WO1995002585A1 - Preparation enantioselective de derives de thiazole - Google Patents

Preparation enantioselective de derives de thiazole Download PDF

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Publication number
WO1995002585A1
WO1995002585A1 PCT/IB1994/000062 IB9400062W WO9502585A1 WO 1995002585 A1 WO1995002585 A1 WO 1995002585A1 IB 9400062 W IB9400062 W IB 9400062W WO 9502585 A1 WO9502585 A1 WO 9502585A1
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WO
WIPO (PCT)
Prior art keywords
borane
process according
reaction inert
formula
reacting
Prior art date
Application number
PCT/IB1994/000062
Other languages
English (en)
Inventor
George Joseph Quallich
Original Assignee
Pfizer Inc.
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 Pfizer Inc. filed Critical Pfizer Inc.
Priority to EP94910017A priority Critical patent/EP0708764A1/fr
Priority to JP6520398A priority patent/JPH08507310A/ja
Publication of WO1995002585A1 publication Critical patent/WO1995002585A1/fr
Priority to FI960180A priority patent/FI960180A0/fi

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Definitions

  • This invention relates to a particularly useful process for preparing the compounds of formulas (I) and (II),
  • optically pure compounds of formulas (I) and (II) are useful intermediates in the synthesis of useful antidiabetic compounds of formula (IV),
  • the present invention provides a process for enantioselectively preparing the compound of formula (I)
  • R 1 is hydrogen, (C,-C 8 )alkyl, benzyl, heterocyclyl or phenyl optionally substituted independently with up to three (C,-C 8 )alkyl, (C C 8 )alkoxy or halo groups;
  • R 2 and R 3 are syt7, are taken separately, and are each independently (O,-C 8 )alkyl, benzyl, heterocyclyl or phenyl optionally substituted with up to three (C ⁇ CoJalkyl, (C,- C 8 )alkoxy or halo groups, provided that when R 2 is CH 3 and R 3 is phenyl, R 1 is H, or with a chiral oxazaborolidine catalyst of the formula (VI),
  • R 1 is as defined above and D is a cis-fused 4-6 membered carbomonocyclic ring optionally substituted independently with up to three (C,-C 8 )alkyl, heterocyclyl or phenyl optionally substituted independently with up to three (C
  • a preferred process of this invention is the above process wherein said oxazaborolidine catalyst is
  • a particularly preferred process within the preferred process is the process wherein said reaction inert solvent is tetrahydrofuran, dioxane, diethyl ether, toluene or benzene; said reaction inert atmosphere is nitrogen and said borane reducing agent is borane methylsulfide complex.
  • a more particularly preferred process within the particularly preferred process is the process wherein said chiral oxazaborolidine catalyst is prepared in situ prior to the addition of said prochiral ketone of formula (III).
  • the present invention also provides a process for enantioselectively preparing the compound of the formula (II),
  • the present invention provides a process for preparing the optically active compounds of formulas (I) and (II) hereinabove in substantially enantiomerically pure form.
  • the scheme for this process is shown in Scheme I, below.
  • the process of this invention is readily carried out.
  • the compound of formula (I) is prepared in substantially enantiomerically pure form via the reduction of the prochiral ketone, 4-bromoacetyl-2-trifluoromethylthiazole (III).
  • the precursor to the chiral oxazaborolidine catalyst in the form of a chiral 1 ,2-disubstituted aminoethanol derivative, is dissolved in a reaction inert solvent under a reaction inert atmosphere at ambient temperature.
  • the chiral 1 ,2-disubstituted amino-ethanol derivative can be chosen from among any of the 1 ,2-disubstituted aminoethanol derivatives which give rise to the chiral oxazaborolidine catalysts which are used in the process of this invention.
  • preferred 1 ,2-disubstituted amino-ethanol derivatives are (1S, 2R)- (+)-2-amino-1 ,2-diphenylethanol and (1S, 2R)-(+)-norephedrine.
  • the reaction inert solvents which are particularly preferred include but are not limited to dioxane, tetrahydrofuran, diethyl ether, toluene and benzene. More particularly preferred solvents are tetrahydrofuran and toluene.
  • a suitable borane reducing agent is added to the reaction mixture and the reaction mixture is left at ambient temperature for 2 to 24 hours.
  • the borane reducing agent may be selected from borane methylsulfide complex and borane tetrahydrofuran complex, but most preferred is borane methylsulfide complex.
  • the chiral oxazaborolidine catalyst will have formed within 10-16 hours.
  • the prochiral ketone of formula (III) is added to the reaction mixture at ambient temperature.
  • the reaction reducing the ketone to the alcohol is generally complete within 10-15 minutes after addition is complete. However, occasionally a longer amount of time may be required to ensure complete reaction depending upon a variety of factors including the particular solvents chosen or amounts of materials used and so on.
  • the reaction mixture is then cooled, generally to about 0°C, and quenched by the careful addition of a proton source, generally methanol.
  • the compound of formula (I) is isolated according to the standard methods of organic chemistry.
  • the reduction process of this invention can be carried out by reacting a prochiral ketone of the formula R 4 R 5 CO, wherein R 4 and R 5 are defined hereinbelow with a borane reducing agent in the presence of a chiral oxazaborolidine catalyst according to formula (V) or formula (VI).
  • Said process results in the enantioselective reduction of said prochiral ketone, such that only one of two possible alcohol enantiomers is formed in preference to the corresponding enantiomer.
  • the degree of enantio-selectivity which is obtained will vary depending upon the size of the R 4 and R 5 groups attached to the carbonyl group forming the prochiral ketone.
  • the degree of enantioselection will be lower. As the R 4 and R s groups become increasingly disparate in size, the degree of enantio ⁇ selection will be greater. However, it should be understood that the size of the R 4 and R 5 groups is not the sole determining factor affecting the degree of enantioselectivity achieved. Ordinarily, with prochiral ketones wherein R 4 and R 5 are at least moderately different in size, at least 90% of the desired enantiomer will be obtained. However, typically greater than 90% of the desired enantiomer is obtained
