Process for preparation of biguanide salts and triazines

Abstract

A process for preparing a biguanide compound of formula (I) and a triazine compound of formula (IV); wherein R1, R2 and R3 are each independently hydrogen or optionally substituted C1-C4 alkyl, and an optional substituent is selected from the group consisting of halogen, an aliphatic group, a halogenated aliphatic group, an alicyclic group, an alkoxy group, a thioalkyl group, a cyano group or a nitro group; a is-CH2-,-O-or a direct bond; and n is 0, 1, 2 or 3. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of agrochemistry. The invention relates to a process for preparing biguanides and triazines, wherein these triazines are suitable as herbicides for controlling weeds. Background Art

[0002] Triazine compounds are a class of compounds suitable for use as herbicides. Triazine compounds such as atrazine, ametryn, indazine fluazifop or triazine fluazifop belong to compounds used as herbicides.

[0003] The prior art discloses different methods for preparing indoxazine fluazifop in EP 1592674 A1, EP 2231679 A1 or EP 3347342 A1. One of the methods disclosed in the prior art document EP 1592674 A1 involves preparing a biguanide intermediate having formula (I) by the following method:

[0004]

[0005] 1-Cyanoguanidine is reacted with an amine having the formula (II):

[0006]

[0007] The reaction is carried out in a solvent such as 1,2-dichlorobenzene, decalin or white mineral oil at a temperature of 20°C to the reflux temperature of the solvent, preferably at 50°C to 200°C.

[0008] According to the document, when (1R,2S)-1-amino-2-methylindan hydrochloride reacts with 1-cyanoguanidine in 1,3-dichlorobenzene at 140°C-150°C, a biguanide intermediate having formula (I) is obtained in a yield of 67.7%.

[0009] In addition, according to this document EP 1592674 A1, a biguanide intermediate having the formula (I) or an acid addition salt thereof is reacted with a carboxylic acid derivative having the formula (III): ZR 3 , in the presence of a base, in an inert solvent (such as, for example, a polar organic solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide, methanol or ethanol), at a temperature of 0°C to the reflux temperature of the solvent, preferably at 20°C to 100°C, to produce a triazine compound having formula (IV):

[0010]

[0011] This synthesis of compounds of formula (IV) according to the synthesis disclosed therein in EP 1592674 A1 exhibits the disadvantage of low yields in the preparation of the biguanide intermediate of formula (I) or its acid addition salt.

[0012] The additional method described in the prior art is described in EP 2231679 A1. The document mentions the use of aluminum alkoxide as an additive to form a biguanide-aluminum complex in the first step. The addition of the aluminum alkoxide allows the first reaction to be carried out at low temperatures and forms a stable biguanide-aluminum complex intermediate, which also reacts in a "one pot" manner to provide the final indoxazine fluazifop, and its yield is better than the yield reported in EP 1592674 A1. However, the method in this prior art document requires the use of a large amount of excess aluminum alkoxide, which later leads to a large amount of waste, which requires expensive and complicated disposal and it is a major disadvantage in industrial production. Each step of the method also requires a combination of several different solvents, which is also a kind of operational challenge when trying to recycle and separate each of these solvents.

[0013] A third method known in the prior art for preparing indazine fluazifop is disclosed in EP 3347342 A1. According to the document, when an autocatalytic amount of a biguanide intermediate of formula (I) is added to prepare the biguanide intermediate of formula (I) and the reaction is preferably carried out at a temperature of 140° C. to 148° C., the preparation of indazine fluazifop disclosed above according to EP 1592674 A1 is achieved in a higher yield than in EP 1592674 A1. The method also mentions a "one-pot" synthesis, while the second step from the biguanide intermediate of formula (I) to indazine fluazifop involves the addition of a phase transfer catalyst and potassium carbonate as a base. However, the first step is still carried out at very high temperatures and the method also requires filtering of excess potassium carbonate salt, which makes the separation more complicated in operation.

[0014] The present invention therefore provides an alternative to existing processes for preparing indoxazolidinone, and it is an object of the present invention to provide a process which solves some of the following disadvantages: low yields, large amounts of waste to be disposed of, high reaction temperatures or operationally complex separations. Summary of the invention

[0015] The first aspect of the present invention is a method for preparing a biguanide compound having formula (I) or an acid addition salt thereof:

[0016]

[0017] Where R 1 and R 2 are each independently hydrogen or optionally substituted C 1 -C 4 alkyl, wherein the optional substituents are selected from the group consisting of halogen, aliphatic, haloaliphatic, alicyclic, alkoxy, thioalkyl, cyano or nitro; A is -CH 2 -, -O- or a direct bond; and n is 0, 1, 2 or 3;

[0018] The method comprises reacting 1-cyanoguanidine with an amine having formula (II) or an acid addition salt thereof

[0019]

[0020] Where R 1 , R 2 , A and n are as defined in formula (I), reacted in a mixture of a polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and a water-immiscible solvent.

