Process for the preparation of compounds as pi3k inhibitors and intermediate compounds used for the preparation thereof

Abstract

The present invention provides a method for preparing a compound as a PI3K inhibitor with reduced process steps, which includes a process with shortened reaction time in the preparation of a compound as a PI3K inhibitor, and enables reactions to be carried out under mild conditions. Accordingly, the present invention provides a method for preparing a compound as a PI3K inhibitor, which is easy to manage and industrially mass-produce, while achieving process simplification, compared to the existing known preparation method.

Description

Technical Field

[0001] This invention relates to a method for preparing a compound as a PI3K inhibitor and an intermediate compound for preparing the same. Background Technology

[0002] Phosphatidylinositol 3-kinase (PI3 kinase; PI3K) is a lipid kinase that phosphorylates lipid molecules rather than proteins, playing a crucial role in cell survival, signal transduction, and membrane transport control. Problems with its control can lead to cancer, inflammatory diseases, autoimmune diseases, and other health issues.

[0003] Recently, there have been reports of research results on the development of compounds with structures capable of selectively inhibiting PI3K kinase. These compounds, as PI3K inhibitors, could be advantageously used to treat cancer, autoimmune diseases, respiratory diseases, and more. Therefore, simplifying the preparation process of these compounds as PI3K inhibitors has become an important issue. Summary of the Invention

[0004] Technical issues

[0005] One object of the present invention is to provide a novel method for preparing compounds as PI3K inhibitors, the method of which simplifies the process.

[0006] One object of the present invention is to provide a method for preparing an intermediate compound for use in preparing a compound as a PI3K inhibitor, the method being able to simplify the process.

[0007] One object of the present invention is to provide an intermediate compound for the preparation of compounds as PI3K inhibitors, which simplifies the process.

[0008] Technical solution

[0009] To address the above problems, the present invention provides a method for preparing compounds of formula 7. The method for preparing compounds of formula 7 may include:

[0010] (S1) Prepare compound 5 from compound 4;

[0011] (S2) Reacting compound 5 with dimethylformamide-dimethylacetal to prepare compound 6; and

[0012] (S3) Cyclize the compound of formula 6 to prepare the compound of formula 7.

[0013] [Formula 4]

[0014]

[0015] [Formula 5]

[0016]

[0017] [Formula 6]

[0018]

[0019] [Formula 7]

[0020]

[0021] In Equations 4 to 7 above, X1, X2 and X4 can each be a halogen atom independently.

[0022] X1, X2, and X4 can be the same as or different from each other. X1, X2, and X4 can each independently be F, Cl, Br, or I. More specifically, X1, X2, and X4 can each independently be Br or Cl. For example, X1, X2, and X4 can all be Cl. X1 and X4 can both be Cl.

[0023] In Equation 6 above, either R1 or R2 can be a hydrogen atom, and the other can be dimethylamine.

[0024] The method for preparing compound of formula 7 may further include (S1-1) halogenating compound of formula 3 to prepare compound of formula 4.

[0025] [Formula 3]

[0026]

[0027] In Equation 3 above, X1 and X2 can be the same as those defined in Equations 4 to 7 above.

[0028] The method for preparing the compound of formula 7 may further include (S1-2) reacting the compound of formula 1 with the compound of formula 2 to prepare the compound of formula 3 above.

[0029] [Formula 1]

[0030]

[0031] [Equation 2]

[0032]

[0033] In Equations 1 and 2 above, X1 and X2 can each be independently identical to those defined in Equations 4 to 7 above. In Equation 2 above, X3 can be a halogen atom.

[0034] Unless otherwise specified herein, the halogen atom may be selected from F, Cl, Br, and I. For example, the halogen atom may be selected from Cl and Br.

[0035] Methods for preparing compounds as PI3K inhibitors may include the following (S1) to (S3):

[0036] (S1) Amination of compound 4 is performed to prepare compound 5;

[0037] (S2) Reacting compound 5 with dimethylformamide-dimethylacetal to prepare compound 6; and

[0038] (S3) Cyclize the compound of formula 6 to prepare the compound of formula 7.