  • the prochiral ketone is dissolved in a suitable reaction inert solvent such as toluene, diethyl ether, dioxane, tetrahydrofuran or the like. Preferred is tetrahydrofuran.
  • a catalytically effective amount of a chiral oxazaborolidine compound of formula (V) or formula (VI) is added to the reaction mixture at from about -78°C to about room temperature, preferably at room temperature; however, the preferred temperature will vary depending upon the particular borane reducing agent being used.
  • the preferred amount of said catalyst is about 5-10 mole % with, respect to said ketone.
  • reaction mixture is then treated slowly with about 4.2 hydride equivalents of a borane reducing agent such as borane dimethylsulfide complex, borane tetrahydrofuran complex, catecholborane or the like.
  • a borane reducing agent such as borane dimethylsulfide complex, borane tetrahydrofuran complex, catecholborane or the like.
  • additional hydride equivalents of reducing agent are necessary.
  • borane dimethylsulfide complex is preferred for its ease of use.
  • the reducing agent is added at a rate which modulates the rate of the catalytic reduction. The reaction is sometimes complete as soon as all of the reducing agent has been added, as can be determined by monitoring the course of the reaction via thin layer chromatography according to the standard practice of organic chemistry.
  • reaction mixture may be stirred at about room temperature for about fifteen minutes.
  • the temperature of reaction mixture is then adjusted to 0°C and quenched with a proton source.
  • Said proton source usually a lower alkanol such as methanol, is added slowly to control the exothermic reaction.
  • the product is isolated by removing the solvent in vacuo followed by partitioning between an organic solvent and an aqueous acid followed by separation of layers and purification according to the standard techniques of organic chemistry.
  • the compound of formula (II) of this process is also readily prepared.
  • the compound of formula (I) is dissolved in aqueous base and vigorously stirred.
  • the preferred base is sodium hydroxide, however other bases such as potassium hydroxide and potassium t-butoxide may also be utilized.
  • the debromination and cyclization of the compound of formula (I) to the epoxide of formula (II) is effected rapidly and without racemization of the chiral center. Generally the reaction is complete within 5 to 10 minutes, however the reaction may require longer periods depending upon a variety of factors including strength of base, nature of base, amount of materials used and so on.
  • the epoxide is isolated from the reaction mixture utilizing well-known methods of organic chemistry.
  • the chiral 1 ,2-disubstituted aminoethanol derivatives are generally readily available from commercial sources such as Aldrich or Sigma. Where the chiral 1 ,2- disubstituted aminoethanol derivative is not readily available, said erythro aminoethanol derivatives are prepared by methods well known to those of ordinary skill in the art, such as provided by Reetz et al., Angew. Chemie Int. Ed. Eng., 26, 1987, 1141-43 and Matsunaga et al., Tetrahedron Letters, 32, 1991. 7715-18.
  • Alkyl means a branched or unbranched saturated hydrocarbon group containing the specified number of carbon atoms, e.g., C-,-C 8 . Examples include, but are not limited to methyl, ethyl, isopropyl, n-butyl, t-butyl and the like.
  • Alkoxy means a branched or unbranched saturated hydrocarbon containing the specified number of carbon atoms and a single oxygen atom by which said hydrocarbon is attached to a central backbone. Examples include, but are not limited to methoxy, ethoxy and the like.
  • Heterocyclyl means a 5- or 6-membered aromatic group containing up to three heteroatoms, each of said heteroatoms selected from N, O and S and which may be optionally benzo-fused, said heterocyclyl group being optionally substituted independently with up to three (C-,-C 8 )alkyl, (C-,-C 8 )alkoxy or halo groups.
  • a “prochiral ketone”, denoted by R 4 R CO, is a ketone in which R 4 and R 5 are non-identical, so that the secondary alcohol reduction product R 4 R s CHOH has a chiral center at the alcohol carbon.
  • R 4 and R 5 are taken together, forming a ring including the ketone, and that the ring so formed has no plane of symmetry across a plane drawn perpendicular to the plane containing the carbonyl group and the two carbon atoms attached directly thereto, said plane containing both the carbon and oxygen atoms of the carbonyl group as points therein.
  • Reaction inert solvent means a solvent which does not interact with the reactants, intermediates or products in such a way that adversely affects the yield of the desired products.
  • "Syn" means that the substituents substituted on adjacent ring carbon atoms are located on the same side of a plane which encompasses the bond between said carbon atoms and the bonds by which each of said carbon atoms are attached to the ring.
  • Enantiomeric excess or e.e., is the excess of one of two enantiomers over the other, usually expressed as a percentage, i.e., a 90% e.e. reflects the presence of 95% of one enantiomer and 5% of the other in the material in question.
  • "Ambient temperature” means the temperature of the immediate external environment surrounding the reaction flask. This temperature is usually room temperature (20°-25°C).
  • reaction inert atmosphere means a gas which does not interact with the reactants, intermediates or products in such a way that adversely affects the yield of the desired products.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Procédé énantiosélectif servant à la préparation des composés représentés par les formules (I) et (II) à partir du précurseur de cétone prochirale de l'alcool représenté par la formule (I). De ce fait, on obtient les composés correspondants aux formules (I) et (II) sous une forme sensiblement pure énantiomériquement par réduction de la cétone avec un agent réducteur de borane en présence d'un catalyseur d'oxazaborolidine chirale.
PCT/IB1994/000062 1993-07-16 1994-04-06 Preparation enantioselective de derives de thiazole WO1995002585A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP94910017A EP0708764A1 (fr) 1993-07-16 1994-04-06 Preparation enantioselective de derives de thiazole
JP6520398A JPH08507310A (ja) 1993-07-16 1994-04-06 チアゾール誘導体のエナンチオ選択的調製
FI960180A FI960180A0 (fi) 1993-07-16 1996-01-15 Tiatsolijohdannaisten enantioselektiivinen valmistus

