Method for producing 4-aminoindan and method for producing dihydroindenyl-pyrazolo[3,4-b]pyridinamine compounds

Abstract

The present invention relates to a method for producing 4-aminoindan and a method for producing a dihydroindenyl-pyrazolo[3,4-b]pyridinamine compound, wherein the method for producing 4-aminoindan includes the steps of producing compound 2 using compound (Sa) 1 and producing 4-aminoindan using compound (Sb) 2.

Description

[Technical Field]

[0001] The present invention relates to a method for producing 4-aminoindan and a method for producing dihydroindenyl-pyrazolo[3,4-b]pyridinamine compounds. [Background technology]

[0002] 4-aminoindan is a compound widely used in the pharmaceutical and chemical fields as a reactant for the manufacture of itself or various other compounds. The IUPAC name for 4-aminoindan is 2,3-dihydro-1H-inden-4-amine.

[0003] One known method for synthesizing 4-aminoindan is to use indan as a starting material, nitride it to obtain 4-nitroindan, and then reduce it. However, during the nitridation reaction according to reaction equation A below (under HNO3 / H2SO4 conditions), the selectivity for the 5th position of indan is higher than that for the 4th position. As a result, 5-nitroindan is obtained as the main product, making it difficult to separate and purify 4-nitroindan. In other words, there is a problem in that it is difficult to mass-produce 4-aminoindan in high yield using this method.

[0004] [ka] [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Published Patent WO2019 / 211463 [Patent Document 2] International Published Patent WO2019 / 212256 [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] One objective of the present invention is to provide a method for producing 4-aminoindan that can selectively produce only 4-aminoindan in large quantities with high yield. One object of the present invention is to provide a method for producing dihydroindenyl-pyrazolo[3,4-b]pyridineamine compounds. [Means for solving the problem]

[0007] A method for producing 4-aminoindan for one objective of the present invention is: (Sa) A step of reacting compound 1 represented by chemical formula 1 to produce compound 2 represented by chemical formula 2, and (Sb) The step of reacting the compound 2 to produce 4-aminoindan represented by chemical formula 3.

[0008] [ka]

[0009] In one embodiment, step (Sa) may include the step of reacting compound 1 with triethylsilane. In one embodiment, step (Sa) may include the step of reacting compound 4 represented by chemical formula 4 to produce compound 1.

[0010] [ka]

[0011] In one embodiment, the step of producing compound 1 may include the step of reacting compound 4 with trifluoromethanesulfonic acid (TfOH). In one embodiment, step (Sb) may include a step of carrying out a catalytic hydrogenation reaction.

[0012] In one embodiment, the catalyst may be Pd / C. In one embodiment, the step (Sa) may include a step of reacting a compound 5 represented by Chemical Formula 5 to produce the compound 4.

[0013]

Chemical Formula

[0014] In Chemical Formula 5, R1 and R2 are each independently a linear or branched C1-C6 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, 4- to 7-member heterocycloalkyl or 5- to 7-member heteroaryl.

[0015] Here, "alkyl" may be methyl, ethyl, propyl, isopropyl, etc., "cycloalkyl" may be cyclobutyl, cyclopentyl, etc., and "aryl" may be phenyl, biphenyl, naphthyl, etc. "Heterocycloalkyl" may be oxetanyl, piperidinyl, etc., and "heteroaryl" may be pyridinyl, pyrimidinyl, etc.

[0016] In one embodiment, the step (Sa) may include a step of reacting a compound 6 represented by Chemical Formula 6 to produce the compound 5.

[0017]

Chemical Formula

[0018] In Chemical Formula 6, X1 is F, Cl, Br or I. In one embodiment, the step of producing the compound 5 may include a step of reacting the compound 6 with a dialkyl malonate represented by Chemical Formula 7.

[0019]

Chemical Formula

[0020] In the aforementioned chemical formula 7, R1 and R2 are each independently a linear or branched C1-C6 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, 4- to 7-membered heterocycloalkyl, or 5- to 7-membered heteroaryl.

[0021] In one embodiment, the step of producing compound 5 may include the step of reacting compound 6 with lithium hydroxide monohydrate, TBAI (tetrabutylammonium iodide), and acetonitrile.

[0022] Each of the above steps can achieve a production yield of at least 70%, for example, 70%, 60%, 50%, 40%, 30%, or 20%. In one embodiment, step (Sa) is: (S1) A step of producing compound 5 using compound 6, (S2) A step of producing compound 4 using compound 5, and (S3) The step of producing compound 1 using compound 4 may also be included.

