DE2733233C3 - Process for the production of trans-phytol or vitamin K? 1? - Google Patents

Description

CH ₃ CH ₃ CH ₃

(II) ^I0 or

BrMg CH ₃

with a trans compound of the general formula

OR ₁

RO

(HD

wherein R is hydrogen or a removable protecting group under acidic conditions and Ri represents an acyl group, a di- (alkali metal) -tetrahalogenkuprats condensed in the presence of at a temperature of about -80 ⁰ C to about +50 ⁰ C, and that the thus obtained trans -Phytol's formula

CH ₃

CH ₃ CH ₃

CH ₃

(D ^ CH ₃

where R has the above meaning, optionally converted into vitamin Ki in a manner known per se

The present invention relates to the method for the production of trans-Phytol, which can optionally be further processed into vitamin Kj in a manner known per se.

Trans-Phytol is used to produce vitamin Ki of the formula I with a compound of the general formula

(IV)

wherein R2 represents an acyl group, reacted, the Cleaved acyl group and the hydroxyl groups are oxidized.

In the context of the present invention, the expression “a Schulz group which can be split off under acidic conditions” means, for example, groups of the formula RjO-CHR ₄ -. where Rj dC <alkyl or phenyl-lower alkyl with 1-3 carbon atoms in the side chain such as. B. benzyl, phenylethyl or Phcnylpropyl and R4 represents hydrogen or Ci-C * alkyl or together with Rj n-butylene, in particular the 2-tetrahydropyranyl group, radicals of the formula (R5) iA-. wherein R _{5 is} Ci-C. Alkyl, and A carbon

CH ₃ \ C. / CH ₃ O \ ( / CH ₃ CH ₃ C. \ CH ₃ C ₂ H ₅ O / / \

The term "acyl group" means straight chain

or branched alkanoyl groups with up to 10 carbon atoms, such as. B. Formyi, Äcetyi, Propionyi, Butyryl, hexanoyl, etc. as well as aroyl groups with up to 10 carbon atoms such as benzoyl. Phenylacetyl, Naphthoyl and the like, the aromatic Rings unsubstituted or, for example, by lower ones Alkyl groups can be substituted.

The term "lower alkyl" represents straight or branched groups with 1-4 carbon atoms represent, such as B. methyl, ethyl, n-propyl, isopropyl. n-butyl,

Isobutyl, sec-butyl, L-butyl.

“Di (alkali metal) tetrahalogen cuprate” is to be understood as meaning _{, in particular, Li 2 Cu CU.}

In the context of the present invention, all chiral compounds at the asymmetry

3; Centers around the R configuration for the optically active connections and the RS configuration for the corresponding racemates.

The previous processes for the production of vitamin Ki are based on the condensation of a Menadiol derivatives of the formula IV with isophytol or phytol. When using isophytol. as well as from Mixtures of trans- and cis-phytol occur relatively large proportions of cis-vitamin Ki, which only has low vitamin Ki activity and therefore is undesirable. The proportion of cis-vitamin Ki was previously least when using pure trans-Phytol, which, however, only through relatively complex synthesis methods and in an uneconomical manner could be won.

The method according to the invention now opens up a new advantageous way to trans-phytol, or Derivatives thereof, which are then easily converted into vitamin Ki in a manner known per se can.

The reaction of a compound of the formula II with a compound of the general formula III takes place in Presence of an organic solvent which is inert under the reaction conditions, d. H. a solvent for Grignard compounds, such as an ethereal

M) see solvent, e.g. B. a lower alkylether or a cyclic ether such as tetrahydrofuran, dioxane and the like. The reaction occurs at low temperature, ie at a temperature of about -8O ⁰ C to about +50 ⁰ C, preferably from about

bi -70 ⁰ C to about room temperature. The reaction is conveniently carried out at low temperature, ie below about -6O be started ⁰ C. The addition of the catalyst used should also be added at this temperature

Di (alkali metal) tetrahalogen cuprates take place. The temperature can then slowly rise to to about room temperature. The reaction is also expediently carried out under an inert gas such as. B. argon. nitrogen and the same.

