Process for preparation of biguanide and triazine

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.

Description

Technical Field

[0001] The present invention belongs to the field of agrochemistry and 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) are compounds used as herbicides.

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

[0004]

[0005] 1-Cyanoguanidine is reacted with an amine having 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-methylindane hydrochloride is reacted with 1-cyanoguanidine in 1,3-dichlorobenzene at 140-150° C., a biguanide intermediate having formula (I) is obtained in a yield of 67.7%.

[0009] Furthermore, according to the 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 the compound 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 biguanidine-aluminum complex in the first step. The addition of the aluminum alkoxide allows the first reaction to proceed at low temperatures and forms a stable biguanidine-aluminum complex intermediate, which also reacts in a "one-pot" manner to provide final indazine fluazifop, with a yield 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 results in a large amount of waste, which requires expensive and complicated disposal and is a major disadvantage in industrial production. Each step of the method also requires a combination of several different solvents, which is also an operational challenge when attempting to recycle and separate each of these solvents.

[0013] A third method known in the art for preparing indazine fluazifop is disclosed in EP 3347342 A1. According to this 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 according to the above disclosure of EP 1592674 A1 is achieved in a higher yield than in EP 1592674 A1. This 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 the 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 indoxazinflumethane, and it was an object of the present invention to provide a process which overcomes 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 an optionally substituted C1-C4 alkyl group, wherein the optional substituents are selected from the group consisting of halogen, an aliphatic group, a haloaliphatic 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;

[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 comprising a trimethylsilyl-containing compound and an optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or an optionally alkyl-substituted γ-, δ-, ε-lactone.

[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 an optionally substituted C1-C4 alkyl group, wherein the optional substituents are selected from the group consisting of halogen, aliphatic, haloaliphatic, 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

[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 of formula (II) or an acid addition salt thereof

[0028]

[0029] where R 1 、R 2 , A and n are as defined in formula (IV), in a mixture comprising a trimethylsilyl-containing compound and an optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or an optionally alkyl-substituted γ-, δ-, ε-lactone;

[0030] b) adding a base and a carboxylic acid derivative of formula (III) to the biguanide compound of formula (I) or an acid addition salt thereof 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: a carboxylic acid ester, a carboxylic acid orthoester, a carboxylic acid chloride, a carboxylic acid amide, a nitrile, or a carboxylic acid anhydride. DETAILED DESCRIPTION

[0033] definition

[0034] The embodiments of the present invention are discussed in detail below. When describing the embodiments, specific terms are used for the sake of clarity. However, the present invention is not intended to be limited to the specific terms so selected. Although specific exemplary embodiments have been discussed, it should be understood that this is for illustrative purposes only. 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 were 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," where "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 invention 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 present invention belongs.

[0037] The term "optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam" means a lactam having a 5-membered, 6-membered or 7-membered ring, respectively, wherein the nitrogen atom is substituted by an alkyl group and optionally one or several carbon atoms of the ring are substituted by one or several alkyl groups.

[0038] The term "optionally alkyl-substituted γ-, δ-, ε-lactone" means a lactone having a 5-membered, 6-membered or 7-membered ring, respectively, wherein one or several carbon atoms of the ring are optionally substituted by one or several alkyl groups.

[0039] The term "trimethylsilyl group-containing compound" refers to a compound containing at least one trimethylsilyl group in its molecule.

[0040] The term "alkoxy" refers to an alkyl group bonded to an oxygen.

[0041] The term "thioalkyl" refers to an alkyl group bonded to sulfur.

[0042] The term "haloaliphatic" refers to an aliphatic group substituted with at least one halogen atom.

[0043] The term "aliphatic group" is used herein to encompass, for example and without limitation, straight or branched chain alkyl, alkenyl, and alkynyl groups.

[0044] 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.

[0045] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen atom.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] The term "alicyclic group" is used in the present invention to include, for example and without limitation, cycloalkyl or cycloalkenyl or cycloalkynyl groups.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] The term "alkylamide" refers to an amide having at least one alkyl substituent.

[0054] The term "halosulfonate" refers to an ester group of a sulfonic acid having the formula YS(=O)2-O-, wherein Y is a halogen atom.

[0055] As used herein, the term "aprotic solvent" refers to a solvent that lacks acidic protons.

[0056] 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.

[0057] For the purpose of better understanding this teaching content and in no way limiting the scope of these teaching contents, unless otherwise indicated, all numerical values ​​representing amounts, percentages or ratios 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 indicated, 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 scopes related to the same component or characteristic herein include endpoints, are independently combinable, and include all intermediate points and scopes. 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.

[0058] Method for preparing biguanide compounds

[0059] The present disclosure relates to a method for preparing a biguanide compound having formula (I) or an acid addition salt thereof:

[0060]

[0061] where R 1 and R 2 are each independently hydrogen or an optionally substituted C1-C4 alkyl group, wherein the optional substituents are selected from the group consisting of halogen, an aliphatic group, a haloaliphatic 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;

[0062] The method comprises reacting 1-cyanoguanidine with an amine having formula (II) or an acid addition salt thereof

[0063]

[0064] where R 1 、R 2 , A and n are as defined in formula (I), reacted in a mixture comprising a trimethylsilyl-containing compound and an optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or an optionally alkyl-substituted γ-, δ-, ε-lactone.

[0065] This method provides an alternative to existing methods for preparing biguanide compounds and, in particular, provides solutions to some of the problems in the prior art: low yields, large amounts of waste to be disposed of, high reaction temperatures or operationally complex separations. A mixture of a trimethylsilyl-containing compound and an optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or an optionally alkyl-substituted γ-, δ-, ε-lactone allows biguanide compounds of formula (I) to be obtained in high yields. Additionally, we have found that a mixture of a trimethylsilyl-containing compound and an optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or an optionally alkyl-substituted γ-, δ-, ε-lactone allows the reaction temperature to be lowered from 140°C to 148°C and allows good yields of the synthesis of biguanide compounds of formula (I) to be obtained.

[0066] Prior art document Obianom, ON et al., Molecular Pharmaceutics 2017, 14, 2726-2739 discloses the synthesis of 2,3-dihydro-1H-inden-2-yl-biguanide HCl using trimethylsilyl chloride in acetonitrile at 120° C. with a yield of 9%.

[0067] We have found that mixtures of trimethylsilyl-containing compounds and optionally alkyl-substituted N-alkyl gamma-, delta-, epsilon-lactams or optionally alkyl-substituted gamma-, delta-, epsilon-lactones increase the yield of biguanide synthesis and allow for lower reaction temperatures.

[0068] In the method of the present invention, R 1 and R 2 may each independently be a C1-C4 alkyl group, and n may be 1. In the method of the present invention, R 1 and R 2 may each independently be a C1-C4 alkyl group, n may be 1, and A may be a direct bond. In the method of the present invention, R 1 and R 2 can be methyl, and n can be 1. In the method of the present invention, R 1 and R 2 may 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-(biguanidino)-2,6-dimethylindane or (1R, 2S)-1-(biguanidino)-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.

[0069] Acid addition salts of biguanides of formula (I) or amines of formula (II) can 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. Acid addition salts of amines of formula (II) can be produced by reacting an amine of formula (II) with the acid by any conventional method known to those skilled in the art.

[0070] The reaction temperature in the method of the present invention can be in the range of 60°C to 100°C, 65°C to 100°C, or 70°C to 100°C. When the reaction temperature in the method of the present invention is lower than 60°C, the reaction is incomplete or takes a long time to start. When the reaction temperature is higher than 100°C, the yield of the biguanide compound of formula (I) or its acid addition salt begins to decrease due to the generation of impurities. The reaction can be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0071] The trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be added dropwise or all at once to the mixture of 1-cyanoguanidine and the amine of formula (II). The trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be added together or separately.

[0072] The molar ratio of the trimethylsilyl-containing compound to the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15. The molar ratio of the trimethylsilyl-containing compound to the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15, and the temperature of the reaction may be in the range of 60° C. to 100° C. The reaction may be carried out at atmospheric pressure or above atmospheric pressure.