[0023] Here, steps (S1) to (S3) are substantially the same as those described in step (Sa), and therefore, redundant detailed explanations are omitted. A method for producing 4-aminoindan for one objective of the present invention is: A step of producing compound 5 using compound 6, A step of producing compound 4 using compound 5, A step of producing compound 1 using compound 4, A step of producing compound 2 using compound 1, and The process may also include the step of producing 4-aminoindan using compound 2.

[0024] Here, each step is substantially the same as those described in steps (Sa) and (Sb) above, and redundant detailed explanations are omitted. In the method for producing a dihydroindenyl-pyrazolo[3,4-b]pyridineamine compound according to the present invention, the dihydroindenyl-pyrazolo[3,4-b]pyridineamine compound is a compound represented by the following chemical formula X.

[0025] [ka]

[0026] In chemical formula X, R3 and R4 are independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, halogen, COOH, COO(C1-C6 alkyl), or C6-C12 aryl.

[0027] The definitions of alkyl and aryl are substantially the same as those described in R1 and R2, respectively, and "haloalkyl" may be a functional group such as CF3, CF2H, CH2CF3, in which at least one of the H atoms of the alkyl group is substituted with a halogen, and "halogen" may be F, Cl, Br, or I.

[0028] The method for producing a dihydroindenyl-pyrazolo[3,4-b]pyridineamine compound according to the present invention is: A step of producing compound 2 using compound 1, A step of producing 4-aminoindan using compound 2, A step of reacting 4-aminoindan with a compound represented by chemical formula 8 to produce a compound represented by chemical formula 9, and The method includes the step of carrying out a cyclization reaction with a compound represented by chemical formula 9 to produce a dihydroindenyl-pyrazolo[3,4-b]pyridinamine compound represented by chemical formula X.

[0029] [ka]

[0030] In chemical formulas 8 and 9, R3 and R4 are identical to those defined in chemical formula X. In chemical formulas 8 and 9, X2 is either Cl or Br.

[0031] The cyclization reaction may be carried out by reacting the compound represented by chemical formula 9 with hydrazine monohydrate. In one embodiment, the method for producing compound 1 is not particularly limited, but as described above, it can be produced using compound 4 as a starting material, where compound 4 can be produced using compound 5. Furthermore, compound 5 can be produced using compound 6 as a starting material. Detailed explanations that would be redundant are omitted.

[0032] In one embodiment, the present invention can provide a method for producing N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine.

[0033] A method for producing N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine is: A step of producing compound 2 using compound 1, A step of producing 4-aminoindan using compound 2, The steps include reacting 4-aminoindan with 2,6-dichloro-5-fluoronicotinonitrile to produce 2-chloro-6-((2,3-dihydro-1H-inden-4-yl)amino)-5-fluoronicotinonitrile, and The process may also include a step of cyclizing 2-chloro-6-((2,3-dihydro-1H-inden-4-yl)amino)-5-fluoronicotinonitrile to produce N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine.

[0034] In one example, the step of producing 2-chloro-6-((2,3-dihydro-1H-inden-4-yl)amino)-5-fluoronicotinonitrile can utilize DMSO (dimethyl sulfoxide) and DIPEA (N,N-diisopropylethylamine) when reacting 4-aminoindane with 2,6-dichloro-5-fluoronicotinonitrile. The reaction under the aforementioned solvent conditions can easily yield 2-chloro-6-((2,3-dihydro-1H-inden-4-yl)amino)-5-fluoronicotinonitrile without using harmful substances such as NMP or 2-methoxyethanol.

[0035] Here, compound 1 can be produced through the steps of producing compound 5 using compound 6, producing compound 4 using compound 5, and producing compound 1 using compound 4. A redundant detailed explanation is omitted.

[0036] According to the method for producing dihydroindenyl-pyrazolo[3,4-b]pyridinamine compounds of the present invention, 4-aminoindan can be produced in large quantities with high yield. Therefore, the production yield of dihydroindenyl-pyrazolo[3,4-b]pyridinamine compounds that utilize 4-aminoindan as an essential reactant can also be at least 70%, for example, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, or 20% or more, which is a significant improvement compared to conventional methods. Furthermore, dihydroindenyl-pyrazolo[3,4-b]pyridinamine compounds can be obtained in high yield and with high purity.

