KR101506297B1 - Method for the stereoselective preparation of 2-substituted morpholine derivatives - Google Patents

Abstract

The present invention relates to a novel process for the simple and efficient synthesis of 2- (hydroxy-methyl-phenyl) morpholin-3-one derivatives having high optical purity, (hydroxy-methyl-phenyl) morpholin-3-one stereoisomer compound derivative having high optical activity by carrying out asymmetric reduction using a chiral organic ruthenium catalyst and a hydrogen donor .

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for preparing 2-substituted morpholine stereoisomers,

The present invention relates to a novel process for the easy and efficient synthesis of 2-substituted morpholine derivatives having high optical purity using a chiral organometallic catalyst and a hydrogen donor.

Chiral morpholine structural compounds are frequently found in natural products having various physiological activities, and chiral morpholine structural compounds exist even in pharmaceuticals currently under development or on the market. Even in case of a morpholine compound having the same molecular formula, the effect is often very different depending on the three-dimensional structure. Therefore, stereoselectively synthesizing chiral morpholine compounds is of great importance in pharmaceutical synthesis and organic synthesis.

[Figure 1]. Examples of drugs with chiral morpholine structure

However, despite the importance of the chiral morpholine compound, no method has been reported to easily synthesize the chiral morpholine compound. In general, chiral dopamine compounds are synthesized from naturally occurring chiral amino-alcohol compounds or amino acid compounds. However, chiral amino-alcohol compounds or amino acid compounds present in nature are quite expensive and limited in number , Chiral amino-alcohol compounds or amino acid compounds which do not exist in nature have to be recycled through other methods (Synthesis, 2004 , 641-662).

Reboxetine (Reboxetine, Figure 1), which is currently marketed in over 60 countries as an antidepressant drug, is a representative drug with a chiral morpholine structure and can exist in four forms of stereoisomers. Recent studies have shown that (S, S) -Reboxetine is the most effective of levosetine among the four stereoisomers. However, because of the difficulty of effectively synthesizing only (S, S) -Reboxetine stereoselectively, it is now being marketed as an enantiomer mixture of (R, R) - and (S, S) -Reboxetine. Also, (S, S) -Reboxetine is currently in clinical trials to be developed as a treatment for neuropathic pain and fibromyalgia. Therefore, it is very important to stereoselectively synthesize Reboxetine, a chiral morpholine compound (Org. Process Res. Dev., 2007 , 11 , 346. Org. Process Res. Dev., 2007 , 11 , 354).

Initially, (S, S) - Reboxetine was obtained using chiral separation method using selective crystallization using (+) - mandelic acid as a chiral auxiliary after synthesizing Reboxetine as a racemic mixture. However, this method has the disadvantage that a large amount of chiral supplements should be used, the maximum yield does not exceed 50%, and the unused (R, R) -Reboxetine should be discarded.

(S, S) -Reboxetine from (S) -3-amino-1,2-propanediol has been reported. However, this method has a disadvantage in that a large amount of an expensive chiral starting material must be used and that the chiral morpholine diastereomer (60:19), which is an intermediate, is separated by chromatography (Org. Lett., 2005 , 7 , 937).

(S, S) -Reboxetine as a process for the industrial mass production of cinnamyl alcohol has been reported using a chiral epoxide obtained by Sharpless asymmetric epoxidation reaction of cinnamyl alcohol. However, in this process, a complex protection-deprotection reaction is required to selectively use the chiral diol produced in the middle of the reaction, resulting in a long reaction time and a large amount of waste by-products (Org. Process Res. Dev. 2007 , 11 , 354, Process Process Res., 2011 , 15 , 1305).

A method for synthesizing (S, S) -Reboxetine from a morpholine alcohol intermediate obtained by reacting N-benzyl-morpholin-3-one with benzaldehyde in the presence of a base has been reported. However, this method has the disadvantage that since the core intermediate, morpholine alcohol, is obtained as a racemic mixture, the individual stereoisomers must be separated using chiral chromatography and unused stereoisomers must be discarded.

[Reaction Scheme 1]

Therefore, there remains a need for a stereoselective preparation method capable of simply and effectively synthesizing (S, S) -Reboxetine or a chiral morpholine alcohol intermediate compound required therefor.

 Synthesis, 2004, 641  Org. Process Res. Dev. 2007, 11, 346  Org. Process Res. Dev. 2007, 11, 354  Org. Process Res. Dev. 2011, 15, 1305

The present invention provides a process for the efficient preparation of stereoisomerically pure 2-substituted morpholine alcohol compound derivatives, and more particularly to a process for the production of stereoisomerically pure 2- (hydroxy-methyl- phenyl) -morpholin-3-one derivatives in a more efficient and simple manner.

In order to accomplish the above object, the present invention provides a method for preparing a 2-acyl morpholin-3-one derivative represented by the following formula (2) using asymmetric reduction and dynamic kinetic resolution using a chiral organometallic catalyst and a hydrogen donor There is provided a method for selectively producing a chiral morpholine stereoisomer compound represented by the following formula (3) or (5) having high optical activity.

