Method for preparing sulfamoyl chloride

Abstract

The present invention relates to a process for preparing 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 preparing 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 structural 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 structural formula (I) for preparing a compound having structural formula (IVa), (IVb), or (IVc).

[0002] Background of the Invention Sulfamoyl chlorides are not commercially available and are used in the synthesis of a wide variety of more complex compounds, in particular taste modifiers, such as sweetness enhancers, sucrose enhancers and sweet flavor modifiers, in various fields including nutrition, flavors, perfumes, cosmetics or pharmaceuticals, among others.

[0003] Sulfamoyl chlorides are typically obtained from chlorosulfonyl isocyanate. Unfortunately, the hydrolysis of chlorosulfonyl isocyanate is difficult to control and has low selectivity. The most common method for synthesizing sulfamoyl chloride in the literature uses the reaction of chlorosulfonyl isocyanate with formic acid in methylene chloride (CHCl). While this reaction is still easy to control, it proceeds via two intermediates: an anhydride and a carbamic acid. The conversion of the anhydride to the carbamic acid involves the loss of one molecule of carbon monoxide, while the conversion of the carbamic acid to sulfamoyl chloride releases one equivalent of carbon dioxide. Thus, two equivalents of gas are formed, one of which, carbon monoxide, is toxic. Other drawbacks of known processes are the use of chlorinated volatile solvents, such as methylene chloride (CHCl), and the use of formic acid, which is toxic, flammable, corrosive, and unstable, and decomposes to produce toxic carbon monoxide and water.

[0004] As a result, there is a need for improved methods for preparing sulfamoyl chloride, i.e., compounds of structural formula (I), that are safe, environmentally friendly, and scalable for industrial use.

[0005] The present invention solves the above-mentioned problems by using an organic amide or organic amine as a catalyst to prepare a compound of formula (I), i.e., sulfamoyl chloride, by reacting a compound of formula (II), i.e., chlorosulfonyl isocyanate, with water. To the best of our knowledge, this process has not been reported in the prior art. [Brief explanation of the drawings]

[0006] [Figure 1] Figure 1 shows the CO2 release profile in the absence of dimethylacetamide. Conditions: 1 molar equivalent of water (10% w / w in acetonitrile) to a 50% w / w solution of chlorosulfonyl isocyanate in toluene, 2 h addition time at 5°C. Post-addition temperature 5°C. [Figure 2] Figure 1 shows CO2 release profiles in the presence of dimethylacetamide or triethylamine. Conditions: 1 molar equivalent of water (10% w / w in acetonitrile) containing 0.005 molar equivalent of dimethylacetamide or triethylamine to a 33% w / w solution of chlorosulfonyl isocyanate in toluene, 5°C, 2 hour addition time. Post-addition temperature 25°C.

[0007] Detailed Description of the Invention It has surprisingly been found that reacting a compound of formula (II) with water in the presence of an organic amide or organic amine allows for the safe and scalable preparation of a compound of formula (I). The method of the present invention is advantageously applicable to large-scale processes.

[0008] The first object of the present invention is to provide a compound represented by the structural formula (I) [ka] 1. A method for preparing a compound of formula (I), comprising: Structural formula (II) [ka] with water in the presence of an organic amide or an organic amine.

[0009] For clarity, the expression "organic amide" refers to a compound of the general formula RC(=O)NR'R'' where R, R', and R'' can each independently represent hydrogen, alkyl, alkenyl, aryl, heteroaryl, heteroalkyl, arylalkyl, or heteroarylalkyl.

[0010] For clarity, the term "alkyl" as used herein has the meaning commonly understood by one of ordinary skill in the art. The term alkyl as used herein specifically refers to C1-C6 alkyl groups that are straight, branched, or cyclic. 10 Alkyl is understood as being in particular a linear, branched or cyclic C1-C5 alkyl, more particularly a linear, branched or cyclic C1-C4 alkyl, optionally substituted with a hydroxy group, a C1-C3 alkoxy group or a C1-C3 alkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl or isobutyl.

[0011] For clarity, the term "alkenyl" as used herein has the meaning commonly understood by one of ordinary skill in the art. As used herein, the term alkenyl refers to any C2-C alkyl group that is straight, branched, or cyclic. 10 Alkenyl is understood as being, in particular, a linear, branched or cyclic C2-C5 alkenyl, more particularly a linear, branched or cyclic C2-C4 alkenyl, each of which is optionally substituted with a hydroxy group, a C1-C3 alkoxy group or a C1-C3 alkyl group, such as, for example, vinyl, allyl, propenyl, isopropenyl, butenyl or isobutenyl.

