JP2771857B2 - Method for producing terpenes - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel method for producing industrially useful terpenes.

[Problems to be solved by conventional technology and invention]

Terpenes have been reported to have been attracting attention due to various physiological actions centered on in vivo antioxidant action, but these terpenes are widely used not only as such but also as intermediates for pharmaceuticals and foods. It is a very important substance.

Many methods for producing terpenes have been studied and disclosed.

General formula [Where R is the formula Group represented by the formula Group represented by Represents a heterocyclic group containing two oxygen atoms as hetero atoms. ), R ₁ a group represented by a hydroxyl group, a group represented by the formula -OR ₁ (wherein represents an acetyl (Ac) group, -COC ₂ H ₅ group, a benzyl group, a methoxymethyl group or a tetrahydrofurfuryl group. ),formula (Wherein R ₂ represents H or Ac group); (Wherein R ₃ represents H, a methyl group or an ethyl group); (Wherein R ₄ represents a methyl group or an ethyl group); (Where R ₅ and R ₆ represent the same or different H, methyl group, ethyl group or isopropyl group); Wherein R ₇ represents H or a methyl group, or a group represented by the formula: Wherein R ₈ represents H or a hydroxyl-protecting group.

m represents the number of 0-3, n represents the number of 1-3. ] Is used as an intermediate or precursor in the synthesis of vitamins and fragrances, so that a high level of purity is required. However, satisfactory techniques of high purity have not always been obtained by known techniques.

For example, U.S. Pat. Nos. 4,168,271 and 4,292,459 disclose a cross-coupling reaction between a Grignard reagent and an enchlor compound. The reaction is copper,
Iron, nickel, inorganic salts or complex salts of metals selected from cobalt as a catalyst, the reaction rate of the enchlor compound is
It is an extremely low rate of 60-70%.

For example, 3,7-dimethyloctylmagnesium chloride and 3-chloromyrcene (3-chloro-6-
Methylene-2-methyloctadiene-1,7) in the presence of a copper catalyst to give the γ-adduct 3-methylene-7,11,15-trimethyl-1,6-hexadecadiene. The yield is 68%, and the isomer α-adduct is 7 to 8
% Generated. (See Comparative Example 1 below.) On the other hand, French Patent No. 8,414,426, JP-A-61-112069 and JP-A-61-118332 also disclose 1,7.
A cross-coupling reaction between a magnesium compound of -dichloro-3,7-dimethyl-oct-2-ene and 3-chloromyrcene was carried out under a copper catalyst, and the conversion of 3-chloromyrcene was 69%, and the 15- Chloro-3-methylene-7,
Although 11,15-trimethyl-hexadeca-1,6,10-triene was obtained, the α-adduct was also produced in 6 to 8%. Even when α-tocopherol, which is the final product, is produced using the intermediates obtained by these methods, the isomer ratio is unchanged and the content is 6 to 8%.

As described above, in the conventional method, isomers are produced as by-products, and thus the probability of a method for synthesizing a high-purity intermediate or precursor has been required.

[Means for solving the problem]

In view of the above-mentioned circumstances, the present inventors have enthusiastically studied for many years an industrial production method of the terpene represented by the general formula (III), which is an important intermediate for producing pharmaceuticals, fragrances, and the like. As a result of the superposition, the regioselectivity in the cross-coupling reaction is increased, and the isomer (α-adduct)
To obtain only the desired product (γ-adduct), that is, an anhydrous zinc chloride is reacted with a Grignard reagent to form an active alkyl zinc halide compound, which is then reacted with an enchlor compound in the presence of a copper metal compound. It has been found that high purity terpenes can be obtained by regioselective cross coupling reaction, and the present invention has been completed.

