JPS6024108B2 - Process for producing macrocyclic lactones - 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 of the present invention to form a compound of formula (1) from a compound of formula (0) 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 anhar-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, “戊【.Patent,727051(195
2)", according to the following formula, and "Helv.Ch
im.

I ta. , 18, 1087 (1 $5)", according to the following formula,
8, 654 (1936), lactones are synthesized according to the following formula, and according to ``Chem. There is.

In the above-mentioned conventional method, the starting materials are cycloalkanone, 1-oxycarbosoic acid, or -oxycarbosoic acid.

The synthesis of mucarboxylic acid has the disadvantages of requiring a large number of steps, making it difficult and complicated to control operations and reaction conditions, and being expensive. In addition, the lactonization reaction operation is very complicated, and the selectivity and yield are poor. Furthermore, for example, a large dilution method is required, or in order to form a polyester,
Furthermore, there are drawbacks such as the need for a depolymerization operation, making it unsuitable for industrial implementation. The present inventors conducted research to overcome the disadvantages and deficiencies of the conventional methods described above, and to provide a method for industrially advantageous production of the lactone of formula (1) with a selected selectivity and good yield. As a result, the following formula (W), HO
-CH2-(C ratio) n-CH2-OH Formula (W) where n is an integer of 5 to 18, preferably 8 to 16. , the following formula (m), where M is Sj, Q,
Represents a metal element in Group W of the periodic table selected from the group consisting of Sn, Ti, and Zr, and R,, R2, R3, and R4 are:
They may be the same or different, and each halogen atom,
C, ~C8 straight chain or branched alkyl group, C2~C
8 alkenyl group, C8-C, o aryl group, C, ~
Represents a group selected from the group consisting of a C8 alkoxy group, a C2-C8 alkenoxy group, and a C6-C,o aryloxy group, and n represents an integer of 5 to 18. However, in the above, M is Sn When it represents, at least one of R, R2 and R3 is a group other than an alkyl group,
Metal oxy compounds such as easily available metal halides represented by formula (m), alkyl or alkenyl or aryl metal halides, alkoxy or alke/oxy or aryloxy metal halides, metal alkoxides or aryl oxides are reacted with The following formula (b) provided that in the formula, M, n, R
, , R2 and R3 are as defined above, it has been discovered that Q.w-di(metaloxy)alkane can be easily produced with almost quantitative high yield.

Furthermore, simply by bringing this formula (b)Q-di(metaloxy)alkane into contact with an active halogen through a previously unknown reaction mode, it can be produced with excellent selectivity for the macrocyclic lactone compound of formula (1). It has been discovered that oxidative lactonization can be advantageously carried out with good yield.

Therefore, an object of the present invention is to provide an industrially advantageous method for producing the macrocyclic 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.-dihydroxyalkane of the formula (W) compound used in the production of the starting material formula (0) compound of the present invention can be easily synthesized by total reduction of the corresponding Q.-dicarboxylic acid.

Specific examples of the compound of formula (W) include 1.
7-dihydroxyheptane, 1,8-dihydroxyoctane, 1,9-dihydroxynonane, 1,10-dihydroxydecane, 1,11-dihydroxyundecane, 1
・12-dihydroxydodecane, 1,13-dihydroxytridecane, 1,14-dihydroxytetradecane,
1,15-dihydroxybentadecane, 1,16-dihydroxyhexadecane, 1,17-dihydroxyheptadecane, 1,18-dihydroxyoctadecane, 1,1
Examples include 9-dihydroxynonadecane and 1,20-dihydroxyeicosane. The Q-dihydroxyalkane of the formula (N) compound selectively reacts with the Q-di(metaloxy)alkane of the formula (0), which is the raw material compound of the present invention, by acting with the compound of the formula (m). It can be converted with good yield.