[0012] For clarity, the term "alkynyl" as used herein has the meaning commonly understood by one of ordinary skill in the art. As used herein, the term alkynyl refers to any C2-C alkyl group that is straight, branched, or cyclic. 10Alkynyl is understood as being, in particular, a straight-chain, branched or cyclic C2-C5 alkynyl, more particularly a straight-chain, branched or cyclic C2-C4 alkynyl, each of which is optionally substituted with a hydroxy group, a C1-C3 alkoxy group or a C1-C3 alkyl group.

[0013] For clarity, the term "aryl" as used herein has the meaning commonly understood by one of ordinary skill in the art. The term aryl as used herein refers to C6-C 10 Aryl is understood as a group optionally substituted with a hydroxy group, a C1-C3 alkoxy group or a C1-C3 alkyl group, such as a phenyl group.

[0014] For clarity, the term "heteroaryl" as used herein has the meaning commonly understood by one of ordinary skill in the art. The term heteroaryl as used herein refers to a C4-C6 heteroaryl having at least one heteroatom, such as nitrogen or oxygen, in the ring portion of the aryl group. 10 An aryl group is understood as an optionally substituted hydroxy group, a C1-C3 alkoxy group or a C1-C3 alkyl group, such as pyridine or pyrimidine.

[0015] For clarity, the term "heteroalkyl" as used herein has the meaning commonly understood by those skilled in the art. The term heteroalkyl as used herein is understood in particular as a straight-chain, branched-chain, or cyclic alkyl group having at least one heteroatom, such as nitrogen, oxygen, or sulfur, in the alkyl moiety, and in particular as a straight-chain, branched-chain, or cyclic C1-C6 alkyl group. 10 Heteroalkyl is understood as a group, in particular a linear, branched or cyclic C1-C5 heteroalkyl, more particularly a linear, branched or cyclic C1-C4 heteroalkyl, optionally substituted with a hydroxy group, a C1-C3 alkoxy group or a C1-C3 alkyl group.

[0016] For clarity, the term "heteroalkenyl" as used herein has the meaning commonly understood by those skilled in the art. The term heteroalkenyl as used herein is understood in particular as a straight-chain, branched-chain, or cyclic alkenyl group having at least one heteroatom, such as nitrogen, oxygen, or sulfur, in the alkenyl moiety, and in particular as a straight-chain, branched-chain, or cyclic C1-C6 alkenyl group. 10 Heteroalkenyl is understood as a group, in particular a linear, branched or cyclic C1-C5 heteroalkenyl, more particularly a linear, branched or cyclic C1-C4 heteroalkenyl, optionally substituted with a hydroxy group, a C1-C3 alkoxy group or a C1-C3 alkyl group.

[0017] For clarity, the term "arylalkyl" as used herein has the meaning commonly understood by one of ordinary skill in the art. The term arylalkyl herein is specifically understood as an aryl substituted with an alkyl as described herein above.

[0018] For clarity, the term "heteroarylalkyl" as used herein has the meaning commonly understood by those skilled in the art. The term heteroarylalkyl herein is specifically understood as a heteroaryl substituted with alkyl as described herein above.

[0019] The term "optionally" indicates that a group may or may not include a particular substituent functionality.

[0020] Examples of organic amides include, but are not limited to, acetamide, dimethylacetamide, benzamide, dimethylformamide, and combinations thereof.

[0021] In a preferred embodiment, the organic amide is dimethylacetamide.

[0022] The term "organic amine," as used herein, refers to a compound having the structural formula N(R), where each R independently represents a hydrogen, alkyl, alkenyl, aryl, heteroaryl, heteroalkyl, arylalkyl, or heteroarylalkyl, or alternatively, two of the R's may be joined together with the nitrogen atom to which they are attached to form a cyclic heteroalkyl ring. In particular, the organic amine is a tertiary amine, i.e., R represents an alkyl, alkenyl, aryl, heteroaryl, heteroalkyl, arylalkyl, or heteroarylalkyl, or alternatively, two of the R's may be joined together with the nitrogen atom to which they are attached to form a cyclic heteroalkyl ring.

[0023] Examples of organic amines include, but are not limited to, tripropylamine, tributylamine, triethylamine, diisopropylethylamine (DIEA), morpholine, methylpiperidine, ethylpiperidine, propylpiperidine, and combinations thereof.

[0024] In a preferred embodiment, the organic amine is triethylamine.