[0073] The amount of the trimethylsilyl-containing compound can be at least 1 mole, at least 1.02 moles, or at least 1.05 moles based on the moles of the amine of formula (II). The amount of the trimethylsilyl-containing compound can be at least 1 mole, at least 1.02 moles, or at least 1.05 moles based on the moles of the amine of formula (II); and the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15. The amount of the trimethylsilyl-containing compound can be at least 1 mole, at least 1.02 moles, at least 1.05 moles based on the moles of the amine having formula (II); the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C, 70°C to 100°C. The amount of the trimethylsilyl-containing compound may be at least 1.05 moles based on the moles of the amine of formula (II); the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; the molar ratio between the trimethylsilyl-containing compound and 1-cyanoguanidine may be in the range of 0.6:1 to 1:0.6; and the reaction temperature may be in the range of 60° C. to 100° C. This reaction may be carried out at atmospheric pressure or above.

[0074] The amount of the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be at least 1 mole, at least 1.5 moles, at least 2 moles based on the moles of the amine having formula (II). The amount of the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be at least 1 mole, at least 1.5 moles, at least 2 moles based on the moles of the amine having formula (II); and the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15. The amount of optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be at least 1 mole, at least 1.5 moles, at least 2 moles based on the moles of amine having formula (II); the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C, 70°C to 100°C. The amount of optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be at least 1 mole, at least 1.5 moles, at least 2 moles based on the moles of the amine having formula (II); the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; the molar ratio between the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone and 1-cyanoguanidine can be in the range of 1:1 to 5:1, 1.5:1 to 3:1; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C, or 70°C to 100°C.The amount of the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be at least 1 mole, at least 1.5 moles, at least 2 moles based on the moles of the amine having formula (II); the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; in the optional The molar ratio between the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone and 1-cyanoguanidine can be in the range of 1:1 to 5:1, 1.5:1 to 3:1; the molar ratio between the trimethylsilyl-containing compound and 1-cyanoguanidine can be in the range of 0.6:1 to 1:0.6, 0.8:1 to 1:0.8; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C, 70°C to 100°C. The amount of the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be at least 1 mole based on the moles of the amine having formula (II); the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; in the optionally alkyl-substituted N The molar ratio between the alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone and 1-cyanoguanidine can be in the range of 1:1 to 5:1; the molar ratio between the trimethylsilyl-containing compound and 1-cyanoguanidine can be in the range of 0.6:1 to 1:0.6; the amount of the trimethylsilyl-containing compound can be at least 1.05 moles based on the moles of the amine of formula (II); and the reaction temperature can be in the range of 60° C. to 100° C. This reaction can be carried out at atmospheric pressure or above atmospheric pressure.

[0075] The trimethylsilyl-containing compound can be selected from the group consisting of trimethylsilyl halides, trimethylsilyl haloalkylsulfonates, trimethylsilyl halosulfonates, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, optionally halogen-substituted alkyltrimethylsilanes, trimethylsilylalkynes, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, optionally halogen-substituted (trimethylsilyl)alkylamides, or secondary or tertiary (trimethylsilyl)amines. The trimethylsilyl group-containing compound may be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, tetramethylsilane, (trimethylsilyl)methyl chloride, 1-(trimethylsilyl)propyne, trimethylsilylacetylene, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine, or tris(trimethylsilyl)amine. The compound containing a trimethylsilyl group can be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, N, O-bis(trimethylsilyl)acetamide, N, O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine. The compound containing a trimethylsilyl group can be trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate.

[0076] The trimethylsilyl-containing compound can be selected from the group consisting of: trimethylsilyl halide, trimethylsilyl haloalkylsulfonate, trimethylsilyl halosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, optionally halogen-substituted alkyltrimethylsilane, trimethylsilylalkyne, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, optionally halogen-substituted (trimethylsilyl)alkylamide, or secondary or tertiary (trimethylsilyl)amine; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C, or 70°C to 100°C. The trimethylsilyl group-containing compound may be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, tetramethylsilane, (trimethylsilyl)methyl chloride, 1-(trimethylsilyl)propyne, trimethylsilylacetylene, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, N,O-bis(trimethylsilyl)acetamide, N, O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C, 70°C to 100°C. The trimethylsilyl-containing compound may be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine; The molar ratio between the silyl compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; the amount of the trimethylsilyl-containing compound can be at least 1 mole, at least 1.02 moles, at least 1.05 moles based on the moles of the amine having formula (II); and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C.The trimethylsilyl group-containing compound may be trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate; the molar ratio between the trimethylsilyl group-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1.5 to 1:15; the amount of the trimethylsilyl group-containing compound may be at least 1.05 moles based on the moles of the amine having formula (II); the molar ratio between the trimethylsilyl group-containing compound and 1-cyanoguanidine may be in the range of 0.6:1 to 1:0.6; and the reaction temperature may be in the range of 60° C. to 100° C. This reaction may be carried out at atmospheric pressure or above.

[0077] The optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: optionally alkyl-substituted N-(C1-C 18)alkylpyrrolidone, optionally alkyl-substituted N-(C1-C4)alkyl 2-piperidone, optionally alkyl-substituted N-(C1-C4)alkylcaprolactam, optionally alkyl-substituted γ-butyrolactone, optionally alkyl-substituted δ-valerolactone, optionally alkyl-substituted ε-caprolactone. The optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, 1-tert-butylpyrrolidone, 1-pentylpyrrolidone, N-hexyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, N-decyl-2-pyrrolidone, 1-dodecyl-2-pyrrolidone, 1-tetradecyl-2-pyrrolidone, 5-methyl-1- pyrrolidone, -tetradecyl-2-pyrrolidone, 1-octadecyl-2-pyrrolidone, 3-methyl-1-octadecyl-2-pyrrolidone, N-methyl-2-piperidone, 1-ethyl-2-piperidone, 1-propyl-2-piperidone, 1-butyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, γ-valerolactone, γ-caprolactone, γ-octalactone, γ-nonalactone, γ-decalactone, γ-undecalactone, δ-valerolactone, δ-octalactone, δ-decalactone, δ-undecalactone, ε-caprolactone, ε-decalactone or ε-dodecalactone. Alternatively alkyl-substituted N-alkyl gamma-, delta-, epsilon-lactam or alternatively alkyl-substituted gamma-, delta-, epsilon-lactone may be selected from the group consisting of: N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, N-methyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, gamma-butyrolactone, delta-valerolactone or epsilon-caprolactone. Alternatively alkyl-substituted N-alkyl gamma-, delta-, epsilon-lactam or alternatively alkyl-substituted gamma-, delta-, epsilon-lactone may be N-methylpyrrolidone.

[0078] The optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: optionally alkyl-substituted N-(C1-C 18)alkylpyrrolidone, optionally alkyl-substituted N-(C1-C4)alkyl 2-piperidone, optionally alkyl-substituted N-(C1-C4)alkylcaprolactam, optionally alkyl-substituted γ-butyrolactone, optionally alkyl-substituted δ-valerolactone, optionally alkyl-substituted ε-caprolactone; and the trimethylsilyl-containing compound may be selected from the group consisting of trimethylsilyl halide, trimethylsilyl haloalkylsulfonate, trimethylsilyl halosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, optionally halogen-substituted alkyltrimethylsilane, trimethylsilylalkyne, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, optionally halogen-substituted (trimethylsilyl)alkylamide, or secondary or tertiary (trimethylsilyl)amine.The optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, 1-tert-butylpyrrolidone, 1-pentylpyrrolidone, N-hexyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, N-decyl-2-pyrrolidone, 1-dodecyl-2-pyrrolidone, 1-tetradecane 1-octadecyl-2-pyrrolidone, 5-methyl-1-tetradecyl-2-pyrrolidone, 1-octadecyl-2-pyrrolidone, 3-methyl-1-octadecyl-2-pyrrolidone, N-methyl-2-piperidone, 1-ethyl-2-piperidone, 1-propyl-2-piperidone, 1-butyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, γ-valerolactone, γ-caprolactone, γ-octalactone, γ-nonalactone, γ-decanolactone, γ-undecalactone, δ-valerolactone, δ-octalactone, δ- Decanolide, δ-undecalactone, ε-caprolactone, ε-decanolide or ε-dodecalactone; the compound containing a trimethylsilyl group can be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, tetramethylsilane, (trimethylsilyl)methyl chloride, 1-(trimethylsilyl)propyne, trimethylsilylacetylene , tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C, 70°C to 100°C.The optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, N-methyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, δ-valerolactone or ε-caprolactone; the trimethylsilyl-containing compound may be selected from the group consisting of: trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, N,O-bis(2-methyl-1-oxo-1-yl)-1-oxo ... (trimethylsilyl) acetamide, N, O-bis (trimethylsilyl) trifluoroacetamide, N-methyl-N- (trimethylsilyl) trifluoroacetamide, N- (trimethylsilyl) diethylamine, bis (trimethylsilyl) amine or tris (trimethylsilyl) amine; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1: 1 to 1: 20, or 1: 1.5 to 1: 15; and the temperature of the reaction can be in the range of 60 ° C to 100 ° C, 65 ° C to 100 ° C. The optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be N-methylpyrrolidone; the trimethylsilyl-containing compound may be trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; the molar ratio between the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone and 1-cyanoguanidine may be in the range of 1:1 to 5:1; and the reaction temperature may be in the range of 60° C. to 100° C. The reaction may be carried out at atmospheric pressure or above.

