Method for preparing sulfamoyl chloride

Abstract

The invention relates to a method for producing a compound of structural formula (I), comprising reacting a compound of structural formula (II) with water in the presence of an organic amide or an organic amine, and to the use of a compound of structural formula (I) for producing a compound of structural formula (IVa), (IVb) or (IVc).

Description

Technical Field

[0001] The present invention relates to a method for preparing a compound of formula (I). More specifically, the present invention relates to a method for preparing a compound of formula (I), comprising reacting a compound of formula (II) with water in the presence of an organic amide or an organic amine. Furthermore, the present invention relates to the use of a compound of formula (I) for preparing a compound of formula (IVa), (IVb), or (IVc). Background Art

[0002] Sulfamoyl chloride is not commercially available and is used for the synthesis of a variety of more complex compounds in different fields, including nutrition, flavors, perfumery, cosmetics or pharmaceuticals, in particular taste modifiers, such as sweetness enhancers, sucrose enhancers and sweet flavor modifiers.

[0003] Sulfamoyl chloride is typically prepared from chlorosulfonyl isocyanate. However, the hydrolysis reaction of chlorosulfonyl isocyanate is difficult to control and has low selectivity. The most common method for synthesizing sulfamoyl chloride in the literature is the reaction of chlorosulfonyl isocyanate with formic acid in dichloromethane (CH2Cl2). This reaction is easier to control, but it requires two intermediates: anhydride and carbamic acid. The conversion of anhydride to carbamic acid results in the loss of one molecule of carbon monoxide, while the conversion of carbamic acid to sulfamoyl chloride releases one equivalent of carbon dioxide. As a result, two equivalents of gas are formed, one of which, carbon monoxide, is toxic. Other disadvantages of the known methods are the use of chlorinated volatile solvents such as dichloromethane (CH2Cl2) and the use of formic acid, which is toxic, flammable, corrosive, unstable, and decomposes into toxic carbon monoxide and water.

[0004] Therefore, there is a need for an improved process for preparing sulfamoyl chloride (ie, the compound of formula (I)) that is safe, environmentally friendly, and scalable for industrial applications. Summary of the Invention

[0005] The present invention solves the above-mentioned problem by using an organic amide or an organic amine as a catalyst to react a compound of formula (II) (i.e., chlorosulfonyl isocyanate) with water to prepare a compound of formula (I) (i.e., sulfamoyl chloride). To the best of our knowledge, the present invention has not been reported in the prior art. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Figure 1 : CO2 release curve in the absence of dimethylacetamide. Conditions: 1 molar equivalent of water (10% w / w in acetonitrile) was added to a 50% w / w toluene solution of chlorosulfonyl isocyanate at 5°C over 2 hours. The temperature after addition was 5°C.

[0007] Figure 2 CO2 release curves in the presence of dimethylacetamide or triethylamine. Conditions: 1 molar equivalent of water (10% w / w in acetonitrile) and 0.005 molar equivalent of dimethylacetamide or triethylamine were added to a 33% w / w solution of chlorosulfonyl isocyanate in toluene at 5°C over 2 hours. The temperature after addition was 25°C. DETAILED DESCRIPTION

[0008] Surprisingly, it has now been found that the compound of formula (I) can be prepared safely and on a large scale by reacting the compound of formula (II) with water in the presence of an organic amide or an organic amine. The method of the present invention is advantageous for large-scale production.

[0009] The first object of the present invention is a method for preparing a compound of formula (I):

[0010]

[0011] It comprises reacting a compound of formula (II) with water in the presence of an organic amide or an organic amine:

[0012]

[0013] For clarity, by the expression "organic amide" we mean a compound of the general formula RC(=O)NR'R", wherein R, R' and R" can each independently represent hydrogen, alkyl, alkenyl, aryl, heteroaryl, heteroalkyl, aralkyl or heteroaralkyl.

[0014] For the sake of clarity, the term "alkyl" as used herein has the general understanding of those skilled in the art. The term "alkyl" is to be understood herein as a linear, branched or cyclic C1 to C 10 Alkyl, in particular linear, branched or cyclic C1 to C5 alkyl, more in particular linear, branched or cyclic C1 to C4 alkyl, which is optionally substituted with hydroxy, C1-C3 alkoxy or C1-C3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl.

