• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to a process for the enantioselective preparation of prophenes and fenidates, by means of a first enantioselective synthesis reaction of epoxysulfones using chiral catalysts of the PTC type (phase transfer catalyst (Phase Transfer Catalysis), and a second stage of transformation of epoxysulfones in prophenes or fenidates. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2690177A1
    申请号:ES201830342
    申请日:2018-04-05
    公开日:2018-11-19
    发明作者:Florenci Vicent GONZÁLEZ ADELANTADO；Santiago RODRÍGUEZ PASTOR；Lledó BOU ISERTE
    申请人:Universitat Jaume I de Castello；
    IPC主号:
    专利说明:

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    PROCEDURE FOR ENANTIOSELECTIVE PREPARATION OF PROFENOS AND FENIDATES
    Field of the Invention
    The present invention is generally framed in the pharmaceutical sector, and in particular refers to a method for the synthesis of anti-inflammatory drugs, analgesics and drugs indicated for the treatment of attention deficit hyperactivity disorder (ADHD).
    State of the art
    Profenos, such as ibuprofen, and fenidates, are widely marketed drugs. However, although only one of the enantiomeric forms is active, some of the profenos such as ibuprofen are marketed as a mixture of the two enantiomers, in other cases only the active enantiomer is marketed. In those cases where the mixture is marketed it is because the enantiomer that is not active is not toxic and because there are no effective industrial enantioselective synthesis. For example, it is known that the d-threo enantiomer of dexmethyl fenidate is more active than the l-threo enantiomer (Pharmacol. Exp. Ther. 1970, 173, 158-165).
    There are published enantioselective synthesis of prophenes (Tetrahedron: Asymmetry 1992, 3, 163-192; Tetrahedron Letters 1989, 30, 2825-2828; J. Am. Chem. Soc. 1989, 111, 7650-7651; Synlett 1992, 48-50 ). However, these syntheses have the limitation of being a synthesis that employs sophisticated reagents, which makes it difficult to implement them at the industrial level.
    A common way used by the industry for the preparation of drugs in an enantiomeric form is to prepare it as a racemate and then carry out a resolution. For example, dexmethylphenidate (focalin) is prepared by resolution (Int. J. Res. Pharm. L. Sci. 2014, 4, 1066-1069.). However, the resolution has the limitation that half of the product is lost.
    Jin-Mo Ku, et al. Asymmetric synthesis of a, p-epoxysulfones via phase-transfer catalytic Darzens reaction. Tetrahedron 63 (2007) 8099-8103, describes the use of phase transfer catalysts, PTC (Phase Transfer Catalysis) to prepare epoxysulfones enantioselectively. However, by the procedure described in this document, only a particular type of epoxysulfones are obtained, with an enantioselectivity and chemical yield
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    low.
    There is therefore a need to provide a process for the preparation of prophenes and phenanthites in an enantioselective manner at the industrial level, which is simple and that solves the problems described in the prior art.
    Brief Description of the Invention
    The present invention solves the problems described in the state of the art since it provides a simple process for the enantioselective synthesis of prophenes and phenodates, by means of chemical reactions based on the reductive opening of optically active epoxysulfones. The process consists of a first reaction of enantioselective synthesis of epoxysulfones using chiral catalysts of the PTC type (phase transfer catalyst (Phase Transfer Catalysis) and a second stage of transformation of the epoxysulfones into prophenes or phenodates, depending on the epoxysulfone. On the other hand, when small amounts of PTC type catalysts are used, no toxic waste is generated and a final product is obtained without traces of toxic metal contaminants, which can be used in the pharmaceutical industry.
    Thus, in a first aspect, the present invention relates to a process for the enantioselective preparation of prophenes and phenylates (hereinafter, process of the present invention) comprising the following steps:
    a) Enantioselective synthesis of an epoxysulfone of general formula (I) and / or isomeric forms thereof, by reacting a ketone of general formula (II) and a sulfone of general formula (III), in the presence of a PTC catalyst and a base:
    image 1
    + r
    X
    , SO2Ar-
    '2A12
    Base
    PTC
    Ar1
    R1 O
    ,> K ^ S ° 2Ar2
    (II)
    (III)
    (I)
    Where:
    Ar1 is selected from phenyl, i-butylphenyl and 2-pyridyl;
    Ar2 is selected from phenyl and substituted phenyl;
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    X is selected from Cl, Br, and I.
