Intermediates for optically active piperidine derivatives and preparation methods thereof

Abstract

A preparation method according to the present invention makes it possible to industrially produce large amounts of highly pure optically active tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate in high yield by use of commercially available reagents and solvents. In addition, the use of novel intermediates according to the present invention makes it possible to produce highly pure optically active tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate in high yield.

Claims

1. A compound of the following formula II: ##STR00010##

2. The compound of claim 1, wherein the compound of formula II is (R)-1-benzyl-3-methylpiperidin-4-one (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate; or (S)-1-benzyl-3-methylpiperidin-4-one (2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinate.

3. A method for preparing a compound of the following formula II, comprising a step of optically resolving a compound of the following formula I: ##STR00011##

Description

BEST MODE FOR CARRYING OUT THE INVENTION

(1) Hereinafter, the present invention will be described in further detail with reference to examples and experimental examples. It is to be understood, however, that these examples and experimental examples are intended to illustrate the present invention and the scope of the present invention is not limited by these examples and experimental examples.

Example 1: Preparation of (R)-1-benzyl-3-methylpiperidin-4-one (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate (Compound of Formula II)

(2) 278.0 kg of acetonitrile and 58.9 kg of 1-benzyl-3-methylpiperidin-4-one were introduced into a reactor and warmed to 40±2° C. 129.0 kg of (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinic acid hydrate was added thereto. Stirring was performed at 40±2° C. for 12±2 hours. After filtration, the residue was washed with 92.7 kg of acetonitrile. The resulting material was dried under vacuum at 40° C. to afford the title compound (70.7 kg, 83%, 99% ee).

(3) .sup.1H-NMR (400 MHz, DMSO-d6): δ=0.84 (d, 3H), 2.16-2.40 (m, 2H), 2.45 (s, 6H), 2.58-2.71 (m, 3H), 3.08-3.11 (m, 2H), 3.74 (s, 2H), 5.79 (s, 2H), 7.27-7.40 (m, 9), 7.89 (d, 4H).

(4) Optical rotation: [α].sub.D.sup.20=96.0°

(5) ([α].sub.D.sup.20: 20° C., D line of sodium spectrum (589 nm), 1% solution)

Example 2: Preparation of (S)-1-benzyl-3-methylpiperidin-4-one (2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinate (Compound of Formula II)

(6) 18.7 kg of acetonitrile and 3.4 kg of 1-benzyl-3-methylpiperidin-4-one were introduced into a reactor and warmed to 40±2° C. 7.4 kg of (2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinic acid hydrate was added thereto. Stirring was performed at 40±2° C. for 12±2 hours. After filtration, the residue was washed with 5.3 kg of acetonitrile. The resulting material was dried under vacuum at 40° C. to afford the title compound (4.0 kg, 81%, 99% ee).

(7) .sup.1H-NMR (400 MHz, DMSO-d6): δ=0.83 (d, 3H), 2.18-2.27 (m, 2H), 2.40 (s, 6H), 2.56-2.72 (m, 3H), 3.09-3.13 (m, 2H), 3.74 (s, 2H), 5.79 (s, 2H), 7.28-7.40 (m, 9), 7.89 (d, 4H).

Example 3: Preparation of (R)-1-benzyl-3-methylpiperidin-4-one (Compound of Formula III)

(8) 469.1 kg of dichloromethane and 70.7 kg of the (R)-1-benzyl-3-methylpiperidin-4-one (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate prepared in Example 1 were introduced into a reactor, and 353.5 kg of purified water was added thereto, followed by stirring. The pH was adjusted to 10 by addition of 26.2 L of ammonium oxide. The organic layer was separated and 353.5 kg of purified water was added thereto, followed by stirring. The organic layer was separated, concentrated under vacuum at 40° C., and crystallized from n-heptane to afford the title compound (22.4 kg, 92%, 99.8% ee).

(9) .sup.1H-NMR (400 MHz, DMSO-d6): δ=0.85 (d, 3H), 2.03 (t, 1H), 2.16 (d, 1H), 2.33 (t, 1H), 2.53-2.66 (m, 2H), 2.99-3.05 (m, 2H), 3.59 (s, 2H), 7.25-7.35 (m, 5H).

(10) Optical rotation: [α].sub.D.sup.20=18.3°

(11) ([α].sub.D.sup.20: 20° C., D line of sodium spectrum (589 nm), 1% solution).

Example 4: Preparation of (S)-1-benzyl-3-methylpiperidin-4-one (compound of formula III)

(12) 26.4 kg of dichloromethane and 4.0 kg of the (S)-1-benzyl-3-methylpiperidin-4-one (2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinate prepared in Example 2 were introduced into a reactor, and 19.9 kg of purified water was added thereto, followed by stirring. The pH was adjusted to 10 by addition of 1.5 L of ammonium hydroxide. The organic layer was separated and 19.9 kg of purified water was added thereto, followed by stirring. The organic layer was separated and concentrated under vacuum at 40° C. Crystallization from n-heptane was performed to afford the title compound (1.2 kg, 89%, 99.5% ee).

(13) .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=1.04 (d, 3H), 2.08 (t, 1H), 2.32-2.54 (m, 2H), 2.60-2.78 (m, 2H), 3.03-3.24 (m, 2H), 3.64 (S, 2H), 7.46 (s, 5H).

