Process for the production of nafamostat, camostat and their derivatives

Abstract

This invention provides a novel, economical and practical route for the synthesis of esters from acid and alcohol functionalities using trihalo triazines as coupling agents. Specifically, this invention provides a novel, economical and practical route for the production of nafamostat and camostat. The synthesis of p-guanidinobenzoic acid (A1) from thiourea and p-aminobenzoic acid has also been achieved by using trihalo triazines as coupling agents.

Description

[Technical field]

[0001] The present invention provides a process for the compound of general formula (F) or its salts or isomers. More specifically, the present invention provides an effective and economical method for the preparation of highly functionalized ester-based drugs, namely, nafamostat, camostat and their derivatives. [Background technology]

[0002] Nafamostat mesylate, also known as FUT-175 or 6'-amidino-2-naphthyl-4-guanidinobenzoate dihydrochloride, is a broad-spectrum serine protease inhibitor synthesized by Fujii et al. (Biochim Biophys Acta, 1981, 661, 342) and marketed by Japan Tobacco Inc. in 1986 for the treatment of inflammation-related diseases such as pancreatitis (Surgery, 2001, 130, 175), disseminated intravascular coagulation (DIC), and systemic inflammatory response syndrome.

[0003] Camostat, another guanidine analogue, originally known as FOY-305, was first reported by Ono Pharmaceutical Co., Ltd. in 1977, and its mesylate salt was approved in Japan in 1985 for the treatment of reflux esophagitis and chronic pancreatitis ( Org Process Res Dev, 2020, 24, 940; Digestion, 2004, 30, 171;

[0004] Several methods have been published for the synthesis of nafamostat and camostat. The main synthetic strategy for nafamostat and camostat is based on the generation of several fragments, such as fragment A1 as p-guanidinobenzoic acid, fragment B1 as 6-hydroxy-2-naphthimidamide, and fragment C1 as 2-(dimethylamino)-2-oxoethyl 2-(4-hydroxyphenyl)acetate, and the coupling of two fragments (A1 and B1) to generate nafamostat, and the coupling of two main fragments (A1 and C1) to synthesize camostat.

[0005] [ka]

[0006] Most of the processes described above followed a similar basic pathway for the production of fragments A1 and B1. The production of nafamostat from fragments A1 and B1 requires a specific coupling agent.

[0007] China Patent Application Publication No. 103012214A describes a method for producing nafamostat mesylate hydrochloride from amidino-β-naphthol methanesulfonate and guanidine radicals benzoyl chloride hydrochloride salt in pyridine at 0-5°C, and then converting it into nafamostat mesylate in the final step.

[0008] China Patent No. 103641749B and China Patent No. 103641749B from 2013 describe a method for producing nafamostat mesylate from p-guanidinobenzoic acid hydrochloride and 6-amidino-β-naphthol by using 4,5-dicyanoimidazole (DCI) as a coupling agent in a mixture of methylene dichloride, stirring at 0-5°C for 1 hour, then increasing the temperature to 18-22°C, and finally obtaining the mesylate salt after 8-12 hours of adiabatic reaction.

[0009] Korean Patent Registration No. 101595747B1 claims a method for producing nafamostat mesylate from p-guanidinobenzoic acid hydrochloride and 6-amidino-2-naphthol methanesulfonate in the presence of N,N'-diisopropylcarbodiimide (DIC) and 4-dimethylaminopyridine (DMAP) in pyridine as a coupling agent.

[0010] European Patent No. 0465913B1 describes a method for producing diaminotrifluoromethylpyrimidine derivatives using condensing agents such as dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

[0011] China Patent Publication No. 113999145A describes a method for producing nafamostat from p-chlorobenzoic acid and 6-amidino-2-naphthol hydrochloride using carbodiimide-based DCC as a coupling reagent.

[0012] European Patent No. 0048433B1 also describes a method for producing nafamostat mesylate, in which DCC is reacted with 4-guanidinobenzoic acid hydrochloride, followed by coupling with 6-amidino-2-naphthol methanesulfonate.

[0013] Similarly, camostat, another guanidine analogue, was also synthesized using harmful chemicals or coupling reagents such as DIC, EDC, DCC.

[0014] Fuji et al. reported in 1977 in U.S. Patent No. 4,021,472 the synthesis of camostat mesylate by reacting N,N-dimethylcarbamoylmethyl-p-hydroxybenzoate with the acid chloride derivative of p-guanidinobenzoic acid in pyridine at room temperature for 2 hours. Crystals were produced by adding sodium bicarbonate solution, filtering, then dissolving in methanol and acidifying with methanesulfonic acid. Camostat mesylate precipitates when diethyl ether is added.

[0015] Most of the prior art methods for the synthesis of the above mentioned molecules require the coupling of fragment A1 with fragment B1 (or fragment C1) using carbodiimide-based coupling reagents, which makes the process very expensive and the work-up cumbersome.

