JPS6051478B2 - Production method of α-tocotrienol nicotinate ester - Google Patents

Description

[Detailed Description of the Invention] (T: Induction... (I) A compound represented by (I), which is expected to have the same physiological activity as its homolog α-tocopherol nicotinate. .

A possible method for producing the compound of formula (I) is to react α-tocotrienol (■) with nicotinic acid or a reactive derivative thereof, similar to the method for producing α-tocopherol nicotinic acid ester.

As a method for producing α-tocotrienol, the method of O. Isler [Helv, Chim. Act
a) Volume 4, pages 2517-2526 (derivative 19)] The present invention relates to a novel method for producing alpha-tocotrienol nicotinate. α-tocotrienol nicotinic acid ester is produced by the following formula (I), CH■C-CH2pieceH, which is obtained by condensing trimethylhydroquinone (■) and geranyl linalool (■) according to the following reaction formula. Geranylgeranyltrimethylhydroquinone (V)
This was oxidized to give geranylgeranyltrimethylbenzoquinone (■), which was then ring-closed to give 3.
There is a method for producing α-tocotrienol (■) by converting 4-dehydro to α-tocotrienol (■) and then hydrogenating this.

However, this method uses expensive silver oxide as an oxidizing agent, sodium metal, which is highly dangerous to handle, must be used for hydrogenation, and the ring-closing reaction also takes a long time, making it difficult to manufacture industrially. Large amounts of α-tocotrienol (■
), and furthermore, obtaining the target product of formula (1) requires an additional esterification step with nicotinic acid or a reactive derivative thereof.

Therefore, the present inventors have conducted intensive research to overcome these drawbacks and produce α-tocotrienol nicotinate (1) from trimethylhydroquinone (■) and geranyl linalool (■) in an industrially advantageous manner. As a result, air was used to oxidize geranylgeranyltrimethylhydroquinone (■), and geranylgeranyltrimethylbenzoquinone (
When heating (■) in pyridine for ring closure, nicotinic acid chloride is added during the reaction to obtain 3,4-dehydro-α-monotocotrienol nicotinic acid ester represented by the following formula (■). It was discovered that the ring-closing reaction was promoted and that the target substance (■) could be obtained by hydrogenating this reaction.

The reaction between trimethylhydroquinone (■) and geranyl linalool (■) is 0. The reaction is carried out according to the method of Isler, using boron trifluoride ethyl ether complex as a catalyst, and the reaction is carried out in dioxane at room temperature.

Oxidation of geranylgeranyltrimethylhydroquinone (■) can be carried out in the presence of a suitable solvent or in the absence of a solvent at 70 to 90
It is carried out by blowing air at a temperature of °C. This method uses silver oxide. Compared to the method of Isler, it is very advantageous when carried out industrially. The ring-closing reaction of geranylgeranyltrimethylbenzoquinone (■) is carried out by heating under reflux in pyridine, but if nicotinic acid chloride is added during this reaction, 3,4-dehydro α
Monotocotrienol nicotinic acid ester (■) is obtained. Geranylgeranyltrimethylbenzoquinone (■),
The molar ratio of pyridine and nicotinic acid chloride is 1:15~
20:1.2 to 1.5 is preferable, and nicotinic acid chloride is preferably added when the ring-closing reaction of compound (■) has been carried out for about 6 to 8 hours. When doing this, 0. When using Isler's method, it takes more than 24 hours to complete the ring-closing reaction, whereas in the present invention, it takes about 13 hours or more to complete the ring-closing reaction.
1] The ring closure and the esterification of nicotinic acid are performed at once between V. The thus obtained 3,4-dehydro α-tocotrienol nicotinic acid ester (■) is a new compound, and if this is hydrogenated at normal pressure under ice cooling using Raney nickel as a catalyst, α-tocotrienol nicotinic acid can be obtained. Ester (1) is produced. In this reduction reaction, the formation of a perhydro compound in which the pyridine ring and side chain double bond of (■) are saturated is hardly observed. Also,
In the method of the present invention, the geometric structure of the double bond of geranyl linalool (■) is also maintained in the side chain in formula (1) without isomerization, and it is produced using all-trans-geranyl linalool. The side chain of α-tocotrienol nicotinic acid ester is all-trans-coordinated.

As described above, the present invention provides trimethylhydroquinone (■
) and geranyl linalool (■) and then esterifying it, this is an extremely superior industrial method that has shorter steps and can perform the ring-closing reaction in a shorter time. It is. Next, an example will be given and explained.