(2)

(3)

[Chemical Formula 5]

In the above formulas 2, 3 and 5,

Wherein R ₁ is selected from hydrogen, (C ₁ -C 10) alkyl, (C 6 -C 20) aryl, CO ₂ R ₆ , COR ₇ and (C 6 -C 20) C1-C10) may be further substituted with alkyl or (C1-C10) alkoxy, R ₆ and R ₇ are independently selected from (C1-C10) alkyl, (C6-C20) aryl and (C6-C20) aralkyl (C1 each other -C10) alkyl;

R ₂ is selected from halogen, nitro, cyano, (C 1 -C 10) alkyl, (C 1 -C 10) haloalkyl, -OCF ₃ , (C 1 -C 10) alkoxy and (C 6 -C 20) aryl;

n is an integer of 0 to 5;

The substituents comprising " alkyl ", " alkoxy " and other " alkyl " moieties described in this invention encompass both linear and branched forms. The term " aryl " in the present invention means an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen, and may be a single or fused ring containing 4 to 7, preferably 5 or 6 ring atoms, A ring system, and a form in which a plurality of aryls are connected by a single bond. "Heteroaryl" in the present invention includes 1 to 4 heteroatoms selected from B, N, O, S, P (= O), Si and P as aromatic ring skeletal atoms and the remaining aromatic ring skeletal atoms are carbon Means a 5 to 6 membered monocyclic heteroaryl and a polycyclic heteroaryl condensed with at least one benzene ring and may be partially saturated.

R ₁ of Formula 2, 3 and 5 in more detail is (C1-C5) alkyl, (C6-C20) aryl, CO ₂ R _6, COR _7, and (C6-C20) aralkyl (C1-C10) selected from alkyl and, wherein the aryl or aralkyl is (C1-C10) alkyl or (C1-C10) which may further be substituted by alkoxy, R ₆ and R ₇ are, independently of each other (C1-C10) alkyl, (C6-C20) aryl and (C6-C20) aralkyl (C1-C10) may be selected from alkyl, R ₂ is (C1-C5) alkyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, halogen, cyano or (3) or (5), which is characterized in that it is a nitro group.

The present invention also provides a process for selectively preparing a stereoisomer using the chiral organometallic catalyst represented by the general formula (1) or (4).

[Chemical Formula 1]

[Chemical Formula 4]

In the above formula (1) or (4)

R is (C1-C10) alkyl, (C1-C10) alkoxy, (C1-C10) _{haloalkyl, NR 4 R 5, (C6} -C20) aryl and (C3-C20), and heteroaryl, wherein aryl and heteroaryl is independently from each other are selected from halogen, (C1-C10) alkyl, (C1-C10) alkoxy, (C6-C20) may be further substituted with one or more substituents selected from aryl, R _4, and R < ₅ > may be independently selected from (C1-C10) alkyl;

L is one selected from the group consisting of a cyclopentadienyl group, a pentamethylcyclopentadienyl group, a phenyl group, a 1-methyl-4-isopropylphenyl group, a 1,3,5-trimethylphenyl group, and a hexamethylphenyl group;

X may be rhodium (III), iridium (III) or ruthenium (II).

Still more specifically, R is CF _3, (C6-C20) aryl, or may be a NR ₄ R _5, the aryl may be further substituted by at least one substituent selected by halogen or (C1-C10) alkyl group, R ₄ And R ₅ may be independently selected from (C 1 -C 10) alkyl and X may be ruthenium (II).

The chiral organometallic catalyst according to an embodiment of the present invention When 2- (hydroxy-methyl-phenyl) morpholin-3-one is used in high stereochemical purity (ee, dr) Stereoisomeric compound derivatives can be obtained.

The chiral organometallic catalyst for preparing the stereoisomers of Formula 3 of the present invention may be one selected from the following Formulas 1a to 1d.

[Formula 1a]

[Chemical Formula 1b]

[Chemical Formula 1c]

≪ RTI ID = 0.0 &

In the above general formulas (1a) to (1d)

R is CF _3, (C6-C20) aryl, or may be a NR ₄ R _5, the aryl may be further substituted by at least one substituent selected by halogen or (C1-C10) alkyl group, R ₄ and R < ₅ > may be independently selected from (C1-C10) alkyl.

The chiral organometallic catalyst for preparing the stereoisomers of formula (5) of the present invention may be one selected from the following formulas (4a) to (4d).

[Chemical Formula 4a]

(4b)

[Chemical Formula 4c]

[Chemical formula 4d]

In the above formulas (4a) to (4d)

R is CF _3, (C6-C20) aryl, or may be a NR ₄ R _5, the aryl may be further substituted by at least one substituent selected by halogen or (C1-C10) alkyl group, R ₄ and R < ₅ > may be independently selected from (C1-C10) alkyl.

