CN112209859B - Preparation method of Iguratimod intermediate - Google Patents
Preparation method of Iguratimod intermediate Download PDFInfo
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- CN112209859B CN112209859B CN202011041504.XA CN202011041504A CN112209859B CN 112209859 B CN112209859 B CN 112209859B CN 202011041504 A CN202011041504 A CN 202011041504A CN 112209859 B CN112209859 B CN 112209859B
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- 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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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
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Abstract
The invention discloses a preparation method of an Iguratimod intermediate, which comprises the steps of taking formic acid as a starting material, reacting with N, N-Carbonyl Diimidazole (CDI) by an active ester method to obtain formyl imidazole with higher activity, and reacting with 2-amino-1- (2-methoxy-4-methanesulfonamide-5-phenoxyphenyl) ethanone hydrochloride to prepare the important intermediate compound of the Iguratimod. The method has the advantages of safety, environmental protection, simple operation, high yield, good product purity, suitability for industrial production and the like, and is suitable for preparing the Iguratimod intermediate.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of important Iguratimod intermediate formamidomethyl-2-methoxy-4-methanesulfonamide-5-phenoxy phenyl ketone.
Background
Iguratimod, the chemical name of which is N- [3- (formamido) -4-oxo-6-phenoxy-4H-1-benzopyran-7-yl ] -methane sulfonamide, is a novel non-steroidal anti-inflammatory drug for selectively inhibiting cyclooxygenase-2 (COX-2), and has the effects of relieving fever, easing pain, resisting arthritis and regulating immunity.
In 2012, the business of shengyao medicine is approved to be on the market in China first, and the trade name is aidengxin; in the same year 6 months, the drug was approved by the Japanese PMDA under the trade name Kolbet Tablets and Carerm by the pharmaceutical company of Fushan and Wei material, Japan.
At present, the synthesis routes of iguratimod are relatively few, and the following three routes are mainly provided by inquiring and summarizing documents:
route one: inaba T et al in chem. pharm. Bull. report that pivaloyl chloride and sodium formate are used for activation reaction to obtain mixed anhydride, and then the mixed anhydride and 2-amino-1- (2-methoxy-4-methanesulfonamido-5-phenoxyphenyl) ethanone hydrochloride (4) are subjected to carbamylation reaction to obtain formamidomethyl-2-methoxy-4-methanesulfonamido-5-phenoxyphenyl ketone (compound 1), and finally the Ailamode is prepared through methoxy hydrolysis and cyclization reaction.
The sodium formate used in the acylation step in the route is insoluble in solvent acetone, and the sodium formate and the pivaloyl chloride can only prepare mixed anhydride through solid-liquid reaction, so the reaction rate is slow; in addition, sodium chloride generated in the reaction process can be coated on the surface of sodium formate to prevent the sodium formate from reacting with pivaloyl chloride, and pivaloyl chloride which is not reacted can directly react with raw materials to generate a byproduct pivaloyl amide, so that the product quality and the yield are seriously influenced.
And a second route: CN 108727232A improves the synthesis of Iguratimod intermediate, formic acid and pivaloyl chloride are adopted to carry out homogeneous reaction to prepare mixed acid anhydride, and then raw material 2-amino-1- (2-methoxy-4-methanesulfonamido-5-phenoxyphenyl) ethanone hydrochloride (4) is added to carry out acylation reaction to obtain the Iguratimod intermediate.
This method, while increasing the reaction rate, still uses a strong halogen reagent. Pivaloyl chloride has strong corrosivity, is easy to generate smoke, has special odor, is not friendly to equipment and environment, and has the risk of generating a byproduct, namely pivaloyl amide.
And a third route: mealy N et al reported that after bromination and amination, the raw material was formylated with formic acid under acetic anhydride conditions to obtain Iguratimod on Drugs Fut.
The bromine used in the route has high activity, great operation difficulty and easy side reaction; sodium azide is easy to explode, has high danger and is not beneficial to industrial production.
Disclosure of Invention
The invention aims to solve the problems in the above route and find a safe, environment-friendly, convenient to operate, high in yield and suitable for industrial production. The first step of formylation reaction is improved by selecting a route I, and important intermediate compounds (1) of the Iguratimod are synthesized by taking formic acid as raw materials through an active ester method.
