Production method for 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one compound for use in treatment of neurological disorders

Abstract

The present invention relates to a useful production method that can be applied to mass production by enabling production of the 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one compound in high yield, while improving ease of purification, wherein the compound has excellent nerve growth factor-enhancing ability, nerve cell growth-promoting activity, and anti-neuritis activity.

Description

Method for preparing a 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one compound used in the treatment of neurological disorders

[0001] The present invention relates to a method for producing 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one, a substance derived from the natural product Hericium erinaceus, which is used to treat neurological diseases, and specifically, to a method for producing 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one that can increase the yield and productivity.

[0002] 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one is a synthetic substance derived from natural products, and is known to be a substance with excellent ability to increase nerve growth factors, promote the growth of nerve cells, and have anti-neuritis activity (Korean Patent Publication No. 10-2022-0040291).

[0003] In addition, the prior art (Korean Patent Publication No. 10-2021-0069791) has a problem in that the yield is low when using the raw materials presented to manufacture a substance synthesized using an intermediate. As a result, the amount of raw materials used increases, leading to reduced process efficiency, difficulty in mass production, and limitations in introducing a purification process due to reaction selectivity. Therefore, it is necessary to develop a manufacturing method that is applicable to mass production and easy to purify, while increasing the production yield and improving the purity of 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one, a synthetic substance derived from natural products.

[0004] During research for this purpose, a method was discovered that enables mass production with high yield and easy purification at each synthesis step. Having successfully applied this method to the process, the present invention was completed by utilizing it.

[0005] [Prior Art Literature]

[0006] (Patent Document 0001) Republic of Korea Published Patent Application No. 10-2022-0040291,

[0007] (Patent Document 0002) Republic of Korea Published Patent Application No. 10-2021-0069791

[0008] The objective of the present invention is to provide a method for manufacturing 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one that enables high production yield and easy purification at each synthesis step, thereby enabling mass production and high yield.

[0009] For the above purpose, the present invention may provide a method for preparing a 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one compound represented by the following chemical formula 1.

[0010] [Chemical Formula 1]

[0011]

[0012] In addition, the present invention provides a method for preparing a compound represented by Chemical Formula 1 that can minimize the silica gel column chromatography purification process, and a compound represented by Chemical Formula 1 prepared thereby.

[0013] The method for producing 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one according to the present invention has the advantage of increasing process efficiency by improving yield and purity through a four-step reaction process, and can be applied to mass production processes. The 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one synthesized by the method according to the present invention can be usefully used as a substance for treating neurological diseases due to effects such as the promotion of nerve growth factor production.

[0014] Figures 1a and 1b are of a compound represented by <Chemical Formula 1> 1 H NMR and 13 These are the results of the C NMR analysis, respectively.

[0015] FIGS. 2a and 2b are of a compound represented by <Chemical Formula 2> 1 H NMR and 13 These are the results of the C NMR analysis, respectively.

[0016] Figures 3a and 3b show the compound represented by <Chemical Formula 3> 1 H NMR and 13 These are the results of the C NMR analysis, respectively.

[0017] Figures 4a and 4b show the compound represented by <Chemical Formula 4> 1 H NMR and 13 These are the results of the C NMR analysis, respectively.

[0018] Figures 5a and 5b show the compound represented by <Chemical Formula 5> 1 H NMR and 13 These are the results of the C NMR analysis, respectively.

[0019] The present invention can provide a manufacturing method suitable for a large-scale synthesis process by utilizing an overall process reaction equation including the first to fourth steps shown in [Reaction Scheme 1] below to manufacture a compound represented by <Chemical Formula 1>, thereby achieving process simplification, improving manufacturing yield, and making the purification process very easy.

