JP2000136177A - Production of n-alkyl-alpha-dialkylaminoaceto- hydroxamic acid compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently produce an N-alkyl-α-dialkylaminoaceto-hydroxamic acid compound by reacting an α-dialkylaminoacetic ester compound with a base and an N-alkylhydroxylamine in an alcohol in the presence of a specific metal (compound). SOLUTION: An α-dialkylaminoacetic ester compound of formula I (R1 to R3 are each an alkyl) (e.g. a compound of formula II) is reacted with a base and an N-alkylhydroxylamine (e.g. N-methylhydroxylamine) in an alcohol solvent in the presence of at least one kind of metal or metal compound (e.g. scandium salt, lanthanium salt, zinc salt or aluminum salt) selected from a group comprising II A group to IV A group including lanthanoid and II B group to IV B group to provide the objective compound of formula II (e.g. N-methyl-α- dimethylaminoaceto-hydroxamic acid). The amount of the above metal (compound) is preferably 0.01-0.50 mol based on 1 mol α-diaminoacetic ester compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an N-alkyl-α-dialkylaminoacetohydroxamic acid compound useful as a deacylating agent or the like.

[0002]

2. Description of the Prior Art N-alkyl-α-dialkylaminoacetohydroxamic acid derivatives are prepared under substantially neutral conditions.
It is a highly selective reagent useful for hydrolyzing esters in organic solvents (Journal of the Society of Synthetic Organic Chemistry, Vol. 47, 795)
(1989), Tetrahedron Lett., 30, 207 (1989), JP-A-63-316755, JP-B-6-99382, and JP-A-63-316743. Tokuhei 6-9
No. 9382 discloses a typical method for producing N-methyl-α-dimethylaminoacetohydroxamic acid, which comprises adding N, N-dimethylglycine methyl ester to N, N-dimethylglycine methyl ester in the presence of sodium hydroxide in a mixed solvent consisting of water and methanol. A method for reacting -methylhydroxylamine hydrochloride is described.

[0003]

The above-mentioned conventional production method requires a reaction at room temperature for several days, has low productivity in production, and is hardly a practical method. Further, according to the study by the present inventors, it has been clarified that under the above reaction conditions, hydrolysis of N, N-dimethylglycine methyl ester as a raw material occurs as a side reaction and causes a problem. That is, a specific operation is required to remove the by-produced N, N-dimethylglycine, and the removal of water as a solvent takes a longer time than that of an organic solvent. However, it cannot be said that this method is advantageous in view of a decrease in the yield of the target product, and therefore, there has been a demand for the development of an efficient and advantageous production method that does not cause side reactions. Therefore, the object of the present invention is to shorten the reaction time,
Production of by-products is suppressed, and N
To provide a method for producing an -alkyl-α-dialkylaminoacetohydroxamic acid compound.

[0004]

Means for Solving the Problems In view of the above circumstances, the present inventors have conducted intensive studies on the industrial production of N-alkyl-α-dialkylaminoacetohydroxamic acid compounds, and as a result, unexpectedly, certain specific methods have been proposed. The present inventors have found that the desired N-alkyl-α-dialkylaminoacetohydroxamic acid compound can be efficiently produced by carrying out the reaction in an alcohol in the presence of a metal compound, thereby completing the present invention. That is, the present invention provides (1) a general formula (1):

[0005]

Embedded image

[Wherein, R ¹ , R ² and R ³ represent alkyl groups which may be the same or different from each other. And a base and an N-alkylhydroxylamine are reacted with the α-dialkylaminoacetic acid ester compound represented by the general formula (2):

[0007]

Embedded image

[Wherein, R ¹ and R ² have the same meaning as described above, and R ⁴ represents an alkyl group. In producing an N-alkyl-α-dialkylaminoacetohydroxamic acid compound represented by the formula:
(2) a method comprising performing the reaction in an alcohol solvent in the presence of at least one metal (simple substance) selected from the group consisting of metals of Groups IIA to IVA and IIB to IVB or a metal compound thereof. The above metal compound is a scandium salt,
The method according to claim 1, which is a lanthanum salt, a zinc salt or an aluminum salt, and (3).
(1) The method according to (1) or (2), wherein the amount of the metal or the metal compound per 1 mol of the α-dialkylaminoacetic acid ester compound is 0.01 to 0.50 mol. is there.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The general formula (1) or (2) will be described. The alkyl group of R ^{1 to} R ³ is preferably an alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl,
It represents n-propyl, isopropyl, n-butyl, cyclohexyl, preferably methyl or ethyl. R
Preferred examples of the combination of ¹ and R ² include a case where both of them are methyl or ethyl. R ³ may be either methyl or ethyl, but is preferably methyl. R ⁴ has 1 to 1 carbon atoms.
And 7 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclohexyl and benzyl, preferably methyl. Next, specific examples of the compound represented by the general formula (1) are shown below, but the present invention is not limited thereto.

