Title of Invention

"AN OPTICALLY ACTIVE AZOLE-METHYL ALCOHOL DERIVATIVE REPRESENTED BY GENERAL FORMULA (5)"

Abstract An optically active azole-methyl alcohol derivative represented by general formula (5): (wherein R1 represents a substituted or unsubstitrted alkyl group; R2 is a silyl protective group; each of R5 and R6 independently represents a halogen atom; symbol * represents an asymmetric carbon having an R configuration or an S configuration; and Y represents a carbon atom or a nitrogen atom.
Full Text DESCRIPTION
OPTICALLY ACTIVE AZOLE DERIVATIVE AND PROCESS FOR PRODUCING
THE SAME
Technical Field
Tha present invention relates to a new, simple merhod for producing an optically active 2-phenyl-2,3,-dihydroxypropyl azole derivative, which is an important compound in many fields such as medicines and agricultural chemicals
Background Art
Recently, immunocompromised patients due to infection with, for example, AIDS and patients who have a low immuniry due to highly deve_oped medical treatment or due to an increase in old people have been increasing Unfortunately, these phenomena increase the livelihood of fungal infections typified by opportunistic infection A great deal of attention in medical fields should be paid to deep-seated fungal infections such as candidiasis and aspergillosis, oecause these fungal infections often cause serious life-threarening problems to, in particular, par_ents who have a
low immunity Azole antifangal agents typified by fluconazole have been widely used as a curative nedicine for these -nfecxions In recent years, however, the emergence of res_stant strains and insufficient basic behavior of the known artifungal agents have oeen identified Therefore, the development of a curative medicine that is effective for a wider range of strains and is more powerful is desiraole (Iyaku journal, Vol 37 (7), PP 115-119 2001)
According to a recent tendency in the development of azole artifungal agents, antifungal agents have a more complex molecular structure In particular, a significant technical challenge is how to effectively achieve a structure that includes an asymmetric carbon bonded to an azole methyl group and an adjoining asymmetric carbon (J Med Chem , Vol 41, PP 1869-1882, 1998) In terms of industrial production, a stable method for producing an antifungal agent inexpensively nas not been established so far
The known processing technology will now be described In order to produce the adjoining asymmetric portion, an α-hydroxyphenyl ketone derivative is generally used as the intermediate and the ketone group is subjected to diastereoselecrive carflon-increasing epoxidation (Cnem Pnarm Buli , Vox 41 (5), PP 1035-1042 1993) Unfortunately, in terns cf industrial production, the known
method has the following serious disadvantages (1) The diastereoselectivity in the method is as low as about 4 1
(2) The yield in the isolation of the desired isomer is low
(3) The isolation and the purification require very complex
steps (4) The method causes racemization under some
reaction conditions In addition, a metnod for producing
the α-hydroxypheryl ketone derivative also includes complex
steps (Bioorg Med Chem Lett , Vol 1 (7), PP 349-352,
1991), and requires an expensive reaction reagert such as an
asymmetric catalyst (Tetrahedron Letters, Vol 37 (36), PP
6531-6534, 1996) Thus, the known method is not a
satisfactory method in terms of industrial production
Recently, a new, improved method has been reported in which
L-alanme is used as the starting material (U S Pat No
6,300,522) According to this method, however, the
fundamental problem is still not solved, because the method
also uses an α-hydroxyphenyl ketone derivative as the
intermediate Tnerefore, the metnod is still not a
satisfactory method in terms of industrial production
As described above, despite the demand for the development of a new, more useful azole antifungal agent, in terms of industrial production, a stable metnod for producing an antifungal agent inexpens_vely nas not been established in the known processing technology, because the azole antifungal agent is an optically active compound
having two asymmetric carbons Accordingly, the prompt development of a new, more effective method is desirable regarding the intermediate compound
Disclosure of Invention
It is an object of the presenr invention to provide a method for producing an optically active 2-phenyl-2,3,-dihydroxypropyl azo.e derivative, which is a useful compound in the field of medicines and agricultural chemicals, and is, in particular, a significantly important intermediate in the step of producing an optically active azole antifungal agent According to the method of the present invention, or terms of industrial production, the derivative can be produced inexpensively and stably by simple steps It is an object of the present invention to provide new intermediates produced in some steps in rhe method
As a result of intensive study to achieve the 003ect, the present inventors have found that it is possible to produce a new, optically active azole-alkyl ketone derivative that is a significantly important intermediate of medicines and agricultural chem_cals joy using an optically active oc-hydroxycarboxylic acid derivative as the starting material and by allowing the material to react rf.tn an azole acetic acid derivative The present ±nvertors nave also
found a highly diasterecselective reaction in the alkylation of the new, optically active azole-alkyl ketone derivative to produce a new, optically active azole-methyl alcohol derivative that is a significantly important intermediate of medicines and agricultural chemicals According to the diastereoselective reaction, anti or syn configuration can be arbitrarily controlled depending or the selection of the protective group and the reaction conditions Furthermore, the present inventors have found a new route for producing an optically active 2-phenyl-2,3-dihydroxypropyl azole derivative, which is a significantly important intermediate of medicines and agricultural chemicals, by selectively deprotecting the new optically active azole-methyl alcohol derivative According to this reaction, a compound having the desired configuration can be selectively produced with high optical purity without racemization In particular, the present inventors have found the following method An inexpensive lactic acid derivative is used as the optically active α-hydroxycarboxyllc acid derivative A silyl group is used as the protective grojp to produce a new, optically active silyloxy-azole-alkyl ketone derivative, which is an intermediate The intermeaiate is then subjected to alkylation with significantly hign syn selectivity to produce a new, optically active silyloxy-azole-metnyl alconol derivative Zne optically active silylcxy-azole-
methyl alcohol derivative is a significantly important intermediate to produce an optically acnve azole antifungal agent Accordingly, a 2-phenyi-2,3-dihydroxypropyl azole derivative having the desired configuration can be produced with high optical purity According to this metnod, the 2-phenyl-2,3-dihydroxypropyl azo_e derivative, which is a significantly important intermediate to produce the optically active azole antifungal agent, can be produced inexpensively and stably ny simple steps, in terms of industrial production The present invention is cased on this fact found by the inventors
The present invention includes following Items [1] to [14]
[1] A method for producing an optically active 2-phenyl-2,3-dihydroxypropyl azole derivative represented by general formula (6)
(Formula Removed)
(wnerem R1 represents a substituted or unsubstituted alkyl group, a substituted or unsucstitured aralkyl group, a substituted or unsubsituted ary_ group, or a substituted or
unsubstituted heterocyclic group, each of R5 and R6 independently represents a halogen atom, an alkyloxycarbonyl group, an aryloxycarbonyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted amido group, a substituted or unsubstituted aljcyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsuostituted phenyl group, a substituted or unsuostituted phenoxy group, a substituted or unsubstituted heterocyclic group, or a substituted or unsuostituted heterocyclicoxy group, symbol * represents an asymmetric carbon having an R configuration or an S configuration, and Y represents a carbon aton or a nitrogen atom) includes the steps of allowing an optically active α-hydroxycarboxylic acid derivative represented by general formula (1)
(Formula Removed)
(wherein R1 and symool * are as defined above, R2 represents an ether protective group, an acetal protective group, or a silyl protective group, which is a protective group for a hydroxy1 group, R3 represents a hydroxy 1 group, a halogen atom, a substituted or unsubstituted acyl group, a substituted or ursuostitutea carbcrate group, a substituted
or unsubstituted alkyloxy group, a suostituted or unsubstituted aralkyloxy group, a substituted or unsubstituted phenoxy group, or a substituted or unsubstituted amino group) to react with an azole acetic acid derivative represented by general formula (2)
(Formula Removed)
(wherein R4 represents a nydrogen atorr, a substituted or unsubstituted alkyl group, an alkali metal, or an alkaline earth metal salt, and Y is as defined above) under a basic condition to produce an azole-methyl ketone derivative represented by general formula (3)
(Formula Removed)
(wherein R1, R2, symbol *, and Y are as defined above), allowing the optically active azole-methyl ketone derivative represented by general formula (3) to diastereoselectively react with a phenyl metallic reagent represented by general formula (4)
(Formula Removed)
(wherein R5 and R6 are as def_ned above, A represents L1, MgX, ZnX, TiX3, T2(OR7)3, CuX, or Cull, wherein X represents