[0015] For the sake of clarity, the term "alkenyl" as used herein has the general understanding of those skilled in the art. The term is understood herein to mean a linear, branched or cyclic C2 to C 10 Alkenyl, in particular linear, branched or cyclic C2 to C5 alkenyl, more in particular linear, branched or cyclic C2 to C4 alkenyl, each of which is optionally substituted with hydroxy, C1-C3 alkoxy or C1-C3 alkyl, for example vinyl, allyl, propenyl, isopropenyl, butenyl or isobutenyl.

[0016] For the sake of clarity, the term "alkynyl" is used herein with the general understanding of those skilled in the art. The term is understood herein to mean a linear, branched or cyclic C2 to C 10 alkynyl, in particular linear, branched or cyclic C2 to C5 alkynyl, more in particular linear, branched or cyclic C2 to C4 alkynyl, each of which is optionally substituted with hydroxy, C1-C3 alkoxy or C1-C3 alkyl.

[0017] For the sake of clarity, the term "aryl" as used herein has the general understanding of those skilled in the art. The term "aryl" is particularly understood herein to mean C6 to C 10 Aryl, optionally substituted with hydroxy, C1-C3 alkoxy or C1-C3 alkyl, such as phenyl.

[0018] For the sake of clarity, the term "heteroaryl" as used herein has the general understanding of those skilled in the art. The term "heteroaryl" is specifically understood herein to mean C4 to C 10 Aryl, the ring portion of which contains at least one heteroatom such as nitrogen or oxygen, and which is optionally substituted with hydroxy, C1-C3 alkoxy or C1-C3 alkyl, such as pyridine or pyrimidine.

[0019] For the sake of clarity, the term "heteroalkyl" as used herein has the general understanding of a person skilled in the art. The term "heteroalkyl" is understood herein to mean a linear, branched or cyclic alkyl group, the alkyl portion of which contains at least one heteroatom such as nitrogen, oxygen or sulfur, in particular a linear, branched or cyclic C1 to C 10 Heteroalkyl, in particular linear, branched or cyclic C1 to C5 heteroalkyl, more in particular linear, branched or cyclic C1 to C4 heteroalkyl, which is optionally substituted with hydroxy, C1-C3 alkoxy or C1-C3 alkyl.

[0020] For the sake of clarity, the term "heteroalkenyl" as used herein has the general understanding of a person skilled in the art. The term "heteroalkenyl" is understood herein to mean a linear, branched or cyclic alkenyl group, the alkenyl portion of which contains at least one heteroatom such as nitrogen, oxygen or sulfur, in particular a linear, branched or cyclic C1 to C 10 Heteroalkenyl, in particular a linear, branched or cyclic C1 to C5 heteroalkenyl, more particularly a linear, branched or cyclic C1 to C4 heteroalkenyl, which is optionally substituted with hydroxy, C1-C3 alkoxy or C1-C3 alkyl.

[0021] For the sake of clarity, the term "aralkyl" is used herein with the general understanding of a person skilled in the art. The term "aralkyl" is to be understood herein as specifically an aryl group substituted with an alkyl group as described above.

[0022] For the sake of clarity, the term "heteroaralkyl" is used herein with the general understanding of those skilled in the art. The term "heteroaralkyl" is to be understood herein as specifically a heteroaryl group substituted with an alkyl group as described above.

[0023] The term "optionally" means that a group may or may not contain a functional group of a certain substituent.

[0024] Examples of organic amides include, but are not limited to, acetamide, dimethylacetamide, benzamide, dimethylformamide, and combinations thereof.

[0025] In a preferred embodiment, the organic amide is dimethylacetamide.

[0026] As used herein, the term "organic amine" refers to a compound having the structural formula N(R)3, wherein each R can independently represent hydrogen, an alkyl, an alkenyl, an aryl, a heteroaryl, a heteroalkyl, an aralkyl, or a heteroaralkyl, or two Rs, together with the nitrogen atom to which they are attached, form a cyclic heteroalkyl ring. In particular, the organic amine is a tertiary amine; that is, R can represent an alkyl, an alkenyl, an aryl, a heteroaryl, a heteroalkyl, an aralkyl, or a heteroaralkyl, or two Rs, together with the nitrogen atom to which they are attached, form a cyclic heteroalkyl ring.

[0027] Examples of organic amines include, but are not limited to, tripropylamine, tributylamine, triethylamine, diisopropylethylamine (DIEA), morpholine, methylpiperidine, ethylpiperidine, propylpiperidine, and combinations thereof.

[0028] In a preferred embodiment, the organic amine is triethylamine.

[0029] In a particularly preferred embodiment, the organic amide is dimethylacetamide, or the organic amine is triethylamine.