The reaction equation is as follows:
the invention adopts the following technical scheme:
the method comprises the following steps: formic acid (2) is used as a raw material, reacts with N, N-Carbonyl Diimidazole (CDI) through an active ester method to obtain formyl imidazole (3) with higher activity, and then reacts with 2-amino-1- (2-methoxy-4-methanesulfonamide-5-phenoxyphenyl) ethanone hydrochloride (4) to obtain a compound (1), formamidomethyl-2-methoxy-4-methanesulfonamide-5-phenoxyphenyl ketone;
the molar ratio of the N, N-Carbonyldiimidazole (CDI) to the compounds of the formulae (2) and (4) in the above step is 1.0-2.0:1:1, preferably 1.5:1: 1.
The reaction solvent in the above step is at least one of acetonitrile, toluene and dichloromethane, and more preferably dichloromethane.
The reaction temperature in the above step is 10 ℃ to 30 ℃, and more preferably 15 ℃ to 25 ℃.
The reaction time in the above step is 1 to 4 hours, more preferably 1 to 2 hours.
Compared with the prior art, the method has the following technical advantages:
(1) the method accords with the concept of green process, does not use high-activity substances such as pivaloyl chloride, bromine and the like, and is favorable for reducing equipment corrosion and environmental pollution; flammable and explosive reagents such as sodium azide and the like are not used, so that the operation difficulty is low and the safety is high;
(2) the method has the advantages of fast reaction process, low reaction temperature and low production energy consumption, and is beneficial to industrial production;
the method has the advantages of difficult side reaction, good product purity, high yield and higher economic value.
Drawings
In order to more clearly illustrate the embodiments of the present invention, the drawings that are required to be used in the description of the embodiments will be briefly described below.
The intermediate of iguratimod prepared in embodiment 1 of the present invention: FIG. 1 is a hplc map, and FIG. 2 is1H-NMR spectrum, FIG. 3 is13C-NMR spectrum, and FIG. 4 is MS spectrum.
The intermediate of iguratimod prepared in example 4: FIG. 5 is a hplc map.
Detailed Description
The novel preparation of carboxamidomethyl-2-methoxy-4-methanesulfonamido-5-phenoxyphenyl ketone (compound 1) is as follows:
example 1
Dissolving 1.02g of formic acid in 50ml of dichloromethane, adding the mixture into a 250ml three-necked flask, stirring, controlling the temperature to be 15-25 ℃, adding 5.28g (1.5 eq) of N, N-Carbonyl Diimidazole (CDI) in batches, stirring for 1h after the addition is finished, dissolving the system clearly, adding 8.40g (1.0 eq) of 2-amino-1- (2-methoxy-4-methanesulfonamido-5-phenoxyphenyl) ethanone hydrochloride (4) in batches at 15-25 ℃, reacting for 1-2h, monitoring the raw material reaction completion by TLC (thin-layer chromatography), adding 50ml of purified water and 50ml of dichloromethane into the reaction system, stirring for 30min, demixing, concentrating the organic phase under reduced pressure to dryness, adding 50ml of isopropanol, pulping for 30min, and performing suction filtration to obtain a compound 1 (7.54 g, 91.7%) with the purity of 99.95%.1H-NMR（400 MHz, DMSO-d6）δ （ppm）：3.14(s, 3H), 3.95(s, 3H), 4.47～4.48(d, 2H), 6.98～7.00(m, 2H), 7.11～7.15(m, 1H), 7.29～7.32(d, 2H), 7.37～7.41(m, 2H), 8.11～8.12(d, 1H), 8.27～8.29(t, 1H) , 8.84(s, 1H)；13C-NMR（75 MHz, DMSO-d6）δ （ppm）：40.65, 48.56, 56.27, 105.23, 117.87, 120.12, 120.52, 123.31, 129.88, 135.80, 140.35, 156.13, 156.94, 161.36, 193.02。ES-MS m/z：378.9 [M+H]+。
Example 2
Dissolving 1.02g of formic acid in 50ml of dichloromethane, adding the solution into a 250ml three-necked flask, stirring, controlling the temperature at 15-25 ℃, adding 3.52g (1.0 eq) of N, N-Carbonyl Diimidazole (CDI) in batches, stirring for 1h after adding, dissolving the system clearly, adding 8.40g (1.0 eq) of 2-amino-1- (2-methoxy-4-methanesulfonamido-5-phenoxyphenyl) ethanone hydrochloride (4) in batches at 15-25 ℃, reacting for 1-2h, monitoring the raw material reaction completion by TLC, adding 50ml of purified water and 50ml of dichloromethane into the reaction system, stirring for 30min, demixing, concentrating the organic phase under reduced pressure to dryness, adding 50ml of isopropanol, pulping for 30min, and performing suction filtration to obtain the compound 1 (6.44 g, 78.3%).
