JPH0414661B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention is based on the formula () 9-(2,6,6-trimethyl-1-
cyclohexenyl)-3,7-dimethyl-2,4,
This invention relates to a method for producing 7-nonatriene-1,6-diol (hereinafter abbreviated as diol). The diol () produced by the present invention is a vitamin A compound used as a pharmaceutical and feed additive.
It is also useful as a synthetic intermediate for its acetate. That is, by acetylating diol () by a conventional method and then dehydrating it, it can be easily converted into highly purified vitamin A acetate, which has the highest content of total E-form and has the highest physiological activity. By hydrolyzing A acetate by a conventional method, vitamin A having a high total E-form content and high purity can be derived. [Prior Art] Conventionally, it is known that vitamin A is produced by the following method. [In the formula, Ac represents an acetyl group; Helvetica
See Chimica Acta, 30 , 1911 (1947)] [In the formula, Ph represents a phenyl group, X represents a halogen atom, and Ac represents an acetyl group;
See Chemie Ingeniuor Technik, 45 , 646 (1973)] [Problem to be solved by the invention] According to the above method (), vitamin A and its acetate with a high content of total E-forms can be obtained. The method involves many steps, especially in the partial hydrogenation step of acetylene bonds, which requires purification of the raw material acetylene diol to prevent poisoning of the catalyst used, and in order to obtain highly pure vitamin A or its acetate. It involves very complicated operational steps, such as the indispensable purification of the _C20 diol produced by the partial hydrogenation reaction, and the partial hydrogenation reaction itself requires highly skilled techniques. It is hard to say that it is an easy method. In addition, vitamin A and its acetate obtained by method () are E, Z-, in which the 11th position is in the Z configuration.
contains a large amount of mixtures, and this method reduces the total E-
In order to obtain the compound, it is necessary to isomerize the E,Z-mixture. This method requires the use of expensive triphenylphosphine, and after the reaction, triphenylphosphine is oxidized and converted to triphenylphosphine oxide, so the triphenylphosphine oxide is recovered and converted into triphenylphosphine. Reuse requires reduction treatment of triphenylphosphine oxide, followed by separation and recovery operations. Therefore, an object of the present invention is to obtain vitamin A and its acetate that can be easily produced with a high yield from readily available raw materials and have a high content of total E-forms, and can be easily derived with a high yield. The present invention provides a method for producing a compound. [Means for solving the problem] According to the present invention, the above object is achieved by solving the general formula () [In the formula, X represents a halogen atom, R is an alkali metal atom, R ¹ Mg- group, (R ¹ ) ₂ Al- group, R ¹ Zn-
base or

[Formula] represents a group. R ¹ is a lower alkyl group, a lower alkoxy group, or

[Formula] represents a group, R ² represents a lower alkyl group or a lower alkoxyalkyl group, R ³ and R ⁴ represent a hydrogen atom or a lower alkyl group, and R ² and R ³ or R ⁴ represent a bond between them. may form a ring together with an oxygen atom or a carbon atom. ] An organometallic compound produced by the reaction of an anion radical obtained from a dienyl halide and lithium metal or an aromatic compound and 4-(2,6,6-trimethyl-1-cyclohexenyl)- 2-methyl-2-butene-1
This is achieved by providing a process for the production of diols (), characterized in that they are reacted with -R and the resulting product is hydrolyzed. X and R in the above general formula () will be explained in detail. X represents a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, etc., and from an economical point of view, preferably a chlorine atom or a bromine atom. R is an alkali metal atom, R ¹ Mg- group, (R ¹ ) ₂ Al- group, R ¹ Zn
- group or

[Formula] represents a group. Examples of the alkali metal atom include lithium atom, sodium atom, and potassium atom, with lithium atom being particularly preferred. The above R ¹ is a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isobutyl group; a lower alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group; or

[Formula] represents a group. R ² represents a lower alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group; or a lower alkoxyalkyl group such as a methoxymethyl group or an ethoxymethyl group, and R ³ and R ⁴ represent a hydrogen atom or a methyl group or an ethyl group. represents a lower alkyl group such as a group or a propyl group. Further, R ² and R ³ or R ⁴ may be combined with the oxygen atom or carbon atom to which they are bonded to form a ring.