[0030] In a further preferred embodiment, no organic amide or organic amine is added to the reaction mixture after the formation of the sulfamoyl chloride.

[0031] According to any embodiment of the present invention, the organic amine or organic amide is present in a catalytic amount.

[0032] The presence of a catalytic amount of an organic amide or organic amine allows for a smooth reaction, stable and controllable CO release, while preventing the release of toxic carbon monoxide. The reaction with water also suppresses carbon monoxide release. Therefore, from the perspective of gas release, the method of the present invention is safer.

[0033] The CO2 release curve can be used to judge the stability of the reaction in the method of the present invention and can be measured by any method known to those skilled in the art. Advantageously, a calibrated mass flow meter can be used to measure the flow of CO2 as the CO2 release curve.

[0034] These advantages make the method of the present invention safer and more environmentally friendly compared to the methods described in the prior art.

[0035] According to a specific embodiment, the catalytic amount of organic amide or organic amine is no more than 0.3 mol / mol chlorosulfonyl isocyanate, preferably no more than 0.1 mol / mol chlorosulfonyl isocyanate, more preferably no more than 0.07 mol / mol chlorosulfonyl isocyanate, more preferably no more than 0.05 mol / mol chlorosulfonyl isocyanate.

[0036] According to a specific embodiment, the catalytic amount of the organic amide or organic amine is 0.001 to 0.3 mol / mol of chlorosulfonyl isocyanate, preferably 0.002 to 0.1 mol / mol of chlorosulfonyl isocyanate, and more preferably 0.003 to 0.07 mol / mol of chlorosulfonyl isocyanate.

[0037] According to a specific embodiment, the catalytic amount of the organic amide or organic amine is 0.05 mol / mol chlorosulfonyl isocyanate, 0.005 mol / mol chlorosulfonyl isocyanate or 0.003 mol / mol chlorosulfonyl isocyanate.

[0038] The catalytic amount of an organic amide or organic amine described herein facilitates the production of a compound of formula (I), which exhibits improved performance in any subsequent reaction, including but not limited to the conversion of a compound of formula (III) to a compound of formula (IV). Another advantage of the catalytic amount of an organic amide or organic amine according to the present invention is an improved CO2 gas release profile. Surprisingly, the presence of a catalytic amount of an organic amide or organic amine results in a more stable reaction with respect to gas release and heat release.

[0039] Heat release is a further indicator of the smoothness of the process of the present invention and can be easily observed by a person skilled in the art through temperature measurements.

[0040] Advantageously, the method of the present invention prevents the release of toxic carbon monoxide.

[0041] In a particular embodiment, the chlorosulfonyl isocyanate is present in an inert solvent, preferably an inert aromatic solvent, an inert alkane solvent or an inert halogenated solvent.

[0042] The process according to the present invention does not require the handling of chlorinated volatile solvents such as dichloromethane (CH2Cl2) and therefore does not present regulatory restrictions arising from the use of dichloromethane (CH2Cl2).

[0043] For the sake of clarity, by the term "inert solvent" is meant a solvent that does not chemically react with the dissolved compounds.

[0044] Examples of inert solvents according to the present invention are dichloromethane, C 6-10 Aromatic solvents such as xylene, toluene or chlorobenzene, or C 5-12 Hydrocarbon solvents such as hexane, heptane or cyclohexane, preferably toluene or chlorobenzene.

[0045] In a particularly preferred embodiment, chlorosulfonyl isocyanate is present in toluene.

[0046] According to a specific embodiment, the concentration of chlorosulfonyl isocyanate in the inert solvent (preferably toluene or chlorobenzene) is 25% w / w to 50% w / w, preferably 30% w / w to 40% w / w. In a particularly preferred embodiment, the concentration of chlorosulfonyl isocyanate in the inert solvent (preferably toluene or chlorobenzene) is 33% w / w.

[0047] According to a specific embodiment, the amount of the inert solvent, preferably toluene or chlorobenzene, relative to the chlorosulfonyl isocyanate is 0.1 to 3 mol / mol chlorosulfonyl isocyanate, preferably 0.2 to 2.95 mol / mol chlorosulfonyl isocyanate, more preferably 0.5 to 2.5 mol / mol chlorosulfonyl isocyanate, most preferably 1.0 to 2.0 mol / mol chlorosulfonyl isocyanate.

[0048] In any embodiment, water is added as a dilute solution in an inert solvent, preferably an inert polar solvent, more preferably an inert polar water-miscible solvent. In a preferred embodiment, water is added as a solution in acetonitrile.

