PROCESS FOR THE PREPARATION OF VITAMIN K2 AND NOVEL INTERMEDIATES

Abstract

A compound of formula (I): (I) wherein n is an integer between 0 and 10; Y is hydrogen, halide, mesylate, tosylate, ester, SPh, SO2Ph, hydroxyl or protected hydroxyl; with the proviso that if n=0 or 1, Y is not hydrogen.

##STR00001##

Claims

1. A process comprising converting a compound of formula (I) ##STR00056## wherein n is an integer between 2 and 10 to a compound of formula (VII): ##STR00057## preferably by heating, especially in the absence of a solvent.

2. A process as claimed in claim 1, further comprising a step of forming the compound of formula (I) by reaction of compound (II) with a compound of formula (III) ##STR00058## in the presence of a base; wherein X is a leaving group preferably selected from halogen, mesylate, tosylate and triflate.

3. A process as claimed in claim 1, comprising carrying out the following steps in one pot: i) reacting compound (III) ##STR00059## wherein X is a leaving group preferably selected from halogen (preferably Br), mesylate, tosylate and triflate; and n is an integer between 2 and 10; with a compound of formula (II): ##STR00060## in the presence of base (e.g. alkoxide such as a tert-butoxide, e.g. KO.sup.tBu); ii) converting the resulting compound of formula (I): ##STR00061## to the final menadione product (VIII) ##STR00062## by heating, especially in the absence of a solvent.

4. A process as claimed in claim 1, comprising carrying out the following steps in one pot: i) converting a polyprene alcohol of formula (VIII): ##STR00063## wherein n is an integer between 2 and 10; into a polyprene reagent of formula (III) ##STR00064## wherein X is Br, in the presence of PBr.sub.3; and ii) reacting compound (III) with compound (II): ##STR00065## in the presence of base (e.g. alkoxide such as a tert-butoxide, e.g. KO.sup.tBu). iii) converting the resulting compound (I): ##STR00066## to the final menadione product ##STR00067## by heating, especially in the absence of a solvent.

5. A process as claimed in claim 3 or 4 wherein the one pot process occurs in a flow reactor.

6. A process as claimed in claim 1, wherein (I) is obtained by (i) reacting a compound of formula (IV): ##STR00068## with a compound of formula (VI): ##STR00069## in the presence of a base, wherein m+q=n?1; n is 1 to 9; m is an integer between 0 and 9; q is an integer between 9 and 0; Y is halide, hydroxyl or protected hydroxyl and Z is mesylate, tosylate, ester, SPh or SO.sub.2Ph, or Y is mesylate, tosylate, ester, SPh or SO.sub.2Ph and Z is halide, hydroxyl or protected hydroxyl; R.sup.a is independently H or a substituent selected from mesylate, tosylate, SPh or SO.sub.2Ph; and optionally in a step ii), the Z or Y group respectively and any non-H R.sup.a group in the resulting compound are reduced to hydride(s).

7. The process ##STR00070## by heating, especially in the absence of a solvent.

8. A process comprising converting a compound of formula (I) ##STR00071## wherein n is an integer between 2 and 10 and wherein R.sup.a is independently H or a substituent selected from mesylate, tosylate, SPh or SO.sub.2Ph to a compound of formula (VII): ##STR00072## preferably by heating, especially in the absence of a solvent.

9. The process ##STR00073## wherein step (iii) is effected by heating, especially in the absence of a solvent.

10. The process of claim 9, comprising the steps ##STR00074## wherein step (iii) is effected by heating, especially in the absence of a solvent.

11. A compound of formula (I): ##STR00075## wherein n is an integer between 0 and 10; Y is hydrogen, halide, mesylate, tosylate, SPh, SO.sub.2Ph, ester, hydroxyl or protected hydroxyl; with the proviso that if n=0 or 1, Y is not hydrogen.

12. A compound as claimed in claim 11, wherein Y is hydrogen and n is 2 to 10, preferably 5-10, 5-9, 5-8 or 5-7.

13. A compound as claimed in claim 11 or 12, wherein n is between 3 and 9, preferably 6.

14. A compound as claimed in any preceding claim of formula ##STR00076##

15. A compound of formula (I) ##STR00077## wherein n is an integer between 2 and 10 and wherein R.sup.a is independently H or a substituent selected from mesylate, tosylate, SPh or SO.sub.2Ph.

