A Process For Preparing Isoindolinone Derivative, Novel Intermediates Used For The Process, And A Process For Preparing The Intermediates

Abstract

The present invention relates to a process for preparing an isoindolinone derivative represented by Formula 1, novel intermediates used for the process and a process for preparing the intermediates.

Claims

1. A compound selected from the group consisting of Formula 2, Formula 3, Formula 4, and Formula 5 below: ##STR00015##

2. The compound of claim 1, wherein the compound comprises Formula 3 below: ##STR00016##

3. The compound of claim 1, wherein the compound comprises Formula 4 below: ##STR00017##

4. The compound of claim 1, wherein the compound comprises Formula 5 below: ##STR00018##

5. (canceled)

6. (canceled)

7. (canceled)

8. (canceled)

9. A process for preparing a compound of Formula 1 below, comprising (a) a step of preparing a compound of Formula 2 below by reacting a methyl 3-hydroxy-5-methoxybenzoate compound with phenylethylamine and formaldehyde; and (b) a step of preparing a compound of Formula 3 below by reacting the compound of Formula 2 below with an acid and then reacting with a base. ##STR00019##

10. The process according to claim 9, further comprising (c) a step of preparing a compound of Formula 4 below by reacting the compound of Formula 3 below with an allyl halide. ##STR00020##

11. The process according to claim 10, further comprising (d) a step of preparing a compound of Formula 5 below by reacting the compound of Formula 4 below in mesitylene. ##STR00021##

12. The process according to claim 11, further comprising (e) a step of preparing a compound of Formula 6 below by attaching a protecting group to a hydroxy group of the compound of Formula 5 below; (f) a step of preparing a compound of Formula 7 below by performing an oxidation reaction on the compound of Formula 6 below; (g) a step of preparing a compound of Formula 8 below by performing a reduction reaction on the compound of Formula 7 below; and (h) a step of preparing a compound of Formula 1 below by performing a deprotection reaction on the compound of Formula 8 below. ##STR00022## wherein R represents a benzoyl group, an acetyl group, a methoxymethyl group, an ethoxyethyl group, a methylthiomethyl group, a tert-butyl group, an allyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a pivaloyl group, or a β-methoxyethoxymethyl group as a protecting group.

13. The process according to claim 9, wherein the acid is at least one selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, sulfonic acid and p-toluenesulfonic acid, and the base is an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution.

14. (canceled)

15. The process according to claim 10, wherein the allyl halide is selected from the group consisting of allyl chloride, allyl bromide and allyl iodide.

16. (canceled)

17. The compound of claim 1, wherein the compound comprises Formula 2 below: ##STR00023##

18. The process according to claim 12, wherein when the protecting group R is a tert-butyldimethylsilyl group, the compound of Formula 6, the compound of Formula 7, and the compound of Formula 8 are represented by Formula 6a, Formula 7a, and Formula 8a, respectively: ##STR00024##

19. The process according to claim 12, wherein the deprotection reaction comprises a reaction of recovering a hydroxy group by removing the protecting group bonded with the hydroxy group on the compound of Formula 8.

20. The process according to claim 19, wherein the deprotection reaction comprises exposing the compound of Formula 8 to tetra-n-butylammonium fluoride.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0044] FIG. 1 shows the results of .sup.1H NMR analysis of the compound of Formula 2.

[0045] FIGS. 2a and 2b show the results of .sup.1H NMR and .sup.13C NMR analysis of the compound of Formula 3.

[0046] FIGS. 3a and 3b show the results of .sup.1H NMR and .sup.13C NMR analysis of the compound of Formula 4.

[0047] FIGS. 4a and 4b show the results of .sup.1H NMR and .sup.13C NMR analysis of the compound of Formula 5.

[0048] FIGS. 5a and 5b show the results of .sup.1H NMR and .sup.13C NMR analysis of the compound of Formula 6a.

[0049] FIGS. 6a and 6b show the results of .sup.1H NMR and .sup.13C NMR analysis of the compound of Formula 8a.