[0037] 1) The present invention provides a method for producing 4-aminoindane, comprising the steps of (Sa) reacting compound 1 represented by chemical formula 1 to produce compound 2 represented by chemical formula 2, and (Sb) reacting compound 2 to produce 4-aminoindane represented by chemical formula 3:

[0038] [ka]

[0039] 2)1) In step (Sa), step (Sa) may include the step of reacting compound 1 with triethylsilane. 3) In 1) or 2), step (Sa) may include the step of reacting compound 4 represented by chemical formula 4 to produce compound 1:

[0040] [ka]

[0041] In 4)3), the step of producing compound 1 may include the step of reacting compound 4 with trifluoromethanesulfonic acid (TfOH). In 5)3) or 4), step (Sa) may include the step of reacting compound 5 represented by chemical formula 5 to produce compound 4:

[0042] [ka]

[0043] In chemical formula 5, R1 and R2 are, independently, a linear or branched C1-C6 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, 4- to 7-membered heterocycloalkyl, or 5- to 7-membered heteroaryl.

[0044] In 6)5), step (Sa) may include the step of reacting compound 6 represented by chemical formula 6 to produce compound 5. In 7)6), the step of producing compound 5 may include the step of reacting compound 6 with dialkyl malonate.

[0045] In 8)6) or 7), the step of producing compound 5 may include the step of reacting compound 6 with lithium hydroxide monohydrate, TBAI (tetrabutylammonium iodide), and acetonitrile.

[0046] 9) In any one of 1) to 8), step (Sb) may include a step of carrying out a catalytic hydrogenation reaction. 10) The present invention provides a method for producing 4-aminoindan, comprising the steps of: reacting compound 6 represented by chemical formula 6 to produce compound 5 represented by chemical formula 5; reacting compound 5 to produce compound 4 represented by chemical formula 4; reacting compound 4 to produce compound 1 represented by chemical formula 1; reacting compound 1 to produce compound 2 represented by chemical formula 2; and reacting compound 2 to produce 4-aminoindan:

[0047] [ka]

[0048] In chemical formula 5, R1 and R2 are independently a linear or branched C1-C6 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, 4- to 7-membered heterocycloalkyl, or 5- to 7-membered heteroaryl, and in chemical formula 6, X1 is F, Cl, Br, or I.

[0049] In 11)10), the step of producing compound 1 may include the step of reacting compound 4 with trifluoromethanesulfonic acid (TfOH). In 12)10) or 11), the step of producing compound 2 may include the step of reacting compound 1 with triethylsilane.

[0050] In any one of 13)10)~12), the step of producing compound 5 may include the step of reacting compound 6 with dialkyl malonate. In any one of 14)10)~13), the step of producing compound 5 may include the step of reacting compound 6 with a salt of lithium hydroxide monohydrate, TBAI (tetrabutylammonium iodide), and acetonitrile.

[0051] 15) The present invention provides a method for producing a dihydroindenyl-pyrazolo[3,4-b]pyridinamine compound, comprising the steps of: reacting compound 1 represented by chemical formula 1 to produce compound 2 represented by chemical formula 2; reacting compound 2 to produce 4-aminoindane represented by chemical formula 3; reacting 4-aminoindane with a compound represented by chemical formula 8 to produce a compound represented by chemical formula 9; and performing a cyclization reaction on the compound represented by chemical formula 9 to produce a dihydroindenyl-pyrazolo[3,4-b]pyridinamine compound represented by chemical formula X:

[0052] [ka]

[0053] [ka]

[0054] In chemical formulas 8, 9, and X, R3 and R4 are independently H, OH, C1-C6 alkyl, C1-C6 haloalkyl, halogen, COOH, COO(C1-C6 alkyl), or C6-C12 aryl. In chemical formulas 8 and 9, X2 is either Cl or Br.

[0055] In 16)15), the dihydroindenyl-pyrazolo[3,4-b]pyridineamine compound may also be N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine. [Effects of the Invention]

[0056] According to the method for producing 4-aminoindan and the method for producing dihydroindenyl-pyrazolo[3,4-b]pyridineamine compounds of the present invention described above, since no 5-aminoindan is produced during the manufacturing process, the step of separately separating 4-aminoindan can be fundamentally omitted. Furthermore, since each step exhibits a manufacturing yield of at least 70%, the overall manufacturing yield of 4-aminoindan can be significantly improved.