[0016] Considering the importance of these drugs, there is a strong need for cheap, easy to work with and effective coupling conditions. In this direction, the present invention provides an alternative and effective method for the synthesis of nafamostat and camostat utilizing trihalotriazine as a cheap and effective coupling reagent, and further provides an additional advantage for ease of work with regard to workup.

[0017] Object of the invention The object of the present invention is to provide a process for the compound of general formula (F).

[0018] Another object of the present invention is to provide a novel, practical and economical route for producing nafamostat and camostat drugs and their derivatives.

[0019] Yet another object of the present invention is to study trihalotriazine, more preferably trichlorotriazine (TCT), as a novel and highly economical coupling agent for producing esters and explore its application in the synthesis of nafamostat, camostat drugs and their derivatives. Summary of the Invention

[0020] The present invention therefore provides a process for producing a compound of general formula F, comprising:

[0021] [ka]

[0022] In the formula, Z is O, S, or NH; rings X and Y are selected from the group consisting of aryl, heteroaryl, extended, naphthalene, phenanthrene, quinoline, and isoquinoline; R1 is guanidinyl, amidinyl, 2-(dimethylamino)-2-oxoethylacetyl, halogen, alkyl group, amide group, cyano group, nitro group, amino group, methoxy group, O-benzyl ester, N-benzyl ester, hydroxyl group, aryl group, or heteroaryl group; R2 is guanidinyl, amidinyl, 2-(dimethylamino)-2-oxoethylacetyl, halogen, alkyl group, amide group, cyano group, nitro group, amino group, methoxy group, O-benzyl ester, N-benzyl ester, hydroxyl group, aryl group, heteroaryl group, or substituted benzene; The process comprises the following steps: i. 2,4,6-trihalo-1,3,5-triazine and a base are mixed for 25 to 40 0 C for 5 minutes to obtain an active complex; ii. reacting the active complex obtained in step i with fragment A at 40 to 60° C. for 4 hours to obtain an intermediate complex; iii. reacting the intermediate complex obtained in step ii with fragment B in a ratio ranging from 0 to 1 and fragment C in a ratio ranging from 0 to 1 to obtain compound D; iv. treating the compound D obtained in step iii with an aqueous sodium bicarbonate solution; v. Optionally purifying the obtained bicarbonate salt of compound D obtained in step iv; vi. treating the compound D obtained in step iv and step v with methanesulfonic acid in the presence of methanol to obtain compound F.

[0023] In one embodiment of the present invention, the representative compound is selected from nafamostat mesylate and camostat mesylate.

[0024] [ka]

[0025] In another embodiment of the invention, fragment A is produced by reacting p-aminobenzoic acid (1) with thiourea (4) in ethanol in the presence of base.

[0026] In another embodiment of the invention, the base is selected from the group consisting of pyridine (py), N-methylmorpholine (NMM), triethylamine (Et3N), diazabicycloundecene (DBU), more preferably N-methylmorpholine (NMM).

[0027] In another embodiment of the present invention, the trihalotriazine is selected from the group consisting of trichlorotriazine, tribromotriazine, and trifluorotriazine.

[0028] In another embodiment of the present invention, the base is selected from sodium carbonate, cesium carbonate, ammonium carbonate, more preferably potassium carbonate.

[0029] In another embodiment of the present invention, the yield of nafamostat mesylate is 54-70%, and the yield of camostat mesylate is 17-28%.

[0030] In one embodiment of the present invention, representative compounds are selected from the following:

[0031] [ka]

[0032] In another embodiment of the invention, the base is selected from the group consisting of pyridine (py), N-methylmorpholine (NMM), triethylamine (Et3N), diazabicycloundecene (DBU), more preferably N-methylmorpholine (NMM).

[0033] In another embodiment of the present invention, the trihalotriazine is selected from the group consisting of trichlorotriazine, tribromotriazine, and trifluorotriazine.

[0034] List of abbreviations used

[0035]

number

[0036] [Figure 1] FIG. 1 shows a process scheme for the production of nafamostat, camostat and their derivatives. [Diagram 2] FIG. 2 shows the 1H-NMR of nafamostat mesylate. [Diagram 3] FIG. 3 shows the 13C-NMR of nafamostat mesylate. [Figure 4] FIG. 4 shows the DEPT of nafamostat mesylate. [Diagram 5] FIG. 5 shows 1H-NMR of camostat mesylate. [Figure 6] FIG. 6 shows the 13C-NMR of camostat mesylate. [Figure 7] FIG. 7 shows the DEPT of camostat mesilate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] A main aspect of the present invention provides a process for a compound of general formula (F),

[0038] [ka]