The structural formulas of the chiral organometallic catalysts are all known and can be prepared or purchased by conventional methods { la, 4a : J. Am. Chem. Soc., 1996, 118, 2251 .; 1b, 4b : Angew. Chem. Int. Ed. Engl., 1997 , 36 , 285; 1c, 1d, 4c, 4d : Org. Lett., 1999 , 1 , 1119.}.

Ruthenium catalyst 4a is (η ⁶ -mesitylene) As a specific example, ruthenium (II) dichloride dimer ^{_{[RuCl 2 (η 6 -mesitylene)}} ] 2, an optically active (1S, 2S) - N - (p - toluene sulfonic (I-PrOH) -1,2-diphenylethylene-diamine (TsDPEN) and triethylamine in a solvent of isopropanol (i-PrOH) is washed with water and recrystallized to give 64% ({ 1S, 2S ) -RuCl (TsDPEN) (? ⁶ -mesitylene)} (J. Am. Chem. Soc., 1996 , 118 , 2251.). Here, TsDPEN represents N - ( p -toluenesulfonyl) -1,2-diphenylethylene-diamine.

Also 4a is (η ⁶ -mesitylene) ruthenium (II) dichloride dimer ^{_{[RuCl 2 (η 6 -mesitylene)}} ] 2, an optically active (1S, 2S) - N - (p - toluenesulfonyloxy) - 1 , 2-diphenylethylene-diamine (TsDPEN) and triethylamine in a solvent of isopropanol (i-PrOH) can be used as a catalyst without removing the solvent under reduced pressure without further purification.

The preparation of 2- (hydroxy-methyl-phenyl) morpholin-3-one stereoisomeric compound derivatives using the organometallic catalyst and a hydrogen donor can be carried out by using ethyl acetate (EtOAc), toluene, methylene chloride (CH ₂ Cl ₂ ), dichloroethane ClCH ₂ CH ₂ Cl), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, methanol, ethanol, isopropanol, t- butanol, water, or water / alcohol mixed solvent, etc. Can be used, or the reaction can be carried out with only a substrate, a catalyst, and a hydrogen donor without a solvent.

2-acyl morpholin-3-one represented by the formula (2) used as a substrate can be synthesized by reacting N-substituted morpholin-3-one and N-acyl morpholine in the presence of a base such as LDA have.

[Reaction Scheme 2]

The 2- (hydroxy-methyl-phenyl) morpholin-3-one stereoisomer compound derivative prepared by the process of the present invention is an intermediate compound that is very important in the production of stereoisomerically pure medicines and fine chemical products and is used in the production of chiral drugs (Bioorg. Med. Chem. Lett., 2005 , 15 , 699).

In order to prepare the stereoisomers of the formula (3) or (5) of the present invention, the chiral organometallic catalyst may be used in an amount of 0.00001 to 0.5 mol based on 1 mol of the compound represented by the formula (2). More specifically, 0.0001 to 0.1 mol may be used.

The hydrogen donor of the present invention can be selected from formic acid, a metal salt of formic acid, an ammonium salt of formic acid, and a mixture of formic acid and amine. The amine is NR ₁₁ R ₁₂ R _13, and R ₁₁ , R ₁₂ and R ₁₃ are each independently (C 1 -C 10) alkyl, and is a process for selectively producing a stereoisomer represented by Formula 3 or Formula 5 have.

The compound represented by formula (3) or (5) according to the present invention is prepared by asymmetric hydrogenation using 2-acyl morpholin-3-one represented by formula (2) using a chiral organometallic catalyst.

The following four stereoisomeric compounds can be theoretically synthesized by hydrogenating the compound of formula (2): [Reaction formula 3]

[Reaction Scheme 3]

However, according to the production method of the present invention, the asymmetric reduction reaction of the compound of formula (2) with the hydrogen donor in the presence of the chiral organometallic catalyst of formula (1) can produce the stereoisomer of formula (3) with high optical activity. Further, the asymmetric reduction reaction of the compound of formula (2) with the hydrogen donor in the presence of the chiral organometallic catalyst of formula (4) allows the stereoisomers of formula (5) to be prepared with high optical activity. Therefore, when a chiral organometallic catalyst of the present invention is used, a stereoisomer of Formula 3 or Formula 5 having high optical activity can be prepared by a simple and efficient preparation method.

[Reaction Scheme 4]

According to the preparation method of the present invention, 2- (hydroxy-methyl) morpholin-3-one stereoisomer compound derivatives having high optical purity can be selectively obtained and the compound can be produced easily and efficiently.

Hereinafter, the present invention will be described in more detail.

The following schemes are merely illustrative of how to make the compounds of the present invention and are not intended to limit the scope of the invention.

The compound of formula (3) or (5) prepared by the process of the present invention can be purified by conventional extraction, distillation, recrystallization and column chromatography. The optically active purity (ee) Can be determined by HPLC using a Chiralcel OD-H, AD-H, or Chiralpak IA, IB, IC, ID column from Daicel.

