CN114605277A - Synthesis method of mesalazine - Google Patents
Synthesis method of mesalazine Download PDFInfo
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- CN114605277A CN114605277A CN202210404336.9A CN202210404336A CN114605277A CN 114605277 A CN114605277 A CN 114605277A CN 202210404336 A CN202210404336 A CN 202210404336A CN 114605277 A CN114605277 A CN 114605277A
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- mesalazine
- hydroxybenzoic acid
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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Abstract
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of mesalazine, which comprises the following steps: 5-halogenated-2-hydroxybenzoic acid is used as an initial raw material, copper salt is used as a catalyst, and the reaction with ammonia water is carried out at a certain temperature to synthesize the mesalazine (I). The invention only needs one-step reaction without isomer generation, and the whole process takes water as solvent, avoids using highly toxic reagent, and has lower synthesis cost and convenient operation.
Description
Technical Field
The invention relates to the field of organic chemical synthesis, and relates to a synthesis method of mesalazine.
Background
Mesalazine (mesalazine), also known as mesalazine, with the chemical name 5-amino-2-hydroxybenzoic acid (5-ASA), was originally developed by Pharmacia AB, sweden, and was first marketed in the uk 6 months in 1985, as a synthetic inhibitor of prostaglandins and leukotrienes, for the treatment of ulcerative colitis. The mesalazine has the characteristics of colon-specific release, low toxicity, few adverse reactions, strong tolerance and the like, and becomes a clinical preferred medicament for resisting colitis.
The currently reported methods for synthesizing mesalazine bulk drugs mainly comprise the following four methods:
1. salicylic acid nitration reduction method: the method takes salicylic acid (1) as a raw material, synthesizes 5-nitro salicylic acid (2) through nitration reaction, and then reduces the 5-amino salicylic acid (I), namely mesalazine. The synthesis method for preparing mesalazine by taking salicylic acid as a raw material through nitration-reduction is mature, but the selectivity of nitration reaction is poor, so that the product yield is low, the separation and purification of an intermediate are troublesome, and the nitration reaction has strong exothermicity and potential safety production hazards. The reduction reaction usually uses metal powder, hydrochloric acid or hydrazine hydrate, and the environmental pollution is serious, which does not meet the requirements of green industrial production.
2. Reduction of phenylazo salicylic acid: according to the method, aniline (3) is mainly used as a raw material, diazotization is carried out to generate diazobenzene chloride (4) or the diazobenzene chloride (4) is directly used as the raw material, then the diazobenzene chloride (4) is coupled with salicylic acid to obtain phenylazosalicylic acid (5), then sodium hydrosulfite is used for reduction to obtain an intermediate (6), and finally, the intermediate is acidified to obtain the mesalazine (I). The method overcomes the problem of selectivity of salicylic acid nitration in the salicylic acid nitro reduction method. But the reaction route is longer and the operation is complicated. Aniline used in the reaction has high toxicity, and diazo compounds are unstable and easy to decompose and explode, so that the method provides a challenge for safe production.
Kolbe-Schmitt method: the method takes dried sodium p-aminophenolate (7) as a starting material, and the sodium p-aminophenolate reacts with carbon dioxide at high temperature and high pressure to form carboxyl, so as to prepare the compound (I). The method has short process route and high total reaction yield, but needs high temperature and high pressure, has rigorous reaction conditions, high anhydrous requirement and inconvenient operation.
4. Halogenated aromatic hydrocarbon hydrolysis reduction method: the method takes o-chlorobenzoic acid (8) as a starting raw material, 5-nitro-o-chlorobenzoic acid (9) is generated through nitration reaction, or the (9) is directly taken as the starting raw material, chlorinated aromatic hydrocarbon is hydrolyzed under alkaline condition to obtain (10), and then nitro is reduced to obtain mesalazine (I). The method has the advantages that the existence of the electron-withdrawing group on the benzene ring, especially the para-nitro group, ensures that the hydrolysis reaction of the 5-nitro-o-chlorobenzoic acid is easier to carry out, and has better reaction selectivity. However, the problems of high cost or serious pollution and the like exist in the later-stage reduction reaction.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: overcomes the defects and shortcomings of the prior art, and provides a synthesis method of mesalazine with low cost and convenient post-treatment.