[0039] In the formula, Z is O, S, or NH; rings X and Y are selected from the group consisting of aryl, heteroaryl, extended, naphthalene, phenanthrene, quinoline, and isoquinoline; R1 is guanidinyl, amidinyl, 2-(dimethylamino)-2-oxoethylacetyl, halogen, alkyl group, amide group, cyano group, nitro group, amino group, methoxy group, O-benzyl ester, N-benzyl ester, hydroxyl group, aryl group, or heteroaryl group; R2 is guanidinyl, amidinyl, 2-(dimethylamino)-2-oxoethylacetyl, halogen, alkyl group, amide group, cyano group, nitro group, amino group, methoxy group, O-benzyl ester, N-benzyl ester, hydroxyl group, aryl group, heteroaryl group, or substituted benzene; i. reacting 2,4,6-trihalo-1,3,5-triazine with a base at 25-40° C. for 5 minutes to obtain an active complex; ii. reacting the active complex obtained in step i with fragment A at 40-60° C. for 4 hours to obtain an intermediate complex; iii. reacting the intermediate compound obtained in step ii with fragment B in a ratio ranging from 0 to 1 and fragment C in a ratio ranging from 0 to 1 to obtain compound D; iv. treating the compound D obtained in step iii with an aqueous sodium bicarbonate solution; v. Optionally purifying the obtained bicarbonate salt of compound D obtained in step iv; vi. treating the compound D obtained in step iv and step v with methanesulfonic acid in the presence of methanol to obtain compound F.

[0040] In the context of this embodiment, the coupling agent trihalotriazine is selected from trichlorotriazine, tribromotriazine, trifluorotriazine, more preferably the less expensive trichlorotriazine, and the base is selected from pyridine (py), N-methylmorpholine (NMM), triethylamine (EtN), diazabicycloundecene (DBU), more preferably N-methylmorpholine (NMM).

[0041] In one embodiment of the present invention, fragment A is produced by reacting p-aminobenzoic acid (1) with thiourea (4) in ethanol in the presence of base.

[0042] [ka]

[0043] In the context of this embodiment, the base is selected from the list: pyridine (py), N-methylmorpholine (NMM), triethylamine (Et3N), diazabicycloundecene (DBU), more preferably N-methylmorpholine (NMM).

[0044] According to another embodiment, the present invention provides a process for the production of nafamostat by coupling of fragment A1, p-guanidinobenzoic acid, with fragment B1, 6-hydroxy-2-naphthoimidamide, using trichlorotriazine, tribromotriazine, trifluorotriazine, more preferably the cheaper trichlorotriazine (TCT), as a coupling reagent in the presence of a base such as pyridine (py), N-methylmorpholine (NMM), triethylamine (Et3N), diazabicycloundecene (DBU), more preferably N-methylmorpholine (NMM). Nafamostat (D1) is treated with bicarbonate, then precipitated as carbonate, followed by acidification with methanesulfonic acid (MSA) to obtain nafamostat mesylate (F).

[0045] According to another embodiment, the present invention provides a process for the production of fragment A1 by reaction of p-aminobenzoic acid 1 with thioureatrioxide 2 in the presence of a base selected from sodium carbonate, cesium carbonate, ammonium carbonate, more preferably potassium carbonate.

[0046] [ka]

[0047] According to another embodiment, the present invention provides a process for the synthesis of thiourea trioxide 2 from thiourea 4 by oxidation with hydrogen peroxide / peracetic acid system.

[0048] [ka]

[0049] According to another embodiment, the present invention provides a process for the synthesis of fragment B1 from compound 5 via acid-catalyzed conversion of cyano to amidine.

[0050] [ka]

[0051] According to another embodiment, the present invention provides a process for the synthesis of compound 5 from compound 6 via conversion of a bromo group to a cyano group.

[0052] [ka]

[0053] According to another embodiment, the present invention provides a process for the synthesis of compound 6 from β-naphthol 7 via a two-step reaction.

[0054] [ka]

[0055] According to another embodiment, the present invention provides a process for the preparation of camostat by coupling of fragment A1, i.e. p-guanidinobenzoic acid, with fragment C1, i.e. 2-(dimethylamino)-2-oxoethyl 2-(4-hydroxyphenyl)acetate, using trichlorotriazine, tribromotriazine, trifluorotriazine, more preferably the cheaper trichlorotriazine, as coupling reagent in the presence of a base such as pyridine (py), N-methylmorpholine (NMM), triethylamine (Et3N), diazabicycloundecene (DBU), more preferably N-methylmorpholine (NMM). Camostat (D2) is precipitated as carbonate after treatment with bicarbonate, followed by acidification with methanesulfonic acid (MSA) to obtain camostat mesylate (F).

[0056] [ka]

[0057] According to another embodiment, the present invention provides a process for the synthesis of fragment C1 by coupling of 4-hydroxyphenylacetic acid 8 with N,N-dimethylbromoacetamide 9.

[0058] [ka]

[0059] According to another embodiment, the present invention provides a process for the synthesis of compound 9 from the coupling of bromoacetyl bromide 10 with N,N-dimethylamine hydrochloride.

[0060] [ka]

[0061] According to another embodiment, the present invention provides a process for the synthesis of fragment A from the coupling of p-aminobenzoic acid 1 with thiourea 4 using trichlorotriazine, tribromotriazine, trifluorotriazine, more preferably the cheaper trichlorotriazine, as the coupling reagent.