The symbols and regulations used herein to describe the processes, reactions and embodiments of the present invention are consistent with those used in recent scientific literature, such as the Journal of the American Chemical Society. All starting materials were used commercially without further purification, unless otherwise stated herein.

Bn (benzyl)

DCM or MC (dichloromethane)

dr (diasteromeric ratio)

ee (enantiomeric excess)

EtOAc (ethyl acetate)

EtOH (ethanol)

HPLC (high pressure liquid chromatography)

Hz (Hertz)

i-PrOH (isopropanol)

LDA (lithium diisopropyl amide, Lithium di (isopropyl) amide)

MeOH (methanol)

MgSO ₄ (magnesium sulfate)

TEA or Et ₃ N (triethylamine)

TFA (trifluoroacetic acid)

THF (tetrahydrofuran)

TLC (Thin Layer Chromatography)

TsDPEN ( N - ( p -toluenesulfonyl) -1,2-diphenylethylene-diamine)

In this specification, brine refers to a saturated aqueous solution of NaCl. All temperatures are in degrees C unless otherwise noted. All reactions were carried out under an inert atmosphere at room temperature unless otherwise stated and all solvents were used as purchased unless otherwise noted.

¹ H or < ¹³ > C NMR was measured using a Zeol ECX-400 or JNM-LA300 spectrometer. Chemical shifts are expressed in "ppm (δ units)" and binding constants ( J ) in "Hz". The separation pattern represents a multiplicity and is represented as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad)

The mass spectra were obtained using one of the following instruments (Micromass, Quattro LC Triple Quadruple Tandem Mass Spectrometer, ESI or Agilent, 1100 LC / MSD, ESI).

Flash column chromatography analysis was performed using Merck silica gel 60 (230-400 mesh). Most reactions were monitored using a 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution as a colorimetric solution using thin layer chromatography on a 0.25 mm silica gel plate (60F-254) or the progress of the reaction with UV.

PREPARATION EXAMPLE 1-1 Preparation of 2-Benzoyl-4-benzyl-morpholin-3-one (2a)

(2.0 M, 13.8 ml, 27.5 mmol) and THF (60 ml) were added under nitrogen atmosphere, and after cooling to -78 ^° C, 4-benzyl-moles dissolved in THF (20 ml) 3-one (4.78 g, 25 mmol) was slowly added thereto for 20 minutes, and then N-benzoylmorpholine (5.5 g, 28.7 mmol) dissolved in a THF (20 ml) solvent was slowly added dropwise for 20 minutes. The reaction solution was naturally reacted until the temperature reached 10 ^° C., and then the reaction was terminated by addition of a saturated solution of NaHCO ₃ and extracted with ethyl acetate (EtOAc). The organic layer thus obtained was washed with distilled water and brine and dried over MgSO ₄ and filtered. The solvent of the filtrate was distilled off under reduced pressure, and the residue was separated and purified by flash silica column chromatography to obtain 6.9 g (yield 93%) of the title compound.

Enol form; ^{1 H-NMR (500 MHz,} CDCl 3) δ 13.17 (s, 1H), 7.99 (d, 2H, J = 7.6Hz), 7.32-7.44 (m, 8H), 4.74 (s, 2H), 4.05 (t , 2H, J = 4.9 Hz), 3.43 (t, 2H, J = 4.9 Hz). Keto form; ^{1 H NMR (500 MHz, CDCl} 3) δ 8.1 (d, 2H, J = 7.5Hz), 7.62 (t, 1H, J = 7.4Hz), 7.51 (t, 2H, J = 7.8Hz), 7.32-7.44 (m, 5H), 5.64 ( s, 1H), 4.87 (d, 1H, J = 14.6Hz), 4.54 (d, 1H, J = 14.6Hz), 4.16-4.21 (m, 1H), 3.94-3.90 ( m, 1 H), 3.42-3.34 (m, 2H). ^{13 C NMR (75 MHz, CDCl} 3) δ 193.9, 165.8, 164.2, 153.7, 136.1, 135.9, 135.2, 133.9, 133.5, 129.7, 129.5, 129.0, 128.9, 128.7, 128.5, 128.4, 128.2, 128.0, 127.9, 125.2 , 77.9, 64.0, 62.2, 49.9, 49.6, 45.8, 45.5; HRMS (EI): m / z calcd for C 18 H 17 NO 3 295.1208, found 295.1208.

Preparation Example 1-2 Preparation of 2- (4-Chloro-benzoyl) -4-benzyl-morpholin-3-one (2b)

The title compound was prepared according to the procedure of Preparation Example 1-1 using N-4-chlorobenzoylmorpholine instead of N-benzoylmorpholine.

