JP2867847B2 - Method for producing 5-methylene-1,3-dioxolan-4-ones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing 5-methylene-1,3-dioxolan-4-ones having high utility as raw materials for synthesizing various useful substances including pharmaceuticals.

[0002]

2. Description of the Related Art 5-Methylene-1,3-dioxolane-
Since 4-ones are very reactive, they are widely used as dienophiles in the Diels-Alder reaction or as acceptors in the Michael reaction. For example, synthesis of various physiologically active substances from a spironorbornene derivative obtained by a Diels-Alder reaction between 5-methylene-1,3-dioxolan-4-ones having an optically active center introduced at the 2-position and cyclopentadiene. It has been proposed to synthesize optically active 2-norbornanone useful as a raw material (J. Mattay et al.).
al. Chem. Ber. , 122 , 327 (198
9)).

Conventionally, the following three methods have been proposed as methods for producing 5-methylene-1,3-dioxolan-4-ones.

That is, the first method uses the following reaction formula:

[0005]

Embedded image (Wherein R is a substituent such as an alkyl group) as shown in 5-bromo-5-methyl-1,3-dioxolan-4-one in 1.5 equivalents of carbon tetrachloride. By reacting triethylamine with heating under reflux for 4 hours, 5
Methylene-1,3-dioxolan-4-ones to about 6
0% yield (J. Mattay et al.
al. Chem. Ber. , 122 , 327 (19
89)).

The second method uses the following reaction formula:

[0007]

Embedded image (Wherein, R is a substituent such as an alkyl group), as shown in Table 1 with 5-bromo-5-methyl-1,3-dioxolan-4-one in benzene at room temperature. 1,8-diazabicyclo [5,4,0] undec-7-
By reacting ene (DBU), 5-methylene-
1,3-Dioxolan-4-ones are obtained in a yield of about 70% (D. Seebach et al.,
Helv. Chim. Acta. , 70 , 1104 (1
987)).

The third method is based on the following reaction formula:

[0009]

Embedded image (Wherein R is a substituent such as an alkyl group), as shown in 5-phenylsulfonylmethyl-1,3-dioxolan-4-one in dichloromethane at 0 ° C.
By reacting 3 equivalents of DBU for 2 hours, 5-methylene-1,3-dioxolan-4-ones are obtained in a yield of about 76% (WR Roush et a).
l. , J. et al. Org. Chem. , 57, 3380 (19)
92)).

[0010]

However, in the case of the above-mentioned first method, the yield is as low as about 60%, so that a large amount of 5-methylene-1,3-dioxolane is industrially produced.
There was a problem that the method for producing 4-ones was insufficient.

In the case of the second method, the yield is 70%.
%, Which is slightly improved as compared with the first method, but is industrially large in amount of 5-methylene-1,3-dioxolan-4-.
There is a problem that the method for producing onions is still insufficient. In addition, since the DBU used is a very expensive reagent, there is a problem that the production cost of 5-methylene-1,3-dioxolan-4-ones rises.

Also in the case of the third method, there is a problem that the production cost of 5-methylene-1,3-dioxolan-4-ones increases because DBU is used. There is also a problem that the cost of producing 5-phenylsulfonylmethyl-1,3-dioxolan-4-one as a raw material itself is extremely high.

[0013] The present invention is intended to solve the above-mentioned problems of the prior art, and is useful as a raw material for synthesizing various useful substances such as pharmaceuticals, 5-methylene-1,3-dioxolane. An object of the present invention is to make it possible to produce -4-ones efficiently at low cost and easily industrially.

[0014]

Means for Solving the Problems The inventors of the present invention have conducted a dehydrohalogenation reaction of 5-halogeno-5-methyl-1,3-dioxolan-4-ones to give 5-methylene-1,3-
When converting to dioxolan-4-ones, they have found that the above object can be achieved by using a tertiary amine substituted with an alkyl group having a specific number of carbon atoms as a dehydrohalogenating agent, The present invention has been completed.

