CN115536617A - Preparation method of dantrolene intermediate - Google Patents
Preparation method of dantrolene intermediate Download PDFInfo
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- CN115536617A CN115536617A CN202211054773.9A CN202211054773A CN115536617A CN 115536617 A CN115536617 A CN 115536617A CN 202211054773 A CN202211054773 A CN 202211054773A CN 115536617 A CN115536617 A CN 115536617A
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- acid
- furfural
- aqueous solution
- dantrolene
- nitroaniline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/40—Radicals substituted by oxygen atoms
- C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
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Abstract
The invention discloses a preparation method of a dantrolene intermediate, which comprises the following steps: the first step is as follows: preparing raw materials including 4-nitroaniline, an acidic reagent, sodium nitrite and furfural; the second step is that: adding a certain amount of weak acid into an acidic reagent; the third step: 4-nitroaniline reacts with sodium nitrite under an acidic reagent to prepare diazonium salt; the fourth step: condensing with furfural to obtain 5- (p-nitrophenyl) furfural. The invention develops a mature process route which takes the compound B as a technology, improves the solubility of the 4-nitroaniline by adding weak acid and mixing with sulfuric acid, so that the 4-nitroaniline can be quickly and completely dissolved, thereby quickly preparing the compound B, effectively improving the yield of the 5- (p-nitrophenyl) furfural and reducing the quantity of impurities.
Description
Technical Field
The invention relates to the technical field of organic synthetic pharmacy, in particular to a preparation method of a dantrolene intermediate.
Background
Dantrolene sodium is a muscle relaxant, was successfully developed by Norwich corporation of the united states in 1967, first marketed in the united states in 1974, and first approved by the FDA for the treatment of malignant hyperthermia in 1979, and is currently the only drug clinically used for intraoperative malignant hyperthermia.
5- (p-nitrophenyl) furfural is a key intermediate for synthesizing dantrolene sodium, in the prior art, the 5- (p-nitrophenyl) furfural is prepared by using 4-nitroaniline as a raw material and condensing amino diazotized and then condensed with furfural, and the reaction formula is as follows:
the amino diazotization reaction of 4-nitroaniline is inquired by published documents, and is mainly to generate corresponding diazonium salts such as a compound A, a compound B and a compound C by dropwise adding sodium nitrite under the condition of an acidic reagent.
The conventional method is to generate the compound A, but the stability of the compound A is poor, so the yield of the final product 5- (p-nitrophenyl) furfural in a small test can only reach 40-50%, and in the industrial mass production of the route, the yield of the 5- (p-nitrophenyl) furfural is further reduced because the compound A cannot be rapidly combined with the furfural to react under the industrial condition.
Although the structure of the compound B is more stable than that of the compound A, in the prior art, 4-nitroaniline is dissolved in concentrated sulfuric acid or sulfuric acid aqueous solution for reaction, the 4-nitroaniline has low solubility in sulfuric acid to cause partial insolubility, the 4-nitroaniline has insufficient reaction with sulfuric acid and nitrite, and the raw materials are difficult to completely consume; the compound B is easy to be partially decomposed in a sulfuric acid system, so that the yield of the 5- (p-nitrophenyl) furfural is reduced, and the like, and the compound does not form a mature process route.
Disclosure of Invention
The invention aims to provide a preparation method of a dantrolene intermediate, which aims to solve the problem of stable preparation of the dantrolene intermediate.
In order to achieve the purpose, the invention provides the following technical scheme: a preparation method of a dantrolene intermediate comprises the following steps:
the first step is as follows: preparing raw materials including 4-nitroaniline, an acidic reagent, sodium nitrite and furfural;
the second step is that: adding a certain amount of weak acid into an acidic reagent;
the second step: 4-nitroaniline reacts with sodium nitrite under an acidic reagent to prepare diazonium salt;
the fourth step: condensing with furfural to obtain 5- (p-nitrophenyl) furfural.
Preferably, the acidic reagent in the first step is an inorganic strong acid such as hydrochloric acid, sulfuric acid or fluoroboric acid.
Preferably, an aqueous solution of a strong inorganic acid may be used in the second step, the ratio of the strong inorganic acid to water being 1.
Preferably, the weak acid in the second step is an aqueous solution of acetic acid or citric acid.
Preferably, the ratio of the addition amount of the acetic acid to the strong inorganic acid or the strong inorganic acid aqueous solution is 0.25-1.
Preferably, the ratio of the addition amount of the citric acid aqueous solution to the inorganic strong acid or the inorganic strong acid aqueous solution is 0.25-1.
