Novel Synthetic Method of 4,5-Diaminophthalonitrile

Abstract

The present invention relates to a novel synthesis method for 4,5-diaminophthalonitrile, and more specifically, to a novel synthesis method for producing 4,5-diaminophthalonitrile using 4,5-difluorophthalonitrile or 1,2-dibromo-4,5-difluorobenzene as starting materials.

Description

Technology Field

[0001] The present invention relates to a novel synthesis method for 4,5-diaminophthalonitrile, and more specifically, to a novel synthesis method for producing 4,5-diaminophthalonitrile using 4,5-difluorophthalonitrile or 1,2-dibromo-4,5-difluorobenzene as starting materials. . Background Technology

[0002] As shown in Fig. 1, 4,5-diaminophthalonitrile has high symmetry because the electron-donating group, amino (NH2), and the electron-withdrawing group, cyan (CN), are located side by side on both sides of the benzene ring, and it has very high polarity due to a unique electron distribution in which electrons are skewed toward the cyan (CN) group.

[0003] Due to this electron distribution and high symmetry, 4,5-diaminophthalonitrile is utilized as an important intermediate in various fields such as opto-electric materials, dyes, porphyrin derivatives, and liquid crystal materials, and studies have been reported on the synthesis of OLEDs (organic light-emitting diodes) and chromophores with non-linear optical properties used therein, using related derivative compounds as starting materials or intermediates.

[0004] In addition, 1,2-benzenedicarbonitrile, such as 4,5-diaminophthalonitrile, is an efficient starting material used to synthesize phthalocyanine, which has various functional groups, and porphyrazine, a derivative with a higher nitrogen density in its structure than phthalocyanine.

[0005] Meanwhile, in contrast to the wide utility and importance of this material chemistry field, the synthesis process of the material had problems such as low yield due to difficulty in purification or an excessively long synthesis process, and the process of synthesizing 4,5-diaminophthalonitrile in prior studies based on known conventional technology can be broadly classified into three methods.

[0006] All three of the above synthesis routes utilize a Rosenmund-von Braun reaction using copper cyanide (CuCN) to substitute two bromine groups (Br) with cyanide groups (CN), and these are described in detail below.

[0007] The first synthesis method can be synthesized in a total of four steps using ortho-phenyldiamine (ortho-diaminobenzene) as the starting material, as shown in Reaction Scheme 1 below. However, the synthesis process according to the first synthesis method has problems such as the need to directly use highly toxic bromine (Br2) for the bromination reaction, low reproducibility with a synthesis yield of 5–25% in the final synthesis step (cyanation), and a low overall yield [overall yield = 3.5–17%]. This is because the ortho-diaminobenzene structure chelates with residual copper salts, making the process of removing the copper salts remaining after the reaction in the 1,2-diaminobenzene structure very difficult.

[0008] [Reaction Equation 1]

[0009]

[0010] In addition, similar problems associated with chelation also appear in the synthesis method of 4,5-diaminophthalonitrile according to Reaction Scheme 2 of the second synthesis method below. In this method, tin chloride (SnCl2) can be used to reduce the remaining nitro group, but there is a problem in that it is difficult to separate the 1,2-diaminobenzene structure and the tin salt after this reduction reaction. Furthermore, the reactivity of ammonia was insufficient during the process of introducing an amino (NH2) group by reducing ortho-dinitrobenzene with ammonia. That is, once one nitro (NO2) group is reduced by ammonia to become an amino (NH2) group, the additional reduction reactivity decreases, and the remaining nitro group is no longer reduced under the same conditions. Therefore, in this method, after substituting two bromine groups with nitrile groups, the remaining nitro group was reduced using tin chloride (SnCl2), and the total yield of this method is also only 5%.

[0011] [Reaction Equation 2]

[0012]

[0013] As a third method, the synthesis route that is most advanced to date and has optimized yield and conditions is the synthesis of 4,5-diaminophthalonitrile according to Reaction Scheme 3 below, which was reported by the Faust group. This involves first synthesizing 5,6-dicyano-2,1,3-benzothiadiazole and then 4,5-diaminophthalonitrile through a reductive desulfurization reaction using sodium borohydride. 1A new pathway for synthesizing ) was announced, and the Faust research team reported that synthesis could be completed in a good yield in a total of 6 steps using o-dibromobenzene as a starting material. This solved the purification problem caused by chelation between neighboring diaminobenzene and transition metal salts by using the benzothiadiazole structure as the protecting group of diaminobenzene. However, considering the relatively long synthesis steps and the need to use bromine (Br2), which is highly toxic to humans, there is still room for improvement. This synthesis method also has limitations, remaining at a total of 6 steps and a total yield of 16%.

[0014] [Reaction Equation 3]

[0015]

[0016] As mentioned in the prior art above, 4,5-diaminophthalonitrile has electrical and optical properties, so it is utilized as an important intermediate in various fields, including electroluminescent materials and flavin-based electron carriers. However, there was a problem in that the synthesis process for this material was excessively long or the purification conditions were difficult.

[0017] Therefore, there is a continuous demand for the development of novel synthesis methods for 4,5-diaminophthalonitrile that can introduce a method utilizing a deprotection reaction that introduces and then removes an amine protecting group, and a method utilizing a direct amine substitution reaction that uses nucleophilic aromatic substitution reactivity that varies depending on solvent conditions, in order to solve the problem of metal chelation, which was the biggest limitation in existing synthesis research, while simultaneously developing high yield and short synthesis pathways. Prior art literature

[0018] Mitzel, F.; FitzGerald, S.; Beeby, A.; Faust, R. Chem. Eur. J. 2003, 9, 1233Rusanova, J.; Pilkington, M.; Decurtins, S. Chem. Commun. 2002, 2236Faust, R. Eur. J. Org. Chem. 2001, 2797-2803 The problem to be solved

[0019] Accordingly, the technical problem to be solved by the present invention is to provide a novel synthesis method of 4,5-diaminophthalonitrile through a direct amine substitution reaction using nucleophilic aromatic substitution reactivity, or a novel synthesis method of 4,5-diaminophthalonitrile using a deprotection reactivity that introduces an amine protecting group and then removes it, and in particular, to provide a novel synthesis method of 4,5-diaminophthalonitrile having a high yield and a short synthesis route. means of solving the problem

[0020] To achieve the above objective, the present invention comprises gaseous ammonia (NH3) and 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile), according to the following reaction scheme A. 3 Through a reaction with ), or with gaseous ammonia (NH3) and 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthanlonitrile, 4 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, through reaction with ) 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Provides a method for manufacturing ).

[0021] [Reaction Equation A]

[0022]

[0023] Substituent X in the above reaction formula A is F or NH2.

[0024] As one example, the solvent used in the above reaction formula A may be an aprotic polar solvent.

[0025] As one example, the aprotic polar solvent used in the above reaction scheme A may be any one selected from dimethyl sulfoxide, 1,4-dioxane, acetonitrile, hexamethylphosphorous triamide, dimethylformamide, and tetrahydrofuran, or a mixture thereof.

[0026] As one example, the gaseous ammonia (NH3) used in the above reaction scheme A can be reacted under pressure conditions of 1 atm to 100 atm.

[0027] As one example, the gaseous ammonia (NH3) used in the above reaction scheme A can be reacted at a temperature of 100 to 150 °C under pressure conditions of 1 atm to 10 atm.

