JP2002249458A - Method for producing vitamin ks - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce vitamins Ks efficiently and industrially advantageously in a short process. SOLUTION: A mixture of an allyl alcohol compound shown by general formula (I) (wherein, n is an integer of 0-12; a double line made of a dotted line and a solid line shows a single bond or a double bond) and 2-methyl-1,4- naphthoquinone is treated by a palladium compound and then a stannous halide to produce vitamin Ks shown by general formula (II) (wherein, n and a double line made of a dotted line and a solid line are the same as defined above).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to vitamin K, which is known as a fat-soluble vitamin which promotes blood coagulation, and which is useful as an active ingredient of anti-bleeding drugs and osteoporosis drugs.
Particularly to a novel method for producing vitamin K ₁ and vitamin K ₂ class.

[0002]

2. Description of the Related Art Conventionally, vitamin Ks, especially vitamin K ₁
And As a method for producing vitamin K ₂ class, 1 in the presence of equivalent of boron trifluoride ether complex, a method of reacting a polyprenyl tin compounds and 2-methyl-1,4-naphthoquinone [Journal of the American
Chemical Society (J. Am. Chem. So
c. ), 102, 3774 (1980); Chemistry Letters (Chem. Lett.), 881.
Page (1979); Journal of Organic
Chemistry (J. Org. Chem.), Vol. 45,
4097 (1980)], a method comprising the step of reacting 2-methyl-3-bromo-1,4-naphthohydroquinone with a nickel complex obtained by reacting polyprenyl halide with nickel carbonyl [Journal of Chemical Society Chemical Communications (J. Chem. So
c. Chem. Commun. ), P. 953 (197
2 years); Journal of Chemical Society
Parkin Transaction I (J. Chem. S
oc. , Perkin I), p. 2289 (1973).
Year)], and polyprenyl halides are metallized at 3-position.
A method comprising a step of reacting with methyl-1,4-naphthohydroquinone [see Journal of American Chemical Society (J. Am. Chem. Soc.), Vol. 96, p. 8046 (1974)], in the presence of zinc powder. A method of reacting polyprenyl halide with 2-methyl-1,4-naphthoquinone [see Chemistry Letters (Chem. Lett.), Page 901 (1977)], and reacting polyprenyl halide with 2-dextrin in the presence of cyclodextrin. A method of reacting with methyl-1,4-naphthohydroquinone and then oxidizing [Journal of American Chemical Society (J. Am. Chem. S.
oc. 101, p. 1019 (1979)], 2-methyl-1,4-naphthoquinone is subjected to an addition reaction with cyclopentadiene, the α-position of the resulting adduct is polyprenylated with a polyprenyl derivative, and then vitamin K ₂ (See JP-A-60-56935). Reaction of allyl (trifluoro) silane with 2-methyl-3-bromo-1,4-naphthoquinone in the presence of 5 equivalents of ferric chloride [Tetrahedron Letters, Vol. 36,
2773 (1995)], a method of reacting prenyl bromide with 2-methyl-1,4-naphthoquinone using a lead bromide / aluminum powder mixture as a catalyst [Synthetic Communications (Synth. Commun.), No. 20].
Vol., P. 1743 (1990)], and prenylindium and 2-methyl-3-bromo-1,
Method for reacting 4-naphthoquinone [Journal of Organometallic Chemistry (J. Organ)
omet. Chem. 415, pp. 7 (1991).
Year) is known.

[0003]

The above-mentioned methods are all based on the premise that industrially available 2-methyl-1,4-naphthoquinone and allyl alcohol compounds are used as raw materials, but they are subjected to a coupling reaction. Whether it is necessary to convert the allyl alcohol compound to an allyl halide compound and further to an allyl metal compound and then react it with 2-methyl-1,4-naphthoquinone (above,,) or 2-methyl-1,4-naphthoquinone It is necessary to react with an allyl alcohol compound after derivatization into a halogenated derivative, a metalated derivative, or a hydroquinone derivative (the above examples,...). Therefore, both methods involve a problem that the total number of steps required to produce vitamin Ks from 2-methyl-1,4-naphthoquinone and / or an allyl alcohol compound is large when including the raw material preparation step. Therefore, it is difficult to say that the production method is advantageous for industrial implementation. Accordingly, an object of the present invention is to provide a method for producing vitamin Ks in a short step, efficiently and industrially advantageously by directly reacting 2-methyl-1,4-naphthoquinone and an allyl alcohol compound. Is to provide.

[0004]

According to the present invention, the above objects have been achieved by the general formula (I)

[0005]

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(Wherein, n represents an integer of 0 to 12, and a double line represented by a dotted line and a solid line represents a single bond or a double bond). (Abbreviated as (I)) and 2-methyl-
A general formula (II) characterized in that a palladium compound and then a stannous halide are allowed to act on a mixture of 1,4-naphthoquinone.

[0007]

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(Wherein, n and the double line represented by the dotted line and the solid line are as defined above).

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
2-Methyl-1,4-naphthoquinone used in the present invention is produced on a commercial scale as a raw material for sodium menadione bisulfite, sodium menadiol diphosphate, vitamin K ₁ , vitamin K ₂ and is easily available. can do.

As the allyl alcohol compound (I),
Examples include prenol, geraniol, nerol, dihydrogeraniol, dihydronerol, farnesol, dihydrofarnesol, tetrahydrofarnesol, geranylgeraniol, geranylnerol, phytol and the like. These allyl alcohol compounds (I) are produced on an industrial scale as fragrances and raw materials, raw materials for pyrethroid insecticides, and raw materials for pharmaceuticals such as vitamin E or teprenone, and can be easily obtained. The amount of the allyl alcohol compound (I) to be used is preferably an excess as an equivalent to 2-methyl-1,4-naphthoquinone, more preferably 2 to 10 equivalents.

