JPS608257A - Production of 4-hydroxy-4-((e)-3-hydroxy-1-butenyl)-3,5,5- trimethyl-2-cyclohexen-1-one - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as an aromatic or perfumery composition, in high yield, by reducing an acetylene derivative with a specific reducing agent, thereby suppressing the elimination of hydroxyl group and reducing the triple bond selectively to the trans-double bond. CONSTITUTION:The objective compound of formula II is produced by reacting the acetylene derivative of formula I [X and Y are lower alkyl; the dotted line means that X and Y form separate groups or together form a covalent bond via a C atom; R is H, lower acyl, (CH3)3Si-, etc.] with a reducing agent of formula MAlHn(OR<4>)4-n (M is alkali metal; R<4> is lower alkyl or oxygen-substituted lower alkyl; n is 1-3) in a solvent such as benzene, dioxane, etc. at -30- +50 deg.C. The amount of the reducing agent is 1-10mol, preferably 1-6mol per 1mol of the compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 4-hydroxy-4-((E)-6-hydroxy-1-butenyl)-5,5,5-)dimethyl-
The present invention relates to a novel method for producing 2-cyclohexen-1-one.

A compound of formula 2, i.e. 4-hydroxy-4-((E
)-5-hydroxy-1-butenyl]-3,5,5-)
Dimethyl-2-cyclohexen-1-one is found in various plants, e.g. Rauwolfiavomitoria
, Croton 5parsiflorus.

It is a trace aroma component found in the essential oil of Podocarpus blumei and the essential oil of tobacco.

Due to its excellent organoleptic and olfactory properties, this compound is used in aroma and flavor compositions in food, beverages and tobacco products. Also various flavoring substances, e.g.
theaspirone.

blumenol B and 8.9-dehydro
It is also useful as an intermediate for synthesizing theaspirone.

Conventionally, as a method for obtaining the compound of formula 2 by reducing the triple bond in the side chain, the method of the following formula has been proposed.

(1) He1v, Chim, Acta, 57
, 2087 (1974) H However, in the conventionally proposed method, L i A IH
The selectivity of 4-reduction is poor, resulting in not only triple bonds but also hydroxyl bonds;
The main product is compound 5, which has been reduced even to 50%. The target compound 2 rather becomes a by-product. In addition, depending on the degree of reduction, some by-products such as compound 6.7 are obtained, which has the disadvantage that their separation becomes extremely complicated.

The present inventors conducted research to overcome the disadvantages or deficiencies of such conventional proposals, and as a result arrived at the present invention. :Y represents a lower alkyl group, the broken line represents that X and Y each form an independent group, or that X and Y are covalently bonded via the carbon of the alkyl group, R is hydrogen, ( CH3) 58i group, lower 2 represents hydrogen or a lower alkyl group, 几3 represents a lower alkyl group, the broken line indicates B, t and R3 each form an independent group, or are covalently bonded via the carbon of the alkyl group. The triple bond in the side chain of the acetylene derivative of
M represents an alkali metal, 4 represents a lower alkyl group or an oxygen-substituted lower alkyl group, and n represents an integer of 1 to 6), and then selectively reduced to a trans double bond.
Removal of the protecting group provides 4-hydroxy-4- of formula 2 in high yield.
((E)-3-hydroxy-1-butenylcy5.5.
The present invention relates to a method for obtaining 5-1-limethyl-2-cyclohexen-1-one.

In the method of the present invention, LiAtH4 is used as a triple bond reducing agent.
The feature is that MAtHn(OR4)4-n is used instead of O.

In general, it is well known that when a propargyl alcohol type compound having a partial structure of -C=C-C-OH is reduced with LiAtH4, a product in which only the triple bond is reduced to a trans double bond can be obtained in good yield. It is a fact. However, the situation changes completely for compounds that have both substructures of a triple bond.

When such a system is reduced with LiAtH4, an arene-type product from which the hydroxyl group has been eliminated, or a product in which further reduction has proceeded, is not the main product, and only OH 2 is obtained. This is clear from the literature example in (1) above.

