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 (Sa) producing at least one of compound 2a and compound 2b using compound 1, and (Sb) producing 4-aminoindan using at least one of compound 2a and compound 2b.

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 the following reaction equation A (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 project] [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 at least one of compound 2a represented by chemical formula 2a and compound 2b represented by chemical formula 2b, and (Sb) The step of reacting at least one of compound 2a and compound 2b to produce 4-aminoindan represented by chemical formula 3.

[0008] [ka]

[0009] In one embodiment, step (Sa) may include a step of carrying out a decarboxylation reaction of compound 1 using palladium(II) acetate and copper(II) acetate.

[0010] In one embodiment, step (Sb) may include a step of carrying out a catalytic hydrogenation reaction of at least one of compound 2a and compound 2b. In one embodiment, step (Sb) may include a step of carrying out a catalytic hydrogenation reaction on a mixture of compound 2a and compound 2b.

[0011] In one embodiment, the catalyst may be Pd / C. In one embodiment, in the step (Sb), 4-aminoindane can be produced from compound 2a and compound 2b without a separate purification step. In the step (Sb), only 4-aminoindane is selectively produced as the product.

[0012] In one embodiment, the step (Sa) may include a step of reacting a compound 4 represented by Chemical Formula 4 to produce the compound 1.

[0013]

Chemical formula

[0014] In Chemical Formula 4, 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, in Chemical Formula 4, R1 and R2 may each independently be a linear or branched C1-C6 alkyl. For example, in Chemical Formula 4, R1 and R2 may each independently be a C1-C2 alkyl.

[0017] In one embodiment, the compound 4 can be obtained by reacting in a first temperature condition containing 1,4-dioxane and a base, adding an acid, stirring at a second temperature higher than the first temperature, and then precipitating (crystallizing) as a solid using the filtrate from which the organic phase has been separated. The base may be NaOH, and the acid may be HCl. According to the present invention, since the compound 1 can be obtained as a solid from the compound 4, the compound 1 can be produced without a separate purification step.

[0018] 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.

[0019]

Chemical formula

[0020] In Chemical Formula 5, X1 and X2 are each independently F, Cl, Br, or I. In one embodiment, the step of producing the compound 4 may include a step of reacting the compound 5 with a compound represented by the following Chemical Formula A.

[0021]

Chemical formula

[0022] In the Chemical Formula A, R1 and R2 are each independently a linear or branched C1-C6 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, 4-member to 7-member heterocycloalkyl, or 5-member to 7-member heteroaryl.

[0023] In one embodiment, the compound represented by the Chemical Formula A may be a dialkyl malonate in which R1 and R2 are each independently a linear or branched C1-C5 alkyl.

[0024] In one embodiment, step (Sa) may include the step of reacting compound 6 represented by chemical formula 6 to produce compound 5.

[0025] [ka]

[0026] In one embodiment, the step of producing compound 5 may include the step of reacting compound 6 with a halogenated succinimide represented by the following chemical formula B.

[0027] [ka]

[0028] In the aforementioned chemical formula B, X3 is Cl, Br, or I. In one embodiment, step (Sa) is: A step of producing compound 4 using compound 5, and The procedure may also include the step of producing compound 1 using compound 4.

[0029] Here, the steps for producing compound 4 and compound 1 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 4 using compound 5, A step of producing compound 1 using compound 4, A step of using compound 1 to produce at least one of compound 2a and compound 2b, and The method may also include the step of producing 4-aminoindan using at least one of compound 2a and compound 2b.

[0030] 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.

[0031] [ka]

[0032] 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.

[0033] 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.

[0034] The method for producing a dihydroindenyl-pyrazolo[3,4-b]pyridineamine compound according to the present invention is: A step of using compound 1 to produce at least one of compound 2a and compound 2b, A step of producing 4-aminoindan using at least one of compound 2a and compound 2b, A step of reacting 4-aminoindan with a compound represented by chemical formula 7 to produce a compound represented by chemical formula 8, and The method includes the step of carrying out a cyclization reaction with a compound represented by chemical formula 8 to produce a dihydroindenyl-pyrazolo[3,4-b]pyridinamine compound represented by chemical formula X.

