JPS6024107B2 - Production method of cyclic lactone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method capable of producing a lactone compound of formula (1), which is useful particularly in the field of perfumery, with excellent selectivity and good yield.

The oxidative lactonization reaction for forming a compound of formula (1) from a compound of formula (Rho 1) or (Rho 2) of the present invention is a reaction mode unknown heretofore. The lactone represented by the following formula (1), which is the object of the method of the present invention, is a known compound and has a musk-like, civet-like, or amber-like odor, and can be added to a fragrance composition as an active ingredient. For example, it can be used as an aroma modifier that significantly improves the aroma.

1.15-, which is one of the target compounds of formula (1) of the present invention
Pentadecanolide (exaltolide) is a known substance isolated from angelica oil.

Conventionally, various general methods have been proposed for producing the lactone of formula (1).

For example, “Snake r.Patent, 727051 (195
2)", according to the following formula, and "Helv.Ch
im. Acta. , 18, 1087 (1935), according to the following formula,
．． S ratio. , 58, 654 (1936), furthermore, according to the following formula:
, 129 (1947), lactones are synthesized according to the following formula. In the above-mentioned secondary method, the synthesis of the starting materials cycloalkanone, -oxycarboxylic acid, or -fromcarboxylic acid requires a large number of steps, and control of the operation and reaction conditions is difficult and complicated;
It has the disadvantage of being expensive.

In addition, the lactonization reaction operation is very complicated, and the selectivity and yield are poor, and furthermore, it is necessary to use a large dilution method, or to perform an additional depolymerization operation to form polyester. These disadvantages make it unsuitable for industrial implementation. The present inventors have conducted research in order to overcome the disadvantages and deficiencies of the conventional methods described above, and to provide a method that can industrially advantageously produce the lactone of formula (1) with excellent selectivity and good yield. As a result, the following formula (m), HO-CH2
1 (C ratio) n-CH2-OH Formula (m) where n is an integer of 5 to 1 & preferably 8 to 16. (W)R-Mg-×
A Grignard reagent represented by formula (W) where R represents a C, ~C8 linear or branched alkyl group or alkenyl group or the following formula (V) where R,, R2, R3
represents hydrogen, C, to C8 linear or branched alkyl group or alkoxy group, or represents an allyl group, allyloxy group, phenyl group or phenoxy group. Metal oxidation, the following formula (Rho 1) (R) x-Mg-01C
H2-(C is)n-CH2-Mg-(R).
Formula (Rho 1) However, in the formula, R represents halogen,
x represents 1, n represents an integer from 5 to 18, Q.-di(metaloxy)alkane or the following formula (Rho 2) (R) x-N-○-C Koichi (CH2) n-C
Ratio-0 one mountain one (R). Formula (Rho 2) However, in the formula,
R is C, ~C8 linear or branched alkyl group, C
．． ~C8 alkoxy group, allyl group, allyloxy group,
represents a phenyl group or a phenoxy group, x represents 2,
n is an integer from 5 to 18, expressed as q・nage (
We have discovered that metaloxy)alkanes can be easily produced in high, almost quantitative yields.

Furthermore, the Q-di(metaloxy)alkane of the formula (Rho 1) or 'yo (Rho 2) can be reacted with the active halogen by a conventionally unknown reaction mode to form the compound of the formula (1). It has been discovered that lactone compounds can be advantageously oxidatively lactonized with excellent selectivity and good yield.

Therefore, an object of the present invention is to provide an industrially advantageous method for producing a cyclic lactone of the formula (1) compound by easy means, with high purity and high yield.

Next, the method of the present invention will be explained in more detail, and many other objects and advantages of the present invention will become clearer from the following description.

The Q·mono-dihydroxyalkane of the compound of formula (m) used in the production of the compound of the starting material formula (0-1) or (rho-2) of the present invention can be obtained by total reduction of the corresponding Q·■-dicarboxylic acid. Can be easily synthesized.