Preferably, the citric acid of the aqueous citric acid solution: water = 1.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention develops a mature process route which takes the compound B as a technology, improves the solubility of the 4-nitroaniline by adding weak acid and mixing with sulfuric acid, so that the 4-nitroaniline can be quickly and completely dissolved, thereby quickly preparing the compound B, effectively improving the yield of the 5- (p-nitrophenyl) furfural and reducing the quantity of impurities.
2. The invention also surprisingly discovers that the method can prepare the 5- (p-nitrophenyl) furfural by adding a non-sulfuric acid system (such as a hydrochloric acid system), wherein impurities in the 5- (p-nitrophenyl) furfural are easier to remove in post-treatment, and can obtain a product with higher purity compared with the product without adding weak acid, so that the amount of impurities for subsequently synthesizing dantrolene can be effectively reduced.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
Example I
A preparation method of a dantrolene intermediate comprises the following steps:
the first step is as follows: preparing raw materials including 4-nitroaniline, an acidic reagent, sodium nitrite and furfural;
the second step is that: adding a certain amount of weak acid into an acidic reagent;
the third step: 4-nitroaniline reacts with sodium nitrite under an acidic reagent to prepare diazonium salt;
the fourth step: condensing with furfural to obtain 5- (p-nitrophenyl) furfural.
The acidic reagent in the first step is inorganic strong acid such as hydrochloric acid or sulfuric acid or fluoroboric acid.
In the second step, an aqueous solution of a strong inorganic acid may be used, the ratio of strong inorganic acid to water being 1.
The weak acid in the second step is acetic acid or citric acid aqueous solution.
The ratio of the addition amount of the acetic acid to the inorganic strong acid or the inorganic strong acid aqueous solution is 0.25-1.
The ratio of the addition amount of the citric acid aqueous solution to the inorganic strong acid or the inorganic strong acid aqueous solution is 0.25-1.
Citric acid of aqueous citric acid solution: water = 1.
Adding 26g of p-nitroaniline, 50mL of concentrated sulfuric acid and 30mL of 50% citric acid aqueous solution into a three-neck flask in sequence, stirring and heating to dissolve the p-nitroaniline, cooling to 0 ℃, slowly dropwise adding 20mL of 20% sodium nitrite aqueous solution, completing dropwise addition within about 2.5h, keeping the temperature for reaction for 1h, slowly adding 40mL of acetonitrile, 20g of furfural and 10mL of 5% copper chloride aqueous solution, keeping the temperature at 0 ℃, and reacting until no nitrogen escapes.
And (3) carrying out suction filtration, washing a filter cake to be neutral by using water, drying to obtain 49g of a mauve solid crude product, and recrystallizing by using DMF to obtain 26.4g of a light gray solid, wherein the yield is 64.6 percent, and the purity is 99.6 percent.
Example II
This embodiment further illustrates, for example 1, a method for preparing a dantrolene intermediate, comprising:
the first step is as follows: preparing a raw material, namely 4-nitroaniline, an acidic reagent, sodium nitrite and furfural;
the second step is that: adding a certain amount of weak acid into an acidic reagent;
the third step: 4-nitroaniline reacts with sodium nitrite under an acidic reagent to prepare diazonium salt;
the fourth step: condensing with furfural to obtain 5- (p-nitrophenyl) furfural.
The acidic reagent in the first step is inorganic strong acid such as hydrochloric acid, sulfuric acid or fluoboric acid.
In the second step, an aqueous solution of a strong inorganic acid may be used, the ratio of the strong inorganic acid to water being 1.
The weak acid in the second step is acetic acid or citric acid aqueous solution.
The ratio of the addition amount of the acetic acid to the inorganic strong acid or the inorganic strong acid aqueous solution is 0.25-1.
The ratio of the addition amount of the citric acid aqueous solution to the inorganic strong acid or the inorganic strong acid aqueous solution is 0.25-1.
Citric acid of aqueous citric acid solution: water = 1.
Adding 26g of paranitroaniline, 50mL of concentrated sulfuric acid, 20mL of glacial acetic acid and 10mL of water into a three-neck flask in sequence, stirring and heating to dissolve the paranitroaniline, cooling to 0 ℃, slowly dropwise adding 20mL of 20% sodium nitrite aqueous solution, completing dropwise addition within about 2.5h, keeping the temperature for reaction for 1h, slowly adding 40mL of acetonitrile, 20g of furfural and 10mL of 5% copper chloride aqueous solution, keeping the temperature for 0 ℃, and reacting until no nitrogen escapes.
And (3) carrying out suction filtration, washing a filter cake to be neutral by using water, drying to obtain 47g of a mauve solid crude product, and recrystallizing by using DMF to obtain 26.0g of a light gray solid, wherein the yield is 63.6 percent, and the purity is 99.5 percent.