[0079] In one embodiment, the method for preparing a biguanide compound of formula (I) or an acid addition salt thereof may optionally contain an aprotic solvent. The aprotic solvent may be selected from the group consisting of an optionally halogen-substituted aromatic hydrocarbon, an optionally halogen-substituted aliphatic hydrocarbon, a nitrogen heterocyclic compound, an optionally alkyl-substituted cyclic ether, an aliphatic ether, an aromatic hydrocarbon ether, a nitrile, a ketone, an ester, or a tertiary amide. The aprotic solvent may 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, methyl ethyl ketone, ethyl acetate, n-butyl acetate, hexyl acetate, dimethylformamide, or dimethylacetamide. The aprotic solvent may be selected from the group consisting of toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, chloroform, tetrachloromethane, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethylene, hexane, cyclohexane, quinoline, pyridine, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, anisole, acetonitrile, benzonitrile, acetone, ethyl acetate, dimethylformamide, or dimethylacetamide. The aprotic solvent may be selected from the group consisting of toluene, chlorobenzene, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, anisole, or acetonitrile.

[0080] The aprotic solvent may 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 or tertiary amides; and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactams or optionally alkyl-substituted γ-, δ-, ε-lactones may be selected from the group consisting of: optionally alkyl-substituted N-(C1-C 18)alkylpyrrolidone, optionally alkyl-substituted N-(C1-C4)alkyl 2-piperidone, optionally alkyl-substituted N-(C1-C4)alkylcaprolactam, optionally alkyl-substituted γ-butyrolactone, optionally alkyl-substituted δ-valerolactone, optionally alkyl-substituted ε-caprolactone.The aprotic solvent may 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; the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, 1-tert-butylpyrrolidone, 1-pentylpyrrolidone, N-hexyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, N-decyl-2-pyrrolidone, 1-dodecyl-2-pyrrolidone, 1-tetradecyl-2-pyrrolidone, 5-methyl-1-tetradecyl-2-pyrrolidone, 1-octadecyl-2-pyrrolidone, The compound containing a trimethylsilyl group may be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride, trimethylsilyl chloride,

[0014] The present invention also includes methyl trifluoromethanesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, tetramethylsilane, (trimethylsilyl)methyl chloride, 1-(trimethylsilyl)propyne, trimethylsilylacetylene, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine, or tris(trimethylsilyl)amine.The aprotic solvent may be selected from the group consisting of toluene, benzene, ethylbenzene, xylene, cumene, isopropyl toluene, chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, chloroform, tetrachloromethane, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethylene, hexane, cyclohexane, quinoline, pyridine, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, anisole, acetonitrile, benzonitrile, acetone, ethyl acetate, dimethylformamide or dimethylacetamide; the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N- -butyl-2-pyrrolidone, N-methyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, δ-valerolactone or ε-caprolactone; the trimethylsilyl-containing compound can be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine; and the reaction temperature can be in the range of 60°C to 100°C, 65°C to 100°C. The aprotic solvent may be selected from the group consisting of toluene, chlorobenzene, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, anisole, or acetonitrile; the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be N-methylpyrrolidone; the trimethylsilyl-containing compound may be trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20; and the reaction temperature may be in the range of 60° C. to 100° C. The reaction may be carried out at atmospheric pressure or above.

[0081] The reaction in the method of the present invention is carried out under a protective gas atmosphere.

[0082] Method for preparing triazine compounds

[0083] The present invention also relates to a process for preparing a triazine compound having the formula (IV):

[0084]

[0085] where R1 、R 2 and R 3 are each independently hydrogen or an optionally substituted C1-C4 alkyl group, wherein the optional substituents are selected from the group consisting of halogen, aliphatic, haloaliphatic, 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

[0086] a) a first step of preparing a biguanide compound having formula (I) or an acid addition salt thereof by:

[0087]

[0088] where R 1 、R 2 , A and n are as defined in formula (IV);

[0089] 1-cyanoguanidine is reacted with an amine of formula (II) or an acid addition salt thereof

[0090]

[0091] where R 1 、R 2 , A and n are as defined in formula (IV), in a mixture comprising a trimethylsilyl-containing compound and an optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or an optionally alkyl-substituted γ-, δ-, ε-lactone;

[0092] b) adding a base and a carboxylic acid derivative of formula (III) to the biguanide compound of formula (I) or an acid addition salt thereof obtained in step a),

[0093] ZR 3 (III)

[0094] where R 3 is as defined in formula (IV), and ZR 3 Selected from the group consisting of: a carboxylic acid ester, a carboxylic acid orthoester, a carboxylic acid chloride, a carboxylic acid amide, a nitrile, or a carboxylic acid anhydride.

[0095] This method provides an alternative to existing methods for preparing triazine compounds of formula (IV). The mixture of a trimethylsilyl-containing compound and an optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or an optionally alkyl-substituted γ-, δ-, ε-lactone allows the biguanide compound of formula (I) to be obtained in high yield in step a) of the method. Additionally, it has been found that the solvent mixture in step a) allows the reaction temperature to be lowered from 140°C to 148°C, and the preparation of the triazine compound of formula (IV) can be performed in a one-pot synthesis.

[0096] R 1 and R 2 can be independently C1-C4 alkyl, n can be 1, R 3 It may be a halogen-substituted C1-C4 alkyl group, and ZR 3 It can be a carboxylate. 1 and R 2 can each independently be a C1-C4 alkyl, n can be 1, A can be a direct bond, R 3 It may be a halogen-substituted C1-C4 alkyl group, and ZR 3 It can be a carboxylate. 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 methyl, n can be 1, A can be a direct bond, R 3 It can be a (R)-2-fluoropropionate group, and ZR 3 It can be (R)-methyl 2-fluoropropionate. The compound of 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 of formula (I) can be (1R,2S)-1-(biguanidino)-2,6-dimethylindane or (1R,2S)-1-(biguanidino)-2,6-dimethylindane monohydrochloride, and the compound of formula (II) can be (1R,2S)-1-amino-2,6-dimethylindane or (1R,2S)-1-amino-2,6-dimethylindane monohydrochloride.

[0097] The molar ratio between the carboxylic acid derivative having formula (III) and the biguanide compound having formula (I) may be in the range of 1:1 to 5:1, 1:1 to 3:1, 1:1 to 2:1.

[0098] The acid addition salts of the biguanide of formula (I) or the amine of formula (II) in step a) can 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) can be produced by reacting the amine of formula (II) with the acid by any conventional method known to those skilled in the art.

[0099] The reaction temperature in step a) of the present invention can be in the range of 60°C to 100°C, 65°C to 100°C, or 70°C to 100°C. When the reaction temperature in the present invention is lower than 60°C, the reaction is incomplete or takes a long time to start. When the reaction temperature in step a) is higher than 100°C, the yield of the biguanide compound of formula (I) or its acid addition salt begins to decrease due to the generation of impurities. The reaction in step a) can be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0100] In step a) of the process according to the present invention, the trimethylsilyl group-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be added dropwise or all at once to the mixture of 1-cyanoguanidine and the amine of formula (II). In step a) of the process according to the present invention, the trimethylsilyl group-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be added together or separately.