[0025] In particularly preferred embodiments, the organic amide is dimethylacetamide or the organic amine is triethylamine.

[0026] In a further preferred embodiment, no organic amide or organic amine is added to the reaction mixture after formation of the sulfamoyl chloride.

[0027] In any embodiment of the present invention, the organic amine or organic amide is present in a catalytic amount.

[0028] The presence of a catalytic amount of organic amide or organic amine results in a smooth reaction with constant and controllable CO2 evolution, while preventing the release of toxic carbon monoxide, which is prevented by reaction with water. Therefore, the method according to the present invention is extremely safe from the standpoint of gas emissions.

[0029] The CO2 release profile allows for a judgment regarding the smoothness of the reaction of the method of the present invention and can be measured by any means known to those skilled in the art. Advantageously, the CO2 release profile can be measured as the CO2 flow rate using a calibrated mass flow meter.

[0030] These advantages make the method according to the invention safer and more environmentally friendly compared to the methods described in the prior art.

[0031] According to certain embodiments, the catalytic amount of organic amide or organic amine is not more than 0.3 moles per mole of chlorosulfonyl isocyanate, preferably not more than 0.1 moles per mole of chlorosulfonyl isocyanate, more preferably not more than 0.07 moles per mole of chlorosulfonyl isocyanate, more preferably not more than 0.05 moles per mole of chlorosulfonyl isocyanate.

[0032] According to a specific embodiment, the catalytic amount of organic amide or organic amine is 0.001 to 0.3 mol per mol of chlorosulfonyl isocyanate, preferably 0.002 to 0.1 mol per mol of chlorosulfonyl isocyanate, and more preferably 0.003 to 0.07 mol per mol of chlorosulfonyl isocyanate.

[0033] According to specific embodiments, the catalytic amount of organic amide or organic amine is 0.05 moles per mole of chlorosulfonyl isocyanate, 0.005 moles per mole of chlorosulfonyl isocyanate, or 0.003 moles per mole of chlorosulfonyl isocyanate.

[0034] A catalytic amount of organic amide or organic amine as defined herein advantageously provides a compound having structural formula (I) that exhibits improved performance in any subsequent reaction, including, but not limited to, the conversion of a compound having structural formula (III) to a compound having structural formula (IV). A further advantage of the catalytic amount of organic amide or organic amine according to the present invention is an improved process in terms of CO2 outgassing profile. Surprisingly, the presence of a catalytic amount of organic amide or organic amine provides a smooth reaction in terms of outgassing and heat generation.

[0035] The exotherm is a further indicator of the smoothness of the process of the present invention and can be readily observed by one skilled in the art by measuring the temperature.

[0036] Advantageously, the method of the present invention prevents the release of toxic carbon monoxide.

[0037] In certain embodiments, the chlorosulfonyl isocyanate is present in an inert solvent, preferably an inert aromatic solvent, an inert alkane solvent, or an inert halogenated solvent.

[0038] The method according to the present invention does not require the handling of the chlorinated volatile solvent, methylene chloride (CH2Cl2), and therefore is free of the regulatory restrictions that result from the use of methylene chloride (CH2Cl2).

[0039] For clarity, the term "inert solvent" means a solvent that does not chemically react with the dissolved compounds.

[0040] Examples of inert solvents according to the present invention are dichloromethane, C6- 10 Aromatic solvents such as xylene; toluene or chlorobenzene, or C5 12 A hydrocarbon solvent such as hexane, heptane or cyclohexane, preferably toluene or chlorobenzene.

[0041] In a particularly preferred embodiment, the chlorosulfonyl isocyanate is present in toluene.

[0042] 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.

[0043] According to a specific embodiment, the amount of the inert solvent, preferably toluene or chlorobenzene, relative to chlorosulfonyl isocyanate is 0.1 to 3 moles per mole of chlorosulfonyl isocyanate, preferably 0.2 to 2.95 moles per mole of chlorosulfonyl isocyanate, more preferably 0.5 to 2.5 moles per mole of chlorosulfonyl isocyanate, and most preferably 1.0 to 2.0 moles per mole of chlorosulfonyl isocyanate.

[0044] In either embodiment, water is introduced 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.

[0045] Advantageously, the process of the present invention prevents the large accumulation of unstable intermediates that release gases upon conversion to sulfamoyl chloride.

[0046] In particular, the water concentration 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, and more preferably 2.5% w / w to 12% w / w.

[0047] According to a particularly preferred embodiment, the water concentration in the non-reactive solvent, preferably acetonitrile, is between 3% w / w and 12% w / w, preferably between 4% w / w and 10% w / w, most preferably 10% w / w.

