EP1697317A1

EP1697317A1 - Method for producing vitamin a acetate

Info

Publication number: EP1697317A1
Application number: EP04803835A
Authority: EP
Inventors: Kai Michael Exner; Klemens Massonne; Harald Laas; Detlev Glas; Laszlo Szarvas
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2003-12-17
Filing date: 2004-12-14
Publication date: 2006-09-06
Also published as: US20090043121A1; CA2546307A1; CN1894208A; WO2005058811A1; CN100455558C; US20070082950A1; DE10359433A1; JP2007514681A

Abstract

The invention relates to a method for producing vitamin A acetate by reacting β-vinyl ionol with triphenylphosphine in the presence of sulphuric acid in a solvent mixture consisting of between 60 and 80 % methanol, between 10 and 20 % water and between 10 and 20 wt. % aliphatic, cyclic or aromatic hydrocarbons with between 5 and 8 atoms, in order to obtain β-ionylidene ethyltriphenyl phosphonium salts and then by a subsequent Wittig reaction using 4-acetoxy-2-methyl-but-2-enal.

Description

Process for the preparation of vitamin A acetate

Description:

The present invention relates to a process for the preparation of vitamin A acetate (VAA) by reacting? -Vinyl-lonol with triphenylphosphine in the presence of sulfuric acid to yS-lonylidenethyltriphenylphosphonium salts (C15 salt) and subsequent Wittig reaction with 4-acetoxy -2-methyl-but-2-en-al (C5 acetate).

Vitamin A acetate is an important industrial product that is widely used in the pharmaceutical and cosmetic sectors, as well as in food and nutritional supplements and as a feed additive in animal nutrition.

DE-A 2729974 describes a technical synthesis of C15 salt starting from jff-vinyl-ionol by reaction with triphenylphosphine in the presence of sulfuric acid. Lower aliphatic alcohols, in particular methanol, are described as solvents.

Curley et al. describe in J. Org. Chem. 1984, 49, 1941-44 the same reaction in methanolic solution in the presence of HBr.

DE-A 1279677 discloses a continuous process for carrying out the Wittig reaction of C15 salt with C5 acetate in methanolic solution at temperatures below 5 ° C.

DE-A 2636879 describes a reaction in two-phase systems consisting of water and halogenated organic solvents at temperatures from 0 to 60 ° C.

DE-A 2733231 describes an embodiment of the Wittig reaction of various C15 salts with C5 acetate in water at temperatures from 0 to about 100 ° C. In addition to alkali carbonates, ammonia is disclosed as the base. The reaction of the C15 salts obtained using sulfuric acid, a hydrogen sulfate or phosphoric acid is particularly advantageously carried out at room temperature.

In view of the technical complexity of vitamin A acetate syntheses, there is still a need to optimize the individual stages of the overall process and thus the entire manufacturing process and thereby make it more economical.

It was therefore an object of the present invention to provide a process which makes it possible to convert yS-vinyl-ionol to vitamin A acetate in a technically and economically advantageous temperature range with high conversion and a high space-time yield. The object was achieved according to the invention by providing a process for the preparation of vitamin A acetate of the formula (I)

by reacting? -vinyl-lonol of the formula (II)

with triphenylphosphine in the presence of sulfuric acid to give the C15 salt of the formula (III)

where X ^"stands for HSO ₄ ^" and / or CH ₃ SO ₄ ^" , and subsequent Wittig reaction with C5 acetate of the formula (VI)

in water as a solvent and in the presence of a base, characterized in that the synthesis of C15 salt of the formula III starting from? -vinyl-ionol at a temperature of 45 to 55 ° C in a solvent mixture consisting of - 60 to 80 wt .-% methanol, - 10 to 20 wt .-% water and - 10 to 20 wt .-% aliphatic, cyclic or aromatic hydrocarbons with 5 to 8 carbon atoms, the data selected within the ranges mentioned in wt .-% Have to add 100% by weight, performs.

? -Vinyl-lonol produced in any way is suitable for producing the C15 salt. Usually? -VinylI-lonol is used with a purity of about 90 to about 99%, preferably those with a purity of about 90 to about 95%.

All mono- or poly-olefinically unsaturated compounds mentioned in the context of the present invention can be present, used or obtained in the form of their respective double bond isomers or in the form of mixtures thereof.

