Process for preparation of sulfamoylbenzoic acid derivatives

Abstract

The present invention relates to a process for the preparation of sulfamoyl benzoic acid derivatives, in particular derivatives of (3-(dimethyl sulfamoyl)-4-(8, 8, 8-trifluorooctyl amino) benzoic acid.

Description

[0001] Cross-references to related applications This patent application claims priority to Italian Patent Application No. 102023000007521, filed on April 18, 2023, the entire disclosure of which is incorporated herein by reference. Technical Field

[0002] This invention relates to a method for preparing aminosulfonylbenzoic acid derivatives, particularly derivatives of (3-(dimethylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid. Background Technology

[0003] 3-(dimethylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid (1) is an NKCC1 inhibitor that can be used to treat neurological disorders (WO2020202072, Savardi et al.). Chem, 2020; Borgogno et al., J. Med. Chem. 2021 Savardi et al. ACS Pharmacol Transl Sci, (2023).

[0004] Patent WO2020202072 describes the synthesis of 3-(dimethylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, including the following steps: 1) Convert 3-(chlorosulfonyl)-4-fluorobenzoic acid (2) into the corresponding 3-dimethylaminosulfonyl derivative (3)

[0005] 2) Reaction of 8-bromo-1,1,1-trifluorooctane (4) with potassium phthalimide (5) yields 2-(8,8,8-trifluorooctyl)isoindoline-1,3-dione (6).

[0006] 3) Deprotect the derivative (6) obtained in step (2) to 8,8,8-trifluorooctane-1-amine (7).

[0007] 4) React the derivative (3) obtained in step (1) with the derivative (7) obtained in step (3) to obtain the compound of formula (1).

[0008]

[0009] The preparation method described in WO2020202072 can be used as a method for preparing aminosulfonylbenzoic acid derivatives, but there is still much room for improvement in terms of overall yield. Another drawback of the synthesis described in WO2020202072 is the use of hazardous chemicals, particularly for the deprotection of amines (7), which cannot be used for industrial-scale preparation. In fact, hydrazine is suspected of being a human carcinogen. Several chromatographic purification steps are also used in the method of WO2020202072.

[0010] Therefore, there is a need in the art for a new method for preparing aminosulfonylbenzoic acid derivatives that does not have the disadvantages of existing methods.

[0011] Therefore, the purpose of this invention is to provide a method for synthesizing aminosulfonylbenzoic acid derivatives with good overall yield and suitable for industrial scale. Summary of the Invention

[0012] This objective is achieved by the method of claim 1. Detailed Implementation

[0013] According to a first aspect of the present invention, a method is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, tautomer, or zwitterion thereof:

[0014] in: R1 and R2 are independently H, substituted or unsubstituted, straight or branched C. 1-10 -alkyl group, optionally containing one or more unsaturated bonds; substituted or unsubstituted C 3-8 -Cycloalkyl; substituted or unsubstituted, straight or branched C 4-10 -cycloalkyl-alkyl; C 3-8 - Heterocyclic rings; or, R1 and R2 together with the nitrogen atoms to which they are bonded form substituted or unsubstituted saturated heterocyclic rings; R3 and R4 are hydrogen atoms independently; substituted or unsubstituted C atoms 1-10 -alkyl group, optionally containing one or more unsaturated bonds; C 3-10 -cycloalkyl; C 4-10 -cycloalkyl-alkyl; C 2-8 - Haloalkyl; substituted or unsubstituted, straight or branched C 2-8 -Heteroalkyl; optionally substituted phenyl; The condition is that at least one of R3 and R4 is not hydrogen; R5 represents hydrogen; halogen; hydroxyl group; thiophenol; -NO2; R6 is -COOH; Includes the following steps: a) In aqueous solution, the compound of formula (II) is reacted with the amine of formula (III) to give the compound of formula (IV):

[0015] Where X and Y are halogens independently; b) In an aqueous solution, in the presence of a base, the compound of formula (IV) is reacted with the compound of formula (V) to give the compound of formula (I).

[0016]

[0017] Step a) can be performed at a temperature between 0 and 20°C, preferably at 0°C.

