JPS6253983A - Production of 4,5-dimethyl-1,3-dioxolen-2-one - Google Patents

Abstract

PURPOSE:To obtain in high yield the titled compound useful as an intermediate raw material for a modifier for prodrug, by converting acetoin dimer to acetoin under heating, reacting it with phosgene, subjecting the reaction product to ring formation and dehydrochlorinating the resultant product. CONSTITUTION:Acetoin as a starting raw material in which its dimer exists is heated to convert the dimer into acetoin. Then, acetoin is reacted with preferably 1.0-1.6mol (calculated as phosgene) based on 1mol acetoin of phosgene or trichloromethyl chloroformate and its reaction product is subjected to ring formation under heating and dehydrochlorinated to give the aimed compound.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing intermediate raw materials for modifiers for prodrugs.

JP-A No. 57-28884 describes useful prodrugs (in the formula, R1 represents a hydrogen atom, a lower alkyl group, or an aryl group, X represents a halogen atom, aRH is a hydrogen atom, or Ro and a carbon chain 4-chloromethyl-5-methyl-1,3-dioxolene-2-one derivatives are disclosed. -one, 4-bromomethyl-5-methyl-1,3-dioxolen-2-one. These compounds are 4.5
-dimethyl-1,3-dioxolen-2-one (hereinafter [
] is produced by halogenating MDO).

The present invention provides IIM of intermediate raw materials for the above-mentioned prodrug modifiers.
This invention relates to a method for producing IIO.

[Conventional technology]

Tetrahedr 0711 L/Tars
on Letters), 1701 (1972),
As shown in the formula below, acetoin is used as a raw material, N, N-
After reacting phosgene in the presence of dimethylaniline,
DN by heating to 180℃ and dehydrochloric acid.
A manufacturing method for obtaining DO is disclosed, with a yield of 72%.
It is stated that.

MDO [Problems to be Solved by the Invention] When the present inventors repeatedly conducted supplementary trials of the above-mentioned production method for DMDO, the yield of DMDO varied greatly each time, and the L number rate decreased. It turned.

Based on the above results, the inventors conducted various studies regarding improved methods that can produce DNDO with high yield and good reproducibility.

[Means for solving problems]

As a result of various studies, the inventors found that the above production method contains acetoin, which is normally available as a starting material, and
In fact, the dimer (hereinafter the dimer of acetoin is referred to as a dimer) is mixed in various proportions, and the yield varies depending on the dimer content, and the higher the content, the lower the yield. (See comparative test below).

Therefore, they discovered that DMDO could be obtained in high yield and with good reproducibility by converting this dimer into 7cetoin using the method described below and then reacting it with phosgene or trichloromethyl chloroformate, thereby completing the present invention. .

That is, the present invention is implemented as follows.

By heating the starting material containing dimer as it is or in a solvent, the dimer is easily converted to acetoin, and a starting material containing no dimer can be obtained.

Heating conditions depend on the content of dimer, but when heating without solvent, it is preferably under a nitrogen stream, usually at 80°C.
It is sufficient to heat and stir at ~120°C for about 1 hour, and when heating in a solvent, preferably at 40°C under a nitrogen stream.
Preferable solvents include dichloromethane, 1,2-dichloroethane, toluene, etc., which can be used directly as a reaction solvent.

Next, when the acetoin obtained by the heat treatment as described above is heat treated without a solvent, dichloromethane, 1,2-dichloroethane, or toluene is added as a reaction solvent, and acetoin such as N,N-dimethylaniline is added. It is reacted with phosgene or trichloromethyl chloroformate in the presence of an organic amine at -5 to 15°C, preferably 0 to 10°C, for 1 to 8 hours.

The amount of phosgene or trichloromethyl chloroformate to be used for acetoin is 1.0 to 1.
．． 6 times the molar amount is preferred.

The amount of organic amine used for acetoin is 1, ON1
．． 8 times the molar ratio is preferred.

After the reaction is completed, the reaction solution is washed with dilute #i acid and water, and the organic layer is separated and dried.

For example, as a reaction solvent! , 2-dichloroethane, or toluene, the desiccant is filtered off, and the solvent is distilled off after reducing the amount for usually 2 to 15 hours to obtain an oily substance. Heat and stir at 140 to 170°C for 1 to 4 hours. When dichloromethane is used as the reaction solvent, the desiccant is filtered off, the solvent is distilled off under reduced pressure to obtain an oily substance, and then this oily substance is usually evaporated under a nitrogen stream for 80 minutes.
20~SO min at 0~80℃, then 140~170℃
Heat and stir for 1 to 4 hours.

DMDO can be obtained in high yield by dissolving the oily substance obtained as described above in, for example, benzene, and crystallizing it by adding n-hexane after condensation.

Furthermore, in the present invention, the dimer itself can be converted into acetoin in the same manner as in Section L, and then subjected to a reaction with phosgene or trichloromethyl chloroformate.