The present inventors created a compound of general formula 1 with MA7!, which has a partial structure with hydroxyl groups on both sides of the triple bond. )In (OR')
It has been found that reduction with 4-n suppresses the elimination of hydroxyl groups and selectively reduces triple bonds to trans double bonds. According to the method of the present invention, compound 2 can be obtained in a yield of 45% from a compound of general formula 1 in which R is hydrogen and -X・-・Y- is -CH2-CH2-, that is, compound 4. However, in the literature examples using Li At H4 in (1) above, the ratio is only 5% at most.

Furthermore, according to the method of the present invention, in systems in which R is other than hydrogen in general formula 1, the reduction of the triple bond proceeds in a higher yield than when R is hydrogen. This effect of improving the selectivity of reduction of the triple bond by protecting it with one or two of the two hydroxyl groups adjacent to the triple bond is another remarkable feature recognized in the present invention. Such an effect can hardly be expected when LiAtH4 is used as a reducing agent. LiAtH4
In this case, even if the hydroxyl group is protected, elimination takes precedence [eg, J, Chem.

8oc,, Chem+Commun,, 541 (
1969): T, Chem, Soc, Pe
rkin I, 720 (1975): Acta C
hem, 5cand, 26.2540 (1972
), etc.].

The method of the present invention selectively generates a trans double bond by reducing the triple bond of the compound of general formula 1 with MAAHn (OR') 4-n in a solvent. The reduction product can then be derived into Compound 2 by removing the ketone protecting groups -X-, , Y- from the six-membered ring core and the water-protecting group from the side chain. however,
When R is hydrogen, the ketone protecting group -X- of the 6-membered ring mother nucleus
Compound 2 is obtained by removing only Y-.

X and Y of the compound of general formula 1 represent a 1st grade alkyl group,
The broken line indicates whether X and Y each form an independent group or whether X and Y
is covalently bonded through the carbon of the alkyl group. Preferred -X-Y- is -CH, -CH, -1C
In H2CH2CH2tic, both X% and Y are -CH3.

Further, R in the compound of general formula 1 is hydrogen, (CHs)3ki
- group, lower alkyl group, R13 represents a lower alkyl group, and the broken line indicates that R, 1 and R3 each form an independent group or are covalently bonded via the carbon of the alkyl group. (indicates that there is). Here, lower means having 1 to 7 carbon atoms. Preferred examples of the 0-ring alkyl group include formyl, acetyl, propionyl, butyryl, and preferred examples of the R2 CH3 group include -CH, 0CH2C) (3,
etc.

The solvent for the reduction reaction is not particularly limited as long as it does not deactivate the active hydrogen of the reducing agent, but examples include aromatic hydrocarbon solvents such as ztrd, benzene, toluene, and xylene, diethyl ether, dipropyl ether, and diethyl ether. Ether solvents such as butyl ether, tetrahydrofuran, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, dioxane, and any mixtures thereof can be preferably used. Reducing agent MA tHn (
M in OR' ) 4-n is an alkali metal, preferably Li%Na or K. R+4 represents a lower alkali group or an oxygen-substituted 1st class alkali group, and oxygen substitution means that the continuity of the carbon skeleton is interrupted by the presence of an oxygen atom.

Here, lower means having 1 to 7 carbon atoms, and n represents an integer of 1 to 5. Preferred examples of R4 include methyl, ethyl, propyl, butyl, pentyl, 2-methoxyethyl, and 2-ethoxyethyl groups. n is 1 to 5
is an integer.

Preferably n=2. As a specific example of a preferable reducing agent, N aAtHz (0CH2CHaOCH
3) 2, N a A tH2 (OCHa ) 2 ,
NaAlH4(OC2H8) 2, NaAlH4(0-
n-Pr)2, NaAAAH2(o-i-Pr)2, Na
AlH4(0-n-Bu), , NaA/J(2(0-
i-Bu)2, NaAtHz (0-t-Buds, etc.) The amount of the reducing agent used is usually 1 to 10 times the mole of the compound of general formula 1, preferably 1 to 6 times the molar amount.However, the amount is sufficient to supply active hydrogen to groups that consume active hydrogen of the reducing agent, such as free hydroxyl groups and acyl groups contained in the compound of general formula 1, and further reduce the triple bond. It is necessary to use a reducing agent of
0°C, preferably -10 to 20°C.

