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WO2024218681A1 - Process for the preparation of sulfamoylbenzoic acid derivatives - Google Patents

Process for the preparation of sulfamoylbenzoic acid derivatives Download PDF

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Publication number
WO2024218681A1
WO2024218681A1 PCT/IB2024/053748 IB2024053748W WO2024218681A1 WO 2024218681 A1 WO2024218681 A1 WO 2024218681A1 IB 2024053748 W IB2024053748 W IB 2024053748W WO 2024218681 A1 WO2024218681 A1 WO 2024218681A1
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Prior art keywords
benzoic acid
formula
compound
dimethylsulfamoyl
trif
Prior art date
Application number
PCT/IB2024/053748
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French (fr)
Inventor
Marco BORGOGNO
Annalisa SAVARDI
Andrea PATRICELLI MALIZIA
Marco DE VIVO
Laura CANCEDDA
Tommaso ANGELINI
Riccardo GARZELLI
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Iama Therapeutics S.R.L.
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Publication of WO2024218681A1 publication Critical patent/WO2024218681A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
    • C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a method for the preparation of derivatives of the sulfamoylbenzoic acid, in particular of the ( 3- (dimethylsulf amoyl ) -4- ( 8 , 8 , 8- trif luorooctylamino) benzoic acid.
  • 3- (dimethylsulfamoyl) -4- (8, 8, 8- trif luorooctylamino) benzoic acid (1) is an NKCC1 inhibitor useful in the treatment of neurological disorders (W02020202072, Savardi et al., Chem, 2020; Borgogno et al., J. Med. Chem. 2021; Savardi et al., 2023) .
  • Patent WO 2020202072 describes a synthesis of the 3- ( dimethyl sulfamoyl ) -4- ( 8 , 8 , 8-trif luorooctylamino ) benzoic acid comprising the following steps:
  • a further drawback of the synthesis described in W02020202072 is the use of hazardous chemicals, in particular for the deprotection of the amine (7) , which cannot be used for preparation on an industrial scale. Hydrazine is in fact a suspected carcinogen for humans. In the process of W02020202072, several chromatographic purification steps are also used.
  • aim of the present invention is to provide a method for the synthesis of sulfamoylbenzoic acid derivatives with good total yield and suitable for use on an industrial scale.
  • Ri and R2 are, independently, H, substituted or unsubstituted, linear or branched Ci-10-alkyl optionally comprising one or more unsaturations; substituted or unsubstituted Cs-s-cycloalkyl ; substituted or unsubstituted, linear or branched C4-io-cycloalkyl-alkyl ; Cs-s-heterocycle ; or, together with the nitrogen atom to which they are bound, Ri and R2 form a substituted or unsubstituted saturated heterocycle ;
  • R3 and R4 are, independently, hydrogen; substituted or unsubstituted C1-10 -alkyl optionally comprising one or more unsaturations; Cs-io-cycloalkyl ; C4-io-cycloalkyl-alkyl ; C2-8- haloalkyl; substituted or unsubstituted, linear or branched C2-s-heteroalkyl ; optionally substituted phenyl; provided that at least one of R3 and R4 is other than hydrogen;
  • Rs is hydrogen; halogen; hydroxyl; thiophenol; -NO2;
  • R 6 is -COOH; including the steps of : a) reacting, in aqueous solution, a compound of formula (II) with an amine of formula (III) to obtain a compound of formula ( IV) :
  • Step a) can be conducted at a temperature ranging between 0 and 20°C, preferably at 0°C.
  • Step b) may be conducted in the presence of an inorganic base selected from the group consisting of an inorganic phosphate and an inorganic carbonate, preferably selected from the group consisting of tripotassium phosphate and potassium carbonate, or of an organic base, preferably selected from the group consisting of N,N- diisopropylethylamine, triethylamine and trimethylamine.
  • Step al) may be conducted in the presence of a solvent selected from the group consisting of acetonitrile, acetone, isopropanol and methanol.