〔Effect of the invention〕

According to the present invention, MDO, which is useful as an intermediate raw material for the repair agent for prodrugs, can be produced in higher yield and with better reproducibility than in conventional methods.

[Example] Next, the present invention will be described in more detail with reference to Examples and Comparative Test Examples.

The ratio of acetoin to dimer in the starting material was roughly estimated from its NMR spectrum.

Example 1 Starting material (acetoin/dimer ratio; 8G/20)5
After heating and stirring 1 g at 85°C for 1 hour under a nitrogen stream and cooling to room temperature,! , dissolved in 500 d of 2-dichloroethane.

Next, 106 g of N,N-dimethylaniline was added, and 1
After blowing in 87 g of phosgene without exceeding 5°C, the reaction mixture was further stirred at 5-15°C for 3 hours. After the reaction was completed, one reaction vessel was cooled to 0-5°C, and 250 mQ of cold 10% hydrochloric acid was added.
After washing twice and further with cold water 25QIQ, it was dried over anhydrous magnesium sulfate. After filtering off the anhydrous magnesium sulfate, the 1,2-dichloroethane solution was refluxed for 4 hours.Then, the solvent was distilled off under reduced pressure, and the obtained oil was heated and stirred at 160 to 165°C for 3 hours under a nitrogen stream. After cooling, 300% of benzene was added and treated with activated carbon. Most of the solvent was distilled off under reduced pressure, and n-hexane was added to crystallize.
0053g (yield: 80%) was obtained (melting point: 77-80°C).
).

Example 2 Starting material (acetoin/dimer ratio: 80/2G)5
After heating and stirring 1 g at 95°C under a nitrogen stream for 1 hour and cooling to room temperature, 1 osg of N,N-dimethylaniline was added, and this was added to a solution of 87 g of phosgene dissolved in 500 d of 1,2-dichloroethane at a temperature exceeding 15°C. After the completion of the addition, 054 g of DMD was added in the same manner as in Example 1.
A yield of 82%) was obtained.

Example 3 Starting material (acetoin/dimer ratio; 80/20)5
1 g was heated and stirred at 95° C. for 1 hour under a nitrogen stream, cooled to room temperature, and then dissolved in 500 g of dichloromethane together with 83 g of N,N-dimethylaniline. After cooling to 0°C, 87-5 g of trichloromethyl chloroformate was added dropwise over 30 minutes while stirring, and the mixture was further stirred at 0°C for 30 minutes and at 15°C for 2 hours.
After the reaction was completed, the reaction solution was washed twice with cold 10% hydrochloric acid 250°C, further washed with 250°C cold water, and then dried over anhydrous magnesium sulfate. After filtering off the anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting oil was heated to 80-85% under a nitrogen stream.
After heating and stirring at ℃ for 30 minutes, 180-185
The mixture was heated and stirred at ℃ for 2 hours. After cooling, benzene 250@p,
was added and treated with activated carbon, the solvent was concentrated to about 1/5 volume, and 100-n-hexane was added to crystallize the DMDO.
53 g (yield: 80%) was obtained.

Example 4 Starting material (acetoin/dimer ratio; 80/4G) 51
After adding 500 g of 1,2-dichloroethane and refluxing for 2 hours and cooling to room temperature, 83 g of N,N-dimethylaniline was added, and 87.5 g of trichloromethylchloroforme was added dropwise over 30 minutes while stirring at 0°C. and further at 0℃
After completion of the reaction, which was stirred for 2 hours at 15° C., 53 g of DMDO (yield: 80%) was obtained in the same manner as in Example 1.

Example 5 After heating and stirring 51 g of dimer at 120° C. for 30 minutes under a nitrogen stream, 053 g of DMD (yield 8) was prepared in the same manner as in Example 1.
G%) was obtained.

Comparative Test Example 1 Starting material (acetoin/dimer ratio, 80/20)5
042 g (yield: 64%) of DMD was obtained in the same manner as in Example 1, except that 1 g was used as it was without heat treatment.

Comparative Test Example 2 Starting material (acetoin/dimer ratio, 80/20)5
DMD042 was prepared in the same manner as in Example 3, except that 1 g of DMD042 was used as it was without heat treatment, and 87 g of trichloromethyl chloroformate was used.
g (yield B4%) was obtained.

Comparative Test Example 3 Starting material (acetoin/dimer ratio, flO/40)
038 g (yield: 55%) of DMD was obtained in the same manner as in Example 1, except that 51 g was used as it was without heat treatment.

Claims (1)

[Claims] 4,5-dimethyl-, which is characterized by converting the dimer of acetoin into acetoin by heating, then reacting it with phosgene or trichloromethyl chloroformate, and then cyclizing and dehydrochlorinating the product by heating. 1,
Method for producing 3-dioxolene-2-one.