KR20070076549A - Processes for the preparations of optically active cyclopentenones and cyclopentenones prepared therefrom - Google Patents

Abstract

A method for preparing an optically active cyclopentenone is provided to obtain the cyclopentenone having a wider range of the ester functional group selection by introducing an R1 group causing higher crystallinity of a stereoselective cyclopentenone (R)-1. The method for preparing a compound represented by the formula(1), which has at least 95% of optical purity of an (R)-enantiomer, comprises the steps of: (a) stereoselectively (R)-esterifying the compound of the formula(1) having acyl donor and a racemic alcohol mixture of a first lipase to obtain (R)-ester and non-reacted (S)-alcohol; (b) removing the non-reacted (S)-alcohol by reacting the non-reacted (S)-alcohol with acyl donor in the presence of dialkylazodicarboxylate and triarylphosphine to convert the (S)-alcohol into (R)-ester; and (c) deacylating the (R)-ester in the presence of R1OH with a catalyst of a second lipase or in the presence of R1OH. In the formula(1), R1 is C1-10 alkyl, benzyl, naphthyl, or phenyl, each of which is non-substituted or substituted with at least one substituent selected from the group consisting of halogen, alkyl, aryl, alkoxyl, aryloxyl, thioalkoxyl, thioaryloxy, alkylamino, arylamino and cyano or at least one heterocyclic selected from the group consisting of pyridinyl, furanyl, imidazolyl, morpholinyl, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl and pyrrolidinonyl.

Description

PROCESSES FOR THE PREPARATIONS OF OPTICALLY ACTIVE CYCLOPENTENONES AND CYCLOPENTENONES PREPARED THEREFROM}

The present invention is directed to a novel process for preparing optically active cyclopentenone of formula ( R ) -1, which is useful for preparing prostaglandins and their analogs. The present invention also relates to a novel cyclopentanone produced from the above production method.

[Formula ( R ) -1]

Prostaglandins and their derivatives are known as vasodilating action, prophlogistic action, inhibiting platelet coagulation, myometrial contraction, an intestine contraction action, and hypotension. It has a variety of biological activities and can be used in the manufacture of a medicament for the treatment or prophylaxis of myocardial infarction, angina pectoris, arteriosclerosis, hypertension, or duodenal ulcer, which is useful for veterinary use as well as humans.

Over the past decades, many university researchers and industries have done a lot of research to develop a variety of important intermediates and manufacturing methods for the effective and inexpensive synthesis of prostaglandins (Collines, PW et al . , 1993, Chem . Rev. 93, 1533). .

Lolja, D. et al. Reported cyclopentenone of the formula ( R ) -1, wherein R ₁ represents an unsubstituted linear and substituted alkyl, which is a potential intermediate in the synthesis of prostaglandins. (Lolja, D., Etc., Zh. Org. Khim 1985, 21 (4), 782).

[Formula ( R ) -1]

Beraldi (PG) et al also reported that the cyclopentenone of formula ( R ) -1 wherein R ₁ is methyl is an advanced intermediate in prostaglandin synthesis (Beraldi, PG, et al., 1987, Tetrahedron , 43, 4669). Furthermore, in Latvijas Kimijas Zurnals (1995), 1-2, 116 of Weinberga, I., the optically active cyclopentenone of formula ( R ) -1 (R ₁ is a straight and unsubstituted alkyl group or Lower alkyl groups) and their preparation methods have been reported. Therefore, the cyclopentenone of the formula ( R ) -1 has been considered to be useful for the synthesis of prostaglandins. Unfortunately, the R ₁ group portion in the cyclopentenone of formula ( R ) -1 for synthesis up to prostaglandins has not been discussed or studied.

This application forms an important part of the overall synthesis of prostaglandin compounds in conjunction with US patent application Ser. No. 11 / 334,337, entitled "Methods and Intermediates for Prostaglandin Preparation," pending on the same application. In one embodiment of the pending patent application, the synthesis of Dinoprost using the compound of formula ( R ) -1 is disclosed as shown in the following scheme (P ₁ and P ₂ is a protecting group) have:

Since dinoprost is very difficult to crystallize and no intermediates can be crystallized in this process, the solution to remove the various stereoisomers produced during the conjugation addition process to obtain high purity dinoprost is compound 8 Is in high crystallinity. Unfortunately, starting from the cyclopentenone of formula ( R ) -1, wherein R ₁ reported in the prior art is methyl, Compound 8 resulting from them did not crystallize.

On the other hand, in our other invention in which R ₁ was changed from methyl to ethyl only, it was found that the crystallinity of compound 8 was greatly improved (melting point ˜62 ° C.). Crystallized compound 8 is more easily obtained by replacing R ₁ with a large alkyl group such as menthyl, or an aryl group such as naphthyl, or an aralkyl group such as benzyl, or a substituted alkyl, aryl, or aralkyl group. have. Thus, the larger the R ₁ in the compound of formula ( R ) -1, the higher the crystallinity of compound 8, which leads to the conclusion that it is easier to prepare higher purity dinoprost. Similar findings are observed in the preparation of other prostaglandin F ₂ α compounds.

On the other hand, there remains a problem with the commercial preparation of cyclopentenone of the formula ( R ) -1 with high optical purity.

Weinberg et al. Described the enzymatic hydrolysis (Latv. Kim. Z. (1-2), 122, 1995 and Latv to obtain optically active cyclopentenone of Compound ( R ) -1 wherein R ₁ is methyl only). Various enzymatic methods, including Kim. Z. (1-2), 116, 1995) and a two-step enzymatic reaction (Latv. Kim. Z. (1), 103, 1992). Was used. However, none of these enzymatic reactions or biocatalysts used by Weinberg et al. Had good optical selectivity for the substrate. In addition, none of the examples provided cyclopentenone of Compound ( R ) -1, wherein R ₁ is methyl with optical purity higher than 85% ee. There is a need to find suitable enzymes with high optical selectivity for the cyclopentenone of formula ( R ) -1.

To enzyme division method (enzymatic resolution) to the recovering is water undesired break formula (S) -1 a cyclopentenyl tenon, inverted to convert the formula (S) -1 of the substrate by the chemical formula (R) -1 is cyclopentenyl tenon An inversion reaction was performed. However, Lola et al. Zh. Org. Khim. (1985), 21 (10), 2091 reported that the inversion reaction was particularly difficult to succeed when the substrate contained a γ-ketoester structure. Active α-protons of such esters often result in the removal of OX groups, as described below.

Although the prior art has reported a successful reversal of 4-hydroxy cyclopentenone of Formulas 10, 11, and 12 (which may be mentioned in JP61-83141, JP52-156840, and EP 357009), the following 4-hydroxy Since oxypentenone does not contain a γ-ketoester structure, it is not intuitive to speculate on the successful reversal of cyclopentenone of formula ( S ) -1 from the prior art.

In the enzymatic preparation of optically active cyclopentenone ( R ) -1, a regioselective deacylation of compound 7, which is a diester, is required. Otherwise, the following accompaniment may be produced.

In addition, because of the particular γ-ketoester structure of cyclopentenone ( R ) -1, strong acid or strong base conditions resulting from chemical hydrolysis must be avoided in order not to cause further removal. Enzymatic hydrolysis is done as reported below.

Latv. Kim. Z. (1-2), 116, 1995:

Pinot, E. et al., Tetrahedron: Asymmetry 16, 1893, (2005):

However, when we attempted to repeat enzymatic hydrolysis to compound 7 wherein R ₁ is ethyl or benzyl using reaction conditions similar to those reported in the prior art, it was found that significant amounts of ancillary 13 and 14 were observed. This shows that the prior art does not provide a sufficient solution of the regioselective deacylation of compound 7 which is the diester.

In view of the foregoing, there remains a problem to be solved in the commercial preparation of optically active cyclopentenone of formula ( R ) -1. The intention of the present invention is to provide a solution for the commercial preparation of optically active cyclopentenone of formula ( R ) -1. In addition, the intention of the present invention is that the cyclopentenone of formula ( R ) -1, wherein the optically active is preferably higher than 90% ee and more preferably higher than 95% ee , R ₁ is a large alkyl, aralkyl, or aryl group, each of which is unsubstituted or substituted, and is also used for the synthesis of the desired prostaglandin product.

Summary of the invention

The present invention provides a new method for preparing optically active cyclopentenone ( R ) -1 without the drawbacks obtained by conventional methods. More importantly, the methods described herein may be easier, more economical and more useful for industrial production purposes. The present invention also provides new cyclopentenones with a broader range of ester functional group choices by introducing R ₁ groups which result in higher crystallinity of larger or optically active cyclopentenone ( R ) -1.