    In the present invention and as one skilled in the art would understand it, by reference it refers to any substance that in aqueous solution contributes hydroxyl ions to the medium.
    b) reduction of the epoxysulfone of general formula (I) obtained in step a) to obtain the corresponding aldehyde of general formula (IV) or alcohol of general formula (V):
    R1 O
    , ^ S ° 2Ar2
    Ar- |
    Reducing agent
    (I)
    R1
    Ar1
    ^ O
    H
    (IV)
    R1
    Ar1
    OH
    (V)
    c) oxidation of the compound obtained in step b) to give rise to the profenne of the general formula (VI) or phenylate of the general formula (VII):
    Ri
    R
    Ar
    image2
    OR
    (IV)
    H
    Oxidizing agent
    Ar
    image3
    OR
    OH
    R1
    Ar!
    OH
    (V)
    image4
    (SAW)
    (VII)
    In the present invention, by isomeric forms the epoxysulfone of general formula (I) refers to any isomeric form of the epoxysulfone, in particular, refers to any of the following formulas:
    R
    , SO2Ar2
    R
    Ar ^ R)
    kS> SO2Ar2
    Ari O
    3 ^ 4 .SO2Ar2
    Ar
    .SOAr
    Ar1 (S)
    R1 (R) (S)
    R1 (S) (R)
    22
    In a particular embodiment, the PTC catalyst of step a) of the process of the present invention is a PTC catalyst of general formula (VIII):
    R
    R
    ■ 7.
    image5
    ■ 7.
    N
    (
    (VIII)
    Where:
    R5 is selected from -H, -CH3, -CH2CH3, - CH2CH2CH3, Bn, ethyl, allyl and vinyl;
    R6 is selected from -H, -CH3, -CH2CH3, - CH2CH2CH3, Bn, ethyl, allyl and vinyl;
    R7 is selected from ethyl and vinyl; X is selected from Cl, Br, and I.
    More particularly, the PTC catalyst of step a) of the process of the present invention is selected from a catalyst of the N-alkyl cinchonino, cinchonidinium, quininium and quinidinium type.
    In another particular embodiment, the reducing agent of step b) of the process of the present invention is selected from NaBH4, LiAlH4, Dibal-H, Zn (BH4) 2, BH3, Bu3SnH, LiBH4 and H2
    More particularly, step b) of the process of the present invention comprises a metal catalyst, more particularly the metal catalyst is selected from Pd / C and Pt / C.
    In another particular embodiment, the oxidizing agent of step c) of the process of the present invention is selected from NaClO, H2O2 and KMnO4.
    In a particular embodiment, the present invention relates to a process for the enantioselective synthesis of prophenes of general formula (VI) comprising the following steps:
    image6
    + r
    X
    SO2Ar2 PTC
    —----- ►
    (III)
    Ar base
    R1 O
    „.Í ^ .- SO2A'2
    The
    image7
    (II)
    (I)
    (IV)
    (VI) OH
    Where:
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    Ar2 is selected from phenyl and substituted phenyl;
    R1 is selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -NHCH3, -NHCH2CH3, NHCH2CH2CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -Cl, -Br e -Cl, -Br e -Cl, -Br e -Cl ;
    X is selected from Cl, Br, and I.
    In another particular embodiment, the present invention relates to a process for the enantioselective synthesis of phenylates of general formula (VII) comprising the following steps:
    R R1
    l1 + S ° 2Ar2 PTC R ^ O SO2Ar2 Reducing agent 1 .OH Oxidizing agent
    Ar ^ O X Base * Ar1 * 'Ar1%
    R
    (I)
    (II) (III)
    Where:
    Ar1 is selected from phenyl, i-butylphenyl and 2-pyridyl;
    (V)
    Ar
    (VII)
    image8
    OR
    or4
    Ar2 is selected from phenyl and substituted phenyl.
    R1 is selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3 -NHCH3, -NHCH2CH3, NHCH2CH2CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -Cl, -Br, -B, 2-pyridyl;
    X is selected from Cl, Br, and I.
    R4 is selected from -H, -CH3, -CH2CH3, Bn, Allyl and Vinyl. In another aspect, the present invention relates to a compound of general formula (VI) or (VII) obtained by the process of the present invention.
    Detailed description of the invention.
    The following examples illustrate specific embodiments of the present invention, but by no means limited.
