CN110981760A - Simple preparation method of p-hydrazinobenzenesulfonic acid compound - Google Patents
Simple preparation method of p-hydrazinobenzenesulfonic acid compound Download PDFInfo
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- CN110981760A CN110981760A CN201911344051.5A CN201911344051A CN110981760A CN 110981760 A CN110981760 A CN 110981760A CN 201911344051 A CN201911344051 A CN 201911344051A CN 110981760 A CN110981760 A CN 110981760A
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
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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
- C07C303/38—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
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Abstract
The invention provides a preparation method of a p-hydrazino benzenesulfonic acid compound, which takes p-fluorobenzyl chloride as an initial raw material to obtain a target product through methods such as sulfonation, acyl chlorination, condensation, substitution and the like.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a simple and convenient preparation method of a p-hydrazino benzenesulfonic acid compound.
Background
The p-hydrazino benzenesulfonic acid compound is a very important intermediate in medicine synthesis and an indispensable intermediate in new medicine research and development, and is generally synthesized through diazotization in the conventional synthesis process, so that the process is complex, the reaction process is complex, and the reaction risk degree is high. Is a potential method development.
The prior art (WO201964139A1) discloses a preparation method of phenylhydrazine, and particularly relates to a method for preparing phenylhydrazine by taking an anilinium compound as a raw material and performing diazotization, which has the defects of relatively complex reaction operation, higher reaction risk, low yield and complex post-treatment.
Disclosure of Invention
In order to solve the defects, the invention provides a simple and convenient preparation method of a phenylhydrazine compound, p-fluorobenzyl chloride is used as an initial raw material, p-fluorobenzenesulfonic acid b is obtained through sodium sulfite reaction, p-fluorobenzenesulfonyl chloride c is obtained through thionyl chloride chlorination, an amino compound is used for replacing acyl chloride to obtain a compound d, and finally hydrazine hydrate reacts with the compound d to obtain a target compound e, so that the target product can be easily obtained through four steps of reaction.
The phenylhydrazine compound of the present invention has the following structural formula (I):
wherein, R is amino compound;
in another aspect of the present invention, there is provided a process for the preparation of a compound of formula I, comprising the steps of:
step 1, carrying out reflux reaction on p-fluorobenzyl chloride and sodium sulfite by acetone water to generate a compound b;
step 2, reacting the compound b with chloridized maple to generate a compound c;
step 3, substituting the compound c with an amino compound to generate a compound d;
step 4, the compound d and hydrazine hydrate generate substitution reaction to generate a compound e
The reaction conditions of the step 1 are as follows: water and acetone are used as solvents, sulfite is added, and reaction is carried out for 12 hours at 100 ℃;
the reaction conditions of the step 2 are as follows: dichloromethane or thionyl chloride is taken as a solvent, the reaction is carried out for 2 to 5 hours at the temperature of 0 ℃, and the reaction system is anhydrous;
the reaction conditions of the step 3 are as follows: dichloromethane or n-hexane is taken as a solvent, amino compounds are added at 0 ℃, the mixture is reacted for 3 to 5 hours at room temperature, and the reaction system is kept anhydrous;
the reaction conditions of the step 4 are as follows: adding hydrazine hydrate into N, N-dimethylacetamide or dimethyl sulfoxide as solvent, and reacting at 100-120 deg.C for 12 hr.
The invention has the beneficial effects that: the method has the advantages of easily obtained raw materials, simple and convenient operation, low cost and low risk, and the compound has wide application prospect in the field of pharmaceutical chemistry.
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FIG. 1 is a scheme for the synthesis of phenylhydrazine compounds provided by the present invention; wherein R is amino.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
The first embodiment is as follows:
the synthetic scheme for compound e is shown below:
fluorobenzyl chloride (1eq) was dissolved in 30% aqueous acetone (5v) and 1.2eq of sodium sulfite solid was added. Heating to reflux and stirring for 12 hours, detecting by TLC, removing the solvent under reduced pressure after the raw materials are consumed, filtering to obtain a compound b, pulping the solid by petroleum ether, and filtering to obtain the compound b. (yield 82%)
ESI/MS：m/z＝191.2(M+H)+。
Dissolving the compound b (1eq) in DCM (10V), adding 3(eq) of thionyl chloride, then dropwise adding 0.05mLDMF, heating to reflux and stirring until the raw materials are completely consumed. The solvent was removed under reduced pressure to give crude compound c, which was used directly next without further work-up due to the instability of compound c.