[Formula] Groups include, for example, CH ₃ OCH ₂ - group, CH ₃ CH ₂ OCH ₂ - group,

[Formula] group,

[Formula] group,

[Formula] group, CH ₃ OCH ₂ CH ₂ OCH ₂ − group,

Examples include [Formula] groups. The reaction of the dienyl halide represented by the general formula () according to the present invention with an anion radical obtained from lithium metal or lithium metal and an aromatic compound is preferably carried out in a solvent. Examples of aromatic compounds include biphenyl, 4,4'-di-t-
Butylbiphenyl, naphthalene, phenanthrene, anthracene, triphenylene, chrysene,
benzopyrene, picene, benzophenanthrene,
Examples include pyrene, among others naphthalene, biphenyl, phenanthrene, 4,
4'-di-t-butylbiphenyl is preferred. Examples of the solvent that can be used include hydrocarbon solvents such as hexane and toluene; ether solvents such as diethyl ether, tetrahydrofuran, tetrahydropyran, methyltetrahydropyran, dimethoxyethane, methyl t-butyl ether, and methylal; or a mixture thereof. The amount of dienyl halide represented by the general formula () is approximately 0.45 to 3% based on lithium metal or its anion radical.
molar equivalent, preferably about 0.48 to 2.5 molar equivalent. This reaction is normally carried out at a temperature of about -100°C to 0°C, preferably about -60°C to -20°C. The organometallic compound thus obtained and 4-
The reaction between (2,6,6-trimethyl-1-cyclohexenyl)-2-methyl-2-buten-1-al is a reaction between dienyl halide represented by the above general formula () and lithium metal or its anion radical. It is preferable to carry out the reaction in a solvent that can be used in the reaction with. 4-(2,6,6-trimethyl-1-cyclohexenyl)-2-methyl-2-butene-1-
The amount of R used is about 0.3 to 0.5 molar equivalent, preferably about 0.35 to 0.45 molar equivalent, relative to the lithium metal or its anion radical used. This reaction is usually carried out at about -100°C to 0°C, preferably about -
It is carried out at a temperature of 60°C to -20°C. In addition, this reaction is carried out when 4-(2,6,6-trimethyl-1
-cyclohexenyl)-2-methyl-2-buten-1-al can be present in the presence of the organic metal compound production reaction. By hydrolyzing the product obtained by the reaction of the above organometallic compound with 4-(2,6,6-trimethyl-1-cyclohexenyl)-2-methyl-2-buten-1-al, diol () can be manufactured. This hydrolysis reaction can be carried out by a conventional method, but
Preferably it is carried out at a temperature of from 0.degree. C. to 50.degree. C., more preferably from about -50.degree. C. to room temperature. Also, in the general formula (), R is

[Formula] When dienyl halide, which is a group, is used as a raw material,
The above hydrolysis reaction is preferably carried out under acidic conditions. Acidic conditions can be obtained by allowing an acid such as an aqueous ammonium chloride solution, dilute hydrochloric acid, or dilute sulfuric acid to exist in the reaction system. The diol () thus obtained can be separated and recovered by a conventional method. For example, the reaction mixture is washed with water, then with aqueous sodium bicarbonate if necessary, and dried, after which low-boiling substances are distilled off. After the residue is partitioned with hexane/water-methanol to remove nonpolar impurities as necessary, the diol () can be separated by recrystallization or column chromatography. For example, the dienyl halide represented by the general formula () used as a raw material can be prepared by the following method. (In the formula, X is as defined above.) It can be easily produced from the alcohol represented by the formula. In addition, in the following methods (1) to (5), the alkali metal specifically means lithium, sodium, potassium, etc. (1) A method in which the alcohol represented by the general formula () is reacted with an alkali metal hydroxide or an alkali metal, magnesium or aluminum lower alkyl alcoholate while removing water or lower alkyl alcohol from the system.
Examples of lower alkyl alcoholates include methylate, ethylate, and propylate. (2) A method of reacting an alcohol represented by the general formula () with an alkali metal, magnesium or aluminum hydride. (3) Alcohol represented by the general formula () and methyllithium, ethyllithium, butyllithium,
Organic alkali metal compounds such as phenyllithium and phenyl sodium; organic magnesium compounds such as methylmagnesium chloride, ethylmagnesium chloride, butylmagnesium bromide; organic aluminum compounds such as triethylaluminum and triisobutylaluminum; or diethylzinc and dipropylzinc A method of reacting with organic zinc compounds such as. (4) A method of reacting an alkali metal alcoholate of an alcohol represented by the general formula () with a halide of magnesium, aluminum or zinc. Specifically, the halides include chlorides, bromides, and iodides. (5) A method in which a lower aliphatic carboxylic acid ester of an alcohol represented by the general formula () is reacted with a lower alkyl alcoholate of an alkali metal while removing the lower alkyl ester of a lower aliphatic carboxylic acid from the system. (6) Alcohol shown by general formula () and general formula () (In the formula, R ² and R ³ are as defined above,