That is, the present invention relates to the general formula [Where R is the formula Group represented by the formula Group represented by Represents a heterocyclic group containing two oxygen atoms as hetero atoms. ), R ₁ a group represented by a hydroxyl group, a group represented by the formula -OR ₁ (wherein represents an acetyl (Ac) group, -COC ₂ H ₅ group, a benzyl group, a methoxymethyl group or a tetrahydrofurfuryl group. ),formula (Wherein R ₂ represents H or Ac group); (Wherein R ₃ represents H, a methyl group or an ethyl group); (Wherein R ₄ represents a methyl group or an ethyl group); Wherein R ₅ and R ₆ are the same or different and represent H, methyl, ethyl or isopropyl. Wherein R ₇ represents H or a methyl group, or a group represented by the formula: Wherein R ₈ represents H or a hydroxyl-protecting group.

m shows the number of 0-3. ] Is represented by the general formula (Wherein X represents a chloro or bromo atom; n = 1 to 3)
Indicates the number of ) Is reacted with a Grignard reagent represented by the general formula (Where n, m, R have the same meanings as described above). In the production of the terpene represented by the general formula (III), anhydrous zinc chloride and a copper metal compound are allowed to coexist. It is intended to provide a method for producing the represented terpenes.

In this specification, in each formula, Represents a single bond or a double bond, Represents a double bond or a triple bond. or, Represents a cis or trans bond.

In particular, in the present invention, the compound represented by the general formula (III) is produced by reacting the enchlor compound represented by the general formula (I) with the Grignard reagent represented by the general formula (II). Before the reaction, the Grignard reagent represented by the general formula (II) is reacted with anhydrous zinc chloride in advance, (Wherein X and n have the same meanings as described above), and the alkylzinc halide compound is represented by the general formula (I) in the presence of a copper metal compound. It is preferable to react with an enchlor compound.

The reaction of Grignard reagents with enchlor compounds is disclosed in U.S. Patent Nos. 4,168,271, 4,292,459 and French Patent No. 8,414,426. That is, the cross-coupling reaction between the Grignard reagent and the enchlor compound cannot suppress the formation of the α-adduct, which is an isomer. From this, a study was conducted on a reaction reagent which is more active than the Grignard reagent. The reactivity of the alkyl zinc halide was excellent, and the known R′MgX + ZnC
l ₂ → R'ZnCl + MgXCl (Basic Organometallic Chemistr
y, Walter de gruyten, p70, 1985).

That is, an active alkyl zinc halide obtained by previously reacting a Grignard reagent represented by the general formula (II) with anhydrous zinc chloride in an ether solvent at a temperature of -70 ° C to 120 ° C is converted to a copper metal compound. In the presence, the above-mentioned general formula (I)
And a regioselective cross-coupling reaction with the enchlor compound represented by

In the compound represented by the general formula (III) obtained by the present invention, an isomer thereof represented by the following general formula (V) (Wherein R, m, and n have the same meanings as described above), and the production of the α-adduct was 0.6% or less. The conversion of the γ-adduct alone represented by the general formula (III), which is the object of the present invention, from the enchlor compound is 95% or more;
The residual unreacted raw material of the enchlor compound is 5% or less. Its isolation yield can also be obtained at 60-95%.

The copper metal compound used in the present invention is an inorganic copper salt, an organic copper salt or a copper complex salt. For example, CuI, CuBr, CuI
P (C ₂ H ₅ ) ₃ , CuI · P (C ₆ H ₅ ) ₃ , CuBr · (CH ₃ ) ₂ S, C
It is selected from the group consisting of uCl, CuCl ₂ , Cu (CH ₃ COCH ₂ COO) ₂ , and Li ₂ CuCl ₄ . In particular, CuI · P (C ₆ H ₅ ) ₃ and CuBr · (C
H ₃ ) ₂ S is preferred.

The amount of the copper metal compound used is preferably 10 ^-5 to 10 ^{-1 in} terms of gram atoms per equivalent of the reaction, more preferably 0.1 to 0.1.
001-0.05.

Next, the following compounds are exemplified as the enchlor compound represented by the general formula (I).

(1) m = 0 to 1, R = formula derived from myrcene, ocimene, citronellene, β-farnesene The compound group of the group represented by

(2) m = 0 derived from citral, citronellal, farnesal and their protected aldehyde groups
~ 1, R = formula Or a group represented by the formula The compound group of the group represented by

(3) m derived from methylheptenone, geranylacetone, nerylacetone and their protected ketone group
= 0 to 1, R = expression Or a group represented by the formula The compound group of the group represented by

(4) geraniol, nerol, m = 1 to 2 derived from farnesol and their acetate form or their ethers thereof, R = OH group R ₁ or a group represented by the formula -OR ₁ (where the Ac group, -COC ₂ H ₅ group, a benzyl group,
A methoxymethyl group or a tetrahydrofurfuryl group).