[0021] A second aspect of the present invention is a method for preparing a triazine compound having formula (IV):

[0022]

[0023] Where R 1 , R 2 and R 3 are each independently hydrogen or optionally substituted C 1 -C 4 alkyl, wherein the optional substituents are selected from the group consisting of halogen, aliphatic, haloaliphatic, alicyclic, alkoxy, thioalkyl, cyano or nitro; A is -CH 2 -, -O- or a direct bond; and n is 0, 1, 2 or 3; the method comprises

[0024] a) a first step of preparing a biguanide compound having formula (I) or an acid addition salt thereof by:

[0025]

[0026] Where R 1 , R 2 , A and n are as defined in formula (IV);

[0027] 1-cyanoguanidine is reacted with an amine having formula (II) or an acid addition salt thereof

[0028]

[0029] Where R 1 , R 2 , A and n are as defined in formula (IV), reacted in a mixture of a polar aprotic solvent having a dielectric constant greater than 12.0 when measured at 25°C and a water-immiscible solvent;

[0030] b) adding a base and a carboxylic acid derivative of formula (III) to the biguanide compound of formula (I) or its acid addition salt obtained in step a),

[0031] ZR 3 (III)

[0032] Where R 3 is as defined in formula (IV), and ZR 3 Selected from the group consisting of carboxylic acid ester, carboxylic acid orthoester, carboxylic acid chloride, carboxylic acid amide, nitrile, or carboxylic acid anhydride. DETAILED DESCRIPTION

[0033] definition

[0034] Embodiments of the present invention are discussed in detail below. When describing the embodiments, specific terms are used for clarity. However, the present invention is not intended to limit the specific terms so selected. Although specific exemplary embodiments have been discussed, it should be understood that this is only for illustrative purposes. Those skilled in the relevant art will recognize that other components and configurations can be used without departing from the spirit and scope of the present invention. Although multiple embodiments and features are described herein, it should be understood that, unless mutually exclusive or contrary to the specific description, the aspects of the various features and embodiments of the present invention, even if described separately, can also be combined. All references cited herein are incorporated by reference as if each reference was incorporated separately.

[0035] As used herein, the transitional term "comprising" or "that comprises," which is synonymous with "including" or "containing," is inclusive or open-ended, and does not exclude additional, unrecited elements or method steps. However, each time "comprising" is recited herein, as an alternative embodiment, the term is also intended to encompass the phrases "consisting essentially of" and "consisting of," wherein "consisting of" excludes any elements or steps not specified, and "consisting essentially of" permits the inclusion of additional, unrecited elements or steps that do not materially affect the essential or basic and novel characteristics of the composition or method under consideration.

[0036] Before describing the present subject matter in detail, it may be helpful to provide definitions of certain terms used herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter belongs.

[0037] The term "alkoxy" refers to an alkyl group bonded to oxygen.

[0038] The term "thioalkyl" refers to an alkyl group bonded to sulfur.

[0039] The term "haloaliphatic" refers to an aliphatic group substituted with at least one halogen atom.

[0040] The term "aliphatic group" is used herein to include, for example and without limitation, straight or branched chain alkyl, alkenyl, and alkynyl groups.

[0041] The term "alkyl" refers to a saturated, straight or branched chain group having between 1 and 24, between 1 and 16, between 1 and 14, between 1 and 12, 1, 2, 3, 4, 5 or 6 carbon atoms and bonded to the rest of the molecule by a single bond, including, for example and without limitation, methyl, ethyl, isopropyl, isobutyl, tert-butyl, heptyl, octyl, decyl, dodecyl, hexadecyl, octadecyl, pentyl, 2-ethylhexyl, 2-methylbutyl, 5-methylhexyl, and the like.

[0042] The term "alkenyl" refers to a straight or branched chain group having between 2 and 24, between 2 and 16, between 2 and 14, between 2 and 12, 2, 3, 4, 5 or 6 carbon atoms, having 1, 2 or 3 conjugated or non-conjugated carbon-carbon double bonds, bonded to the rest of the molecule by a single bond, including, for example and without limitation, vinyl, allyl, oleyl, linoleyl, and the like.

[0043] The term "alkynyl" refers to a straight or branched chain group having between 2 and 24, between 2 and 16, between 2 and 14, between 2 and 12, 2, 3, 4, 5 or 6 carbon atoms, having 1, 2 or 3 conjugated or non-conjugated carbon-carbon triple bonds, bonded to the rest of the molecule by a single bond, including, for example and without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentynyl such as 1-pentynyl, and the like.

[0044] The term "alkylene" refers to a saturated, straight or branched chain group having between 1 and 24, between 1 and 16, between 1 and 14, between 1 and 12, 1, 2, 3, 4, 5 or 6 carbon atoms and bonded to the rest of the molecule by a double bond, including, for example and without limitation, methylene, ethylene, isopropylene, isobutylene, tert-butylene, heptylene, octylene, decylene, dodecylene, hexadecylene, and the like.

[0045] The term "alicyclic group" is used in the present invention to include, for example and without limitation, cycloalkyl or cycloalkenyl or cycloalkynyl groups.

[0046] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic aliphatic group having between 3 and 24, between 3 and 16, between 3 and 14, between 3 and 12, between 3, 4, 5 or 6 carbon atoms and bonded to the rest of the molecule by a single bond, including, for example and without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, dimethylcyclohexyl, octahydroindene, decahydronaphthalene, dodecahydrophenazone, and the like.

[0047] The term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic aliphatic group having between 5 and 24, between 5 and 16, between 5 and 14, between 5 and 12, 5 or 6 carbon atoms, having 1, 2 or 3 conjugated or non-conjugated carbon-carbon double bonds, and bonded to the rest of the molecule by a single bond, including, for example and without limitation, cyclopent-1-en-1-yl and the like.

[0048] The term "cycloalkynyl" refers to a non-aromatic monocyclic or polycyclic aliphatic group having between 8 and 24, between 8 and 16, between 8 and 14, between 8 and 12, 8 or 9 carbon atoms, having 1, 2 or 3 conjugated or non-conjugated carbon-carbon triple bonds, and bonded to the rest of the molecule by a single bond, including, for example and without limitation, cyclooct-2-yn-1-yl and the like.

[0049] As used herein, the term "water-immiscible solvent" refers to a solvent that is immiscible or nearly immiscible with water, and in particular, the term "water-immiscible solvent" is used in the present invention to encompass any solvent having a water solubility of less than 1 g / l measured at 25° C. The term "water-miscible solvent" has the opposite meaning to "water-immiscible solvent".

