JP2000034277A - Production of 3,3,4,4-tetramethyl-2-azetidinone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing 3,3,4,4-tetramethyl-2-azetidinone, in a high yield, excellent in operability and easy in a waste liquid treatment. SOLUTION: The chlorosulfonyl group of 1-chlorosulfonyl-3,3,4,4-tetramethyl-2- azetidinone is removed by using an alkali in the presence of a phase-transfer catalyst such as benzyltriethylammonium chloride to produce 3,3,4,4- tetramethyl-2-azetidinone.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 3,3,4,4-tetramethyl-2-azetidinone useful as an intermediate such as medicines, agricultural chemicals and additives.

[0002]

2. Description of the Related Art As a method for producing 3,3,4,4-tetramethyl-2-azetidinone, 1-chlorosulfonyl-
1,3,3,4,4-tetramethyl-2-azetidinone
A method for removing a chlorosulfonyl group at the 1-position is exemplified by a method for performing reduction using benzenethiol and pyridine [Journal of Organic Chemistry (J. Org. Chem.) No. 33].
Volume, p. 3448, published in 1968 and the same magazine, 36
Vol. 2841, published in 1971], a method of hydrolysis by adding an aqueous solution of sodium hydroxide in acetone (Journal of Organic Chemistry, Vol. 36, No. 2).
841, p. 1971) and a method of performing reduction using sodium sulfite and potassium hydroxide (Journal of Organic Chemistry, 35, 2
043 page, published in 1970).

[0003]

However, the method using benzenethiol and pyridine involves the use of a large amount (more than stoichiometric) of a strong odorous compound such as benzenethiol or pyridine, and the use of chemicals as by-products. There are problems such as that a stoichiometric amount of diphenyl disulfide or the like is generated and a separation operation is required, that the reaction needs to be performed at a low temperature, that the yield is low, and that waste liquid treatment is troublesome. The method of hydrolysis by adding an aqueous solution of sodium hydroxide in acetone is that acetone is mixed into the aqueous layer during the post-treatment, resulting in poor extraction efficiency, low yield, and troublesome treatment of waste liquid. There's a problem. In addition, the method using sodium sulfite and potassium hydroxide has a relatively high yield as compared with the above method, but it is necessary to supply the reactant while maintaining the pH of the aqueous layer slightly alkaline, There is a problem that a waste liquid containing a large amount of sodium sulfite appears. As described above, all of the conventional methods have various problems in operability, yield, and waste liquid, and are not suitable for industrial production. Therefore, an object of the present invention is to improve operability,
It is an object of the present invention to provide a method for producing 3,3,4,4-tetramethyl-2-azetidinone with a high yield and a small waste liquid load.

The present inventors have conducted intensive studies on a method for producing 3,3,4,4-tetramethyl-2-azetidinone in order to solve the above-mentioned problems of the conventional method. As a result, 1-chlorosulfonyl-3,3 It has been found that all of the above-mentioned problems can be satisfied by removing chlorosulfonyl group using 4,4,4-tetramethyl-2-azetidinone as a raw material and using an alkali in the presence of a phase transfer catalyst. Was completed.

[0005]

That is, the present invention provides:
-Chlorosulfonyl-3,3,4,4-tetramethyl-
An object of the present invention is to provide a method for producing 3,3,4,4-tetramethyl-2-azetidinone, which comprises removing a chlorosulfonyl group from 2-azetidinone using an alkali in the presence of a phase transfer catalyst.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. 1-chlorosulfonyl-3, a raw material used in the present invention,
The method for producing 3,4,4-tetramethyl-2-azetidinone and the types and contents of impurities are not particularly limited. As a production method, for example, 2,3-dimethyl-2
-A method of cycloaddition of butene and chlorosulfonyl isocyanate in an organic solvent. This way 1
-Chlorosulfonyl-3,3,4,4-tetramethyl-
When 2-azetidinone is produced, the reaction mixture may be used as it is in the present invention, or the reaction mixture purified by crystallization or the like may be used in the present invention.

Examples of the phase transfer catalyst used in the present invention include quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium bromide, and quaternary phosphonium salts such as tetrabutylphosphonium bromide. And crown ethers, cryptands, and tris [2- (2-methoxyethoxy) ethyl] amine represented by -crown-6,15-crown-5 and the like, and at least one of them is used. Among them, benzyltriethylammonium chloride is preferably used.

[0008] The present invention is carried out by adding an alkali to the reaction system. The alkali substance used is not particularly limited, but usually includes sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and the like.

The reaction of the present invention is carried out in a solution or suspension, but it is preferable to dissolve the alkali in water.

