JPS593452B2 - Method for producing sterically regulated nerolidol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing sterically restricted nerolidol.

Sterically regulated nerolidol itself has a weak but pleasant floral aroma, and is used as a high-grade fragrance in the preparation of flower essential oils such as diasmine and violet. -Trimethyl-
It is also very important as a synthetic intermediate for 2,6,10-dodecatrienoic acid ester and falnesyl acetate, which has antiulcer activity.

Nerolidol is industrially produced as an intermediate for producing isophytol, which is a raw material for the synthesis of vitamin E, and its typical synthesis route is as follows.

That is, after reacting linalool with an equimolar amount of diketene or ethyl acetoacetate, it is heated and decarboxylated to cause a Carrol rearrangement reaction, or it is heated with isopropenyl ether in the presence of an acidic catalyst such as P-toluenesulfonic acid. Geranylacetone is produced by carrying out a Claisen rearrangement reaction, and nerolidol can be obtained in high yield by reacting this with a vinyl Grignard reagent or by subjecting it to an ethynylation reaction followed by a partial hydrogenation reaction.

However, the nerolidol obtained by this method is a mixture with a cis:trans ratio of approximately 4:6. On the other hand, Δ2-cis 3,7-dimethyl-2,6-octadien-1-ol or Δ2-trans-3,7 as a starting material.
- Using dimethyl-2,6-octadien-1-ol, halogenation is carried out while maintaining its steric structure with, for example, phosphorus tribromide, followed by condensation with ethyl acetoacetate in the presence of an alkali, and further hydrolysis and decarboxylation. It is known that sterically regulated nerolidol can be obtained by reacting this with a vinyl Grignard reagent or by performing an ethynylation reaction followed by partial hydrogenation. However, this method requires a long reaction process and requires complicated operations to maintain the steric structure, so when producing in large quantities industrially,
I can't say it's suitable.

For this reason, a method has also been proposed in which cis or trans geranylacetone is separated from cis and trans mixed geranylacetone and converted to cis or trans nerolidol.

CA. Ofner et al., Helv. Chim. Acta.
, ↓ヱ, 2577-2584, (1959)] o However, in this case, as a separation method for cis and trans mixed geranylacetone, 0. Isler et al. Ch
im. Acta. ．． ydan, 897-904 (1956)
The semicarbazone recrystallization method reported in
Isler et al. Chim. Acta. Low-temperature crystallization methods are known, such as those reported in 1960, Vol. It was difficult to

In addition, separation of cis and trans isomers by distillation is generally performed by R. B. Bates et al. Org. Chem. , 28
, 1086-1089 (1963), it is suitable for separating a mixture of nerol and geraniol, which have 10 carbon atoms.
It has been said that the efficiency of Falnesol and the like of No. 5 is very low.

However, according to the present invention, surprisingly, cis-trans mixed geranylacetone can be efficiently separated into the cis-isomer and trans-isomer by precision distillation.

We also found that cis-momi-trans isomerization of geranylacetone can be easily carried out using an appropriate catalyst. The method of the present invention has been perfected based on these findings, and involves precision distillation of Δ5-cis, trans mixed geranylacetone represented by the formula to obtain cis-geranylacetone or trans-geranylacetone, and By (1) reacting trans-geranylacetone with acetylene to ethynylate it and then partially hydrogenating it, or (2) reacting it with a vinyl Grignard reagent, it is sterically restricted to △6-cis or trans represented by the formula. This is a method for producing nerolidol.

According to this method, sterically restricted nerolidol can be produced with simpler operations and at lower cost than conventional methods. When obtaining cis-geranylacetone or trans-geranylacetone by the above-mentioned precision distillation, if desired, the remaining components (i.e. trans-geranylacetone to obtain cis-geranylacetone, conversely, cis-geranyl to obtain trans-geranylacetone) A mixture mainly consisting of acetone) is heated in the presence of an isomerization catalyst to isomerize trans-geranylacetone to cis-geranylacetone, or cis-geranylacetone to trans-geranylacetone, and then subjected to precision distillation again to produce additional Cis-geranylacetone or trans-geranylacetone can be obtained. It is also possible to separate cis- and trans-mixed nerolidol by precision distillation, but since it has a higher boiling point than geranyl acetone, it is difficult to maintain thermal stability during distillation, distillation separation efficiency, etc. Therefore, it is not very desirable. According to the method of the present invention, it is possible to produce the desired cis-isomer or trans-isomer almost quantitatively with simple operations, regardless of the ratio of the cis-isomer and trans-isomer in the raw materials.