[0057] This allows for the mass production of 4-aminoindan in high yield, and also enables the production of dihydroindenyl-pyrazolo[3,4-b]pyridineamine compounds in high yield and high purity. [Brief explanation of the drawing]

[0058] [Figure 1] This figure shows the HPLC analysis graph of the result obtained in step 5 of Example 1 of the present invention. [Figure 2] This figure shows the HPLC analysis graph of the result obtained in step 4 of Example 1 of the present invention. [Modes for carrying out the invention]

[0059] The terms used herein are used solely to describe specific embodiments and are not intended to limit the invention. In this application, terms such as “includes” or “having” are intended to specify the existence of features, steps, operations, components, or combinations thereof described in the specification, and should not be understood to preemptively exclude the existence or possibility of adding one or more other features, steps, operations, components, or combinations thereof. Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by a person of ordinary skill in the art to which this invention pertains.

[0060] Example 1: Method for producing 4-aminoindan (Step 1) Preparation of dimethyl 2-(2-nitrobenzyl)malonic acid (compound 5)

[0061] [ka]

[0062] Dimethylformamide (DMF) and 60% NaH (1.6 eq.) were added to a nitrogen-filled reactor at room temperature (20-30°C), and the temperature was adjusted to 0-10°C. The amount of DMF added was determined by first determining the weight (in grams) of compound 6 to be used as the starting material, and then using 3.7 times the volume (mL) of compound 6 equivalent to 1 eq. of compound 6. Next, dimethyl malonate was gradually added to the reaction mixture and stirred at 20-30°C for 1 hour. Compound 6 (1 eq.) was dissolved in DMF (twice the volume (mL) of compound 6 equivalent to 1 eq. of compound 6), and then gradually added to the reaction mixture and stirred at 20-30°C for 1 hour. Water (three times the weight (g) of compound 6 in volume (mL)) and ethyl acetate (three times the weight (g) of compound 6 in volume (mL)) were added, and the mixture was stirred for 10 minutes. After separating the organic phase, it was washed with NH4Cl solution. The organic phase was separated again, dehydrated with magnesium sulfate (MgSO4), and filtered. The filtered filtrate was concentrated to obtain compound 5, the subject of the title.

[0063] Furthermore, dimethyl 2-(2-nitrobenzyl)malonic acid (compound 5) can be produced by the following method.

[0064] [ka]

[0065] Compound 6 (1 eq.), diethyl malonate (2 eq. of Compound 6), lithium hydroxide monohydrate (2 eq. of Compound 6), TBAI (0.05 eq. of Compound 6), and acetonitrile were added to a nitrogen-filled reactor at room temperature (20-30°C), and the mixture was stirred at 20-30°C for 1.5 hours. Here, the amount of acetonitrile (ACN) added was 20 times the volume (ml) of the weight (g) of 1 eq. of Compound 6.

[0066] After adding 10% HCl (20 times the volume (ml) of the weight (g) of compound 6) and ethyl acetate (20 times the volume (ml) of the weight (g) of compound 6), the mixture was stirred for 10 minutes. After separating the organic phase, it was washed with water (20 times the volume (ml) of the weight (g) of compound 6). The organic phase was further separated, dehydrated with magnesium sulfate, and filtered. The filtered filtrate was concentrated to obtain compound 5, the compound of the title.

[0067] 1 H NMR: 7.977-7.960 (1H, m), 7.679-7.646 (1H, m), 7.526-7.491 (2H, m), 3.932 (1H, t, J=7.82 Hz), 3.613 (6H, s), 3.401 (2H, m) 13 C NMR: 168.474, 133.423, 132.286, 132.004, 128.456, 124.687, 52.503, 51.695, 30.614. (Step 2) Preparation of compound 4

[0068] [ka]

[0069] Compound 5 (1 eq.), 6N HCl (6.1 times the weight (g) of Compound 5 in mL), and acetic acid (6.1 times the weight (g) of Compound 5 in mL) were added to a nitrogen-filled reactor. The same weight of Compound 5 obtained in Step 1 was used. After raising the temperature to 100°C, the mixture was stirred for 5 hours to concentrate the reaction solution. Water (10 times the weight (g) of Compound 5 in mL) was added to the concentrated residue, and the pH of the reaction solution was adjusted to 12 with 10% NaOH. Then, ethyl acetate (5 times the weight (g) of Compound 5 in mL) was added, and the mixture was stirred for 10 minutes to separate the aqueous phase. The pH of the separated aqueous phase was adjusted to 1 with 5% HCl. Ethyl acetate (5 times the weight (g) of 1 eq. of compound 5 in volume (mL)) was added to the reaction mixture and stirred for 10 minutes. After separating the organic phase, it was dehydrated with magnesium sulfate and filtered. The filtrate was concentrated and purified by column chromatography with ethyl acetate and hexane to obtain the title compound 4 (a pale brown solid, 81% overall yield from steps 1 and 2).