For example, commercially available triphenylphosphine is suitable for the implementation of the yff vinyl ionol. Triphenylphosphine with a purity of about 95 to about 99.9%, preferably of about 98 to about 99.9%, is advantageously used in the process according to the invention. Usually, based on β-vinyl-ionol, an approximately equimolar amount of triphenylphosphine, preferably from about 0.95 to about 1.05 equivalents, is used. It is often advantageous to use triphenylphosphine in a slight deficit, i.e. in an amount of, based on yff-vinyl-ionol, about 0.95 to about 0.995 equivalents.

Mixtures of methanol and water, which additionally contain further organic solvents, serve as the dissolving medium in carrying out the C15 synthesis according to the invention. Aqueous methanol is usually used, with an excess of methanol usually being present. Another organic component is added to the solvent mixture, for example a hydrocarbon with 5 to 8 carbon atoms, which can be aliphatic, cyclic or aromatic, such as e.g. Hexane, heptane, octane, isooctane, cyclohexane, toluene, cyclopentane, methylcyclopentane, dimethylcyclopentane (1, 1-, 1, 2-, 1,3-, 1, 4-), ethylcyclopentane, 2-methylhexane, 3- Methylhexane, 2-methylheptane, 3-methylheptane, 4-methylheptane, 2-ethylhexane, 3-ethylhexane, methylcyclohexane, dimethylcyclohexane (1, 1-, 1, 2-, 1, 3-, 1, 4-) and the like more or mixtures thereof added. Instead of adding the hydrocarbons mentioned, it is also possible to use methanol which already contains the hydrocarbons as an impurity. The addition of alkanes such as heptane, cyclohexane, octane, isooctane or mixtures thereof has proven to be particularly advantageous. It has been shown that the course of the reaction depends on the composition of the dissolving medium. Good results are generally achieved using ternary solvent mixtures which consist of methanol, water and heptane, the heptane used also being able to contain up to about 40% by weight of further hydrocarbons with about 5 to about 8 carbon atoms.

In the production of C15 salt according to the invention, preference is given to using solvent mixtures which consist of about 64 to 72% by weight of methanol and about 14 to 18% by weight. Water and about 14 to 18 wt .-% of heptane, which can contain up to 40 wt.% Of other hydrocarbons. Very particular preference is given to solvent mixtures which consist of about 66.5% by weight of methanol, about 16.5% by weight of water and about 17% by weight of heptane, with heptane in the mixture instead of heptane can be used with other hydrocarbons as mentioned above.

The concentration of the reagents in the selected solvent mixture can in principle be varied over a wide range. Taking into account the economic aspect, however, it is advantageous not to work with excessive dilution. Concentrations based on the amount of the total reaction mixture of about 16 to about 24% by weight, preferably about 18 to about 22% by weight? -Vinyl-ionol and about 18 to about 26% by weight, have been found to be expedient about 20 to about 24 weight percent triphenylphosphine.

After the reaction has ended, the solvent mixtures used are separated off from the reaction products and preferably recycled, for example in the course of a further reaction according to the invention of yff-vinyl-ionol with triphenylphosphine to give the C15 salt. Changes in the composition of the solvent mixture caused thereby can be compensated for by adding additional amounts of the respective components. Changes in the composition of the alkane component, for example due to the enrichment or depletion of individual hydrocarbons, are not critical as long as they do not appreciably affect the course of the reaction.

According to the invention, the reaction of α-vinyl ionol with triphenylphosphine to form the C15 salt is carried out in the presence of sulfuric acid. The concentration of sulfuric acid can be varied over a wide range and is usually about 50 to about 96% by weight. Sulfuric acid is preferably used at a concentration of about 60 to about 90% by weight, particularly preferably from about 70 to about 80% by weight. About 73 to about 77% by weight sulfuric acid is very particularly preferably used. It is expressed in an approximately equimolar amount, based on the jff vinyl alcohol to be reacted, i.e. used in an amount of about 0.9 to about 1.1 equivalents. It is advantageous to use a slight excess of sulfuric acid, i.e. about 1.01 to about 1.1 equivalents.