That is, the present invention provides the following formula (1)

[0016]

Embedded image (Wherein, R ¹ is a substituted or unsubstituted alkyl group such as methyl, ethyl, isopropyl, cyclohexyl, or a substituted or unsubstituted aryl group such as phenyl, toluyl, naphthyl, furoyl). In a process for producing -methylene-1,3-dioxolan-4-ones: formula (2)

[0017]

Embedded image (Wherein R ¹ is as defined in formula (1), and X is a halogen such as chloro, bromo, etc.)
A halogeno-5-methyl-1,3-dioxolan-4-one derivative is converted to a compound of the formula (3)

[0018]

Embedded image (Wherein R ² , R ³ and R ⁴ are each independently an alkyl group having 4 to 12 carbon atoms), whereby the compound is converted to a compound of the formula (1) by reacting with a tertiary amine represented by the formula: A manufacturing method is provided.

Hereinafter, the present invention will be described in detail.

In the present invention, the 5-halogeno-5-methyl-dioxolan-4-one derivative of the formula (2) is dehalogenated by reacting with a tertiary amine of the formula (3) as a dehydrohalogenating agent. It is characterized by performing a hydrogen reaction. Specifically, a mixture of a 5-halogeno-5-methyl-dioxolan-4-one derivative of the formula (2) and a tertiary amine of the formula (3) is preferably used at room temperature to 150 ° C., more preferably 50 ° C. The dehydrohalogenation reaction can be performed by heating and stirring within a temperature range of 〜100 ° C. In this case, the tertiary amine of the formula (3) is preferably used in an amount of 1.0 to 10.0 equivalents, more preferably 1 to 10 equivalents to the 5-halogeno-5-methyl-dioxolan-4-one derivative of the formula (2). .
Use 0-1.5 equivalents.

The tertiary amine used in the present invention must be substituted with an alkyl group having 4 to 12 carbon atoms, preferably 8 to 10 carbon atoms, as shown in the formula (3). . This is because when the number of carbon atoms is less than 4 or more than 12, the yield of the dehydrohalogenation reaction decreases. Here, the alkyl groups R ² , R ³ and R ⁴ in the tertiary amine of the formula (3) may be linear, branched or cyclic, for example, butyl, isobutyl, hexyl, cyclohexyl, Examples thereof include a 2-ethylhexyl group and an octyl group. In addition, alkyl groups R ² , R
³ and R ⁴ may be the same or different.

In the present invention, a solvent may not be used at the time of the dehydrohalogenation reaction, but if necessary, aromatic hydrocarbons such as benzene and toluene, pentane, hexane, and the like, which do not adversely affect the reaction. Aliphatic hydrocarbons such as heptane, ethers such as tetrahydrofuran and diethyl ether, and aliphatic halides such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane may be used.

After the dehydrohalogenation reaction, the desired product, 5-methylene-1,3-dioxolan-4-one, can be isolated from the reaction solution according to a conventional method. For example, after washing the reaction solution with water, the solvent is distilled off from the organic layer under reduced pressure,
The residue was distilled under reduced pressure to give 5-methylene-1,3-
Dioxolan-4-ones can be obtained.

The 5-halogeno-dioxolan-4-one derivative of the formula (2), which is a starting material for the production method of the present invention, can be produced by various methods. For example, J. Mattay et al. Chem. Be
r. , 122 , 327 (1989).

[0025]

In the present invention, 5-halogeno-5-methyl-1,3-dioxolan-4-ones are reacted with a dehydrohalogenating agent to give 5-methylene-1,3-dioxolan-4-ones. Convert to As the dehydrohalogenating agent, a tertiary amine substituted with an alkyl group having a specific number of carbon atoms is used. This makes it possible to carry out the dehydrohalogenation reaction with high yield. Further, such a tertiary amine is easily available and inexpensive, and therefore, it is easy to industrially scale up the dehydrohalogenation reaction, and therefore, the production cost of the target product is suppressed. be able to.

[0026]

EXAMPLES Hereinafter, the production method of the present invention will be specifically described with reference to examples.