[0062] [ka]

[0063] All product mixtures were analyzed by thin layer chromatography. UV-inactive compounds were visualized in a staining solution and UV-active compounds were detected with a UV lamp (λ=254 nm). All reactions were carried out under an inert atmosphere where necessary.

[0064] NMR spectrum ( 1 HNMR, 13 C, DEPT) were recorded on a 400 MHz spectrometer using CDCl3 and CD3OD solvents.

[0065] ES1-MS and HRMS spectra were recorded on an LC-MS / MS and HRMS-6540-UHD instrument. Optical rotations were measured on a Perkin-Elmer polarimeter.

[0066] Column chromatography was carried out using silica gel (60-120, 230-400 mesh).

[0067] Trichlorotriazine (TCT) is an inexpensive and stable coupling reagent that provides a cost-effective route to the synthesis of nafamostat, camostat, and their derivatives.

[0068] Consuming TCT as a coupling reagent facilitates the production of nafamostat and camostat, with higher yields and fewer impurities, making them suitable for industrial production.

[0069] The synthesis schemes of fragments A1, B1, C1, and nafamostat mesylate and camostat mesylate are shown in the Examples. Tables 1 and 2 show the reactants and reaction conditions used, together with the products obtained and their yields.

[0070] [Table 1]

[0071] [Table 2]

[0072] example The following examples are offered for illustrative purposes and should not be construed as limiting the scope of the present invention.

[0073] Example 1: Synthesis of fragment A1 (p-guanidinobenzoic acid hydrochloride)

[0074] [ka]

[0075] Step 1: Synthesis of thiourea dioxide (3) and thiourea trioxide (2):

[0076] [ka]

[0077] 50 g (0.657 mol, 1 equivalent) of thiourea (4) was added to 200 mL of hot water at 40°C and thoroughly stirred to completely dissolve the thiourea. The thus-prepared thiourea aqueous solution was cooled, and then 371.42 mL of hydrogen peroxide (concentration: 30%) (4.6 mol, 7 equivalents) was slowly added at a rate sufficient to keep the solution temperature below 10°C. The solution was then cooled to 0°C and stirred for about 30 minutes to grow crystals. After crystal growth, the solid-liquid mixture at 0°C was quickly filtered, and the fractionated crystals were dried at 50°C. Furthermore, the reaction mixture was treated with ethanol to remove unreacted thiourea. The yield of the crystals thus obtained was 64%, and 45 g of thiourea dioxide (3) was obtained respectively. Peracetic acid (48.54 mL, 0.664 mol) was stirred at 0° C. for 0.5 h, followed by the addition of thiourea dioxide (3) (18 g, 0.664 mol) in water (100 mL), which was allowed to warm slowly to room temperature and stirred overnight. The precipitate (2) (thiourea trioxide) was removed by filtration, and the resulting solution was evaporated in a rotavapor and washed with ethanol to give thiourea trioxide (2) (17 g, yield: 67%). mp=132-134 0 C, MS(ESI+)m / z calcd. for CH5N2O3S,125.01(M+H);found 125.12.

[0078] Step 2: Synthesis of 4-guanidinobenzoic acid (A1)

[0079] [ka]

[0080] Potassium carbonate (6.01 g, 0.0435 mol) was added to 4-aminobenzoic acid (1) (6 g, 0.0435 mol) in water (40 ml). The mixture was stirred at room temperature for 0.5 h, then thiourea trioxide (2) (8.14 g, 0.0653 mol) was added slowly. A white solid precipitated and the mixture was stirred at room temperature for another 1 h. After filtration, the white solid was dissolved in a 1N solution of hydrogen chloride in methanol (50 mL) and stirred for 0.5 h. The solvent was removed by rotavapor and the product was obtained as its hydrochloride salt (6.5 g, yield: 83%). mp=280-285 0 C. 1 H NMR (400 MHz, DMSO-d 6 )δ 11.16(s,1H),10.19(s,1H),7.97-7.99(d,J=8Hz,2H),7.70(s,3H),7.33-7.35(d,J=8Hz,2H),MS(ESI+)m / z calcd for C8H 10 N3O2,180.07(M+H);found 180.18.

[0081] Example 2: Synthesis of Fragment B1 (6-hydroxy-2-naphthoimidamide methanesulfonate)

[0082] [ka]

[0083] Step 1: Synthesis of 6-bromonaphthalen-2-ol (6):

[0084] [ka]

