Vitamin K2 synthesis

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## the process comprising reacting a compound of formula (II): ##STR00016## wherein R is ##STR00017## with a compound of formula (III): ##STR00018## in the presence of a heterogeneous triflate catalyst which is a compound of formula (IV): ##STR00019## wherein M is Al, Bi or Sc.

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

3. The process according to claim 1, wherein the process is carried out at elevated temperatures.

4. The process according to claim 1, wherein the compounds of formulas (II) and (III) are reacted in equimolar amounts.

5. The process according to claim 1, wherein the compounds of formulas (II) and (III) are present in a molar ratio of the compound of formula (II) to the compound of formula (III) of 1:2 to 2:1.

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

7. The process according to claim 6, wherein the substrate to catalyst ratio is from 1500:1 to 30000:1.

8. The process according to claim 1, wherein the process is carried out at an elevated temperature of 30 C. to 150 C.

9. The process according to claim 1, wherein the process achieves >99% conversion of the compounds of formulas (II) and (III).

Description

EXAMPLES

Example 1

(1) 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 Mol, 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.

(2) 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.

(3) 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.

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

Example 2

(5) 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 Mol, 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.

(6) 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

(7) 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 Mol, 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.

(8) 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).