JPH0226609B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula () The present invention relates to a method for producing a substituted alcohol shown in the following. The substituted alcohol represented by the above formula () is known as tetrahydrolavandilol and is used as a fragrance. The inventors of the present invention have conducted intensive studies on the method for producing the substituted alcohol, and have found a method for producing the substituted alcohol using lower alkyl ester of chrysanthemum acid as a raw material, which is extremely advantageous from an industrial perspective. The invention was completed. That is, in the present invention, a lower alkyl ester of primary chrysanthemum acid is treated with a sulfonic acid or sulfuric acid to obtain the general formula () [In the formula, R ₁ is the general formula

[expression] or

Represents a group represented by the formula (where R' represents a lower alkyl group). ] to a substituted dienecarboxylic acid ester represented by the formula, and then reduce the lower alkoxycarbonyl group of the compound to form the general formula (). [In the formula, R ₂ is the formula

[expression] or

Represents a group represented by [Formula]. ] Obtain a substituted diene alcohol represented by the formula and further hydrogenate it, or hydrogenate a substituted diene carboxylic acid ester represented by the general formula () to obtain the general formula () [In the formula, R' has the same meaning as above. ] Provides a method for producing a substituted alcohol represented by the above formula () by obtaining a substituted carboxylic acid ester represented by the following and then reducing the lower alkoxyl carbonyl of the compound. Next, the method of the present invention will be sequentially explained. First, a process for producing a substituted dienecarboxylic acid ester represented by the general formula () from a lower alkyl ester of chrysanthemum acid will be described. Conventionally, the following methods are known as related to methods for producing substituted diene carboxylic acid esters represented by the general formula (). For example, the primary chrysanthemum acid ethyl ester is heated to high temperature (500℃).
A method for obtaining substituted diene carboxylic acid ethyl ester by heating has been reported (Tetraahedron Letters, 3795 (1965)).
The configuration of the double bond at the 3,4-position is said to be E type. However, according to the studies of the present inventors, the product obtained by this method is of Z type,
It is not a substituted diene carboxylic acid ester with an E-configuration as the object of the present invention. Also, trans-2,2-dimethyl-3-(1
Method for obtaining alkyl esters of substituted dienecarboxylic acids by dehydrating and ring-opening alkyl esters of cyclopropane-1-carboxylic acids (Japanese Patent Publication No. 41-19056
No. Publication, Agr.Bio.Chem., 28 , 456 (1976),
Tetrahedron Letters, 2441 (1976)), but in this case, the raw material must be synthesized from trans-caronic acid or isobutyric acid chloride through a complicated multi-step process, and it is difficult to implement it industrially. This is not a satisfactory method. Furthermore, although the method differs from the method of the present invention in that carboxylic acid is used as a raw material, it has been reported that dienecarboxylic acid is obtained by heating trans-synthetic chrysanthemum acid together with pyridine hydrochloride to 210°C (J .
Chem. Soc. PerkinTrans. That is simply not possible. Under these circumstances, the present inventors have conducted intensive studies on the method for producing substituted dienecarboxylic acid esters represented by the above general formula (), and as a result, the lower alkyl esters of Daiichichrysanthemum acid have been converted into sulfonic acids or sulfuric acids. By treating with , cleavage occurs selectively between the 2 and 3-positions of the three-membered ring, resulting in a substituted diene carbon having the double bond at the 3,4-positions shown in the general formula () having an E-type configuration. It has been found that acid esters can be obtained in good yield. In carrying out this step, the raw material lower alkyl ester of chrysanthemum acid may be either the trans form, the cis form, or a mixture thereof. Also,
As the sulfonic acids, aryl or alkyl sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and methanesulfonic acid are used. The amount of sulfonic acids, sulfuric acid, etc. used is usually in the range of 1/100 to 1 mole, preferably 1/10 to 1/12 mole, per mole of primary chrysanthemum acid ester as the raw material. Although a solvent is not essential in the method of the present invention,
In order to make the reaction proceed more smoothly, it is preferable to use a solvent that does not essentially inhibit this reaction.