[0039] The method for preparing compounds as PI3K inhibitors may further include the following (S1-1):

[0040] (S1-1) Halogenation of compound 3 is carried out to prepare compound 4.

[0041] The method for preparing compounds as PI3K inhibitors may further include the following (S1-2):

[0042] (S1-2) React the compound of formula 1 with the compound of formula 2 to prepare the compound of formula 3.

[0043] According to one embodiment, a method for preparing compound of formula 7 may include:

[0044] (S1-2) React the compound of formula 1 with the compound of formula 2 to prepare the compound of formula 3;

[0045] (S1-1) Halogenate the compound of formula 3 to prepare the compound of formula 4;

[0046] (S1) Prepare compound 5 from compound 4;

[0047] (S2) Reacting compound 5 with dimethylformamide-dimethylacetal to prepare compound 6; and

[0048] (S3) Cyclize the compound of formula 6 to prepare the compound of formula 7. Unless otherwise contradictory, the references to compounds of formulas 1 to 7 are equally applicable.

[0049] Furthermore, according to one embodiment, a method for preparing compound formula 7 may include:

[0050] (S1-2) React the compound of formula 1 with the compound of formula 2 to prepare the compound of formula 3;

[0051] (S1-1) Halogenate the compound of formula 3 to prepare the compound of formula 4;

[0052] (S1) Amination of compound 4 is performed to prepare compound 5;

[0053] (S2) Reacting compound 5 with dimethylformamide-dimethylacetal to prepare compound 6; and

[0054] (S3) Cyclize the compound of formula 6 to prepare the compound of formula 7. Unless otherwise contradictory, the references to compounds of formulas 1 to 7 are equally applicable.

[0055] The above (S1) can be carried out in a polar aprotic solvent. For example, the solvent for the above (S1) may include dimethyl sulfoxide. The above (S1) can also be carried out under basic conditions. For example, in the above (S1), a basic compound (such as ammonium hydroxide) can participate in the reaction.

[0056] The above (S1-2) can be carried out in a polar aprotic solvent. For example, the solvent for the above (S1-2) may include acetonitrile. The above (S1-2) can also be carried out under basic conditions. For example, in the above (S1-2), a basic compound may participate in the reaction. The basic compound may be, for example, a tertiary amine (such as triethylamine).

[0057] In this specification, polar aprotic solvents may include, but are not limited to, at least one of dichloromethane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, dimethylformamide, and acetonitrile.

[0058] In the above (S1-2), the equivalent ratio of the compound of Formula 1, the compound of Formula 2 and triethylamine can be 1:1.1:1.5.

[0059] X1 and X2 above can be Cl.

[0060] More specifically, the above (S1-2) may include: adding the compound of Formula 1 and the compound of Formula 2 to an organic solvent (e.g., a mixture of acetonitrile and triethylamine), refluxing and stirring for about one to three hours; cooling to room temperature, adding purified water, and stirring at room temperature; filtering and washing (e.g., the washing solvent may be purified water); and drying.

[0061] The above (S1-1) can be used to react the above compound of formula 3 with N-chlorosuccinimide to carry out a chlorination reaction. In (S1-1), the equivalent ratio of the above compound of formula 3 and the above N-chlorosuccinimide can be 1:1.13.

[0062] The above (S1-1) can be carried out in a polar aprotic solvent. More specifically, the above (S1-1) can be carried out in at least one solvent selected from dichloromethane and acetonitrile.

[0063] More specifically, the above (S1-1) may include: adding the compound of formula 3 and N-chlorosuccinimide to an organic solvent (e.g., dichloromethane), refluxing and stirring for about three hours; cooling to room temperature, concentrating, adding an organic solvent (e.g., acetonitrile), and concentrating again; adding acetonitrile, cooling to about 0°C or above and 5°C or below, and stirring; filtering and washing (the washing solvent used herein may be an organic solvent, such as acetonitrile); and drying.

[0064] The above (S1) may include reacting the compound of Formula 4 with ammonium hydroxide (NH4OH) to produce the crude product of Formula 5. The above (S1) may include purifying the crude product.

[0065] Purification of the crude product may include at least one selected from ethanol, isopropanol, and acetone as a purification solvent. Isopropanol may be used as a purification solvent in the purification of the crude product.