[0049] Advantageously, the process of the present invention prevents the accumulation of large amounts of unstable intermediates that release gas when converted to sulfamoyl chloride.

[0050] In particular, the concentration of water in the non-reactive solvent (preferably acetonitrile) is 0.5% w / w to 20% w / w, preferably 1% w / w to 18% w / w, more preferably 1.5% w / w to 15% w / w, more preferably 2% w / w to 13% w / w, more preferably 2.5% w / w to 12% w / w.

[0051] According to a particularly preferred embodiment, the concentration of water in the non-reactive solvent (preferably acetonitrile) is 3% w / w to 12% w / w, preferably 4% w / w to 10% w / w, most preferably 10% w / w.

[0052] According to a specific embodiment, the amount of water is 0.5 to 1.5 mol / mol of chlorosulfonyl isocyanate, preferably 0.95 to 1.05 mol / mol of chlorosulfonyl isocyanate, most preferably 1 mol / mol of chlorosulfonyl isocyanate.

[0053] According to one embodiment, the reaction temperature is -5°C to 35°C, preferably 5°C to 25°C, more preferably 5°C to 20°C, most preferably 5°C to 15°C.

[0054] The term "reaction temperature" refers to the temperature at which water is added to a non-reactive solvent (preferably acetonitrile) or chlorosulfonyl isocyanate is added to an inert solvent (preferably toluene or chlorobenzene) in the presence of an organic amide or an organic amine.

[0055] In one embodiment, the temperature after addition is from 15°C to 65°C, preferably from 20°C to 60°C. In a specific embodiment, the temperature after addition is from 25°C to 60°C.

[0056] As used herein, the term "post-addition temperature" refers to the temperature applicable one hour after the addition of water to acetonitrile. The reaction mixture is maintained at the reaction temperature during the addition of water to acetonitrile and for one hour thereafter. The reaction mixture is then heated to the post-addition temperature. Raising the post-addition temperature to a temperature between 25°C and 60°C helps suppress gas release from the resulting compound of formula (I) during storage and unexpectedly improves the performance of the compound of formula (I) in subsequent reactions, including but not limited to the preparation of a compound of formula (IV) from a compound of formula (III).

[0057] In a preferred embodiment, the addition time of water in a non-reactive solvent, preferably acetonitrile, to chlorosulfonyl isocyanate in an inert solvent, preferably toluene or chlorobenzene, in the presence of an organic amide or an organic amine is 1 to 8 hours, preferably 1 to 6 hours, more preferably 1 to 4 hours, and most preferably 2 to 4 hours.

[0058] As used herein, the term "addition time" is understood to mean the time during which water in a non-reactive solvent, preferably acetonitrile, is added to the reaction mixture.

[0059] The process for preparing the compound of formula (I) of the present invention can be carried out batchwise and / or continuously. In a preferred embodiment, the process is carried out continuously.

[0060] According to a particular embodiment, the method is used to convert a compound of formula (III) into a compound of formula (IV):

[0061]

[0062] Where R represents C1 to C 20 The hydrocarbyl group may optionally contain one or more heteroatoms, such as oxygen, nitrogen and sulfur.

[0063] For the sake of clarity, the term "hydrocarbon" as used herein has the general understanding of a person skilled in the art. The term "hydrocarbon" is to be understood as meaning that the group is composed of hydrogen and carbon atoms and may be in the form of a linear, branched or cyclic aromatic, alkyl, alkenyl or alkynyl group, for example a linear alkyl group; or may be in the form of a mixture of the types of groups mentioned, for example, unless specifically limited to only one type mentioned, a particular group may contain linear alkyl groups, branched alkenyl groups (for example with one or more carbon-carbon double bonds), (poly)cyclic alkyl groups and aryl moieties. Similarly, in all embodiments of the present invention, when a group is mentioned in the form of more than one type of topology (for example linear, cyclic or branched) and / or saturation or unsaturation (for example alkyl, aromatic or alkenyl), it is also intended to mean a group that may contain moieties having any of the described topologies or saturation or unsaturation as explained above. Similarly, in all embodiments of the present invention, when a group is referred to as being in one form (e.g., alkyl) that is saturated or unsaturated, it is meant that the group can be of any type of topology (e.g., linear, cyclic, or branched) or have several moieties with various topologies.

[0064] For the sake of clarity, the expression "optionally containing one or more heteroatoms, such as oxygen, nitrogen and sulfur" or similar expressions in the present invention means that the mentioned group may contain functional groups such as amine, ether, thioether, acetal, ester, aldehyde, ketone, amide, carboxylate or alcohol.