(5) nerol, dehydronerol, nerolidol,
M = 0 to 1, R = formula derived from dehydronerolidol and their acetates Wherein R ₂ represents H or an Ac group.

(6) m = 0 to 1, R = formula derived from gellanic acid, γ-gellanic acid, farnesylic acid and esters thereof Wherein R ₃ represents H, a methyl group or an ethyl group.

(7) m = 0 derived from a ketocarboxylic acid derivative obtained by coupling prenyl chloride, geranyl chloride or neryl chloride with acetoacetic ester
~ 1, R = formula Wherein R ₄ represents a methyl group or an ethyl group.

(8) m = 0 to 2, R = formula derived from prenylamine, geranylamine, nerylamine, farnesylamine and its dialkylamine derivative Wherein R ₅ and R ₆ are the same or different and represent H, methyl, ethyl or isopropyl.

(9) m = 0 to 2, R = formula derived from a prenylsulfone derivative, a geranylsulfine derivative, a nerylsulfone derivative, a farnesylsulfone derivative Wherein R ₇ represents H or a methyl group.

(10) m = 0, R = formula derived from 2,5,7,8-tetramethyl-2- (4'-methyl-3'-pentenyl) -6-chromanol and protected ether thereof Wherein R ₈ is H or a protecting group for a hydroxyl group.

Specific examples include compounds having the following structural formula.

The reaction solvent of the present invention may be an ether-based solvent such as diethyl ether or tetrahydrofuran alone, or a mixture of such an ether-based solvent and a non-polar solvent such as n-hexane, toluene, benzene or the like.

Next, a series of the above reactions using the compound of the present invention will be described in detail.

To a reaction vessel filled with an inert gas such as nitrogen or argon, a Grignard reagent prepared in advance is added, and -70 ° C in a solvent-free or ethereal solvent such as tetrahydrofuran.
Anhydrous zinc chloride is added and reacted at a temperature of 120120 ° C., preferably -20 ° C. to 20 ° C. to form an alkyl zinc halide, then a copper metal compound is added, and then an enchlor compound dissolved in an inert solvent is added. To react. After stopping the reaction, the contents are taken out and extracted with a suitable solvent,
A pure product can be obtained by purifying the terpene compound by distillation or column chromatography.

According to the method of the present invention, terpenes of high purity can be obtained in a very high yield. By using the terpenes obtained by the method of the present invention as starting materials, various useful substances can be obtained with high purity and high yield. In particular, if the terpene obtained by the method of the present invention is used as a starting material to produce vitamin E having a wide range of actions such as antioxidant action and lipid metabolism improving action, it is possible to produce vitamin E with high purity and high yield. it can. Specifically, it is shown in the following Example 24, and as apparent from Example 24, the purity was 98.
% And a high purity of 95% or more. On the other hand, the conventional method (U.S. Pat.
No. 168,271, No. 4,292,459) Grignard method has a purity of 92
% And the yield is 80%. Therefore, the method of the present invention can obtain a target product with high purity and high yield, and its usefulness is high.

〔Example〕

Hereinafter, the present invention will be described in more detail with reference to Examples, but it is needless to say that the present invention is not limited thereto.

Also, as shown in Example 1, 3-methylene-7,11,15-
Comparative Example 1 shows the results of additional tests of known methods for producing trimethyl-16-hexadecadiene (U.S. Pat. Nos. 4,168,271 and 4,292,489).

Example 1 Synthesis of 3-methylene-7,11,15-trimethyl-1,6-hexadecadiene 33 g (0.15 mol) of 3,7-dimethyloctyl bromide, 3.65 g of magnesium metal, and 400 ml of tetrahydrofuran were placed in a 14-neck flask purged with argon gas, and 5 drops of ethylene dibromide as a reaction initiator were added. The mixture was stirred and refluxed for 2 hours. By doing so, the magnesium metal is dissolved to obtain a solution of 3,7-dimethyloctylmagnesium bromide in tetrahydrofuran.

