Method for preparation of (S)-N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride

Abstract

The present invention relates to a novel method for preparing (S)N.sup.1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride.

Claims

1. A method for preparing (S)N.sup.1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride, comprising the following steps: (1) preparing a compound of Formula 2 by Grignard coupling of a compound of Formula 1; (2) preparing a compound of Formula 3 by azide substitution of the compound of Formula 2 in a reaction with sodium azide; (3) preparing an aziridine derivative of Formula 4 having an amino group protected by an amino-protecting group by cyclization of the compound of Formula 3 using triphenylphosphine; (4) preparing a compound of Formula 5 by ring opening of the compound of Formula 4; (5) preparing a compound of Formula 6 by a reaction for removing the amino-protecting group of the compound of Formula 5: ##STR00007## ##STR00008## wherein X is bromo or chloro, and R is C.sub.1-6 alkyl.

2. The method of claim 1, wherein step (1) comprises the following steps: (1-1) preparing a Grignard compound by reacting the compound of Formula 1 with a metallic or organometallic compound; and (1-2) reacting the Grignard compound with a compound of Formula 7: ##STR00009##

3. The method of claim 1, wherein step (1) is performed using tetrahydrofuran (THF), 1,4-dioxane, diethylether, or a mixture thereof as a solvent.

4. The method of claim 2, wherein step (1-1) is performed at a temperature of 20 C. to 60 C.

5. The method of claim 2, wherein step (1-2) is performed at a temperature of 20 C. to 30 C.

6. The method of claim 2, wherein step (1-2) is performed by further comprising a Lewis acid.

7. The method of claim 1, wherein step (2) is performed using dimethylformamide as a solvent.

8. The method of claim 1, wherein step (2) is performed at a temperature of 70 C. to 100 C.

9. The method of claim 1, wherein step (3) comprises the following steps: (3-1) forming an aziridinyl group of Formula 3-1 by cyclization by triphenylphosphine; and (3-2) introducing a protecting group to an amino group by reacting the compound including the aziridinyl group obtained by step (3-1) with di-tert-butyl dicarbonate: ##STR00010## wherein R is the same as defined in claim 1.

10. The method of claim 9, wherein step (3-2) is performed by further comprising a catalyst selected from 4-dimethylaminopyridine and iodine (I.sub.2), or an alkaline substance selected from triethanolamide (TEA), N,N-diisopropylethylamine (DIEA), and NaHCO.sub.3.

11. The method of claim 1, wherein step (3) is performed using acetonitrile, toluene, or a mixture thereof as a solvent.

12. The method of claim 9, wherein step (3-1) is performed at a temperature of 55 C. to 70 C.

13. The method of claim 9, wherein step (3-2) is performed at a temperature of 20 C. to 30 C.

14. The method of claim 1, wherein step (4) is performed using acetonitrile, tetrahydrofuran, toluene, or a mixture thereof as a solvent.

15. The method of claim 1, wherein step (4) is performed at a temperature of 45 C. to 55 C.

16. The method of claim 1, wherein the reaction of step (5) is performed with trifluoroacetic acid, hydrochloric acid, methanolic hydrochloric acid, or a mixture thereof.

17. The method of claim 1, wherein step (5) is performed using methanol, dichloromethane, tetrahydrofuran, or a mixture thereof as a solvent.

18. The method of claim 1, wherein the reaction of step (5) is performed with acetyl chloride in a methanol solvent.

19. The method of claim 1, wherein step (5) is performed at a temperature of 45 C. to 55 C.

20. The method of claim 1, wherein steps (4) and (5) further comprise either step (4-1) or (5-1), respectively, for independently crystallizing the prepared compounds, or both steps.

Description

MODE FOR INVENTION

(1) Hereinafter, the present invention will be described in detail with accompanying exemplary embodiments. However, the exemplary embodiments disclosed herein are only for illustrative purposes and should not be construed as limiting the scope of the present invention.

(2) Hereinafter, samples and solvents without a specific disclosure were purchased from Sigma-Aldrich Korea, and .sup.1H-NMR spectroscopy was performed using a Bruker 400 MHz NMR spectrometer.