Light yellow solid, yield: 93%, mp: 107.7-109.6 ^o C; _{^{1 HNMR (500 MHz, CDCl 3}} ) δ 13.13 (s, 1H), 7.94 (d, 2H, J = 8.8Hz), 7.40-7.33 (m, 7H), 4.74 (s, 2H), 4.07 (t, 2H , J = 4.9 Hz), 3.46 (t, 2H, J = 5.0 Hz) .; ^{13 C NMR (75 MHz, CDCl} 3) δ 165.5, 152.3, 135.9, 135.2, 131.9, 129.8, 128.9, 128.1, 128.1, 127.9, 125.3, 64.0, 49.6, 45.6 .; HRMS (EI): m / z calcd for C 18 H 17 NO 3 295.1208, found 295.1208.

Preparation Example 1-3 Preparation of 2- (4-Methyl-benzoyl) -4-benzyl-morpholin-3-one (2c)

The title compound was prepared according to the procedure of Preparation Example 1-1 using N-4-methylbenzoylmorpholine in place of N-benzoylmorpholine.

Pale yellow oil, yield: 81%, (keto and enol mixture; enol form: keto form = 1: 0.1 ~ 0.2 by ¹ H-NMR analysis); Enol form; _{^{1 HNMR (500 MHz, CDCl 3}} ) δ 13.11 (s, 1H), 7.86 (d, 2H, J = 8.3Hz), 7.39-7.32 (m, 5H), 7.23 (d, 2H, J = 8.2Hz), 4.74 (s, 2H), 4.06 (t, 2H, J = 5.0 Hz), 3.45 (t, 2H, J = 5.0 Hz), 2.40 (s, 3H). Keto form; _{^{1 HNMR (500 MHz, CDCl 3}} ) δ 8.00 (d, 2H, J = 8.2Hz), 7.41-7.30 (m, 7H), 5.63 (s, 1H), 4.86 (d, 1H, J = 14.8Hz), 4.56 (d, 1H, J = 14.7Hz), 4.20-4.18 (m, 1H), 3.94-3.91 (m, 1H), 3.43-3.41 (m, 1H), 3.38-3.37 (m, 1H), 2.45 ( s, 3H); ^{13 C NMR (75 MHz, CDCl} 3) δ 193.4, 165.7, 164.2, 153.9, 144.8, 139.6, 136.1, 135.9, 132.7, 130.6, 129.7, 129.3, 128.9, 128.8, 128.6, 128.3, 128.3, 128.1, 127.8, 124.8 , 77.7, 63.9, 62.1, 49.8, 49.5, 45.8, 45.5, 21.8, 21.5; HRMS (EI): m / z calcd for C ₁₉ H ₁₉ NO ₃ 309.1365, found 309.1357.

Preparation Example 1-4 Preparation of 2- (4-Methoxy-benzoyl) -4-benzyl-morpholin-3-one (2d)

The title compound was prepared according to the procedure of Preparation Example 1-1 using N-4-methoxybenzoylmorpholine instead of N-benzoylmorpholine.

Pale yellow oil, yield: 75%, (keto and enol mixture; enol form: keto form = 1: 0.4-0.5 by ¹ H-NMR analysis); Enol form; _{^{1 HNMR (500 MHz, CDCl 3}} ) δ 13.18 (s, 1H), 8.08 (d, 2H, J = 9.0Hz), 7.40-7.32 (m, 5H), 6.98 (d, 2H, J = 8.9Hz), 4.74 (s, 2H), 4.07 (t, 2H, J = 4.8 Hz), 3.87 (s, 3H). 3.45 (t, 2H, J = 4.7 Hz). Keto form; _{^{1 HNMR (500 MHz, CDCl 3}} ) δ 8.09-8.05 (m, 1H), 7.96 (d, 1H, J = 9.1Hz), 7.40-7.32 (m, 5H), 7.00-6.96 (m, 1H), 6.94 (d, 1H, J = 9.0Hz ), 5.62 (s, 1H), 4.86 (d, 1H, J = 14.6Hz), 4.55 (d, 1H, J = 14.6Hz), 4.23-4.19 (m, 1H) , 3.95-3.91 (m, 1H), 3.91 (s, 1H), 3.46-3.41 (m, 1H), 3.38-3.35 (m, 1H). ^{13 C NMR (75 MHz, CDCl} 3) δ 192.2, 165.8, 164.4, 164.1, 160.4, 153.7, 136.1, 135.8, 132.2, 132.0, 130.0, 128.8, 128.8, 128.3, 128.2, 128.1, 127.8, 126.0, 124.4, 113.8 , 113.7, 113.3, 63.9, 62.0, 55.5, 55.3, 49.8, 49.4, 45.8, 45.5; HRMS (EI): m / z calcd for C 19 H 19 NO 4 325.1314, found 325.1308.

≪ Example 1 > 2R, 7S ) -4-Benzyl-2- (hydroxy-phenyl-methyl) -morpholin-3-one [ 2R, 7S ) -3a]

Method 1.