a ha_ogen atom, and R7 represents a substituted or unsubstituted alkyl group}) to produce an optically active azole-methyl alcohol derivative represented by general formula (5)
(Formula Removed)
(wherein R1, R2, R5, R6, symbol *, and Y are as defined above) , and selectively deprotecnng nhe protective groap R2 for a hydroxyl group of the optically active azole-methyl alcohol derivative represented by general formula (5) [2] A method for producing an azole-methyl ketone derivative represented by general formula (3) (wherein R1, R2, Y, and symbol * are as defined above) includes allowing an α-hydroxycarboxylic ac_d derivative represented by general formula (1) (wherein R1, R2, R3, and symbol * are as defined above) to react with an azole acetic acid derivative represented by general formula (2) (wherein R4 and Y are as defined above) under a basic condition
[3] A method for producing an optically active azo_e-methyl alcohol derivative represerted by general formula (5) (wherein R1, R2, R5, R6, Y, and symbol * are as def_ned above) includes allowing an optically active azole-methyl ketone derivative represented by general formula (3)
(wherein R1, R2, Y, and symool * are as defired above) ro d_astereoselectively react with a phenyl metallic reagent represented by general formula (4) (therein R5, R6, A, X, and R7 are as defined above)
[4] A method for producing an optically active azole-methyl alcohol derivative represented by general formula (5) (whereir R1, R2, R5, R6, Y, and symbol * are as defined above) includes allowing an optically active azole-methyl ketone derivative represented by general formula (3) (wherein R1, R2, Y, and symbol * are as defined above) to anti-selectively react with a phenyl metallic reagent represented by general formula (4) (wherein R5, R6, A, X, and R7 are as defined above)
[5] A method for producing an optically active azole-methyl alcohol derivative represented by general formula (5) (wherein R1, R2, R5, R6, Y, and symbol * are as defined above) includes allowing an optically active azole-methyl ketone derivative represented by general formula (3) (wherein R1, R2, Y, and symbol * are as defined above) to syn-selectively react with a phenyl metallic reagent represented oy general formula (4) (wherein R5, R6, A, X, and R7 are as def_ned above)
[6] A method for producing an optically active 2-phenyl-2,3-dihydroxypropyl azole derivative represented by general formula (6) (wherein R1, R5, R5, Y, and symbol * are as
defined above) includes selectively deprotectmg the protective group R2 for a hydroxyl group of an optically active azole-methyl alcohol derivative represented by general formula (5) (wherein R1, R2 , R5, R6, Y, and symbol * are as defined above)
[7] The method according to any one of Item [1] to Item [6] wherein Rl is a methyl group, and each of R5 and R6 is a fluorine or chlorine atom
[8] An optically active azole-methyl ketone represented by general formula (3) (wherein R1, R2, Y, and symbol * are as defined above)
[9] The optically active azole-methyl ketone according to Item [8], wherein Rl is a methyl group
[10] The optically active azole-methyl ketone according to Item [9], wherein R2 is a silyl protective group [11] An optically active azole-methyl alcohol derivative represented by general formula (5) (wherein R1, R5, R6, Y, and symbol * are as defined above), wherein R2 is a silyl protective group
[12] The optically active azole-methyl alcohol derivative according to Item [11], wherein Rl is a methyl group [i3] The optically active azole-methyl alcohol derivative according to Item [12], wherein each of R5 and R6 is a halogen atom [14] The optically active azoie-Tethy_ alcohol derivative
according to Item [13] , wherein Y is a nitrogen atore
Best Mode for Carrying Out the Invention
The compounds of the present invention will now be described in detail
According to the present invention, "a substituted or unsubstiruted alkyl group" represents an alkyl group in which any position of the alkyl group may be substituted Examples of the alkyl group include methyl, ethyl, isopropyl, tert-butyl, pentyl, hexyl, octyl, decyl, and allyl groups Examples of the substituent include, hydroxyl group, alkoxy groups such as methoxy, benzyloxy, and methoxysthoxy groups, a phenoxy group, a nitro group, an amino group, an amido group, a carboxyl group, alkoxycarbonyl groups, a phenoxycarbonyl group, and halogen atoms such as fluorine, chlorine, bromine, and iodine atoms
According to the present: invention, "a substituted or unsubstituted aralkyl group" represents an aralkyl group in which any position of the aralkyl group may be substituted Examples of the aralkyl group include benzyl, naphthylmethyl, phenyletoyl, and 9-fiuorenylmethyl groups Examples of the substituent include alkyl groups such as methyl, tert-butyl, and benzy- groups, cycloalkyl groups such as cyclopropane, cyciopentare, and cyclohexar.e, a pneryl group, hydroxyl
group, alkoxy groups sucn as methoxy, berizyloxy, and methoxyethoxy groups, a ohenoxy group, a nitro group, an amino group, an amido group, a carbcxyl group, alkoxycarbonyl groups, a phenoxycarboryl group, and halogen atoms such as fluorine, chlorine, bromine, and iodine atoms
According to the present invention, "a substituted or unsubstituted aryl group" represents an aryl group in which any position of the aryl group may be substituted Examples of the aryl group include phenyl, naphthyl, anthracenyl, fluorenyl, and phenanthryl groups Examples of the substituent include alkyl groups such as methyl, tert-butyl, and benzyl groups, cycloalkyl groups such as cyclopropane, cyclopentane, and cyclohexane, a phenyl group, hydroxyl group, alkoxy groups such as methoxy, benzyloxy, and methoxyetnoxy groups, a pnenoxy group, a nitro group, an amino group, an amicto group, a carboxyl group, alkoxycarbonyl groups, a phenoxycarbonyl group, and halogen atoms such as fluorine, chlorine, bromine, and iodine atoms
According to the present invention, "a substituted or unsubstituted heterocyclic group" represents a heterocyclic group in which any position of the heterocyclic group having a beteroatom such as oxygen, nitrogen, and sulfur atoms may be substituted Examples of the beterocyclic group include tetranydropyranyl, tetrahydrofuranyl, tetraryarothenyl, piperidyl, morphoiny, plperazinyl, pyrrolyl, furyl,
thienyl, pyridyl, furfaryl, thenyl, pyndylmethyl, pyrimidyl, pyrazyl, imidazolyl, imidazolylmethy_, indolyl, indolylmethyl, isoquinolyl, qumolyl, and -chiazolyl groups Examples of the substituent include alkyl groups such as methyl, tert-batyl, and benzyl groups, cycloalkyl groups such as cyclopropane, cyclopentane, and cyclohexane, a phenyl group, hydroxyl group, alkoxy groups such as methoxy, benzyloxy, and methoxyethoxy groups, a phenoxy group, a nitro group, an amino group, an amido group, a carboxyl group, alkoxycarbonyl groups, a pnenoxycarbonyl group, and halogen atoms such as fluorine, chlorine, bromine, ana iodine atoms
According to the present invention, "an ether protective group which is a protective group for a hydroxyl group" represents a protective group that protects the hydroxyl group, and the protect.ve group having an ether bond Examples of the protective group include methyl, ethyl, tert-butyl, octyl, allyl, benzyl, p-methoxybenzyl, fluoreryl, trityl, and benzhydryl groups
According to the present invention, "an acetal protective group" represents a protective group that protects the hydroxyl group, and the protective group having an acetal bond Examples of the protective group include methoxymethyl, ethoxyethyl, methoxyethoxymethyl, tetrahydropyranyl, and tetrarydrofararyl groups
According to the present invention, "a silyl protective group" represents a protective group tnat protects the hydroxyl group, ana the protective group having a silyloxy bond Examples of the protective group include trimethyls-lyl, triethylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl groups
According to the present invention, examples of "a halogen atom" include fluorine, chlorine, bromine, and iodine atoms
According to the present invention, "a substituted or unsubstituted acyl group" represents an acyl group in which any position of the acyl group may be substituted Examples of the acyl group include formyl, acetyl, propionyl, povaloyl, and benzoyl groups Examples of the substituent include alkyl groups such as methyl, tert-butyl, and benzyl groups, cycloalkyl groups such as cyclopropane, cyclopentane, and cyclohexane, a phenyl group, hydroxyl group, alkoxy groups such as methoxy, benzyloxy, and methoxyethoxy groups, a phenoxy group, a nitro group, an amino group, an amido group a carboxyl group, alkoxycarbonyl groups, a phenoxycarbonyl group, and halogen atoms such as fluorine, cnlorine, bromine, and iodine atoms
According to the present invention, "a substituted or unsubstituted carbonate group" represents a carbonate group in wruch any position of the caroonate group may oe
substituted Exairples of the carbonate group include methyl carbonate, ethyl carbonate, isopropyl caroonate, and benzyl carbonate groups Examples of the substituent include alkyl groups such as methyl, tert-butyl, and benzyl groups, cycloalkyl groups sucn as cyclopropane, cyclopentane, and cyclohexane, a phenyl group, hydroxyl group, alkoxy groups such as methoxy, benzyloxy, and metnoxyethoxy groups, a phenoxy group, a nitro group, an amino group, an amido group, a carboxyl group, alkoxycarbonyl groups, a phenoxycaroonyl group, and halogen atoms such as fluorine, chlorine, bromine, and iodine atoms