Specific examples of the compound of formula (m) include 1.
7-dihydroxyheptane, 1,8-dihydroxyoctane, 1,9-dihydroxynonane, 1,10-dihydroxydecane, 1,11-dihydroxyundecane, 1
・12-dihydroxydodecane, 1,13-dihyde. oxytridecane, 1,14-dihydroxytetradecane,
1,15-dihydroxybentadecane, 1,15-dihydroxyhexadecane, 1,17-dihydroxyheptadecane, 1,18-dihydroxyoctadecane, 1,1
Examples include 9-dihydroxynonadecane, 1,20-dihydroxyceicosane, and the like. The Q-dihydroxyalkane of the formula (m) compound can be prepared by reacting with a Grignard reagent of the formula (N) compound or an organoaluminum compound of the formula (V) compound to obtain a compound of the formula (Roh 1) or (Roh 2). It can be selectively converted to Q.-di(metaloxy)alkane, which is the starting material compound for the invention, in a good yield. This metal oxidation reaction is carried out, for example, by bringing the q.mono-dihydroxyalkane of formula (m) into contact with the Grignard reagent of formula (W) or the organoaluminium compound of formula (V) in an inert organic solvent. I can do it. The reaction temperature can be, for example, about 11°C to about 180°C, preferably about 0°C to about 140°C. As the Grignard reagent of formula (W) to be used, C, to C8 mirror-like or branched alkyl or alkenyl magnesium chloride (or bromide or iodide) is generally used, but other Grignard reagents may also be used. There are no restrictions on the type of Grignard reagent.

As the organoaluminum compound represented by formula (V),
C, ~ C8 linear or branched trialkylaluminum, alkylalkoxyaluminum, trialkoxyaluminum, alkylaluminum hydride, alkylaluminum sesqui/·lide, alkylalkoxyaluminum/·hydride, a/rekoxyaluminum/, hydride , alkyl aluminum hydride, etc., and trialkylaluminum or trialkoxyaluminum is preferably employed.

The amount of the compound of formula (N) or compound of formula (V) to be used is about 1 to about 5 times the mole of the compound of formula (m), preferably about 1.5 to 3 times the mole of the compound of formula (m).

As the inert solvent used in the above terminal oxidation reaction, any organic solvent that is inert to the reaction components and products can be used, such as n-hexane, n-heptane,
Examples include n-octane, isooctane, petroleum ether, cyclohexane, benzene, toluene, xylene, diethyl ether, diisopropylether, and tetrahydrofuran.

These solvents may be used alone or in a mixture of two or more. There is no particular restriction on the amount of the solvent to be used, but it is usually about 1 to about 10 times the weight of the compound of formula (m), preferably about 5 to about 5 times the weight of the compound. . After the completion of the above terminal oxidation reaction, the inert solvent used from the reaction system is concentrated under normal pressure or reduced pressure to obtain the raw material formula (Row 1) or (Row 2) used in the present invention in good yield and purity. Q. No di(metaloxy) alkanes can be obtained.

Since the compound of formula (Rho 1) or (Rho 2) obtained as described above has a good purity, it can be used as it is in the next oxidative lactonization reaction without any particular purification operation. Specific compounds of the Q-di(metaloxy)alkane of the above formula (Roh 1) or (Roh 2) used in the method of the present invention include, for example, 1,7-di(halogenated magnesium oxy)-hebutane. , 1,8-di(halogenated magnesium oxy)octane, 1,9-di(halogenated magnesium oxy)nonane, 1,10-di(halogenated magnesium oxy)decane, 1,11-di(halogenated magnesium oxy) ) undecane, 1,12-di(halogenated magnesium oxy)dodecane, 1,13
-di(halogenated magnesium oxy)tridecane, 1
・14-di(halogenated magnesium oxy)tetradecane, 1,15-di(halogenated magnesium oxy)
Pentadecane, 1,16-di(halogenated magnesium oxy) hexadecane, 1,17-di(halogenated magnesium oxy)heptadecane, 1,18-di(halogenated magnesium oxy)octadecane, 1,19-di(halogenated magnesium oxy)heptadecane magnesium oxy)nonadecane, 1,2
0-di(halogenated magnesium oxy) eicosan;
1,7-di(disubstituted furkyl or alkoxyaluminiumoxy)hebutane, 1,8-di(disubstituted alkyl or alkoxyaluminiumoxy)octane, 1
09-di(disubstituted alkyl or alkoxyaluminumoxy)nonane, 1,10-di(disubstituted alkyl or alkoxyaluminumoxy)decane, 1,1
1-di(disubstituted alkyl or alkoxyaluminiumoxy)undecane, 1,12-di(disubstituted alkyl or alkoxyaluminiumoxy)dodecane, 1
・13-di(disubstituted alkyl or alkoxyaluminumoxy)tridecane, 1.14-di(disubstituted alkyl or alkoxyaluminumoxy)tetradecane 1,15-di(disubstituted alkyl or alkoxyaluminumoxy)pentadecane, 1・16-ji (
1,17-di(disubstituted alkyl or alkoxyaluminumoxy)heptadecane, 1.
18-di(disubstituted alkyl or alkoxyaluminiumoxy)octadecane, 1,19-di(disubstituted alkyl or alkoxyaluminiumoxy)nonadecane, 1,20-di(disubstituted alkyl or alkoxyaluminiumoxy)eicosane, 1 .10-di(methylallylaluminumoxy)decane, 1,12-di(
Isof.