[0028] As one example, 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthalonitrile, in the above reaction formula A, 4 ) is 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, according to reaction scheme A-1 below 3 It can be produced by the reaction of ) and water ammonia (NH4OH).

[0029] [Reaction Equation A-1]

[0030]

[0031] In addition, the present invention relates to, according to the following reaction scheme A-2, i) 1,2-dibromo-4,5-difluorobenzene (1,2-dibromo-4,5-difluorobenzene, 24,5-difluorophthalonitrile (4,5-difluorophthalonitrile, through the cyanide reaction of ) 3 ) to produce, and ii) gaseous ammonia (NH3) and the above 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 Through a reaction with ), 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Provides a method for manufacturing ).

[0032] [Reaction Equation A-2]

[0033]

[0034] In addition, the present invention relates to, according to the following reaction scheme A-3, i) 1,2-dibromo-4,5-difluorobenzene (1,2-dibromo-4,5-difluorobenzene, 2 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, through the cyanide reaction of ) 3 ) to manufacture, and ii) the obtained 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthalonitrile, by the reaction of ) and water ammonia (NH4OH, 4 After preparing ), iii) gaseous ammonia (NH3) and the above 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthalonitrile, 4 Through a reaction with ), 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Provides a method for manufacturing ).

[0035] [Reaction Equation A-3]

[0036]

[0037] In addition, the present invention relates to an amine (NH2-Prot) to which a Prot group (protecting group) is attached as a substituent and 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, according to the following reaction scheme B. 3 ), or 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthalonitrile, 4 A compound containing a secondary amine group (NH-Prot) in which a Prot group is bonded instead of a fluorine group in a phthalonitrile compound through a reaction with ) 6 or 11 ) to prepare, and ii) a compound comprising a secondary amine group (-NH-Prot) to which the above Prot group is bonded ( 6 or 11 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, by deprotecting the Prot group within ) 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Provides a method for manufacturing ).

[0038] [Reaction Equation B]

[0039]

[0040] Here, the Prot group in the above reaction scheme B may be a functional group to which the secondary amine group (-NH-Prot) to which the Prot group is attached can be converted into a primary amine group (-NH2) by a deprotection reaction under acidic conditions.

[0041] In one embodiment, in the above reaction scheme B, the solvent used in the protection reaction may be an aprotic polar solvent.

[0042] In one embodiment, the aprotic polar solvent used in the protection reaction in the above reaction scheme B may be any one selected from dimethyl sulfoxide, 1,4-dioxane, acetonitrile, hexamethylphosphorous triamide, dimethylformamide, tetrahydrofuran, dichloromethane, and chloroform, or a mixture thereof.

[0043] As one example, in the above reaction scheme B, the protection reaction can be carried out at a temperature of 100 to 150°C.

[0044] As one example, in the above reaction scheme B, the Prot group in the amine (NH2-Prot) to which the Prot group is attached as a substituent may be a substituted or unsubstituted benzyl group.

[0045] As one example, in the above reaction scheme B, the Prot group as a substituent may be a C1 to C10 alkoxybenzyl group in which an alkoxy group is attached to a phenyl ring within the benzyl group.

[0046] As one example, in the above reaction scheme B, a compound comprising a secondary amine group (NH-Prot) to which the Prot group is bonded ( 6 or 11 The deprotecting reaction of the Prot group within can occur under acidic conditions.

[0047] As one example, 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthalonitrile, in the above reaction scheme B, 4 ) is 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, according to reaction scheme A-1 below 3 It can be produced by the reaction of ) and water ammonia (NH4OH).

[0048] [Reaction Equation A-1]

[0049]

[0050] In addition, the present invention relates to, according to the following reaction scheme B-2, i) 1,2-dibromo-4,5-difluorobenzene (1,2-dibromo-4,5-difluorobenzene, 2 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, through the cyanide reaction of ) 3 ) to prepare, and ii) an amine (NH2-Prot) to which a Prot group is attached as a substituent and 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 A compound containing a secondary amine group (NH-Prot) in which a Prot group is bonded instead of a fluorine group in a phthalonitrile compound through a reaction with ) 11 After preparing ), iii) a compound comprising a secondary amine group (NH-Prot) to which the above Prot group is bonded ( 11 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, by deprotection of the Prot group within ) 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Provides a method for manufacturing ).

[0051] [Reaction Equation B-2]

[0052]

[0053] Here, the Prot group in reaction scheme B-2 is a functional group to which the secondary amine group (-NH-Prot) to which the Prot group is attached can be converted into a primary amine group (-NH2) by a deprotection reaction under acidic conditions.

[0054] In addition, the present invention relates to, according to the following reaction scheme B-3, i) 1,2-dibromo-4,5-difluorobenzene (1,2-dibromo-4,5-difluorobenzene, 2 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, through the cyanide reaction of ) 3 ) to manufacture, and ii) the obtained 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthalonitrile, by the reaction of ) and water ammonia (NH4OH, 4 After preparing ), iii) an amine (NH2-Prot) to which a Prot group is attached as a substituent and 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthalonitrile, 4 A compound containing a secondary amine group (NH-Prot) in which a Prot group is bonded instead of a fluorine group in a phthalonitrile compound through a reaction with ) 6 ) to prepare, and iii) a compound comprising a secondary amine group (NH-Prot) to which the above Prot group is bonded ( 6 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, by deprotection of the Prot group within ) 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Provides a method for manufacturing ).

[0055] [Reaction Equation B-3]

[0056]

[0057] Here, the Prot group in reaction scheme B-3 is a functional group to which the secondary amine group (-NH-Prot) to which the Prot group is attached can be converted into a primary amine group (-NH2) by a deprotection reaction under acidic conditions. Effects of the invention

[0058] The synthesis method of 4,5-diaminophthalonitrile according to the present invention can synthesize the final target compound in a relatively high yield through short steps of at least two and up to four steps using 1,2-dibromo-4,5-difluorobenzene or 1,2-dibromo-4,5-difluorobenzene as a starting material, thereby enabling the development of a synthesis route for 4,5-diaminophthalonitrile with higher added value at a low cost.

[0059] In addition, the synthesis method of 4,5-diaminophthalonitrile according to the present invention introduces an amine protecting group that can be removed under weak acid conditions, thereby solving the problem of dependence on transition metal catalysts in the deprotection reaction, which was the biggest limitation of previously reported synthesis methods. Furthermore, since the amine protecting group is easily removed under acid conditions after the reaction is finished, the purification process is simple, and 4,5-diaminophthalonitrile can be synthesized in high yield. Brief explanation of the drawing

[0060] Figure 1 is a schematic diagram showing the electron distribution of 4,5-diaminophthalonitrile. Specific details for implementing the invention

[0061] The present invention will be described in more detail below. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a skilled expert in the art to which the present invention pertains. In general, the nomenclature used herein is well known and commonly used in the art.

[0062] Throughout this specification, when a part is described as "comprising" a certain component, this means that, unless specifically stated otherwise, it does not exclude other components but may include additional components.

[0063] The present invention relates to gaseous ammonia (NH3) and 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile), according to the following reaction scheme A. 3 Through a reaction with ), or with gaseous ammonia (NH3) and 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthalonitrile, 4 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, through reaction with ) 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Provides a method for manufacturing ).

[0064] [Reaction Equation A]

[0065]

[0066] Substituent X in the above reaction formula A is F or NH2.