This metal oxidation reaction is carried out, for example, in an inert organic solvent with Q.-dihydroxyalkane of formula (N) and -dihydroxyalkane of formula (m).
This can be carried out by bringing the metal compounds into contact with each other. The reaction temperature is, for example, about 12 piC to about 180 qo
It can be carried out at a temperature range of about 0°C to about 140°C, preferably about 0°C to about 140°C. The metal compound of formula (m) used includes Group N metal halides such as silicon tetrahalide, germanium tetrahalide, tin tetrahalide, titanium tetrahalide, zirconium tetrahalide, etc.; trimethylsilyl halide, diethyl germanium; jihalide,
C.I. ~C8 linear or branched alkyl or alkenyl or aryl group W metal halide;
Trimethoxysilyl halide, diethoxygermanium dihalide, propoxytin trihalide, diisopropoxybutoxytitanium halide, methoxyf.

C, to C8 linear or branched alkoxy, such as lopoxybutenoxyzirconium halide, triprobenoxytitanium halide, triphenoxytin halide, etc.
Alkenoxy or aryloxy Group W metal halide: C, such as dimethylethoxy germanium halide;
~C8 linear or branched alkyl alkoxy group N
Group metal halides: C, to C8 linear or branched Group W metal alkoxides or alkenoxides or aryl oxides such as tetramethoxytitanium, tetraethoxyzirconium, tetraprobenoxysilane, tetraphenoxytin, etc. be able to. The amount of these compounds of formula (m) to be used is about 1 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of the compound of formula (W).

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-hebutane,
Examples include n-octane, isooctane, petroleum ether, cyclohexane, benzene, toluene, xylene, diethyl ether, diisopropyl ether, 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 (W), 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 and removed under normal pressure or reduced pressure to obtain the Q/Yamaji of the raw material formula (0) used in the present invention in good yield and purity. (Metaloxy)alkanes can be obtained.

Since the compound of formula (0) obtained as described above has good purity, it can be used as it is in the next oxidative lactonization reaction without any particular purification operation, but if desired, it can be used in the next oxidative lactonization reaction. It can also be purified by Specific examples of the Q.-(metaloxy)alkane of formula (0) used in the method of the present invention include 1,7-di(trihalogenated metaloxy)hebutane, 1,8-di( Trihalogenated metaloxy)octane, 109-di(trihalogenated metaloxy)nonane, 1,10-di(trihalogenated metaloxy)decane, 1,11-di(trihalogenated metaloxy)undecane, 1. 12-di(trihalogenated metaloxy)dodecane, 1,13-di(
trihalogenated metaloxy)tridecane, 1,14-
Di(trihalogenated metaloxy)tetradecane, 1.
15-di(trihalogenated metaloxy)pentadecane, 1,16-di(trihalogenated metaloxy)hexadecane, 1,17-di(trihalogenated metaloxy)heptadecane, 1,18-di(trihalogenated metaloxy)pentadecane, 1,19-di(trihalogenated metaloxy)octadecane, 1,20-di(trihalogenated metaloxy)eicosane; 1,7-di(alkyl or alkenyl or aryl dihalogenated metaloxy) ) hebutane, 1,8-di(alkyl or alkenyl or aryl dihalogenated metaloxy)
Octane to 1,19-di(alkyl or alkenyl or aryl dihalogenated metaloxy) nonadecane, 1,20-di(alkyl or alkenyl or aryl dihalogenated metaloxy) eicosane; 1
・7-di(alkyl or alkenyl or aryl dihalogenated metaloxy)hebutane, 1,8-di(dialkyl or alkenyl or aryldihalogenated metaloxy)octane to 1,19-di(alkyl or alkenyl or aryl dihalogenated metaloxy) oxy)/nadecane, 1120-di(dialkyl or alkenyl or arylhalogenated metaloxy)eicosane; 1,7-di(alkoxy or alkenoxy or aryloxydihalogenated metaloxy)hebutane, 1,8-di(alkoxy or alkenoxy) or aryloxydihalogenated metaloxy) octane to 1,19-di(alkoxy or alkenoxy or aryloxydihalogenated metaloxy) nonadecane, 1,20-di(alkoxy or alkenoxy or aryloxydihalogenated metaloxy) icosane: 1. 7-di(alkoxy or alkenoxy or aryloxyhalogenated metaloxy)hebutane to 1,20-di(dialkoxy or alkenoxy or aryloxydihalogenated metaloxy)eicosane; 1,7-di(trialkyl or alkenyl or aryl or alkoxy or alkenoxy or aryloxymetaloxy) to butane to 1,20-di(trialkyl or fulkenyl or aryl or alkoxy or alkenoxy or aryloxymetaloxy)eicosane; 1,7-di(alkyldialkoxymetaloxy) Butane to 1,20-di(alkyldialkoxymetaloxy)eicosane; 1,7-di(dialkylalkoxymetaloxy)butane to 1,20-di(
Dialkyl alkoxy metal oxy) eicosane: 1.
7-di(alkylalkoxyhalogenated metaloxy)
Examples include hebutane to 1,20-di(alkylalkoxyhalogenated metaloxy)eicosane.