According to the present invention, "a substituted or unsubstituted alkyloxy group" represents an alkyloxy group in which any position of the alkyloxy group may be substituted Examples of the alkyloxy group include methoxy, ethoxy, isopropoxy, tert-butoxy, pentyloxy, hexyloxy, octyloxy, decyloxy, ard allyloxy groups Examples of the substituent include hydroxyl group, alkoxy groups such as methoxy, ben2yloxy, and methoxyethoxy groups, a phenoxy group, a nitro group, an amino group, an amido group, a carboxyl group, alkoxycarbonyl groups, a phenoxycarbonyl group, and halogen atoms such as fluorine, chlorine, bromine, and _odme atoms
According to the present invention, "a substituted or ansubstituted aralkyloxy group" represents an aralkyloxy
group in which any positior of the aralkyloxy group may be substituted Examples of the aralkyloxy group include oerzyloxy, naphthylmetnyloxy, phenylethyloxy, and 9-fluorenylmethyioxy groups Examples of the substituent include alkyl groups such as methyl, tert-butyl, and benzyl groups, cycloalkyl groups such as cyclopropane, cyclcpentane, and cj-clohexane, a phenyl group, hydroxyl group, alkoxy groups such as methoxy, r>enzyloxy, and methoxyethoxy groups, a phenoxy group, a nirro group, an amino group, an amido group, a carboxyl group, alkoxycaroonyl groups, a phenoxycarbonyl group, and halogen atoms such as fluorine, chlorine, bromine, and iodine atoms
According to the presert invention, "a substituted or unsubatituted phenoxy group" represents a phenoxy group in which any position of the phenoxy group may be substituted Examples of the substituent Include alkyl groups such as methyl, tert-butyl, and benzyl groups, cycloalky- groups such as cyclopropane, cyclcpentane, and cyclohexane, a phenyl group, hydroxyl group, alkoxy groups such as methoxy, benzyloxy, and methoxyethoxy groups, a phenoxy group, a nitro group, an amino group, an amido group, a carboxyl group, alkoxycarboryl groups, a phenoxycarbonyl group, and ralogen atoms such as fluorme, chlorire, bromine, and odme atoms
According to the present invention, "a substituted or
unsubstituted amino group" represents an amino group xn which any position of the amino group may be substituted Examples of the substituent include alkyl groups such as methyl, tert-butyl, and benzyl groups, cycloalkyl groups such as cyclopropane, cyclopentane, and cyclohexane, and a phenyl group
According to rhe present invention, examples of "an alkali metal" include lithium, sodium, potassium, rubidium, and cesium
According to the present invention, "an alkaline earth metal salt" represents a salt of, for example, magnesium, calcium, strontium, barium, or beryllium Examples of the alkaline earth metal salt include magnesium halides, magnesium alkoxides, calcium halides, calcium a_koxides, strontium halides, barium halides, and beryllium halides In more detail, examples of the alkaline earth metal salt include magnesium salts such as -MgCl, -MgBr, -MgOMe, and -MgOEt, calcium salts such as -CaCl, -CaBr, -CaOMe, and -CaOEt, and barium salts such as -BaCl, -BaBr, -BaOMe, and -BaOEt Two molecules of an azole acetic acid derivative may form a single alkaline earth metal salt
According -co the present invention, examples of "an alkyloxycarbonyl group" inciae metnoxycarbonyl, etnoxycarbonyl, and tert-batoxycarbonyl groups
According to the present irvention, examples of "an
aryloxycarbonyl group" include phenoxycarbonyl and naphthyloxycarbonyl groups
According to the present invention, "a substituted or unsubstituted amido group" represents an amido group in which any position of the amido group may be substituted Examples of the suostituent include alkyl groups such as -methyl, tert-butyl, and benzyl groups, cycloalkyl groups such as cyclopropane, cyclopentane, and cyclohexane, ana a phenyl group
According to the present invention, "a substituted or unsubstituted heterocyclicoxy group" represents a heterocycliccxy group in which any position of the heterocyclicoxy group may be substituted Examples of the heterocyclicoxy group include tetrahydropyranyloxy, tetrahydrofuranyloxy, tetrahydrothienyloxy, piperidyloxy, morpholmyloxy, piperazmyloxy, pyrrolyloxy, furyloxy, thienyloxy, pyridyloxy, furfuryloxy, thenyloxy, pyndylmethyloxy, pyrimidyloxy, pyrazyloxy, midazolyloxy, imidazolylirethyloxy, mdolyloxy, mdclylmethyloxy, isoquinolyloxy, qumolyloxy, ana thiazolyloxy groups Examples of the substituent include alkyl groups such as methyl, tert-butyl, and benzyl groups, cycloalkyl groups such as cyclopropane, cyclopentane, and cyclohexane, a phenyl group, hydroxy1 group, alkcxy groups such as methoxy, benzyloxy, and methcxyethoxy groups, a phenoxy group, a
nitro group, an amino group, an amido group, a carboxyl group, alkoxycarbonyl groups, a phenoxycarbonyl group, and halogen atoms such as fluorine, chlorine, bromine, and iodine atoms
According to the present invention, "allowing the compound represented by general formula (3) to diastereoselecrively react with the reagent represented by general formula (4) to produce the compound represented by general formula (5)" means to selectively produce a new asymmetric carbon adjoining an asymmetric carbon in general formula (3) The term "anti-selectively" has the following meaning In a plane on which a carbon chain is disposed in a zigzag, a hydroxyl group is produced at the opposite side of the R20-group bonded to the optically active carbon atom The term "syn-selectively" has the following meaning In a plane on which a carbon chain is disposed in a zigzag, a hydroxyl group is produced at the same side of the R20-group bonded to the optically active carbon atom In other words the selectivity represented by "anti-selectively" is the diastereoselectivity represented by general formula (7)
(Formula Removed)
As shown in general formula (7), an (S)-enantiomer produces an (S, R)-diastereomer, and an (R)-enantiomer produces an (R, S)-diastereomer
The selectivity represented by "syn-selectively" is the diastereoselectivity represented by general formula (8)
(Formula Removed)
As shown in general formula (8), the (S)-enantiomer produces an (S, S)-diastereomer, and the (R)-enantiomer produces an (R, R)-diastereomer
Tables 1 to 10 shew examples cf the compounds
represented by general formulae (3), (5), (6), (8), (9), and (10) The compounds of the present nvsntion are not limited to the following compounds
Table 1
(Table Removed)
A typical nethod of the present invention will now be described
[1] A method for producing an optically active azole-methyl ketone derivative represented by general formula (3) will now be described
An azole-methyl ketone derivative represented by general formula (3) is produced by allowing an optically active α-alkoxycarboxylic acia derivative represented by general formula (1) to react with an azole acetic acid derivative represented by general formula (2) under a basic condition According to this reaction, a decarboxylation proceeds after or during a carbon-carbon bonding reaction, thereby effectively introducing an azole methyl group Although an optically active substance is used as the starting material, this reaction hardly decreases the optical purity of the resultant product
The base used for the above reaction is not limited Examples of the base include inorganic bases such as litnium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassxum caroonate, and sodium nydrogencarbonate Examples of the base include organic amine bases such as trlethylamine, pyridine, and 1, 8-diazabicycloundecene Examples of the base include alkoxides such as sodium methoxide, sodium etnoxide, and potassium tert-butoxiae Examples of zhe case _include meta_ hydrictes sucr as within
hydride and sodium hydride Examples of the base include organometallic bases such as alkyl lithium and Grignard reagents, e g , in particular, n-butyllitmum, ethyl magnesium bromide, n-butyl magnesium chloride, and tert-butyl magnesium chloride Examples of the base include metallic amide base such as sodium amide, lithium amide, and magnesium amide In particular, examples of the metallic amide base include lithium dusopropylamide and magnesium halide dialkylamide, e g , iragnesium chloride dusopropylamide These bases may be used alone or in combination of two or more
Any solvent may be used as long as the reaction is not inhibited Examples of the solvent include water, alcohols such as methanol, ethanol, and butanol, hydrocarbons such as hexane, toluene, and xylenes, esters such as ethyl acetate ard butyl acetate, ethers such as diethyl ether, dioxane, ethylene glycol dimethyl ether, and tetrahydrofuran, halogenated hydrocarbors such as chloroform and dichloromethane, acetomtrile, dimethylformamide, dimethylsulfcxide, and dimetnylimidazolidmone These solvents may be used alone or in combination of two or more at any mixing ratio The reaction temperature is generally in the range of -78°C to the boling point of the solvent used, and preferably -20°C to the boiling point of the solvent Although the reacticn t-ma is r.oi limited, the
reaction time is generally in the range of several minutes to 2 4 hours, and preferably, 30 minutes to 6 hours
[2] A method for producing an optically active azole-metnyl alcohol derivative represented by general formula (5) will now be described
An optically active azole-methyl alcohol derivative represented by general formula (5) is produced by allowing an optically active azole-methyl ketore derivative represented by general formula (3) to react with a phenyl metallic reagent represented by general formula (4) In this reaction, the diastereoselectivity depends on the combination of a protective group R2 for a hydroxyl group and a metal represented by A Anti or syn configuration can be arbitrarily synthesized depending on the appropriate selection of the protective group and the metal
In short, in this reaction, an organometailic reagent is allowed to react with the optically active azole-methyl ketone derivative according to a chelation model wherein the configuration of the oxygen atom in the R20-group and the carbonyl group relating to the reaction is determined by the coordination of the metal Thus, a desired product can be produced with h_gh anti diastereoselectivity In more detail, a compound having an S configuration selectively produces a compound having an S-R configuration, and a compound having an R configuration selectively produces a