[0020] [Reaction Equation 1]

[0021] <Stage 1>

[0022]

[0023] Stage 2

[0024]

[0025] Stage 3

[0026]

[0027] Stage 4

[0028]

[0029] Specifically, the present invention may provide a method for producing 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one represented by Formula 1, wherein 4-(allyloxy)-6-methoxy-2-phenethylisoindolin-1-one represented by Formula 2 is used as a raw material. According to one example of the present invention, the method may include a first step of obtaining 5-allyl-4-hydroxy-6-methoxy-2-phenethylisoindolin-1-one represented by Formula 3 by a Claisen rearrangement reaction of 4-(allyloxy)-6-methoxy-2-phenethylisoindolin-1-one represented by Formula 2 under mesitylene.

[0030] The manufacturing method of the present invention may include, following the first step, a second step of reacting 5-allyl-4-hydroxy-6-methoxy-2-phenethylisoindolin-1-one represented by Formula 3 obtained in the first step with osmium tetroxide and N-methylmorpholin-N-oxide to obtain 4-hydroxy-5-(2,3-dihydroxypropyl)-6-methoxy-2-phenethylisoindolin-1-one represented by Formula 4.

[0031] The manufacturing method of the present invention may include, following the second step, a third step of reacting 4-hydroxy-5-(2,3-dihydroxypropyl)-6-methoxy-2-phenethylisoindolin-1-one represented by Formula 4 obtained in the second step with sodium periodate to obtain 2-(4-hydroxy-6-methoxy-1-oxo-2-phenethylisoindolin-5-yl)acetaldehyde represented by Formula 5.

[0032] As such, a reaction in which a compound represented by Chemical Formula 4 and / or a compound represented by Chemical Formula 5 is used as an intermediate can increase the yield of the compound represented by Chemical Formula 1 to be finally produced and facilitate purification. On the other hand, as disclosed in prior art such as Korean Patent Publication No. 10-2021-0069791, if a method is used in which a protecting group is attached to a hydroxyl group of a compound represented by Chemical Formula 3 and subsequent oxidation-reduction and deprotection reactions are performed, the yield of the intermediate is very low, resulting in a low overall process yield and a limitation of prolonged reaction time. Conversely, a reaction in which a compound represented by Chemical Formula 4 and / or a compound represented by Chemical Formula 5 is used as an intermediate, as in the present invention, has the advantage of increasing the yield of the compound represented by Chemical Formula 1 to be finally produced, facilitating purification, and shortening the overall reaction time.

[0033] In the manufacturing method of the present invention, following the third step, 2-(4-hydroxy-6-methoxy-1-oxo-2-phenethylisoindolin-5-yl)acetaldehyde represented by Chemical Formula 5 obtained in the third step is reacted with sodium borohydride to finally obtain 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one represented by Chemical Formula 1. Subsequently, a purification process using silica gel flash column chromatography or the like can be further performed.

[0034] The present invention will be explained in more detail through the following examples. The following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0035] [Example 1] Preparation of a compound represented by <Formula 3> in <Formula 2>

[0036]

[0037] Mesitylene (200 ml) was added to 4-(allyloxy)-6-methoxy-2-phenethylisoindoline-1-one (30 g, 92.7 mmol) <Chemical Formula 2> and stirred under reflux for 24 hours. Afterward, the reaction was cooled to room temperature, DCM (dichloromethane) (500 ml) was added, and the organic layer formed was washed with brine (100 ml) and dried with MgSO4. Then, after concentration under reduced pressure, the mixture was purified by silica gel flash chromatography to obtain a white solid 5-allyl-4-hydroxy-6-methoxy-2-phenethylisoindoline-1-one (26.1 g, 87%) <Chemical Formula 3>.

[0038] of the compound represented by the above chemical formula 2 1 H NMR and 13 The C NMR analysis results are as follows, and each graph is shown in Figures 2a and 2b.