[0085] 40 g (1 mole) of β-naphthol (7) and 100 ml of glacial acetic acid were placed in a round-bottom flask fitted with a dropping funnel and a reflux condenser. A solution of 88 g (2 moles) of bromine in 30 ml of acetic acid was added through the dropping funnel over a period of 15-30 minutes. The flask was gently shaken during the addition, and β-naphthol dissolved during this time and heat was evolved. The mixture was cooled somewhat towards the end of the addition to avoid excessive loss of hydrogen bromide, then 30 ml of water was added and the mixture was heated to boiling. The reaction mixture was subsequently cooled to 100°C and 5 g of mossy tin was added and boiled until the metal had dissolved. A second portion of 5 g of tin was then added and dissolved by boiling, and finally a third portion of 32 g (42 g in total) of tin was charged. The mixture was boiled for 3 hours, cooled to 50°C and filtered with suction. The crystalline tin salt thus removed was washed on the funnel with 100 ml of cold acetic acid, and the washings were added to the main part of the filtrate. This filtrate was stirred in cold water. The precipitated 6-bromo-2-naphthol (6) was filtered off with suction, removed from the funnel and washed with 100 ml of cold water by stirring. After filtering again and drying at 100 °C, 60 g (91% yield) of 6-bromo-2-naphthol (6) was obtained. The crude product melts at 123-127 °C and contains some tin, but is of sufficient purity for most purposes. 1 H NMR(400 MHz,CDCl3)δ 10.08(s,1H),7.96(s,1H),7.72-7.70(d,1H,J=8 Hz),7.62-7.60(d,1H,J=8Hz),7.45-7.42(m,1H),7.13-7.11(m,2H),MS(ESI+)m / z calcd for C 10 H8BrO,222.97(M+H);found 224.08.

[0086] Step 2: Synthesis of 6-hydroxy-2-naphthonitrile (5):

[0087] [ka]

[0088] A mixture of 30 g of 6-bromo-2-naphthol (6) and 15 g of CuCN in DMF was vigorously stirred at 150° C. for 5-6 h. After cooling to room temperature, 10% NaOH was added to the mixture and stirred for 5 min. The reaction was filtered and the filtrate was washed with water. The pH was then adjusted to 2-3 with 3N HCl. The precipitate was collected by filtration to give 6-hydroxy-2-naphthonitrile (5) as a brown solid (20 g, 87%). mp=165-170 0 C. 1 H NMR(400 MHz,CDCl3)δ 10.05(s,1H),8.50(s,1H),8.07-8.05(d,1H,J=8 Hz),7.95(m,1H)7.50-7.45(m,2H),7.04-7.02(m,1H),MS(ESI+)m / z calcd for C 11 H8NO,170.06(M+H);found 170.19.

[0089] Step 3: Synthesis of 6-hydroxy-2-naphthoimidamide methanesulfonate (B1):

[0090] [ka]

[0091] 10 g (50 mmol) of 6-hydroxy-2-naphthonitrile (5) was added to a cooled saturated MeOH-HCl solution (50 ml) and the mixture was stirred at room temperature overnight and concentrated. The residue was dissolved in MeOH (50 ml) and gaseous NH3 was introduced into the solution at 50 °C for 3 h. The mixture was concentrated in vacuo and saturated NaHCO3 solution was added to the residue with stirring. The precipitate was collected and washed with water, then acetone and a suspension of the precipitate in MeOH (10 ml) was treated with MSA (5.8 g, 60 mmol). Et2O was added to the solution and the precipitate was collected to give 6-hydroxy-2-naphthoimidamide methanesulfonate (B1) (9.2 g, 65%). The analytical sample was obtained as a pale yellow powder by recrystallization from EtOH. mp 227-228 °C. 1H NMR(400 MHz,CDCl3)δ 9.20(s,2H),8.95(s,2H),8.37(s,1H),7.92-7.90(d,J=8Hz 1H),7.85-7.83(d,J=8Hz,1H),7.72-7.70(d,J=8Hz,1H),7.23(s,2H),2.49(s,1H),2.45(s,3H),MS(ESI+)m / z calcd for C 11 H 11 N2O,187.08(M+H);found 187.22.

[0092] Example 3: Synthesis of fragment C1 (2-(dimethylamino)-2-oxoethyl 2-(4-hydroxyphenyl)acetate)

[0093] [ka]

[0094] Step 1: Synthesis of 2-bromo-N,N-dimethylacetamide (9).

[0095] [ka]

[0096] Bromoacetyl bromide (10) (1.52 mL, 17.28 mmol) was dissolved in CHCl (20 mL) and dimethylammonium chloride (1 g, 12.34 mmol) was added at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then worked up with DCM and water. The organic layer was dried (NaSO) and concentrated in vacuo. The crude product (9) was obtained as a yellow oil (0.450 g, 54%) and can be used further without purification. 1 H NMR (400 MHz, DMSO-d 6 )δ 4.34(s,2H),3.04(s,3H),2.89(s,3H), m / z=164.97,MS(ESI+)m / z calcd for C4H9BrNO,165.98(M+H);found 167.02.