compourd having an R-S configuration In particular, for example, a bsnzyl or methoxymethyl group is used as the protective group and a Grigrard reagent is usea as the organometailic reagent In this case, the desired reaction proceeds with high anti seiectivity (>6 1)
On the otner hand, a desired product can be produced with high syn selectivity by using a bulky protective group R2 for the hydroxyl group, and an appropriate metallic reagent In more detail, a compound having an S configuration selectively produces a compound having an S-S configuration, and a compound having a R configuration selectively produces a compound having an R-R configuration with high syn selectivity (>4 1) The use of a silyl protective group allows the desired reaction to take place with significantly high syn selectivity (>20 1) Examples of the silyl protective group include tnmethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triethylsilyl groups
Although an optically active substance is used as the starting material, this reaction hardly decreases the optical purity of the resultant product Examples of a prenyl metallic compound include pnenyl-lithxum derivatives, pnenyl-magnesium aerivatives, pheryl-zinc derivatives, phenyl-titanium derivatives, pienyl-copper derivatives, and phenyl-copper derivatives Additives may be aaded
to the reaction system in order to cnange the diastereoselectivity and to improve the yield Examples of the additives include Lewis acids and quaternary aminonium salts In more detail, examples of the additives .include CeCl3, MgBr2, MgCl2, ZnCl2, ZnBr2, CuCl2, TiCl4, BF3, AlCl3, SnCl4, and SnCl2
Any solvent may be used as long as the reaction is not inhibited Examples of the solvent include water, alcohols such as methanol, ethanol, and butanol, hydrocarbons such as hexane, toluene, and xylenes, esters such as ethyl acetate and butyl acetate, ethers such as diethyl ether, dioxane, etnylene glycol dimethyl ether, and tetrahydrofuran, halogenated hydrocarbons such as chloroform and dichloromethane, acetoritnle, dimethylformamide, dimethylsulfoxide, and dimethylimidazolidmone These solvants may be used alone or in combination of two or more at any mixing ratio The reaction temperature is generally in the range of -78°C to the boiling point of the solvent used, and preferably, -40°C to room temperature Although the reaction time is nor limited, the reaction time is generally in the range of several minutes to 24 hcurs, and preferably, 30 minutes to 6 hours
[3] A method for producing an optically active 2-pnenyi-2,3-dihydrcxyprcpyl azcle derivative represented by gereral formula (6) will new be aescribea
An optically active 2-phenyl-2,3-dihydroxypropyl azole derivative represented by general formula (6) is produced by selectively deproteting the protective group R2 for a hydroxyl group in an optically active azole-methyl a_cohol derivative represented by general formula (5) The method for deprotectmg the hydroxyl group is not limited as long as the molecular structure other than the deprotected portion is not changed An ether protective group is deprotected by acid treatment using, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluene sulfonic acid, or acetic acid, or by catalytic hydrogenation using a catalyst such as palladium-carbon An acetal protective group is deprotected by acid treatment using, for example, nydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluene sulfonic acid, pyridinium p-toluene sulfonic acid, or acetic acid A silyl protective group is deprotected by acid treatment using, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluene sulfonic acid, pyridimum p-toluene sulfonic acid, or acetic acid, or by fluoride anion treatment using, for example, tetra-n-butyl-aminonium fluoride Any solvent may be used as long as the reaction is not innibited Examples of the solvert include water, alccnols such as methanol, etnanol, and butanol, bydrocaroons sich as hexane, toluene, and xylenes, esters such as etoyl acetate and butyl acetate,
ethers such as diethyl ether, dioxane, ethylene glycol dimethyl ether, and tetrahydrofuran, halogenated hydrocarbons such as chloroform and dichlorometnane, acetontrile, dimethylformamide, and dimethylsulfoxide These solvents may be used alone or in combination of two or more at any mixing ratio The reaction temperature is generally in the range of -20°C to the boiling point of the solvent used Although the reaction time is not limited, the reaction time is generally in the range of several minutes to 24 hours, and preferably, 30 minutes to 6 hours
The optically active α-hydroxycarboxylic acid derivative represented by general formula (1) is readily and commercially available or can be synthesized by generally known methods For example, the optically active α-hydroxycarboxylic ac_d derivative can be synthesized by using lactic acid (Chem Pharm Ball , Vol 41 (6), PP 1035-1042, 1993), various amino acids (Synthesis, 1987, P 479), or an α-nalocarboxylic acia derivative (Tetrahedron Lett , 1985, Vo_ 26, P 5257) The azole acetic acid derivative represented by general formula (2) can be readily synthesized by cnown methods (for example, Tetrahearon Lett , 2000, 41 (8), i297) In the present invention, methods for producing some reagents and starting materials are net specxfically descrioed In general, tnese reagents and materials are commercially available, and therefore readily
available
Although examples of the present invention will now be described, the present invention is not limited to the following examples
[Example 1] Syntnesis of (3R)-1- (1H-1,2,4-triazol-l-yl)-3-(triphenylmetHyloxy) -2-butanone
(Formula Removed)
Tetrahydrofuran (4 mL) and triethylamine (0 44 g) were added to triazole acetic acid (0 55 g) and the mixture was stirred at room temperature for two hours Subsequently, methyl (2R)-2-(triphenylmethyloxy) propionate (1 00 g) was mixed with the mixture at room temperature The resultant homogeneous mixture is hereinafter referred to as Solution A A solution (25 mL) of tetrahydrofuran containing tert-butyl magnesium chloride (0 91 M) was heated at 40°C to 45°C Solution A was added dropwise to the solution for one hour The mixture was then stirred at 40°C to 45°C for four hours The reaction mixture was cooled on ice to 5°C, and sulfuric acid (2 N, 30 mL) was added dropwise to the mixture Ethyl acetate (53 mL) was added to the rrixture to extract the target compound Inus, an organic layer was separated The
organic layer was washed with saturated sodium bicarbonate
(40 mL), and subseqaently washed with a saturated saline
solution (40 mL) The washed organic layer was dried with
anhydrous sodium sulfate, and was then concentrated The
resultant substance was purified by silica gel column
chromatography (equivalent to Merck C-300, 15 g, pure
chloroform to chloroform metnanol=8 2) The resultant
suostance was crystallized with hexane to recover light
yellow crystals of the target compound (0 60 g, 52%)
Melting point 162"C (decomposition)
XH-N y R (270 MHz, CDCl3) δ=7 84 (s, 1H) , 7 48 (s, Ik) , 7 45-
7 25(m, 15H) , 5 01 (d, IK, J=8 8 Hz) , 4 40(q, 1H, J=6 9 HZ),
4 07 (d, 1H, J=8 8 Hz), and 1 51 (d, 3H, J=6 9 Hz)
[Example 2] Synthesis of (3R)-3- (benzyloxy)-1- (1H-1,2,4-triazol-1-yl)-2-butanone
(Formula Removed)
The target compound (7 6 g, 30%), which was a
transparent and colorless syrup, was recovered as in Example
1, except netnyl (2R)-2-(berzy^oxy) propionate (20 0 g) was
used _nstead of methyl (2R)-2-(tr_pnenylmetnyloxy)
propionate
-J-N in R (270 MHz, DMSO-d6) δ=8 44 (s, IP) 7 98 (s, 1-3),
7 50-7 20(m, 5H) , 5 55(d, 1H, J=18 6 Fz) , 5 43(d, 1H, J=18 6 Hz), 4 61(5, 2H), 4 26(q, 1H, J=6 9 hz), and 1 34(d, 3H, J=6 9 Hz)
[Example 3, Synthesis of (3S)-3-(benzyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone
(Formula Removed)
The target compound (340 mg, 19%), which was a transparent and colorless syrup, was recovered as in Example 1, except benzyl (2S)-2-(benzyloxy) propionate (1 88 g) was used instead of methyl (2R)-2-(tnphenylmethyloxy) propionate The values of the physical properties corresponded with those in Example 2
[Example 4} Synthesis of (3R)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-l-yl)-2-butanone
(Formula Removed)
The target compound (1 59 g, 40%), which was a transparent and color_ess syrup, was recovered as in Example 1, except methyl (2R)-2-(metncxymethy-cxy) propionate (2 96 g, 20 rranol) was ased instead of methyl (2R)-2-
(tnphenylmethyloxy) propionate 1H-N K R (270 MHz, CDCl3) δ-8 14 (s, 1H) , 7 97 (s, 1H) ,
5 36 (d, IK, J=8 8 Hz) , 5 22(d, 1H, J=8 8 hz) , 4 73-4 70(m,
1H), 4 40(q, 1H, J=6 9 Hz), 3 95-3 87 (m, 1H) , 3 59-3 52 (m,
1H) , 1 91-1 55(m, 6H) , and 1 48 (d, 3H, J=6 9 Hz)
[Example 5] Syntnesis of (3R)-3-(tert-butyldimethylsilyioxy)-1-(1H-1,2,4-triazol-l-yl)-2-butanone
(Formula Removed)
Tetrahydrofuran (15 mL) was added to tnazole sodium acetate (1 02 g, 6 87 mmol) and annydrous magnesium chloride (1 31 g, 13 7 mnol), and the mixture was stirred at room temperature for two hours A solution (15 1 mL) of tetrahydrofuran containing tert-butyl magnesium chloride (0 91 M) was added to the mixture, and the mixture was heated at 40°C to 45°C Subsequently, a solution of tetrahydrofuran (3 mL) containing metnyl (2R)-2-(tert-butyldimethylsilyioxy) propionate (1 00 g 4 58 mmol) was added dropwise to the mixture at 40°C to 45 °C for one hour The mixture was tnen stirred at 40°C to 45CC for four hours Sulfuric acid (10%) was added to the reaction mixture so tnat the pH of the reaction mixture was controlled in the range of 2 to 4 Tne target corrpound was extracted with