[0039] 1 H NMR (400MHz): δ 2.83 (2H, t,J= 6.9 Hz), 3.41 (2H, t,J= 6.9 Hz), 3.85 (3H, s), 4.33-4.54 (4H, 4.40 (d,J= 15.5 Hz), 4.48 (d,J= 7.5 Hz)), 4.93-5.10 (2H, 5.00 (dd,J= 16.5, 1.3 Hz), 5.04 (dd,J= 10.7, 1.3 Hz)), 5.99 (1H, ddt,J= 16.5, 10.7, 7.5 Hz), 6.45 (1H, d,J= 2.3 Hz), 6.95-7.35 (6H, 7.00 (d,J= 2.3 Hz), 7.10 (dddd,J= 7.8, 1.3, 1.2, 0.5 Hz), 7.19 (tt,J= 7.7, 1.3 Hz), 7.29 (tdd,J= 7.8, 1.8, 0.5 Hz)).

[0040] 13C NMR (101 MHz): δ 34.4 (1C, s), 50.0 (1C, s), 52.0 (1C, s), 56.0 (1C, s), 69.6 (1C, s), 104.7 (1C, s), 108.8 (1C, s), 118.0 (1C, s), 124.2 (1C, s), 127.2 (1C, s), 128.5 (2C, s), 128.8 (2C, s), 132.7 (1C, s), 135.5 (1C, s), 137.6 (1C, s), 148.4 (1C, s), 162.4 (1C, s), 168.4 (1C, s).

[0041] of the compound represented by the above chemical formula 3 1 H NMR and 13 The C NMR analysis results are as follows, and each graph is shown in Figures 3a and 3b.

[0042] 1 H NMR (400MHz): δ 2.83 (2H, t,J= 6.9 Hz), 3.41 (2H, t,J= 6.9 Hz), 3.65 (2H, d,J= 6.6 Hz), 3.77 (3H, s), 4.43 (2H, d,J= 15.6 Hz), 7.04-7.35 (6H, 7.10 (dddd,J= 7.8, 1.3, 1.2, 0.5 Hz), 7.20 (tt,J= 7.7, 1.3 Hz), 7.20 (s), 7.29 (tdd,J= 7.8, 1.8, 0.5 Hz)), 9.72 (1H, t,J= 6.6 Hz).

[0043] 13C NMR (101 MHz): δ 34.4 (1C, s), 35.7 (1C, s), 50.0 (1C, s), 52.0 (1C, s), 56.3 (1C, s), 105.1 (1C, s), 113.6 (1C, s), 124.2 (1C, s), 127.2 (1C, s), 128.5 (2C, s), 128.8 (2C, s), 135.5 (1C, s), 137.6 (1C, s), 158.5 (1C, s), 158.7 (1C, s), 168.4 (1C, s), 198.9 (1C, s).

[0044] [Example 2] Preparation of a compound represented by <Formula 4> in <Formula 3>

[0045]

[0046] OsO4 (osmium tetroxide) (0.02 equivalents) and NMO (N-methylmorpholine-N-oxide) (2.0 equivalents) were added to a solution of 5-allyl-4-hydroxy-6-methoxy-2-phenethylisoindolin-1-one (26 g, 80.4 mmol) <Formula 3> obtained in Example 1 in DCM (dichloromethane). The reaction mixture was stirred at room temperature (rt) for 3 hours. Then, the reaction was quenched by adding a saturated aqueous solution of NaHCO3 (1000 ml) and extracted with EA (ethyl acetate, 1000 ml x 2 times). The organic layer bound by extraction was dried with MgSO4, filtered, and concentrated to obtain the intermediate compound 4-hydroxy-5-(2,3-dihydroxypropyl)-6-methoxy-2-phenethylisoindolin-1-one (28.1g, 98%) <Chemical Formula 4>.

[0047] of the compound represented by the above chemical formula 4 1 H NMR and 13 The C NMR analysis results are as follows, and each graph is shown in Figures 4a and 4b.

