Intermediates for the preparation of diuretic compounds and processes for their preparation

Abstract

Intermediates of the compound of formula (I) and the preparation method thereof. Through the intermediates and the preparation method thereof, the compound of formula (I) and the salt thereof can be prepared in a very effective manner, the preparation operation steps of the compound of formula (I) are simple, the total yield is significantly improved, the product reaches a very high purity, the cost is low, and the industrial implementation on a large scale is suitable.

Description

Technical Field

[0001] This invention relates to intermediates for the preparation of diuretic compounds and methods for their preparation, specifically to intermediate (IV) compounds and methods for their preparation.

[0002] Background Technology

[0003] The disodium salt of compound (I) shown below is a clinical drug that has good water solubility and maintains good diuretic effect, obtained by optimizing and modifying the molecular structure of M3, the in vivo active metabolite of the new generation of highly effective loop helix diuretic torasemide.

[0004]

[0005] Compound (I) and its salt, along with their preparation method, are described in CN110606860A. Compound II and compound I are condensed together in an ethanol system by heating to obtain compound 2. In acetone, compound 2 and compound V are amidated and ionized in the presence of sodium hydroxide to obtain compound M3. Using diisopropylethylamine as an acid-binding agent, M3 is esterified with phosphorus oxychloride at low temperature, and the esterified compound (I) (free acid) is obtained by column chromatography. The free acid is then salted with sodium hydroxide to obtain the disodium salt of compound (I).

[0006]

[0007] The above-mentioned synthetic methods have the following main problems: the use of phosphorus oxychloride in the synthetic route generates a large amount of acidic corrosion, there are many side reactions during the reaction, and the reaction selectivity is poor; the purification of compound (I) (free acid) requires column chromatography, which requires a large amount of solvent, greatly limiting production efficiency, yield, cost, and environmental impact. Some synthetic steps, such as the salt formation step, are carried out in large amounts of solvent (under high dilution conditions), which is costly, environmentally unfriendly, and results in a relatively low overall yield (approximately 29%). Therefore, it is difficult to produce on an industrial scale. Summary of the Invention

[0008] The inventors provide a highly efficient method for synthesizing compounds of formula (I) and their salts, which can meet the requirements of industrial-scale production.

[0009] The present invention starts with commercially available basic raw materials or easily prepared organic raw materials, using compound II as the starting point, and obtains the disodium salt of compound (I) in four stages with a theoretical overall yield of 68% (the yield in the prior art starting from formula II is 29%), without any intermediate chromatographic purification process. The synthetic route is shown below for example.

[0010]

[0011] This invention provides a method for preparing a compound of formula (I) or a salt thereof.

[0012]

[0013] This includes: A) the step of subjecting compound (VI) to transesterification with compound (VII) and further degrading the silanol to prepare compound (I),

[0014]

[0015] In equation (VI), R is independently C. 1-6 Alkyl, preferably methyl, ethyl, propyl, isopropyl, or butyl; in formula (VII), X is a halogen, preferably chlorine, bromine, or iodine, more preferably bromine.

[0016] Preferably, the above method further includes: B) a step of preparing compound (VI) by condensing compound (IV) with compound (V).

[0017]

[0018] In equation (IV), the definition of R is the same as that in equation (VI).

[0019] Preferably, the above method further includes: C) a step of coupling compound (II) with compound (III) to prepare compound (IV).

[0020]

[0021] In equation (III), the definition of R is the same as that in equation (IV).

[0022] Preferably, the above method is a method for preparing the disodium salt of the compound of formula (I) shown below.

[0023]

[0024] This also includes: D) the step of preparing the disodium salt of the compound of formula (I).

[0025] In another aspect, the present invention provides intermediate (IV) compounds:

[0026]

[0027] In equation (IV), the definition of R is the same as that in equation (VI).

[0028] In another aspect, the present invention provides a method for preparing an intermediate compound of formula (IV), comprising: C) reacting a compound of formula (II) with a compound of formula (III) to prepare a compound of formula (IV).

[0029]

[0030] In equation (III), the definition of R is the same as that in equation (IV).

[0031] In another aspect, the present invention provides an intermediate compound of formula (III):

[0032]

[0033] In equation (III), the definition of R is the same as that in equation (IV).

[0034] Preferably, in step A) of the above method, 2.0-7.0 equivalents, more preferably 4.0-6.0 equivalents, and even more preferably 5.5 equivalents of the compound of formula (VII) are added relative to the compound of formula (VI);

[0035] Preferably, the reaction solvent is one or more selected from dichloromethane, chloroform, dichloroethane, acetone, butanone, acetonitrile, propionitrile, methyl tert-butyl ether, and isopropyl ether; more preferably, it is selected from one or more of dichloromethane, acetone, and acetonitrile; more preferably, it is dichloromethane.

[0036] Preferably, the reaction time is 8-42 hours, more preferably 10-24 hours, and even more preferably 18 hours;

[0037] Preferably, the recrystallization solvent is selected from one or more of water, methanol, ethanol, isopropanol, acetone, butanone, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide to recrystallize the compound of formula (I); more preferably, the recrystallization solvent is selected from one or more of water, methanol, acetone, and acetonitrile; more preferably, the recrystallization solvent is a mixture of methanol and water; preferably, the weight ratio of methanol to water in the recrystallization solvent is 1:2 to 20:1; more preferably, 1:1 to 10:1; more preferably, 5:1; preferably, the amount of recrystallization solvent used is 4 to 15 times (by weight) the compound of formula (I), more preferably 8 to 13 times, and more preferably 10 times.