Detailed description of the invention

I. Justice

As used herein, the term "alkyl" refers to a straight or branched chain containing 1 to 30 carbon atoms, such as methyl, ethyl, isopropyl, tert-butyl, etc. Type hydrocarbon group; Or a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms such as cyclopropyl, cyclopentyl, cyclohexyl, menthyl and the like.

As used herein, the term "lower alkyl" refers to alkyl containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, and the like.

As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon containing from 3 to 20 carbon atoms and one or more carbon to carbon double bonds, such as pentenyl, propenyl, and the like. group; Or a cyclic unsaturated hydrocarbon group having 5 to 20 carbon atoms and at least one carbon-to-carbon double bond such as cyclopentenyl, cyclohexenyl, and the like.

As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon group containing from 3 to 20 carbon atoms and at least one carbon to carbon triple bond, such as pentynyl, propynyl, and the like. ; Or a cyclic unsaturated hydrocarbon group having from 6 to 20 carbon atoms and at least one carbon to carbon triple bond.

The term "aryl" as used herein refers to monocyclic or polycyclic aromatic hydrocarbon radicals such as phenyl, naphthyl, anthryl, phenanthryl, etc. aromatic hydrocarbon radical). The aryl may be optionally substituted with one or more substituents including, but not limited to, halogen, alkoxyl, thioalkoxyl, alkyl, and aryl. .

The term "aralkyl" as used herein refers to a cloth containing one or more aryl groups such as benzyl, benzhydryl, fluorenylmethyl, and the like, containing from 1 to 20 carbon atoms. It means a chain or branched hydrocarbon.

Each of the above-mentioned alkyl, alkenyl, alkynyl, aryl, and aralkyl may optionally be halogen, alkyl, aryl, Alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino, arylamino, cyano, alkoxycarbonyl At least one substituent selected from the group consisting of arylcarbonyl, arylaminocarbonyl, arylaminocarbonyl, alkylaminocarbonyl, and carbonyl, or pyridinyl, thiophenyl , Furanyl, imidazolyl, morpholinyl, oxazolinyl, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyranyl, Selected from the group consisting of pyrrolidinyl, pyrrolidinonyl, and the like It may be substituted with a heterocycle.

The term "protective group" means a term that is commonly defined in the field of organic synthetic chemistry, that is, a group capable of protecting a portion of a compound or a functional group against attack of a chemical reaction. Examples of such protecting groups are methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis (2-chloroethoxy) methyl [bis (2-chloroethoxy) methyl], tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl, tetra Tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl ( triphenylmethyl), allyl (allyl), benzyl (benzyl), substituted benzyl (substituted benzyl), and SiR _a R _b R _c (where, R _a, R _b and R _c are each independently a c _{1 -4} alkyl, Phenyl, benzyl, substituted phenyl, or substituted benzyl).

)은 베타-배향에 있는 치환물(분자 또는 페이지 단면의 위)을 의미하고, 깨진 플레어 라인(

)은 알파-배향에 있는 치환물(분자 또는 페이지 단면의 아래)을 의미한다.In the description of the compounds provided throughout this specification, the

) Stands for a beta-orientated substituent (above the molecule or page cross-section), and the broken flare line (

) Denotes a substitution in the alpha-orientation (below the molecule or page cross section).

II. First aspect of the invention

II-1. Of formula 1 Racemic Cyclopentenone  Manufacturing method

Cyclopentenyl of Formula 1 wherein R ₁ is alkyl, alkenyl, alkynyl, aryl, or aralkyl, each of which is unsubstituted or halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, One or more substituents selected from the group consisting of thioaryloxy, alkylamino, arylamino, cyano, alcoholcarbonyl, arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl, and carbonyl Pyridinyl, thiophenyl, furanyl, imidazolyl, morpholinyl, oxazolinyl, piperidinyl, piperazinyl (piperidinyl) piperazinyl), tetrahydropyranyl, pyrrolidinyl and pyrrolidinyl, or a heterocycle group selected from the group consisting of pyrrolidinonyl or a protecting group for a carboxyl group), as shown in Scheme A below. 2- It is prepared from 2-furaldehyde.

Scheme A

In step (a) of Scheme A, 2-furaldehyde is reacted with formula AcOR ₁ , wherein R ₁ is as defined above to obtain furancarbinol of formula 2.

In step (b), furcarvinol of formula (2) is converted (or reversed) to obtain a mixture of cyclopentenols of formulas (3) and (1). In step (c), the mixture further undergoes an isomerization reaction to convert the cyclopentenone of Formula 3 to the cyclopentenone of Formula 1.

In Scheme A, step (a) is an aldol condensation reaction between 2-furaldehyde and a compound of formula AcOR ₁ , wherein R ₁ is as defined above, said reaction being a salt, preferably May be performed in the presence of lithium diisopropyl amide (LDA). Step (b) is a conversion (ie, potential) reaction, which can be carried out in an aqueous medium containing 100% water or water mixed with a small amount of organic solvent. The pH is maintained in the range of about 2.5 to about 6.5 in a buffered solution of an organic or inorganic acidic or basic substance, preferably dipotassium hydrogen phosphate / phosphoric acid. The temperature at which the rearrangement reaction is carried out is preferably in the range of about 60 ° C to about 200 ° C, more preferably about 80 ° C to about 140 ° C. In one preferred embodiment, the cyclopentenone mixtures of Formulas 3 and 1 produced through the rearrangement reaction are subjected directly to step (c) without further purification. Step (c) is an isomerization reaction, which may be carried out in the presence of chloral hydrate and triethylamine. By the isomerization reaction, cyclopentenone of Formula 3 is isomerized to cyclopentenone of Formula 1. As a result, the crude cyclopentenone of formula 1 is a racemate.

In addition, cyclopentenone of Formula 1 ^, wherein R ₁ is as defined above, is derived from cyclopentenone of Formula 1 ^, wherein R ₂ is lower alkyl by transesterification. Can be prepared.

According to the invention, the formula ^(1), the cyclopentenone ester exchange reaction to the formula (1) of the tenon, is shown in Reaction Scheme B.

Scheme B

In Scheme B, the reaction of step (d) is a protective reaction. Preferred protecting groups are base stable, methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis (2-chloroethoxy) methyl (bis (2- chloroethoxy) methyl), tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl , Tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenyl methyl (triphenylmethyl), allyl (allyl), benzyl (benzyl), substituted benzyl, and SiR _a R _b R _c (where, R _a, R _b and R _c are each independently a c _{1 -4} alkyl, phenyl, Benzyl, substituted phenyl, or substituted benzyl). No. Reaction conditions for carrying out protection are well known in the art. Examples of suitable protecting groups are described in TW Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., 1981. For example, cyclopentenone of Formula 1 is dissolved in dichloromethane and p-toluenesulfonic acid is added to them in catalytic amounts. The reaction mixture was placed in an ice bath, and an appropriate amount of (3,4-dihydro-2H-pyran) was added thereto, followed by stirring at room temperature for about 10 minutes to 10 hours to give the following formula (4). To obtain a protected cyclopentenone.

Step B in Reaction Scheme (e) is a hydrolysis reaction, the reaction is an enzyme, preferably a Candida antak urticae lipase (Candida in an aqueous phase (water or buffer) in the presence of antarcitica lipase, and / or an organic solvent. In Scheme B, step (f) is esterified with a condensation reagent in which the carbonyl group of the hydrolyzed cyclopentenone is used to activate the carboxyl group or the alcohol moiety, and the alcohol of formula R ₁ OH in the presence of a base. It is a reaction (esterification reaction). Examples of the condensation reagent include 1,3-dicyclohexylcarbodiimide, chloride, 2-chloro-1-methyl-pyridium iodide (2-chloro-1-methyl -pyridium iodide), 2-chloro-4,5-dihydro-1,3-dimethyl-1H-imidazolium chloride (2-chloro-4,5-dihydro-1,3-dimethyl-1H-imidazolium chloride) And N, N-diphenylchlorophenylmethyleniminium chloride, and the like, but are not limited thereto. Examples of the base include pyridine, triethylamine, di Diisopropylethylamine, N, N-dimethylaminopyridine, and the like, and suitable solvents include dichloromethane, tetrahydrofuran, and 1,2-dichloroethane (1). , 2-dichloroethane), and mixtures thereof.

Step (g) of Scheme B is a deprotection reaction, which can be carried out in a typical manner. For example, cyclopentenone of formula 6 (wherein R ₁ is 2-naphthyl and P is tetrahydropyranyl protecting group) is dissolved in a suitable solvent such as methanol, hydrogen chloride, treated with a suitable deprotective agent such as p-toluenesulfonic acid or pyridium p-toluenesulfonate and then stirred at room temperature for 10 minutes to 10 hours. Of formula I Deprotected results were obtained.