Dissolving the compound c (1eq) in DCM (2V) and dropwise adding the mixture into DCM solution (5V) in which 1.5eq of methylamine hydrochloride are dissolved under an ice bath (0 ℃), after dropwise adding, slowly heating to room temperature, stirring for 3 hours under the condition of room temperature, and detecting the reaction by TLC. After the starting material was consumed, water (50mL) was added to quench the excess sulfonyl chloride, the reaction was extracted with DCM (60 × 3mL), the organic phases were combined and washed with saturated brine, 20g anhydrous sodium sulfate was added and dried until the system was anhydrous, filtered and concentrated under reduced pressure to give crude product, which was purified by column chromatography to give compound d as a chromatography (DCM: MeOH: 20:1) yield: 60 percent.
ESI/MS：m/z＝204.2(M+H)+。
Compound d (1eq) was dissolved in DMSO (3V), 3eq of hydrazine hydrate was added, the temperature was raised to 100 ℃ and stirring was carried out for 12 hours. After TLC detection, the raw material is completely consumed, DMSO is removed by reduced pressure distillation, water (20mL) is added, 2N hydrochloric acid (40mL) is added to adjust the pH to 2, DCM (60X 3mL) is added to wash off excessive impurities in the reaction system, the water phase is rotated to the residual small amount of solution, solid is separated out, and the target compound e is obtained by filtration. 1H-NMR (300MHz, DMSO-d6) δ 10.30(s, 3H), 7.24 (d, J ═ 8.4Hz, 2H), 6.94(d, J ═ 8.4Hz, 2H), 4.22(s, 2H), 2.50(s, 3H).
Example two:
compound e1The synthetic scheme of (a) is as follows:
p-fluorobenzyl chloride (1eq) was dissolved in 30% aqueous acetone (5v) and 1.2eq of sodium sulfite solid was added. Heating to reflux and stirring for 12 hr, detecting by TLC, removing solvent under reduced pressure when the raw material is consumed, filtering to obtain compound 2, pulping the solid with petroleum ether, and filtering to obtain compound b1(yield 78%)
ESI/MS：m/z＝191.2(M+H)+。
Compound b1(1eq) was dissolved in DCM (10V), 3(eq) thionyl chloride was added, then one drop of DMF was added dropwise, and the mixture was heated to reflux and stirred until the consumption of the starting material was complete. Removing the solvent under reduced pressure to obtain a compound c1Crude product due to compound c1The instability of (2) is directly used in the next place without further post-treatment.
Compound c1(1eq) dissolved in DCM (as little as possible) was added dropwise to the solution of ethylamine hydrochloride in DCM in ice bath (0 ℃ C.), after addition, the temperature was slowly raised to room temperature, and the mixture was stirred at room temperature for 3 hours and subjected to TLC detection. Adding water (50mL) to quench excessive sulfonyl chloride until the raw materials are completely consumed, extracting the reaction solution with DCM (60X 3mL), combining organic phases, washing with saturated common salt water, drying with a proper amount of anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, and performing column chromatography to obtain a compound d1Chromatography was (DCM: MeOH ═ 20:1), yield: (72) % of the total weight of the composition.