(3) According to the reaction formula below, Examples 1 to 5 were conducted.

(4) ##STR00006##

Example 1: Preparation of (R)-1-chloro-3-(4-ethoxyphenyl)propane-2-ol

(5) In a reactor substituted with a nitrogen atmosphere, magnesium (14.50 g, 596.84 mmol) was added to 600 mL of THF, and the mixture was stirred to dissolve. While maintaining the temperature at 20 C. to 30 C., 4-bromophenetole (120.0 g, 596.84 mmol) was slowly added. After the completion of the addition, the temperature was raised to 60 C., and the mixture was stirred for 2 hours, followed by cooling to 5 C., adding copper iodide (0.76 g, 2.98 mmol), and stirring the mixture for an additional 30 minutes. Thereafter, (R)-epichlorohydrin (49.70 g, 537.15 mmol) was slowly added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the temperature was reduced to 5 C., and aqueous hydrochloride acid (3 M, 600 mL) and isopropyl ether (360 mL) were added to separate into layers. The organic layer was washed twice with a 10% aqueous EDTA solution (480 mL) and a 20% aqueous sodium chloride solution (240 mL), dried over sodium sulfate, and the mixture was filtered. The filtrate was concentrated to obtain the title compound, (R)-1-chloro-3-(4-ethoxyphenyl)propane-2-ol (123.2 g, 100% yield).

(6) .sup.1H-NMR (CDCl.sub.3, 400 MHz): (ppm) 1.41 (t, 3H), 2.17 (d, 1H), 2.83 (d, 2H), 3.49-3.61 (m, 2H), 4.00-4.04 (m, 3H), 6.85 (d, 2H), 7.14 (d, 2H).

Example 2: Preparation of (R)-1-azido-3-(4-ethoxyphenyl)propane-2-ol

(7) (R)-1-Chloro-3-(4-ethoxyphenyl)propane-2-ol (115.33 g, 537.15 mmol) prepared in Example 1 above was added to 580 mL of dimethylformamide, and the mixture was stirred to dissolve, followed by addition of sodium iodide (8.05 g, 53.72 mmol) and sodium azide (69.85 g, 1074.39 mmol) thereto. The temperature inside the reactor was raised to 85 C., and the mixture was stirred for 16 hours. After the completion of the reaction, the mixture was cooled to room temperature, and 580 mL of purified water and 580 mL of isopropyl ether were added to separate into layers. And then, the obtained water layer was further extracted with isopropyl ether (190 mL) twice. The recovered organic layer was washed with aqueous hydrochloric acid (1 M, 580 mL), a 5% aqueous sodium bicarbonate solution (580 mL), and a 10% aqueous sodium chloride solution (580 mL), dried over sodium sulfate, and the mixture was filtered. The filtrate was concentrated to obtain the title compound, (R)-1-azido-3-(4-ethoxyphenyl)propane-2-ol (113.5 g, 95.5% yield).

(8) .sup.1H-NMR (CDCl.sub.3, 400 MHz): (ppm) 1.41 (t, 3H), 1.97 (d, 1H), 2.71-2.79 (m, 2H), 3.28 (dd, 1H), 3.38 (dd, 1H), 3.94-4.01 (m, 1H), 4.04 (q, 2H), 6.86 (d, 2H), 7.10 (d, 2H).

Example 3: Preparation of (S)-tert-butyl 2-(4-ethyoxybenzyl)aziridine-1-carboxylate

