CN114213261A - Preparation method of 4-methoxy-2-nitroaniline - Google Patents
Preparation method of 4-methoxy-2-nitroaniline Download PDFInfo
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- CN114213261A CN114213261A CN202111650994.8A CN202111650994A CN114213261A CN 114213261 A CN114213261 A CN 114213261A CN 202111650994 A CN202111650994 A CN 202111650994A CN 114213261 A CN114213261 A CN 114213261A
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- 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
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Abstract
The invention provides a preparation method of 4-methoxy-2-nitroaniline, which relates to the technical field of synthesis of medical intermediates and comprises the following steps: to be provided withNDissolving the (4-methoxyaniline) in 1, 2-dichloroethane, and reacting with copper nitrate trihydrate in the presence of pyridine to obtain the (4-methoxyaniline)N-benzenesulfonyl-4-methoxy-2-nitroaniline, and reactingNDissolving benzenesulfonyl-4-methoxy-2-nitroaniline in 1, 2-dichloroethane, and adding p-toluenesulfonic acid under the condition of argon protection to react to obtain 4-methoxy-2-nitroaniline; the synthetic route has mild reaction conditions, simple operation of the reaction and post-treatment processes, lower reaction danger coefficient, low production cost and reaction reduction of the traditional nitration reactionThe environmental problem brought by the method meets the requirement of green chemistry, has higher application value and better economic benefit, and is suitable for industrial mass production.
Description
Technical Field
The invention relates to the technical field of chemical intermediate synthesis, and particularly relates to a preparation method of 4-methoxy-2-nitroaniline.
Background
The 4-methoxy-2-nitroaniline is an important organic synthesis intermediate, has wide application prospect and can be mainly used for preparing omeprazole and the like. The compound synthesized in the prior art has the defects of severe reaction conditions, low process yield and longer reaction route.
Disclosure of Invention
The invention aims to provide a preparation method of 4-methoxy-2-nitroaniline, which does not adopt a high-pollution reagent, has the overall reaction temperature of not more than 100 ℃ and mild reaction conditions, effectively improves the process yield compared with the prior art, and is suitable for industrial mass production.
In order to achieve the above purpose, the invention provides the following technical scheme: a preparation method of 4-methoxy-2-nitroaniline comprises the following synthetic route:
the specific synthesis steps comprise:
1) compound (1)NThe benzene sulfonyl-4-methoxyaniline is subjected to nitration reaction in a first organic solvent to obtain a compound (2)N-benzenesulfonyl-4-methoxy-2-nitroaniline;
2) compound (2)NReacting the benzenesulfonyl-4-methoxy-2-nitroaniline with p-toluenesulfonic acid in a second organic solvent in an acidic environment to obtain a compound (3), namely 4-methoxy-2-nitroaniline;
further, the reaction process of the step 1) is as follows: compound (1)NDissolving the-benzenesulfonyl-4-methoxyaniline in a first organic solvent, adding pyridine and copper nitrate trihydrate, and reacting when the solution temperature reaches 90-115 ℃ to obtain the (E) -benzenesulfonyl-4-methoxyanilineN-benzenesulfonyl-4-methoxy-2-nitroaniline; after the reaction was completed, the reaction solution was poured into ice water, pH = 6 was adjusted, 1, 2-dichloroethane was extracted 3 times, organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filter cake was washed with 1, 2-dichloroethane, and the solvent was removed under reduced pressure to obtain (2)N-benzenesulfonyl-4-methoxy-2-nitroaniline crude product. The first organic solvent is 1, 2-dichloroethane.
