JPS5938946B2 - Method for producing hydroquinone compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel hydroquinone compound useful as a synthetic intermediate for vitamin K, coenzyme Q, and polyprenyltrimethylquinone, and a method for producing the same.

Quinones having an isoprene skeleton, such as vitamin K2, polyprenyltrimethylquinones, and coenzyme Q, occupy an important position as medicines.

* [n represents the number of isoprene units] In the above formula, those where n is 1 to about 12 exist naturally, but what is considered to be particularly important from the viewpoint of pharmacological activity is that for coenzyme Q, where n is For polyprenyltrimethylquinones, n is 4, and for vitamin K2, n is 4 or more.

Regarding the stereochemistry of the double bond in these compounds, all-trans isomers are preferred. Taking coenzyme Q as an example, as a method for synthetically producing such quinones,
A method in which 2,3-dimethoxy-5-methylhydroquinone (mother nucleus) is reacted with prenyl alcohol or its derivatives, the resulting condensation reaction product is oxidized to the corresponding quinone, and then purified (cis-isomer separation) has been known for a relatively long time (for example, Special Publication No. 38-26372,
39-17513, 46-3967).

The reaction is shown by the following formula.

The above condensation reaction with fluorine is carried out using acidic catalysts such as formic acid, sulfuric acid, hydrochloric acid,
This can be carried out in the presence of a protonic acid such as phosphoric acid or p-toluenesulfonic acid, or a Lewis acid such as zinc chloride, aluminum chloride, or boron trifluoride ether complex, but ring closure and condensation reactions within the polyprenyl side chain can be carried out. Because side reactions such as chroman ring formation occur, the yield of the target product is at most 30%.
It is.

In order to improve this drawback, 2,3-
Dimethoxy-5-methylhydroquinone dimethoxymethyl ether-6-magnesium halide is reacted with a π-allylic nickel complex of polyprenyl halide, or palladium chloride or dichlorbis-(triphenylphosphine)- is used as a catalyst. Method of reacting polyprenyl chloride in the presence of nickel (JP-A-51-11723, JP-A-51-11724)
No.), a method of reacting a π-allylic nickel complex of polyprenyl halide using 2,3-dimethoxy-5-methyl-6-halogenohydroquinone diacetate as a nucleation substance (JP-A No. 48-85546, same) 50-5
8021), a method of reacting boric acid ester of 2,3-dimethoxy-5-methylhydroquinone with prenyl alcohol or its derivatives (JP-A-51-6313)
Many methods have been proposed, such as (No. 9, No. 52-42838). Although these methods do improve the reaction yield, they do not improve the stereoselectivity for obtaining all-trans isomers, which is another important issue.

For example, when solanesol (C45 all-trans polyprenyl alcohol) extracted from natural leaf tobacco etc. is elongated to C5O and then condensed with the mother nucleus, the stereoisomerism is usually about cis/trans-3/7 to 2/8. However, the problem is that the purification operation to recover the trans isomer from the mixture is extremely complicated, and the constituent components (side chains and core) of the separated cis isomer are lost. There are issues that need to be addressed. The present invention has solved the above-mentioned problems, and the present invention provides the following general formula (1) [wherein R1 represents a lower alkyl group or a methoxymethyl group, and R2 and R3 each represent a methyl group or a methoxy group , or a member constituting a benzene ring together with the carbon atom to which they are bonded, R4 represents an optionally substituted aromatic hydrocarbon group, and n is 1 to 1.
represents an integer of 1] is provided, and the compound is capable of producing coenzymes Q, vitamin K, and polyprenyltrimethylquinones in high yield and with high stereoselectivity. It is a novel intermediate for

Rather than applying a chain elongation reaction to a prenyl alcohol derivative, such as solanesol, and then condensing it with the mother nucleus, the present invention produces an intermediate in which a C5 prenyl group is introduced into the mother nucleus in a trans configuration, and then the isoprene skeleton in the final product. This is based on the idea and knowledge that it is advantageous in terms of stereoselectivity to bond a polyprenyl chain having fewer C5 carbon atoms than the prenyl group introduced previously.

