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VITAMIN K2 SYNTHESIS

20230159429 · 2023-05-25

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to a new process of production of menaquinone 4, which is also known as vitamin K2.

    Claims

    1. A process for the production of the compound of formula (I) ##STR00014## wherein R is ##STR00015## wherein the compound of formula (II) ##STR00016## wherein R is ##STR00017## is reacted with the compound of formula (III) ##STR00018## in the presence of a heterogeneous triflate catalyst.

    2. Process which is process according to claim 1, wherein the heterogeneous catalyst is a compound of formula (IV) ##STR00019## wherein M is Al, Bi or Sc.

    3. The process according to claim 1, wherein the process is carried out in an inert solvent system.

    4. The process according to claim 1, wherein the process is carried out at elevated temperatures (preferably at 30° C. to 150° C.).

    5. The process according to claim 1, wherein the compound of formula (II) and (III) are used in an equimolar amount.

    6. The process according to claim 1, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:2 to 2:1.

    7. The process according to claim 1, wherein the substrate to catalyst ratio (based on the molar amount of the compound of formula (II) to the catalyst of formula (IV)) is from 2000:1 to 50000:1.

    8. The process according to claim 7, wherein the substrate to catalyst ratio is from 1500:1 to 30000:1.

    Description

    EXAMPLES

    Example 1

    [0058] In a 100 ml flask equipped with a stirrer, an Argon inlet, a dosage inlet, water separator with a water cooled intensive condenser and a bubble counter, 4.22 g (99%, 15 mMol, 1.5 eq) of menadiol-1-benzoate together with 12 g ethylene carbonate, 15 ml n-heptane and 0.949 mg (99.9%, 2.0 μMol, 0.0002 eq) of Al(OTf).sub.3 were weighed in. Further ˜10 ml n-heptane were placed in the separator. Under strong stirring (1000 rpm) at 100° C., the dosage of 3.23 g (90%, 10 mMol, 1 eq) geranyl geraniol solved in ˜2 ml n-heptane over 2 hours was started.

    [0059] At the same temperature 30 minutes was stirred, then cooled down to 80° C. and add 15 ml n-heptane. The reaction mixture was placed in a separating funnel and separate the lower ethylene carbonate phase.

    [0060] The organic phase is concentrated on a rotary evaporator at 40° C. to 17 mbar and degassed for 30 minutes at high vacuum to <0.1 mbar at 40° C.

    [0061] The product (compound of formula (I)) was obtained in 52.5% yield (conversion >99%, selectivity 0.52).

    Example 2

    [0062] In a 100 ml flask equipped with a stirrer, an Argon inlet, dosage inlet, water separator with a water cooled intensive condenser and a bubble counter, 4.22 g (99%, 15 mMol, 1.5 eq) of menadiol-1-benzoate together with 12 g ethylene carbonate, 15 ml n-heptane and 1.326 mg (99.9%, 2.0 μMol, 0.0002 eq) of Bi(OTf).sub.3 were weighed in. Further ˜10 ml n-heptane were placed in the separator. Under strong stirring (1000 rpm) at 100° C., the dosage of 3.23 g (90%, 10 mMol, 1 eq) geranyl geraniol solved in ˜2 ml n-heptane over 2 hours was started.

    [0063] At the same temperature 30 minutes was stirred, then cooled down to 80° C. and add 15 ml n-heptane. The reaction mixture was placed in a separating funnel and separate the lower ethylene carbonate phase. The organic phase is concentrated on a rotary evaporator at 40° C. to 17 mbar and degassed for 30 minutes at high vacuum to <0.1 mbar at 40° C. The product (compound of formula (I)) was obtained in 57.5% yield of crude product (conversion >99%, selectivity 0.57).

    Example 3

    [0064] In a 100 ml flask equipped with a stirrer, an Argon inlet, dosage inlet, water separator with a water cooled intensive condenser and a bubble counter, 3.35 g (96.7%, 15 mMol, 1.5 eq) of menadiol-1-acetate together with 12 g ethylene carbonate, 15 ml n-heptane and 0.949 mg (99.9%, 2.0 μMol, 0.0002 eq) of Al(OTf).sub.3 were weighed in. Further ˜10 ml n-heptane were placed in the separator. Under strong stirring (1000 rpm) at 100° C., the dosage of 3.23 g (90%, 10 mMol, 1 eq) geranyl geraniol solved in ˜2 ml n-heptane over 2 hours was started.

    [0065] At the same temperature 30 minutes was stirred, then cooled down to 80° C. and add 15 ml n-heptane. The reaction mixture was placed in a separating funnel and separate the lower ethylene carbonate phase. The organic phase is concentrated on a rotary evaporator at 40° C. to 13 mbar and degassed for 30 minutes at high vacuum to <0.1 mbar at 40° C. The product (compound of formula (I)) was obtained in 23.2% yield of crude product (conversion >99%, selectivity 0.23).