Synthetic method of 6-amidinyl-2-naphthol mesylate

Abstract

The invention discloses a novel synthesis method of an intermediate 6-amidino-2-naphthol methane sulfonate of nafamostat mesylate. The method comprises the following steps: taking 6-methoxy-2-naphthaldehyde as a raw material, reacting with hydroxylamine hydrochloride to generate (E)-6-methoxy-2-naphthaldehyde oxime, reacting (E)-6-methoxy-2-naphthaldehyde oxime with thionyl chloride to obtain 6-methoxy-2-naphthylacetonitrile, carrying out Demethylation reaction on 6-methoxy-2-naphthylacetonitrile to remove methyl so as to obtain 6-cyano-2-naphthol, and carrying out column chromatography on the 6-cyano-2-naphthol so as to obtain the 6-cyano-2-naphthol. The preparation method comprises the following steps: carrying out a pinner reaction on 6-cyano-2-naphthol, thionyl chloride and methanol to generate 6-hydroxy-2-naphthyl methylimidic acid methyl ester hydrochloride, and carrying out a reaction on the 6-hydroxy-2-naphthyl methylimidic acid methyl ester hydrochloride and ammonium carbonate to obtain 6-amidino-2-naphthol carbonate. And finally, the 6-amidino-2-naphthol carbonate reacts with methane sulfonic acid to generate the 6-amidino-2-naphthol methane sulfonate.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis in organic chemistry, and in particular to a method for synthesizing 6-amidino-2-naphthol mesylate, an intermediate of nafamostat mesylate. Background Art

[0002] Nafamostat Mesylate, CAS No. 82956-11-4, molecular formula C 19 H 17 N5O2·(CH4O3S)2, the structural formula is:

[0003]

[0004] Nafamostat mesylate was developed by JanpanTobacco and was first launched in Japan in 1986. It is mainly used to treat symptoms such as acute pancreatitis, acute exacerbation of chronic pancreatitis, acute pancreatitis after pancreatography, traumatic pancreatitis, and acute pancreatitis after surgery. It belongs to the guanidine ester protease inhibitor class and has a strong selective inhibitory effect on trypsin-like serine proteases such as trypsin, fibrinase, fibrinase, kallikrein (vasodilator), and Clr and ClS of the classical pathway of the complement system. It also has an inhibitory effect on phospholipase A2 and trypsin bound to a2 macroglobulin in vitro. It can also inhibit the increase in pancreatic enzyme activity caused by pancreatitis and the enzyme activity entering the blood. It has a good therapeutic effect on various experimental pancreatitis caused by retrograde injection of trypsin, enterokinase and endotoxin through the pancreatic duct. This product has good efficacy, is safer, and has fewer toxic and side effects.

[0005] The earliest synthesis of nafamostat mesylate is to use 6-bromo-2-naphthol as a raw material to react with cuprous cyanide to obtain 6-cyano-2-naphthol, then pass HCl gas into anhydrous methanol until saturated, add 6-cyano-2-naphthol to undergo pinner reaction to obtain 6-hydroxy-2-naphthol iminomethyl ester hydrochloride, then pass ammonia gas into it to undergo ammonolysis reaction to obtain 6-amidino-2-naphthol, and then react with potassium bicarbonate and methanesulfonic acid to convert it into 6-amidino-2-naphthol methanesulfonate. In this method, cuprous cyanide is used, which is extremely easy to produce highly toxic hydrogen cyanide gas in an acidic environment, causing environmental pollution and personal injury, and industrial production is extremely dangerous. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a method for synthesizing 6-amidino-2-naphthol methanesulfonate. The method is simple to operate, has few side reactions, avoids the use of cuprous cyanide, and the 6-amidino-2-naphthol methanesulfonate product finally obtained has high purity.