[0050] As used herein, the term "polar aprotic solvent" refers to a polar solvent lacking acidic protons. Polar solvent is a synonym for a water-miscible solvent. In particular, the term "polar aprotic solvent" is used in the present invention to encompass any water-miscible solvent lacking acidic protons and having a dielectric constant of 12 or more measured at 25°C.

[0051] Unless otherwise specifically stated, the terms "a / an" as used herein include the singular and the plural. Therefore, the terms "a / an" or "at least one" can be used interchangeably in this application.

[0052] For the purpose of better understanding the content of this teaching and in no way limiting the scope of these teaching contents, unless otherwise specified, all numerical values ​​of expression amount, percentage or ratio and other numerical values ​​used in the specification and claims should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise specified, the numerical parameters listed in the following specification and the appended claims are approximate values, which can change according to the desired characteristics sought to be obtained. At least, each numerical parameter should at least be interpreted according to the number of reported significant figures and by applying ordinary rounding techniques. In this regard, the term "about" used herein specifically includes ± 10% of the indicated value within the range. In addition, the endpoints of all ranges of the same component or characteristic herein include endpoints, are independently combinable, and include all intermediate points and ranges. Similarly, the scope and amount of each element of the technology described herein can be used together with the scope or amount of any other element.

[0053] Method for preparing biguanide compounds

[0054] The present disclosure relates to a method for preparing a biguanide compound having formula (I) or an acid addition salt thereof:

[0055]

[0056] Where R 1 and R 2 are each independently hydrogen or optionally substituted C 1 -C 4 alkyl, wherein the optional substituents are selected from the group consisting of halogen, aliphatic, haloaliphatic, alicyclic, alkoxy, thioalkyl, cyano or nitro; A is -CH 2 -, -O- or a direct bond; and n is 0, 1, 2 or 3;

[0057] The method comprises reacting 1-cyanoguanidine with an amine having formula (II) or an acid addition salt thereof

[0058]

[0059] Where R 1 , R 2 , A and n are as defined in formula (I), reacted in a mixture of a polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and a water-immiscible solvent.

[0060] This method provides an alternative to existing methods for preparing biguanide compounds, and in particular, it provides solutions to some of the following problems in the prior art: low yield, large amounts of waste to be disposed of, high reaction temperatures or operationally complex separations. A mixture of a polar aprotic solvent having a dielectric constant greater than 12.0 when measured at 25°C and a solvent that is not miscible with water allows biguanide compounds of formula (I) to be obtained in high yield. Additionally, we found that a mixture of a polar aprotic solvent having a dielectric constant greater than 12.0 when measured at 25°C and a solvent that is not miscible with water allows the reaction temperature to be reduced from 140°C-148°C, and a good yield of the synthesis of biguanide compounds of formula (I) is obtained.

[0061] Prior art document EP 3347342 A1 mentions the reaction of an amine compound having formula (II) with cyanoguanidine in a polar aprotic solvent. According to the document, suitable polar aprotic solvents include anisole, n-hexyl acetate, dichlorobenzene and mixtures thereof, wherein anisole is a preferred solvent. Anisole has a dielectric constant of 4.33 at 25°C; n-hexyl acetate has a dielectric constant of 4.42; and o-dichlorobenzene, m-dichlorobenzene, and p-dichlorobenzene have dielectric constants of 9.93, 5.00, and 2.41, respectively. All of these solvents are water-immiscible solvents, and their water solubility is: hexyl acetate 0.4 g / l, anisole 0.14 g / l, o-dichlorobenzene 0.08 g / l, m-dichlorobenzene 0.11 g / l, and p-dichlorobenzene 0.049 g / l, respectively. Although EP3347342A1 discloses anisole, n-hexyl acetate and dichlorobenzene as polar aprotic solvents, these solvents show low polarity and they must be considered as non-polar solvents, and in fact they are water-immiscible solvents. The present invention is different from the prior art in that it contains a mixture of a polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and a solvent that is immiscible with water.

[0062] In the method of the present invention, R 1 and R 2 Can be C independently 1 -C 4 alkyl, and n may be 1. In the method of the present invention, R 1 and R 2 Can be C independently 1 -C 4 alkyl, n may be 1, and A may be a direct bond. In the method of the present invention, R 1 and R 2 may be methyl, and n may be 1. In the method of the present invention, R 1 and R 2may be methyl, n may be 1, and A may be a direct bond. The compound of formula (I) in the method of the present invention may be (1R, 2S)-1-(biguanidinyl)-2,6-dimethylindane or (1R, 2S)-1-(biguanidinyl)-2,6-dimethylindane monohydrochloride, and the compound of formula (II) may be (1R, 2S)-1-amino-2,6-dimethylindane or (1R, 2S)-1-amino-2,6-dimethylindane monohydrochloride.

[0063] The acid addition salts of the biguanide of formula (I) or of the amine of formula (II) may be, for example, salts of acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, carbonic acid, monofunctional or difunctional carboxylic acids and hydroxycarboxylic acids such as acetic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid or lactic acid, and also sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid or 1,5-naphthalenedisulfonic acid. The acid addition salts of the amine of formula (II) may be produced by reaction of the amine of formula (II) with the acid by any conventional method known to those skilled in the art.

[0064] The temperature of the reaction in the method of the present invention may be in the range of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C. The temperature of the reaction in the method of the present invention may be the reflux temperature of the solvent mixture. A mixture of a polar aprotic solvent having a dielectric constant higher than 12.0 and a solvent that is not miscible with water may have a boiling point of at least 105°C when measured at 25°C. The temperature of the reaction in the method of the present invention may be the reflux temperature of a mixture of a polar aprotic solvent having a dielectric constant higher than 12.0 and a solvent that is not miscible with water when measured at 25°C, the boiling point of the mixture being 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C. This reaction may be carried out at atmospheric pressure or at a pressure higher than atmospheric pressure.