[0035] [ka]

[0036] In chemical formulas 7 and 8, R3 and R4 are identical to those defined in chemical formula X. In chemical formulas 7 and 8, X4 and X5 are independently Cl or Br.

[0037] The cyclization reaction may be carried out by reacting the compound represented by chemical formula 8 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.

[0038] 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.

[0039] 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: A step of using compound 1 to produce at least one of compound 2a and compound 2b, A step of producing 4-aminoindan using at least one of compound 2a and compound 2b, 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 the step of carrying out a cyclization reaction with 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.

[0040] 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.

[0041] Here, compound 1 of the method for producing N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine 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.

[0042] According to the present invention's method for producing dihydroindenyl-pyrazolo[3,4-b]pyridineamine compounds, 4-aminoindan can be produced in large quantities with high yield. Therefore, the production yield of dihydroindenyl-pyrazolo[3,4-b]pyridineamine compounds, which utilize 4-aminoindan as an essential reactant, can also be at least 70%, representing a significant improvement compared to conventional methods. Furthermore, dihydroindenyl-pyrazolo[3,4-b]pyridineamine compounds can be obtained in high yield and with high purity.

[0043] 1) The present invention provides a method for producing 4-aminoindan, comprising the steps of: (Sa) reacting compound 1 represented by chemical formula 1 to produce at least one of compound 2a represented by chemical formula 2a and compound 2b represented by chemical formula 2b; and (Sb) reacting at least one of compound 2a and compound 2b to produce 4-aminoindan represented by chemical formula 3:

[0044] [ka]

[0045] 2)1) In step (Sb), step (Sb) may include a step of carrying out a catalytic hydrogenation reaction of at least one of compound 2a and compound 2b. 3)2) The catalyst may be Pd / C.

[0046] 4) In any one of 1) to 3), step (Sa) may include a step of carrying out a decarboxylation reaction of compound 1 using palladium(II) acetate and copper(II) acetate.

[0047] 5) In any one of 1) to 4), step (Sa) may include the step of reacting compound 4 represented by chemical formula 4 to produce compound 1:

[0048] [ka]

[0049] In chemical formula 4, 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.

[0050] In 6)5), step (Sa) may include the step of producing compound 4 using compound 5 represented by chemical formula 5:

[0051] [ka]

[0052] In chemical formula 5, X1 and X2 are independently F, Cl, Br, or I. In 7)6), the step of producing compound 4 may include the step of reacting compound 5 with a compound represented by chemical formula A:

[0053] [ka]

[0054] In chemical formula A, R1 and R2 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 compounds.

[0055] In 8)6) or 7), in the step of producing the compound 4, the compound 4 may be obtained from a solid crystal. 9) The present invention provides a method for producing 4-aminoindan, comprising the steps of: 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 at least one of compound 2a represented by chemical formula 2a and compound 2b represented by chemical formula 2b; and reacting at least one of compound 2a and compound 2b to produce 4-aminoindan represented by chemical formula 3:

[0056] [ka]

[0057] In chemical formula 4, 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, and in chemical formula 5, X1 and X2 are each independently F, Cl, Br, or I.

[0058] In 10)9), the step of producing 4-aminoindan may include the step of carrying out a catalytic hydrogenation reaction of at least one of compound 2a and compound 2b.

[0059] In 11)9) or 10), the step of producing at least one of compound 2a and compound 2b may include the step of carrying out a decarboxylation reaction of compound 1 using palladium(II) acetate and copper(II) acetate.

[0060] In any one of 12)9)~11), the step of producing compound 4 may include the step of reacting compound 5 with dialkyl malonate. 13) 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 at least one of compound 2a represented by chemical formula 2a and compound 2b represented by chemical formula 2b; reacting at least one of compound 2a and compound 2b to produce 4-aminoindane represented by chemical formula 3; reacting 4-aminoindane with a compound represented by chemical formula 7 to produce a compound represented by chemical formula 8; and performing a cyclization reaction on the compound represented by chemical formula 8 to produce a dihydroindenyl-pyrazolo[3,4-b]pyridinamine compound represented by chemical formula X:

[0061] [ka]

[0062] [ka]

[0063] In chemical formulas 7, 8, 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, and in chemical formulas 7 and 8, X4 and X5 are independently Cl or Br.