Examples of such solvents include halogenated hydrocarbons such as chloroform and dichloroethane, aromatic hydrocarbons such as benzene and toluene, saturated hydrocarbons such as hexane and heptane, and mixed solvents thereof. The reaction temperature is usually in the range of 30°C to 150°C or the boiling point of the solvent used, preferably in the range of 70°C to 150°C. Although the reaction time varies depending on the reaction conditions, the objective is sufficiently achieved within 10 minutes to 50 hours, and the progress of the reaction can be confirmed by gas chromatography or thin layer chromatography. Although the reaction can be carried out either under reduced pressure or under increased pressure, the purpose can be easily achieved even under normal pressure. In addition, when carrying out the present invention, it can be carried out in either a batch format or a continuous format. It is possible to adopt either a system in which the power is input continuously or intermittently. From the reaction solution that has completed the reaction as described above,
After the sulfonic acids or sulfuric acid used are removed by extraction, filtration, washing, etc., the reaction solution is concentrated to obtain the desired substituted diene carboxylic acid ester. This product can be further purified by means such as distillation and chromatography, if necessary. Next, a process for producing a substituted alcohol represented by the formula () from a diene carboxylic acid ester represented by the general formula () will be described. In this step, the order of reduction of the lower alkoxycarbonyl group of the substituted diene carboxylic acid ester and hydrogenation to the double bond is not limited at all, and the method is to reduce the lower alkoxycarbonyl group and then add hydrogen. Alternatively, after hydrogenation, the lower alkoxycarbonyl group may be reduced. When reducing the lower alkoxycarbonyl group of the substituted diene carboxylic acid ester represented by the general formula () and the substituted carboxylic acid ester represented by the general formula (), examples of the reducing agent include aluminum hydride compounds, borohydride compounds, etc. be able to. Specific examples of aluminum hydride compounds include:
Examples include lithium aluminum hydride, lithium ethoxy aluminum hydride, sodium aluminum hydride, sodium bis(2-methoxyethoxy) aluminum hydride, and alane. Examples of the boron hydride compound include lithium borohydride, lithium triethylborohydride, and lithium tri-sec-butylborohydride. Further, at this time, it is preferable to carry out the reaction in an inert solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, diglyme, etc. Depending on the purpose, these may be used in combination with an aromatic hydrocarbon such as benzene or toluene. The reaction temperature is not particularly limited, and is −78
It can be carried out arbitrarily within the range from °C to the boiling point of the solvent. After performing the reduction reaction in this way, the reaction solution is treated with a mineral acid such as dilute hydrochloric acid or an alkaline aqueous solution such as sodium hydroxide, and then extracted with an organic solvent to obtain the desired general formula (). A substituted diene alcohol and a substituted alcohol represented by the formula () can be obtained. Catalysts used for hydrogenation to the double bond of the substituted diene carboxylic acid ester represented by the general formula () and the substituted diene alcohol represented by the general formula () include nickel, palladium, platinum, or oxides thereof; Alternatively, there may be mentioned a catalyst in which these are supported on a suitable carrier, and activated carbon, alumina, etc. are used as the carrier. At this time, the hydrogen pressure is usually from atmospheric pressure to 100 atmospheres, and the solvent is not particularly limited as long as it does not participate in the reaction, and lower alcohols such as methanol and ethanol are preferably used. The reaction temperature can be set arbitrarily within the range of usually 0° C. to the boiling point of the solvent used. After performing catalytic reduction in this manner, the catalyst is removed by filtration or the like, and the reaction solution is concentrated to obtain a substituted carboxylic acid ester represented by the general formula () and a substituted alcohol represented by the formula (), respectively. It will be done. The products obtained as described above have high purity as they are, but if necessary, they can be further purified by means such as distillation or chromatography. The present invention will be explained in more detail with reference to Examples below. Example 1 400 ml of toluene was added to 20.0 g of 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-1-carboxylic acid ethyl ester (cis/trans = 35/65), and para 5.0 g of toluenesulfonic acid was added and reacted at 110°C for 6 hours. The reaction solution was washed with water and concentrated to obtain 15.2 g of a residue. This was then distilled (b.p50-75°C/1.5mmHg) to obtain 12.8g of pale yellow oil as distillate. According to its gas chromatograph, this product consists of two main components, the ratio of which is 49.4% for compound (1) and 50.6% for compound (2).