[0101] In step a) of the method of the present invention, the molar ratio between the trimethylsilyl group-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15. In step a) of the method of the present invention, the molar ratio between the trimethylsilyl group-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15, and the reaction temperature may be in the range of 60° C. to 100° C. The reaction of step a) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0102] In step a) of the process of the present invention, the amount of the trimethylsilyl-containing compound may be at least 1 mole, at least 1.02 moles, or at least 1.05 moles, based on the moles of the amine having formula (II). In step a) of the process of the present invention, the amount of the trimethylsilyl-containing compound may be at least 1 mole, at least 1.02 moles, or at least 1.05 moles, based on the moles of the amine having formula (II); and the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15. In step a) of the process of the present invention, the amount of the trimethylsilyl-containing compound can be at least 1 mole, at least 1.02 moles, at least 1.05 moles, based on the moles of the amine having formula (II); the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C, or 70°C to 100°C. In step a) of the present invention, the amount of the trimethylsilyl-containing compound may be at least 1.05 moles based on the moles of the amine of formula (II); the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; the molar ratio between the trimethylsilyl-containing compound and 1-cyanoguanidine may be in the range of 0.6:1 to 1:0.6; and the reaction temperature may be in the range of 60° C. to 100° C. The reaction of step a) may be carried out at atmospheric pressure or above atmospheric pressure.

[0103] In step a) of the process of the present invention, the amount of the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be at least 1 mole, at least 1.5 moles, or at least 2 moles, based on the moles of the amine having formula (II). In step a) of the process of the present invention, the amount of the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be at least 1 mole, at least 1.5 moles, or at least 2 moles, based on the moles of the amine having formula (II); and the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15. In step a) of the process of the present invention, the amount of optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be at least 1 mole, at least 1.5 moles, at least 2 moles based on the moles of the amine having formula (II); the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C, or 70°C to 100°C. In step a) of the process of the present invention, the amount of optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone may be at least 1 mole, at least 1.5 moles, at least 2 moles based on the moles of the amine having formula (II); the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; the molar ratio between the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone and 1-cyanoguanidine may be in the range of 1:1 to 5:1, 1.5:1 to 3:1; and the temperature of the reaction may be in the range of 60°C to 100°C, 65°C to 100°C, or 70°C to 100°C.In step a) of the process of the present invention, the amount of the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be at least 1 mole, at least 1.5 moles, at least 2 moles based on the moles of the amine having formula (II); the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15. range; the molar ratio between the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone and 1-cyanoguanidine can be in the range of 1:1 to 5:1, 1.5:1 to 3:1; the molar ratio between the trimethylsilyl-containing compound and 1-cyanoguanidine can be in the range of 0.6:1 to 1:0.6, 0.8:1 to 1:0.8; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C, 70°C to 100°C. In step a) of the process of the present invention, the amount of the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be at least 1 mole based on the moles of the amine having formula (II); the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; in the optional The molar ratio between the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone and 1-cyanoguanidine can be in the range of 1:1 to 5:1; the molar ratio between the trimethylsilyl-containing compound and 1-cyanoguanidine can be in the range of 0.6:1 to 1:0.6; the amount of the trimethylsilyl-containing compound can be at least 1.05 moles based on the moles of the amine of formula (II); and the temperature of the reaction can be in the range of 60° C. to 100° C. The reaction of step a) can be carried out at atmospheric pressure or above atmospheric pressure.

[0104] In step a) of the process according to the invention, the trimethylsilyl-containing compound may be selected from the group consisting of trimethylsilyl halides, trimethylsilylhaloalkylsulfonates, trimethylsilylhalosulfonates, trimethylsilylazide, trimethylsilylcyanide, hexamethyldisilane, optionally halogen-substituted alkyltrimethylsilanes, trimethylsilylalkynes, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, optionally halogen-substituted (trimethylsilyl)alkylamides, or secondary or tertiary (trimethylsilyl)amines. In step a) of the process of the present invention, the trimethylsilyl group-containing compound may be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, tetramethylsilane, (trimethylsilyl)methyl chloride, 1-(trimethylsilyl)propyne, trimethylsilylacetylene, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine. In step a) of the method of the present invention, the trimethylsilyl group-containing compound may be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine. In step a) of the method of the present invention, the trimethylsilyl group-containing compound may be trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate.

[0105] In step a) of the process of the present invention, the trimethylsilyl-containing compound may be selected from the group consisting of trimethylsilyl halides, trimethylsilyl haloalkylsulfonates, trimethylsilyl halosulfonates, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, optionally halogen-substituted alkyltrimethylsilanes, trimethylsilylalkynes, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, optionally halogen-substituted (trimethylsilyl)alkylamides, or secondary or tertiary (trimethylsilyl)amines; and the reaction temperature may be in the range of 60°C to 100°C, 65°C to 100°C, or 70°C to 100°C. In step a) of the process of the present invention, the trimethylsilyl group-containing compound may be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, tetramethylsilane, (trimethylsilyl)methyl chloride, 1-(trimethylsilyl)propyne, trimethylsilylacetylene, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, N,O-bis(trimethylsilyl) )acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C, or 70°C to 100°C.In step a) of the process of the present invention, the trimethylsilyl group-containing compound may be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine; The molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; the amount of the trimethylsilyl-containing compound can be at least 1 mole, at least 1.02 moles, at least 1.05 moles based on the moles of the amine having formula (II); and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C. In step a) of the method of the present invention, the trimethylsilyl group-containing compound may be trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate; the molar ratio between the trimethylsilyl group-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1.5 to 1:15; the amount of the trimethylsilyl group-containing compound may be at least 1.05 moles based on the moles of the amine having formula (II); the molar ratio between the trimethylsilyl group-containing compound and 1-cyanoguanidine may be in the range of 0.6:1 to 1:0.6; and the reaction temperature may be in the range of 60° C. to 100° C. The reaction of step a) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0106] In step a) of the process of the present invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: optionally alkyl-substituted N-(C1-C 18)alkylpyrrolidone, optionally alkyl-substituted N-(C1-C4)alkyl 2-piperidone, optionally alkyl-substituted N-(C1-C4)alkylcaprolactam, optionally alkyl-substituted γ-butyrolactone, optionally alkyl-substituted δ-valerolactone, optionally alkyl-substituted ε-caprolactone. In step a) of the process according to the invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, 1-tert-butylpyrrolidone, 1-pentylpyrrolidone, N-hexyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, N-decyl-2-pyrrolidone, 1-dodecyl-2-pyrrolidone, 1-tetradecyl-2-pyrrolidone, 5-methyl-1-tetradecyl-2-pyrrolidone, 1-octadecyl-2-pyrrolidone, 3-methyl-1-octadecyl-2-pyrrolidone, N-methyl-2-piperidone, 1-ethyl-2-piperidone, 1-propyl-2-piperidone, 1-butyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, γ-valerolactone, γ-caprolactone, γ-octalactone, γ-nonalactone, γ-decalactone, γ-undecalactone, δ-valerolactone, δ-octalactone, δ-decalactone, δ-undecalactone, ε-caprolactone, ε-decalactone or ε-dodecalactone. In step a) of the process according to the invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, N-methyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, δ-valerolactone or ε-caprolactone. In step a) of the process according to the invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be N-methylpyrrolidone.

