EP3818037A1

EP3818037A1 - Process for the selective acylation of primary hydroxy groups in the presence of secondary hydroxy groups and catalyst therefor

Info

Publication number: EP3818037A1
Application number: EP19734409.6A
Authority: EP
Inventors: Ferdy COUMANS; Jonathan Alan Medlock; Sharon Mitchell; Javier Pérez-Ramirez; Jan Schuetz
Original assignee: DSM IP Assets BV
Current assignee: DSM IP Assets BV
Priority date: 2018-07-02
Filing date: 2019-07-02
Publication date: 2021-05-12
Also published as: CN112368258B; CN112368258A; WO2020007856A1; CN116440889A

Abstract

The present invention is directed towards a process for the selective acylation of a primary hydroxy group in a compound that may optionally further comprise at least one secondary hydroxy group and/or one tertiary hydroxy group comprising the step of reacting the compound with an acylating agent in the presence of a solid base catalyst, whereby the solid base catalyst is a hydrotalcite-like compound or a mixed metal oxide derived by activation thereof. The present invention is also directed towards a mixed metal oxide derived by activation of a hydrotalcite-like compound characterized by a BET surface area in the range of from 50 to 300 m2/g and a pore volume in the range of from 0.15 to 0.8 cm3/g, which has been thermally activated in air at a temperature in the range of from 70°C to 1010°C, and which contains magnesium and aluminium with a Mg/Al ratio in the range of from 0.5:1 to 10:1, and exchangeable anions such as e.g. CO3 2-, NO3-and OH-, as well as to its manufacture and its use as catalyst for the acylation of primary hydroxy groups, preferably for the acylation of primary hydroxy groups in compounds that may optionally further comprise at least one secondary hydroxy group and/or one tertiary hydroxy group.

Description

Process for the selective acylation of primary hydroxy groups in the presence of secondary hydroxy groups and catalyst therefor

The present invention is directed towards a process for the selective acylation of a primary hydroxy group in a compound that may optionally further comprise at least one secondary hydroxy group and/or one tertiary hydroxy group comprising the step of reacting the compound with an acylating agent in the presence of a solid base catalyst, whereby the solid base catalyst is a hyd rota lcite- like compound or a mixed metal oxide derived by activation thereof as defined and described in more detail below.

The present invention is also directed to the catalyst itself as to its manufacture and to its use in acylation reactions. Detailed description

Starting materials

Preferably the compound to be acylated is a primary allylic alcohol that may optionally further comprise at least one secondary hydroxy group and/or one tertiary hydroxy group. More preferably the compound to be acylated is a primary allylic alcohol of formula (A) that may optionally further comprise at least one secondary hydroxy group and/or one tertiary hydroxy group, so that a preferred process of the present invention is the acylation of a compound of formula (A) to a compound of formula (B),

comprising the step of reacting the compound of formula (A) with an acylating agent in the presence of a solid base catalyst, whereby the solid base catalyst is a hyd rotalcite- like compound or a mixed metal oxide derived by activation thereof, whereby one of R¹ and R² is methyl and the other of R¹ and R² is a terpenoid moiety “CH_{2 +} n (C5)”, whereby C5 is an isoprene subunit and n is an integer from 1 to 5, preferably from 1 to 3, and R is a Ci_-2o alkyl group, preferably a Ci-₆ alkyl group, more preferably R is methyl or ethyl.

Ci-₂₀-alkyl encompasses Ci_-2o linear alkyl, as well as C_3-20 cyclic alkyl and C_3-20 branched alkyl. Ci-₆-alkyl encompasses C_1-6 linear alkyl, as well as C_3-6 cyclic alkyl and C_3-6 branched alkyl.

Also, referred to as terpenoids or prenol lipids, isoprenoids are any of a class of organic compounds composed of two or more units of hydrocarbons, with each unit consisting of five carbon atoms arranged in a specific pattern. These compounds are, thus, derived from five-carbon isoprene units and are biosynthesized from a common intermediate known as mevalonic acid, which is itself synthesized from acetyl-Coenzyme A.