[0018] Step b) can be carried out in the presence of an inorganic base selected from the group consisting of inorganic phosphates and inorganic carbonates (preferably selected from the group consisting of tripotassium phosphate and potassium carbonate), or in the presence of an organic base (preferably selected from the group consisting of N,N-diisopropylethylamine, triethylamine and trimethylamine).

[0019] According to one embodiment, when applied to obtain a compound of formula (I) (where R4=H), the method of the present invention includes, prior to step b), step a1) reacting a compound of formula (VI) with a compound of formula (VII) to obtain a compound of formula (VIII), and subsequently reducing the obtained compound to obtain a compound of formula (V).

[0020]

[0021] Step a1) can be carried out in the presence of a solvent selected from the group consisting of acetonitrile, acetone, isopropanol, and methanol. The reduction can be carried out in the presence of a reducing agent selected from the group consisting of: sodium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum hydride, and diisobutylaluminum hydride.

[0022] The method of the present invention can be used to prepare compounds of formula (I), wherein R6 is COOH.

[0023] The method of the present invention can be used to prepare compounds of formula (I), wherein R5 is selected from the group consisting of H, OH, Cl and methoxy.

[0024] The method of the present invention can be used to prepare compounds of formula (I), wherein R1 and R2 are independently substituted or unsubstituted, straight-chain or branched H and C. 1-10 -alkyl group, optionally containing one or more unsaturated bonds; substituted or unsubstituted C 3-8 -Cycloalkyl; substituted or unsubstituted, straight or branched C 4-10-cycloalkyl-alkyl; C 3-8 - Heterocyclic rings; or, R1 and R2 together with the nitrogen atoms to which they are bonded form substituted or unsubstituted saturated heterocyclic rings.

[0025] In one embodiment, R1 and R2 are selected from the group consisting of CH3, H, morpholine, cyclopentyl, and cyclohexyl.

[0026] The method of the present invention can be used to prepare compounds of formula (I) selected from the group consisting of: 4-(Butylamino)-3-(Methylaminosulfonyl)benzoic acid, 4-(hexylamino)-3-(methylaminosulfonyl)benzoic acid, 3-(methylaminosulfonyl)-4-(octylamino)benzoic acid, 4-(3,3-Dimethylbutylamino)-3-(methylaminosulfonyl)benzoic acid, 3-(methylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 4-(Butylamino)-3-(dimethylaminosulfonyl)benzoic acid, 3-(dimethylaminosulfonyl)-4-(hexylamino)benzoic acid, 3-(dimethylaminosulfonyl)-4-(octylamino)benzoic acid, 4-(3,3-Dimethylbutylamino)-3-(dimethylaminosulfonyl)benzoic acid, 3-(dimethylaminosulfonyl)-4-(4,4,4-trifluorobutylamino)benzoic acid, 3-(dimethylaminosulfonyl)-4-(6,6,6-trifluorohexylamino)benzoic acid, 3-(dimethylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3-(dimethylaminosulfonyl)-4-(2-methoxyethylamino)benzoic acid, 3-(dimethylaminosulfonyl)-4-(4-methoxybutylamino)benzoic acid, 3-(dimethylaminosulfonyl)-4-(6-methoxyhexylamino)benzoic acid, 3-(cyclopentylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3-(cyclohexylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5-(dimethylaminosulfonyl)-2-hydroxy-4-(8,8,8-trifluorooctylamino)benzoic acid, 3-Morpholinyl-4-(8,8,8-trifluorooctylamino)benzoic acid.

[0027] Specifically, the compound of formula (I) is 3-(dimethylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid.

[0028] The present invention will be illustrated by some examples below, but these examples are not intended to limit the scope of the invention.

