KR101446017B1 - Method for the stereoselective preparation of 4-alkyl-5-aryl 5-membered ring sulfamidates - Google Patents

Abstract

The present invention relates to a novel process for the simple and efficient synthesis of 4-alkyl-5-aryl 5-membered ring sulfamidates having a high optical purity, Alkyl-5-aryl 5-membered ring sulfimidate stereoisomer compound having high optical activity by carrying out asymmetric reduction using a cyclic imine compound with a chiral organotitanium catalyst and a hydrogen donor do.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for preparing 4-alkyl-5-aryl 5-membered ring sulfamidates having high stereospecificity,

The present invention relates to a novel process for the easy and efficient synthesis of 4-alkyl-5-aryl 5-membered ring sulfamidates having high optical purity using a chiral organometallic catalyst and a hydrogen donor.

The 5-membered ring sulfamidate with high optical purity can be converted into a chiral amine derivative such as chiral amino alcohol, chiral diamine and chiral amino acid through a simple reaction, which is an important intermediate compound in organic synthesis and medicinal synthesis (Org. Biomol. Chem., 2010, 8, 1505; Tetrahedron, 2003, 59, 2581).

Conventionally, a chiral 5-membered ring sulfamidate has been known to synthesize chiral 1,2-aminoalcohol through several steps. However, this method is disadvantageous in that expensive chiral 1,2-aminoalcohol compounds should be used from the beginning, and chiral 1,2-aminoalcohol compounds which are commercially available are also limited (Org. Biomol. Chem., 2010 , 8, 1505, J. Org. Chem., 2010, 75, 937) (Scheme 1).

[Reaction Scheme 1]

It is also known to synthesize a chiral 5-membered ring sulfamidate by reacting a chiral 1,2-diol with 2 equivalents of Burgess reagent. However, this method also has a disadvantage in that an expensive chiral 1,2-diol must be used as a starting material and a mixture of positional isomers having different positions of nitrogen and oxygen is obtained (Chem. Eur. J., 2004, 10, 5581) (Scheme 2).

[Reaction Scheme 2]

A chiral 5-membered ring sulfamidate with a single substituent at the 4-position can be prepared by reacting a 5-membered ring imine with Pd (CF ₃ CO) in a 2,2,2-trifluoroethanol (TFE) _{2) 2} and (S, S) - f - a bar or a plate ((S, S) - f -binaphane) are known methods for producing the hydrogenation under high hydrogen pressure of 600 psi in the presence of a catalyst (Org Lett 2008.. , 10, 2071) (Scheme 3).

[Reaction Scheme 3]

However, this method can yield a chiral 5-membered ring sulfamidate with a single substituent at the 4-position with high optical purity, but high pressure hydrogen (600 psi) should be used and 2,2,2 ( S, S ) - f - bar or plate is required to be used in an amount of 2.4 mol%. By the above method are (4S) - is obtained only sulfamic US date, the enantiomers of (4R) - in order to obtain the sulfamic US date (R, R) - f-one (R, R) must use a bar or plate- Since f -bars and plates are not commercialized, ( 4R ) -sulfamidate is not easy to obtain.

( 4R ) - or ( 4S ) -isomer of a chiral 5-membered ring sulfamidate having a single substituent at the 4-position has recently been reported (Org. Lett. 2010, 12, 4184 ) (Scheme 4).

[Reaction Scheme 4]

In this method, a chiral rhodium catalyst is used and a chiral 5-membered ring sulfamidate of high optical purity is produced in a short time at room temperature and atmospheric pressure using a HCO ₂ H / Et ₃ N mixture as a hydrogen donor instead of high pressure hydrogen can do. Also, since both ( R, R ) - or ( S, S ) - rhodium catalysts can be easily obtained, it is possible to selectively synthesize both enantiomeric ( 4S ) - or ( 4R ) -sulfamidate with each other. However, this method exhibits a very high enantiomeric excess (ee, mostly 95% ee or more) only when the 5-membered ring sulfamidate has a single substituent at the 4-position and no substituent at the 5-position .

The 4-aryl-5-alkyl substituted 5-membered ring sulfamidate, which has all substituents in the 4- and 5-positions, has enantiomeric excess (ee) as high as 75% ee (Scheme 5)

[Reaction Scheme 5]

Therefore, there is a need to develop a process which can produce 5-membered ring sulfamidates with alkyl or aryl substituents both in the 4- and 5-positions with high optical purity.