[0065] In a particular embodiment, R represents C1 to C 20 alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroaryl, or C1 to C 20 an amide or ester group of an alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroaryl group, optionally substituted with C1 to C 20 alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroaryl.

[0066] In a specific embodiment, the compound having structure (III) is:

[0067]

[0068] Where n is 0 or 1;

[0069] R1 and R2 are independently a hydrogen atom or a C1 to C4 alkyl group; or, R1 and R2 together with the carbon atom to which they are attached form a C3 to C7 cycloalkyl group;

[0070] R3 and R4 are independently a hydrogen atom or a C1 to C4 alkyl group; or, R3 and R4 together with the carbon atom to which they are attached form a C3 to C7 cycloalkyl group;

[0071] X is a NRC(O)-R5 group, wherein R is hydrogen or a C1 to C6 alkyl group; or R2 or R4 together with R form a C3 to C7 cycloalkyl group, and R5 is C 1-6 alkyl, alkenyl, aryl, heteroaryl, or substituted heteroaryl; or

[0072] X is C(O)NR6, wherein R6 is C 1-6 Alkyl, alkenyl, aryl, heteroaryl or substituted heteroaryl.

[0073] In a specific embodiment, the compound having structure (IV) is:

[0074]

[0075] wherein n, R1, R2, R3, R4 and X are as described above.

[0076] For clarity, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroaryl or the corresponding C1 to C 20 Particular embodiments of amide or ester groups of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroaryl groups.

[0077] Accordingly, the present invention also relates to a method for preparing a compound having structural formula (IV), which comprises the following steps:

[0078] - preparing a compound of formula (I) as disclosed above,

[0079] - reacting a compound of formula (I) with a compound of formula (III).

[0080] In a specific embodiment, the compound of formula (III) is:

[0081]

[0082] The compound having structural formula (IV) is:

[0083]

[0084] According to a particular embodiment, the compound of formula (IV) is converted, preferably in situ or in a stepwise manner, into a compound of formula (V):

[0085]

[0086] or any orally acceptable salt thereof, wherein R represents C1 to C 20 The hydrocarbyl group may optionally contain one or more heteroatoms, such as oxygen, nitrogen and sulfur.

[0087] In a particular embodiment, R represents C1-C 20 Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroaryl, or C1-C 20 an amide or ester group of an alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroaryl group, optionally substituted with a C1-C 20 alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroaryl.

[0088] In a specific embodiment, the compound having structure (V) is:

[0089]

[0090] wherein n, R1, R2, R3, R4 and X are as described above.

[0091] In an alternative embodiment, the compound of formula (IVa), (IVb) or (IVc) is converted, preferably in situ or in a stepwise manner, to a compound of formula (Va), (Vb) or (Vc):

[0092]

[0093] or any orally acceptable salt thereof.

[0094] For the sake of clarity, the expression "in situ" is to be understood as "in the reaction mixture".

[0095] In a specific embodiment, the compound of structural formula (V) is a taste modifier.

[0096] In a specific embodiment, the compound of structural formula (V) is a sweetness enhancer.

[0097] According to a preferred embodiment, the compound having structural formula (V) is a sucrose enhancer.

[0098] In a specific embodiment, a compound of formula (I) is used to convert a compound of formula (III) to a compound of formula (IV).

[0099] The yield of the conversion of the compound of formula (III) to the compound of formula (IV) can be measured by any method known to those skilled in the art. Preferably, the yield of the conversion can be measured by high performance liquid chromatography (HPLC).

[0100] In another aspect, the present invention relates to the use of a compound of formula (I),

[0101]

[0102] For the preparation of compounds of formula (IV) or (V), in particular compounds of formula (IVa), (IVb) or (IVc):

[0103]

[0104] The following examples report typical ways of implementing the method of the present invention, but these examples should not be considered as limiting the present invention. In the examples, unless otherwise indicated, abbreviations have common meanings in the art and temperatures are expressed in degrees Celsius (°C).

[0105] Example

[0106] Example 1

[0107] The equipment used was a 1 L autoreactor equipped with a condenser and a calibrated mass flow meter (for measuring CO2 flow). The equipment was made of glass and Teflon.

[0108] Sulfamide chloride was prepared by reacting 1 molar equivalent (eq.) of water (10% w / w in acetonitrile) with chlorosulfonyl isocyanate (50% w / w in toluene) in acetonitrile. The addition of water to acetonitrile was performed over 2 hours, with the temperature at 5°C during the addition. The temperature after the addition was 5°C. The CO2 evolution curve was used as an indicator of reaction stability.