Examples of the palladium compound include palladium chloride, palladium acetate, palladium acetylacetonate, dichlorobis (benzonitrile) palladium,
Examples thereof include dichlorobis (acetonitrile) palladium, dichlorobis (triphenylphosphine) palladium, and tetrakis (triphenylphosphine) palladium. Among these, dichlorobis (benzonitrile) palladium is particularly preferred. Although the amount of the palladium compound used is not particularly limited, it is usually 2-methyl-1,4-
It is preferably in the range of 0.1 to 30 mol%, more preferably 1 to 10 mol%, based on naphthoquinone.

Examples of the stannous halide include stannous chloride and stannous bromide. Although there is no particular limitation on the amount of stannous halide used, usually, 2-methyl-1,1 is used.
It is preferably in the range of 1 to 10 equivalents to 4-naphthoquinone, and more preferably in the range of 3 to 7 equivalents.

The method of the present invention is preferably performed in the presence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include amides such as dimethylformamide, diethylformamide, and N-methylpyrrolidone; water; ethers such as diethyl ether and tetrahydrofuran. Of these, dimethylformamide is particularly preferred. These solvents may be used alone or as a mixture of two or more. The amount of the solvent used is not particularly limited, but is usually preferably at least 5 times by mass, more preferably 10 to 50 times by mass, with respect to 2-methyl-1,4-naphthoquinone. .

The method of the present invention is preferably performed in an atmosphere of an inert gas such as helium or argon.

The process of the present invention is preferably carried out at a temperature in the range of 0 to 80 ° C, more preferably at a temperature in the range of 20 to 50 ° C. The reaction time varies depending on the reaction temperature, the type and amount of the allyl alcohol compound (I), the palladium compound and the stannous halide, and is usually in the range of 10 minutes to 24 hours.

The process according to the invention is, for example, 2-methyl-1,
4-naphthoquinone and allyl alcohol compound (I)
Is dissolved in a solvent, a palladium compound is added to this solution, and then stannous halide is added, followed by stirring at a predetermined temperature. The progress of the reaction can be monitored by gas chromatography, liquid chromatography, thin-layer chromatography, and the like.

The vitamin Ks thus obtained are:
Isolation and purification can be performed by a method used for isolation and purification of ordinary organic compounds. For example, an aqueous hydrochloric acid solution is added to the reaction solution, and the mixture is extracted with ethyl acetate, propyl acetate, diethyl ether, diisopropyl ether, benzene, toluene, xylene, etc., and the extract is washed with a saturated aqueous solution of sodium hydrogen carbonate, anhydrous sodium sulfate, anhydrous magnesium sulfate. After drying, the mixture is concentrated. The purity of the obtained product can be further increased by ordinary purification means such as silica gel column chromatography, if necessary.

[0018]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention.

Example 1 Synthesis of Vitamin K _{2 (5)} A mixed solvent of dimethylformamide and water (dimethylformamide: water = 3: 1 (volume ₎ was placed in a 25 ml-capacity eggplant-shaped flask at room temperature under an argon gas atmosphere at room temperature. Ratio)) 4m
1,172 mg of 2-methyl-1,4-naphthoquinone
(1.0 mmol) and 861 mg of prenol (10 m
mol) was added and dissolved, and 88.4 mg (0.1 mmol) of dichlorobis (benzonitrile) palladium was further added.
l) was added and dissolved. Next, 1188 mg (6.0 mmol) of stannous chloride was added to this solution, and 2
The reaction was performed for 4 hours. 5% of 10% hydrochloric acid aqueous solution was added to the reaction mixture.
After stopping the reaction by adding 1 l, 3 ml with 5 ml of ethyl acetate.
Extracted twice, the extracts were combined, washed with 10 ml of a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate,
Concentrated under reduced pressure. A part of the obtained crude product was analyzed by gas chromatography. As a result, it was found that the crude product contained 48 mg of vitamin K2 ₍₅₎ (yield: 20%). The crude product was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 30/1 (volume ratio) ₎ to obtain pure vitamin K2 ₍₅₎ .

Example 2 Synthesis of Vitamin K _{1 In} a 25 ml-capacity eggplant-shaped flask having a capacity of 25 ml, at room temperature under an argon gas atmosphere, 3 ml of dimethylformamide and 172 mg of 2-methyl-1,4-naphthoquinone (1.0 mmol) were added.
l) and 593 mg (2 mmol) of phytol were added and dissolved, and 88.4 mg (0.1 mmol) of dichlorobis (benzonitrile) palladium was further added and dissolved. Then, 1114 mg of stannous bromide was added to this solution.
(4.0 mmol) and reacted at an internal temperature of 50 ° C. for 24 hours. The reaction mixture was quenched by adding 5 ml of a 10% aqueous hydrochloric acid solution and then extracted three times with 5 ml of ethyl acetate.
Combine the extracts with a saturated sodium bicarbonate aqueous solution 10m
1 and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. As a result of analyzing a part of the obtained crude product by ¹ HNMR, it was found that the crude product contained 162 mg of vitamin K ₁ (36% yield). The crude product was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 30/1).
(Volume ratio)) to obtain a vitamin _{K 1} of the pure product.

[0021]

According to the present invention, in a short process, efficiently
Vitamin K can be produced industrially advantageously.

Claims (1)

[Claims] 1. A compound of the general formula (I) (Wherein, n represents an integer of 0 to 12, and a double line represented by a dotted line and a solid line represents a single bond or a double bond) and 2-methyl-1,4- A compound of the general formula (II) characterized in that a palladium compound and then a stannous halide are allowed to act on a mixture of naphthoquinone. (In the formula, n and a double line represented by a dotted line and a solid line are as defined above.)