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EP0489804A1 - Asymmetrische chemische synthese und zwischenprodukte zur herstellung von fungiziden - Google Patents

Asymmetrische chemische synthese und zwischenprodukte zur herstellung von fungiziden

Info

Publication number
EP0489804A1
EP0489804A1 EP90913083A EP90913083A EP0489804A1 EP 0489804 A1 EP0489804 A1 EP 0489804A1 EP 90913083 A EP90913083 A EP 90913083A EP 90913083 A EP90913083 A EP 90913083A EP 0489804 A1 EP0489804 A1 EP 0489804A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
substituted
reacting
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP90913083A
Other languages
English (en)
French (fr)
Inventor
Viyyoor M. Girijavallabhan
Ashit K. Ganguly
Patrick Pinto
Olga Z. Sarre
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Original Assignee
Schering Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Corp filed Critical Schering Corp
Publication of EP0489804A1 publication Critical patent/EP0489804A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40—Halogenated unsaturated alcohols
    • C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • Ph is a phenyl group or a phenyl group substituted with one or two halogen atoms
  • R 1 is a C 1 -C3 alkyl group
  • R 2 is a hydrogen atom or a C 1 -C 3 alkyl group
  • R 3 is a d-C ⁇ alkyl group, a C4-C-8 cycloalkylalkyl group or a C 3 -C 6 cyclalkyl group and n is 0, 1 or 2, and their acid addition salts.
  • n is an integer of 3 or 4, and its acid addition salts, by diastereomeric separation using an optically active carboxylic acid ester. This is not suitable for large scale commercial synthesis. It is laborious, low yielding and expensive..
  • the present invention involves a series of important novel intermediates useful in making chemically pure, enantiomeric compounds having antifungal activity.
  • One aspect of the invention involves an intermediate compound of the formula II, HI, IV, v ⁇ i, XI or XII, wherein said compound has an asymmetric center(s) as indicated by the single asterisk ( * ) and the double asterisk ( ** ) and wherein the compound is substantially free from compound(s) having the same chemical structure but having other absolute stereochemical configurations at the asterisked carbon centers (e.g., the double asterisks (* * ) in formula XII both represent the R absolute stereochemical configurations, and such RR compound is substantially free from its SS, RS and SR forms):
  • Ar represents phenyl, substituted phenyl, 3-thienyl, substituted 3- thienyl, 3-furanyl or substituted 3-furanyl;
  • R represents alkyl, substituted alkyl or-cycloalkyl;
  • R 1 represents H or alkyl;
  • X represents chloro, bromo or iodo;
  • X 1 represents OH, chloro, bromo, iodo or P 1 where P 1 represents alkoxy- substituted phenyloxy, benzyloxy, substituted benzyloxy, acyloxy, alkylthio, phenylthio, substituted phenylthio or -NHP 2 where P 2 is an amino protecting group such as phenyl, substituted phenyl, benzyl, substituted benzyl, alkanoyl, alkoxycarbonyl, phenoxycarbonyl or substituted phenoxycarbonyl; and P represents H or a hydroxy protecting group.
  • the double asterisked ( ** ) carbon atoms in the compound of formula XII are both in their R absolute stereochemical configuration, i.e., the RR form of the compound.
  • the SS form of formula XII also is within the scope of this invention.
  • Another preferred intermediate of the invention is of formula XI, wherein Ar, P and R are as defined above: In the preferred form of the compound of formula XI the carbon atom indicated by the double asterisk ( ** ) is in its R absolute stereochemical configuration.
  • the asymmetric centers indicated by the single asterisk (*) in the compounds of formulas II and III are preferably in their S absolute stereochemical configuration, while the asymmetric centers indicated by the double asterisk ( ** ) in the compounds of formulas IV and VIII are preferably in their R absolute stereochemical configuration.
  • Ar is preferably substituted phenyl, more preferably Ar is mono, di or tri- substituted halo phenyl, e.g., 2,4- difluoro, 2,6-difluoro, 4-fluoro, 2-fluoro, 2,4-dichloro, 2,6-dichloro, 4- chloro or 2-chloro substituted phenyl.
  • a particularly preferred Ar group is 2,4-difluorophenyl.
  • R is preferably alkyl and in particular methyl.
  • P is preferably
  • R 1 is preferably H.
  • X is preferably chloro or bromo.
  • X 1 is preferably chloro, bromo, alkoxy-substituted phenyloxy, benzyloxy or substituted benzyloxy.
  • Ar represents phenyl, substituted phenyl, 2- or 3- thienyl, substituted 2- or 3-thienyl, 2- or 3-furanyl, substituted 2- or 3- furanyl, 2-, 4- or 5-imidazolyl, 3- or 5-(1 ,2,4-triazolyl), 5-tetrazolyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 3- or 4-pyridinyl, 2- or 3-pyrrolyl, 3- or 4-pyrrazolyl, 2-benzimidazolyl, 2-benzthiazolyl, or 2-, 4- or 6-purinyl, wherein the saturated nitrogen atoms on said imidazolyl, triazolyl, tetrazolyl, wherein the saturated nitrogen atoms on said imidazolyl, triazolyl, tetrazolyl, wherein the saturated nitrogen atoms on said imidazolyl, triazolyl, tetrazol