Example III
This embodiment further illustrates, in another example, a method for preparing a dantrolene intermediate, comprising:
the first step is as follows: preparing raw materials including 4-nitroaniline, an acidic reagent, sodium nitrite and furfural;
the second step is that: adding a certain amount of weak acid into an acidic reagent;
the third step: 4-nitroaniline reacts with sodium nitrite under an acidic reagent to prepare diazonium salt;
the fourth step: condensing with furfural to obtain 5- (p-nitrophenyl) furfural.
The acidic reagent in the first step is inorganic strong acid such as hydrochloric acid or sulfuric acid or fluoroboric acid.
In the second step, an aqueous solution of a strong inorganic acid may be used, the ratio of the strong inorganic acid to water being 1.
The weak acid in the second step is acetic acid or citric acid aqueous solution.
The ratio of the addition amount of the acetic acid to the inorganic strong acid or the inorganic strong acid aqueous solution is 0.25-1.
The ratio of the addition amount of the citric acid aqueous solution to the inorganic strong acid or the inorganic strong acid aqueous solution is 0.25-1.
Citric acid of aqueous citric acid solution: water =1, 0.6-2.
Adding 26g of p-nitroaniline, 45mL of concentrated hydrochloric acid and 20mL of 50% citric acid aqueous solution into a three-neck flask in sequence, stirring and heating to dissolve the p-nitroaniline, cooling to 0 ℃, slowly dropwise adding 20mL of 20% sodium nitrite aqueous solution, completing dropwise addition within about 2.5h, keeping the temperature for reaction for 1h, slowly adding 40mL of acetonitrile, 20g of furfural and 10mL of 5% copper chloride aqueous solution, keeping the temperature for 0 ℃, and reacting until no nitrogen escapes.
And (3) carrying out suction filtration, washing a filter cake to be neutral by using water, drying to obtain a mauve solid crude product 43g, and recrystallizing by using DMF to obtain a light gray solid 22.4g, wherein the yield is 52.8 percent, and the purity is 99.4 percent.
Example IV
This embodiment further illustrates, in another example, a method for preparing a dantrolene intermediate, comprising:
the first step is as follows: preparing raw materials including 4-nitroaniline, an acidic reagent, sodium nitrite and furfural;
the second step is that: adding a certain amount of weak acid into an acidic reagent;
the third step: 4-nitroaniline reacts with sodium nitrite under an acidic reagent to prepare diazonium salt;
the fourth step: condensing with furfural to obtain 5- (p-nitrophenyl) furfural.
The acidic reagent in the first step is inorganic strong acid such as hydrochloric acid or sulfuric acid or fluoroboric acid.
In the second step, an aqueous solution of a strong inorganic acid may be used, the ratio of strong inorganic acid to water being 1.
The weak acid in the second step is acetic acid or citric acid aqueous solution.
The ratio of the addition amount of the acetic acid to the inorganic strong acid or the inorganic strong acid aqueous solution is 0.25-1.
The ratio of the addition amount of the citric acid aqueous solution to the inorganic strong acid or the inorganic strong acid aqueous solution is 0.25-1.
Citric acid of aqueous citric acid solution: water = 1.
Table comparing yield and purity of weak acid and non-weak acid added in example 3
Example V
This embodiment further illustrates, for additional examples, a method of preparing a dantrolene intermediate, comprising:
the first step is as follows: preparing a raw material, namely 4-nitroaniline, an acidic reagent, sodium nitrite and furfural;
the second step is that: adding a certain amount of weak acid into an acidic reagent;
the third step: 4-nitroaniline reacts with sodium nitrite under an acidic reagent to prepare diazonium salt;
the fourth step: condensing with furfural to obtain 5- (p-nitrophenyl) furfural.
The acidic reagent in the first step is inorganic strong acid such as hydrochloric acid or sulfuric acid or fluoroboric acid.
In the second step, an aqueous solution of a strong inorganic acid may be used, the ratio of the strong inorganic acid to water being 1.
The weak acid in the second step is acetic acid or citric acid aqueous solution.
The ratio of the addition amount of the acetic acid to the inorganic strong acid or the inorganic strong acid aqueous solution is 0.25-1.
The ratio of the addition amount of the citric acid aqueous solution to the inorganic strong acid or the inorganic strong acid aqueous solution is 0.25-1.
Citric acid of aqueous citric acid solution: water =1, 0.6-2.