The compound represented by (1) is an intermediate that conforms to this idea, and is a compound of great industrial significance because it is easy and inexpensive to produce. According to the present invention, the compound of formula (1) has the following general formula () [in formula (), R1, R2 and R3 have the same meanings as in formula (1), and Y is
・represents a rogene atom] and the following formula (V
) In formula (V), R4 has the same meaning as in formula (I), and X represents a halogen atom or a tosyl group] in the presence of a copper compound catalyst to form the following general formula ( ) [In formula (), R1, R2, R3 and R4 are as defined above] is produced,
This is condensed with a prenyl derivative represented by the following general formula () [in formula (), n has the same meaning as in formula (I), and X represents a halogen atom or a tosyl group] in the presence of a basic compound. Manufactured by reaction.

Furthermore, the compound represented by formula (V) can be prepared by using the corresponding sulfonyl rad (R4SO2) in the presence of a cuprous halide catalyst.
X) and isoprene [J. Org. Chem. 35, 4217
(1970)] [in the above formula, R4 and The isoprene and sulfonyl halide used are inexpensive, the reaction yield of both is high, and it is extremely easy to separate the trans isomer from the cis isomer.

Therefore, it is still economical to discard the separated cis isomer. Generally, the trans isomer and the cis isomer can be separated into solid (trans isomer) and liquid (cis isomer) by utilizing the difference in melting point. The Grignard reagent of formula () used as a nucleation substance in the present invention is prepared by adding magnesium to the corresponding halide under conditions known per se (for example, in a solvent such as diethyl ether or tetrahydrofuran at a temperature of 0 to 6
0°C).

The thus prepared Grignard reagent of formula () and the formula (v
) is carried out in the presence of a copper compound such as cuprous halide (CuY.Y is a halogen atom), lithium copper chloride (LiCuCl2, Li2CuCl4), etc. The reaction method may be a method of reacting a Grignard reagent with a copper compound to derive a compound represented by the following formula (R), and then reacting it with a compound of formula (V).
) The Grignard reagent may be added to a mixed solution of the compound and the copper compound catalyst. The aforementioned Grignard reagent () production reaction and the subsequent reaction between compound (V) and Grignard reagent () and/or its copper derivative (') (hereinafter sometimes referred to as Grignard reagents) are carried out using nitrogen, argon, helium, etc. It is preferable to carry out the reaction under an inert gas atmosphere.

Solvents that can be used in the reaction between Grignard reagents and compound (V) include ethers such as diethyl ether, tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, hexane, heptane, and octane. aliphatic hydrocarbons, hexamethylphosphoric triamide, etc. alone or in mixtures. These solvents do not need to be the same as the solvent for the Grignard reagent production reaction. The reaction can be carried out at a temperature in the range of about -70°C to about 60°C, but in consideration of operational simplicity, reaction selectivity, etc., it is preferably carried out at -20°C to room temperature. The reaction time varies depending on the temperature, but is 1 to 20 hours. The compound (V) used in the present invention is difunctional, and the hydrogen atom bonded to the α-1 carbon with respect to the -SO2R4 group is also activated, so at the initial stage of the reaction, the following difunctional Two reactions proceed competitively.

This suggests that it is preferable to add Grignard reagents into compound (V) rather than adding compound (v) into Grignard reagents as a reaction method.

Therefore, specifically, (a) a Grignard reagent () is added to a mixture solution of compound (V) and a copper compound catalyst;
Alternatively, it is appropriate to adopt a method (b) of adding the copper derivative (') of the Grignard reagent to the solution of compound (V).

In both methods a) and (b) above, the copper catalyst is regenerated as the reaction progresses, so either method may be selected in consideration of the reaction rate. Grignard reagents are preferably used in an equimolar amount to 4 times the molar amount of compound (V). When cuprous halide is used as a catalyst, chlorine, bromine or iodine is suitably used as the halogen. The amount of the copper compound catalyst to be used should be determined appropriately depending on the reaction method as described above, but usually the amount of the copper compound catalyst (
The amount is within the range of 1 mol % to 2 times the amount of V). In the Grignard reagent of formula () used in the present invention,
Examples of lower alkyl groups in which R1 is methyl, ethyl, propyl, butyl, and pentyl; however, since the group is ultimately eliminated, methyl is the most suitable group from the economic point of view. be.