[0048] 1H NMR (400MHz): δ 2.71 (2H, d,J= 6.0 Hz), 2.83 (2H, t,J= 6.9 Hz), 3.41 (2H, t,J= 6.9 Hz), 3.55 (2H, d,J= 4.3 Hz), 3.72-3.91 (4H, 3.77 (s), 3.85 (tt,J= 6.0, 4.3 Hz)), 4.37-4.51 (2H, 4.44 (d,J= 15.6 Hz), 4.44 (d,J= 15.6 Hz)), 7.04-7.35 (6H, 7.10 (dddd,J= 7.8, 1.3, 1.2, 0.5 Hz), 7.19 (tt,J= 7.7, 1.3 Hz), 7.19 (s), 7.29 (tdd,J= 7.8, 1.8, 0.5 Hz)).

[0049] 13 C NMR (101 MHz): δ 34.4 (1C, s), 35.7 (1C, s), 50.0 (1C, s), 52.0 (1C, s), 56.3 (1C, s), 65.3 (1C, s), 69.2 (1C, s), 105.1 (1C, s), 113.6 (1C, s), 124.2 (1C, s), 127.2 (1C, s), 128.5 (2C, s), 128.8 (2C, s), 135.5 (1C, s), 137.6 (1C, s), 158.5 (1C, s), 158.7 (1C, s), 168.4 (1C, s).

[0050] [Example 3] Preparation of a compound represented by <Formula 5> in <Formula 4>

[0051]

[0052] 4-hydroxy-5-(2,3-dihydroxypropyl)-6-methoxy-2-phenethylisoindolin-1-one (28.1 g, 78.6 mmol) <Formula 4> obtained in Example 2 and NaIO4 (sodium periodate) (2.0 equivalents) were dissolved in a mixed solvent of ACT (acetone) and H2O (3:1, 0.1 M), and the mixture was stirred at room temperature for 3 hours. Then, a saturated aqueous solution of NaHCO3 (1000 ml) was added to the stirred mixture to quench the reaction, and the mixture was extracted with EA (ethyl acetate) (1000 ml x 2 times). The organic layer bound by extraction was dried with MgSO4, filtered, and concentrated to obtain the intermediate compound 2-(4-hydroxy-6-methoxy-1-oxo-2-phenethylisoindolin-5-yl)acetaldehyde (21.8 g, 85%) <Chemical Formula 5>.

[0053] of the compound represented by the above chemical formula 5 1 H NMR and 13 The C NMR analysis results are as follows, and each graph is shown in Figures 5a and 5b.

[0054] 1 H NMR (400MHz): δ 2.83 (2H, t,J= 6.9 Hz), 3.41 (2H, t,J= 6.9 Hz), 3.65 (2H, d,J= 6.6 Hz), 3.77 (3H, s), 4.43 (2H, d,J= 15.6 Hz), 7.04-7.35 (6H, 7.10 (dddd,J= 7.8, 1.3, 1.2, 0.5 Hz), 7.20 (tt,J= 7.7, 1.3 Hz), 7.20 (s), 7.29 (tdd,J= 7.8, 1.8, 0.5 Hz)), 9.72 (1H, t,J= 6.6 Hz).

[0055] 13C NMR (101 MHz): δ 34.4 (1C, s), 35.7 (1C, s), 50.0 (1C, s), 52.0 (1C, s), 56.3 (1C, s), 105.1 (1C, s), 113.6 (1C, s), 124.2 (1C, s), 127.2 (1C, s), 128.5 (2C, s), 128.8 (2C, s), 135.5 (1C, s), 137.6 (1C, s), 158.5 (1C, s), 158.7 (1C, s), 168.4 (1C, s), 198.9 (1C, s).

[0056] [Example 4] Preparation of the compound represented by <Formula 1> in <Formula 5>

[0057]

[0058] NaBH4 (sodium borohydride) (2.0 equivalents) was added at 0°C to a solution containing 2-(4-hydroxy-6-methoxy-1-oxo-2-phenethylisoindolin-5-yl)acetaldehyde (21.8 g, 67 mmol) <Chemical Formula 5> in 1000 ml of methanol, and the mixture was stirred at room temperature for 3 hours. Then, 1000 ml of a saturated aqueous solution of NH4Cl was added to quench the reaction, and the mixture was extracted with DCM (dichloromethane) (1000 ml x 3 times). The organic layer bound by extraction was dried with MgSO4, filtered, and concentrated under reduced pressure. Then, by purification with silica gel flash column chromatography, a white solid 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one (17.1 g, 78%) <Chemical Formula 1> was obtained.