Adding 26g of p-nitroaniline, 40mL of fluoboric acid and 20mL of 70% citric acid aqueous solution into a three-neck flask in sequence, stirring and heating to dissolve the p-nitroaniline, cooling to 0 ℃, slowly dropwise adding 20mL of 20% sodium nitrite aqueous solution, completing dropwise addition within about 2.5h, keeping the temperature for reaction for 1h, slowly adding 40mL of acetonitrile, 20g of furfural and 10mL of 5% copper chloride aqueous solution, keeping the temperature for 0 ℃, and reacting until no nitrogen escapes.
And (3) carrying out suction filtration, washing a filter cake to be neutral by using water, drying to obtain 38g of a mauve solid crude product, and recrystallizing by using DMF to obtain 19.1g of a light gray solid, wherein the yield is 46.7 percent, and the purity is 98.6 percent.
It should be noted that, in this document, relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (7)
1. A preparation method of a dantrolene intermediate is characterized in that: the preparation method of the dantrolene intermediate comprises the following steps:
the first step is as follows: preparing raw materials including 4-nitroaniline, an acidic reagent, sodium nitrite and furfural;
the second step: adding a certain amount of weak acid into an acidic reagent;
the third step: 4-nitroaniline reacts with sodium nitrite under an acidic reagent to prepare diazonium salt;
the fourth step: condensing with furfural to obtain 5- (p-nitrophenyl) furfural.
2. The method of claim 1, wherein the dantrolene intermediate is prepared by: the acidic reagent in the first step is inorganic strong acid such as hydrochloric acid or sulfuric acid or fluoroboric acid.
3. The method of claim 1, wherein the dantrolene intermediate is prepared by: in the second step, an aqueous solution of a strong inorganic acid may be used, the ratio of the strong inorganic acid to water being 1.
4. The method of claim 1, wherein the dantrolene intermediate is prepared by the following steps: the weak acid in the second step is acetic acid or citric acid aqueous solution.
5. The method of claim 5, wherein the dantrolene intermediate is prepared by: the ratio of the addition amount of the acetic acid to the inorganic strong acid or the inorganic strong acid aqueous solution is 0.25-1.
6. The method of claim 5, wherein the dantrolene intermediate is prepared by: the ratio of the addition amount of the citric acid aqueous solution to the inorganic strong acid or the inorganic strong acid aqueous solution is 0.25-1.
7. The method of claim 6, wherein the dantrolene intermediate is prepared by: citric acid of the aqueous citric acid solution: water =1, 0.6-2.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101613305A (en) * | 2009-06-29 | 2009-12-30 | 杭州吉华江东化工有限公司 | A kind of preparation method of ortho-chlor-para nitraniline diazonium salt |
| CN104119303A (en) * | 2014-03-06 | 2014-10-29 | 西北师范大学 | Receptor compound for identifying mercury ions by virtue of colorimetry-fluorometry dual channels as well as preparation and application of receptor compound |
| CN111377909A (en) * | 2020-03-18 | 2020-07-07 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of dantrolene |
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- 2022-08-31 CN CN202211054773.9A patent/CN115536617A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101613305A (en) * | 2009-06-29 | 2009-12-30 | 杭州吉华江东化工有限公司 | A kind of preparation method of ortho-chlor-para nitraniline diazonium salt |
| CN104119303A (en) * | 2014-03-06 | 2014-10-29 | 西北师范大学 | Receptor compound for identifying mercury ions by virtue of colorimetry-fluorometry dual channels as well as preparation and application of receptor compound |
| CN111377909A (en) * | 2020-03-18 | 2020-07-07 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of dantrolene |
Non-Patent Citations (4)
| Title |
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| FERNANDO PINACHO CRISOSTOMO ET AL: "Ascorbic Acid as an Initiator for the Direct C-H Arylation of (Hetero)arenes with Anilines Nitrosated In Situ", ANGEW. CHEM. INT. ED., vol. 53, no. 8, pages 2181 - 2185, XP072073162, DOI: 10.1002/anie.201309761 * |
| MOLKI MOHAGHNEZHAD ET AL: "synthesis and charccterization of two novel poly(amide-imide)s containing pendent (5-(4, 5)-diphenyl-1H-imidazol-2-yl)furan-2-yl)phenyl moieties and natural amino acids linkages for adsorption of Cu(II)", POLYMERBULLETIN, vol. 2020, no. 77, pages 4739 - 4757 * |
| SAMINA ASLAM ET AL: "Syhthesis of movel arylfurfurylchalcones", ASIAN JOURNAL OF CHEMISTRY, vol. 25, no. 14, pages 7738 - 7742 * |
| 苏秋宁等: "重氮化反应及其应用", 重氮化反应及其应用, vol. 42, no. 3, pages 13 - 16 * |
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