II-2. Racemic Alcohol ( Racemic  Alcohol) ( R Enantioselective of) -1 ( R )- Esterification  reaction

As shown in Scheme C, the racemic compound of racemic cyclopentenone of Formula 1 is reacted with an acyl donor of Formula A.

[Formula A]

Here, R ₃ and R ₄ are independently lower alkyl, in the presence of an optically selective adult lipase, wherein the acyl donor is (R) - selectively react with and form a cyclopentane tenon, optical of Formula (R) -7 To produce a mixture of the active ester and the unreacted alcohol of formula ( S ) -1 (Scheme C).

Scheme C

According to the invention, the resulting ester of formula ( R ) -7 has at least 85% ee, preferably at least 90% ee, most preferably at least 95% ee and up to 99% optical activity. In addition, according to Formula 1, which is a preferred embodiment of the present invention, R ₁ is C ₁ -C ₁₅ alkyl, benzyl, naphthyl, or phenyl, each of which is unsubstituted or substituted, more preferably methyl , Ethyl, benzyl, naphthyl or trichloroethyl.

In one embodiment, the isomeric selective lipase in the present invention is swine Pi liver, a porcine pancrease or acromobacter genus (Achromobacter spp .), Alkali genus (Alcaligenes spp .), Aspergillus NigerAspergillus niger), Candida AntakicaCandida antarcitica), Candida LugosaCandida rugosa), Candida RipoliticaCandida lypolytica), Chromobacterium Biscotti (Chromobacterium viscosum), Muco Javanicus (Mucor janvanicus), Muko Mihai (Mucor miehei), Penicillum Carmenberti (Penicillum Camenberti), Penicillum RoqueforteiPenicillium roqueforteii), Monastery Sephacia (Pseudomonas cepacia), Pseudomonas fluorescence lessons (Pseudomonas fluorescence), Genus Monas (Pseudomonas spp.), Monastery Stutzry (Pseudomonas stutzuri), Resopers Delmar (Rhizopus Delmar), Reiferus Niveus (Rhizopus Niveus), Reoper's DuckRhizopus oryze), And Regenus genus (Rhizopus spp .) Such as Derived from microorganisms. More preferably, the stereoselective lipase is Candida antaxica (Candida antarcitica), Genus AcromobacterAchromobacter spp.), Alkali genus (Alcaligenese spp .), Monas fluorescence lessonsPseudomonas fluorescens), Monastery StutzryPseudomonas stutzri), Or Monastery Sephacia (Pseudomonas cepaciaIs derived from.

The lipase includes a purified form, or a crude form, or a natural state in which the lipase is associated with its own harmful microorganism, so long as it retains its optical selectivity in the esterification reaction. It can exist in various forms in the method according to the invention. The chemical stability, activity, or optical selectivity of the lipase may be further increased by gene modification, DNA recombination, or immobilization. In a preferred embodiment, the lipase is Pseudomonas lipase, which is called "AK" or "PS" (which is commercially available from Amano Pharmaceuticals), or Achromobacter genus. spp . ) Resulting from a lipase, or an alkali presence in (Alcaligenese spp.) Harmful lipase, or Novo Nordisk (Novo Nordisk) is called to get a commercial "Li polar claim (Lipolase)" or "Novozymes (Novozyme)" from the in Lipase.

The optically selective esterification reaction is carried out with one organic solvent or hexane, cyclohexane, toluene, tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone in an organic solvent mixture selected from isobutyl ketone, ether, isopropyl ether, methyl isopropyl ether, and tert-butyl methyl ether and mixtures thereof Can be performed. The amount of lipase used will vary depending on many factors such as the activity of the lipase, the amount of substrate, or the solvent used. In one embodiment of the present invention, the lipase is used in the range of 0.01 mass equivalent to 10 mass equivalent per mass equivalent of cyclopentenone of the formula (1).

The reaction mixture is continuously stirred, shaken or sonicated to improve contact between the reactant and the lipase. Moreover, the temperature suitable for the said reaction is between 5 degreeC and 50 degreeC, Preferably it is an ambient temperature. In addition, enantiomerically selective esterification reactions can be stopped when the lipase is removed from the reaction mixture to obtain proper conversion of the starting material. In one embodiment, when the conversion rate is 30% to 70%, more preferably about 50%, the lipase is removed to stop the enzymatic esterification reaction. In one embodiment, the acyl donor used in the present invention is vinyl acetate, isopropenyl acetate, vinyl valerate, isopropenyl valerate, vinyl Butyrate, or isopropenyl butyrate or mixtures thereof.

II-3 Unprocessed ( S )- Alcoholic  remove

Untreated (S) - and the removal of alcohol comprises the separation of the Formula (R) -7 esters and alcohols (S) -1 unprocessed directly from the reaction mixture from step (h). The structure and properties of the esters of formula ( R ) -7 are distinctly different from those of the alcohols of formula ( S ) -1, so that the esters of formula ( R ) -7 are the same as flash chromatography on silica gel. It can be easily separated from the mixture by conventional methods:

Optionally, according to one embodiment of the present invention, the unreacted alcohol ( S ) -1 is formulated with an OH group in the presence of dialkylazodicarboxylate and triarylphosphine in a suitable solvent. Conversion to an ester of formula ( R ) -7 or ( R ) -7 ′ by conversion to an acyloxy group with an acyl donor of R ₅ COOH, where R ₅ is as defined in R ₁ or R ₃ Can be. Preferably, the dialkylazodicarboxylate is diethylazodicarboxylate, diisopropylazodicarboxylate, or dibenzylazodicarboxylate, and / or the tree Triarylphosphine is triphenylphosphine, and / or the solvent is toluene, and / or the acyl donor is carboxylic acid, and / or R ₅ is lower alkyl or R ₃ In step (I-2), about 100% of the alcohols of formula ( S ) -1 in the mixture Converted to an ester of ( R ) -7 '.

In order to obtain the optically active cyclopentenone of formula ( R ) -1, the ester of formula ( R ) -7 is isolated or the alcohol of formula ( S ) -1 is removed from the mixture obtained in step (h). It is not necessary to. Instead, the mixture undergoes the inversion reaction of step (I-2) directly to obtain a mixture of formulas ( R ) -7 and ( R ) -7 ′.

II-4. Chemical formula ( R ) -7 and / or chemical formula ( R Of the ester Deacylation  reaction( Deacylation )

According to the invention step (J) is a deacylation reaction. In one embodiment of the invention, the deacylation reaction is chemically hydrolyzed to obtain cyclopentenone of formula ( R ) -1 by cleaving esters of ( R ) -7 and / or ( R ) -7 ', Or alcohols and phosphoric acid, p-toluenesulfonic acid, hydrobromic acid, hydrochloric acid, nitric acid or sulfuric acid or mixtures thereof Alcoholic reaction is carried out in the presence of an acid catalyst. Preferably, the acid is sulfuric acid and the alcohol is R ₁ OH, wherein R ₁ is as defined above.

In another embodiment of the invention, the deacylation reaction of step (J) is an enzymatic cleavage reaction. The enzymatic digestion reaction is either hydrolysis or alcoholysis, which is water, buffer, water- or buffer-saturated organic solvent (s), alkyl or aryl alcohols, or aqueous or non-aqueous systems. It can be carried out in the presence of an alcohol containing). In addition, the reaction system for the enzymatic deacylation reaction may be homogenous or a two-phase system comprising water or buffer and a water-insoluble solvent or solvent. The ester must be well dissolved or finely dispersed within the reaction system in order to contact well with the lipase therein. If necessary, phase transfer catalysts, such as salts or surfactants, can be added to the system to speed up the reaction. The organic solvent may be incompatible with water, or must be saturated with an organic solvent that is soluble in water, such as water, a buffer, or alcohol. Suitable buffers are prepared from, but are not limited to, halides, carbonates, phosphates, sulfates, nitrates, bicarbonates, and / or acetates. Preferred pH is in the range of 5-8. Suitable organic solvents used in the reaction include alkyl alcohols, aryl alcohols, alkenyl alcohols, methyl sulfoxide, acetone, dimethyl formamide solvents that can be mixed with water, including formamide, acetonitrile, and mixtures thereof, or hexane, toluene, ether, petroleum ether, isopropyl Isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone, dioxane Water-immiscible solvents that are incompatible with water, and mixtures thereof.

The enzyme used is a lipase suitable for hydrolysis or alcoholysis of esters. Preferably, the lipase used in step (J) is candidiasis antak urticae (Candida antarcitica ) , genus Achromobacter spp ., genus Alcaligenese spp . ), Pseudomonas fluorescens ), Pseudomonas stutzri , or Pseudomonas cepacia . More preferably, the lipase is Candida antak urticae (Candida antarcitica), also in Pseudomonas (Psudomonas spp . ), Or is derived from the genus Achromobacter (Achromobacter spp.), Are most preferably derived from Candida antak urticae (Candida antarcitica.).

