JPS5838434B2 - Method for producing 2,3,6-trimethylhydroquinone-1-nicotinic acid ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 2,3,6-trimethylhydroquinone-1
- This relates to a method for producing nicotinic acid ester.

2,3,6-trimethylhydroquinone-1-nicotinic acid ester is a substance useful as an intermediate for vitamin E nicotinic acid ester.

Vitamin E nicotinic acid ester is a long-acting drug that has an excellent peripheral vasodilatory effect and is a pharmaceutically useful substance.

* Conventionally, methods for producing vitamin E nicotinic acid ester include (1) a method in which vitamin E is reacted with a reactive derivative of nicotinic acid (see Japanese Patent Publication No. 39-24968), (2) a method in which vitamin E is reacted with a reactive derivative of nicotinic acid in the presence of diketene. A method of reacting nicotinic acid with free nicotinic acid (see Japanese Patent Publication No. 47-62) is known.

However, in the method (1) above, the yield of the product,
Both purity is low, and the yield will drop significantly if purified.

In addition, in the method (2) above, not only the purity of the product is low, but also a special solvent is required for the reaction, and it is hardly an industrial production method.

As a result of various studies aimed at eliminating these deficiencies, the present inventors have discovered a series of industrial production methods that are easy to operate and lead to vitamin E nicotinic acid ester in high yield.

In the method of the present invention, 2,3,6-trimethylhydroquinone-1-nicotinic acid ester is obtained by reacting 2,3,6-trimethylhydroquinone with nicotinic acid or a reactive derivative thereof, followed by hydrolysis. 2,3,6-trimethylhydroquinone-1-nicotinic acid ester (I) and phytol obtained as shown in the following formula,
Vitamin E nicotinic acid esters are obtained by reacting with infitol or one or more of their halides (9).

or OH, Y represents a nicotinic acid group) 2.3.
When reacting 6-trimethylhydroquinone 1-nicotinic acid ester with phytol, isophytol or their halides, the ratio of the raw materials may be equimolar, but
It is preferable to carry out the reaction using a slightly excess amount of the latter compound relative to the former compound.

As the catalyst, a Brønsted acid such as sulfuric acid, a Lewis acid such as aluminum chloride, ferric chloride, boron trifluoride ether complex, zinc chloride, or a mixture thereof may be used.

This catalyst is 2,3,6-trimethylhydroquinone-1
- It is necessary to use an equivalent molar amount or more based on the nicotinic acid ester.

It is not necessary to use a solvent, but an inert organic solvent that dissolves the raw materials, such as lower carboxylic acids such as formic acid and acetic acid, or ketones such as acetone and methyl ethyl ketone,
Alternatively, better results can be obtained by using ethers such as dioxane and tetrahydrofuran.

The reaction temperature and time vary depending on the catalyst and solvent, but
The reaction is completed by reacting at 70 to 80°C for 2 hours.

When the reaction mixture obtained as described above is treated according to a conventional method, vitamin E nicotinic acid ester is obtained in a yield of 93.
Obtained in %.

This product can be purified, if necessary, by, for example, silica gel column chromatography.

Note that 2,3,6-trimethylhytroquinone-1-nicotinic acid ester, which is the target product of the present invention, is a new compound that has not been described in any literature, and can be produced quantitatively by the method of the present invention.

Next, the specific manufacturing method is as follows.

The first method involves ester condensation of trimethylhydroquinone and a reactive derivative of nicotinic acid in the presence of a basic substance, resulting in 2,3,6-trimethylhydroquinone-
1,4-dinicotinic acid ester is obtained.

Examples of reactive derivatives of nicotinic acid include acid chlorides and acid anhydrides, and examples of basic substances include tertiary amines such as triethylamine, pyridine, and dimethylaniline.

Although dimethylformamide, dimethyl sulfoxide, etc. may be used as the solvent, it is preferable to use chloroform from the viewpoint of post-treatment.

The reaction temperature is preferably about 30 to 80°C, and the reaction may be carried out for 2 to 10 hours.

2,3,6-trimethylhydroquinone thus obtained
The 1,4-dinicotinic acid ester is dissolved in chloroform-methanol (1:1) and hydrolyzed with a catalytic amount of sodium hydroxide to yield the 2,3,6-trimethylhydroquinone-1-nicotinic acid ester.

In the second method, trimethylhydroquinone and nicotinic acid are subjected to ester condensation in the presence of a basic substance by the action of diketene to obtain 2,3,6 trimethylhydroquinone-1,4-dinicotinic acid ester.