[0007] The purpose of the present invention can be achieved through the following technical solutions:

[0008] 6-amidino-2-naphthol methane sulfonate, the synthesis of which comprises the following steps:

[0009] Step a, adding 6-methoxy-2-naphthaldehyde to dichloromethane and stirring for 5-10 minutes, then adding hydroxylamine hydrochloride, N,N-diisopropylethylamine and anhydrous sodium sulfate, refluxing and stirring at 38-42° C. for 10-12 hours, filtering and washing the filter cake to obtain filtrate a;

[0010] Further, the dosage ratio of 6-methoxy-2-naphthaldehyde, hydroxylamine hydrochloride, N,N-diisopropylethylamine and anhydrous sodium sulfate is 1 mol: 1.05-1.2 mol: 1.05-1.2 mol: 1.4-1.5 mol, the dosage ratio of 6-methoxy-2-naphthaldehyde and the total amount of dichloromethane is 1 g: 8-12 ml, and the volume ratio of dichloromethane used for reaction to dichloromethane used for washing filter cake is 12-14: 1;

[0011] Step b, cooling the filtrate a to 10-20° C. and then adding dichlorothionyl thereto dropwise, maintaining the temperature at 20-30° C. during the addition of dichlorothionyl, stirring the reaction at 15-25° C. for 30-40 min, and then adding potassium carbonate solution 1 to quench, and after separation, drying the organic phase with silica gel, filtering and washing the filter cake to obtain a dichloromethane solution containing 6-methoxy-2-naphthonitrile, i.e., filtrate b;

[0012] Further, the dosage ratio of filtrate a and thionyl chloride is 1580-1620 mL: 180-250 mol, and the mass fraction of potassium carbonate solution 1 is 20-25%;

[0013] Step c, in a protective gas atmosphere, cooling the filtrate b to 5-15° C., adding boron tribromide dropwise thereto, stirring the reaction at 20-30° C. for 6-6.5 hours, adding potassium carbonate solution 2 for quenching, concentrating under reduced pressure at 40-45° C., cooling and filtering, washing with water, and post-treating the filter cake to obtain 6-cyano-2-naphthol;

[0014] Furthermore, the dosage ratio of filtrate b and boron tribromide is 1650-1680 mL: 180-300 mol, and the mass fraction of potassium carbonate solution 2 is 40-45%; the post-treatment method of the filter cake is to add 1-2 g of the filter cake to 2-4 g of methanol and stir for 30-40 min at 35-40 ° C, then add water to precipitate the solid, filter, and dry at 45-55 ° C for 8-12 hours;

[0015] Step d, stirring and cooling the methanol to 0-15°C, adding thionyl chloride dropwise, and then adding 6-cyano-2-naphthol, stirring and reacting at 25-35°C for 18-20h, and post-treating the reaction solution to obtain 6-hydroxy-2-naphthylcarboximidic acid methyl ester hydrochloride;

[0016] Furthermore, the ratio of thionyl chloride to 6-cyano-2-naphthol is 6-10 mol:1 mol; the ratio of methanol to 6-cyano-2-naphthol is 8-12 mL:1 g; the post-treatment method of the reaction solution is to filter the reaction solution, wash the filtered solid with methyl tert-butyl ether, and then dry it at 40-55° C. for 8-12 hours;

[0017] Step e, stirring methanol, 6-hydroxy-2-naphthylcarboximidic acid methyl ester hydrochloride and ammonium carbonate at 35-45° C. for 6-6.5 hours, concentrating under reduced pressure at 40-55° C. for 6-6.5 hours, adding potassium carbonate solution 3, stirring at room temperature for 4-4.5 hours, centrifuging, filtering and washing with water to obtain a wet product containing 6-amidino-2-naphthol carbonate;

[0018] Further, the dosage ratio of 6-hydroxy-2-naphthyl methyl ester hydrochloride and ammonium carbonate is 1 mol: 2-6 mol; the dosage ratio of 6-hydroxy-2-naphthyl methyl ester hydrochloride and methanol is 1 g: 8-12 mL, and the mass fraction of potassium carbonate solution 3 is 10-15%;