The reaction is determined by HPLC using a chiral column and is preferably stopped by removing the lipase when the optical purity of the product decreases to about 95% ee. Optionally, unreacted esters of ( R ) -7 and / or ( R ) -7 'may be removed after the deacylation reaction. According to the invention, the alcohol of formula ( R ) -1 is at least 95% ee. Preferably with optical activity of at least 95% ee.

II-5. Optically active chemical formula ( R ) -1 Cyclopentenone  Transesterification reaction ( Transesterification )

In one embodiment of the invention, cyclopentenone of formula ( R ) -1 undergoes transesterification to replace R ₁ of the cyclopentenone with another substituent. The ester of an optically active cyclopentenone of formula ( R ) -1 according to the present invention is the above-mentioned II-1 (Scheme B) except that the starting material is an optically active cyclopentenone instead of a racemic compound In the same manner as shown in In the transesterification reaction, the optical purity of the substrate is maintained.

III. Second Aspect of the Invention

The present invention further provides a compound of formula 1A

[Formula 1A]

Wherein X ₁ is H or a protecting group for a hydroxyl group; R ₁ is alkyl, alkenyl, alkynyl, aryl, or aralkyl, each of which is unsubstituted or halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxy, thioaryloxy, alkylamino, arylamino, One or more substituents selected from the group consisting of cyano, alcoholcarbonyl, arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl, and carbonyl or pyridinyl, thiophenyl ), Furanyl, imidazolyl, morpholinyl, oxazolinyl, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl And a heterocycle group selected from the group consisting of pyrrolidinyl and pyrrolidinonyl, or a protecting group for a carboxyl group, and conditionally R ₁ is not straight and is unsubstituted alkyl.

In one embodiment, the compound of Formula 1A has a high R configuration and has an optical purity of at least 95% enantiomeric excess (e.e.).

In particular, the invention is alkyl, alkenyl or alkynyl having R ₁ , each of which is unsubstituted or halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino, aryl One or more substituents or pyridinyl, thiophenyl, selected from the group consisting of amino, cyano, alcoholcarbonyl, arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl, and carbonyl (thiophenyl), furanyl, imidazolyl, morpholinyl, oxazolinyl, piperidinyl, piperazinyl, piperazinyl, tetrahydropyranyl ( tetrahydropyranyl), pyrrolidinyl and pyrrolidinonyl is substituted with a heterocyclic group selected from the group consisting of, or a protecting group for a carboxyl group, preferably R ₁ is unsubstituted or halogen , Alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino, arylamino, cyano, alcoholcarbonyl, arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl ( alkylaminocarbonyl), and aralkyl substituted with one or more substituents selected from the group consisting of carbonyl, preferably the aralkyl is unsubstituted or halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy Benzyl substituted with one or more substituents selected from the group consisting of alkylamino, arylamino, cyano, alcoholcicarbonyl, arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl, and carbonyl; Or aryl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxyl, thioalkoxyl, alcoholcarbonyl, carbonyl and cyano; And aryl is selected from the group consisting of phenyl, naphthyl, pyrenyl and phenanthrenyl, each of which is unsubstituted or halogen, alkyl, alcohol, thioalcohol, alkoxycarbonyl, carbono It is preferably substituted with one or more substituents selected from the group consisting of niyl and cyano.

More specifically, the present invention provides a compound of Formula 1A wherein R ₁ is naphthyl, benzyl, 2-cyanoethyl, menthyl, methoxy Benzyl (methoxybenzyl), piperonyl, phenyl, phenyl alcoholcarbonylphenyl, trichloroethyl, or diphenylmethyl.

In addition, the present invention will be further described in the following examples. However, this example should not be construed as limiting the scope of the invention. Any change or modification of the present invention which can be easily accomplished by those skilled in the art is included in the specification of the above description and the appended claims.

EXAMPLE

Example 1

2- Ethoxycarbonylmethyl -4- Hydroxy -2- Cyclopentene -1-one (2- Ethoxycarbonylmethyl -4- hydroxy -2- cyclopenten -1-one)

This example is carried out through the process shown in Scheme B.

Step (a)

The reaction flask (2 liters) was flame dried in vacuo and then placed under nitrogen. 400 mL of anhydrous THF, 59.68 g of diisopropylamine, and about 352 mL of 1.6 M n-butyl lithium in hexanes were added to the reaction flask and about 1 at a temperature ranging from -20 ° C to 0 ° C. Stir for hours. Then, the reaction temperature was lowered to about −70 ° C. using a dry ice / acetone bath. Ethyl acetate solution (47.2 g) diluted with 100 mL THF was added to the reaction mixture using a dropping funnel. Then 51.5 g of furfural was added to the reaction mixture to complete the reaction, which was allowed to settle into a saturated aqueous solution of ammonium chloride and then stirred for 1 hour. Upon completion the phases were separated and the aqueous phase was extracted twice with ethyl acetate (2 × 500 mL). The organic layer was combined and washed with brine (500 mL), dried over anhydrous magnesium sulfate, filtered and condensed in vacuo (40 ° C., 2 mmHg). A dark yellow to brown oil (about 120 g) was recovered.

Step (b) :

The product obtained in step (a) was used in step (b) without further purification. To a three-necked flask equipped with a stirrer and a condenser, the product of step (a), water (4800 g), and dipotassium hydrogen phosphate (5.1 g) were added and stirred. The pH of the reaction solution was adjusted to about 3 using phosphoric acid. The reaction mixture is refluxed at ambient temperature or above 100 ° C. under a nitrogen stream. After the reflux reaction is complete, the reaction mixture is cooled and extracted with ethyl acetate until the aqueous phase does not contain the desired product. The ethyl acetate was evaporated from the extracted product, 2-ethoxycarbonylmethyl-4-hydroxy-2-cyclopenten-1-one And a mixture containing 2-ethoxycarbonylmethyl-3-hydroxy-4-cyclopenten-1-one (about 120 g in total) Is generated.

Step (c) :

To the reaction mixture (about 120 g) obtained in reaction (b) was added 6 g of triethylamine, 0.6 g of chloral monohydrate, and 250 ml of toluene. The mixture was converted to 2-ethoxycarbonylmethyl-3-hydroxy-4-cyclopenten-l-one completely into 2-ethoxycarbonylmethyl-4-hydroxy-2-cyclopenten-l-one. Stir at room temperature for 1-24 hours, and this conversion was measured using thin layer chromatography (TLC). The reaction mixture was further condensed to give a dark brown oily material, which was subsequently subjected to flash chromatography, and the column was wrapped with silica gel and eluted with a solvent mixture containing hexane and ethyl acetate in different proportions. Finally, a pure form of 2-ethoxycarbonylmethyl-4-hydroxy-2-cyclopenten-l-one (about 57 g) was obtained. ¹ H-NMR (CDCl ₃ / TMS): δ 7.44 (s, 1H), 4.98 (m, 1H), 4.16 (q, 2H), 3.25 (s, 2H), 3.11 (br, 1H), 2.83 (dd , 1H), 2.34 (dd, 1H), 1.27 (t, 3H).

Example 2

2- Methoxycarbonylmethyl -4- Hydroxy -2- Cyclopentene -1-one (2- Methoxycarbonylmethyl -4- hydroxy -2- cyclopenenten -1-one)

The method of Example 1 was repeated except that methyl acetate (40 g) was used instead of ethyl acetate. The title compound was obtained in the form of a dark oil (24 g). ¹ H-NMR (CDCl ₃ / TMS): δ 7.45 (s, 1H), 5.01 (m, 1H), 3.72 (s, 3H), 3.28 (s, 2H), 2.85 (dd, 1H), 2.35 ( dd, 1 H), 1.67 (br s, 1 H).

Example 3

2- Benzoxycarbonylmethyl -4- Hydroxy -2- Cyclopentene -1-one (2- Benzoxycarbonylmethyl -4- hydroxy -2- cyclopenten -1-one)

The method of Example 1 was repeated except that benzyl acetate (80.8 g) was used instead of ethyl acetate. The title compound was obtained in the form of a dark oil (55 g). ¹ H-NMR (CDC1 ₃ / TMS): δ 7.15 to 7.55 (m, 6H), 5.17 (s, 2H), 5.01 (m, 1H), 3.31 (s, 2H), 2.83 (dd, 1H), 2.33 (m, 1 H).

