JPS60190737A - Preparation of (s)-(-)-7-methyl-3-alkyl-6-octene compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound of high optical purity useful as an intermediate for perfume components, by reacting a (3R)-7-methyl-6-octene-1,3-diol derivative as a raw material with a lithium dialkylcopper complex. CONSTITUTION:(3R)-3-Hydroxy-7-methyl-6-octenoic acid is reduced with a reducing agent and reacted in the presence of a base to give a (3R)-7-methyl-6-octene- 1,3-diol derivative of 100% optical purity expressed by formula I (R<1> is lower alkyl; R<2> is mesyl or tosyl), which is then reacted with a lithuium dialkylcopper complex expressed by formula II (R<3> is lower alkyl) to afford the aimed compound of high optical purity expressed by formula III. The resultant compound expressed by formula III is then deacylated by hydrolysis with an aqueous solution of NaOH under mild conditions, etc. to give (S)-(-)-citronellol and homology thereof, which have >=96% optical purity and sweet rosy fragrance and are expressed by formula IV and a perfume component in perfumes and cosmetics, etc.

Description

Detailed Description of the Invention The present invention provides (S)-←)-citronellol, which has a sweet rose-like aroma and is an important fragrance ingredient in perfumes, cosmetics, etc.
and its homology, as well as methods for producing derivatives of these compounds.

a) Prior Art and Problems Terpene fragrances have traditionally been manufactured by processing isolated fragrances obtained from easily available essential oils. Due to the recent increase in consumption and the instability of essential oil prices, the method of producing these natural essential oils by isolating them is being replaced by a method of producing them by synthesis from readily available raw materials.

Citronellol is one of the above-mentioned terpene fragrances, and includes @)-(t)-citronellol contained in citronelli oil, and (81-(i)-citronellol and (S)-←)-citronellol contained in geranium oil. , especially 0)−←
)-Citronellol is the fragrance ingredient with the best odor among these citronellols.

These citronellols were also produced by separation from essential oils, reduction of citronellal, and semi-synthesis from brevon and α-pinene. However, the optical purity of naturally-obtained citronellol is at most about 80%, which is 4-j.
(G, 0hlof, f c) Angev.

Chem, Dan, 24 (1961): l.

Therefore, it was desired to develop a simple manufacturing method using readily available raw materials for citronellolt with high optical purity, and in 1982
In 2010, Mori et al. used β-ketoester as a raw material (S)-←)
- Synthesized citronellol ◎ [K, Mori et al. 8yn
thesig+ 1982, 752 pages].

However, in this synthesis method, the raw material (3R)-3
-The optical purity of hydroxybutyate remains at 84%.

b) Purpose of the invention The present invention provides (J3)-←)-citronellol with high optical purity by a simple synthesis method using a readily available (3R)-7-methyl-6-octene-1,3-diol derivative as a raw material. A method for producing (S)-←)-citronellol and a homology of (S)-←)-citronellol, which has the same odor intensity tW as that of (S)-←)-citronellol, which is not conventionally found in essential oils. The purpose is to provide

C) Structure of the Invention The present invention provides (3R)-7-methyl-6-octe/-1,3 having the general formula (wherein R1 represents a lower alkyl group and R2 represents a mesyl group or a tosyl group)
-Diol derivative with general formula Ll(R')2cu (■)
A lithium dialkyl copper complex represented by the formula (wherein R3 represents a lower alkyl group) is reacted with a lithium dialkyl copper complex having the general formula (wherein R1 and R3 have the same meanings as above) t'') -
←) Method for producing -7-methyl-3-alkyl-6-octene compound, and deacylated compound (S) having the general formula (in the formula, R3 has the same meaning as above)
-←)-A method for producing citronellol and its homology.