A compound of the formula I obtained in which R is different from hydrogen can be converted into such be converted, wherein R is hydrogen. This conversion can easily under acidic conditions, for example by heating in alcoholic Solution with p-toluenesulfonic acid or with aqueous Mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., or Lewis acids such as boron trifluoride, boron trichloride, etc. can be carried out.

A compound of formula 1 is further converted into vitamin Ki by reaction with a menadiol derivative of formula IV in a manner known per se. The reaction is expediently carried out in the presence of pti \ er acidic compound such. B. zinc chloride, sulfuric acid. Trichioracetic acid, acetic acid or oxalic acid and the like. However, sulfuric acid in small amounts, formic acid in large amounts and also boron trifluoride, the latter in particular in the form of its etherate, are particularly preferred. Advantageously, open-chain or ring-shaped ethers, such as ethyl ether, isopropyl ether, butyl ether, dioxane and the like, are used as the solvent. The temperature is not critical here and is usually between about room temperature and the reflux temperature of the reaction mixture. When using ^{Bortr; fI} uoridäthylätherat as a condensing agent, the most advantageous way is for example about 50 ° -1GÜ ° C. subsequent to the reaction described above, the y> cleavage of the acyl group and the oxidation of the hydroxyl groups also take place in a manner known per se. For example, the saponification can be carried out in an aqueous organic solvent with an alkali metal hydroxide, for example with sodium or potassium hydroxide: this reaction is expediently carried out with the exclusion of air. The subsequent oxidation of the hydroxyl groups can be carried out, for example, by means of silver oxide or also by means of atmospheric oxygen.

The compound of the above formula II used as a starting material can, depending on whether it is the Racemai is or the optically active form can be produced in different ways. For example, the optically active compound can be produced according to the following scheme.

C ₂ H ₅ O

C ₂ Il ₅ O

55

bO

HO

(XI)

CH ₃ CH

(VII)

(VIII)

(XII)

The compound of the above formula V (ethyl-trans- ^ -dimethoxy-S-methylcrotonate) can by fermentation with a microorganism of the genus Saccharomyces cerevisiae and subsequent cyclization of the compound of the formula thus obtained

V CH ₃ C! OH

/ WC ₂ H ₅ O

be converted into the compound of formula VI. The cyclization can be carried out using an acid such as. B. dilute p-toluenesulfonic acid. The compound of the formula VI can be converted into the compound of the formula VII by treatment with alcoholic HBr solution. This compound of the formula VII in turn can be converted into the compound of the formula VIII by reducing the ester group with diisobutylaluminum hydride at a temperature of about -20 ° C. to about ⁰ ° C. and subsequent reaction with 3,4-dihydro-2H-pyran. The further conversion of the compound of the formula

VIII into the compound of formula IX is expediently carried out by treatment with isoamyl magnesium bromide using Li ₂ Cu CU in an ethereal solvent at a temperature of etwc 0 ⁰ C to about room temperature, followed by cleavage of the 2-tetrahydropyranyl group by acid hydrolysis. The compound of the formula IX can be converted into the bromide of the formula X in a manner known per se by treatment with N-bromosuccinimide and triphenylphosphine. The compound of the formula X is converted into that of the formula Xl by reacting with activated magnesium in an ethereal solvent and coupling with the compound of the formula VIII using Li ₂ Cu CU in an ethereal solvent at a temperature of about ⁰ ° C. to about room temperature.

The bromination of the compound of the formula Xl can be carried out in analogy to that of the compound of the formula

IX. The conversion of the bromide of the formula XII in the compound of formula II can by reacting with activated magnesium in one

essential solvents in a manner known per se take place.

The racemic compound of the formula ίΐ can for example from a compound of the formula

(A)

getting produced. The compound of the formula A is known and can be obtained by reduction with hydrogen in The presence of basic Raney nickel can be converted into the corresponding saturated alcohol. This alcohol can then by treatment with N-bromosuccinimide and triphenylphosphine in itself be converted into the corresponding bromide in a known manner. This bromide in turn can in itself known way, e.g. B. by treatment with activated Magnesium converted into the Grignard compound of the formula II in an ethereal solvent will.

The compounds of the formula III, which are likewise used as starting materials and in which R is different from hydrogen, are new compounds. Those compounds in which R is lower alkyl or phenyl-lower alkyl can be prepared according to the following scheme.