[0019] Step f, adding the wet product containing 6-amidino-2-naphthol carbonate to methanol, adding methanesulfonic acid dropwise under stirring, continuing stirring for 25-35 minutes, then adding methyl tert-butyl ether, stirring at room temperature for 2-2.5 hours, centrifuging, filtering, washing the filter cake with methyl tert-butyl ether, and drying at 40-45° C. for 8-12 hours to obtain 6-amidino-2-naphthol sulfonate;

[0020] Furthermore, the usage ratio of the wet product containing 6-amidino-2-naphthol carbonate and methanesulfonic acid is 28.5-29.5kg:105-150mol; the usage ratio of the wet product containing 6-amidino-2-naphthol carbonate, methanol and the total amount of methyl tert-butyl ether is 1.5-2.5g:3-5ml:25-35ml, and the volume ratio of methyl tert-butyl ether participating in the reaction and methyl tert-butyl ether used for washing the filter cake is 10-12:1.

[0021] The synthetic route of the 6-amidino-2-naphthol methanesulfonate is as follows:

[0022]

[0023] Among them, compound 1 is 6-methoxy-2-naphthaldehyde, compound 2 is (E)-6-methoxy-2-naphthaldehyde oxime, compound 3 is 6-methoxy-2-naphthonitrile, compound 4 is 6-cyano-2-naphthol, compound 5 is 6-hydroxy-2-naphthylmethanilide methyl ester hydrochloride, compound 6 is 6-amidino-2-naphthol carbonate, and compound 7 is 6-amidino-2-naphthol methane sulfonate.

[0024] Beneficial effects of the present invention: The present invention provides a method for synthesizing 6-amidino-2-naphthol methane sulfonate, wherein the 6-amidino-2-naphthol methane sulfonate is prepared by reacting 6-methoxy-2-naphthaldehyde with hydroxylamine hydrochloride to generate (E)-6-methoxy-2-naphthaldehyde oxime, and then reacting (E)-6-methoxy-2-naphthaldehyde oxime with thionyl chloride to obtain 6-methoxy-2-naphthonitrile, and 6-methoxy-2-naphthonitrile is obtained by Demet The methyl group is removed by hylation reaction to obtain 6-cyano-2-naphthol, 6-cyano-2-naphthol reacts with thionyl chloride and methanol through pinner reaction to generate 6-hydroxy-2-naphthyl methyl imidate hydrochloride, 6-hydroxy-2-naphthyl methyl imidate hydrochloride is then reacted with ammonium carbonate to obtain 6-amidino-2-naphthol carbonate, and finally 6-amidino-2-naphthol carbonate is reacted with methanesulfonic acid to generate 6-amidino-2-naphthol methanesulfonate. The synthesis method of 6-amidino-2-naphthol methanesulfonate of the present invention has the following beneficial effects:

[0025] 1. The synthesis method of the present invention does not use highly toxic substances for reaction, has little environmental pollution, and is environmentally friendly.

[0026] 2. The reaction conditions are mild, the operation is simple, the equipment requirements are low, and the industrial feasibility is high.

[0027] 3. The synthesis process has few side reactions, high purity and cost savings. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0029] Example 1: 6-methoxy-2-naphthaldehyde (20.0 kg, 107.4 mol) was added to dichloromethane (1600 mL) and stirred for 5 min, and then hydroxylamine hydrochloride (8.21 kg, 118.1 mol), N,N-diisopropylethylamine (15.27 kg, 118.1 mol), anhydrous sodium sulfate (20.0 kg) were added, and the mixture was refluxed and stirred at 40° C. for 10 h, filtered, and the filter cake was washed with dichloromethane (135 mL) to obtain filtrate a;

[0030] Example 2: After cooling the filtrate a (1605 mL) to 15 ° C, dichlorothionyl (214.8 mol, 25.56 kg) was added dropwise thereto, and the temperature was maintained at 23 ° C during the addition of dichlorothionyl. After stirring the reaction at 25 ° C for 30 min, potassium carbonate solution 1 (240 kg) was added to quench, and after separation, the organic phase was stirred and dried with silica gel (20.0 kg) for 1 h, filtered, and the filter cake was washed with dichloromethane (20 kg) to obtain a dichloromethane solution containing 6-methoxy-2-naphthonitrile, i.e., filtrate b; the mass fraction of potassium carbonate solution 1 was 20%;

