CN115417785A - Balsalazide sodium amide substance and preparation method and application thereof - Google Patents
Balsalazide sodium amide substance and preparation method and application thereof Download PDFInfo
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- CN115417785A CN115417785A CN202211352524.8A CN202211352524A CN115417785A CN 115417785 A CN115417785 A CN 115417785A CN 202211352524 A CN202211352524 A CN 202211352524A CN 115417785 A CN115417785 A CN 115417785A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/14—Phosphorus; Compounds thereof
- B01J27/186—Phosphorus; Compounds thereof with arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium
- B01J27/188—Phosphorus; Compounds thereof with arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium with chromium, molybdenum, tungsten or polonium
- B01J27/19—Molybdenum
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/02—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides
- C07C245/06—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings
- C07C245/08—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings with the two nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings, e.g. azobenzene
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a balsalazide sodium amide compound and a preparation method and application thereof, relating to the field of biological medicine. The method comprises dissolving 4-nitrobenzoyl-beta-alanine in methanol, and adding catalyst H 3 PMo 12 O 40 and/C and a reducing agent, adjusting the pH value with acid after reaction, filtering, washing with water and drying to obtain the balsalazide sodium amino compound. The invention adopts high-activity H 3 PMo 12 O 40 The catalyst/C, hydrazine hydrate is reducing agent, the reaction time is short, the selectivity of the reaction is high, the conversion rate is high, replace expensive Pd-C catalyst, cancel the use of hydrogen, greatly improve the operational safety, reduce the synthetic cost and have low reaction danger coefficient, this stepThe reaction yield of (2) is improved to over 99%.
Description
Technical Field
The invention relates to the field of biological medicine, and particularly relates to a balsalazide disodium amino compound, and a preparation method and application thereof.
Background
The balsalazide disodium amide (4-aminobenzoyl-beta-alanine) is an intermediate for synthesizing the balsalazide disodium, and the balsalazide disodium is a novel prodrug of 5-aminosalicylic acid. Compared with the similar medicines, the Chinese medicinal composition has the characteristics of quick response, good curative effect, less side effect and the like. The balsalazide disodium amide is synthesized by catalytic hydrogenation of 4-nitrobenzoyl-beta-alanine, and the traditional process method adopts palladium carbon as a catalyst.
Synthesis path:
however, the metal catalyst palladium carbon is greatly influenced by the reaction environment, the catalytic activity is reduced, the catalyst cannot be circulated for many times, a large amount of Pd catalyst needs to be added, the reaction conversion rate is low, pollutants such as heavy metals and organic solvents are generated, the cost is increased due to the factors, and inevitable disasters are brought to people and the environment. Therefore, the key steps in the process need to be improved and optimized.
Disclosure of Invention
Therefore, the invention provides a balsalazide sodium amide as well as a preparation method and application thereof, and aims to solve the problems of low conversion rate, high cost, environmental friendliness and the like of the existing catalyst for preparing the balsalazide sodium amide.
In order to achieve the above purpose, the invention provides the following technical scheme:
according to a first aspect of the present invention, there is provided a method for preparing balsalazide sodium amide, comprising: dissolving 4-nitrobenzoyl-beta-alanine in methanol, adding catalyst H 3 PMo 12 O 40 and/C and a reducing agent, adjusting the pH value with acid after reaction, filtering, washing with water and drying to obtain the balsalazide sodium amino compound.
Synthesis path:
further, the mass-volume ratio of the 4-nitrobenzoyl-beta-alanine to the methanol is 1:1.
further, the reducing agent is hydrazine hydrate.
Further, the reaction time is 1-3h.
Further, hydrochloric acid is used for the acid adjustment.
Further, the pH is 1.5.
Further, the filtration uses a filter.
Further, the drying condition is vacuum drying at 50 ℃.
According to a second aspect of the present invention, there is provided balsalazide sodium amide, which is prepared by the method as described above.
According to a third aspect of the present invention, there is provided a use of balsalazide sodium amide in the preparation of balsalazide sodium.