CH ₃ -CO CH CH

OCH ₃

OCH ₃

OCH ₃

HO CH CH

V \

(XIV)

OCH,

OCH ₃

RO CH

OCH ₃

RO

RO

RO

CHO

OH

OR ₁

P (VII)

(XVIII)

The compound of the above formula XIIi is known and can be prepared in a manner known per se by treatment with a base. z. B. an alkali metal or alkaline earth metal hydroxide, such as sodium or potassium hydroxide or barium hydroxide to be saponified to the compound of formula XIV. The compound of the formula XIV obtained in this way can then be used in a manner known per se, in the presence of a base such as, for example, sodium hydride. Phenyllithium and the like, can be etherified by means of a lower alkyl halide, a phenyl-lower alkyl halide or di-lower alkyl sulfate. The thus obtained ether of the formula XV is then through

ίο hydrolysis with p-toluenesulfonic acid in a cyclic ether containing about 8-12% water, such as B. dioxane or tetrahydrofuran, converted into the aldehyde of the formula XVI at about room temperature. Under the reaction conditions mentioned, the double bond is also quantitatively isomerized from cis to trans. The resulting trans compound of formula XVI is then in a manner known per se, for. B. by means of Na BH ₄ , reduced to the alcohol of the formula XVII. This alcohol of the formula XVII is then treated with a compound which donates the radical Ri, e.g. B. acid anhydno · 'with pyridine, acid halides with pyridine or chloroformic acid with pyridine and the like, converted to a compound of the formula XVIII.

Those new compounds of the formula III in which R is different from lower alkyl and phenyl-lower alkyl can be selected from the trans compounds of the formula

HO

OR ₁

P <IX)

where Rj has the above meaning, by introducing the corresponding group which can be split off under acidic conditions. This introduction can in a manner known per se, e.g. B. by Treatment with the corresponding olefinic compound, such as 3,4-dihydro-2H-pyran, methyl vinyl ether or 2-Methyl-propcn or with the corresponding halide, z. B. with chloromethyl methyl ether or Trimethylsilyl chloride and the like.

example 1

(E) -2-methyl-4 - [(tetrahydro-2H-pyran-2-y!) Oxy] -2-butanyl acetate

To 11.5 g (80 mmol) of (E) -4-hydroxy-2-methyl-2-butenyl acetate are with exclusion of moisture at 0 ° C I drops of POCIj. followed by 7 g (83.2 mmol) fresh distilled 3,4-dihydro-2H-pyran was added dropwise. After the addition of the 3,4-dihydro-2H-pyran is complete stirred for 30 minutes at room temperature. The crude reaction mixture is then over a Vigreux column distilled. The yield of (E) -2-methyl-4 - [(tetrahydro-2H-pyran-2-yl) oxy] -2-b'jtenyl acetate is 17.0g (94%). Bp 98 "C / 53.3 Pa.

Production of

Example 2

(i;) - 4-Mc! h <> xy-2-nicthy | -2-buk-nyl acctsit

To a mixture of 2.3 g (20 mmol) (l ") -4-methyloxy-2-methyl-2-buten-l-ol and 2.5 g (3 millimoles) of pyridine 3 ml of acetic anhydride are added dropwise at - 1./C. The reaction mixture is stirred for 3 hours at room temperature and then neutralized as well saturated sodium bicarbonate solution. After extraction

with ether, drying the organic phase with sodium sulfate and removing the solvent the residue freed from pyridine by standing over the conc. Sulfuric acid in the excicator. You get after distillation at 45 ° C / 1333 Pa, 2.1 g (67%) (E) -4-methoxy-2-methyl-2-butenyl acetate, which according to GC contains less than 0.4% of the Z isomer.