[0031] Embodiment 3: In nitrogen atmosphere, after filtrate b (1659mL) is cooled to 10 ℃, boron tribromide (20.1kg, 200mol) is added dropwise thereto, and the reaction is stirred at 25 ℃ for 6.2h, potassium carbonate solution 2 (250kg) is added to quench, concentrated under reduced pressure at 45 ℃, cooled and filtered, the filter cake is washed with water (20.0kg), and the filter cake is added to methanol (53.0kg) and stirred at 35 ℃ for 30min, then water (333.0kg) is added to precipitate solid, filtered, and dried at 50 ℃ for 10h to obtain 6-cyano-2-naphthol 16.9kg, HPLC purity 99.8%, yield 93%; the mass fraction of potassium carbonate solution 2 is 40%.

[0032] Example 4: Methanol (135.2 L) was stirred and cooled to 10°C, thionyl chloride (11.9 kg, 600 mol) was added dropwise, and 6-cyano-2-naphthol (16.9 kg) was added. After stirring and reacting at 25°C for 19 h, the reaction solution was filtered, and the filtered solid was washed with methyl tert-butyl ether (20 kg) and dried at 45°C for 9 h; 22.1 kg of 6-hydroxy-2-naphthylmethanilide methyl ester hydrochloride was obtained, with a yield of 93.0%;

[0033] Example 5: Methanol (176.8 L), 6-hydroxy-2-naphthylcarboximidic acid methyl ester hydrochloride (22.1 kg, 92.9 mol) and ammonium carbonate (17.9 kg, 185.8 mol) were stirred at 40° C. for 6.2 h, and then concentrated under reduced pressure at 45° C. for 6.5 h. Potassium carbonate solution 3 (240 kg) was added and stirred at room temperature for 4.2 h, then centrifuged, filtered and washed with water (10 kg) to obtain a wet product containing 6-amidino-2-naphthol carbonate; the mass fraction of potassium carbonate solution 3 was 10%;

[0034] Example 6: A wet product (29.0 kg) containing 6-amidino-2-naphthol carbonate was added to methanol (60.2 L), and methanesulfonic acid (10.2 kg, 106.1 mol) was added dropwise under stirring. After continuing to stir for 25 min, methyl tert-butyl ether (50.5 L) was added and stirred at room temperature for 2.2 h. The mixture was centrifuged, filtered, and the filter cake was washed with methyl tert-butyl ether (5.05 L). The filter cake was dried at 45 ° C for 11 h to obtain 23.2 kg of 6-amidino-2-naphthol sulfonate with HPLC purity of 99.9% and a yield of 88.6%.

[0035] The applicant declares that the present invention illustrates the 6-amidino-2-naphthol sulfonate of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned detailed methods, that is, it does not mean that the present invention must rely on the above-mentioned detailed methods to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for synthesizing 6-amidino-2-naphthol methanesulfonate, characterized in that: The steps include: Step a, adding 6-methoxy-2-naphthaldehyde to dichloromethane and stirring, then adding hydroxylamine hydrochloride, N,N-diisopropylethylamine and anhydrous sodium sulfate, reflux stirring to react, filtering and washing the filter cake to obtain filtrate a; Step b, adding thionyl chloride dropwise to the cooled filtrate a, stirring for reaction, adding potassium carbonate solution 1 for quenching, and drying the organic phase after separation, filtering and washing the filter cake to obtain filtrate b; Step c, in a protective gas atmosphere, dropwise adding boron tribromide to the cooled filtrate b, stirring for reaction, adding potassium carbonate solution 2 for quenching, concentrating under reduced pressure, cooling and filtering, and post-treating the filter cake to obtain 6-cyano-2-naphthol; Step d, after stirring and cooling the methanol, thionyl chloride is added dropwise, and then 6-cyano-2-naphthol is added, and after stirring for reaction, the reaction solution is post-treated to obtain 6-hydroxy-2-naphthylcarboximidic acid methyl ester hydrochloride; Step e, stirring methanol, 6-hydroxy-2-naphthylcarboximidic acid methyl ester hydrochloride and ammonium carbonate for reaction, concentrating under reduced pressure, adding potassium carbonate solution 3, stirring at room temperature, centrifuging, filtering and washing to obtain a wet product containing 6-amidino-2-naphthol carbonate; Step f, adding the wet product containing 6-amidino-2-naphthol carbonate to methanol, adding methanesulfonic acid dropwise under stirring, then adding methyl tert-butyl ether, stirring at room temperature, centrifuging, filtering and washing the filter cake, and drying to obtain 6-amidino-2-naphthol sulfonate.