Further, the reaction process of the step 2) is as follows: compound (2)NAdding the crude product of the-benzenesulfonyl-4-methoxy-2-nitroaniline into a second organic solvent, adding p-toluenesulfonic acid into the solution, heating the reaction solution to 65-85 ℃ under the protection of argon, and fully reacting; after the reaction was completed, 0.01 equivalent of triethylamine was added, and 10% sodium hydroxide was addedAdjusting the pH of the aqueous solution to = 7, extracting the aqueous solution with 1, 2-dichloroethane for 3 times, combining organic phases, drying the organic phases with anhydrous sodium sulfate, filtering the organic phases, washing a filter cake with 1, 2-dichloroethane, and removing the solvent under reduced pressure to obtain a crude product of (3) 4-methoxy-2-nitroaniline. Recrystallizing the methanol to obtain (3) a refined 4-methoxy-2-nitroaniline product, wherein the second organic solvent is 1, 2-dichloroethane.
Further, the compound (1) in the step 1)NThe mass ratio of the substances of the reaction of the benzenesulfonyl-4-methoxyaniline and the copper nitrate trihydrate is 1: (1-5).
Further, the compound (2) in the step 2)NThe mass ratio of the substances of the reaction of the crude product of the (E) -benzenesulfonyl-4-methoxy-2-nitroaniline and the p-toluenesulfonic acid is 1: (1-5).
Further, the reaction process in step 2) includes two stages, which are respectively: first stage, Compound (2)NReacting the crude product of the-benzenesulfonyl-4-methoxy-2-nitroaniline with p-toluenesulfonic acid; in the second stage, after completion of the first stage, 0.01 equivalent of triethylamine of the compound (2) was added, and then a 10% aqueous solution of sodium hydroxide was added dropwise to neutralize the solution until pH = 7.
According to the technical scheme, the technical scheme of the invention has the following beneficial effects:
the invention discloses a preparation method of 4-methoxy-2-nitroaniline, which comprises the steps of firstly adopting reaction conditions of an optimized preparation process, particularly selecting a reaction solvent and a reaction additive, so that the reaction conditions are mild, and the reaction risk coefficient is reduced; secondly, the post-reaction treatment and purification modes are simplified, so that the reaction operation is simple, the preparation difficulty of the target product is greatly reduced, the product yield is improved, and the aims of reducing the production cost and realizing industrial mass production are fulfilled; the specific preparation process comprises the following steps:Nreaction of-benzenesulfonyl-4-methoxyaniline with cupric nitrate trihydrateNDissolving the product of the (E) -benzenesulfonyl-4-methoxy-2-nitroaniline in 1, 2-dichloroethane, and adding p-toluenesulfonic acid to react to obtain the 4-methoxy-2-nitroaniline.
The comprehensive yield of the target product of the preparation method disclosed by the invention under the preferable reaction condition is calculated and researched to be more than 68%; in addition, the reaction solvent is less and single in dosage, can be recycled, greatly reduces a large amount of solvents used for purification, plays an important role in improving the reduction of environmental pollution, energy conservation and emission reduction, and has the characteristic of environmental friendliness.
It should be understood that all combinations of the foregoing concepts and additional concepts described in greater detail below can be considered as part of the inventive subject matter of this disclosure unless such concepts are mutually inconsistent.
The foregoing and other aspects, embodiments and features of the present teachings can be more fully understood from the following description taken in conjunction with the accompanying drawings. Additional aspects of the present invention, such as features and/or advantages of exemplary embodiments, will be apparent from the description which follows, or may be learned by practice of specific embodiments in accordance with the teachings of the present invention.
Drawings
The drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. Embodiments of various aspects of the present invention will now be described, by way of example, with reference to the accompanying drawings, in which:
FIG. 1 shows a compound (2) of the present inventionN-nuclear magnetic hydrogen spectrum of benzenesulfonyl-4-methoxy-2-nitroaniline;
FIG. 2 shows a compound (2) of the present inventionN-nuclear magnetic carbon spectrum of benzenesulfonyl-4-methoxy-2-nitroaniline;
FIG. 3 shows a compound (2) of the present inventionN-high resolution mass spectrum of benzenesulfonyl-4-methoxy-2-nitroaniline;
FIG. 4 is a nuclear magnetic hydrogen spectrum of compound (3) 4-methoxy-2-nitroaniline according to the invention;
FIG. 5 is a nuclear magnetic carbon spectrum of compound (3) 4-methoxy-2-nitroaniline according to the invention;
FIG. 6 is a high-resolution mass spectrum of the compound (3), 4-methoxy-2-nitroaniline.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the drawings of the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention. Unless defined otherwise, technical or scientific terms used herein shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs.