The (F.) -4-Methoxy-2-methyl-2-buten-1-ol used as starting material can be made as follows:

a) To 188.2 g (1 mol) of (E / Z) -4,4-dimeihoxy-1-acetoxy-3-methyl-2-butene a solution of 56.1 g of KOH (1 mol) in 60 ml of water were added. Then, with good cooling, 30 ml of methanol are added dropwise to the reaction mixture. After a reaction time of about 30 minutes at room temperature, the saponification is complete. Man dilute with water and shake out three times with ether. The combined ether phases become saturated with Washed salt solution neutral and dried over NajSO ^ KjCOj. After removing the solvent on a rotary evaporator and distillation of the residue over a Vigreux column 68-69'C / 66.7 Pa, the yield of E / Z-4,4-dimethoxy-3-methyl-2-buten-1-ol is 107.3 g (73%).

b) To a suspension of 9.6 g (0.4 mol) of sodium hydride in 50 ml of abs. Ether is added dropwise at 0 ml abs ⁰ C a solution of 58.4 g (0.4 mol) of (E / Z) -4.4-dimethoxy-3-methyl-2-buten-l-ol in the 50th Ether and stir for 3 hours at room temperature. 900 ml of abs are added to the alcoholate formed. Ether and 71 g (0.5 mol) of methyl iodide are added and this reaction mixture is stirred for about 14 hours. After filtering off the precipitated sodium iodide, removing the solvent on a rotary evaporator and distilling the residue, 39.5 g (62%) (E / Z) -4-methyloxy-2-methylcrotaldehyde dimethyl acetal (boiling point 74 "C / 1733.2 Pa) are obtained.

c) 5 g (31 mmol) of the isomer mixture (E / Z) -4-methoxy-2-methylcrotonaldehyde dimethylacetal are added together with 70 mg of p-toluenesulfonic acid in a mixture of 7 ml of tetrahydrofuran and 0.7 ml of water in a nitrogen atmosphere at room temperature touched. After a reaction time of about 13 to 16 hours, the hydrolysis of the acetal is complete with cis to trans isomerization. The reaction mixture is diluted with methylene chloride and shaken with sat. Sodium bicarbonate solution neutralized. After the organic phase has been dried over Na2SO ₄ , the solvent is distilled off at normal pressure. After distillation of the residue at 68 ° C./2666.4 Pa, 3.27 g (92%) of E-4-methoxy-2-methyl-2-crotonaldehyde are obtained. which contains less than 0.4% of the Z-isomer (GC, NMR).

d) A solution of 2.14 g (18.SmMoI) (E) -4-methoxy-2methyl-2-crotonaldehyde in 20 ml of ethanol is mixed with 0.38 g (10 mmol) of sodium borohydride in portions at 0 "C." Hour stirred. After removing the ethanol on a rotary evaporator, the residue is taken up in water and extracted twice with ether. The combined ether phases are with sat. NaCl solution and then dried _{over Na ^ SO 4.} After removal of the ether and destination of the residue, 1.96 g (90%) of (E) -4-.meihoxy-2-methy! -2-but-en-lo! (Bp. 89-90 "C / 1466.5 Pa). Which contains less than 0.4% of the Z-isomer (GC. NMR).

In a manner analogous to the preceding, this can

(E) -4-ethoxy-2-methyl-2-bulenyl-acetate prepared will. Bp. 105 ° C / 1599.9 Pa in the spherical tube.

Example 3

Preparation of '^) - 4-Methoxy-2-methyl-2-buienyl-ben / .oai

To a stirred solution of 580 mg (5 mmol) of (E) -4-methoxy-2-methyl-2-buten-1-ol in 3 ml of abs. Pyndin 775 mg (5.5 mmol) of benzoyl chloride are added dropwise with ice cooling. Then the The reaction mixture was stirred first for 5 minutes at room temperature, then for a further 15 minutes at 70 °. The reaction mixture is worked up

Poured ice water and extracted twice with η-hexane. The combined hexane phases are washed with sat. Washed saline solution and then over Dried sodium sulfate. After removing the solvent on a rotary evaporator uiiu Desiiüäiiun the residue in the bulb tube at 100 ° C./1.3 Pa gives 1.0 g (91%) of pure (E) -4-methoxy-2-methyl-2-butynyl-benzoate.

In a manner analogous to the above, starting from 580 mg (5.0 mmol) of (E) -4-methoxy-2-methyl-2-buten-1-ol and 740 mg (5.5 mmol) of caproic acid chloride - 0.93 g (87%) of (E) -4-methoxy-2-methyl-2-butenyl-hexanoate from bp 65 ° / 1.3 Pa (Kugelrohr).