The thus obtained reduction product is then converted into compound 2 by removing the ketone protecting group -XY- of the 6-membered ring mother nucleus and the hydroxyl protecting group of the side chain by acid hydrolysis. be guided. However, when R is hydrogen, only the ketone protecting group -X·-Y- of the 6-membered ring mother nucleus may be removed by hydrolysis. In addition, when a compound in which R is a lower acyl group in general formula 1 is reduced with MAJJIn (O 几') 4-n, the lower acyl group, which is 几, is reduced and removed at the same time as the triple bond is reduced in the reduction reaction step. Therefore, in the next acidic hydrolysis step, Compound 2 can be obtained by hydrolyzing only the ketone protecting groups -X and -Y- of the ring nucleus.

Hydrolysis is carried out using an inorganic or organic acid. As acids, mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid, and perchloric acid, and organic acids such as formic acid, acetic acid, propionic acid, and oxalic acid are preferably used. The solvent used for hydrolysis is not particularly limited as long as it dissolves the reduction product and the above acid and does not reduce the activity of the acid, but methanol,
Alcohol solvents such as ethanol, propanol, phthanol, ethylene glycol, and propylene glycol; ketone solvents such as acetone and methyl ethyl ketone;
Ether solvents such as diethyl ether, dipropyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, ester solvents such as methyl acetate and ethyl acetate, organic acid solvents such as formic acid and acetic acid, water, or mixed solvents thereof. is preferred. The hydrolysis temperature is -50 to 100°C, preferably -10 to 40°C.

Even if the corresponding intermediate in which the triple bond of the compound of formula 1 is reduced to a trans double bond is purified using a means such as column chromatography and then the protecting group is removed, the crude product remains protected. It may be subjected to a step of removing the group.

The compound of the general formula 9 (wherein, X1Y and the broken line have the same meaning as the In, 几 is R in general formula 1
It can be produced by adding an acetylene derivative (having the same meaning as ) using a Grignard reagent. Alternatively, another method may be used in which a compound of general formula 1 in which R is hydrogen is once synthesized, and then a phosphorus group other than hydrogen is introduced into the secondary hydroxyl group of the side chain. When R is a group that reacts with a Grignard reagent, such as when R is a 1st class acyl group, the latter method is suitable, using a compound of general formula 10 in an amount of 1 to 2 times the mole, and using an ether solvent. Do it inside. Examples of Grignard reagents used include methyl, ethyl, propyl, butyl, vinyl, and allyl Grignard reagents. The halogen part of the Nyar reagent is chlorine, bromine,
Any iodine may be used. Examples of the ether solvent used include diethyl ether, cyphthyl ether, cyphthyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and diethylene glycol dimethyl ether.

Note that the compound of general formula 1 has stereoisomers based on asymmetric carbon atoms, and each isomer can be equally used in the present invention.

Next, the present invention will be specifically explained with reference to Examples.0 Example 1 Tetrahydrofuran (25m6) was mixed with metallic magnesium (
A solution of ethyl bromide (3.25t, 29.6mmo7) in tetrahydrofuran (7rttl) was added dropwise over 65 minutes under ice-cooling. After completion of the dropwise addition, stir for 1 hour. Add 5-butyn-2-olk (1,05
fs 15. Ommot) was added dropwise and then heated at 60℃ for 4 hours.
Heat and stir for 5 minutes. here 4-ethylenedioxy-2
,6,6-drimethyl-2-cyclohexen-1-one 6 (196F, 10, Ommot) and stirred at 60°C for 1 hour. The reaction mixture is added to water and extracted with ethyl acetate. After washing the organic layer with water, the solvent is distilled off.

The residue was purified by silica gel column chromatography (ethyl acetate-hexane 3:1) to obtain compound 1 (⇠=
H, -X ・-Y -= -CHx -CH2)C2
, 21f, 85%). This item is a standard item and IH-N
The MR%I and mass spectra were in perfect agreement.