[0048] According to a specific embodiment, the amount of water relative to chlorosulfonyl isocyanate is 0.5 to 1.5 moles per mole of chlorosulfonyl isocyanate, preferably 0.95 to 1.05 moles per mole of chlorosulfonyl isocyanate, and most preferably 1 mole per mole of chlorosulfonyl isocyanate.

[0049] 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, and most preferably 5°C to 15°C.

[0050] By "reaction temperature" is meant the temperature at which water in a non-reactive solvent, preferably acetonitrile, is added to chlorosulfonyl isocyanate in an inert solvent, preferably toluene or chlorobenzene, in the presence of an organic amide or organic amine.

[0051] In one embodiment, the post-addition temperature is 15°C to 65°C, preferably 20°C to 60°C. In a particular embodiment, the post-addition temperature is 25°C to 60°C.

[0052] As used herein, the term "post-addition temperature" refers to the temperature applied one hour after the addition of water in acetonitrile. The reaction mixture is maintained at the reaction temperature during the addition of water in acetonitrile and until one hour after the addition of water. The reaction mixture is then brought to the post-addition temperature. Increasing the post-addition temperature to 25°C to 60°C suppresses any gas evolution that may occur during storage of the resulting compound having structural formula (I) and unexpectedly enhances the performance of the compound having structural formula (I) in subsequent reactions, including, but not limited to, preparing a compound having structural formula (IV) from a compound having structural formula (III).

[0053] 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 organic amine is 1 hour to 8 hours, preferably 1 hour to 6 hours, more preferably 1 hour to 4 hours, and most preferably 2 hours to 4 hours.

[0054] The term "addition time" as used herein should be understood as the time during which water in a non-reactive solvent, preferably acetonitrile, is added to the reaction mixture.

[0055] The process of the present invention for preparing a compound of formula (I) can be carried out batchwise and / or continuously. In a preferred embodiment, the process is carried out continuously.

[0056] According to certain embodiments, the method comprises providing a compound of structural formula (III): [ka] The compound of structural formula (IV) [ka] used to convert into the compound wherein R is a C1-C optionally containing one or more heteroatoms such as oxygen, nitrogen, and sulfur. 20 represents a hydrocarbon group.

[0057] For clarity, the term "hydrocarbon" as used herein has the meaning commonly understood by those skilled in the art. The term hydrocarbon is understood to mean that the group in question consists of hydrogen and carbon atoms and can take the form of a linear, branched, or cyclic, aromatic alkyl, alkenyl, or alkynyl group, e.g., a linear alkyl group, or can take the form of a mixture of the aforementioned types of groups; for example, a particular group can include a linear alkyl group, a branched alkenyl group (e.g., a group having one or more carbon-carbon double bonds), a (poly)cyclic alkyl group, and an aryl group, unless specifically limited to only one type. Similarly, in all embodiments of the present invention, when a group is referred to as being in the form of more than one type of topology (e.g., linear, cyclic, or branched) and / or as being saturated or unsaturated (e.g., alkyl, aromatic, or alkenyl), it also means that the group can contain a moiety having any one of the aforementioned topologies, or a moiety that is saturated or unsaturated, as explained above. Similarly, in all embodiments of the present invention, when a group is referred to as being in one type of saturated or unsaturated form (e.g., alkyl), it means that said group can be of any type of topology (e.g., linear, cyclic, or branched) or can have multiple moieties with different topologies.

[0058] For clarity, in this invention, when "optionally containing one or more heteroatoms, such as oxygen, nitrogen and sulfur," or similar expressions, it is meant that the referenced group may contain functional groups such as, for example, amines, ethers, thioethers, acetals, esters, aldehydes, ketones, amides, carboxylates, or alcohols.

[0059] In certain embodiments, R is C1-C 20 Alkyl groups, C1-C 20 Alkenyl groups, C1-C 20 Alkynyl groups, C1-C 20 Heteroalkyl groups, C1-C 20Heteroalkenyl group or C1-C 20 Heteroaryl group or C1-C 20 Alkylamide or C1-C 20 Alkyl ester group, C1-C 20 Alkenyl amide or C1-C 20 Alkenyl ester group, C1-C 20 Alkynyl amide or C1-C 20 Alkynyl ester groups, C1-C 20 Heteroalkylamide or C1-C 20 Heteroalkyl ester group, C1-C 20 Heteroalkenyl amide or C1-C 20 Heteroalkenyl ester group or C1-C 20 Heteroaryl amide or C1-C 20 Heteroaryl ester groups, which are C1-C 20 Alkyl groups, C1-C 20 Alkenyl groups, C1-C 20 Alkynyl groups, C1-C 20 Heteroalkyl groups, C1-C 20 Heteroalkenyl group or C1-C 20 The heteroaryl group may be optionally substituted.