Benzoyl-4-benzyl-morpholin-3-one ( 2a , 3.48 g, 11.8 mmol) and [ R, R ] -TsDPEN- RuCl-Mesitylene ( 1a , 37 mg, 0.005 eq.) Was dissolved in DCM (60 ml). To this was added 7 ml of a mixed solution of HCO ₂ H and Et ₃ N (molar ratio = 5: 2) and stirred at room temperature for 24 hours. The reaction solution was diluted with DCM and washed sequentially with distilled water, saturated NaHCO ₃ solution and brine. The obtained organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent of the filtrate was removed by evaporation, and the residue was purified by flash silica chromatography to obtain the title compound (3.35 g). ^One HNMR spectral analysis showed that one diastereomer was detected in a 97: 3 ratio. (dr = 97: 3)

Method 2.

Except that a mixed solution of HCO ₂ H and Et ₃ N (molar ratio = 0.2: 1) was used as the hydrogen donor and solvent instead of the mixed solution of HCO ₂ H and Et ₃ N (molar ratio = 5: 2) The reaction was carried out in the same process. In method 2, the reaction was completed within 3 hours.

Yield of the title compound: 98.4%, > 99% ee.

White solid, yield: 96-98%; mp 117.3-118.2 ^o C .; 98 ~ 99% ee: Chiralpak IB , 10% isopropanol / n-hexane, 1.5 mL / min, 254 nm, t R (minor) = 8.9 min, t R (major) = 10.2 min; [?] _D ¹⁸ = +95.6 (c 1.2, CHCl ₃ ) .; ^{1 H NMR (500 MHz, CDCl} 3) δ 7.50-7.48 (m, 2H), 7.39-7.34 (m, 3H), 7.29-7.26 (m, 3H), 7.00-6.98 (m, 2H), 5.24 (dd , 1H, J = 9.7Hz, J = 3.4Hz), 4.79 (d, 1H, J = 14.7Hz), 4.57 (d, 1H, J = 3.4Hz), 4.35 (d, 1H, J = 14.9Hz), 4.32 (d, 1H, J = 9.8Hz), 3.98 (ddd, 1H, J = 1.6, 4.2, 11.9Hz), 3.76 (dt, 1H, J = 3.1, 11. 2 Hz), 3.25 (dt, 1H, J = 4.3, 12.0 Hz), 2.95 (d, 1H, J = 12.3 Hz) .; ¹³ C NMR (125 MHz, CDCl ₃ )? 168.4, 140.6, 135.5, 128.8, 128.1, 128.0, 127.7, 127.6, 126.8, 79.7, 73.6, 63.1, 49.8, 45.7; HRMS (EI): m / z calcd for C 18 H 19 NO 3 297.1365, found 297.1365.

≪ Example 2 > ( 2S, 7R ) -4-Benzyl-2- (hydroxy-phenyl-methyl) -morpholin-3-one [ 2S, 7R ) -5a]

Except that the [ S, S ] -TsDPEN-RuCl-Mesitylene catalyst ( 4a , 0.005 equivalent) was used instead of the [ R, R ] -TsDPEN-RuCl-Mesitylene catalyst in Example 1, . ^{The 1} H NMR spectral analysis gave the title compound in a diastereomer ratio of 97: 3. (dr = 97: 3)

Yield: 97%, > 98.3% ee.

White solid, yield: 97%; mp 117.3-118.2 ^o C .; 98.3% ee: Chiralpak IB, 10 % isopropanol / n-hexane, 1.5 mL / min, 254 nm, t R (major) = 8.7 min, t R (minor) = 10.7 min; [?] _D ¹⁹ = -96.8 (c 0.8, CHCl ₃ ) .; ^{1 H NMR (500 MHz, CDCl} 3) δ 7.49 (d, 2H, J = 7. 1Hz), 7.39-7.32 (m, 3H), 7.30-7.27 (m, 3H), 7.02-6.99 (m, 2H) , 5.25 (dd, 1H, J = 9.6Hz, J = 3.2Hz), 4.78 (d, 1H, J = 14.8Hz), 4.57 (d, 1H, J = 3.1Hz), 4.37-4.34 (m, 2H) , 4.00-3.96 (m, 1H), 3.75 (dt, 1H, J = 3.0, 11.6 Hz), 3.26 (dt, 1H, J = 4.1, 12.1 Hz), 2.97-2.93 (m, 1H). ^{13 C NMR (75 MHz, CDCl} 3) δ 168.3, 140.6, 135.5, 128.8, 128.1, 127.9, 127.7, 127.6, 126.8, 79.7, 73.6, 63.0, 49.8, 45.7 .; HRMS (EI): m / z calcd for C 18 H 19 NO 3 297.1365, found 297.1364

≪ Example 3 > ( 2R, 7S ) -4-Benzyl-2- (hydroxy- (4-chloro-phenyl) -methyl) -morpholin-3-one [ 2R, 7S ) -3b]

The starting material in Example 1, Method 2 was prepared in the same manner as in Example 1, except that 2- (4-chloro-benzoyl) -4-benzyl-mol 3-one ( 2b ) was used as the starting material.