 Example 4

2- Ethoxycarbonylmethyl -4- Tetrahydropyranyloxy -2- Cyclopentene -1-one (2- Ethoxycarbonylmethyl -4- tetrahydropyranyloxy -2- cyclopenten -One- one )

100 g of 2-ethoxycarbonylmethyl-4-hydroxy-2-cyclopenten-l-one are dissolved in 1000 ml of dichloromethane and then 55 g of 3,4-dihydro-2H-pyran And 2 g of p-toluenesulfonic acid monohydrate were added and stirred at room temperature for about 3 hours. After completion of the reaction, the reaction mixture was washed with 400 ml of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and condensed to give 2-ethoxycarbonylmethyl-4-tetrahydropira. Neyl-2-cyclopenten-l-one was obtained (138.5 g). ¹ H-NMR (CDC1 ₃ / TMS): δ 7.40 ~ 7.68 (m, 1H), 4.70 ~ 5.02 (m, 2H), 4.15 (q, 2H), 3.88 (m, 1H), 3.54 (m, 1H) , 3.23 (q, 2H), 2.79 (m, 1H), 2.37 (m, 1H), 1.77 (m, 2H), 1.55 (m, 4H), 1.25 (t, 3H).

Example 5

2- Hydroxycarbonylmethyl -4- Tetrahydropyranyloxy -2-cyclo Pentene -1-on

50 g of 2-ethoxycarbonylmethyl-4-tetrahydropyranyloxy-2-cyclopenten-l-one and 5 g of Candida antaxica lipase obtained in Example 4 were added with 500 ml of phosphate buffer (10 mM, pH 6.5-7.5). ) And stirred at room temperature. The pH of the solution was maintained with 1N sodium hydroxide solution, finally adjusted to 8.0 at the completion of the reaction. The reaction mixture was washed twice with 300 ml of ethyl acetate. The pH of the aqueous layer was adjusted to 3.0 with saturated sodium hydrogen sulfate solution. The aqueous layer was washed twice with 300 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and then filtered and concentrated to afford 2-hydroxycarbonylmethyl-4-tetrahydropyranyloxy-2-cyclopenten-l-one (31.5 g, 75% yield).

¹ H-NMR (CDCl ₃ / TMS): δ 7.45 to 7.61 (m, 1H), 4.73 to 5.02 (m, 2H), 3.88 (m, 1H), 3.55 (m, 2H), 3.31 (m, 2H ), 2.82 (m, 1H), 2.38 (m, 1H), 1.42-1.88 (m, 6H).

Example 6

2- (1,1,1- Trichloroethoxycarbonylmethyl )-4- Hydroxy -2-cyclo Pentene -1-on

2-hydroxycarbonylmethyl-4-tetrahydropyranyloxy-2-cyclopenten-l-one obtained in Example 5, 5 g, 2,2,2-trichloroethanol (4.7 g), dichloromethane (50 Ml) and 0.2 g of 4- (dimethylamine) pyridine were added together to a 30 ml dichloromethane solution containing 1,3-dicyclohexylcarbodiimide (7 g). The reaction mixture was stirred at room temperature for about 4 hours. The precipitate was filtered off. The filtrate was washed with 20 ml of dilute hydrochloride solution and water, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum. The crude product was dissolved in 30 ml of acetone and 6 ml of water, 3 ml of 3N HCl (aq) was added and then stirred overnight. At the completion of the reaction, acetone was evaporated and the reaction mixture was diluted with ethyl acetate and then washed with aqueous sodium bicarbonate solution and brine solution. The organic layer was subjected to a work-up procedure involving dehydration, filtration and evaporation described above and purified by silica gel chromatography to yield the title compound (4.8 g, 80%).

¹ H-NMR (CDCl ₃ / TMS): δ 7.49 (m, 1H), 5.02 (m, 1H), 4.75 (s, 2H), 3.42 (s, 2H), 2.86 (dd, 1H), 2.35 ( dd, 1 H), 1.78 (br s, 1 H).

Example 7

2- (2- Naphthyloxycarbonylmethyl )-4- Hydroxy -2-cyclo Pentene -1-on

5 g (21 mmol) of 2-hydroxycarbonylmethyl-4-tetrahydropyranyloxy-2-cyclopenten-l-one obtained in Example 5, 2-naphthol (4.7 g, 32 mmol) and dichloromethane (50 mL) ) And 0.2 g of 4- (dimethylamine) pyridine were added together to 50 ml of dichloromethane solution containing 1,3-dicyclohexylcarbodiimide (7 g, 34 mmol). The reaction mixture was stirred at room temperature for about 4 hours. The precipitate was filtered off. The filtrate was washed with 20 ml of dilute hydrochloride solution and water, dried over anhydrous magnesium sulfate, then filtered and evaporated under vacuum. The crude product was dissolved in 30 ml of acetone and 6 ml of water, 0.3 g of p-toluenesulfonic acid was added and then stirred overnight. At the completion of the reaction, acetone was evaporated and the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution and brine solution. The organic layer was subjected to the workup process including dehydration, filtration and evaporation described above and purified by silica gel chromatography to give the title compound as a white solid (4.2 g, 71%).

MP: 81 ℃

¹ H-NMR (CDCl ₃ / TMS): δ 7.82 (m, 2H), 7.78 (d, 1H), 7.55 (m, 2H), 7.46 (m, 2H), 7.21 (dd, 1H), 5.04 ( m, 1H), 3.56 (s, 2H), 2.89 (dd, 1H), 2.38 (dd, 1H), 1.60 (brs, 1H).

Example 8

( R )-2- Benzoxycarbonylmethyl -4- Acetyloxy -2-cyclo Pentene -1-one and ( S )-2- Benzoxycarbonylmethyl -4- Hydroxy -2-cyclo Pentene -1-on

10 g of racemic 2-benzoxycarbonylmethyl-4-hydroxy-2-cyclopenten-l-one obtained in Example 3, 10 ml of vinyl acetate, 1 g of lipase derived from Pseudomonas cepacia , and 100 ml of methyl isobutyl ketone (referred to as "MIBK") was added to a 250 ml reaction flask and stirred at a temperature from 0 ° C to 50 ° C. When about 45% -55% esterification reaction occurred, the reaction was stopped by removing the lipase. The reaction mixture was concentrated under vacuum evaporation (50 ° C., 20 mm Hg) to give ( R ) -ester, ie ( R ) -2-benzoxycarbonylmethyl-4-acetyloxy-2-cyclopentene- as a dark brown oil. A product containing 1-one and unreacted ( S ) -alcohol, ie ( S ) -2-benzoxycarbonylmethyl-4-hydroxy-2-cyclopenten-l-one, was formed. Optionally, ( R ) -ester (4.8 g, 99% ee) and unreacted ( S ) -alcohol (4.2 g, 99% ee) were separated by flash column.

[Examples 9 to 26]

Examples 9-26 were carried out in the same manner as described in Example 8 except that the acyl donor, solvent and lipase forms used were different. The results are shown in Table 1 below.

Example number Substrate R ₁ Acyl donor menstruum Lipase form ( R ) -ester ( S ) -ester yield Optical purity (% e.e.) yield Optical purity (% e.e.) 9 methyl Isopropenyl Acetate MIBK Monas fluorescence lessons 35% 95 43% 89 10 methyl Vinyl acetate --- Candida Antatica 36% 92 48% 82 11 ethyl Isopropenyl Acetate toluene Candida Antatica 30% 85 45% 78 12 ethyl Vinyl acetate MIBK Monas fluorescence lessons 42% 98 44% 94 13 ethyl Vinyl acetate IPE Mukor Miehei 32% 86 42% 80 14 benzyl Vinyl acetate MTBE Monas fluorescence lessons 37% 93 45% 94 15 benzyl Vinyl acetate IPE Monastery Sephacia 40% 99 42% 98 16 benzyl Vinyl acetate MIBK Alkaligens 41% 97 45% 94 17 benzyl Vinyl acetate toluene Acromobacter 37% 92 38% 88 18 2-naphthyl Vinyl acetate MIBK Monastery Sephacia 42% 98 39% 99 19 2-naphthyl Vinyl acetate MIBK Monas fluorescence lessons 45% 90 36% 98 20 2-naphthyl Vinyl acetate MIBK Candida Antatica 36% 75 37% 89 21 2-naphthyl Vinyl acetate MIBK Alkaligens 41% 98 35% 99 22 2-naphthyl Vinyl acetate MIBK Monastery Stuszri 36% 90 28% 98 23 1,1,1-trichloroethyl Vinyl acetate MIBK Monastery Sephacia 38% 98 42% 98 24 1,1,1-trichloroethyl Vinyl acetate MIBK Monas fluorescence lessons 36% 95 41% 98 25 1,1,1-trichloroethyl Vinyl acetate MIBK Candida Antatica 36% 92 31% 96 26 1,1,1-trichloroethyl Vinyl acetate MIBK Alkaligens 34% 97 37% 99

"---" indicates that no solvent or diluent was added.