The use of "first," "second," and similar terms in the description and claims of the present application do not denote any order, quantity, or importance, but rather the terms are used to distinguish one element from another. Similarly, the singular forms "a," "an," or "the" do not denote a limitation of quantity, but rather denote the presence of at least one, unless the context clearly dictates otherwise. The terms "comprises," "comprising," or the like, mean that the elements or items listed before "comprises" or "comprising" encompass the features, integers, steps, operations, elements, and/or components listed after "comprising" or "comprising," and do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
Based on the prior art, 4-methoxy-2-nitroaniline is an important organic synthesis intermediate, has wide application prospect and can be mainly used for preparing omeprazole and the like, and the disclosed synthesis method has the technical problems of severe reaction conditions, high reaction risk coefficient, low product yield and longer reaction route; the invention aims to disclose a new method for preparing 4-methoxy-2-nitroaniline, the synthesis route provided by the method has the advantages of mild reaction conditions, low reaction risk coefficient, simple post-reaction treatment and purification process and high product yield, and is more suitable for industrial mass production compared with the prior art.
A preparation method of 4-methoxy-2-nitroaniline comprises the following synthetic route:
the specific synthesis steps comprise:
1) compound (1)NDissolving the-benzenesulfonyl-4-methoxyaniline in 1, 2-dichloroethane, adding pyridine and copper nitrate trihydrate, and reacting at 90-115 deg.CN-benzenesulfonyl-4-methoxy-2-nitroaniline; after the reaction was completed, the reaction solution was poured into ice water, pH = 6 was adjusted, 1, 2-dichloroethane was extracted 3 times, organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filter cake was washed with 1, 2-dichloroethane, and the solvent was removed under reduced pressure to obtain (2)N-benzenesulfonyl-4-methoxy-2-nitroaniline crude product. Wherein, Compound (1)NThe mass ratio of the substances of the reaction of the benzenesulfonyl-4-methoxyaniline and the copper nitrate trihydrate is 1: (1-5).
2) Compound (2)NAdding the crude product of the-benzenesulfonyl-4-methoxy-2-nitroaniline into 1, 2-dichloroethane, adding p-toluenesulfonic acid into the solution, heating the reaction solution to 65-85 ℃ under the protection of argon, and fully reacting; after the reaction is finished, 0.01 equivalent of triethylamine is added, 10% sodium hydroxide aqueous solution is added, the pH is adjusted to be 6, 1, 2-dichloroethane is extracted for 3 times, organic phases are combined, anhydrous sodium sulfate is dried, filtration is carried out, 1, 2-dichloroethane is used for washing filter cakes, and the solvent is removed under reduced pressure, so that a crude product of (3) 4-methoxy-2-nitroaniline is obtained. Recrystallizing the methanol to obtain the refined 4-methoxy-2-nitroaniline (3). Wherein, the intermediate compound (2)NThe mass ratio of the substances of the reaction of the crude product of the (E) -benzenesulfonyl-4-methoxy-2-nitroaniline and the p-toluenesulfonic acid is 1: (1-5). The reaction process comprises two stages which are respectively: first stage, Compound (2)NReacting the crude product of the-benzenesulfonyl-4-methoxy-2-nitroaniline with p-toluenesulfonic acid; in the second stage, after completion of the first stage, 0.01 equivalent of triethylamine of the compound (2) was added, and then a 10% aqueous solution of sodium hydroxide was added dropwise to neutralize the solution until pH = 7.
The preparation of 4-methoxy-2-nitroaniline disclosed by the present invention is further described in detail with reference to the following specific examples.
The starting materials and reagents used in the examples of the present invention are commercially available, and in the present document, "at room temperature" means a temperature range of 10 ℃ to 30 ℃.