toluene (20 mL) The extracted solution was wasned with
water, and was then dried with anhydrous magnesium sulfate
The drying agent was filtered, and the filtrate was
concentrated under reduced pressure The resultant crude
product was purified by silica gel column chromatography
(equivalent to Merck C-300, 15 g, hexane ethyl acetate=3 1
to 2 1 to 1 1) to recover the target compound (1 09 g, 82%),
which was a transparent and colorless syrup
1H-NMR (270 MHZ, CDCl3) δ=8 14 (s, 1H) , 7 98 (s, 1H) ,
5 42(d, 1H, J=19 1 Hz) , 5 22 (d, 1H, J=19 1 Hz) , 4 39(q, 1H,
J=6 9 Hz), 1 40 (d, 3H, J-6 9 Hz), 0 97 (s, 9H) , and 0 16(s,
6H)
Optical purity by a chiral HPLC area method 99%ee Analytical conditions/ DAICEL CHIRALPAK AD, Eluent composition hexane 2-propanol diethylamme=90 10 0 1, Detection method UV 220 nm
[Example 6] Synthesis of (3R)-3-(3,4, 5,6-tetrahydro-2H-pyran-1-yloxy) -1- (1H-1,2 , 4-tnazol-l-yl) -2-butanone
(Formula Removed)
The target compound (2 15 g, 45%) , which was a transparent and co_orless syrup and was a mixture of two
diastereomers derived from the THP group, was recovered as
_r Example 1, except methyl (2R)-2-(3,4,5,6-tetrahydro-2H-
pyran-1-yloxy) propionate (3 77 g, 20 mmol) was used
THP group-derived diastereomer A, lH-N M R (270 M4z , CDCl3)
5-8 11(3, 1H) , 7 97 (s, 1P), 5 36(d, 1H, J=8 8 Hz) , 5 22 (d,
_H, J-8 8 Hz), 4 73-4 70 (m, 1H) , 4 40(q, 1H, J=6 9 Hz) ,
3 95-3 87(m, 1H) , 3 59-3 52 (m, 1H) , 1 91-1 55(m, 6H) , and
1 48(d, 3H, J=6 9 Kz)
THP group-derived diastereomer B, XH-N M R (270 MHz, CDCl3)
5=8 11 (s, 1H) , 7 96(s, 1H) , 5 50(d, 1H, J=8 8 Hz), 5 32(d, 1H, J-8 8 Hz) , 4 57-4 54 (m, 1H) , 4 24(q, 1H, J=6 9 Hz), 3 95-3 89 (m, 1H) , 3 52-3 42 (m, 1H) , 1 89-1 84 (m, 2H) , 1 57-1 54 (m, 4H) , and 1 39 (d, 3H, J=6 9 Hz)
[Example 7] Synthesis of (2R, 3R)-2-(2,4-difluorophenyl)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-l-yl)-2-butanol and {2S, 3R)-2-(2,4-diflaoropnenyl)-3-(methcxymethyloxy)-1- (1H-1,2,4-tnazol-l-yl)-2-butanol
(Formula Removed)
2,4-DiflacroDroiriobenzene (202 mg, 1 05 mmol) was dissolved in ether (4 ml) A solution of hexane (0 66 mL,
I 05 mmol) containing n-butyllithxum (1 59 M) was added dropwise to the mixture at -70°C to -65°C, and the mixture was stirred for 30 minutes Tne resultant mixture is hereinafter referred to as Mixture A Anhydrous cerium chloriae (258 mg, 1 05 mmol) was dried at 140°C for one hour under reduced pressure, and was then cooled to room temperature Tetrahydrofuran (3 mL) was added to the anhydrous cerium chloride, and was subsequently subjected to ultrasonic treatment for 30 minutes The resultant suspension is hereinafter referred to as Suspension B Suspension B was added dropwise to Mixture A, which was cooled at a temperature in the range of -70°C to -65°C Subsequently, a solution of ether (2 mL) containing (3R)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-l-yl)-2-butanone (70 mg, 0 35 mmol) was added dropwise to the mixture at -70°C to -65°C The mixture was stirred at this temperature for 30 minutes The temperature of the mixture was tnen increased to room temperature Ethyl acetate (10 mL) and water (10 mL) were added to the reaction mixture and an organic layer was separated The organic layer was washed with a saturated saline soution (5 mL) and was then dried with anhydrous magnesium sulfate The drying agent was filtered and the filtrate was concentrated under reduced pressure The resultant product was rsurified by preparative silica gel than layer chromatography (Merck:, 2 0 cmx2 0 cmx2 mm,
developing solution pure ethyl acetate) to recover the
rarget compound (38 mg, 35%), which was a mixture of
diastereomers The compourd was a transparent and colorless
syrup The ratio of the diastereomers was (2R, 3R) (2S,
3R)™6 1 The ratio of the diastereomers was determined by
derivatives, as will be described in Example 18, in which
the methoxymethyl group was deprotected
(2R, 3R)-Diastereomer, lH-N M R (270 MHz, CDCl3) δ-7 89(s,
1H) , 7 73(s, 1H) , 7 48-7 38(m, 1H) , 6 79-6 71 (m, 2H) , 4 91-
4 72 (m, 4-1), 4 29 (q, _H, J=6 6 4z), 4 13(s, 1H) , 3 46(s, 3H) ,
and 1 03(d, 3H, J-6 6 Hz)
(2S, 3R)-D_astereomer, 1H-N M R (270 MHz , CDCl3) δ=8 02 (s,
1H), 7 72(s, 1H), 7 49-7 40(m, 1H), 6 79-6 69(m, 2H), 4 99(d,
1H, J=13 8 Hz) , 4 59 (d, 1H, J=7 0 Hz), 4 48 (d, 1H, J=13 8
Hz), 4 42(d, 1H, J=7 0 Hz), 4 41(s, 1H), 4 15(q, 1H, J=6 3
Hz), 3 08 (s, 3H) , and 1 28 (d, 3H, J=6 3 Hz)
[Example 8] Synthesis of (2R, 3R)-3-(benzyloxy)-2-(2 ,4-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)-2-butanol and (2S, 3R)-3-(benzyloxy)-2-(2,4-difluorophenyl) -1-(lH-1,2,4-triazol-1-yl)-2-butanol
(Formula Removed)
Magnesium (6 0 g, 46 mmol) was dispersed in tetrahydrofuran (120 mL) in a nitrogen atmosphere Iodine (5 mg) was added and the mixture was stirred A solution of tetrahydrofuran (120 mL) containing 2,4-difluorobromobenzere (48 g, 248 mmol) was added dropwise to the mixture so that the internal temperature was controlled 30°C to 35°C The resultant mixture is hereinafter referred to as Grignard reagent A Anhydrous ceriuur chloride (10 g, 40 8 mmol) was dried at 130°C for one hour under reduced pressure, and was then cooled to room temperature Tetrahydrofuran (40 mL) was aaded to the annydrous cerium chloride in a nitrogen atmosphere, and the resultant suspension was subsequently subjected to ultrasonic treatment for 30 minutes The suspension is hereinafter referred to as Suspension B Subsequently, a solution of tetrahydrofuran (10 mL) containing (3R)-3-(benzyloxy)-1-(1H-1,2,4-triazol-l-yl)-2-butanone (5 0 mg, 20 4 mmol) was added to Suspension B, and the mixture was further subjected to ultrasonic treatment for 30 minutes Tetrahydrofuran (4 mL) was added to the resultant Suspension B, and then the temperature of the suspension was kept at 0°C to -5°C _ Grignard reagent A (24 mL, 24 mmol) was added aropwisa to the suspension Subsequently, the mixture was further stirred for 12 hours The reaction mixture was cooled on ice and hydrochloric acid (1 N, 200 mL) was aaded dropwise to the mixture Etnyl
acetate (400 mL) was added to the mixture to extract the
target compound Thus, an organic layer was separated The
organic layer was washed with a saturated aqueous solution
of sodium hydrogencarbonate (400 mL), and subsequently
washed with a saturated saline solution (400 mL) The
organic layer was then dried with magnesium sulfate The
drying agent was filtered and the filtrate was concentrated
to produce an oily product (10 g) The product was purified
by silica gel column chromatography (equivalent tc Merck C-
300, 10 g, hexane ethyl acetate=2 1 to 1 1) to recover the
target compound (900 mg, 12%) The compound was a
transparent and colorless syrup The ratio of the
diastereomers was (2R, 3R) (2S, 3R)=1 14 The ratio of the
diastereomers was determined by derivatives, as will be
described in Example 14, in which the benzyl group was
deprotected
(2R, 3R)-Diasterecmer, 1H-N M R (400 MHz, CDCl3) δ=7 85(s,
1H), 7 67(s, 1H) , 7 42-7 30 (m, 6H) , 6 76-6 68(m, 2H), 4 77(d,
1H, J=ll 5 Hz), 4 72(s, 2A) , 4 51 (d, 1H, J=ll 5 Hz) , 4 15(q,
1H, J=6 3 Hz) , 4 02 (s, 1H) , and 1 04(d, 1H, J=6 3 Hz)
(2S, 3R)-Diastereomer, M-N M R (400 MHz, CDCl3) δ=7 99 (s,
1H), 7 72(s, 1H), 7 49-7 43(m IE), 7 29-7 26(m, 3H), 7 10-
7 08 (m, 2t) , 6 20-6 75 (rr, IF), 6 71-6 65 (IP , 1H) , 4 96 (d, 1H,
=14 5 Pz) , 4 53(d, 1H, J=10 4 Hz), 4 45 {d, 1H, J=14 5 hz) ,
4 36 (s, -.H) , 4 27 (d, 1H, J=10 4 kz) , 3 90 (q, lri, J-6 1 Hz),
and 1 25 (d, 3H, J=6 1 Hz)
The above mixture of diastereomers, which was a transparent and colorless syrup, was crystallized by using hexane and ethyl acetate as the crystallization solvent White crystals (40 g, 10%) of the (2R, 3S)-diastereomer were preferentially recovered Melting point 103°C to 105"C, Diastereomenic excess 98%de The diastereomeric excess was determined by derivatives, as will be described in Example 14, in which the benzyl group was deprotected
[Example 9] Synthesis of (2S, 3S)-2-(2,4-difluorophenyl)-3-(methoxymethyioxy) -1- (1H-1, 2 , 4-tnazo_-l-yl) -2-butanol and (2R, 3S)-2-(2,4-difluorophenyl)-3- (methoxymethyloxy)-1-(1H-1,2, 4-triazol-l-yl)-2-butanol
(Formula Removed)
2,4-Difluorobromobenzene (139 mg, 0 72 mmol) was dissolved in tetrahydrofuran (4 mL) A solution of hexane (0 45 mL, 0 72 mmol) containing n-butyllithium (1 59 M) was added dropwise to the mixture at -70°C to -65°C, and the mixture was stirred for 30 minutes Subsequently, a soiutior of etner (1 mL) containing (3S)-3-
(methoxymethyioxy)-1-(1F-1,2,4-triazol-l-yl)-2-butanone (47 5 mg, 0 24 mmoi) was added dropwise to the mixture at -70°C to -65°C The mixture was stirred at this temperature for 30 minutes The temperature of the mixture was tren increased to room temperature Ethyl acetate (10 mL) and water (10 mL) were added to the reaction mixture and an organic layer was separated The organic layer was washed with a saturated saline solution (5 mL) and was then dried with anhydrous magnesium sulfate The drying agent was filtered and the filtrate was concentrated under reduced pressure The resultant product was purified by preparative silica gel thin layer chromatography (Merck, 20 cmX20 cmX2 mm, developing solution pure ethyl acetate) to recover the target compound (15 mg, 20%), which was a mixture of diastereomers The compound was a transparent and colorless syrup The ratio of the diastereomers was (2S, 35) (2R, 3S)=5 1 The ratio of the diastereomers was determined by derivatives, as will ce described in Example 18 in whicn the methoxymethyl group was deprotected The values of the physical properties corresponded with those in Example 7
[Example 10] Synthesis of (2R, 3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-l-yl)-3-(tr_phenylmethyloxy)-2-butanol and (25, 3R) -2-(2,4-difluorcpnenyl)-1-(1H-1,2,4-triazol-l-yl) -3-(triprenylmethyicxy)-2-potanol