The amount of the alkali used may be at least a stoichiometric amount (3 times the mole of 1-chlorosulfonyl-3,3,4,4-tetramethyl-2-azetidinone), and preferably 1-chlorosulfonyl. -3,3,4,4-tetramethyl-2-azetidinone The molar amount is in the range of about 3.05 to about 5.0 moles. At this time, when impurities that consume alkali are contained in the raw material 1-chlorosulfonyl-3,3,4,4-tetramethyl-2-azetidinone, it is necessary to consider the amount of consumption.

The amount of the phase transfer catalyst used is about 0.001 to about 0.05 times by mass relative to the amount of 1-chlorosulfonyl-3,3,4,4-tetramethyl-2-azetidinone.
Preferably it is selected from the range of about 0.002 to about 0.02 times. If the amount of the catalyst used is less than the above range, the progress of the reaction is not sufficient, while if the amount is large, the reaction proceeds but the production cost increases.

[0012] The reaction temperature is selected from the range of about 40 ° C to about 100 ° C, preferably about 45 ° C to about 60 ° C. The reaction time varies depending on the amount of the reactants, the reaction temperature, etc., but is about 0.5.
Hours to about 48 hours.

The reaction is not particularly limited. For example, a solution in which an alkali and a phase transfer catalyst are dissolved or suspended in water is heated, and 1-chlorosulfonyl-3,
It may be carried out by supplying a solution in which 3,4,4-tetramethyl-2-azetidinone is dissolved or suspended in an organic solvent, or 1-chlorosulfonyl-3,3,4,4-tetramethyl-2. May be carried out by heating a liquid in which azetidinone and the phase transfer catalyst are dissolved or suspended in an organic solvent, and supplying a liquid in which alkali is dissolved or suspended in water,
A mixture of an alkali, a phase transfer catalyst, water, and an organic solvent is heated, and 1-chlorosulfonyl-3,
3,4,4-Tetramethyl-2-azetidinone may be supplied, but from the viewpoint of reactivity and operability, a solution obtained by dissolving an alkali and a phase transfer catalyst in water is heated. It is preferable to supply a solution in which 1-chlorosulfonyl-3,3,4,4-tetramethyl-2-azetidinone is dissolved in an organic solvent.

The post-treatment operation after the completion of the reaction is not particularly limited. For example, the reaction mixture may be used as it is, or after adding water or an organic solvent if necessary, liquid separation may be performed, and if necessary, water may be added. The layer may be extracted with an organic solvent and the organic layer concentrated.

The organic solvent used for dissolving the raw material and / or the organic solvent used for the post-treatment is usually selected from the group consisting of the reactivity with the raw material and the product, the separation from water, and the like.
Aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene and mesitylene, and ethers such as diethyl ether, diisopropyl ether and t-butyl methyl ether can be used. Among these, toluene is preferably used from the viewpoints of operability, solubility of raw materials, and good extractability of products.

The thus obtained 3,3,4,4-
Tetramethyl-2-azetidinone is further purified as necessary by means such as recrystallization and chromatography.

The waste liquid generated by the method of the present invention contains a small amount of raw materials, products and solvents in addition to the alkali salts of hydrochloric acid and sulfuric acid generated when excess alkali and chlorosulfonyl groups are removed. Therefore, the load of the waste liquid treatment is smaller than that of the conventional method, and the treatment is easy.

[0018]

According to the method of the present invention, operability is better than that of the conventional method, and 1-chlorosulfonyl-3,3,3 is obtained in high yield.
3,4 from 4,4-tetramethyl-2-azetidinone
4,4-Tetramethyl-2-azetidinone can be produced, and the treatment of waste liquid is easy, and its industrial utility value is extremely high.

[0019]

Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples.

Example 1 A 2 liter round bottom flask equipped with a thermometer, dropping funnel, condenser and mechanical stirrer was charged with 25%
375.0 g of an aqueous sodium hydroxide solution (3.53 moles of 1-chlorosulfonyl-3,3,4,4-tetramethyl-2-azetidinone) was added, and 1.50 g of benzyltriethylammonium chloride (1-chloroform) was added thereto. Sulfonyl-3,3,4,4-tetramethyl-2-azetidinone) at room temperature, and the mixture was heated to 50 ° C.
150.0 g (0.6646) of 1-chlorosulfonyl-3,3,4,4-tetramethyl-2-azetidinone was added thereto.
Mol) dissolved in 600 g of toluene was dropped from the dropping funnel over 1 hour. After incubating at 50 ° C for 1 hour, water 10
After adding 0.60 g and separating the oil layer, the aqueous layer was washed with toluene 30
Extracted with 0 g. The oil layers were combined, and toluene was distilled off under reduced pressure at 40 ° C. or lower, and dried under reduced pressure.
82.81 g of 4-tetramethyl-2-azetidinone was obtained (yield 98%). The obtained 3,3,4,4-tetramethyl-2-azetidinone was analyzed by gas chromatography to find that the content was 99.8% by area percentage.