[0038] Preferably, in step B) of the above method,

[0039] Relative to compound (IV), 1.0-5.0 equivalents, preferably 2.0-4.0, more preferably 3.0 equivalents of triethylamine are added;

[0040] Preferably, 1.0-5.0 equivalents, more preferably 1.2-1.8 equivalents, and more preferably 1.5 equivalents of the compound of formula (IV) are added relative to the compound of formula (IV);

[0041] Preferably, the reaction solvent is one or more selected from dichloromethane, chloroform, dichloroethane, acetone, butanone, acetonitrile, propionitrile, and N,N-dimethylformamide and N,N-dimethylacetamide; more preferably, it is selected from one or two of dichloromethane, acetonitrile, and acetone, more preferably dichloromethane; preferably, the amount of solvent used is 15-40 times (volume (L) / weight (kg)) relative to the compound of formula (V); more preferably 20-30 times, more preferably 25 times;

[0042] Preferably, the reaction temperature is -10 to 50°C, more preferably 0 to 40°C, even more preferably 25 to 40°C; and even more preferably 35 to 40°C.

[0043] Preferably, the reaction time is 1-8 hours, more preferably 2-5 hours, and even more preferably 3 hours.

[0044] Preferably, in step C) of the above method, 1.0-2.0 equivalents, preferably 1.1-1.3 equivalents, and more preferably 1.2 equivalents of compound (III) are added relative to compound (II);

[0045] Preferably, the reaction solvent is one or more selected from water, methanol, ethanol and n-butanol; more preferably, it is selected from one or two of ethanol and water; more preferably, it is ethanol; preferably, the amount of solvent used is 2-10 times (volume (L) / weight (kg)) relative to the compound of formula (II); more preferably, it is 3-6 times; more preferably, it is 4 times.

[0046] Preferably, the reaction temperature is 40-80℃, more preferably 65-78℃, and even more preferably 70-75℃;

[0047] Preferably, the reaction time is 0.25-4 hours, more preferably 0.4-1 hour, and even more preferably 0.5 hours.

[0048] Preferably, in step D) of the above method, the solvent is a water / acetone mixture, and sodium carbonate is used as the sodium donor; preferably, 0.95-1.5 equivalents, more preferably 0.95-1.05 equivalents, and more preferably 1.0 equivalents of sodium carbonate are added relative to the compound of formula (I);

[0049] Preferably, the reaction is carried out with 4-6 times the weight of water relative to the compound of formula (I), followed by the addition of 5-8 times the weight of acetone for crystallization; more preferably 3-5 times the weight of water and 6-7 times the weight of acetone; more preferably 4 times the weight of water and 6.5 times the weight of acetone.

[0050] Compounds of formula (III) can be prepared by, for example, the following methods.

[0051]

[0052] Starting with o-methyl-p-nitrophenol (III-1), a phosphate compound (III-2) was prepared by using a phosphate triester, which was then hydrogenated in ethanol under atmospheric pressure with palladium on carbon catalysis to obtain the target phosphate amino compound (III).

[0053] Compound (II) is a commercially available, mature pharmaceutical intermediate that can be purchased commercially.

[0054]

[0055] Starting with the coupling reaction of chloropyridine sulfonamide (compound of formula (II)) with phosphoester amino compound (compound of formula (III) above), phosphoester pyridine sulfonamide (compound of formula (IV) above) is obtained:

[0056]

[0057] Preferably, the reaction is carried out in one or more solvents selected from water, methanol, ethanol, isopropanol, or n-butanol, more preferably in ethanol or water or a mixture of ethanol and water, and even more preferably in ethanol. Preferably, the solvent used for compound (II) is 2-10 times (volume (L) / kg); more preferably 3-6 times; more preferably 4 times. Surprisingly, it has been found that using this solvent system, even by simply filtering the reaction solution, high-purity hydrochloride solids of the above-mentioned compound (IV) can be obtained, and after simple slurrying with alkaline water, high-purity phospholipid pyridine sulfonamides (compound (IV) above-mentioned) can be obtained. Preferably, relative to compound (II), compound (III) is added in the reaction in an amount of 1.0-2.0 equivalents, more preferably 1.1-1.3 equivalents, and even more preferably 1.2 equivalents. Preferably, the reaction temperature is 40-80°C, more preferably 65-78°C, and even more preferably 70-75°C. Preferably, the reaction time is 0.25-4 hours, more preferably 0.4-1 hour, and even more preferably 0.5 hours. Preferably, after the reaction is completed, the reaction solution is cooled to 20-25°C and filtered. The filter cake is slurried and washed with an aqueous sodium carbonate solution, filtered, washed with ethanol, and dried to obtain a pale yellow to yellow phospholipid pyridine sulfonamide (compound of formula (IV) above).