The invention has the following advantages:
the invention adopts high-activity H 3 PMo 12 O 40 The catalyst/C and hydrazine hydrate are reducing agents, the reaction time is short, the reaction selectivity is high, the conversion rate is high, expensive Pd-C catalysts are replaced, the use of hydrogen is omitted, the operation safety is greatly improved, the synthesis cost is reduced, the reaction danger coefficient is low, and the reaction yield of the step is improved to more than 99%. The preparation method of the invention reduces the environmental pollution caused by heavy metal and organic solvent, and solves the problems of difficulty in post-treatment, operation danger and the like. The invention optimizes the intermediate reaction, greatly simplifies the flow, reduces the production cost, greatly improves the experimental safety and meets the requirement of green modern production.
Detailed Description
The present invention is described in terms of particular embodiments, other advantages and features of the invention will become apparent to those skilled in the art from the following disclosure, and it is to be understood that the described embodiments are merely exemplary of the invention and that it is not intended to limit the invention to the particular embodiments disclosed. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
This embodiment provides a method for preparing balsalazide sodium amide:
300g of 4-nitrobenzoyl-. Beta. -alanine and 300mL of methanol were placed in a 2000mL round-bottomed flask, and after dissolution, 3g of catalyst H were added at room temperature 3 PMo 12 O 40 Reaction of/C and 600g reducing agent hydrazine hydrate for 1.5 hours, then adjusting pH value to 1.5 with hydrochloric acid, filtering, washing with water and drying to obtain p-aminobenzoyl-beta-alanine, yield is 99.1%, mp:154-156 deg.C, and purity (HPLC) is greater than 99.7%.
Example 2
This example provides a method for preparing balsalazide sodium amide:
to a 2000mL round bottom flask was added 1.5 Kg of 4-nitrobenzoyl-. Beta. -alanine and 1.5L of methanol, dissolved and then added 15 g of catalyst H at room temperature 3 PMo 12 O 40 Reaction of C and 3 Kg reducing agent hydrazine hydrate for 1.5 hours, then adjusting pH value to 1.5 with hydrochloric acid, filtering, washing with water, drying to obtain p-aminobenzoyl-beta-alanine with yield of 99.1%, mp:154-156 deg.C, and purity (HPLC) is greater than 99.5%.
Example 3
This embodiment provides a method for preparing balsalazide sodium amide:
to a 2000mL round bottom flask was added 3.0 Kg of 4-nitrobenzoyl-beta-alanine and 3L of methanol, dissolved and then added 30 g of catalyst H at room temperature 3 PMo 12 O 40 Reaction of C and 6 Kg reducing agent hydrazine hydrate for 3 hours, then adjusting pH value to 1.5 with hydrochloric acid, filtering, washing with water, drying to obtain p-aminobenzoyl-beta-alanine with yield of 99.0%, mp:154-156 deg.C, and purity (HPLC) is greater than 99.3%.
Comparative example 1
The comparative example provides a preparation method of balsalazide sodium amide: reference is made to patent No. CN 201410148619.7:
adding 40g of p-nitrobenzoyl-beta-alanine and 100ml of solvent water into a reactor, adding a catalyst FeCl at room temperature after dissolving 3 ·6H 2 Reacting O with a reducing agent hydrazine hydrate for 2 hours, wherein the catalyst FeCl 3 ·6H 2 The dosage of O is 2.5 percent of the mass of the p-nitrobenzoyl-beta-alanine, and the molar ratio of the p-nitrobenzoyl-beta-alanine to the hydrazine hydrate is 1:2.5; then hydrochloric acid is used for adjusting the pH value to 1-2, and the p-aminobenzoyl-beta-alanine is obtained through filtration, water washing and drying, wherein the yield is 90.4%.
Comparative example 2
The comparative example provides a preparation method of balsalazide sodium amide:
adding 300g of 4-nitrobenzoyl-beta-alanine and 300mL of methanol into a 2000mL round-bottom flask, dissolving, and adding 3g of palladium carbon and hydrogen serving as catalysts at room temperature; reacting for 1.5 hours, then adjusting the pH value to 1.5 by hydrochloric acid, filtering, washing and drying to obtain the p-aminobenzoyl-beta-alanine, wherein the yield is 76%, and mp:154-156 deg.C, purity (HPLC) is greater than 98.2%.
Test example 1
The catalyst was used repeatedly and its catalytic activity was examined, and the results are shown in Table 1.