The optionally substituted aromatic hydrocarbon group represented by R4 in the compound of formula (V) is one that does not react with Grignard reagents, such as phenyl, tolyl, xylyl, naphthyl, and the like. In the present invention, the condensation reaction between the compound of formula () obtained as described above and the prenyl derivative of formula () is carried out in the presence of a basic compound, that is, under basic conditions. The compound of the formula () has a high reaction yield with the prenyl derivative, and in this respect, the compound of the formula () is also used in the present invention.
There are advantages to using compounds such as Particularly preferred examples of basic compounds are organic lithium compounds such as n-butyllithium, methyllithium, phenyllithium, etc., Grignard reagents such as ethylmagnesium bromide, phenylmagnesium bromide, diisopropyllithium amide, lithium amide, sodium amide. Amides such as, potassium t-butoxide, etc. can also be used. The condensation reaction involves reacting a basic compound with a compound of formula () in an anhydrous organic solvent under an inert gas atmosphere such as nitrogen, helium, or argon to produce an anion of the compound of formula (). Preferably this is carried out by gradual addition of the prenyl derivative. The appropriate amount of the basic compound to be used is about 1 to 2 times the stoichiometric amount. There is no particular limit to the amount of the compound of formula () relative to the compound of formula (), but approximately equimolar amounts are generally used. Although the reaction is possible over a range of temperatures from as low as -78°C to room temperature, the formula ()
The temperature at the time of addition of the prenyl derivative is preferably 0° C. or lower. By gradually increasing the temperature to room temperature after mixing the compounds of formula () and formula (), the reaction can be almost completely terminated. After the reaction, acetic acid, hydrochloric acid,
The compound of formula (1) produced by adding a small amount of acid such as phosphoric acid to neutralize it, then extracting with a solvent such as chloroform, isopropyl ether, diethyl ether, petroleum ether, n-hexane, washing with water, and drying. It can be recovered. Examples of novel compounds (1) that exhibit advantages in terms of yield and stereoselectivity in producing coenzymes Q, vitamin K, and polyprenyltrimethylquinones and can be produced by the method of the present invention are shown below. Listed below.

In the above formula, R4 is phenyl as defined above,
It represents a substituted or unsubstituted aromatic hydrocarbon group such as tolyl, xylyl, naphthyl, etc., and n represents an integer of 1 to 11.

These compounds are derived into the above-mentioned quinones useful as pharmaceuticals through the steps shown by the following formula. Next, the present invention will be further explained by examples.

Reference Example 1 Preparation of bromotrimethylhydroquinone dimethyl etherL. I. The method of Smith et al. [J. Am. C
hem. SOc. , 64.440 (1942)], trimethylquinone 4207 was first dissolved in carbon tetrachloride 41, bromine 4487 was added dropwise at room temperature (3 hours), and the mixture was stirred for 1 hour after the dropwise addition.

The reaction mixture was treated with a saturated aqueous sodium hydrogen carbonate solution, washed with water, and the precipitated crystals were separated and dried. The black crystals obtained by concentrating the mother liquor under reduced pressure were dissolved in hot ethanol, and solid sodium hydrogen carbonate was added until the evolution of carbon dioxide gas stopped. Nitric acid was added little by little, and when the liquid changed from red to yellow, it was cooled and the crystals were taken out.The mother liquor was further concentrated and the crystals were taken out. 4757 (yield 75%) was obtained by recrystallizing the obtained crystals from hot ethanol.
of bromoquinone was obtained. This material was suspended in 31 parts of acetic acid/2 parts of water, and 280y of zinc was added thereto and reacted at 80 to 90°C for 2 hours and then under reflux for 2 hours. After separating unreacted zinc by decantation, the reaction solution was poured into water, and white crystals of trimethylbromohydroquinone 3837 were extracted.
was obtained (yield 80%). The above bromohydroquinone 18
8y was suspended in 1060 ml of dimethyl sulfate and mixed with potassium hydroxide (1700 m9)/water (3400 ml) under nitrogen atmosphere.
The m0 solution was added in small portions at approximately 10°C.