"MIBK" represents methylisobutyl ketone.

"IPE" stands for isopropyl ether.

Pseudomonas Pseudomonas fluorescens

Candida Antarctica: Candida antarctica

Muco Mihai: Mucor miehei

Monastery Sephacia: Pseudomonas cepacia

Alkaline: Alcaligenese spp .

Acromobacter: Achromobacter spp .

Monastery stutsri: Pseudomonas stutzri

[Examples 27 and 28]

( R )-2- Benzoxycarbonylmethyl -4- Acetyloxy -2-cyclo Pentene -1-on

Example  27

In a closed reaction flask, the unreacted ( S ) -alcohol obtained in Example 8, i.e. ( S ) -2-benzoxycarbonylmethyl-4-hydroxy-2-cyclopenten-l-one (4.2 g, 98 % ee), acetic acid (1.54 g, 1.5 mol. Eq.) and triphenylphosphine (6.74 g, 1.5 mol. Eq.) were dissolved together in toluene. The reaction mixture was then cooled to a temperature of about 0-10 ° C., followed by the slow addition of diisopropylazocarbosylate (4.5 g, 1.3 mol. Eq.). The temperature was maintained at 0-10 ° C. until the reaction was complete, and then the reaction mixture was raised to room temperature. The obtained precipitate was filtered off, and the filtrate was evaporated in vacuo to remove toluene. A crude product, i.e. ( R ) -2-benzoxycarbonylmethyl-4-acetyloxy-2-cyclopenten-l-one (5.4 g, 98% ee) was obtained.

¹ H-NMR (CDCl ₃ / TMS): δ 7.43 (m, 1H), 7.33 (m, 5H), 5.78 (m, 1H), 5.13 (s, 2H), 3.31 (s, 2H), 2.87 ( dd, 1 H), 2.37 (dd, 1 H), 2.06 (s, 3 H).

Example  28

( R ) -ester obtained in Example 15: 2-benzoxycarbonylmethyl-4-acetyloxy-2-cyclopenten-l-one and unreacted ( S ) -alcohol: 2-benzoxycarbonylmethyl- A mixture (5.75 g) containing 4-hydroxy-2-cyclopenten-l-one was added to toluene (50 mL), acetic acid (1.06 g, 1.5 mol. Eq.) And triphenylphosphine (4.6 g, 1.5 mol). eq.). The reaction mixture was stirred at room temperature until a homogeneous reaction mixture was formed. The reaction mixture was cooled down and diisopropylazocarboxylate (about 3.1 g, 1.3 mol. Eq.) Was added slowly. After the reaction was completed, the reaction mixture was heated to ambient temperature and stirred for 1 day. The obtained precipitate was filtered off, and the filtrate was evaporated in vacuo to remove toluene. Crude product (9.7 g) was obtained containing ( R ) -ester, residue and by-product from Mitsunobu reaction. The crude product was used directly in the next reaction or purified by flash column. The optical purity of the title compound (about 4.8 g) was about 99% ee.

Example 29

( R )-2- Ethoxycarbonylmethyl -4- Acetyloxy -2-cyclo Pentene -1-on

( R ) -ester: 2-ethoxycarbonylmethyl-4-acetyloxy-2-cyclopenten-l-one and ( S ) -alcohol: 2-ethoxycarbonylmethyl-4-hydroxy-2-cyclo The mixture containing penten-1-one was reacted as described in Example 28 to give the title compound (7.2 g).

¹ H-NMR (CDCl ₃ / TMS): δ 7.44 (s, 1 H), 5.79 (d, 1 H), 4.15 (q, 2H), 3.25 (s, 2H), 2.88 (dd, 1H), 2.37 ( dd, 1H), 2.07 (s, 3H), 1.25 (s, 3H).

Example 30

Example 30 was carried out according to the method of Example 28 except that butyric acid was used instead of acetic acid. The title compound was obtained as a dark oil (yield: about 90%).

[Examples 31 to 33]

( R )-2- Ethoxycarbonylmethyl -4- Hydroxy -2-cyclo Pentene -1-on

Example  31

5 g of ( R ) -2-ethoxycarbonylmethyl-4-acetyloxy-2-cyclopenten-l-one (96% ee) was dissolved in 40 ml of ethanol. 5 g of sulfuric acid was gradually added to the reaction mixture, followed by stirring at 40 ° C. for 4 to 5 hours. The reaction mixture was poured into iced water and the pH of the solution was adjusted to 4-6 with saturated aqueous sodium bicarbonate solution. The reaction mixture was concentrated in vacuo to evaporate ethanol, then diluted with 300 ml ethyl acetate for extraction and allowed to phase separate. The aqueous layer was washed twice with about 100 ml of ethyl acetate. The organic layers were collected and combined and washed with brine and saturated sodium bicarbonate solution respectively. The reaction mixture was dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was purified by silica gel flash chromatography to give the title compound as an oil (4.1 g, 96% ee).

Example  32

5 g of ( R ) -ethoxycarbonylmethyl-4-acetyloxy-2-cyclopenten-l-one (96% ee) was added to 50 ml of MIBK, 5 g of ethanol and 0.5 g of Candida antarctica lipase. Lipase) (obtained from Novo Industry) was added to the reaction flask and stirred at room temperature. The reaction was monitored by HPLC to stop the reaction by filtering the lipase when the optical purity of the reaction substrate was lowered to 99% ee. The reaction mixture was concentrated to remove solvent and then the short compound was used to remove unreacted ester to give the title compound having high optical purity (4.2 g, 99% ee).

Example  33

Example 33 was carried out according to the method of Example 32, except that Achromobacter- derived lipases were used instead of Candida Antaxica lipase. The title compound was obtained (4.1 g, 99% ee) with high optical purity.

Examples 34 and 35

( R )-2- Benzoxycarbonylmethyl -4- Hydroxy -2-cyclo Pentene -1-on

Example  34

( R ) -Benzoxycarbonylmethyl-4-acetyloxy-2-cyclopentene- instead of ( R ) -ethoxycarbonylmethyl-4-acetyloxy-2-cyclopenten-l-one and ethanol as starting materials Example 34 was carried out according to the method of Example 32 except for using 1-one (4 g, 97% ee) and benzyl alcohol. The title compound was obtained (3.4 g, 99% ee) with high optical purity.

Example  35

5 g of ( R ) -2-benzoxycarbonylmethyl-4-acetyloxy-2-cyclopenten-l-one (5 g, 98% ee), 0.5 g of Candida antaxica lipase and 50 ml of phosphate buffer (10 mM , pH 7) were added together and stirred at room temperature. The pH of the reaction mixture was maintained between about 6.5 and 7.5 using 0.1 N sodium hydroxide solution. After about 3-4 hours, the reaction was stopped by filtering the lipase. The product was extracted twice from the aqueous layer with ethyl acetate (50 mL). The collected organic layers were then washed with saturated sodium bicarbonate solution and brine solution respectively, then dried over anhydrous magnesium sulfate and evaporated under vacuum. The residue was purified by silica gel flash chromatography to give the title compound as an oil (3.2 g, 98% ee).

Example 36

( R )-2- Ethoxycarbonylmethyl -4- Triethylsilyloxy -2-cyclo Pentene -1-on

25 g of ( R ) -2-ethoxycarbonylmethyl-4-hydroxy-2-cyclopenten-l-one (5 g, 98% ee) is dissolved in ethyl acetate and the solution is a nitrogen purge flask (notrogen- pureged flask). Imidazole (13.87 g, 204 mmol) was added. The solution was cooled to 0 ° C. and triethylchlorosilane (26.6 g, 176 mmol) was added slowly. The reaction mixture was warmed to room temperature and stirred for another 15 hours. After filtration, the filtrate was washed with saturated sodium bicarbonate solution and brine solution, dried over anhydrous magnesium sulfate, and then concentrated to give the title compound (38.5 g, 95%).

[α] _D : + 27.8 ° (c 1.0, CH ₃ CN)

¹ H-NMR (CDCl ₃ / TMS): δ 7.36 (s, 1 H), 4.96 (m, 1 H), 4.16 (q, 2H), 3.23 (dd, 2H), 2.84 (dd, 1H), 2.32 ( dd, 1H), 1.26 (t, 3H), 0.99 (t, 9H), 0.65 (q, 6H).