[0070] 1 H NMR: 12.248 (1H, brs), 7.915 (1H, m), 7.643 (1H, m), 7.526 (1H, m), 7.448 (1H, m), 3.020 (2H, t, J=7.57 Hz), 2.572 (2H, t, J=7.57 Hz) 13 C NMR: 173.52, 149.38, 135.31, 133.51, 131.95, 127.88, 124.55, 34.44, 27.36. (Step 3) Preparation of Compound 1

[0071] [ka]

[0072] Compound 4 (1 eq.) obtained in step 2 and trifluoromethanesulfonic acid (10 times the weight (g) of compound 4 in volume (mL)) were added to a reactor filled with nitrogen. After raising the temperature to 110-120°C, the mixture was stirred for 2.5 hours and then cooled to 25°C to obtain a reaction solution containing the title compound 1 (dark brown solid, yield 74.25%).

[0073] 1 H NMR: 8.495 (1H, d, J=8.30 Hz), 8.058 (1H, d, J=7.33 Hz), 7.734 (1H, t, d=7.82 Hz), 3.531-3.509 (2H, m), 2.755-2.731 (2H, m) 13 C NMR: 204.63, 149.80, 146.08, 139.71, 129.90, 129.27, 129.20, 35.59, 26.49. (Step 4) Preparation of Compound 2

[0074] [ka]

[0075] Triethylsilane (13 eq.) was added to the reaction mixture obtained in step 3, and the temperature was raised to 50°C, followed by stirring for 12 hours. After cooling to 25°C, water (10 times the weight (g) of compound 1 in volume (mL)) and ethyl acetate (10 times the weight (g) of compound 1 in volume (mL)) were added to the reaction mixture, and the mixture was stirred for 10 minutes. After separating the organic phase, it was washed with NaHCO3 solution. After further separating the organic phase, it was washed with water, and after further separating the organic phase, it was dehydrated with magnesium sulfate and filtered. After concentrating the filtrate, compound 2 of the title was prepared by column chromatography using 10% ethyl acetate (pale yellow solid, yield 85.41%).

[0076] 11H NMR: 8.486 - 8.469 (1H, m), 8.048 - 8.034 (1H, m), 7.732 - 7.701 (1H, m), 3.514 - 3.491 (2H, m), 2.737 - 2.714 (2H, m) 13 13C NMR: 147.94, 145.19, 139.88, 130.40, 127.68, 121.54, 33.31, 24.28. (Step 5) Production of 4 - aminoindane (Compound 3)

[0077] [Chemical formula]

[0078] Compound 2 (1 eq.) obtained by the process of Step 4 and ethyl acetate were charged into a reactor filled with nitrogen at room temperature (20 - 30 °C). Then, 10% Pd / C (20 wt%) was charged into the mixture, and a balloon filled with H2 gas was placed into the reaction solution to inject H2 gas. After stirring this at 24 - 30 °C for 2 hours, it was filtered to remove foreign substances, and the filtrate was concentrated to obtain the title compound 3 (brown oil, yield 81.22%).

[0079] 1 1H NMR: 7.026 - 6.996 (1H, m), 6.727 - 6.713 (1H, m), 6.527 - 6.511 (1H, m), 2.935 (2H, t, J = 7.33 Hz), 2.750 (2H, t, J = 7.33 Hz), 2.152 - 2.092 (2H, m) 13 13C NMR: 144.29, 144.02, 127.09, 126.83, 112.10, 111.37, 32.80, 29.62, 24.23

[0080] Comparative Example 1 4 - aminoindane was produced by sequentially performing step A and step B of "Intermediate R4" in International Publication Patent WO2019 / 211463.

[0081] The yield of the result (nitroindan) obtained by step A of "Intermediate R4" was 53.51%, and the yield of the result (aminoindan) obtained by step B of "Intermediate R4" was 42.55%.