Example 4

Preparation of tetrahydro-2 - [(7R.11 R) -trans-phyty! Oxy} 2H-pyran

In a three-

J5 neck flasks will hold 250 mg (10.3 mmol) of magnesium shavings in 5 ml abs. Tetrahydrofuran (TH F) activated by adding 2-3 drops of Meih ^ l'odid. Still a minute Let the solution stand and remove the magnesium several times with abs. THF washed.

After adding 10 ml of abs. THF is added dropwise to the activated magnesium, 2.3 g (7.85 mmol) of (3R, 7R) - (-) - l-bromo-3,7, ll-trimethyldodecane at such a rate that the solution just boils. After the addition of the (3R, 7R) - (-) - 1-bromo-3.7,11-trimethyldodecane is complete is about 10-15 minutes at 85 ° C stirred until, according to GC, no (3R.7R) - (-) - l-bromo-3,7,11-trimethyldodecane there is more.

The Grignard solution is flushed with argon filtered through a glass frit into a two-necked flask

cooled to -78 ° C with magnetic stirring. By a dropping funnel are slowly 1.8 g (7.85 mmol / (E) -2-methyl-4 - [(tetrahydro-2H-pyran-2-yl) oxy] -2-butenyl acetate (prepared according to Example 1) added, followed by 03 ml of a 0.1 molar solution of

ν; LiiCuCU in abs. THF. This reaction mixture is kept at -78 ° C for 10 minutes. then stirred for 2 hours at 0 ^° C. and then for a further 15 hours at room temperature. The formation of (7 R ₁ R 11) trans-Phyiyl tctrahydropyranyläthers can be by means of thin-

follow layer chromatograms (hexane / ether = 4: 1; Rf = 0.5). The reaction mixture is poured onto ice and weakly acidified with 1N sulfuric acid (pH 5-6). This mixture is extracted three times with ether and the combined organic

ti phases one after the other first with saturated NaHCOr solution, then with sat. NaCl solution washed. After drying the organic phase over Na ^ SO ₄ / NaiCOj and removing the solvent on a Rota

tion evaporator gives 3.1 g of the crude product, which is purified by chromatography on 90 g of silica gel with hexane / ether = 4: 1. The yield of pure Tcirahydro-2 - [(7R.I t R) -trans-phytyloxy] -2H-pyran is, according to Kugelrohrdcsiillalion, 2.14 g (72%) at 150 "C / 13.3 Pa. [A] - -0.56 "(C = 10 inCHCI ₃ ).

The (3R, 7R) - (-) - l-Pi> m-3.7, l l-trimethyldodecane used as starting material can be prepared as follows:

(b)

O-

OH

O H

CH,

A clean, but not sterilized fermenter with 31 I total volume is charged with the following ingredients:

- deionized water 9.9 l

- compressed yeast 1.1 kg

- sugar 0.55 kg

- Ethyl ^ -dimethoxy-S-methyl-

crotonat 135 g

- polypropylene glycol mono-

butyl ether 10 ml

The fermentation is carried out under the following conditions:

temperature Stirring frequency

Air flow rate c

pH

Fermentation time

30 °

(thermostatically controlled)

1000 rpm

600 l / h

3.4-3.8

(no pH control)

56 h

The fermentation is stopped after 56 h and the desired fermentation product is as follows isolated:

The broth is saturated with NaCl and extracted continuously with diethyl ether for 4 days. That Solvent is separated off and dried over NajSO4 and removed again under reduced pressure. 122 g of crude extract are obtained, which largely contains (S) -3-methyl-4-hydroxy-butyric acid ethyl ester. These The substance can be purified by chromatography (on silica gel which has been deactivated with 0.5% NH3).

The crude extract obtained above is mixed with 100 mg of p-toluene sulfonic acid and distilled in a nitrogen atmosphere under reduced pressure (S) -Dihydro-4-methyl-2 (3H) -furanone formed during the distillation is distilled at 86-88 ° C / 18663 Pa (Bath temperature 125-140 °). 26.2 g of product are obtained, which, according to GC, contains 93% (S) -dihydro-4-methyl-2 (3H) -furanone and an optical rotation of -21 ° (4% in Methanol).