The lactone compound of formula (1), which is the object of the present invention, has the formula (
The Q.-di(metaloxy)alkanes of 0) can be oxidatively lactonized by contacting them with active halogens to obtain them in good yields and with excellent selectivity.

This oxidative lactonization reaction can be carried out, for example, by forming an active halogen in the reaction system with Q-di(metaloxy)alkane of formula (0) in a solvent inert to the reaction.
The reaction can be carried out by adding the haloacylamide at the same time, or by adding the N-haloacylamide in a solvent and adding the compound of formula (0) dropwise therein in any order. The reaction temperature can be carried out in a wide range, for example, from about 0 to about 150 o'clock, but from about 10 to about 800 o'clock.
This is a characteristic advantage of this oxidative lactonization reaction, as it can be carried out in a moderate temperature range. In this oxidative lactonization reaction, in addition to the target compound of formula (1), acylamide is quantitatively produced.

Another characteristic advantage of the present invention is that the N-haloacylamide used in the oxidative lactonization reaction of the present invention can be converted to the acylamide by the action of halogen, and the reagent used is not wasted. In addition to the preferred embodiments described above, the oxidative lactonization reaction of the compound of formula (0) according to the novel reaction mode of the present invention can be carried out by any means that can bring the active halogen and the compound of formula (n) into contact. Here, the active halogen is not limited to the halogen atom formed in the reaction system as shown in the above-mentioned preferred embodiments, but includes all embodiments of halogen atoms that can be brought into contact with the compound of formula (0) in the form of a halogen atom. do. 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-monobromoacetamide, N-monoiodoacetamide, N-monochloropropionic acid amide, - Monobromopropionic acid amide, N-monobromopropionic acid amide, N-monochlorobutyric acid amide, N-monobromoscalic acid amide, N-monoodobutyric acid amide, N-chlorosuccinimide, N-bromosuccinimide, N-
Examples include dosuccinimide, N-chlorophthalimide, N-bromphthalimide and N-iodophthalimide. The amount of these N-haloacylamides to be used is approximately 2 to 1 mole of the compound of formula (b) as a raw material.
~about 10 mol, preferably from about 2 to about 4 mol, is most currently employed. Examples of solvents inert to the reaction used in the oxidative lactonization reaction include:
Dichloromethane, chloroform, carbon tetrachloride, dichloroethane, n-pentane, n-hexane, petroleum
n-hebutane, n-octane, isooctane, cyclohexane, diethyl ether, diisopropyl ether,
Examples include tetrahydrofuran and benzene.

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 bride price formula (0
) About 1 to about 50 times the weight of the compound, preferably about 10 to about 20 times the weight of the compound.
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 bitter nitrogen, the solvent is concentrated and distilled under reduced pressure to obtain a good yield. , the lactone formula (1
) compound can be obtained.

During this oxidative lactonization reaction, the oligomers that may be formed can be converted into the target compound of formula (1) with high yield by heat in the presence of a depolymerization catalyst, so almost all of the oxidation reaction products are wasted. It also has the advantage that it becomes the target compound of formula (1) without having to do so. Specific examples of the macrocyclic lactone compound of formula (1), which is the final target product of the present invention obtained by the above-mentioned oxidative lactonization reaction, include 1.7-hef.