[0109] Figure 1 The CO2 release curve for Example 1 is shown. The gas release curve consists of multiple narrow peaks, but a large CO2 peak suddenly appears about 15 minutes after the addition is completed. From a safety perspective, this sudden and uncontrolled gas release is unacceptable.

[0110] The sulfamoyl chloride solution thus prepared is used to convert the compound of formula (IIIa) into the compound of formula (IVa).

[0111] In a round-bottom flask equipped with a magnetic stirrer, 2 g of the compound of formula (IIIa) (1 mol equivalent), 0.34 g of dimethylacetamide, and 4.48 g of acetonitrile were added. To this suspension was added 1.4 mol equivalents [mol sulfamoyl chloride / compound of formula (IIIa)] of the sulfamoyl chloride solution prepared above, and the mixture was stirred and allowed to stand at 20°C for 1 hour. To this reaction mixture, 1.03 g (1.4 mol equivalents) of triethylamine was added over 1 hour at 20°C. The yield of the compound of formula (IVa) in the crude sample was evaluated using high-performance liquid chromatography (HPLC).

[0112] The yield was 78.3%.

[0113] Example 2

[0114] The equipment used was a 1 L autoreactor equipped with a condenser and a calibrated mass flow meter (for measuring CO2 flow). The equipment was made of glass and Teflon.

[0115] Sulfamide chloride is prepared by reacting 1 molar equivalent (eq.) of water (10% w / w in acetonitrile) with chlorosulfonyl isocyanate (33% w / w in toluene) in the presence of triethylamine or dimethylacetamide (0.005 mol per mole of chlorosulfonyl isocyanate). The addition time of the water to the acetonitrile is 2 hours, and the temperature during the addition is 5°C. The temperature after the addition is 25°C. The CO2 evolution curve is used as an indicator of the smoothness of the reaction.

[0116] Figure 2 The CO2 evolution curve for Example 2 is shown. When using dimethylacetamide and triethylamine, the gas flow rate during the addition was constant and smooth. In the post-addition period at 5°C, there was no additional CO2 evolution. When reheating to the post-addition temperature of 25°C, there was additional CO2 evolution, but the amount of CO2 evolution was significantly lower than the cumulative gas evolution when the process was performed without dimethylacetamide or triethylamine ( Figure 1 ), making it safe for industrial applications.

[0117] The sulfamoyl chloride solution thus prepared is used to convert the compound of formula (IIIa) into the compound of formula (IVa).

[0118] In a round-bottom flask equipped with a magnetic stirrer, 2 g of the compound of formula (IIIa) (1 mol equivalent), 0.34 g of dimethylacetamide, and 4.48 g of acetonitrile were added. To this suspension was added 1.4 mol equivalents [mol sulfamoyl chloride / compound of formula (IIIa)] of the sulfamoyl chloride solution prepared above, and the mixture was stirred and allowed to stand at 20°C for 1 hour. To this reaction mixture, 1.03 g (1.4 mol equivalents) of triethylamine was added over 1 hour at 20°C. The yield of the compound of formula (IVa) in the crude sample was evaluated using high-performance liquid chromatography (HPLC).

[0119] The yield of sulfamoyl chloride prepared in the presence of dimethylacetamide was 73.4%; the yield of sulfamoyl chloride prepared in the presence of triethylamine was 71.8%.

[0120] Example 3

[0121] Sulfamoyl chloride was prepared in a 1500-liter enameled reactor. One molar equivalent (eq.) of water in acetonitrile (10% w / w in acetonitrile) and chlorosulfonyl isocyanate in toluene (33% w / w in toluene) were reacted in the presence of triethylamine or dimethylacetamide (0.003 mol per mole of chlorosulfonyl isocyanate). The addition of water to acetonitrile was performed over 4 hours, with the temperature during the addition at 15°C. The temperature after the addition was 60°C.

[0122] To assess the regularity (smoothness) of the reaction, the heat release was observed. The reaction showed a smooth heat release curve.

[0123] The sulfamoyl chloride solution was used to convert the compound of formula (IIIa) to the compound of formula (IVa). The yield of the compound of formula (IVa) in the crude sample was evaluated by high performance liquid chromatography (HPLC) under the conditions described in Examples 1 and 2.

[0124] The yield of the compound of formula (IVa) relative to the compound of formula (IIIa) was 69.2%, indicating that the process was robust.