Example 37

( R )-2- Hydroxycarbonylmethyl -4- Triethylsilyloxy -2-cyclo Pentene -1-on

20 g of ( R ) -2-ethoxycarbonylmethyl-4-triethylsilyloxy-2-cyclopenten-l-one and 2 g of Candida antaxica lipase obtained in Example 35 were added to 200 ml of phosphate buffer (10 mM, pH 6.5-7.5) and stirred at room temperature. The pH of the solution was maintained using 1N sodium hydroxide solution, finally adjusted to 7.0 at the completion of the reaction, and the lipase was removed by filtration. The reaction mixture was extracted twice with 100 mL ethyl acetate. The pH of the aqueous layer was adjusted to 6.0 using saturated sodium hydrogen sulfate solution. The aqueous layer was extracted twice with 100 ml ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give ( R ) -2-hydroxycarbonylmethyl-4-triethylsilyloxy-2-cyclopenten-l-one (12 g, 65%). yield).

[α] _D : + 19.8 ° (c 1.0, CH ₃ CN)

¹ H-NMR (CDCl ₃ / TMS): δ7.35 (m, 1H), 4.93 (m, 1H), 3.26 (m, 2H), 2.78 (dd, 1H), 2.31 (dd, 1H), 0.95 ( t, 9H), 0.64 (q, 6H).

Example 38

( R ) -2- [2- (4- Morpholineethoxycarbonylmethyl )]-4- Triethylsilyloxy -2-cyclo Pentene -1-on

5 g (18.5 mmol) of ( R ) -2-hydroxycarbonylmethyl-4-triethylsilyloxy-2-cyclopenten-l-one obtained in Example 37, 4- (2-hydroxyethyl) -mor 30 ml of dichloro containing 1,3-dicyclohexylcarbodiimide (6 g, 29 mmol) of Pauline (2.9 g, 22.1 mmol), dichloromethane (50 ml) and 0.2 g 4- (dimethylamine) -pyridine It was added together to the methane solution. The reaction mixture was stirred at room temperature for 4 hours. The precipitate was filtered off. The filtrate was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum. The residue was purified by silica gel flash chromatography to give the title compound as an oil (4.4 g, 62%).

[α] _D : + 26.0 ° (c 1.0, CH ₃ CN)

¹ H-NMR (CDCl ₃ / TMS): δ 7.40 (m, 1H), 4.97 (m, 1H), 4.28 (t, 2H), 3.75 (t, 4H), 3.28 (q, 2H), 2.80 ( dd, 1H), 2.69 (t, 2H), 2.57 (s, 4H), 2.33 (dd, 1H), 1.01 (t, 9H), 0.68 (q, 6H).

Example 39

( R ) -2- (2- Cyanoethoxycarbonylmethyl )-4- Triethylsilyloxy -2-cyclo Pentene -1-on

Example 39 was carried out according to the method of Example 38 except that 3-hydroxypropionitrile was used instead of 4- (2-hydroxyethyl) morpholine for the reaction. The title compound was obtained as an oil (yield: 64%).

[α] _D : + 30.9 ° (c 1.0, CH ₃ CN)

¹ H-NMR (CDCl ₃ / TMS): δ 7.37 (s, 1 H), 4.96 (m, 1 H), 4.30 (t, 2 H), 3.30 (q, 2H), 2.79 (dd, 1H), 2.72 ( t, 2H), 2.31 (dd, 1H), 0.98 (t, 9H), 0.65 (q, 6H).

Example 40

( R ) -2- (3- Ethoxycarbonylphenoxycarbonylmethyl )-4- Triethylsilyloxy -2-cyclo Pentene -1-one)

Example 40 was carried out according to the method of Example 38 except that ethyl 3-hydroxybenzoate was used instead of 4- (2-hydroxyethyl) -morpholine in the reaction. The title compound was obtained as an oil (yield 67%).

[α] _D : + 21.0 ° (c 1.0, CH ₃ CN)

¹ H-NMR (CDCl ₃ / TMS): δ 7.96 (m, 1H), 7.79 (m, 1H), 7.49 (m, 2H), 7.32 (m, 1H), 5.03 (m, 1H), 4.41 ( q, 2H), 3.56 (q, 2H), 2.87 (dd, 1H), 2.40 (dd, 1H), 1.43 (t, 3H), 1.03 (t, 9H), 0.70 (q, 6H).

Example 41

2-[( 1R, 2S, 5R )- Menthoxycarbonylmethyl ]-(4 R )- Hydroxy -2-cyclo Pentene -1-on

2-hydroxycarbonylmethyl-4-triethylsilyloxy-2-cyclopenten-l-one 5 g (18.5 mmol) obtained in Example 37, ( 1R, 2S, 5R )-(-)-menthol (3.44 g, 22.0 mmol), dichloromethane (50 mL) and 0.2 g of 4- (dimethylamine) pyridine were added together in a 30 mL dichloromethane solution containing 1,3-dicyclohexylcarbodiimide (6 g, 29 mmol). It was. The reaction mixture was stirred at room temperature for about 4 hours. The precipitate was filtered off. The filtrate was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum. The crude product was dissolved in 50 ml of THF and 5 ml of water, then 1 ml of 3N HCl (aq) was added and stirred at room temperature for 1 hour. At the completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution and brine solution. The organic liquid was subjected to the above work-up procedure, including filtration and evaporation. The residue was purified by silica gel flash chromatography to give the title compound as an oil (4.3 g, 79%).

Example 42

( R ) -2- (4- Methoxyphenylmethoxycarbonylmethyl )-4- Hydroxy -2-cyclo Pentene -1-on

Example 42 was carried out according to the method of Example 41 except that 4-methoxybenzyl alcohol was used instead of (-) menthol in the reaction. The title compound was obtained as an oil (yield 67%).

¹ H-NMR (CDCl ₃ / TMS): δ 7.39 (s, 1H), 7.25 (d, 2H), 6.87 (d, 2H), 5.06 (s, 3H), 4.95 (m, 1H), 3.79 ( s, 3H), 3.26 (s, 2H), 2.81 (dd, 1H), 2.31 (d, 1H).

Example 43

( R ) -2- (2- Naphthoxycarbonylmethyl )-4- tert - Butyldimethylsilyloxy -2-cyclo Pentene -1-on

5 g (27.1 mmol, 98% ee) of ( R ) -2-ethoxycarbonylmethyl-4-hydroxy-2-cyclopenten-l-one was dissolved in ethyl acetate and the solution was placed in a nitrogen purge flask. Imidazole (2.77 g, 40.7 mmol) was added. The solution was cooled to 0 ° C. and tert-butyldimethylchlorosilane (5.3 g, 35 mmol) was added in portions. The reaction mixture was warmed to room temperature and stirred for 15 hours. After filtration, the filtrate was washed with saturated sodium bicarbonate solution and brine solution respectively, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue and 1 g of Candida antarctica lipase were suspended in 100 ml of phosphate buffer (10 mM, pH 6.5-7.5) and stirred at room temperature. The pH of the solution was maintained using 1N sodium hydroxide solution to finally adjust to 7.0 at the completion of the reaction and to remove lipase by filtration. The reaction mixture was extracted twice with 50 ml of toluene. The pH of the aqueous layer was adjusted to 6.0 using saturated sodium hydrogen sulfate solution. The aqueous layer was extracted twice with 100 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue and 2-naphthol (5.0 g, 34.7 mmol) were dissolved in dichloromethane (50 mL) and together with 0.2 g 4- (dimethylamine) pyridine 1,3-dicyclohexylcarbodiimide (7.5 g, 36 mmol) was added to 30 mL of dichloromethane solution. The reaction mixture was stirred at room temperature for 4 hours. The precipitate was filtered off. The filtrate was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum. The residue was purified by silica gel chromatography to give the title compound as a white solid (5.2 g, 48%).

¹ H-NMR (CDCl ₃ / TMS): δ7.78 (m, 2H), 7.74 (d, 1H), 7.50 (s, 1H), 7.42 (m, 3H), 7.17 (dd, 1H), 4.95 ( m, 1H), 3.50 (q, 2H), 2.77 (dd, 1H), 2.30 (dd, 1H), 0.82 (s, 9H), 0.08 (s, 6H).

Example 44

( R )-2- Hydroxycarbonylmethyl -4- Tetrahydropyranyloxy -2-cyclo Pentene -1-on

Optically active 2-ethoxycarbonylmethyl-4-hydroxy-2-cyclopentene-1 instead of racemic 2-ethoxycarbonylmethyl-4-hydroxy-2-cyclopenten-1-one in the reaction Example 44 was carried out according to the methods of Examples 4 and 5 except that -98% ee) was used. The title compound was obtained as an oil.