[0058] The resulting phospholipid pyridine sulfonamide (compound of formula (IV) above) reacts with isopropyl isocyanate (compound of formula (V) above) via a condensation reaction to produce phospholipid pyridine sulfonamide urea (compound of formula (VI) above):

[0059]

[0060] Preferably, 1.0-5.0 equivalents, more preferably 2.0-4.0 equivalents, and even more preferably 3.0 equivalents of triethylamine are added relative to the compound of formula (IV). Preferably, the reaction is carried out in one or more solvents selected from dichloromethane, chloroform, dichloroethane, acetone, butanone, acetonitrile, propionitrile, and N,N-dimethylformamide, N,N-dimethylacetamide, etc., more preferably one or two selected from dichloromethane, acetonitrile, and acetone, and even more preferably dichloromethane. Preferably, the amount of solvent used is 15-40 times (volume (L) / weight (kg)) relative to the compound of formula (V); preferably 20-30 times, more preferably 25 times. Preferably, isopropyl isocyanate (compound of formula (V)) is added in an amount of 1.0-5.0 equivalents, more preferably 1.2-1.8 equivalents, and even more preferably 1.5 equivalents, relative to the compound of formula (IV). Preferably, the reaction temperature is -10 to 50°C, more preferably 0 to 40°C, even more preferably 25 to 40°C; further preferably 35 to 40°C. Preferably, the reaction time is 1 to 8 hours, more preferably 2 to 5 hours, and even more preferably 3 hours. Surprisingly, this reaction time ensures complete reaction while maintaining significant stability of the diethyl phosphate group in diethyl phosphate pyridine sulfonamide (compound of formula (IV) above), and also greatly reduces the formation of dimer compounds. Preferably, after the reaction is complete, the reaction solution is cooled to 25 to 30°C, and the organic phase is washed twice with water. The organic phase is concentrated to obtain an oily phospholipid pyridine sulfonamide urea (compound of formula (VI) above), which can be directly used in subsequent reactions.

[0061] The compound of formula (VI) above reacts with trimethylhalosilane (the compound of formula (VII) above), followed by alcoholysis to obtain the compound of formula (I) (free acid):

[0062]

[0063] Preferably, the reaction solvent is one or more selected from dichloromethane, chloroform, dichloroethane, acetone, butanone, acetonitrile, propionitrile, methyl tert-butyl ether, and isopropyl ether, more preferably selected from one or more of dichloromethane, acetone, and acetonitrile; more preferably, dichloromethane; preferably, 2.0-7.0 equivalents, more preferably 4.0-6.0 equivalents, and more preferably 5.5 equivalents of trimethylhalosilane (compound of formula (VII) above) are added relative to the compound of formula (VI). Surprisingly, the reaction can proceed very smoothly in dichloromethane. More advantageously, the trimethylhalosilane used in the reaction has suitable reactivity, allowing the reaction to proceed very cleanly (with few side reactions), while also exhibiting better storage stability and cost advantages, making it particularly suitable for industrial-scale production. Preferably, the reaction temperature is 0-40°C, more preferably 15-35°C, and even more preferably 25-30°C; preferably, the reaction time is 8-42 hours, more preferably 10-24 hours, and more preferably 18 hours. This reaction can completely remove the ethyl group under mild conditions and within a short time (18 hours), while avoiding degradation side reactions. Preferably, after the reaction is complete, the reaction solution is maintained at 25-30°C, methanol is added to quench the reaction, and the reaction solution is concentrated to an oily state. After recrystallization, the crystals are filtered and dried to obtain compound (I) (free acid). Preferably, the recrystallization solvent is selected from one or more of water, methanol, ethanol, isopropanol, acetone, butanone, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide to recrystallize the compound of formula (I); more preferably, the recrystallization solvent is selected from one or more of water, methanol, acetone, and acetonitrile; more preferably, the recrystallization solvent is a mixture of methanol and water; preferably, the weight ratio of methanol to water in the recrystallization solvent is 1:2 to 20:1; more preferably, 1:1 to 10:1; more preferably, 5:1; preferably, the amount of recrystallization solvent used is 4 to 15 times (by weight) the compound of formula (I), more preferably 8 to 13 times, and more preferably 10 times.

[0064] To obtain the salt of compound (I), the compound (free acid) needs to undergo a salt-forming reaction. In CN110606860A, sodium hydroxide is used as the sodium donor, and the salt of compound (I) is formed in an ethanol / acetone mixture. This method has two main drawbacks: firstly, the use of the strong base sodium hydroxide allows the sulfonamide group of compound (I) to also form a sodium salt, objectively increasing the difficulty of accurately preparing the target disodium salt; secondly, the salt-forming yield based on the ethanol / acetone system is not ideal, only 65%.

[0065]

[0066] Through research, the inventors have surprisingly discovered that, in a water / acetone mixed solvent system, using sodium carbonate as the sodium donor can effectively solve the previous problem of not being able to accurately form disodium salts, and the salt yield can reach over 88%, with an HPLC purity of over 99.80%.

[0067]

[0068] Preferably, 0.95-1.5 equivalents, more preferably 0.95-1.05 equivalents, and even more preferably 1.0 equivalent of sodium carbonate are added to react with the compound of formula (I) (free acid) in water to form a salt, followed by the addition of acetone for crystallization. Preferably, the reaction is carried out with 4-6 times the weight of water relative to the compound of formula (I), more preferably 3-5 times the weight of water, and even more preferably 4 times the weight of water; preferably, the crystallization is carried out with 5-8 times the weight of acetone relative to the compound of formula (I), more preferably 6-7 times the weight of acetone, and even more preferably 6.5 times the weight of acetone.

[0069] Surprisingly, this water / acetone solvent system exhibits excellent purification and impurity removal capabilities. After the salt formation reaction is complete, the mixture is filtered, the solid crystals are dried, and the disodium salt of compound (I) is obtained with a chemical purity of over 99.80%.