It was %. Next, 10 g of this distillate was distilled (theoretical plate number: 80
stage, reflux ratio: 50/1), boiling point 98-100℃/11mmHg
fraction 4.0g (content of compound (1): 95.5%) and boiling point 71
~73℃/1.2mmHg fraction 4.1g (Content of compound (2):
95.6%) were obtained separately. These compounds were determined from the following spectral data as compound (1): (E)-5-methyl-2-(1-methyl-ethenyl)-3-ethylhexenoate compound (2): (E)-5-methyl- It was confirmed to be ethyl 2-(1-methyl-ethylidene)-3-hexenoate. Infrared absorption spectrum (NaCl, liquid film method)
cm ^-1 1740, 1650, 900 NMR spectrum (CDCl ₃ , TMS, 200MHz) δ (ppm) 5.54 (H-3, H-4, m) 4.87 (H-9a, s, s) 4.15 (H-10, q, J ₁₀ , ₁₁ = 6.8Hz 3.60 (H-2, d, J ₂ , ₃ = 6.8Hz) 2.36 (H-5, m) 1.76 (H-8, s) 1.26 (H-11, t, J ₁₀ , ₁₁ = 6.8Hz) 1.00 (H-6, d, J ₅ , ₆ = 6.8Hz) The configurations of H-3 and H- ₄ are determined by the 60MHz NMR spectrum (J ₃ , ₄ = 15Hz), it was found to be type E. Infrared absorption spectrum (NaCl, liquid film method)
cm ^-1 1735, 1650, 2630, 970 NMR spectrum (CDCl ₃ , TMS, 60MHz) δppm6,2 (H-3, d, J ₃ , ₄ = 17Hz) 5.45 (H-4, dd, J ₃ , ₄ = 17Hz, J ₄ , ₅ = 7Hz) 4.25 (H-10, q, J ₁₀ , ₁₁ = 7Hz) 2.2 (H-5, m) 1.8 (H-8, H-9, s) 1.3 (H-11, t, J ₁₀ , ₁₁ = 7 Hz) 0.95 (H-6, d, J ₅ , ₆ = 6 Hz) Since the configuration of H-3 and H-4 is J ₃ , ₄ = 17 Hz, it is E type. There was found. Example 2 Under a nitrogen gas atmosphere, 2.61 g of lithium aluminum hydride was added to 100 ml of dry ether, and while stirring at -20°C, (E)-5-methyl-2-(1-methyl-ethenyl)-3-hexene was added. acid ethyl ester
A solution of 17.9 g dissolved in 100 ml of dry ether was gradually added dropwise. After the dropwise addition was completed, the mixture was stirred at -20°C for 1 hour, and then the reaction mixture was gradually added to ice water under a nitrogen atmosphere to deactivate the lithium aluminum hydride, and the mixture was made acidic with dilute hydrochloric acid. After separating the ether layer, the aqueous layer is extracted with ether, and the ether layers are combined and concentrated.