The (3R)-7-methyl-6-octey-L3-diol salt conductor represented by the formula (III) used as the starting material of the present invention is a pancreatic acid salt of 3-ketocaldate, which was previously discovered by the present inventors. A 3-(6)-hydroxycarboxylic acid Ti material having an optical purity of #1 or less than 100 m obtained by reduction with yeast. This reaction involves hydrolyzing 7-methyl-3-oxo-6-octenoic acid ester with an aqueous solution of potassium hydroxide or sodium hydroxide.
Add D-glucose and reduce the ketone at position 1 to obtain (3B)-3-hydroxy-7-methyl-6-octenoic acid (IV) (M, Hlrama et al. J, Chs
m, 8oa, +Ch*m, Commun, *198
3.599) The thus obtained fc(3B)-3-hydroxy-7-methyl-6-octenoic acid (IV) can be reduced with a common reducing agent such as lithium aluminum hydride (3R,)
-7-methyl-6-octe7-L3-diol (V)
shall be. The solvent used here is preferably an ether solvent, and the reaction proceeds satisfactorily at room temperature.

The primary hydroxyl group of this (3R)-7-methyl-6-octene-1,3-diol (V) is protected to form an ester (vi).
,! : L, after, tosyl chloride, mesyl chloride IJ
)4 etc. in the presence of a base such as pyridine/triazylamine to prepare the starting material (3R)-1-acyloxy-7-methyl-3-tosyloxy-6-octene (III) or (3R) of the present invention. -1-acyloxy-7-methyl-3-mesyloxy-6-octene (III) is obtained.

t+, the lithium dialkyl copper complex which is the reactant of the present invention is a compound represented by the above formula (■).

Also included are lithium dimethyl copper complex, lithium diethyl copper complex, lithium dibutyl copper complex, and the like. These compounds, such as lithium dimethyl copper complex, can be easily obtained using commercially available copper iodide and methyl lithium using known methods.

Note that lithium diethyl copper complexes, lithium dipropyl copper complexes, lithium dibutyl copper complexes, etc. can be similarly obtained by using ethyl lithium, propyl lithium, butyl lithium, etc. in place of methyl lithium in the above method.

The reaction of the present invention is (3R)-1-acyloxy-7-methyl-3-tosyloxy-6-octene (Ill) or (
3R)-1-acyloxy-7-methyl-3-mesyloxy-6-octey (III) By undergoing a substitution reaction with a lithium dialkyl copper complex (■) (3B)
-1-acyloxy-7-methyl-3-alkyl-6-
Octene (1) t- can be obtained.

7'c(3S)-1-acryoxy-7
-Methyl-3-alkyl-6-octene (1)' is converted to acyl by mild hydrolysis with an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution, or by a reduction reaction with a common reducing agent such as lithium aluminum laminate. fi (3S)-3-alkyl-7-mether-6-octe/-1-ol (ff) can be obtained by conversion.

(38)-3-Methyl-7-methyl-6-octen-1-ol [in formula (If), R is a methyl group] represented by the above formula (...) has an optical purity of 96% or more; This is based on the fact that the optical purity of the (3R)-7-methyl-6-octey-L3-diol derivative represented by the formula (III), which is the starting material of the present invention, is approximately 100%.

Also, (38)-3-alkyl- represented by the above formula (II)
The same applies to 7-methyl-6-octen-1-ol [in formula (II), R is an ethyl group, a propyl group, or a butyl group].

The compound in which the alkyl group is a methyl group in (38)-3-alkyl-7-methyl-6-octen·-1-ol represented by the formula (It) of the present invention is (S)-←)-
For compounds that are citronellol and the alkyl group is an ethyl group, propyl group, or butyl group, (S)-←)
- The homology notation of citronellol was used.

The above steps are shown in a reaction formula.

(In the formula, R1 and R3 represent a lower alkyl group, and R2 represents a mesyl group or a tosyl group.) d) Production Examples Next, production examples will be given to explain in more detail, but the present invention is limited to these scopes. Needless to say, it is nothing.