[0060] In certain embodiments, the compound having structure (III) is [ka] and wherein n is 0 or 1; R1 and R2 are, independently of each other, a hydrogen atom or a C1-C4 alkyl group; or alternatively, R1 and R2 together with the carbon atom to which they are attached form a C3-C7 cycloalkyl; R3 and R4 are, independently of each other, a hydrogen atom or a C1-C4 alkyl group; or alternatively, R3 and R4 together with the carbon atom to which they are attached form a C3-C7 cycloalkyl; X is a group NRC(O)-R5, where R is hydrogen or C1-C6 alkyl; or alternatively, R2 or R4 and R together form a C3-C7 cycloalkyl, and R5 is C 1~6 is alkyl, alkenyl or aryl, heteroaryl, or substituted heteroaryl; or X is C(O)NR6, where R6 is C1-6 alkyl, alkenyl, or aryl, heteroaryl, or substituted heteroaryl.

[0061] In certain embodiments, the compound having structure (IV) is [ka] and wherein n, R1, R2, R3, R4 and X are as defined herein above.

[0062] For clarity, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, or a heteroaryl group, or a corresponding C1-C 20 Particular embodiments of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroaryl amide or ester groups are as described herein above.

[0063] Therefore, the present invention provides a method for preparing a compound of formula (IV), comprising: - preparing a compound having structural formula (I) as disclosed herein above; - reacting a compound of formula (I) with a compound of formula (III) The present invention also relates to a method, including:

[0064] In specific embodiments, the compound of structural formula (III) is [ka] and The compound of structural formula (IV) [ka] is.

[0065] According to a particular embodiment, the compound of structural formula (IV) is preferably prepared in situ or stepwise by reacting the compound of structural formula (V): [ka] or any orally acceptable salt thereof, wherein R is a C1-C aryl group optionally containing one or more heteroatoms, such as oxygen, nitrogen, and sulfur. 20 represents a hydrocarbon group.

[0066] In certain embodiments, R is C1-C 20 Alkyl groups, C1-C 20 Alkenyl groups, C1-C 20 Alkynyl groups, C1-C 20 Heteroalkyl groups, C1-C 20 Heteroalkenyl group or C1-C 20 Heteroaryl group or C1-C 20 Alkylamide or C1-C 20 Alkyl ester group, C1-C 20 Alkenyl amide or C1-C 20 Alkenyl ester group, C1-C 20 Alkynyl amide or C1-C 20 Alkynyl ester groups, C1-C 20 Heteroalkylamide or C1-C 20 Heteroalkyl ester group, C1-C 20 Heteroalkenyl amide or C1-C 20 Heteroalkenyl ester group or C1-C 20 Heteroaryl amide or C1-C 20 Heteroaryl ester groups, which are C1-C 20 Alkyl groups, C1-C 20Alkenyl groups, C1-C 20 Alkynyl groups, C1-C 20 Heteroalkyl groups, C1-C 20 Heteroalkenyl group or C1-C 20 The heteroaryl group may be optionally substituted.

[0067] In certain embodiments, the compound having structure (V) is [ka] and wherein n, R1, R2, R3, R4 and X are as defined herein above.

[0068] In an alternative embodiment, a compound of structural formula (IVa), (IVb) or (IVc) is preferably prepared by reacting a compound of structural formula (Va), (Vb) or (Vc), preferably in situ or stepwise, with a compound of structural formula (Va), (Vb) or (Vc) [ka] or an orally acceptable salt thereof.

[0069] For clarity, the expression "in-situ" should be understood as "in the reaction mixture."

[0070] In certain embodiments, the compound of structural formula (V) is a taste modifier.

[0071] In a specific embodiment, the compound of structural formula (V) is a sweetness enhancer.

[0072] According to a preferred embodiment, the compound of structural formula (V) is a sucrose enhancer.

[0073] In a specific embodiment, a compound of structural formula (I) is used to convert a compound of structural formula (III) to a compound of structural formula (IV).

[0074] The conversion yield of the compound of formula (III) to the compound of formula (IV) can be measured by any means known to those skilled in the art. Advantageously, the conversion yield can be measured by high performance liquid chromatography (HPLC).