Since stereomerically pure 4,5-substituted 5-membered ring sulfamidates are very important intermediates in organic synthesis and in the synthesis of medicines, it is very important to develop a method for preparing these compounds in a stereomerically pure form .

The present invention provides a process for the efficient preparation of stereoisomerically pure 4,5-substituted 5-membered ring sulfamidates, and more particularly to a process for the preparation of 4- 5-aryl-5-membered ring sulfamidate having the formula (I) in which R < 1 >

In order to accomplish the above object, the present invention provides a process for producing a 4-alkyl-5-aryl 5-membered ring imine compound represented by the following formula 2 by using a chiral organometallic catalyst and a hydrogen donor simultaneously with asymmetric reduction and dynamic kinetic resolution ) To give a stereoisomeric compound represented by the following formula (1a) or (1b) having high optical activity.

(2)

[Formula 1a]

[Chemical Formula 1b]

Wherein R ₁ is (C6-C18) aryl or (C5-C18) heteroaryl; R < ₂ > is (C1-C10) alkyl; (C6-C18) aryl, (C5-C18) heteroaryl and (C1-C10) alkyl are optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, nitro, cyano, (C6-C18) aryl (C1-C6) haloalkyl, (C1- C6) alkoxycarbonyl,

Preferably, in the above general formulas (1a), (1b) and (2), R ₁ is phenyl, naphthyl, furanyl, benzofuranyl, pyridinyl, thiophenyl or benzothiophenyl; R ₂ may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.

The chiral organometallic catalyst of the present invention also includes a compound represented by the following general formula (3a) or (3b).

[Chemical Formula 3]

(3b)

[In the above formula (3a) and 3b, R ₁₁ is (C1-C6) alkyl, (C1-C6) _{haloalkyl, CF 3, (C6-C18} ) aryl or (C5-C18), and heteroaryl, wherein said (C6-C18 (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) alkoxycarbamoyl, (C6-C18) aryl, (C6-C18) aryl (C1-C6) alkyl; X is rhodium (III), iridium (III), ruthenium (II); L is one selected from the group consisting of a cyclopentadienyl group, a pentamethylcyclopentadienyl group, a 1-methyl-4-isopropylphenyl group, a phenyl group and a hexamethylphenyl group.

The chiral organometallic catalysts of the present invention may also contain one or two equivalents of a hydrochloric acid / tri (C 1 -C 6) alkylamine salt, a hydrochloric acid / (C 3 -C 8) cyclic alkylamine salt and a hydrochloric acid / (C 5 -C 12) heteroarylamine salt Or a compound represented by the above formula (3a) or (3b).

The chiral organometallic catalyst of the present invention may be one compound selected from compounds of the following formulas (4a) to (4f), and more particularly, the chiral organometallic catalyst of the above general formula (3a) is represented by the following formula (4a), (4c) or The chiral organometallic catalyst of Formula 3b may be a compound of Formula 4b, 4d or 4f.

[Chemical Formula 4a]

(4b)

[Chemical Formula 4c]

[Chemical formula 4d]

[Chemical Formula 4e]

[Formula 4f]

[In the formulas (4a), (4b), (4c), (4d), (4e) and (4f), Ph is a phenyl group and Ts is a tosyl group.

The chiral organometallic catalyst of the present invention may also be selected from the compounds of formulas (4a) to (4f) comprising 1 to 2 equivalents of a hydrochloric acid / triethylamine salt.

Alkyl-5-aryl 5-membered ring imine compound represented by the general formula (2) and a hydrogen donor in the presence of the chiral organometallic catalyst of the present invention, the chiral organometallic catalyst is a 4-alkyl- 0.00001% to 50% of the 5-aryl 5-membered ring imine compound can be used.

The hydrogen donor of the present invention is 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 in the mixture of formic acid and amine can be selected from, but is not limited to, tri (C1-C6) alkylamine, (C3-C8) cyclic alkylamine and (C5-C12) heteroarylamine, C5-C12) heteroarylamines may be pyridine, pyrimidine, pyrazine, pyridazine, imidazole, triazole, 2-methylimidazole and N, N-dimethylaminopyridine.

More specifically, the compounds represented by the general formulas (Ia) and (Ib) according to the present invention are prepared by asymmetric hydrogenation using a chiral organometallic catalyst as a 4-alkyl-5-aryl 5-membered ring imine compound.