Example 1
Synthesis of Compound (2) in the first stepN-benzenesulfonyl-4-methoxy-2-nitroaniline
Mixing the compound (1)NAdding benzenesulfonyl-4-methoxyaniline (0.2 mol), pyridine (0.3 mol) and copper nitrate trihydrate (0.3 mol) into 200 mL of 1, 2-dichloroethane, heating the reaction system to 95-105 ℃, generally 100 ℃ after the raw materials are dissolved, monitoring the reaction process by LCMS and HPLC, and processing when the reaction time reaches 12 h. Pouring the reaction solution into ice water with the volume of 1 time, adjusting the pH value to be = 6, separating out a large amount of solid, extracting three times by 100mL of 1, 2-dichloroethane each time, combining organic phases, drying by anhydrous sodium sulfate, filtering, and washing a filter cake by the 1, 2-dichloroethane. The filtrate was removed in vacuo to give 47.7 g of Compound (2)N-benzenesulfonyl-4-methoxy-2-nitroaniline, yield 74%, HPLC purity 95%.
Compound (2)NThe nuclear magnetic resonance hydrogen spectrum of the (E) -benzenesulfonyl-4-methoxy-2-nitroaniline is shown in figure 1:1H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (s, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 3.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.19 (dd, J = 8.9, 3.0 Hz, 1H), 7.05 (d, J = 8.9 Hz, 1H), 3.79 (s, 3H), 2.36 (s, 3H). 。
compound (2)NThe nuclear magnetic resonance carbon spectrum of the (E) -benzenesulfonyl-4-methoxy-2-nitroaniline is shown in figure 2:13C NMR (101 MHz, DMSO-d 6 ) δ 157.93, 146.45, 143.92, 136.94, 130.16, 129.62, 127.21, 122.49, 120.17, 110.29, 56.52, 21.45.
compound (2)NThe high resolution mass spectrum of the (E) -benzenesulfonyl-4-methoxy-2-nitroaniline is shown in FIG. 3: HRMS (ESI +), scaled for C14H14N2O5S, [M+Na]+ 345.0521. Found 345.0524.
The second step of synthesizing the compound (3), 4-methoxy-2-nitroaniline
Mixing the compound (2)NAdding benzenesulfonyl-4-methoxy-2-nitroaniline (1 mol) into 2L of 1, 2-dichloroethane, and dissolving; then add into the pairToluene sulfonic acid (2 mol). Heating to 85-95 ℃ under the protection of argon to react for 8 hours; the reaction was complete by LCMS and HPLC. Triethylamine (0.01 mol) was added and 10% sodium hydroxide solution was added to neutralize the pH = 7. Three extractions with 100mL of 1, 2-dichloroethane each time were performed, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with 1, 2-dichloroethane. The filtrate was removed in vacuo to give 4-methoxy-2-nitroaniline (3) as an orange solid, about 155g, 92% yield, 95% purity by HPLC.
The NMR spectrum of the compound (3), 4-methoxy-2-nitroaniline, is shown in FIG. 4:1H NMR (400 MHz, DMSO-d 6 ) δ 7.36 (d, J = 3.0 Hz, 1H), 7.28 (s, 2H), 7.16 (dd, J = 9.2, 3.0 Hz, 1H), 7.00 (d, J = 9.2 Hz, 1H), 3.72 (s, 3H).
the nuclear magnetic resonance carbon spectrum of the compound (3), 4-methoxy-2-nitroaniline, is shown in figure 5:13C NMR (101 MHz, DMSO-d 6 ) δ 149.63, 142.45, 129.48, 127.67, 121.27, 105.25, 55.94.
the high resolution mass spectrum of the compound (3), 4-methoxy-2-nitroaniline, is shown in FIG. 6: HRMS (ESI +), scaled for C7H8N2O3, [M+H]+ 169.0613. Found 169.0602.