Note that when producing cis-geranylacetone, the cis-form has a lower boiling point than the trans-form, so it is not necessarily necessary to use a batch method; instead, the reaction is carried out in the presence of an isomerization catalyst and the cis-form is produced at the same time. A continuous method of taking out the liquid may be adopted.

The number of theoretical plates in the distillation column used in carrying out the present invention is, of course, that separation is possible in principle even if a distillation column with a low number of theoretical plates is used. If you try to obtain it by one distillation, you will need at least 10 actual plates.

Since geranylacetone used in the separation of the present invention has a high boiling point, vacuum distillation must be employed for distillation. A distillation column with a high number of theoretical plates is preferable in order to obtain the target product in high yield, but if such a distillation column is used, the pressure loss during distillation will be high. In the case of vacuum distillation, this high pressure drop impairs the stability of the distillation and increases the temperature rise of the bottom liquid.
The temperature cannot be increased indefinitely because it causes disadvantages such as a decrease in the stability of the substance. In this sense, the distillation column used in the present invention is preferably a distillation column having about 10 to 100 actual plates, and preferably 20 to 60 plates in consideration of economic efficiency.
A column having an actual number of plates on the order of 100 plates is preferred. It goes without saying that the structure of the column is preferably such that the pressure loss per stage is small. The reflux ratio varies depending on the tower, but it is between 2 and
100, preferably about 5 to 30.

The distillation of the present invention can be carried out in a batch, continuous or semi-batch manner, and which method is better should be determined depending on economic factors such as production volume. The isomerization reaction is a reversible equilibrium reaction, and the ratio of the cis isomer and the trans isomer at the equilibrium value is determined by the temperature, for example, 170 to 200.
At °C, the ratio of cis to trans is about 4 to 6, and 130 to 14
At 0°C, the ratio is approximately 35:65.

Examples of catalysts used in the isomerization reaction include tungsten catalysts, ruthenium catalysts, and organic sulfur compounds.

Specifically, the tungsten catalyst and the ruthenium catalyst are suitably used in the form of the following various derivatives. halides, sulfide compounds, chalcogenites, chalcohalides, nitrosochlorides and nitrosyl halides,
Salts of inorganic oxoacids such as sulfates, nitrates, carbonates, arsonates, arsenates, germanium salts, perchlorates, sulfites and nitrites: aliphatic, cycloaliphatic or aromatic acids or alcohols or phenols salts, such as acetic acid,
Salts of propionic acid, oxalic acid, naphthenic acid, sulfonic acid, etc.

Chelates such as acetylacetonate, benzoylacetonate, glyoxymate, quinolate, salicylaldehydate, etc. as complex catalysts.

Compounds coordinated with carbon monoxide, monoolefins, diolefins, and polyolefins, and cyclopentadienyl groups. Further, there is no problem even if nitrogen compounds, phosphine compounds, arsine, stipine nitrile, etc. are coordinated. Of course, these compounds can also be insolubilized by forming a carbon-phosphorus bond and coordinating with a nitrogen-containing polymer compound such as polyvinylpyridine or a polystyrene compound to facilitate the catalyst recovery process.

Naturally, it can also be supported on activated alumina, silica, pumice, Fura's earth, diatomaceous earth, and the like. Among tungsten and ruthenium catalysts, those showing particularly high activity and selectivity are tungsten disulfide, ruthenium acetylacetonate, ruthenium glyoximate,
These include complex catalysts such as ruthenium salicylaldehydate and salts such as ruthenium salicylate and ruthenium propionate.

Organic sulfur compounds that can be used as isomerization catalysts include:
For example, phenyl disulfide, alkyl disulfide,
Examples include phenylmercaptan, thiocresol, alkylmercaptan, thiocarboxylic acid, and the like.

Although it is possible to carry out the reaction under an air atmosphere, it is preferable to carry out the reaction under an inert gas atmosphere in order to improve selectivity.

The reaction temperature can range from 50 to 300°C, but preferably from 120 to 210°C.

The amount of catalyst should be determined depending on conditions such as the type of catalyst used, reaction temperature, economic efficiency, and reaction selectivity.
Although it cannot be generalized, it is 0.00 for geranylacetone.
1 to 20% by weight, and 120% by weight using organic sulfur compounds.
When carried out at ~160°C, it is preferably 0.1 to 10% by weight. When using an organic sulfur compound as a catalyst, a radical initiator [
For example, azobisisobutyronitrile (AIBN), benzoyl peroxide (BPO)] to the organic sulfur compound.
．． Although it is possible to perform radical isomerization by adding 01 to 20% by weight, it is also possible to perform isomerization using the organic sulfur compound alone.

Although it is not necessary to use a reaction solvent, a substance that is stable under the reaction conditions and does not participate in the reaction, such as a hydrocarbon such as squalane, may be used as the reaction solvent.