[0065] In the solvent mixture used for the reaction of the present method, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the solvent immiscible with water may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3. The ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the solvent immiscible with water may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of at least 105°C. The ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the solvent immiscible with water may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and the solvent mixture may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C. The ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the solvent immiscible with water may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, the solvent mixture may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C, and the temperature of the reaction in the method of the present invention may be the reflux temperature of the solvent mixture. This reaction can be carried out at atmospheric pressure or at a pressure higher than atmospheric pressure.

[0066] The polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C may be added dropwise, or may be added all at once to a mixture of 1-cyanoguanidine with an amine of formula (II) and a water-immiscible solvent, or may be added dropwise together with 1-cyanoguanidine to a mixture of an amine of formula (II) and a water-immiscible solvent.

[0067] Polar aprotic solvents having a dielectric constant above 12.0 when measured at 25°C may have a dielectric constant above 15.0, above 20.0, above 25.0.

[0068] The polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25° C. may be selected from the group consisting of: N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, nitromethane, nitrobenzene, γ-butyrolactone, sulfolane, nitromethane, tetramethylurea, propylene carbonate, hexamethylphosphoramide, butanone, methyl isobutyl ketone, acetone, pyridine or N,N-dimethylpropylene urea. The polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25° C. may be selected from the group consisting of: N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, butanone, methyl isobutyl ketone or acetone. The polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C may be selected from the group consisting of: N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide. The polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C may be N-methylpyrrolidone.

[0069] The polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, nitromethane, nitrobenzene, γ-butyrolactone, cyclopentane, nitromethane, tetramethylurea, propylene carbonate, hexamethylphosphoramide, butanone, methyl isobutyl ketone, acetone, pyridine or N,N-dimethylpropylene urea, and the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3. The polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, butanone, methyl isobutyl ketone or acetone, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of at least 105°C. The polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, or 125°C to 139°C. The polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C may be N-methylpyrrolidone, the weight ratio between the polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, the solvent mixture may have a boiling point of 120°C to 139°C, 125°C to 139°C, and the temperature of the reaction in the method of the present invention may be the reflux temperature of the solvent mixture. The reaction may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0070] The solvent that is not miscible with water can be selected from the group consisting of: chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, decalin, n-butyl acetate, hexyl acetate, white mineral oil, tetrachloroethylene or dibutyl ether. The solvent that is not miscible with water can be selected from the group consisting of: chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, isopropylbenzene, n-butyl acetate, hexyl acetate, white mineral oil. The solvent that is not miscible with water can be selected from the group consisting of: o-chlorobenzene, dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, hexyl acetate or white mineral oil. The solvent that is not miscible with water can be chlorobenzene.

[0071] The water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, decalin, n-butyl acetate, hexyl acetate, white mineral oil, tetrachloroethylene or dibutyl ether, and the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, nitromethane, nitrobenzene, γ-butyrolactone, cyclopentane, nitromethane, tetramethylurea, propylene carbonate, hexamethylphosphoramide, butanone, methyl isobutyl ketone, acetone, pyridine or N,N-dimethylpropylene urea. The water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, isopropylbenzene, n-butyl acetate, hexyl acetate, white mineral oil, and the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25° C. may be selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, butanone, methyl isobutyl ketone or acetone. The water-immiscible solvent may be selected from the group consisting of o-chlorobenzene, dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, hexyl acetate or white mineral oil, and the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25° C. may be selected from the group consisting of N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide. The water-immiscible solvent may be chlorobenzene, and the polar aprotic solvent having a dielectric constant greater than 25.0 when measured at 25°C may be N-methylpyrrolidone.

[0072] The water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, decalin, n-butyl acetate, hexyl acetate, white mineral oil, tetrachloroethylene or dibutyl ether, and the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3. The water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, isopropylbenzene, n-butyl acetate, hexyl acetate, white mineral oil, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of at least 105°C. The water-immiscible solvent may be selected from the group consisting of o-chlorobenzene, dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, hexyl acetate or white mineral oil, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C. The water-immiscible solvent may be chlorobenzene, the weight ratio between the polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, the solvent mixture may have a boiling point of 120°C to 139°C, 125°C to 139°C, and the temperature of the reaction in the method of the present invention may be the reflux temperature of the solvent mixture. The reaction may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0073] The water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, decalin, n-butyl acetate, hexyl acetate, white mineral oil, tetrachloroethylene or dibutyl ether, and the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25° C. may be selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methyl The invention can be selected from the group consisting of 1, 2, 4, 5-dimethylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, nitromethane, nitrobenzene, γ-butyrolactone, cyclopentane, nitromethane, tetramethyl urea, propylene carbonate, hexamethylphosphoramide, butanone, methyl isobutyl ketone, acetone, pyridine or N,N-dimethylpropylene urea, and the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25° C. and the water-immiscible solvent can be in the range of 1:1 to 1:5, or 1:1.5 to 1:3. The water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, isopropylbenzene, n-butyl acetate, hexyl acetate, white mineral oil, the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, butanone, methyl isobutyl ketone or acetone, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of at least 105°C. The water-immiscible solvent may be selected from the group consisting of o-chlorobenzene, dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, hexyl acetate or white mineral oil, the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, or 125°C to 139°C.The water-immiscible solvent may be chlorobenzene, the polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C may be N-methylpyrrolidone, the weight ratio between the polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, the solvent mixture may have a boiling point of 120°C to 139°C, 125°C to 139°C, and the temperature of the reaction in the method of the present invention may be the reflux temperature of the solvent mixture. The reaction may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0074] The reaction in the method of the present invention is carried out under a protective gas atmosphere.

