JPH04210686A - Production of tocopheryl retinoate - Google Patents

Abstract

PURPOSE:To obtain the title compound in high yield by reacting a retinoic acid-alkyl carbonate mixed acid anhydride with tocopherol. CONSTITUTION:1mol retinoic acid-alkyl carbonate mixed acid anhydride is reacted with preferably 1.0-1.05mol tocopherol preferably at 0-25 deg.C in the presence of a catalyst of dimethylaminopyridine in an inert organic solvent to give the objective compound. The retinoic acid-alkyl carbonate mixed acid anhydride is obtained by reacting 1mol retinoic acid witch preferably 1.0-1.01mol alkyl halocarbonate (e.g. methylchlorocarbonate) preferably at -5 to 5 deg.C in the presence of a hydrogen halide binder in an inert organic solvent.

Description

[Detailed description of the invention]

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing tocopheryl retinoate, which is an ester of retinoic acid, or vitamin A acid, and tocopherol. [0002]

[Prior Art] Tocopheryl retinoate, which is an ester of retinoic acid and tocopherol, is used as a therapeutic agent for gastrointestinal ulcers (Japanese Patent Publication No. 60-26770), a therapeutic agent for skin diseases (Japanese Patent Application Laid-Open No. 61-207332), etc. It is known as a compound useful in pharmaceutical applications and as a component of cosmetics (Japanese Unexamined Patent Publication No. 73137/1983). [0003] So far, methods for producing tocopheryl retinoate include direct condensation of retinoic acid and tocopherol in the presence of a dehydrating reagent such as dicyclohexylcarbodiimide or trifluoroacetic anhydride, and retinoic acid or its alkali salt. A known method is to treat retinoic acid chloride with a chlorinating agent such as oxalyl chloride to produce retinoic acid chloride, and to react this retinoic acid chloride with tocopherol in the presence of a base such as pyridine or triethylamine (Japanese Patent Publication No. 49-26632). Public bulletin). [0004]

[Problems to be Solved by the Invention] In the conventional method for producing tocopheryl retinoate by direct condensation of retinoic acid and tocopherol, when trifluoroacetic anhydride is used as a condensing agent, in this esterification reaction, At the same time, trifluoroacetic acid ester of tocopherol is generated competitively, so there is a problem in that it is necessary to use an extra amount of tocopherol, and it is also necessary to separate this by-product. [0005] Furthermore, in the acid chloride method using retinoic acid chloride described above, the chlorinating agent used, oxalyl chloride, is expensive and volatile, making it difficult to handle. [0006] Therefore, there is a need to find a method for producing tocopheryl retinoate that does not have these problems. [0007]

[Means for Solving the Problems] As a result of intensive research in order to solve the above-mentioned problems, the present inventors have found that retinoic acid - which is obtained by reacting retinoic acid with a halogenated alkyl carbonate -
The present invention was completed by discovering that tocopheryl retinoate can be obtained in good yield by reacting an alkyl carbonate mixed acid anhydride with tocopherol. [0008] That is, the present invention relates to a manufacturing capability and method for tocopheryl retinoate, which comprises reacting a retinoic acid-alkyl carbonate mixed acid anhydride and tocopherol. The retinoic acid-alkyl carbonate mixed acid anhydride used in the present invention described above can be easily obtained by reacting retinoic acid with a halogenated alkyl carbonate. [0009] In this reaction between retinoic acid and halogenated alkyl carbonate, the amount of halogenated alkyl carbonate is 1.0 to 1.1 mol, preferably 1.0 to 1.1 mol, per 1 mol of retinoic acid.
Using 1.01 mol, -70 to 50°C, preferably -5 to
It can be carried out in an inert organic solvent in the presence of a hydrogen halide binder at a temperature of 5°C. [00101 Specific examples of the halogenated alkyl carbonate used here include methyl chlorocarbonate, ethyl chlorocarbonate, n-propyl chlorocarbonate, 1so-propyl chlorocarbonate, n-butyl chlorocarbonate, 1so-butyl chlorocarbonate, and chlorocarbonate. n-pentyl, methyl bromocarbonate, ethyl bromocarbonate, n-propyl bromocarbonate, 1s bromocarbonate
O-propyl, n-butyl bromocarbonate, 1S bromocarbonate
Examples include O-butyl. [00111 The inert organic solvent used here is:
Any organic solvent that dissolves retinoic acid and is inert to the subsequent reaction can be used, including hydrocarbon solvents such as hexane, benzene, toluene, ethereal solvents such as ethyl ether, isopropyl ether, Aprotic organic solvents such as tetrahydrofuran and dioxane, ketone solvents such as acetone and methyl ethyl ketone, and halogenated hydrocarbon solvents such as chloroform, methylene chloride, and carbon tetrachloride can be used, and tetrahydrofuran and dioxane are particularly preferred. [0012] The hydrogen halide binding agent used herein also includes organic basic compounds such as triethylamine,
Examples include pyridine. [0013] The retinoic acid-alkyl carbonate mixed acid anhydride thus obtained can be isolated from the reaction mixture or used as it is in the next esterification reaction with tocopherol without isolation. Isolation of the mixed acid anhydride can be carried out by any means such as concentration by distilling off the solvent from the reaction mixture, washing away by-produced salts, and separation of the target product by extraction. However, it is advantageous to use this mixed acid anhydride as it is in the next esterification reaction step without isolating it from the reaction mixture because the isolation step can be omitted. [0014] The esterification reaction between the retinoic acid-alkyl carbonate mixed acid anhydride and tocopherol is carried out using 1.0 to 1.5 mol, preferably 1.0 mol, of tocopherol per 1 mol of the retinoic acid-alkyl carbonate mixed acid anhydride. ~1.05
It can be carried out in an inert organic solvent using dimethylaminopyridine as a catalyst at a temperature of -50 DEG to 80 DEG C., preferably 0 DEG to 25 DEG C., using molar. The inert organic solvent used is the same as that used to obtain the retinoic acid-alkyl carbonate mixed acid anhydride from the above-mentioned retinoic acid and halogenated alkyl carbonate. [0015] The tocopheryl retinoate thus produced is concentrated by distilling off the reaction solvent from the reaction mixture;
It is isolated by means such as extraction and chromatography purification of the extract and taken out as a purified product. In this case glue