Production example 1 (3B)-7-methyl-6-octene-1,3-dio:
2A2(3R)-3-hydroxy-7-methyl-6-octenoic acid 31.6I! 3001ug of anhydrous tetrahydrofuran
Lithium aluminum 14.1
Suspension of F (2 equivalents) in anhydrous tetrahydrofuran 900
ml under cooling with water. - After stirring overnight, the mixture was heated under reflux for 2 hours. Under water cooling, the excess reducing agent was decomposed with water, and 4N hydroxide was added. After removing the organic solvent, extraction was performed by successive extractions with ether. This ether layer was washed with a saturated aqueous ammonium chloride solution, dried, and concentrated. The residue was purified by silica dull column chromatography to obtain the title compound 15.851 (yield 54%).
l- Obtained O Properties: Colorless oil [α), +5.9° (C = 2.0, chloroform)
NMR spectrum (CDCl2 *δ): 1.47~
1.80 (4H, m) 1.63 (3H, s), 1
．． 69(3H,d, J-1,1Hz)2.10(
2H, brq, J = 7.2Hz), 2.22
(2H, s) 3.76-4.03 (3H, m) 5.14 (IH, tq, J-7.2, 1.1Hz)
IR spectrum (film, crn-'): 360
0~310.0.2950°1670.1445.10
55.840 Mass spectrum (ITI/z): 158
(M"), 107(b,p) Production Example 2 (3R)-1,3-dihydroxy-7-methyl-6-octene t150mA' was dissolved in pyridine, and piparoyl chloride 8.8II (1 equivalent ) was added.

After further stirring for 1.5 hours, 0 piparoyl chloride,
4&'iiH was further added and stirred for 30 minutes.

The mixture was extracted with ether (21), washed with 2N hydrochloric acid, a saturated aqueous sodium carbonate solution, and a saturated aqueous ammonium solution, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was coated with silica Dull Column Chromadog 2F to obtain the title compound 14.3.9 (yield: 81%).

Properties: Colorless oil [α) 20' 2.8° (C = 2°O, chloroform) NMR spectrum # (CDC131δ): 1.20 (
9H, s), 1.38-1.91 (4H, m), 1
．． 62 (3H, a), 1.68 (3H, d, J
=1.1Hz), 1.98-2.23 (3H, m)
, 3.52-3.80 (IH, rn).

3.98-4.52 (2H, m), 5.12 (IH
,tq, J=7.2, 1.1Hz) IR spectrum/I/(74lAlcm-'): 360(1
~3200 +2960.2920,2870,172
51480,1460゜1285.1160,1110
．． 835 mass spectrum (m/z): 242 (M+)
, 122 ('b,p,) Production Example 3 (3-hydroxy-7-methyl-1 obtained in Production Example 2)
- Dissolve 13.1 g of piparoyloxy-6-octene in pyridine 580a, triethyl ai: / 9.81n
1 and 103 g (10 equivalents) of tosyl chloride were added, and the mixture was stirred overnight in a room. Concentrate under reduced pressure and add ether to the residue.
o odi added. The ether layer was washed successively with 2N hydrochloric acid, a saturated aqueous sodium carbonate solution, and a saturated aqueous ammonium chloride solution. The organic layer was dried, concentrated, and purified by silica gel column chromatography to obtain 14.2 g (yield: 66%) of the title compound.

Properties Dicolorless oil [α), -8,9° (C=2.0.Chloroform) NM
R spectrum (CDC4, Iδ): 1.18 (9H,
s) 1.48-1.75 (2H, m), 1.53 (
3H, s), 1.64 (3H, s) 1.94 (4H,
brq, J=6.5Hz), 2.45(3H,5)4-
00(IH+ddd, J-=17.4.11-2.6-
2Hz) 4.05 (IH, ddd, J=17.4.11
．． 2.6.2Hz) 4.69(IH,q, J=5.7
Hz), 4.88-5.04 (IH, m) 7.32 (
2H, d, J=10.1Hz), 7.82 (2H, d,
J=101Hz) IR spectrum (film, Confucian-')
:2970,2930.2870゜1725.1600
．． 1495,1480.1460.1360.1285
゜1190.1175.1140.1120.905.
815 mass spectrum (m/z); 122 (b, p),
224,107 Production Example 4 (S)-←)-citronellol piparoyl ester 1
An ether solution (1.5 molar solution) of methyllithium was added to excess cuprous iodide suspended in anhydrous ether under water cooling.
A lithium dimethyl copper test was prepared by adding 42.6 FIL1. This lithium dimethyl copper reagent obtained in Production Example 3 (
3R)-7-Methyl-1-piparoyloxy-3-tosyloxy-6-octe/7.031! Anhydrous ether solution (200ml)'1 was added at 78°C and stirred for 30 minutes.