  • Ar 1 represents 1-(1 ,2,4-thiazolyl). 1-(1 ,3,4-triazoly.) or 1- imidazolyl;
  • R 2 is alkyl, cycloalkyl or cycloalkylalkyl; and wherein n is 1 or 2.
  • R, R 1 , X, X 1 , and P are as defined above unless otherwise indicated.
  • the wavy lines indicate mixtures of the possible isomers (as also indicated by R/S) and the asterisks ( * ) indicate (here and throughout this specification) an asymmetric carbon center in its absolute stereochemical R or S form, which is substantially free of its opposite enantiomeric form.
  • the double asterick ( ** ) represents an asymmetric carbon center which has the opposite absolute stereochemical configuration than a single asterisk ( * ) carbon in the reaction scheme. For example, if the asterisk ( * indicates an absolute stereochemical R form, the double asterisk ( ** ) indicates an absolute stereochemical S form and vise versa.
  • one process aspect of the invention involves reacting a compound of the formula ArH with a compound of formula I substantially free from its opposite enantiomeric form:
  • the compound of formula VIII may then be reacted in one or two steps with an oxidizing agent to form a compound of the formula XI
  • the compound of the formula X may be oxidized to the compound of the formula XI.
  • the compound of formula XI may then be reacted with an epoxidizing agent, e.g., a dialkyl sulfoxide anion, to form a compound of the formula XII
  • R 1 will be H.
  • the stereochemical configuration at the newly formed asymmetric center attached to Ar is substantially the same as the configuration at the center attached to R.
  • the compound of the formula XII may then be employed to prepare the desired antifungal end products of formula XVI by reaction with a nucleophilic Ar 1 anion and subsequent removal of any protecting group P to form a compound of the formula XIII
  • Ar 1 represents 1-(1 , 2, 4-triazolyl), 1-(1 , 3, 4- triazolyl) or 1-imidazolyl.
  • This intermediate compound of formula XIII is disclosed in racemic form in European published application No.
  • the compound of formula XIII is then converted into the " compound of formula XVI by applying methods known per se to compound of formula XIII such as those as described in the European publication i.e. for example, XIII is reacted with a methane sulfonating agent such as methane sulfonyl chloride to form a compound of the formula XIV
  • R 2 is alkyl, cycloalkyl or cycloalkylalkyl, which in turn is reacted with an oxidizing agent to form a compound of the formula XVI
  • n is 1 or 2.
  • Ar 1 is preferably 1-(1 , 2, 4-triazolyl)
  • Ar is preferably 2,4-diflourophenyl
  • R and R 2 are preferably methyl
  • R 1 is preferably H
  • n is preferably 2
  • both of the carbon atoms indicated by the double asterisk ( ** ) are in the R absolute stereochemical configuration.
  • compound XVI could be obtained possessing S absolute stereochemical configuration at both the double asterisked ( ** ) asymmetric carbons.
  • This invention relates to substantially pure enantiomers and to processes for making such substantially pure enantiomers.
  • substantially pure we mean substantially free from any of the other enantiomeric forms of such compounds, e.g., one enantfomer is present in amounts greater than about 95 molar %, more preferably greater than about 97 molar %, most preferably greater than about 99 molar %, with respect to any other enantiomer.
  • acyl - represents alkanoyl, halo-substituted alkyl carbonyl, benzoyl and substituted benzoyl; alkyl (including the alkyl portions of alkylthio, alkoxy, alkyloxyalkyl, alklythioalkyl, alkanoyl, alkoxycarbonyl, hydroxyalkyl, etc.) - represents a straight or branched hydrocarbon chain having from 1 to 12, preferably from 1 to 6, carbon atoms; substituted alkyl - represents an alkyl group as defined above wherein 1 to 3 of the hydrogen atoms are replaced with halo, protected hydroxy, phenyl, substituted phenyl which is not reactive with a Lewis acid, etc.; cycloalkyl (including the cycloalkyl portion of cycloalkylalkyl) - represents a saturated carbocyclic ring having from 3 to 8,
  • substituted phenyl, substituted benzyl, substituted benzoyl, substituted 3-thienyl and substituted 3-furanyl - represent groups in which the phenyl, thienyl or furanyl rings thereof are substituted with one or more subsituent groups each independently selected from halo, alkyl, hydroxyalkyl, hydroxy, alkoxy, alkylthio, phenoxy, alkanoyl, benzoyl, alkanoyloxy, benzoyloxy, amino, alkylamino, dialkylamino, etc.
  • the asymmetric carbon center indicated by the single asterisk ( * ) in formula I is preferably in its S absolute stereochemical , form and will thus result in an end product of formula XVI having R absolute stereochemical configuration at both of the double asterisked ( ** ) carbon centers, i.e., the RR form of the compound of formula XVI. If the compound of formula I has the R absolute stereochemical configuration at the single asterisked ( * ) carbon, both of the carbon atoms indicated by the double asterisked ( ** ) in the final product XVI will be in their S absolute stereochemical configuration, i.e., the SS form of the compound of formula XVI.