This solution was gradually cooled to 18 ° C under a stream of argon,
Then, 20 g (0.15 mol) of anhydrous zinc chloride is added, and the mixture is vigorously stirred for 1 hour, and the reaction solution gradually becomes cloudy to obtain a tetrahydrofuran solution containing 3,7-dimethyloctyl zinc chloride.

1 g (0.0048 mol) of CuBr · (CH ₃ ) ₂ S was added to this solution, and the mixture was stirred for 30 minutes. The cloudy liquid gradually turned gray-black, and then 70% of 3-chloro-6-methylene-2-methyl-octadiene- 200 ml of a tetrahydrofuran solution of 1,717 g (0.07 mol) was gradually added dropwise over 30 minutes,
After stirring for an hour and confirming disappearance of the raw materials by TLC and HPLC, 500 ml of a saturated aqueous solution of ammonium chloride is added dropwise to stop the reaction.

The product is extracted twice with 500 ml of n-hexane. The extract is dried and the solvent is distilled off to obtain 36 g of a colorless liquid.

The ratio of the desired product (γ-adduct) to the isomer (α-adduct) of this crude product by HPLC was 99.5: 0.5. The reaction rate is 97.5%.

36 g of the crude product obtained above was purified by column chromatography with 2.8 kg of 200 mesh silica gel and n-hexane single solvent system to obtain 14.4 g of the desired product as a colorless liquid (yield 74.4 g).
%, Purity 99.1%).

Elemental _{analysis: C 20 H 36 (MW =} 276.508) C (%) H (%) Calculated: 86.88 13.12 _{Found; 86.98 13.03 NMR (CDCl 3,} δ); 6.3 (d, d, 1H), 4.9~ 5.4 (m, 5H) Mass; M ⁺ = 276 Example 2 Synthesis of 3-methylene-7,11-dimethyl-1,6-dodecadiene 22.6 g (0.15 mol) of 1-bromo-3-methylbutane,
Magnesium metal 3.65 g, tetrahydrofuran 400 ml, ethylene dibromide 5 drops, zinc 20 g (0.15 mol) anhydrous _{chloride, CuBr · (CH 3) 2} S2g (0.01 mol), 70% of 3-chloro-6-methylene-2-methyl Octadiene-1,7 17
g (0.07 mol), 200 ml of tetrahydrofuran and 500 ml of a saturated aqueous solution of ammonium chloride in the same manner as in Example 1 to obtain 12.0 g of the desired product as a colorless liquid (yield 83.2).
%).

The ratio of the target compound (γ-adduct) to the isomer (α-adduct) by HPLC was 99.5: 0.5, and the reaction rate was 98%.
%.

Elemental analysis: C ₁₅ H ₂₆ (MW = 206.378) C (%) H (%) Calculated; 87.30 12.70 Actual; 87.41 12.60 NMR (CDCl ₃ , δ); 6.3 (d, d, 1H), 4.9- 5.4 (m, 5H) Mass; M ⁺ = 206 Examples 3 to 18 Example 1 to Example 2 were repeated except that the type of catalyst, molar ratio, solvent and reaction conditions were changed as shown in Table 1. Was performed in the same manner as described above. Table 1 shows the obtained results.

Example 19 Synthesis of 3,7,11,15-tetramethylhexadec-2 (E), 6-dien-1-ol acetate 3,7-dimethyloctyl bromide 6.64 g (0.03 mol), magnesium metal 0.73 g, tetrahydrofuran 40 m
l, a tetrahydrofuran solution containing 3,7-dimethyloctylmagnesium bromide was obtained in the same manner as in Example 1 by using 3 drops of a reaction initiator ethylene dibromide,
While maintaining the temperature at 10 ° C., 4.08 g (0.03 mol) of anhydrous zinc chloride was added, and the mixture was stirred at the same temperature for 1 hour to obtain a cloudy tetrahydrofuran solution containing 3,7-dimethyloctyl zinc chloride.