Example 2
Synthesis of Compound (2) in the first stepN-benzenesulfonyl-4-methoxy-2-nitroaniline
Mixing the compound (1)NAdding benzenesulfonyl-4-methoxyaniline (0.2 mol), pyridine (0.3 mol) and copper nitrate trihydrate (0.2 mol) into 200 mL of 1, 2-dichloroethane, heating the reaction system to 95-105 ℃, generally 100 ℃ after the raw materials are dissolved, monitoring the reaction process by LCMS and HPLC, and processing when the reaction time reaches 12 hours. Pouring the reaction solution into ice water with the volume of 1 time, adjusting the pH to be PH = 6, separating out a large amount of solid, extracting three times by 100mL of 1, 2-dichloroethane each time, combining organic phases, drying by anhydrous sodium sulfate, filtering, and washing a filter cake by the 1, 2-dichloroethane. The filtrate was removed in vacuo to give 41g of Compound (2)N-benzenesulfonyl-4-methoxy-2-nitroaniline, yield 63%, HPLC purity94 %。
The second step of synthesizing the compound (3), 4-methoxy-2-nitroaniline
Mixing the compound (2)NAdding benzenesulfonyl-4-methoxy-2-nitroaniline (1 mol) into 2L of 1, 2-dichloroethane, and dissolving; further, p-toluenesulfonic acid (2.0 mol) was added. Heating to 85-95 ℃ under the protection of argon to react for 8 hours; the reaction was complete by LCMS and HPLC. Triethylamine (0.01 mol) was added and then 10% sodium hydroxide solution was added to neutralize PH = 7. Three extractions with 100mL of 1, 2-dichloroethane each time were performed, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with 1, 2-dichloroethane. The filtrate was removed in vacuo to give 4-methoxy-2-nitroaniline (3) as an orange solid, about 155g, 92% yield, 95% purity by HPLC.
Example 3 differs from example 1 only in the compound (1)N-the ratio of the quantities of the substances of reaction of benzenesulfonyl-4-methoxyaniline with copper nitrate trihydrate varies;
example 4 differs from example 1 only in the compound (1)N-the ratio of the amounts of the substances reacting benzenesulfonyl-4-methoxyaniline with pyridine is different;
example 5, example 6, example 7 differ from example 1 only in the substitution of pyridine by another base;
example 8 and example 9 differ from example 1 only in (2)N-benzenesulfonyl-4-methoxy-2-nitroaniline (1 mol) in different quantitative ratios with p-toluenesulfonic acid reacted substance;
example 10 and example 11 differ from example 1 only in (2)NThe mass ratios of benzenesulfonyl-4-methoxy-2-nitroaniline (1 mol) to triethylamine were different; the target products obtained in the examples are shown in table 1 below.
TABLE 1 reaction conditions for the preparation of Compound (4) and product yield
Examples 2 and 3 for example 1, the amount of copper nitrate trihydrate was varied; in example 3, the amount of copper nitrate trihydrate was reduced, resulting in a lower reaction yield. Example 4 the amount of copper nitrate trihydrate was increased and the reaction yield obtained was less reduced than in example 1.
Example 4 compared with example 1, the amount of pyridine used is reduced, the reaction rate of the reaction in the step is slowed down, and the reaction yield is reduced.
Examples 5 to 7 compared to example 1, pyridine was replaced by a different base; compared with pyridine, potassium acetate, potassium tert-butoxide and cesium carbonate all promote side reactions and also reduce the reaction yield.
Examples 8 to 9 the amount of p-toluenesulfonic acid was varied compared to example 1; in example 8, the amount of p-toluenesulfonic acid used is increased, which is not favorable for the reaction, and the reaction yield is reduced; in example 9, the amount of p-toluenesulfonic acid used was reduced, so that the side reactions of the reaction increased, the reaction became complicated, and the reaction yield was lowered.
In examples 10 and 11, compared with example 1, the amount of triethylamine is changed; in example 10, the occurrence of side reactions was promoted without adding triethylamine, increasing impurities and decreasing the reaction yield; in example 11, the amount of triethylamine was increased, and the reaction yield was also decreased.