The yield of isolated, optically pure (S) -dihydro-4-methyl-2 (3H) -furanone is 34.4% of the theoretical possible product quantity.

To 110 ml of a freshly prepared ethanolic hydrogen bromide solution (approx. 8-N) are added, with stirring, 100 ° / 1.Og (O ₁ Il mol) (S) -dihydro-4-methyl-2 (3H) -fiiranone within 10 min. dripped in. The reaction mixture is then continued for two hours at room temperature. For work-up, the reaction mixture is poured onto ice, diluted to about 1 liter with water and extracted twice with chloroform. The combined organic phases

to are washed neutral first with water, then with saturated sodium bicarbonate solution and over Dried sodium sulfate. After removing the chloroform on a rotary evaporator, the colorless one distills Ethyl (S) -4-bromo-3-methylbutyrate in a water jet vacuum at 90-92 ° in a yield of 18.5 g (80%); [α] ■■ - -2.3 ° (c »4.0, CHCl ₃ ).

204 ml (0.204 mol) of a 1-m solution of diisobiitylaluminum hydride are in an argon atmosphere at «... ι. ,,, " _{β K} ", ^^ ... »,., ..... j. ^,. "." ...-... ^. N>! DJ tyrate was added dropwise with stirring over the course of 15 minutes. The excess reducing agent is decomposed by adding dropwise methanol at 0 °. Then the reaction mixture on Eif. poured and angc by adding 2N aqueous sulfuric acid acidifies, with the precipitated aluminum hydroxide partially goes into solution. The (S) -4-bromo-3-methyl-1-butanol formed is extracted by shaking several times absorbed into ether. The combined ether phases are first washed with saturated sodium bicarbonate solution solution, then neutral with saturated saline washed and dried over sodium sulfate. After removing the solvent on a rotary evaporator, the yield is 14.0 g (98%); the product leaves can be used further without distillation. For analytical

Purpose is a sample in the Kugelrohr at 60 ° / 5.3 Pa

distilled; [«] V 2.0 ° (c = 33, CHCl ₃ ).

14 pounds (0.084 mol) of (S) -4-bromo-3-methyl-1-butanol are added dropwise at 0 ° with 50 ml of freshly distilled 3,4-dihydro-2H-pyran. The reaction mixture

is then stirred for 1 hour at 0 ". Excess 3,4-dihydro-2H-pyran is removed on a rotary evaporator at 35 ° Removal of the 3,4-dihydro-2H-pyran, chloroform is added repeatedly, each followed by Distillation on a rotary evaporator. The crude product [(S) -4-bromo-3-methylbutoxy] -tetrahydro-2H-pyran is distilled at 75 ° / 4.0 Pa in a yield of 17.5 g (83%); [α]? = + 3.4 ° (c - 4.0.CHCI ₃ ).

To a Grignard solution (prepared in

going analogous way) from 03 g (12.4 mmol)

Magnesium and 1.51 g (10 mmol) i-bromo-3-methylbu-

tan in 25 ml of absolute tetrahydrofuran, is at 0 ° in

Argon atmosphere and with stirring 1.26 g (5 mmol)

2 - {(S) -4-Bromo-3-methylbutoxy] -tetrahydro-2H-pyran added dropwise within a minute. Then 03 ml of a 0.1 μm solution of Li] CuCU in Tetrahydrofuran was added and the reaction mixture was stirred for a further 3 hours at 0 °. The work-up as well the hydrolysis of 2 - [(R) -3.7; dimethyioctar! cxy] tetra hydro-2H-pyran to (R) -3.7-dimethyl-1-octanol takes place in the manner indicated above. The yield of (R) -3,7-dimethyl-1-octancl after Kugclrohrdcstillation at 95.71866.5 Pa is 0.56 g (71%); [λ] - ¹ , ¹ = +4.0 (r = 1.03.CHCI ₁ )

b5 To a solution of 5 g (31.5 mmol) of (R) -3.7-l) iniethyl-1-octanol and 9.05 g (34.5 mmol) of triphynylphosphine in 20 ml of methyl chloride are added 5.65 g (3! .SmMoI) N-bromosuccinimide in portions unier