The reaction is not necessarily continued until an equilibrium composition is obtained, and may be terminated midway.

Furthermore, when the target product is a cis-form, it is possible to shift the equilibrium toward the production system by carrying out distillation while performing the isomerization reaction, thereby obtaining the target product almost quantitatively. If the catalyst is not separated after the reaction, there is a risk that a reverse isomerization reaction will occur, for example, when performing precision distillation and heating for a long time in order to separate the trans isomer in the next step.

Therefore, the reaction solution was subjected to simple distillation as a catalyst separation step.
Preferably, the distillate is subjected to precision distillation and the residue containing the catalyst is reused in the isomerization reaction. Of course, it is also possible to deactivate the catalyst chemically, to perform physical adsorption, to perform separation by steam distillation, or in the case of a low-boiling organic sulfur catalyst, to perform distillation separation. Next, a detailed description will be given with reference to examples. Example 1 Linalool 60167 (95% purity) and diketene 34
After reacting 44y in the presence of triethylamine 163y, aluminum isopropoxide 240y is added and heated to carry out Carroll rearrangement reaction.

By vacuum distilling the reaction solution, Bp68-74℃ (0
．． Cis/trans=4/6 mixed geranyl acetone 52007 was obtained from the fraction (4 mmHg). When this material is distilled and separated using precision distillation with approximately 40 theoretical plates at a reflux ratio of 10, cis-geranylacetone is obtained with a Bp of 74 to 7.
From the fraction at 6℃ (0.42m77!Hg), 8307 (distillation yield 40% based on the cis monomer in the raw material) and trans-geranylacetone were obtained with a Bp of 77-79℃ (0.4m
2420y (distillation yield 78% based on the total transformer in the raw material) was obtained from the fraction of T1LHg). Furthermore, mixed geranylacetone 19207 with cis/trans ratio of 66/34 was obtained as a middle distillate. The refractive index of cisgeranylacetone is N3O-1.4628D, and its nuclear magnetic resonance spectrum is shown in FIG.

The refractive index of transgeranylacetone is N3OD - 1.4
634, and its nuclear magnetic resonance spectrum is shown in FIG.

Next, 11 liquid ammonia was placed in a 21-tri-neck flask, 55.2 y of sodium metal was added thereto, and then acetylene gas was passed through the flask.

When the reaction solution changed from purple to white, the injection of acetylene gas was stopped and cis-geranylacetone 38 was added.
Add 8y. Next, while refluxing liquid ammonia, acetylene was blown in for 4 hours to stop the reaction. After removing ammonia, 110y of ammonium chloride was added for neutralization, and the reaction solution was poured into water and extracted with ether. After washing the oil layer with water, it is dried with boronic acid, and the solvent is distilled off, followed by vacuum distillation. Cis-dehydronerollidol 3727 was obtained in a yield of 85% from the Bpl 33-135°C (5mmHg) fraction.
The refractive index of this material is N37=1.4750, and its nuclear magnetic resonance D spectrum is as shown in FIG.

Next, 0.15 ml of quinoline and 5.07 ml of 0.25% Pd-Lindra catalyst were added to a solution of cis-dehydronerolidol 3207 in 1000 ml of n-hexane, and a hydrogenation reaction was carried out at room temperature and pressure. The reaction progress is PEG
-20M (5%) was analyzed using a gas chromatograph (column temperature: 150°C). The reaction is terminated when the raw material cis-dehydronerollidol disappears, and the reaction solution is passed through a glass filter. After removing the solvent from the oral fluid, the remaining liquid was distilled under high vacuum, resulting in a Bp of 99-102°C (0.
31! Cisune lolidol 3147 was obtained from the fraction of TTlLHg). The refractive index of this material is N3OODl. 4
753, and its nuclear magnetic resonance spectrum is as shown in FIG.

Similarly, transgeranylacetone 1360y was subjected to an ethynylation reaction in the presence of metallic sodium 176y,
After post-treatment, vacuum distillation is carried out at Bpll2℃ (0.5m
transdehydronerollidol 12 from the fraction of mHg)
807 was obtained in a yield of 83%.

The refractive index of this material was n-1.4771, and its nuclear magnetic resonance spectrum is shown in FIG. Next, trans-dehydronerollidol 10007 n-hexane 200
0.5 ml of quinoline and 0.25% Pd in 0 ml solution
- Add Lindlar catalyst 157 and hydrogenate at normal temperature and normal pressure.

After post-treatment, high vacuum distillation yields BplO7~1
Trans-nerolidol 9807 was obtained from the 10°C (0.5m71LHg) fraction. The refractive index of this material is N3O
-1.4754, and its nuclear magnetic resonance spectrum is shown in FIG.

