EP0708764A1 - Preparation enantioselective de derives de thiazole - Google Patents
Preparation enantioselective de derives de thiazoleInfo
- Publication number
- EP0708764A1 EP0708764A1 EP94910017A EP94910017A EP0708764A1 EP 0708764 A1 EP0708764 A1 EP 0708764A1 EP 94910017 A EP94910017 A EP 94910017A EP 94910017 A EP94910017 A EP 94910017A EP 0708764 A1 EP0708764 A1 EP 0708764A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- borane
- process according
- reaction inert
- formula
- reacting
- 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- Withdrawn
Links
- 238000002360 preparation method Methods 0.000 title description 3
- 150000007979 thiazole derivatives Chemical class 0.000 title description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 150000002576 ketones Chemical class 0.000 claims abstract description 28
- BDOLXPFAFMNDOK-UHFFFAOYSA-N oxazaborolidine Chemical compound B1CCON1 BDOLXPFAFMNDOK-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 20
- 229910000085 borane Inorganic materials 0.000 claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical group [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 21
- 239000011541 reaction mixture Substances 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 239000012442 inert solvent Substances 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 239000012298 atmosphere Substances 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 238000011065 in-situ storage Methods 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- GEJJWYZZKKKSEV-KGLIPLIRSA-N (1s,2r)-2-amino-1,2-diphenylethanol Chemical compound C1([C@H](O)[C@H](N)C=2C=CC=CC=2)=CC=CC=C1 GEJJWYZZKKKSEV-KGLIPLIRSA-N 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- DLNKOYKMWOXYQA-VXNVDRBHSA-N (+)-norephedrine Chemical compound C[C@@H](N)[C@@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-VXNVDRBHSA-N 0.000 claims description 5
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- GEJJWYZZKKKSEV-UHFFFAOYSA-N 2-amino-1,2-diphenylethanol Chemical compound C=1C=CC=CC=1C(N)C(O)C1=CC=CC=C1 GEJJWYZZKKKSEV-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 6
- 230000001603 reducing effect Effects 0.000 abstract description 4
- 239000002243 precursor Substances 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- -1 1 ,2-disubstituted aminoethanol Chemical class 0.000 description 9
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical compound BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 150000002924 oxiranes Chemical class 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- SQXLLLBFLXKVBC-SCSAIBSYSA-N 4-[(2s)-oxiran-2-yl]-2-(trifluoromethyl)-1,3-thiazole Chemical compound S1C(C(F)(F)F)=NC([C@@H]2OC2)=C1 SQXLLLBFLXKVBC-SCSAIBSYSA-N 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- SSBSIIIFOMFHGK-SCSAIBSYSA-N (1s)-2-bromo-1-[2-(trifluoromethyl)-1,3-thiazol-4-yl]ethanol Chemical compound BrC[C@@H](O)C1=CSC(C(F)(F)F)=N1 SSBSIIIFOMFHGK-SCSAIBSYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000011946 reduction process Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- UAXQBCQWFKWRTA-UHFFFAOYSA-N 2-bromo-1-[2-(trifluoromethyl)-1,3-thiazol-4-yl]ethanone Chemical compound FC(F)(F)C1=NC(C(=O)CBr)=CS1 UAXQBCQWFKWRTA-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000007256 debromination reaction Methods 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
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.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Endocrinology (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.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US9283293A | 1993-07-16 | 1993-07-16 | |
PCT/IB1994/000062 WO1995002585A1 (fr) | 1993-07-16 | 1994-04-06 | Preparation enantioselective de derives de thiazole |
US92832 | 1998-06-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0708764A1 true EP0708764A1 (fr) | 1996-05-01 |
Family
ID=22235378
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP94910017A Withdrawn EP0708764A1 (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) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0426164D0 (en) | 2004-11-29 | 2004-12-29 | Novartis Ag | Organic compounds |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4943635A (en) * | 1987-08-27 | 1990-07-24 | President & Fellows Of Harvard College | Enantioselective reduction of ketones |
CA2111446C (fr) * | 1991-07-22 | 1997-12-16 | George J. Quallich | Intermediaires chiraux servant a l'obtention de thiazoles antidiabetiques |
NZ249302A (en) * | 1992-05-14 | 1996-11-26 | Pfizer | 4,5-diphenyl-1,3,2-oxazaborolidine derivatives and their use as catalysts in reduction of ketones to chiral alcohols |
-
1994
- 1994-04-06 WO PCT/IB1994/000062 patent/WO1995002585A1/fr not_active Application Discontinuation
- 1994-04-06 EP EP94910017A patent/EP0708764A1/fr not_active Withdrawn
- 1994-04-06 JP JP6520398A patent/JPH08507310A/ja active Pending
- 1994-04-06 CA CA002167287A patent/CA2167287A1/fr not_active Abandoned
-
1996
- 1996-01-15 FI FI960180A patent/FI960180A0/fi not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO9502585A1 * |
Also Published As
Publication number | Publication date |
---|---|
FI960180A (fi) | 1996-01-15 |
FI960180A0 (fi) | 1996-01-15 |
WO1995002585A1 (fr) | 1995-01-26 |
JPH08507310A (ja) | 1996-08-06 |
CA2167287A1 (fr) | 1995-01-26 |
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