[0082] HPLC analysis of the result (nitroindan) obtained in step A of "Intermediate R4" confirmed that 4-nitroindan and 5-nitroindan were mixed in a ratio of 35:75 to 40:60. The result (aminoindan) obtained by applying the result (nitroindan) obtained in step A of "Intermediate R4" directly to step B also contained a mixture of 4-aminoindan and 5-aminoindan within the aforementioned ratio range. When 4-aminoindan was obtained from the result obtained in step B, that is, when 5-aminoindan was removed from the result obtained via steps A and B using indan as the starting material, the production yield of 4-aminoindan was 7.9 to 9.1%.

[0083] Rating 1-5 - Aminoindan encapsulation content unconfirmed HPLC analysis was performed on the product obtained in step 5 of Example 1 of the present invention. A mixture of 4-aminoindan and 5-aminoindan was used as a control sample. The HPLC analysis results are shown in Figure 1.

[0084] Referring to Figure 1, it can be confirmed that in a mixture of 4-aminoindan and 5-aminoindan, separate peaks for 4-aminoindan and 5-aminoindan appear (see Data 1 graph). On the other hand, in the result obtained in step 5 of Example 1 of the present invention, only one peak appears (see DATA 2 graph), and when this is compared with the peak of the control sample, the corresponding peak is the peak for 4-aminoindan. In other words, it has been confirmed that only 4-aminoindan can be selectively produced through steps 1 to 5 of the present invention.

[0085] According to this, it can be confirmed that the result obtained in step 5 of Example 1 of the present invention is 100% selective, yielding only 4-aminoindanes, even though there is no separate purification step in step 5.

[0086] Rating 2-5 - Nitroindan content unconfirmed HPLC analysis was performed on the result obtained in step 4 of Example 1 of the present invention. A mixture of 4-nitroindane and 5-nitroindane was used as a control sample. The HPLC analysis results are shown in Figure 2.

[0087] Referring to Figure 2, it can be confirmed that in a mixture of 4-nitroindane and 5-nitroindane, separate peaks for 4-nitroindane and 5-nitroindane appear (see Data 1 graph). On the other hand, in the result obtained in step 4 of Example 1 of the present invention, only one peak appears (see Data 2 graph), and when this is compared with the peak of the control sample, the corresponding peak is the peak for 4-nitroindane. In other words, it has been confirmed that only 4-nitroindane can be selectively produced through steps 1 to 4 of the present invention.

[0088] Example 2: Preparation of N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine Steps 1-5: Manufacturing of 4-Aminoindan 4-aminoindan was produced by substantially the same process as described in steps 1 to 5 of Example 1.

[0089] Step 6: Preparation of 2-chloro-6-((2,3-dihydro-1H-inden-4-yl)amino)-5-fluoronicotinonitrile

[0090] [ka]

[0091] In a dry and nitrogen-filled reactor, 4-aminoindan, 2,6-dichloro-5-fluoronicotinonitrile, and DMSO (dimethyl sulfoxide) obtained in step 5 were added at room temperature (20-30°C), followed by the addition of DIPEA (N,N-diisopropylethylamine). Here, the amounts used were 1.58 times the weight (kg) of 2,6-dichloro-5-fluoronicotinonitrile, 11 times the weight (kg) of DMSO, and 1.18 times the weight (kg) of DIPEA relative to the weight (kg) of 4-aminoindan.

[0092] The reactor temperature was raised to 100±5°C and stirred for 3 hours, then cooled to 25±5°C. When the reactor temperature reached 25±5°C, distilled water was immediately added without temperature control. Here, 10 times the weight (kg) of the initially added 4-aminoindan was used as distilled water. After the addition of distilled water was complete, the reactor temperature was cooled to 25±5°C and stirred for 15 minutes. The resulting crystallized liquid was filtered and washed with distilled water (20 times the weight (kg) of the initially added 4-aminoindan). The resulting filtration cake was dried under reduced pressure at an external temperature of 40°C or less. This yielded 2-chloro-6-((2,3-dihydro-1H-inden-4-yl)amino)-5-fluoronicotinonitrile (hereinafter referred to as crude-WA) as the crude.

[0093] Next, the crude-WA and DCM (dichloromethane) obtained in the previous step were added to a dry and nitrogen-filled reactor at room temperature (20-30°C). Here, the amount of DCM added was 13.3 times the weight (kg) of the crude-WA.