0.2 g (0.001 mol) of CuBr. (CH ₃ ) ₂ S
And stirred for 30 minutes, then 6-chloro-7-methylene-3-
Methyl-2 (E) -octen-1-ol acetate 4.
A solution of 4 g (0.02 mol) of tetrahydrofuran (40 ml) is added dropwise at 20 ° C. over 30 minutes. After completion of the dropwise addition, the mixture was stirred at 25 ° C. for 3 hours. The disappearance of the raw material chloro form was confirmed by TLC and HPLC, and the reaction was stopped by adding 20 ml of a saturated aqueous ammonium chloride solution.

The reaction solution was poured into 200 ml of ice water, and the product was n-hexane 1
Extract with 00 ml, dry and evaporate the solvent to obtain 8.2 g of a colorless liquid. This is a silica gel (200 mesh) 200g, n
-Purification by column chromatography using hexane and benzene to obtain 4.4 g of the desired product as a colorless liquid (yield 65.5%).

Elemental analysis: C ₂₂ H ₄₀ O ₂ (MW = 336.54) C (%) H (%) Calculated; 78.52 11.98 Found; 78.72 11.96 IR (cm ^-1 ); 1740 (OCOCH ₃ ) NMR (CDCl ₃ , δ); 5.4 (t, 1H), 5.2 (t, 1H), 4.6 (d, 2
H), 2.05 (s, 3H) Mass; M ⁺ = 336 Example 20 Synthesis of 3,7,11,15-tetramethylhexadec-2 (Z), 6-dien-1-ol acetate 3,7-dimethyloctyl bromide 6.64 g (0.03 mol), magnesium metal 0.73 g, tetrahydrofuran 40 m
l, a tetrahydrofuran solution containing 3,7-dimethyloctylmagnesium bromide was prepared in the same manner as in Example 1 using three drops of ethylene dibromide, and then 4.08 g (0.03 mol) of anhydrous zinc chloride was added thereto. , 7-dimethyl-octyl zinc chloride was tetrahydrofuran solution containing, this _{CuBr · (CH 3) 2 S} 0.2g (0.001 mol), 6
The same procedure as in Example 20 was carried out using 4.4 g (0.02 mol) of -chloro-7-methylene-3-methyl-2 (Z) -octen-1-ol acetate to give the target compound as a colorless liquid.
0 g is obtained (59.7% yield).

IR (cm ^-1 ); 1740 (OCOCH ₃ ) NMR (CDCl ₃ , δ); 5.4 (t, 1 H), 5.25 (t, 1 H), 4.6 (d, 2
H), 2.0 (s, 3H) Mass; M ⁺ = 336 Example 21 3,7,11,15-Tetramethylhexadeca-1,6-diene-3
-Synthesis of all acetate 3,7-dimethyloctyl bromide 6.64 g (0.03 mol), magnesium metal 0.73 g, tetrahydrofuran 40 m
l, a tetrahydrofuran solution containing 3,7-dimethyloctylmagnesium bromide was prepared in the same manner as in Example 1 using three drops of ethylene bromide, and 4.08 g (0.03 mol) of anhydrous zinc chloride was added. , 7-dimethyl-octyl zinc chloride was tetrahydrofuran solution containing, this _{CuBr · (CH 3) 2 S} 0.2g (0.001 mol), 6
-Chloro-7-methylene-3-methyl-1-octene-
Example using 4.4 g (0.02 mol) of 3-all acetate
Operating in the same manner as in 20, 20 g of the desired product was obtained as a colorless liquid (yield: 61.2%).

IR (cm ⁻¹ ); 1740 (OCOCH ₃ ) NMR (CDCl ₃ , δ); 6.0 (d, d, 1H), 5.3-5.0 (m, 3H), 2.
0 (s, 3H) Mass; M ⁺ = 336 Example 22 3,7,11,15-tetramethylhexadeca-2 (E), 6
(E) Synthesis of 10-trien-1-ol acetate 4.53 g (0.03 mol) of 1-bromo-3-methylbutane,
The same operation as in Example 1 was performed using 0.73 g of magnesium metal, 40 ml of tetrahydrofuran, and 3 drops of ethylene dibromide to prepare a tetrahydrofuran solution containing 3-methylbutylmagnesium bromide, and then anhydrous zinc chloride.
4.08 g (0.03 mol) was added to obtain a tetrahydrofuran solution containing 3-methylbutylzinc chloride.
Br · (CH ₃ ) ₂ S 0.2 g (0.001 mol), 10-chloro-11-
The same operation as in Example 20 was carried out using 6.0 g (0.02 mol) of methylene-3,7-dimethyl-2 (E), 6 (E) -dodecadien-1-ol acetate to give the desired product as a colorless liquid.
3.8 g (56.8% yield) are obtained.