Example 45

( R ) -2- (2- Naphthoxycarbonylmethyl )-4- Tetrahydropyranyloxy -2-cyclo Pentene -1-on

2-hydroxycarbonylmethyl-4- ( R ) -tetrahydropyranyloxy-2-cyclopenten-l-one 5 g (21 mmol) obtained in Example 44, 2-naphthol (4.7 g, 32 mmol), dichloro 0.2 g of methane (50 mL) and 4- (dimethylamine) pyridine were added together to 50 mL of dichloromethane solution containing 1,3-dicyclohexylcarbodiimide (7 g 34 mmol). The reaction mixture was stirred at room temperature for about 4 hours. The precipitate was filtered off. The filtrate was washed with 20 ml of dilute hydrochloride solution and water, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum. The residue was purified by silica gel flash chromatography to give the title compound as a white solid (3.8 g, 64%).

MP: 75 ℃

[α] _D : + 29.3 ° (c 1.0, CH ₃ CN)

¹ H-NMR (CDCl ₃ / TMS): δ 7.10 to 7.90 (m, 8H), 4.72 to 5.11 (m, 2H), 3.90 (m, 1H), 3.60 (m, 3H), 2.89 (m, 1H ), 2.35-2.60 (m, 1H), 1.40-1.92 (m, 6H).

Example 46

2- Menthoxycarbonylmethyl -4-( R )- Tetrahydropyranyloxy -2-cyclo Pentene -1-on

The title compound was prepared in the same manner as in Example 45, except that equimolar ( 1R, 2S, 5R )-(-)-menthol was used instead of 2-naphthol as a substrate for the reaction, to obtain an oil. Obtained.

¹ H-NMR (CDCl ₃ / TMS): δ 7.44 to 7.58 (m, 1H), 4.65 to 5.04 (m, 3H), 3.91 (m, 1H), 3.57 (m, 1H), 3.24 (m, 2H ), 2.74-2.88 (m, 1H), 2.35-2.54 (m, 1H).

Example 47

( R )-2- Diphenylmethoxycarbonylmethyl -4- Tetrahydropyranyloxy -2-cyclo Pentene -1-on

The title compound was prepared as an oil according to the same method as Example 45 except for using equimolar benzhydrol instead of 2-naphthol as a substrate used for the reaction.

¹ H-NMR (CDCl ₃ / TMS): δ 7.20 to 7.42 (m, 11H), 6.81 (s, 1H), 4.85 (m, 1H), 4.68 (m, 1H), 3.79 (m, 1H), 3.46 (m, 1H), 3.30 (m, 2H), 2.74 (m, 1H), 2.20-2.41 (m, 1H), 1.15-1.90 (m, 6H).

Example 48

( R ) -2- (3,4- Methylenedioxyphenylmethoxycarbonylmethyl )-4- Tetrahydropyranyloxy -2-cyclo Pentene -1-on

The title compound was prepared as an oil according to the same method as Example 45 except for using an equimolar amount of piperonyl alcohol instead of 2-naphthol as a substrate used for the reaction.

¹ H-NMR (CDCl ₃ / TMS): δ 7.42-7.60 (m, 1H), 6.81 (m, 3H), 5.98 (s, 2H), 5.05 (s, 2H), 4.97 (m, 1H), 4.80 (m, 1H), 3.91 (m, 1H), 3.57 (m, 1H), 3.31 (m, 2H), 2.80 (m, 1H), 2.30-2.55 (m, 1H), 1.45-2.04 (m, 6H).

The present invention provides a new method for preparing optically active cyclopentenone ( R ) -1 without the drawbacks obtained by conventional methods. More importantly, the methods described herein may be easier, more economical and more useful for industrial production purposes. The present invention also provides new cyclopentenones with a broader range of ester functional group choices by introducing R ₁ groups which result in higher crystallinity of larger or optically active cyclopentenone ( R ) -1.

Claims (18)

A process for preparing a compound of formula (I), which is rich in ( R ) -enantiomer and has an optical purity of at least 95% ee (enantiomeric excess): [Formula 1]

R ₁ is C ₁ -C ₁₀ alkyl, benzyl, naphthyl, or phenyl, Each of which is unsubstituted or at least one substituent selected from the group consisting of halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino, arylamino and cyano or pyridinyl, thiophenyl, furanyl At least one heterocycle group selected from the group consisting of imidazolyl, morpholinyl, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl and pyrrolidinoneyl, The method is (a) optically ( R ) -esterifying the racemic alcohol mixture of the compound of formula 1 with the acyl donor and the first lipase to obtain ( R ) -ester and unreacted ( S ) -alcohol; (b) removing unreacted ( S ) -alcohol; And (c) a second lipase in the presence of an alcohol wherein the ( R ) -ester is of the formula R ₁ OH; Or deacylating with a catalyst in the presence of an alcohol of formula R ₁ OH, wherein R ₁ is as defined above. The method of claim 1, The unreacted (S) - removing the alcohol, the dialkyl azodicarboxylate and a tree in the presence of an aryl phosphine, unreacted (S) - wherein by acylating the alcohol donor with the reaction (S) - alcohol ( Converting to R ) -ester Way. The method of claim 1, The acyl donor is vinyl acetate, isopropenyl acetate, vinyl valerate, isopropenyl valerate, vinyl butyrate, or isopropenyl butyrate Way. The method of claim 1, The first lipase is Candida antaxica , genus Acromobacter , genus Alkagen, Monas Fluorescence, Derived from Pseudomonas stutzry, or Pseudomonas sefacia Way. The method of claim 2, The acyl donor is a carboxylic acid Way. The method of claim 2, The dialkyl azodicarboxylate is diethyl azodicarboxylate, diisopropyl azodicarboxylate, or dibenzyl azodicarboxylate Way. The method of claim 2, The triaryl phosphine is triphenyl phosphine Way. The method of claim 1, The second lipase comprises a lipase derived from the genus Pseudomonas, Acromobacter, or Candida Antaxica. Way. The method of claim 1, The second lipase comprises a lipase derived from Candida antaxica Way. The method of claim 1, The catalyst comprises an acid selected from the group consisting of phosphoric acid, p-toluenesulfonic acid, hydrobromic acid, hydrochloric acid, nitric acid and sulfuric acid and mixtures thereof. Way. A compound of Formula 1A having a lot of R configuration and an optical purity of at least 95% ee, [Formula 1A]

X ₁ is H or a protecting group for a hydroxyl group; R ₁ is alkyl, alkenyl, alkynyl, aryl, or aralkyl, each of which is unsubstituted or halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino, arylamino One or more substituents selected from the group consisting of cyano, alcoholcarbonyl, arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl, and carbonyl or pyridinyl, thiophenyl, furanyl, imidazolyl, morphpoly Optionally substituted with a protecting group for a cyclic group, or a heterocycle group selected from the group consisting of nil, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl and pyrrolidinyl, and R ₁ is Compounds that are not straight and are unsubstituted alkyl. The method of claim 11, The protecting group for the hydroxyl group is base stable and is methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis (2-chloroethoxy) methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4 -Methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl , benzyl, substituted benzyl, and SiR _a R _b R _c (where, R _a, R _b and R _c are each independently mean a c _{1 -4} alkyl, phenyl, benzyl, substituted phenyl, or substituted benzyl Selected from the group consisting of compound. The method of claim 11, R ₁ is branched alkyl, alkenyl or alkynyl, each of which is unsubstituted or halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino, arylamino, cyano , At least one substituent selected from the group consisting of alcoholcarbonyl, arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl, and carbonyl or pyridinyl, thiophenyl, furanyl, imidazolyl, morpholinyl, oxa Substituted with a protecting group for a heterocycle group selected from the group consisting of zolinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl and pyrrolidinyl, or a carboxyl group compound. The method of claim 11, R ₁ is unsubstituted or halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino, arylamino, cyano, alcoholcarbonyl, arylcarbonyl, arylaminocarbonyl and Aralkyl substituted with one or more substituents selected from the group consisting of alkylaminocarbonyl compound. The method of claim 11, R ₁ is aryl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxyl, thioalkoxyl, alcoholcarbonyl and cyano. compound. The method of claim 11, The aralkyl is unsubstituted or halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxy, thioaryloxy, alkylamino, arylamino, cyano, alcoholcarbonyl, arylcarbonyl, arylaminocarbonyl and Benzyl substituted with one or more substituents selected from the group consisting of alkylaminocarbonyl compound. The method of claim 11, The aryl is selected from the group consisting of phenyl, naphthyl, pyrenyl and phenanthrenyl, each of which is unsubstituted or at least one selected from the group consisting of halogen, alkyl, alcoholyl, thioalcohol, alkoxycarbonyl and cyano Substituted with a substituent compound. The method of claim 11, R ₁ is naphthyl, benzyl, 2-cyanoethyl, menthyl, methoxybenzyl, piperonyl, phenyl, alcoholcarbonylphenyl, trichloroethyl or diphenylmethyl compound.