[0070] The intermediates and preparation method of the present invention can be used to prepare compounds of formula (I) and their salts in a very efficient manner. The operation steps are simple, the overall yield is significantly improved, the product reaches a very high purity, the cost is low, and it is suitable for large-scale industrial implementation. Example

[0071] The present invention will be described in more detail below through embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0072] Example 1

[0073]

[0074] In a 100-liter reactor, 39.2 mol (1.2 eq) of triphosphate, 3870 g (49.0 mol, 1.5 eq) of pyridine, and 50 liters of dichloromethane were added sequentially. The mixture was stirred and cooled under nitrogen protection until the internal temperature reached 10-15°C. Then, 12.92 kg (45.8 mol, 1.4 eq) of trifluoromethanesulfonic anhydride was added dropwise, maintaining the internal temperature at 10-15°C. 5 kg (32.7 mol, 1.0 eq) of 2-methyl-4-nitrophenol (compound (III-1)) was added in portions. After the reaction was complete, 50 liters of water were added, and the mixture was stirred and allowed to stand to separate the aqueous phase. The organic phase was then washed once more with 50 liters of water, and the mixture was separated. The organic phase was concentrated to obtain an oily compound (III-2), which was directly used in the next reaction step.

[0075] 2-Methyl-4-nitrophenyl phosphate dimethyl ester (compound of formula (III-2), where R is methyl)

[0076] 5.49 kg (39.2 mol, 1.2 eq) of trimethyl phosphate (compound of formula (III-1), where R is methyl) was weighed and synthesized according to the process in Example 1 to obtain 7.60 kg of compound of formula (III-2) (R is methyl), with a yield of 89%. MS (m / z): 262 [M+H] + . 1 H NMR (CDCl3): δ: 8.19-8.21 (d, 1H); 8.12 (s, 1H); 7.49-7.51 (d, 1H); 3.81 (s, 6H); 2.17 (s, 3H).

[0077] 2-Methyl-4-nitrophenyl phosphate diethyl ester (compound of formula (III-2), where R is ethyl)

[0078] 7.13 kg (39.2 mol, 1.2 eq) of triethyl phosphate (formula (III-1), where R is ethyl) was weighed and synthesized according to the process in Example 1 to obtain 8.88 kg of compound (III-2), where R is ethyl, with a yield of 94%. MS (m / z): 290 [M+H] + . 1 H NMR (CDCl3): δ: 8.19-8.22 (d, 1H); 8.11 (s, 1H); 7.48-7.51 (d, 1H); 4.19-4.24 (m, 4H); 2.18 (s, 3H); 1.32-1.37 (t, 6H).

[0079] 2-Methyl-4-nitrophenyl phosphate dipropyl ester (compound of formula (III-2), where R is propyl)

[0080] 8.78 kg (39.2 mol, 1.2 eq) of tripropyl phosphate (formula (III-1), R being propyl) was weighed and synthesized according to the process in Example 1 to obtain 9.43 kg of compound (III-2), R being propyl, with a yield of 91%. MS (m / z): 318 [M+H] + . 1 H NMR (CDCl3): δ: 8.19-8.22 (d, 1H); 8.11 (s, 1H); 7.48-7.51 (d, 1H); 4.09-4.12 (m, 4H); 2.15 (s, 3H); 1.62-1.65 (m, 4H); 0.91-0.93 (t, 6H).

[0081] 2-Methyl-4-nitrophenyl phosphate diisopropyl ester (compound of formula (III-2), where R is isopropyl)

[0082] 8.78 kg (39.2 mol, 1.2 eq) of triisopropyl phosphate (compound of formula (III-1), R being isopropyl) was weighed and synthesized according to the process in Example 1 to obtain 9.64 kg of compound of formula (III-2) (R being isopropyl), with a yield of 93%. MS (m / z): 318 [M+H] + . 1 H NMR (CDCl3): δ: 8.17-8.20 (d, 1H); 8.10 (s, 1H); 7.48-7.50 (d, 1H); 4.66-4.68 (m, 2H); 2.15 (s, 3H); 1.25-1.28 (t, 12H).

[0083] 2-Methyl-4-nitrophenyl dibutyl phosphate (compound of formula (III-2), where R is butyl)

[0084] 13.52 kg (39.2 mol, 1.2 eq) of tributyl phosphate (compound of formula (III-1), R being butyl) was weighed and synthesized according to the process in Example 1 to obtain 10.72 kg of compound of formula (III-2) (R being butyl), with a yield of 95%. MS (m / z): 346 [M+H] + . 1 H NMR (CDCl3): δ: 8.19-8.21 (d, 1H); 8.12 (s, 1H); 7.47-7.49 (d, 1H); 4.02-4.05 (m, 4H); 2.16 (s, 3H); 1.66-1.68 (m, 4H); 1.44-1.46 (m, 4H); 0.95-0.97 (t, 6H).

[0085] Example 2

[0086]

[0087] Compound (III-2) (28.0 mol, 1.0 eq) and 60 liters of ethanol were added sequentially to a 100-liter hydrogenation reactor. After stirring and dissolving, 800 g of 10% Pd / C (50% water) was added. The reaction system was purged with nitrogen once and hydrogen three times. Then, hydrogen was introduced at room temperature and the reaction was carried out for 4 hours (slightly positive pressure). The mixture was then filtered. The filtrate was concentrated to obtain an oily compound (III).

[0088] 2-Methyl-4-aminophenyl phosphate dimethyl ester (compound of formula (III), where R is methyl)

[0089] 7.31 kg (28.0 mol, 1.0 eq) of compound (III-2) (R being methyl) was weighed and synthesized according to the process in Example 2 to obtain 5.95 kg of compound (III) (R being methyl), with a yield of 92%. MS (m / z): 232 [M+H] + . 1H NMR (CDCl3): δ: 7.08-7.05 (m, 1H); 6.60-6.54 (m, 2H); 3.82-3.85 (m, 6H); 2.22 (s, 3H).