When the compound 2 is hydrogenated, the following four stereoisomeric compounds 1a, 1b, 1c, and 1d can be theoretically synthesized. (Scheme 6)

[Reaction Scheme 6]

Techniques for preparing 4-aryl-5-alkyl substituted 5-membered ring sulfamidates by asymmetric hydrogenation reactions using chiral organometallic catalysts and hydrogen donors are already known in the literature (Org. Lett. 2010, 12 , 4184-4187). The enantiomeric excess (ee) of the 4-aryl-5-alkyl substituted 5-membered cyclic sulfamidate compound prepared was not as high as 75% ee.

[Reaction Scheme 7]

As a result of close examination of this reaction, it was confirmed that optical activity was exhibited by dynamic kinetic resolution under the above reaction conditions.

In studying the development of a method capable of increasing the optical activity purity of the reaction by more efficiently proceeding with dynamic kinetic resolution, 4-alkyl-5-aryl substituted 5-membered ring sulfamidate 2 (96% ee, dr> 99: 1) with an asymmetric hydrogenation reaction using a chiral organometallic catalyst and a hydrogen donor. )

[Reaction Scheme 8]

Accordingly, this patent discloses a process for selectively producing a stereoisomer compound represented by the following formula (1a) or (1b) having high optical activity through kinetic kinetics resolution simultaneously with asymmetric reduction using a chiral organometallic catalyst and a hydrogen donor . ≪ / RTI >

When the compound 2 is subjected to an asymmetric reduction reaction with the 3a compound as a chiral organometallic catalyst in the presence of a hydrogen donor according to the method of the present invention, the stereoisomer 1a is produced with high optical activity. Further, when the compound 2 is subjected to an asymmetric reduction reaction in the presence of a chiral organometallic catalyst 3b compound and a hydrogen donor, the stereoisomer 1b is produced with high optical activity (Scheme 9).

[Reaction Scheme 9]

The chiral organometallic catalyst used in the present invention is the organometallic rhodium catalysts 4a and 4b, the organic iridium catalysts 4c and 4d and the organic ruthenium catalysts 4e and 4f, 4a and 4b are most preferred.

The chiral organometallic catalysts represented by the above general formulas (4a) to (4f) are all known substances and can be prepared by a conventional method {4a, 4b: Org. Lett., 1999,1, 841; Chem. Lett., 1998, 1199.} {4c, 4d: Chem. Lett., 1998, 1199.} {4e, 4f: Angew. Chem. Int. Ed. Engl., 1997, 36, 285}.

Rhodium catalyst 4a Specific examples are (pentamethyl cyclopentadienyl) rhodium (III) dichloride dimer _{[RhCl 2 Cp *] (1R} , 2R) has a _second, optically active - N - (p - toluenesulfonyloxy) -1,2-diphenylethylene-diamine (TsDPEN) and triethylamine in a solvent of dichloromethane (CH ₂ Cl ₂ ) was washed with water and then recrystallized to obtain a yield of 91% (( 1R, 2R ) -RhCl (TsDPEN) Cp *} (Org. Lett., 1999, 1, 841). Wherein Cp * represents a pentamethylcyclopentadienyl group and TsDPEN represents N - ( p -toluenesulfonyl) -1,2-diphenylethylene-diamine.

Also 4a is (pentamethyl cyclopentadienyl) rhodium (III) dichloride dimer [RhCl ₂ Cp *] _2, an optically active (1R, 2R) - N - (p - toluenesulfonyloxy) 1,2 -Diphenylethylene-diamine (TsDPEN) and triethylamine in a solvent of dichloromethane (CH ₂ Cl ₂ ), the solvent is removed as it is without further purification under reduced pressure, and the obtained product can be used as a catalyst { 1R, 2R) -RhCl (TsDPEN) Cp * (Et 3 N / HCl) 2}. In this case, 4a contains 2 equivalents of triethylamine hydrochloride (Tetrahedron: Asymmetry, 2009, 20, 2639). The two kinds of the preparation prepared in 4a or _{4a / (Et 3 N / HCl} ) 2 did not differ neunge catalyst.

And (pentamethyl-cyclopentadienyl) rhodium (III) dichloride dimer _{[RhCl 2 Cp *] (1R} , 2R) has a _second, optically active - N - (p - toluenesulfonyl) -1,2- Hydrogenation may be carried out by adding a substrate and a hydrogen donor to the reaction solution obtained by reacting phenylethylene-diamine (TsDPEN) and triethylamine in dichloromethane (CH ₂ Cl ₂ ) solvent without directly separating or purifying the reaction solution.