〔Example〕

EXAMPLES The present invention will be explained below with reference to Examples, but the present invention is not limited to these Examples. Example 1 1.326 g (10 mmol) of 5-chloro-3-methyl-2E,4E-pentadien-1-ol and 28 ml of methylal were placed in a 100 ml three-necked flask purged with argon, and the flask was placed on dry ice.
Soaked in acetone bath. n to the mixture in the flask
-butyllithium n-hexane solution 6.25 ml (10
mmol) was added dropwise over a period of 8 minutes at a temperature below -55°C. After stirring at the same temperature for 10 minutes, 40 ml (20 ml) of a lithium-naphthalene solution in tetrahydrofuran
mmol) was added dropwise over a period of 16 minutes at a temperature below -50°C. After stirring at the same temperature for 10 minutes, 4-(2,
6,6-trimethyl-1-cyclohexenyl)-
1.44 g of 2-methyl-2-buten-1-al (7
−46 mmol) of tetrahydrofuran in 3.5 ml
The dropwise addition took 4 minutes at a temperature of 0.degree. C. or lower. Next, after stirring at the same temperature for 10 minutes, a mixed solution of 1 ml of water and 5 ml of tetrahydrofuran was added. Remove the dry ice-acetone bath and make sure the internal temperature of the flask is 5.
When the temperature rose to 0.degree. C., a saturated aqueous ammonium chloride solution was added, followed by extraction twice with diethyl ether. The ether extract was washed with saturated brine and dried over anhydrous sodium sulfate. Low-boiling substances were distilled off from this extract under reduced pressure, and the residue was subjected to chromatography using an alumina column in which 9% by weight of water and 1% by weight of pyridine were adsorbed on alumina. 9-(2,6,6-trimethyl-
1-cyclohexenyl)-3,7-dimethyl-2,
1.71 of 4,7-nonatriene-1,6-diol
g was obtained as a yellow oil. Yield 80%. The NMR spectrum of the product is shown below. NMR spectrum (90MHz) δ ^HMS _CDCl3 : 1.9 (s, 6H); 1.2-2.0 (m, 17H); 2.66 (d, J=7Hz, 2H); 4.17 (t, J=6Hz, 2H); 4.45-6.33 (m,
5H) Example 2 5-chloro-3-methyl-2, under nitrogen atmosphere
4-E-pentadien-1-ol (2E/2Z=
82/18) Add 27.5 ml (43.7 mmol) of n-hexane solution of butyllithium to a mixture of 5.79 g (43.7 mmol) and 100 ml of tetrahydrofuran at a temperature below -40°C.
was added dropwise over a period of 10 minutes. After stirring at the same temperature for 15 minutes, 123 ml (88 mmol) of a lithium-naphthalene solution in tetrahydrofuran was added dropwise over a period of 15 minutes at a temperature below -40°C. Then, after stirring at the same temperature for 10 minutes, 4-(2,6,6-trimethyl-1-cyclohexenyl)-2-methyl-
A solution of 7.0 g (34 mmol) of 2-buten-1-al in 20 ml of tetrahydrofuran was added dropwise at a temperature of -40° C. or lower over a period of 4 minutes. After stirring at the same temperature for 30 minutes, the mixture was poured into water and extracted with diethyl ether. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. Low-boiling substances were distilled off from this extract under reduced pressure, and the residue was purified by alumina column chromatography to obtain 9-(2,6,
6-trimethyl-1-cyclohexenyl)-3,
7-dimethyl-2,4,7-nonatriene-1,
5.69g of 6-diol was obtained (yield 55.1%). Examples 3 to 10 In Example 1, 4-methyltetrahylopyran, diethyl ether, 1,2
- dimethoxyethane, a mixed solvent of equal amounts of n-hexane and tetrahydrofuran, a mixed solvent of equal amounts of acetone dimethyl acetal and tetrahydrofuran, a mixed solvent of equal amounts of tetrahydropyran and tetrahydrofuran, a mixed solvent of equal amounts of methyl t-butyl ether and tetrahydrofuran, or tetrahydrofuran. 9-(2, 6,
6-trimethyl-1-cyclohexenyl)-3,
7-dimethyl-2,4,7-nonatriene-1,
6-diol was obtained. The respective yields are shown in Table 1.

[Table] Solvent

[Table] Examples 11-13 In Example 1, instead of 10 mmol of the n-hexane solution of n-butyllithium, 10 m of the n-hexane solution of diisobutylaluminum hydride was used.
mol, using 5 mmol of diethylmagnesium in tetrahydrofuran solution and 5 mmol of diethylzinc,
9-(2,6,6-trimethyl-1-cyclohexenyl)-3,7-dimethyl- 2,4,7-nonatriene-1,6-diol was obtained. The respective yields are shown in Table 2.