[0064] In 14)13), 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]

[0065] According to the method for producing 4-aminoindan and 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.

[0066] 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]

[0067] [Figure 1] 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]

[0068] 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.

[0069] Example 1: Method for producing 4-aminoindan (Step 1) Preparation of dimethyl 4-nitro-1H-indene-2,2(3H)-dicarboxylate (Compound 4)

[0070] [ka]

[0071] After determining the weight (in grams) of compound 5 to be used as a starting material in units of 1 eq., methanol (1.6 times the volume (mL) of the weight (g) of compound 5) and diethyl ether (4.8 times the volume (mL) of the weight (g) of compound 5) were added to a nitrogen-filled reactor at room temperature (20-30°C). Then, sodium hydride (60%) (2.4 eq.) was added to the mixture and stirred for 5 minutes to obtain a suspension. Dimethyl malonate (1.2 eq.) and compound 5 (1 eq.) obtained in step 1 were sequentially added to the obtained suspension. The obtained mixture was stirred at 20-30°C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated. After adding DCM (dichloromethane) to the concentrated residue, the precipitated solid was filtered. Water was added to the filtrate and stirred, the aqueous phase was discarded, and the organic phase was collected and concentrated. The concentrated residue was purified by column chromatography to obtain compound 4 (grayish solid, yield 81.35%).

[0072] 1 H NMR: 8.034-8.018 (1H, m), 7.697-7.687 (1H, m), 7.505-7.482 (1H, m), 3.957 (2H, s), 3.715 (6H, s), 3.632 (2H, s). 13 C NMR: 170.95, 144.71, 143.93, 136.03, 130.73, 128.76, 122.51, 58.91, 53.18, 40.80, 39.48. (Step 2) Preparation of 4-nitro-2,3-dihydro-1H-indene-2-carboxylic acid (Compound 1)

[0073] [ka]

[0074] Compound 4 (1 eq.) obtained in step 1 at room temperature (20-30°C) and 1,4-dioxane (8 times the weight (g) of compound 4 in volume (mL)) were added to a reactor filled with nitrogen. Then, 2N NaOH (8 times the weight (g) of compound 4 in volume (mL)) was added to the mixture and stirred for 5 minutes. The temperature was raised to 50°C and stirred for 2 hours. Next, after cooling to 20-30°C, the pH of the mixture was adjusted to 1 with concrete HCl. The pH of the mixture was adjusted to 1, and the temperature was raised to 100°C and stirred for 6 hours. After cooling to 20-30°C, water (18 times the volume (mL) of the initial 1 eq. amount of compound 4 added in step 2) and ethyl acetate (18 times the volume (mL) of the initial 1 eq. amount of compound 4 added in step 2) were added and the mixture was stirred for 10 minutes. After separating the organic phase, MgSO4 was added to dehydrate the mixture, and it was filtered. The filtered filtrate was concentrated. The concentrated residue was added to the reactor, and ethyl acetate (5 times the volume (mL) of the initial 1 eq. amount of compound 4 added in step 2) was added. The temperature was raised to 50°C to dissolve the compound. After gradually cooling the mixture, when solid precipitation was confirmed, heptane (20 times the volume (mL) of the initial 1 eq. amount of compound 4 added in step 2) was added, and the suspension was stirred at 20-30°C for 1 hour. The product was filtered and washed with heptane (10 times the volume (mL) of the initial amount (g) added to compound 4 in step 2), and then vacuum-dried for 12 hours to obtain compound 1 of the title (brown powder, yield 87.90%).

[0075] 1 H NMR: 12.697 (1H, m), 7.986 (1H, d, J=8.3 Hz), 7.663 (1H, d, J=4.89 Hz), 7.453-7.439 (1H, m), 3.633-3.500 (2H, m), 3.386-3.210 (3H, m) 13 C NMR: 175.699, 172.365, 146.004, 138.039, 130.592, 128.181, 122.009, 42.119, 36.649, 35.482. (Step 3) Preparation of nitro-1H-indene (compound 5a, compound 5b)

[0076] [ka]

[0077] Compound 1 (1 eq.), Pb(OAc)4 (0.806 eq.), Cu(OAc)2·H2O (0.177 eq.), benzene, and acetic acid (Benzene:AcOH = 20:1, (12.5 times the weight (g) of 1 eq. of Compound 1 in volume (mL))) obtained in step 2 were added to a reactor filled with nitrogen at room temperature (20-30°C). The temperature was raised to 100-110°C and stirred at the same temperature for 3 hours. After concentrating the reaction mixture, it was purified by column chromatography (hexane:ethyl acetate = 5:1) to produce a mixture of the title compounds 2a and 2b (yellow powder, yield 70.51%).