  • L can be any suitable leaving group such as a halo, acid anhydride or OH, preferably halo such as chloro.
  • the reaction mixture may include a suitable solvent such as a nonreactive, nonpolar solvent, e.g., the reactant ArH itself, CH2CI2, meta- dichlorobenzene, CS2, etc. Any suitable temperature may be employed.
  • the reaction mixture is cooled, e.g., to about 0°C, and a suitable Lewis acid is added.
  • Exemplary Lewis acids include AICI3, SnCU, FeCl3, etc.
  • the Lewis acid may be present in amounts from about 1 equivalents to about 3 equivalents, preferably in about equivalent amounts.
  • the reaction may be quenched by pouring into water, preferably ice water and the product extracted with a suitable solvent.
  • Step B the ketohalide of formula II is reacted with a suitable non-basic, reducing agent such as NaBHsCN, borane, alkyl - boranes, etc.
  • a suitable solvent such as methanol, tetrahydrofuran, diethylether, etc.
  • the reducing agent is preferably employed in excess, e.g., in about a 0.5 to about 1.0 molar excess.
  • the reaction may be run at any suitable temperature, e.g., room temperature.
  • Step C the halohydrin of formula III is reacted with a suitable base or acid scavenger such as K2CO3, OH-, organic base, etc.
  • a suitable base or acid scavenger such as K2CO3, OH-, organic base, etc.
  • the reaction is preferably performed in a suitable polar solvent such as methanol, ethanol, dimethyl sulfoxide (DMSO), etc.
  • DMSO dimethyl sulfoxide
  • the reaction may be run at any suitable temperature, e.g., from about 0 to about 80°C.
  • the base is preferably employed in amounts of from about 1 to about 1.5 molar amounts, preferably in about equal molar amounts.
  • the solvent is removed and the residue washed with water and extracted in CH2CI 2 .
  • the epoxide of formula IV can be selectively opened at the aryl substituted carbon by using any suitable epoxide opening reagent such as halotrialkylsilane, phenoxide, substituted phenoxides, aniline, substituted anilines, benzyl alcohol, substituted benzyl alcohols, acylamines, alkoxycarbonylamino, alkyl or aryl mercaptan, etc.
  • suitable epoxide opening reagent such as halotrialkylsilane, phenoxide, substituted phenoxides, aniline, substituted anilines, benzyl alcohol, substituted benzyl alcohols, acylamines, alkoxycarbonylamino, alkyl or aryl mercaptan, etc.
  • the reaction may be run neat or in a suitable solvent, e.g., with halotrialkylsilane, dry solvent such as CH2CI2, or with an alkoxy substituted sodium phenoxy salt in methanol, etc. Any suitable temperature may be employed, preferably low temperature below about -20°C to about 80°C.
  • the ring opening agent is typically added slowly to the epoxide solution in amounts of from about 1.0 equivalent to about 5.0 equivalents.
  • the reaction is neutralized and the product extracted in a suitable solvent such as methylene chloride.
  • Step F the compound of formula V is reacted with a suitable protecting agent such as dihydrofuranyl ether, dihydropyranyl ether, alkoxyalkyl or alkylthioalkyl ether unsaturated or halo derivatives (such as a vinyl alkyl ether or a chloro-alkyl alkyl ether), halo- trisubstituted silyl ethers, etc.
  • a preferred protecting agent is for example dihydropyranyl ether.
  • the compound of formula V is reacted with an excess of the protecting agent.
  • a catalyst such as a Lewis acid may be employed.
  • a preferred catalyst is POCI 3 .
  • the reaction may be run at any suitable temperature, e.g., 0°C to room temperature.
  • Step G the protected compound of formula VIII is reacted with a suitable oxidizing agent such as DMSO if X 1 is halo.
  • a suitable oxidizing agent such as DMSO
  • the X 1 group is first converted to the hydroxide and then to the keto group.
  • eerie ammonium nitrate can be employed if X 1 is for example alkoxy phenoxy or dialkylaminophenoxy, and the resulting hydroxy group can be oxidized by a conventional oxidizing agent such as manganese dioxide, Jones reagent, chromium trioxide, etc.
  • X 1 is an alkyl or aryl mercapto group
  • an oxidizing agent such as chlorine or sulfuryl chloride may be employed, which after hydrolysis results in the ketone of formula XI.
  • X 1 is an acyloxy group
  • hydrolysis with a suitable hydrolizing agent such as aqueous sodium hydroxide can be performed and the resulting hydroxy group oxidized to a keto group using a conventional oxidizing agent as explained above.
  • Ketone XI can also be prepared from compound IV by following Step E.
  • the epoxide IV is reacted with a dialkyl sulfoxide such as dimethyl sulfoxide in presence of a Lewis acid such as- boron trifluoride, trimethyl silyl triflate, metal Lewis acids like Zn++, Ti 4+ , Zr 4 *, Sn 4+ , Mg 2+ , etc.
  • the reaction may be run either neat, in DMSO or in a nonparticipating solvent like CH CI2 at temperatures ranging from about -20°C to about 60°C, preferably at about 10°C to about 30°C.
  • the ratio of the hydroxy ketone VII to the diol VI varies with the conditions and the Lewis acid.