In order to prepare the 4-alkyl-5-aryl 5-membered ring sulfamidate stereoisomer compound using the organometallic catalyst and the hydrogen donor, ethyl acetate (EtOAc), toluene, methylene chloride (CH ₂ Cl ₂ ) A solvent such as dichloroethane (ClCH ₂ CH ₂ Cl), dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, methanol, ethanol, isopropanol, t- Or the reaction can proceed with only the substrate, the catalyst, and the hydrogen donor without a solvent.

Alkyl 5-aryl 5-membered ring imine compound 2 used as a substrate can be prepared by reacting 2-hydroxy ketone compound 5 with chlorosulfamide (ClSO ₂ NH ₂ ) or sulfamide (NH ₂ SO ₂ NH ₂ ) (J. Am. Chem. Soc., 2001, 123, 6935; Org. Lett. 2008, 10, 2071; Chem. Comm., 2011, 47, 2372). The 2-hydroxyketone compound 5 can be prepared from an aromatic aldehyde by a known method.

[Reaction Scheme 10]

The 4-alkyl-5-aryl 5-membered ring amine compound stereoisomeric compounds prepared by the process of the present invention are chiral amino alcohols which are very important intermediates in the production of stereomerically pure pesticides, pharmaceuticals and fine chemicals, Can be converted to a chiral amine derivative such as a chiral amino acid or a chiral amino acid (Org. Biomol. Chem., 2010, 8, 1505; Tetrahedron, 2003, 59, 2581).

According to the process of the present invention, 4-alkyl-5-aryl 5-membered ring sulfamidate stereoisomeric compounds can be obtained with higher stereochemical purity (96% ee, dr> 99: 1) have.

As used herein, "(C1-C6) alkyl" means a linear or branched, saturated C1 to C6 hydrocarbon radical chain. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl and hexyl.

As used herein, "(C1-C6) alkoxy" refers to the group -OR _a where R _a is (C1-C6) alkyl as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and the like.

As used herein, "(C1-C6) haloalkyl" means a (C1-C6) alkyl group substituted with one or more halogens wherein (C1-C6) alkyl is as defined above. Specific examples thereof include, but are not limited to, trifluoromethyl, trichloroethyl, and the like.

The term "(C6-C18) aryl" as used herein refers to an aryl group having 6 to 18 carbon atoms and includes not only fused groups such as naphthyl, phenanthrenyl and the like but also monocyclic or bicyclic groups such as phenyl, And a cyclic aromatic ring. Specific examples include, but are not limited to, phenyl, toluyl, xylyl, biphenyl and naphthyl.

As used herein, "(C6-C18) aryl (C1-C6) alkyl" refers to a (C1-C6) alkyl group substituted with a (C6-C18) aryl group and the aryl and alkyl groups are as previously defined. Specific examples thereof include, but are not limited to, benzyloxy, phenethyloxy, phenylpropyloxy and the like.

As used herein, "(C5-C18) heteroaryl" means that at least one N, S, O is substituted for an aryl group having 5 to 18 carbon atoms, and specific examples thereof include pyridine, thiophene, furan, benzothiophene, benzo Furan, and the like, but the present invention is not limited thereto.

As used herein, "(C5-C12) heteroarylamine" means that at least one N is substituted for an aryl group having 5 to 12 carbon atoms, and specific examples thereof include pyridine, pyrimidine, pyrazine, pyridazine, imidazole, triazole , 2-methylimidazole, N, N-dimethylaminopyridine, but are not limited thereto.

As the hydrogen donor used in the present specification, a metal salt of formic acid, formic acid, an ammonium salt of formic acid, a mixture of formic acid and organic amine, or an azeotropic mixture of formic acid and triethylamine may be used as a substance which provides hydrogen by catalysis.

As used herein, the hydrochloric acid / tri (C1-C6) alkylamine salt refers to an amine salt having three linear or branched, saturated C1 to C6 hydrocarbon radical chains. Also, the hydrochloric acid / (C5-C12) heteroarylamine salt includes pyridine, pyrimidine, pyrazine, pyridazine, imidazole, triazole, 2-methylimidazole, N, N-dimethylaminopyridine.