16. A compound of formula (I): ##STR00078## wherein R.sup.a is independently H or a substituent selected from mesylate, tosylate, SPh or SO.sub.2Ph; Y is hydrogen, halide, mesylate, tosylate, SPh, SO.sub.2Ph, ester, hydroxyl or protected hydroxyl n is an integer between 0 and 10 when R.sup.a is H, and n is an integer between 2 and 10 when Y is H; with the proviso that if n=0 or 1, Y is not hydrogen.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0045] This invention provides a new synthetic route to vitamin K2 and to the menaquinones that form part of naturally occurring vitamin K2. The invention also relates to new intermediate compounds that are prepared during the synthesis. The Diels-Alder adducts of the invention are preferably precursors to MK-4, MK-6, MK-7, MK-8, or MK-10. Most preferably, they are precursors to MK-7 and n is 6. It is thus preferred if the long chain isoprenoid at position 2 on the naphthoquinone ring is

##STR00011##

Diels-Alder Intermediate and its Formation

[0046] In a first aspect of the invention, the invention provides a Diels-Alder (DA) adduct of formula (I):

##STR00012## [0047] wherein n is an integer between 0 and 10, [0048] Y is hydrogen, halide, mesylate, tosylate, SPh, SO.sub.2Ph, ester, hydroxyl or protected hydroxyl; [0049] with the proviso that if n=0 or 1, Y is not hydrogen.

[0050] The ester is typically of formula COOR.sup.1 with R.sup.1 being a C.sub.1-C.sub.6 hydrocarbyl group, such as a linear or branched C.sub.1-C.sub.6 alkyl group or Ph. Typically R.sup.1 is methyl and the ester group is acetate.

[0051] By protected hydroxyl is meant an OH group protected by a protecting group. Protected hydroxyl is thus typically an OR group wherein R is MOM, THP, tBu, allyl, benzyl, TBDMS, TBDPS, C(?O)tBu, C(?O)Ph.

[0052] The integer n is typically between 2 and 10, preferably between 3 and 9. Preferably the compound of formula (I) is a Diels-Alder Adduct of MK-4, MK-6, MK-7, MK-8 or MK-10, i.e. n is 3, 5, 6, 7, 9. Most preferably n is 6 (i.e. the Diels-Alder adduct (1) is a precursor to MK-7). When Y is hydrogen, n is typically in the range 5-10, 5-9, 5-8, or 5-7, preferably 5-7, most preferably 6. The above definitions for n also apply at least to compounds of formula (I), (I) and (I), where technically viable, and unless stated otherwise.

[0053] Longer chains, i.e. higher values of n, are surprisingly stable, e.g. during the retro Diels Alder step, and enable the facile preparation of higher MK-n compounds.

[0054] In one embodiment, e.g. where n is 0 or 1, the functionality at Y can be used to attach a further polyprenyl, such as a pentaprenyl substituent in a [2+5] reaction or a hexaprenyl substituent in a [1+6] reaction. More preferably Y is H and the compound of formula (I) becomes:

##STR00013## [0055] wherein n is 2 to 10, such as 3 to 9, or 5-10, 5-9, 5-8, or 5-7, especially 6.

[0056] Teitelbaum et al. (Synthesis 2015, 47, 944-948) describes the above compound (1) in which n is 0 or 1 and Y?H, but these intermediates are then further reacted to form short chain acid metabolites.

[0057] The presence of a Y functionality (i.e. when Y is not hydrogen) enables chain lengthening chemistry to be performed at the end of the polyisoprene chain once the attachment to menaquinone Diels-Alder adduct has been performed. Thus, the Diels-Alder intermediate (1) can be converted directly to the final menaquinone or can undergo further chain lengthening at Y before the retro DA reaction.

[0058] In a further embodiment, a compound of formula (I) is provided:

##STR00014## [0059] wherein n is an integer between 2 and 10, such as 3 to 9, especially 6. and wherein Ra is independently H or a substituent selected from mesylate, tosylate, SPh or SO.sub.2Ph.

[0060] The Ra group(s) are typically present when the polyisoprene chain has been constructed using Bielmann chemistry. The retro Diels Alder reaction can be performed after removing the R.sup.a group(s), or before.