In conclusion, the preparation method of 4-methoxy-2-nitroaniline disclosed by the invention has the advantages of mild overall reaction conditions, low reaction risk coefficient and simple post-reaction treatment and purification process; under the preferable reaction conditions, as in example 1, the side reaction impurities are less, the comprehensive yield of the product reaches more than 68%, and the product purity is high.
While the foregoing is directed to embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.
Claims (7)
1. A preparation method of 4-methoxy-2-nitroaniline is characterized by comprising the following steps: the synthetic route is as follows:
the specific synthesis steps comprise: 1) compound (1)NThe benzene sulfonyl-4-methoxyaniline is subjected to nitration reaction in a first organic solvent to obtain a compound (2)N-benzenesulfonyl-4-methoxy-2-nitroaniline; 2) compound (2)NReacting the benzenesulfonyl-4-methoxy-2-nitroaniline with p-toluenesulfonic acid in a second organic solvent in an acidic environment to obtain the compound (3), namely the 4-methoxy-2-nitroaniline.
2. The process for the preparation of 4-methoxy-2-nitroaniline according to claim 1, characterized in that: the reaction process of the step 1) is as follows: compound (1)NDissolving the-benzenesulfonyl-4-methoxyaniline in a first organic solvent, adding pyridine and copper nitrate trihydrate, and reacting when the temperature of the solution reaches 90-115 ℃ to obtain the compoundN-benzenesulfonyl-4-methoxy-2-nitroaniline; after the reaction was completed, the reaction solution was poured into ice water, pH = 6 was adjusted, 1, 2-dichloroethane was extracted 3 times, organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filter cake was washed with 1, 2-dichloroethane, and the solvent was removed under reduced pressure to obtain (2)N-benzenesulfonyl-4-methoxy-2-nitroaniline crude product.
3. The process for producing 4-methoxy-2-nitroaniline according to claim 2, characterized in that: the first organic solvent is 1, 2-dichloroethane.
4. The process for the preparation of 4-methoxy-2-nitroaniline according to claim 1, characterized in that: the reaction process of the step 2) is as follows:
compound (2)NAdding the crude product of the-benzenesulfonyl-4-methoxy-2-nitroaniline into a second organic solvent, adding p-toluenesulfonic acid into the solution, heating the reaction solution to 65-85 ℃ under the protection of argon, and fully reacting; after the reaction is finished, 0.01 equivalent of triethylamine is added, 10% sodium hydroxide aqueous solution is added, the pH is adjusted to be = 7, 1, 2-dichloroethane is extracted for 3 times, organic phases are combined, anhydrous sodium sulfate is dried, 1, 2-dichloroethane is obtained by filtering to wash filter cakes, and the solvent is removed under reduced pressure to obtain (3) 4-methoxy-2-nitroaniline crude productAnd (3) recrystallizing the methanol to obtain a refined product of the 4-methoxy-2-nitroaniline, wherein the second organic solvent is 1, 2-dichloroethane.
5. The process for producing 4-methoxy-2-nitroaniline according to claim 2, characterized in that: compound (1) in step 1)NThe mass ratio of the (E) -benzenesulfonyl-4-methoxyaniline to the copper nitrate trihydrate is 1 (1-5).
6. The process for producing 4-methoxy-2-nitroaniline according to claim 2, characterized in that: compound (2) in said step 2)NThe mass ratio of the (E) -benzenesulfonyl-4-methoxy-2-nitroaniline crude product to the p-toluenesulfonic acid is 1 (1-5).
7. The process for producing 4-methoxy-2-nitroaniline according to claim 2, characterized in that: the step 2) is divided into two stages: first stage, Compound (2)NReacting the crude product of the-benzenesulfonyl-4-methoxy-2-nitroaniline with p-toluenesulfonic acid; in the second stage, after completion of the first stage, 0.01 equivalent of triethylamine of the compound (2) was added, and then a 10% aqueous solution of sodium hydroxide was added dropwise to neutralize the solution until pH = 7.
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