To carry out the C15 salt synthesis according to the invention, triphenylphosphine is generally introduced in the selected solvent mixture and the necessary amount of sulfuric acid is added at from about 30 to about 50.degree. The sulfuric acid is advantageously added in portions or continuously over a longer period of time (about 1 to about 10 h). Then the selected amount of jff-vinyl-ionol is added and a temperature of about 45 to about 55 ° C. is advantageously set. The The reaction is usually complete after about 2 to about 20 hours. The reaction mixture obtained can be worked up in a manner known per se to the person skilled in the art.

The C15 salt of formula III thus obtained is usually obtained in the form of a mixture consisting of the hydrogen sulfate (X = HSO ₄ ) and the methyl sulfate (X = CH ₃ SO ₄ ). In addition to the predominantly formed hydrogen sulfate, preferred reaction products contain as little as possible, for example about 0.1 to about 15 mol% of the methyl sulfate. C15 salt, which contains only about 0.1 to about 5 mol% of the methyl sulfate, is particularly preferred, especially in the context of the further reaction according to the invention to give vitamin A acetate.

According to the invention, the C15 salt obtained is converted into vitamin A acetate by reaction with the aldehyde of the formula IV (4-acetoxy-2-methyl-but-2-en-al) referred to as C5 acetate. There are no special requirements for the C5 acetate to be used. As a rule, it is obtained in a purity that is usually expected from chemical intermediates, i.e. a purity of about 90 to about 99%. The reaction with the C15 salt obtained according to the invention is carried out in water or aqueous solvent mixtures which can contain, for example, alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, propanol or isopropanol. The reaction is preferably carried out in water.

To carry out the Wittig reaction, a solution or a mixture of the C15 salt in the chosen solvent medium is advantageously placed at about 45 to about 55 ° C, preferably at about 48 to about 52 ° C, and a suitable base such as e.g. Sodium hydroxide solution, potassium hydroxide solution, alkali or alkaline earth hydroxides, alkaline earth oxides such as MgO or BaO, sodium carbonate, potassium carbonate or other basic carbonates, alcoholates or amines such as e.g. Triethylamine or mixtures of the compounds mentioned. A base which is preferred in the process according to the invention is ammonia, which is advantageously used in an amount of about 2 to about 2.3 equivalents, based on the amount of C15 salt to be reacted. Ammonia is particularly preferably used in an amount of from 2.1 to about 2.2 equivalents.

The selected amount of ammonia can be introduced into the reaction mixture or the reaction solution in various forms. For example, gaseous or liquid ammonia can be introduced into the reaction mixture or evaporated or dripped onto its surface. Ammonia is preferably added in the form of aqueous solutions, which can contain, for example, about 5 to about 20% by weight of ammonia. Preferred solutions contain about 9 to about 15 weight percent ammonia. In parallel with the addition of the base or with a time delay, a molar amount approximately equal to the amount of C15 salt to be reacted, ie about 0.9 to about 1.1 equivalents, of C5 acetate is added to the reaction mixture. The reagents are advantageously added in portions or continuously. As a rule, they are metered in over a period of about 1 to about 5 hours. Subsequently, the reaction mixture can be stirred in the specified temperature range or, if appropriate, also at lower or higher temperatures. The reaction mixture can be worked up by methods known per se to the person skilled in the art, for example extractively.

The method according to the invention is suitable for reactions on any scale. It can be carried out batchwise, semi-continuously or fully continuously with good success. The special efficiency of the process is particularly important for implementations on a technical scale. In this case, the semi-continuous or fully continuous design of the process steps offers clear advantages in terms of process technology as well as economically. In the case of a continuous or semi-continuous design of the method, all of the time data influenced thereby are understood, e.g. Response times, dosing times and the like as average times.

Particularly in the case of semi-continuous or fully continuous process control, but also when the method according to the invention is carried out in batches, it is found that the specified process parameters can often not be varied independently of one another.

In a particularly preferred embodiment of the process according to the invention, 0.98 equivalents of triphenylphosphine are accordingly in a solvent mixture consisting of 66.5% by weight of methanol, 16.5% by weight of water and 17% by weight of heptane in a concentration of 32% by weight .-% submitted at 40 ° C with stirring and 1, 02 equivalents of about 75 wt .-% sulfuric acid added dropwise within about 1 h. Subsequently, 1.0 equivalents of? -Vinyl-ionol are added at about 50 ° C. and stirring is continued at about 50 ° C. until the reaction is complete. The work-up and isolation of the C15 salt obtained as a reaction product can be carried out in a manner known per se in the art.