[0061] The compounds of formula (I) and (I) can be combined to give the following compound definition (I), which forms a further embodiment of the invention:

##STR00015## [0062] wherein R.sup.a is independently H or a substituent selected from mesylate, tosylate, SPh or SO.sub.2Ph; [0063] Y is hydrogen, halide, mesylate, tosylate, SPh, SO.sub.2Ph, ester, hydroxyl or protected hydroxyl [0064] n is an integer between 0 and 10 when R.sup.a is H, and n is an integer between 2 and 10 when Y is H; [0065] with the proviso that if n=0 or 1, Y is not hydrogen.

[0066] The Diels-Alder adduct of formula (I) of the invention is typically prepared from the reaction of a compound of formula (II) and (Ill)

##STR00016## [0067] in the presence of a base; [0068] wherein X is a leaving group preferably selected from halogen, mesylate, tosylate and triflate. X is preferably a halogen, and most preferably Br. Y can be as defined for compound (1). Preferably, Y is hydrogen, mesylate, tosylate, SPh, SO.sub.2Ph, ester, hydroxyl or protected hydroxyl. In a particular embodiment, Y is an ester, such as an ester of formula COOR.sup.1, with R.sup.1 being a C1-C6 hydrocarbyl group, such as a linear or branched C1-C6 alkyl group or Ph.

[0069] Any base can be used, typically a non-nucleophilic base. The base is typically an alkoxide, such as a tert-butoxide (e.g. KO.sup.tBu). The base deprotonates the hydrogen in compound (II) which is alpha to the bottom carbonyl group. The base is typically added once compound (II) and compound (Ill) have been mixed; however, it may also be added to compound (II) before addition of compound (Ill).

[0070] Typically, Y is H in all embodiments of the invention. Thus, in a particular embodiment of the invention, no chain extension chemistry as described herein or below is performed. In such an embodiment, the invention provides a compound of formula:

##STR00017## [0071] wherein n is an integer between 2 and 10, preferably between 2 and 8. Preferably compound (I) is a Diels-Alder Adduct of MK-4, MK-6, MK-7, MK-8 or MK-10, i.e. n is 3, 5, 6, 7, 9. Preferably n is 6 (i.e. the Diels-Alder intermediate (IV) is a precursor to MK-7). These preferences are valid for all embodiments of the invention, where technically viable. I.e. these preferred values of n also apply to any embodiments relating to other compounds or processes described herein.

[0072] The integer n is preferably 6, and thus in a preferred embodiment the invention provides a compound of formula:

##STR00018##

[0073] Typically, the compound of formula (I) is formed from the reaction of a compound of formula (II) and (III)

##STR00019## [0074] in the presence of a base; [0075] wherein X is a leaving group preferably selected from halogen, mesylate, tosylate and triflate and n is an integer between 2 and 10, preferably between 2 and 8 . . . X may also be an ester, such as an ester of formula COOR.sup.1, with R.sup.1 being a C1-C6 hydrocarbyl group, such as a linear or branched C1-C6 alkyl group or Ph. It is envisaged that such polyprene esters may react with the menadione Diels-Alder adduct (II) in the presence of a base. X is preferably a halogen, and most preferably Br.

[0076] Diels-Alder adduct (V) is preferably formed from the menaquinone adduct (II)

##STR00020##

and the polyprene reagent:

##STR00021## [0077] wherein n is 6; [0078] in the presence of a base; [0079] wherein X is a leaving group selected from halogen, mesylate, tosylate and triflate. X may also be an ester, such as an ester of formula COOR.sup.1, with R.sup.1 being a C1-C6 hydrocarbyl group, such as a linear or branched C1-C6 alkyl group or Ph. It is envisaged that such polyprene esters may react with the menadione adduct (II) in the presence of a base. X is preferably a halogen, and most preferably Br.

[0080] Other preferred adducts of formula (I) include:

##STR00022##

Chain Lengthening Using Bielmann Chemistry

[0081] As mentioned above, the chain can be further lengthened, typically using Bielmann chemistry. In a particular embodiment, the invention provides a process whereby a compound of formula (IV):

##STR00023## [0082] is (i) reacted with a compound of formula (VI):

##STR00024## [0083] in the presence of a base, [0084] wherein m+q=n?1; [0085] n is 1 to 9; [0086] m is an integer between 0 and 9; [0087] q is an integer between 9 and 0; [0088] Y is halide, hydroxyl or protected hydroxyl and Z is mesylate, tosylate, ester, SPh or SO.sub.2Ph, or Y is mesylate, tosylate, ester, SPh or SO.sub.2Ph and Z is halide, hydroxyl or protected hydroxyl; [0089] R.sup.a is independently H or a substituent selected from mesylate, tosylate, SPh or SO.sub.2Ph; [0090] and optionally in a step ii), the Z or Y group respectively and any non-H R.sup.a group in the resulting compound are reduced to hydride(s). In a further embodiment, the Z or Y group respectively and any non-H R.sup.a group in the resulting compound are reduced to hydride(s) after the retro-Diels Alder reaction.