  • the reduction may be conducted in the presence of a reducing agent selected from the group consisting of sodium borhydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum hydride, and diisobutylaluminum hydride.
  • a reducing agent selected from the group consisting of sodium borhydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum hydride, and diisobutylaluminum hydride.
  • the method of the invention can be used for the preparation of compounds of formula (I) wherein Rs is COOH.
  • the method of the invention can be used for the preparation of compounds of formula (I) wherein Rs is selected from the group consisting of H, OH, Cl and methoxyl.
  • the method of the invention can be used for the preparation of compounds of formula (I) wherein Ri and R2 are, independently, substituted or unsubstituted, linear or branched H, Ci-10-alkyl optionally comprising one or more unsaturations; substituted or unsubstituted Cs-s-cycloalkyl ; substituted or unsubstituted, linear or branched C4-10- cycloalkyl-alkyl ; Cs-s-heterocycle ; or, together with the nitrogen atom to which they are bound, Ri and R2 form a substituted or unsubstituted saturated heterocycle.
  • Ri and R2 are, independently, substituted or unsubstituted, linear or branched H, Ci-10-alkyl optionally comprising one or more unsaturations; substituted or unsubstituted Cs-s-cycloalkyl ; substituted or unsubstituted, linear or branched C4-10- cycloalkyl-alkyl
  • Ri and R2 are selected from the group consisting of CH3, H, morpholine, cyclopentyl and cyclohexyl.
  • the method of the invention can be used for the preparation of a compound of formula (I) selected from the group consisting of:
  • STEP 2 8 , 8 , 8-trif luorooctane-l-amine (INT-7) .
  • 8-Bromo- 1 , 1 , 1-trif luoro-octane (INT-4) (300.00 g, 1.21 mol) and ( 1 , 3-dioxoisoindolin-2-yl ) potassium (INT-5) (337.31 g, 1.82 mol) were charged to a 2 L reactor along with acetonitrile (1500 mL, 5 vol) . The mixture was stirred and refluxed at 110°C overnight.
  • reaction mixture Upon completion of the reaction (controlled by UPLC) the reaction mixture was cooled to 20°C and 11.6 M sodium hydroxide (1501 mL, 17.4 mol) (5 vol 35% NaOH) was added dropwise. The mixture was separated into phases and the organic phase was collected and diluted with methyl- t-butyl ether (MTBE) (1500 mL, 5 vol) . The IPA/MTBE mixture was washed with 3 vol of 17.5% NaOH (35% solution dilution) to remove residual phthalide carboxylate (about lOmol % at NMR) . 12 M hydrogen chloride (152 mL, 1.82 mol) was then added dropwise leading to the formation of a turbidity (small sedimentation) .
  • MTBE methyl- t-butyl ether
  • the suspension was allowed to stir at 0°C overnight.
  • the solvent was evaporated under vacuum (115 mBar, jacket at 50 °C) up to a minimum stirrable volume (ca. 500-450 ml) and MTBE (3000 mL, 10 vol) was added.
  • the suspension was allowed to stir at 0°C (jacket temperature) overnight.
  • the resulting precipitated solid was collected by filtration, transferred to a crystallization dish and dried overnight in a vacuum oven at 40°C.
  • the reaction mixture was stirred at 120°C for 24 hours. Upon completion of the reaction (controlled by HPLC) , the reaction mixture was diluted with water (1610 mL, 7 vol) after transfer to a 10 L JLR equipped with condenser. The mixture was heated to internal 95-100°C and 12 M hydrochloric acid (349 mL, 4.19 mol) was added dropwise over 10-15 min. At the end of the addition the pH was 6/7 and the product as a solid separated upon reaching 20°C. The suspension was subjected to hot/cold treatment (over 1 h at 90°C, kept at 90°C for 1 h, over 20 min at 40°C, kept at 40°C for 2 h, over 4 h at 20°C) . The product was filtered and the cake was washed with water (3x690 mL, 3x3 vol) . The filtered solid was then transferred to a vacuum oven overnight at 50°C.