After gradually raising the temperature of the reaction solution and stirring at -20°C for 2 hours, a saturated ammonium chloride aqueous solution of gold was added to the reaction solution, and the organic layer was separated. The organic layer t-1/ was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The concentrated residue was purified by silica dull column chromatography to obtain the title compound 3.03.9 (yield: 71).Property: colorless oil [α) D-1,0 (C=2.0. Chloroform〕IR
Spectrum (film, cy+-'): 2970.2
930.28751730.1480.1460.12
85.1160.835 NMR spectrum (CDCl2
．． δ) 20, 92 (3H, d, J=5.8Hz) 1.1
9 (9H, a), 1.25-1.72 (5H, m), 1
．． 60 (3H, a) 1.68 (3H, d, J = 1.1H
z) 1.96 (2H, brq, J=7.2Hz), 4.
10 (2H, t, J = 7.2Hz) 5.09 (IH, t
q, J = 7.2 + 1.1 Hz) Production Example 5 (S) -(-)-Citronellol obtained in Production Example 4 fc ■) = ←) - Citronellol Piparoyl Ester 2.7711 to 10 qb Sodium hydroxide/methanol Solution 150111't- was added and stirred at room temperature for 20 hours. Saturated ammonium chloride was added to the reaction solution, extracted with ether, the ether layer was completely dried, and then concentrated. The residue was purified using silica gel column chromatography and togelafy.
)t-obtained@ Here 'fc@r formation□□□)-←)-The optical purity of citronellol was 96%@, @, 0 Properties: Colorless oil IR spectrum (film, cm ) :3600~31
00,2920°1450.1055.825 NMR spectrum (CDC1, Iδ): 0.92
(311, d, J=6.8Hz) 1.17-1.
75 (5H, m), 1.61 (3H, s), 1.
69 (3H, d.

J=1.1Hz)+1.96(2H, brqyJ=7.
2Hz).

3.68 (2H, t, J = 6.4Hz), 5.10 (1
)1. tq, J=7.2°1.1Hz) Mass spectrum (n+/z): 156(M), 9t(
b, p,) element cumulative analysis C1゜H2oO C (%) H (%) Calculated value? 6.85 12.89 Actual value 76.80 12.99 The optical purity of citronellol obtained was determined as follows.

The synthesized product was t-oxidized and converted to citronel acid, and then converted to acid chloride with oxalyl chloride.

The results of analyzing the diastereomer mixing ratio of the acid amide obtained by reacting it with this acid chloride t''@i(+3-1- (1-7thyl)ethyl amide) using high performance liquid chromatography. , However, it was found that the -configuration was 98% and the enantiomer was 2 groups.

Claims (1)

[Claims] 1. (3R)-7-methyl-6-octene-1,3 having the general formula (wherein R1 represents a lower alkyl group and R2 represents a mesyl group or a tosyl group)
- A diol derivative is reacted with a lithium dialkyl copper complex represented by the general formula Li(R')zcu (wherein R3 represents a lower alkyl group) (wherein R' and R' are which has the same meaning as (
S)-←)-7-methyl-3-alkyl-6-octene compound manufacturing method. 2. General formula (in the formula, R1 represents a lower alkyl group, R2 represents a mesyl group or a tosyl group) t-(3R)-7-methyl-6-octene-1,
The 3-diol derivative is reacted with a lithium dialkyl copper complex represented by the general formula Li(R5)2Cu (in the formula, R3 represents a lower alkyl group) to obtain the general formula (in the formula, R1 and R3 have the same meanings as above). C with
)-←)-7-methyl-3-alkyl-6-octene compound having the general formula (wherein R3 has the same meaning as above) (81- ←) - Process for producing citronellol and its homology.