The technical scheme for solving the technical problems is as follows:
a synthesis method of mesalazine is characterized by comprising the following steps: 5-halogenated-2-hydroxybenzoic acid is used as an initial raw material, copper salt is used as a catalyst, and the reaction with ammonia water is carried out at a certain temperature to synthesize mesalazine (I); the specific reaction structural formula is as follows:
preferably, the 5-halo-2-hydroxybenzoic acid is selected from 5-chloro-2-hydroxybenzoic acid, 5-bromo-2-hydroxybenzoic acid, or 5-iodo-2-hydroxybenzoic acid.
Preferably, the copper catalyst is selected from the group consisting of CuCl, CuBr, CuI, CuOAc, Cu (OAc)2、Cu2O or CuSO4。
Preferably, the molar amount of the copper catalyst is 1-20% of the molar amount of the 5-halo-2-hydroxybenzoic acid.
Further, the molar amount of the copper catalyst is 1-5% of that of the 5-halogenated-2-hydroxybenzoic acid.
Preferably, the molar ratio of the 5-halo-2-hydroxybenzoic acid to the amine is 1: 1 to 20.
Further, the molar ratio of the 5-halo-2-hydroxybenzoic acid to the amine is 1: 5 to 15.
Preferably, in the synthesis method of mesalazine, the reaction temperature is 20-100 ℃, and the reaction time is 1-24 h.
Further, in the synthesis method of mesalazine, the reaction temperature is 40-60 ℃, and the reaction time is 3-20 hours.
Preferably, the mass of the solvent water added in the synthesis method of mesalazine is 1-10 times of the mass of 5-halo-2-hydroxybenzoic acid.
The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.
The synthesis method of mesalazine provided by the invention avoids the use of nitration and reduction reactions, and only one-step reaction is needed to obtain mesalazine; cheap copper salt is used as a catalyst, no ligand is added, and water is selected as a reaction solvent. The cost is low, the post-treatment is convenient, and the problems of high toxicity of raw materials, serious production pollution and the like are avoided.
Drawings
Fig. 1 is a mesalamine MS spectrum prepared by a specific embodiment of the present invention;
FIG. 2 shows mesalazine prepared according to an embodiment of the present invention1H NMR spectrum.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1:
the starting materials 5-iodo-2-hydroxybenzoic acid (11, 2.64g, 10mmol), cuprous iodide (1.9mg, 0.1mmol) and water (5mL) were sequentially added to a reaction flask, and after adding ammonia water (3mL, ammonia content 0.9g/mL), the mixture was reacted at 60 ℃ for 3 hours. After the reaction is finished, the reaction bottle is placed in an ice-water bath, stirring is carried out for 1h, suction filtration is carried out, a filter cake is pulped with water, and drying is carried out to obtain a white-like solid (I), namely mesalazine (1.36g, yield 89%), purity is 97.0% [ HPLC peak area normalization method: chromatographic column Agilent-C18Columns (4.6 mm. times.100 mm, 3.5 μm); mobile phase: acetonitrile/water containing 0.1% trifluoroacetic acid, acetonitrile 10% -100%, time 15 minutes; the column temperature is 25 ℃; the flow rate is 1.0 mL/min; the detection wavelength was 214 nm. The retention time is 2.08min]。ESI-MS m/z：154.1(M+H)+；1H NMR(400MHz,DMSO-d6)δ9.08(br,4H),7.36–7.34(m,1H),7.00(dd,J＝8.7,3.0Hz,1H),6.74(dd,J＝8.7,1.2Hz,1H)。
Example 2:
the starting materials 5-iodo-2-hydroxybenzoic acid (11, 2.64g, 10mmol), copper acetate (6.0mg, 0.3mmol) and water (5mL) were sequentially added to the reaction flask, followed by addition of aqueous ammonia (3mL, ammonia content 0.9g/mL) and reaction at 60 ℃ for 3 hours. After the reaction is finished, the reaction bottle is placed in an ice-water bath, stirring is carried out for 1 hour, suction filtration is carried out, a filter cake is pulped by water, and drying is carried out to obtain a white-like solid (I), namely the mesalazine (1.15g, yield is 75%).