  • n-heptane 1.5 vol. was added over 15 minutes.
  • the mixture was seeded with compound (1) ( 0.7 wt % seed) and the mixture was stirred for 1 hour. Over 100 minutes additional n-heptane (2.5 Vol) was added and the mixture was allowed to mature for 20 minutes. Over 40 minutes additional n-heptane (2.0 vol.) was added and the mixture was subjected to 40 minutes ageing. Finally, n-heptane (5.1 vol.) was added over 60 minutes and the amalgam was allowed to mature for 30 minutes. The mixture was then filtered and the solid in the filter was washed with a mixture of 2-Me THE/ n-heptane (25:75, 1 vol) . Finally, the product was dried under vacuum at room temperature (307.64 g, yield 80%) .
  • Aqueous kinetic solubility of derivative compounds of the benzoic acid starting from a solution of 10 mM DMSO in phosphate buffered saline (PBS) at pH 7.4
  • the target concentration was 250 pM with a final concentration of 2.5% DMSO.
  • Aqueous kinetic solubility was determined by UV quantification at 215 nm. The kinetic solubility was then calculated by dividing the peak area of the supernatant by the peak area of the reference and multiplying by the reference concentration (pM) and the dilution factor (1.25) .
  • the compounds of formula (I) have a solubility ranging from 188 pM to greater than 250 pM, indicating a good aqueous solubility and a solubility comparable to that of compound 1, the synthesis of which is exemplified in Example 1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a method for the preparation of derivatives of the sulfamoylbenzoic acid, in particular of the ( 3- (dimethylsulf amoyl ) -4- ( 8, 8, 8- trifluorooctylamino) benzoic acid.

Description

"PROCESS FOR THE PREPARATION OF SULFAMOYLBENZOIC ACID
DERIVATIVES"
Cross-Reference to Related Applications
This Patent Application claims priority from Italian Patent Application No. 102023000007521 filed on April 18, 2023, the entire disclosure of which is incorporated herein by reference.
Technical Field
The present invention relates to a method for the preparation of derivatives of the sulfamoylbenzoic acid, in particular of the ( 3- (dimethylsulf amoyl ) -4- ( 8 , 8 , 8- trif luorooctylamino) benzoic acid.
BACKGROUND OF THE INVENTION
3- (dimethylsulfamoyl) -4- (8, 8, 8- trif luorooctylamino) benzoic acid (1) is an NKCC1 inhibitor useful in the treatment of neurological disorders (W02020202072, Savardi et al., Chem, 2020; Borgogno et al., J. Med. Chem. 2021; Savardi et al., 2023) .
Figure imgf000002_0001
Patent WO 2020202072 describes a synthesis of the 3- ( dimethyl sulfamoyl ) -4- ( 8 , 8 , 8-trif luorooctylamino ) benzoic acid comprising the following steps:
1) conversion of the 3- (chlorosulfonyl) -4- f luorobenzoic acid (2) to the corresponding 3- dimethylsulf amoyl derivative (3)
Figure imgf000003_0001
2) reaction of 8-bromo-l , 1 , 1-trif luorooctane (4) with potassium phthalimide (5) to obtain 2- (8,8,8- tri fluorooctyl ) isoindoline-1 , 3 -di one
Figure imgf000003_0002
Figure imgf000003_0003
3) deprotection of 8 , 8 , 8-trif luorooctane-l-amine (7) from the derivative (6) obtained in step (2)
Figure imgf000003_0005
4) reaction of the derivative (3) obtained in step (1) with the derivative (7) obtained in step (3) to provide the com
Figure imgf000003_0004
The preparation process described in W02020202072 is useful as a process for the preparation of sulfamoylbenzoic acid derivatives, but there is still much room for improvement in terms of total yield.