14.4 g of pale yellow oil was obtained. This was then distilled to obtain 12.9 g of a fraction with a boiling point of 75-77°/6 mmHg as an oil. From the spectrum data below, the distillate is (E)
-5-methyl-2-(1-methyl-ethenyl)-
It was confirmed that it was 3-hexen-1-ol. Infrared absorption spectrum (NaCl, liquid film) cm
^-1 3360, 3080, 1640, 980, 900 NMR spectrum (CCl ₄ , TMS, 200MHz) δ (ppm) 5.54 (H-3, dd, J ₃ , ₄ = 15.1 Hz, J ₂ , ₃ = 6.3 Hz) 5.26 (H-4, dd, J ₃ , ₄ D=15.1 Hz, J ₄ , ₅ = 8.3 Hz) 4.87 (H-8s, s) 4.78 (H-8a, s) 3.58 (H-1, m) 2.83 ( H-2, m) 2.28 (H-5, m) 1.77 (H-10, s) 1.72 (H-9, s) 0.99 (H-6, d, J ₅ , ₆ = 6.8Hz) H-3, The steric configuration of H-4 was found to be E type because J ₃ , ₄ = 15.1 Hz. Example 3 6.61 g of lithium aluminum hydride was suspended in 200 ml of dry ether under a nitrogen gas atmosphere, and a mixed solution of 8.02 g of dry ethanol and 50 ml of dry ether was gradually added dropwise at 0°C. After dropping, 0℃
After stirring for 1 hour, the solution was cooled to -20°C, and 24.9 g of (E)-5-methyl-2-(1-methyl-ethylidene)-3-hexenoic acid ethyl ester was dissolved in 75 ml of dry ether. The liquid was gradually added dropwise.
After the completion of the dropwise addition and stirring at -20°C for 7 hours, Example 2
The organic layer was separated and the aqueous layer was extracted with ether. The organic layers were combined and concentrated to obtain 17.5 g of pale yellow oil as a residue. This is distilled and the boiling point is 72℃/2mm.
12.9 g of a fraction of Hg ~73°C/1 mmHg was obtained as an oil. This one is based on the spectrum data below.
It was confirmed that it was (E)-5-methyl-2-(1-methyl-ethylidene)-3-hexen-1-ol. Infrared absorption spectrum (NaCl, liquid film) cm
^-1 3450, 1382, 1160, 1020 NMR spectrum (CCl ₄ , TMS, 60MHz) δ (ppm) 6.23 (H-3, d, J ₃ , ₄ = 16Hz) 5.65 (H-4, dd, J ₃ , ₄ = 16Hz, J ₄ , ₅ = 6.5Hz) 4.17 (H-1, s) 2.57 (H-9, s) 2.3 (H-5, m) 1.83 (H-8, s) 1.80 (H-8, s) ) 1.0 (H-6, d, J ₅ , ₆ = 7 Hz) Example 4 1.5 g of 5% palladium-carbon was suspended in 100 ml of dry ethanol at room temperature under a nitrogen gas atmosphere. Next, (E)-5-methyl-2-(1-methyl-
ethenyl)-3-hexenoic acid ethyl ester
20.0 g was added, and the system was vigorously stirred at room temperature for 7 hours while maintaining a hydrogen atmosphere. The reaction was stopped when about 5.2 liters of hydrogen gas was absorbed, the catalyst was removed, and the mixture was concentrated to obtain 17.5 g of a pale yellow oil. This was then distilled to obtain 16.3 g of a fraction with a boiling point of 69-71°C/5 mmHg as an oil. This product was confirmed to be 2-isopropyl-5-methyl-hexanoic acid ethyl ester from the spectrum data below. NMR spectrum (CCl ₄ , TMS, 60MHz) δ (ppm) 4.05 (H-9, q, J ₉ , ₁₀ = 7 Hz) 2.1 to 0.7 (H-2, 3, 4, 5, 7, m) 1.25 (H -10, t, J ₉ , ₁₀ = 7Hz 0.85 (H-6, H-8, d, J ₅ , ₆ = J ₇ , ₈ = 5.5
Hz) The ester was then reduced as in Example 2 using 1.95 g of lithium aluminum hydride and 210 ml of dry ether to give 13.1 g of a pale yellow oil. This was then distilled to a boiling point of 72-73℃/4mm.