Talide, 1,8-octaride, 1,9 nonalide, 1,10-de force/ride, 1,11-undecanolide, 1,12-dodecanolide, 1,13-tridecanolide, 1,14-tetradecano Ride, 1,15-bentadecanolide (exaltolide), 1,16-hexadecanolide (dihydroambrectolide), 1
-17-heptadeca/lide, 1,18-octadecanolide, 1,19-/nadecanolide, 1,20-eicosa/lide, etc. can be mentioned. The present invention will be explained in more detail below using reference examples and examples.

Reference Example 1 Production of 1,15-di(trimethylsilyloxy)pentadecane 1. In a reaction flask, 24.4 g (0.1 mol) of 1115-dihydroxybentadecane and 20 g of chloroform were added.
A chloroform solution containing 0.25 mol of trimethylsilyl chloride (Z) was added for 30 minutes at a temperature of 1.0 to 2 mm, and the mixture was reacted for 4 hours at a temperature of 60 to 65 mm.

As a result of GLC and TLC analysis of the reaction mixture, the existing raw materials disappeared, indicating that the reaction had proceeded completely. By recovering the solvent, crude Z1.15-
Di(trimethylsilyloxy)pentadecane Satoshi. I got 9 nights. The crude product (liquid weight method) shows no absorption of hydroxyl groups (raw material), and therefore the yield is quantitative. This crude product is used in the next oxidation reaction without purification. Reference example
2 Production of 1,7-di(trichlorotitaniumoxy)hebutane A reaction flask was charged with 132 moles (0.1 mol) of 1,7-dihydroxyhebutane and 200 moles of benzene, containing 0.2 mole of titanium tetrachloride. Carbon tetrachloride solution 100 ml
After addition over a period of 1 hour at 0 to 30°C, the reaction was continued at the same temperature for 30 minutes, and the solvent was recovered to obtain 24.99 g of 1,7-di(trichlorotitaniumoxy)butane.

The yield was quantitative. Reference Example 3 Production of 1.12-di(trimethoxyzirconiumoxy)dodecane In a reaction flask, 20.2 units (0.1 mol) of 1,12-dihydroxydodecane, 600 units of toluene, and 30.2 units of tetramethoxyzirconium (0 .

It took 4 hours to produce 400 tons of ethanol-toluene.

After the reaction was completed, the solvent was recovered to obtain 44 ml of 1,12-di(trimethoxyzirconiumoxy)dodecane. (Quantitative yield) Example 1 Production of 1,15-pentadecanolide 38.8 g of 1,15-di(trimethylsilyloxy)pentadecane obtained in Reference Example 1 was dissolved in 200 g of chloroform. Add succinimide 35.62 and 1
The reaction was carried out for 12 hours at a temperature of 0 to 2.

After completion of the reaction, the reaction mixture was washed with water, washed with an aqueous sodium bicarbonate solution, dried with nitric oxide, and then the solvent was recovered and distilled under reduced pressure to obtain 4.1 units of 1.15-bentadecanolide (32% yield). The fact that the obtained substance is the target substance is based on the standard substance, specific gravity, refractive index, and G.
Confirmed by matching LC, ash, MS and NM old. In addition, IR and NMR of distillation pot residue 61 are 1115.
- It was presumed to be the target oligomer as it matched with bentadecanolide. Therefore, 5% by weight of aluminum sec-butoxide was added to the pot residue at ~300℃~0.01 skin H.
By carrying out a depolymerization reaction under g, 1,15-ventadecanolide was obtained in a yield of 49% based on the residue of the charging tank. The total yield was 55%. Example 2 Production of various macrocyclic lactones 1,8-di(trimethylsilyloxy)octane, 1,10-di(triethylgermaniumoxy)decane, 1,12-di(triisopropyl) synthesized in the same manner as in Reference Example 1 The reaction and treatment were carried out in the same manner as in Example 1 using titaniumoxy)dodecane and 1,14-di(trialylzirconiumoxy)tetradecane, and the following results were obtained.