A further drawback of the synthesis described in W02020202072 is the use of hazardous chemicals, in particular for the deprotection of the amine (7) , which cannot be used for preparation on an industrial scale. Hydrazine is in fact a suspected carcinogen for humans. In the process of W02020202072, several chromatographic purification steps are also used.
The need is therefore felt in the art for new methods for the preparation of sulfamoylbenzoic acid derivatives, without the disadvantages of the methods of the prior art.
Therefore, aim of the present invention is to provide a method for the synthesis of sulfamoylbenzoic acid derivatives with good total yield and suitable for use on an industrial scale.
Summary of the Invention
This aim is achieved thanks to the method of Claim 1.
Description of Embodiments
According to a first aspect of the invention there is provided a method for the preparation of a compound of formula (I) or its salts, pharmaceutically acceptable, stereoisomers, enantiomers, diastereoisomers, tautomers, geometric zwitterions:
Figure imgf000004_0001
wherein :
Ri and R2 are, independently, H, substituted or unsubstituted, linear or branched Ci-10-alkyl optionally comprising one or more unsaturations; substituted or unsubstituted Cs-s-cycloalkyl ; substituted or unsubstituted, linear or branched C4-io-cycloalkyl-alkyl ; Cs-s-heterocycle ; or, together with the nitrogen atom to which they are bound, Ri and R2 form a substituted or unsubstituted saturated heterocycle ;
R3 and R4 are, independently, hydrogen; substituted or unsubstituted C1-10 -alkyl optionally comprising one or more unsaturations; Cs-io-cycloalkyl ; C4-io-cycloalkyl-alkyl ; C2-8- haloalkyl; substituted or unsubstituted, linear or branched C2-s-heteroalkyl ; optionally substituted phenyl; provided that at least one of R3 and R4 is other than hydrogen;
Rs is hydrogen; halogen; hydroxyl; thiophenol; -NO2;
R6 is -COOH; including the steps of : a) reacting, in aqueous solution, a compound of formula (II) with an amine of formula (III) to obtain a compound of formula ( IV) :
Figure imgf000005_0001
(II) (IV) wherein X and Y are independently a halogen; b) reacting, in aqueous solution and in the presence of a base, the compound of formula (IV) with a compound of formula (V) t
Figure imgf000005_0002
Step a) can be conducted at a temperature ranging between 0 and 20°C, preferably at 0°C. Step b) may be conducted in the presence of an inorganic base selected from the group consisting of an inorganic phosphate and an inorganic carbonate, preferably selected from the group consisting of tripotassium phosphate and potassium carbonate, or of an organic base, preferably selected from the group consisting of N,N- diisopropylethylamine, triethylamine and trimethylamine.
According to one embodiment, the method of the invention when applied to obtain compounds of formula (I) wherein R4=H, comprises, prior to step b) , step al) of 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) .
Figure imgf000006_0001
Step al) may be conducted in the presence of a solvent selected from the group consisting of acetonitrile, acetone, isopropanol and methanol.
The reduction may be conducted in the presence of a reducing agent selected from the group consisting of sodium borhydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum hydride, and diisobutylaluminum hydride.
The method of the invention can be used for the preparation of compounds of formula (I) wherein Rs is COOH.
The method of the invention can be used for the preparation of compounds of formula (I) wherein Rs is selected from the group consisting of H, OH, Cl and methoxyl.
The method of the invention can be used for the preparation of compounds of formula (I) wherein Ri and R2 are, independently, substituted or unsubstituted, linear or branched H, Ci-10-alkyl optionally comprising one or more unsaturations; substituted or unsubstituted Cs-s-cycloalkyl ; substituted or unsubstituted, linear or branched C4-10- cycloalkyl-alkyl ; Cs-s-heterocycle ; or, together with the nitrogen atom to which they are bound, Ri and R2 form a substituted or unsubstituted saturated heterocycle.