[0067] That is, according to the above reaction formula A, 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 Performing an amination reaction with ) and gaseous ammonia, or 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthalonitrile, 4 ) through an amination reaction with gaseous ammonia, 4,5-diaminophthalonitrile(4,5-diaminophthalonitrile, 1 ) can be manufactured, and the reaction solvent used in the above reaction formula A may be an aprotic polar solvent.

[0068] Here, the aprotic polar solvent is a solvent having a pKa value of 20 or higher, preferably 30 or higher, more preferably 36 or higher, in which hydrogen contained in the solvent is not ionized into protons and has polar properties according to the asymmetry of the molecular structure, and preferably may be any one selected from dimethyl sulfoxide, 1,4-dioxane, acetonitrile, hexamethylphosphorous triamide, dimethylformamide, tetrahydrofuran, or a mixture thereof.

[0069] In addition, the gaseous ammonia (NH3) used in the above reaction equation A can be reacted under pressure conditions of 1 to 100 atm, preferably within a pressure range of 1.1 to 50 atm, and more preferably within a pressure range of 1.5 to 40 atm, and in addition to the ammonia gas in the reaction gas, an inert gas may be additionally used.

[0070] In addition, as one example, the gaseous ammonia (NH3) used in the above reaction formula A can be reacted at a temperature of 100 to 150 ℃ under pressure conditions of 1 atm to 10 atm.

[0071] In addition, as one embodiment, when the reaction gas in the amination reaction according to the above reaction formula A contains an inert gas in addition to ammonia, the partial pressure of gaseous ammonia (NH3) is preferably in the pressure range of 0.1 to 100 atm, preferably 1 to 50 atm, and more preferably 1.5 to 40 atm.

[0072] For example, in the above reaction scheme A, 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3Through the amination reaction of ) 4,5-diaminophthalonitrile(4,5-diaminophthalonitrile, 1 The method of manufacturing ) can be explained more specifically from the synthesis example according to reaction process 1 below, and the above 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthalonitrile, 4 The amination reaction between ) and gaseous ammonia can also be carried out under similar process conditions.

[0073] [Reaction Process 1]

[0074]

[0075] The 4,5-difluorophthalonitrile in the above reaction process 1 ( 3 As an exemplary solvent for the amination reaction of ), it can be carried out under a non-protic polar solvent that has relatively high solubility for ammonia, and preferably using dimethyl sulfoxide (DMSO) as a solvent, it can be carried out in a high-pressure reactor of 1 atm or more.

[0076] At this time, the reaction temperature can be stirred in the range of 50 to 180 ℃, preferably 80 to 160 ℃, more preferably 90 to 150 ℃ for 30 minutes to 10 days, preferably 3 hours to 5 days, more preferably 12 hours to 3 days. Afterward, to remove the solvent used in the reaction, dimethyl sulfoxide (DMSO), the mixture is diluted with ethyl acetate, and then the reaction mixture is washed with water to remove the solvent and impurities. In addition, to obtain a product of higher purity, a white solid can be obtained with a yield of 62% by recrystallizing with methanol and toluene.

[0077] In addition, 4-amino-5-fluorophthalonitrile used in the above reaction formula A in the present invention, 4 ) is 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, according to reaction scheme A-1 below3 It can be produced by the reaction of ) and water ammonia (NH4OH).

[0078] [Reaction Equation A-1]

[0079]

[0080] For example, the reaction process according to the above reaction scheme A-1 can be explained more specifically from the synthesis example according to the reaction process 2 below.

[0081] [Reaction Process 2]

[0082]

[0083] The 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophathalonitrile) in the above reaction process 2, 4 To synthesize ), a solution of 28 wt% ammonia water mixed with acetonitrile in a ratio of 5:1 to 1:5 (v:v), preferably 1:1 (v:v), was used as a reactant and reaction solvent to aminate the fluorine group.

[0084] Here, when one of the two fluorine atoms is substituted with an amine, the electron density within the benzene structure increases, making it impossible to stabilize the anion of the intermediate in the amine substitution reaction. Consequently, the reactivity of the amine substitution reaction is significantly reduced. Furthermore, in polar protic solvents such as water or methanol, the ammonium ion (NH4) rather than ammonia (NH3, pKa = ~35) + , pKa = 10 Because it mainly exists as ), it exhibits low nucleophilicity in amine substitution reactions. As a result, 4-amino-5-fluorophthalonitrile in which only one fluorine is selectively substituted with an amine within 8 hours under heating conditions of 50 °C ( 4 ) can be obtained with a yield of 98%.

[0085] In addition, the present invention relates to, according to the following reaction scheme A-2, i) 1,2-dibromo-4,5-difluorobenzene (1,2-dibromo-4,5-difluorobenzene, 2 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, through the cyanide reaction of ) 3 ) to produce, and ii) gaseous ammonia (NH3) and the above 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 Through a reaction with ), 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Provides a method for manufacturing ).

[0086] [Reaction Equation A-2]

[0087]

[0088] For example, the reaction process according to the above reaction scheme A-2 can be explained more specifically from the synthesis example according to the reaction process 3 below.

[0089] [Reaction Process 3]

[0090]

[0091] 4,5-difluorophthalonitrile in the above reaction process 3 ( 3 ) is commercially purchased 1,2-dibromo-4,5-difluorobenzene ( 2 It can be synthesized through a selective reaction between an ortho-dibromobenzene structure and zinc cyanide (ZnCN2) using ). The catalysts used in the reaction are tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] and 1,1'-bis(diphenylphosphino)ferrocene (DPPF), and the mechanism of the cyanation reaction of benzene using a palladium catalyst is shown in Figure 1 below.

[0092] [Figure 1]

[0093]

[0094] At this time, polymethylhydrosiloxane was used to maintain catalytic activity through the reduction of palladium, which is a catalyst, and was used to reduce palladium (II), which has a divalent oxidation state after being oxidized during the reaction, back to a zero-valent state.

[0095] By introducing a silicon-based reducing agent into the reaction, there was an advantage in that the reaction proceeded even in an environment other than inert gas conditions such as nitrogen or argon, unlike other transition metal catalyst reactions. After the reaction was completed at 100°C for 4 hours, the transition metal catalyst, ligand, and excess zinc cyanide could be removed by diatomite filtration. Subsequently, a transparent solid crystal could be obtained with an 86% yield by purification using column chromatography with Hex:EtOAc = 4:1 as the developing solvent and recrystallization with n-hexane.

[0096] Subsequently, the 4,5-difluorophthalonitrile in the above reaction process 3 ( 3 The amination reaction of ) can proceed in the same manner as described in the above reaction process 1 explained earlier, thereby 4,5-diaminophthalonitrile ( 1 ) can be obtained with a yield of 62%.

[0097] That is, 4,5-diaminophthalonitrile according to the above reaction process 3 ( 1 The synthesis method of ) is commercially readily obtainable 1,2-dibromo-4,5-difluorobenzene ( 2 Using ) as a starting material, 4,5-diaminophthalonitrile ( 1 It shows that ) can be synthesized.

[0098] In addition, the present invention relates to, according to the following reaction scheme A-3, i) 1,2-dibromo-4,5-difluorobenzene (1,2-dibromo-4,5-difluorobenzene, 2 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, through the cyanide reaction of ) 3 ) to manufacture, and ii) the obtained 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthalonitrile, by the reaction of ) and water ammonia (NH4OH, 4 After preparing ), iii) gaseous ammonia (NH3) and the above 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthalonitrile, 4 Through a reaction with ), 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Provides a method for manufacturing ).

