DE2360382A1 - IMPROVED PROCESS FOR THE SYNTHESIS OF 1,4-HYDROQUINONE DIACETATE COMPOUNDS - Google Patents

Description

24 767 n / wa

EISAI CO., LTD., TOKYO / JAPAN

Improved Method for the Synthesis of 1> 4-Hydroquinone Diacetate Compounds

■ ■ -

The invention relates to an improved method for the synthetic production of 1,4-hydroquinone diacetate compounds. It relates in particular to an improved method for making the 1,4-

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Hydroquinone diacetate compounds in which stereo isomers of the trans form predominate, which can be used in particular as intermediates _t for the preparation of vitamins K ₁ and Ko and coenzyme Q.

That contemplated in the present invention 1,4-hydroquinone diacetate, is represented by the formula

OCOCH,

CHp-CII-C-R. (I)

f \

OCOCH

represented, wherein R is a linear hydrocarbon radical means that by the formula

CH ₂ -CH-C-CH ₂ - ^ H (a)

AWAY.

where η is zero (O) or an integer is from 1 to 9 inclusive; A and B each represent a hydrogen atom or a direct bond between them-

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represent and -sqwphl ^ IW.als also Rp-methoxy groups or together-a - "" double-bonded hydrocarbon chain of the formula -. ·.-'.-.-. - -. "·. ·" ■ - ' ·,,

V '

. -CH = CH-CH = CH-

represent. *:.:. ■ '·. ■. ■■ ■ "■■". ".

■ The compounds' of the formula (i) can, depending on the stereoconfiguration of the hydrogen atom in the 2'-position with respect to zkx of the methyl group in the J ^! - Position in the linear hydrocarbon radical of the formula (a) in both of the two possible "or probable stereoisomers, ie the trans- and cis-form iso-

mers are available, each of which is represented by the formulas ^:

ÜCÜCH _V

trans form (I ¹ )

UCOCH ₇

OCOCH,

H CH

- / -cis form (II ¹ )

AWAY -

The dial soldering compounds of formula (i) can easily by saponification and subsequent oxidation into the corresponding quinone compounds of the formula

0 j 3 ι 5

R ₂ ^ «L CH ₂ -CH = C-CIIp-£ CKp-CH-e ^ Cttp-9-H

O "

are converted, in which n, R ₂ , A and B each have the above meanings. More precisely, the quinone compounds of the above formula encompass the group of compounds including a) coenzyme

Q, in which the radicals R and R _{2 are} -OCH-, and A and B together form a direct bond, b) vitamin K, in which the radicals R ₂ and R ₂ together form a double-bonded hydrocarbon radical -CH = CH-CH = CH - Form and A and B represent hydrogen atoms, and c) vitamin K ₂ , in which the radicals R ₂ and R ^ together form a divalent hydrocarbon radical -CH = CH-CH = CH- and A and B together form a direct bond.

It is apparent that the di-acetate compound of the * trans-form isomer of the above formula (I ¹ ), when subjected to saponification and subsequent oxidation, naturally gives the corresponding quinone compound in the trans-form configuration, while the

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Diacetate compound of the cis-form isomer of the above formula (II ¹ ) when subjected to saponification and subsequent oxidation in the same way
will, of course, give the corresponding quinone compound in the cis-form-j configuration.

Although the naturally occurring coenzyme Q, vitamin
Κ ·· and vitamin Kp are normally present in their trans-form isomers, the corresponding compounds produced by synthetic processes are present in a mixture of their trans- and cis-form compounds.
Since the trans-form compounds have superior biological activity over the corresponding cis-form compounds, the first-mentioned compounds are highly valued as drugs and these compounds are obtained from their mixture with the coexisting cis-form isomer by a suitable separation methodology been won.

The production of an increased yield of the compound ■ of the above formula (i) has already been achieved by using a nickel complex compound of the
TT allyl type of the formula

R ₁ \ CH ' \ /

311

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In the formula, the R .. substituents have those in the the meanings given above for the formula (i), the X (e) represent halogen atoms; each of the

simple dotted lines (. ..) denote a

Semi-bond and each of the combined solid and dashed lines ( ........ ) denote a semi-double bond 7 of a reaction with a 2-halo-3-methyl-hydroquinone diacetate compound, which is represented by the formula üCOCJI-

-kj

CII ₇ ^(III)

OGOC ₁ I ₇

in which X is a halogen atom and the Rp substituents are those above with regard to the formula (i) have the meanings mentioned, reacted in a reaction medium which is selected from the group of amides, such as dimethylformamide, Dimethylacetamide, hexamethylphosphoramide, N-methylpyrrolidone and tetramethylurea are selected (cf. DT-PA 22 58 520.2, registered on November 29, 1972).