[0075] In a further aspect, the present invention provides a compound of structural formula (I): [ka] of the compound Compounds of formula (IV) or (V), in particular compounds of formula (IVa), (IVb) or (IVc) [ka] The present invention relates to the use of the compound of formula (I) for preparing the compound of formula (I).

[0076] Exemplary methods for carrying out the method of the present invention are reported herein below in the Examples, which are not intended to limit the invention, in which abbreviations have their usual meaning in the art and temperatures are given in degrees Celsius (°C), unless otherwise specified. [Example]

[0077] [Example 1] The apparatus used was a 1 L automatic reactor equipped with a condenser and a calibrated mass flow meter for measuring the CO2 flow rate. The apparatus was made of glass and Teflon.

[0078] Preparation of sulfamoyl chloride by reacting 1 molar equivalent (eq.) of water in acetonitrile (10% w / w in acetonitrile) with chlorosulfonyl isocyanate in toluene (50% w / w in toluene). The addition time of water in acetonitrile was 2 hours, and the temperature during the addition of water was 5°C. The temperature after the addition was 5°C. The CO2 release profile was used as an indicator of the smoothness of the reaction.

[0079] Figure 1 shows the CO2 release profile of Example 1. The gas release profile consists of a narrow peak, with a sudden large CO2 peak occurring approximately 15 minutes after the end of addition. This sudden and uncontrolled gas release is unacceptable from a safety standpoint.

[0080] Using the sulfamoyl chloride solution thus prepared, the compound of structural formula (IIIa) was converted into the compound of structural formula (IVa).

[0081] A round-bottom flask equipped with a magnetic stirrer was charged with 2 g of the compound of formula (IIIa) (1 molar equivalent), 0.34 g of dimethylacetamide, and 4.48 g of acetonitrile. To this suspension was added 1.4 molar equivalents of the sulfamoyl chloride solution prepared above (1 mole of sulfamoyl chloride per compound of formula (IIIa)), and the mixture was stirred at 20°C for 1 hour. To this reaction mixture was added 1.03 g (1.4 molar equivalents) of triethylamine over 1 hour at 20°C. The yield of the compound of formula (IVa) in the crude sample was evaluated by high-performance liquid chromatography (HPLC).

[0082] The yield was 78.3%.

[0083] [Example 2] The apparatus used was a 1 L automated reactor equipped with a condenser and a calibrated mass flow meter for measuring the CO2 flow rate. The apparatus was made of glass and Teflon.

[0084] Preparation of sulfamoyl chloride by reacting 1 molar equivalent (eq.) of water in acetonitrile (10% w / w in acetonitrile) with chlorosulfonyl isocyanate in toluene (33% w / w in toluene) in the presence of triethylamine or dimethylacetamide (0.005 mole per mole of chlorosulfonyl isocyanate). The addition time of water in acetonitrile was 2 hours, and the temperature during the addition of water was 5°C. The temperature after the addition was 25°C. The CO2 release profile was used as an indicator of the smoothness of the reaction.

[0085] Figure 2 shows the CO2 release profile for Example 2. With dimethylacetamide and triethylamine, the gas flow rate is constant and smooth during the addition period. There is no additional CO2 release during the 5°C post-addition period. Reheating the post-addition temperature to 25°C results in additional CO2 release, which is significantly less than the cumulative gas release when the process is carried out in the absence of dimethylacetamide or triethylamine (Figure 1), and is therefore safe for industrial use.

[0086] Using the sulfamoyl chloride solution thus prepared, the compound of structural formula (IIIa) was converted into the compound of structural formula (IVa).

[0087] A round-bottom flask equipped with a magnetic stirrer was charged with 2 g of the compound of formula (IIIa) (1 molar equivalent), 0.34 g of dimethylacetamide, and 4.48 g of acetonitrile. To this suspension was added 1.4 molar equivalents of the sulfamoyl chloride solution prepared above (1 mole of sulfamoyl chloride per compound of formula (IIIa)), and the mixture was stirred at 20°C for 1 hour. To this reaction mixture was added 1.03 g (1.4 molar equivalents) of triethylamine over 1 hour at 20°C. The yield of the compound of formula (IVa) in the crude sample was evaluated by high-performance liquid chromatography (HPLC).

[0088] The yield was 73.4% when sulfamoyl chloride prepared in the presence of dimethylacetamide was used, and 71.8% when sulfamoyl chloride prepared in the presence of triethylamine was used.