[0099] [Reaction Equation A-3]

[0100]

[0101] For example, the reaction process according to the above reaction scheme A-3 can be explained more specifically from the synthesis example according to the reaction process 4 below.

[0102] [Reaction Process 4]

[0103]

[0104] Here, the above i) 1,2-dibromo-4,5-difluorobenzene (1,2-dibromo-4,5-difluorobenzene, 2 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, through the cyanide reaction of )3 ii) a step of manufacturing ); ii) the obtained 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthalonitrile, by the reaction of ) and water ammonia (NH4OH, 4 A step of manufacturing ); and 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthalonitrile, 4 The reaction step with ) and gaseous ammonia; each can be carried out under the same conditions as specifically described above.

[0105] In addition, the present invention relates to 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 ) or 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthanlonitrile, 4 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, through a deprotection reaction that introduces an amine protecting group and then removes it 1 ) can be synthesized, and a brief reaction equation for this is described in reaction equation H below.

[0106] [Reaction Equation H]

[0107]

[0108] The amine protecting group in the above reaction equation H ( The ) group is a secondary amine group (containing an amine protecting group on an aromatic ring carbon atom within phthalonitrile) When ) is combined, under certain reaction conditions (e.g., acidic conditions), the amine protecting group is deprotected and detached, thereby enabling the amino group (-NH2) to be bonded to the aromatic ring carbon atom within phthalonitrile.

[0109] In the following, 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, through a deprotection reaction in which an amine protecting group according to the present invention is introduced and then removed 1 We will examine the method of manufacturing ) in more detail.

[0110] The present invention relates to an amine (NH2-Prot) to which a Prot group is attached as a substituent and 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, according to the following reaction scheme B, 3 ) or 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthanlonitrile, 4 A compound containing a secondary amine group (NH-Prot) in which a Prot group is bonded instead of a fluorine group in a phthalonitrile compound through a reaction with ) 6 or 11 ) to prepare, and ii) a compound comprising a secondary amine group (-NH-Prot) to which the above Prot group is bonded ( 6 or 11 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, by deprotection of the Prot group within ) 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Provides a method for manufacturing ).

[0111] [Reaction Equation B]

[0112]

[0113] The 'Prot' group in the above reaction scheme B is a functional group that can be converted into a primary amine group (amino group, -NH2) under acidic conditions, in which the secondary amine group (-NH-Prot) to which the 'Prot' group is attached is deprotected by a deprotection reaction in which the 'Prot' group is removed and a hydrogen atom is attached.

[0114] Here, in the above reaction scheme B, the protective reaction is formed by an amine (NH2-Prot) to which a Prot group is attached and 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 ) or 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthanlonitrile, 4 A compound containing a secondary amine group (NH-Prot) to which a Prot group in a phthalonitrile compound is bonded through a reaction with ) 6 or 11 ) can be manufactured, and the reaction solvent used in the protection reaction may be an aprotic polar solvent.

[0115] Here, the aprotic polar solvent is a solvent having a pKa value of 20 or higher, preferably 30 or higher, more preferably 36 or higher, in which hydrogen contained in the solvent is not ionized into protons and has polar properties according to the asymmetry of the molecular structure, and preferably may be any one selected from dimethyl sulfoxide, 1,4-dioxane, acetonitrile, hexamethylphosphorous triamide, dimethylformamide, tetrahydrofuran, dichloromethane, and chloroform, or a mixture thereof.

[0116] In addition, as one example, in the above reaction scheme B, the protection reaction can be carried out at a temperature of 100 to 150 ℃.

[0117] The Prot group in the amine (NH2-Prot) to which the Prot group is attached as a substituent in the above reaction scheme B can be used without limitation as long as it is a protecting group to which the 'Prot' group is detached and a hydrogen atom is bonded by a deprotection reaction of the secondary amine group (-NH-Prot) to which the 'Prot' group is attached under acidic conditions, and preferably, it can be a substituted or unsubstituted benzyl group.

[0118] Here, 'substitution' in the substituted or unsubstituted benzyl group in the above reaction scheme B refers to hydrogen, deuterium, halogen group, amine group, C1-C 24 alkyl group of, C1-C 24 halogenated alkyl group of, C2-C 24 alkenyl group of, C2-C 24 The alkynyl group of, C1- 24 heteroalkyl group of, C6-C 24 aryl group of, C7-C 24 arylalkyl group of, C2-C 24 The heteroaryl group of, C2-C 24 heteroarylalkyl group of, C1-C 24 alkoxy group, C1-C 24 alkylamino group of, C6-C 24 The arylamino group of, C1-C 24 heteroarylamino group of, C1-C 24 alkylsilyl group of, C6-C 24 arylsilyl group of, C6-C 24 It may be any one selected from the aryloxy groups, preferably hydrogen, deuterium, halogen group, amine group, C1-C 12 alkyl group of, C1-C 12 halogenated alkyl group of, C2-C 12 alkenyl group of, C2-C 12 The alkynyl group of, C1- 12 heteroalkyl group of, C6-C 18 aryl group of, C7-C 18 arylalkyl group of, C2-C 18 The heteroaryl group of, C2-C 18 heteroarylalkyl group of, C1-C12 alkoxy group, C1-C 12 alkylamino group of, C6-C 18 The arylamino group of, C1-C 18 heteroarylamino group of, C1-C 12 alkylsilyl group of, C6-C 18 arylsilyl group of, C6-C 18 It may be any one selected from the aryloxy groups, and more preferably, the 'substitution' may be a substituent corresponding to an electron donating group, and the substituent corresponding to an electron donating group is specifically a halogen group, an amine group, or a C1-C 12 It can be any one selected from the alkoxy groups.

[0119] As one example, in the above reaction scheme B, the Prot group as a substituent is a C1 to C group in which an alkoxy group is attached to a phenyl ring within a benzyl group. 10 It may be an alkoxybenzyl group, and C1~C 10 An exemplary substituent of the alkoxybenzyl group may be any one selected from methoxybenzyl group, dimethoxybenzyl group, ethoxybenzyl group, and diethoxybenzyl group, and thus, the amine (NH2-Prot) group to which a Prot group is attached as a substituent may be a substituted or unsubstituted benzylamine group, and more preferably may be any one selected from methoxybenzylamine group, dimethoxybenzylamine group, ethoxybenzylamine group, and diethoxybenzylamine group.

[0120] In this case, when the amine (NH2-Prot) to which the above Prot group is attached is an alkoxybenzylamine group, it is preferable that the alkoxy group be substituted at a carbon atom at a meta or para position relative to the carbon atom to which the amine group is attached to the phenyl ring within the benzyl group.

[0121] In addition, in the above reaction scheme B, a compound comprising a secondary amine group (NH-Prot) to which the Prot group is bonded ( 6 or 11The deprotection reaction of the Prot group within the ) can be carried out under acidic conditions, and the acid used here may be any one selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, propionic acid, and trifluoroacetic acid (TFA), or a mixture thereof.

[0122] For example, the reaction process according to the above reaction scheme B can be explained more specifically from the synthesis example according to reaction process 5 below.