[0075] Method for preparing triazine compounds

[0076] The present invention also relates to a process for preparing a triazine compound having the formula (IV):

[0077]

[0078] Where R 1 , R 2 and R 3 are each independently hydrogen or optionally substituted C 1 -C 4 alkyl, wherein the optional substituents are selected from the group consisting of halogen, aliphatic, haloaliphatic, alicyclic, alkoxy, thioalkyl, cyano or nitro; A is -CH 2 -, -O- or a direct bond; and n is 0, 1, 2 or 3; the method comprises

[0079] a) a first step of preparing a biguanide compound having formula (I) or an acid addition salt thereof by:

[0080]

[0081] Where R 1 , R 2 , A and n are as defined in formula (IV);

[0082] 1-cyanoguanidine is reacted with an amine having formula (II) or an acid addition salt thereof

[0083]

[0084] Where R 1 , R 2 , A and n are as defined in formula (IV), reacted in a mixture of a polar aprotic solvent having a dielectric constant greater than 12.0 when measured at 25°C and a water-immiscible solvent;

[0085] b) adding a base and a carboxylic acid derivative of formula (III) to the biguanide compound of formula (I) or its acid addition salt obtained in step a),

[0086] ZR 3 (III)

[0087] Where R 3 is as defined in formula (IV), and ZR 3 Selected from the group consisting of carboxylic acid ester, carboxylic acid orthoester, carboxylic acid chloride, carboxylic acid amide, nitrile, or carboxylic acid anhydride.

[0088] This method provides an alternative to existing methods for preparing triazine compounds of formula (IV). In step a) of the method, a mixture of a polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and a solvent that is not miscible with water allows the biguanide compound of formula (I) to be obtained in high yield. Additionally, we found that the solvent mixture in step a) allows the reaction temperature to be reduced from 140°C to 148°C and the preparation of the triazine compound of formula (IV) to be carried out in a one-pot synthesis.

[0089] R 1 and R 2 Can be C independently 1 -C 4 Alkyl, n can be 1, R 3 C may be halogen substituted 1 -C 4 Alkyl, and ZR 3 It can be a carboxylic acid ester. 1 and R 2 Can be C independently 1 -C 4 Alkyl, n can be 1, A can be a direct bond, R 3 C may be halogen substituted 1 -C 4 Alkyl, and ZR 3 It can be a carboxylic acid ester. 1 and R 2 can be methyl, n can be 1, and R 3 It may be a (R)-2-fluoropropionate group. 1 and R 2 can be a methyl group, n can be 1, A can be a direct bond, R 3 may be a (R)-2-fluoropropionate group, and ZR 3It can be (R)-2-fluoropropionic acid methyl ester. The compound with formula (IV) in the method of the present invention can be N-[(1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-yl]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine, the compound with formula (I) can be (1R, 2S)-1-(biguanidinyl)-2,6-dimethylindane or (1R, 2S)-1-(biguanidinyl)-2,6-dimethylindane monohydrochloride, and the compound with formula (II) can be (1R, 2S)-1-amino-2,6-dimethylindane or (1R, 2S)-1-amino-2,6-dimethylindane monohydrochloride.

[0090] The amount of the carboxylic acid derivative of formula (III) in step b) of the process of the present invention may be in the range of 1 to 5 moles, 1 to 3 moles, 1 to 2 moles based on the mole of the biguanide compound of formula (I).

[0091] The acid addition salt of the biguanide of formula (I) or the amine of formula (II) in step a) can be, for example, a salt of an acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, carbonic acid, monofunctional or difunctional carboxylic acids and hydroxycarboxylic acids such as acetic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid or lactic acid, and also a sulfonic acid such as methanesulfonic acid, p-toluenesulfonic acid or 1,5-naphthalene disulfonic acid. The acid addition salt of the amine of formula (II) can be produced by any conventional method known to those skilled in the art by reacting the amine of formula (II) with the acid.

[0092] The base in step b) of the process of the present invention may be selected from the group consisting of hydroxides, hydrides, alkoxides, carbonates, bicarbonates, phosphates, hydrogen phosphates or dihydrogen phosphates of alkali metals, alkaline earth metals or ammonium, or tertiary amines or aromatic amines or mixtures thereof. The base in step b) of the process of the present invention may be selected from the group consisting of hydroxides, alkoxides, carbonates, bicarbonates or mixtures thereof of alkali metals or alkaline earth metals. The base in step b) of the process of the present invention may be selected from the group consisting of hydroxides, methoxides, ethoxides, propoxides, butoxides, carbonates or mixtures thereof of alkali metals.

[0093] The amount of the base in step b) of the process of the present invention may be in the range of 1 to 5 moles, 1 to 4 moles, 1 to 3 moles based on the mole of the biguanide compound having formula (I).

[0094] The amount of the base in step b) of the process of the present invention may be in the range of 1 to 5 moles of the biguanide compound of formula (I), and the base may be selected from the group consisting of: hydroxides, hydrides, alcoholates, carbonates, bicarbonates, phosphates, hydrogen phosphates or dihydrogen phosphates of alkali metals, alkaline earth metals or ammonium, or tertiary amines or aromatic amines or mixtures thereof. The amount of the base in step b) of the process of the present invention may be in the range of 1 to 4 moles of the biguanide compound of formula (I), and the base may be selected from the group consisting of: hydroxides, alcoholates, carbonates, bicarbonates, or mixtures thereof of alkali metals or alkaline earth metals. The amount of the base in step b) of the process of the present invention may be in the range of 1 to 3 moles of the biguanide compound of formula (I), and the base may be selected from the group consisting of: hydroxides, methoxides, ethoxides, propoxides, butoxides, carbonates or mixtures thereof of alkali metals.