[0050] FIGS. 7a and 7b show the results of .sup.1H NMR and .sup.13C NMR analysis of the compound of Formula 1.

DETAILED DESCRIPTION FOR WORKING THE INVENTION

[0051] Hereinafter, the present invention is to be described in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1

Preparation of Compound of Formula 2

[0052] ##STR00008##

[0053] To a solution of methyl 3-hydroxy-5-methoxybenzoate (4.0 g, 21.98 mmol) in methanol (10 ml), phenylethylamine (4.0 mL, 33.03 mmol) was added, and 30% formaldehyde solution (4.0 mL) was added dropwise at room temperature. Thereafter, the temperature of the reaction mixture was elevated up to 60° C. and stirred for 3 hours. After the reaction was completed (confirmed by TLC), the reaction mixture was cooled to room temperature and quenched by slowly adding a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted three times with EtOAc, and the combined organic layer was washed with brine, and dried over sodium sulfate, evaporated to dryness, and then purified by column chromatography to obtain methyl 7-methoxy-3-phenethyl-3,4-dihydro-2H-benzo[e][1,3]oxazine-5-carboxylate (3.21 g, 45%) represented by Formula 2 as a yellow oil.

[0054] .sup.1H NMR (400 MHz) δ 7.32-7.23 (m, 2H), 7.19 (d, J=7.3 Hz, 3H), 7.13 (s, 1H), 7.07 (s, 1H), 4.85 (s, 2H), 4.00 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.08-2.95 (m, 2H), 2.93-2.77 (m, 2H).

Example 2

Preparation of Compound of Formula 3

[0055] ##STR00009##

[0056] Methyl 7-methoxy-3-phenethyl-3,4-dihydro-2H-benzo[e][1,3]oxazine-5-carboxylate (3.21 g, 9.82 mmol) represented by Formula 2 was added to ethanol at room temperature, and HCl was added dropwise to the reaction mixture heated to reflux for 3 hours. After confirming that the starting material disappeared, the reaction mixture was cooled to 0° C., and an aqueous sodium hydroxide solution was added until the pH reached 8, and then the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with brine (30 mL) and washed with CHCl.sub.3 (3×30 mL). The organic layers were combined, dried over MgSO.sub.4, filtered and then concentrated. The crude product was purified by column chromatography to obtain 4-hydroxy-6-methoxy-2-phenethylisoindolin-1-one (1.52 g, 55%) represented by Formula 3, the desired compound, as a white solid.

[0057] .sup.1H NMR (400 MHz) δ 7.27-7.13 (m, 5H), 6.76 (d, J=2.1 Hz, 1H), 6.50 (d, J=2.1 Hz, 1H), 4.14 (s, 2H), 3.81 (dd, J=9.3, 5.2 Hz, 2H), 3.77 (s, 3H), 2.96 (t, J=7.3 Hz, 2H). .sup.13C NMR (101 MHz) δ 169.56, 161.73, 153.10, 138.79, 134.31, 128.46, 128.27, 126.21, 120.75, 105.10, 97.57, 54.70, 44.11, 34.20.

Example 3

Preparation of Compound of Formula 4

[0058] ##STR00010##

[0059] Potassium carbonate (2.5 equiv) was added to a DMF solution of 4-hydroxy-6-methoxy-2-phenethylisoindolin-1-one (1.50 g, 5.30 mmol) represented by Formula 3, and then allyl bromide (1.27 g, 10.60 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 5 hours. The reaction was quenched by adding a saturated aqueous NaHCO.sub.3 solution (30 mL), and then washed with CHCl.sub.3 (3×30 mL). The combined organic layer was dried over MgSO.sub.4, filtered and then concentrated. The crude product was purified by silica gel column chromatography (hexane/Et.sub.2O, 20:1) to obtain 4-(allyloxy)-6-methoxy-2-phenethylisoindolin-1-one (1.55 g, 91%) represented by Formula 4 as a white solid.