Example 2 Helv-Chim-Acta, by A. Ofner et al.
↓g, 2577-2584 (1959) to obtain cis- or trans-nerolidol from cis- or trans-geranylacetone, respectively.

That is, 12.5 ml of freshly prepared metal magnesium powder was placed in 420 ml of tetrahydrofuran, and 60 y.
of vinyl bromide is added dropwise under water cooling to form a Grignard reagent, and further cis-geranylacetone or trans-geranylacetone 507 is added dropwise at 25°C. The reaction solution was neutralized with an aqueous ammonium chloride solution and extracted with ether. After drying with boronic acid, the solvent was distilled off under reduced pressure, and the residue was distilled under vacuum to obtain cisnerolidol from cisgeranylacetone in a yield of 82%. The product was confirmed using the standard material obtained by the method of Example 1. ]*Examples 3 to 9 Similar to Example 1, mixed geranyl acetone with a cis to trans ratio of 4 to 6 was precision distilled, and the pre-distillate obtained when the trans form was taken out was distilled in the presence of various isomerization catalysts. Isomerization was carried out by heating to a lower temperature.

Next, the reaction solution was subjected to rough distillation at a tower bottom temperature of 120 to 130°C, and then precision distilled again to obtain the trans isomer. The results are shown in Table 1. In addition, in Examples 4 and 7, the catalyst was distilled out during the crude distillation, but this was separated as a low boiling point during the precision distillation. Trans-geranylacetone thus obtained was subjected to an ethynylation reaction in liquid ammonia in the same manner as in Example 1, and then partially hydrogenated to obtain trans-nerolidol.

Example 10 A flask containing 2.0 y of ruthenium () acetylacetonate added to geranyl acetone 10007 with a cis to trans ratio of about 4 to 6 was installed at the bottom of a precision distillation column with about 40 theoretical plates, and the bottom temperature was lowered. 175-179
℃, tower top temperature 130-135℃, degree of vacuum 5-71! Tm
Vacuum distillation was performed with Hg and reflux ratio of 10, resulting in a distillate of 968
I got y.

Gas chromatography analysis of the distillate revealed that the purity of the cis isomer was 99.4%. The obtained cis-geranylacetone was converted into cis-nerolidol according to the method of Example 2. Example 11 Cis-geranylacetone 5 obtained by the method of Example 10
00t was added with 1.5t of ruthenium acetylacetonate and heated to 190°C under a nitrogen atmosphere.

The reaction solution was analyzed using gas chromatography.
After 2 hours of reaction, the conversion rate of the cis isomer was 32%, and the selectivity of the generated trans isomer was 99%. After a further 5 hours, the conversion rate of the cis isomer was 41%, and the selectivity of the generated trans isomer was 97.4%.

The product was crudely distilled to obtain cis and trans mixed geranyl acetone 4727, and by precision distillation, the cis form 1 was obtained.
047, trans isomer 1287, and middle distillate 2407 were obtained. The obtained transgeranylacetone was used in Example 2.
Transtone lolidol was prepared according to the method of .

[Brief explanation of the drawing]

FIG. 1 is a nuclear magnetic resonance spectrum of cis-geranylacetone in a carbon tetrachloride solution.

Claims (1)

[Claims] 1 Precision distillation of △^5-cis, trans mixed geranyl acetone represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ to obtain cis-geranyl acetone or trans-geranyl acetone; - A formula characterized by reacting geranylacetone or trans-geranylacetone with acetylene, ethynylating it, and then partially hydrogenating it ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Represented by △^6-cis or trans Regulated method of manufacturing nerolidol. 2 Precision distillation of cis and trans mixed geranylacetone in the presence of an isomerization catalyst to isomerize trans-geranylacetone to cis-geranylacetone, extracting cis-geranylacetone, and reacting the obtained cis-geranylacetone with acetylene. 1. A method for producing cis-nerolidol, which comprises ethylating it and then partially hydrogenating it. 3 Formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ △＾5-cis, trans mixed geranyl acetone is precision distilled to obtain cis-geranyl acetone or trans-geranyl acetone, and the cis-geranyl acetone or trans- A method for producing △^6-cis- or trans-stereoregulated nerolidol, which is represented by ▲mathematical formula, chemical formula, table, etc.▼, and is characterized by reacting geranylacetone with a vinyl Grignard reagent. 4 Precision distillation of cis and trans mixed geranylacetone in the presence of an isomerization catalyst to isomerize trans-geranylacetone to cis-geranylacetone, extracting cis-geranylacetone, and converting the obtained cis-geranylacetone to vinyl Grignard reagent. A method for producing cis-nerolidol, which comprises reacting with.