[0066] In (S1) above, the equivalence ratio of the compound of Formula 4 above to ammonium hydroxide (NH4OH) can be from 1:5 to 1:15.

[0067] More specifically, in the above (S1), the generation of the crude product may include: adding the compound of Formula 4 above and ammonium hydroxide (NH4OH) to an organic solvent (e.g., dimethyl sulfoxide), heating (to about 70°C to 90°C, for example, about 80°C) for about three hours and stirring; stirring at room temperature for about one to two hours (or about two hours or longer, until a solid is produced), adding purified water and stirring again at room temperature; filtering and washing (the washing solvent used herein may be purified water); and drying.

[0068] More specifically, in the above (S1), the purification of the crude product may include: adding an organic solvent (e.g., isopropanol) to the crude product, refluxing and stirring for about 30 minutes; stirring at room temperature for about one to two hours; filtering and washing (the washing solvent used herein may be an organic solvent, such as isopropanol); and drying.

[0069] In (S2) above, the equivalent ratio of the compound of Formula 5 above and the dimethylformamide-dimethylacetal above can be 1:2.

[0070] More specifically, (S2) above may include: refluxing the compound of formula 5 and dimethylformamide-dimethylacetal in an organic solvent (e.g., dichloromethane) and stirring for about one hour; cooling to room temperature and concentrating; adding an organic solvent (e.g., isopropanol), refluxing and stirring; cooling to room temperature and stirring; filtering and washing (the washing solvent used herein may be an organic solvent, such as isopropanol); and drying.

[0071] In (S3) above, the cyclization reaction may include reacting the compound of Formula 6 above with a base and then adding an acid. The addition of the acid may occur after the reaction of the compound of Formula 6 above with the base. The base may be a tert-butoxide salt. For example, the base may be potassium tert-butoxide or sodium tert-butoxide. The acid may be an organic acid or an inorganic acid, such as acetic acid or hydrochloric acid.

[0072] In (S3) above, the equivalence ratio of the compound of Formula 6 above to the base can be 1:1.5. The equivalence ratio of the compound of Formula 6 above to the acid can be 1:3.

[0073] More specifically, (S3) above may include: adding the compound of formula 6 to an organic solvent (e.g., a mixture of tetrahydrofuran and acetonitrile), cooling to about -5°C, and stirring; adding base in batches (e.g., about two to three times), cooling and stirring for about 30 minutes to two hours; adding purified water, adding acid (e.g., acetic acid) dropwise to produce a solid, and stirring at room temperature for about one to two hours; filtering and washing (purified water may be used as the washing solvent in this document); and drying.

[0074] In one embodiment, the method for preparing the compound of formula 7 may further include purifying the crude product of the compound of formula 7.

[0075] Furthermore, the present invention can provide a method for preparing a compound of formula 6. According to one embodiment, the method for preparing a compound of formula 6 may include reacting a compound of formula 5 with dimethylformamide-dimethylacetal.

[0076] [Formula 5]

[0077]

[0078] [Formula 6]

[0079]

[0080] In Equations 5 and 6 above, X1 and X4 can each be halogen atoms independently. In Equation 6 above, either R1 or R2 can be a hydrogen atom, and the other can be dimethylamine.

[0081] The method for preparing the above-mentioned compound of formula 6 can provide the compound of formula 6, which is an intermediate compound used in the preparation of the compound of formula 7 of the present invention, thereby reducing the process steps and shortening the process time for preparing the compound of formula 7.

[0082] According to one embodiment, a method for preparing the compound of formula 7 may include subjecting the compound of formula 6 above to a cyclization reaction.

[0083] According to one embodiment of the present invention, a compound represented by formula 6 can be provided.

[0084] [Formula 6]

[0085]

[0086] In Equation 6 above, X1 and X4 can each be a halogen atom independently. Either R1 or R2 can be a hydrogen atom, and the other can be dimethylamine.

[0087] The compound represented by Equation 6 above can participate as an intermediate compound in the preparation of a compound as a PI3K inhibitor in one embodiment, thereby reducing process steps and process costs.