[For purification by chromatography, porous resins such as Diaion HP-20 (manufactured by Mitsubishi Kasei Corporation) and Amberlite XAD-4 (manufactured by Organo Corporation) can be used as adsorbents. [0016] The reaction formula for the above-mentioned reaction operation step of the present invention using a chloroalkyl carbonate as the halogenated alkyl carbonate is as follows. [0017] [Chemical formula 1] (Retinoic acid) + IC0OR (Alkyl chlorocarbonate)

【base】

(Retinoin - Anhydrous anhydrous) Retinoin - Alkyl mixture #Non-ice ÷ Tocof 10-l [dimethylaminopyridine] Tocopheryl retinoate [0018] The tocopherols used in this method are: α,
It may be β-1γ- and δ-tocopherol or a mixture thereof. Further, these tocopherols may be derived from natural products or may be synthetically obtained. Considering its physiological activity, α-tocopherol is preferred, but it is not limited thereto. [0019] Next, the present invention will be explained in more detail by way of examples. [0020]

[Example 1] Retinoic acid 15g (49.9 mmol), triethylamine 5. 56g (49.9X1.
7.5 g of isobutyl chlorocarbonate (1 mmol) and 180 ml of tetrahydrofuran in a N2 stream.
49゜9X1.1 mmol), tetrahydrofuran 1
0ml solution was added dropwise over about 10 minutes while cooling at 0±1°C. After stirring the reaction solution for 1 hour, 23.7 g of α-tocopherol was added dropwise. Next, 500 mg of 4-dimethylaminopyridine
added. After dropping, at -5~2℃ for 3 hours at 18~20℃
The reaction was stirred for hours. The reaction solution was concentrated under reduced pressure, the concentrated residue was extracted with 300 ml of ethyl acetate, the extract was washed with water until neutral, and the extract was concentrated to dryness under reduced pressure. Concentrate HP-20
Perform column chromatography purification using 800ml, 25%
After elution with acetone-methanol solution, 50-80%
Elution with an acetone-methanol solution yielded 24.1 g of α-tocopheryl retinoate. [00211 Example 2] Retinoic acid 45. 24.8 g of isobutyl chlorocarbonate was added dropwise over 15 minutes to a solution of 5 g of triethylamine, 18.4 g of triethylamine, and 500 ml of dioxane under cooling in a water bath, and the mixture was stirred and reacted at 11 to 12° C. for 1 hour. Next, 78.3 g of α-tocopherol, 15.3 g of triethylamine
, add 30 ml of dioxane solution dropwise and heat at 10-12°C.
After stirring for 4 hours, the cooling bath was removed and the reaction was stirred for an additional 3 hours. - The mixture was left at room temperature overnight and the solvent was concentrated under reduced pressure. The concentrate was extracted with 500 ml of isopropyl ether, washed with water until neutral, and the solvent was concentrated under reduced pressure to obtain 122 g of a crude product. Next, column chromatography purification was performed using HP-2010100O, eluting with a 25% acetone-methanol solution, and then eluting with a 50-80% acetone-methanol solution to obtain 71.0 g of tocopheryl retinoate.

Claims (3)

[Claims] 1. A method for producing tocopherol retinoate, which comprises reacting a retinoic acid-alkyl carbonate mixed acid anhydride with tocopherol. 2. The method according to claim 1, wherein the retinoic acid-alkyl carbonate mixed acid anhydride is obtained by reacting retinoic acid with a halogenated alkyl carbonate. 3. A method for purifying tocopherol retinoate using a porous resin.