After dropping, the reaction temperature was raised to 50-60°C and stirred for 1 hour.
The mixture was poured into water and extracted with ether, and the ether layer was washed with a 5% aqueous sodium hydroxide solution, washed with water, dried, and concentrated. The precipitated crystals were recrystallized from methanol to give bromotrimethylhydroquinone dimethyl ether 1307 (
A yield of 62% was obtained. Reference Example 2 Preparation of bromomethylnaphthohydroquinone dimethyl etherR. The method of Adams et al. [J. Am. Chem. S
Oc. , 528 (1941)].

2-Methylnaphthoquinone 2007, dry sodium acetate 400y1 acetic acid 1800ml were heated to 50°C, and bromine 2
047 was added dropwise, and the mixture was stirred at the same temperature for 18 hours.

The reaction solution was poured into 41ml of water, cooled, and the precipitated crystals were separated and recrystallized with methanol to obtain yellow bromoquinone 225y. Add 130y of the above bromoquinone to 1750ml of 95% ethanol, and add 36ml of stannous chloride.
A solution of 07 in 360 ml of concentrated hydrochloric acid was added under ice cooling, and the mixture was stirred at the same temperature for 4 hours. Note that the reaction was conducted under a nitrogen gas atmosphere. 1,700 ml of water was added to the reaction mixture, and the precipitated crystals were redissolved by heating and then allowed to cool to form white crystals.
47 (yield 87%) was taken out. The bromohydroquinone 1037 was suspended in 530 ml of dimethyl sulfate, and potassium hydroxide (8467) was added under a nitrogen gas atmosphere while cooling on ice.
/water (1700m0) was added little by little. After the dropwise addition, the reaction temperature was raised to 50-60°C and stirred for 1 hour. The reaction mixture was poured into water and extracted with ether, and the ether layer was mixed with a 5% aqueous sodium hydroxide solution and then water. After washing with
．． 3%). Example 1 12.96 f (50 mm 01) of bromotrimethylhydroquinone dimethyl ether prepared by the method of Reference Example 1 was reacted with 1.447 g of magnesium in the presence of a small amount of ethyl bromide in tetrahydrofuran (THF) at room temperature.
A Grignard reagent of the hydroquinone derivative was obtained.

1-(benzenesulfonyl)-2-methyl-4chloro-
6.17 (25 mm01) of 2-butene (trans isomer) and 4.17 cuprous bromide were suspended in 50 ml of THF, and the Grignard reagent (TH
A solution of F1 in 50 ml) was added dropwise over about 2 hours.

After the dropwise addition, the mixture was further stirred for 2 hours to complete the reaction. The reaction solution was poured into water, neutralized with 37 acetic acid/20 ml of water, extracted with chloroform, washed with water, dried, and the solvent was evaporated from the chloroform layer. 200 TILI of methanol was added to the residue to collect the precipitated crystals, and the mother liquor was concentrated to collect further crystals. The thus obtained white crystals of 2,3,5-trimethyl-5-(3'-methyl-
The yield of 4'-benzenesulfonyl-2'-butene-1/-yl)-hydroquinone dimethyl ether was 6.67 f.
(yield 68.5%). The structure was confirmed as follows. Then, the above compound 3.17 (8.4 mm01) was added to T
HF (48m) was dissolved in a mixed solvent of 0-hexamethylphosphoric triamide (HMPA) (16ml), and 6.7ml of a 15% n-hexane solution of n-butyllithium was added dropwise to this solution at -60°C. After 15 minutes, all-trans geranylgeranyl bromide 2,96f7 (
A solution of 8.4Ttm01) in THF4Oml was added dropwise.

