Process of vitamin K2 derivatives preparation
AssigneeSiec Badawcza Lukasiewicz-Instytut Chemii Przemyslowej imienia Profesora Ignacego Moscickiego
InventorsKatarzyna Sidoryk, Marek Napiorkowski, Agnieszka Burzynska-Prajzner, Marcin Cybulski, Marek Kubiszewski, Kamil Jatczak, Lukasz Jedynak, Jerzy Winiarski, Dorota Pietrzkowska, Konrad Zielinski
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Abstract
Provided is an improved process of vitamin K2 derivatives preparation, represented by formula (I) wherein n is an integer from 3 to 13.
Claims18
A process of preparation of vitamin K2 derivatives, represented by formula (I)
- wherein n is an integer from 3 to 13,
- comprising the steps of:
- (a) reacting an α-sulfonyl carbanion generated in situ from a phenylsulfone of menadiol derivative of formula (II)
- wherein R represents an allyl protecting group,
- in the presence of an organometallic base,
- with a polyprenyl halide of formula (VII)
- wherein
- X is a halogen atom selected from the group consisting of bromine, chlorine and fluorine atoms,
- Y is H or —SO2Ph,
- m is an integer from 0 to 5,
- as an alkylating agent;
- to yield a phenylsulfonyl derivative of menadiol of formula (VIII)
- wherein R, Y, and m have the meaning defined above,
- (b) removing the phenylsulfonyl groups from the menadiol derivative of formula (VIII) by reductive elimination, to yield a menadiol derivative of formula (IX)
- wherein R and m have the meaning defined above;
- (c) subjecting the menadiol derivative of formula (IX) to an oxidative deeterification, to yield a crude menadione compound of formula (I),
- wherein
- n is the integer from 3 to 13, and
- (d) optionally, purifying the crude menadione compound of formula (I) to yield pure vitamin K2.
The process according to any of the preceding claims, wherein phenylsulfonyl groups are removed with sodium amalgam in MeOH, buffered with Na2HPO4.
The process according to any of the preceding claims, wherein the oxidative deesterification is accomplished with the use of Pd(OAc)2/Ph3P and 1,3-dimethylbarbituric acid.
The process according to any of the preceding claims, wherein the alkylating agent in (a) is the polyprenyl halide of formula (VII)
- wherein
- X is a halogen atom selected from the group consisting of bromine, chlorine and fluorine atoms,
- Y is —SO2Ph,
- m is an integer from 0 to 5.
The process according to any of the preceding claims, wherein the alkylating agent in (a) is the polyprenyl halide of formula (VII)
- wherein
- X is a bromine atom,
- Y is —SO2Ph, and
- m is an integer from 0 to 5.
The process according to any of the preceding claims, wherein the polyprenyl halide used as the alkylaing agent is obtained in a stepwise process of:
- (i) coupling a phenylsulfonyl-geranyl unit of formula (III),
- with a compound of formula (IV)
- and repeating said coupling process with the use of compound of formula (IV) until a compound of formula (V) of desired chain length m is obtained
- wherein
- Y is —SO2Ph,
- m is an integer from 1 to 4;
- (ii) hydrolysis of the compound of formula (V), to yield a polyisoprenol derivative of formula (VI)
- wherein Y is —SO2Ph, and
- m is an integer from 0 to 5;
- (iii) optionally, removing the phenylsulfonyl groups to yield a polyisoprenol derivative of formula (VI)
- wherein Y is H, and
- m is defined above,
- and
- (iv) substituting the hydroxyl group of the compound of formula (VI) for a halogen atom selected from the group consisting of bromine, chlorine, an fluorine atoms in a reaction with a halogenating agent, to yield a polyprenyl halide of formula (VII),
- wherein X is a halogen atom selected from the group consisting of bromine, chlorine and fluorine atoms,
- Y is H or —SO2Ph, and
- m is defined above.
The process according to any of the preceding claims, wherein MK-7 type of vitamin K2 is obtained.
New menadiol phenylsulfone compound of formula (II)
- wherein R is an allyl protecting group.
A process of preparation of the menadiol phenylsulfone of formula (II)
- wherein R of formula (II) represents the allyl protecting group,
- in a Friedel-Crafts reaction catalysed by a Lewis acid, wherein InCl3 is used as the Lewis acid in the presence of a solid inorganic base as an alkylation promoter.
An intermediate compounds selected from the group comprising of:
- wherein
- R is an allyl protecting group,
- m is an integer from 0 to 5, and
- n is an integer from 0 to 5.
Dependencies are inferred from the claim text.