Preparation method of N-[4-2-(formylamino acetyl)-5-methoxy-2-phenoxy phenyl]-methanesulfonamide

Abstract

The invention provides a preparation method of N-[4-2-(formylamino acetyl)-5-methoxy-2-phenoxy phenyl)]-methanesulfonamide, which comprises the following steps: carrying out formylation reaction on a compound shown in a formula I and a compound shown in a formula III to obtain N-[4-2-(formylamino acetyl)-5-methoxy-2-phenoxy phenyl)]-methanesulfonamide, the preparation method disclosed by the invention adopts an ester compound as an acylating agent, has the advantages of small solvent dosage, no need of strong acid, high controllability, convenience and easiness in post-treatment operation and the like, and is suitable for industrial mass production.

Description

Technical Field

[0001] The invention relates to the field of medical technology, in particular to a method for preparing N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide, which is used for preparing iguratimod. Background Art

[0002] Rheumatoid arthritis (RA) is a common systemic autoimmune disease. The basic lesion is chronic synovial inflammation, abnormal proliferation of the synovium, thickening of the lining layer, and destruction of vascular cartilage and bone tissue, which will eventually lead to joint deformity and loss of function, causing serious impact on human health and quality of life. In recent years, its incidence and disability rate have been increasing year by year.

[0003] Aguratimod is a nonsteroidal anti-inflammatory drug, with the chemical name of 3-formamido-7-methanesulfonamido-6-phenoxy-4H-benzopyran-4-one. It was jointly developed by Toyama Pharmaceuticals and Eisai Pharmaceuticals of Japan. It can relieve joint damage and immune abnormalities in chronic arthritis and autoimmune diseases, and inhibit the production of inflammatory cytokines and immunoglobulins. It has significant effects and safety in the treatment of rheumatoid arthritis. It has anti-inflammatory and analgesic effects on acute and chronic inflammation. Unlike traditional nonsteroidal anti-inflammatory drugs, Aguratimod basically does not show adverse reactions such as ulcers in the digestive tract. It can selectively inhibit cyclooxygenase COX-2, regulate T cells, and has autoimmune regulatory effects. This product can activate osteoclasts, promote bone resorption, and lead to bone loss. Inhibiting these proinflammatory factors can play a dual role in controlling rheumatoid arthritis and bone loss caused by it. Compared with previous therapeutic drugs, it has a rapid effect, its efficacy is equivalent to that of highly effective anti-rheumatic drugs, and its toxicity is low. It can also be administered orally.

[0004] In the prior art, Iguratimod is usually prepared by using N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide as an intermediate.

[0005] CN102807515 reports that pivaloyl chloride and sodium formate are used as acylating agents and acetone is used as solvent to formylate the amino group on α-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone to prepare N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide.

[0006] CN108727232 uses formic acid and pivaloyl chloride as acylating agents and acetone as solvent for reaction. This method uses formic acid as a raw material, and the formic acid maintains a relatively acidic environment, thereby avoiding the side reaction of the α-amino ketone compound in the raw material undergoing self-condensation reaction under alkaline conditions to generate piperazine compounds.

[0007] CN112375018 reports that due to the small amount of water contained in acetone, pivaloyl chloride decomposes and generates impurities during the reaction process, which continue to react with the raw materials to form impurities that are difficult to remove. This patent adopts the method of first adding sodium carbonate to generate sodium salts of impurities generated during the reaction of pivaloyl chloride and sodium formate, so that the impurities cannot continue to react with α-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone.

[0008] CN112209859 reports that formic acid is used as a raw material, and reacts with N,N-carbonyldiimidazole (CDI) through an active ester method to obtain a highly active formyl imidazole, which is then reacted with α-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone in dichloromethane to obtain the iguratimod intermediate N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide.

[0009] In the current process, the preparation of the intermediate N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide mostly uses the mixed anhydride method, which has a slow reaction rate, many impurities, low yield and is not equipment-friendly. Therefore, it is very necessary to develop a simple and efficient preparation method for the intermediate N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide for industrial large-scale production. Summary of the invention

[0010] The present invention provides a method for preparing N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide. The method comprises the steps of performing a formylation reaction on a compound of formula I and a compound of formula III to obtain N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide.

[0011]

[0012] wherein R is selected from a linear or branched C1-C4 alkyl group; R is preferably methyl, ethyl, isopropyl and tert-butyl; R is preferably ethyl;

[0013] In some embodiments, the formylation reaction temperature is 20°C to 100°C, preferably 30°C to 60°C;

[0014] In some embodiments, the formylation reaction time is 1 to 24 hours, preferably 3 to 12 hours;

[0015] In some embodiments, the usage ratio of the compound of formula I to the compound of formula III is 1:1 to 1:20 g / ml, more preferably 1:5 to 1:15 g / ml.