[0088] According to the present invention, unlike conventional known methods for preparing compounds as PI3K inhibitors, the process steps required for preparing compounds as PI3K inhibitors can be reduced, and compounds as PI3K inhibitors can be synthesized without prolonged reflux and stirring reactions (which can take several days or more). Furthermore, the reaction can be carried out under mild reaction conditions, thus significantly reducing potential risk factors during synthesis and allowing for easy management of the preparation process.

[0089] Therefore, the process can be simplified to shorten the required time, the process cost is lower, and the process management is easier. Thus, according to one embodiment, the method for preparing compounds as PI3K inhibitors is suitable for the industrial production of these compounds.

[0090] Beneficial effects

[0091] The method for preparing compounds as PI3K inhibitors according to the present invention simplifies the preparation process, thereby reducing preparation steps and costs. Furthermore, in the preparation process of the compounds as PI3K inhibitors, intermediate compounds used for preparing the compounds as PI3K inhibitors according to the present invention can be used, further reducing preparation steps and costs. Therefore, the productivity of compounds as PI3K inhibitors can be improved. Detailed Implementation

[0092] The advantages and features of the invention, as well as methods for implementing the invention, will be described in detail below with reference to the following exemplary embodiments. However, the invention is not limited to the exemplary embodiments disclosed below, but will be practiced in various different forms. The following exemplary embodiments are presented to better understand the invention; these embodiments are provided only to fully illustrate the scope of the invention to those skilled in the art, and therefore the invention will be limited only by the scope of its claims.

[0093] Example 1: Synthesis of (S)-4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one

[0094] 1. Plan

[0095]

[0096] 2. Synthesis of step (1) - intermediate compound QHK

[0097] According to the above protocol, acetonitrile (AN, 80 ml), DCK (1-(4,6-dichloropyrimidin-5-yl)ketene, 7.0 g, 36.8 mmol), and triethylamine (Et3N, 7.0 ml, 50.2 mmol) were added to the intermediate compound IQA ((S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinoline-1(2H)-one, 10 g, 33.5 mmol), and stirred under reflux for three hours. After cooling to room temperature (25°C), purified water (20 ml) was added and stirred at room temperature (25°C). The obtained solid was filtered, washed with purified water (25 ml), and dried with hot air at 40 °C to obtain the intermediate compound QHK((S)-3-(1-((5-acetyl-6-chloropyrimidin-4-yl)amino)ethyl)-8-chloro-2-phenylisoquinoline-1(2H)-one (13.8 g, yield: 91%).

[0098] 1 H-NMR (400MHz, CDCl3): δ1.43(d,3H), δ2.78(s,3H), δ4.92(t,1H) δ6.48(s,1H), δ7.26-7.46(m,8H), δ8.18(s,1H), δ8.97(d,1H).

[0099] 3. Step (2) - Synthesis of intermediate compound IQCK

[0100] Dichloromethane (MC, 35 ml) and N-chlorosuccinimide (NCS, 2.0 g, 15 mmol) were added to the intermediate compound QHK (6.0 g, 13 mmol) obtained in step (1) above, and stirred under reflux for three hours. After cooling to room temperature (25 °C), the reaction mixture was concentrated under reduced pressure. Acetonitrile (18 ml) was added to the concentrated residue, cooled, and stirred at 0–5 °C for one hour. The solid was then filtered, washed with acetonitrile (6 ml), and dried with hot air at 40 °C to obtain the intermediate compound IQCK ((S)-3-(1-((5-acetyl-6-chloropyrimidin-4-yl)amino)ethyl)-4,8-dichloro-2-phenylisoquinoline-1(2H)-one) (5.7 g, yield: 89%).

[0101] 1 H-NMR (400MHz, CDCl3): δ1.62 (d, 3H), δ2.74 (s, 3H), δ4.98 (t, 1H), δ7.17-7.95 (m, 8H), δ8.26 (s, 1H), δ9.37 (broad peak, 1H).