[0029] Example 1 Preparation of 3-(dimethylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid (1). Step 1) Preparation of 3-(dimethylaminosulfonyl)-4-fluorobenzoic acid (INT-2). An aqueous solution of N-dimethylamine (600 mL, 4.74 mol) was dissolved in water (600 mL). The solution was cooled to 0°C and stirred. Then, 3-chlorosulfonyl-4-fluorobenzoic acid (300.00 g, 1.26 mol), approximately 37.5 g per fraction, was added in five portions over a total of 82 minutes. After the last fraction was added, the reaction was verified to be complete (HPLC). Then, 12 M hydrogen chloride (300 mL, 3.60 mol) was added dropwise at 0°C over a total addition time of 45 minutes. During the addition, a product precipitate was observed. The mixture was heated to 20°C, and the precipitate was collected by filtration and washed with water (7 × 600 mL, 7 × 2 vol). The filter cake was completely dehydrated under high vacuum for 4 h and then dried in a vacuum oven at 50°C for 48 h.

[0030] 3-(dimethylaminosulfonyl)-4-fluorobenzoic acid (INT-2) (299.0 g, 95% yield). 1 H NMR (400MHz, DMSO-d6) δ 8.29 - 8.24 (m, 2H), 7.67 - 7.58 (m, 1H), 2.75 (d, J = 1.9Hz, 6H).

[0031] Step 2) 8,8,8-Trifluorooctane-1-amine (INT-7). 8-Bromo-1,1,1-Trifluorooctane (INT-4) (300.00 g, 1.21 mol) and potassium (1,3-dioxoisoindoline-2-yl) (INT-5) (337.31 g, 1.82 mol) were added to a 2 L reactor along with acetonitrile (1500 mL, 5 vol). The mixture was stirred and refluxed overnight at 110°C. After the reaction was complete (controlled by NMR), water at room temperature (1500 mL, 5 vol) was added to the mixture and transferred to a separatory funnel. The phases were separated and the inorganic phase was removed. The organic phase was evaporated to 1.5 vol (450 mL), and the resulting viscous liquid was transferred to a 10 L jacketed reactor containing isopropanol (IPA) (2700 mL, 9 vol). Then add water (300 mL, 1 vol) at 20°C. Add NaBH4 (184.012 g, 4.86 mol) in four portions, each containing one equivalent. After the final addition, the mixture was heated and refluxed. After reflux for 1 hour, the reaction reached complete conversion to the benzyl alcohol amide product (INT-8) (controlled by UPLC). The internal temperature was adjusted to 70°C, and water (1200 mL, 4 vol) was added dropwise over 20–25 minutes, with a maximum gas release rate of 0.3 m. 3 / h. After the gas release weakens, during the initial stage of addition (maximum gas release rate maintained at 0.8 m³ / h). 3 Slowly add acetic acid (450 mL, 7.87 mol) at a rate of 30-35 min after half of the solution has been added and gas release has ceased. Then stir the mixture overnight at 70°C. After the reaction is complete (controlled by UPLC), cool the reaction mixture to 20°C and add dropwise 11.6 M sodium hydroxide (1501 mL, 17.4 mol) (5 vol 35% NaOH). Separate the mixture phases, collect the organic phase and react it with methyl tert-butyl ether (MTBE) (1500 mL, 5 vol). dilution.The IPA / MTBE mixture was washed with 3 vol of 17.5% NaOH (diluted with 35% solution) to remove residual phthalide carboxylate (approximately 10 mol%, NMR). Then, 12 M hydrogen chloride (152 mL, 1.82 mol) was added dropwise, resulting in turbidity (fine precipitate). The suspension was stirred overnight at 0°C. The solvent was evaporated to the minimum stirable volume (approximately 500–450 mL) under vacuum (115 mBar, jacket temperature 50°C), and MTBE (3000 mL, 10 vol) was added. The suspension was stirred overnight at 0°C (jacket temperature). The resulting precipitate was collected by filtration, transferred to a crystallizing dish, and dried overnight in a vacuum oven at 40°C.

[0032]

[0033] 8,8,8-Trifluorooctylamine hydrochloride (INT-7) (237.0 g, 80% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (s width, 3H) 2.78 - 2.68 (m, 2H), 2.30 - 2.15 (m, 2H), 1.61 - 1.41 (m, 4H), 1.38 - 1.21 (m, 6H).