[0016] In some embodiments, during the formylation reaction, 0.5-10% formic acid by mass of the compound of formula I may be added; preferably 0.5-5% formic acid by mass of the compound of formula I is added, for example 0.5%, 1%, 2%, 3%, 4%, 5% or any value or range therebetween.

[0017] In some embodiments, after the formylation reaction is completed, the reaction solution is cooled, stirred, and filtered to obtain N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide;

[0018] In some embodiments, the reaction solution is cooled to 0°C to 25°C, preferably 0°C to 10°C;

[0019] In some embodiments, the stirring time is 1 to 5 hours, preferably 1 to 2 hours.

[0020] On the other hand, the present invention also provides a method for preparing iguratimod, which comprises further converting the N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide prepared according to the method provided by the present invention into iguratimod.

[0021] Compared with the prior art, the present invention has the following positive technical effects:

[0022] 1. The preparation method provided by the present invention uses ester compounds as acylating agents, and does not use highly corrosive reagents such as acyl chlorides and acid anhydrides, thereby reducing harm to equipment and the environment and being green and environmentally friendly.

[0023] 2. In the preparation method provided by the present invention, the ester compound serves as a substrate and also as a reaction solvent, which is more in line with the principles of green chemistry, and the esterified product can be recycled and reused, which is economical and environmentally friendly.

[0024] 3. The N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide prepared by the method provided by the present invention has a high yield and high product purity, and does not require the use of a large amount of solvent or multiple crystallization purification, and the purification method is simple.

[0025] The method of the present invention has the advantages of less solvent usage, safety, environmental protection, high controllability, simple solvent recovery and reuse, high atom economy, convenient and easy post-processing, etc., under the premise of ensuring product quality and purity, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the specific implementation methods or technical solutions in the prior art, the drawings required for use in the specific implementation methods or the prior art description are briefly introduced below.

[0027] Figure 1This is a liquid chromatogram of N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide prepared in an example of the present invention.

[0028] Figure 2 This is the H NMR spectrum of N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide prepared in the example of the present invention. DETAILED DESCRIPTION

[0029] The following examples are used to further describe the specific embodiments of the present invention. The following examples are only used to illustrate the present invention, but are not used to limit the scope of the present invention.

[0030] All ranges recited herein include those endpoints of the range between the two values ​​listed, whether stated or not, all values ​​recited herein include the expected experimental error, technical error, and instrument error for a given technique used to measure the value, and when the error degree is not stated, all values ​​recited herein include a range of ±10% of the stated value.

[0031] In the present invention, unless otherwise specified, % is a percentage of weight / weight (w / w).

[0032] The HPLC analytical method used for measuring purity of the present invention is:

[0033] Chromatographic column: ACE EXCEL3 C18-Amide 150×4.6mm, 3.5μm

[0034] Mobile phase: Mobile phase A: buffer: acetonitrile = 95:5 (% V / V) Mobile phase B: acetonitrile

[0035] Buffer solution: accurately weigh 1.15 g of ammonium acetate and dissolve it in 1000 mL of water, mix well, filter, and sonicate.

[0036] Flow rate: 1.0mL / min Column temperature: 40℃ Run time: 35min Detection wavelength: 220nm

[0037] The ethyl formate and methyl formate used in the present invention come from:

[0038] Ethyl formate: Manufacturer McLean

[0039] Methyl formate: Manufacturer Adamas

[0040] Reference Example 1: Preparation of α-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone (Compound I) Nitrobenzene (200 mL) was stirred at room temperature, and aluminum chloride (43.64 g, 2.4 eq) and aminoacetonitrile hydrochloride (15.14 g, 1.2 eq) were added in several portions. The reaction solution was heated to 40°C and stirred at constant temperature for 1 h. The reaction solution was placed in an ice bath and cooled to 10°C. 4-phenoloxy-3-methanesulfonylaminoanisole (40.00 g, 1.0 eq) was added with stirring, and dry saturated hydrogen chloride gas was introduced continuously at 10-30°C for 10 h until the reaction was complete. The solution was poured into hydrochloric acid and filtered with suction. The filter cake was added into ethanol (200 mL), heated to 70°C, stirred for 2 h, cooled to 25°C, filtered, and the filter cake was added into methanol aqueous solution. The pH of the system was adjusted to 9.0-9.5 with NaOH solution, filtered, and the filter cake was dried to obtain α-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone.

[0041] Embodiment 1:

[0042] 30.00 g of N-(4-glycyl-5-methoxy-2-phenoxyphenyl)methanesulfonamide was added to 300.00 mL of ethyl formate solution, and stirring was started. The temperature was raised to 55° C. and stirred at this temperature for 12 h. After naturally cooling to room temperature, the temperature was lowered to 0-5° C. and stirred at this condition for 1-2 h. The mixture was filtered, and the filter cake was rinsed with 15.00 mL of ethanol and then dried to obtain N-(4-formamide-5-methoxy-2-phenoxyphenyl)methanesulfonamide with a yield of 81.39% and a purity of 99.58%.