Examples 2 and 3 The reaction was carried out in the same manner as in Example 1 except that the amount of sodium hydroxide used was changed so that the molar ratio was as shown in Table 1. Table 1 shows the yields of the obtained 3,3,4,4-tetramethyl-2-azetidinone.

[0022]

[Table 1]

Example 4, Comparative Example 1 A reaction was carried out in the same manner as in Example 1, except that the amount of benzyltriethylammonium chloride used was changed so as to have the mass ratio shown in Table 2. Table 2 shows the yields of the obtained 3,3,4,4-tetramethyl-2-azetidinone.

[0024]

[Table 2] * In Table 2 means the following. Four hours after the incubation, 66% of the used amount of the reaction reagent 1-chlorosulfonyl-3,3,4,4-tetramethyl-2-azetidinone remained unreacted.

Example 5 Using the same apparatus as in Example 1, 248 g (1.55 mol) of a 25% aqueous sodium hydroxide solution was added, 0.5 g of benzyltriethylammonium chloride was added thereto, and the temperature was raised to 50 ° C. 200 g of a reaction mixture obtained by reacting chlorosulfonyl isocyanate with 2,3-dimethyl-2-butene in a toluene solvent (including 1-chlorosulfonyl-3,3,4,4-tetramethyl-2 Azetidinone content 78 g, 0.346 mol) in toluene 300
The solution diluted with g was dropped from the dropping funnel over 1 hour.
After keeping the temperature at 50 ° C. for 1 hour, 50 g of toluene and 75 g of water were added. After separating the oil layer, the aqueous layer was extracted with 200 g of toluene. When the oil layers were combined and concentrated to dryness, 48 g of crude crystals were obtained.
(Of which 3,3,4,4-tetramethyl-2-azetidinone content 40 g, 0.314 mol, yield 91%) was obtained. After dissolving 48 g of the crude crystals in 48 g of toluene at 70 ° C., the mixture was cooled to 5 ° C. and recrystallized.
35 g of crystals of 4-tetramethyl-2-azetidinone (purity 99% or more) were obtained.

Comparative Example 2 2.4 g of sodium sulfite was dissolved in 24 g of water,
To 1-chlorosulfonyl-3,3,4,4
20.0 g of 4-tetramethyl-2-azetidinone (0.
(08861 mol) in 80 g of toluene was added dropwise over 1 hour. During this time, a 23% aqueous sodium hydroxide solution was added dropwise so that the pH was maintained at 7 to 8. After keeping the temperature at 40 ° C. for 1.5 hours and separating the oil layer, the aqueous layer was washed with toluene 40
g. The oil layers were combined, washed with 40 g of water, and concentrated to dryness to obtain 8.72 g of 3,3,4,4-tetramethyl-2-azetidinone (purity 99.8%, yield 77%). In addition, in the aqueous layer at the time of extraction and washing, 3,3,4,4-tetramethyl-2 for a total yield of 14% was added.
-Contains azetidinone.

Claims (6)

[Claims] 1. 1-chlorosulfonyl-3,3,4,4
3,3,4,4-tetramethyl-2-tetramethyl-2-azetidinone, wherein the chlorosulfonyl group is removed using an alkali in the presence of a phase transfer catalyst.
A method for producing azetidinone. 2. A phase transfer catalyst comprising a quaternary ammonium salt,
The production method according to claim 1, wherein the production method is at least one selected from the group consisting of quaternary phosphonium salts, crown ethers, cryptands, and tris [2- (2-methoxyethoxy) ethyl] amine. 3. The method according to claim 1, wherein the phase transfer catalyst is benzyltriethylammonium chloride. 4. 1-Chlorosulfonyl-3,3,4,4
The process according to claim 1, wherein the reaction mixture obtained by cycloaddition of 2,3-dimethyl-2-butene and chlorosulfonyl isocyanate is used as the tetramethyl-2-azetidinone as it is. 5. The method according to claim 1, wherein the amount of the phase transfer catalyst used is 0.001 to 0.05 times in terms of mass ratio to 1-chlorosulfonyl-3,3,4,4-tetramethyl-2-azetidinone. Production method. 6. The production method according to claim 1, wherein the amount of the alkali used is 3.05 to 5.0 times mol of 1-chlorosulfonyl-3,3,4,4-tetramethyl-2-azetidinone.