[0123] [Reaction Process 5]

[0124]

[0125] In the above reaction process 5, 4-amino-5-fluorophthalonitrile ( 4 ) and 4-methoxybenzylamine ( 5 Nucleophilic aromatic substitution with ) (S N After introducing an amine functional group containing a protecting group via an Ar) reaction, 4-amino-5-(4-methoxybenzylamino)phthalonitrile ( 6 Synthesized ).

[0126] As such, the rate-determining step of a nucleophilic aromatic substitution reaction is the first intermediate step, the introduction of the nucleophile. Therefore, a method to increase the reactivity of the reaction is to introduce a nucleophile with high nucleophilicity (Nu - When using ), the electron pulling effect of the leaving group is large, so when stabilizing the anion of an adjacent carbon, it can be increased when using a polar aprotic solvent.

[0127] At this time, since the electronegativity of fluorine in the above reaction process 5 is the highest, the attack of the nucleophile on the carbon that is relatively electron-deficient in the first step of the reaction can be facilitated, and thus, among the halobenzene structures, the nucleophilic aromatic substitution reactivity of the fluoride is the highest.

[0128] The mechanism of the nucleophilic aromatic substitution reaction (SnAr) is illustrated below.

[0129]

[0130] Subsequently, 4-amino-5-(4-methoxybenzylamino)phthalonitrile ( 6 ) my Conditions without transition metals were used for the deprotection reaction to remove the introduced protecting group, paramethoxybenzyl (PMB).

[0131] More specifically, 4-amino-5-(4-methoxybenzylamino)phthalonitrile at 0 ℃ ( 6 TFA (trifluoroacetic acid) was added to a suspension of ) and toluene to make the reaction mixture transparent, and the mixture was reacted at room temperature for 2 hours. The solid precipitated during the reaction was filtered, and the white solid was dissolved in ethyl acetate. The organic layer was then washed with an aqueous solution of saturated sodium bicarbonate to neutralize the solution, after which the solvent was removed. Through recrystallization using methanol and toluene, the white solid 4,5-diaminophthalonitrile ( 1 ) can be obtained with a yield of 98%.

[0132] The figure below illustrates the mechanism of the deprotection reaction of the paramethoxybenzyl group, which served as an amine protecting group, under acidic conditions using trifluoroacetic acid. The electron-pushing effect caused by the methoxy (OCH3) group, a strong electron-donating functional group at the para position, allowed the bond at the benzyl-amino position to be easily broken. Additionally, the weak base trifluoroacetate deprotonated the proton at the benzyl position, thereby increasing reactivity. The 4-methoxyphenylmethyl 2,2,2-trifluoroacetate produced as a byproduct of the reaction did not require special removal after the reaction was complete, as it decomposed easily under acidic conditions.

[0133] The deprotection reaction mechanism of the paramethoxybenzyl (PMB) group is illustrated below.

[0134]

[0135] In addition, to compare the reactivity of the deprotection reaction of the paramethoxybenzyl (PMB) group according to the solvent, several solvents and their respective reactivity and reaction characteristics are shown in Table 1 below.

[0136]

[0137] [Table 1]

[0138]

[0139] In non-polar solvents such as toluene and benzene, the pre-neutralization ammonium salt formed after the reaction does not dissolve; therefore, in deprotection reactions using these solvents, it was observed that a solvent-insoluble solid precipitated as the reaction progressed. When the precipitated solid was filtered and neutralized under basic conditions, 4,5-diaminophthalonitrile ( 1 You can obtain ).

[0140] On the other hand, thin-layer chromatography was used to confirm whether the reaction had finished in acetonitrile and dichloromethane. After removing the solvent and the remaining trifluoroacetic acid under low pressure and neutralizing, a clean white solid was obtained as a result with the same yield as shown in Table 1 above.

[0141] In addition, to compare the differences in reactivity due to the electron-donating functional group in the deprotection reaction of PMB (p-methoxylbenzyl), 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophathalonitrile) ( 4The reaction was also carried out with 3,4-dimethoxybenzylamine and 2,4-dimethoxybenzylamine, which have two methoxy (-OCH3) groups, which are representative electron-donating functional groups, and the reaction process is shown in reaction process 6 and reaction process 7 below, respectively.

[0142] [Reaction Process 6]

[0143]

[0144] [Reaction Process 7]

[0145]

[0146] 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophathalonitrile) using dimethyl sulfoxide (DMSO) as a solvent ( 4 ) and two types of dimethoxybenzylamine ( 5 Each 4-amino-5-(3,4-dimethoxybenzylamino)phthalonitrile ( 6 ) and 4-amino-5-(2,4-dimethoxybenzylamino)phthalonitrile ( 6 ) They were obtained with yields of 55% and 52%, respectively.

[0147] This is because the purification of the product was difficult due to side reactions during the nucleophilic aromatic substitution reaction. On the other hand, regarding the removal of the protecting group, there was no significant difference in yield or reaction time compared to the previous paramethoxybenzyl (PMB). It appears that the removal reactivity is excellent even with only a single methoxy functional group.

[0148] Meanwhile, in the above reaction scheme B, an amine (NH2-Prot) to which a Prot group is attached as a substituent and 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3The reaction process with ) can be explained more specifically from the synthesis example according to reaction process 8 below.

[0149] More specifically, in the following reaction process 8, 4,5-difluorophthalonitrile ( 3 ) and paramethoxybenzylamine ( 5 By reacting ) with 4,5-bis(4-methoxybenzylamino)phthalonitrile ( 11 After synthesizing ), 4,5-diaminophthalonitrile (by deprotection reaction) 1 Specific examples of synthesizing ) were described.

[0150] [Reaction Process 8]

[0151]

[0152] Here, 4,5-diaminophthalonitrile ( 1 As a first step to manufacture ), 4,5-bis(4-methoxybenzylamino)phthalonitrile having two paramethoxybenzyl (PMB) groups ( 11 ) can be synthesized, and secondly, a process can be carried out to remove the protecting group from the obtained intermediate using trifluoroacetic acid.

[0153] Since the first nucleophilic aromatic substitution reaction between fluorine and paramethoxybenzylamine is an exothermic reaction, the reactants were mixed at 0 °C. Subsequently, to substitute the second fluorine with an amino group, the reaction was heated to 120 °C and carried out for one day to obtain a pale yellow solid. Through a deprotection reaction, 4,5-diaminophthalonitrile ( 1 ) could be obtained. The total yield of this synthesis route is 55% in three steps from the starting material 1,2-dibromo-4,5-difluorobenzene, which is a very high yield compared to existing synthesis methods.

[0154] In addition, in the present invention, 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthanlonitrile in reaction scheme B, 4) is 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, according to reaction scheme A-1 below 3 It can be prepared by the reaction of ) and water ammonia (NH4OH), and the specific reaction conditions according to the above reaction formula A-1 are the same as those previously described.

[0155] [Reaction Equation A-1]

[0156]

[0157] In addition, the present invention relates to, according to the following reaction scheme B-2, i) 1,2-dibromo-4,5-difluorobenzene (1,2-dibromo-4,5-difluorobenzene, 2 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, through the cyanide reaction of ) 3 ) to prepare, and ii) an amine (NH2-Prot) to which a Prot group is attached as a substituent and 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 A compound containing a secondary amine group (NH-Prot) in which a Prot group is bonded instead of a fluorine group in a phthalonitrile compound through a reaction with ) 11 ) to prepare, and iii) a compound comprising a secondary amine group (NH-Prot) to which the above Prot group is bonded ( 11 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, by deprotection of the Prot group within ) 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Provides a method for manufacturing ).