  • the desired product VII is then reacted with a hydroxy protecting agent (step L) as discussed above in presence of non- enolizing acid catalyst.
  • a hydroxy protecting agent such as water
  • the by-product VI formed in the reaction step E when a hydrolyzing agent such as water is present can also be converted to the ketone XI by first selectively protecting the hydroxy group (Step U) using a suitable hydroxy protecting agent as discussed above to give the compound of formula X, where R is attached to the carbon bearing the group OP.
  • the remaining unprotected hydroxyl group where Ar is attached is then oxidized to a ketone in step K by conventional agents, such as Mn ⁇ 2, Cr ⁇ 3, Jones reagent, KMnO.4 etc.
  • keto compound of formula XI can also be prepared from compound IX (Step J) by oxidation with reagents such as KMn ⁇ 4,
  • Compound IX may be prepared from compound VIII in step H, where the X 1 group is halo, OH or a hydroxy derived leaving group such as acyloxy or mesylate, by reduction to a methylene group by reagents such as H2, trialkyl tin or hydride, zinc, tin, sodium, or magnesium metals, etc. in an appropriate solvent as known in the art.
  • Step M the keto compound XI is reacted with the anion of a dialkyl sulfoxide of the formula R CH-S(0)CH 3 wri ere R1 is H or alkyl as defined.
  • the reaction may be conducted in a nonparticipating polar solvent such as dimethyl formamide (DMF), dimethyl sulfoxide and the like.
  • the reaction may be run at a suitable temperature from 0°C to 50°C, preferably at 0°C to 10°C.
  • the anion of the sulfoxide may be prepared by employing strong bases such as sodium hydride, lithium or sodium hexa-alkyl disilazane, sodium or potassium amide, etc., neat or in the same eluant as the keto compound XI.
  • strong bases such as sodium hydride, lithium or sodium hexa-alkyl disilazane, sodium or potassium amide, etc.
  • the reaction is complete, it is neutralized, e.g., to pH 7, and the epoxide XII is isolated by extraction with a suitable solvent such as methylene dichloride or ethyl acetate.
  • a suitable solvent such as methylene dichloride or ethyl acetate.
  • the stereochemistry of the ketone of formula XI is R where indicated by the double asterisk (' * )
  • the newly formed center at the carbon attached to the epoxy group also has R stereochemistry
  • ketone XI is S where indicated by the double asterisk (")
  • the new product has S stereochemistry at the other the double asterisked ( ** ) center.
  • the stereochemistry of the compounds of formulas XII, x ⁇ i, XIV, XV and XVI can be predetermined as desired.
  • Step N the epoxide XII is reacted with an Ar 1 anion.
  • the reaction favors regioselectivity at the center where R 1 is attached.
  • Ar 1 is a heterocycle like 1 -(1 ,2,4 triazolyl), 1 -(l , 3, 4-triazolyl) or imidazolyl
  • the anion is formed by reaction with a strong base such as sodium hydride, sodium or potassium amide, cesium hydroxide etc.
  • the choice of the solvent is a polar nonparticipating solvent such as dimethyl formamide, N-methyl pyrrolidinone, hexamethyl phosphoramide (catalytic amounts), dimethyl sulfoxide, etc., at temperatures ranging from about 0°C to about 120°C, preferably in dimethyl formamide at 70 to 80°C.
  • step N When the reaction is over, it is acidified in step N with a strong acid such as aqueous HCI, H2SO4, phosphoric or trifluoroacetic acids.
  • a strong acid such as aqueous HCI, H2SO4, phosphoric or trifluoroacetic acids.
  • This procedure enables cleavage of the oxygen protecting group generating the free hydroxyl group.
  • Compound XIII is isolated by adjusting the pH of the reaction, e.g., to a pH of about 8 to 9, and extracting the product in a suitable solvent.
  • product Xi ⁇ can be precipitated out of the medium during adjusting the pH to a value of 8 to 9.
  • Steps P, Q and W may be performed as described in European published application No. 0178533.
  • the compound of formula XIII is reacted with a methane sulfonating agent such as methane sulfonyl chloride in an inert solvent (e.g., benzene, dichloromethane, etc.) in the presence of a base at about 0°C. to about 30°C to give the methane sulfonate of the formula XIV.
  • the sulfonating agent is typically employed in excess (1 to 2 equivalents).
  • the base can be, for example, an organic amine, e.g., pyridine.
  • the methane sulfonate of formula XIV is then reacted with a mercaptan anion of the formula R 2 S- where R 2 is alkyl, cycloalkyl or cycloalkylalkyl.
  • the counterion is preferably an alkali metal salt and the solvent is preferably inert (e.g., DMSO, DMF, etc.).
  • the thiol salt may be employed in excess (2 to 10 equivalents) and the temperature is typically 0 to 80°C.
  • the sulfide of the formula XV is then oxidized in step W using an oxidizing agent such as a peracid, e.g., meta-chloroperbenzoic acid, in an inert solvent, e.g., chloroform, at a temperature of from about -30C to reflux.
  • an oxidizing agent such as a peracid, e.g., meta-chloroperbenzoic acid
  • an inert solvent e.g., chloroform

