KR101815001B1 - 4-Substituted-5-membered-ring-sulfamidate-5-phosphonate compounds and Method for the stereoselective preparation thereof - Google Patents

Abstract

The present invention relates to novel 4-substituted-5-membered ring-sulfamidate-phosphonate compounds and a manufacturing method thereof and, more specifically, to 4-substituted-5-membered ring-sulfamidate-phosphonate compounds having high stereogenic purity and a method for stereoselectively manufacturing the same.

Description

4-Substituted-5-membered ring-sulfamidate-5-phosphonate compounds having high stereospecificity and methods for preparing the same stereoselective preparation thereof}

The present invention relates to a novel 4-substituted-5-membered ring-sulfamidate-5-phosphonate compound and a process for its preparation, and more particularly to a 4-substituted 5- Ring-sulfamidate-5-phosphonate compounds and a novel process for synthesizing them in a simple, efficient and selective manner.

The 5-membered ring-sulfamidate-5-phosphonate having a high optical purity can be converted into a phosphoric acid compound derivative containing a chiral amino alcohol or a chiral diamine group through a simple reaction, (Org. Biomol. Chem., 2010, 8, 1505; Tetrahedron, 2003, 59, 2581).

Conventionally, a method of synthesizing a phosphoric acid compound derivative containing a chiral amino alcohol group, that is, a 2-amino-1-hydroxy phosphonic acid derivative compound, from a chiral amino acid or a chiral amino-aldehyde compound is known, but an expensive chiral amino acid or a chiral amino- (Tetrahedron: Asymmetry 2002, 13, 2509., Tetrahedron: Asymmetry 2007, 18, 1134 .; Scheme A).

[Reaction Scheme A]

Also, it has been reported that a chiral 2-amino-1-hydroxy phosphonic acid derivative compound is synthesized through asymmetric aminohydroxylation reaction using a chiral catalyst from a vinylphosphonate compound, and the synthesis yield and the optical activity of the product are not so high 1999, 64, 8379, Scheme B).

[Scheme B]

Recently, 4,5-diaryl cyclic sulfamidates and cyclic sulfamidate-5-carboxylates compounds were prepared by stereoselective addition of 4,5-diaryl cyclic sulfamidates and 5-membered cyclic sulfamidate- A simple synthesis method has been reported (Chem. Commun., 2011, 47, 4004., Scheme C, Chem. Commun., 2014, 50, 13706., Scheme D).

[Scheme C]

[Reaction Scheme D]

In this method, a chiral rhodium catalyst is used and, in place of hydrogen at a high pressure, a mixture of HCO ₂ H / Et ₃ N is used as a hydrogen donor. In a short time at room temperature and pressure, a chiral 5-membered ring-sulfamidate compound Can be prepared. Also, since both ( R, R ) - or ( S, S ) - rhodium catalysts can be easily obtained, all of the 5-membered ring-sulfamidate compounds which are enantiomers with each other can be selectively synthesized. However, stereoselective synthesis of chiral 4-substituted-5-membered ring-sulfamidate-5-phosphonate compounds has not been reported yet.

Stereoisomerically pure 4-substituted 5-membered ring-sulfamidate-5-phosphonate compounds are very important intermediates in organic synthesis and in the synthesis of medicines, so that these compounds are prepared stereomerically pure Development of methods is very important.

Korean Patent No. 10-1446017 Korean Patent No. 10-1345749

 Org. Biomol. Chem., 2010, 8, 1505  Tetrahedron, 2003, 59, 2581  Tetrahedron: Asymmetry 2002, 13, 2509  Tetrahedron: Asymmetry 2007, 18, 1134  J. Org. Chem. 1999, 64, 8379  Chem. Commun. 2011, 47, 4004  Chem. Commun. 2014, 50, 13706

The present invention provides novel 4-substituted 5-membered ring-sulfamidate-5-phosphonate compounds, and more particularly to the use of the stereosomerically pure 4-substituted 5-membered ring- -5-phosphonate compound.

The present invention also provides a process for the efficient preparation of stereoisomerically pure 4-substituted-5-membered ring-sulfamidate-5-phosphonate compounds, more particularly, Substituted 5-membered ring-sulfamidate-5-phosphonate compound from a 5-membered ring-imine compound having a phenate substituent in a more simple manner.

In order to accomplish the above object, the present invention provides a novel 4- (4-tert-butylphenyl) -4-methylpyridine derivative represented by the following Chemical Formula 1, which can be converted into a phosphate compound derivative containing a chiral amino alcohol or a chiral diamine group, Substituted 5-membered ring-sulfamidate-5-phosphonate compound.

[Chemical Formula 1]

In Formula 1,

R ₁ is _{- (CH 2) n -R,} C 6 ~ C 12 aryl vinyl, C ₃ ~ C ₇ cycloalkyl, C ₆ ~ C ₁₂ aryl or an aryl C ₄ ~ C ₁₂ heteroaryl, aryl of the above R _1, and heteroaryl with one or more substituents selected from halogen, cyano, halo C ₁ ~ C ₇ alkyl, nitro, C ₁ ~ C ₇ alkyl, C ₁ ~ C ₇ alkoxy, C ₁ ~ C ₇ alkoxycarbonyl group consisting of Lt; / RTI > may be further substituted;

R is C ₁ -C ₇ alkyl or C ₆ -C ₁₂ aryl;

R ₂ is C ₁ -C ₇ alkyl or C ₆ -C ₁₂ aryl C ₁ -C ₇ alkyl;

n is an integer from 1 to 5;

Wherein said heteroaryl comprises at least one heteroatom selected from N, O and S;

The present invention also relates to a process for preparing a 4-substituted-5-membered ring-imine-5-phosphonate compound of the formula (2) by asymmetric transfer hydrogenation using a chiral organometallic catalyst and a hydrogen donor, A method for selectively producing a 4-substituted-5-membered ring-sulfamidate-5-phosphonate stereoisomer compound represented by the following formula (1a) or (1b) having high optical activity through dynamic kinetic resolution .

[Formula 1a]

[Chemical Formula 1b]

(2)

In the above general formulas (1a), (1b) and (2)

R ₁ is _{- (CH 2) n -R,} C 6 ~ C 12 aryl vinyl, C ₃ ~ C ₇ cycloalkyl, C ₆ ~ C ₁₂ aryl or an aryl C ₄ ~ C ₁₂ heteroaryl, aryl of the above R _1, and heteroaryl with one or more substituents selected from halogen, cyano, halo C ₁ ~ C ₇ alkyl, nitro, C ₁ ~ C ₇ alkyl, C ₁ ~ C ₇ alkoxy, C ₁ ~ C ₇ alkoxycarbonyl group consisting of Lt; / RTI > may be further substituted;

R is C ₁ -C ₇ alkyl or C ₆ -C ₁₂ aryl;

R ₂ is C ₁ -C ₇ alkyl or C ₆ -C ₁₂ aryl C ₁ -C ₇ alkyl;

n is an integer from 1 to 5;

Wherein said heteroaryl comprises at least one heteroatom selected from N, O and S;

The 4-substituted 5-membered ring-sulfamidate-5-phosphonate compound of the present invention is a stereoisomer having high optical purity and can be converted into a phosphoric acid compound derivative containing a chiral amino alcohol or a chiral diamine group And can be used as an intermediate compound which is very important for organic synthesis and medicinal synthesis.

Further, according to the preparation method of the present invention, it is possible to selectively obtain 4-substituted-5-membered ring-sulfamidate-5-phosphonate stereoisomer compounds having high optical purity, .

Although the present invention has been described in detail below, unless otherwise defined, technical terms and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Descriptions of known functions and configurations that may unnecessarily obscure the gist of the invention are omitted.

The present invention relates to a novel 4-substituted-5-member compound represented by the following general formula (1), which can be converted into a phosphoric acid compound derivative containing a chiral amino alcohol or a chiral diamine group and serves as an intermediate compound very important for organic synthesis and medicinal synthesis Ring-sulfamidate-5-phosphonate compound.

[Chemical Formula 1]

In Formula 1,

R ₁ is _{- (CH 2) n -R,} C 6 ~ C 12 aryl vinyl, C ₃ ~ C ₇ cycloalkyl, C ₆ ~ C ₁₂ aryl or an aryl C ₄ ~ C ₁₂ heteroaryl, aryl of the above R _1, and heteroaryl with one or more substituents selected from halogen, cyano, halo C ₁ ~ C ₇ alkyl, nitro, C ₁ ~ C ₇ alkyl, C ₁ ~ C ₇ alkoxy, C ₁ ~ C ₇ alkoxycarbonyl group consisting of Lt; / RTI > may be further substituted;

R is C ₁ -C ₇ alkyl or C ₆ -C ₁₂ aryl;

R ₂ is C ₁ -C ₇ alkyl or C ₆ -C ₁₂ aryl C ₁ -C ₇ alkyl;

n is an integer from 1 to 5;

Wherein said heteroaryl comprises at least one heteroatom selected from N, O and S;

In one embodiment of the present invention, the 4-substituted 5-membered ring-sulfamidate-5-phosphonate compound may be a stereoisomer having high optical purity represented by the following formula (1a) or (1b).

[Formula 1a]

[Chemical Formula 1b]

In the above formulas (1a) and (1b), R ₁ and R ₂ are the same as defined in the above formula (1).

The term " alkyl " of the present invention means a monovalent straight or branched saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms. Examples of such alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, , Pentyl, hexyl, octyl, nonyl, and the like.

The term " cycloalkyl " of the present invention means a monovalent saturated carbocyclic radical consisting of one or more rings. Examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term " alkoxy " of the present invention means an -O-alkyl radical, wherein alkyl is as defined above. Examples of such alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and the like.

The term " alkoxycarbonyl ", as used herein, refers to an alkoxy C (= O) - radical in which 'alkoxy' is as defined above. Examples of such alkoxycarbonyl radicals include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl and the like, But is not limited to.

The term " halo " or " halogen " of the present invention means a fluorine, chlorine, bromine or iodine atom.

The term " haloalkyl " of the present invention means an alkyl radical in which at least one of the halogens is substituted, wherein the term " alkyl " is as defined above. Examples of such haloalkyl radicals include, but are not limited to, fluoromethyl, trifluoromethyl, bromomethyl, perfluoroethyl, and the like.

The term " aryl " of the present invention refers to an aromatic ring monovalent organic radical derived from an aromatic hydrocarbon by one hydrogen elimination, suitably containing 4 to 7, preferably 5 or 6 ring atoms in each ring Includes a single or fused ring system, and includes a form in which a plurality of aryls are connected by a single bond. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like.

The term " arylalkyl ", as used herein, refers to an alkyl radical substituted with aryl, wherein 'aryl' and 'alkyl' are as defined above. Examples of such arylalkyl radicals include, but are not limited to, benzyl and the like.

The term " heteroaryl ", as used herein, refers to a heteroaromatic ring monovalent radical that is an aromatic group backbone atom containing 1 to 4 heteroatoms selected from N, O and S and the remaining aromatic ring backbone atoms are aryl groups 5-membered monocyclic heteroaryl, and polycyclic heteroaryl condensed with one or more benzene rings, which may be partially saturated. The heteroaryl in the present invention also includes a form in which one or more heteroaryl is connected to a single bond. Examples of the heteroaryl group include pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, imidazolyl, benzoimidazolyl, iso But are not limited to, oxazolyl, benzoisooxazolyl, thiophenyl, benzothiophenyl, furyl, benzofuryl, and the like.

In the 4-substituted -5-membered ring-sulfamidate-5-phosphonate compound according to an embodiment of the present invention, R ₁ is - (CH ₂ ) _n -R, -CH═CH-Ar _1, phenyl, naphthyl, furanyl or tea and thiophene-yl, wherein R ₁ of phenyl, naphthyl, furanyl and thiophene thing halogen, cyano, CF _3, nitro, C ₁ ~ C ₅ alkyl, C ₁ ~ C ₁ -C ₅ alkoxy, and C ₁ -C ₅ alkoxycarbonyl; R ₂ is C ₁ -C ₅ alkyl or - (CH ₂ ) _m -Ar ₂ ; R is C ₁ ~ C ₅ alkyl or phenyl; Ar ₁ and Ar ₂ are each independently phenyl; n and m each independently may be an integer of 1 to 3.

The 4-substituted 5-membered ring-sulfamidate-5-phosphonate compound according to an embodiment of the present invention may be selected from the following structures, but is not limited thereto.

The present invention also relates to a process for preparing a 4-substituted-5-membered ring-imine-5-phosphonate compound of the formula (2) by asymmetric transfer hydrogenation using a chiral organometallic catalyst and a hydrogen donor, 5-cyclic-sulfamidate-5-phosphonate stereoisomer compound represented by the following formula (I) or (Ib) having high optical activity purity by dynamic kinetic resolution ≪ / RTI >

[Formula 1a]

[Chemical Formula 1b]

(2)

In the above general formulas (1a), (1b) and (2)

R ₁ is _{- (CH 2) n -R,} C 6 ~ C 12 aryl vinyl, C ₃ ~ C ₇ cycloalkyl, C ₆ ~ C ₁₂ aryl or C ₄ ~ C ₁₂ heteroaryl group, the R ₁ Aryl and heteroaryl is at least one selected from halogen, cyano, halo C ₁ ~ C ₇ alkyl, nitro, C ₁ ~ C ₇ alkyl, C ₁ ~ C ₇ alkoxy, C ₁ ~ C ₇ alkoxycarbonyl group consisting of Further substituted as a substituent;

R is C ₁ -C ₇ alkyl or C ₆ -C ₁₂ aryl;

R ₂ is C ₁ -C ₇ alkyl or C ₆ -C ₁₂ aryl C ₁ -C ₇ alkyl;

n is an integer from 1 to 5;

Wherein said heteroaryl comprises at least one heteroatom selected from N, O and S;

In the preparation method according to an embodiment of the present invention, R ₁ is preferably - (CH ₂ ) _n -R, -CH═CH-Ar ₁ , phenyl, naphthyl, furanyl, Phenyl, naphthyl, furanyl and thiophenyl of R ₁ are optionally substituted with one or more substituents selected from halogen, cyano, CF ₃ , nitro, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy and C ₁ -C ₅ Alkoxycarbonyl, < / RTI > and < RTI ID = 0.0 > R ₂ is C ₁ -C ₅ alkyl or - (CH ₂ ) _m -Ar ₂ ; R is C ₁ ~ C ₅ alkyl or phenyl; Ar ₁ and Ar ₂ are each independently phenyl; n and m each independently may be an integer of 1 to 3.

In the production method according to an embodiment of the present invention, the chiral organometallic catalyst is a rhodium (III), iridium (III) or ruthenium (II) based catalyst, preferably a compound represented by the following formula .

[Chemical Formula 3]

(3b)

In the above formulas (3a) and (3b)

Wherein R is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₆ -C ₁₈ aryl and wherein the aryl of R is halogen, nitro, cyano, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ and C ₁ ~ C ₆ may further be substituted by one or more substituents selected from the group consisting of alkoxy, and;

X is rhodium (III), iridium (III) or ruthenium (II);

L is a cyclopentadienyl group, a pentamethylcyclopentadienyl group, a 1-methyl-4-isopropylphenyl group, a phenyl group, a 1,3,5-trimethylphenyl group or a hexamethylphenyl group.

In the production method according to an embodiment of the present invention, in the chiral organometallic catalysts of the above general formulas (3a) and (3b), preferably, X may be rhodium (III).

In the production process according to one embodiment of the present invention, preferably, the chiral organometallic catalyst of the present invention may be selected from compounds of the following general formulas (4a) to (4h).

[Chemical Formula 4a]

(4b)

[Chemical Formula 4c]

[Chemical formula 4d]

[Chemical Formula 4e]

[Formula 4f]

[Chemical Formula 4g]

[Chemical Formula 4h]

In the general formulas (4a) to (4h), Ph is a phenyl group and Ts is a tosyl group.

In one embodiment of the present invention, the chiral organometallic catalyst comprises 1 to 2 equivalents of a hydrochloric acid / tri C ₁ to C ₆ alkylamine salt, a hydrochloric acid / C ₃ to C ₈ cycloalkylamine salt or a hydrochloric acid / C ₅ -C ₁₂ heteroarylamine salts. The hydrochloric acid / tri C ₁ -C ₆ alkylamine salt comprises an amine salt having three linear or branched, saturated C ₁ to C ₆ hydrocarbon radical chains, wherein the hydrochloric acid / C ₅ -C ₁₂ heteroarylamine salt Includes pyridine, pyrimidine, pyrazine, pyridazine, imidazole, triazole, 2-methylimidazole, N, N-dimethylaminopyridine and the like.

In the production method according to an embodiment of the present invention, the chiral organometallic catalyst may be used in an amount of 0.001 to 50 mol% based on the 5-membered ring imine-5-phosphonate compound of the general formula (2) Can be used in the range of 0.01 to 5.0 mol%.

In the production method according to an embodiment of the present invention, the hydrogen donor may be selected from a substance which provides hydrogen by catalysis, such as formic acid, a metal salt of formic acid, an ammonium salt of formic acid, and a mixture of formic acid and amine.

In a mixture of formic acid and the amine-amine include, but are not particularly limited in the tree C ₁ ~ C ₆ alkyl amines, C ₃ -C ₈ cycloalkyl-amine and C ₄ may be selected from -C ₁₂ hetero aryl amine, the C ₄ The -C ₁₂ heteroarylamine may be pyridine, pyrimidine, pyrazine, pyridazine, imidazole, triazole, 2-methylimidazole or N, N-dimethylaminopyridine.

In the preparation method according to an embodiment of the present invention, it may be preferable to use formic acid or a mixture of formic acid and triethylamine as the hydrogen donor, wherein the molar ratio of formic acid: triethylamine is 1: 5 to 5: 1 < / RTI >

Although the amount of the hydrogen donor to be used is not limited, it is preferable that the amount of the hydrogen donor is 1 equivalent of the 4-substituted-5-membered ring-imine-5-phosphonate compound of Formula 2 1 to 100 equivalents.

In more detail, the compounds represented by formulas (Ia) and (Ib) according to the present invention can be synthesized by asymmetric hydrogenation using a chiral organometallic catalyst with a 4-substituted-5-membered ring-imine-5-phosphonate compound of formula .

The following four stereoisomeric compounds 1a, 1b, 1c and 1d can be theoretically synthesized by hydrogenating the 4-substituted-5-membered ring-imine-5-phosphonate compound of the formula (2) E).

[Reaction Scheme E]

However, when the 4-substituted-5-membered ring-imine-5-phosphonate compound of formula 2 is reacted with a hydrogen donor in the presence of a chiral organometallic catalyst according to the preparation method of the present invention, It has been confirmed that the 4-substituted-5-membered ring-sulfamidate-5-phosphonate stereoisomer compound of formula (Ia) or (Ib) having high optical activity is selectively produced through resolution.

However, if the 4-substituted-5-membered ring-imine-5-phosphonate compound of formula (2) is subjected to an asymmetric reduction reaction with the 3a compound as a chiral organometallic catalyst in the presence of a hydrogen donor, Can be prepared with high optical activity purity. When the 4-substituted-5-membered ring-imine-5-phosphonate compound of Formula 2 is subjected to an asymmetric reduction reaction with a 3b compound as a chiral organometallic catalyst in the presence of a hydrogen donor, the stereoisomer 1b has a high optical activity purity (Scheme 1).

[Reaction Scheme 1]

In the above Reaction Scheme 1, R ₁ , R ₂ , R, X and L are the same as defined in the above Chemical Formulas 1a, 1b, 2, 3a and 3b.

The chiral organometallic catalysts used in the present invention include organic rhodium catalysts (4a, 4b), organic iridium catalysts (4c, 4d), organic ruthenium catalysts (4e, 4f, 4g, 4h) Most preferred are the catalysts of formulas (4a) and (4b).

The above chiral organometallic catalysts are all known substances and can be prepared by a conventional method.

As a specific example, the rhodium catalyst 4a {( 1R, 2R ) -RhCl (TsDPEN) Cp *} is a (pentamethylcyclopentadienyl) rhodium (III) dichloride dimer [RhCl ₂ Cp *] ₂ , 1R, 2R) - N - ( p - toluenesulfonyl) -1,2-diphenyl-ethylene-diamine (TsDPEN) and triethylamine washing the reaction product obtained reacts in dichloromethane (CH ₂ Cl ₂₎ solvent, water, Followed by recrystallization to give a yield of 91% (Org. Lett., 1999, 1, 841). Wherein Cp * represents a pentamethylcyclopentadienyl group and TsDPEN represents N - ( p -toluenesulfonyl) -1,2-diphenylethylene-diamine.

Also _{4a / (Et 3 N / HCl} ) 2 {(1R, 2R) -RhCl (TsDPEN) Cp * (Et 3 N / HCl) 2} is (pentamethyl cyclopentadienyl) rhodium (III) dichloride dimer [RhCl ₂ Cp *] _2, an optically active (1R, 2R) - N - (p - toluenesulfonyl) -1,2-diphenyl-ethylene-diamine-dichloro (TsDPEN) and triethylamine methane (CH ₂ Cl ₂ ) solvent, the solvent is removed as it is without further purification under reduced pressure, and the obtained product can be used as a catalyst. In this case, 4a contains 2 equivalents of triethylamine hydrochloride (Tetrahedron: Asymmetry, 2009, 20, 2639). The two pieces of recipe 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 the production method according to an embodiment of the present invention, the reaction may be carried out in a solvent or neat, and it is not necessary to limit the solvent so far as it is capable of dissolving the reaction material. The term neat refers to a reaction in which a 4-substituted-5-membered ring-imine-5-phosphonate compound of Formula 2, a chiral organometallic catalyst, and a hydrogen donor are mixed without using a solvent . As the solvent for the reaction, ethyl acetate (EtOAc), toluene, methylene chloride (CH ₂ Cl ₂ ), ethylene dichloride (ClCH ₂ CH ₂ Cl), dimethylformamide (DMF), dimethylsulfoxide (DMSO) A solvent such as tetrahydrofuran (THF), acetonitrile, methanol, ethanol, isopropanol, t-butanol or water may be used.

In addition, in the production method according to an embodiment of the present invention, the reaction can be carried out at 0 ° C to 70 ° C, preferably at 10 ° C to 40 ° C, and the reaction time varies depending on the kind of the reactant, And it is confirmed through TLC or the like that the 4-substituted-5-membered ring-imine-5-phosphonate compound of the above formula 2 as a starting material is completely consumed, and then the reaction is completed. When the reaction is completed, the solvent can be distilled off under reduced pressure, and the desired product can be separated and purified through a conventional method such as silica gel chromatography or recrystallization.

The 4-substituted-5-membered ring-imine-phosphonate compound of formula (2) used as a starting material in the present invention can be prepared by reacting a 1-hydroxy-2-ketophosphonate compound ) and chloro-sulfamic polyimide (ClSO ₂ NH _2), but it can be synthesized through the reaction of, not limited to this, and may be synthesized by a known organic reaction.

[Reaction Scheme 2]

In the above Reaction Scheme 2, R ₁ and R ₂ are the same as defined in the above formulas (1a) and (1b).

The 4-substituted-5-membered ring-sulfamidate-5-phosphonate stereoisomeric compound made by the process of the present invention is an intermediate compound which is very important in the production of stereomerically pure pesticides, medicaments and fine chemicals Chiral amino acids, chiral amino acids, chiral diamines, chiral amino acids, etc. (Org. Biomol. Chem., 2010, 8, 1505; Tetrahedron, 2003, 59, 2581).

According to the preparation process according to the present invention, a 4-substituted-5-membered ring-sulfamidate-5-phosphonate stereoisomer compound can be obtained with higher stereochemical purity (ee, dr) .

Hereinafter, the present invention will be described in more detail. For a detailed understanding of the present invention, a method for stereoselectively preparing a 4-substituted-5-membered ring-sulfamidate-5-phosphonate compound according to the present invention will be described. And are not intended to limit the scope of protection of the present invention.

The 4-substituted-5-membered ring-sulfamidate-5-phosphonate compound of formula (Ia) and (Ib) prepared by the production method of the present invention can be obtained by conventional extraction, distillation, recrystallization, silica gel chromatography or the like And the optically active purity (ee) of the resulting compound can be determined by HPLC using a column equipped with Chiralcel (TM) OD-H, AD-H or OJ-H 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.

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.

Manufacturing example 1: 5 - Immigration to the circle -5- Phosphonate  The compound (formula 2) of  Produce

1-hydroxy-2-ketophosphonate Compound A (5.32 mmol) was added to a 100 ml round-bottomed flask, and 20 ml of DMA ( N, N -dimethylacetamide) was added thereto. The solution was cooled to 0 ° C and chlorosulfamide ) (1.3 g, 10.64 mmol) was added slowly and stirred at room temperature for 2 hours. Dilute with EtOAc (30 ml) and wash with saturated brine. The organic layer was dried over anhydrous MgSO _4, and the solvent was removed by distillation under reduced pressure. Toluene (20 ml) and PTSA (0.73 mmol) were added and the mixture was refluxed for 2 hours and cooled to room temperature. Dilute with EtOAc (30 ml) and wash with saturated brine. The organic layer was dried over anhydrous MgSO ₄ and distilled under reduced pressure to remove the solvent. The residue was purified by recrystallization with EtOAc / n- Hexane solvent or silica gel column chromatography ( n- Hexane / EtOAc, 1: 4) to obtain the corresponding product Respectively.

< Manufacturing example  1-1> Dimethyl 4-phenyl-5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2- (Compound a) &lt; / RTI &gt;  Produce

2-phenyl-1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester (1.3 g, 5.32 mmol) was used as compound A to give the title compound.

Yield: 54% (0.86 g as a white solid), mp = 160.5-162.7 ^o C; _{^{1 HNMR (500 MHz, CDCl 3}} ) δ 8.14-8.16 (m, 2H), 7.74-7.76 (m, 1H), 7.59-7.62 (m, 2H), 6.19 (d, 1H, J = 10.8 Hz), 3.95 (d, 3H, J = 11.1 Hz), 3.71 (d, 3H, J = 11.1 Hz). _{^{13 CNMR (75 MHz, CDCl 3}} ) δ 173.5, 136.0, 130.7, 129.2, 126.9, 82.7 (d, J cp = 155.3 Hz), 55.4 (d, J &lt; / RTI &gt; _cp = 7.0 Hz), 55.3 (d, J _cp = 6.1 Hz) .; HRMS (EI): m / z calcd for C 10 H 12 NO 6 PS 305.0123, found 305.0096.

< Manufacturing example  1-2> Diethyl  4-phenyl-5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2- (Compound b) &lt; / RTI &gt;  Produce

The title compound was prepared using 2-phenyl-1-hydroxy-2-oxoethyl-phosphoric acid diethyl ester as the 1-hydroxy-2-ketophosphonate compound A.

Yield: 57% (0.41 g as a white solid), mp = 146.8-147.6 ^o C; _{^{1 HNMR (500 MHz, CDCl 3}} ) δ 8.01-8.12 (m, 2H), 7.69-7.72 (m, 1H), 7.53-7.56 (m, 2H), 6.10 (d, 1H, J = 10.7 Hz), 4.16 (M, 2H), 1.37 (t, 3H, J = 7.2 Hz), 1.16 (t, 3H, J = 7.1 Hz). _{^{13 CNMR (75 MHz, CDCl 3}} ) δ 173.8, 135.8, 130.7, 129.1, 127.1, 83.2 (d, J cp = 154.5 Hz), 65.4 (d, J &lt; / RTI &gt; _cp = 7.1 Hz), 65.2 (d, J _cp = 7.3 Hz), 16.3 (d, J &lt; / RTI &gt; _cp = 5.7 Hz), 16.0 (d, J _cp = 5.8 Hz) .; HRMS (EI): m / z calcd for C ₁₂ H ₁₆ NO ₆ PS 333.0436, found 333.0434.

< Manufacturing example  1-3> Dimethyl 4- (3- methyl -Phenyl) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide (Compound c)

The title compound was prepared using 2- (3-methyl-phenyl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as the 1-hydroxy-2-ketophosphonate compound A.

Yield: 55% (0.66 g as a white solid); mp = 155.4-157.5 ^o C; _{^{1 HNMR (500 MHz, CDCl 3}} ) δ 7.95 (s, 1H), 7.89 (d, 1H, J = 7.9 Hz), 7.52 (d, 1H, J = 7.7 Hz), 7.45 (t, 1H, J = 7.8 Hz), 6.12 (d, 1H , J = 10.7 Hz), 3.91 (d, 3H, J = 11.1 Hz), 3.71 (d, 3H, J = 11.1 Hz), 2.45 (s, 3H) .; _{^{13 CNMR (75 MHz, CDCl 3}} ) δ 173.8, 139.3, 136.9, 130.9, 129.0, 128.0, 126.8, 82.8 (d, J &lt; / RTI &gt; _cp = 155.4 Hz), 55.3 (d, _{J cp = 7.0 Hz), 55.2} (d, J cp = 7.3 Hz), 21.3 .; HRMS (EI): m / z calcd for C ₁₁ H ₁₄ NO ₆ PS 319.0279, found 319.0284.

< Manufacturing example  1-4> Dimethyl 4- (4- methyl -Phenyl) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide (compound d)

The title compound was prepared using 2- (4-methyl-phenyl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as the 1-hydroxy-2-ketophosphonate compound A.

Yield: 73% (0.42 g as a white solid); mp = 208.8-211.5 ^o C; ^{1 HNMR (300 MHz, acetone- d} 6) δ 8.10 (d, 2H, J = 7.8 Hz), 7.48 (d, 2H, J = 7.9 Hz), 6.97 (d, 1H, J = 11.3 Hz), 3.87 ( d, 3H, J = 11.1 Hz), 3.73 (d, 3H, J = 11.1 Hz), 2.49 (s, 3H). ^{13 CNMR (75 MHz, acetone- d} 6) δ 175.4, 147.3, 130.7, 129.7, 123.9, 83.7 (d, J &lt; / RTI &gt; _cp = 151.1 Hz), 54.7 (d, J &lt; / RTI &gt; _cp = 6.9 Hz), 54.6 (d, J &lt; / RTI &gt; _cp = 6.6 Hz), 21.5; HRMS (EI): m / z calcd for C ₁₁ H ₁₄ NO ₆ PS 319.0279, found 319.0300.

< Manufacturing example  1-5> Dimethyl 4- (4- Methoxy -Phenyl) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide &lt; / RTI &gt; (Compound e)

The title compound was prepared using 2- (4-methoxy-phenyl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as the 1-hydroxy-2-ketophosphonate compound A.

Yield: 75% (1.185 g as a white solid); mp = 178.8-180.3 ^o C; _{^{1 HNMR (500 MHz, CDCl 3}} ) δ 8.17 (d, 2H, J = 9.0 Hz), 7.06 (d, 2H, J = 9.0 Hz), 6.12 (d, 1H, J = 10.1 Hz), 3.98 (d, 3H, J = 11.1 Hz), 3.95 (s, 3H), 3.74 (d, 3H, J = 11.0 Hz). ^{13 CNMR (75 MHz, DMSO- d} 6) δ 174.2, 165.6, 133.4, 118.7, 114.7, 83.4 (d, J cp = 151.0 Hz), 56.0, 54.7 (d, J cp = 7.0 Hz), 54.6 (d, J _cp = 6.8 Hz) .; HRMS (EI): m / z calcd for C ₁₁ H ₁₄ NO ₇ PS 335.0229, found 335.0234.

< Manufacturing example  1-6> Dimethyl 4- (3- Chloro -Phenyl) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide (Compound f)

Hydroxy-2-ketophosphonate The title compound was prepared using 2- (3-chloro-phenyl) -l-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as Compound A.

Yield: 78% (0.94 g as a white solid); mp = 176.7-180.8 ^o C; _{^{1 HNMR (300 MHz, CDCl 3}} ) δ 8.14-8.15 (m, 1H), 8.00-8.03 (m, 1H), 7.68-7.71 (m, 1H), 7.53 (t, 1H, J = 7.9 Hz), 6.10 (d, 1H, J = 10.9 Hz), 3.94 (d, 3H, J = 11.2 Hz), 3.76 (d, 3H, J = 11.1 Hz). ^{13 CNMR (75 MHz, acetone- d} 6) δ 179.7, 140.4, 139.6, 136.0, 135.5, 134.5, 134.3, 88.9 (d, _{J cp = 152.8 Hz), 59.7} (d, J cp = 9.3 Hz), 59.6 (d, J cp = 6.7 Hz) .; HRMS (EI): m / z calcd for C ₁₀ H ₁₁ ClNO ₆ PS 338.9733, found 338.9734.

< Manufacturing example  1-7> Dimethyl 4- (4- Chloro -Phenyl) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide (compound g)

The title compound was prepared using 2- (4-chloro-phenyl) -l-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as compound 1-hydroxy-2-ketophosphonate.

Yield: 83.3% (1.0 g as a white solid); mp = 174.7-177.7 ^o C; _{^{1 HNMR (500 MHz, CDCl 3}} ) δ 8.01 (d, 2H, J = 8.7 Hz), 7.54 (d, 2H, J = 8.7 Hz), 6.10 (d, 1H, J = 10.7 Hz), 3.94 (d, 3H, J = 11.1 Hz), 3.72 (d, 3H, J = 11.1 Hz). _{^{13 CNMR (75 MHz, CDCl 3}} ) δ 172.6, 142.9, 132.0, 129.6, 125.2, 82.6 (d, J cp = 154.9 Hz), 55.4 (d, J _cp = 7.0 Hz), 55.3 (d, J _cp = 7.4 Hz) .; HRMS (EI): m / z calcd for C 10 H 11 ClNO 6 PS 338.9733, found 338.9737.

< Manufacturing example  1-8> Dimethyl 4- (4- Fluoro -Phenyl) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide (Compound h)

The title compound was prepared using 2- (4-fluoro-phenyl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as the 1-hydroxy-2-ketophosphonate compound A.

Yield: 67% (0.98 g as a white solid); mp = 138.4-142.9 ^o C; _{^{1 HNMR (500 MHz, CDCl 3}} ) δ 8.21-8.24 (m, 2H), 7.27-7.30 (m, 2H), 6.15 (d, 1H, J = 10.6 Hz), 3.98 (d, 3H, J = 11.2 Hz ), 3.77 (d, 3H, J = 11.1 Hz). _{^{13 CNMR (75 MHz, CDCl 3}} ) δ 172.1, 167.4 (d, J _cf = 259.5 Hz), 133.7 (d, J _CF = 9.9 Hz), 123.1 (d, J _cf = 3.0 Hz), 116.8 (d, J _cf = 22.3 Hz), 82.5 (d, J &lt; / RTI &gt; _cp = 154.7 Hz), 55.4 (d, _{J cp = 7.1 Hz), 55.3} (d, J cp = 7.3 Hz). ; HRMS (EI): m / z calcd for C ₁₀ H ₁₁ FNO ₆ PS 323.0029, found 323.0033.

< Manufacturing example  1-9> Dimethyl 4- (2- Fluoro -Phenyl) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide &lt; / RTI &gt; (Compound i)

The title compound was prepared using 2- (2-fluoro-phenyl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as the 1-hydroxy-2-ketophosphonate compound A.

Yield: 60% (1.19 g as a white solid); mp = 117.9-118.6 ^{o C, 1 HNMR (500 MHz} , CDCl 3) d 8.03-8.06 (m, 1H), 7.69-7.74 (m, 1H), 7.35-7.38 (m, 1H), 7.23-2.27 (m, 1H), 6.30 (dd, 1H, J = 1.4, 151.2 Hz), 3.87 (d, 3H, J = 11.3 Hz), 3.74 (d, 3H, J = 11.1 Hz). ^{13 C} NMR (125 MHz, CDCl ₃ )? 171.6, 162.4 (d, J _cf = 256.0 Hz), 137.5 (d, _{J cf = 9.6 Hz), 131.5} , 125.4 (d, J cf = 3.1 Hz), 116.7 (d, J cf = 21.6 Hz), 116.4 (d, J _cf = 11.0 Hz), 84.4 (dd, J _cp = 11.1, 156.1 Hz), 55.2 (d, J &lt; / RTI &gt; _cp = 7.3 Hz), 55.2 (d, J _cp = 7.4 Hz) .; HRMS (EI): m / z calcd for C ₁₀ H ₁₁ FNO ₆ PS 323.0029, found 323.0029.

< Manufacturing example  1-10> Dimethyl 4- (4- Cyano -Phenyl) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide (Compound j)

The title compound was prepared using 2- (4-cyano-phenyl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as the 1-hydroxy-2-ketophosphonate compound A.

Yield: 78% (1.12 g as a white solid), mp = 158.5-161.3 ^{o C 1 HNMR (500 MHz,} CDCl 3) δ 8.27 (d, 2H, J = 7.9 Hz), 7.88 (d, 2H, J = 7.9 Hz), 6.17 (d, 1H, J = 11.1 Hz), 3.97 ( d, 3H, J = 11.1 Hz), 3.76 (d, 3H, J = 11.1 Hz). _{^{13 CNMR (125 MHz, CDCl 3}} ) δ 172.2, 132.7, 131.0, 130.5, 118.9, 117.2, 82.7 (d, _{J cp = 154.8 Hz), 55.5} (d, J cp = 7.2 Hz), 55.4 (d, J cp = 7.4 Hz). ; HRMS (EI): m / z calcd for C ₁₁ H ₁₁ N ₂ O ₆ PS 330.0075, found 330.0088.

< Manufacturing example  1-11> Dimethyl 4- (4- Methoxycarbonyl -Phenyl) -5 H - [1,2,3] - Oxathiazole -5-phosphonate-2,2-dioxide (Compound k)

1-hydroxy-2-ketophosphonate The title compound was prepared using 2- (4-methoxycarbonyl-phenyl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as Compound A.

Yield: 44.4% (0.4 g as a white solid), mp = 149.5-152.9 o C; _{^{1 HNMR (500 MHz, CDCl 3}} ) δ 8.16-8.17 (m, 4H), 6.14 (d, 1H, J = 11.1 Hz), 3.94 (s, 3H), 3.89 (d, 3H, J = 11.2 Hz), 3.69 (d, 3H, J = 11.1 Hz). _{^{13 CNMR (75 MHz, CDCl 3}} ) δ 173.0, 165.5, 136.2, 130.6, 130.4, 130.0, 82.9 (d, J cp = 155.3 Hz), 55.4 (d, _{J cp = 6.9 Hz), 55.2} (d, J cp = 7.2 Hz), 52.8 .; HRMS (EI): m / z calcd for C ₁₂ H ₁₄ NO ₈ PS 363.0178, found 363.0159.

< Manufacturing example  1-12> Dimethyl [4- (naphthalen-2-yl) -5 H - [1,2,3] - Oxathiazole ] -5- Phosphonate -2,2-dioxide (Compound 1)

The title compound was prepared using 2- (naphthalen-2-yl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as the 1-hydroxy-2-ketophosphonate compound A.

Yield: 43% (681.7 mg as a ivory solid), mp = 219.3-220.6 o C; _{^{1 HNMR (500 MHz, CDCl 3}} ) δ 8.11-8.13 (m, 1H), 7.90-8.02 (m, 3H), 7.60-7.71 (m, 2H) 6.27 (d, 1H, J = 10.45 Hz), 3.95 ( d, 3H, J = 11.1 Hz), 3.69 (d, 3H, J = 11.1 Hz). ^{13 C} NMR (125 MHz, CDCl ₃ )? 173.2, 136.8, 134.1, 132.2, 130.3, 130.1, 129.3, 128.1, 127.7, 124.7, 124.1, J _cp = 29.88 Hz), 55.44 (d, _{J cp = 7.16 Hz), 55.22} (d, J cp = 7.17 Hz); HRMS (EI): m / z calcd for C ₁₄ H ₁₄ NO ₆ PS 355.0279, found 355.0248.

< Manufacturing example  1-13> Dimethyl 4- ( Furan Yl) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide (Compound m)

The title compound was prepared using 2- (furan-2-yl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as the 1-hydroxy-2-ketophosphonate compound A.

Yield: 48.4% (0.61 g as a ivory solid), mp = 138.0-142.3 o C; _{^{1 HNMR (500 MHz, CDCl 3}} ) δ 7.85 (d, 1H, J = 1.3 Hz), 7.82 (d, 1H, J = 3.8 Hz), 6.72 (dd, 1H, J = 1.7, 3.8 Hz), 5.87 ( d, 1H, J = 10.1 Hz), 3.94 (d, 3H, J = 11.2 Hz), 3.77 (d, 3H, J = 11.0 Hz). _{^{13 CNMR (75 MHz, CDCl 3}} ) δ 160.7, 150.8, 143.1, 126.1, 114.3, 81.4 (d, J cp = 155.9 Hz), 55.4 (d, _{J cp = 3.9 Hz), 55.3} (d, J cp = 3.7 Hz) .; HRMS (EI): m / z calcd for C ₈ H ₁₀ NO ₇ PS 294.9916, found 294.9918.

< Manufacturing example  1-14> Dimethyl 4- (thiophen-2-yl) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide (compound n)

The title compound was prepared using 2- (thiophen-2-yl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as the 1-hydroxy-2-ketophosphonate compound A.

Yield: 43% (73.6 mg as a ivory solid), mp = 145.3-146.7 ^{o C, 1 HNMR (500 MHz} , acetone- d 6) δ 8.40-8.41 (m, 1H), 8.29-8.30 (m, 1H), 7.42-7.44 (m, 1H), 6.87 (d, 1H, J = 10.6 Hz), 3.96 (d, 3H, J = 11.1 Hz), 3.79 (d, 3H, J = 11.0 Hz). ^{13 CNMR (75 MHz, acetone- d} 6) δ 173.0, 145.5, 144.1, 135.5, 134.9, 88.2 (d, J cp = 153.2 Hz), 59.8 (d, J _cp = 7.1 Hz), 59.7 (d, J _cp = 6.6 Hz). ; HRMS (EI): m / z calcd for C ₈ H ₁₀ NO ₆ PS ₂ 310.9687, found 310.9689.

< Manufacturing example  1-15> Dimethyl 4- (2- Phenylethyl ) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide (Compound o)

Hydroxy-2-ketophosphonate The title compound was prepared using 2- (2-phenylethyl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as Compound A.

Yield: 67% (1.8 g as a white solid), mp = 100.5-101.4 ^{o C, 1 HNMR (500 MHz} , CDCl 3) δ 7.23-7.33 (m, 5H), 5.33 (d, 1H, J = 12.5 Hz), 3.91 (d, 3H, J = 11.2 Hz), 3.80 (d, 3H, J = 11.0 Hz), 3.24-3.31 (m, 1H), 3.03-3.18 (m, 3H). _{^{13 CNMR (125 MHz, CDCl 3}} ) δ 181.1, 138.8, 128.8, 128.5, 126.9, 83.9 (d, J cp = 157.4 Hz), 55.3 (d, _{J cp = 7.4 Hz), 55.1} (d, J cp = 6.9 Hz), 33.7, 31.4; HRMS (EI): m / z calcd for C ₁₂ H ₁₆ NO ₆ PS 333.0436, found 333.0436.

< Manufacturing example  1-16> Dimethyl 4-isobutyl-5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide (compound p)

The title compound was prepared using 2- (isobutyl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as the 1-hydroxy-2-ketophosphonate compound A.

Yield: 20% (180 mg as a yellow oil), 1 H NMR (500 MHz, CDCl 3) δ 5.42 (d, 1H, J = 12.4 Hz), 3.95 (d, 3H, J = 11.1 Hz), 3.89 ( d, 3H, J = 11 Hz), 2.76-2.8 (m, 1H), 2.63-2.68 (m, 1H), 2.29-2.30 (m, 1H), 1.03-1.06 (m, 6H). _{^{13 CNMR (125 MHz, CDCl 3}} ) δ 180.9, 83.9 (d, J cp = 158 Hz), 55.4 (d, J cp = 7.4 Hz), 55.2 (d, J cp = 6.8 Hz), 40.5, 26.3, 22.6 , 22.0 .; HRMS (EI): m / z calcd for C ₈ H ₁₆ NO ₆ PS 285.0436, found 285.0422

< Manufacturing example  1-17> Dimethyl 4- (isopropyl) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide (Compound q)

1-hydroxy-2-ketophosphonate The title compound was prepared using 2- (isopropyl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as Compound A.

Yield: 9.8% (324 mg as a yellow oil), 1 H NMR (500 MHz, CDCl 3) δ 5.58 (d, 1H, J = 12.45 Hz), 3.94 (d, 3H, J = 11.15 Hz), 3.83 ( d, 3H, J = 11 Hz), 3.19-3.24 (m, 1H), 1.32-1.36 (m, 6H). _{^{13 CNMR (125 MHz, CDCl 3}} ) δ 186.2, 82.8 (d, J cp = 158 Hz), 55.4 (d, J cp = 7.5 Hz), 55.1 (d, J cp = 6.8 Hz), 31.7, 20.7, 18.9 .; HRMS (EI): m / z calcd for C ₇ H ₁₄ NO ₆ PS 271.0279, found 271.0264

< Manufacturing example  1-18> Dimethyl 4- ( Cyclohexyl ) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide (compound r)

1-Hydroxy-2-ketophosphonate The title compound was prepared using 2- (cyclohexyl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as Compound A.

Yield: 48.45% (1.25 g as a yellow oil), 1 HNMR (500 MHz, CDCl 3) δ 5.53-5.56 (m, 1H), 3.83-3.93 (m, 6H), 2.87-2.89 (m, 1H), 1.26-2.01 (m, 10H). _{^{13 CNMR (125 MHz, CDCl 3}} ) δ 185.17 (d, J cp = 5.3 Hz), 82.74 (d, _{J cp = 157.8 Hz), 55.32-55.37} (d, J cp = 7.37), 55.08 (d, J cp = 6.7), 40.6, 31.5, 25.7, 28.8, 25.3, 24.8; HRMS (EI): m / z calcd for C ₁₀ H ₁₈ NO ₆ PS 311.0592, found 3 11.0583.

< Manufacturing example  1-19> Dimethyl 4- (t-butyl) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide (compound s)

The title compound was prepared using 2- (t-butyl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as the 1-hydroxy-2-ketophosphonate compound A.

Yield: 36% (348 mg as a yellow oil), 1 H NMR (500 MHz, CDCl 3) δ 5.61 (d, 1H, J = 12.15 Hz), 3.95 (d, 3H, J = 11.1 Hz), 3.89 ( d, 3H, J = 11.1 Hz), 1.44 (s, 9H). _{^{13 CNMR (125 MHz, CDCl 3}} ) δ 188.4, 83.5 (d, J cp = 156 Hz), 55.3 (d, J cp = 7.8 Hz), 55.0 (d, J cp = 7.0 Hz), 38.2, 28.0 .; HRMS (EI): m / z calcd for C ₈ H ₁₆ NO ₆ PS 285.0436, found285.0427.

< Manufacturing example  1-20> Dimethyl 4- ( E - Stiryl ) -5 H - [1,2,3] - Oxathiazole -5- Phosphonate -2,2-dioxide (compound t)

The title compound was prepared using 2- ( E -styryl) -1-hydroxy-2-oxoethyl-phosphoric acid dimethyl ester as the 1-hydroxy-2-ketophosphonate compound A.

Yield: 67% (0.57 g as a ivory solid); mp = 157.0-158.4 ^{o C, 1 HNMR (500 MHz} , CDCl 3) δ 8.13 (d, 1H, J = 16.0 Hz), 7.63-7.65 (m, 2H), 7.44-7.49 (m, 3H), 7.09 (d, 1H, J = 16.0 Hz), 5.69 (d, 1H, J = 11.3 Hz), 3.97 (d, 3H, J = 11.1 Hz), 3.84 (d, 3H, J = 11.0 Hz). _{^{13 CNMR (75 MHz, CDCl 3}} ) δ 171.9, 150.3, 133.5, 132.5, 129.4, 129.3, 114.2, 82.6 (d, J cp = 155.9 Hz), 55.5 (d, _{J cp = 7.2 Hz), 55.3} (d, J cp = 7.0 Hz); HRMS (EI): m / z calcd for C ₁₂ H ₁₄ NO ₆ PS 331.0279, found 331.0282.

Example  I: having high optical purity ( 4 S , 5 R ) -4-substituted-5-membered ring- Sulfamidate -5- Phosphonate  Preparation of compounds

The 4-substituted-5-membered ring-imine-phosphonate compound (0.23 mmol) prepared in Preparation Example 1 was dissolved in EtOAc (2.3 ml) and then [ R, R ] -TsDPEN -RhCl-Cp * catalyst (0.5 mol% based on the substrate) and stirred at room temperature. HCO ₂ H / Et ₃ N (molar ratio 5: 2 or 1: 1 mixed solution, 0.23 ml) is added dropwise through a syringe and stirred at room temperature for 0.5 to 1 hour. EtOAc (10 ml) was added and the whole solution was washed with water (10 ml). The organic solution was dried and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / MeOH, Or n- Hexane / EtOAc, 1: 1 to 1: 4) and / or recrystallization (EtOAc / n- Hexane) to give the corresponding product.

< Example  1> dimethyl ( 4 S , 5 R ) -4- (phenyl) -5 H - [1,2,3] - Oxathiazolidine -5- Phosphonate -2,2-dioxide

Using the compound a (Preparation 1-1) (70 mg, 0.23 mmol), the title compound was prepared.

Mp: 166.8-170.8 ^° C, 98% ee: Chiralpak IB, 20% ethanol / n -hexane, 1.0 ml / min, 215 nm t _R (minor) = 8.9 min, t _R (major) = 9.9 min; [?] _D ²⁹ = +8.49 ( c 0.8, CHCl ₃ ); ^{1 H-NMR (500 MHz,} CDCl 3) δ 7.23-7.43 (m, 5H), 5.69 (brs, 1H), 5.33 (d, 1H, J = 26.4 Hz), 5.12 (dd, 1H, J = 2.3, 6.2 Hz), 3.71 (d, 3H, J = 10.7 Hz), 3.17 (d, 3H, J = 11.1 Hz). ^{13 C-NMR (125 MHz,} CDCl 3) δ 131.2 (d, J cp = 6.0 Hz), 129.3, 128.8, 127.1, 162.8, 61.0, 55.1 (d, J cp = 6.5 Hz), 52.7 (d, J cp = 6.8 Hz) .; HRMS (EI): m / z calcd for C ₁₀ H ₁₄ NO ₆ PS 307.0279, found 307.0276.

< Example  2> Diethyl  ( 4 S , 5 R ) -4- (phenyl) -5 H - [1,2,3] - Oxathiazolidine -5- Phosphonate -2,2-dioxide

Compound b (Preparation 1-2) was used to prepare the title compound.

Yield: 95% (31.9 mg as a white solid), mp = 172.9-176.0 o C; [?] _D ²² = +116.61 ( c 0.33, CHCl ₃ ); ^{1 H-NMR (500 MHz,} CDCl 3) δ 7.36-7.46 (m, 5H), 6.27-6.29 (m, 1H), 5.27-5.36 (m, 1H), 5.07 (dd, 1H, J = 2.4, 6.4 3H, J = 7.0 Hz), 0.92 (t, 3H, J = 7 Hz), 4.01-4.12 (m, 2H), 3.71-3.76 (m, 7.1 Hz) .; ^{13 C-NMR (75 MHz,} CDCl 3) δ 131.5 (d, J cp = 2.6 Hz), 129.1, 128.6, 127.3, 81.3 (d, J cp = 168.6 Hz), 64.9 (d, J cp = 6.7 Hz) _{, 62.7 (d, J cp =} 7.0 Hz), 61.2, 16.3 (d, J _cp = 5.5 Hz), 15.9 (d, J _cp = 6.0 Hz); HRMS (EI): m / z calcd for C ₁₂ H ₁₈ NO ₆ PS 335.0592, found 335.0591.

< Example  3> dimethyl ( 4 S , 5 R ) -4- (3- methyl -Phenyl) -5 H - [1,2,3] - Oxathiazolidine -5-phosphonate-2,2-dioxide &lt; / RTI &gt;

Compound c (Preparation 1-3) was used to prepare the title compound.

Yield: 94.17% (47.19 mg as a white solid, mp = 163.3-164.4 o C; [α] D 21 = +125.40 (c 0.33, CHCl 3); 1 H-NMR (500 MHz, acenone- d 6) δ 1H), 7.41-7.48 (m, 2H), 7.35 (t, 1H, J = 7.6 Hz), 7.24 (d, 1H, J = 7.6 Hz), 5.50-5.52 , 3.52 (d, 3H, J = 10.8 Hz), 3.40 (d, 3H, J = 11.0 Hz), 2.40 (s, 3H) .; 13 C-NMR (75 MHz, acenone- d 6) δ 138.7, 134.4 _{(d, J cp = 3.2 Hz} ), 130.2, 129.4, 129.0, 125.9, 81.2 (d, J cp = 169.0 Hz), 61.7, 54.2 (d, J cp = 6.7 Hz), 53.2 (d, J cp = 6.6 Hz), 21.4 .; HRMS (EI): m / z calcd for C ₁₁ H ₁₆ NO ₆ PS 321.0436, found 321.0426.

< Example  4> dimethyl 4 S , 5 R ) -4- (4- methyl -Phenyl) -5 H - [1,2,3] - Oxathiazolidine -5-phosphonate-2,2-dioxide &lt; / RTI &gt;

Compound d (Preparation 1-4) was used to prepare the title compound.

Mp: 134.5-136.0 ^o C, 96.7% ee: Chiralpak AD-H, 20% isopropanol / n -hexane, 1.0 ml / min, 215 nm t _R (major) = 9.2 min, t _R (minor) = 11.8 min; [?] _D ²¹ = +126.27 ( c 0.3, CHCl ₃ ); ^{1 H-NMR (500 MHz,} acenone- d 6) δ 7.55 (d, 2H, J = 8.2 Hz), 7.30 (d, 2H, J = 8.0 Hz), 7.15-7.20 (brs, 1H), 5.50-5.52 (m, 1H), 5.43-5.48 (m, 1H), 3.53 (d, 3H, J = 10.8 Hz), 3.43 (d, 3H, J = 1.6 Hz), 2.40 (s, 3H). ^{13 C-NMR (75 MHz,} acenone- d 6) δ 139.4, 131.6, 129.7, 128.8, 81.2 (d, J cp = 169.0 Hz), 61.6, 54.2 (d, J &lt; / RTI &gt; _cp = 6.6 Hz), 53.2 (d, J &lt; / RTI &gt; _cp = 6.6 Hz), 21.1. HRMS (EI): m / z calcd for C ₁₁ H ₁₆ NO ₆ PS 321.0436, found 321.0408.

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

Compound e (Preparation 1-5) was used to prepare the title compound.

Mp: 132.5-134.1 ^° C, 96% ee: Chiralpak AD-H, 20% isopropanol / n -hexane, 1.0 ml / min, 215 nm t _R (major) = 10.5 min, t _R (minor) = 15.0 min; [?] _D ²¹ = +107.68 ( c 0.44, CHCl ₃ ); ^{1 H-NMR (500 MHz,} CDCl 3) δ 7.56 (d, 2H, J = 8.7 Hz), 7.00 (d, 2H, J = 8.8 Hz), 5.45 (dd, 1H, J = 3.4, 6.5 Hz), 5.40 (dd, 1H, J = 6.5,17.2 Hz), 3.84 (s, 3H), 3.52 (d, 3H, J = 10.8 Hz), 3.44 (d, 3H, J = 11.0 Hz). ¹³ C-NMR (75 MHz, CDCl ₃ )? 160.1, 128.7, 123.8, 114.0, 80.9 (d, J _cp = 169.8 Hz), 60.7, 55.4, 54.8 (d, J &lt; / RTI &gt; _cp = 6.6 Hz), 53.0 (d, J &lt; / RTI &gt; _cp = 6.9 Hz); HRMS (EI): m / z calcd for C ₁₁ H ₁₆ NO ₇ PS 337.0385, found 337.0383.

< Example  6> dimethyl 4 S , 5 R ) -4- (3- Chloro -Phenyl) -5 H - [1,2,3] - Oxathiazolidine -5-phosphonate-2,2-dioxide &lt; / RTI &gt;

Compound f (Preparation 1-6) was used to prepare the title compound.

Yield: 90.9% (31 mg as a white solid), mp = 96.8-98.5 o C; [?] _D ²¹ = +118.13 ( c 0.33, CHCl ₃ ); ^{1 H-NMR (500 MHz,} acenone- d 6) δ 7.74 (s, 1H), 7.60-7.62 (m, 1H), 7.47-7.51 (m, 2H), 5.50-5.56 (m, 2H), 3.56 ( d, 3H, J = 3.6 Hz), 3.53 (d, 3H, J = 3.4 Hz). ^{13 C-NMR (75 MHz,} acenone- d 6) δ 137.7, 134.5, 130.7, 129.6, 129.1, 127.7, 80.3 (d, J cp = 169.3 Hz), 61.1, 54.2 (d, J &lt; / RTI &gt; _cp = 6.7 Hz), 53.5 (d, J _cp = 6.6 Hz) .; HRMS (EI): m / z calcd for C ₁₀ H ₁₃ ClNO ₆ PS 340.9890, found 340.9895.

< Example  7> dimethyl 4 S , 5 R ) -4- (4- Chloro -Phenyl) -5 H - [1,2,3] - Oxathiazolidine -5-phosphonate-2,2-dioxide &lt; / RTI &gt;

Compound g (Preparation 1-7) was used to prepare the title compound.

Mp: 128.7-130.8 ^° C, 96.8% ee: Chiralpak AD-H, 20% isopropanol / n -hexane, 1.0 ml / min, 215 nm t _R (major) = 10.0 min, t _R (minor) = 13.9 min .; [?] _D ²⁵ = +60.54 ( c 0.52, CHCl ₃ ); ^{1 H-NMR (500 MHz,} CDCl 3) δ 7.40 (m, 4H), 5.29 (dd, 1H, J = 6.4, 22.0 Hz), 5.16 (dd, 1H, J = 3.1, 6.3 Hz), 3.65 (d , 3H, J = 10.8 Hz), 3.37 (d, 3H, J = 10.8 Hz). ¹³ C-NMR (75 MHz, CDCl ₃ )? 135.3, 130.5, 128.8, 128.8, 80.5 (d, J &lt; / RTI &gt; _cp = 169.8 Hz), 60.5,55.0 (d, _{J cp = 6.8 Hz), 53.0} (d, J cp = 7.0 Hz) .; HRMS (EI): m / z calcd for C ₁₀ H ₁₃ ClNO ₆ PS 340.9890, found 340.9898.

< Example  8> dimethyl 4 S , 5 R ) -4- (4- Fluoro -Phenyl) -5 H - [1,2,3] - Oxathiazolidine -5-phosphonate-2,2-dioxide &lt; / RTI &gt;

Compound h (Preparation 1-8) was used to prepare the title compound.

Mp: 181.0-185.4 ^° C, 96% ee: Chiralpak AD-H, 20% isopropanol / n -hexane, 1.0 ml / min, 215 nm t _R (major) = 9.2 min, t _R (minor) = 11.8 min; [?] _D ²² = +100.22 ( c 0.38, CHCl ₃ ); ^{1 H-NMR (500 MHz,} acetone- d 6) δ 7.68-7.72 (m, 2H), 7.40-7.41 (brs, 1H), 7.20-7.25 (m, 2H), 5.49-5.52 (m, 2H), 3.54 (d, 3H, J = 8.7 Hz), 3.45 (d, 3H, J = 8.8 Hz). ¹³ C-NMR (75 MHz, acetone- d ₆ )? 165.4, 162.1, 131.3 (q, J _cf = 8.5 Hz), 115.8 (d, J _CF = 21.6 Hz), 80.6 (d, J _cp = 169.9 Hz), 61.1, 54.2 (d, J &lt; / RTI &gt; _cp = 6.6 Hz), 53.4 (d, J _cp = 6.6 Hz); HRMS (EI): m / z calcd for C 10 H 13 FNO 6 PS 325.0185, found 325.0195.

< Example  9> dimethyl 4 S , 5 R ) -4- (2- Fluoro -Phenyl) -5 H - [1,2,3] - Oxathiazolidine -5-phosphonate-2,2-dioxide &lt; / RTI &gt;

Compound i (Preparation 1-9) was used to prepare the title compound.

Mp: 173.1-175.8 ^° C, 81.4% ee: Chiralpak AD-H, 10% isopropanol / n -hexane, 1.5 ml / min, 215 nm t _R (major) = 9.6 min, t _R (minor) = 13.1 min; [?] _D ²⁹ = + 117.6 ( c 0.3, CHCl ₃ ); ^{1 H-NMR (500 MHz,} CDCl 3) δ 7.41-7.48 (m, 2H), 7.27-7.30 (m, 1H), 7.14-7.18 (m, 1H), 6.14 (brs, 1H), 5.58 (dd, 1H, J = 6.2, 30.0 Hz), 5.29-5.31 (m, 1H), 3.88 (d, 3H, J = 10.6 Hz), 3.21 (d, 3H, J = 11.0 Hz). ^{13 C-NMR (125 MHz,} CDCl 3) δ 160.2 (d, J cf = 245.7 Hz), 131.0 (d, J cf = 8.4 Hz), 127.5 (d, J cf = 3.1 Hz), 124.7 (d, J _{cf = 3.2 Hz), 118.5 (} d, J cf = 13.9 Hz), 115.2 (d, J cf = 20.9 Hz), 81.0 (dd, J cp = 3.4, 168.1 Hz), 55.9 (d, J cp = 4.2 Hz _{), 55.5 (d, J cp} = 6.4 Hz), 52.6 (d, J cp = 7.1 Hz) .; HRMS (EI): m / z calcd for C 10 H 13 FNO 6 PS 325.0185, found 325.0171.

< Example  10> dimethyl ( 4 S , 5 R ) -4- (4- Cyano -Phenyl) -5 H - [1,2,3] - Oxathiazolidine -5-phosphonate-2,2-dioxide &lt; / RTI &gt;

Compound j (Preparation 1-10) was used to prepare the title compound.

Min., 215 nm t _R (minor)), 95% (31.5 mg as a white solid), mp = 188.1-189.0 ^o C, 100% ee: Chiralpak AD-H, 20% isopropanol / n- = 9.2 min, t _R (major) = 13.8 min; [?] _D ³⁰ = +110.79 ( c 0.3, CHCl ₃ ); ^{1 H-NMR (500 MHz,} CDCl 3) δ 7.73 (d, 2H, J = 8.0 Hz), 7.56 (d, 2H, J = 8.0 Hz), 6.02 (brs, 1H), 5.36 (dd, 1H, J = 6.2, 21.7 Hz), 5.19-5.21 (m, 1H), 3.69 (d, 3H, J = 10.7 Hz), 3.39 (d, 3H, J = 11.0 Hz). ¹³ C-NMR (125 MHz, CDCl ₃ )? 137.0, 132.3, 128.2, 117.9, 113.3, 80.3 (d, J &lt; / RTI &gt; _cp = 169.1 Hz), 60.6,55.3 (d, J &lt; / RTI &gt; _cp = 6.5 Hz), 53.0 (d, J &lt; / RTI &gt; _cp = 6.9 Hz); HRMS (EI): m / z calcd for C ₁₁ H ₁₃ N ₂ O ₆ PS 332.0232, found 332.0232.

< Example  11> dimethyl ( 4 S , 5 R ) -4- (4- Methoxycarbonyl -Phenyl) -5 H - [1,2,3] - Oxathiazolidine -5- Phosphonate -2,2-dioxide

Compound k (Preparation 1-11) was used to prepare the title compound.

Mp: 153.5-156.1 ^o C, 99.2% ee: Chiralpak AD-H, 20% isopropanol / n -hexane, 1.0 ml / min, 215 nm t _R (major) = 12.9 min, t _R (minor) = 15.2 min; [?] _D ²⁰ = +91.05 ( c 0.33, CHCl ₃ ); ^{1 H-NMR (500 MHz,} acenone- d 6) δ 8.07 (d, 2H, J = 8.5 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.45 (brs, 1H), 5.56-5.61 (m , 3.91 (s, 3H), 3.50 (d, 3H, J = 10.8 Hz), 3.47 (d, 3H, J = 11.0 Hz). ¹³ C-NMR (125 MHz, acenone- d ₆ )? 166.8, 140.2, 131.4, 129.9, 129.3, 80.4 (d, J _cp = 169.0 Hz), 61.4, 54.2 (d, J &lt; / RTI &gt; _cp = 6.8 Hz), 53.4 (d, J &lt; / RTI &gt; _cp = 6.6 Hz), 52.5; HRMS (EI): m / z calcd for C ₁₂ H ₁₆ NO ₈ PS 365.0334, found 365.0334.

< Example  12> dimethyl 4 S , 5 R ) -4- (naphthalen-2-yl) -5 H - [1,2,3] - Oxathiazolidine -5-phosphonate-2,2-dioxide &lt; / RTI &gt;

Compound l (Preparation 1-12) was used to prepare the title compound.

^{Yield: 96.6%, mp = 60.5 o} C, 96.6% ee: Chiralpak IB, 20% ethanol / n -hexane, 1.0 ml / min, 215 nm, t R (minor) = 14.8 min, t R (major) = 18.3 min; [?] _D ²¹ = +57.9 ( c 1.0, CHCl ₃ ); ^{1 H-NMR (500 MHz,} CDCl 3) δ 7.83-7.89 (m, 4H), 7.53 (m, 3H), 6.19 (d, 1H, J = 9.5Hz) 5.44-5.53 (m, 1H), 5.22- 5.24 (m, 1H), 3.64 (d, 3H, J = 10.7 Hz), 3.05 (d, 3H, J = 11.05 Hz). ^{13 C-NMR (125 MHz,} CDCl 3) δ 133.3, 132,8,128.5, 128.2, 127.7, 127.1, 126.9, 128.4, 126.5, 124.2, 81.51 (d, J cp = 76.01 Hz), 61.2, 55.15 (d, _{J cp = 6.46 Hz), 52.65} (d, J cp = 6.8 Hz); HRMS (EI): m / z calcd for C ₁₄ H ₁₆ NO ₆ PS 357.0436, found 357.0467.

< Example  13> dimethyl 4 S , 5 R )-4-( Furan Yl) -5 H - [1,2,3] - Oxathiazolidine -5- Phosphonate -2,2-dioxide

Compound m (Preparation 1-13) was used to prepare the title compound.

Yield: 90% (45 mg as a white solid), mp = 98.0-100.2 ^° C, [α] _D ³¹ = +45.2 ( c 0.25, CHCl ₃ ); ^{1 H-NMR (500 MHz,} acenone- d 6) δ 7.63-7.64 (m, 1H), 6.70 (d, 1H, J = 3.4 Hz), 6.49-6.50 (m, 1H), 5.45 (dd, 1H, J = 6.3, 13.2 Hz), 5.39 (dd, 1H, J = 4.2, 6.3 Hz), 3.69 (d, 3H, J = 10.9 Hz), 3.67 (d, 3H, J = 10.9 Hz). ¹³ C-NMR (75 MHz, acetone- d ₆ )? 148.1, 144.2, 111.5, 111.1, 79.7 (d, J _cp = 169.8 Hz), 55.9, 54.4 (d, J &lt; / RTI &gt; _cp = 6.6 Hz), 53.9 (d, J _cp = 6.6 Hz) .; HRMS (EI): m / z calcd for C ₈ H ₁₂ NO ₇ PS 297.0072, found 297.0076.

< Example  14> dimethyl 4 S , 5 R ) -4- (thiophen-2-yl) -5 H - [1,2,3] - Oxathiazolidine -5-phosphonate-2,2-dioxide &lt; / RTI &gt;

Compound n (Preparation 1-14) was used to prepare the title compound.

Mp: 130.1-134.6 ^° C, 99% ee: Chiralpak AD-H, 20% isopropanol / n -hexane, 1.0 ml / min, 215 nm, t _R (major ) = 10.1 min, t _R (minor) = 11.1 min; ^{_{[α] D 21 = + 106.04}} (c 0.46, CHCl 3); ^{1 H-NMR (500 MHz,} acenone- d 6) δ 7.53-7.54 (m, 1H), 7.41-7.42 (m, 1H), 7.08-7.10 (m, 1H), 5.70 (dd, 1H, J = 6.2 , 12.8 Hz), 5.44 (dd, 1H, J = 5.0, 6.2 Hz), 3.60 (d, 3H, J = 11.0 Hz), 3.55 (d, 3H, J = 10.8 Hz). ^{13 C-NMR (75 MHz,} acenone- d 6) δ 137.6, 129.0, 127.7, 127.5, 80.7 (d, J cp = 170.0 Hz), 57.9, 54.3 (d, J &lt; / RTI &gt; _cp = 6.8 Hz), 53.5 (d, J _cp = 6.6 Hz) .; HRMS (EI): m / z calcd for C ₈ H ₁₂ NO ₆ PS ₂ 312.9844, found 312.9835.

< Example  15> dimethyl 4 S , 5 R ) -4- (2- Phenylethyl ) -5 H - [1,2,3] - Oxathiazolidine -5-phosphonate-2,2-dioxide &lt; / RTI &gt;

Compound o (Preparation 1-15) was used to prepare the title compound.

Mp: 134.9-138.8 ^° C, 96.5% ee: Chiralpak AD-H, 10% isopropanol / n -hexane, 1.5 ml / min, 215 nm, t _R (minor ) = 10.3 min, t _R (major) = 12.7 min; [?] _D ³⁰ = +67.61 ( c 0.6, CHCl ₃ ); ^{1 H-NMR (500 MHz,} CDCl 3) δ 7.22-7.34 (m, 5H), 5.48 (brs, 1H), 4.84 (d, 1H, J = 6.2 Hz), 4.10-4.13 (m, 1H), 3.94 (d, 3H, J = 10.5Hz), 3.84 (d, 3H, J = 10.9Hz), 2.89-2.95 (m, 1H), 2.74-2.80 2.13-2.20 (m, 1H); ^{13 C-NMR (125 MHz,} CDCl 3) δ 139.7, 128.7, 128.5, 126.6, 80.8 (d, J cp = 166.3 Hz), 57.7, 55.6 (d, J &lt; / RTI &gt; _cp = 6.7 Hz), 53.1 (d, _{J cp = 6.8 Hz), 32.6} , 30.1 (d, J cp = 1.8 Hz); HRMS (EI): m / z calcd for C ₁₂ H ₁₈ NO ₆ PS 335.0592, found 335.0593.

< Example  16> dimethyl 4 S , 5 R ) -4- (isobutyl) -5 H - [1,2,3] - Oxathiazolidine -5- Phosphonate -2,2-dioxide

Compound p (Preparation 1-16) was used to prepare the title compound.

Yield: 50% (90 mg as a colorless oil), [?] _D ²⁸ = +57.2 ( c 0.23, CHCl ₃ ), 75% ee; ^{1 H-NMR (500 MHz,} CDCl 3) δ 5.00 (d, 1H, J = 12.7 Hz), 4.79 (d, 1H, J = 6.2 Hz), 4.14-4.23 (m, 1H), 3.95 (d, 3H (M, 2H), 1.33-1.40 (m, 1H), 0.96-1.00 (m, 6H). J = 13.5 Hz), 3.83 (d, 3H, J = 11 Hz). ^{13 C-NMR (125 MHz,} CDCl 3) δ 81.5 (d, J cp = 166 Hz), 57.1, 55.7 (d, J cp = 6.6 Hz), 52.9 (d, J cp = 7.4 Hz), 36.9, 25.8 , 22.9, 21.8; HRMS (EI): m / z calcd for C ₈ H ₁₈ NO ₆ PS 287.0592, found 287.0574.

< Example  17> dimethyl 4 S , 5 R )-4-( E - Stiryl ) -5 H - [1,2,3] - Oxathiazolidine -5- Phosphonate -2,2-dioxide

Compound (t) (preparation 1-20) was used to prepare the title compound.

Yield: 42% (14 mg as a ivory solid), mp = 130.1-134.6 o C ,: 99% ee; Chiralpak AD-H, 10% isopropanol / n -hexane, 1.5 ml / min, 215 nm, t R (minor) = 15.2 min, t R (major) = 16.9 min. ^{1 H-NMR (500 MHz,} CDCl 3) δ 7.30-7.45 (m, 5H), 6.80 (d, 1H, J = 15.8 Hz), 6.43 (dd, 1H, J = 8.1, 15.7 Hz), 4.92-4.93 (m, 1H), 4.77-4.89 (m, 1H), 3.90 (d, 3H, J = 10.6 Hz), 3.73 d, 3H, J = 11.0 Hz). ^{13 C-NMR (125 MHz,} CDCl 3) δ 137.4, 135.0, 129.0, 128.9, 126.9, 118.5 (d, J cp = 3.5 Hz), 80.7 (d, J _cp = 168.8 Hz), 60.1, 55.5 (d, J &lt; / RTI &gt; _cp = 6.6 Hz), 53.2 (d, J _cp = 7.1 Hz); HRMS (EI): m / z calcd for C ₁₂ H ₁₆ NO ₆ PS 333.0436, found 333.0441.

Example  II: High optical purity ( 4 R , 5 S ) -4-substituted-5-membered ring- Sulfamidate -5- Phosphonate  Preparation of compounds

The 4-substituted-5-membered ring-imine-phosphonate compound (0.23 mmol) prepared in Preparation Example 1 was dissolved in EtOAc (2.3 ml) and then [ S, S ] -TsDPEN -RhCl-Cp * catalyst (0.5 mol% based on the substrate) and stirred at room temperature. HCO ₂ H / Et ₃ N (molar ratio 5: 2 or 1: 1 mixed solution, 0.23 ml) is added dropwise through a syringe and stirred at room temperature for 0.5 to 1 hour. EtOAc (10 ml) was added and the whole solution was washed with water (10 ml). The organic solution was dried and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ / MeOH, ) To give the corresponding product.

< Example  18> Diethyl  ( 4 R , 5 S ) -4- (phenyl) -5 H - [1,2,3] - Oxathiazolidine -5- Phosphonate -2,2-dioxide

Compound b (Preparation 1-2) was used to prepare the title compound.

Yield: 92.2% (28.39 mg as a white solid), mp = 173-174.2 o C, [α] D 29 = -92.26 (c 0.6, CHCl 3); ^{1 H-NMR (500 MHz,} acetone- d 6) δ 7.65-7.67 (m, 2H), 7.44-7.46 (m, 3H), 5.45-5.51 (m, 2H), 3.65-4.01 (m, 4H), 1.09 (m, 3H), 1.07 (m, 3H). ^{13 C-NMR (75 MHz,} acetone- d 6) δ 134.7 (d, J cp = 2.9 Hz), 129.5, 129.0, 129.0, 81.3 (d, J cp = 168.4 Hz), 64.1 (d, J cp = 6.6 Hz), 63.1 (d, J cp = 6.6 Hz), 61.9, 16.5 (d, J cp = 5.5 Hz), 16.3 (d, J cp = 5.9 Hz).

< Example  19> dimethyl 4 R , 5 S ) -4- (4- Chloro -Phenyl) -5 H - [1,2,3] - Oxathiazolidine -5-phosphonate-2,2-dioxide &lt; / RTI &gt;

Compound g (Preparation 1-7) was used to prepare the title compound.

Mp: 132-133.2 ^° C, 97.9% ee: Chiralpak AD-H, 20% isopropanol / n -hexane, 1.0 ml / min, 215 nm t _R (minor) = 10.1 min, t _R (major) = 12.9 min; [?] _D ³⁰ = -86.26 ( c 0.5, CHCl ₃ ); ^{1 H-NMR (500 MHz,} CDCl 3) δ 7.39 (m, 4H), 6.20 (brs, 1H), 5.29 (dd, 1H, J = 6.4, 22.1 Hz), 5.16 (dd, 1H, J = 3.1, 6.3 Hz), 3.65 (d, 3H, J = 10.8 Hz), 3.37 (d, 3H, J = 10.8 Hz). ¹³ C-NMR (75 MHz, CDCl ₃ )? 135.3, 130.5, 128.9, 128.8, 80.6 (d, J &lt; / RTI &gt; _cp = 169.7 Hz), 60.5,55.0 (d, _{J cp = 6.8 Hz), 53.0} (d, J cp = 7.0 Hz) .; HRMS (EI): m / z calcd for C ₁₀ H ₁₃ ClNO ₆ PS 340.9890, found 340.9889.

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 (9)

delete delete In the presence of a chiral organometallic catalyst selected from compounds of formulas (4a) and (4b)
A method for selectively producing a stereoisomer compound represented by formula (Ia) or (Ib) having an optically active compound by reacting a 4-substituted-5-membered ring imine-5-phosphonate compound represented by the following formula (2) with a hydrogen donor.
[Formula 1a]

[Chemical Formula 1b]

(2)

In the above general formulas (1a), (1b) and (2)
R ₁ is _{- (CH 2) n -R,} C 6 ~ C 12 aryl vinyl, C ₃ ~ C ₇ cycloalkyl, C ₆ ~ C ₁₂ aryl or C ₄ ~ C ₁₂ heteroaryl and aryl, said R ₁ is Which may be further substituted with one or more substituents selected from the group consisting of halogen, cyano, C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy and C ₁ -C ₇ alkoxycarbonyl;
R is C ₁ -C ₇ alkyl or C ₆ -C ₁₂ aryl;
R ₂ is C ₁ -C ₇ alkyl;
n is an integer from 1 to 5;
Wherein said heteroaryl comprises at least one heteroatom selected from N, O and S;
[Chemical Formula 4a]

(4b)

In the general formulas (4a) to (4b), Ph is a phenyl group and Ts is a tosyl group. The method of claim 3,
Wherein R ₁ is _{- (CH 2) n -R,} -CH = CH-Ar 1, phenyl, naphthyl, furanyl or tea is one thiophene, phenyl and naphthyl of the R ₁ is halogen, cyano, C ₁ Which may be further substituted with one or more substituents selected from the group consisting of C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy and C ₁ -C ₅ alkoxycarbonyl; R ₂ is C ₁ -C ₅ alkyl; R is C ₁ ~ C ₅ alkyl or phenyl; Ar ₁ is phenyl; and n is an integer from 1 to 3. 3. A process for the selective preparation of a stereoisomer compound according to claim 1,
delete The method of claim 3,
Wherein the chiral organometallic catalyst further comprises 1 to 2 equivalents of a hydrochloric acid / tri C ₁ to C ₆ alkylamine salt, a hydrochloric acid / C ₃ to C ₈ cycloalkylamine salt or a hydrochloric acid / C _{5 to} C ₁₂ heteroarylamine salt Lt; RTI ID = 0.0 &gt; (Ia) &lt; / RTI &gt; or 1b.
delete The method of claim 3,
Wherein the chiral organic metal catalyst is used in an amount of 0.001 to 50 mol% based on the 4-substituted-5-membered ring-imine-5-phosphonate compound of the general formula (2) A method for the selective preparation of stereoisomeric compounds. The method of claim 3,
Wherein the hydrogen donor is a mixture of formic acid, a metal salt of formic acid, an ammonium salt of formic acid, or a mixture of formic acid and an amine.