    Example 1: synthesis of prophenes
    Acetophenone and 4-isobutyl acetophenone were transformed into the corresponding epoxysulfones as a mixture of diastereoisomers which at the same time are a
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    mixture of enantiomers enriched in one of the two possible enantiomers. The epoxysulfone mixture was transformed into the alcohol first which was then converted into the corresponding prophene by oxidation, as shown in scheme I:
    OR
    image9
    F----------------------'
    Ar = Ph, 4- / BuPh
    k_________________________________________.
    image10
    S02Ph
    dr 67% (60% ee) / 33% (22%)
    LÍAIH4
    image11
    image12
    Scheme I
    For this, a solution of chloromethyl phenyl sulfone (2 mmol) in diethyl ether (6 mL) was treated at room temperature, with the corresponding acetophenone (2.4 mmol), the N- (4-trifluoromethylbenzyl) quininium bromide phase transfer catalyst (0.2 mmol) and finally with potassium hydroxide (7.8 mmol). The resulting mixture was stirred at room temperature for 16 hours. After this time, the reaction mixture was filtered through celite washing with ethyl acetate, the filtrate was concentrated on the rotary evaporator and the resulting residue was purified by chromatography using hexane-ethyl acetate mixtures.
    To a suspension of lithium aluminum hydride (0.63 mmol) in freshly distilled tetrahydrofuran (3 mL) under an inert atmosphere of nitrogen and cooled with an ice bath was added a solution of the epoxysulfone obtained above (0.21 mmol) in tetrahydrofuran (1 mL) . The resulting mixture was stirred at room temperature for 16 hours. After this time, ethyl acetate (1 mL) was added and stirred for 15 minutes. Then, ethyl acetate (6 mL) and a 0.1M solution of HCl (12 mL) was added and poured into an extraction funnel. The aqueous phase was extracted with ethyl acetate (3 x 15 mL), the organic extracts were combined, dried (MgSO4) and concentrated on the rotary evaporator. The resulting oily residue was purified by chromatography with hexane / ethyl acetate.
    To a solution of the alcohol (0.4 mmol) in acetonitrile (3 mL) was added a solution of sodium chlorite (1.6 mmol) in water (0.8 mL), then 2,2,6,6-tetramethyl-1-piperidinyloxy (0.016 mmol), phosphate buffer (0.67 M, 3 mL) and finally a solution of sodium hypochlorite (5.25%, 21 mL) diluted with water (0.4 mL). The reaction was monitored by thin layer chromatography and after completion it was cooled in an ice bath and water (6 mL), a saturated solution of sodium bicarbonate to pH 8 and sodium sulphite (2.8 mmol) was added. After stirring the mixture for half an hour, ethyl acetate was added and stirred an additional fifteen minutes. Then, the reaction mixture was poured into an extraction funnel and the organic phase
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    was discarded, then the aqueous phase was cooled in an ice bath, brought to pH 2 and then poured into an extraction funnel where it was extracted with ethyl acetate (2 x 3 mL), the organic extracts were combined, dried (sodium sulfate), was filtered and concentrated on the rotary evaporator to give rise to the corresponding prophene or fenidate.
    Example 2: Synthesis of Phenidates
    The phenyl pyridinyl ketone was transformed into the corresponding epoxysulfone as a mixture of diastereoisomers which at the same time are a mixture of enantiomers enriched in one of the two possible enantiomers. The epoxysulfone mixture was subjected to hydrogenation under high pressure to give the corresponding piperidine alcohol which was then converted to the oxidation phenylate, as shown in Scheme II:
    image13
    (Scheme II)
    Step 1 and 3 follow the same procedure as steps 1 and 3 above for the synthesis of profane.
    To a suspension of the Pt / C catalyst (20 mg) in acetic acid (2 mL) was added a solution of the epoxysulfone (2 mmol) in acetic acid (6 mL) at room temperature. The resulting mixture was stirred at room temperature for 18 hours under hydrogen atmosphere. After this time, the reaction mixture was treated with a saturated sodium bicarbonate solution with caution and then brought to pH 9 with a 2M aqueous soda solution. Finally it was poured into an extraction funnel where it was extracted with ethyl acetate (2 x 3 mL), the organic extracts were washed with an aqueous solution of 1M hydrochloric acid and then with brine, then dried (sodium sulfate), dried. filtered and concentrated on the rotary evaporator to give rise to the corresponding alcohol.