[0090] 2-Methyl-4-aminophenyl phosphate diethyl ester (compound of formula (III), where R is ethyl)

[0091] 8.09 kg (28.0 mol, 1.0 eq) of compound (III-2) (R being ethyl) was weighed and synthesized according to the process in Example 2 to obtain 6.89 kg of compound (III) (R being ethyl), with a yield of 96%. MS (m / z): 260 [M+H] + . 1 H NMR (CDCl3): δ: 7.07-7.04 (m, 1H); 6.59-6.52 (m, 2H); 4.23-4.18 (m, 4H); 2.22 (s, 3H); 1.36-1.31 (t, 6H).

[0092] 2-Methyl-4-aminophenyl phosphate dipropyl ester (compound of formula (III), where R is propyl)

[0093] 8.88 kg (28.0 mol, 1.0 eq) of compound (III-2) (R being propyl) was weighed and synthesized according to the process in Example 2 to obtain 7.15 kg of compound (III) (R being propyl), with a yield of 89%. MS (m / z): 288 [M+H] + . 1 H NMR (CDCl3): δ: 7.08-7.06 (m, 1H); 6.58-6.51 (m, 2H); 4.20-4.23 (m, 4H); 2.20 (s, 3H); 1.60-1.62 (m, 4H); 0.91-0.93 (t, 6H).

[0094] 2-Methyl-4-aminophenyl phosphate diisopropyl ester (compound of formula (III), where R is isopropyl)

[0095] 8.88 kg (28.0 mol, 1.0 eq) of compound (III-2) (R is isopropyl) was weighed and synthesized according to the process in Example 2 to obtain 7.39 kg of compound (III) (R is isopropyl), with a yield of 92%. MS (m / z): 288 [M+H] + . 1 HNMR (CDCl3): δ: 7.08-7.05 (m, 1H); 6.59-6.51 (m, 2H); 4.66-4.68 (m, 2H); 2.19 (s, 3H); 1.29-1.31 (m, 12H).

[0096] 2-Methyl-4-aminophenyl dibutyl phosphate (compound of formula (III), where R is butyl)

[0097] 9.66 kg (28.0 mol, 1.0 eq) of compound (III-2) (R being butyl) was weighed and synthesized according to the process in Example 2 to obtain 7.50 kg of compound (III) (R being butyl), with a yield of 85%. MS (m / z): 316 [M+H] + . 1 H NMR (CDCl3): δ: 7.09-7.06 (m, 1H); 6.56-6.49 (m, 2H); 4.02-4.05 (m, 4H); 2.21 (s, 3H); 1.65-1.67 (m, 4H); 1.40-1.42 (m, 4H); 0.95-0.97 (t, 6H).

[0098] Example 3

[0099]

[0100] 18 liters of ethanol and compound (III) (27.6 mol, 1.2 eq) were added sequentially to a 30-liter reactor, and the mixture was heated to an internal temperature of 70–75°C. 4.42 kg (23.0 mol, 1.0 eq) of 4-chloropyridine-3-sulfonamide (compound (II)) was added in portions, maintaining the internal temperature at 70–75°C. After the addition was complete, the mixture was stirred at 70–75°C for another half hour. After the reaction was complete, the reaction solution was cooled to 20–25°C and filtered. The filter cake was slurried with 12.20 kg of a 10% sodium carbonate aqueous solution for half an hour, filtered, washed with water, and dried to obtain compound (IV).

[0101] 4-(3-Sulfanamidopyridine-4-amino)-2-methylphenyl phosphate dimethyl ester (Formula (IV), R is methyl)

[0102] 6.38 kg (27.6 mol, 1.2 eq) of compound (III) (R being methyl) was weighed and synthesized according to the process in Example 3 to obtain 7.56 kg of compound (IV) (R being methyl), with a yield of 85%. MS (m / z): 388 [M+H] + . 1 HNMR (CDCl3): δ: 9.38 (s, 1H); 8.74 (s, 1H); 8.34-8.30 (m, 3H); 7.41-7.32 (m, 3H); 7.05-7.04 (d, 1H); 4.03-4.00 (m, 6H); 2.26 (s, 3H).

[0103] 4-(3-Sulfanamidopyridine-4-amino)-2-methylphenyl phosphate diethyl ester (compound of formula (IV), where R is ethyl)

[0104] 7.15 kg (27.6 mol, 1.2 eq) of compound (III) (R being ethyl) was weighed and synthesized according to the process in Example 3 to obtain 8.50 kg of compound (IV) (R being ethyl), with a yield of 89%. MS (m / z): 416 [M+H] + . 1 HNMR (CDCl3): δ: 9.39 (s, 1H); 8.74 (s, 1H); 8.36-8.33 (m, 3H); 7.41-7.31 (m , 3H); 7.04-7.03 (d, 1H); 4.23-4.16 (m, 4H); 2.30 (s, 3H); 1.31-1.22 (m, 6H).