However, the process did not contribute to increasing the proportion or amount of the trans-form isomer present in the resulting reaction products. In fact, in the subsequent saponification and the subsequent oxidation process, starting from the reaction products, a mixture of the stereoisomeric vitamins K is obtained which has a ratio of about 70: Z> 0

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from trans form to cis form. A similar numerical ratio is obtained in the formation of vitamin Kp, starting from the corresponding reaction product, and in the same way a ratio of about 6 $ : '35 "is achieved in the case of coenzyme Q.

It has now been found that an increase in the amount or the proportion of the tear-form compound in the resulting reaction product of the formula (i) can be achieved without a significant reduction in the effectiveness of the condensation if the reaction of the compound (II ) and the compound (III) is performed in a mixed reaction medium, which is carried out in a nonpolar solvent and a solvent of the Amidserie and at a temperature in the range of 30 to 80 ⁰ C, preferably from 50 to 7O ⁰ C.

The relative ratio of the non-polar solvent and the amide series solvent in the mixed one Reaction medium can be from 25: 1 to 10: 1, and preferably 20: 1.

Exemplary of the compounds of the amide series that can be used as a component of the mixed reaction medium used in the process of the present invention is used, dimethylformamide, dimethylacetamide, Hexamethyl phosphoramide, _ N-methylpyrroliaeone, Tetramethylurea and the like can be mentioned. These are the same solvents as those that are in the procedures of the aforementioned German patent application be used. .

- 8 - ■ 0 9 8 2 4/1 Ο 9 2 .'-

As examples of the non-polar solvents that as the other component of the mixed reaction medium Which can be used in the practice of the invention can be the aromatic solvents Hydrocarbons such as benzene, toluene and xylene; the Solvents of the aliphatic hydrocarbons such as pentane, hexane and cyclohexane and the solvents the ethers such as diethyl ether, di-isopropyl ether, tetrahydrofuran and mono- and di-glymes can be used.

The ratios of the trans-form isomer to the cis-form isomer in the compounds of the formula (i) obtained by the process according to the invention are usually about 85:15 in the case of dihydro-yitamin-Kj-diacetate of the formula (i), in which two R -S substituents together form the double-bonded chain -CH = CH-CH = CH-, both A and B are equal to H and η denotes the integer j5 «The ratio is about 85:15 in the case of dihydro "vitamin K ₂ (20) diacetate of the formula (i), in which the two Rp substituents together form the divalent group -CH = CH-CH = CH- and A and B together form a direct bond and η j5 Finally, the ratio of about 80:20 is achieved in the case of dihydro-coenzyme-Q (10) -diacetate of the formula (i), in which each of the two Rp substituents is -OCH, A and B together form a direct bond and η represents the integer 9. It has been found that these numerical values maintain the ratio as such old when these 1, Λ-dihydroquinone diacetate compounds of the formula (l) below in the

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corresponding modified compounds such as vitamin K ₁ , vitamin K ₂ (20) and coenzyme ¹ Q (IO) are transferred. '-

The contents of the trahs-form isomer in the above said reaction products were obtained by the method of L.M. Jackmann et al in HeIy. "Chim, Acta, 48, 1352 (1965) measured. ®; .v

Accordingly, the primary object of the invention is " To provide an improved process for the preparation of the compounds of formula (I), predominantly from consist of their trans-form isomers.

According to the inventive method, further ■ technical advantages achieved by the fact that the entire process steps required for the production of the compound under consideration compared to the similar known process steps as those of the German patent application mentioned above.