Elemental analysis; C ₂₂ H ₃₈ O ₂ (MW = 334.54) C (%) H (%) Calculated; 78.99 11.45 Actual; 79.12 11.50 IR (cm ⁻¹ ); 1740 (OCOCH ₃ ) NMR (CDCl ₃ , δ); 5.4 (t, 1H), 5.2 (t, 2H), 4.6 (d, 2
H), 2.05 (s, 3H) Mass; M ⁺ = 334 Example 23 Synthesis of 3 ', 4'-dehydro-α-tocopheryl benzyl ether A Grignard reagent was prepared using 3.63 g (0.016 mol) of 3,7-dimethyloctyl bromide, 0.363 g (0.015 mol) of Mg metal, 40 ml of tetrahydrofuran, and three drops of ethylene dibromide as an initiator, and prepared 3,7-dimethyloctyl. 2.09 g (0.015 mol) of anhydrous zinc chloride while maintaining the tetrahydrofuran solution containing magnesium bromide at 20 ° C
And stirred at the same temperature for 1 hour to obtain a cloudy tetrahydrofuran solution containing 3,7-dimethyloctylzinc chloride. To this solution was added 0.3 g (0.0007 mol) of CuI · (C ₆ H ₅ ) ₃ P, and the mixture was stirred for 5 minutes, and then 98% pure 2,5,7,8-tetramethyl-2- (3′-chloro-4) '-Methylenepentyl)
A solution of 1.0 g (0.0024 mol) of -6-ol benzyl ether in 20 ml of tetrahydrofuran was added dropwise at 20 ° C for 5 minutes. After completion of the dropwise addition, the mixture was stirred at the same temperature for 2 hours, and disappearance of the raw material chloro form was confirmed by TLC and HPLC. At this time, the γ-adduct and α-
The ratio of the adduct was γ: α = 98: 2.

95% conversion.

Example 24 2- (4,8,12-Trimethyl-dodeca-3,7-dienyl)
Synthesis of 2,4-dimethyl-1,3-dioxolane 2.27 g (0.015 mol) of 1-bromo-3-methylbutane,
The same operation as in Example 1 was performed using 0.36 g of magnesium metal, 40 ml of tetrahydrofuran, and 3 drops of ethylene dibromide to prepare a tetrahydrofuran solution containing 3-methylbutylmagnesium bromide, and then anhydrous zinc chloride.
1.5 g (0.01 mol) was added to obtain a tetrahydrofuran solution containing 3-methylbutylzinc chloride.
・ (CH ₃ ) ₂ S 0.15 g (0.00075 mol), 2- (7-chloro-4,8-dimethyl-3,8-nonadienyl) -2,4-dimethyl-1,3-dioxolane 1.43 g, tetrahydrofuran 20 ml
By using the same method as in Example 20, 0.87 g of the desired product was obtained as a colorless liquid (54% yield).

The product was subjected to a deketanol reaction by a conventional method, followed by catalytic reduction to give phyton, and the content of the α-adduct was measured by GLC to be 0.5% or less.

Comparative Example 1 Synthesis of 3-methylene-7,11,15-trimethyl-1,6-hexadecadiene 3,7-dimethyloctyl bromide 6.64 g (0.03 mol), magnesium metal 0.73 g, tetrahydrofuran 50 m
l, a tetrahydrofuran solution containing 3,7-dimethyloctylmagnesium bromide was prepared in the same manner as in Example 1 using three drops of ethylene dibromide, the reaction solution was cooled to 5 ° C, and then CuBr · ( CH ₃ ) ₂ S 0.6 g (0.
003 mol), and the mixture was stirred at the same temperature for 30 minutes.
Chloro-6-methylene-2-methyloctadiene-1,7
A solution of 3.4 g (0.02 mol) in tetrahydrofuran (50 ml) is added dropwise over 30 minutes. After the completion of the dropwise addition, the mixture is stirred at the same temperature for 1 hour, and the disappearance of the raw material chloro form is confirmed by TLC and HPLC.