According to the preparation method of the present invention, 4-alkyl-5-aryl 5-membered ring sulfamidate stereoisomer compounds having high optical purity can be selectively obtained and the compound can be produced simply 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 (Ia) or (Ib) prepared by the process of the present invention can be purified by conventional extraction, distillation, recrystallization, column chromatography, etc. The optically active purity (ee) Can be determined by HPLC using a Chiralcel OD-H, AD-H, or OJ-H equipped column.

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.

Ac (acetyl)

Bn (benzyl)

Boc (tert-butyloxycarbonyl)

Bz (benzoyl)

Cbz (benzyloxycarbonyl)

Cp * (pentamethylcyclopentadienyl group)

DCM or MC (dichloromethane)

DMA (N, N - dimethylacetamide, N, N -dimethylacetamide)

DMAP ( N, N -dimethyaminopyridine, N, N- dimethylaminopyridine)

DMF ( N, N -dimethylformamide)

DMSO (dimethylsulfoxide)

dr (diasteromeric ratio)

ee (enantiomeric excess)

EtOAc (ethyl acetate)

EtOH (ethanol)

HPLC (high pressure liquid chromatography)

Hz (Hertz)

i-PrOH (isopropanol)

MeOH (methanol)

MgSO ₄ (magnesium sulfate)

PTSA (p-toluenesulfonic acid)

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.

<Production Example 1-1> [ R, R ] -TsDPEN-RhCl-Cp * catalyst

309 mg (0.5 mmol) of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer and ( 1R, 2R ) - (-) - N- p -tosyl-1,2-diphenylethylenediamine 366 (1 mmol) was dissolved in anhydrous methylene chloride (10 ml), and then triethylamine (202 mg, 2 mmol) was added thereto. The mixture was stirred at room temperature for 1 hour. The reaction solution was washed with water, dried over anhydrous MgSO ₄ , and the solvent was removed under reduced pressure. The resulting solid was recrystallized to give 580 mg (yield 91%) of the title compound as an orange powder (chloroform / n-hexane).

^{1 H-NMR (300 MHz,} CDCl 3) δ 7.44 (d, 2H, J = 8.2 Hz), 7.10-7.15 (m, 3H), 6.77-6.89 (m, 8H), 6.67 (d, 2H, J = 7.0 Hz), 3.96-4.00 (m, 1H), 3.98 (d, 1H, J = 10.6 Hz), 3.67-3.75 (m, 1H), 3.27-3.30 (m, 1H), 2.22 (s, 3H), 1.86 (s, 15 H).

&Lt; Preparation Example 1-2 > S, S ] -TsDPEN-RhCl-Cp * catalyst

( 1S, 2S ) - (-) - N- p -tosyl-1,2-diphenylethylenediamine and triethylamine were used in place of the dichloromethane 1-1. &Lt; / RTI &gt;

&Lt; Preparation Example 1-3 > [ R, R ] -TsDPEN-RhCl-Cp * / 2 (HClEt ₃ N) catalyst

309 mg (0.5 mmol) of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer and ( 1R, 2R ) - (-) - N- p -tosyl-1,2-diphenylethylenediamine 366 (1 mmol) was dissolved in anhydrous methylene chloride (10 ml), and then anhydrous triethylamine (202 mg, 2 mmol) was added thereto, followed by stirring at room temperature for 2 hours. The resulting reaction mixture was distilled under reduced pressure to remove the solvent and then dried under high vacuum for 4 hours to obtain 868 mg (yield 95%) of the title compound in the form of an orange powder.

&Lt; Preparation Example 1-4 > S, S ] -TsDPEN-RhCl-Cp * / 2 (HClEt ₃ N) catalyst

( 1S, 2S ) - (-) - N- p -tosyl-1,2-diphenylethylenediamine in place of the dichloro (pentamethylcyclopentadienyl) rhodium Were prepared by the same process.

< Manufacturing example  2-1> 4- methyl -5- Phenyl -5 H - [l, 2,3] -oxathiazol-2,2- Of  Produce

Chlorosulfonyl isocyanate (522 ul, 6 mmol) is added to a 10 ml round-bottomed flask, cooled to 0 ° C and formic acid (226 ul, 6 mmol) is slowly added dropwise with rapid stirring. The mixture was further stirred at 0 DEG C for 5 minutes, DMA (2 ml) was added to the obtained solid, and the mixture was stirred at room temperature for 5 minutes. The solution was cooled to 0 캜 again, and a solution prepared by dissolving 1-hydroxy-1-phenyl-propan-2-one (0.6 g, 4.0 mmol) in DMA (7 ml) was slowly added dropwise. After further reaction at room temperature for 1 hour, dilute with EtOAc (30 ml) and wash with saturated brine. The solvent was removed by distillation under reduced pressure, toluene (10 ml) and PTSA (0.4 mmol) were added, and water was removed by heating under reflux for 0.5 hour. The solvent was distilled off under reduced pressure, and the residue was separated and purified by flash silica column chromatography to obtain the title compound.