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP90913083A 1989-09-01 1990-08-30 Asymmetrische chemische synthese und zwischenprodukte zur herstellung von fungiziden Withdrawn EP0489804A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US40201489A 1989-09-01 1989-09-01
US402014 1989-09-01

Publications (1)

Publication Number Publication Date
EP0489804A1 true EP0489804A1 (de) 1992-06-17

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EP90309479A Pending EP0421600A1 (de) 1989-09-01 1990-08-30 Asymmetrische chemische Synthese und Zwischenprodukte zur Herstellung von Fungiziden
EP90913083A Withdrawn EP0489804A1 (de) 1989-09-01 1990-08-30 Asymmetrische chemische synthese und zwischenprodukte zur herstellung von fungiziden

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EP (2) EP0421600A1 (de)
KR (1) KR927003494A (de)
AU (1) AU636163B2 (de)
CA (1) CA2065741A1 (de)
IE (1) IE903146A1 (de)
IL (1) IL95540A0 (de)
NZ (1) NZ235102A (de)
PT (1) PT95156A (de)
WO (1) WO1991003451A1 (de)
ZA (1) ZA906932B (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE903395A1 (en) * 1989-09-26 1991-04-10 Takeda Chemical Industries Ltd Triazole compounds, their production and use
TW211006B (de) * 1990-08-24 1993-08-11 Mochida Pharm Co Ltd
US6133485A (en) * 1998-04-15 2000-10-17 Synphar Laboratories, Inc. Asymmetric synthesis of 2-(2,4-difluorophenyl)-1-heterocycl-1-yl butan-2,3-diols
US6884892B2 (en) 2002-06-20 2005-04-26 Sumitomo Chemical Company, Limited Production methods of epoxytriazole derivative and intermediate therefor

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DE1270022B (de) * 1966-08-26 1968-06-12 Kalk Chemische Fabrik Gmbh Verfahren zur Herstellung von alpha-Bromalkylarylketonen
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WO1991003451A1 (en) 1991-03-21
ZA906932B (en) 1991-06-26
IL95540A0 (en) 1991-06-30
PT95156A (pt) 1991-05-22
IE903146A1 (en) 1991-03-13
CA2065741A1 (en) 1991-03-02
AU6296590A (en) 1991-04-08
AU636163B2 (en) 1993-04-22
NZ235102A (en) 1993-05-26
KR927003494A (ko) 1992-12-18
EP0421600A1 (de) 1991-04-10

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