After stirring at the same temperature for 1 hour, the reaction temperature was gradually raised to room temperature, and the reaction was continued at room temperature for 2 hours to complete. The reaction mixture was poured into water and made acidic with acetic acid, extracted with isopropyl ether, and the isopropyl ether layer was washed with water and dried. The solvent was distilled off from the isopropyl ether solution under reduced pressure, and the precipitated unreacted 2.3.5-trimethyl-5-
(3'-Methyl-4'-benzenesulfonyl-2'-buten-1'-yl)-hydroquinone dimethyl ether was separated out and washed with a 3/7 mixture of isopropyl ether/hexane. The mother liquor and washing solution were combined and concentrated, and then purified by silica gel column chromatography (isopropyl ether/hexane-3/7) to obtain the desired condensation product 4.167 (yield 75%). The structure confirmation is as follows. [Although it is unclear due to the overlap with the CH3O- peak (-CH2 → is around 3.10-3,25), it was confirmed from the NOυ2 integrated value that protons are also included at this position] Example 2 Bromomethylnaphthohydroquinone dimethyl ether prepared by the method of Reference Example 2 was dissolved in THF in the same manner as in Example 1.
The corresponding Grignard reagent was prepared by reaction with magnesium in the presence of a moderate amount of ethyl bromide.

An equimolar amount of cuprous bromide was suspended in a solution of 1.77 (7 mm01) of 1-(benzenesulfonyl)-2-methyl-4-chloro-2-butene (trans form) dissolved in 10 ml of THF. Then, the Grignard reagent (16 mm 0/40 ml THF solution) was added dropwise at 0° C. over 1 hour.

Then, the reaction temperature was raised to room temperature and stirred for 3 hours. The reaction solution was poured into ice water, acidified with acetic acid, extracted with chloroform, and the chloroform layer was washed with water, dried, and concentrated. Methanol was added to the residue to collect the precipitated crystals, and after concentrating the mother liquor, an additional amount of crystals was collected in the same manner. The yield of the desired product in the form of white crystals with a melting point of 156-157°C was 70.4%. The structure was confirmed as follows. Next, the above compound 2. Dissolve O5y (5 mmol) in 40 ml of THF/HMPA-3/1 mixed solvent,
In the same manner as in Example 1, 4.34 ml of a 15% n-hexane solution of n-butyllithium was added to this solution, followed by 1.957 ml of all-transgeranyl bromide (5.5 mmol).
) was added dropwise to react.

The reaction solution was poured into water, neutralized with acetic acid, and then extracted with isopropyl ether. The yield of the crude product recovered from the isopropyl ether layer was 3.70y, and this product was purified by silica gel column chromatography (isopropyl ether/n-hexane-3/7) to obtain the desired condensation reaction product 2. .517 (73% yield was obtained). The structure was confirmed as follows. Example 3 In Example 2, 1-(benzenesulfonyl)2-methyl-4-tosyl- was used instead of 1-(benzenesulfonyl)-2-methyl-4-chloro-2-butene (7 mmol).
2-methyl-3-(3/-methyl-4'-benzenesulfonyl-2) was prepared in the same manner as in Example 2, except that 2-butene (7 mmol) was used and the reaction was carried out at room temperature for 6 hours after dropping the Grignard reagent. '-Buten-1'-yl) naphthohydroquinone was prepared (yield 35.2%), and then using this product, a condensation reaction product was obtained in the same manner as in Example 2.

Example 4 20.64f7 (60 mmol) of bromomethylnaphthohydroquinone dimethoxymethyl ether and 1.737 g of magnesium were reacted in THF at room temperature in the presence of a small amount of ethyl bromide to obtain a Grignard reagent of the hydroquinone derivative.

1-(benzenesulfonyl)-2-methyl-4-chloro-2-butene (trans form) 7.32f7 (30mmo
1) and 4.937 cuprous bromide were suspended in 100 ml of THF, and the above Grignard reagent (THF 200 ml) was suspended in 100 ml of THF.
ml solution) was added dropwise over 3 hours at 0°C.

After the dropwise addition, the reaction was continued for another 2 hours at the same temperature. The reaction mixture was poured into water, neutralized with a solution of 4.07 acetic acid in 40 ml of water, and then extracted with chloroform. After washing with water and drying, the chloroform layer was evaporated, and 200 ml of methanol was added to the residue to precipitate crystals at 0°C. The yield of the desired product in the form of white crystals with a melting point of 73-75°C was 10,
2y (yield 72%). The structure was confirmed as follows. The above compound 7.17 (15 mm01) was dissolved in THF (9
0m0/HMPA (dissolved in a mixed solvent of 30m0), and added 1% of n-butyllithium to the solution in the same manner as in Example 1.
22.5ml of 5% n-hexane solution, then all-transgeranylgeranylfuromide 5,31y (15mm
The reaction was carried out by dropping a solution of 01) in 20 ml of THF.