[0043] Embodiment 2:

[0044] 1.8 kg of N-(4-glycyl-5-methoxy-2-phenoxyphenyl)methanesulfonamide was added to 18 L of ethyl formate solution, and stirring was started. The temperature was raised to 55° C. and stirred at this temperature for 12 h. After naturally cooling to room temperature, the temperature was lowered to 0-5° C. and stirred at this condition for 1-2 h. The mixture was filtered, and the filter cake was rinsed with 0.9 L of ethanol and then dried to obtain N-(4-formamide-5-methoxy-2-phenoxyphenyl)methanesulfonamide with a yield of 81.86% and a purity of 99.84%.

[0045] Embodiment 3:

[0046] 2.50 g of N-(4-glycyl-5-methoxy-2-phenoxyphenyl)methanesulfonamide was added to 25.00 mL of methyl formate solution, and stirring was started. The temperature was raised to 30° C. and stirred at this temperature for 21 h. After naturally cooling to room temperature, the temperature was lowered to 0-5° C. and stirred at this condition for 1-2 h. The mixture was filtered, and the filter cake was rinsed with 2.50 mL of ethanol and then dried to obtain N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide with a yield of 73.33% and a purity of 99.62%.

[0047] Embodiment 4:

[0048] 0.4 g of anhydrous formic acid was added to 210 mL of ethyl formate to form an ethyl formate solution, and then 20.0 g of N-(4-glycyl-5-methoxy-2-phenoxyphenyl)methanesulfonamide was added to the above solution, stirring was started, the temperature was raised to reflux reaction, and the mixture was kept warm and stirred at this temperature for 21 hours. After naturally cooling to room temperature, the temperature was lowered to 0-5° C. and kept warm and stirred for 1-2 hours under this condition, and the mixture was filtered. The filter cake was rinsed with 20 mL of ethyl formate and then dried to obtain N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide with a yield of 80.5% and a purity of 99.62%.

[0049] Comparative Example 1:

[0050] Add 19.77g acetone and 3.14g pivaloyl chloride to the reaction bottle, start stirring, control the temperature at 20-30°C, add 4.42g sodium formate, and stir for 4h. Then weigh 8.40g 2-amino-1-(2-methoxy-4-methanesulfonamido-5-phenoxyphenyl) acetone hydrochloride and add it to the reaction bottle, control the temperature at 20-30°C, react, and take samples to monitor the complete reaction of the raw materials. Add 39.54g water to the reaction bottle, stir for 30 minutes, filter, rinse the filter cake with 8.4g water and dry it to obtain N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide, with a yield of 73.08% and a purity of 85.01%.

[0051] Process yield and purity comparison

[0052] Comparative Example 1 Example 1 Technology Mixed anhydride method Ethyl formate method Yield 73.08％ 81.39％ purity 85.01％ 99.58％

[0053] The specific embodiments described in the present invention are merely examples of the spirit of the present invention. Those skilled in the art of the present invention may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the attached claims.

Claims

1. A method for preparing N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide, characterized in that: The preparation method comprises the steps of subjecting a compound of formula I to a compound of formula III formylation reaction to obtain N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide, Wherein R is selected from a linear or branched C1-C4 alkyl group; R is preferably a methyl group, an ethyl group, an isopropyl group and a tert-butyl group; R is preferably an ethyl group.

2. The preparation method according to claim 1, characterized in that: The formylation reaction temperature is 20°C to 100°C, preferably 30°C to 60°C.

3. The preparation method according to claim 1, characterized in that: The formylation reaction time is 1 to 24 hours, preferably 3 to 12 hours.

4. The preparation method according to claim 1, characterized in that: The dosage ratio of the compound of formula I to the compound of formula III is 1:1 to 1:20 g / ml, more preferably 1:5 to 1:15 g / ml.

5. The preparation method according to claim 1, characterized in that: During the formylation reaction, 0.5-10% formic acid based on the mass of the compound of formula I may be added; preferably 0.5-5% formic acid based on the mass of the compound of formula I is added.

6. The preparation method according to claim 1, characterized in that: After the formylation reaction is completed, the reaction solution is cooled, stirred, and filtered to obtain N-[4-2-(formylaminoacetyl)-5-methoxy-2-phenoxyphenyl]-methanesulfonamide.

7. The preparation method according to claim 6, characterized in that: The reaction solution is cooled to 0°C to 25°C, preferably 0°C to 10°C.

8. The preparation method according to claim 6, characterized in that: The stirring time is 1 to 5 hours, preferably 1 to 2 hours.

9. A method for preparing iguratimod, wherein the method comprises the steps according to any one of claims 1 to 8.

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