[0102] 4. Step (3) - Synthesis of intermediate compound IQNK

[0103] Dimethyl sulfoxide (DMSO, 304 ml) and ammonium hydroxide (48.6 ml, 642 mmol) were added to the intermediate compound IQCK (30.4 g, 62 mmol) obtained in step (2) above. The mixture was then heated and stirred at 80 °C for five hours, cooled to room temperature, and stirred overnight. Purified water (304 ml) was added to the reaction mixture that had formed a solid, and the mixture was stirred further at room temperature for 1.5 hours. The solid from the reaction mixture was filtered, washed with purified water (610 ml), and dried with hot air at 40 °C to obtain crude IQCK (29.8 g). The crude IQCK (29.8 g) was added to isopropanol (300 ml), stirred under reflux for 10 minutes, cooled to room temperature, and stirred further for two hours. The resulting solid was filtered, washed with isopropanol (75 ml), and dried with hot air at 40 °C to obtain purified IQNK((S)-3-(1-((5-acetyl-6-aminopyrimidin-4-yl)amino)ethyl)-4,8-dichloro-2-phenylisoquinoline-1(2H)-one) (26.9 g, yield: 92%).

[0104] 1 H-NMR (400MHz, CDCl3): δ1.60(d,3H), δ2.56(s,3H), δ5.03(t,1H), δ5.77(br,2H), δ7.15-7.97(m,9H).

[0105] Although isopropanol was used as the solvent for purifying the crude IQNK product in step (3) above, the examples are not limited thereto, and various organic solvents can be used. For example, any one or more organic solvents selected from ethanol, isopropanol, and acetone can be used. Preferably, isopropanol solvent can be used.

[0106] 5. Step (4) - Synthesis of intermediate compound IQVK

[0107] Dichloromethane (130 ml) and dimethylformamide-dimethylacetal (DMF-DMA, 15.2 ml, 114.4 mmol) were added to the intermediate compound IQNK (26.8 g, 57.2 mmol) obtained in step (3) above. The mixture was stirred under reflux for one hour, cooled to room temperature (25 °C), and concentrated under reduced pressure. Isopropanol (190 ml) was added to the concentrated residue, stirred under reflux, cooled to room temperature, and then the solid was filtered. The filtered solid was washed with isopropanol (80 ml) and dried with hot air at 40 °C to obtain the intermediate compound IQVK ((S)-N'-(5-acetyl-6-((1-(4,8-dichloro-1-)oxo-2-phenyl-1,2-dihydroisoquinoline-3-yl)ethyl)amino)pyrimidin-4-yl)-N,N-dimethylformimide) (26.2 g, yield: 88%).

[0108] 1 H-NMR (400MHz, CDCl3): δ1.60(d,3H), δ2.75(s,3H), δ3.11(s,3H), δ3.14(s,3H), δ4.99(t,1H), δ7.26-7.96(m,8H), δ8.10(s,1H), δ8.55(s,1H).

[0109] 6. Step (5) - Synthesis of the final product

[0110] Tetrahydrofuran (6 ml) was added to the intermediate compound IQVK (1 g, 1.9 mmol) obtained in step (4) above, and the mixture was cooled and stirred at -5 °C. Potassium tert-butoxide (0.32 g, 2.9 mmol) was added in three portions, and the mixture was stirred for 0.5 hours while maintaining the temperature at -5 °C. Then, purified water (12 ml) and acetic acid (0.33 ml, 5.7 mmol) were added, and the mixture was stirred at room temperature for two hours. The resulting solid was filtered, washed with purified water (10 ml), and dried with hot air at 40 °C to obtain the final product ((S)-4-((1-(4,8-dichloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrido[2,3-d]pyrimidin-5(8H)-one) (0.85 g, yield: 77%).

[0111] 1 H-NMR (400MHz, CDCl3): δ1.67(d,3H), δ5.03(t,1H), δ6.31(d,1H), δ7.20-7.95(m,9H), δ8.25(s,1H).