ropylaryloxyaluminumoxy)dodecane, 1
．． Examples include 14-di(phenylmethoxyaluminumoxy)tetradecane and 1,16-di(ethylphenoxyaluminumoxy)hexadecane. The lactone compound of the formula (1), which is the object of the present invention, can be produced by contacting a Q-dimetal alkoxyalkane of the formula (Rho 1) or (Rho 2) with an active halogen to produce an oxidative lactone compound. It can be obtained in good yield and with excellent selectivity. In this oxidative lactonization reaction, for example, an active halogen can be formed in a reaction system with Q.yama-dimetal alkoxyalkane of formula (0-1) or (Rho 2) in a solvent inert to the reaction. For example, N-haloacylamide is added at the same time, or N-haloacylamide is added to the solvent and the formula (0-1) or (rho2
) The reaction can be carried out by adding the compounds in any order of addition, such as dropwise addition. The reaction temperature can be carried out in a wide range of about 0 to about 150°C, for example, but the reaction temperature is about 10°C.
A characteristic advantage of this oxidative lactonization reaction is that it can be carried out in a mild temperature range of about 80°C. In this oxidative lactonization reaction, acylamide is quantitatively produced in addition to the target compound of formula (1).

Another characteristic advantage of the present invention is that the acylamide can be converted into the N-haloacylamide used in the oxidative lactonization reaction of the present invention by the action of a halogen, and there is no waste of the reagent used. In addition to the preferred embodiments described above, the oxidative lactonization reaction of a compound of formula (Rho 1) or (Rho 2) according to the novel reaction mode of the present invention can be carried out using an active halogen and a compound of formula (Rho 1) or (Rho 2). This can be done by any means that can bring them into contact.

Here, the active halogen is not limited to the halogen atom formed in the reaction system as shown in the preferred embodiment above, but also any compound that can come into contact with the compound of the formula (Rho 1) or (Rho 2) in the form of a halogen atom. It includes halogen atoms in the following embodiments. For example, it may be supplied to the reaction system in the form of an amide and a halogen, or it may be supplied as a halogen in the presence of light or in the presence of a radical initiator. I can do it. Examples of the N-haloacylamide used in the preferred embodiment of the oxidative lactonization reaction include N-monochloroacetamide, N-monopromacetamide, N-monoiodoacetamide,
N-monochloropropionic acid amide, N-monopromopropionic acid amide, N-monopropionic acid amide, N
-monochlorobutyric acid amide, N-monochlorobutyric acid amide,
N-monoodobutyric acid amide, N-chlorosuccinimide, N-bromosuccinimide, N-yodosuccinimide, N-chlorophthalic acid imide, N-promphthalic acid imide, N-iodophthalic acid imide, and the like can be mentioned.

The amount of these N-haloacylamides to be used is determined by the raw material formula (
Rho 1) If (Rho 2) About 2 to about 10 mol is most preferably employed per 1 mol of the compound. Examples of solvents inert to the reaction used in the oxidative lactonization reaction include dichloromethane, chloroform, carbon tetrachloride, dichloroethane, n-bentane, n-hexane, petroleum alcohol, n-hebutane, n-octane,
Examples include isooctane, cyclohexane, benzene, diethyl ether, diisopropyl ether, and tetrahydrofuran.