[0107] In step a) of the process of the present invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: optionally alkyl-substituted N-(C1-C 18)alkylpyrrolidone, optionally alkyl-substituted N-(C1-C4)alkyl 2-piperidone, optionally alkyl-substituted N-(C1-C4)alkylcaprolactam, optionally alkyl-substituted γ-butyrolactone, optionally alkyl-substituted δ-valerolactone, optionally alkyl-substituted ε-caprolactone; and the trimethylsilyl-containing compound may be selected from the group consisting of trimethylsilyl halide, trimethylsilyl haloalkylsulfonate, trimethylsilyl halosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, optionally halogen-substituted alkyltrimethylsilane, trimethylsilylalkyne, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, optionally halogen-substituted (trimethylsilyl)alkylamide, or secondary or tertiary (trimethylsilyl)amine.In step a) of the process of the present invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, 1-tert-butylpyrrolidone, 1-pentylpyrrolidone, N-hexyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, N-decyl-2-pyrrolidone, 1-dodecyl-2-pyrrolidone, Pyrrolidone, 1-tetradecyl-2-pyrrolidone, 5-methyl-1-tetradecyl-2-pyrrolidone, 1-octadecyl-2-pyrrolidone, 3-methyl-1-octadecyl-2-pyrrolidone, N-methyl-2-piperidone, 1-ethyl-2-piperidone, 1-propyl-2-piperidone, 1-butyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, γ-valerolactone, γ-caprolactone, γ-octalactone, γ-nonalactone, γ-decanolactone, γ-undecalactone, δ-valerolactone, δ- Octalactone, δ-decanolide, δ-undecalactone, ε-caprolactone, ε-decanolide or ε-dodecalactone; the compound containing a trimethylsilyl group can be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, tetramethylsilane, (trimethylsilyl)methyl chloride, 1-(trimethylsilyl)propyne, trimethylsilane The reaction mixture may be prepared from methyl acetylene, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine; and the reaction temperature may be in the range of 60°C to 100°C, 65°C to 100°C, or 70°C to 100°C.In step a) of the process of the present invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, N-methyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, δ-valerolactone or ε-caprolactone; the trimethylsilyl group-containing compound may be selected from the group consisting of: trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyltrifluoromethanesulfonic acid Ester, N, O-bis(trimethylsilyl)acetamide, N, O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C. In step a) of the method of the present invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be N-methylpyrrolidone; the trimethylsilyl-containing compound may be trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; the molar ratio between the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone and 1-cyanoguanidine may be in the range of 1:1 to 5:1; and the reaction temperature may be in the range of 60° C. to 100° C. The reaction of step a) may be carried out at atmospheric pressure or above.

[0108] In one embodiment, step a) for preparing a biguanide compound of formula (I) or an acid addition salt thereof may optionally contain an aprotic solvent. In step a) of the method of the present invention, the aprotic solvent may be selected from the group consisting of an optionally halogen-substituted aromatic hydrocarbon, an optionally halogen-substituted aliphatic hydrocarbon, a nitrogen heterocyclic compound, an optionally alkyl-substituted cyclic ether, an aliphatic ether, an aromatic hydrocarbon ether, a nitrile, a ketone, an ester, or a tertiary amide. In step a) of the process of the present invention, the aprotic solvent may 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. In step a) of the process of the present invention, the aprotic solvent may be selected from the group consisting of toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, chloroform, tetrachloromethane, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethylene, hexane, cyclohexane, quinoline, pyridine, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, anisole, acetonitrile, benzonitrile, acetone, ethyl acetate, dimethylformamide or dimethylacetamide. In step a) of the process of the present invention, the aprotic solvent may be selected from the group consisting of toluene, chlorobenzene, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, anisole or acetonitrile.

[0109] In step a) of the process of the present invention, the aprotic solvent may 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 or tertiary amides; and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactams or optionally alkyl-substituted γ-, δ-, ε-lactones may be selected from the group consisting of: optionally alkyl-substituted N-(C1-C 18)alkylpyrrolidone, optionally alkyl-substituted N-(C1-C4)alkyl 2-piperidone, optionally alkyl-substituted N-(C1-C4)alkylcaprolactam, optionally alkyl-substituted γ-butyrolactone, optionally alkyl-substituted δ-valerolactone, optionally alkyl-substituted ε-caprolactone.In step a) of the process of the present invention, the aprotic solvent may 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; the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, 1-tert-butylpyrrolidone, 1-pentylpyrrolidone, N-hexyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, N-decyl-2-pyrrolidone, 1-dodecyl-2-pyrrolidone, 1-tetradecyl-2-pyrrolidone, 5-methyl-1-tetradecyl-2-pyrrolidone, 1-decylpyrrolidone, Octaalkyl-2-pyrrolidone, 3-methyl-1-octadecyl-2-pyrrolidone, N-methyl-2-piperidone, 1-ethyl-2-piperidone, 1-propyl-2-piperidone, 1-butyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, γ-valerolactone, γ-caprolactone, γ-octalactone, γ-nonalactone, γ-decalactone, γ-undecalactone, δ-valerolactone, δ-octalactone, δ-decalactone, δ-undecalactone, ε-caprolactone, ε-decalactone or ε-dodecalactone; and the compound containing a trimethylsilyl group may be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, ... Silyl trifluoromethanesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, tetramethylsilane, (trimethylsilyl)methyl chloride, 1-(trimethylsilyl)propyne, trimethylsilylacetylene, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine, or tris(trimethylsilyl)amine.In step a) of the process of the present invention, the aprotic solvent may be selected from the group consisting of toluene, benzene, ethylbenzene, xylene, cumene, isopropyl toluene, chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, chloroform, tetrachloromethane, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethylene, hexane, cyclohexane, quinoline, pyridine, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, anisole, acetonitrile, benzonitrile, acetone, ethyl acetate, dimethylformamide or dimethylacetamide; the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2- Pyrrolidone, N-butyl-2-pyrrolidone, N-methyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, δ-valerolactone or ε-caprolactone; the trimethylsilyl-containing compound can be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine; and the reaction temperature can be in the range of 60°C to 100°C, 65°C to 100°C. In step a) of the method of the present invention, the aprotic solvent may be selected from the group consisting of toluene, chlorobenzene, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, anisole, or acetonitrile; the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be N-methylpyrrolidone; the trimethylsilyl group-containing compound may be trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate; the molar ratio between the trimethylsilyl group-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20; and the reaction temperature may be in the range of 60° C. to 100° C. The reaction of step a) may be carried out at atmospheric pressure or above.

[0110] 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).

[0111] In one embodiment, the biguanide compound having formula (I) or its acid addition salt can be isolated after step a) 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, including but 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.

[0112] In other embodiments, the biguanide compound of formula (I) or its acid addition salt is not isolated, but the triazine compound of formula (IV) is prepared in a one-pot synthesis, and the solvent from step a) is removed before the reaction of step b) of the process of the present invention. The 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.

[0113] 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, hydrogenphosphates, or dihydrogenphosphates 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.

[0114] 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 moles of the biguanide compound having formula (I).

[0115] 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 based on the moles of the biguanide compound having formula (I), and the base may be selected from the group consisting of hydroxides, hydrides, alkoxides, carbonates, bicarbonates, phosphates, hydrogenphosphates or dihydrogenphosphates 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 based on the moles of the biguanide compound having formula (I), and the base may be selected from the group consisting of hydroxides, alkoxides, carbonates, bicarbonates of alkali metals or alkaline earth metals, 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 3 moles based on the moles of the biguanide compound having formula (I), and the base may be selected from the group consisting of hydroxides, methoxides, ethoxides, propoxides, butoxides, carbonates of alkali metals, or mixtures thereof.

[0116] 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, isopropyl toluene, 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.

[0117] 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).

[0118] Steps a) and b) of the process of the present invention are carried out under a protective gas atmosphere.

[0119] The following examples are included for illustrative purposes only and should not be construed as limitations on the invention claimed herein.

[0120] Examples

[0121] 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 at 90°C using N-methylpyrrolidone and trimethylsilyl chloride.

[0122] Under nitrogen atmosphere, 112ml of NMP (N-Methylpyrrolidone) is loaded into a three-necked round-bottom flask equipped with a nitrogen inlet and a Teflon-coated magnetic stirring bar. Add TMSCl (trimethylsilyl chloride) (1.05 equivalents, 105mmol, 13.32ml) and the reaction mixture is heated to 90°C. At this temperature, 2-cyanoguanidine (1.1 equivalents, 110mmol, 9.24g) and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 equivalent, 100mmol, 16.1g) were added dropwise in NMP (23ml) over a period of 1.5 hours to form a viscous, off-white mixture. Once component addition is complete, reactants are mixed for 14 hours. Once the first step is terminated via HPLC, the reactants are cooled to room temperature and (R)-methyl 2-fluoropropionate (1.7 equivalents, 170 mmol, 18.02 g) is added in one go, followed by a NaOMe / MeOH solution (2.1 equivalents, 210 mmol, 30% w / w, 37.82 g). Once termination is seen, the mixture is transferred to a round-bottom flask and concentrated under reduced pressure. The resulting solid wax is then recrystallized according to the following procedure: MeOH (5 ml / g reactant has an amine of formula II) is added to the product and heated until complete dissolution is seen. The mixture is stirred at room temperature and water (2.8 ml / g reactant has an amine of formula II) is added dropwise over 0.5 hours, followed by additional stirring for 2 hours (it can also be left to stand overnight). During this period, a pale white precipitate forms. The resulting suspension is filtered, and the pale white solid obtained is washed twice with 100 ml of hot water. Finally, the material is dried in an oven at 70° C. under vacuum. The chemical yield obtained is 70%.