Stir added. Occasional cooling of the reaction vessel keeps the temperature below 25 °. After stirring for 30 minutes at room temperature, the solvent is removed on a rotary evaporator. The residue is washed out several times with η-hexane, then filtered and rinsed again with η-hexane. The combined n-hexane phases are concentrated on a Rots.ionsverdampfer and the crude product is chromatographed on 2u0g silica gel with η-hexane. Distillation in a bulb tube at 1.05 ° / 1999.8 Pa gives 6.1 g (87%) (R) -l-bromo-3,7-dimethyloctane ·, [ft] = -5.0 ^ c = 0.82, CHCI ₃ ).

A Grignard solution of 0.3 g (12.4 mmol) of magnesium and 2.54 g (l 1.5 mmol) of (R) -l-bromo-3,7-dimethyloctane in 10 ml of absolute tetrahydrofuran is in Analogy made to the previous one. 1.45 g (5.57 mmol) of 2 - [(S) -4-bromo-3-methylbutoxy] -tetrahydro-2H-pyran are added dropwise to this solution at 0 °, followed

i! CCU

gel with pentane / ether = 4: 1 and Kugelrohr distillation at 110 ° C / 5.3Pa 3 <Λ mg (80%); based on (E) -4-methoxy-2-methyl-2-butenyl acetate. [λ] = -0.48 ' (C = 5.35%, CHCl ₃ ).

In a manner analogous to the preceding, the Ethyl- (7R, 11R) - (E) -phytyl ether are produced. Sdp. I25 ° C / 4, O Pa in the spherical tube.

In a manner analogous to the above, the methyl (7R, I lR) - (E) phytyl ether can also be prepared by reacting the Grignard compound with (E) -4-methoxy-2-methyl-2-butenyl benzoate or (E) - 4-methoxy-2-methyl-2-hexanoate can be produced.

Example 7

Production of 1- 0-Benzoyl-trans- (7'R, II'R) -phyllohydroquinone

In a three-necked flask equipped with a reflux condenser

from ^ 3 m! be a 01 molar Lösun ^CT of Li ^-1 CUCU in b n?

Tetrahydrofuran. This reaction mixture is stirred at 0 ° for 3 hours. The work-up, as well as the Hydrolysis of the tetrahydro-2- | [(3R.7R) -3,7,11-trimethyldodecyl] -oxy} -2H-pyran obtained to (3R, 7R) -3,7,11-trimethyl-1-dodecanol takes place accordingly to Example 4. The yield of (3R, 7R) -3,7,11-trimethyl-1-dodecanol after Kugelrohr distillation is around 90-95 ° / 6.7 Pa 0.5 g (43% based on 2 - [(S) -4-Bromo-3-methylbutoxy] -tetrahydro-2H-pyran); [«] '= + 3.9 ° (c = 1.05, n-Ocian).

3.1 g (13.6 mmol) of (3R, 7R) -3,7,11-trimethyl-1-dodecanol are mixed with 4.02 g (15.3 mmol) of N-bromosuccinimide and 2.62 g (14.7 mmol ) Treated triphenylphosphine in 13 ml of methylene chloride by the method described above. After chromatography and distillation, 3.54 g (90%) (3R, 7R) -bromo-3.7,11-trimethyldodecane are obtained. Bp 90 ° C / 6.7 Pa; [α]? = -3.6 ° (c = 1.005, n-octane).

Example 5 Production of (7R.11 R) -trans-Phytol

1.32 g of tetrahydro-2 - [(7R URHrans-phytyioxy ^ H-pyran (prepared according to Example 4) are in 15 ml Ethanol together with 20 mg p-toluenesulfonic acid heated at 60 ° C. for 10 minutes. The cooled reaction mixture is diluted with 150 ml of water and extracted three times with ether. The combined organic phases are ιη · ι gcs by shaking several times. NaHCOi solution washed neutral and then dried over NajSO-s. After removal of the solvent on a rotary evaporator, the residue is distilled in a bulb tube at 140 ° C / 85.3 Pa. The yield of (7R.1 IRJ-trans-Phytol is 0.8 g (80%).