[0059] In this way, a compound represented by <Chemical Formula 1> was finally synthesized and purified to obtain 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one.

[0060] of the compound represented by the above chemical formula 1 1 H NMR and 13The C NMR analysis results are as follows, and each graph is shown in Figures 1a and 1b.

[0061] 1 H NMR (400 MHz): δ 2.77-2.99 (4H, 2.83 (t,J= 6.9 Hz), 2.94 (t,J= 6.8 Hz)), 3.35-3.54 (4H, 3.41 (t,J= 6.9 Hz), 3.49 (t,J= 6.8 Hz)), 3.77 (3H, s), 4.43 (2H, d,J= 15.6 Hz), 7.04-7.35 (6H, 7.10 (dddd,J= 7.8, 1.3, 1.2, 0.5 Hz), 7.18 (s), 7.20 (tt,J= 7.7, 1.3 Hz), 7.29 (tdd,J= 7.8, 1.8, 0.5 Hz)).

[0062] 13 C NMR (101 MHz): δ 32.8 (1C, s), 34.4 (1C, s), 50.0 (1C, s), 52.0 (1C, s), 56.3 (1C, s), 61.1 (1C, s), 105.1 (1C, s), 120.3 (1C, s), 124.2 (1C, s), 127.2 (1C, s), 128.5 (2C, s), 128.8 (2C, s), 135.5 (1C, s), 137.6 (1C, s), 158.5 (1C, s), 158.7 (1C, s), 168.4 (1C, s).

Claims

1. A method for preparing 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one represented by the following chemical formula 1, wherein A manufacturing method characterized by using 4-(allyloxy)-6-methoxy-2-phenethylisoindole-1-one represented by the following chemical formula 2 as a raw material, <Chemical Formula 1> <Chemical Formula 2> 2. In Paragraph 1, A method for manufacturing comprising a first step of obtaining 5-allyl-4-hydroxy-6-methoxy-2-phenethylisoindolin-1-one represented by the following chemical formula 3 by a Claisen rearrangement reaction of 4-(allyloxy)-6-methoxy-2-phenethylisoindolin-1-one represented by the above chemical formula 2 under mesitylene. <Chemical Formula 3> 3. In Paragraph 2, A method for manufacturing comprising a second step of reacting 5-allyl-4-hydroxy-6-methoxy-2-phenethylisoindolin-1-one represented by the above chemical formula 3 with osmium tetroxide and N-methylmorpholin-N-oxide to obtain 4-hydroxy-5-(2,3-dihydroxypropyl)-6-methoxy-2-phenethylisoindolin-1-one represented by the following chemical formula 4. <Chemical Formula 4> 4. In Paragraph 3, A method for manufacturing comprising a third step of reacting 4-hydroxy-5-(2,3-dihydroxypropyl)-6-methoxy-2-phenethylisoindolin-1-one represented by the above chemical formula 4 with sodium periodate to obtain 2-(4-hydroxy-6-methoxy-1-oxo-2-phenethylisoindolin-5-yl)acetaldehyde represented by the following chemical formula 5. <Chemical Formula 5> 5. In Paragraph 4, A method for manufacturing comprising a fourth step of reacting 2-(4-hydroxy-6-methoxy-1-oxo-2-phenethylisoindolin-5-yl)acetaldehyde represented by Chemical Formula 5 with sodium borohydride to obtain 4-hydroxy-5-(2-hydroxyethyl)-6-methoxy-2-phenethylisoindolin-1-one represented by Chemical Formula 1.

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