[0158] [Reaction Equation B-2]

[0159]

[0160] The Prot group in reaction scheme B-2 above is a functional group to which the secondary amine group (-NH-Prot) to which the Prot group is attached can be converted into a primary amine group (-NH2) by a deprotection reaction under acidic conditions.

[0161] The specific reaction conditions for each step in the above reaction scheme B-2 are the same as those previously explained, and can be easily carried out.

[0162] In addition, the present invention relates to, according to the following reaction scheme B-3, i) 1,2-dibromo-4,5-difluorobenzene (1,2-dibromo-4,5-difluorobenzene, 2 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, through the cyanide reaction of ) 3 ) to manufacture, and ii) the obtained 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthanlonitrile) by the reaction of ) and water ammonia (NH4OH), 4 After preparing ), iii) an amine (NH2-Prot) to which a Prot group is attached as a substituent and 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthanlonitrile, 4 A compound containing a secondary amine group (NH-Prot) in which a Prot group is bonded instead of a fluorine group in a phthalonitrile compound through a reaction with ) 6 ) to prepare, and iii) a compound comprising a secondary amine group (NH-Prot) to which the above Prot group is bonded ( 6 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, by deprotection of the Prot group within ) 1 4,5-diaminophthalonitrile characterized by obtaining ) 1Provides a method for manufacturing ).

[0163] [Reaction Equation B-3]

[0164]

[0165] The Prot group in reaction scheme B-3 above is a functional group to which the secondary amine group (-NH-Prot) to which the Prot group is attached can be converted into a primary amine group (-NH2) by a deprotection reaction under acidic conditions.

[0166] For example, the reaction process according to the above reaction scheme B-3 can be explained more specifically from the synthesis example according to the reaction process 9 below.

[0167] [Reaction Process 9]

[0168]

[0169] Here, 4-amino-5-fluorophthalonitrile in the above reaction process 9 ( 4 The specific synthesis method up to ) is the same as previously described, and 4-amino-5-fluorophthalonitrile ( 4 ) and 4-methoxybenzylamine ( 5 Nucleophilic aromatic substitution with ) (S N 4-amino-5-(4-methoxybenzylamino)phthalonitrile ( 6 The specific reaction process for synthesizing ) is identical to that described above, so it can be easily manufactured by following it.

[0170] The present invention will be described in more detail below with reference to preferred embodiments. However, it will be obvious to those skilled in the art that these embodiments are intended to explain the invention more specifically and that the scope of the invention is not limited by them.

[0171] 실시예

[0172] (1) Materials and analysis methods

[0173] Reagents commercially purchased from Aldrich, Acros, TCI, and Alfa aesa were used without further purification. Additionally, the following solvents purchased from Daejeong and Samjeon were purified before use. Anhydrous dichloromethane, anhydrous dimethyl sulfoxide, anhydrous benzene, and anhydrous toluene were obtained by distillation with calcium hydride, and anhydrous acetonitrile was obtained by distillation using P2O5. Tetrahydrofuran was distilled using sodium and benzophenone.

[0174] Analytical thin-layer chromatography uses Merck silica gel 60 F 254 A glass plate was used, and fluorescence was observed using dual short-wavelength (254 nm) and long-wavelength (365 nm) UV lamps. Merk silica gel 60 (70-230 mesh) was used for column chromatography. Hydrogen nuclear magnetic resonance ( 1 HY NMR) and carbon nuclear magnetic resonance ( 13 The 3C NMR spectrum was obtained using a Varian Inova 400 (400 MHz for 1 H, and 100 MHz for 13 C) Obtained using a spectrometer. All chemical shifts were determined using tetramethylsilane (d 0.00) or deuteraninated chloroform (d 7.26 for CDCl3in). 1 ¹H NMR, d 77.2 for CDCl3in 13 13C NMR), and deuterized dimethylacetamide (d 2.50 for DMSO in 1 ¹H NMR, d 39.52 for DMSO in 13 It was expressed in ppm units based on 3C NMR.

[0175] (2) Synthesis of 4,5-diaminophthalonitrile (1,2-diamino-4,5-phthalonitrile)(1)

[0176] (합성예 1) 4,5-difluorophthalonitrile

[0177]

[0178] 1,2-dibromo-4,5-difluorobenzene (12.0 g, 44.14 mmol) is dissolved in 40.0 mL of dimethylacetamide in a 200 mL glass culture tube containing a magnetic stirrer. At room temperature, polymethylhydrosiloxane (0.960 mL) is added, followed by the addition of Pd2(dba)3 (432 mg, 0.474 mmol 1.0 mol%) and dppf (360 mg, 0.648 mmol 1.35 mol%) at the same temperature. Zn(CN)2 (10.4 g, 88.28 mmol 2.0 equiv.) is added all at once. The reaction mixture is stirred at 100 °C for 4 hours, then cooled to room temperature. The reaction mixture is diluted with dichloromethane, and the solid precipitate is filtered using diatomite and a silica gel pad, followed by extraction with water and dichloromethane. The organic layer is collected and washed with a saturated aqueous NaCl solution, then anhydrous Na-2SO4 is added to remove the remaining water. The desiccant is filtered out using a glass filter, and the solvent is removed as much as possible using a rotary evaporator. Hex : EtOAc = 4 : 1 (R f After purification by column chromatography using a developing solvent having a composition of =0.34, a white solid was obtained by recrystallization with hexane to obtain a cleaner compound; 6.36 g (38.75 mmol, 87%)

[0179] 1 H NMR (400 MHz, CDCl3): δ 7.69 (t, 2H, J=8.0Hz).

[0180] 13 C NMR (100 MHz, CDCl3): δ 154.30(d), 151.66(d), 123.83-123.35(m), 113.71(t).

[0181] 19 F NMR (375 MHz, CDCl3): δ -123.45.

[0182] (합성예 2) 4-Amino-5-fluorophthalonitrile

[0183]

[0184] 4,5-difluorophthalonitrile (in a 200 mL glass culture tube containing a magnetic stirrer) 3 ) 5.8 g (35.34 mmol) was dissolved in acetonitrile (20.0 mL), and 28 wt% ammonia solution (20.0 mL) was added at room temperature and stirred. The mixture was stirred at 50 °C for 8 hours, and the reaction was confirmed by thin-layer chromatography using a Hex : EtOAc = 1 : 1 developing agent (Rf starter = 0.66, Rf result = 0.34). The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was collected, washed with a saturated aqueous NaCl solution, and the remaining water was removed by adding anhydrous Na-2SO4. The desiccant was filtered through a glass filter, and the solvent was removed using a rotary evaporator to obtain a white solid; 5.68 g (35.0 mmol, 99%)

[0185] 1 H NMR (400 MHz, DMSO): δ 7.86 (d, J = 11.2, 1H), 7.23 (d, J = 8.0, 1H), 6.83 (s, 2H).

[0186] 13 C NMR (100 MHz, DMSO): δ 150.59, 142.27, 142.27, 120.55, 119.51, 116.47, 115.95, 112.16, 98.68 .

[0187] 19 F NMR (375 MHz, DMSO): δ -125.32 .

[0188] FT-IR (KBr pellet): 3562(m), 3425(m), 3342(m), 3230(m), 3060(m), 2229(m), 1654(m), 1605(m), 1658(m), 1439(m), 1362(m), 1258(m), 1232(m) 894(m) .