White solid, yield: 84.1%, 1 H-NMR (500 MHz, CDCl 3) δ 7.50-7.52 (m, 3H), 7.37-7.39 (m, 2H), 6.03 (s, 1H), 2.22 (s, 3H ); ¹³ C-NMR (75 MHz, CDCl ₃ ) 隆 182.4, 131.2, 131.0, 129.9, 127.5, 91.7, 17.5; HRMS (EI): m / z calcd for C ₉ H ₉ NO ₃ S 211.0303, found 211.0308.

< Manufacturing example  2-2 > 5- (4- Fluoro - Phenyl )-4- methyl -5 H - [l, 2,3] -oxathiazol-2,2- Dioxide Manufacturing

The title compound was prepared according to the procedure of Preparation Example 2-1 using 1-hydroxy-l- (4-fluoro-phenyl) -propan-2-one instead of l- Lt; / RTI &gt;

White solid, yield: 80.7%, 1 H-NMR (500 MHz, CDCl 3) δ 7.36-7.40 (m, 2H), 7.18-7.22 (m, 2H), 6.05 (s, 1H), 2.23 (s, 3H ). ; ¹³ C-NMR (125 MHz, CDCl ₃ )? 182.0, 165.0, 163.0, 129.6, 129.6, 127.05, 127.02, 117.1, 116.9, 90.7, 17.4; HRMS (EI): m / z calcd for C ₉ H ₈ FNO ₃ S 229.0209, found 229.0217.

< Manufacturing example  2-3> 5- ( Phenyl ) -4-ethyl-5H- [1,2,3] -oxathiazole-2,2- Of  Produce

The title compound was prepared according to the procedure of Preparation 2-1 using 1-hydroxy-1-phenyl-butan-2-one instead of 1-hydroxy-1-phenyl-propan-2-one.

Colorless oil, yield: 81%, 1 H-NMR (300 MHz, CDCl 3) δ 7.46-7.48 (m, 3H), 7.34-7.36 (m, 2H), 6.04 (s, 1H), 2.30-2.52 (m , 2H), 1.21 (t, 3H, J = 7.2 Hz). ¹³ C-NMR (75 MHz, CDCl ₃ ) 隆 186.7, 131.5, 130.9, 129.8, 127.5, 91.2, 24.8, 9.4. HRMS (EI): m / z calcd for C 10 H 11 NO 3 S 225.0460, found 225.0458.

< Example  1> ( 4S, 5R )-4- methyl -5- Phenyl - [1,2,3] - Oxathiazolidine -2,2- Of  Produce

The 4-methyl was prepared in Preparative Example 2-1 5-phenyl -5 H - [1,2,3] - thiazol-oxa-2,2-dioxide (3.7 mg, 0.003 eq.) Prepared in Preparation Example 1-1 was dissolved in ethyl acetate (20 ml), and thereto was added HCO 3 (410 mg, 1.94 mmol) and [ R, R ] -TsDPEN-RhCl- ₂ mL of a mixed solution of ₂ H and Et ₃ N (molar ratio = 5: 2) was added, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was diluted with EtOAc 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. Only one diastereomer was detected in the ¹ H NMR spectral analysis. (dr > 20: 1)

White soild, yield: 93.2%, 96.1% ee (Chiralcel AD-H, 10% isopropanol / hexanes, 1.5 mL / min, 254 nm, tr min = 9.1 min, tr max = 10.6 min); [?] _D ²¹ = -30.9 ( c 0.3, CH ₃ OH); ^{1 H-NMR (500 MHz,} CDCl 3) δ 7.42-7.49 (m, 3H), 7.36-7.38 (m, 2H), 5.84 (d, 1H, J = 5.8 Hz), 4.33-4.41 (m, 2H) , 1.02 (d, 3H, J = 6.6Hz). ¹³ C-NMR (75 MHz, CDCl ₃ ) 隆 133.1, 129.5, 129.1, 126.1, 88.3, 56.3, 15.7; HRMS (EI): m / z calcd for C ₉ H ₁₁ NO ₃ S 213.0460, found 213.0464.