[0095] The solvent for the reaction in step b) can be any organic solvent. The solvent for the reaction in step b) can be selected from the group consisting of: optionally halogen-substituted aromatic hydrocarbons, optionally halogen-substituted aliphatic hydrocarbons, nitrogen heterocyclic compounds, optionally alkyl-substituted cyclic ethers, aliphatic ethers, ethers of aromatic hydrocarbons, nitriles, ketones, esters, amides, alcohols or diols. The solvent for the reaction in step b) can be selected from the group consisting of: toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, chloromethane, dichloromethane, chloroform, tetrachloromethane, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethylene, pentane, hexane, heptane, cyclohexane, decalin, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, pyridine , pyridazine, pyrimidine, pyrazine, triazine, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, dibutyl ether, tert-butyl methyl ether, anisole, acetonitrile, benzonitrile, acetone, butanone, ethyl acetate, n-butyl acetate, hexyl acetate, dimethylformamide or dimethylacetamide, ethanol, methanol, butanol, tert-butanol, propanol, isopropanol, isopentanol, phenol, ethylene glycol, propylene glycol, diethylene glycol or dimethoxyethane. The solvent for the reaction in step b) can be selected from the group consisting of toluene, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, anisole, acetonitrile, dimethylformamide, dimethylacetamide, ethanol, methanol or butanol. The solvent for the reaction in step b) can be ethanol or methanol.

[0096] The temperature of the reaction in step a) of the process of the present invention may be in the range of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C. The temperature of the reaction in step a) of the process of the present invention may be the reflux temperature of the solvent mixture. The mixture of a polar aprotic solvent having a dielectric constant higher than 12.0 and a water-immiscible solvent in step a) may have a boiling point of at least 105°C. The temperature of the reaction in step a) of the process of the present invention may be the reflux temperature of a mixture of a polar aprotic solvent having a dielectric constant higher than 12.0 and a water-immiscible solvent when measured at 25°C, the boiling point of the mixture being 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C. This reaction of step a) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0097] In the solvent mixture used for the reaction in step a) of the process of the present invention, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the solvent immiscible with water may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3. The ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the solvent immiscible with water may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture in step a) may have a boiling point of at least 105°C. The ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the solvent immiscible with water may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture in step a) may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C. The ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the solvent immiscible with water may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, this solvent mixture in step a) may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C, and the temperature of the reaction in step a) of the process of the present invention may be the reflux temperature of the solvent mixture. This reaction of step a) can be carried out at atmospheric pressure or at a pressure higher than atmospheric pressure.

[0098] The polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C may be added dropwise, or may be added all at once to the mixture of 1-cyanoguanidine with the amine of formula (II) and the water-immiscible solvent in step a), or may be added dropwise together with 1-cyanoguanidine to the mixture of the amine of formula (II) and the water-immiscible solvent in step a) of the process of the present invention.

[0099] The polar aprotic solvent in step a) having a dielectric constant higher than 12.0 when measured at 25°C may have a dielectric constant higher than 15.0, higher than 20.0, higher than 25.0.

[0100] In step a) of the method of the present invention, the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25° C. may be selected from the group consisting of: N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, nitromethane, nitrobenzene, γ-butyrolactone, sulfolane, nitromethane, tetramethylurea, propylene carbonate, hexamethylphosphoramide, butanone, methyl isobutyl ketone, acetone, pyridine or N,N-dimethylpropylene urea. The polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25° C. in step a) may be selected from the group consisting of: N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, butanone, methyl isobutyl ketone or acetone. The polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25° C. in step a) may be selected from the group consisting of: N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide. The polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25° C. in step a) may be N-methylpyrrolidone.

[0101] In step a) of the process of the present invention, the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, nitromethane, nitrobenzene, γ-butyrolactone, cyclopentane, nitromethane, tetramethylurea, propylene carbonate, hexamethylphosphoramide, butanone, methyl isobutyl ketone, acetone, pyridine or N,N-dimethylpropylene urea, and the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3. In step a) of the process of the present invention, the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C may be selected from the group consisting of: N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, butanone, methyl isobutyl ketone or acetone, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of at least 105°C. In step a) of the process of the present invention, the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C. The polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C may be N-methylpyrrolidone, the weight ratio between the polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, this solvent mixture may have a boiling point of 120°C to 139°C, 125°C to 139°C, and the temperature of the reaction in step a) of the process of the present invention may be the reflux temperature of the solvent mixture. This reaction of step a) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0102] In step a) of the method of the present invention, the water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, decalin, n-butyl acetate, hexyl acetate, white mineral oil, tetrachloroethylene or dibutyl ether. The water-immiscible solvent in step a) may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, isopropylbenzene, n-butyl acetate, hexyl acetate, white mineral oil. The water-immiscible solvent in step a) may be selected from the group consisting of o-chlorobenzene, dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, hexyl acetate or white mineral oil. The water-immiscible solvent in step a) may be chlorobenzene.

[0103] In step a) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, decalin, n-butyl acetate, hexyl acetate, white mineral oil, tetrachloroethylene or dibutyl ether, and the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, nitromethane, nitrobenzene, γ-butyrolactone, cyclopentane, nitromethane, tetramethylurea, propylene carbonate, hexamethylphosphoramide, butanone, methyl isobutyl ketone, acetone, pyridine or N,N-dimethylpropylene urea. In step a) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, isopropylbenzene, n-butyl acetate, hexyl acetate, white mineral oil, and the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, butanone, methyl isobutyl ketone or acetone. In step a) of the process of the present invention, the solvent immiscible with water may be selected from the group consisting of o-chlorobenzene, dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, hexyl acetate or white mineral oil, and the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide. In step a) of the process of the present invention, the solvent immiscible with water may be chlorobenzene, and the polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C may be N-methylpyrrolidone.