The terpenoid moiety“CH_{2 +} n (C5)” is a hydrocarbon residue which may be saturated or unsaturated, optionally substituted with 1 -3 oxygen containing groups (alcohol, aldehyde, ketone, ether), and which may be linear or contain 1 or more ring systems.

The optimal reaction time is < 24 hours. If secondary and/or tertiary hydroxy groups are present in the compound to be acylated, the content of the undesired by-product, i.e. the diacetates, is preferably < 10%, more preferably < 5%.

This is especially the case if the compound to be acylated is hydroxenin.

“Hydroxenin” is the trivial name for (2Z,4Z,7E)-3,7-dimethyl-9-(2’,2’,6’-trimethyl- cyclohex-6’-en-1’-yl) nona-2,4,7-trien-1 ,6-diol, i.e. the compound of formula (I). In the context of the present invention the term“hydroxenin”, however,

encompasses also the other stereoisomers as shown as compound of formula (IA) in Fig. 2.

Since mono- and diacetates of hydroxenin are very difficult to separate from each other, whereas unreacted hydroxenin can be separated from the hydroxenin monoacetate, the process of the present invention is very advantageous especially when carried out on industrial scale.

There had been a need for a process that overcomes these difficulties.

Furthermore, the catalyst should be usable in a fixed bed. This need is fulfilled by the process of the present invention.

Organic solvent

The process of the present invention is preferably carried out in an organic solvent if the compound to be acylated is solid at room temperature, i.e. that it has a melting point above 15 °C.

The process of the present invention can be carried out without an organic solvent, if the compound to be acylated is liquid at room temperature, i.e. that it has a melting point below 15 ° C.

Suitable organic solvents are carbonates, ethers, hydrocarbons, halogenated hydrocarbons and any mixtures thereof, preferably ethers, hydrocarbons, halogenated hydrocarbons and any mixtures thereof.

Examples of preferred carbonates are ethylene carbonate, propylene carbonate and any mixture thereof such as e.g. commercially available as Jeffsols®, dimethyl carbonate, diethyl carbonate, and butylene carbonate, as well as any mixtures thereof. Since carbonates have a limited stability against strong acids and strong bases, it is necessary to maintain a pH < 9 and > 3 during the reaction, because otherwise the solvent could partly be degraded.

Examples of preferred ethers are symmetric of asymmetric ethers of the formula R³-0-R⁴ with R³ and R⁴ being independently from each other Ci- -alkyl or C₆-io- aromatic or ethers of formula (V) with m being an integer from 1 to 10, preferably from 3 to 5, more preferably from 3 to 4, and dihydrolevoglucosenone (= cyrene™ = compound of formula (VI); see James Sherwood et al., ChemCommun 2014, 50, 9650-9652:“Dihydrolevoglucosenone (Cyrene) as a bio-based alternative for dipolar aprotic solvents”), as well as any mixtures thereof. The ethers of formula (V) can further be substituted by one or more alkyl groups, preferably by one or more methyl groups.

Ci-io-alkyl encompasses C_MO linear alkyl, as well as C3-10 cyclic alkyl and C3-10 branched alkyl. The alkyl groups are preferably aliphatic, but they may also contain olefinic C=C double bonds. The C₆-io-aromatic groups (phenyl, naphthyl etc.) may optionally be substituted with C1-4 alkyl groups, whereby Ci_-4-alkyl encompasses Ci_-4 linear alkyl, as well as C3-4 cyclic alkyl and C3-4 branched alkyl. Preferably the total amount of carbon atoms in the ethers is 10.

More preferred examples of ethers are tetrahydrofuran (“THF”), 2-methyl-THF, 1 ,4-dioxane, methyl tert- butyl ether (“MTBE”), ethyl tert- butyl ether, methyl tert- amyl ether, methoxycyclopentane, methoxypentane (= tert- pentyl methyl ether, H₃C-0-C(CH₃)₂-CH₂-CH₃, CAS 994-05-8), cyrene, as well as any mixtures thereof.