    权利要求:
    Claims (6)
    [1]
    1. Procedure for the enantioselective preparation of prophenes and phenanthates comprising
    5 the following steps: a) Enantioselective synthesis of an epoxysulfone of the general formula (I) and / or isomeric forms thereof, by the reaction of an epoxide of the general formula (II) and a sulfone of the general formula (III), in presence of a PTC catalyst and a base:
    PTC
    image 1 R1 image2 SO2Ar2 image3 R1 O
    SO2Ar2
    +
    Base
    Ar1 O X Ar1
    (II) (III) (I)
    Where: Ar1 is selected from phenyl, i-butylphenyl and 2-pyridyl; Ar2 is selected from phenyl and substituted phenyl. R1 is selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, 15 NHCH3, -NHCH2CH3, NHCH2CH2CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -Cl, -Br, -Cl and 2-pyridyl; X is selected from Cl, Br, and I. b) reduction of the epoxysulfone of general formula (I) obtained in step a) to obtain the corresponding aldehyde of general formula (IV) or alcohol of general formula (V), in presence of a metallic catalyst: 20
    image4 R1 O
    (IV)
    image5 R1 O Reducing agent Ar1
    SO2Ar2 H Ar1
    image6 R1
    (V)
    (I)
    OH
    25 Ar1
    c) oxidation of the compound obtained in step b) to give rise to the profenne of the general formula
    (VI) or phenidate of the general formula (VII):
    image7 R1 image8 R1 (VI) OO (IV) Ar1 Oxidizing agent
    5 Ar1 H
    OH R1
    (V) image9 R1
    OH Ar1
    OR (VII) 10
    Ar1 OR4
    Method according to claim 1, wherein the PTC catalyst of step a) is a PTC catalyst of general formula (VIII):
    image10
    (VIII) Where:
    R5 is selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, Bn, ethyl, allyl and vinyl; R6 is selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, Bn, ethyl, allyl and vinyl; R7 is selected from ethyl and vinyl; X is selected from Cl, Br, and I;
    Method according to any of the preceding claims, wherein the PTC catalyst of step a) is selected from a catalyst of the N-alkyl cinchonino, cinchonidinium, quininium and quinidinium type.
    [4]
    Four. Process according to any of claims 1-3, wherein the reducing agent of step b) is selected from NaBH4, LiAlH4 and H2.
    [5]
    5. Process according to any of the preceding claims, wherein the metal catalyst of step b) is selected from Pd / C and Pt / C.
    [6]
    6. Process according to any of the preceding claims, wherein the oxidizing agent is selected from NaClO, H2O2 and KMnO4.
    [7]
    7. Process for the enantioselective synthesis of prophenes of general formula (VI) according to any of the preceding claims, comprising the following steps:
    a) Enantioselective synthesis of an epoxysulfone of the general formula (I) and / or isomeric forms thereof, by the reaction of an epoxide of the general formula (II) and a sulfone of the general formula (III), in the presence of a PTC catalyst and a base:
    R1 Ar1 O + SO2Ar2 XPTCOR1 Ar1SO2Ar2
    (II) (III)(I)
    Where:
    Ar1 is selected from phenyl, i-butylphenyl and 2-pyridyl; Ar2 is selected from phenyl and substituted phenyl. R1 is selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3,
    -NHCH3, -NHCH2CH3, NHCH2CH2CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -Cl, -Br and -I; X is selected from Cl, Br, and I. b) reduction of the epoxysulfone of general formula (I) obtained in step a) to obtain the
    corresponding aldehyde of general formula (IV):
    image11 R1
    image12 R1 O
    SO2Ar2 Reducing agent image13
    OR
    Ar1 Ar1
    H
    (I) (IV)
    c) oxidation of the compound obtained in step b) to give rise to the profenne of general formula (VI):
    image14
    [8]
    8. Procedure for enantioselective synthesis of phenylates of general formula (VII) according to
    Any one of the preceding claims, comprising the following steps a) Enantioselective synthesis of an epoxysulfone of general formula (I) and / or isomeric forms thereof, by reacting an epoxide of general formula (II) and a sulfone of formula general (III), in the presence of a PTC catalyst and a base:
    R1 image15 R1
    image16 SO2Ar2 PTC O
    SO2Ar2
    +
    Ar image17 1 O Ar1X
    (II) (III) (I)
    Where: Ar1 is selected from phenyl, i-butylphenyl and 2-pyridyl; Ar2 is selected from phenyl and substituted phenyl. R1 is selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3,
    -NHCH3, -NHCH2CH3, NHCH2CH2CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -Cl, -Br, -I and 2-pyridyl; X is selected from Cl, Br, and I. b) reduction of the epoxysulfone of general formula (I) obtained in step a) to obtain the
    corresponding alcohol of general formula (V):
    R1 image18 R1
    image19 OH Ar1 Ar1
    O SO2Ar2 Reducing agent
    (I) (V)
    c) oxidation of the compound of the general formula (V) obtained in step b) to give rise to the phenidate of the general formula (VII):
    R1 R1 Oxidizing agent
    image20 OH
    image21 O Ar1 Ar1
    OR4
    (V) (VII)
    9. Compound of general formula (VI) or (VII), obtained by a process according to any of claims 1-8.
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