[0078] 1 H NMR (500 MHz, DMSO-d6) δ ppm 2.500 (dt, J=3.417, 1.709 Hz, 1 H) 3.595 - 3.656 (m, 1 H) 3.862 - 3.920 (m, 2 H) 6.772 - 6.883 (m, 1 H) 6.999 - 7.102 (m, 1 H) 7.336 - 7.381 (m, 1 H) 7.407 - 7.473 (m, 1 H) 7.496 - 7.538 (m, 1 H) 7.542 - 7.549 (m, 1 H) 7.548 - 7.622 (m, 1 H) 7.856 (d, J=7.5 Hz, 1 H) 7.890 (d, J=7.323 Hz, 1 H) 8.005 (d, J=8.055 Hz, 1 H) 8.087 (d, J=8.299 Hz, 1 H) 13C NMR: 147.86, 146.83, 144.30, 141.88, 139.40, 138.71, 137.25, 130.50, 129.85, 129.60, 128.23, 128.00, 127.21, 125.42, 121.89, 119.74, 40.63, 39.25. (Step 4) Preparation of 4-aminoindan (compound 3)

[0079] [ka]

[0080] A mixture of compounds 2a and 2b obtained in step 3 (1 eq.) and a sufficient amount of ethyl acetate were added to a nitrogen-filled reactor at room temperature. Subsequently, 10% Pd / C (20 wt%) was added to the mixture, and a balloon containing H2 gas was placed in the reaction mixture to inject H2 gas. After stirring at 24-30°C for 2 hours, the mixture was filtered to remove impurities, and the filtrate was concentrated to obtain compound 3 (brown oil, yield 86.72%).

[0081] 1 H 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 C NMR: 144.29, 144.02, 127.09, 126.83, 112.10, 111.37, 32.80, 29.62, 24.23.

[0082] Comparative Example 1 4-aminoindan was produced by sequentially performing steps A and B of "Intermediate R4" in the internationally published patent WO2019 / 211463.

[0083] 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%.

[0084] HPLC analysis of the result (nitroindan) obtained by 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 by 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 by 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 just 4-aminoindan was 7.9 to 9.1%.

[0085] 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.

[0086] 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 compared with the peak of the control sample, this peak is found to be the peak for 4-aminoindan.

[0087] 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.

[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 1-4: Manufacturing of 4-aminoindan 4-aminoindan was produced by substantially the same process as described in steps 1 to 4 of Example 1.

[0089] Step 5: 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 4 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 4-aminoindan initially added was used for the 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 initial weight (kg) of 4-aminoindan). The resulting filtered 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. 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.

[0093] 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 5, 181.73g of 2-chloro-6-((2,3-dihydro-1H-inden-4-yl)amino)-5-fluoronicotinonitrile yield, 88.25% yield, 99.6% purity).

[0094] Step 6: Preparation of N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine

[0095] [ka]

[0096] After adding the 2-chloro-6-((2,3-dihydro-1H-inden-4-yl)amino)-5-fluoronicotinonitrile and n-BuOH obtained in step 5 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).

[0097] After raising the temperature inside the reactor to 105 ± 5°C, it was stirred for 7 hours while maintaining the internal temperature. Subsequently, after cooling the inside of the reactor to 0 ± 5°C, it was additionally stirred for 1 hour. The obtained crystallization liquid was filtered and washed with distilled water (10 times the weight (kg) relative to the weight (kg) of 2-chloro-6-((2,3-dihydro-1H-inden-4-yl)amino)-5-fluoronicotinonitrile introduced into the reactor). The filtration cake was dried under reduced pressure with the external temperature set at 40°C or lower. Thereby, N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine (hereinafter referred to as crude-product) was obtained as a crude product.