Examples of preferred hydrocarbons are aliphatic hydrocarbons and aromatic hydrocarbons, as well as any mixture thereof. The aliphatic hydrocarbons are preferably aliphatic linear, branched or cyclic alkanes. The aromatic hydrocarbons are preferably C₆-io aromatic hydrocarbons which may optionally be substituted with alkyl groups, especially with C_1-4 alkyl groups.

Examples of preferred halogenated hydrocarbons, whereby chlorinated

hydrocarbons are especially preferred, are aliphatic Ci_-4 halogenated hydrocarbons as well as aromatic C₆-io halogenated hydrocarbons, whereby aromatic C₆ halogenated hydrocarbons are especially preferred, as well as any mixtures thereof. Most preferred examples are methylene chloride, chloroform,

chlorobenzene, 1 ,2-dichlorethane, and any mixture thereof. For simplifying the work-up the use of a single organic solvent is preferred.

Preferably the amount of the starting material, i.e. the compound to be acylated, in the organic solvent is in the range of from 0.1 to 50 weight-%, more preferably in the range of from 1 to 20 weight-%, based on the total weight of the starting material and the solvent.

Catalyst

Hyd rota lcite- like compounds, also known as layered double hydroxides, or anionic clays, have a general formula M(ll)i-_xM(lll)_x(0H)_2*Aⁿ _x/n»mH₂0 where M(ll) and M(lll) are divalent and trivalent metals, Aⁿ is an exchangeable anionic species with charge n- such as CO₃ ² , NO₃ , or Cl , x is the fractional molar amount of M(lll) with respect to M(ll), and m is the stoichiometric amount of water molecules. The name comes from the mineral hydrotalcite having a chemical structure of the formula Mg₆Al₂(0H).16C0_{3 *}4H₂0 or Al₂0_{3 *}6Mg0*C0_2* 12H₂0.

Hyd rota lcite -like compounds can be prepared or can be purchased from suitable suppliers, for example Merck/Sigma-Aldrich, product number 652288. A preferred catalyst is a hydrotalcite-like compound or a mixed metal oxide derived by activation thereof, preferably by thermal activation thereof, preferably a hydrotalcite-like compound or a mixed metal oxide derived by activation thereof comprising magnesium and aluminum and a thermally- removable anionic species, more preferably a hydrotalcite-like compound or a mixed metal oxide derived by activation thereof containing magnesium and aluminium with a Mg/Al ratio in the range of from 0.5:1 to 10: 1 , preferably with a Mg/Al ratio in the range of from 0.5:1 to 8:1 , more preferably with a Mg/Al ratio in the range of from 0.5:1 to 5: 1 , most preferably with a Mg/Al ratio in the range of from 1 : 1 to 4:1 and containing CO₃ ² , NO₃ , OH as the exchangeable anion.

The molar ratio of Mg and Al is determined by inductively coupled plasma optical emission spectroscopy (ICP OES) using a Horiba Ultima 2 instrument equipped with photomultiplier tube detection. Prior to analysis, samples were dissolved in 10 wt.% HNO₃ and diluted using decarbonized water. A mixed metal oxide that has been thermally activated in air at a temperature in the range of from 70 °C to 1010°C, preferably in the range of from 350 to 1300 K (= 77°C to 1007°C), more preferably in the range of from 300 to 750°C, most preferably in the range of from 600 to 1000 K (327° C to 727° C), is especially preferred.

Most preferred is a mixed metal oxide derived from a hyd rota lcite- like compound that has been thermally activated in air at a temperature in the range of from 70°C to 1010°C, preferably in the range of from 350 to 1300 K (= 77°C to 1007°C), more preferably in the range of from 300 to 750 °C, most preferably in the range of from 600 to 1000 K, and which contains magnesium and aluminium with a Mg/Al ratio in the range of from 0.5: 1 to 10:1 , preferably with a Mg/Al ratio in the range of from 0.5:1 to 8:1 , more preferably with a Mg/Al ratio in the range of from 0.5:1 to 5:1 , most preferably with a Mg/Al ratio in the range of from 1 : 1 to 4:1 and containing C0₃ ² , NO₃ , OH as the exchangeable anion.