In particular, according to the known prior art the -halogen backing complex compound of the / Hi-AHyI type of above formula (il) initially by reacting a Halogen compound of the isoprene series, of the formula

R ₁ -C = CH-CH ₂ -X (IV)

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generated with Ni ckel carbonyl, Ni (CO) u and the resulting halogen-nickel complex compound (il) isolated in the second stage from its solution by distilling off the reaction medium used as solvent. In the third process stage, the isolated nickel complex compound is then subjected to the subsequent condensation reaction in a reaction medium of the amide series. In contrast to the known prior art, the improved process according to the invention enables the intended reaction of the formation of the compounds of the formula (i) without the process stage of changing the solvent in the course of the process stages, in that the intermediate resulting solution of the halogenated nickel complex compound 'des % -allyl -Type of the above formula (II) is used in combination with a relatively small amount of the compound of the amide series. The compound under consideration, which consists predominantly of its trans-form isomer, is thus obtained.

The following examples, along with the comparative reference examples of the known prior art, the invention.

Reference example 1

Synthesis of dihydro-vitamin K-p-diacetate

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a) Manufacture of.

connection i,

A solution was made by dissolving 7.6 g of phytyl bromide 90% purity made in 50 ml of benzene.

A further solution was obtained by dissolving 5.Λ g -Ni (CO) ^ made in 35 ml of benzene. -

The first-mentioned solution would dropwise over 2 hours in-the züle.tzgenannte solution hei 50 to 5 >> ^O C under a nitrogen atmosphere is added dropwise. The resulting reaction mixture was kept under the above-described conditions for an additional 2 hours to complete the reaction. The solvent was then distilled off from the reaction mixture under reduced pressure. '- ■ _v .

It became the desired phytylbromial nickel complex compound obtain. The latter was applicable for use in the subsequent reaction by known methods. '_. '..

b) synthesis of dihydro-vitamin K ^ -diacetate

To the phytyl bromide "nickel complex compound obtained in the previous section were 4. ^ g of anaphthohydroquinone diacetate with a melting point of 209 ° C added, viobei the last-mentioned dietetate through redulctive diacetylation of 2-bromine -> - methyl-l, if-naphtho quinone was made with "glacial acetic acid with zinc dust.

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The resulting mixture was dissolved in 80 ml of hexamethylphosphoramide and the whole was heated to 50 ° C. for 5 hours. After completion of the reaction, the solution of the reaction product was poured into cold water and extracted with a mixture of benzene and hexane. The extract was washed with water, dried and subjected to distillation to drive off the solvent.

A yellowish oily substance was thereby obtained, which was purified by silica gel column chromatography. -5.97 g of the desired compound were obtained as a light yellow, oily substance in an amount of 85.3 % of the theoretical yield.

Identification of the substance was made by the infrared (IR) absorption spectrum and the nuclear magnetic one Resonance (NMR) spectrum performed. The elemental analysis of the purified product, for which the formula C-t-Hp-pOj, was assumed, gave:

C H

Calculated %: 7SV ^ l 9.77

Found %: 78.36 9.96

Ratio of trans-form isomers to cis-form isomers 68: 32 ..

The above ratio of the trans-F.orm isomer to the cis form isomer in the product was determined by comparison the relative areas of their absorption determined; the by the nuclear magnetic resonance process with

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100 megahertz were detected in a deuterated chloroform solvent. The olefinic methyl group in the trans-form in the next the Hydronaphthochinonkern position absorption assigned area appeared at 8.15.TJwährend the olefinic methyl group in the cis-form in the next the Dihydronaphthochlnonkern of the product position absorption assigned area at 8:33 Ύ ■ appeared .wobei the latter surface overlapped the absorption surface assigned to the terminal olefinic methyl group of the cis form of the side chain.

Reference example 2

Synthesis of dihydrovitamin K ^ (20) diacetate

a) Production of geranyl-geranyl-bromide-nickel- ■ complex compound .

A solution was made by dissolving 12.0 g of geranylgeranyl bromide generated in 70 ml of benzene.

Another solution was made by dissolving 9. ^ g Ni (CQ ") jj. Produced in 55 ml of benzene.

The last-mentioned solution was added dropwise to the first-mentioned solution ¹ over a period of 3 hours under a nitrogen atmosphere at a temperature of '50' to 53 ° C. The resulting reaction mixture was under

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Calculated %: 79.20 8.74

Found fo: 79.32. 8..55

Ratio of trans-form isomers to cis-form isomers 70:30

The above ratio of the trans-form isomer to the cis-form isomer in the product was made by comparison the relative areas of their absorption determined by using the nuclear magnetic resonance method 100 megahertz in a deuterated chloroform solvent were found. That of the olefinic methyl group in trans form in the one closest to the hydronaphthoquinone nucleus Position assigned absorption area appeared at 8.22 X, while that of the olefinic methyl group appeared in the cis form in the position next to the dihydronaphthoehinone core of the product at 8.33

J appeared, the latter area overlapping the absorption area, that of the terminal, olefinic methyl group is assigned to the cis form of the side chain.