[0125] Example 4

[0126] Sulfamoyl chloride was prepared in a 1500-liter enameled reactor. One molar equivalent (eq.) of water in acetonitrile (10% w / w in acetonitrile) and chlorosulfonyl isocyanate in toluene (33% w / w in toluene) were reacted in the presence of 0.003 mol / mol of chlorosulfonyl isocyanate dimethylacetamide (0.003 mol per mole of chlorosulfonyl isocyanate). The addition of water to acetonitrile was performed over 4 hours, with the temperature during the addition at 20°C. The temperature after the addition was 60°C.

[0127] To assess the regularity (smoothness) of the reaction, the heat release was observed. The reaction showed a smooth heat release curve.

[0128] The sulfamoyl chloride solution was used to convert the compound of formula (IIIa) to the compound of formula (IVa). The yield of the compound of formula (IVa) in the crude sample was evaluated by high performance liquid chromatography (HPLC) under the conditions described in Examples 1 and 2.

[0129] The yield of the compound of formula (IVa) relative to the compound of formula (IIIa) was 67.7%, indicating that the process was robust.

[0130] Example 5

[0131] Sulfamoyl chloride was prepared in a 1500-liter enameled reactor. One molar equivalent (eq.) of water in acetonitrile (10% w / w in acetonitrile) and chlorosulfonyl isocyanate in toluene (33% w / w in toluene) were reacted in the presence of dimethylacetamide (0.002 mol per mole of chlorosulfonyl isocyanate). The addition of water to acetonitrile was performed over 4 hours, with the temperature during the addition being 15°C. The temperature after the addition was 60°C.

[0132] To assess the regularity (smoothness) of the reaction, the heat release was observed. The reaction showed a smooth heat release curve.

[0133] The sulfamoyl chloride solution was used to convert the compound of formula (IIIa) to the compound of formula (IVa). The yield of the compound of formula (IVa) in the crude sample was evaluated by high performance liquid chromatography (HPLC) under the conditions described in Examples 1 and 2.

[0134] The yield of the compound of formula (IVa) relative to the compound of formula (IIIa) was 69.5%, indicating that the process was robust.

[0135] Example 6

[0136] Sulfamoyl chloride was prepared in a 1500-liter enameled reactor. One molar equivalent (eq.) of water in acetonitrile (10% w / w in acetonitrile) and chlorosulfonyl isocyanate in toluene (33% w / w in toluene) were reacted in the presence of dimethylacetamide (0.003 mol per mole of chlorosulfonyl isocyanate). The addition of water to acetonitrile was performed over 5 hours, with the temperature during the addition at 15°C. The temperature after the addition was 60°C.

[0137] To assess the regularity (smoothness) of the reaction, the heat release was observed. The reaction showed a smooth heat release curve.

[0138] The sulfamoyl chloride solution was used to convert the compound of formula (IIIa) to the compound of formula (IVa). The yield of the compound of formula (IVa) in the crude sample was evaluated by high performance liquid chromatography (HPLC) under the conditions described in Examples 1 and 2.

[0139] The yield of the compound of formula (IVa) relative to the compound of formula (IIIa) was 67.6%, indicating that the process was robust.

[0140] Example 7

[0141] The equipment used was a 1 L autoreactor equipped with a condenser and a calibrated mass flow meter (for measuring CO2 flow). The equipment was made of glass and Teflon.

[0142] Sulfamide chloride was prepared by reacting 1 molar equivalent (eq.) of water (10% w / w in acetonitrile) with chlorosulfonyl isocyanate (33% w / w in toluene) in the presence of dimethylacetamide (0.002 mol per mole of chlorosulfonyl isocyanate). The addition of water to acetonitrile was performed over 2 hours, with the temperature maintained at 5°C during the addition. The temperature after the addition was 60°C. The CO2 evolution curve was used as an indicator of reaction stability.

[0143] The sulfamoyl chloride solution thus prepared is used to convert the compound of formula (IIIa) into the compound of formula (IVa).

[0144] The yield of the compound of formula (IVa) in the crude sample was assessed using high performance liquid chromatography (HPLC).

[0145] The yield using sulfamoyl chloride prepared in the presence of dimethylacetamide was 78.2%.

[0146] Example 8

[0147] The equipment used was a 1 L autoreactor equipped with a condenser and a calibrated mass flow meter (for measuring CO2 flow). The equipment was made of glass and Teflon.