[0105] 4-(3-Sulfanamidopyridine-4-amino)-2-methylphenyl phosphate dipropyl ester (compound of formula (IV), where R is propyl)

[0106] 7.92 kg (27.6 mol, 1.2 eq) of compound (III) (R is propyl) was weighed and synthesized according to the process in Example 3 to obtain 8.76 kg of compound (IV) (R is propyl), with a yield of 86%. MS (m / z): 444 [M+H] + . 1 HNMR (CDCl3): δ: 9.38 (s, 1H); 8.73 (s, 1H); 8.37-8.34 (m, 3H); 7.40-7.31 (m, 3H); 7.0 4-7.03 (d, 1H); 4.18-4.11 (m, 4H); 2.28 (s, 3H); 1.71-1.63 (m, 4H); 1.05-0.97 (m, 6H).

[0107] 4-(3-sulfonamidopyridine-4-amino)-2-methylphenyl phosphate diisopropyl ester (compound of formula (IV), where R is isopropyl) base)

[0108] 7.92 kg (27.6 mol, 1.2 eq) of compound (III) (R is isopropyl) was weighed and synthesized according to the process in Example 3 to obtain 8.97 kg of compound (IV) (R is isopropyl), with a yield of 88%. MS (m / z): 444 [M+H] + . 1 H NMR (CDCl3): δ: 9.40 (s, 1H); 8.71 (s, 1H); 8.35-8.38 (m, 3H); 7.32-7.41 (m, 3H); 7.03-7.04 (d, 1H); 4.69-4.67 (m, 2H); 2.30 (s, 3H); 1.35-1.32 (m, 12H).

[0109] 4-(3-Sulfanilamide pyridine-4-amino)-2-methylphenyl phosphate dibutyl ester (compound of formula (IV), where R is butyl)

[0110] 8.69 kg (27.6 mol, 1.2 eq) of compound (III) (R being butyl) was weighed and synthesized according to the process in Example 3 to obtain 9.10 kg of compound (IV) (R being butyl), with a yield of 84%. MS (m / z): 472 [M+H] + . 1 HNMR (CDCl3): δ: 9.37 (s, 1H); 8.72 (s, 1H); 8.35-8.38 (m, 3H); 7.30-7.41 (m, 3H); 7.02-7.03 (d , 1H); 4.08-4.15 (m, 4H); 2.30 (s, 3H); 1.67-1.69 (m, 4H); 1.41-1.43 (m, 4H); 0.98-1.01 (t, 6H).

[0111] Example 4

[0112]

[0113] Under nitrogen protection, 60 L of dichloromethane, 18.5 mol (1.0 eq) of compound (IV), and 5.61 kg (55.5 mol, 3.0 eq) of triethylamine were added sequentially to a 200 L reactor. After stirring until dissolved, 2.36 kg of isopropyl isocyanate (compound (V)) (27.8 mol, 1.5 eq) was added dropwise. After the addition was complete, the mixture was heated to an internal temperature of 35-40 °C and reacted for 3 hours. After the reaction was complete, the mixture was cooled to an internal temperature of 25-30 °C, and 60 kg of water was added. The mixture was stirred at 25-30 °C for another 0.5 hours. The mixture was separated, and the aqueous phase was extracted once with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to an oily compound (VI).

[0114] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenyl phosphate dimethyl ester (formula) (VI) Compound, where R is methyl)

[0115] 7.16 kg (18.5 mol, 1.0 eq) of compound (IV) (R being methyl) was weighed and synthesized according to the process in Example 4 to obtain 7.51 kg of compound (VI) (R being methyl), with a yield of 86%. MS (m / z): 473 [M+H] + . 1 HNMR (CDCl3): δ: 8.67 (s, 1H); 8.25-8.23 (d, 1H); 8.37-8.34 (m, 2H); 7.31-7.15 (m, 3H); 6.95-6 .94 (d, 1H); 6.61 (s, 1H); 4.02-3.98 (m, 6H); 3.68-3.61 (m, 1H); 2.25 (s, 3H); 1.04-1.02 (d, 6H).

[0116] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenyl phosphate diethyl ester (formula) (VI) Compound, where R is an ethyl group.

[0117] 7.68 kg (18.5 mol, 1.0 eq) of compound (IV) (R being ethyl) was weighed and synthesized according to the process in Example 4 to obtain 8.79 kg of compound (VI) (R being ethyl), with a yield of 95%. MS (m / z): 501 [M+H] + . 1 HNMR (CDCl3): δ: 8.66 (s, 1H); 8.25-8.23 (d, 1H); 8.36-8.33 (m, 2H); 7.30-7.15 (m, 3H); 6.95-6.94 (d, 1H ); 6.60 (s, 1H); 4.22-4.14 (m, 4H); 3.69-3.61 (m, 1H); 2.27 (s, 3H); 1.31-1.27 (m, 6H); 1.04-1.02 (d, 6H).

[0118] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenyl phosphate dipropyl ester (formula) (VI) Compound, where R is propyl)

[0119] 8.20 kg (18.5 mol, 1.0 eq) of compound (IV) (R being propyl) was weighed and synthesized according to the process in Example 4 to obtain 8.69 kg of compound (VI) (R being propyl), with a yield of 89%. MS (m / z): 529 [M+H] + . 1 HNMR (CDCl3): δ: 8.68 (s, 1H); 8.25-8.23 (d, 1H); 8.38-8.34 (m, 2H); 7.28-7.15 (m, 3H); 6.95-6.94 (d, 1H); 6.61 (s , 1H); 4.22-4.16 (m, 4H); 3.65-3.60 (m, 1H); 2.28 (s, 3H); 1.68-1.59 (m, 4H); 1.05-1.03 (d, 6H); 0.94-0.90 (m, 6H).