These solvents are preferably in a dry state, and may be used alone or in a mixture of two or more. There are no special restrictions on the amount of solvent used, but usually the formula of the raw material (
Low 1) If < is about 1 to about 5 for (0-2) compound
A ratio of about 0 times the weight, preferably about 10 to about 20 times the weight, is finally adopted. After the completion of the above oxidative lactonization reaction, in order to remove the acylamides, the product is washed with alkaline water, and further washed with water if desired. For example, after drying with reed sulfate, the solvent is concentrated and distilled under reduced pressure to obtain a good yield. The desired lactone formula (1) compound can be obtained with good purity.

Hatake during this oxidative lactonization reaction. The oligomers that can be formed are converted into the target compound (formula (1)) by heating in the presence of a depolymerization key medium.
Since it can be converted into a compound in a high yield, it has the advantage that almost all of the oxidation reaction product can be converted into the target compound of formula (1) without any waste. Specific examples of the cyclic compound of formula (1), which is the final target product of the present invention obtained by the above oxidative lactonization reaction, include 1,7-heptalide, 1,8-octalide, 1,9-nonalide, 1
・10-Decanoride, 1.11-Unde Force/Ride,
1,12-dodecanolide, 1,13-tridecanolide, 1,14-tetradecanolide, 1,15-pentadecanolide (exaltolide), 1,16-hexadecanolide (dihydroambrectolide), 1・1
Examples include 7-heptadecanolide, 1,18-octadecanolide, 1,19-nonadecanolide, 1,20-eicosannolide, and the like.

The present invention will be explained in more detail below using reference examples and examples.

Reference Example 1 Production of 1,7-di(bromomagnesiumoxy)heptane 1 1 1,7-dihydroxyheptane in a reaction flask
3.2 hours (0.1 mol), tetrahydrofuran 300
200 g of a previously prepared diethyl ether solution containing 0.21 mol of ethylmagnesium bromide was added to 1. After dropping at 35 to 40° C. over a period of time, the mixture was reacted at the same temperature for 2 hours.

GLC and TLC analysis of the reaction mixture confirmed that the existing raw materials disappeared and the reaction progressed. By recovering the solvent, crude 1,7-di(bromomagnesiumoxy)butane 34 was obtained. IR (KBn method) of the crude product shows no absorption of hydroxyl groups (raw material), so the yield is quantitative. This crude product is used in the next oxidation reaction without purification. Reference Example 2 Production of 1,12-di(dibutylaluminumoxy)dodecane 1.20.2 hours of 1,12-dihydroxydodecane (0.1
mole), benzene 400 and tributyl aluminum 0
．． 2-hexane solution containing 2 mol 100 ~
The reaction mixture was added dropwise for 1 hour at 15:00, and reacted for 30 minutes at 15 to 25 qo, and the solvent was recovered to obtain 37.0 q of crude 1,12-di(dibutylaluminumoxy)dodecane.

Yield quantitative. Reference Example 3. Preparation of 1.15-di(diisopropoxyaluminumoxy)pentadecane 1. Add 1115-dihydroxybentadecane to the reaction flask 2.
4 moles (0.1 mole), 600 moles of xylene, and 40.8 moles (0.2 mole) of aluminum isoproxide were charged.
Add isopropanol-xylene slowly over 40 minutes.
I made 0 crabs come out.

Thereafter, the solvent was completely removed under reduced pressure to obtain crude 1015-di(diisopropoxyaluminumoxy)pentadecane 38.
．． I got 9 nights. Yield quantitative. Example 1 Production of 1,7-heptanolide Crude 1,7-di(bromomagnesiumoxy)hebutane bound in Reference Example 1, 500 ml of chloroform, N-
Bromosuccinimide 35.6 times 20-3 times less than 1
Time reacted.

After completion of the reaction, the reaction mixture was washed with water, washed with an aqueous solution of sodium monocarbonate, and dehydrated with sulfur, and the solvent was recovered and distilled under reduced pressure to obtain 35% of 1,7-heptanolide (yield: 27% of theory). It was confirmed that the obtained substance was the target substance by matching the specific gravity, refractive index, GLC, IR, MS, and NMR with the standard substance. Since the IR and NMR spectra of distillation pot residue 6 matched those of the target product, it was presumed to be the target oligomer. Therefore, 5% by weight of aluminum 2nd oxide was added to the pot residue at ~300℃~0.01 foot Hg.
By depolymerizing, 107-heptanolide was obtained with a yield of 46% based on the residue from the pot. The total yield of both was 49%. Example 2 Production of various macrocyclic lactones 1,8-di(chloromagnesiumoxy)octane, 1,10-di(chlormagnesiumoxy)decane, 1,13-di bound by reaction in the same manner as in Reference Example 1 (bromomagnesiumoxy)tridecane, 1,15-di(iodomagnesiumoxy)pentadecane, 1,18-di(
A reaction was carried out in the same manner as in Example 1 using bromomagnesiumoxy)octadecane and 1,20-di(bromomagnesiumoxy)eicosane, and the following results were obtained.