Preferably the amount of the catalyst is in the range of from 0.1 to 50 weight%, more preferably in the range of from 1 to 30 weight%, most preferably in the range of from 5 to 25 weight%, based on the amount of the compound to be acylated.

An advantage of the catalyst, with the preferences as given above, is that it can be regenerated. By regeneration organic species deposited on the catalyst during the reaction may be removed or the oxide may be reformed if the structure had become partially rehydrated. The regeneration is preferably achieved by thermal treatment in air at a temperature in the range of from 773 to 973 K (500 to 700°C).

Manufacture of the catalyst

Hydrotalcites can be prepared by various methods, commonly by co-precipitation of an aqueous mixture of suitable metal salts, at controlled pH values, for example magnesium and aluminium salts. The metal salts are preferably water soluble and are added to aqueous medium. The mixing of the entire metal salt containing aqueous solution is performed so that the pH is at least 8, preferably above 9.5. In order to maintain the pH of the aqueous metal salt containing solution above 8 alkaline substances such as alkali hydroxide and or alkali carbonate may also be suitably added to the aqueous medium. The temperature conditions for the reaction vary considerably depending on the types of aluminum or magnesium component employed, but normally the range of 0-180° C is preferred. The reaction time also to some extent is a dependent factor on reaction temperature and specific types of starting material, but if starting materials that have good reactivity are chosen, hydrotalcite-like compounds are formed within 10 mins even if the temperature is around 50° C. The pressure is typically ambient or

autogenous. As the hydrotalcite formed is obtained in the form of a precipitate, the product is filtered, washed with water, and thereafter the solid is dried at temperatures of around 65 °C to remove excess water.

Thermal activation /calcination of the hydrotalcite-like compounds in air produces mixed metal oxide catalysts with higher porosity than that of the parent hydrotalcite-like compound. While one may encounter a chemical method for creating activated metal oxides of oxyhydroxides, the thermal method is expected to be the easiest and least expensive method. If the hydrotalcite-like compound is heated to ultra-high temperatures, one may surpass the dehydration temperature at which the activated oxides are produced and can ceramicize or otherwise fuse the oxides into substantially inert substances often with spinel-type structures. Selection of an appropriate dehydration temperature is within the skill or practitioners or the relevant arts. Generally, a dehydration temperature in the range of 400-900°C, often above 500 or 600°C, i.e. in the range of from 500 to 900 °C, especially in the range of from 600 to 900 °C, is preferred.

Other synthesis methods (e.g. ion exchange, hydrothermal synthesis,

reconstruction) are e.g. disclosed by F. Cavani et al. in Catal. Today 1991 , 1 1 , 173- 301 and by J. He et al. in Struct. Bond. 2006, 1 19, 89-1 19. A preferred process for the manufacture of the catalyst is the following one:

A process for the manufacture of a mixed metal oxide derived by activation of a hydrotalcite-like compound comprising the following steps: (a) Co-precipitation of the corresponding water-soluble metal salts (e.g., nitrate or carbonate), in the desired metal ratios, in a magnetically stirred solution of Na₂C0₃ at a temperature in the range of from 15 to 30°C, preferably at room temperature (298 K = 25 °C), while maintaining a constant pH (> 10); (b) stirring the suspension obtained in step (a), preferably for 6 hours, at a

temperature in the range of from 25°C to 100°C to obtain a solid;

(c) Filtering and washing the solid produced in step (b);

(d) Drying the solid obtained after having performed step (c);

(e) Calcination of the solid from step (d) at a temperature in the range of from 70°C to 1010°C to obtain the mixed metal oxide derived by activation of a hydrotalcite-like compound.