(Formula Removed)
The target compound (200 mg, 10%) , which was a mixture of diastereomers, was recovered as in Example 7, except
(3R)-1- (1H-1,2,4-triazol-l-yl)-3-(triphenylmethyloxy)-2-butanone (1 55 g) was used instead of (3R)-3-
(methoxymethyloxy) -1- (1H-1,2 , 4-triazol-l-yl) -2-butanor.e
The target compound was a light yellow syrup The ratio of
the diastereomers was (2R, 3R) (2S, 3R) =4 3 1 The ratio of
the diastereomers was determined by derivatives, as will be
described in Example 17, in which the trityl group was
deprotected
(2R, 3R)-Diastereorrer, 1H-N M R (270 MHz, CDCl3) δ=8 10-
7 08 (n, 18H) , 6 79-6 49 (m, 2H) , 4 47 (d, 1H, J=15 Hz), 4 40-
4 20 (in, 2H) , 3 79 (q, 1H, J=6 9 Hz), and 0 80 (d, 3K, J-6 9
Hz)
(2S, 3R)-Diastereomer, 1H-N M R (270 MKz, CDCl3) δ=8 10-
7 08 (m, 18-i) , 6 79-6 49 (m, 2H) , 4 58 (d, 1H, J=15 Hz), 4 46 (s,
1H), 4 30-4 20(m, 1H), 3 71(q, 1H, J=6 9 Hz), and 1 00(d, 3H,
J=6 9 Hz)
[Example 11] Syntnes_s of (2R, 3R)-2-(2,4-aifluoroohenyl)-3- (methoxymetnyloxy) -_- (I1—1,2, 4-trj.azo_-l-yl) -2-outancl and
(2S, 3R)-2-(2,4-dzfluorophenyl)-3-(methoxymethyloxy)-1-(1H-1,2, 4-triazol-l-yl) -2-butancl
(Formula Removed)
The target compound (28 mg, 37%), wnich was a mixture of diastereomers, was recovered as in Example 8, except (3R) -3- (methoxymethyloxy) -1- (1H-1, 2 , 4-triazol-l-yl) -2-butanone (48 mg, 0 35 mmol) was used instead of (3R)-3-(benzyloxy)-1-(1H-1,2,4-tr_azol-l-yl)-2-butanone The target compound was a transparent and colorless syrup The ratio of the diastereomers was (2R, 3R) (2S, 3R) =1 B The ratio of the diastereomers was determined by derivatives, as will be described in Example 18, in which the methoxymethyl group was deprotected The values of the physical properties corresponded with those in Example 9
[Example 12] Synthesis of (2R, 3R)-3-(tert-butyldimetn/lsilyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-l-yl)-2~butano and (2S, 3R)-3-(tert-butyldiirethylsilyloxy) -2- (2 , 4-difluorophenyl)-1- (1R-1,2,4-triazol-1-yl)-2-butanol
(Formula Removed)
Magnesium (5 96 g, 245 mmol) was dispersed in tetrahydrofuran (175 g), and iodine (5 mg) was added to the dispersion liquid A solution of tetrahydrofuran (60 g) containing 2,4-difluorobromobenzene (47 3 g, 245 mmol) was added dropwise to the mixture at room temperature to prepare a Grignard reagent (3R)-3-(Tert-butyldimethylsilyloxy)-1-(lH-l,2,4-tnazol-l-yl)-2-butanone (20 g, 74 2 mmol) ana anhydrous magnesium chloride (21 2 g, 223 mmol) were suspended in tetrahydrofuran (100 g), and the suspension was cooled to -35*C The above Grignard reagent was added dropwise to the suspension for 45 minutes Subsequently, the suspension was stirred for 15 minutes and then hydrochloric acid (1 N, 245 mL) was added to stop the reaction Toluene (180 mL) was aaded to the mixture to extract the target compound Tnus, an organic layer was separated The organic layer was washed with water (90 mL) The organic layer was then dried with anhydrous magnesium sulfate The drying agent was filtered and the filtrate was concentrated under reduced pressure The product was purified by silica gel colimn chromatography (equivaiert to Merck C-300, 300 g, hexane ethyl acetate=3 1 to 3 2 to 11)
to recover the target compound (21 9 g, 77%), which was a
mixture of diastereomers The compound was a light yellow
syrop The ratio of the diastereomers was (2R, 3R) (2S,
3R)=23 1 The ratio of the diastereoirers was determined by
derivatives, as will be described in Example 15, in which
the tert-butyldimetnylsilyl group was deprorected
(2R, 3R)-Dia9tereomer, 1H-N M R (270 MHz, CDCl3) δ-7 94 (s,
1H) , 7 68 (s, 1H) , 7 42-7 33 (ir, 1H) , 6 80-6 71 (m, 2H) , 4 82 (d,
1H, J=13 8 Hz), 4 55(d, 1H, J=13 8 Hz), 4 45-4 42(m, 1H),
3 77(s, 1H) 0 98 (d, 3H, J=6 0 Hz) , 0 98(s, 9H) , and 0 18(s,
6H)
(2S, 3R)-Diastereoner, 1H-N M R (270 MHz, CDCl3) δ=8 17(s,
1H), 7 80(s, 1H) , 7 42-7 33 (in, 1H) , 6 80-6 71 (m, 2H) , 4 96(d,
1H, J=13 8 Hz), 4 57(d, 1H, J=13 8 Hz), 4 35-4 25(m, 1H),
3 77(s, 1H), 1 22 (d, 3H, J=6 0 Hz), 0 90(s, 9H), and 0 09(s,
6H)
The above mixture of diastereomers, which was a light yellow syrup, was crystallized by using hexane as the crystallization solvent White crystals (_7 3 g, 61%) of the (2R, 3R)-diastereomer were preferentially recovered Melting point 106°C to 107°C, Diastereomeric excess 99 5%de Tne diastereomeric excess was determined by derivatives, as will the described in Example 15, in which the tert-butyldimethylsilyl group was deprotected Optical parity by a chiral KPLC area metnod 99%ee
Analytical conditions/ DAICEL CPIRALPAK AD, Eluent composition hexane 2-propanol diethylamine=90 10 0 1, Detection nethod UV 2 54 nm
[Example 13] Synthesis of (2R, 3R)-3-(tert-butyldimethylsilyloxy)-2-(2,4-diflaorophenyl)-1-(1H-1,2,4-tnazol-1-yl) -2-butanol and (23, 3R)-3-(tert-butyldimethylsilyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-buranol
(Formula Removed)
The target compound (36 mg, 46%), which was a mixture of diastereomers, was recovered as in Example 7, except (3R) -3- (tert-butyldimetbylsilyloxy) -1- (1H-1,2 , 4-triazol-l-yl)-2-butanone (55 mg, 0 204 mmol) was used instead of (3R) -3- (methoxymethyloxy) -1- (1H-1,2 , 4-tnazol-l-yl) -2-butanone The target compound was a light yellow syrup The ratio of the diastereomers was (2R, 3R) (2S, 3R)=6 1
The ratio of the diastereomers was determined by derivatives, as will the descnoed in Example 15, in which the tert-Dityldimethyisilyi group was deprotected The values of the physical properties corresponded with those _n
Example 12
[Example 14] Synthesis of (2S, 3R)-2-(2,4-difluorophenyl) -1- (lH-l,2,4-triazol-l-yl)-2,3-outanediol
(Formula Removed)
The (2S, 3R)-3-(benzyloxy)-2-(2,4-difluorophenyl)-1-
(1H-1,2,4-tnazol-l-yl)-2-butanol (719 g, 2 mmo_)
synthesized in Example 8 was dissolved in methanol (30 mL)
Fifty percent-hydrated 10%-palladium-carbon (0 3 g) was
added to the solution and the mixture was stirred in an
autoclave at 1 0 MPa of hydrogen initial pressure, at 50°C
for eight hours The catalyst was filtered from the
reaction solution and the filtrate was concentrated under
reduced pressure to recover the target compound (480 mg,
89%) The compound was a white amorphous solid
Diastereomeric excess 98%de
Analytical conditions/ YMC-PACK ODS A-303, Eluent
composition methanol water acetic acid=70 30 0 2, Detection
method UV 254 nm
1H-N M R (270 MHz, CDCl3) δ-8 04(s, IF), 7 77(s, 1H) , 7 58-
7 52 (m, 1H) , 6 83-6 69 (2, 2P), 5 03 (d, IF, .7=14 Pz) , 5 02 (s,
1H) , 4 56(d, 1H, J-14 Hz), 4 03-3 97 (m, lb), 2 59(d, 1H, J=5 3 Hz), ard 1 26(d, 3H, J=6 6 Pz)
[Example 15] Synthesis of (2R, 3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-l-yl)-2,3-butanediol
(Formula Removed)
The (2R, 3R)-3-(tert-butyldimethylsilyloxy)-2-(2,4~ difluorophenyl)-1-(1H-1,2,4-triazol-l-yl)-2-butanol (2 0 g, 5 22 mmol) synthesized in Example 12 was dissolved in tetrahydrofuran (20 g) Tetra-n-butyl-aminonium fluoride (2 05 g, 7 83 mmol) was added to the solution and the mixture was stirred at room temperature for 30 minutes Water (20 g) and ethyl. acetate (40 g) were added to the reaction mixture and the mixture was stirred for 10 minutes Subsequently, an organic layer was separated The organic layer was dried with anhydrous magnesium sulfate The arying agent was filtered and the filtrate was concentrated under reduced pressure The resultant light yellow syrup was crystallized with toluene to recover white crystals of the target compound (1 31 g, 94%) Melting point 116°C to 17°C, Optical purity 99%ee, Diastereomeric excess 99 5%de Analytical conditions/ YMC-PACK ODS A-303, Eluent
composition metnano_ water acetxc ac±d=70 30 0 2, Detection
method UV 254 nm
1H-N M R (270 MHz, 3) δ=7 84 (s, 1H) , 7 82 (s, 1H) , 7 46-
7 37 (m, 1H) , 6 80-6 72 (m, 2H) , 4 87-4 77 (m, 3H) , 4 36-4 29(111, 1H), 2 63(d, IF, J=9 2 hz), and 0 97(d, 3H, J=6 5 Hz)
[Example 16] Synthesis of (2R, 3R)-2-(2,4-difluorophenyl)-1- (1H-1, 2 , 4-tnazol-l-yl) -2 , 3-butanediol
(Formula Removed)
The (2R, 3R)-3-(tert-butyldimethylsilyloxy)-2-(2,4-difluorcphenyl)-!-(1H-1,2,4-triazol-l-yl)-2-butanol (12 2 g) synthesized in Example 12 was dissolved in methanol (41 mL) Hydrochloric acid (3 N, 21 g) was added to the solution and the mixture was stirred at 50°C for four hours Toluene (120 g) was added to the reaction mixture and was then stirred Subsequently, an aqueous layer was separated An aqueous solution (2 N, 41 g) of sodium hydroxide was added to the aqueous layer so that the pH of the mixture was controlled to be 9 The target compound was extracted with etnyl acetate (120 mL) Ire extracted organic layer was dried with arhydrous magnesium sulfate The drying agent
was filtered, and the filtrate was concentrated under reduced pressure The resultant light yellow syrup was crystallized witn toluene to recover white crystals of the target compound (7 9 g, 92%) The values of the physical properties corresponded with those in Example 15 Diastereomeric excess 99 5%de
[Example 17] Synthesis of (2R, 3R)-2-(2,4-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)-2,3-outanediol and (2S, 3R)-2-(2,4-dif luorophenyl) -1- (1H-1,2 , 4-triazcl-l-yl) -2,3-butanediol
(Formula Removed)
The mixture (225 mg, 0 5 mmol) of (2R, 3R)-2-(2,4-difluorophenyl)-3-(methcxynethyloxy)-1-(1H-1,2,4-triazol-l-yl)-2-butanol and (2S, 3R) (2R, 3R)-2-(2,4-difluorophenyl)-3-(methoxymethyloxy)-i-(1H-1,2,4-triazol-l-yl)-2-buuancl synthesized in Example 7 was treated as in Example 17 to recover the target compound (12± mg, 90%), which was a
mix-cure of diastereomers The ratio of the diastereomers was (2R, 3R) (2S, 3R) =4 3 1
Analytical conditions/ YMC-PACK ODS A-303, Eluent composition methanol water acetic acid=70 30 0 2, Detection method UV 254 nm
The spectral data of 1H-N M R corresponded witn those in Examples 15 and 16
[Example 18] Synthesis of (2R, 3R)-2-(2,4-difluorophenyl)-1- (lH-l,2,4-mazol-l-yl) -2 ,3-butanediol and (2S, 3R)-2-(2,4-difluorophenyl)-l-(1H-1,2,4-triazol-l-yl)-2,3-butanediol
(Formula Removed)
The mixture (38 mg, 0 121 mmol) of (2R, 3R)-2-(2,4-difluorophenyl)-3-(mezhcxymethyloxy)-1- (1H-1,2,4-tnazol-l-yl)-2-outanol and (2S, 3R)-2-(2,4-difluorophenyl)-3-(methoxymethyloxy) -1- (1H , 2 , 4-tr_azol-l-yl) -2-butanol syrthesized in Example 10 was treated as in Example 17 to
recover the target corrpound (28 mg, 85%) , which was a mixture of diastereomers The ratio of the diastereomers was (2R, 3R) (2S, 3R) =6 1
Analytical conditions/ YMC-PACK ODS A-303, Eluent composition methanol water acetic acid-70 30 0 2, Detection method UV 2 54 nm
The spectral data of 1H-N M R corresponded with those in Examples 15 and 16
Industrial Applicability
The present invention provides a new method for producing a new, optically active azole alkyl ketone derivative and a new, optically active azole-methyl alcohol derivative, which are significantly important intermediates of medicines and agricultural chemicals Furthermore, the present invention provides a stable method for irexpensively producing an optically active 2-phenyl-2,3,-dihydroxypropyl azole derivative by simple steps