[Table] Example 14 10 mmol of lithium t-butoxide was added to a solution of 1.326 g (10 mmol) of 5-chloro-3-methyl-2E,4E-pentadien-1-ol in 30 ml of toluene.
Add t-butanol solution and add 10% of toluene.
ml and then concentrated under reduced pressure. 10 ml of toluene was added to the residue, and the mixture was again concentrated under reduced pressure. Add 28 ml of tetrahydrofuran to the resulting residue, -
20 mmol of lithium-naphthalene at a temperature below 40℃
A tetrahydrofuran solution of was added dropwise. at the same temperature
After stirring for 10 minutes, 4-(2,6,6-trimethyl-1-cyclohexenyl)-2-methyl-2
A solution of 1.44 g (7 mmol) of -butene-1-al in 3.5 ml of tetrahydrofuran was added dropwise at a temperature of -40°C or lower. After stirring at the same temperature for 30 minutes, 9-(2,6,
6-trimethyl-1-cyclohexenyl)-3,
7-dimethyl-2,4,7-nonatriene-1,
1.67g of 6-diol was obtained (yield 78%). Examples 15-16 In Example 14, t of lithium t-butoxide
- Lithium ethoxide instead of butanol solution
9-(2,6,6-trimethyl-1
-cyclohexenyl)-3,7-dimethyl-2,
1.42 g (yield (67%)) and 1.38 g (yield 65%) of 4,7-nonatriene-1,6-diol, respectively.
Obtained. Example 17 A solution of 3.98 g (30 mmol) of 5-chloro-3-methyl-2,4-pentadien-1-ol in 14 ml of ethyl vinyl ether was dropped into 2 ml of ethyl vinyl ether containing a catalytic amount of p-toluenesulfonic acid under water cooling. did. After the dropwise addition, the mixture was stirred at room temperature for 2 hours, and then the reaction mixture was poured into aqueous sodium bicarbonate solution and extracted with diethyl ether. Wash the extract with saturated saline,
After drying, low-boiling substances were distilled off from this extract under reduced pressure. By distilling the residue under reduced pressure, 1 fraction with a boiling point of 64-70℃/0.65mmHg
4.48 g of -(5-chloro-3-methyl-2,4-pentadiene-1-oxy)-1 ethoxyethane
(yield 73%). The obtained 1-(5-chloro-3-methyl-2,
A solution of lithium-naphthalene in tetrahydrofuran (40 ml (20 m
mol) was added dropwise. After dropping, stir for 10 minutes and then add 4-(2,6,6-trimethyl-1-cyclohexenyl)-2-methyl-2-buten-1-al.
A solution of 1.44 g (7 mmol) in 3.5 ml of tetrahydrofuran was added dropwise at a temperature below -40°C. 30 at the same temperature
After stirring for a minute, the reaction solution was poured into water and extracted with diethyl ether. After the extract was concentrated under reduced pressure, tetrahydrofuran and dilute hydrochloric acid were added and stirred at room temperature for 1 hour. The reaction solution was extracted with diethyl ether, and the extract was washed successively with aqueous sodium bicarbonate and saturated brine, and dried. From this extract, low-boiling substances were distilled off under reduced pressure, and the residue was purified by alumina column chromatography to obtain 9-(2,6,
6-trimethyl-1-cyclohexenyl)-3,
7-dimethyl-2,4,7-nonatriene-1,
0.81g of 6-diol was obtained (yield 38%). Examples 18-20 In Example 1, lithium-naphthalene 20m
Lithium biphenyl, lithium instead of mol
4,4'-di-t-butylbiphenyl or lithium-
9-(2,6,6-trimethyl-1-cyclohexenyl)-3,7-dimethyl-2,4,
7-nonatriene-1,6-diol was obtained. The respective yields are shown in Table 3.

〔Effect of the invention〕

According to the method of the present invention, as is clear from the above examples, diol () can be easily produced in good yield from readily available raw materials. Furthermore, the diol () produced by the method of the present invention can be easily converted into vitamin A acetate with a high content of total E-form in a good yield, as is clear from the above-mentioned examples.

Claims (1)

[Claims] 1. General formula [In the formula, X represents a halogen atom, R is an alkali metal atom, R ¹ Mg- group, (R ¹ ) ₂ Al- group, R ¹ Zn-
Represents a group or [Formula] group. R ¹ represents a lower alkyl group, a lower alkoxy group, or a [Formula] group, R ² represents a lower alkyl group or a lower alkoxyalkyl group, R ³ and R ⁴ represent a hydrogen atom or a lower alkyl group, and R ² and R ³ or R ⁴ may be combined with the oxygen atom or carbon atom to which they are bonded to form a ring. ] An organometallic compound produced by the reaction of an anion radical obtained from a dienyl halide and lithium metal or an aromatic compound and 4-(2,6,6-trimethyl-1-cyclohexenyl)- 2-methyl-2-butene-1
9-(2,6,6-trimethyl-1-cyclohexenyl)-3,7-dimethyl-2,4,7-nonatriene, characterized by reacting with -R and hydrolyzing the obtained product. - A method for producing 1,6-diol.