[0091] In a particular embodiment, m is 1 and q is 4. In a further embodiment, m is 0 and q is 5. Both of these lead to MK-7-based structures. Typically, m is 0-4 and q is 6-2, preferably m is 0-2 and q is 5-3.

[0092] Preferably, n is 6. Typically, therefore, m+q=5.

[0093] In a further embodiment, Y is SO.sub.2Ph or SPh and Z is a halide (e.g. Br).

[0094] In a particular embodiment, the reduction in step ii) is performed using lithium metal or a metal hydride.

[0095] The compound resulting from step (i) is typically the following intermediate (I.sub.int):

##STR00025##

If Y is halide, hydroxyl or protected hydroxyl and Z is mesylate, tosylate, SPh or SO.sub.2Ph, then Y/Z will be Z. If Y is mesylate, tosylate, SPh or SO.sub.2Ph and Z is halide, hydroxyl or protected hydroxyl, then Y/Z will be Y. Typically, in compound (IV), Y is mesylate, tosylate, SPh or SO.sub.2Ph and in compound (VI), Z is halide, hydroxyl or protected hydroxyl, most preferably Y is SPh or SO.sub.2Ph (preferably SO.sub.2Ph) and Z is halide (preferably Br).

[0096] In compound (VI) (and (I.sub.int)), the R.sup.a group can be different for each repeating unit. In a particular embodiment, at least one R.sup.a substituent, preferably one R.sup.a substituent, is selected from mesylate, tosylate, SPh or SO.sub.2Ph, and the other R.sup.a groups are H. In another embodiment, all R.sup.a groups are H. Any non-H R.sup.a groups in compound (VI) typically come from the construction chemistry used to form compound (VI) (typically Bielmann chemistry).

[0097] Typically, step (ii) produces compound (I). In a particular embodiment, therefore, I.sub.int is reduced in step (ii) to form (I):

##STR00026##

[0098] Alternatively, the retro Diels-Alder reaction is performed on I.sub.int to form

##STR00027## [0099] after which step ii) is performed (i.e. the Z or Y group respectively and any non-H R.sup.a group in the resulting compound are reduced to hydride(s)).

[0100] Alternatively viewed, the invention provides the following process which comprises converting a compound of formula (I)

##STR00028## [0101] wherein n is an integer between 2 and 10 [0102] and wherein R.sup.a is independently H or a substituent selected from mesylate, tosylate, SPh or SO.sub.2Ph [0103] to a compound of formula (VII):

##STR00029## [0104] preferably by heating.

[0105] The compound (I) per se forms an embodiment of the invention.

[0106] To perform the chain extension coupling of step i), Biellmann chemistry can preferably be employed. This reaction involves the formation of phenylthio or phenylsulfonyl substituted compounds and reaction of these sulphur compounds with an electrophile, such as a halide, in the presence of a base. Suitable bases include n-butyl lithium, tert butyl lithium, and non nucleophilic bases such as tertbutoxides. After coupling, the phenylthio or phenylsulfonyl groups are removed reductively for example with lithium metal or a metal hydride. Alternatively, the phenylthio or phenylsulfonyl groups are removed reductively, for example with lithium metal or a metal hydride, after the retro-Diels-Alder reaction. The inventors have found that this method is ideal for coupling together two isoprenoid chains to make a new isoprenoid chain of, for example, 7 or more units.

[0107] The chemistry here is previously explained in WO2010/03500. Thus in a particular embodiment, the invention provides a process represented by the following scheme:

##STR00030##

In a particular embodiment, the invention provides the following process (i.e. a [1+6] process):

##STR00031##

or

##STR00032##

[0108] In a further particular embodiment, the invention provides the following process (i.e. a [2+5] process):

##STR00033##

or

##STR00034##

In any of the above schemes 1-4, the last two steps can be interchanged, i.e. the retro Diels-Alder can be performed before the removal of the SO.sub.2PH groups. For scheme 1, for example, the last two steps would then be:

##STR00035##

Furthermore, in any of the above schemes 1-4, the beginning of the process can be modified to use an OR group instead of a SO.sub.2PH group in the starting isoprene or polyisoprene compound. The compound with the Br and OR functionalities can be coupled with the Diels Alder adduct via attack of the Br moiety. After coupling, the OR group can be converted to Br, and coupled with a further pentaprene or hexaprene SO.sub.2Ph compound. For scheme 4, for example, this would give:

##STR00036##

Preparation of Polyprene Reagent

[0109] In a particular embodiment, X is Br in the polyprene reagent (III):

##STR00037##

[0110] Compound (III) with X?Br can be prepared upon reaction of the corresponding polyprenol and PBr.sub.3. This can be made in situ and does not require isolation. In comparison, Teitelbaum et al. (Synthesis 2015, 47, 944-948) and Ji (Synthetic Communications 2003, 33:5, 763-772), use a purified bromide starting material.

[0111] The integer n is preferably 6, i.e. compound (III) is preferably a heptaprene reagent.

[0112] X is a leaving group. Whilst Br is preferred, X may be selected from other halogens, mesylate, tosylate and triflate.

[0113] In a further embodiment, X is an ester, such as an ester of formula COOR.sup.1, with R.sup.1 being a C1-C6 hydrocarbyl group, such as a linear or branched C1-C6 alkyl group or Ph. It is envisaged that such polyprene esters may react with the menadione Diels Alder adduct (II) in the presence of a base.

[0114] In a particular embodiment, compound (III) is heptaprenylbromide, i.e.

##STR00038##

Heptaprenol is commercially available or can be synthesised according to WO2010/035000. Heptaprenyl bromide can be synthesised from heptaprenol using PBr.sub.3, for example.

Retro-Diels-Alder Reaction

[0115] A key benefit of the intermediate of formula (I) is that it can be converted to the final menaquinone upon simple heating. The final heating step also removes by-products as the cyclopentadiene by-product can be removed at low temperature.

[0116] Previous reactions have required the use of ammonium catalysts and acid (see Teitelbaum et al. (Synthesis 2015, 47, 944-948) and Ji (Synthetic Communications 2003, 33:5, 763-772)). Whilst the use of such reagents is possible, this is less favoured. These reagents are a cost and there is an increased risk of isomerization of bonds in the polyisoprene chains.

[0117] In a particular embodiment, upon heating or reacting with an ammonium catalyst and/or an acid, compound (I)

##STR00039##

is converted by retro-Diels-Alder reaction to the desired menaquinone (VII).

##STR00040##

The retro-Diels-Alder reaction is accompanied by loss of cyclopentadiene.

[0118] The ammonium catalyst is typically a tetraalkylammonium salt, such as dodecyltrimethylammonium bromide. The acid is typically a carboxylic acid, such as acetic acid. Preferably, however, the retro-Diels-Alder reaction is carried out in the absence of an ammonium catalyst and acid.

[0119] In a particular embodiment, the retro-Diels Alder reaction is carried out in the absence of a dehydrogenating agent or oxidising agent.

[0120] In a particular embodiment, the retro-Diels Alder reaction, i.e. the conversion of a compound (I) into a compound (VII), is carried out upon heating to a temperature in the range 50-150? C., such as 60-120? C., 70-110? C. or 80-100? C. It is surprising that this final retro-Diels Alder step can be performed upon simple heating, and is advantageous as it does not require additional reagents. The reaction is high yielding and achieves high purity. The only by-product, cyclopentadiene, with a boiling point of 40.8? C., is removed upon heating. Yields in the range of 80-95%, based on the starting polyprene reagent can be obtained.

[0121] The integer n is preferably 6, and thus in a preferred embodiment the invention provides a process comprising the following step:

##STR00041##

in particular wherein the retro Diels-Alder reaction above is effected by heating.

One-Pot Method

[0122] In a particular embodiment, the invention provides a one-pot method for preparing the target menaquinone of the present invention starting from a simple polyprene reagent. By one-pot synthesis is meant a process whereby the starting reactants are subjected to successive chemical reactions in just one reactor without inter stage separation steps of the formed products. The reactor is preferably a flow reactor. The starting reactant in this case could be a polyprenol (e.g. heptaprenol) or a modified polyprene compound of formula (III) (e.g. heptaprenyl bromide). The one-pot method is highly advantageous as it avoids lengthy separation processes and purifications of the intermediate chemical compounds which can save time and resources while increasing chemical yield. Note therefore that in Teitelbaum each intermediate compound is isolated between steps.