[0123] 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 at 100° C. using N-methylpyrrolidone and trimethylsilyl chloride.

[0124] Under nitrogen atmosphere, 112ml of NMP (N-Methylpyrrolidone) is loaded into a three-necked round-bottom flask equipped with a nitrogen inlet and a Teflon-coated magnetic stirring bar. Add TMSCl (1.05 equivalents, 105mmol, 13.32ml) and the reaction mixture is heated to 100°C. At this temperature, a pre-prepared solution of 2-cyanoguanidine (1.1 equivalents, 110mmol, 9.24g) and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 equivalent, 100mmol, 16.1g) in NMP (23ml) is added dropwise over 1.5 hours to form a viscous off-white mixture. Once component addition is complete, reactants are mixed for 12 hours. Once the first step is terminated via HPLC, the reactants are cooled to room temperature and (R)-methyl 2-fluoropropionate (1.7 equivalents, 170 mmol, 18.02 g) is added in one go, followed by a NaOMe / MeOH solution (2.1 equivalents, 210 mmol, 30% w / w, 37.82 g). Once termination is observed, the mixture is transferred to a round-bottom flask and concentrated under reduced pressure. The resulting solid wax is then recrystallized according to the following procedure: MeOH (5 ml / g reactant has an amine of formula II) is added to the product and heated until complete dissolution is observed. The mixture is stirred at room temperature and water (2.8 ml / g reactant has an amine of formula II) is added dropwise over 0.5 hours, followed by an additional 2 hours of stirring (it can also be left to stand overnight). During this period, an off-white precipitate forms. The resulting suspension is filtered, and the off-white solid obtained is washed twice with 100 ml of hot water. Finally, the material is dried in an oven at 70° C. under vacuum. The chemical yield obtained is 56%.

[0125] Example 3: 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 at 90°C using N-methylpyrrolidone, monochlorobenzene and trimethylsilyl chloride.

[0126] Under nitrogen atmosphere, be equipped with the monochlorobenzene of 112ml in the three-necked round-bottom flask of nitrogen inlet and Teflon coating magnetic stirring bar.Add TMSCl (1.05 equivalents, 105mmol, 13.32ml) and reaction mixture is heated to 90 ℃.At this temperature, in 1.5 hours, drip 2-cyanoguanidine (1.1 equivalents, 110mmol, 9.24g) and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 equivalent, 100mmol, 16.1g) pre-prepared solution in NMP (23ml), form viscous off-white mixture during this period.Once component addition is complete, reactant is mixed 14 hours. Once the first step is terminated via HPLC, the reactants are cooled to room temperature and (R)-methyl 2-fluoropropionate (1.7 equivalents, 170 mmol, 18.02 g) is added in one go, followed by a NaOMe / MeOH solution (2.1 equivalents, 210 mmol, 30% w / w, 37.82 g). Once termination is observed, the mixture is transferred to a round-bottom flask and concentrated under reduced pressure. The resulting solid wax is then recrystallized according to the following procedure: MeOH (5 ml / g reactant has an amine of formula II) is added to the product and heated until complete dissolution is observed. The mixture is stirred at room temperature and water (2.8 ml / g reactant has an amine of formula II) is added dropwise over 0.5 hours, followed by additional stirring for 2 hours (it can also be left to stand overnight). During this period, a pale white precipitate forms. The resulting suspension is filtered, and the pale white solid obtained is washed twice with 100 ml of hot water. Finally, the material is dried in an oven at 70° C. under vacuum. The chemical yield obtained is 85%.

[0127] Example 4: 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 at 100°C using N-methylpyrrolidone, monochlorobenzene and trimethylsilyl chloride.

[0128] Under nitrogen atmosphere, be equipped with the monochlorobenzene of 112ml in the three-necked round-bottom flask of nitrogen inlet and Teflon coating magnetic stirring bar.Add TMSCl (1.05 equivalents, 105mmol, 13.32ml) and reaction mixture is heated to 100 ℃.At this temperature, in 1.5 hours, drip 2-cyanoguanidine (1.1 equivalents, 110mmol, 9.24g) and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 equivalent, 100mmol, 16.1g) pre-prepared solution in NMP (23ml), form viscous off-white mixture during this period.Once component addition is complete, reactant is mixed 12-13 hours. Once the first step is terminated via HPLC, the reactants are cooled to room temperature and (R)-methyl 2-fluoropropionate (1.7 equivalents, 170 mmol, 18.02 g) is added in one go, followed by a NaOMe / MeOH solution (2.1 equivalents, 210 mmol, 30% w / w, 37.82 g). Once termination is observed, the mixture is transferred to a round-bottom flask and concentrated under reduced pressure. The resulting solid wax is then recrystallized according to the following procedure: MeOH (5 ml / g reactant has an amine of formula II) is added to the product and heated until complete dissolution is observed. The mixture is stirred at room temperature and water (2.8 ml / g reactant has an amine of formula II) is added dropwise over 0.5 hours, followed by additional stirring for 2 hours (it can also be left to stand overnight). During this period, a pale white precipitate forms. The resulting suspension is filtered, and the pale white solid obtained is washed twice with 100 ml of hot water. Finally, the material is dried in an oven at 70° C. under vacuum. The chemical yield obtained is 85%.

[0129] Example 5: 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 at 83°C using N-methylpyrrolidone, acetonitrile and trimethylsilyl chloride.

[0130] Under nitrogen atmosphere, 112ml of acetonitrile was loaded into a three-necked round-bottom flask equipped with a nitrogen inlet and a Teflon-coated magnetic stirring bar. TMSCl (1.05 equivalents, 105mmol, 13.32ml) was added and the reaction mixture was heated to 83°C. 2-cyanoguanidine (1.1 equivalents, 110mmol, 9.24g) and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 equivalent, 100mmol, 16.1g) were added dropwise in NMP (23ml) over a period of 1.5 hours to give a viscous, off-white mixture. The mixture was mixed for 48 hours. Once the first step is terminated via HPLC, the reactants are cooled to room temperature and (R)-methyl 2-fluoropropionate (1.7 equivalents, 170 mmol, 18.02 g) is added in one go, followed by a NaOMe / MeOH solution (2.1 equivalents, 210 mmol, 30% w / w, 37.82 g). Once termination is observed, the mixture is transferred to a round-bottom flask and concentrated under reduced pressure. The resulting solid wax is then recrystallized according to the following procedure: MeOH (5 ml / g reactant has an amine of formula II) is added to the product and heated until complete dissolution is observed. The mixture is stirred at room temperature and water (2.8 ml / g reactant has an amine of formula II) is added dropwise over 0.5 hours, followed by additional stirring for 2 hours (it can also be left to stand overnight). During this period, a pale white precipitate forms. The resulting suspension is filtered, and the pale white solid obtained is washed twice with 100 ml of hot water. Finally, the material is dried in an oven at 70° C. under vacuum. The chemical yield obtained is 85%.

[0131] Comparative Example 6: 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 at 83° C. using acetonitrile and trimethylsilyl chloride.

[0132] Under nitrogen atmosphere, 112ml of acetonitrile was loaded into a three-necked round-bottom flask equipped with a nitrogen inlet and a Teflon-coated magnetic stirring bar. TMSCl (1.05 equivalents, 105mmol, 13.32ml) was added and the reaction mixture was heated to 83°C. 2-cyanoguanidine (1.1 equivalents, 110mmol, 9.24g) and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 equivalent, 100mmol, 16.1g) were added in batches over 1.5 hours. Coagulation occurred during this period and the solution was not miscible. After 48 hours, only slight conversion was observed, and the reaction was terminated.