[0094] The reactor temperature was raised to 40±5°C, and it was confirmed that all of the crude WA inside the reactor had dissolved. The mixture was then stirred at the same temperature for 15 minutes. Subsequently, the reactor temperature was cooled to 25±5°C, and when crystals precipitated, heptane was added. The amount of heptane added was 20.52 times the weight (kg) of the crude WA initially added to the reactor. After the heptane was added, the reactor temperature was cooled to 0±5°C. After cooling was complete, the mixture was cooled and aged at the same temperature for 1 hour, and the resulting crystallized liquid was filtered and washed with heptane. Here, the amount of heptane used was 10.26 times the weight (kg) of the crude WA initially added to the reactor. The resulting filtered cake was dried under reduced pressure at an external temperature of 40°C or lower. This yielded 2-chloro-6-((2,3-dihydro-1H-inden-4-yl)amino)-5-fluoronicotinonitrile (100g of 4-aminoindan used in step 6, 181.73g of 2-chloro-6-((2,3-dihydro-1H-inden-4-yl)amino)-5-fluoronicotinonitrile yield, 88.25% yield, 99.6% purity).

[0095] Step 7: Preparation of N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine

[0096] [ka]

[0097] After adding the 2-chloro-6-((2,3-dihydro-1H-inden-4-yl)amino)-5-fluoronicotinonitrile and n-BuOH obtained in step 6 to a dry and nitrogen-filled reactor, hydrazine monohydrate was added. Here, the amount of n-BuOH added was 4.05 times the weight (kg) of 2-chloro-6-((2,3-dihydro-1H-inden-4-yl)amino)-5-fluoronicotinonitrile, and the amount of hydrazine monohydrate was 1.16 times the weight (kg).

[0098] The reactor was heated to 105±5°C and then stirred for 7 hours while maintaining the internal temperature. Next, the reactor was cooled to 0±5°C and stirred for an additional hour. The resulting crystallized liquid was filtered and washed with distilled water (10 times the weight (kg) of 2-chloro-6-((2,3-dihydro-1H-inden-4-yl)amino)-5-fluoronicotinonitrile introduced into the reactor). The filtered cake was dried under reduced pressure at an external temperature of 40°C or less. This yielded N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine (hereinafter referred to as the crude product) as the crude.

[0099] Next, the crude product obtained in the previous step and DMSO were added to a dry and nitrogen-filled reactor at room temperature (20-30°C). Here, the amount of DMSO added was 5.5 times the weight (kg) of the crude product. Once it was confirmed that all of the crude product inside the reactor had dissolved, distilled water was added dropwise while maintaining the internal temperature at 25±5°C. Here, the amount of distilled water added was 3 times the weight (kg) of the crude product added to the reactor. After the addition of distilled water was complete, the reactor was stirred and aged for 1 hour while maintaining the internal temperature at 25±5°C. The resulting crystallized liquid was filtered and washed with distilled water (10 times the weight (kg) of the crude product added to the reactor). The resulting filtered cake was dried under reduced pressure at an external temperature of 40°C or less. This allowed for the production of N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine (using the final product obtained in step 7 as is, 139.64 g of N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine was obtained, yield 82.73%, purity 99.7%).

[0100] 1H NMR : 11.426 (s, 1 H), 11.392-11.468 (m, 1 H), 8.315 (s, 1 H), 7.731 (s, 1 H), 7.678-7.761 (m, 1 H), 7.359 (d, J=7.816 Hz, 1 H), 7.112 (t, J=7.572 Hz, 1 H), 7.011 (d, J=7.328 Hz, 1 H), 6.978-7.046 (m, 1 H), 5.213 (s, 2 H), 2.891 (t, J=7.328 Hz, 2 H), 2.754 (t, J=7.328 Hz, 2 H), 1.967 (quin, J = 7.328 Hz, 2 H).

[0101] Evaluation 3 - Quality and Yield The purity of the final product obtained in Example 2, N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine, was confirmed to be excellent at 99.7%. In particular, it was confirmed that the purity obtained by the method for producing N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine according to the present invention was improved compared to the purity of N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine produced by a conventional method using 4-aminoindan.

[0102] Furthermore, the overall production yield of the method for producing N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine according to the present invention is significantly improved by at least four times compared to the production yield when producing 4-aminoindan using the conventional method and then using it to produce N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine.