A fraction of 10.5 g of Hg was obtained as an oil. This substance is 2-isopropyl-
It was confirmed that it was 5-methyl-hexan-1-ol. Infrared absorption spectrum (NaCl, liquid film) cm
^-1 3330, 1460, 1380, 1365, 1050 NMR spectrum (CCl ₄ , TMS, 60MHz) δ (ppm) 3.43 (H-1, d) 3.07 (H-9, br) 2.1-0.6 (H-2, 3 , 4, 5, 7, m) 0.87 (H-6, 8, d, J ₅ , ₆ = J ₇ , ₈ H = 6 Hz) Example 5 5% palladium-carbon at room temperature under nitrogen atmosphere
0.2 g was suspended in 15 ml of dry ethanol. Next, 2.0 g of (E)-5-methyl-2-(1-methyl-ethenyl)-3-hexen-1-ol was added to this.
was added, and the system was vigorously stirred at room temperature while maintaining a hydrogen atmosphere. The reaction was stopped when 650 ml of hydrogen gas was absorbed, the catalyst was removed, and the mixture was concentrated to obtain 1.8 g of a pale yellow oil. This was then distilled to obtain 1.5 g of a fraction with a boiling point of 71-73°C/4 mmHg. The infrared absorption spectrum and NMR spectrum of this product matched those of 2-isopropyl-5-methyl-hexan-1-ol obtained in Example 4. Example 6 In Example 5, (E)-5-methyl-2-(1-
Example 5 except that 2.0 g of (E)-5-methyl-2-(1-methyl-ethylidene)-3-hexen-1-ol was used instead of methyl-ethenyl)-3-hexen-1-ol. Catalytic reduction was carried out in the same manner as above. The reaction was stopped when 650 ml of hydrogen was absorbed, and the same procedure as above was carried out to obtain 1.63 g of a pale yellow oil as a concentrated residue. Furthermore, this is distilled,
1.4 g of a fraction with a boiling point of 70-73°C/4 mmHg was obtained. The infrared absorption spectrum and NMR spectrum of this product matched those of 2-isopropyl-5-methyl-hexan-1-ol obtained in Example 4 above. Example 7 2.5 g of 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-1-carboxylic acid ethyl ester (cis/trans=99/1)
Add 47.5g of 1.2-dichloroethane and add concentrated sulfuric acid to this.
0.31g was added and reacted at 70°C for 1 hour. The reaction solution was washed with water and concentrated to obtain 2.3 g of a residue. This is then distilled (bp50-75℃/1.5mmHg) to obtain the distillate.
1.9g of pale yellow oil was obtained. The gas chromatograph showed that this product contained 52.2% of the compound (1).
(2) The composition was 22.3% and the raw material was 15.7%. Example 8 Add 47.5 g of 1,2-dichloroethane to 2.5 g of 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-1-carboxylic acid ethyl ester (cis/trans=99/1) Add 0.19g of trifluoromethanesulfonic acid to this, and heat at 21°C.
It reacted for 26 hours. The reaction solution was washed with water, concentrated, and the residue
Obtained 2.4g. This was then distilled (bp52-75℃/
1.5 mmHg), and 2.2 g of pale yellow oil was obtained as a distillate. The gas chromatograph shows that the compound (1) is 58.5%, the compound (2) is 18.9%, and the raw material is 21.9%.