Yield of the title compound: 90%, 92: 8 dr, 95.3% ee.

White solid, yield: 95% (170 mg) at F / T = 5: 2, 90% at F / T = 0.2: 1; mp: 125.8-127.6 ^o C; dr = 92: 8 .; 95.3% ee (Chiralpak IB, 10 % isopropanol / n-hexane, 1.0 mL / min, 254 nm, t R (minor) = 13.8 min, t R (major) = 16.5 min); [?] _D ³¹ = +62.6 (c 0.3, CHCl ₃ ) .; ^{1 H NMR (500 MHz, CDCl} 3) δ 7.42 (d, 2H, J = 8.3Hz), 7.32-7.29 (m, 5H), 6.92-6.91 (m, 2H), 5.15 (d, 1H, J = 5.6 Hz), 4.85 (d, 1H , J = 14.7Hz), 4.58 (d, 1H, J = 9.3Hz), 4.55 (d, 1H, J = 3.5Hz), 4.23 (d, 1H, J = 14. 7Hz ), 3.96 (dd, 1H, J = 3.1Hz, J = 11.9Hz), 3.78 (dt, 1H, J = 3.0Hz, J = 11.5Hz), 3.23 (dt, 1H, J = 4.2Hz, J = 12.0 Hz), 2.94 (d, 1H, J = 12.3 Hz) .; ^{13 C NMR (75 MHz, CDCl} 3) δ 168.3, 139.1, 135.3, 133.4, 128.9, 128.3, 128.2, 127.9, 127.9, 79.3, 73.0, 63.1, 49.9, 45.7 .; HRMS (EI): m / z calcd for C ₁₈ H ₁₉ NO ₃ 331.0975, found 331.0972.

≪ Example 4 > 2R, 3S ) -4-Benzyl-2- (hydroxy- (4-methyl-phenyl) -methyl) -morpholin-3-one [ 2R, 3S ) -3c]

The starting material was prepared in the same manner as in Example 1, Method 2, except that 2- (4-methyl-benzoyl) -4-benzyl-mol prepared in Production Example 1-3 was used instead of 2-benzoyl- 3-one ( 2C ) was used as the starting material.

Yield of the title compound: 96%, dr = 98: 2, 98.9% ee.

White solid, yield: 96%; mp: 113.4-115.2 ^o C; dr = 98: 2 .; 98.9% ee; Chiralcel IB, 20% isopropanol / n -hexane, 1.5 mL / min, 254 nm, t R (minor) = 4.9 min, t R (major) = 5.4 min; [?] _D ³¹ = +92.3 (c 0.3, CHCl ₃ ) .; ^{1 H NMR (500 MHz, CDCl} 3) δ 7.37 (d, 2H, J = 7.9Hz), 7.29-7.27 (m, 3H), 7.18 (d, 2H, J = 7.9Hz), 7.02 (m, 2H) , 5.22 (dd, 1H, J = 9.5Hz, J = 3.0Hz), 4.81 (d, 1H, J = 14.8Hz), 4.55 (d, 1H, J = 3.2Hz), 4.36 (d, 1H, J = 14.8Hz), 4.15 (d, 1H , J = 9.6Hz), 4.00-3.97 (m, 1H), 3.76 (dt, 1H, J = 3.1Hz, J = 11.2Hz), 3.28 (dt, 1H, J = 4.4 Hz, J = 12.2 Hz), 2.96 (d, 1H, J = 12.3 Hz), 3.85 (s, 3H). ^{13 C NMR (75 MHz, CDCl} 3) δ 168.4, 137.7, 137.2, 135.6, 128.9, 128.8, 128.0, 127.8, 126.7, 79.8, 73.5, 63.1, 49.9, 45.8, 21.3 .; HRMS (EI): m / z calcd for C ₁₈ H ₁₉ NO ₃ 311.1521, found 311.1516.

≪ Example 5 > 2R, 7S ) -4-Benzyl-2- (hydroxy- (4-methoxyl-phenyl) -methyl) -morpholin-3- 2R, 7S ) -3d]

The starting material was prepared in the same manner as in Example 1, Method 2, except that 2- (4-methoxy-benzoyl) -4-benzyl- The reaction was carried out by the same procedure except that morpholin-3-one ( 2d ) was used.

Yield of the title compound: 98%, dr = > 99: 1, 99.3% ee.