[0034] Step 3) (3-(dimethylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid (1). 3-(dimethylaminosulfonyl)-4-fluorobenzoic acid (258.85 g, 1.05 mol), 8,8,8-trifluorooctyl-1-amine hydrochloride (230.00 g, 1.05 mol), and tripotassium phosphate (888.95 g, 4.19 mol) were added to a 2 L hydrogenation reactor. Water (1150 mL, 5 vol) was added, and the container was sealed. The reaction mixture was stirred at 120°C for 24 hours. After the reaction was complete (controlled by HPLC), the reaction mixture was transferred to a 10 L JLR equipped with a condenser and diluted with water (1610 mL, 7 vol). The mixture was heated to an internal temperature of 95–100°C, and 12 M hydrochloric acid (349 mL, 4.19 mol) was added dropwise over 10–15 min. (mol). The pH was 6 / 7 at the end of the addition, and the product separated as a solid when the temperature reached 20°C. The suspension was subjected to heat / cold treatment (1 h at 90°C, 1 h at 90°C, 20 min at 40°C, 2 h at 40°C, 4 h at 20°C). The product was filtered and the filter cake was washed with water (3 × 690 mL, 3 × 3 vol). The filtered solid was then transferred to a vacuum oven at 50°C overnight.

[0035] (3-(dimethylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid (3.17) (98.0% w / w qNMR, 382.6 g, 87.3% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.05 (d, J = 2.1Hz, 1H), 7.93 (dd, J = 8.8, 2.1 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.75 (t, J= 5.0 Hz, 1H).75 (t, J = 5.4 Hz, 1H), 3.24 (q, J = 6.6 Hz, 2H), 2.29 - 2.14(m, 2H), 1.64 - 1.52 (m, 2H), 1.52 - 1.39 (m, 2H), 1.40 - 1.25 (m, 6H).

[0036] Step 4) Crystallization of (3-(dimethylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid. The crude material (3.17 g) (382.6 g, 0.93 mmol, 1 wt. unit) was dissolved in 2-Me THF (5.5 Vol) at 20°C. The mixture was heated to 40°C and filtered through a precision filter (0.45 µm); the filter was washed with another 2-Me THF (0.5 Vol). The temperature was set to 20°C, and then n-heptane (1.5 vol.) was added over 15 minutes. The mixture was crystallized with compound (1) (0.7 wt% seed crystals) and stirred for 1 hour. Additional n-heptane (2.5 vol.) was added over 100 minutes, and the mixture was aged for 20 minutes. Additional n-heptane (2.0 vol.) was added over 40 minutes, and the mixture was aged for 40 minutes. Finally, n-heptane (5.1 vol.) was added over 60 minutes, and the mixture was aged for 30 minutes. The mixture was then filtered, and the solids in the filter were washed with a mixture of 2-Me THF / n-heptane (25:75, 1 vol). Finally, the product was vacuum dried at room temperature (307.64 g, 80% yield).

[0037] Example 2 Hydrodynamic solubility of benzoic acid derivatives in 10 mM DMSO in phosphate-buffered saline (PBS) at pH 7.4 A 30 µL stock solution of the test compound in 10 mM DMSO was aliquoted and incubated in phosphate-buffered saline (PBS) at pH 7.4 at 25°C for 24 hours. After centrifugation, the compound dissolved in the supernatant was quantified by LC-MS / MS. The target concentration was 250 µM, and the final concentration was 2.5% DMSO. Hydrodynamic solubility was determined by UV quantification at 215 nm. Kinetic solubility was then calculated by dividing the peak area of ​​the supernatant by the reference peak area, multiplying by the reference concentration (µM), and the dilution factor (1.25).

[0038] As shown in Table 1, the compounds of formula (I) have a solubility of 188 µM to greater than 250 µM, exhibiting good water solubility, and their solubility is comparable to that of compound 1, the synthesis of which is shown in Example 1.