ESI/MS：m/z＝216.2(M+H)+。
Compound d1(1eq) was dissolved in DMF (10V) and 3eq of hydrazine hydrate was added, the temperature was raised to 120 ℃ and the mixture was stirred for 12 hours. TLC detection raw material consumption is finished, DMF is removed by reduced pressure distillation, water (20mL) is added, 2N hydrochloric acid (40mL) is added to adjust the pH to 2, DCM (60X 3mL) is added to wash off excessive impurities in the reaction system, the water phase is rotated to the residual small amount of solution, solid is separated out, and the target compound e is obtained by filtration1。1H-NMR(300MHz，DMSO-d6)δ10.30(s，3H)， 7.24(d，J＝8.4Hz，2H)，6.94(d，J＝8.4Hz，2H)，4.27(s，2H)，1.68 (d，2H)2.48(s，3H)。
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 (10)
1. A simple preparation method of p-hydrazino benzenesulfonic acid compound is characterized by comprising the following steps: the preparation method comprises the following steps:
step one, carrying out reflux reaction on p-fluorobenzyl chloride and sodium sulfite by acetone water to generate a compound b,
step two, reacting the compound b with thionyl chloride to generate a compound c,
step three, the compound c and the amino compound are substituted to generate a compound d,
and fourthly, carrying out substitution reaction on the compound d and hydrazine hydrate to generate a target product compound e.
2. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: dissolving p-fluorobenzyl chloride in 30% acetone aqueous solution in the first step, adding sodium sulfite solid, heating to reflux and stirring, removing the solvent under reduced pressure, pulping the obtained fixed petroleum ether, and filtering to obtain a compound b.
3. The process according to claim 2, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: in the first step, the temperature is raised to 100 ℃, and reflux stirring is carried out for 12 hours.
4. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: and dissolving the compound b in the second step in a solvent, adding thionyl chloride, dropwise adding DMF, heating, refluxing and stirring until the raw materials are completely consumed, and removing the solvent under reduced pressure to obtain a compound c.
5. The process according to claim 4, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: and in the second step, the solvent in which the compound b is dissolved is at least one of dichloromethane, trichloromethane and tetrahydrofuran.
6. The process according to claim 4, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: and in the second step, 0.05mL of DMF is dropwise added, and the reaction is carried out for 2 to 5 hours at the temperature of 0 ℃ until the raw materials are completely consumed.
7. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: dissolving the compound c in the third step in a solvent, dropwise adding the mixture into a DCM solution in which methylamine hydrochloride is dissolved, heating to room temperature, stirring until the raw materials are completely consumed, adding water to quench redundant sulfonyl chloride, extracting the reaction solution by DCM, combining organic phases, washing by saturated salt water, adding anhydrous sodium sulfate, drying until the system is anhydrous, filtering, concentrating under reduced pressure to obtain a crude product, and performing column chromatography to obtain a compound d.
8. The simple process for preparing p-hydrazinobenzenesulfonic acid compound as claimed in claim 7, wherein: and (3) dissolving the compound c in the step three in at least one solvent selected from dichloromethane and n-hexane, dropwise adding the mixture into a 5V DCM solution of 1.5eq methylamine hydrochloride dissolved in the mixture at 0 ℃ in an ice bath, stirring and reacting for 3-5 hours at room temperature, starting detection, and obtaining a chromatography liquid in column chromatography, wherein the chromatography liquid is DCM, MeOH is 20: 1.
9. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: and in the fourth step, dissolving the compound d in a solvent, adding hydrazine hydrate, heating to 100 ℃, stirring for 12 hours, removing the solvent by reduced pressure distillation after the raw materials are completely consumed, adding water, then adding 2N hydrochloric acid to adjust the pH to be 2, adding DCM (DCM) to wash off excessive impurities in the reaction system, rotating the water phase to a small amount of residual solution, separating out solids, and filtering to obtain the target compound e.
10. The process according to claim 9, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: in the fourth step, the solvent in which the compound d is dissolved is N, N-dimethylacetamide or dimethyl sulfoxide.
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| CN201911344051.5A CN110981760A (en) | 2019-12-24 | 2019-12-24 | Simple preparation method of p-hydrazinobenzenesulfonic acid compound |
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| CN201911344051.5A CN110981760A (en) | 2019-12-24 | 2019-12-24 | Simple preparation method of p-hydrazinobenzenesulfonic acid compound |
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