As the basic substance, tertiary amines such as triethylamine, pyridine, and dimethylaniline may be used.

As the solvent, dimethylformamide, dimethylsulfoxide, or the above-mentioned amines may be used in large excess, but chloroform is preferably used.

The reaction is completed by reacting for 1 hour at a reaction temperature of 60 to 80°C.

2,3,6-trimethylhytroquinone thus obtained
1,4-dinicotinic acid ester is hydrolyzed by the above method to produce novel 2,3,6-trimethylhydroquinone-1.
- obtain nicotinic acid ester.

In addition, 2,3,6-trimethylhydroquinone 1-nicotinic acid ester has the following properties.

Melting point 193.0℃ Elemental analysis Calculated value as C15H15NO3 C: 70.02% H: 5.88% N: 5.4
4% Analysis value C: 69.81% H: 5.86% N: 5.3
3% Infrared absorption spectrum (nujol) 30 80, 1
730, 1600, 1280CrrL-l, nuclear magnetic resonance absorption spectrum (in acetone-D6, δ value) 2.07 (
s, 6H), 2.17 (s, 3H), 6.66 (s, I
H), 7. 6 5 (dd, IH) 8.15 (bs
, IH), s. 5o (at, IH), 8.8 7 (
dd, IH), 9.3 5 (d, IH) Example 1 Trimethylhydroquinone 10. (1 (0.066 mol) and nicotinic acid chloride hydrochloride 29.3P (0.16 mol)
5 mol) of dry chloroform was suspended in 15 OrrLl of dry chloroform and mixed with dry pyridine 35,0P (0.45 mol) under stirring at room temperature.
f mol) was added dropwise, and the mixture was left overnight.

The reaction solution was poured into about 200rrLl of water, the chloroform layer was separated, and then washed sequentially with 50ml of IN hydrochloric acid, 50ml of IN sodium bicarbonate aqueous solution, and 5Qml of water.
Filter it dry with anhydrous sodium sulfate and remove the solvent under reduced pressure to obtain white crystals 2.
2.6S' was obtained (yield 95%).

The crystals were dissolved in 200 TL of a 1:1 mixed solvent of chloroform and methanol, and 8 TL of a methanol solution (5%) of sodium hydroxide was added dropwise to the solution under stirring while cooling with water, and the mixture was allowed to stand at room temperature for 2 hours.

The reaction solution was poured into 300 ml of water, the chloroform layer was separated, the aqueous layer was further extracted with 100 ml of chloroform, and both layers were combined.

The chloroform solution was sequentially washed with 50 ml each of IN hydrochloric acid, IN sodium bicarbonate aqueous solution, and water, then dried and filtered with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2,3,6-trimethylhydroquinone-1-nicotine. 15.5f of the acid ester was obtained as pale yellowish white crystals (yield 97%).

2,3,6-trimethylhydroquinone thus obtained
1-Nicotinic acid ester 5.14P (0.02 mol) was added to isophytol 7. 4 f (0.025 mol) in 20 rul of acetic acid and 2.0 ml of concentrated sulfuric acid was added under stirring at room temperature. 0 ml was added dropwise and stirred for 1 hour.

The temperature was raised to 80° C. and the reaction was continued for an additional 2 hours, then cooled to room temperature and extracted with about 50 rrLl of isopropyl ether.

After washing with 30 increments of IN sodium bicarbonate and water, the residue was dried and filtered with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 11.6 P of a brown oil.

When purified by silica gel chromatography, vitamin E nicotinic acid ester was obtained as a pale yellow oil with a concentration of 8.77%.
1? (yield 82%).

The mixture was left in a cold place to obtain 850 g of needle-like crystals.

Melting point 37-40℃ λ 2 64nm (MeOH) maX E1 each 82.5 Elemental analysis Calculated value as C35H5:303N C: 78.46% H: 9.97% N: 2.6
1% Analysis value C: 78.43% H: 10.02% N: 2.
50% Reference Example 1 5.142 of 2,3,6-trimethylhytroquinone-1-nicotinic acid ester obtained by the method of Example 1 was dissolved in 20 ml of acetic acid together with 3.01 of zinc chloride and 2 ml of concentrated hydrochloric acid.

Phytol 7.41 was added dropwise while stirring at room temperature, and after stirring for 1 hour, the temperature was raised to 80° C. and the reaction was further continued for 1 hour.