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US9283293A 1993-07-16 1993-07-16
US08/092,832 1993-07-16

Publications (1)

Publication Number Publication Date
WO1995002585A1 true WO1995002585A1 (fr) 1995-01-26

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ID=22235378

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB1994/000062 WO1995002585A1 (fr) 1993-07-16 1994-04-06 Preparation enantioselective de derives de thiazole

Country Status (5)

Country Link
EP (1) EP0708764A1 (fr)
JP (1) JPH08507310A (fr)
CA (1) CA2167287A1 (fr)
FI (1) FI960180A0 (fr)
WO (1) WO1995002585A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8076489B2 (en) 2004-11-29 2011-12-13 Novartis Ag 5-hydroxy-benzothiazole derivatives having beta-2-adrenoreceptor agonist activity

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0305180A2 (fr) * 1987-08-27 1989-03-01 The President And Fellows Of Harvard College Réduction énantiosélective de cétones
WO1993002061A1 (fr) * 1991-07-22 1993-02-04 Pfizer, Inc. Intermediaires chiraux pour la preparation de thiazols antidiabetiques
WO1993023408A1 (fr) * 1992-05-14 1993-11-25 Pfizer Inc. Catalyseurs a oxazaborolidine enantioselectifs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0305180A2 (fr) * 1987-08-27 1989-03-01 The President And Fellows Of Harvard College Réduction énantiosélective de cétones
WO1993002061A1 (fr) * 1991-07-22 1993-02-04 Pfizer, Inc. Intermediaires chiraux pour la preparation de thiazols antidiabetiques
WO1993023408A1 (fr) * 1992-05-14 1993-11-25 Pfizer Inc. Catalyseurs a oxazaborolidine enantioselectifs

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8076489B2 (en) 2004-11-29 2011-12-13 Novartis Ag 5-hydroxy-benzothiazole derivatives having beta-2-adrenoreceptor agonist activity

Also Published As

Publication number Publication date
JPH08507310A (ja) 1996-08-06
FI960180A (fi) 1996-01-15
FI960180A0 (fi) 1996-01-15
CA2167287A1 (fr) 1995-01-26
EP0708764A1 (fr) 1996-05-01

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