[0104] In step a) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, decalin, n-butyl acetate, hexyl acetate, white mineral oil, tetrachloroethylene or dibutyl ether, and the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3. In step a) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, isopropylbenzene, n-butyl acetate, hexyl acetate, white mineral oil, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of at least 105°C. In step a) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of o-chlorobenzene, dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, hexyl acetate or white mineral oil, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C. The water-immiscible solvent may be chlorobenzene, the weight ratio between the polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, this solvent mixture may have a boiling point of 120°C to 139°C, 125°C to 139°C, and the temperature of the reaction in step a) of the process of the present invention may be the reflux temperature of the solvent mixture. This reaction of step a) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0105] In step a) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, decalin, n-butyl acetate, hexyl acetate, white mineral oil, tetrachloroethylene or dibutyl ether, and the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25° C. may be selected from the group consisting of N,N-dimethylformamide, dimethyl ethyl ether. amide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, nitromethane, nitrobenzene, γ-butyrolactone, cyclopentane, nitromethane, tetramethyl urea, propylene carbonate, hexamethylphosphoramide, butanone, methyl isobutyl ketone, acetone, pyridine or N,N-dimethylpropylene urea, and the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the water-immiscible solvent can be in the range of 1:1 to 1:5, or 1:1.5 to 1:3. In step a) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, isopropylbenzene, n-butyl acetate, hexyl acetate, white mineral oil, the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, butanone, methyl isobutyl ketone or acetone, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of at least 105°C. In step a) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of o-chlorobenzene, dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, hexyl acetate or white mineral oil, the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, or 125°C to 139°C.The water-immiscible solvent may be chlorobenzene, the polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C may be N-methylpyrrolidone, the weight ratio between the polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, this solvent mixture may have a boiling point of 120°C to 139°C, 125°C to 139°C, and the temperature of the reaction in step a) of the process of the present invention may be the reflux temperature of the solvent mixture. This reaction in step a) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0106] The process for preparing the triazine compound of formula (IV) can be carried out in a one-pot synthesis without isolating the biguanide compound of formula (I) or its acid addition salt, or it can be carried out in two separate steps, wherein the biguanide compound of formula (I) or its acid addition salt is isolated after step a).

[0107] In one embodiment, the biguanide compound having formula (I) or its acid addition salt can be isolated by any conventional method known to those skilled in the art or by crystallization of the biguanide compound having formula (I) or its acid addition salt, which conventional method includes but is not limited to filtering, washing the reaction product with a solvent or a solvent mixture to dissolve impurities of the biguanide compound having formula (I) or its acid addition salt.

[0108] In other embodiments, the biguanide compound of formula (I) or its acid addition salt is not isolated, but the preparation of the triazine compound of formula (IV) is carried out in a one-pot synthesis, and the water-immiscible solvent from step a) is removed before the reaction of step b) of the process of the present invention. The water-immiscible solvent can be removed by any conventional method known to those skilled in the art, including but not limited to distillation, or distillation under vacuum.

[0109] The temperature of step b) of the process of the present invention may be from room temperature to the reflux temperature of the solvent in step b).

[0110] Steps a) and b) of the process of the present invention are carried out under a protective gas atmosphere.

[0111] The following examples are included for illustrative purposes only and should not be construed as limitations of the invention claimed herein.

[0112] Examples

[0113] Example 1: Synthesis of N-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-yl]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine using monochlorobenzene and N-methylpyrrolidone as solvents

[0114] (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine HCl salt (15g, 0.077mol, 1 equivalent) was dissolved in 75ml monochlorobenzene and the mixture was heated to 130°C under a protective gas atmosphere. Next, 1-cyanoguanidine (13g, 0.154mol, 2 equivalents) pre-dissolved in 45ml N-methylpyrrolidone was added dropwise. Then, the reaction mixture was stirred at 130°C for 8h. After completion, the mixture was cooled to 50°C, and then monochlorobenzene was distilled out under vacuum. Afterwards, the reaction mixture was cooled to room temperature under a protective gas atmosphere, and then 30ml MeOH was added to the flask, followed by the addition of NaOMe 30% solution (34.7g, 0.193mol, 2.5 equivalents) and (R)-2-fluoropropionic acid methyl ester (16g, 0.154mol, 2 equivalents) in MeOH. The mixture was stirred for an additional 4 h. At the end of the reaction, water was added dropwise and stirred for an additional 0.5 h. Afterwards, the mixture was filtered and the filter cake was washed with water. Finally, the material was dried in an oven at 70 ° C under vacuum. The chemical yield obtained was 84%.

[0115] Comparative Example 2: Synthesis of N-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-yl]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine using anisole as a solvent

[0116] (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine HCl salt (10 g, 0.05 mol, 1 eq) was dissolved in 100 ml of anisole and the mixture was heated to 140 ° C under a protective gas atmosphere. Next, 1-cyanoguanidine (6.4 g, 0.076 mol, 1.5 eq) was added in portions, followed by tetrabutylammonium bromide (0.8 g, 0.0025 mol, 0.05 eq). The reaction mixture was then stirred at 140 ° C for 3.5 h. After completion, the mixture was cooled to room temperature, and anisole was then distilled off under vacuum. Afterwards, under protective gas atmosphere, the reaction mixture was cooled to room temperature, and then 50ml MeOH was added to the flask, followed by dropwise addition of NaOMe 30% solution (22.5g, 0.125mol, 2.5 equivalents) and (R)-2-fluoropropionic acid methyl ester (10.6g, 0.1mol, 2 equivalents) in MeOH. The mixture was stirred for an additional 4h. When the reaction was finished, water was added dropwise and stirred for an additional 0.5h. Afterwards, the mixture was filtered, and the filter cake was washed with water. Finally, the material was dried in an oven at 70°C under vacuum. The chemical yield obtained was 67%.