[0060] .sup.1H NMR (400 MHz) δ 7.39-7.14 (m, 5H), 6.92 (d, J=1.9 Hz, 1H), 6.54 (d, J=2.0 Hz, 1H), 6.06-5.90 (m, 1H), 5.33 (ddd, J=13.9, 11.9, 1.4 Hz, 2H), 4.54 (dt, J=5.3, 1.5 Hz, 2H), 4.16 (s, 2H), 3.93-3.76 (m, 5H), 2.96 (dd, J=14.3, 7.1 Hz, 2H). .sup.13C NMR (101 MHz) δ 168.52, 161.63, 154.09, 138.79, 135.21, 132.65, 128.80, 128.70, 126.58, 122.49, 118.13, 103.33, 98.11, 69.00, 55.93, 48.16, 44.29, 34.93.

Example 4

Preparation of Compound of Formula 5

[0061] ##STR00011##

[0062] 4-(allyloxy)-6-methoxy-2-phenethylisoindolin-1-one (1.55 g, 4.8 mmol) represented by Formula 4 was refluxed in mesitylene (10 ml) for one day. The cooled reaction mixture was concentrated in vacuo and then dissolved in AcOEt (30 ml). The combined organic layer was washed with a saturated aqueous NaCl solution (100 ml). The organic layer was dried over MgSO.sub.4 and then concentrated. The crude product was purified by silica gel column using a mixture of AcOEt and hexane (1:3) as an eluent, and as a result, 5-allyl-4-hydroxy-6-methoxy-2-phenethylisoindolin-1-one (1.26 g, 84%) represented by Formula 5 as a white solid was obtain.

[0063] .sup.1H NMR (400 MHz) δ 7.31-7.15 (m, 5H), 6.97 (s, 1H), 5.95 (ddt, J=16.2, 10.1, 6.1 Hz, 1H), 5.22-5.04 (m, 2H), 4.18 (s, 2H), 3.89-3.80 (m, 5H), 3.58-3.46 (m, 2H), 3.01-2.89 (m, 2H). .sup.13C NMR (101 MHz) δ 168.92, 158.66, 150.25, 138.75, 135.80, 132.70, 128.76, 128.70, 126.60, 121.06, 116.80, 116.48, 97.93, 56.24, 48.23, 44.35, 34.96, 27.96.

Example 5

Preparation of Compound of Formula 6a

[0064] ##STR00012##

[0065] Tert-butyldimethylchlorosilane (1.20 g, 8.04 mmol) was added to a solution of 5-allyl-4-hydroxy-6-methoxy-2-phenethylisoindolin-1-one (1.3 g, 4.02 mmol) represented by Formula 5 and 1H imidazole (2.5 equiv) dissolved in DMF (25 mL). The reaction mixture was stirred at room temperature for 2 hours. Thereafter, the reaction was quenched by adding a saturated aqueous NaHCO.sub.3 solution, and washed with CH.sub.2Cl.sub.2 (3×30 mL). The combined organic layer was dried over MgSO.sub.4, filtered and then concentrated. The crude compound was purified by silica gel column chromatography (hexane/Et.sub.2O, 20:1) to obtain 5-allyl-4-((tert-butyldimethylsilyl)oxy)-6-methoxy-2-phenethylisoindolin-1-one (1.48 g, 84%) represented by Formula 6a as a white solid.

[0066] .sup.1H NMR (400 MHz) δ 7.27-7.21 (m, 5H), 7.07-7.02 (m, 1H), 5.95-5.79 (m, 1H), 4.90 (ddd, J=18.8, 13.6, 1.8 Hz, 2H), 3.98 (s, 2H), 3.88-3.83 (m, 5H), 3.44-3.34 (m, 2H), 2.97 (t, J=7.0 Hz, 2H), 0.96 (s, 9H), 0.09 (s, 6H). .sup.13C NMR (101 MHz) δ 168.72, 159.47, 148.67, 144.78, 139.12, 136.03, 132.48, 128.77, 126.63, 124.24, 123.24, 114.79, 99.29, 56.15, 49.73, 44.25, 35.17, 28.40, 25.98, 18.67, −3.26.