The target substance can be confirmed using standard materials, GC-MS, melon, and NMR.
By matching. 1.8-Octanolide (3
2% yield), 1,10-decanolide (37% yield),
1,12-dodecanolide (43% yield), 1,14(
Tetradecanolide (49% yield).

Example 3 Production of 1,7-heptanolide 1,7-di(trichlorotitasooxy)hebutane obtained in Reference Example 2 25 tadiethyl ether 3000 mg, N-
React 40 minutes of iodoacetamide under 3500 for 8 hours,
Treated in the same manner as in Example 1, 1.7-heptanolide 3.3
I got the evening.

(26% yield). Example 4 Production of various macrocyclic lactones 1,9-di(trichlorosilyloxy)nonane, 1,11-di(tribromotitanoxy)undecane, 1,13-di( The reaction and treatment were carried out in the same manner as in Example 3 using triiodogermanium)tridecane and 1,20-di(trichlorosilyloxy)eicosane, and the following results were obtained.

1,9-nonalide (18% yield), 1,11-undecanolide (17% yield), 1,13-to-IJ decanolide (19% yield), 1,20-eicosanolide (1
4% yield).

Example 5 Production of 1,12-dodecanolide 44 hours of 1,12-di(trimethoxyzirconiumoxy)dodecane obtained in Reference Example 3, 300 hours of benzene, N
-73 units of chlorophthalic acid imide were reacted at 50 to 60°C for 2 hours and treated in the same manner as in Example 1 to obtain 87 units of 1.12 dodecanolide (44% yield).

Example 6 Production of various macrocyclic lactones 1,14-di(triisopropoxytitanoxy)tetradecane, 1,16-di(triisopropoxytitanoxy)tetradecane synthesized in the same manner as in Reference Example 3
Di(triallyloxytitanoxy)hexadecane, 1
・0.1 mole of 18-di(triphenoxytinoxy)octadecane, 500 moles of tetrahydrofuran, and 75 moles of N-monobromopropionic acid amide were reacted for 10 to 3 hours for 2 hours to obtain the following results. .

1,14-tetradecanolide (38% yield), 1,1
6-hexadecanolide (35% yield), 1,18-octadecanolide (27% yield).

Example 7 Production of various macrocyclic lactones 1,8-di(dimethylchlorosilyloxy)-octane, 1,10-di(allyldichlorotitaniumoxy)decane, 1,12-di(diisopropoxybromstinoxy)
A reaction was carried out in the same manner as in Example 1 using undecane, 1,14-di(butenylisopropoxychlorotitanoxy)tetradecane, and 1,16-di(methylethylmethoxysilyloxy)hexasadecane, and the following results were obtained.

1,8-octanolide (29% yield), 1,10-deca/lide (21% yield), 1,12-dodecanolide (28% yield), 1,4-tetradecanolide (total % yield) ), 1,16-hexadecanolide (36% yield).

Claims (1)

[Claims] 1 The following formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ However, in the formula, M is a group IV of the periodic table selected from the group consisting of Si, Ge, Sn, Ti, and Zr. Metal element, R_
1, R_2, and R_3 may be the same or different,
respectively, a halogen atom, a linear or branched alkenyl group of C_1 to C_8, an alkenyl group of C_2 to C_8, an aryl group of C_6 to C_1_0, an alkoxy group of C_1 to C_8, an alkenoxy group of C_2 to C_8, and a C_1 to C_8 alkoxy group, respectively.
Represents a group selected from the group consisting of aryloxy groups of _6 to C_1_0, and n represents an integer of 5 to 18. However, in the above, when M represents Sn, R_1
, at least one of R_2 and R_3 is a group other than an alkyl group, α・ω-di(metaloxy)
There are the following formula (I), ▲ mathematical formula, chemical formula, table, etc., which is characterized by bringing an alkane into contact with activated haloban. However, in the formula, n has the same meaning as described for formula (II). Lactone production method.