Recrystallization from EtOAc / n-Hexane gave the stereomerically pure title compound. (> 99% ee)

< Example  2> ( 4R, 5S )-4- methyl -5- Phenyl - [1,2,3] - Oxathiazolidine -2,2- Of  Produce

Prepared in Preparation Example 2-1, 4-methyl-5-phenyl -5 H - [1,2,3] - use the oxa-2,2-thiazol-dioxide [R, R] -TsDPEN-RhCl- The title compound was prepared according to the procedure of Example 1 using [ S, S ] -TsDPEN-RhCl-Cp * prepared in Preparation Example 1-2 instead of Cp *. Only one diastereomer was detected in the ¹ H NMR spectral analysis.

White soild, yield: 99.6%, 96.4% ee (Chiralcel AD-H, 10% isopropanol / hexanes, 1.5 mL / min, 254 nm, tr = 9.1 min, tr (minor) = 10.6 min); [?] D ²² = +38.0 ( c 0.3, CH ₃ OH); ^{1 H-NMR (500 MHz,} CDCl 3) δ 7.44-7.48 (m, 3H), 7.36-7.40 (m, 2H), 5.84 (d, 1H, J = 5.7 Hz), 4.32-4.40 (m, 2H) , 1.02 (d, 3H, J = 6.5 Hz). ¹³ C-NMR (75 MHz, CDCl ₃ )? 133.1, 129.5, 129.1, 126.1, 88.2, 56.2, 15.7; HRMS (EI): m / z calcd for C ₉ H ₁₁ NO ₃ S 213.0460, found 213.0463.

Recrystallization from EtOAc / n-Hexane gave the stereomerically pure title compound. (> 99% ee)

< Example  3> ( 4S, 5R )-4- methyl -5- (4- Fluoro - Phenyl ) - [1,2,3] - Oxathiazolidine -2,2- Diox Manufacture of side

(4-fluoro-phenyl) The 4-methyl-5 obtained in Preparation Example 2-2 -5 H - [1,2,3] - use the oxa-2,2-thiazol-dioxide Example 1, the titled compound was prepared. Only one diastereomer was detected in the ¹ H NMR spectral analysis.

White soild, yield: 83.8%, 92.8% ee (Chiralcel AD-H, 10% isopropanol / hexanes, 1.5 mL / min, 254 nm, tr min = 9.3 min, tr max = 12.1 min); [?] _D ²² = -18.0 ( c 0.3, CH ₃ OH); ^{1 H-NMR (500 MHz,} CD 3 OD) δ 7.41-7.46 (m, 2H), 7.13-7.19 (m, 2H), 5.83 (d, 1H, J = 6.2 Hz), 4.24-4.28 (m, 1H ), 0.91 (d, 3H, J = 6.8 Hz). ¹³ C-NMR (75 MHz, CD ₃ OD)? 166.2, 162.9, 131.90, 131.86, 130.0, 129.9, 116.7, 116.4, 89.0, 57.0, 15.4; HRMS (EI): m / z calcd for C ₉ H ₁₀ FNO ₃ S 231.0365, found 231.0372.

< Example  4> 4S, 5R ) -4-ethyl-5- Phenyl - [1,2,3] - Oxathiazolidine -2,2- Of  Produce

The 4-ethyl-5-phenyl -5 H obtained in Preparation Example 2-3 - [l, 2,3] - using the oxa-2,2-thiazol-dioxide The title compound according to the procedure of Example 1 . Only one diastereomer was detected in the ¹ H NMR spectral analysis.

White soild, yield: 79.0%, 93.4% ee (Chiralcel AD-H, 10% isopropanol / hexanes, 1.0 mL / min, 254 nm, tr (minor) = 12.0 min, tr (major) = 13.8 min); [?] _D ²² = -31.9 ( c 0.3, CH ₃ OH); ^{1 H-NMR (500 MHz,} CDCl 3) δ 7.37-7.46 (m, 5H), 5.85 (d, 1H, J = 6.0 Hz), 4.56 (br, d, 1H, J = 8.7 Hz), 4.09-4.13 (m, 1H), 1.16-1.31 (m, 2H), 0.95 (t, 3H, J = 7.3 Hz). ¹³ C-NMR (75 MHz, CDCl ₃ )? 133.3, 129.5, 129.0, 126.3, 88.3, 62.4, 23.3, 11.1; HRMS (EI): m / z calcd for C ₁₀ H ₁₃ NO ₃ S 227.0616, found 213.0624.