Example 6

Preparation of Compound of Formula 7a and Compound of Formula 8a

[0067] ##STR00013##

[0068] 5-allyl-4-((tert-butyldimethylsilyl)oxy)-6-methoxy-2-phenethylisoindolin-1-one (1.4 g, 1.20 mmol) represented by Formula 6a was dissolved in Et.sub.2O (24 mL), and then to the solution, 0.05 M of an OsO.sub.4 acetone solution (2.5 equiv) was added. The resulting dark brown solution was stirred for 1 hour, and water (24 mL) was added to the solution, and then fine powder of NaIO.sub.4 (1.28 g, 6.0 mmol) was added in portions 5 times over 5 hours. The yellowish brown slurry was further stirred for 45 minutes and then diluted with Et.sub.2O, and the layers were separated. The organic layer was washed with saturated brine, and dried over Na.sub.2SO.sub.4, and filtered and then concentrated in vacuo to obtain the crude product represented by Formula 7a.

[0069] The crude product was dissolved in CH.sub.3OH (6.0 mL), cooled to 0° C., and then treated with NaBH.sub.4 (1.36 g, 3.60 mmol). After 30 minutes, an excess hydride was quenched by adding 10% HCl, and the resulting mixture was extracted with Et.sub.2O. The combined organic extract was washed with saturated brine, dried over Na.sub.2SO.sub.4, filtered through a SiO.sub.2 plug (1.0 in.) on a Celite pad, and then concentrated in vacuo to obtain 4-((tert-butyldimethylsilyl)oxy)-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one (437 mg, 31%) represented by Formula 8a as a white solid.

[0070] .sup.1H NMR (400 MHz) δ 7.28-7.10 (m, 5H), 6.99 (s, 1H), 4.86 (s, 2H), 4.00 (s, 2H), 3.90-3.80 (m, 5H), 3.58-3.50 (m, 2H), 2.98-2.93 (m, 4H), 0.99-0.96 (m, 9H), 0.11-0.09 (m, 6H). .sup.13C NMR (101 MHz) δ 169.31, 159.85, 149.20, 139.05, 131.84, 128.20, 126.29, 124.60, 122.10, 98.32, 96.20, 60.18, 55.10, 50.01, 44.02, 34.39, 27.58, 25.12, 18.18, −4.52.

Example 7

Preparation of Compound of Formula 1

[0071] ##STR00014##

[0072] To a solution of 4-((tert-butyldimethylsilyl)oxy)-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one (430 mg, 0.97 mmol) represented by Formula 8a in THF, a 1.0 M solution (1.46 mL) of tetra-n-butylammonium fluoride (1.46 mmol) in THF was added dropwise at 0° C. The solution was stirred for 2 hours at room temperature and then added to a saturated NH.sub.4Cl solution. The mixture was extracted with Et.sub.2O, and then the combined organic layer was dried over Na.sub.2SO.sub.4, filtered and then concentrated in vacuo to obtain an oil, which was purified by SiO.sub.2 chromatography (50% EtOAc/hexane) to obtain 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one (261 mg) represented by Formula 1 as a pale white solid.

[0073] .sup.1H NMR (400 MHz) δ 7.34-7.19 (m, 5H), 7.19-7.14 (m, 1H), 6.85 (s, 1H), 4.15 (s, 2H), 3.86-3.79 (m, 5H), 3.64 (t, J=7.0 Hz, 2H), 2.96 (td, J=7.1, 1.8 Hz, 4H). .sup.13C NMR (101 MHz) δ 169.72, 159.34, 151.01, 138.80, 131.45, 128.46, 128.29, 126.22, 121.27, 118.33, 96.17, 61.14, 55.01, 48.44, 44.06, 34.24, 26.57.