[0098] Next, the crude-product obtained in the previous step and DMSO were introduced at room temperature (20 - 30°C) into a reactor filled with drying and nitrogen. Here, the amount of DMSO introduced was 5.5 times the weight (kg) relative to the weight (kg) of the crude-product. When 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 introduced was 3 times the weight (kg) relative to the weight (kg) of the crude-product introduced into the reactor. After the introduction of distilled water was completed, it was aged and stirred for 1 hour while maintaining the temperature inside the reactor at 25 ± 5°C. The obtained crystallization liquid was filtered and washed with distilled water (10 times the weight (kg) relative to the weight (kg) of the crude-product introduced into the reactor). The obtained filtration cake was dried under reduced pressure with the external temperature set at 40°C or lower. Thereby, N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-...

[0099] 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).

[0100] Evaluation 2 - 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.

[0101] 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.

[0102] 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 was superior when 4-aminoindan was 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 was produced compared to when 4-aminoindan was obtained by the conventional method and N6-(2,3-dihydro-1H-inden-4-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3,6-diamine was produced.

[0103] 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 at least one of compound 2a represented by chemical formula 2a and compound 2b represented by chemical formula 2b, and (Sb) The step of reacting at least one of compound 2a and compound 2b to produce 4-aminoindan represented by chemical formula 3, Method for producing 4-aminoindan: 【Chemistry 1】

2. The aforementioned step (Sb) is, A method for producing 4-aminoindan according to claim 1, comprising the step of carrying out a catalytic hydrogenation reaction of at least one of compound 2a and compound 2b.

3. The method for producing 4-aminoindan according to claim 2, wherein the catalyst is Pd / C.

4. The aforementioned step (Sa) is, A method for producing 4-aminoindan according to claim 1, comprising the step of carrying out a decarboxylation reaction of compound 1 using palladium(II) acetate and copper(II) acetate.

5. 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】 In chemical formula 4, 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 aforementioned step (Sa) is, A method for producing 4-aminoindan according to claim 5, comprising the step of producing the compound 4 using a compound 5 represented by chemical formula 5: 【Transformation 3】 In chemical formula 5, X １ and X ２ These are, independently, F, Cl, Br, or I.

7. The step of producing the compound 4 is: A method for producing 4-aminoindan according to claim 6, comprising the step of reacting the compound 5 with a compound represented by chemical formula A: 【Chemistry 4】 In chemical formula A, 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.

8. The method for producing 4-aminoindan according to claim 6, wherein in the step of producing the compound 4, the compound 4 is obtained from a solid crystal.

9. 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 at least one of compound 2a represented by chemical formula 2a and compound 2b represented by chemical formula 2b, and The process includes the step of reacting at least one of compound 2a and compound 2b to produce 4-aminoindan represented by chemical formula 3, Method for producing 4-aminoindan: 【Transformation 5】 In chemical formula 4, 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 5, X １ and X ２ are each independently F, Cl, Br, or I.

10. The method for producing 4-aminoindan according to claim 9, wherein the step of producing 4-aminoindan includes the step of carrying out a catalytic hydrogenation reaction of at least one of compound 2a and compound 2b.

11. The step of producing at least one of the compounds 2a and 2b is: A method for producing 4-aminoindan according to claim 9, comprising the step of carrying out a decarboxylation reaction of compound 1 using palladium(II) acetate and copper(II) acetate.

12. The step of producing the compound 4 is: A method for producing 4-aminoindan according to claim 9, comprising the step of reacting the compound 5 with a dialkyl malonate.

13. A step of reacting compound 1 represented by chemical formula 1 to produce at least one of compound 2a represented by chemical formula 2a and compound 2b represented by chemical formula 2b, A step of reacting at least one of compound 2a and compound 2b to produce 4-aminoindan represented by chemical formula 3, A step of reacting 4-aminoindan with a compound represented by chemical formula 7 to produce a compound represented by chemical formula 8, and The process includes the step of carrying out a cyclization reaction with a compound represented by chemical formula 8 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 6】 【Transformation 7】 In chemical formulas 7, 8, 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 7 and 8, X ４ and X ５ These are, independently, either Cl or Br.

14. The dihydroindenyl-pyrazolo[3,4-b]pyridinamine compound is A method for producing the dihydroindenyl-pyrazolo[3,4-b]pyridinamine compound according to claim 13, 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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