5.5.5-Trimethyl-2-cyclohexen-1-one? Preparation of the above compound 1 (n+=H, -X-Y, -
OH, -CH, -) (506πc 1.15 mmot
) was dissolved in tetrahydrofuran (7d) and NaAtH2 (0CH2CH20CH3), with stirring at room temperature.
A 70% toluene solution (2.5d) of was added dropwise over 3 minutes. After dropping, react for 1 hour. The reaction mixture is added to water and extracted with ethyl acetate. After washing the organic layer with water, the solvent is distilled off. Acetone (19ie) and IN-hydrochloric acid (6ie) were added to the residue.
, 5d) and stirred at room temperature for 1 hour. Add water to the reaction mixture and extract with ethyl acetate. After washing the organic layer with water, the solvent is distilled off.

The residual liquid was separated by silica gel column chromatography (ethyl acetate) to obtain Compound 2 (111yq, 46%). The IH-NM, IR and mass spectra of this product completely matched those of the standard product.

Example 2 Tetrahydrofuran (25ie) with 4 magnesium gold (
o, 72r, 2θ6 mmol), and ethyl bromide (3.25 g, 29.6 mmol) was added dropwise while cooling with water. Stirring was continued for 2 hours after the dropwise addition was completed.

Butyne alcohol derivative 10 (R=-8i(CHa)s) (445f150
, 9 ns mot). 1 at 40℃ after dropping
Stir for 4 Jt. here 4-ethylenedioxy-2,
Add 6,6-)IJ methyl-2-cyclohexen-1-one 6 (3,92f, 20.Ommot) in one portion and
Stir at 0°C for 1 hour. The reaction mixture is poured into water and extracted with ethyl acetate. After washing the organic layer with water, the solvent was distilled off to give compound 1 [R=-8i(CHs)s, -X-Y-=-C
H2-CH2-) (6,79f, 96%) was obtained.

■几(Liquid film) 3470.1670.1245.1090.840.7
50cm-1') (-NMR(CDCLs)δo, 15 (ss9H), 1.08 (s,
3H), 1.15 (s,!,H), 1.41 (ds
J=6Hz%gH), 1.8-2.1 (m-5H)%
3.92 (A2B2.4)1), 4.54 (Q%
J=6Hzs 2H), 5.35(br, s, IH
) (2) 4-Hydroxy-4-((E)-5-hydroxy Compound 1 (R=-8i (CH3)5 , -X.
−・Y−= −CH2−CH2) (6,79t, 19
．． 5 mmoL) in tetrahydrofuran (62+e)
of NaAlH4 (OCH) while stirring under water cooling.
, CH2OCH3) 2 in 70% toluene solution (21,
8 ml) was added dropwise.

After completing the dropwise addition, the mixture was returned to room temperature and stirred for 1 hour. The reaction mixture is poured into ice water and extracted with ethyl acetate.

The organic layer is washed with water and the solvent is distilled off. ace on the residue) 7
(70m6) and IN-hydrochloric acid (14ml?),
Stir for an hour. The reaction mixture was added to an aqueous solution of hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water;
The solvent is distilled off. The residue was separated by silica gel column chromatography (ethyl acetate) and compound 2 (3,24
4r, yield of 72% from 5) was obtained.

Example 3 Butyne alcohol derivative 10 was prepared in the same manner as in Example 2.
The reaction was carried out using butyne instead of (R=-Si(CHs)s). 4-ethylenedioxy-2
,6,6-)dimethyl-2-cyclohexen-1-one 4-hydroxy-4-((E)
-5-hydroxy-1-butenyl)-! 1,5.5-)
Dimethyl-2-cyclohexen-1-one 2 was obtained. The spectral data of the intermediate generated = -c) (2-cIi, -) is shown below.

L (liquid film) 5460.1550.1205.1095.10201
980s 955.815cm-” ”)(-NMR(CDC63)δ 1.10.1.16.1.14 (6H, CH3X C
H'), 1.69, t42, t46.1.49 (5H
.

Man. ), 1.89 (5H, included.□3), 3 (I H, -= J(H), 4.7-5.0 (1H1
HH Example 4 In the same manner as in Example 2, butyne alcohol derivative io
Butyn H3 alcohol derivative 10 (R=-CHOCH, CH3
) was used to carry out the reaction. 4-ethylenedioxy-
2,6,6-17methyl-2-cyclohexen-1-one 4-hydroxy-4-C(E
)-3-hydroxy-1-butenyl)-5,5,5-)
Dimethyl-2-cyclohexen-1-one 2 was obtained. Compound 1 (R=-CHOCH2CH3, -X, -
Spectral data of Y -= -CI42-CHs) are shown below.