[0089] [Example 3] Sulfamoyl chloride was prepared in a 1500-liter enameled reactor. One molar equivalent (eq.) of water in acetonitrile (10% w / w in acetonitrile) was reacted with chlorosulfonyl isocyanate in toluene (33% w / w in toluene) in the presence of dimethylacetamide (0.003 moles per mole of chlorosulfonyl isocyanate). The addition time of the water in acetonitrile was 4 hours, the temperature during the water addition was 15°C, and the temperature after the addition was 60°C.

[0090] To evaluate the regularity (smoothness) of the reaction, the exotherm was observed, and the reaction showed a smooth exothermic profile.

[0091] The compound of formula (IIIa) was converted to the compound of formula (IVa) using a sulfamoyl chloride solution. 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.

[0092] The yield of compound of formula (IVa) was 69.2% based on compound of formula (IIIa), demonstrating that this is a robust method.

[0093] [Example 4] Sulfamoyl chloride was prepared in a 1500-liter enameled reactor. One molar equivalent (eq.) of water in acetonitrile (10% w / w in acetonitrile) was reacted with chlorosulfonyl isocyanate in toluene (33% w / w in toluene) in the presence of 0.003 moles per mole of chlorosulfonyl isocyanate dimethylacetamide (0.003 moles per mole of chlorosulfonyl isocyanate). The addition time for the water in acetonitrile was 4 hours, and the temperature during the water addition was 20°C. The temperature after the addition was 60°C.

[0094] To evaluate the regularity (smoothness) of the reaction, the exotherm was observed, and the reaction showed a smooth exothermic profile.

[0095] The compound of formula (IIIa) was converted to the compound of formula (IVa) using a sulfamoyl chloride solution. 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.

[0096] The yield of compound of formula (IVa) was 67.7% relative to compound of formula (IIIa), demonstrating that this is a robust method.

[0097] [Example 5] Sulfamoyl chloride was prepared in a 1500-liter enameled reactor. One molar equivalent (eq.) of water in acetonitrile (10% w / w in acetonitrile) was reacted with chlorosulfonyl isocyanate in toluene (33% w / w in toluene) in the presence of dimethylacetamide (0.002 moles per mole of chlorosulfonyl isocyanate). The addition time of the water in acetonitrile was 4 hours, the temperature during the addition was 15°C, and the temperature after the addition was 60°C.

[0098] To evaluate the regularity (smoothness) of the reaction, the exotherm was observed, and the reaction showed a smooth exothermic profile.

[0099] The compound of formula (IIIa) was converted to the compound of formula (IVa) using a sulfamoyl chloride solution. 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.

[0100] The yield of compound of formula (IVa) was 69.5% relative to compound of formula (IIIa), demonstrating that this is a robust method.

[0101] [Example 6] Sulfamoyl chloride was prepared in a 1500-liter enameled reactor. One molar equivalent (eq.) of water in acetonitrile (10% w / w in acetonitrile) was reacted with chlorosulfonyl isocyanate in toluene (33% w / w in toluene) in the presence of dimethylacetamide (0.003 moles per mole of chlorosulfonyl isocyanate). The addition time of the water in acetonitrile was 5 hours, the temperature during the addition was 15°C, and the temperature after the addition was 60°C.

[0102] To evaluate the regularity (smoothness) of the reaction, the exotherm was observed, and the reaction showed a smooth exothermic profile.

[0103] The compound of formula (IIIa) was converted to the compound of formula (IVa) using a sulfamoyl chloride solution. 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.

[0104] The yield of compound of formula (IVa) was 67.6% relative to compound of formula (IIIa), demonstrating that this is a robust method.

[0105] [Example 7] The apparatus used was a 1 L automated reactor equipped with a condenser and a calibrated mass flow meter for measuring the CO2 flow rate. The apparatus was made of glass and Teflon.

[0106] Preparation of sulfamoyl chloride by reacting 1 molar equivalent (eq.) of water in acetonitrile (10% w / w in acetonitrile) with chlorosulfonyl isocyanate in toluene (33% w / w in toluene) in the presence of dimethylacetamide (0.002 moles per mole of chlorosulfonyl isocyanate). The addition time of water in acetonitrile was 2 hours, and the temperature during the addition of water was 5°C. The temperature after addition was 60°C. The CO2 release profile was used as an indicator of the smoothness of the reaction.

[0107] Using the sulfamoyl chloride solution thus prepared, the compound of structural formula (IIIa) was converted into the compound of structural formula (IVa).

[0108] The yield of the compound of structural formula (IVa) in the crude sample was evaluated by high performance liquid chromatography (HPLC).

[0109] The yield was 78.2% when sulfamoyl chloride prepared in the presence of dimethylacetamide was used.