[0123] In a particular embodiment, the invention provides a one pot process comprising the following steps: [0124] i) reacting compound (III)

##STR00042## [0125] wherein X is a leaving group preferably selected from halogen (preferably Br), mesylate, tosylate and triflate; [0126] and n is an integer between 2 and 10;
with a compound (II):

##STR00043##

in the presence of base (e.g. alkoxide such as a tert-butoxide, e.g. KO.sup.tBu). [0127] ii) converting the resulting compound of formula (I):

##STR00044##

to the menaquinone product (VII)

##STR00045##

[0128] By a one pot process is meant that the product of step (i) is not isolated before step (ii) is carried out, e.g. is not isolated before the addition of the reagents required to effect step (ii). This last reaction can be performed by heating (preferred), or reaction with an ammonium catalyst and/or an acid.

[0129] In a further particular embodiment, the process of the invention comprises a one pot reaction in which in a first step i), wherein the polyprene alcohol of formula (VIII)

##STR00046##

is converted to the polyprene reagent of formula

##STR00047##

upon reaction with a suitable reagent. X is a leaving group selected from halogen, mesylate, tosylate and triflate. For X?Br, such a suitable reagent could be PBr.sub.3.

[0130] In a second step ii), compound (III) is then reacted with the menadione Diels adduct (II):

##STR00048##

in the presence of base (e.g. alkoxide such as a tert-butoxide, e.g. KO.sup.tBu).
In a third step iii), the resulting compound:

##STR00049##

is then converted to the final menadione product.

##STR00050##

All these reactions are effected in a single pot without interstage isolation.

[0131] This latter reaction can be performed by heating (preferred), or reaction with an ammonium catalyst and/or an acid.

[0132] The advantage of this latter reaction sequence is that the entire reaction from the starting polyprenol can be carried out without the need for intermediate purifications.

[0133] In a further particular embodiment, the process is a flow process. Such a process can be effected in a flow reactor.

[0134] It will be appreciated that the reactions described herein may be carried out in an appropriate solvent. The skilled person can select solvents necessary. For example, the reaction of compounds of formula (II) and (III) can be effected in a non-aqueous solvent such as THF. The retro Diels Alder can be effected in the absence of a solvent by just heating the material.

[0135] In a particularly preferred embodiment, the invention provides a process comprising steps (i) to (iii) or steps (ii) to (iii) in the schemes below.

##STR00051##

[0136] Step (iii) is preferably effected by heating. All steps are preferably carried out in a single pot, ideally a flow reactor.

[0137] The invention will now be explained with reference to the following non limiting examples.

Example 1

(1S,4R)-4a-((2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl)-9a-methyl-1,4,4a,9a-tetrahydro-1,4-methanoanthracene-9,10-dione (F)

[0138] ##STR00052##

[0139] To a solution of heptaprenylbromide E (5.25 g, 9.42 mmol) in dry THF (25 ml) at 0? C. (ice bath), was added menadione adduct D (2.39 g, 10 mmol) and stirring continued for one minute before addition of potassium tert-butoxide (3.37 g, 30 mmol) in one portion. The cooling bath was removed and stirring continued for 30 minutes. The reaction mixture was quenched with 2 M HCl (25 ml), the aqueous layer extracted with heptane (2?25 ml). The combined organic extract was filtered through a short pad of silica gel (5 grams) and concentrated on the rotary evaporator to give the title compound (F) as a yellow oil.

Example 2

2-((2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl)-3-methylnaphthalene-1,4-dione (G)

[0140] ##STR00053##

[0141] Compound F was heated at 90? C. for 30 min. After cooling to room temperature, the residue (6.33 g) was dissolved in acetone (50 ml) and cooled to ?20? C. Left at this temperature overnight, filtered, washed with cold acetone and dried to give 5.06 g (83% from heptaprenol) of the title compound as a bright yellow solid.

Example 3

2-((2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl)-3-methylnaphthalene-1,4-dione (G)

[0142] ##STR00054##

[0143] Compound F was dissolved in AcOH (0.1 mmol in 1.2 mL) followed by the addition of dodecyltrimethylammonium bromide (2 mg). The solution was heated to 90? C. for 60 min. After cooling to r.t., the solvent was evaporated, and the crude product was purified as above.

Example 4

[0144] By similar reactions the following MK-6, MK-8 and MK-10 adducts and subsequently MK-6, MK-8 and MK-10 can be obtained:

##STR00055##