[0103] Furthermore, in a similar method for synthesizing N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine using 4-aminoindan as a starting material, it was confirmed that the production yield is superior when 4-aminoindan is obtained by the present invention and N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine is produced using the conventional method of obtaining 4-aminoindan.

[0104] While preferred embodiments of the present invention have been described above with reference to those skilled in the art, a person skilled in the art will understand that the present invention can be modified and altered in various ways without departing from the spirit and scope of the invention as set forth in the following claims.

Claims

1. (Sa) A step of reacting compound 1 represented by chemical formula 1 to produce compound 2 represented by chemical formula 2, and (Sb) The step of reacting the compound 2 to produce 4-aminoindan represented by chemical formula 3, Method for producing 4-aminoindan: 【Chemistry 1】

2. The aforementioned step (Sa) is, A method for producing 4-aminoindan according to claim 1, comprising the step of reacting the compound 1 with triethylsilane.

3. The aforementioned step (Sa) is, A method for producing 4-aminoindan according to claim 1, comprising the step of reacting a compound 4 represented by chemical formula 4 to produce the compound 1: 【Chemistry 2】

4. The method for producing 4-aminoindan according to claim 3, wherein the step of producing the compound 1 includes the step of reacting the compound 4 with trifluoromethanesulfonic acid (TfOH).

5. The aforementioned step (Sa) is, A method for producing 4-aminoindan according to claim 3, comprising the step of reacting a compound 5 represented by chemical formula 5 to produce the compound 4: 【Transformation 3】 In chemical formula 5, R １ and R ２ These are, independently, linear or branched C1-C6 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, 4- to 7-membered heterocycloalkyl, or 5- to 7-membered heteroaryl groups.

6. The method for producing 4-aminoindan according to claim 1, wherein the aforementioned step (Sb) includes a step of carrying out a catalytic hydrogenation reaction.

7. A step of reacting compound 6 represented by chemical formula 6 to produce compound 5 represented by chemical formula 5, A step of reacting compound 5 to produce compound 4 represented by chemical formula 4, A step of reacting compound 4 to produce compound 1 represented by chemical formula 1, A step of reacting compound 1 to produce compound 2 represented by chemical formula 2, and A method for producing 4-aminoindan, comprising the step of reacting compound 2 to produce 4-aminoindan: 【Chemistry 4】 In chemical formula 5, R １ and R ２ Each of these is independently a linear or branched C1-C6 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, 4- to 7-membered heterocycloalkyl, or 5- to 7-membered heteroaryl, In chemical formula 6, X １ is F, Cl, Br, or I.

8. The step of producing the compound 1 is: A method for producing 4-aminoindan according to claim 7, comprising the step of reacting the compound 4 with trifluoromethanesulfonic acid (TfOH).

9. The step of producing the compound 2 is: A method for producing 4-aminoindan according to claim 7, comprising the step of reacting the compound 1 with triethylsilane.

10. The step of producing the compound 5 is: A method for producing 4-aminoindan according to claim 7, comprising the step of reacting the compound 6 with a dialkyl malonate.

11. The step of producing the compound 5 is: A method for producing 4-aminoindan according to claim 7, comprising the step of reacting the compound 6 with lithium hydroxide monohydrate, TBAI (tetrabutylammonium iodide), and acetonitrile.

12. A step of reacting compound 1 represented by chemical formula 1 to produce compound 2 represented by chemical formula 2, The steps include: reacting compound 2 to produce 4-aminoindan represented by chemical formula 3, A step of reacting 4-aminoindan with a compound represented by chemical formula 8 to produce a compound represented by chemical formula 9, and The process includes the step of carrying out a cyclization reaction with a compound represented by chemical formula 9 to produce a dihydroindenyl-pyrazolo[3,4-b]pyridinamine compound represented by chemical formula X, Method for producing dihydroindenyl-pyrazolo[3,4-b]pyridinamine compounds: 【Transformation 5】 【Transformation 6】 In chemical formulas 8, 9, and X, R ３ and R ４ These are, independently, H, OH, C1-C6 alkyl, C1-C6 haloalkyl, halogen, COOH, COO(C1-C6 alkyl), or C6-C12 aryl. In chemical formulas 8 and 9, X ２ It is either Cl or Br.

13. The dihydroindenyl-pyrazolo[3,4-b]pyridinamine compound is A method for producing the dihydroindenyl-pyrazolo[3,4-b]pyridinamine compound according to claim 12, wherein the compound is N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridinamine-3,6-diamine.

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