[0133] Example 7: 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 at 90°C using N-methylpyrrolidone, toluene and trimethylsilyl chloride.

[0134] Under nitrogen atmosphere, 112ml of toluene was loaded into a three-necked round-bottom flask equipped with a nitrogen inlet and a Teflon-coated magnetic stirring bar. TMSCl (1.05 equivalents, 105mmol, 13.32ml) was added and the reaction mixture was heated to 90°C. At this temperature, a pre-prepared solution of 2-cyanoguanidine (1.1 equivalents, 110mmol, 9.24g) and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 equivalent, 100mmol, 16.1g) in NMP (23ml) was added dropwise over 1.5 hours to form a viscous off-white mixture. Once component addition was complete, reactants were mixed for 14 hours. Once the first step is terminated by HPLC, the reactants are cooled to room temperature and (R)-methyl 2-fluoropropionate (1.7 equivalents, 170 mmol, 18.02 g) is added in one go, followed by a NaOMe / MeOH solution (2.1 equivalents, 210 mmol, 30% w / w, 37.82 g). Once termination is observed, the mixture is transferred to a round-bottom flask and concentrated under reduced pressure. The resulting solid wax is then recrystallized according to the following procedure: MeOH (5 ml / g reactant has an amine of formula II) is added to the product and heated until complete dissolution is observed. The mixture is stirred at room temperature and water (2.8 ml / g reactant has an amine of formula II) is added dropwise over 0.5 hours, followed by an additional 2 hours of stirring (it can also be left to stand overnight). During this period, an off-white precipitate forms. The resulting suspension is filtered, and the off-white solid obtained is washed twice with 100 ml of hot water. Finally, the material is dried in an oven at 70° C. under vacuum. The chemical yield obtained is 71%.

[0135] Example 8: 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 at 100°C using N-methylpyrrolidone, toluene and trimethylsilyl chloride.

[0136] Under nitrogen atmosphere, be equipped with the toluene of 112ml in the three-necked round-bottom flask of nitrogen inlet and Teflon coating magnetic stirring bar.Add TMSCl (1.05 equivalents, 105mmol, 13.32ml) and reaction mixture is heated to 100 ℃.At this temperature, in 1.5 hours, drip 2-cyanoguanidine (1.1 equivalents, 110mmol, 9.24g) and (1R, 2S) -2,6- dimethyl -2,3- dihydro -1H- indene -1- amine (1 equivalent, 100mmol, 16.1g) pre-prepared solution in NMP (23ml), form viscous off-white mixture during this period.Once component addition is complete, reactant is mixed 48 hours. Once the first step is terminated via HPLC, the reactants are cooled to room temperature and (R)-methyl 2-fluoropropionate (1.7 equivalents, 170 mmol, 18.02 g) is added in one go, followed by a NaOMe / MeOH solution (2.1 equivalents, 210 mmol, 30% w / w, 37.82 g). Once termination is seen, the mixture is transferred to a round-bottom flask and concentrated under reduced pressure. The resulting solid wax is then recrystallized according to the following procedure: MeOH (5 ml / g reactant has an amine of formula II) is added to the product and heated until complete dissolution is seen. The mixture is stirred at room temperature and water (2.8 ml / g reactant has an amine of formula II) is added dropwise over 0.5 hours, followed by additional stirring for 2 hours (it can also be left to stand overnight). During this period, a pale white precipitate forms. The resulting suspension is filtered, and the pale white solid obtained is washed twice with 100 ml of hot water. Finally, the material is dried in an oven at 70° C. under vacuum. The chemical yield obtained is 50%.

[0137] Comparative Example 9: 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 at 90° C. using toluene and trimethylsilyl chloride.

[0138] Under nitrogen atmosphere, a three-necked round-bottom flask equipped with a nitrogen inlet and a Teflon-coated magnetic stirring bar was charged with 112 ml of toluene. TMSCl (1.05 equivalents, 105 mmol, 13.32 ml) was added and the reaction mixture was heated to 90° C. At this temperature, 2-cyanoguanidine (1.1 equivalents, 110 mmol, 9.24 g) and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 equivalent, 100 mmol, 16.1 g) were added in batches over 1.5 hours, forming a viscous off-white mixture during this period. The mixture was mixed for 48 hours, but no termination of step 1 was seen. Therefore, the reaction was stopped.

[0139] Example 10: 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 at 90°C using N-methylpyrrolidone, dioxane and trimethylsilyl chloride.

[0140] Under nitrogen atmosphere, be equipped with the dioxane of 112ml in the three-necked round-bottom flask of nitrogen inlet and Teflon coating magnetic stirring bar.Add TMSCl (1.05 equivalents, 105mmol, 13.32ml) and reaction mixture is heated to 90 ℃.At this temperature, in 1.5 hours, drip 2-cyanoguanidine (1.1 equivalents, 110mmol, 9.24g) and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 equivalent, 100mmol, 16.1g) pre-prepared solution in NMP (23ml), form viscous off-white mixture during this period.Once component addition is complete, reactant is mixed 14 hours. Once the first step is terminated by HPLC, the reactants are cooled to room temperature and (R)-methyl 2-fluoropropionate (1.7 equivalents, 170 mmol, 18.02 g) is added in one go, followed by a NaOMe / MeOH solution (2.1 equivalents, 210 mmol, 30% w / w, 37.82 g). Once termination is observed, the mixture is transferred to a round-bottom flask and concentrated under reduced pressure. The resulting solid wax is then recrystallized according to the following procedure: MeOH (5 ml / g reactant has an amine of formula II) is added to the product and heated until complete dissolution is observed. The mixture is stirred at room temperature and water (2.8 ml / g reactant has an amine of formula II) is added dropwise over 0.5 hours, followed by additional stirring for 2 hours (it can also be left to stand overnight). During this period, an off-white precipitate forms. The resulting suspension is filtered, and the off-white solid obtained is washed twice with 100 ml of hot water. Finally, the material is dried in an oven at 70° C. under vacuum. The chemical yield obtained is 79%.

[0141] Example 11: 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 at 90°C using N-methylpyrrolidone, anisole and trimethylsilyl chloride.

[0142] Under nitrogen atmosphere, be equipped with the three-necked round-bottom flask of nitrogen inlet and Teflon-coated magnetic stirring bar and pack into the anisole of 112ml.Add TMSCl (1.05 equivalents, 105mmol, 13.32ml) and reaction mixture is heated to 90 ℃.At this temperature, in 1.5 hours, drip 2-cyanoguanidine (1.1 equivalents, 110mmol, 9.24g) and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 equivalent, 100mmol, 16.1g) pre-prepared solution in NMP (23ml), form viscous off-white mixture during this period.Once component addition is complete, reactant is mixed 48 hours. Once the first step is terminated via HPLC, the reactants are cooled to room temperature and (R)-methyl 2-fluoropropionate (1.7 equivalents, 170 mmol, 18.02 g) is added in one go, followed by a NaOMe / MeOH solution (2.1 equivalents, 210 mmol, 30% w / w, 37.82 g). Once termination is observed, the mixture is transferred to a round-bottom flask and concentrated under reduced pressure. The resulting solid wax is then recrystallized according to the following procedure: MeOH (5 ml / g reactant has an amine of formula II) is added to the product and heated until complete dissolution is observed. The mixture is stirred at room temperature and water (2.8 ml / g reactant has an amine of formula II) is added dropwise over 0.5 hours, followed by an additional 2 hours of stirring (it can also be left to stand overnight). During this period, an off-white precipitate forms. The resulting suspension is filtered, and the off-white solid obtained is washed twice with 100 ml of hot water. Finally, the material is dried in an oven at 70° C. under vacuum. The chemical yield obtained is 84%.

[0143] Example 12: 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 at 90°C using N-methylpyrrolidone, methyltetrahydropyran and trimethylsilyl chloride.