Reference example

Synthesis of 2,3-diwethoxy-5-methyl-6-decaprenyl-1,4 dihydrobenzoquinone diacetate .

a) Preparation of the decaprenyl bromide-nickel complex compound.

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It became "a" solution by dissolving 23 g of deeaprenyl bromide generated in 60 ml of benzene.

Another solution was made by dissolving 9 g of Ni (CO) ^ made in 50 ml of benzene.

The former solution was added dropwise during 2 Hours to the last-mentioned solution under a nitrogen atmosphere added at a temperature of 50 to 55 ° C. The resulting reaction mixture was under the the same conditions as above, for a further 2 hours to ensure complete conversion of the Reaction held. The solvent became from the reaction mixture removed by distillation. It became the desired decaprenyl bromide Nickeikömpiexverbindungen received. ,.; ■ ';

b) Synthesis of .'- "2, ^ -DJmgithoxy - ^ - ynethyl-e-'decaprenyl ^ -I ₃ h- aihydrobenzoquinone diacetate .,

5.2g 2, 3-dimethoxy-5-methyl-6-bromo-1,4-dihydro-benzochinondiacetat having a melting point of 68-69 ⁰ C ■ was added to the obtained in the above section Decaprenylbromid-Nickelkompiexverbindung. The resulting mixture was dissolved by adding 100 ml of hexamethylphosphoramide, and the whole was heated to 60 ° C. for 7 hours. After completion of the reaction, the reaction mixture was poured into cold water and washed with. a mixed solvent of benzene and hexane. The extract was washed with water, dried over Glauber

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dried salt and subjected to distillation to remove the solvent. This gave the desired product as a pale yellow, oily substance. The yield was 8.57 g, corresponding to 60.3 % of theory. The oily substance was purified by silica gel column chromatography to obtain 7.15 g of a light yellow oily substance. The yield was 50.2 % of theory.

The elemental analysis of the product gave, assuming ^c g-5 ^H g6 ° 5L

CH '

Calculated $: 79.70 10.19 Found% \ ^{79.5 2} I- 10.50

Ratio of trans-form isomers to cis-form isomers 65: 35

The above ratio of the trans-form isomer to the cis-form isomer in the product was determined by comparing the relative areas of their absorptions found by the nuclear magnetic resonance method with ... 100 megahertz in a deuterated chloroform solvent. The absorption area assigned to the olefinic methyl group in trans form in the position closest to the dihydrobenzoehinone nucleus appeared at 8.26 ¹ J ^,. while the absorption area of the olefinic methyl group in cis form in the position closest to the dihydrobenzoeinone nucleus of the product appeared at 8.34 'V , the latter area being the

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Overlapped absorption area, which is assigned to the terminal olefinic methyl group of the cis-Porm of the side chain . '''- ^: - ■' ■■ .--.

example 1

Synthesis of dihydro-vitamin K ^ diacetate .

A solution was obtained by dissolving 7 x 6 g of Phytyl bromide of 90% purity in 50 ml of benzene.

Another solution was made by dissolving 5 · ^ S generated in 35 ml of benzene.

The first-mentioned solution was added dropwise over 2 hours to the zuletzgenannten solution under a nitrogen atmosphere and at a temperature from 53 to 5 ^ ^O C.

The resulting reaction mixture was kept under the same conditions as above for 2 more hours to ensure the completion of the reaction. After cooling, 5 E dimethylformamide was added dropwise and then Ψ.4 g of 2-bromo-3-methyl-1, K-naphth ohydrochinondiacetat a melting point of 209 ° C was added. The resulting mixture vnirde subjected at 50 ⁰ C for 5 hours to a reaction. After the completion of the reaction, the reaction mixture was poured into cold dilute hydrochloric acid. the