Preferably the metal salts of step (a) are magnesium and aluminum nitrates, and/or the calcination temperature of step (e) is in the range of from 300°C to 650°C, preferably in the range of from 600 (327°C) to 1000 K (627°C)

Characterization of the catalyst

The pore volume of the catalyst is preferably in the range of from 0.05 to 1.0 cm³/g, more preferably in the range of from 0.1 to 0.8 cm³/g.

The BET Surface Area of the catalyst is preferably in the range of from 50 to 300 m²/g, more preferably in the range of from 100 to 200 m²/g.

The pore volume and BET Surface Area are calculated from the nitrogen isotherms which can be measured e.g. on a Micromeritics TriStar analyser. Prior to analysis, samples are degassed overnight at 423 K (150°C). The degassing temperature should not exceed 150°C to avoid unintentional thermal activation of the samples.

Acylating agent

Preferred examples of acylating agents are acid anhydrides and acid halides, whereby acid anhydrides are more preferred, alkanoic acid anhydrides with alkyl being an aliphatic C1-20 alkyl. Alkanoic acid anhydrides with an aliphatic Ci_-6 alkyl are even more preferred and most preferred are acetic anhydride and propionic anhydride. Preferably 0.9 to 2.0 mole equivalent of the acylating agent, more preferably 1 .0 to 1 .5 mole equivalent of the acylating agent, most preferably 1 .2 to 1 .4 mole equivalent of the acylating agent, based on the molar amount of the compound to be acylated, are used.

Reaction conditions

When hydroxenin (compound of formula (l)/(IA)) is the starting material to be acylated, the process according to the present invention is preferably carried out at a temperature in the range of from 20 to 90 °C, more preferably at a

temperature in the range of from 30 to 80°C.

Product

Products obtained by the process of the present invention are compounds, where the primary hydroxy group has been acylated, whereby the optionally present secondary and/or tertiary hydroxy group(s) remain(s) unreacted.

If the compound to be acylated is hydroxenin, the process of the present invention results in“hydroxenin monoacetate” which is the trivial name for (2Z,4Z,7E)- carboxylic acid 3,7-dimethyl-6-hydroxy-9-(2’,2’,6’-trimethyl-cyclohex-6’-en-r-yl) nona-2,4,7-trienyl esters, i.e. the compound of formula (II). In the context of the present invention the term“hydroxenin monoacetate”, however, encompasses also the other stereoisomers as shown as compound of formula (IIA) in Fig. 2. Preferred embodiment of the present invention

A preferred embodiment of the present invention is a process for the selective acylation of the primary hydroxy group in hydroxenin by reacting the primary hydroxy group with an acylating agent in the presence of a solid base catalyst, whereby the solid base catalyst is a hydrotalcite-like compound or a mixed metal oxide derived by activation thereof (see Fig. 1 and 2).

The preferences given above for the organic solvent, the catalyst, the acylating agent and the reaction conditions also apply here. Especially preferred as organic solvents, when hydroxenin is used as starting material, are aliphatic and aromatic hydrocarbons and halogenated hydrocarbons such as e.g. o-/m-/p-xylene and dichloromethane, as well as any mixture thereof. Hydroxenin (compound of formula (I)) is an intermediate in the industrial manufacture of Vitamin A acetate. Thus, the present invention is also directed to a process for the manufacture of Vitamin A acetate comprising the following steps: i) C1 -elongating b-ionone to obtain the C14-aldehyde of formula (III);

ii) adding a Grignard reagent to the C14-aldehyde of formula (III) to obtain the diol of formula (IV);

iii) semi-hydrogenating the diol of formula (IV) to obtain hydroxenin of formula (I);

iv) mono-acetylating the hydroxenin of formula (I) to the hydroxenin monoacetate of formula (II) according to the process according to the present invention;

v) eliminating water and isomerizing the resulting compound to obtain vitamin A acetate. Steps i), ii), iii) and v) may be manufactured as e.g. disclosed by W. Bonrath et al. in Kirk-Othmer Encyclopedia of Chemical Technology 2015, 1 -22; or by M.