[0189] Anal. Calcd for C8H4FN3: C, 59.63; H, 2.50; F, 11.79; N, 26.08. Found: C, 59.59; H, 2.61; N, 26.10.

[0190] (합성예 3-1) 4-Amino-5-(4-methoxybenzylamino) phthalonitrile

[0191]

[0192] 4-amino-5-fluorophthalonitrile (1.6 g, 9.93 mmol) was dissolved in 8.0 mL of dimethyl sulfoxide in a 50 mL glass culture tube containing a magnetic stirrer, and then 4-methoxybenzylamine (1.632 g, 1.55 mL, 11.915 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at 120 °C for 24 hours. The reaction mixture, cooled to room temperature, was diluted with ethyl acetate, and the dimethyl sulfoxide was removed by washing the organic layer with water. The collected organic layer was washed with a saturated aqueous NaCl solution, and the remaining water was removed with anhydrous Na-2SO4. The desiccant was filtered through a glass filter, and the solvent was removed as much as possible using a rotary evaporator. A small amount of dichloromethane was added to the solid mixture to filter out the undissolved precipitate, and the mixture was dried under reduced pressure to obtain an ivory solid; 2.71 g (98%)

[0193] 1H NMR (400 MHz, DMSO): δ 7.28 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 8.1 Hz, 2H), 6.89 (s, 1H), 6.78 (s, 1H), 6.37 (t, J = 5.6 Hz, 1H), 6.07 (s, 2H), 4.35 (d, J = 5.4 Hz, 2H), 3.73 (s, 3H).

[0194] 13 C NMR (100 MHz, DMSO): δ 158.85, 140.11, 138.53, 130.52, 129.12, 118.47, 118.21, 115.03, 114.30, 112.29, 102.03, 101.93, 55.47, 45.86.

[0195] (합성예 3-2) 4-Amino-5-(3,4-dimethoxybenzylamino) phthalonitrile

[0196]

[0197] 4-amino-5-fluorophthalonitrile (200 mg, 1.24 mmol) was dissolved in 1.0 ml of dimethyl sulfoxide in a 10 mL glass culture tube containing a magnetic stirrer, and then 3,4-dimethoxybenzylamine (249 mg, 0.222 ml, 1.49 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at 120 °C for 24 hours. The reaction mixture cooled to room temperature was diluted with ethyl acetate, and the dimethyl sulfoxide was removed by washing the organic layer with water. The collected organic layer was washed with a saturated aqueous NaCl solution, and the remaining water was removed with anhydrous Na-2SO4. The desiccant was filtered through a glass filter, and the solvent was removed as much as possible using a rotary evaporator. The solid mixture was mixed with dichloromethane, the precipitated solid was filtered, and the mixture was dried under reduced pressure to obtain an ivory-colored solid; 213 mg (56%)

[0198] 1H NMR (400 MHz, DMSO): δ 6.99 (d, J = 2.1 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 1.2 Hz, 1H), 6.86 (s, 1H), 6.80 (s, 1H), 6.35 (t, J = 5.5 Hz, 1H), 6.08 (s, 2H), 4.34 (d, J = 5.3 Hz, 2H), 3.74 (s, 3H), 3.73 (s, 3H).

[0199] 13 C NMR (100 MHz, DMSO): δ 148.80, 148.02, 139.76, 138.25, 130.62, 119.52, 118.12, 117.86, 114.72, 112.02, 111.76, 111.53, 101.72, 101.60, 55.56, 55.50, 45.95.

[0200] (합성예 3-3) 4-Amino-5-(2,4-dimethoxybenzylamino) phthalonitrile

[0201]

[0202] 4-amino-5-fluorophthalonitrile (200 mg, 1.24 mmol) was dissolved in 1.0 ml of dimethyl sulfoxide in a 10 mL glass culture tube containing a magnetic stirrer, and then 2,4-dimethoxybenzylamine (249 mg, 0.222 ml, 1.49 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at 120 °C for 24 hours. After cooling the reaction mixture to room temperature, it was diluted with ethyl acetate, and the dimethyl sulfoxide was removed by washing the organic layer with water. The collected organic layer was washed with a saturated aqueous NaCl solution, and the remaining water was removed with anhydrous Na-2SO4. The desiccant was filtered through a glass filter, and the solvent was removed as much as possible using a rotary evaporator. The solid mixture was mixed with dichloromethane, the precipitated solid was filtered, and the mixture was dried under reduced pressure to obtain an ivory-colored solid; 198 mg (52%)

[0203] 1 H NMR (400 MHz, DMSO): δ 7.07 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 0.9 Hz, 1H), 6.70 (s, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.46 (dd, J = 8.3, 2.4 Hz, 1H), 6.12 (t, J = 5.4 Hz, 1H), 6.04 (s, 2H), 4.22 (d, J = 5.3 Hz, 2H), 3.79 (s, 3H), 3.71 (s, 3H).

[0204] 13 C NMR (100 MHz, DMSO) δ 160.46, 158.54, 139.99, 138.70, 129.82, 118.50, 118.27, 117.94, 114.91, 111.99, 105.01, 101.98, 101.85, 98.84, 55.88, 55.63, 41.40.

[0205] (합성예 3-4) 4,5-bis(4-methoxybenzyamino) phthalonitrile

[0206]

[0207] 4-amino-5-fluorophthalonitrile (200 mg, 1.24 mmol) was dissolved in 3.0 mL of dimethyl sulfoxide in a 10 mL glass culture tube containing a magnetic stirrer, and then 4-methoxybenzylamine (417.9 mg, 0.397 mL, 3.046 mmol, 2.5 equiv) was slowly added dropwise at 0 °C. Once the exothermic reaction was complete, the reaction mixture was stirred at 120 °C for 24 hours. After the reaction was complete, the reaction mixture cooled to room temperature was diluted with ethyl acetate, and the dimethyl sulfoxide was removed by washing the organic layer three times with water. The collected organic layer was washed with a saturated aqueous NaCl solution, and the remaining water was removed with anhydrous Na2SO4. The desiccant was filtered through a glass filter, and the solvent was removed as much as possible using a rotary evaporator. Dichloromethane was added to the solid mixture, the precipitated solid was filtered, and the mixture was dried under reduced pressure to obtain a white solid; 410 mg (84%)

[0208] 1 H NMR (400 MHz, DMSO): δ 7.29 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 8.2 Hz, 2H), 6.79 (s, 1H), 6.56 (t, J = 5.4 Hz, 1H), 4.35 (d, J = 5.1 Hz, 2H), 3.73 (s, 3H).

[0209] 13 C NMR (100 MHz, DMSO) δ 158.54, 138.68, 129.97, 128.91, 118.05, 113.95, 111.06, 101.90, 55.11, 45.75.