Example 1 Trimethylhydroquinone 160y (1.05 mol) was dissolved in dioxane 1f, and boron trifluoride ether complex salt 150y (1.05 mol) was added dropwise with stirring at room temperature.
Stir between the samurai.

After cooling in a salt and ice bath and gradually adding 300f (1.05 mol) of all-trans-geranyl linalool,
Let react for 2 hours. The reaction solution was poured into ice water 2e, extracted 4 times with ethyl ether 1e11f1500ml11500ml, the ether layer was washed with water and concentrated, 1.5' of n-hexane was added to the residue, and 7007nt of a 70% methanol aqueous solution was added.
Wash with 1700ml and 300ml. Concentrating the n-hexane layer yields 358 g of crude 6″-trans-, 10″-trans-geranylgeranyl trimethylhydroquinone.
is obtained. Example 2 358 dA of crude 6"-trans-, 10"-trans-geranylgeranyltrimethylhydroquinone is heated to 80° C., and air is blown into it for 3 times at a rate of 1 e per minute.

The reaction mixture was poured into a silica gel column. Purification by chromatography yielded 23.1y of 6"-1trans, 10"-1trans-geranylgeranyltrimethylbenzoquinone. I
R: 1640cm-1PMR: 1.60, 1.67, 1
．． 75 (each ratio), 2.00 (s), 3.22 (BdN
J=6.5Hz1sa015.10(Bl4H)PpmO
Example 3 6″-trans, 10″-trans-geranylgeranyltrimethylbenzoquinone 123y to pyridine 420km
1 and heated under reflux for 7 hours while stirring.

Add 65f of nicotine acid chloride/hydrochloride to this, and then add 65f of nicotine acid chloride/hydrochloride.
Allow time to react. The reaction solution was cooled to room temperature, added with ice water 1', and extracted with ethyl ether. The ether layer was washed with water, concentrated, and the residue was subjected to silica gel column chromatography (
Purified with n-hexane ethyl ether (5:1)
″1 transformer, 7″1 transformer-3,4-dehyde draw α
Monotocotrienol nicotinic acid ester 93y was obtained.
In addition, 30y of raw material 6''-trans, 10''-trans-geranylgeranyltrimethylbenzoquinone was recovered. The double bonds at the 3″ and 7″ positions of the product are both
The fact that it has a three-dimensional structure is 1.58 on the grudge spectrum.
It was confirmed that the signal intensity ratio of double bond methyl at 1.65 ppm was 3:1.

IR: 1735s Ao-1. PMR: 1.35 (Sl
3H), 1.58 (BSl9H), 1.65 (BS..
3H) 5.05 (B..3H), 5.53 (D..J=
9.0Hz11H), 6.48 (D..J=9.0Hz
．． ．． 1H), 7.35 (DdlJ=8.0Hz16.0
Hz11H), 8.37 (Dt..J=8.0Hz12
．． 0Hz11H), 8.75 (Dd..J=6.0Hz
12.0Hz11H), 9.34 (Bd..J=2.0
Hz11H) PpmO Example 4 Dissolve 3″-1 trans, 7″1-trans-3,4-dehydro α-tocotrienol nicotinic acid ester 93y in 250 g of ethyl alcohol, and dissolve Raneynickel (TW
-7; manufactured by Kawakami Fine Chemical Co., Ltd.) 2.5y (wet) was added and hydrogenated under ice cooling at normal pressure, and when 4.4f of hydrogen was absorbed, the reaction was stopped.

The reaction solution was filtered, the aqueous solution was concentrated, and the residue was purified by silica gel column chromatography (n-hexane ethyl ether 5:1) to obtain 3"-1trans, 7"1-trans-α-tocotrienol nicotinic acid ester 89y. I got it. It was confirmed from the signal intensity ratio of the double bond methyl at 1.60 and 1.67 ppm in the PMR spectrum that the double bonds at the 3'' and 7'' positions of the side chain were both trans conformations.

1R:1745s1590C77! -1.

Claims (1)

[Scope of Claims] 1 Geranylgeranyltrimethylhydroquinone is oxidized with heated air to form geranylgeranyltrimethylbenzoquinone, which is heated to react with pyridine, and nicotinic acid chloride is added during the reaction to form 3,4-dehydro-
producing α-tocotrienol nicotinic acid ester,
A method for producing α-tocotrienol nicotinic acid ester, which comprises then hydrogenating the same. 2. The production method according to claim 1, wherein the hydrogenation is carried out in the presence of a Raney-nickel catalyst.