At this time, the ratio of the target compound (γ-adduct) to the isomer (α-adduct) was 91.6: 8.4.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 41/30 C07C 41/30 41/48 41/48 43/166 43/166 43/30 43/30 45/68 45/68 47/21 47/21 49/04 49/04 E 69/007 69/007 C 211/24 211/24 315/04 315/04 317/14 317/14 C07D 311/72 102 C07D 311/72 102 317 / 12 317/12 C07F 3/02 C07F 3/02 B 3/06 3/06 // B01J 27/125 B01J 27/125 X 31/04 31/04 X 31/24 31/24 X C07B 61/00 300 C07B 61/00 300 (72) Inventor Shizumasa Takashima 999-18 Kashiwa, Kashiwa City, Chiba Prefecture (56) Reference JP-A-3-148228 (JP, A) JP-A-60-78927 (JP, A) JP-A Sho 59-118780 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07B 49/00 C07F 3/02 C07F 3/06

Claims (5)

(57) [Claims] (1) General formula [Where R is the formula Group represented by the formula Group represented by Represents a heterocyclic group containing two oxygen atoms as hetero atoms. ), R ₁ a group represented by a hydroxyl group, a group represented by the formula -OR ₁ (wherein represents an acetyl (Ac) group, -COC ₂ H ₅ group, a benzyl group, a methoxymethyl group or a tetrahydrofurfuryl group. ),formula (Wherein R ₂ represents H or Ac group); A group represented by COOR ₃ (where R ₃ represents H, a methyl group or an ethyl group); (Wherein R ₄ represents a methyl group or an ethyl group); (Where R ₅ and R ₆ represent the same or different H, methyl group, ethyl group or isopropyl group); Wherein R ₇ represents H or a methyl group, or a group represented by the formula: Wherein R ₈ represents H or a hydroxyl-protecting group. m shows the number of 0-3. ] Is represented by the general formula (Wherein X represents a chloro or bromo atom; n = 1 to 3), and reacted with a Grignard reagent represented by the following formula: (Where n, m, and R have the same meanings as described above), wherein anhydrous zinc chloride and a copper metal compound are allowed to coexist.
A method for producing a terpene represented by I). 2. The general formula [Where R is the formula Group represented by the formula Group represented by Represents a heterocyclic group containing two oxygen atoms as hetero atoms. ), R ₁ a group represented by a hydroxyl group, a group represented by the formula -OR ₁ (wherein represents an acetyl (Ac) group, -COC ₂ H ₅ group, a benzyl group, a methoxymethyl group or a tetrahydrofurfuryl group. ),formula (Wherein R ₂ represents H or Ac group); (Wherein R ₃ represents H, a methyl group or an ethyl group); (Wherein R ₄ represents a methyl group or an ethyl group); (Where R ₅ and R ₆ represent the same or different H, methyl group, ethyl group or isopropyl group); Wherein R ₇ represents H or a methyl group, or a group represented by the formula: Wherein R ₈ represents H or a hydroxyl-protecting group. m shows the number of 0-3. In the presence of a copper metal compound, an enchlor compound represented by the general formula (Wherein X represents a chloro or bromo atom; n = 1 to 3). An active alkyl zinc halide compound represented by the following formula: (Wherein, R, m, and n have the same meanings as described above). 3. The method according to claim 1, wherein the copper metal compound is an inorganic copper salt, an organic copper salt, or a copper complex salt. 4. The method according to claim 1, wherein the copper metal compound is CuI, CuBr, CuCl, CuCl ₂ , Cu.
(CH ₃ COCH ₂ COO) ₂ , CuI · P (C ₂ H ₅ ) ₃ , CuI · P (C ₆ H
_{5) 3, CuBr · (CH} 3) 2 S and Li ₂ The method of claim 1, 2 or 3, wherein any one of from CuCl ₄ was chosen. 5. The method according to claim 1, wherein the amount of the copper metal compound added is 10 ^-5 to 10 ^-1 in terms of gram atoms per equivalent of the reaction.