■几(Liquid film) 5450.1670.1205.1090.1025.
950.795crrL-''H-NMR, (CDCAs) δ 1.20,12B, 1.60.1.56.1,40, ■ Examples 5 to 7 In the same manner as in Example 4, NaA7H2 (OC) 12C
During the reduction reaction of triple bonds using a 70% toluene solution of Hz OCHs)2, diethyl ether and 1,2-dimethoxyethane are used as co-solvents in place of tetrahydrofuran, or the reaction is carried out with l-toluene alone to obtain the primary Got the results.

Examples 8 to 9 In the same manner as in Example 4, NaALH2(OCH2CH2
NaAtH2(On Bu)2 instead of 0CH3)2
, L 1AtH2(0-n-Bu)2 and the following results were obtained.

Example 10 Compound 1 (几=H1-X-,,Y-=-CH,-CH2
-) (tl 27 f, 4.24 mmot) was dissolved in viridi:' (5 ml), acetic anhydride (5 resistant) was added, and the mixture was stirred at room temperature for 16 hours. Pyridine and acetic anhydride are distilled off using a vacuum pump, and the remaining liquid is dissolved in ethyl acetate. The ethyl acetate layer is washed with an aqueous sodium bicarbonate solution and then with water, and then the solvent is distilled off. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate 2:1).
) to obtain compound 1 (几=cn3co, -X, -,Y
-=-CH.

CH2) (1,267f, 97%) was obtained.

IR (liquid film) 5480.1740.1670.1370.1250°1090b 1020% 940cm-''H-NMR
(CDCl2)δ I08 (s, 5H), 1.12 (s, 5H), 1, 4
7 (d, J=7Hz, 5H), 1.88-2.0
8 (m, 5H), 2.05 (s, 5H), 2. ! +5(
ss 1H), 3.93 (S, 4H), 5.35 (br
, s, I H), 5.45 (q%J=7H2゜1H
) CH2-C)12) (1,267f, 4.11m
mot) in tetrahydro-7ran (10 ml). N aA7H2 (OCH2CH
,0CH3)2 in toluene (4,07d) is added dropwise.

Thereafter, the mixture was stirred for 50 minutes under water cooling and for 1 hour at room temperature. The reaction mixture is poured into ice water and extracted with ethyl acetate. The organic layer is washed with water and the solvent is distilled off.

Add acetone (15d) and IN-hydrochloric acid (4.4ml) to the remaining residue.
) and stir at room temperature for 1 hour. The reaction mixture is added to an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is washed with water and the solvent is distilled off. The residue was separated by silica gel column chromatography (ethyl acetate) to obtain Compound 2 (495μ, 54% yield from !1).

Patent applicant Higashi Shikikai Co., Ltd.

Claims (6)

[Claims] (1) General formula: R is hydrogen,
(CH3)3Si-2, R1 and R'' are hydrogen or a lower alkyl group, Bs is a lower alkyl group, and the broken line indicates whether R1 and R3 each form an independent group or are shared through the carbon of the alkyl group. The acetylene derivative of
AtHn (OR' ) 4-n (where M represents an alkali metal, R14 represents a lower alkyl group or an oxygen-substituted lower alkyl group, and n represents an integer of 1 to 5) 4 -Hydroxy-4-((E)
-5-hydroxy-1-butenyl]-! 1,5.5-)
A method for producing dimethyl-2-cyclohexen-1-one. (2) The manufacturing method according to claim (1), wherein R in the general formula is (CHs) or ssi - group. CH3 (3) The method for creating a shin according to claim 11, wherein in general formula 1, R is a CH3CH20CH- group. (4) The manufacturing method according to claim (1), wherein -X-Y- in General Formula 1 is -CH2-CH2-. (5) In general formula 1, R is a (CH3)38i- group υ, -
The manufacturing method according to claim (1), wherein X=Y- is -CH, -CH, -. CH3 (6) The manufacturing method according to claim (1), wherein in the general formula, R is a C)i30H,0CR- group, and -X, -, Y- are -0H2-CH2-. (Force The reducing agent is Na AlH3 (OCH2CH2OC
H3) 2 The manufacturing method according to claim (1).