The product can be confirmed using standard materials such as GC, MS, IR, and NM.
According to R. 1,8-octanolide (50.5% yield), 1,10-decanolide (51% yield), 1,13
- trideca/lide (53% yield), 1,15-pentadeca/lide (57% yield), 1,8-octadecanolide (56% yield), 1,20-eicosanolide Do (4
3% yield). Example 3 Production of 1,12-dodecanolide 1,12-di(dibutylaluminumoxy)dodecane obtained in Reference Example 2 37 days, carbon tetrachloride 3700 days, N
-Monoku.

1,12-dodecanolide (m.p.
270-28qo) was obtained. Example 4 Reference Example 2 for the production of 1.9 nonanolide and 1.11-undeca/lide
0.1 mol of 1,9-(dietylaluminumoxy)/nan or 1,11-di(diisopropylaluminumoxy)undecane obtained in the same manner as above, 1,000 g of benzene as a solvent, and N-monopropylene. After reacting 35 ml of pionic acid amide under 50 to 80 qo for 1 hour, the same treatment as in Example 1 was performed to obtain 1,9-/nanolide (32% yield) and 1,11-undecanolide (35% yield). Obtained.

Example 5 Production of 1,15-pentadecanolide 1,15-di(diisopropoxyaluminumoxy)pentadecane obtained in Reference Example 3 was added for 39 hours, tetrahydrofuran for 500 hours, and N-chlorosuccinimide for 26 hours for 30 hours. The reaction was carried out at ~40°C for 4 hours, and treated in the same manner as in Example 1.
°C/15 side Hg) was obtained.

Yield 58% of theory. Example 6 Production of 1,8-octanolide and 1,14-tetradecanolide 1,8-di(
In the same manner as in Example 5 using dimethoxyaluminumoxy)octane and 1.14-di(ethoxyaluminumoxy)tetradecane, 1,8-octadecanolide (42% yield), 1,14- Tetradecanolide (5
6% yield) was obtained.

Example 7 Production of various macrocyclic lactones 1,8-di(methylethylaluminumoxy)octane, 1,10-di(methylallylaluminumoxy)
Examples using decane, 1,12-di(isopropylallyloxyaluminumoxy)dodecane, 1,14-di(phenylmethoxyaluminumoxy)tetradecane, and 1,16-di(ethylphenoxyaluminumoxy)hexadecane The reaction and treatment were carried out in the same manner as in 1, and the following results were obtained.

1,8-octadecanolide (44% yield), 1,10
-decanolide (45% yield), 1,12-dodecanolide (49% yield), 1,14-tetradecanolide (
50% yield), 1,16-hexadeca/lide (46%
yield).

Claims (1)

[Claims] 1 The following formula (II-1) (R)_x-Mg-O-CH_2-(CH_2)_n-
CH_2-O-Mg-(R)_x Formula (II-1) However, in the formula, R represents halogen, x represents 1, and n represents 5 to
The following formula (I) is characterized by contacting an α・ω-di(metaloxy)alkane represented by an integer of 18 with an active halogen ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ However, in the formula, n is the same as described for formula (II-1),
A method for producing a cyclic lactone represented by 2 Formula (II-2) (R)_x-Al-O-CH_2-(CH_2)_n-
CH_2-O-Al(R)_x Formula (II-2) However, in the formula, R is a linear or branched alkyl group of C_1 to C_8, an alkoxy group of C_1 to C_8, an allyl group, an allyloxy group, a phenyl group or represents a phenoxy group, x
represents 2 and n represents an integer from 2 to 18, the following formula (I) is characterized by contacting an α·ω-di(metaloxy)alkane with an active halogen etc.▼ However, in the formula, n is a method for producing a cyclic lactone, which has the same meaning as described for formula (II-2).