Eggersdorfer et al. in Angewandte Chemie, International Edition 2012, 51 (52), 12960-12990:“One Hundred Years of Vitamins - A Success Story of the Natural Sciences.” or by 0. Isler et al. in Helv. Chimica Acta 1947, XXX (VI), 191 1 -1927.

The invention is now further illustrated in the following non-limiting examples.

Examples

Manufacture of the catalysts

Four Mg-Al-C0₃ hydrotalcites with nominal Mg/Al ratios of x = 1 , 2, 3, and 4 (coded HTx) are synthesized via coprecipitation. A 500 cm³ solution of 0.25-1.0 M

Mg(N0₃)₂-6H₂0 (Sigma -Aid rich, >98%) and 0.25 M Al(N0₃)₃-9H₂0 (Sigma-Aldrich, >98%) is slowly added to a magnetically stirred (500 rpm) solution of 600 cm³ of 2 M

Na₂C0₃ (Sigma-Aldrich, >99.5%) at 298 K. The pH is kept constant at ca. 10 through the dropwise addition of a 40 wt.% NaOH solution. The resulting slurry is aged for 6 hours at 333 K under stirring. Finally, the material is filtered and extensively washed with deionised water and dried overnight at 338 K. The corresponding mixed metal oxides are obtained via calcination in static air at 673-1273 K for 6 hours (5 K min-1 ) and are labelled as MMOx-y, where x indicates the Mg/Al ratio and y denotes the activation temperature. Reconstructed r-HT3 is obtained via rehydration of MM03-973 by treatment in deionised water (100 cm³ per gram of solid) for 6 hours at 298 K under magnetic stirring (500 rpm). The resulting material is collected by filtration, washed with equivalent amounts of ethanol (100 cm3 per gram of solid), and dried under N₂ atmosphere. All solids are stored in a desiccator under reduced pressure.

Catalytic tests

Acetylation reactions are carried out in a Radleys Carousel 6+ equipped with 100 cm³ two-necked round-bottom flasks and reflux cooling. In a typical experiment, the catalyst (250 mg unless otherwise indicated), acetic anhydride (4.3 mmol, Merck, >98.5%), and 3.3 mmol of hydroxenin in p-xylene (Acros, >99%) are reacted in a total volume of 10 cm³ at T = 303-363 K at ambient pressure. Catalyst recyclability is investigated over five consecutive reaction followed by regeneration at 973 K, the total amount of material is maintained at 250 mg. Samples are analysed using an Agilent 1260 Infinity HPLC equipped with an Agilent Zorbax C18 column and both DAD and RID detectors. The concentrations of substrates and products are calibrated with reference to pure standards. The conversion of hydroxenin is calculated as the number of moles reacted divided by initial amount.

The results are shown in the following Tables 1 -6. Table 1 reports results with the unactivated hydrotalcites.

Table 2 reports results with hydrotalcite-derived mixed metal oxides that are activated at different temperatures.

Table 3 reports results with different amounts of hydrotalcite-derived mixed metal oxide catalysts.

Table 4 reports the results of experiments at different temperatures and Table 5 reports reactions at different reaction times.

Table 6 reports results reusing the same hydrotalcite-derived mixed metal oxide catalyst 5 times and then one additional time after the hydrotalcite-derived mixed metal oxides is regeneration at 973 K (700° C).

In all examples (according to the present invention and comparison examples), hydroxenin ((2Z, 4Z,7E)-3,7-dimethyl-9- (2’, 2’, 6’ -trimethyl-cyclohex-6’ -en-1’-yl) nona-2,4,7-trien-1 ,6-diol), the compound of formula (I), is used as substrate. The monoacetate product is the compound of formula (II) with R = methyl.