After distilling off the solvent under reduced pressure, extraction was performed with about 50 ml of hexane, and the same procedure as in Example 1 was performed to obtain 8.67 f of vitamin E nicotinic acid ester (yield: 81%).

Melting point 37-40℃ λmax 264 nm (MeOH)E{
83.0 Example 2 Trimethylhydroquinone 10. OS' and nicotinic anhydride 3 7. 5f was added to 100 $:l of chloroform, 150 ml of pyridine was added, and the mixture was reacted at 65° C. for 5 hours.

After the reaction, filter the filtrate, concentrate the filtrate under reduced pressure, and add 15 chloroform.
After adding 0TLl and removing the soluble portion and washing with 50rrtl of water, 100mA' of methanol was added to the solution, and a methanol solution (5%) of sodium hydroxide (5%) was added to the solution with stirring at room temperature.
Hydrolysis was carried out by dropping 0 mA.

The reaction solution was poured into 500,771 liters of water, the chloroform layer was separated, the aqueous layer was further extracted with 100 liters of chloroform, and both were combined.

Thereafter, the treatment was carried out according to a conventional method, the solvent was distilled off under reduced pressure, and 2
・3,6-trimethylhydroquinone-1-nicotinic acid ester as white crystal 15.8? (yield 93%)
).

The thus obtained 2,3,6-trimethylhydroquinone-1-nicotinic acid ester 5.14P was mixed with 1.4P of zinc chloride. Oz
30 TLl of acetone with 1.01 aluminum chloride
of isophyl chloride under stirring at room temperature.
1 was added dropwise, and stirring was continued for 1 hour.

After distilling off the solvent, the temperature was raised to 80°C and the reaction was continued for 2 hours.

After extraction with about 701 rL of hexane, the same operation as in Example 1 was carried out to extract 8.6 rL of vitamin E nicotinic acid ester.
0S' was obtained (yield 80%).

Melting point 37-40°C λm2, Inphytol 7.4z dissolved in dioxane 60rrLl
Boron trifluoride ether complex 4. was added and stirred at room temperature in a nitrogen stream. Oz was added dropwise and stirred for 1 hour.

After raising the temperature to 80°C, concentrated hydrochloric acid 2S' was added and the reaction was continued for an additional hour, and then the solvent was distilled off under reduced pressure.

The residue was extracted with isoprobyl ether, and the same procedure as in Example 1 was performed to obtain vitamin E nicotinic acid ester 8.
．． 6El was obtained (yield 81%) C Melting point 37-40°C λmax 264nrrL (MeOH) E {layer 83,0 Example 3 Trimethylhydroquinone 10.0P and nicotinic acid 20
．． 0F with 50 ml of dimethylformamide and 30 ml of pyridine
ml of the mixed solution, and add 12.ml of diketene to it. A solution of OS' in 20 ml of dimethylformamide was gradually added.

After stirring was continued for 2 hours while keeping the reaction temperature at 70° C., the mixture was cooled to room temperature and poured into about 300 ml of water.

Extraction was carried out three times using 100 ml of chloroform, and the combined chloroform layers were sequentially washed with 50 TrL each of IN hydrochloric acid, 1 N sodium bicarbonate, and water, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was recrystallized from a mixed solvent of methanol and acetone to obtain white crystals 19.1
' was obtained (yield 80%).

The crystals were dissolved in 200 mA' of a 1:1 mixed solvent of chloroform and methanol, and the same procedure as in Example 1 was carried out to obtain 2,3,6-trimethylhydroquinone-1-nicotinic acid ester as pale yellow crystals. .9f was obtained (yield 96%).

The thus obtained 2,3,6-trimethylhydroquinone-1-nicotinic acid ester 1 0.3 f? 5. Ferric chloride. Dissolve in 50 ru of acetic acid with OS' and add 15. Drop the Of,
After stirring for 1 hour, the temperature was raised to 80°C and the reaction was continued for an additional 1 hour.

After acetic acid was distilled off under reduced pressure, it was extracted with 7100 ml of n-hexane, and the same procedure as in Example 1 was carried out to extract vitamin E.
Nicotinic acid ester 17.6F was obtained (yield 82%).

Melting point 37-40℃ λmax 264 nm (MeOH)E{
Standard 83.0

Claims (1)

[Claims] 1. A method for producing 2,3,6-trimethylhydroquinone-1-nicotinic acid ester, which comprises reacting 2,3,6-trimethylhydroquinone with nicotinic acid or a reactive derivative thereof, followed by hydrolysis. .