In one embodiment, Ri and R2 are selected from the group consisting of CH3, H, morpholine, cyclopentyl and cyclohexyl.
The method of the invention can be used for the preparation of a compound of formula (I) selected from the group consisting of:
4- (butylamino) -3- (methylsulfamoyl) benzoic acid,
4- (hexylamino) -3- (methylsulfamoyl) benzoic acid,
3- (methylsulfamoyl) -4- (octylamino) benzoic acid,
4- (3, 3-dimethylbutylamino ) -3- (methylsulfamoyl) benzoic acid,
3- (methylsulfamoyl) -4- (8, 8, 8- trif luorooctylamino) benzoic acid,
4- (butylamino) -3- (dimethylsulfamoyl) benzoic acid, 3- (dimethylsulfamoyl) -4- (hexylamino ) benzoic acid,
3- (dimethylsulfamoyl) -4- (octylamino) benzoic acid,
4- (3, 3-dimethylbutylamino) -3- (dimethylsulf amoyl ) benzoic acid,
3- (dimethylsulfamoyl) -4- (4,4,4 trifluorobutylamino) benzoic acid, 3- (dimethylsulfamoyl) -4- (6, 6, 6- trif luorohexylamino) benzoic acid,
3- (dimethylsulfamoyl) -4- (8, 8, 8- trif luorooctylamino) benzoic acid,
3- (dimethylsulfamoyl) -4- ( 2-methoxyethylamino ) benzoic acid,
3- (dimethylsulfamoyl) -4- ( 4-methoxybutylamino ) benzoic acid,
3- (dimethylsulfamoyl) -4- ( 6-methoxyhexylamino ) benzoic acid,
3- (cyclopentylsulfamoyl) -4- (8, 8, 8- trifluorooctylamino) benzoic acid,
3- (cyclohexylsulfamoyl) -4- (8, 8, 8- trif luorooctylamino) benzoic acid,
5- (dimethylsulfamoyl) -2-hydroxy-4- (8, 8, 8- trif luorooctylamino) benzoic acid,
3-morpholinosulfonyl-4- (8, 8, 8- trif luorooctylamino) benzoic acid.
In particular the compound of formula (I) is 3- ( dimethyl sulfamoyl ) -4- ( 8 , 8 , 8-trif luorooctylamino ) benzoic acid .
In the following, the present invention will be shown by means of some examples, which are not intended to be considered limiting of the scope of the invention.
EXAMPLE 1
Preparation of the 3- (dimethylsulf amoyl ) -4- ( 8 , 8 , 8- trif luorooctylamino) benzoic acid (1) .
STEP 1) Preparation of the 3- (dimethylsulf amoyl ) -4- f luoro-benzoic acid (INT-2) . Aqueous 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- f luoro-benzoic acid (300.00 g, 1.26 mol) was added in 5 portions of about 37.5 g each, under stirring for a total time of 82 minutes. After the last portion was added, it was verified that the reaction was complete (HPLC) . Then 12 M hydrogen chloride (300 mL, 3.60 mol) was added dropwise at
0°C for a total addition time of 45 min. During the addition, precipitation of the product was observed. The mixture was allowed to heat to 20°C and the precipitated product was collected by filtration and washed with water (7x600 mL, 7x2 vol) . The cake was completely de-liquored under high vacuum for 4 h and then dried in a vacuum oven for 48 h at 50°C.
Figure imgf000009_0001
INT-1 INT-2
3- (Dimethylsulf amoyl ) -4-f luoro-benzoic acid (INT-2) (299.0 g, 95% yield) . 3H NMR (400 MHz, DMSO-de) 5 8.29 - 8.24 (m, 2H) , 7.67 - 7.58 (m, 1H) , 2.75 (d, J = 1.9 Hz, 6H) .