The reaction solution was poured into water, neutralized with acetic acid, and then extracted with isopropyl ether. 13.0y of the crude product recovered from the isopropyl ether layer was subjected to silica gel column chromatography (isopropyl ether/n-hexane = 4/6
) to obtain the desired condensation product with a yield of 7.27 (yield: 64
, 3%) obtained. The structure was confirmed as follows. Example 5 A Grignard reagent was prepared by reacting 14.5y (50mm01) of 2,3,4,5-tetramethoxy-6-methyl-1-bromobenzene and 1.6f7 (66mm01) of metallic magnesium in 120ml of tetrahydrofuran.

1-(Benzenesulfonyl)-2-methyl-4-1chloro-2-butene (trans form) 6.1y (25mm01)
The above Grignard reagent was added dropwise to a suspension of 7.17 (50 mm01) of cuprous bromide in 100 ml of tetrahydrofuran at 0° C. over 2 hours.

After the dropwise addition was completed, the mixture was further stirred at the same temperature for 2 hours to complete the reaction. The reaction solution was poured into ice water, acidified with acetic acid, extracted with chloroform, and the chloroform layer was washed with water and dried. The solvent was distilled off from the chloroform solution under reduced pressure, and the residue (17.87) was purified by silica gel column chromatography (chloroform developing solvent). 8.57% of 5-tetramethoxy6-methylbenzene was obtained, and the desired product 8 was obtained as the after-distillate.
．． 77 (yield 80%) was obtained. Although this product is obtained in liquid form, it crystallizes when left for a long time (crude product melting point: 71-75°C). The structure confirmation is as follows. Ca. 3.
6O-3.9: Although it was unclear due to the overlap with the CH3O- peak, it was confirmed from the integrated value that two -CH2SO2- protons were mixed in at .degree.

The above compound 5y (12mm01) was dissolved in THF (72m0/
HMPA (24ml) was dissolved in a mixed solvent, and 15% n-butyllithium was added to the solution in the same manner as in Example 1.
11 ml of hexane solution, then 2.737 (9.6 mm) of all-transfernesyl bromide in THF
The reaction was carried out by dropping each solution in 30ml.

The reaction solution was extracted with chloroform, the solvent was distilled off from the chloroform layer under reduced pressure, and the remaining residue 6037 was fractionated using high performance liquid chromatography (isopropanol/n-hexane-2/98). As a result, 2.34y of unreacted sulfone was recovered (recovery rate of 4
7%), and 2.52y of the desired condensation product (yield 42% based on the charged farnesyl bromide) was obtained. The structure was confirmed as follows. [It was not clear due to the overlap with the CH3O- peak, but it was confirmed from the integrated value] Example 6 2,3-dimethoxy-5-methyl-6-bromobenzohydroquinone dimethoxymethyl ether 10.207 (
29mm01) and metal magnesium 0.87(33mm
01) in 100 ml of tetrahydrofuran to prepare a Grignard reagent.

1-(benzenesulfonyl)-2-methyl-4-1-chloro-2-butene (trans form) 4.887 (20mm01
) and cuprous bromide 4.267 (30 mm01) in 100 ml of tetrahydrofuran, the above Grignard reagent was added dropwise at 0° C. over 2 hours.

Claims (1)

[Claims] 1 General formula (IV) below ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ (IV) [In formula (IV), R^1 represents a lower alkyl group or a methoxymethyl group, and R^2 and R^3 each represents a methyl group or a methoxy group, or represents a member constituting a benzene ring together with the carbon atom to which they are bonded, and Y represents a halogen atom] and the following general formula (V
) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) [Formula (V)
R^4 is an optionally substituted aromatic ▲ Numerical formula, chemical formula, table, etc. ▼ (III) [In formula (III), X represents a halogen atom or a tosyl group, and n is an integer from 1 to 11. The following general formula (
I ) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I ) [Formula (
I) A method for producing a hydroquinone compound, wherein R^1, R^2, R^3, R^4 and n are as defined above.