It was %. Example 9 (1R)-2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-1-carboxylic acid ethyl ester (cis/trans=19/8
1) 190.0 g of dichloroethane was added to 10.0 g, 1.8 g of methanesulfonic acid was added thereto, and the mixture was reacted at 70°C for 2 hours. After washing the reaction solution with water, it was concentrated and distilled under reduced pressure to obtain 9.12 g of a distillate with a boiling point of 52 to 74°C/1.5 mmHg. The gas chromatograph revealed that the composition was 40.2% of the compound (1), 39.0% of the compound (2), and raw materials (cis form; 0.5%, trans form 14.8%). Then, 8.95 g of this distillate was rectified to a boiling point of 99-101
Compounds that are optically active as a fraction of °C/16 mmHg (1)
Obtained 2.9g. This is ethyl l-(E)-5-methyl-2-(1-methylethenyl)-3-hexenoate, which has an optical rotation α of ^20.5 _D -18.04° (neat) and a chemical purity of 97.5% as determined by gas chromatography. The compound (1) was found to be optically active. Example 10 A flask purged with nitrogen gas was charged with 0.06 g of platinum oxide and 3 ml of ethanol. After replacing the mixture with hydrogen gas, the mixture was vigorously stirred at room temperature under the same atmosphere. After 30 minutes, a solution prepared by dissolving 0.5 g of the optically active compound (1) obtained in Example 9 in 2 ml of ethanol was added dropwise to the same flask, and the mixture was vigorously stirred at room temperature until absorption of hydrogen gas stopped. After the reaction, the catalyst was removed, concentrated under reduced pressure, and distilled using a Kugelrohr to reduce the boiling point to 65.
0.44g of distillate was obtained at ~75°C/5mmHg. This is ethyl d-2-isopropyl-5-methyl-hexanoate with a light intensity α ²¹ _D +9.27° (neat).
The NMR spectrum was consistent with that of Example 4. A part of this was hydrolyzed to the corresponding carboxylic acid, and the following optically active alcohol and diastereomeric ester were synthesized.The optical isomer ratio of the carboxylic acid was analyzed by gas chromatography, and the results were as follows. .

[Table] Example 11 Add 0.2 g of lithium aluminum hydride and 3 ml of dried ethyl ether to a flask purged with nitrogen gas, cool to -30°C and stir, and then add d-2-isopropyl-5 obtained in Example 10. - A solution of 0.42 g of ethyl methylhexanoate and 2 ml of dry ethyl ether was added dropwise. After stirring at -30 to 10°C for 3 hours, ethyl acetate was added to inactivate the mixture, and the mixture was poured into ice water. The reaction solution was washed with dilute hydrochloric acid, dilute alkali, and water, and then dried by adding sodium sulfate. After concentration, distill using a Kugelrohr and boil at a boiling point of 130-135℃/20mmHg.
0.32g of distillate was obtained. The optical rotation of this product was α ²⁰ _D +12.89° (neat), and it was confirmed from the spectrum data shown below that it was d-tetrahydrolavandilol. NMR spectrum C ¹³ (22.5MHz, CDCl ₃ ) δ (ppm); 63.8 (t, C-1) 47.0 (d, C-2) 37.2 (t, C-3 or 4) 28.5 (d, C-8) 28.0 (d, C-5) 25.5 (t, C-4 or 3) 22.8 (q, C-6 or 7 or 9 or 10) 22.5 (q, 〃) 19.8 (q, 〃) 19.3 (q, 〃) H ¹ (90MHz, CDCl ₃ ) δ (ppm); 3.55 (bm, H-1) Around 1.7 (bm, H-5, H-8, H-2) 1.62 (bs, OH) 1.25 (bm, H- 3, H-4) 0.89 (d, H-6, 7, 9, 10)

Claims (1)

[Scope of Claims] 1. A lower alkyl ester of primary chrysanthemum acid is treated with sulfonic acids or sulfuric acid to obtain the general formula [In the formula, R ₁ represents a group represented by the general formula [Formula] or [Formula] (where R' represents a lower alkyl group). ] A formula characterized by leading to a substituted diene carboxylic acid ester represented by the formula, followed by reduction of the lower alkoxycarbonyl group of the compound and hydrogenation of the double bond. A method for producing a substituted alcohol shown in