[0210] (합성예 4) 1,2-diamino-4,5-phthalonitrile

[0211]

[0212] 4-Amino-5-(4-methoxybenzylamino)phthalonitrile (12.0 g, 44.14 mmol) was suspended in 20.0 mL of toluene in a 50 mL round-bottom flask containing a magnetic stirrer. At 0 °C, trifluoroacetic acid (2.0 mL, 26.13 mmol) was slowly added dropwise to produce a clear solution. The reaction temperature was raised to room temperature and stirred for 6 hours. As the reaction proceeded, a precipitate was formed. The progress of the reaction was confirmed using nuclear magnetic resonance (NMR). After the reaction was complete, the precipitate was filtered and washed with small amounts of toluene and diethyl ether to obtain a solid mixture. The precipitate was dissolved again in ethyl acetate, and the organic layer was washed twice with a saturated aqueous sodium bicarbonate solution and once with a saturated aqueous sodium chloride solution. The organic layer was collected, the remaining water was removed using anhydrous Na-2SO4, and the desiccant was filtered out using a glass filter. The solvent was removed as much as possible from the filtrate below using a rotary evaporator. The solid mixture was recrystallized using small amounts of methanol and toluene to obtain a white solid; 0.48 g (3.035 mmol, 84%)

[0213] 1 H NMR (400 MHz, DMSO): δ. 6.87 (s, 2H), 5.83(s, 4H)

[0214] 13 C NMR (100 MHz, DMSO): δ. 139.10, 117.89, 115.52, 101.38

[0215] Calcd for C8H6N4: C, 60.75; H, 3.82; N, 35.42. Found: C, 60.82; H, 3.70; N, 35.43

[0216] (합성예 5) 1,2-diamino-4,5-phthalonitrile

[0217]

[0218] 4,5-difluorophthalonitrile (200 mg, 1.24 mmol) was dissolved in 5.0 mL of vacuum-distilled dimethyl sulfoxide in a Teflon reaction vessel inside a high-pressure reactor (Hanwool HR-8200) containing a magnetic stirrer. At room temperature, ammonia (NH3) gas was injected at 2.0 atm for 5 minutes. The reaction mixture was reacted in the high-pressure reactor at 120 °C for 48 h while stirring. After the reaction was complete, the reaction mixture cooled to room temperature was diluted with ethyl acetate. To remove the dimethyl sulfoxide, the organic solvent layer was washed three times with water and twice with a saturated aqueous sodium chloride solution. The organic layer was collected, the remaining water was removed using anhydrous Na-2SO4, the desiccant was filtered out using a glass filter, and the solvent was removed as much as possible using a rotary evaporator. The solid mixture was purified by recrystallization using methanol, toluene, and n-hexane; 110 mg (0.695 mmol, 62%)

[0219] 1 H NMR (400 MHz, DMSO): δ. 6.87 (s, 2H), 5.83(s, 4H)

[0220] 13 C NMR (100 MHz, DMSO): δ. 139.10, 117.89, 115.52, 101.38

[0221] Calcd for C8H6N4: C, 60.75; H, 3.82; N, 35.42. Found: C, 60.82; H, 3.70; N, 35.43

[0222] Although preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements by those skilled in the art using the basic concept of the present invention as defined in the following claims are also included within the scope of the present invention.

Claims

Claim 1 According to the following reaction scheme A, gaseous ammonia (NH3) and 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 Through a reaction with ), or with gaseous ammonia (NH3) and 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthanlonitrile, 4 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, through reaction with ) 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Method of manufacturing ).[Reaction Scheme A] Substituent X in the above reaction formula A is F or NH2. Claim 2 In claim 1, the solvent used in the reaction formula A is characterized as being an aprotic polar solvent, 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, 1 Method of manufacturing ). Claim 3 In claim 2, the aprotic polar solvent used in the above reaction formula A is characterized as being any one selected from dimethyl sulfoxide, 1,4-dioxane, acetonitrile, hexamethylphosphorous triamide, dimethylformamide, and tetrahydrofuran, or a mixture thereof, 4,5-diaminophthalonitrile 1 Method of manufacturing ). Claim 4 In paragraph 2, the gaseous ammonia (NH3) used in the above reaction formula A is characterized by being reacted under pressure conditions of 1 atm to 100 atm, diaminophthalonitrile (4,5-diaminophthalonitrile, 1 Method of manufacturing ). Claim 5 In claim 1, the gaseous ammonia (NH3) used in the above reaction formula A is characterized by being reacted at a temperature of 100 to 150 ℃ under pressure conditions of 1 atm to 10 atm, 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, 1 Method of manufacturing ). Claim 6 In paragraph 2, 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthanlonitrile, in the above reaction formula A, 4 ) is 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, according to reaction scheme A-1 below 3 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, characterized by being obtained by the reaction of ) and water ammonia (NH4OH), 1 Method of manufacturing ).[Reaction Scheme A-1] Claim 7 According to the following reaction scheme A-2, i) 1,2-dibromo-4,5-difluorobenzene (1,2-dibromo-4,5-difluorobenzene, 2 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, through the cyanide reaction of ) 3 ) to produce, and ii) gaseous ammonia (NH3) and the above 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 Through a reaction with ), 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Method of manufacturing ).[Reaction Scheme A-2] Claim 8 According to the following reaction scheme A-3, i) 1,2-dibromo-4,5-difluorobenzene (1,2-dibromo-4,5-difluorobenzene, 2 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, through the cyanide reaction of ) 3 ) to manufacture, and ii) the obtained 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthanlonitrile) by the reaction of ) and water ammonia (NH4OH), 4 After preparing ), iii) gaseous ammonia (NH3) and the above 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthanlonitrile, 4 Through a reaction with ), 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Method of manufacturing ). [Reaction Scheme A-3] Claim 9 delete Claim 10 delete Claim 11 delete Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 According to the following reaction scheme B-2, i) 1,2-dibromo-4,5-difluorobenzene (1,2-dibromo-4,5-difluorobenzene, 2 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, through the cyanide reaction of ) 3 ) to prepare, and ii) an amine (NH2-Prot) to which a Prot group is attached as a substituent and 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 A compound containing a secondary amine group (NH-Prot) in which a Prot group is bonded instead of a fluorine group in a phthalonitrile compound through a reaction with ) 11 ) to prepare, and iii) a compound comprising a secondary amine group (NH-Prot) to which the above Prot group is bonded ( 11 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, by deprotection of the Prot group within ) 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Method for manufacturing ). [Reaction Scheme B-2] The Prot group in reaction scheme B-2 above is a functional group to which the secondary amine group (-NH-Prot) to which the Prot group is attached can be converted into a primary amine group (-NH2) by a deprotection reaction under acidic conditions. Claim 18 According to the following reaction scheme B-3, i) 1,2-dibromo-4,5-difluorobenzene (1,2-dibromo-4,5-difluorobenzene, 2 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, through the cyanide reaction of ) 3 ) to manufacture, and ii) the obtained 4,5-difluorophthalonitrile (4,5-difluorophthalonitrile, 3 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthanlonitrile) by the reaction of ) and water ammonia (NH4OH), 4 After preparing ), iii) an amine (NH2-Prot) to which a Prot group is attached as a substituent and 4-amino-5-fluorophthalonitrile (4-amino-5-fluorophthanlonitrile, 4 A compound containing a secondary amine group (NH-Prot) in which a Prot group is bonded instead of a fluorine group in a phthalonitrile compound through a reaction with ) 6 ) to prepare, and iii) a compound comprising a secondary amine group (NH-Prot) to which the above Prot group is bonded ( 6 4,5-diaminophthalonitrile (4,5-diaminophthalonitrile, by deprotection of the Prot group within ) 1 4,5-diaminophthalonitrile characterized by obtaining ) 1 Method of manufacturing ).[Reaction Scheme B-3] The Prot group in reaction scheme B-3 above is a functional group to which the secondary amine group (-NH-Prot) to which the Prot group is attached can be converted into a primary amine group (-NH2) by a deprotection reaction under acidic conditions.

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