STEP 2) 8 , 8 , 8-trif luorooctane-l-amine (INT-7) . 8-Bromo- 1 , 1 , 1-trif luoro-octane (INT-4) (300.00 g, 1.21 mol) and ( 1 , 3-dioxoisoindolin-2-yl ) potassium (INT-5) (337.31 g, 1.82 mol) were charged to a 2 L reactor along with acetonitrile (1500 mL, 5 vol) . The mixture was stirred and refluxed at 110°C overnight. Upon completion of the reaction (controlled by NMR) , water (1500 mL, 5 vol) at room temperature 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 at 1.5 vol (450 ml) and the resulting viscous liquid was transferred to a 10 L jacketed reactor with isopropanol (IPA) (2700 mL, 9 vol) . Water (300 mL, 1 vol) was then added at 20°C. NaBH4 (184.012 g, 4.86 mol) was added in 4 portions of 1 eq. each.
After the last addition, the mixture was heated and refluxed. After 1 hour of reflux the reaction reached the completion of the transformation into benzylalcoholic 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 (maximum gas evolution: 0.3 m3/h) . Once the gaseous evolution was attenuated, acetic acid (450 mL, 7.87 mol) was added slowly at the initial step of addition (maximum gaseous development kept at 0.8 m3/h) and increasing the speed after half the addition since the gaseous development ceased (addition time: 30-35 min) . The mixture was then stirred at 70°C all night. Upon completion of the reaction (controlled by UPLC) the reaction mixture was cooled to 20°C and 11.6 M sodium hydroxide (1501 mL, 17.4 mol) (5 vol 35% NaOH) was added dropwise. The mixture was separated into phases and the organic phase was collected and diluted with methyl- t-butyl ether (MTBE) (1500 mL, 5 vol) . The IPA/MTBE mixture was washed with 3 vol of 17.5% NaOH (35% solution dilution) to remove residual phthalide carboxylate (about lOmol % at NMR) . 12 M hydrogen chloride (152 mL, 1.82 mol) was then added dropwise leading to the formation of a turbidity (small sedimentation) . The suspension was allowed to stir at 0°C overnight. The solvent was evaporated under vacuum (115 mBar, jacket at 50 °C) up to a minimum stirrable volume (ca. 500-450 ml) and MTBE (3000 mL, 10 vol) was added. The suspension was allowed to stir at 0°C (jacket temperature) overnight. The resulting precipitated solid was collected by filtration, transferred to a crystallization dish and dried overnight in a vacuum oven at 40°C.
Figure imgf000010_0001
8 , 8 , 8-Trif luorooctylamine hydrochloride (INT-7) (237.0 g,
80% yield) . TH NMR (400 MHz, DMSO-de) 5 8.08 (s wide, 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) .
STEP 3) ( 3- (Dimethylsulf amoyl ) -4- ( 8 , 8 , 8- trif luorooctylamino) benzoic acid (1) . 3- (Dimethylsulf amoyl ) -4-f luoro-benzoic acid (258.85 g, 1.05 mol) , 8 , 8 , 8-trif luorooctan-l-amine hydrochloride (, 230.00 g, 1.05 mol) and tripotassium phosphate (888.95 g, 4.19 mol) were charged to a 2 L hydrogenation vessel. After addition of water (1150 mL, 5 vol) , the vessel was sealed. The reaction mixture was stirred at 120°C for 24 hours. Upon completion of the reaction (controlled by HPLC) , the reaction mixture was diluted with water (1610 mL, 7 vol) after transfer to a 10 L JLR equipped with condenser. The mixture was heated to internal 95-100°C and 12 M hydrochloric acid (349 mL, 4.19 mol) was added dropwise over 10-15 min. At the end of the addition the pH was 6/7 and the product as a solid separated upon reaching 20°C. The suspension was subjected to hot/cold treatment (over 1 h at 90°C, kept at 90°C for 1 h, over 20 min at 40°C, kept at 40°C for 2 h, over 4 h at 20°C) . The product was filtered and the cake was washed with water (3x690 mL, 3x3 vol) . The filtered solid was then transferred to a vacuum oven overnight at 50°C.