Example 5: Preparation of tert-butyl (R)-3-methyl-4-oxopiperidine-1-carboxylate (Compound of Formula IV)

(14) 141.6 kg of ethyl acetate and 22.4 kg of the (R)-1-benzyl-3-methylpiperidin-4-one prepared in Example 3 were introduced into a hydrogen reactor and completely dissolved by stirring. 28.9 kg of di-tert-butyl dicarbonate and 1.12 kg of 10% palladium/carbon were added thereto, followed by stirring. Stirring was performed for 24 hours under controlled conditions of temperature of 25±2° C. and hydrogen pressure of 50 psi (3.7±0.2 atm). After completion of the reaction, the palladium/carbon was filtered out, and the residue was concentrated under vacuum at 40° C. 15.3 kg of n-heptane was added to the concentrate, followed by cooling to 0±5° C. and crystallization. The resulting material was dried under vacuum at room temperature to afford the title compound (21.4 kg, 91%, 99.5% ee).

(15) .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=1.02 (d, 3H), 1.47 (s, 9H), 2.36-2.55 (m, 3H), 2.55 (m, 1H), 3.24 (t, 1H), 4.15-4.19 (m, 2H).

(16) Optical rotation: [α].sub.D.sup.20=−1.2°

(17) ([α].sub.D.sup.20: 20° C., D line of sodium spectrum (589 nm), 1% solution).

Example 6: Preparation of tert-butyl (S)-3-methyl-4-oxopiperidine-1-carboxylate (Compound of Formula IV)

(18) 7.7 kg of ethyl acetate and 1.2 kg of the (S)-1-benzyl-3-methylpiperidin-4-one prepared in Example 4 were introduced into a hydrogen reactor and completely dissolved by stirring. 1.6 kg of di-tert-butyl dicarbonate and 0.06 kg of 10% palladium/carbon were added thereto, followed by stirring. Stirring was performed for 24 hours under controlled conditions of temperature of 25±2° C. and hydrogen pressure of 50 psi (3.7±0.2 atm). After completion of the reaction, the palladium/carbon was filtered out, and the residue was concentrated under vacuum at 40° C. 1.7 kg of n-heptane was added to the concentrate, followed by cooling to 0±5° C. and crystallization. The resulting material was dried under vacuum at room temperature to afford the title compound (1.0 kg, 78%, 99.2% ee).

(19) .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=1.02 (d, 3H), 1.47 (s, 9H), 2.34-2.56 (m, 3H), 2.70-2.89 (m, 1H), 3.22 (t, 1H), 4.16-4.19 (m, 2H).

Example 7: Preparation of 1-benzyl-3-methylpiperidin-4-one (Compound of Formula I) by Racemization from Formula ent-II and Formula II (Recycle)

(20) The filtrate remaining after preparing the compound of formula II (Example 1) was introduced into a reactor and concentrated under vacuum at 45° C. The concentrate was cooled to 0 to 5° C., and 83 L of 10% NaOH aqueous solution was added slowly thereto. The reaction solution was warmed to 35 to 40° C. and stirred for 6 hours. 221.9 kg of dichloromethane was added thereto, followed by stirring for 30 minutes, after which the organic layer was separated. 133.4 kg of dichloromethane was added to the aqueous layer, followed by stirring for 30 minutes, after which the organic layer was separated. 59 kg of anhydrous magnesium sulfate was added to the organic layer and stirred for 30 minutes, followed by filtration. The residue was concentrated under vacuum at 40° C. to afford the title compound (23.6 kg, 80%).

(21) .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=0.85 (d, 3H), 2.02 (t, 1H), 2.16 (d, 1H), 2.32 (t, 1H), 2.50-2.67 (m, 2H), 2.98-3.23 (m, 2H), 3.58 (s, 2H), 7.23-7.36 (m, 5H).

Example 8: Preparation of 1-benzyl-3-methylpiperidin-4-one (Compound of Formula I) by Racemization from Formula Ent-II and Formula II (Recycle)

(22) The filtrate remaining after preparing the compound of formula II (Example 2) was introduced into a reactor and concentrated under vacuum at 45° C. The concentrate was cooled to 0 to 5° C., and 4.8 L of 10% NaOH aqueous solution was added slowly thereto. The reaction solution was warmed to 35 to 40° C. and stirred for 6 hours. 12.8 kg of dichloromethane was added thereto, followed by stirring for 30 minutes, after which the organic layer was separated. 12.8 kg of dichloromethane was added to the aqueous layer, followed by stirring for 30 minutes, after which the organic layer was separated. 7.7 kg of dichloromethane was added to the aqueous layer, followed by stirring for 30 minutes, after which the organic layer was separated. 3.4 kg of anhydrous magnesium sulfate was added to the organic layer and stirred for 30 minutes, followed by filtration. The residue was concentrated under vacuum at 40° C. to afford the title compound (1.3 kg, 75%).

(23) .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=0.85 (d, 3H), 2.02 (t, 1H), 2.16 (d, 1H), 2.32 (t, 1H), 2.50-2.67 (m, 2H), 2.98-3.23 (m, 2H), 3.58 (s, 2H), 7.23-7.36 (m, 5H).