[0097] Step 2: Synthesis of 2-(dimethylamino)-2-oxoethyl 2-(4-hydroxyphenyl)acetate (C1):

[0098] [ka]

[0099] 2-Bromo-N,N-dimethylacetamide (9) (0.50 g, 3.01 mmol) and p-hydroxyphenylacetic acid (8) (0.450 g, 3.01 mmol) were dissolved in 10 ml of acetonitrile, and triethylamine (0.425 g, 4.21 mmol) was added to the solution. The resulting mixture was refluxed for 7 hours. Upon completion of the reaction (as determined by TLC), the solvent was evaporated and the fragment C1 was purified by column chromatography. TLC (hexane / EtOAc, 2:8) R f =0.4; yield (0.60 g, 81%); white solid; mp: 103-107°C. 1 H NMR (400 MHz, DMSO-d 6 )δ 9.39(s,1H),7.10-7.08(d,J=8Hz,2H),6.74-6.72(d,J=8Hz,2H),4.75(s,2H),3.61(s,2H),2.85(s,3H),2.79(s,3H),MS(ESI+)m / z calcd for C 12 H 16 NO4238.10(M+H);found 238.26.

[0100] Example 4: Synthesis of 6-carbamimidoylnaphthalen-2-yl 4-guanidinobenzoate dimesylate (Nafamostat mesylate):

[0101] [ka]

[0102] 2,4,6-Trichloro-1,3,5-triazine (5 g, 26.88 mmol) and 4-methylmorpholine (70 ml) were taken in a round bottom flask and stirred at room temperature for 5 minutes. 4-Guanidinobenzoic acid, i.e., fragment A1 (9.62 g, 53.76 mmol) was added to the reaction mixture and stirred at 40° C. for 4 hours. 6-Hydroxy-2-naphthimidamide, i.e., fragment B1 (10 g, 53.76 mmol) was then added and the reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, i.e., formation of product D1 (as observed by TLC), bicarbonate solution was added to the reaction mixture and stirred for 10 minutes for precipitation of the product. The precipitate was collected by filtration and subsequently washed with water, acetone and methanol. The precipitate was then dissolved in methanol and treated with methanesulfonic acid. Addition of diethyl ether precipitates nafamostat mesylate (F) (13 g, 70% yield). mp=257-262 0 C. 1 H NMR (400 MHz, DMSO-d 6 )δ 10.33(s,1H),9.50(s,2H),9.29(s,2H),8.60(s,1H),8.25-8.17(m,4H),8.02-7.88(m,6H),7.66-7.64(d,J=8 Hz,1H),7.47-7.45(d,J=8Hz,2H),2.47(s,6H). 13 C NMR (101 MHz, DMSO-d 6 )δ 166.0,164.4,155.8,150.9,142.1,136.1,132.0,131.4,130.2,129.9,128.9,125.9,125.3,124.9,123.8,123.0,119.4, MS(ESI+)m / z calcd for C 19 H 18 N5O2348.14(M+H);found 348.38.

[0103] Example 5: Synthesis of 6-carbamimidoylnaphthalen-2-yl 4-guanidinobenzoate dimesylate (Nafamostat mesylate):

[0104] [ka]

[0105] 2,4,6-Trichloro-1,3,5-triazine (5 g, 26.88 mmol) and 4-methylmorpholine (70 ml) were taken in a round bottom flask and stirred at room temperature for 5 minutes. 4-Guanidinobenzoic acid, i.e., fragment A1 (9.62 g, 53.76 mmol) was added to the reaction mixture and stirred at 40° C. for 4 hours. 6-Hydroxy-2-naphthimidamide, i.e., fragment B1 (10 g, 53.76 mmol) was then added and the reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, i.e., formation of product D1 (as observed by TLC), bicarbonate solution was added to the reaction mixture and stirred for 10 minutes for precipitation of the product. The precipitate was collected by filtration and subsequently washed with water, acetone and methanol. The precipitate was then dissolved in methanol and treated with methanesulfonic acid. Addition of diethyl ether precipitates nafamostat mesylate (F) (11.7 g, 63% yield).

[0106] Example 6: Synthesis of 6-carbamimidoylnaphthalen-2-yl 4-guanidinobenzoate dimesylate (nafamostat mesylate):

[0107] [ka]

[0108] 2,4,6-Trichloro-1,3,5-triazine (5 g, 26.88 mmol) and 4-methylmorpholine (70 ml) were taken in a round bottom flask and stirred at room temperature for 5 minutes. 4-Guanidinobenzoic acid, i.e., fragment A1 (9.62 g, 53.76 mmol) was added to the reaction mixture and stirred at 40° C. for 4 hours. 6-Hydroxy-2-naphthimidamide, i.e., fragment B1 (10 g, 53.76 mmol) was then added and the reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, i.e., formation of product D1 (as observed by TLC), bicarbonate solution was added to the reaction mixture and stirred for 10 minutes for precipitation of the product. The precipitate was collected by filtration and subsequently washed with water, acetone and methanol. The precipitate was then dissolved in methanol and treated with methanesulfonic acid. Addition of diethyl ether precipitates nafamostat mesylate (F) (11 g, 60% yield).