[0110] [Example 8] The apparatus used was a 1 L automated reactor equipped with a condenser and a calibrated mass flow meter for measuring the CO2 flow rate. The apparatus was made of glass and Teflon.

[0111] Sulfamoyl chloride was prepared by reacting 1 molar equivalent (eq.) of water in acetonitrile (12% w / w in acetonitrile) with chlorosulfonyl isocyanate in toluene (33% w / w in toluene) in the presence of dimethylacetamide (0.001 mole per mole of chlorosulfonyl isocyanate). The addition time of water in acetonitrile was 1.5 hours, and the temperature during the addition of water was 15°C. The temperature after addition was 60°C. The CO2 release profile was used as an indicator of the smoothness of the reaction.

[0112] Using the sulfamoyl chloride solution thus prepared, the compound of structural formula (IIIa) was converted into the compound of structural formula (IVa).

[0113] The yield of the compound of structural formula (IVa) in the crude sample was evaluated by high performance liquid chromatography (HPLC).

[0114] The yield was 74.6% when sulfamoyl chloride prepared in the presence of dimethylacetamide was used.

Claims

1. Structural formula (I) 【Chemistry 1】 1. A method for preparing a compound of formula (I), comprising: Structural formula (II) 【Chemistry 2】 with water in the presence of an organic amide or an organic amine.

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

3. 3. The method of claim 1, wherein the organic amide is dimethylacetamide and the organic amine is triethylamine.

4. 4. The process of claim 3, wherein the catalytic amount of said organic amide or said organic amine is 0.001 to 0.3 moles per mole of chlorosulfonyl isocyanate, preferably 0.002 to 0.1 moles per mole of chlorosulfonyl isocyanate, more preferably 0.003 to 0.07 moles per mole of chlorosulfonyl isocyanate, more preferably 0.05 moles per mole of chlorosulfonyl isocyanate, more preferably 0.005 moles per mole of chlorosulfonyl isocyanate, and most preferably 0.003 moles per mole of chlorosulfonyl isocyanate.

5. 5. The process according to claim 1, 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. Chlorosulfonyl isocyanate is C ６～１０ Aromatic solvents, dichloromethane or C ５～１２ present in a hydrocarbon solvent, ５～１２ The hydrocarbon solvent is selected from the group consisting of hexane, heptane, and cyclohexane; ６～１０ The aromatic solvent is selected from the group consisting of xylene, toluene, and chlorobenzene, and preferably ６～１０ The aromatic solvent is toluene or chlorobenzene, and most preferably, ６～１０ 6. The method of claim 5, wherein the aromatic solvent is toluene.

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

8. 8. The process according to any one of claims 1 to 7, wherein the water is added as a solution in an inert solvent, preferably in an inert polar solvent, preferably in acetonitrile.

9. 9. The method of 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. 10. The process of any one of claims 1 to 9, wherein the amount of water is from 0.5 to 1.5 moles per mole of chlorosulfonyl isocyanate, preferably from 0.95 to 1.05 moles per mole of chlorosulfonyl isocyanate, most preferably 1 mole per mole of chlorosulfonyl isocyanate.

11. The process according to any one of claims 1 to 10, wherein the time for adding water in acetonitrile to chlorosulfonyl isocyanate in an inert solvent in the presence of the organic amide or the organic amine is from 1 hour to 8 hours, preferably from 1 hour to 6 hours, more preferably from 1 hour to 4 hours, and most preferably from 2 hours to 4 hours.

12. the method comprising: 【Transformation 3】 with a compound of structural formula (IV) 【Chemistry 4】 used to convert into the compound wherein R is a C group optionally containing one or more heteroatoms such as oxygen, nitrogen, and sulfur. １ ~C ２０ 12. The method of claim 1, wherein the alkyl group represents a hydrocarbon group.

13. The compound of structural formula (III) 【Transformation 5】 and the compound of structural formula (IV) is 【Transformation 6】 13. The method of claim 12, wherein:

14. The compound of structural formula (IV) is preferably reacted in situ or stepwise with a compound of structural formula (V) 【Transformation 7】 or any orally acceptable salt thereof, wherein R is as defined in claim 12; or a compound of structural formula (IVa), (IVb) or (IVc) 【Transformation 8】 or any orally acceptable salt thereof.

15. Structural formula (I) 【Chemistry 9】 of the compound Structural Formula (IVa), (IVb) or (IVc) 【Chemistry 10】 20. The use of a compound of formula (I) for preparing a compound of formula (I).

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