(9) In a reactor substituted with a nitrogen atmosphere, (R)-1-azido-3-(4-ethoxyphenyl)propane-2-ol (113.0 g, 510.71 mmol) prepared in Example 2 was added to acetonitrile (AN, 1130 mL), and the mixture was stirred, followed by addition of triphenylphosphine (PPh.sub.3, 120.56 g, 459.64 mmol), stirring at room temperature for 2 hours, and refluxing for 4 hours. After completion of the reaction, the mixture was cooled to 20 C., and 4-dimethylaminopyridine (DMAP, 0.62 g, 122.17 mmol) and di-tert-butyl dicarbonate ((Boc).sub.2O, 100.32 g, 459.64 mmol) were slowly added, and the mixture was stirred for 30 minutes. After adding hydrogen peroxide (11.60 g, 102.14 mmol) to the mixture and stirring it for an additional 30 minutes, the resultant was concentrated, and the acetonitrile was removed. The obtained concentrate was charged with heptane (1130 mL), and the mixture was stirred at 20 C. to 25 C. for 30 minutes, followed by filtration of the resultant. The filtrate was concentrated to obtain the title compound, (S)-tert-butyl 2-(4-ethyoxybenzyl)aziridine-1-carboxylate (113.05 g, 93.9% yield).

(10) .sup.1H-NMR (CDCl.sub.3, 400 MHz): b (ppm) 1.39-1.45 (m, 12H), 2.01 (d, 1H), 2.29 (d, 1H), 2.57-2.62 (m, 2H), 2.91 (q, 1H), 4.02 (q, 2H), 6.84 (d, 2H), 7.20 (d, 2H).

Example 4: Preparation of (S)-tert-butyl 1-(2-aminoethylamino)-3-(4-ethoxyphenyl)propane-2-ylcarbamate dihydrochloride

(11) (S)-tert-Butyl 2-(4-ethyoxybenzyl)aziridine-1-carboxylate (133.05 g, 479.70 mmol) prepared in Example 3 was added to acetonitrile (400 mL), and the mixture was stirred to dissolve, followed by addition of ethylenediamine (432.45 g, 7195.52 mmol) and stirring at 50 C. for 6 hours. After completion of the reaction, the resultant was concentrated and the inside temperature was reduced to 5 C., and an aqueous hydrochloric acid solution (2 M, 480 mL) and ethyl acetate (266 mL) were added to separate into layers. To the aqueous layer, a 50% aqueous sodium hydroxide solution (200 mL) was added, and the mixture was separated with ethyl acetate (530 mL). The organic layer was washed with 20% sodium chloride (266 mL), dried over sodium sulfate, and the mixture was filtered. The filtrate was dried under vacuum at 50 C. to obtain the title compound, (S)-tert-butyl 1-(2-aminoethylamino)-3-(4-ethoxyphenyl)propane-2-ylcarbamate dihydrochloride (135.5 g, 68.8% yield).

(12) .sup.1H-NMR (D.sub.2O, 400 MHz): (ppm) 1.02 (s, 2H), 1.14 (s, 9H), 1.24 (t, 3H), 2.46 (dd, 1H), 2.82 (dd, 1H), 3.07 (t, 1H), 3.25-3.39 (m, 6H), 3.94-4.00 (m, 3H), 6.83 (d, 2H), 7.10 (d, 2H).

Example 5: Preparation of (S)N1-(2-aminoethyl)-3-(4-ethoxyphenyl)propane-1,2-diamine trihydrochloride

(13) In a reactor, methanol (950 mL) and acetyl chloride (77.75 g, 990.55 mmol) were added, and the mixture was stirred to dissolve. To the solution, (S)-tert-butyl 1-(2-aminoethylamino)-3-(4-ethoxyphenyl)propane-2-ylcarbamate dihydrochloride (135.5 g, 330.18 mmol) prepared in Example 4 was added, and the mixture was stirred at 50 C. for 1 hour. After completion of the reaction, methyl tert-butyl ether (950 mL) was added, and the mixture was crystallized and filtered. The obtained crystals were dried under vacuum at 50 C. to obtain the title compound, (S)N.sup.1-(2-aminoethyl)-3-(4-ethoxyphenyl)propane-1,2-diamine trihydrochloride (105.2 g, 99.8% yield).

(14) .sup.1H-NMR (D.sub.2O, 400 MHz): (ppm) 1.38 (t, 3H), 3.00 (dd, 1H), 3.17 (dd, 1H), 3.43-3.58 (m, 6H), 3.94-4.01 (m, 1H), 4.13 (q, 2H), 7.03 (d, 2H), 7.31 (d, 2H).