We Claim:
1. An optically active azole-methyl alcohol compound represented by general formula (5):
(Formula Removed)
(wherein Rl represents a substituted or unsubstitrted alkyl group; R2 is a silyl protective group; each of R5 and R6 independently represents a halogen atom; symbol * represents an asymmetric carbon having an R configuration or an S configuration; and Y represents a carbon atom or a nitrogen atom.
2. The optically active azole-methyl alcohol compound as claimed in claim 1, wherein Rl is a methyl group.
3. The optically active azole-methyl alcohol compound as claimed in claim 1, wherein each of R5 and R6 is a flourine or chlorine atom.
4. The optically active azole-methyl alcohol compound as claimed in claim 1, wherein Y is a nitrogen atom.
5. The optically active azole-methyl alchol derivative as claimed in claim 1, wherein R2 is one selected from the group consisting of trimethylsilyl, triethylsilyl, tert-butyldi methylsilyl, and tert-butyldiphenylsilyl groups.
6. A method for producing an azole-methyl alcohol compound as claimed in claim 1, the method comprising:
allowing an optically active azole-methyl ketone derivative represented by general formula (3):
(Formula Removed)
(wherein Rl, R2, Y, and symbol * are as defined in claim 1) to diastereoselectively react with a phenyl metallic reagent represented by general formula (4):
(Formula Removed)
(wherein R5 and R6 are as defined above; A represents Li, MgX, ZnX, TiX3, Ti(OR7)3, CuX, or CuLi, {wherein X represents a halogen atom, and R7 represents a substituted or unsubstituted alkyl group}) in the presence of ether type solvent.
7. The method as claimed in claim 6 wherein Rl is a methyl group, and each of R5 and R6 is a fluorine or chlorine atom.
8. The method as claimed in claim 6, wherein the optically active azole-methyl ketone derivative represented by general formula (3) is allowed to anti-selectively react with a phenyl metallic reagent represented by general formula (4).,
9. The method as claimed in claim 8 wherein Rl is a methyl group, and each of R5 and R6 is a fluorine or chlorine atom.
10. The method as claimed in claim 6, wherein the optically active azole-methyl ketone derivative represented by general formula (3) is allowed to syn-selectively react with a phenyl metallic reagent represented by general formula (4).
11. The method as claimed in claim 10 wherein Rl is a methyl group, and each of R5 and R6 is a fluorine or chlorine atom.
12. The method as claimed in any one of claims 6 to 8 and 10, wherein R2 is one selected from the group consisting of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl groups.

