acetic acid (0.5 mL) were added thereto, hydrogen gas was introduced thereinto, the pressure was increased to 0.1MPa, and the reaction was stirred at 20 to 25 ℃ for 2 hours. After the reaction, the reaction product was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative liquid phase, and the main peak fraction was collected and concentrated under reduced pressure to obtain 3.47g of white solid compound 1 with a yield of 58.3%. Preparative liquid phase purification process the chromatographic conditions were the same as in example 1, with a chiral purity of 99.527% for compound 1.
Example 4
The synthetic route is the same as that of example 1.
S1, synthesis of an intermediate 3:
substantially the same as in step S1 in example 1, except that "potassium carbonate (0.174mol, 24.05g)" was replaced with "potassium carbonate (0.365mol, 50.45g)", the yield of intermediate 3 was 88.6%.
S2, synthesis of an intermediate 4:
substantially the same as in step S2 of example 1, except that "trifluoroacetic acid (95.4 mL)" was replaced with "acetic acid (95.4 mL)", the yield of intermediate 4 was 62.8%.
S3, synthesis of a compound 1:
exactly the same as step S3 in example 1.
Comparative example 1
The synthetic route is the same as that of example 1.
Steps S1 and S3 are identical to steps S1 and S3 in embodiment 1.
S2, synthesis of an intermediate 4:
adding the intermediate 3 (0.060mol, 19.08g) into trifluoroacetic acid (57.24 mL) solvent, stirring to dissolve, cooling to 10-15 ℃, adding sodium nitrite (0.072mol, 4.97g) in three batches, finishing adding within half an hour, controlling the temperature to 10-15 ℃, and after adding, heating to room temperature for reacting for 3 hours. After the reaction is finished, dropwise adding water (400 mL) into the reaction solution, controlling the temperature to be 25-30 ℃ to perform a diazonium salt hydrolysis reaction, wherein the heat release of the reaction system is obvious, monitoring the reaction by TLC, adding dichloromethane (200 mL) after the diazonium salt hydrolysis reaction is finished, stirring and extracting, separating, extracting the water phase once with dichloromethane (200 mL), combining organic phases, concentrating the organic phases under reduced pressure, and performing column chromatography separation and purification (eluent: dichloromethane/methanol =5/1 (volume ratio)) to obtain 9.33g of faint yellow solid intermediate 4, wherein the yield is 48.8%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (8)

1. A method for preparing benzenesulfonic acid compounds by hydrolyzing benzenesulfonamide compounds is characterized by comprising the following steps:
Figure 303265DEST_PATH_IMAGE001
in the formula, R 1 Represents a methyl group; r 2 Is hydrogen;
s1, synthesis of an intermediate III:
carrying out secondary amine group protection reaction on the compound II and a secondary amine group protective agent in a first reaction solvent in the presence of an acid-binding agent to obtain an intermediate III;
s2, synthesis of an intermediate IV:
carrying out diazotization reaction on the intermediate III and a diazotization reagent in a second reaction solvent to obtain a solution containing a diazonium salt of the intermediate III, and carrying out hydrolysis reaction on the diazonium salt of the intermediate III to obtain an intermediate IV;
s3, synthesis of a compound I:
carrying out a secondary amino protecting group removing reaction on the intermediate IV to obtain a compound I;
in step S2:
adding the second reaction solvent into the intermediate III, cooling to 10-15 ℃, then adding the diazotization reagent, controlling the temperature to 10-15 ℃, after the diazotization reagent is added, heating to 24-28 ℃ to carry out the diazotization reaction to obtain a solution containing the diazonium salt of the intermediate III, adding water into the solution containing the diazonium salt of the intermediate III, controlling the temperature to 10-30 ℃, and carrying out the hydrolysis reaction of the diazonium salt to obtain the intermediate IV.
2. The method for preparing benzenesulfonic acid compounds by hydrolysis of benzenesulfonylamine compounds of claim 1, wherein in step S1:
the secondary amino protective agent is at least one of benzyl bromide, benzyl chloride, p-methoxybenzyl chloride and p-methoxybenzyl bromide;
the acid-binding agent is at least one of potassium carbonate, sodium bicarbonate, triethylamine and N, N-diisopropylethylamine;
the first reaction solvent is at least one of N, N-dimethylformamide, tetrahydrofuran, acetone and acetonitrile;
the molar ratio of the compound II to the acid-binding agent to the secondary amino protective agent is 1 (2.0-10.0) to 1.0-5.0.
3. The method for preparing benzenesulfonic acid compound by hydrolyzing benzenesulfonamide compound according to claim 1, wherein in step S2:
the diazotization reagent is at least one of sodium nitrite and isoamyl nitrite;
the second reaction solvent is at least one of trifluoroacetic acid and acetic acid;
the temperature of the hydrolysis reaction is 10 to 30 ℃;
the molar ratio of the intermediate III to the diazotization reagent is 1: (1 to 2);
the ratio of the volume of the second reaction solvent to the mass of the intermediate III is 5-10 mL/g.
4. The method for preparing benzenesulfonic acid compounds by hydrolysis of benzenesulfonylamine compounds of claim 1, wherein in step S3, said secondary amine protecting group is removed by hydrogenation reduction, oxidation or acidic conditions.
5. The method for preparing benzenesulfonic acid compounds by hydrolyzing benzenesulfonamide compounds according to claim 4, wherein said step of removing secondary amine protecting groups by hydrogenation-reduction comprises the steps of:
and in the presence of hydrogen or a hydrogen transfer reagent, carrying out a secondary amine protecting group removing reaction on the intermediate IV in a third reaction solvent in the presence of a catalyst to obtain the compound I.
6. The method for preparing benzenesulfonic acid compounds by hydrolysis of benzenesulfonamide compounds as claimed in claim 5,
the hydrogen transfer reagent is at least one of formic acid and ammonium formate;
the catalyst is at least one of palladium carbon and Raney nickel;
the third reaction solvent is at least one of methanol, ethanol, dichloromethane, ethyl acetate and tetrahydrofuran;
the mass ratio of the intermediate IV to the catalyst is 1: (0.1 to 0.5).
7. The method for preparing benzenesulfonic acid compounds by hydrolyzing benzenesulfonamide compounds according to claim 6, wherein said step of removing secondary amine protecting groups by hydrogenation-reduction comprises the steps of:
and in the presence of hydrogen or a hydrogen transfer reagent, carrying out a secondary amine protecting group removing reaction on the intermediate IV in a third reaction solvent in the presence of palladium-carbon and a palladium-carbon activating agent to obtain the compound I.
8. The method for preparing benzenesulfonic acid compounds by hydrolyzing benzenesulfonamide compounds according to claim 7, wherein the palladium-carbon activator is at least one of acetic acid, formic acid and hydrochloric acid.
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Denomination of invention: A method for preparing benzenesulfonic acid compounds by hydrolysis of benzenesulfonamide compounds

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