TABLE 1
| 5 times (twice) | 10 times of | 20 times (twice) | |
| H 3 PMo 12 O 40 /C | 99 | 98.7 | 98.3 |
| Palladium on carbon | 75 | 70 | 63 |
| FeCl 3 ·6H 2 O | 88 | 82 | 78 |
It can be seen that in the present invention, high activity H is used for the catalytic reduction of 4-nitrobenzoyl-beta-alanine 3 PMo 12 O 40 The catalyst method using the/C heteropoly acid as the catalyst optimizes the reaction scheme, greatly improves the selectivity of the reaction, increases the recycling times of the reaction catalyst, and does not obviously reduce the activity of the catalyst after the novel catalyst is recycled for 20 times. And because the selectivity is greatly improved, the loss of products is reduced, and the yield is improved. High activity of H 3 PMo 12 O 40 the/C heteropoly acid is used as a catalyst to replace an expensive Pd-C catalyst, and the use of hydrogen is eliminated, so that the operation safety is greatly improved, the synthesis cost is reduced, the reaction risk coefficient is low, heavy metals generated in the reaction are improved, and the problems of environmental pollution, operation risk and the like are reduced; the optimized reaction scheme has the advantages of improved yield, reduced cost, environmental friendliness and accordance with the requirements of green modern production.
Although the invention has been described in detail above with reference to a general description and specific examples, it will be apparent to one skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. A method for preparing balsalazide sodium amide, which is characterized by comprising the following steps: dissolving 4-nitrobenzoyl-beta-alanine in methanol, adding catalyst H 3 PMo 12 O 40 and/C and a reducing agent, adjusting the pH value with acid after reaction, filtering, washing and drying to obtain the balsalazide sodium amide.
2. The method for preparing balsalazide disodium amide as claimed in claim 1, wherein the mass-to-volume ratio of 4-nitrobenzoyl-beta-alanine to methanol is 1:1.
3. the method for preparing balsalazide sodium amide as claimed in claim 1, wherein the reducing agent is hydrazine hydrate.
4. The method for preparing balsalazide disodium amide as claimed in claim 1, wherein the reaction time is 1-3h.
5. The method for preparing balsalazide sodium amide as claimed in claim 1, wherein hydrochloric acid is used for said acid adjustment.
6. The method of claim 1, wherein the pH is about 1.5.
7. The method for preparing balsalazide sodium amide as claimed in claim 1, wherein said filtering is performed with a filter.
8. The method for preparing balsalazide disodium amide as claimed in claim 1, wherein the drying condition is vacuum drying at 50 ℃.
9. Balsalazide sodium amide, prepared by the method of any of claims 1-8.
10. An application of balsalazide disodium amide in preparing balsalazide disodium is provided.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6169189B1 (en) * | 1996-06-05 | 2001-01-02 | Basf Aktiengesellschaft | Process for preparing tetrahydrofuran from dialkoxybutenes |
| CN101704716A (en) * | 2009-11-06 | 2010-05-12 | 华东理工大学 | Method for directly preparing methanol by partially oxidizing methane |
| CN104974061A (en) * | 2014-04-14 | 2015-10-14 | 辽宁省药物研究院 | Preparation method of balsalazide disodium |
| CN108997165A (en) * | 2018-08-09 | 2018-12-14 | 大连万福制药有限公司 | A method of synthesis Balsalazide sodium intermediate |
-
2022
- 2022-11-01 CN CN202211352524.8A patent/CN115417785B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6169189B1 (en) * | 1996-06-05 | 2001-01-02 | Basf Aktiengesellschaft | Process for preparing tetrahydrofuran from dialkoxybutenes |
| CN101704716A (en) * | 2009-11-06 | 2010-05-12 | 华东理工大学 | Method for directly preparing methanol by partially oxidizing methane |
| CN104974061A (en) * | 2014-04-14 | 2015-10-14 | 辽宁省药物研究院 | Preparation method of balsalazide disodium |
| CN108997165A (en) * | 2018-08-09 | 2018-12-14 | 大连万福制药有限公司 | A method of synthesis Balsalazide sodium intermediate |
Non-Patent Citations (3)
| Title |
|---|
| 徐蕾: "《负载型杂多酸光催化材料及应用》", 31 March 2015 * |
| 秦合法等: "杂多酸（盐）的催化问题", 《化学世界》 * |
| 苏丽: "巴柳氮钠合成的研究", 《中国优秀硕士学位论文全文数据库》 * |
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