Documents:

2219-DELNP-2004-Abstract-(07-03-2011).pdf

2219-delnp-2004-abstract.pdf

2219-DELNP-2004-Claims-(07-03-2011).pdf

2219-DELNP-2004-Claims-(21-07-2011).pdf

2219-delnp-2004-claims.pdf

2219-DELNP-2004-Correspondence Others-(21-07-2011).pdf

2219-DELNP-2004-Correspondence Others-(22-03-2011).pdf

2219-DELNP-2004-Correspondence-Others-(07-03-2011).pdf

2219-delnp-2004-correspondence-others.pdf

2219-DELNP-2004-Description (Complete)-(07-03-2011).pdf

2219-delnp-2004-description (complete).pdf

2219-DELNP-2004-Form-1-(07-03-2011).pdf

2219-delnp-2004-form-1.pdf

2219-delnp-2004-form-18.pdf

2219-DELNP-2004-Form-2-(07-03-2011).pdf

2219-delnp-2004-form-2.pdf

2219-DELNP-2004-Form-3-(07-03-2011).pdf

2219-delnp-2004-form-3.pdf

2219-delnp-2004-form-5.pdf

2219-DELNP-2004-GPA-(07-03-2011).pdf

2219-delnp-2004-gpa.pdf

2219-delnp-2004-pct-210.pdf

2219-DELNP-2004-Petition 137-(07-03-2011).pdf

abstract.jpg


Patent Number 248868
Indian Patent Application Number 2219/DELNP/2004
PG Journal Number 36/2011
Publication Date 09-Sep-2011
Grant Date 02-Sep-2011
Date of Filing 30-Jul-2004
Name of Patentee MITSUI CHEMICALS INC.
Applicant Address 5-2, HIGASHI-SHIMBASHI, 1-CHOME, MINATO-KU, TOKYO 105-7117, JAPAN
Inventors:
# Inventor's Name Inventor's Address
1 TSUNEJI SUZUKI C/O MITSUI CHEMICALS INC., OF 580-32, NAGAURA, SODEGAURA-CITY, CHIBA 299-0265, JAPAN
2 HIDETOSHI TSUNODA C/O MITSUI CHEMICALS INC., OF 580-32, NAGAURA, SODEGAURA-CITY, CHIBA 299-0265, JAPAN
PCT International Classification Number C07D 249/08
PCT International Application Number PCT/JP2003/01308
PCT International Filing date 2003-02-07
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2002-37966 2002-02-15 Japan
2 2002-236368 2002-08-14 Japan