The starting materials of Examples and Comparative Examples, 2-tert-butyl-5-bromo-5-methyl-1,
3-Dioxolan-4-one is described in J. Am. Matte e
tal. Chem. Ber. , 122 , 327 (19
89) was used according to the method disclosed in the above.

Example 1 2-tert-butyl- 5 - bromo- 5 - methyl-1,
2.37 g of 3-dioxolan-4-one was dissolved in 50 ml of cyclohexane. 0.50 n-decane was added to the solution.
g (internal standard for gas chromatography analysis)
3.89 g of trioctylamine was added, and the mixture was heated under reflux for 2 hours to carry out a dehydrohalogenation reaction. When the reaction solution was analyzed by gas chromatography, the conversion rate was 1
It was confirmed that 2-tert-butyl-5-methylene-1,3-dioxolan-4-one was produced at a yield of 00% and a yield of 93%.

After allowing the reaction mixture to cool, it is washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and the solvent cyclohexane is distilled off under reduced pressure. tert-butyl-5-methylene-
1.33 g of 1,3-dioxolan-4-one was obtained (isolation yield: 85%). The physical properties data of this compound are shown below.

Boiling point: 59.0-61.5 ° C./6 Torr ¹ H-NMR (300 MHz, CDCl _{3 ′} δ):
97 (9H, s), 4.85 (1H, d, J = 2.7H
z), 5.12 (1H, d, J = 2.7 Hz), 5.4
3 (1H, s) ¹³ C-NMR (75.5 MHz, CDCl _{3 ′} δ):
24.4, 37.5, 92.6, 111.1, 146.
0,162.6.

Example 2 A dehydrohalogenation reaction was carried out in the same manner as in Example 1 except that carbon tetrachloride was used instead of cyclohexane.
2-t with 100% conversion and 90% yield in 1 hour reaction time
It was confirmed that ert-butyl-5-methylene-1,3-dioxolan-4-one was produced.

Example 3 Tributylamine 2.04 instead of trioctylamine
A dehydrohalogenation reaction was carried out in the same manner as in Example 1 except that g was used.
%, And the yield was 77%. It was confirmed that 2-tert-butyl-5-methylene-1,3-dioxolan-4-one was produced.

Example 4 A dehydrohalogenation reaction was carried out in the same manner as in Example 1 except that heptane was used instead of cyclohexane and 2.04 g of tributylamine was used instead of trioctylamine. 2-tert-butyl-5-methylene-1,3 with 100% conversion and 78% yield in 1 hour.
It was confirmed that -dioxolan-4-one was produced.

Comparative Example 1 Triethylamine 5.06 instead of trioctylamine
The dehydrohalogenation reaction was carried out in the same manner as in Example 1 except that g was used. Even if the reaction time was extended to 6 hours, the conversion was 92% and did not reach 100%.
-Butyl-5-methylene-1,3-dioxolan-4-
The ON yield was as low as 53%.

Comparative Example 2 Tripropylamine 7.1 was used instead of trioctylamine
A dehydrohalogenation reaction was carried out in the same manner as in Example 1 except that 6 g was used. Even when the reaction time was extended to 6 hours, the conversion was 80% and did not reach 100%, and 2-tert.
t-butyl-5-methylene-1,3-dioxolan-4
The yield of -one was as low as 38%.

[0036]

According to the present invention, 5-methylene-1,3-dioxolan-4-ones, which are highly useful as raw materials for synthesizing various useful substances including pharmaceuticals, can be produced at low cost and efficiently. It can be easily manufactured industrially.

Claims (1)

(57) [Claims] (1) Formula (1) (Wherein, R ¹ is a substituted or unsubstituted alkyl group or aryl group).
In a process for producing dioxolan-4-ones: formula (2) (Wherein R ¹ is as defined in formula (1), and X is halogen), and a 5-halogeno-5-methyl-1,3-dioxolan-4-one derivative represented by formula (3) ) (Wherein R ² , R ³ and R ⁴ are each independently an alkyl group having 4 to 12 carbon atoms), whereby the compound is converted to a compound of the formula (1) by reacting with a tertiary amine represented by the formula: A manufacturing method characterized in that: