KR20050098826A - Kinetic resolution method - Google Patents

Abstract

A method for stereoselective chemical synthesis, includes the steps of: (A) reacting a nucleophile and a chiral or prochiral cyclic substrate, said substrate comprising a carbocycle or a heterocycle having a reactive center susceptible to nucleophilic attack by the nucleophile, in the presence of a chiral non-racemic catalyst to produce a product mixture comprising a stereoisomerically enriched product wherein the product mixture further comprises a catalyst residue, at least a portion of the catalyst residue is in a first oxidation state, and the catalyst residue in the first oxidation state is active in catalyzing degradation of the stereoisomerically enriched product, and (B) chemically or electrochemically changing the oxidation state of the catalyst residue form the first oxidation state to a second oxidation state, wherein catalyst residue in the second oxidation state is less active in catalyzing degradation of the stereoisomerically enriched product than is catalyst residue in the first oxidation state. The method reduces erosion of the chiral purity of the stereoisomerically enriched product and reduces the chemical transformation to side products of the stereoisomerically enriched product and co-product(s). The deactivated catalyst is recoverable and recyclable.

Description

Kinetic decomposition method {KINETIC RESOLUTION METHOD}

The present invention relates to a process for the synthesis of chemicals, and more particularly to a process for the synthesis of stereoselective chemicals by kinetic decomposition of racemic terminal epoxides.

In the commercial preparation of epoxides and 1,2-diols containing large amounts of enantiomeric isomers, the use of kinetic decomposition reactions, in particular the hydrolytic kinetic resolution (HKR) of racemic terminal epoxides, It can manufacture efficiently and practically. The HKR method utilizes a catalytic reaction with a cobalt (III) complex of a chiral salen ligand, wherein the catalyst is obtained from the corresponding Co (II) complex, or from the salen ligand and Co (II) in air or oxygen. Can be prepared via direct reaction of salts (see, eg, US Pat. No. 6,262,278 B1, “STEREOSELECTIVE RING OPENING REACTIONS”, issued by Eric N. Jacobsen et al. On July 17, 2001, and Ready, JM, Jacobsen, EN, “ Highly Active Oligomeric (salen) Co Catalysts for Asymmetric Epoxide Ring Opening Reactions ”, J. AM. Chem. Soc. 2001, 123, 2687 to 2688).

However, the residues of the HKR catalyst catalyze unwanted reactions and decompose the desired reaction product. For example, it has been known that glycidol is produced from the HKR product 3-chloro-1,2-propanediol by the catalytic reaction of the Co (III) complex (Furrow, ME, Schaus, SE, Jacobsen). , EN “Practical Access to Highly Enantioenriched C-3 Building Blocks via Hydrolytic Kinetic Resolution”, J. Org. Chem. 1998, 63, 6776). As such unwanted side reactions lower the yield of the product and the chirality and chemical purity of the product, there is a problem that the production process of the product having high chiral purity is inefficient and expensive.

An object of the present invention is to provide a nucleophile in the presence of a chiral non-racemic catalyst in a method for synthesizing stereoselective chemicals and a reactive center capable of being subjected to nucleophilic attack by the nucleophile. Reacting a chiral or prochiral cyclic substrate comprising a carbocycle or a heterocycle to produce a mixed product comprising a stereoisomerically enriched product, the mixed product containing the catalyst moiety. Further comprising at least a portion of said catalyst moiety in a first oxidation state, said catalyst moiety in said first oxidation state being active to promote degradation of a product containing said stereoisomer in a large amount. Generation step; And the oxidation state of the catalyst moiety from the first oxidation state to a second oxidation state, in which the catalytic activity for the decomposition reaction of the product containing a large amount of the stereoisomer is smaller than that of the catalyst in the first oxidation state, To provide a method comprising the step of chemically changing.

According to the method of the present invention, the chiral purity of the product containing a large amount of the stereoisomer, which appears after the HKR reaction, and the chemical conversion reaction from the product and the corresponding product (s) to by-products can be reduced. . In addition, it is possible to recover and regenerate the catalyst lost activity, it is possible to reduce the cost of performing the process at the time of manufacturing a key chiral building block (key chiral building block) that is the core of the process.

In one embodiment, the present invention comprises a product containing a large amount of stereoisomers by reacting a nucleophile with a chiral or prochiral substrate in the presence of a chiral non-racemic Co (III) salen catalyst, wherein the stereoisomer is contained in a large amount. Producing a mixed product further comprising a Co (III) salen catalyst moiety that is catalytically active for the decomposition reaction of the product containing; And the mixed product is contacted with at least one reducing agent selected from the group consisting of L-ascorbic acid, hydroquinone, hydroquinone derivatives, catechol and catechol derivatives to form the Co (III) salen catalyst moiety. Synthesizing a chemoselective chemical, comprising reducing the catalytic activity to a Co (II) salen catalyst moiety having less catalytic activity for the decomposition reaction of the product containing a greater amount of the stereoisomer than the Co (III) salen catalyst moiety. Provide a method.

In another embodiment, the present invention includes a product containing a large amount of stereoisomers by reacting a chiral or prochiral substrate with a nucleophile in the presence of a chiral non-racemic Co (III) salen catalyst, wherein the stereoisomer Growing a mixed product further comprising a Co (II) salen catalyst moiety that is catalytically active for the decomposition reaction of the product containing a large amount; And the mixed product is selected from the group consisting of hydrogen peroxide, peracid, persulfate, perborate, perchlorate, oxygen and air in the presence of a complexing agent effective to stabilize the Co (III) salen catalyst moiety. In contact with at least one oxidizing agent, wherein the Co (II) salen catalyst moiety, in a stabilized state, is more catalytically active against the decomposition reaction of the product containing a larger amount of the stereoisomer than the Co (II) salen catalyst moiety. Provided is a method for synthesizing chemoselective chemicals, comprising reducing with a small Co (III) salen catalyst.

In a preferred embodiment, the step of reacting the nucleophile and the cyclic substrate is carried out in the stereoselective synthesis method described in US Pat. No. 6,262,278 B1, “STEREOSELECTIVE RING OPENING REACTIONS,” issued by Eric N. Jacobsen et al. On July 17, 2001. The patent document described above is incorporated herein by reference as the reference document of the present invention, and may be adjusted even when the content of the present specification and the content of the '278 patent do not coincide.

Hereinafter, specific terms used in the present specification will be summarized.

“Nucleophile” is a term known in the art and refers to a chemical moiety having reactive electron pairs, as meant herein. Examples of such nucleophiles include uncharged compounds such as amines, mercaptans and alcohols, and charged moieties such as alkoxides, thiolates, carbanions and various organic and inorganic anions. Can be mentioned.

In addition, "electrophilic atoms", "electrophilic centers" and "reactive centers" refer to atoms of a substrate which are attacked by the nucleophile and form new bonds with the nucleophile. In most cases (but not all), leaving groups may be further released from the atom.

"Leaving group" is a term known in the art and refers to a chemical moiety bound to an electrophilic center of a substrate, as meaning herein, wherein a new bond with the substrate is formed by attack of the nucleophile. When the leaving group is substituted with the nucleophile. Examples of the leaving group include sulfonates, carboxylates, carbonates, carbamates, phosphates and halides.

"Electron-withdrawing group" is a term known in the art and means a functional group that attracts more electrons than hydrogen atoms present at the same position, as meant herein. Examples of such electron attracting groups include nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, -CN, chloride and the like. Also, "electron-donating group" means a functional group that attracts fewer electrons than hydrogen atoms present at the same position. Examples of such electron donating groups include amino and methoxy.

"Chiral" means molecules that do not superimpose each other, such as the relationship between an object and its mirror image, and "achiral" can be superimposed on a mirror image "Prochiral molecule" means a molecule that has the potential to be converted into a chiral molecule in a particular process.

"Stereoisomer" means a compound that has chemically the same structure but differs in the arrangement of atoms or groups in space. In particular, "enantiomer" refers to two stereoisomers that do not overlap in a mirror image, and diastereomers are stereoisomers having two or more asymmetric centers, the molecules of which are Not in a mirror relationship.

"Regioisomer" means a compound having the same molecular formula but different bonds of atoms. Therefore, a "regioselective process" is a process in which a reaction for generating a specific regioisomer is superior to other isomers. For example, by such a reaction, the yield of the regioisomer is statistically determined. Significantly increased.

"Reaction product" means a compound produced by the reaction of a nucleophile with a substrate. The term "reaction product" may be used herein to refer to a stable and separable compound, but does not mean an unstable intermediate or transition state.

"Asymmetric" with respect to a ligand means that the ligand comprises a chiral center that is independent of the plane of symmetry or the symmetry point and / or the ligand is, for example, a rotation, a helicity, It is meant to include an asymmetric axis by reactions including but not limited to molecular knotting or complexation of chiral metals.

In addition, with respect to a ligand, “tetradentate” refers to a ligand comprising four Lewis base substituents, for example an oxygen atom; Sulfur atom; Nitrogen-containing substituents such as amino, amido or imino groups; Phosphorus containing substituents such as phosphine or phosphonate groups; And arsenic-containing substituents such as arsine groups.

With respect to the complex of metal atoms and tetradentate ligands, the term "rectangular planar" means that each Lewis base atom of the complex is arranged in a substantially orthogonal arrangement on substantially the same plane, and By metal atoms of the complex is meant a geometry with some distortion, which is on substantially the same plane.

In addition, with respect to complexes of metal atoms and tetradentate ligands, the term “rectangular pyramid” means that each Lewis base atom of the complex is arranged in a substantially orthogonal arrangement on substantially the same plane. And the metal atoms of the complex mean a slightly warped geometry, present on or below the plane.

By "complex" is meant a coordinating compound formed by the combination of one or more molecules or atoms, each lacking an electron that can be present independently, and one or more molecules or atoms rich in an electron that can be present independently.

“Substrate” means a chemical compound capable of reacting with a nucleophile or ring-expansion reagent according to the method of the present invention to produce one or more compounds having a stereogenic center. it means.

The term "catalytic amount" is a concept known in the art and means an incidental stoichiometric amount of a catalyst for a reactant. As used herein, the amount of catalyst is 0.0001 to 90 mol% of the catalyst, preferably 0.001 to 50 mol%, more preferably 0.01 to 10 mol% of the catalyst, even more preferably 0.1 to the reactant. To 5 mol% of the catalyst.

The term “stereoselective process” refers to a process that produces certain stereoisomers predominantly over other stereoisomers in the reaction product. “Enantiomeric stereoisomer selectivity process” refers to a process that predominantly produces one of two enantiomeric isomers that can be produced in a reaction product. In addition, in the present invention, when the yield of a particular stereoisomer in the product is statistically significantly greater than the yield of other stereoisomers produced from the same reaction, except that it is carried out without the use of a chiral catalyst, "Stereoselectively-enriched" products (e.g., products containing large amounts of enantiomers, or products containing large amounts of diastereomers). For example, when enantioselective selective reactions are carried out under catalysis by one of the chiral catalysts of the present invention, specific enantiomers having e.e. greater than e.e. in a reaction without the chiral catalyst can be obtained.

By “enantioselective reaction” is meant a reaction that converts an achiral reactant into a chiral non-racemic product containing a large amount of one enantiomeric isomer. Typically, enantioselectivity is evaluated as “% enantiomeric excess” (“e.e.”), defined by the formula:

(Equation)

(Wherein A and B represent the amount of enantiomeric stereoisomers produced).

By enantioselective selective reactions, products with e.e. greater than zero can be obtained. In addition, preferably enantioselective reactions yield products with ee greater than 20%, more preferably products with ee greater than 50%, even more preferably products with greater than 70% ee. , Most preferably, a product having an ee greater than 80%.

In addition, with respect to a stereoisomerically enriched product containing a large amount of stereoisomer, “degradation” means a reduction in the yield of the product or the enantiomeric excess.

The term "diastereoselective reaction" refers to a reaction that converts a chiral reactant (which may be a racemate or a pure enantiomer) into a product that largely dissociates one diastereomer.

In addition, when the chiral reactant is a racemate, one enantiomeric reactant can be reacted more slowly with the other under a chiral non-racemate or catalyst. Such reactions are referred to as “kinetic decomposition reactions,” in which the enantiomeric reactants are degraded by increasing the reaction rate, resulting in a product containing a large amount of the enantiomeric isomers. Kinetic decomposition reactions are typically carried out with sufficient reactant to react with only one enantiomeric reactant (ie ½ mole of reactant per mole of racemate based). Illustrative catalytic reactions used in the dynamic decomposition reactions of racemic reactants include Sharpless epoxidation reactions and Noyori hydrogenation reactions.

The term "regioselective reaction" refers to a reaction when the reaction takes place predominantly in the first reaction center than in the second reaction center. For example, the regioselective reaction of an asymmetrically substituted epoxide substrate may occur more prominently at one of the two carbons of the epoxide ring.

In the context of such chiral catalysts, "non-racemic" refers to a catalyst formulation comprising the desired stereoisomer in an amount greater than 50%, more preferably in an amount greater than 75%. By “substantially non-racemate” is meant a catalyst formulation in which the e.e. of the desired stereoisomer in the catalyst is greater than 90%, more preferably greater than 95%.

In the present invention, the chemical element is according to the periodic table (CAS version, Handbook of Chemistry and Physics, 67 ^th Ed., 1986-87, inside cover). In addition, "hydrocarbon" includes all acceptable compounds having at least one hydrogen and one carbon atom. In a broad sense, acceptable hydrocarbons, as substituted or unsubstituted, include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds.

In addition, "alkyl" means a radical of a saturated aliphatic group including a straight chain alkyl group, a branched chain alkyl group, a cycloalkyl (alicyclic) group, an alkyl substituted cycloalkyl group, and a hydrocycloalkyl substituted alkyl group. In a preferred embodiment, straight or branched chain alkyl has up to 30 carbon atoms in the main chain (e.g., C ₁ -C ₃₀ straight chain, C ₃ -C ₃₀ branched chain), more preferably 20 in the main chain It has the following carbon atoms. As mentioned above, the cycloalkyl preferably has 4 to 10 carbon atoms in the ring structure, more preferably 5, 6 or 7 carbons in the ring structure.

In addition, as used herein, “alkyl” includes terms “unsubstituted alkyl” and “substituted alkyl” wherein substituted alkyl is substituted for hydrogen on one or more carbons of the hydrocarbon backbone. It means an alkyl moiety having. Illustrative of such substituents, halogen, hydroxyl, carbonyl, alkoxyl, ester, phosphoryl, amine, amide, imine, thiol, thioether, thioester, sulfonyl, amino, nitro and organometallic moieties Can be mentioned. The moiety substituted in the hydrocarbon chain may, if desired, be substituted by itself, which will be understood by those skilled in the art. For example, substituents of the substituted alkyl may be substituted, in addition to ether, thioether, selenoether, carbonyl (including ketones, aldehydes, carboxylates and esters), -CF ₃ , -CN Amines, imines, amides, phosphoryls (including phosphonates and phosphines), sulfonyls (including sulfates and sulfonates), and silyl groups in substituted or unsubstituted form. Examples of the substituted alkyl as described above include the following ones. In addition, cycloalkyl may be further substituted with alkyl, alkenyl, alkoxy, thioalkyl, aminoalkyl, carbonyl substituted alkyl, CF ₃ , CN, and the like.

"Alkenyl" means an aliphatic group having at least one or more double bonds, similar in length to each other, and which may be substituted by the aforementioned alkyl, and alkynyl "having at least one or more triple bonds, Are similar to each other, and mean an aliphatic group which may be substituted with the aforementioned alkyl.

As meaning herein, “nitro” means —NO ₂ ; "Halo" means -F, -Cl, -Br or -I; "Carboxyl" means -COOH; "Aldehyde" means -C (O) H; "Thio" means -SH, in each of the above, R is H, alkyl or aryl, and "organic metal" means a metal atom directly bonded to a carbon atom (eg mercury, zinc) , Lead, magnesium or lithium), or metalloids (eg, silicon, arsenic or selenium), and examples of such organic metals include diphenylmethoylsilyl groups.

Thus, the term "alkylamine", as described above, means an alkyl group having a substituted or unsubstituted amine as bonded to alkyl. In one embodiment, “amine” can be represented by the following general formula:

(In the above formula,

R ¹ and R ² are each independently hydrogen, alkyl, alkenyl, — (CH ₂ ) _m —R ³ —C (═O) -alkyl, —C (═O) -alkenyl, —C (═O ) -Alkynyl, or —C (═O) — (CH ₂ ) _m R ³ (where R ³ represents aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle, m is 0 or 1 to 8) Is an integer of), or

R ¹ and R ² together with the N atom to which R ¹ and R ² are bonded form a heterocycle having 4 to 8 atoms in the ring structure).

In addition, "amido" means a substituent represented by the following general formula:

(Wherein R ¹ and R ² are defined the same as above).

"Imino" means a substituent represented by the following general formula:

(Doedoe said general formula, R ¹ is defined the same as above, with the proviso that, R ¹ is not be H).

"Thioether" means -S-alkyl, -S-alkenyl, -S-alkynyl, and -S- (CH ₂ ) _m R ³ , wherein m and R ³ are defined as above; The moiety represented by one.

"Carbonyl" means -C (O)-. In addition, "carbonyl substituted alkyl" means an alkyl group, as defined above, having a substituted or unsubstituted carbonyl group as bound to alkyl, for example aldehydes, ketones, carboxylates and esters. Can be mentioned. In one embodiment, the “carbonyl” moiety is represented by the general formula:

(In the above formula,

 X is absent or X represents oxygen or sulfur,

R ⁴ represents hydrogen, alkyl, alkenyl, or — (CH ₂ ) _m R ³ , wherein m and R ³ are defined as above.

When X is oxygen, the general formula represents "ester". When X is sulfur, the general formula represents "thioester". When X is absent and R ⁴ is not hydrogen, the above general formula represents a "ketone" group. When the oxygen atom of the said general formula is substituted by sulfur, the said general formula represents a "thiocarbonyl" group.

In addition, as used herein, "alkoxy" or "alkoxy" refers to an alkyl group having an oxygen radical as bonded to an alkyl group. Examples of the alkoxyl group include methoxy, ethoxy, propoxy, tert-butoxy and the like. In addition, "ether" is two hydrocarbons covalently bonded by oxygen. Thus, the substituents of alkyl are -O-alkyl, -O-alkenyl, -O-alkynyl, -O- (CH ₂ ) _m -R ³ , wherein m and R ³ are defined as above. As may be represented by one, it may be similar to an alkoxyl.

Typically, “phosphoryl” can be represented by the following general formula:

(In the above formula,

Q ¹ represents S or O and R ⁵ represents hydrogen, lower alkyl or aryl).

When said phosphoryl group is used to substitute alkyl, the phosphoryl group of phosphorylalkyl can be represented by the following general formula:

(In the above formula,

Q ¹ represents S or O, each R ⁵ independently represents hydrogen, lower alkyl or aryl, and Q ² represents O, S or N).

As used herein, the term “phosphino” includes —PR ₂ and “phosphonate” means —P (OR) ₂ , provided that R is H, alkyl, aryl, heterocycle, or polycycle. ).

In a preferred embodiment, “silyl” moieties which may be substituted in alkyl may be represented by the following general formula:

(In the above formula,

Each R ⁶ independently represents hydrogen, alkyl, alkenyl or — (CH ₂ ) _m —R ³ , wherein m and R ³ are defined the same as above.

"Selenoether" which may be substituted in the alkyl is one selected from the group represented by -Se- (CH ₂ ) _m -R ³ (wherein m and R ³ are defined the same as above).

In addition, the term “sulfonyl” refers to an S (O) ₂ moiety bonded to two carbon atoms, and the term “sulfonate” refers to a sulfonyl group as described above, with an alkoxy group, an aryloxy group or a hydroxyl It means a sulfonyl group bonded at the time. Thus, in a preferred embodiment, the sulfonate has the structure

(Wherein R ⁷ is H, alkyl, or aryl).

"Sulfate" means a sulfonyl group as described above, but a sulfonyl group having a hydroxyl group or an alkoxy group bonded thereto. Thus, in a preferred embodiment, the sulfate has the structure

(Wherein R ⁸ and R ⁹ are independently absent or independently hydrogen, alkyl or aryl).

In addition, R ⁸ and R ⁹ in the structural formula may form a 5-membered to 10-membered ring structure together with the sulfonyl group and oxygen atom to which R ⁸ and R ⁹ are bonded.

For example, alkenylamine, alkynylamine, akenylamide, alkynylamide, alkenylimine, alkyleneimine, thioalkenyl, thio, by substituting the substituents described above for the alkenyl group and the alkynyl group Alkynyl, carbonyl substituted alkenyl, carbonyl substituted alkynyl, alkenoxyl, alkynoxyl, metalloalkenyl or metalloalkynyl can be obtained.

“Aryl” includes four-membered, five-membered, six-membered and seven-membered monocyclic aromatic groups, which may contain 0-4 heteroatoms, for example benzene , Pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine. An aryl group having a hetero atom at the position of the ring may be substituted with a substituent as described above, and examples of the substituent include halogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, nitro, thiol amine, imine, amide , Phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester,-(CH ₂ ) _m -R ³ (where m and R ³ Are defined the same as above), -CF ₃ , -CN and the like.

"Hetero atom" means an atom of any element except carbon or hydrogen. Preferred heteroatoms in the present invention include nitrogen, oxygen, sulfur, phosphorus and selenium.

"Heterocycle" or "heterocyclic group" refers to a 4 to 10 membered ring structure, more preferably a 5 to 7 membered ring, containing 1 to 4 heteroatoms in the ring structure. . The heterocycle group includes pyrrolidine, oxolane, thiolane, imidazole, oxazole, piperidine, piperazine, and morpholine. The heterocycle ring may be substituted with a substituent as described above at one or more positions, such as halogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, nitro, thiol, amine, imine, amide , Phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester,-(CH ₂ ) _m R ³ (where m and R ³ are Defined as above), -CF ₃ , -CN and the like.

Usually, “carbocycle” is a ring structure, meaning that each member constituting the ring is a carbon atom.

A “polycycle” or “polycyclic group” is a cyclic ring in which two or more carbons in a cyclic ring share two adjacent rings (eg, cycloalkyl, cycloalkenyl, cyclo Alkynyl, aryl and / or heterocycle), for example, said adjacent ring is a “fused ring. In addition, rings bonded through atoms that are not adjacent to each other are referred to as "bridged" rings. Each ring of the polycycle may be substituted with the substituents described above, and examples of such substituents include halogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, nitro, thiol, amine, imine, amide, phospho Nate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester,-(CH ₂ ) _m R ³ (where m and R ³ are the same as above) , -CF ₃ , -CN and the like.

"Bridge-bonding substituent" is substituted on the core structure of the catalyst by two or more (or two or more) sites of the same kind of substituents (as different from the same meaning), and the substitution site It means a substituent in which a covalent bridge is formed. For example, the bridge-bonding substituent is a general formula -R ¹⁰ -R ¹¹ -R ^12- , provided that R ¹¹ is absent or represents alkyl, alkenyl or alkynyl, preferably C ₁ to C ₁₀ R ¹⁰ and R ¹² may be each independently, absent or represented as amine, imine, amide, phosphoryl, carbonyl, silyl, oxygen, sulfonyl, sulfur, selenium or ester).

As used herein, “substituted” means including all acceptable substituents of organic compounds. In broad terms, the permissible substituents include acyclic and cyclic substituents, branched and unbranched substituents, carbocycle and heterocycle substituents, aromatic and nonaromatic substituents of organic compounds. And the substituents mentioned above as an example of the said substituent. In addition, the permissible substituents may be one or more, the same or different substituents relative to the appropriate organic compound. In the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or any acceptable substituent of an organic compound, which satisfies the valence of the heteroatom. In addition, the present invention is not limited to any method using an acceptable substituent of the organic compound.

In one embodiment of the invention, the cyclic substrate comprises one or more compounds represented by the following structural formula (1):

(In Structural Formula (1),

R ²⁰ , R ²¹ , R ^22, and R ²³ may each independently form a covalent bond with a carbon atom bonded to R ²⁰ , R ²¹ , R ^22, and R ²³ , and may form a stable ring structure including Y; Organic or inorganic substituents;

Y is O, S, -NR ²⁴ (wherein R ²⁴ is H, alkyl, carbonyl substituted alkyl, carbonyl substituted aryl, or sulfonate), -C (R ²⁵ ) R ²⁶ (where R ²⁵ And R ²⁶ are each independently an electron attracting group, or represented by the formula ABC, provided that A and C are each independently absent, or are each independently (C ₁ -C ₅ ) alkyl, O, S, Carbonyl or -NR ²⁴ and B is carbonyl, phosphoryl or sulfonyl).

In addition, as a preferred embodiment of the present invention, in the formula (1), R ²⁰ , R ²¹ , R ²² and R ²³ are each independently H, hydroxyl, halo, alkyl, alkenyl, alkynyl, amino , Imino, amido, nitro, thio, phosphoryl, phosphonate, phosphino, carbonyl, carboxyl, silyl, sulfonyl, ketone, aldehyde, ester, thioether, selenoether, or-(CH ₂ ) _n R ²⁷ (wherein R ²⁷ is aryl, cycloalkyl, cycloalkenyl or heterocyclyl, n is a number of 0 ≦ n ≦ 8), and in another embodiment, in formula (1) , R ²⁰ , R ²¹ , R ²² and R ²³ may be a carbocycle ring structure or a heterocycle ring structure together with a carbon atom fused to another of R ²⁰ , R ²¹ , R ²² and R ²³ substituents and bonded to the substituents. Can be formed.

In another preferred embodiment, the substrate comprises a cyclic compound containing an electrophilic center and a leaving group, and examples of the cyclic compound include epoxides such as epichlorohydrin, aziridine such as 1,2-propylene imine , Episulfides such as 1,2-propylene sulfide, cyclic carbonates such as 1,2-propylene glycol cyclic carbonate, cyclic thiocarbonates such as 1,2-propylene glycol cyclic thiocarbonate, 1, Cyclic phosphates such as 2-propylene glycol cyclic phosphate, cyclic sulfates such as 1,2-propylene glycol cyclic sulfate, cyclic sulfites such as 1,2-propylene glycol cyclic sulfite, lactams such as β-butyrolactam thiolactams such as β-butyrothiolactam, thiolactones such as β-methyl-γ-butyrothiolactone, and sultones such as 1,3-butyrolsultone.

Typically, chemical compounds having reactive electron pairs are suitable as nucleophiles of the present invention. Illustrative compounds which are suitably used as nucleophiles in the process of the present invention under appropriate reaction conditions include hydrides; Uncharged compounds such as amines, mercaptans and alcohols, including phenols; Charged compounds such as alkoxides, phenoxides, thiolates; Organic or inorganic anions, such as carbo anions, azide anions, cyanide anions, thiocyanate anions, acetate anions, formate anions, chloromate anions and bisulfite anions; Organic metal reagents such as organocuprate, organozinc, organolithium, and Grignard reagents, enolates and acetylides.

In addition, as a preferred embodiment of the present invention, the nucleophile is at least one compound selected from the group consisting of water, phenoxide, hydroxide, alkoxide, alcohol, thiol, thiolate, carboxylic acid, and carboxylate, preferably Preferably, it comprises at least one compound selected from the group consisting of water, phenol, in particular silanated phenol, and carboxylic acid.

In one preferred embodiment of the invention, the chiral catalyst comprises a complex of a transition metal atom of the first row and an asymmetric tetradentate ligand, the complex having an orthogonal planar or orthogonal pyramidal structure. Tetradentate ligands suitable for the present invention are derived from, for example, salen, porphyrin, crown ether, azacrown ether, cyclam or phthalocyanine. . In the present invention, it is highly preferred that the tetradentate ligand is derived from chiral salen or a ligand similar to salen.

In a preferred embodiment, the metal-asymmetric tetradentate ligand complex comprises at least one chiral metallosalenate represented by formula (2) or formula (3):

,

(In the above formula (2) and formula (3),

R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , X ¹⁴ , X ¹⁵ , X ¹⁶ , X ¹⁷ , X ¹⁹ , and X ²⁰ are each independently H, hydroxyl, Halo, alkyl, alkynyl, amino, nitro, thio, imino, amido, phosphoryl, phosphonate, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, Ester, or-(CH ₂ ) _{n '} -R ³⁶ , provided that R ³⁶ is aryl, cycloalkyl, cycloalkenyl, or heterocyclyl

R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , X ¹⁴ , X ¹⁵ , X ¹⁶ , X ¹⁷ , X ¹⁹ , and X ²⁰ fused with another one of the substituents to the ring It may form a carbocycle ring or heterocycle ring structure having 4 to 8 carbon atoms, provided that in each case described above, the substituent is selected to provide a compound having an asymmetric structure, and R ³⁰ and R ³⁰ are covalently bonded to each other to provide a compound of formula (2) as a tetradentate ligand, R ³² and R ³³ are covalently bonded to each other, and R ³⁴ and R ³⁵ are covalently bonded to each other, Providing a compound of formula (3) above as a tetradentate ligand;

R ¹⁰ , R ¹¹ and R ¹² are defined the same as above, more preferably R ¹⁰ and R ¹² are each -OC (O)-or are each absent, and each R ¹¹ is alkyl, more preferably Is-(CH ₂ ) _{n "} -or CH (Cl) (CH ₂ ) _m CH (Cl)-;

 M is a first periodic transition metal atom;

 n is a number of 1 ≦ n ≦ 10, n 'is a number of 1 ≦ n' ≦ 15, n ″ is a number of 1 ≦ n ″ ≦ 13, and m is a number of 1 ≦ m ≦ 9;

 A 'is a counterion or nucleophile).

In each case, R ³⁰ and R ³¹ , R ³² and R ³³ , and R ³⁴ and R ³⁵ are covalently bonded to each other directly or indirectly via a substituent which is bonded to each other, for example, a bridge can do.

As used herein, the term “first periodic transition metal atom” refers to an atom of an element listed in Groups 3 to 12 in the first period among the elements of the periodic table, that is, Sc, Ti, V, Cr, Mn, Fe , Co, Ni, Cu, Zn. In the present invention, more preferably, the first periodic transition metal atom of the ligand metal atom complex is selected from Co, Cr and Mn.

In a preferred embodiment, the catalyst is at least one ligand-transition metal complex represented by the above formula (2), wherein, in the above formula (2), R ³⁰ and R ³¹ are fused to 1,2-cyclohexylene Form a group, Y ¹ , Y ² , X ² , X ⁴ , X ⁶ , and X ⁸ are each H, X ¹ , X ³ , X ⁵ and X ⁷ are each t-butyl and M is Co Characterized by a ligand-transition metal complex.

In another preferred embodiment, the catalyst is at least one ligand-transition metal complex represented by the above formula (3), wherein, in the above formula (3), R ³² and R ³³ are fused, and R ³⁴ and R ³⁵ is fused to form each 1,2-cyclohexylene group, and Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , X ¹³ , X ¹⁶ , X ¹⁷ And X ²⁰ are each H, R ¹⁰ and R ¹² are each -OC (O)-, R ¹¹ is-(CH ₂ ) _5- , and X ¹⁴ , X ¹⁵ , X ¹⁸ and X ¹⁹ are each t- Butyl, each M is Co, and n is 1-10, a ligand-transition metal complex.

In some cases, the catalyst is suitable in an oxidation state other than the first oxidation state and is relatively inert in promoting the desired reaction of the nucleophile with the substrate. In other cases, the oxidation state of the catalyst can be changed to activate the catalyst, followed by the step of synthesizing the stereoselective chemicals of the present invention. For example, in one preferred embodiment of the invention, the catalyst is contacted with acetic acid (“HOAc”) and air in dichloromethane to activate the Co (II) -salen complex and then the Co (III) -salen complex Form.

Generally, the mixture of the nucleophile, the cyclic substrate, and the catalytic amount of the chiral catalyst having catalytic activity for the desired reaction of the substrate and the nucleophile is maintained in an appropriate state so that the catalyst is electrophilic of the cyclic substrate by the nucleophile. It is possible to promote the stereoselective ring-opening reaction occurring at the atom.

Kinetic decomposition reactions of the enantiomers occur as ring-based ring-opening reactions using chiral catalysts. In one embodiment, one enantiomer is reacted with a nucleophile to form the desired reaction product and other enantiomers recovered as unwanted substrates. In another embodiment, the unwanted enantiomer can react with the nucleophile and the preferred enantiomer recovered unreacted from the reaction mixture.

Catalytic residues are present in the mixed product. The catalyst moiety may comprise the same catalyst moiety as the catalyst used to catalyze the preferred reaction of the nucleophile with the substrate and may also be decomposed in the catalyst used to catalyze the preferred reaction, e.g. For example, it may include catalytic residues in reduced or oxidized form.

As mentioned above, during the product separation process, because of the presence of catalyst moieties in the mixed product, the chemical or chiral purity of the product is promoted by promoting undesired decomposition reactions of the product containing large amounts of stereoisomers. For example, it can be degraded as follows:

(i) In kinetic hydrolysis reactions, the catalyst in the first oxidation state can exhibit catalytic activity against unwanted racemization reactions, e.g., under ordinary HKR reaction conditions, the Co (III) complex may be epoxide The addition reaction of HCl to the catalyst acts as a catalyst for the racemization of the degraded epichlorohydrin, resulting in an achiral 1,3-dichloro-2-propanol and a reverse enantiomer selectivity with low enantioselectivity. Known to be;

(Ii) In the reaction of a nucleophile such as phenol with epoxide having a leaving group at position 3, the catalyst in the first oxidation state can exhibit catalytic activity against unwanted epoxide formation reactions, as in the following scheme:

(Wherein LG is a leaving group); And

(Iii) In the reaction of the epoxide with the electron deficient phenol, the catalyst in the first oxidation state exhibits catalytic activity against the regioisomer equilibrium reaction through the unwanted Smiles Rearrangement, as shown in the following scheme: May be:

(Wherein EWG represents an electron withdrawing group).

In one embodiment, the catalyst moiety corresponding to the type of catalyst used to catalyze the desired reaction may also be catalytically active for a reaction that is not dynamically superior to decompose the desired product. For example, as a highly preferred embodiment of HKR of epichlorohydrin, the Co (III) -salen catalyst is catalytically active for the preferred reaction of nucleophiles and substrates, and the Co (III) -salen catalyst residues are steric There is catalytic activity for the decomposition reaction of products containing large amounts of isomers.

In one embodiment, the catalyst moiety corresponding to the type of catalyst used to catalyze the desired reaction may be catalytically active for the decomposition reaction of the desired product. For example, as a preferred embodiment of HKR of styrene oxide, the Co (III) -salen catalyst is catalytically active for the desired reaction of the nucleophile with the substrate, and the Co (II) -salen catalyst residues generated during the reaction are steric There is catalytic activity in the decomposition reaction of products containing large amounts of isomers.

In another embodiment, during the separation of the product, by contacting the catalyst moiety with the preferred product, a decomposition reaction of the product containing a large amount of stereoisomers may occur. Due to the presence of catalyst residues on the separation of such products, the chemical and chiral purity of the product are lowered, and by using the method of the present invention, the reduction in chemical and chiral purity of the product can be minimized.

When the product containing a large amount of a stereoisomer exhibiting a target excess ratio of the stereoisomer, for example, the target enantiomeric excess ratio, is an excess ratio of the enantiomeric target targeted to the decomposed product, By treating the catalyst moiety by a chemical method, an electrochemical method, or a combination thereof, the oxidation state of the catalyst moiety in the first oxidation state exhibiting catalytic activity to the decomposition reaction of the product is obtained in the first oxidation state. It is possible to change the catalytic activity of the catalyst moiety to a second oxidation state with relatively little decomposition reaction of. In a preferred embodiment, a product containing a large amount of stereoisomers having a desired degree of stereoisomer is 95% or more, more preferably 99% or more, of the enantiomeric isomer.

In one embodiment, to the mixed product is added an organic or inorganic complexing agent effective to stabilize the catalytic moiety in the second oxidation state. The complexing agent can be any compound comprising a charged or uncharged component having a lone pair of electrons capable of forming a bond with the transition metal complex, such as ammonium hydroxide, amine , Hydroxyamines, phosphines, sulfides, sulfoxides, amine N-oxides, amidines, quanidines, imidate ester phosphine oxides, carbon monoxide and cyanide.

In a preferred embodiment, the complexing agent comprises at least one amine represented by the following structural formula:

(In the above structural formula,

R ⁴⁰ , R ⁴¹ and R ⁴² are each independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkaryl, or heterocycle, or R ⁴⁰ , R ⁴¹ and R ⁴² is a R ⁴⁰ group, R ⁴¹ group and R ⁴² is fused with the other of the groups, R ⁴⁰ groups, R ⁴¹ groups and R ⁴² groups together with the nitrogen atoms to which they are attached, form a heterocyclic ring of 4 to 8 won May be, and these heterocycle rings may be further substituted).

In a first embodiment, the catalytic moiety is reduced to change the oxidation state of the catalyst moiety from the first oxidation state to the second oxidation state.

In one embodiment, the organic reducing agent or the inorganic reducing agent in an amount sufficient to reduce the mixed product to the catalytic residue in the second state, under conditions suitable for reducing the catalytic residue in the first state to the catalytic residue in the second state. Is introduced to reduce the catalyst moiety chemically. Reducing agents suitable for the present invention have undesirable effects on products containing active ligand-transition metal atom complexes (e.g., Co (III) complexes or Cr (III) complexes) in large quantities containing stereoisomers under appropriate conditions. It may be any compound having a reduction potential and a reactivity sufficient to reduce to a complex of a form less reactive than the complex, such as a Co (II) complex or a Cr (II) complex, without being interrupted. Typically, the reduction potential of the reactant used to reduce the active catalyst may be +0.1 to 0.6 V. The range of reduction of the reactant depends on the reaction conditions under which the desired reaction occurs and on the conditions of measurement of the reduction potential.

In another preferred embodiment, the reducing agent consists of L-ascorbic acid, alcohol (eg isopropanol), hydroquinone, hydroquinone derivatives (eg t-butylhydroquinone), catechol, catechol derivatives, and mixtures thereof Selected from the group.

In a preferred embodiment, the reducing agent is contacted with the catalyst moiety in an amount of from about 0.5 molar equivalents to about 10 molar equivalents relative to moles of the catalyst moiety.

In general, the deactivation treatment step is carried out under appropriate conditions which do not adversely affect the product. In a preferred embodiment, the deactivation treatment step is carried out at a temperature of about 5 ° C to about 50 ° C, more preferably at a temperature of about 15 ° C to about 25 ° C.

In a preferred embodiment, the Co (III) -salen complex is treated with L-ascorbic acid and reduced. For example, the treatment step is performed by contacting L-ascorbic acid with a Co (III) -salen complex. In a preferred embodiment, the L-ascorbic acid in an amount of about 0.5 to about 10 moles, more preferably in an amount of about 1 to about 2 moles, of the L-ascorbic acid per Co (III) -salen complex. Is contacted with the Co (III) -salen complex. In a preferred embodiment, the L-ascorbic acid is contacted with the Co (III) -salen complex at a temperature of about 5 ° C. to about 25 ° C. for about 30 minutes to about 180 minutes. In the present invention, it is preferred to carry out the treatment step by adding the L-ascorbic acid to the reaction mixture and then stirring the mixture under appropriate treatment conditions. The Co (III) -salen complex was observed to determine whether the Co (II) -salen complex was reduced to the Co (II) complex by color change and precipitation. Through the above-described processing step, it is possible to completely delay the production of by-products and to suppress the removal of excess enantiomers in the decomposed product and the timing of degradation.

In another embodiment, an amount sufficient to reduce the catalytic moiety in the first oxidation state to the second oxidation state under conditions suitable for reducing the catalytic moiety in the first oxidation state to the second oxidation state. Is applied to reduce the catalyst moiety electrochemically. As another embodiment, a chemical reducing agent may be added to the reaction mixture, and a current may be applied to the mixed product to reduce the catalyst moiety.

In a second embodiment, by oxidizing the catalyst moiety, the oxidation state of the catalyst moiety is changed from the first oxidation state to the second oxidation state.

In a preferred embodiment, the mixed product is organic to the mixed product under conditions suitable to oxidize the catalytic moiety in the first oxidation state to the second oxidation state with less catalytic activity than the catalyst moiety in the first oxidation state. An oxidizing agent or an inorganic oxidizing agent is introduced in an amount sufficient to oxidize to the above-described second oxidation state, thereby chemically oxidizing the catalyst residue. As an oxidizing agent suitable for the present invention, an active catalyst residue (e.g., Co (II), Cr (II)), under appropriate conditions, without adversely affecting a product containing a large amount of stereoisomers, It may be any compound having an oxidation potential and a reactivity sufficient to oxidize to a complex of a form less reactive than the complex (eg, Co (III), Cr (III)). Examples of such an oxidizing agent include hydrogen and peroxide. , Peracids, persulfates, perborates, perchlorates, oxygen and air.

In a preferred embodiment, an organic or inorganic complexing agent capable of stabilizing the Co (II) (salen) catalyst residue obtained from the kinetic hydrolysis of styrene oxide, and the Co (II) (salen) catalyst residue in the second oxidation state. In the presence of, oxidize from the first oxidation state to the second oxidation state. The Co (III) (salen) catalyst moiety-ammonium complex thus obtained has less catalytic activity for the reaction of lowering e.e. containing a large amount of enantiomers than the Co (II) (salen) catalyst moiety.

In a more preferred embodiment, the catalyst moiety is oxidized with oxygen, preferably in the form of an air stream, in the presence of ammonium hydroxide to produce a Co (III) (salen) catalyst moiety-ammonia complex. do.

In another embodiment, under a condition suitable for oxidizing any catalytic residue in a first state to a second oxidation state, a current is applied to the mixed product in an amount sufficient to oxidize to the second oxidation state, thereby providing the catalyst residue. Is oxidized electrochemically. In another embodiment, the catalyst moiety can be oxidized to the mixed product in combination with the addition of a chemical oxidant and the application of a current.

Regeneration of the HKR catalyst was not possible in the usual HKR reaction. However, by treating the HKR catalyst which lost activity according to the method of the present invention, the product can be purified, and the catalyst which lost activity can be recovered from the mixed product using conventional methods such as distillation, filtration and extraction. have. As such, after recovering the catalyst having lost activity, a reactivation process of the catalyst, that is, a process of increasing the catalytic activity of the catalyst by changing the oxidation state of the recovered catalyst, is performed.

As a preferred embodiment of HKR of epoxides using Co (III) -salen complexes, the degraded epoxides can be separated from the mixed product by a distillation process, followed by the addition of water, followed by filtration of the insoluble complex or organic solvent. By extraction into, Co (II) -salen complex with reduced soluble complex activity can be recovered from the diol co-product. In addition, by treating the recovered catalyst with carboxylic acid or sulfonic acid in air or oxygen and oxidizing to Co (III), the catalyst can be activated without losing reactivity or selectivity as described above.

In the HKR reaction, with or without an organic cosolvent, a treatment process as described above may be carried out comprising an initial activation step of the metal-salen complex.

Example 1

According to the following reaction scheme, the racemic epichlorohydrin was decomposed into (R) -epichlorohydrin:

.

The (S, S) -Co (II) -salen complex (60.06 g) was mixed with o -dichlorobenzene (304 g) and then acetic acid (11.98 g, 2 equiv) was added to the mixture to activate.

The active catalyst solution (369 g) was placed in a jacketed 2.5 L reaction vessel, followed by the addition of racemic epichlorohydrin (1740 g). For 3 hours at a constant flow rate, water (258 g) was added to the reaction vessel and kinetic hydrolysis of the epichlorohydrin was carried out at a temperature of 5 ° C. The mixture was further stirred for about 1.5 hours until the mixture product showed excess enantiomers greater than 99%. The mixed product contained 35% by weight of (R) -epichlorohydrin (theoretical yield: 47%), 0.2% by weight of (S) -epichlorohydrin, 3.4% by weight of water, 46% by weight of CPD, 0.8 Wt% glycidol, 0.9 wt% dichloropropanol, and 13.6 wt% o -dichlorobenzene.

A portion (1130 g) of the mixed product was removed from the reaction vessel. Then, L-ascorbic acid (1 mol% catalyst relative to epoxide) was added to the remaining product, which was stirred for 30 minutes at room temperature.

After about 2 hours (when the (R) -epichlorohydrin product has already decreased from 35% to 33.5% by weight), for the removed mixed product, at a jacket temperature of 55 ° C. and a pressure of 27 millibars, The (R) -epichlorohydrin product was isolated by short-path distillation in a wiped film distiller (Luwa) at 630 mL / hr for a retention time of 20 seconds.

In the distillation process, an organic phase (257.7 g), an aqueous phase (23.3 g), and a tar residue (510.5 g) each having a composition (weight percent unit) as shown in Table 1 below were collected (however, gas chromatography). Measured by, (R) -epi = (R) -epichlorohydrin, CPD = 3-chloro-1,2-propanediol, DCP = 1,3-dichloro-3-propanol, and o- DCB = ortho Dichlorobenzene).

Table 1: Without performing L-ascorbic acid treatment Wiped  (R) —separated by shot pad distillation in film stills Epichlorohydrin  Results for the product

From this organic phase, the (R) -epichlorohydrin product (216 g, theoretical yield: 37%) was separated.

After 24 hours of ascorbic acid treatment, a viscous mixture remained in the reaction vessel. DCB (200 mL) was added to the reaction vessel to lower the viscosity of the scrambled mixture. Then, the mixture (1080 g) was vacuum distilled for 5 hours at a pot temperature of 50 ° C. under a pressure of 25 millibars, and the organic phase (278 g) having the composition (% by weight) of Table 2 below. , Water phase (25 g), and residue (710.8 g) were obtained (provided by gas chromatography, (R) -epi = (R) -epichlorohydrin, CPD = 3-chloro-1,2-). Propanediol, DCP = 1,3-dichloro-3-propanol, and o- DCB = ortho-dichlorobenzene).

Table 2: After L-ascorbic acid treatment, Wiped  (R) —separated by shot pad distillation in film stills Epichlorohydrin  Results for the product

The organic phase consisting of the two-component mixture of (R) -epichlorohydrin / o- DCB, and the residue is a product having a very low level of decomposition compared to the residue obtained by the shot pad distillation method, that is, glycidol and DCP was included. Through these results, in particular, the mild shot pad distillation conditions used to classify the mixed product not treated with L-ascorbic acid, and the vigorous vacuum distillation conditions used to classify the L-ascorbic acid treated mixed product. In view of this, it can be seen that the stability of the L-ascorbic acid treated mixed product is greater.

( R) -Epichlorohydrin product (247 g, theoretical yield: 38.5%) was separated from the organic phase. Given that the content of ( R) -epichlorohydrin product in the distilled moiety was relatively large, the distillation was continued at high temperature and / or low pressure to provide a greater amount of ( R) -epichlorohydrin product (potentially The total yield of less than about 46% of the possible theoretical yields of 50%) was recovered.

In the conventional kinetic hydrolysis reaction of epichlorohydrin (HKR), the active Co (III) complex contains a decomposed epoxide and diol product (3-chloro-1,2) containing an excess of enantiomeric isomers. Catalyses the degradation reaction of the mixture by propanediol) and the decomposition reaction of the mixture by the conversion to byproducts. By treatment of the degraded HKR mixture with ascorbic acid, however, the Co (III) -salen catalyst is reduced to a less soluble Co (II) -salen complex, which is thermally stable and e.e. Alternatively, a heterogeneous mixture can be obtained without lowering the degree of decomposition into by-products. In addition, the Co (II) complex may be recovered plural times or regenerated plural times by filtration or extraction without decreasing the reactivity or selectivity.

Example 2

Racemic epichlorohydrin was digested with (S) -epichlorohydrin. And a 125 mL round bottom three necked flask equipped with a jacket and a mechanical stirrer was charged with (R, R) -Co (II) -salen complex (3 g; 4.97 mmol; 0.5 mol%).

The flask was then charged with CH ₂ Cl ₂ (12 mL, 4 vol). A portion of the flask was then charged with glacial acetic acid (0.57 mL; 9.96 mmol; 1.0 mol%; 2 equivalents to catalyst). The mixture thus obtained was stirred for 0.5 hours while being open in the air, to obtain a dark mixture. The reaction mixture was visually inspected to confirm the absence of a bright red solid and the presence of a dark brown solution. The flask was then equipped with a cold (dry ice / IPA) cold finger trap. Dried at ambient temperature under house vacuum (house vacuum) to remove the CH ₂ Cl _2, followed by discarding the CH ₂ Cl ₂ distilled water to waste.

And the flask was charged with racemate epichlorohydrin (78 mL; 1.0 mol). The reaction mixture was stirred and the temperature of the reaction mixture was adjusted to 5 ° C. while circulating water / ethylene glycol cooling solution. The reaction vessel was then charged with water (11.7 mL, 0.65 mol, 0.65 equivalents to Epi) via a syringe at a flow rate of about 1 mL / 5 minutes. As a result of observing the above reaction, an exothermic reaction of 8 ° C appeared. The reaction mixture was then stirred at a temperature of 5 ° C. for 4.5 hours. Samples were taken via pipette from the reaction to completion (chiral GC assay NLT 99.0% e.e.). It took 4 hours to reach 99% e.e. (3 hours after the water was fully charged).

Then, L-ascorbic acid (1.75 g; 9.94 mmol; 2 equivalents to catalyst) was added to the cooled mixture and stirred overnight while heating to ambient temperature. H ₂ O (25 mL) was added to the reaction vessel and the mixture was filtered through analytical paper to collect a red Co (II) -salen complex. The filter cake was then washed with additional H ₂ O (25 mL) and then dried in a vacuum oven overnight under house vacuum at 55 ° C. to 60 ° C. temperature. Thus, 1.9 g (theoretical amount: 3 g) of red Co (II) -salen catalyst was recovered.

The filtrate was transferred to a 250 mL round bottom flask, and the reaction vessel was equipped with a short-pad distiller, a vacuum of 50 torr was applied, and the pressure was gradually reduced to 20 torr. The color of the filtrate was dark red, thereby confirming that it was a dissolved catalyst. The filtrate was then distilled to a temperature of 20 ° C. and a pressure of 20 torr, and then the reaction mass contained in the reaction vessel was cooled to ambient temperature. The distillate was collected at a temperature of 20 ° C. and a pressure of 20 torr, resulting in 32.85 g of (S) -epichlorohydrin (> 99% ee,> 99% chemical purity, GC,% area), and co-distillation Water was obtained as water, which did not mix with each other.

Example 3

In a similar manner as in Example 1, the racemic epichlorohydrin was decomposed using the (R, R) -Co (II) -salen complex, yielding> 99% ee of degraded (S) -epichlorohydrin. Drin was obtained and the mixture was treated with several additives, each of which was a potential reducing agent. The reaction mixture was divided into eight portions (12 g each) and placed in each scintillation vial, each with a magnetic bar for stirring. Then, the deactivation effect of the catalyst and stabilization effect of the degraded (S) -epichlorohydrin were analyzed with time and temperature. Two of the eight vials were used as controls with no additives added, and the remaining six (6) portions were each treated with 5.51 mmol (about 2 equivalents of the catalyst) of various additives.

The composition of the mixed product was monitored over time by gas chromatography analysis using an ortho-dichlorobenzene cosolvent as internal standard. The results according to each case are based on the type of additive, the amount of additive used, the time elapsed since the addition of the additive, and the temperature at which the sample was maintained during the elapsed time (in the table below, “RT” means room temperature). And the composition of the sample (in the table below, ee = enantiomeric excess, (R) -epi = (R) -epichlorohydrin, CPD = 3-chloro-1,2-propanediol, DCP = 1,3-dichloro-3-propanol, and o- DCB = ortho-dichlorobenzene), shown in Tables 3 and 4 below.

TABLE 3

Table 4

As can be seen from the above results, the treatment with each additive showed improved stability at room temperature compared to the control. In addition, when treated with L- ascorbic acid or hydroquinone, the stability at high temperature was improved compared to the control, and when treated with L- ascorbic acid, the stability was better than that treated with hydroquinone.

Example 4

According to the following reaction scheme, racemic styrene oxide was decomposed into (S) -styrene oxide and (R) -styrene glycol using (S, S) -Co (salen).

In a 500 mL flask equipped with a temperature probe, mechanical stirrer, vacuum adapter and dip tube, (S, S) -Co (salen) (5.51 g, 0.0083 mmol, 0.500 mol%), styrene oxide (200.0 g, 1.66 mol, 100 mol%), and water (59.8 g, 3.32 mol, 200 mol%) were charged. A slight vacuum was applied to the flask to draw air through the dip tube (under the surface) into the reaction mixture and to initiate stirring. The flask was placed in a water bath and added to a portion of p -nitrobenzoic acid (2.83 g, 0.0166 mol, 1.00 mol%). The mixture was stirred overnight at room temperature and then the reaction was deemed complete by analysis by high performance liquid chromatography (HPLC). The reaction mixture was a brown solution suspended in an orange solid. Aluminum hydroxide (4.15 g, 4.63 mL, 28% NH ₃ , 0.0332 mol, 2.00 mol%) was added to the reaction mixture, which was then stirred for 1 hour at room temperature under air inlet. In this way, a dark brown solution was obtained. After the air inlet to the reaction mixture was stopped, the reaction mixture was washed with water (2 x 200 mL). The organic layer was classified to give (S) -styrene oxide (67.86 g, yield: 67.9%, ee: 99.6%). The aqueous layer was then cooled and filtered, then concentrated to afford (R) -styrene glycol (95.25 g, yield: 95.3%, ee: 93.9%).

Example 5

The stability of (S) -styrene oxide was tested under several different test conditions. The following mixtures were prepared as test samples:

(S) Example 7A, consisting of styrene oxide;

Example 7B consisting of 91 pbw (S) -styrene oxide, 6.4 pbw Co (III) -salen catalyst, 1.2 pbw acetic acid, and 1.6 pbw sodium acetate; And

Example 7C consisting of 91.3 pbw (S) -styrene oxide, 6.4 pbw Co (III) -salen catalyst, 1.2 pbw acetic acid, and 1.1 pbw aqueous ammonia solution.

The mixture of Examples 7B-7C was heated and maintained at a temperature of 70 ° C. for 48 hours. Over time, the relative amounts of (R)-and (S) -styrene oxides present in each mixture were monitored to calculate the percent enantiomeric excess of the (S) -enantiomers. The enantiomeric excess of each mixture of Examples 7A-7C over time is shown in Table 5 below.

Table 5: Over time (S) % Enantiomeric excess for styrene oxide mixtures

Claims (39)

In the method for synthesizing stereoselective chemicals, In the presence of a chiral non-racemic catalyst, a chiral or prochiral cyclic substrate comprising a carbocycle or heterocycle having a nucleophile and a reactive center capable of being subjected to a nucleophilic attack by said nucleophile Reacting to produce a mixed product comprising a stereoisomerically enriched product, the mixed product further comprising the catalyst moiety, wherein at least a portion of the catalyst moiety is present in the first oxidation state. Generating a mixed product, wherein the catalytic moiety in the first oxidation state is active to promote decomposition of the product containing a large amount of the stereoisomer; And The oxidation state of the catalyst moiety is changed from the first oxidation state to the second oxidation state in which the catalytic activity for the decomposition reaction of the product containing a large amount of the stereoisomer is smaller than that of the catalyst in the first oxidation state. Step to change Comprising a method of synthesizing stereoselective chemicals. The method of claim 1, Wherein said cyclic substrate comprises at least one compound represented by the following structural formula (1): [In the structural formula (1), R ²⁰ , R ²¹ , R ^22, and R ²³ may each independently form a covalent bond with a carbon atom bonded to R ²⁰ , R ²¹ , R ^22, and R ²³ , and may form a stable ring structure including Y; Organic or inorganic substituents; Y is O, S, -NR ²⁴ (wherein R ²⁴ is H, alkyl, carbonyl substituted alkyl, carbonyl substituted aryl, or sulfonate), -C (R ²⁵ ) R ²⁶ (where R ²⁵ And R ²⁶ are each independently an electron withdrawing group, or are represented by the formula ABC, provided that A and C are each independently absent or are each independently (C ₁ -C ₅ ) alkyl , O, S, carbonyl or -NR ²⁴ , and B is carbonyl, phosphoryl or sulfonyl. The method of claim 2, R ²⁰ , R ²¹ , R ²² and R ²³ are each independently H, hydroxyl, halo, alkyl, alkenyl, alkynyl, amino, imino, amido, nitro, thio, phosphoryl, phosphonate, Phosphino, carbonyl, carboxyl, silyl, sulfonyl, ketone, aldehyde, ester, thioether, selenoether, or-(CH ₂ ) _n R ²⁷ (where R ²⁷ is aryl, cycloalkyl, Cycloalkenyl or heterocyclyl, n is a number of 0 ≦ n ≦ 8), or R ²⁰ , R ²¹ , R ²² and R ²³ may be fused with another one of the R ²⁰ , R ²¹ , R ²² and R ²³ substituents to form a carbocycle ring structure or heterocycle ring structure together with the carbon atom bonded to the substituent. Characterized in that it can be formed. The method of claim 1, The cyclic substrate is epoxide, aziridine, episulfide, cyclic carbonate, cyclic thiocarbonate, cyclic phosphate, cyclic sulfate, cyclic sulfite, lactam, thiolactam, lactone, thiolactone, and sultone A method comprising at least one compound selected from. The method of claim 1, Wherein said nucleophile comprises at least one compound selected from the group consisting of water, phenoxide, hydroxide, alkoxide, alcohol, thiol, thiolate, carboxylic acid, and carboxylate. The method of claim 1, Wherein said nucleophile comprises at least one compound selected from the group consisting of water, phenol, and carboxylic acid. The method of claim 1, The catalyst is And a complex of a transition metal atom of the first cycle and an asymmetric tetradentate ligand and having an orthogonal planar or orthogonal pyramidal structure. The method of claim 1, Wherein said catalyst comprises at least one chiral metallosalenate represented by formula (2) or formula (3) , (In the above formula (2) and formula (3), R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , X ¹⁴ , X ¹⁵ , X ¹⁶ , X ¹⁷ , X ¹⁹ , and X ²⁰ are each independently H, hydroxyl, Halo, alkyl, alkynyl, amino, nitro, thio, imino, amido, phosphoryl, phosphonate, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, Ester, or-(CH ₂ ) _{n '} -R ³⁶ , provided that R ³⁶ is aryl, cycloalkyl, cycloalkenyl, or heterocyclyl R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , X ¹⁴ , X ¹⁵ , X ¹⁶ , X ¹⁷ , X ¹⁹ , and X ²⁰ fused with another one of the substituents to the ring It may form a carbocycle ring or heterocycle ring structure having 4 to 8 carbon atoms, provided that in each case described above, the substituent is selected to provide a compound having an asymmetric structure, and R ³⁰ and R ³⁰ are covalently bonded to each other to provide a compound of formula (2) as a tetradentate ligand, R ³² and R ³³ are covalently bonded to each other, and R ³⁴ and R ³⁵ are covalently bonded to each other, Providing a compound of formula (3) above as a tetradentate ligand; R ¹⁰ , R ¹¹ and R ¹² are defined the same as above, more preferably R ¹⁰ and R ¹² are each -OC (O)-or are each absent, and each R ¹¹ is alkyl, more preferably Is-(CH ₂ ) _{n "} -or CH (Cl) (CH ₂ ) _m CH (Cl)-;  M is a first periodic transition metal atom;  n is a number of 1 ≦ n ≦ 10, n 'is a number of 1 ≦ n' ≦ 15, n ″ is a number of 1 ≦ n ″ ≦ 13, and m is a number of 1 ≦ m ≦ 9;  A 'is a counterion or nucleophile). The method of claim 8, Each of R ¹⁰ and R ¹² is —OC (O) — or is absent respectively, Wherein each R ¹¹ is — (CH ₂ ) _{n ″} — or —CH (Cl) (CH ₂ ) _m CH (Cl) —. The method of claim 8, Wherein said catalyst comprises at least one complex represented by formula (2). The method of claim 10, R ³⁰ and R ³¹ are fused to form a 1,2-cyclohexylene group, each of Y ¹ , Y ² , X ² , X ⁴ , X ⁶ , and X ⁸ is H, and each of X ¹ , X ³ , X ⁵ , and X ⁷ are t-butyl and M is Co. The method of claim 8, Wherein said catalyst comprises at least one complex represented by formula (3). The method of claim 12, R ³² and R ³³ are fused and R ³⁴ and R ³⁵ are fused to form respective 1,2-cyclohexylene groups, each of Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , X ¹³ , X ¹⁶ , X ¹⁷ , and X ²⁰ are H, each of R ¹⁰ and R ¹² is -OC (O)-, R ¹¹ is-(CH ₂ ) _5- , Each X ¹⁴ , X ¹⁵ , X ¹⁸ , and X ¹⁹ is t-butyl, each M is Co, n is 1 to 10. The method of claim 1, Wherein said stereoselective synthesis method comprises the step of dynamic hydrolysis of enantiomers or diastereomers, said catalyst in said first oxidation state exhibiting catalytic activity against undesirable racemization of said degraded product How to. The method of claim 1, The nucleophile comprises phenol, the cyclic substrate comprises an epoxide having a leaving group at position 3, and the catalyst in the first oxidation state exhibits catalytic activity against the reaction of formation of an undesirable epoxide How to. The method of claim 1, Equilibrium reaction of the regioisomer via Smiles Rearrangement where the nucleophile comprises an electron deficient phenol, the cyclic substrate comprises an epoxide and the catalyst in the first oxidation state is undesirable Characterized by exhibiting catalytic activity against. The method of claim 1, By reducing the catalyst moiety, the oxidation state of the catalyst moiety is changed. The method of claim 17, A Co (III) catalyst residue or Cr (III) catalyst residue is reduced to a Co (II) catalyst residue or Cr (II) catalyst residue. The method of claim 17, The catalytic residue is reduced by contacting the catalytic moiety with at least one reducing agent selected from the group consisting of L-ascorbic acid, alcohol hydroquinone, hydroquinone derivatives, catechol, catechol derivatives, and mixtures thereof. How to. The method of claim 1, By oxidizing the catalyst moiety, the oxidation state of the catalyst moiety is changed. The method of claim 20, A Co (II) catalyst residue or Cr (II) catalyst residue is oxidized to a Co (III) catalyst residue or Cr (III) catalyst residue. The method of claim 20, Wherein said catalytic moiety is oxidized by contacting said catalytic moiety with at least one oxidant selected from the group consisting of hydrogen peroxide, peracid, persulfate, perborate, perchlorate, oxygen, and air. The method of claim 1, Adding a complexing agent effective to stabilize the catalytic moiety in said second oxidation state to said mixed product. The method of claim 23, The complexing agent is selected from the group consisting of ammonium hydroxide, amine, hydroxyamine, phosphine, sulfide, sulfoxide, amine N-oxide, amidine, quanidine, imidate ester, phosphine oxide, carbon monoxide and cyanide At least one compound selected. The method of claim 23, Wherein said complexing agent comprises at least one amine represented by the following structural formula: (In the above structural formula, R ⁴⁰ , R ⁴¹ and R ⁴² are each independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkaryl, or heterocycle, or R ⁴⁰ , R ⁴¹ and R ⁴² is a R ⁴⁰ group, R ⁴¹ group and R ⁴² is fused with the other of the groups, R ⁴⁰ groups, R ⁴¹ groups and R ⁴² groups together with the nitrogen atoms to which they are attached, form a heterocyclic ring of 4 to 8 won May be, and these heterocycle rings may be further substituted). The method of claim 1, Recovering and regenerating said catalyst moiety. In the method of synthesizing chemoselective chemicals, Reaction of a nucleophile and a chiral or prochiral substrate in the presence of a chiral non-racemic Co (III) salen catalyst, comprising a product containing a large amount of stereoisomers, for the decomposition reaction of a product containing a large amount of the stereoisomers Producing a mixed product further comprising a catalytically active Co (III) salen catalyst residue; And The mixed product is contacted with at least one reducing agent selected from the group consisting of L-ascorbic acid, hydroquinone, hydroquinone derivatives, catechol and catechol derivatives, to form the Co (III) salen catalyst moiety. III) A method for synthesizing a chemoselective chemical, comprising reducing to a Co (II) salen catalyst moiety that is less catalytically active for the decomposition reaction of the product containing a larger amount of stereoisomer than the salen catalyst moiety. The method of claim 27, And said nucleophile comprises water. The method of claim 27, Wherein said substrate comprises a mixture of epoxide enantiomers. The method of claim 27, Wherein said substrate comprises a mixture of epichlorohydrin enantiomers. The method of claim 27, Wherein said reducing agent comprises L-ascorbic acid. The method of claim 27, Recovering said Co (II) salen catalyst residue and oxidizing said recovered catalyst residue to produce a Co (III) salen catalyst. In the presence of a chiral non-racemic Co (III) salen catalyst, a mixture of (R) -epichlorohydrin and (S) -epichlorohydrin enantiomer is reacted with water to give said epichlorohydrin enantiomer Producing a mixed product containing a large amount of one of the compounds further comprising a Co (III) salen catalyst residue; And Contacting the mixed product with L-ascorbic acid to reduce the Co (III) salen catalyst moiety to a Co (II) salen catalyst moiety. Comprising a method of synthesizing stereoselective chemicals. As a method for synthesizing stereoselective chemicals, In the presence of a chiral non-racemic Co (III) salen catalyst, a chiral or prochiral substrate is reacted with a nucleophile, containing a large amount of stereoisomers, and catalytically active for decomposition of a product containing a large amount of the stereoisomers. (II) producing a mixed product further comprising a salen catalyst moiety; And Contacting the mixed product with at least one oxidant selected from the group consisting of hydrogen peroxide, peracid, persulfate, perborate, perchlorate, oxygen and air, in the presence of a complexing agent effective to stabilize the Co (III) salen catalyst moiety. Oxidizing the Co (II) salen catalyst moiety to a Co (III) salen catalyst moiety, Wherein the stabilized Co (III) salen catalyst moiety has a smaller catalytic activity for the decomposition reaction of the product containing the stereoisomer than the Co (II) salen catalyst, Method of Synthesis of Stereoselective Chemicals. The method of claim 34, wherein And said nucleophile comprises water. The method of claim 34, wherein The substrate is a mixture of styrene oxide enantiomers. The method of claim 34, wherein Wherein said oxidant comprises air. The method of claim 34, wherein Wherein said complexing agent comprises ammonium hydroxide. In the presence of a chiral non-racemic Co (III) salen catalyst, a mixture of (R) -styrene oxide and (S) -styrene oxide enantiomer is reacted with water to contain a large amount of one of the styrene oxide enantiomers Generating a mixed product further comprising Co (II) salen catalyst residues; And Contacting the mixed product with air in the presence of ammonium hydroxide to oxidize the Co (II) salen catalyst moiety to a Co (III) salen catalyst moiety. Comprising a method of synthesizing stereoselective chemicals.