Table 1

Reaction conditions: 303 K, 250 mg of catalyst, 3.3 mmol of hydroxenin, 10 ml of p- xylene, 4.3 mmol of acetic anhydride, 6 hours Table 2

Reaction conditions: 303 K, 250 mg of catalyst, 3.3 mmol of hydroxenin, 10 ml of p- xylene, 4.3 mmol of acetic anhydride, 6 hours

Table 3

p-xylene, 4.3 mmol of acetic anhydride, 6 hours

Table 4

Reaction conditions: 250 mg of catalyst MM03-973, 3.3 mmol of hydroxenin, 10 ml of p-xylene, 4.3 mmol of acetic anhydride, 6 hours

Table 5

Reaction conditions: 323 K, 250 mg of catalyst MM03-973, 3.3 mmol of hydroxenin, 10 ml of p-xylene, 4.3 mmol of acetic anhydride

Table 6

Reaction conditions: 323 K, 500 mg of catalyst MM03-973, 6.6 mmol of hydroxenin, 20 ml of p-xylene, 8.6 mmol of acetic anhydride

Characterization of the catalyst

The specific parameters of the catalysts are shown in the following Table 7.

The molar ratio of Mg and Al is determined by inductively coupled plasma optical emission spectroscopy (ICP OES) using a Horiba Ultima 2 instrument equipped with photomultiplier tube detection. Prior to analysis, samples are dissolved in 10 wt.% HNO₃ and diluted using decarbonized water.

The pore volume and BET Surface Area are calculated from the nitrogen isotherms which are measured on a Micromeritics TriStar analyser. Prior to analysis, samples are degassed overnight at 423 K (150°C).

Table 7

Comparison examples

Catalysts not according to the present invention

3.3 mmol of hydroxenin are being reacted with 4.3 mmol acetic anhydride in 10 ml of p-xylene at 30° C for 6 hours in the presence of 250 mg of the catalyst as shown in Table 8. The results are shown in Table 8.

NaX and CsX are basic zeolite catalysts that can purchased or can be prepared according to known literature methods (see for example Applied Catalysis A:

General, 1998, vol 167, p. 271 -276).

Table 8

Pyridine (catalyst not according to the present invention) used as catalyst

3.3 mmol of hydroxenin are reacting with 4.3 mmol acetic anhydride in 10 ml of p- xylene at 30°C for 4 hours in the presence of 2.6 mmol of pyridine (= catalyst). The results are shown in Table 9. Table 9

Claims

1 . A process for the selective acylation of a primary hydroxy group in a compound that may optionally further comprise at least one secondary hydroxy group and/or one tertiary hydroxy group comprising the step of reacting the compound with an acylating agent in the presence of a solid base catalyst, whereby the solid base catalyst is a hyd rota lcite- like compound or a mixed metal oxide derived by activation thereof.

2. The process according to claim 1 , whereby the compound comprising the

primary hydroxy group and optionally at least one secondary hydroxy group and/or one tertiary hydroxy group is a primary allylic alcohol.

3. The process according to claim 2, whereby the primary allylic alcohol is a

compound of formula (A),

whereby one of R¹ and R² is methyl and the other of R¹ and R² is a terpenoid moiety“CH_{2 +} n (C5)”, whereby C5 is an isoprene subunit and n is an integer from 1 to 5, preferably from 1 to 3, and R is a C1-20 alkyl group, preferably a Ci- 6 alkyl group, more preferably R is methyl or ethyl, whereby the terpenoid moiety“CH_{2 +} n (C5)” is a hydrocarbon residue which may be saturated or unsaturated, optionally substituted with 1 -3 oxygen containing groups (alcohol, aldehyde, ketone, ether), and which may be linear or contain 1 or more ring systems.

4. The process according to claim 1 and/or 2, whereby the compound comprising the primary hydroxy group further comprises a secondary hydroxy group.

5. The process according to claim 4, whereby the compound comprising the primary hydroxy group and a secondary hydroxy group is 3,7-dimethyl-9- (2’,2’,6’-trimethyl-cyclohex-6’-en-1’-yl) nona-2,4,7-trien-1 ,6-diol.

6. The process according to claim 5, whereby the process is carried out at a

temperature in the range of from 20 to 90° C, preferably at a temperature in the range of from 30 to 80° C.