[0120] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenyl phosphate diisopropyl ester (Compound of formula (VI), where R is isopropyl)

[0121] 8.20 kg (18.5 mol, 1.0 eq) of compound (IV) (R is isopropyl) was weighed and synthesized according to the process in Example 4 to obtain 8.89 kg of compound (VI) (R is isopropyl), with a yield of 91%. MS (m / z): 529 [M+H] + . 1H NMR (CDCl3): δ: 8.70 (s, 1H); 8.26-8.24 (d, 1H); 8.36-8.34 (m, 2H); 7.30-7.19 (m, 3H); 6.95-6.93 (d, 1H) ; 6.60 (s, 1H); 4.62-4.54 (m, 2H); 3.69-3.61 (m, 1H); 2.27 (s, 3H); 1.33-1.30 (m, 12H); 1.04-1.02 (d, 6H).

[0122] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenyl phosphate dibutyl ester (formula) (VI) Compound, where R is butyl)

[0123] 8.71 kg (18.5 mol, 1.0 eq) of compound (IV) (R being butyl) was weighed and synthesized according to the process in Example 4 to obtain 9.05 kg of compound (VI) (R being butyl), with a yield of 88%. MS (m / z): 557 [M+H] + . 1 HNMR (CDCl3): δ: 8.66 (s, 1H); 8.25-8.23 (d, 1H); 8.38-8.33 (m, 2H); 7.29-7.17 (m, 3H); 6.95-6.94 (d, 1H); 6.60 (s, 1H); 4.1 8-4.10 (m, 4H); 3.65-3.61 (m, 1H); 2.28 (s, 3H); 1.67-1.61 (m, 4H); 1.46-1.40 (m, 4H); 1.06-1.04 (d, 6H); 0.97-0.93 (m, 6H).

[0124] Example 5

[0125]

[0126] Under nitrogen protection, 7 liters of dichloromethane and compound (VI) (1.58 mol, 1.0 eq) were added sequentially to a 20 L reactor. After stirring and dissolving, trimethylsilane TMSX (compound (VII), where X is chlorine, bromine, or iodine) (8.69 mol, 5.5 eq) was added dropwise at 25-30 °C. After the addition was complete, the reaction was carried out at 25-30 °C for 18 hours. After the reaction was complete, 0.9 kg of methanol was added at 25-30 °C, and stirring was continued at 25-30 °C for 1 hour. The reaction solution was then concentrated to an oily state. 1.2 kg of methanol was added to the oily state, and the mixture was stirred and dissolved at 25-30 °C. 6 kg of water was then added dropwise. The mixture was then cooled to 20-25 °C, stirred and crystallized for 2 hours, filtered, and the filter cake was washed and dried to obtain compound (I) (free acid).

[0127] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenylphosphonic acid (formula (I) compound) (substances, free acid)

[0128] 0.746 kg (1.58 mol, 1.0 eq) of compound (VI) (R is methyl) and 1.330 kg (8.69 mol, 5.5 eq) of compound (VII) (X is bromine) were weighed and synthesized according to the process in Example 5 to obtain 0.610 kg of compound (I) (free acid), with a yield of 87% and an HPLC purity of 99.25%. MS (m / z): 445 [M+H] + . 1 H NMR (D2O): δ: 8.61 (s, 1H); 7.95-7.97 (d, 1H); 7.39-7.42 (d, 1H); 7.11-7.12 (d, 1H); 7.0 5-7.08 (dd, 1H); 6.97-6.99 (d, 1H); 3.66-3.73 (m, 1H); 2.29 (s, 3H); 1.07-1.08 (d, 6H).

[0129] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenylphosphonic acid (formula (I) compound) (substances, free acid)

[0130] 0.746 kg (1.58 mol, 1.0 eq) of compound (VI) (R is methyl) and 0.943 kg (8.69 mol, 5.5 eq) of compound (VII) (X is chlorine) were weighed and synthesized according to the process in Example 5 to obtain 0.631 kg of compound (I) (free acid), with a yield of 90% and an HPLC purity of 98.96%.

[0131] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenylphosphonic acid (formula (I) compound) (substances, free acid)

[0132] 0.790 kg (1.58 mol, 1.0 eq) of compound (VI) (R is ethyl) and 0.943 kg (8.69 mol, 5.5 eq) of compound (VII) (X is chlorine) were weighed and synthesized according to the process in Example 5 to obtain 0.575 kg of compound (I) (free acid), with a yield of 82% and an HPLC purity of 99.02%.

[0133] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenylphosphonic acid (formula (I) compound) (substances, free acid)

[0134] 0.790 kg (1.58 mol, 1.0 eq) of compound (VI) (R is ethyl) and 1.330 kg (8.69 mol, 5.5 eq) of compound (VII) (X is bromine) were weighed and synthesized according to the process in Example 5 to obtain 0.645 kg of compound (I) (free acid), with a yield of 92% and an HPLC purity of 99.67%.

[0135] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenylphosphonic acid (formula (I) compound) (substances, free acid)

[0136] 0.790 kg (1.58 mol, 1.0 eq) of compound (VI) (R is ethyl) and 1.738 kg (8.69 mol, 5.5 eq) of compound (VII) (X is iodine) were weighed and synthesized according to the process in Example 5 to obtain 0.624 kg of compound (I) (free acid), with a yield of 89% and an HPLC purity of 98.12%.