[0148] Sulfamide chloride was prepared by reacting 1 molar equivalent (eq.) of water (12% w / w in acetonitrile) with chlorosulfonyl isocyanate (33% w / w in toluene) in the presence of dimethylacetamide (0.001 mol per mole of chlorosulfonyl isocyanate) in acetonitrile. The addition of water to acetonitrile was performed over 1.5 hours, with the temperature maintained at 15°C during the addition. The temperature after the addition was 60°C. The CO2 evolution curve was used as an indicator of reaction stability.

[0149] The sulfamoyl chloride solution thus prepared is used to convert the compound of formula (IIIa) into the compound of formula (IVa).

[0150] The yield of the compound of formula (IVa) in the crude sample was assessed using high performance liquid chromatography (HPLC).

[0151] The yield using sulfamoyl chloride prepared in the presence of dimethylacetamide was 74.6%.

Claims

1. A method for preparing a compound having structural formula (I): It comprises reacting a compound of formula (II) with water in the presence of an organic amide or an organic amine:

2. The method according to claim 1, wherein the organic amine or the organic amide is present in a catalytic amount.

3. The process according to any one of the preceding claims, wherein the organic amide is dimethylacetamide and the organic amine is triethylamine.

4. The method according to claim 3, wherein the catalytic amount of the organic amide or organic amine is 0.001 to 0.3 mol / mol chlorosulfonyl isocyanate, preferably 0.002 to 0.1 mol / mol chlorosulfonyl isocyanate, more preferably 0.003 to 0.07 mol / mol chlorosulfonyl isocyanate, more preferably 0.05 mol / mol chlorosulfonyl isocyanate, more preferably 0.005 mol / mol chlorosulfonyl isocyanate, most preferably 0.003 mol / mol chlorosulfonyl isocyanate.

5. The process according to any one of the preceding claims, wherein the chlorosulfonyl isocyanate is present in an inert solvent, preferably an inert aromatic solvent, an inert alkane solvent or an inert halogenated solvent.

6. The process according to claim 5, wherein chlorosulfonyl isocyanate is present in C 6-10 Aromatic solvents, dichloromethane or C 5-12 In hydrocarbon solvents, the C 5-12 The hydrocarbon solvent is selected from hexane, heptane or cyclohexane, wherein the C 6-10 The aromatic solvent is selected from xylene, toluene or chlorobenzene, preferably, wherein the C 6-10 The aromatic solvent is toluene or chlorobenzene, most preferably, wherein the C 6-10 The aromatic solvent is toluene.

7. A process according to claim 6, wherein the concentration of chlorosulfonyl isocyanate in the inert solvent, preferably toluene or chlorobenzene, is from 25% w / w to 50% w / w, preferably 33% w / w.

8. The process according to any one of the preceding claims, wherein water is added as a solution in an inert solvent, preferably an inert polar solvent, preferably acetonitrile.

9. The process according to claim 8, wherein the concentration of water in acetonitrile is from 0.5% w / w to 20% w / w, preferably from 1% w / w to 18% w / w, more preferably from 1.5% w / w to 15% w / w, more preferably from 2% w / w to 13% w / w, more preferably from 2.5% w / w to 12% w / w.

10. The process according to any one of the preceding claims, wherein the amount of water is 0.5 to 1.5 mol / mol chlorosulfonyl isocyanate, preferably 0.95 to 1.05 mol / mol chlorosulfonyl isocyanate, most preferably 1 mol / mol chlorosulfonyl isocyanate.

11. The method of claim 1 , wherein the water in acetonitrile is added to the chlorosulfonyl isocyanate in the inert solvent in the presence of an organic amide or an organic amine over a period of 1 to 8 hours, preferably 1 to 6 hours, more preferably 1 to 4 hours, and most preferably 2 to 4 hours.

12. The process according to any one of the preceding claims, wherein the process is used to convert a compound of formula (III) into a compound of formula (IV): Where R represents C1 to C 20 The hydrocarbyl group may optionally contain one or more heteroatoms, such as oxygen, nitrogen and sulfur.

13. The method according to claim 12, wherein the compound of formula (III) is: Among them, the compound having structural formula (IV) is:

14. The process according to claims 12 and 13, wherein the compound of formula (IV) is converted, preferably in situ or stepwise, into the compound of formula (V): or any orally acceptable salt thereof, and wherein R is as defined in claim 12, or converting a compound of formula (IVa), (IVb) or (IVc) into a compound of formula (Va), (Vb) or (Vc): or any orally acceptable salt thereof.

15. Use of a compound of formula (I) For preparing a compound having structural formula (IVa), (IVb) or (IVc):

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