[0144] Under nitrogen atmosphere, in the three-necked round-bottom flask equipped with nitrogen inlet and Teflon-coated magnetic stirring bar, pack into 112ml of Me-THP (methyltetrahydropyran).Add TMSCl (1.05 equivalents, 105mmol, 13.32ml) and reaction mixture is heated to 90 ℃.At this temperature, in 1.5 hours, drip 2-cyanoguanidine (1.1 equivalents, 110mmol, 9.24g) and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 equivalent, 100mmol, 16.1g) pre-prepared solution in NMP (23ml), form viscous off-white mixture during this period.Once component addition is complete, reactant is mixed 14 hours. Once the first step is terminated via HPLC, the reactants are cooled to room temperature and (R)-methyl 2-fluoropropionate (1.7 equivalents, 170 mmol, 18.02 g) is added in one go, followed by a NaOMe / MeOH solution (2.1 equivalents, 210 mmol, 30% w / w, 37.82 g). Once termination is observed, the mixture is transferred to a round-bottom flask and concentrated under reduced pressure. The resulting solid wax is then recrystallized according to the following procedure: MeOH (5 ml / g reactant has an amine of formula II) is added to the product and heated until complete dissolution is observed. The mixture is stirred at room temperature and water (2.8 ml / g reactant has an amine of formula II) is added dropwise over 0.5 hours, followed by an additional 2 hours of stirring (it can also be left to stand overnight). During this period, an off-white precipitate forms. The resulting suspension is filtered, and the off-white solid obtained is washed twice with 100 ml of hot water. Finally, the material is dried in an oven at 70° C. under vacuum. The chemical yield obtained is 84%.

[0145] Example 13: 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 at 90°C using N-methylpyrrolidone, monochlorobenzene and trimethylsilyl trifluoromethanesulfonate

[0146] Under nitrogen atmosphere, 50ml of monochlorobenzene was loaded into a three-necked round-bottom flask equipped with a nitrogen inlet and a Teflon-coated magnetic stirring bar. TMSOTf (trimethylsilyl trifluoromethanesulfonate) (1.05 equivalents, 32mmol, 5.76ml) was added and the reaction mixture was heated to 90°C. At this temperature, a pre-prepared solution of 2-cyanoguanidine (1.1 equivalents, 0.36mmol, 3.05g) and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 equivalent, 0.30mmol, 5g) in NMP (15ml) was added dropwise over 1.5 hours. Once the components were added, the reactants were mixed for 14 hours. Once the first step is terminated via HPLC, the reactant is cooled to room temperature and (R)-methyl 2-fluoropropionate (1.7 equivalents, 53mmol, 5.64g) is added in one go, followed by a NaOMe / MeOH solution (2.1 equivalents, 65mmol, 30% w / w, 11.71g). Once termination is seen, the mixture is transferred to a round-bottom flask and concentrated under reduced pressure. The resulting solid wax is then recrystallized according to the following procedure: MeOH (5ml / g reactant has an amine of formula II) is added to the product and heated until complete dissolution is seen. The mixture is stirred at room temperature, and water (2.8ml / g reactant has an amine of formula II) is added dropwise over 0.5 hours, followed by additional stirring for 2 hours. During this period, the formation of an off-white precipitate occurs. The resulting suspension is filtered, and the off-white solid obtained is washed twice with 100ml hot water. Finally, the material is dried in an oven at 70°C under vacuum. The chemical yield obtained is 87%.

[0147] Comparative Example 14: 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 at 90° C. using dimethyl sulfoxide, monochlorobenzene and trimethylsilyl chloride.

[0148] Under nitrogen atmosphere, in the three-necked round-bottom flask equipped with nitrogen inlet and the magnetic stirring bar of Teflon coating, pack into the monochlorobenzene of 112ml.Add TMSCl (1.05 equivalents, 105mmol, 13.32ml) and reaction mixture is heated to 90 ℃.At this temperature, in 1.5 hours, drip 2-cyanoguanidine (1.1 equivalents, 110mmol, 9.24g) and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 equivalent, 100mmol, 16.1g) pre-prepared solution in DMSO (23ml).Once component addition is complete, then reactant is mixed until seeing termination via HPLC.After 14 hours, see a large amount of impurities and observe partial conversion via HPLC.Therefore, reaction is stopped.

[0149] Comparative Example 15: 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 at 90° C. using dimethylformamide, monochlorobenzene and trimethylsilyl chloride.

[0150] Under nitrogen atmosphere, be equipped with the monochlorobenzene of 112ml in the three-necked round-bottom flask of nitrogen inlet and Teflon coating magnetic stirring bar.Add TMSCl (1.05 equivalents, 105mmol, 13.32ml) and reaction mixture is heated to 90 ℃.At this temperature, in 1.5 hours, drip 2-cyanoguanidine (1.1 equivalents, 110mmol, 9.24g) and (1R, 2S) -2,6- dimethyl -2,3- dihydro -1H- indene -1- amine (1 equivalent, 100mmol, 16.1g) pre-prepared solution in DMF (23ml).Once component addition is complete, reactant is mixed 14 hours.After 14 hours, except partial conversion, also observe a large amount of impurities.Therefore, reaction is stopped.

Claims

1. A process for preparing a biguanide compound of 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 substituents are selected from the group consisting of halogen, an aliphatic group, a haloaliphatic 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 comprising a trimethylsilyl-containing compound and an optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or an optionally alkyl-substituted γ-, δ-, ε-lactone. 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.- The method according to any one of the preceding claims, wherein The compound of formula (I) is (1R,2S)-1-(biguanidino)-2,6-dimethylindane or (1R,2S)-1-(biguanidino)-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.- The method according to any one of the preceding claims, wherein The temperature of the reaction is in the range of 60°C to 100°C. 5.-The method according to any one of the preceding claims, wherein The molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone is in the range of 1:1 to 1:

20. 6.- The method according to any one of the preceding claims, wherein The trimethylsilyl-containing compound is selected from the group consisting of trimethylsilyl halides, trimethylsilyl haloalkylsulfonates, trimethylsilyl halosulfonates, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, optionally halogen-substituted alkyltrimethylsilanes, trimethylsilylalkynes, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, optionally halogen-substituted (trimethylsilyl)alkylamides, or secondary or tertiary (trimethylsilyl)amines. 7.- The method according to any one of the preceding claims, wherein The optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone is selected from the group consisting of: optionally alkyl-substituted N-(C1-C 18 )alkylpyrrolidone, optionally alkyl-substituted N-(C1-C4)alkyl 2-piperidone, optionally alkyl-substituted N-(C1-C4)alkylcaprolactam, optionally alkyl-substituted γ-butyrolactone, optionally alkyl-substituted δ-valerolactone, optionally alkyl-substituted ε-caprolactone. 8.- The method according to any one of the preceding claims, wherein The method further comprises an aprotic solvent. 9.-A process for preparing a triazine compound of formula (IV): where R 1 、R 2 and R 3 are each independently hydrogen or an optionally substituted C1-C4 alkyl group, wherein the optional substituents are selected from the group consisting of halogen, aliphatic, haloaliphatic, 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: a carboxylic acid ester, a carboxylic acid orthoester, a carboxylic acid chloride, a carboxylic acid amide, a nitrile, or a 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-(biguanidino)-2,6-dimethylindane or (1R,2S)-1-(biguanidino)-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 60°C to 100°C. 13.-The method according to any one of claims 9 to 12, wherein The trimethylsilyl-containing compound in step a) is selected from the group consisting of trimethylsilyl halides, trimethylsilyl haloalkylsulfonates, trimethylsilyl halosulfonates, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, optionally halogen-substituted alkyltrimethylsilanes, trimethylsilylalkynes, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, optionally halogen-substituted (trimethylsilyl)alkylamides, or secondary or tertiary (trimethylsilyl)amines. 14.-The method according to any one of claims 9 to 13, wherein The optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone in step a) is selected from the group consisting of: optionally alkyl-substituted N-(C1-C 18 )alkylpyrrolidone, optionally alkyl-substituted N-(C1-C4)alkyl 2-piperidone, optionally alkyl-substituted N-(C1-C4)alkylcaprolactam, optionally alkyl-substituted γ-butyrolactone, optionally alkyl-substituted δ-valerolactone, optionally alkyl-substituted ε-caprolactone. 15.-The method according to any one of claims 9 to 14, wherein The process further comprises an aprotic solvent in step a).

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