2. The method for synthesizing 6-amidino-2-naphthol methanesulfonate according to claim 1, wherein: The synthetic route of the 6-amidino-2-naphthol methanesulfonate is as follows: Among them, compound 1 is 6-methoxy-2-naphthaldehyde, compound 2 is (E)-6-methoxy-2-naphthaldehyde oxime, compound 3 is 6-methoxy-2-naphthonitrile, compound 4 is 6-cyano-2-naphthol, compound 5 is 6-hydroxy-2-naphthylmethanilide methyl ester hydrochloride, compound 6 is 6-amidino-2-naphthol carbonate, and compound 7 is 6-amidino-2-naphthol methane sulfonate.

3. The synthetic method of 6-amidino-2-naphthol methanesulfonate according to claim 1, characterized in that: In step a, the usage ratio of 6-methoxy-2-naphthaldehyde, hydroxylamine hydrochloride, N,N-diisopropylethylamine and anhydrous sodium sulfate is 1 mol: 1.05-1.2mol:1.05-1.2mol:1.4-1.5mol, the usage ratio of 6-methoxy-2-naphthaldehyde and dichloromethane is 1g:8-12ml, and the volume ratio of dichloromethane used for reaction and dichloromethane used for washing filter cake is 12-14:

1.

4. The method for synthesizing 6-amidino-2-naphthol methanesulfonate according to claim 1, characterized in that: In step b, the usage ratio of filtrate a and thionyl chloride is 1580-1620 mL: 180-250 mol, and the mass fraction of potassium carbonate solution 1 is 20-25%.

5. The method for synthesizing 6-amidino-2-naphthol methanesulfonate according to claim 1, characterized in that: In step c, the usage ratio of filtrate b and boron tribromide is 1650-1680 mL: 180-300 mol, and the mass fraction of potassium carbonate solution 2 is 40-45%.

6. The method for synthesizing 6-amidino-2-naphthol methanesulfonate according to claim 1, characterized in that: In step d, the usage ratio of thionyl chloride to 6-cyano-2-naphthol is 6-10 mol:1 mol; the usage ratio of methanol to 6-cyano-2-naphthol is 8-12 mL:1 g.

7. The method for synthesizing 6-amidino-2-naphthol methanesulfonate according to claim 1, characterized in that: In step e, the usage ratio of 6-hydroxy-2-naphthyl methyl ester hydrochloride and ammonium carbonate is 1 mol: 2-6 mol; the usage ratio of 6-hydroxy-2-naphthyl methyl ester hydrochloride and methanol is 1 g: 8-12 mL, and the mass fraction of potassium carbonate solution 3 is 10-15%.

8. The method for synthesizing 6-amidino-2-naphthol methanesulfonate according to claim 1, characterized in that: In step f, the usage ratio of the wet product containing 6-amidino-2-naphthol carbonate and methanesulfonic acid is 28.5-29.5kg:105-150mol; the usage ratio of the wet product containing 6-amidino-2-naphthol carbonate, methanol and the total amount of methyl tert-butyl ether is 1.5-2.5g:3-5mL:25-35mL, and the volume ratio of methyl tert-butyl ether participating in the reaction and methyl tert-butyl ether used for washing the filter cake is 10-12:1.

Images