Example 3
Dissolving 1.02g of formic acid in 50ml of dichloromethane, adding the solution into a 250ml three-necked flask, stirring, controlling the temperature at 15-25 ℃, adding 7.05g (2.0 eq) of N, N-Carbonyl Diimidazole (CDI) in batches, stirring for 1h after the addition is finished, dissolving the system clearly, adding 8.40g (1.0 eq) of 2-amino-1- (2-methoxy-4-methanesulfonamido-5-phenoxyphenyl) ethanone hydrochloride (4) in batches at 15-25 ℃, reacting for 1-2h, monitoring the raw material reaction completion by TLC, adding 50ml of purified water and 50ml of dichloromethane into the reaction system, stirring for 30min, demixing, concentrating the organic phase under reduced pressure to dryness, adding 50ml of isopropanol, pulping for 30min, and performing suction filtration to obtain a compound 1 (7.02 g, 85.4%).
Examples 1-3, the results of which are shown in Table 1.
Table 1: molar ratio of N, N-Carbonyldiimidazole (CDI) to 2-amino-1- (2-methoxy-4-methanesulfonamido-5-phenoxyphenyl) ethanone hydrochloride
The formylation reaction in scheme one is prepared as follows:
example 4
19.77g of acetone and 3.14g of pivaloyl chloride are sequentially added into a 250mL three-necked flask, magnetic stirring is started, the temperature is controlled to be 25 +/-5 ℃, 4.42g of anhydrous sodium formate is added, and stirring is carried out for 4 hours. 8.40g of 2-amino-1- (2-methoxy-4-methanesulfonamido-5-phenoxyphenyl) ethanone hydrochloride was weighed out and added into a three-necked flask, the temperature was controlled at 25. + -. 5 ℃ for reaction for 5 hours, and sampling TLC was used for monitoring. After the reaction is finished, 84.00g of purified water is added into a three-mouth bottle, the mixture is stirred for 30 +/-5 min, the filtration is carried out, and a filter cake is washed once by 16.80g of purified water. Adding the filter cake into a three-necked bottle, adding 13.20g of isopropanol, stirring for 60min, and performing suction filtration to obtain an off-white solid, namely the compound 1 (5.66 g, 67.4%) with the purity of 88.23%.
Example 4, the results are shown in table 2.
Table 2: comparison of yield of new and old process
The above examples are detailed descriptions of the method for synthesizing important intermediate of iguratimod provided by the present invention. Compared with the prior art, the advantages, the implementation mode and the preferred conditions of the invention are explained, and the description of the embodiment is provided to help understand the method and the core idea of the invention.
Claims (4)
1. A method for synthesizing an Iguratimod intermediate compound 1 is characterized in that the reaction equation is as follows:
the method comprises the following specific steps:
the method comprises the following steps: formic acid (2) is used as a raw material, reacts with N, N-Carbonyl Diimidazole (CDI) through an active ester method to obtain formyl imidazole (3) with high activity, and then reacts with 2-amino-1- (2-methoxy-4-methanesulfonamide-5-phenoxyphenyl) ethanone hydrochloride (4) to obtain an Iguratimod intermediate compound 1, formamidomethyl-2-methoxy-4-methanesulfonamide-5-phenoxyphenyl ketone.
2. The method for synthesizing Iguratimod intermediate compound 1 according to claim 1, wherein the molar ratio of N, N-Carbonyldiimidazole (CDI) to formula (2) or formula (4) in step (II) is 1.0-2.0:1: 1.
3. The method for synthesizing iguratimod intermediate compound 1 according to claim 1, wherein the reaction solvent in step (a) is at least one of acetonitrile, toluene, and dichloromethane.
4. The method for synthesizing the Iguratimod intermediate compound 1 according to claim 1, wherein the reaction temperature in the step (A) is 10-30 ℃, and the reaction time is 1-4 h.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108727232A (en) * | 2018-05-16 | 2018-11-02 | 康美（北京）药物研究院有限公司 | A kind of preparation method of Ailamode formylated intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108727232A (en) * | 2018-05-16 | 2018-11-02 | 康美（北京）药物研究院有限公司 | A kind of preparation method of Ailamode formylated intermediate |
Non-Patent Citations (1)
| Title |
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| N-Formylimidazole;Maurus Marty;《e-EROS Encyclopedia of Reagents for Organic Synthesis》;20011231;1-2 * |
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