Following this, 1 equivalent of the C15 salt thus obtained is preferably initially introduced at a temperature of about 50 ° C. and, with stirring, 2.1 to 2.2 equivalents of an about 12% by weight aqueous ammonia solution and 1.0 to 1.1 equivalents of C5 acetate were metered in. After the reaction has ended, the mixture is worked up or purified in the customary manner.

The following examples serve to illustrate the invention without, however, restricting it in any way: Example 1: Preparation of C15 salt

139.7 g of triphenylphosphine were placed in a solvent mixture consisting of 206.8 g of methanol, 44.46 g of water and 40.68 g of heptane at 40 ° C. with stirring. 72.7 g of 75% sulfuric acid were added dropwise within 1 h. Subsequently, 130 g of? -Vinyl-lonol with a purity of 92.1% were metered in over the course of 2 h, the temperature was raised to 50 ° C. and the mixture was stirred for 4 h. After extractive work-up, C15 salt was obtained in a yield of 99.9% (based on triphenylphosphine used).

Examples 2 to 5: Production of vitamin A acetate

A solution of 100 g of C15 salt in 150 g of water was initially introduced at 50 ° C. and the amount of ammonia given in Table 1 and 1.0 to 1.1 equivalents of C5 acetate were metered in and, after the addition had ended, for 30 minutes at the selected reaction temperature (see table 1) stirred. After extractive workup of the reaction mixture, vitamin A acetate was obtained in yields of 82 to 89%.

Table 1

Claims

claims

Process for the preparation of vitamin A acetate of formula (I)

by reacting β-vinyl-lonol of the formula (II)

where X ^"stands for HSO ₄ ^" and / or CH ₃ SO ₄ ^" , and subsequent Wittig reaction with C5 acetate of the formula (IV)

O ^ X ^. (IV) OAc in water as a solvent and in the presence of a base, characterized in that the synthesis of C15 salt of the formula IM starting from β-vinyl-ionol in a solvent mixture consisting of

60 to 80% by weight of methanol, 10 to 20% by weight of water and 10 to 20% by weight of aliphatic, cyclic or aromatic hydrocarbons with 5 to 8 carbon atoms, the details chosen within the ranges mentioned being in% by weight add up to 100% by weight, performs.

2. The method according to claim 1, characterized in that one carries out the Wittig reaction at a temperature of 45 to 55 ° C in the presence of, based on the C15 salt used, 2 to 2.3 equivalents of ammonia as the base.

3. The method according to claim 1 or 2, characterized in that one carries out the synthesis of C15 salt of formula III at a temperature of 45 to 55 ° C.

4. The method according to any one of claims 1 to 3, characterized in that one carries out the synthesis of C15 salt of formula III in the presence of sulfuric acid at a concentration of 70 to 80 wt .-%.

Method according to one of claims 1 to 4, characterized in that a. the synthesis of C15 salt of the formula IM at a temperature of 48 to 52 ° C in a solvent mixture consisting of

64 to 72% by weight of methanol, 14 to 18% by weight of water and 14 to 18% by weight of heptane, which can contain up to 40% by weight of further hydrocarbons, and b. the Wittig reaction at a temperature of 48 to 52 ° C in the presence of, based on the C15 salt used, 2.1 to 2.2 equivalents of ammonia as the base.

6. The method according to any one of claims 1 to 5, characterized in that one carries out the synthesis of C15 salt of formula III in the presence of sulfuric acid with a concentration of 73 to 77 wt .-%.

7. The method according to any one of claims 1 to 6, characterized in that to carry out the Wittig reaction C15 salt of formula III in the form of a mixture consisting of the hydrogen sulfate (X = HSO ₄ ) and the methyl sulfate (X = CH _3rd SO) is used, the proportion of methyl sulfate being 0.1 to 15%.

8. The method according to any one of claims 1 to 7, characterized in that the proportion of methyl sulfate is 0.1 to 5%.

9. The method according to any one of claims 1 to 8, characterized in that ammonia is used in the form of an aqueous solution with a concentration of 5 to 20 wt .-% in the Wittig reaction.

10. The method according to any one of claims 1 to 8, characterized in that it is carried out semi or continuously.

11. The method according to any one of claims 1 to 10, characterized in that the solvent mixture used for the synthesis of the C15 salt is recycled back into the process, if appropriate after re-setting the desired composition by adding at least one of the solvent components.