[0109] Example 7: Synthesis of 6-carbamimidoylnaphthalen-2-yl 4-guanidinobenzoate dimesylate (Nafamostat mesylate):

[0110] [ka]

[0111] 2,4,6-Trichloro-1,3,5-triazine (5 g, 26.88 mmol) and 4-methylmorpholine (70 ml) were taken in a round bottom flask and stirred at room temperature for 5 minutes. 4-Guanidinobenzoic acid, i.e., fragment A1 (9.62 g, 53.76 mmol) was added to the reaction mixture and stirred at 40° C. for 4 hours. 6-Hydroxy-2-naphthimidamide, i.e., fragment B1 (10 g, 53.76 mmol) was then added and the reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, i.e., formation of product D1 (as observed by TLC), bicarbonate solution was added to the reaction mixture and stirred for 10 minutes for precipitation of the product. The precipitate was collected by filtration and subsequently washed with water, acetone and methanol. The precipitate was then dissolved in methanol and treated with methanesulfonic acid. Addition of diethyl ether precipitates nafamostat mesylate (F) (10 g, 54% yield).

[0112] Example 8: Synthesis of 4-(2-(2-(dimethylamino)-2-oxoethoxy)-2-oxoethyl)phenyl 4-guanidinobenzoate methanesulfonate (camostat mesylate):

[0113] [ka]

[0114] 2,4,6-Trichloro-1,3,5-triazine (TCT) (0.250 g, 1.39 mmol) and 4-methylmorpholine (20 ml) were added to a round-bottom flask and stirred at room temperature for 5 min. To the reaction mixture, 4-guanidinobenzoic acid A1 (0.500 g, 2.79 mmol) was added and stirred at 40° C. for 4 h. Then, 2-(dimethylamino)-2-oxoethyl 2-(4-hydroxyphenyl)acetate C1 (0.662 g, 2.79 mmol) was added and the reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, i.e., formation of product D2 (as confirmed by TLC), the solvent was evaporated and purified by column chromatography. Product D2 was then dissolved in methanol, treated with methanesulfonic acid, and camostat mesylate (F) was precipitated by the addition of diethyl ether. TLC (DCM / MeOH, 7:3) R f =0.6; (0.75 g, 28% yield); white solid; mp: 153-158°C. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.28-8.26 9(d,J=8Hz,2H),7.48-7.43(m,4H),7.21-7.19(d,J=8Hz,2H),4.87(s,2H),3.85(s,2H),3.02(s,3H),2.97(s,3H),2.72(s,3H). 13 C{ 1 H} NMR(101 MHz,CD3OD)δ 171.4,167.6,164.2,156.2,149.9,140.4,131.9,131.4,130.4,127.2,123.4,121.3,61.3,39.2,38.0,34.7,34.4, MS(ESI+)m / z calcd for C 20 H 23 N4O5399.16(M+H);found 399.42.

[0115] Example 9: Synthesis of 4-(2-(2-(dimethylamino)-2-oxoethoxy)-2-oxoethyl)phenyl 4-guanidinobenzoate methanesulfonate (camostat mesylate):

[0116] [ka]

[0117] 2,4,6-Trichloro-1,3,5-triazine (TCT) (0.250 g, 1.39 mmol) and 4-methylmorpholine (20 ml) were added to a round-bottom flask and stirred at room temperature for 5 min. To the reaction mixture, 4-guanidinobenzoic acid A1 (0.500 g, 2.79 mmol) was added and stirred at 40° C. for 4 h. Then, 2-(dimethylamino)-2-oxoethyl 2-(4-hydroxyphenyl)acetate C1 (0.662 g, 2.79 mmol) was added and the reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, i.e., formation of product D2 (as confirmed by TLC), the solvent was evaporated and purified by column chromatography. Product D2 was then dissolved in methanol, treated with methanesulfonic acid, and camostat mesylate (F) was precipitated by addition of diethyl ether (0.20 g, 23% yield).

[0118] Example 10: Synthesis of 4-(2-(2-(dimethylamino)-2-oxoethoxy)-2-oxoethyl)phenyl 4-guanidinobenzoate methanesulfonate (camostat mesylate):

[0119] [ka]

[0120] 2,4,6-Trichloro-1,3,5-triazine (TCT) (0.250 g, 1.39 mmol) and 4-methylmorpholine (20 ml) were added to a round-bottom flask and stirred at room temperature for 5 min. To the reaction mixture, 4-guanidinobenzoic acid A1 (0.500 g, 2.79 mmol) was added and stirred at 40° C. for 4 h. Then, 2-(dimethylamino)-2-oxoethyl 2-(4-hydroxyphenyl)acetate C1 (0.662 g, 2.79 mmol) was added and the reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, i.e., formation of product D2 (as confirmed by TLC), the solvent was evaporated and purified by column chromatography. Product D2 was then dissolved in methanol, treated with methanesulfonic acid, and camostat mesylate (F) was precipitated by addition of diethyl ether (0.17 g, 20% yield).