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Solution was extracted with diethyl ether. The essential extract was washed with water and dried over anhydrous Dried sodium sulfate. The solvent was then distilled off from the dry extract and it became a light yellow oily substance obtained by Sillkagelsäulenchromatographie purified using a mixture of η-hexane and diethyl ether as the eluting medium became. The desired product was obtained in the form of a light yellow oil. The yield was 6.01 g corresponding to an 85.9 show yield of theory. That Product was determined by means of infrared and nuclear magnetic resonance spectrum identified. The elemental analysis of the product, assuming C ^ p-Hf-gOj, showed:

Calculated j £: 78.31 9.77

Found % x. ■ ' ^ ⁸ · - ⁵ ^ 9.75

Ratio of trans-form isomers to cis-form isomers 86: 14 ", -

The above ratio of the trans-porm isomer to the cis-porm isomer in the product was determined by comparing the relative areas of absorptions found by the nuclear magnetic resonance method with 100 megahertz in a deuterated chloroform solvent. The absorption area assigned to the olefinic methyl group in trans form in the position closest to the dihydronaphthoquinone nucleus appeared at 8.15 ¹ T ^ _f, while that of the olefinic methyl group in

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cis form in the dihydronaphthoquinone core of the product The absorption area assigned to the next position appeared at 8.33 Λ ', the latter area being the The absorption area overlapped that of the terminal, olefinic methyl group of the cis-Porra of the side chain assigned. .

Example 2

Synthesis of Dihydro Vitamin K ^ (20) diacetate .

To a solution of 7 · 1 g Gera _n yx_geranylbromid :, dissolved in 30 ml of benzene was added dropwise at 50 to. 53 ° C for 90 minutes a solution of 5.2 g Ni (CO) ₂ J. in 30 ml. Benzene added. The resulting solution was allowed to react at that temperature with stirring for an additional 3 hours. After the completion of the reaction, the reaction mixture was cooled with ice and the unreacted nickel carbonyl was removed under reduced pressure.

A reddish benzene solution was obtained which contained geranyl-geranylbromide-nickel complex compound. To the solution was added 6 ml of dimethylformamide and 6.8 g of 2-bromo-3-methyl - rapht-ohydBoehinondiacetat added and the whole was subjected to a Reaktion.bei 50 ⁰ C under stirring for 8 hours. After completion of the reaction, a 2% hydrochloric acid was added to the reaction mixture and the solution was extracted with ether. The essential extract was made

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dried and subjected to distillation to remove the solvent. The pale oil thus obtained was ranked by silica gel column chromatography using a mixture of 10% η-hexane and ethyl ether as the eluent. 9.64 g of an oily substance, corresponding to 91-3 % of theory of the desired compound, were obtained.

The identification of the product was carried out by means of the infrared absorption spectrum and the nuclear magnetic resonance spectrum. The elemental analysis of the product gave, assuming CZ ₁ -Hh5

C H

Calculated #: 79.20 8.74 Found % i 79.44 8.59

Ratio of trans-form isomers to cis-form isomers 85:15

The above ratio of the trans-porm isomers to the cis-porm isomer in the product was determined by comparing the relative areas of their absorptions determined by the Hesonand nuclear magnetic method with 100 megahertz in "a deuterated chloroform solvent. Those of the olefinic methyl group in trans form in the position assigned to the dihydrnaphthoquinone nucleus appeared at 8 * 22 Ύ, while that of the olefinic methyl group

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in cis form in der'dem Dihydronaphtoquinone nucleus. the absorption area assigned to the next position of the product appeared at 8.33 Ύ , the latter area overlapping the absorption area assigned to the terminal olefinic methyl group of the cis form of the side chain, ■ '

Example 3

Synthesis of 2,3 ~ DinietJioxy-5-methyl-6-decaprenyl-1,4-dihydrobenzoquinone diacetate (dihydro-coenzyme Q _{1 Q} diacetate)

-To a solution of 10.3 g Ni (CO) ^ dissolved in 30 mL of η-hexane, was dropwise added at 50 ⁰ C for 2 hours, a solution of 30.5 S Decaprenylbromid dissolved in 80 ml n ~ hexane. The resulting mixture was allowed to stand under the above conditions for further 2 hours to complete the reaction. To. Cooling the n-hexane solution were dropwise. 5 g. Dimethylacetamide was added. - A solution of 13.9 S ^^ - dimethoxy-S-methyl-o-bromo-l, ^ - älhydrobenzdquinonedi-acetate was dissolved in 40 ml of benzene, therein dropwise at 50 ° C for 1 hour added, -After completion of the addition, was the whole thing under those conditions during further? Allowed to stand for hours to complete the reaction. At the end of this period, the reaction mixture was poured into dilute hydrochloric acid and the solution with