[0137] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenylphosphonic acid (formula (I) compound) (substances, free acid)

[0138] 0.834 kg (1.58 mol, 1.0 eq) of compound (VI) (R is propyl) and 1.330 kg (8.69 mol, 5.5 eq) of compound (VII) (X is bromine) were weighed and synthesized according to the process in Example 5 to obtain 0.610 kg of compound (I) (free acid), with a yield of 87% and an HPLC purity of 99.18%.

[0139] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenylphosphonic acid (formula (I) compound) (substances, free acid)

[0140] 0.834 kg (1.58 mol, 1.0 eq) of compound (VI) (R is isopropyl) and 1.330 kg (8.69 mol, 5.5 eq) of compound (VII) (X is bromine) were weighed and synthesized according to the process in Example 5 to obtain 0.624 kg of compound (I) (free acid), with a yield of 89% and an HPLC purity of 99.15%.

[0141] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenylphosphonic acid (formula (I) compound) (substances, free acid)

[0142] 0.834 kg (1.58 mol, 1.0 eq) of compound (VI) (R is isopropyl) and 1.738 kg (8.69 mol, 5.5 eq) of compound (VII) (X is iodine) were weighed and synthesized according to the process in Example 5 to obtain 0.589 kg of compound (I) (free acid), with a yield of 84% and an HPLC purity of 98.45%.

[0143] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenylphosphonic acid (formula (I) compound) (substances, free acid)

[0144] 0.878 kg (1.58 mol, 1.0 eq) of compound (VI) (R is butyl) and 1.330 kg (8.69 mol, 5.5 eq) of compound (VII) (X is bromine) were weighed and synthesized according to the process in Example 5 to obtain 0.568 kg of compound (I) (free acid), with a yield of 81% and an HPLC purity of 99.07%.

[0145] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenylphosphonic acid (formula (I) compound) (substances, free acid)

[0146] 0.878 kg (1.58 mol, 1.0 eq) of compound (VI) (R is butyl) and 1.738 kg (8.69 mol, 5.5 eq) of compound (VII) (X is iodine) were weighed and synthesized according to the process in Example 5 to obtain 0.575 kg of compound (I) (free acid), with a yield of 82% and an HPLC purity of 98.82%.

[0147] Example 6

[0148]

[0149] 4-{3-[N-(isopropylaminocarbonyl)sulfonamide]-pyridine-4-amino}-2-methylphenyl phosphate disodium salt (formula) (I) disodium salt)

[0150] 12 kg of water and 0.716 kg (6.76 mol, 1.0 eq) of sodium carbonate were added sequentially to a 50 L reactor and stirred until dissolved. 3.00 kg (6.76 mol, 1.0 eq) of compound (I) (free acid) was added at 25-30 °C and stirred until dissolved. Then, 19.5 kg of acetone was added dropwise. After the addition was complete, the mixture was stirred to induce crystallization. The crystals were filtered, washed, and dried to obtain 2.90 kg of disodium salt of compound (I), with a yield of 88%, HPLC purity of 99.81%, and content of 100.02%. MS (m / z): 445 [M+H] + 467[M+Na] + 489[M-H+2Na] + . 1 H NMR (D2O): δ: 8.61 (s, 1H); 7.95-7.97 (d, 1H); 7.39-7.42 (d, 1H); 7.11-7.12 (d, 1H); 7.0 5-7.08 (dd, 1H); 6.97-6.99 (d, 1H); 3.66-3.73 (m, 1H); 2.29 (s, 3H); 1.07-1.08 (d, 6H).

[0151] UV spectral data of the disodium salt of compound (I):

[0152]

[0153] Infrared spectral data of the disodium salt of compound (I):

[0154]

[0155]

[0156] PXRD test data of disodium salt of compound (I):

[0157] 2Theta d-value I％ 9.33 9.47 46.2 11.45 7.72 55.9 12.00 7.37 59.0 16.56 5.35 46.4 16.97 5.22 46.2 18.65 4.75 43.3 19.82 4.48 100.0 20.68 4.29 46.3 21.11 4.20 44.3 22.04 4.03 66.2 22.54 3.94 67.4 22.91 3.88 57.6 26.70 3.34 48.0 27.37 3.26 64.2 28.07 3.18 45.8

Claims

1. Compounds of formula (IV) In equation (IV), R is independently C. 1-6 Alkyl groups, preferably methyl, ethyl, propyl, isopropyl, or butyl.

2. A method for preparing formula (IV) compounds, include: C) The step of reacting compound (II) with compound (III) to prepare compound (IV), In equation (IV), R is independently C. 1-6 Alkyl, preferably methyl, ethyl, propyl, isopropyl, or butyl; in formula (III), the definition of R is the same as that in formula (IV).

3. The method according to claim 2, wherein, Compared with compound (II), 1.0-2.0 equivalents, preferably 1.1-1.3 equivalents, more preferably 1.2 equivalents of compound (III) are added; Preferably, the reaction solvent is one or more selected from water, methanol, ethanol, isopropanol and n-butanol; more preferably, it is selected from one or two of ethanol and water; more preferably, it is ethanol; preferably, the amount of solvent used is 2-10 times (volume (L) / weight (kg)) relative to the compound of formula (II); more preferably 3-6 times; more preferably 4 times; Preferably, the reaction temperature is 40-80℃, more preferably 65-78℃, and even more preferably 70-75℃; Preferably, the reaction time is 0.25-4 hours, more preferably 0.4-1 hour, and even more preferably 0.5 hours.

4. Compounds of formula (III), In equation (III), R is independently C. 1-6 Alkyl groups, preferably methyl, ethyl, propyl, isopropyl, or butyl.

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