[0121] Example 11: Synthesis of 4-(2-(2-(dimethylamino)-2-oxoethoxy)-2-oxoethyl)phenyl 4-guanidinobenzoate methanesulfonate (camostat mesylate):

[0122] [ka]

[0123] 2,4,6-Trichloro-1,3,5-triazine (TCT) (0.250 g, 1.39 mmol) and 4-methylmorpholine (20 ml) were added to a round-bottom flask and stirred at room temperature for 5 min. To the reaction mixture, 4-guanidinobenzoic acid A1 (0.500 g, 2.79 mmol) was added and stirred at 40° C. for 4 h. Then, 2-(dimethylamino)-2-oxoethyl 2-(4-hydroxyphenyl)acetate C1 (0.662 g, 2.79 mmol) was added and the reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, i.e., formation of product D2 (as confirmed by TLC), the solvent was evaporated and purified by column chromatography. Product D2 was then dissolved in methanol, treated with methanesulfonic acid, and camostat mesylate (F) was precipitated by addition of diethyl ether (0.15 g, 17% yield).

[0124] Example 12: Synthesis of p-guanidinobenzoic acid (A):

[0125] [ka]

[0126] TCT (1 eq.) and thiourea (4) (12 g, 1 eq.) in ethanol were taken in a round bottom flask and stirred for 2 h to consume both reactants. The solvent was removed using a rotary evaporator to obtain a white solid. 1.5 g of the resulting solid was taken in a 10 mL round bottom flask along with 0.699 g of p-aminobenzoic acid (1) and stirred for 15 min. 3.56 mL of N-methylmorpholine was added into the reaction mixture. After 1 h, both reactants were consumed (TLC analysis) and 4-guanidinobenzoic acid A was formed along with other spots. N-methylmorpholine was removed under vacuum and the product was isolated using column chromatography (0.15 g, 15% yield).

[0127] Advantages of the Invention 1. The use of trichlorotriazine (TCT) as an inexpensive and stable coupling reagent offers advantages over those used in the prior art. 2. The present invention also provides ease of operation during work-up in contrast to the prior art, avoiding repeated solvent treatments and washings. 3. The use of trichlorotriazine (TCT) also provides a cost-effective route for the synthesis of nafamostat, camostat and their derivatives. 4. The consumption of TCT as a coupling reagent facilitates the production of nafamostat and camostat, with higher yields and fewer impurities, making them suitable for industrial production.

Claims

1. A process for producing a compound of formula F, comprising: 【Chemistry 1】 wherein Z is O, S, or NH; Rings X and Y are aryl, heteroaryl, or expanded rings selected from the group consisting of naphthalene, phenanthrene, quinoline, and isoquinoline; R １ is guanidinyl, amidinyl, 2-(dimethylamino)-2-oxoethylacetyl, a halogen, an alkyl group, an amide group, a cyano group, a nitro group, an amino group, a methoxy group, an O-benzyl ester, an N-benzyl ester, a hydroxyl group, an aryl group, or a heteroaryl group; R ２ is guanidinyl, amidinyl, 2-(dimethylamino)-2-oxoethylacetyl, a halogen, an alkyl group, an amide group, a cyano group, a nitro group, an amino group, a methoxy group, an O-benzyl ester, an N-benzyl ester, a hydroxyl group, an aryl group, a heteroaryl group, or a substituted benzene; The process comprises the steps of: i. reacting 2,4,6-trihalo-1,3,5-triazine with a base at 25-40° C. for 5 minutes to obtain an activated complex; ii. reacting the activated complex obtained in step i with fragment A at 40 to 60° C. for 4 hours to obtain an intermediate compound; 【Chemistry 2】 iii. reacting the intermediate compound obtained in step ii with fragment B in a ratio ranging from 0 to 1 and fragment C in a ratio ranging from 0 to 1 to obtain compound D; 【Chemistry 3】 iv. treating the compound D obtained in step iii with an aqueous sodium bicarbonate solution to produce a bicarbonate salt of the compound D; v. Optionally purifying the bicarbonate salt of compound D obtained in step iv; vi. treating the compound D obtained in step iv and step v with methanesulfonic acid in the presence of methanol to obtain the compound of formula F.

2. 2. The process of claim 1, wherein compound D is selected from nafamostat mesylate and camostat mesylate. 【Chemistry 4】

3. The process of claim 1, wherein fragment A is produced by reacting p-aminobenzoic acid (1) with thiourea (4) in ethanol in the presence of a base. 【Chemistry 5】

4. The base is pyridine (py), N-methylmorpholine (NMM), triethylamine (Et ３ 2. The process of claim 1, wherein the aryl group is selected from the group consisting of N) diazabicycloundecene (DBU), and more preferably N-methylmorpholine (NMM).

5. 2. The process of claim 1, wherein the trihalotriazine is selected from the group consisting of trichlorotriazine, tribromotriazine, and trifluorotriazine.

6. 2. The process of claim 1, wherein the base is selected from sodium carbonate, cesium carbonate, ammonium carbonate, and more preferably potassium carbonate.

7. 2. The process of claim 1, wherein the yield of nafamostat mesylate is 54-70% and the yield of camostat mesylate is 17-28%.

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