Example 6 Production of methyl (7R.l 1 R) - (E) -phytyl ether

In analogy to Example 4, from 620 mg (2.13 mmol) (3R.7R) - (-) - l-bromo-3.7, l 1-trimethyldodecane and

60 mg (2.5 mmol) of magnesium, the corresponding Grignard compound prepared, which with 256 mg (1.14 mmol) of (E) -4-methoxy-2-methyl-2-butenyl-acetai (prepared according to Example 2) using 0.1 ml a 0.1 M solution of Li ₂ CuCl ₄ in tetrahydrofuran is reacted. The yield of methyl (7R.l 1 R) - (E) -phytyl ether (less than 03% of the cis isomer.) Is after chromatography on silica (6 mmol) 1 -O-Benzoyl-menadiol in 25 ml of abs. n-dibutyl ether suspended and under an argon atmosphere Heated to 85 ° C. After adding 0.3 ml (3 mmol)

Boron trifluoride ethyl ether, 1.13 g (3 mmol) are added dropwise Tetrahydro-2 - [(7R, l 1 R) -trans-phytyloxy] -2H-pyran

(prepared according to Example 4) in 2 ml of abs. n-Dibutyl ether within 2-3 minutes under vigorous Stir too. The reaction mixture is stirred for a further 10 minutes at 85 ° C., then rapidly cooled and several times with warm water

washed neutral. The organic phase is dried then over sodium sulfate and removed the n-dibutyl ether on a rotary evaporator at 50 ° C The last residues of the solvent are removed in a high vacuum at room temperature. The fixed one

20 ml of hexane are added to the residue and the mixture is stirred vigorously, whereby the 1-O-benzoyl- (7'R, 1'RJ-phyllohydroquinone formed preferably goes into solution The solution is filtered through Hyflo, after removal of the hexane on a rotary evaporator i.69g

AO of the crude product is obtained which, according to high pressure liquid chromatography (LC), contains the ί-0-Bfizoyl- (7'R, ll'R) -phyllohydroquinone in a trans: cis ratio of 88%: 12%. Obtained by chromatography on silica gel with benzene / methylene chloride = 1: 1 1.25 g (77%) of the lQ-benzoyl-trans- (7'R, l 1'R) -phyllohydroquinone. which has a melting point of 88 ° C. after recrystallization from methanol / toluene. [λ] = -0.8Vc = 1.0.CHCI ₃ ).

In a manner analogous to the preceding, this can

so is l-O-Benzoyl-trans- (7'R, irR) -phyllohydroquinone by condensation of 1-O-benzoyl-menadiol with methyl (7R.IIIR) - (E) -phytyl ether or with trans- (7R.II RJ-Phytol).

Example 8 Production of trans- (7'R.l'R) -phylloquinone

03 g (1.62 mmol) of l-O-benzoyl-trans- (7'R.l l'RJ-phyllohydroquinone (prepared according to Example 7) are in a mixture of 10 ml of hexane, Z6g of KOH, 13 ml of chloroform and 2.3 ml of water with the exclusion of air saponified for 2 hours at room temperature. After removing the organic phase, the aqueous Reaction mixture washed with hexane. After adding 10 ml of hexane to the aqueous phase, the mixture is passed through Introduction of air into the reaction mixture is oxidized. For work-up, the organic phase is separated off and with sat. Washed saline solution neutral. To

13 14

Removal of the solvent on the rotary evaporator - 0.473 g (66%), which according to the high pressure liquid kit

: r one increases 0.76 g of the crude trans- (7'R, H'R) -Phyllo- chromatography with an internal standard a purity

hinoni, which is used for cleaning on aluminum oxide of 100%, as well as a trans: ice ratio of

eutral (activity IV) with hexane chromatography 96.5%: 3.5%. [«] ·"'«■ -0.26 ° (c = 10.0. Di-

'ird. The yield of (7'R, H'R) -Phylloquinone is 5 oxane).

Claims (1)

Claim: Process for the production of trans-PhytoI or vitamin Ki, characterized in that one is a Grignard compound of the formula or silicon, e.g. B. t-butyl or trimethylsilyl or the groups of formulas