7. The process according to any of the preceding claims, whereby the acylating agent is an alkanoic acid anhydride or an acyl halide, whereby the acyl halide is preferably an acyl chloride and/or an acyl bromide.

8. The process according to any of the preceding claims, whereby the mixed

metal oxide derived by activation of the hyd rota lcite- like compound comprises magnesium and aluminum.

9. The process according to claim 8, whereby the Mg/Al ratio in said mixed metal oxide comprising magnesium and aluminum is in the range of from 0.5:1 to 10:1 , preferably it is in the range of from 0.5:1 to 8: 1 , more preferably it is in the range of from 0.5:1 to 5:1 , most preferably it is in the range of from 1 :1 to 4: 1 .

10. A process for the selective acylation of the primary hydroxy group in 3,7- dimethyl-9-(2’,2’,6’-trimethyl-cyclohex-6’-en-1’-yl) nona-2,4,7-trien-1 ,6-diol by reacting 3,7-dimethyl-9-(2’,2’,6’-trimethyl-cyclohex-6’-en-r-yl) nona-2,4,7- trien-1 ,6-diol with an acylating agent in the presence of a solid base catalyst, whereby the solid base catalyst is a hyd rota lcite -like compound or a mixed metal oxide derived by activation thereof.

1 1 . The process according to any one or more of the preceding claims, whereby the catalyst can be regenerated, preferably by thermal treatment in air at a temperature in the range of from 500 to 700°C.

12. A process for the manufacture of Vitamin A acetate comprising the following steps:

vi) C1 -elongating b-ionone to obtain the C14-aldehyde of formula (III);

vii) adding a Grignard reagent to the C14-aldehyde of formula (III) to obtain the diol of formula (IV);

viii) semi-hydrogenating the diol of formula (IV) to obtain hydroxenin of formula (I);

ix) mono-acetylating the hydroxenin of formula (I) to the hydroxenin monoacetate of formula (II) according to the process according to any one or more of claims 5 to 11 ;

x) eliminating water and isomerizing the resulting compound to obtain vitamin A acetate.

13. A mixed metal oxide derived by activation of a hyd rota lcite- like compound in air at a temperature in the range of from 70°C to 1010°C, characterized by a BET surface area in the range of from 50 to 300 m²/g and a pore volume in the range of from 0.15 to 0.8 cm³/g, and which contains magnesium and aluminium with a Mg/Al ratio in the range of from 0.5:1 to 10:1 , preferably with a Mg/Al ratio in the range of from 0.5:1 to 8:1 , more preferably with a Mg/Al ratio in the range of from 0.5: 1 to 5:1 , most preferably with a Mg/Al ratio in the range of from 1 : 1 to 4:1 and C0₃ ² , NO₃ , OH as exchangeable anions.

14. A process for the manufacture of a mixed metal oxide derived by activation of a hydrotalcite-like compound comprising the following steps:

(a) Co-precipitation of the corresponding water-soluble metal salts in the

desired metal ratios, in a magnetically stirred solution of Na₂C03 at a temperature in the range of from 15 to 30° C while maintaining a constant pH (> 10);

(b) stirring the suspension obtained in step (a) at a temperature in the range of from 25 °C to 100°C to obtain a solid;

(c) Filtering and washing the solid produced in step (b);

(d) Drying the solid obtained after having performed step (c);

15. The process according to claim 14, where the metal salts of step (a) are magnesium and aluminum nitrates, and/or the calcination temperature of step (e) is in the range of from 300°C to 650°C, preferably in the range of from 600 (327°C) to 1000 K (627° C)

16. The mixed metal oxide derived by activation of a hydrotalcite-like compound as obtained according to the process according to any one or more of claims 14 to 15.

17. Use of a hydrotalcite-like compound or a mixed metal oxide derived by activation thereof, preferably according to claim 13 or claim 16, as catalyst for the acylation of primary hydroxy groups, preferably for the acylation of primary hydroxy groups in compounds that may optionally further comprise at least one secondary hydroxy group and/or one tertiary hydroxy group.