Figure imgf000011_0001
(3- (Dimethyl sulfamoyl ) -4- ( 8 , 8 , 8-trif luorooctyl amino ) benzoic acid (3.17) (98.0% w/w qNMR, 382.6 g, 87.3% yield) . TH NMR (400 MHz, DMSO-de ) 5 12.62 (s, 1H) , 8.05 (d, J = 2.1 Hz, 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) .
STEP 4) Crystallization of the (3- (dimethylsulfamoyl)-4- ( 8 , 8 , 8-trif luorooctylamino ) benzoic acid. The crude matter (3.17) (382.6 g, 0.93 mmol, 1 weight unit) was dissolved in 2-Me THE (5.5 Vol) at 20°C. The mixture was heated to 40°C and filtered through a polish filter (0.45 pm) ; the filter was washed with another 2-Me THE (0.5 Vol) .
The temperature was set to 20°C, then n-heptane (1.5 vol.) was added over 15 minutes. The mixture was seeded with compound (1) ( 0.7 wt % seed) and the mixture was stirred for 1 hour. Over 100 minutes additional n-heptane (2.5 Vol) was added and the mixture was allowed to mature for 20 minutes. Over 40 minutes additional n-heptane (2.0 vol.) was added and the mixture was subjected to 40 minutes ageing. Finally, n-heptane (5.1 vol.) was added over 60 minutes and the amalgam was allowed to mature for 30 minutes. The mixture was then filtered and the solid in the filter was washed with a mixture of 2-Me THE/ n-heptane (25:75, 1 vol) . Finally, the product was dried under vacuum at room temperature (307.64 g, yield 80%) .
EXAMPLE 2
Aqueous kinetic solubility of derivative compounds of the benzoic acid starting from a solution of 10 mM DMSO in phosphate buffered saline (PBS) at pH 7.4
Aliquots of 30 pL of stock solution of the test compound in 10 mM DMSO were 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 pM with a final concentration of 2.5% DMSO. Aqueous kinetic solubility was determined by UV quantification at 215 nm. The kinetic solubility was then calculated by dividing the peak area of the supernatant by the peak area of the reference and multiplying by the reference concentration (pM) and the dilution factor (1.25) .
As shown in Table 1, the compounds of formula (I) have a solubility ranging from 188 pM to greater than 250 pM, indicating a good aqueous solubility and a solubility comparable to that of compound 1, the synthesis of which is exemplified in Example 1.
Table 1
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001

Claims

1.- Method for the preparation of a compound of formula (I) or its salts, pharmaceutically acceptable stereoisomers, enantiomers, diastereoisomers, tautomers, geometric zwitterions :
Figure imgf000019_0001
wherein :
Ri and R2 are, independently, H, substituted or unsubstituted, linear or branched Ci-10-alkyl optionally comprising one or more unsaturations; substituted or unsubstituted Cs-s-cycloalkyl ; substituted or unsubstituted, linear or branched C4-io-cycloalkyl-alkyl ; Cs-s-heterocycle ; or, together with the nitrogen atom to which they are bound, Ri and R2 form a substituted or unsubstituted saturated heterocycle ;
R3 and R4 are, independently, hydrogen; substituted or unsubstituted C1-10 -alkyl optionally comprising one or more unsaturations; Cs-io-cycloalkyl ; C4-io-cycloalkyl-alkyl ; C2-8- haloalkyl; substituted or unsubstituted, linear or branched C2-s-heteroalkyl ; optionally substituted phenyl; provided that at least one of R3 and R4 is other than hydrogen;
Rs is hydrogen; halogen; hydroxyl; thiophenol; -NO2;
R6 is -COO^- including the steps of : a) reacting, in aqueous solution, a compound of formula (II) with an amine of formula (III) to obtain a compound of formula (IV) :
Figure imgf000020_0001
wherein X and Y are independently a halogen; b) reacting, in aqueous solution and in the presence of a base, the compound of formula (IV) with a compound of formula (V) to obtain a compound of formula (I) .