[0112] Referring to Example 1, in the method for preparing a compound as a PI3K inhibitor according to one embodiment, the compound as a PI3K inhibitor can be synthesized in only five steps from step (1) to step (5). Furthermore, since the reaction time of each step is short, the process time can be shortened. More specifically, steps (1) to (5) may not involve pressure reaction conditions requiring reflux and stirring for several days or longer. In particular, steps (1) to (5) may include a reflux and stirring step of about one hour to about five hours, and may not include a reflux and stirring step requiring more than these hours. Therefore, the total working days of the method for preparing a compound as a PI3K inhibitor according to one embodiment can be shortened by several days or longer. Furthermore, since strong acids (such as trifluoroacetic acid (TFA) or methanesulfonic acid (MsOH)) are not used, the reaction can be carried out under mild reaction conditions. Therefore, the risk factors that may occur during the synthesis process can be significantly reduced, and the preparation process can be easily managed.

[0113] In a method for preparing a PI3K inhibitor according to one embodiment, the PI3K inhibitor can be prepared by a preparation method including steps (S1) to (S5), which simplifies the process and reduces the number of preparation steps and preparation costs. Furthermore, the preparation process can be easily managed by preparing the PI3K inhibitor under mild reaction conditions.

Claims

1. A method for preparing a compound of formula 7, the method comprising: (S1) React the compound of formula 4 with ammonium hydroxide (NH4OH) to produce the compound of formula 5; (S2) Reacting compound 5 with dimethylformamide-dimethylacetal to prepare compound 6; and (S3) Cyclize the compound of formula 6 to prepare the compound of formula 7: [Formula 4] [Formula 5] [Formula 6] [Formula 7] In equations 4 to 7 above, X1, X2, and X4 are each independently a halogen atom, and In Equation 6 above, either R1 or R2 is a hydrogen atom, and the other is dimethylamine. The above (S1) is carried out in a polar aprotic solvent selected from dichloromethane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, dimethylformamide, and acetonitrile. The above (S2) is carried out in dichloromethane. In the above (S3), the cyclization reaction includes reacting the above compound of formula 6 with a base and adding an acid.

2. The method according to claim 1, further comprising: (S1-1) Halogenate the compound of formula 3 to prepare the compound of formula 4: [Formula 3] In Equation 3 above, X1 and X2 are each independently the same as those defined in Equations 4 to 7 above.

3. The method according to claim 2, further comprising: (S1-2) React the compound of formula 1 with the compound of formula 2 to prepare the compound of formula 3 above: [Formula 1] [Equation 2] In Equations 1 and 2 above, X1 and X2 are each independently identical to those defined in Equations 4 to 7 above, and In Equation 2 above, X3 is a halogen atom.

4. The method according to claim 1, wherein the polar aprotic solvent in (S1) above is dimethyl sulfoxide.

5. The method according to claim 2, wherein the above (S1-1) is to react the above compound of formula 3 with N-chlorosuccinimide to carry out a chlorination reaction.

6. The method according to claim 1, wherein the above (S1) is carried out at 70°C to 90°C.

7. The method according to claim 6, wherein the above (S1) includes purifying the crude product.

8. The method of claim 7, wherein purifying the crude product comprises at least one selected from ethanol, isopropanol and acetone as a purification solvent.

9. The method of claim 7, wherein isopropanol is used as the purification solvent in purifying the crude product.

10. The method according to claim 1, wherein the above (S2) is performed under reflux.

11. The method according to claim 10, wherein the base is a tert-butoxide.

12. The method according to claim 10, wherein the acid is acetic acid or hydrochloric acid.

13. A method for preparing a compound of formula 6, the method comprising: The compound of formula 5 is reacted with dimethylformamide-dimethylacetal in dichloromethane: [Formula 5] [Formula 6] In equations 5 and 6 above, X1 and X4 are each independently a halogen atom, and In Equation 6 above, either R1 or R2 is a hydrogen atom, and the other is dimethylamine.

14. A method for preparing a compound of formula 7, the method comprising: To cause a cyclization reaction of the compound of formula 6, wherein the cyclization reaction comprises reacting the compound of formula 6 with a base and adding an acid: [Formula 6] [Formula 7] In Equations 6 and 7 above, X1 and X4 are each independently halogen atoms, and in Equation 6 above, either R1 or R2 is a hydrogen atom, and the other is dimethylamine.

15. A compound represented by the following formula 6: [Formula 6] In Equation 6 above, X1 and X4 are each independently halogen atoms, and either R1 or R2 is a hydrogen atom, while the other is dimethylamine.

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