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 (11)

In the presence of a chiral organometallic catalyst represented by the following formula (3a) or (3b)
A method for selectively producing a stereoisomer compound represented by formula (1a) or (1b) having an optically active compound by reacting a 4-alkyl-5-aryl 5-membered ring imine compound represented by the following formula (2) with a hydrogen donor.
(2)

[Formula 1a]

[Chemical Formula 1b]

[In the above formulas (1a), (1b) and (2)
R &lt; ₁ &gt; is (C6-C18) aryl;
R &lt; ₂ &gt; is (C1-C10) alkyl;
Said (C6-C18) aryl and (C1-C10) alkyl being optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, nitro, cyano, (CrC6) alkyl, (CrC6) alkoxy, C6) alkoxycarbonyl, (C6-C18) aryl and (C6-C18) ar (C1-C6)
[Chemical Formula 3]

[In the formula (3a)
R ₁₁ is (C1-C6) alkyl, (C1-C6) haloalkyl, CF _3, (C6-C18) aryl or (C5-C18), and heteroaryl, wherein said (C6-C18) aryl and (C5-C18) (C1-C6) alkoxy, (CrC6) haloalkyl, (CrC6) alkoxycarbonyl, (C6-C18) aryl , (C6-C18) ar (C1-C6) alkyl;
X is rhodium (III);
L is one selected from the group consisting of a cyclopentadienyl group, a pentamethylcyclopentadienyl group, a 1-methyl-4-isopropylphenyl group, a phenyl group and a hexamethylphenyl group.
(3b)

[In the above formula (3b)
R ₁₁ is (C1-C6) alkyl, (C1-C6) haloalkyl, CF _3, (C6-C18) aryl or (C5-C18), and heteroaryl, wherein said (C6-C18) aryl and (C5-C18) (C1-C6) alkoxy, (CrC6) haloalkyl, (CrC6) alkoxycarbonyl, (C6-C18) aryl , (C6-C18) ar (C1-C6) alkyl;
X is rhodium (III);
L is one selected from the group consisting of a cyclopentadienyl group, a pentamethylcyclopentadienyl group, a 1-methyl-4-isopropylphenyl group, a phenyl group and a hexamethylphenyl group.
The method according to claim 1,
Wherein R &lt; ₁ &gt; is phenyl or naphthyl;
Wherein R ₂ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.
delete delete The method according to claim 1,
The chiral organometallic catalyst of formula 3a or 3b may be prepared by reacting 1 to 2 equivalents of a hydrochloric acid / tri (C1-C6) alkylamine salt, a hydrochloric acid / (C3-C8) cyclic alkylamine salt and a hydrochloric acid / (C5-C12) A process for the selective preparation of a stereoisomer compound represented by the formula (Ia) or (Ib), wherein the compound comprises an amine salt.
The method according to claim 1,
Wherein the chiral organometallic catalyst of formula (3a) is represented by the following formula (4a).
[Chemical Formula 4a]

[In the above formula (4a)
Ph is a phenyl group, and Ts is a tosyl group.
The method according to claim 1,
Wherein the chiral organometallic catalyst of Formula 3b is represented by Formula 4b: &lt; EMI ID = 19.1 &gt;
(4b)

[In the above formula (4b)
Ph is a phenyl group, and Ts is a tosyl group.
8. The method according to claim 6 or 7,
Wherein the chiral organometallic catalyst is a compound of formula (4a) or (4f) comprising 1 to 2 equivalents of a hydrochloric acid / triethylamine salt.
The method according to claim 1,
Wherein the hydrogen donor is one selected from formic acid, a metal salt of formic acid, an ammonium salt of formic acid, and a mixture of formic acid and an amine.
10. The method of claim 9,
Wherein said amine is one selected from tri (C1-C6) alkylamine, (C3-C8) cyclic alkylamine and (C5-C12) heteroarylamine. Selective manufacturing method.
11. The method of claim 10,
Wherein the (C5-C12) heteroarylamine is one selected from pyridine, pyrimidine, pyrazine, pyridazine, imidazole, triazole, 2-methylimidazole and N, N-dimethylaminopyridine. RTI ID = 0.0 &gt; 1 &lt; / RTI &gt; or 1b.