White solid, yield: 98%; mp: 128.4-129.1 ^o C; dr => 99: 1 .; 99.3% ee (Chiralpak IB, 20 % isopropanol / n-hexane, 1.5 mL / min, 254 nm, t R (minor) = 6.5 min, t R (major) = 7.3 min); [?] _D ³¹ = +75.3 (c 0.3, CHCl ₃ ) .; ^{1 H NMR (500 MHz, CDCl} 3) δ 7.40 (d, 2H, J = 8.7Hz), 7.29-7.27 (m, 3H), 6.99-6.98 (m, 2H), 6.90 (d, 2H, J = 8.7 Hz), 5.17 (dd, 1H , J = 9.6Hz, J = 3.2Hz), 4.82 (d, 1H, J = 14.8Hz), 4.54 (d, 1H, J = 3.3Hz), 4.32 (d, 1H, J = 14.7Hz), 4.31 (d , 1H, J = 9.4Hz), 4.00-3.97 (m, 1H), 3.85 (s, 3H), 3.77 (dt, 1H, J = 3.0Hz, J = 11.5Hz) , 3.25 (dt, 1H, J = 4.2 Hz, J = 12.1 Hz), 2.95 (d, 1H, J = 12.3 Hz). ¹³ C NMR (75 MHz, CDCl ₃ )? 168.5, 159.2, 135.6, 132.7, 128.8, 128.0, 128.0, 127.8, 113.5, 79.7, 73.3, 63.1, 55.3, 49.8, 45.8; HRMS (EI): m / z calcd for C 18 H 19 NO 3 327.1471, found 327.1466.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.

Claims (8)

A process for the selective preparation of a stereoisomer (3) by reacting a compound of formula (2) with a hydrogen donor in the presence of a chiral organometallic catalyst of formula (1).
[Chemical Formula 1]

(2)

(3)

In Formula 1,
R is CF _3, NR ₄ R _5, or (C6-C20) aryl, and the aryl may be further substituted with one or more substituents selected from halogen, and (C1-C10) alkyl, R ₄ and R < ₅ > independently from each other may be selected from (C1-C10) alkyl;
L is one selected from a phenyl group, a 1-methyl-4-isopropylphenyl group, a 1,3,5-trimethylphenyl group and a hexamethylphenyl group;
X is ruthenium (II);
In the general formula (2) or (3)
R ₁ is selected from (C ₁ -C 10) alkyl, (C 6 -C 20) aryl and (C 6 -C 20) aryl (C 1 -C 10) alkyl;
R ₂ is selected from halogen, (C 1 -C 10) alkyl, (C 1 -C 10) haloalkyl, -OCF ₃ , and (C 1 -C 10) alkoxy;
and n is an integer of 0 to 1.] A process for the selective preparation of a stereoisomer (5) by reacting a compound of formula (2) with a hydrogen donor in the presence of a chiral organometallic catalyst of formula (4).
[Chemical Formula 4]

(2)

[Chemical Formula 5]

In the above formulas (2), (4) and (5)
R, R ₁ , R ₂ , n, X and L are as defined in claim 1. The method according to claim 1,
Wherein the chiral organometallic catalyst of Formula 1 is selected from the following Formulas 1a to 1d.
[Formula 1a]

[Chemical Formula 1b]

[Chemical Formula 1c]

≪ RTI ID = 0.0 &

Wherein R is CF ₃ , NR ₄ R ₅ , or (C 6 -C 20) aryl, and the aryl may be further substituted with at least one substituent selected from halogen and (C 1 -C 10) alkyl, The R < ₄ & R ₅ is independently selected from (C 1 -C 10) alkyl. 3. The method of claim 2,
Wherein the chiral organometallic catalyst of formula (4) is selected from the following formulas (4a) to (4d).
[Chemical Formula 4a]

(4b)

[Chemical Formula 4c]

[Chemical formula 4d]

In the general formulas (4a) to (4d), R is CF ₃ , NR ₄ R ₅ , or (C 6 -C 20) aryl, and the aryl may be further substituted with at least one substituent selected from halogen and (C 1 -C 10) The R < ₄ & R ₅ is independently selected from (C 1 -C 10) alkyl. 3. The method according to claim 1 or 2,
R ₁ is (C ₁ -C 5) alkyl, (C 6 -C 20) aryl, or (C6-C20) aralkyl (C1-C10) alkyl, R ₂ is Formula (3) or the general formula to, wherein (C1-C5) alkyl, methoxy, ethoxy, trifluoromethyl, trifluoro the Romero ethoxy or halogen Lt; RTI ID = 0.0 > 5. ≪ / RTI > 3. The method according to claim 1 or 2,
Wherein the chiral organometallic catalyst is used in an amount of 0.00001 to 0.5 mol based on 1 mol of the compound represented by the general formula (2). 3. The method according to claim 1 or 2,
Wherein the hydrogen donor is selected from the group consisting of formic acid, a metal salt of formic acid, an ammonium salt of formic acid, and a mixture of formic acid and amine. 8. The method of claim 7,
The amine is NR ₁₁ R ₁₂ R _13,
R ₁₁ , R ₁₂ and R ₁₃ are each independently (C 1 -C 10) alkyl, with the proviso that the stereoisomer of formula (3) or (5)