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Diethyl ether extracted. The essential extract was washed with water, dried and subjected to distillation to remove the solvent. 37 g of a light yellow oil were obtained. The oil was purified by silica gel column chromatography using a mixture of η-hexane and diethyl ether as an eluent. There were 19.5 g of a white, waxy substance that. melted at 36 to 38 C, obtained as the desired substance in a yield of 51.4 % of theory. The elemental analysis of the product, assuming Cz-JHqZ-O / - showed:

Calculated % i 79.70 10.19

Found #: 79.54 10.30.

Ratio of trans-form isomers to cis-form isomers 76: 24

The above ratio of the trans-form isomer to the cis-form isomer in the product was determined by comparing the relative areas of their absorption determined by the nuclear magnetic resonance method with 100 megahertz in a deuterated chloroform solvent. The absorption area assigned to the olefinic methyl group in trans form in the position closest to the dihydrobenzoquinone nucleus appeared at 8.26 / _9, while that of the olefinic methyl group in cis form in the position assigned to the dihydrobenzoquinone nucleus of the product appeared at 8.34 Ύ, the latter area being the Absorption »

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area overlapped that of the terminal olefinic methyl group is assigned to the cis form of the side chain.

The ones obtained in the experiments cited above The main results are summarized in the table.

Tabel

attempt

Reference example 1 Example 1
Reference example 2 Example 2
Reference example 3 Example 3

yield

85.1 85.9 91.5 91; 5 50.2

§1.4

Ratio of trans form isomers to cis form isomers in the product

trans form cis-shape: 68 - 86 : U 70. 50 85 15th 65 '■■■ 55 76

As can be seen from the results in the table above, the process according to the invention is that of the prior art with regard to the ratios of the transForm isomers to cis-form isomers in the resulting Products. Superior. -

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Claims (2)

P aten't ans-claims 1. Process for the preparation of 1,4-hydroquinone acetate Compounds of the formula CCGCH- CH, -CJi ₇ (I) OCÜCK, wherein R _{1 is} a hydrocarbon radical represented by the formula -CH ₂ - (- AWAY is represented j where η is zero (0) or one _; represents an integer from 1 to 9; A and B each represent hydrogen atoms or a direct bond between them and R and R _{2 represent} methoxy groups or together represent a double-bonded chain of the formula 409824/1092 - 25 - ■. - -CH = CH-CH = CH- mean, by reaction, of 2-halo; 5-methyl-1,4-hydroquinone diacetate the formula UCUCII ₃ CCOOiL wherein both Rp substituents in the the above formula (i) ■ have defined meanings and X is a halogen atom with a halogen-nickel complex compound of the T ^ -AlIyItypus of the formula CH. CiI Kv - 26 409824 / ^: iu92 - ^v - ^ ' wherein both R- and R are those relating to above Formula (I) have defined meanings, thereby, marked that the response in a mixed reaction medium is carried out, which consists of a non-polar solvent and a Amide series solvents. 2. Production of dihydro-vitamin-IC-diaeetat according to • Claim 1, characterized in that 2-halo-3-methyl-1,4-naphthohydroquinone diacetate a reaction with a phytyl-halogen-nickel complex compound is subjected in a mixed reaction medium consisting of a non-polar Solvent and an amide series solvent. J5. Preparation of dihydro-vitamin Kp diacetate according to claim 1, characterized in "that the 2 ~ bromo -> - is methyl-naphtochinondiacetat a reaction with a ^/ jT-phytyl ~ halogen-nickel complex compound in a mixed reaction medium subjected consisting of a non-polar solvent and an amide series solvent. K, production of 2,; 5-dimethoxy-5-methyl-6-decaprenyl-1,4-dihydrobenzoquinone diacetate, ie dihydro-coenzyme Q ₁₀ diacetate according to claim 1, characterized in that 2, ^ - dimethoxy-S-methyl- obrom-l, ^ - dihydrobenzoquinone diacetate of a reaction 409824/1092 with ^ -decaprenyl-halogen-Mekelkomplexverbindungen subjected in a mixed reaction medium ' which consists of a non-polar solvent and ■ a solvent of the amide series. 409824/10 92