Example 3:
the starting materials 5-iodo-2-hydroxybenzoic acid (11, 2.64g, 10mmol), copper sulfate (9.0mg, 0.5mmol) and water (5mL) were sequentially added to the reaction flask, and after adding aqueous ammonia (2mL, ammonia content 0.9g/mL), the mixture was reacted at 60 ℃ for 3 hours. After the reaction, the reaction flask was placed in an ice-water bath, stirred for 1 hour, filtered, the filter cake was slurried with water and dried to obtain a white-like solid (I), which was mesalamine (1.20g, yield: 78%).
Example 4:
the starting materials 5-iodo-2-hydroxybenzoic acid (11, 2.64g, 10mmol), cuprous iodide (9.0mg, 0.5mmol) and water (5mL) were sequentially added to a reaction flask, and after adding ammonia water (1mL, ammonia content 0.9g/mL), the mixture was reacted at room temperature for 24 hours. After the reaction, the reaction flask was placed in an ice-water bath, stirred for 1h, filtered, the filter cake was slurried with water and dried to give a white-like solid (I) which was mesalazine (1.34g, yield: 88%).
Example 5:
the starting materials 5-bromo-2-hydroxybenzoic acid (12, 2.17g, 10mmol), cuprous iodide (5.4mg, 0.3mmol) and water (5mL) were sequentially added to a reaction flask, and after adding ammonia water (3mL), the mixture was reacted at 80 ℃ for 5 hours. After the reaction, the reaction flask was placed in an ice-water bath, stirred for 1h, filtered, the filter cake was slurried with water and dried to give a white-like solid (I) which was mesalazine (1.29g, yield: 84%).
Example 6:
the starting materials 5-chloro-2-hydroxybenzoic acid (13, 1.72g, 10mmol), cuprous iodide (9.0mg, 0.5mmol) and water (5mL) were sequentially added to a reaction flask, and after adding ammonia water (3mL), the mixture was reacted at 100 ℃ for 12 hours. After the reaction is finished, the reaction bottle is placed in an ice-water bath, stirring is carried out for 1 hour, suction filtration is carried out, a filter cake is pulped by water, and drying is carried out to obtain a white-like solid (I), namely the mesalazine (1.25g, the yield is 82%).
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (10)
1. A synthesis method of mesalazine is characterized by comprising the following steps: 5-halogenated-2-hydroxybenzoic acid is used as an initial raw material, copper salt is used as a catalyst, and the reaction with ammonia water is carried out at a certain temperature to synthesize mesalazine (I); the specific reaction structural formula is as follows:
2. the process for the synthesis of mesalazine according to claim 1, characterized in that: the 5-halo-2-hydroxybenzoic acid is selected from 5-chloro-2-hydroxybenzoic acid, 5-bromo-2-hydroxybenzoic acid, or 5-iodo-2-hydroxybenzoic acid.
3. The method for synthesizing mesalazine according to claim 1, wherein: the copper catalyst is selected from the group consisting of CuCl, CuBr, CuI, CuOAc, Cu (OAc)2、Cu2O or CuSO4。
4. The process for the synthesis of mesalazine according to claim 1, characterized in that: the molar amount of the copper catalyst is 1-20% of that of the 5-halogenated-2-hydroxybenzoic acid.
5. The process for the synthesis of mesalazine according to claim 4, characterized in that: the molar amount of the copper catalyst is 1-5% of that of the 5-halogenated-2-hydroxybenzoic acid.
6. The process for the synthesis of mesalazine according to claim 1, characterized in that: the molar ratio of the 5-halo-2-hydroxybenzoic acid to the amine is 1: 1 to 20.
7. The process for the synthesis of mesalazine according to claim 6, characterized in that: the molar ratio of the 5-halo-2-hydroxybenzoic acid to the amine is 1: 5 to 15.
8. The process for the synthesis of mesalazine according to claim 1, characterized in that: the reaction temperature in the synthesis method of mesalazine is 20-100 ℃, and the reaction time is 1-24 hours.
9. The process for the synthesis of mesalazine according to claim 8, characterized in that: in the synthesis method of mesalazine, the reaction temperature is 40-60 ℃, and the reaction time is 3-20 hours.
10. The method for synthesizing mesalamine according to any one of claims 1 to 9, wherein: in the synthesis method of mesalazine, the mass of the added solvent water is 1-10 times of the mass of 5-halogenated-2-hydroxybenzoic acid.
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