[0117] Comparative Example 3: When using anisole as a solvent and K 2 CO 3 Synthesis of N-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indenyl]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine as a base

[0118] (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine HCl salt (7 g, 0.035 mol, 1 eq.) was dissolved in 70 ml of anisole and the mixture was heated to 145°C under a protective gas atmosphere. Next, 1-cyanoguanidine (5.9 g, 0.07 mol, 2 eq.) was added in portions. The reaction mixture was then stirred at 145°C for 8.5 h. Upon completion, the mixture was cooled to 90°C. Thereafter, K was added in one portion. 2 CO 3 (19.3 g, 0.14 mol, 4 eq.), followed by the addition of (R)-methyl 2-fluoropropionate (7.8 g, 0.07 mol, 2.1 eq.) under a protective gas atmosphere. The reaction mixture was stirred at 90 ° C for 16 h. At the end of the reaction, the salt was filtered and washed with hot anisole. The chemical yield obtained in the combined filtrate was 61%.

Claims

1. A method for preparing a biguanide compound having formula (I) or an acid addition salt thereof: Where R 1 and R 2 are each independently hydrogen or an optionally substituted C1-C4 alkyl group, wherein the optional substituent is selected from the group consisting of halogen, an aliphatic group, a halogenated aliphatic group, an alicyclic group, an alkoxy group, a thioalkyl group, a cyano group or a nitro group; A is -CH2-, -O- or a direct bond; and n is 0, 1, 2 or 3; The method comprises reacting 1-cyanoguanidine with an amine having formula (II) or an acid addition salt thereof Where R 1 , R 2 , A and n are as defined in formula (I), reacted in a mixture of a polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and a water-immiscible solvent.

2. The method according to claim 1, wherein: R 1 and R 2 are each independently a C1-C4 alkyl group, and n is 1.

3. A method according to any one of the preceding claims, wherein: The compound of formula (I) is (1R,2S)-1-(biguanidinyl)-2,6-dimethylindane or (1R,2S)-1-(biguanidinyl)-2,6-dimethylindane monohydrochloride, and the compound of formula (II) is (1R,2S)-1-amino-2,6-dimethylindane or (1R,2S)-1-amino-2,6-dimethylindane monohydrochloride.

4. A method according to any one of the preceding claims, wherein: The temperature of the reaction is in the range of 105°C to 150°C.

5. A method according to any one of the preceding claims, wherein: The polar aprotic solvent has a dielectric constant greater than 15.0 when measured at 25°C.

6. A method according to any one of the preceding claims, wherein: The ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25° C. and the water-immiscible solvent is in the range of 1:1 to 1:

5.

7. A method according to any one of the preceding claims, wherein: The polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C is selected from the group consisting of: N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, nitromethane, nitrobenzene, γ-butyrolactone, cyclopentane, nitromethane, tetramethylurea, propylene carbonate, hexamethylphosphoramide, butanone, methyl isobutyl ketone, acetone, pyridine or N,N-dimethylpropylene urea.

8. A method according to any one of the preceding claims, wherein: The water-immiscible solvent is selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, decalin, n-butyl acetate, hexyl acetate, white mineral oil, tetrachloroethylene or dibutyl ether.

9. A method for preparing a triazine compound having formula (IV): Where R 1 , R 2 and R 3 are each independently hydrogen or an optionally substituted C1-C4 alkyl, wherein the optional substituent is selected from the group consisting of halogen, aliphatic, halogenated aliphatic, alicyclic, alkoxy, thioalkyl, cyano or nitro; A is -CH2-, -O- or a direct bond; and n is 0, 1, 2 or 3; the method comprising a) a first step of preparing a biguanide compound of formula (I) or an acid addition salt thereof according to any one of the preceding claims; b) adding a base and a carboxylic acid derivative of formula (III) to the biguanide compound of formula (I) or its acid addition salt obtained in step a), Z-R 3 (III) Where R 3 is as defined in formula (IV), and ZR 3 Selected from the group consisting of carboxylic acid ester, carboxylic acid orthoester, carboxylic acid chloride, carboxylic acid amide, nitrile, or carboxylic acid anhydride.

10. The method according to claim 9, wherein: R 1 and R 2 are each independently C1-C4 alkyl, n is 1, R 3 is a halogen-substituted C1-C4 alkyl group, and ZR 3 It is a carboxylate.

11. The method according to any one of claims 9 to 10, wherein: The compound of formula (IV) is N-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-yl]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine, the compound of formula (I) is (1R,2S)-1-(biguanidinyl)-2,6-dimethylindane or (1R,2S)-1-(biguanidinyl)-2,6-dimethylindane monohydrochloride, and the compound of formula (II) is (1R,2S)-1-amino-2,6-dimethylindane or (1R,2S)-1-amino-2,6-dimethylindane monohydrochloride.

12. The method according to any one of claims 9 to 11, wherein: The temperature of the reaction in step a) is in the range of 105°C to 150°C.

13. The method according to any one of claims 9 to 12, wherein: In step a), the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the water-immiscible solvent is in the range of 1:1 to 1:

5.

14. The method according to any one of claims 9 to 13, wherein: The polar aprotic solvent in step a) having a dielectric constant higher than 12.0 when measured at 25° C. is selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, nitromethane, γ-butyrolactone, cyclopentane, nitromethane, tetramethylurea, propylene carbonate, hexamethylphosphoramide, butanone, acetone, pyridine or N,N-dimethylpropylene urea.

15. The method according to any one of claims 9 to 14, wherein: The water-immiscible solvent in step a) is selected from the group consisting of chlorobenzene, bromobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, decalin, n-butyl acetate, hexyl acetate, white mineral oil, tetrachloroethylene, and dibutyl ether.

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