Figure imgf000020_0002
2.- Method for the preparation of a compound of formula (I) according to Claim 1, wherein step b) is conducted in the presence of a base selected from the group consisting of an inorganic phosphate, an inorganic carbonate, N,N- diisopropylethylamine, triethylamine, and trimethylamine.
3.- Method for the preparation of a compound of formula (I) according to Claim 2, wherein said base is selected from the group consisting of tripotassium phosphate and potassium carbonate .
4.- Method for the preparation of a compound of formula (I) according to Claim 1 wherein R4=H, characterized in that it comprises, prior to step b) , step al) of 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)
Figure imgf000021_0001
5.- Method for the preparation of a compound of formula (I) according to Claim 4, wherein step al) is conducted in a solvent selected from the group consisting of acetonitrile, acetone, isopropanol and methanol.
6.- Method for the preparation of a compound of formula (I) according to Claim 4, wherein the reduction is conducted in the presence of a reducing agent selected from the group consisting of sodium borhydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum hydride, and diisobutylaluminum hydride.
7.- Method according to any one of the preceding Claims, wherein said Rs is selected from the group consisting of H, OH, Cl and methoxyl.
8.- Method according to any one of the preceding Claims, wherein said Ri and R2 are selected from the group consisting of CH3, H, morpholine, cyclopentyl and cyclohexyl.
9.- Method according to any one of the preceding Claims, wherein said compound of formula (I) is selected from the group consisting of
4- (butylamino) -3- (methylsulfamoyl) benzoic acid,
4- (hexylamino) -3- (methylsulfamoyl) benzoic acid,
3- (methylsulfamoyl) -4- (octylamino) benzoic acid,
4- (3, 3-dimethylbutylamino ) -3- (methylsulfamoyl) benzoic acid
3- (methylsulfamoyl) -4- (8, 8, 8- trif luorooctylamino) benzoic acid,
4- (butylamino) -3- (dimethylsulfamoyl) benzoic acid,
3- (dimethylsulfamoyl) -4- (hexylamino ) benzoic acid,
3- (dimethylsulfamoyl) -4- (octylamino) benzoic acid,
4- (3, 3-dimethylbutylamino) -3- (dimethylsulf amoyl ) benzoic acid,
3- (dimethylsulfamoyl) -4- (4,4,4 trifluorobutylamino) benzoic acid,
3- (dimethylsulfamoyl) -4- (6, 6, 6- trif luorohexylamino) benzoic acid,
3- (dimethylsulfamoyl) -4- (8, 8, 8- trif luorooctylamino) benzoic acid,
3- (dimethylsulfamoyl) -4- ( 2-methoxyethylamino ) benzoic acid,
3- (dimethylsulfamoyl) -4- ( 4-methoxybutylamino ) benzoic acid,
3- (dimethylsulfamoyl) -4- ( 6-methoxyhexylamino ) benzoic acid,
3- (cyclopentylsulfamoyl) -4- (8, 8, 8- trif luorooctylamino) benzoic acid,
3- (cyclohexylsulfamoyl) -4- (8, 8, 8- trif luorooctylamino) benzoic acid,
5- (dimethylsulfamoyl) -2-hydroxy-4- (8, 8, 8- trif luorooctylamino) benzoic acid, 3-morpholinosulfonyl-4- (8, 8, 8- trif luorooctylamino) benzoic acid.
10.- Method according to Claim 9, wherein said compound of formula (I) is 3- (dimethylsulf amoyl ) -4- ( 8 , 8 , 8- trif luorooctylamino) benzoic acid (1) .
PCT/IB2024/053748 2023-04-18 2024-04-17 Process for the preparation of sulfamoylbenzoic acid derivatives WO2024218681A1 (en)

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