[0039] Table 1

Claims

1. A method for preparing a compound of formula (I) or a salt thereof, a pharmaceutically acceptable stereoisomer, enantiomer, diastereomer, tautomer, or geometric zwitterion: in: R1 and R2 are independently H, substituted or unsubstituted, straight or branched C. 1-10 -alkyl group, optionally containing one or more unsaturated bonds; substituted or unsubstituted C 3-8 -Cycloalkyl; substituted or unsubstituted, straight or branched C 4-10 -cycloalkyl-alkyl; C 3-8 - Heterocyclic rings; or, R1 and R2 together with the nitrogen atoms to which they are bonded form substituted or unsubstituted saturated heterocyclic rings; R3 and R4 are hydrogen atoms independently; substituted or unsubstituted C atoms 1-10 -alkyl group, optionally containing one or more unsaturated bonds; C 3-10 -cycloalkyl; C 4-10 -cycloalkyl-alkyl; C 2-8 - Haloalkyl; substituted or unsubstituted, straight or branched C 2-8 -Heteroalkyl; optionally substituted phenyl; The condition is that at least one of R3 and R4 is not hydrogen; R5 represents hydrogen; halogen; hydroxyl group; thiophenol; -NO2; R6 is -COOH; Includes the following steps: a) In aqueous solution, the compound of formula (II) is reacted with the amine of formula (III) to give the compound of formula (IV): Where X and Y are halogens independently; b) In an aqueous solution, in the presence of a base, the compound of formula (IV) is reacted with the compound of formula (V) to give the compound of formula (I). 。 2. The method for preparing a compound of formula (I) according to claim 1, wherein step b) is carried out in the presence of a base selected from the group consisting of: inorganic phosphates, inorganic carbonates, N,N-diisopropylethylamine, triethylamine and trimethylamine.

3. The method for preparing a compound of formula (I) according to claim 2, wherein the base is selected from the group consisting of tripotassium phosphate and potassium carbonate.

4. The method for preparing a compound of formula (I) according to claim 1, wherein R4 = H, characterized in that... The method includes, prior to step b), step a1), reacting the compound of formula (VI) with the compound of formula (VII) to obtain the compound of formula (VIII), and subsequently reducing the obtained compound to obtain the compound of formula (V). 。 5. The method for preparing a compound of formula (I) according to claim 4, wherein step a1) is carried out in a solvent selected from the group consisting of acetonitrile, acetone, isopropanol and methanol.

6. The method for preparing a compound of formula (I) according to claim 4, wherein the reduction is carried out in the presence of a reducing agent selected from the group consisting of: sodium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum hydride, and diisobutylaluminum hydride.

7. The method according to claim 1, wherein the R5 is selected from the group consisting of H, OH, Cl and methoxy.

8. The method according to claim 1, wherein R1 and R2 are selected from the group consisting of CH3, H, morpholine, cyclopentyl and cyclohexyl.

9. The method according to claim 1, wherein the compound of formula (I) is selected from the group consisting of: 4-(Butylamino)-3-(Methylaminosulfonyl)benzoic acid, 4-(hexylamino)-3-(methylaminosulfonyl)benzoic acid, 3-(methylaminosulfonyl)-4-(octylamino)benzoic acid, 4-(3,3-Dimethylbutylamino)-3-(methylaminosulfonyl)benzoic acid, 3-(methylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 4-(Butylamino)-3-(dimethylaminosulfonyl)benzoic acid, 3-(dimethylaminosulfonyl)-4-(hexylamino)benzoic acid, 3-(dimethylaminosulfonyl)-4-(octylamino)benzoic acid, 4-(3,3-Dimethylbutylamino)-3-(dimethylaminosulfonyl)benzoic acid, 3-(dimethylaminosulfonyl)-4-(4,4,4-trifluorobutylamino)benzoic acid, 3-(dimethylaminosulfonyl)-4-(6,6,6-trifluorohexylamino)benzoic acid, 3-(dimethylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3-(dimethylaminosulfonyl)-4-(2-methoxyethylamino)benzoic acid, 3-(dimethylaminosulfonyl)-4-(4-methoxybutylamino)benzoic acid, 3-(dimethylaminosulfonyl)-4-(6-methoxyhexylamino)benzoic acid, 3-(cyclopentylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3-(cyclohexylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5-(dimethylaminosulfonyl)-2-hydroxy-4-(8,8,8-trifluorooctylamino)benzoic acid, 3-Morpholinyl-4-(8,8,8-trifluorooctylamino)benzoic acid.

10. The method according to claim 9, wherein the compound of formula (I) is 3-(dimethylaminosulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid (1).

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