[0010]

Embedded image

The N-alkyl-α-dialkylaminoacetohydroxamic acid compounds produced by the method of the present invention include, for example, N-methyl-α-dimethylaminoacetohydroxamic acid, N-methyl-α-diethylaminoacetohydroxamic acid, N-ethyl-α-dimethylaminoacetohydroxamic acid, N-benzyl-α-dimethylaminoacetohydroxamic acid, N-benzyl-α-di-n-
Propylaminoacetohydroxamic acid, N-cyclohexyl-α-dimethylaminoacetohydroxamic acid, N-
Ethyl-α-di-n-butylaminoacetohydroxamic acid, N-methyl-α-dicyclohexylaminoacetohydroxamic acid and the like, among which N-methyl-α-dimethylaminoacetohydroxamic acid, N-methyl-α- Diethylaminoacetohydroxamic acid is preferably prepared by the method of the present invention.

Next, the reaction conditions and the like in the production method of the present invention will be described in detail. The method of the present invention comprises reacting an N-alkyl-α-dialkylaminoacetohydroxam oxide represented by the general formula (2) with an α-dialkylaminoacetic acid ester compound represented by the general formula (1) and N-alkylhydroxylamine A lanthanoid-containing group IIA-IVA and IIB-IV
It is carried out in an alcohol solvent in the presence of at least one metal selected from the group consisting of Group B metals or a metal compound thereof.

Groups IIA-IVA and IIB containing lanthanoids
The metal or its metal compound selected from the group consisting of metals of Groups IV to IVB includes alkaline earth metals, scandium,
Ytterbium, lanthanum, zinc, aluminum, tin, titanium, copper, iron, cobalt or nickel
A simple substance, an oxide thereof, a fluoride, a chloride, a bromide, a nitrate, a sulfate, an organic acid salt, an alkoxide, a hydroxide and the like are preferable. , Aluminum or titanium oxides, chlorides, bromides, perfluoroalkyl sulfonates or alkoxides are more preferably used, and scandium, zinc, aluminum or titanium chlorides, bromides, perfluoroalkyl sulfonates or alkoxides Is particularly preferred. Further, a metal complex or the like may be used. These can be used alone or in combination of two or more. In the present invention, the metals of groups IIA to IVA and IIB to IVB refer to elements of those groups other than boron, carbon and silicon. The amount of at least one metal selected from the group consisting of IIA to IVA and IIB to IVB metals including lanthanoids or a metal compound thereof is based on 1 mol of α-dialkylaminoacetic acid ester compound as a raw material. , 0.001 to 0.5 mol, preferably 0.02 to
It is 0.2 mol, more preferably 0.05 to 0.1 mol.

The N-alkylhydroxylamine which is a reactant may be a free N-alkylhydroxylamine or a salt thereof. Specifically, for example, N-methylhydroxylamine, N-methylhydroxylamine sulfate, N-methylhydroxylamine hydrochloride Salts, N-ethylhydroxylamine hydrochloride, N-benzylhydroxylamine hydrochloride and the like are mentioned, and N-methylhydroxylamine is preferable.
When N-alkylhydroxylamine hydrochloride or N-hydroxylamine sulfate is used, for neutralization,
0.9 to 1.2 equivalents, preferably 1.0 to 1.1 equivalents of alkali, specifically, for example, sodium methoxide,
The reaction is performed in the presence of sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like.

The amount of N-methylhydroxylamine to 1 mol of the α-dialkylaminoacetic acid ester compound represented by the general formula (1) is preferably 0.9 to 6.0 mol, more preferably 0.9 to 3.0 mol. 0 mol, more preferably 0.9 to 1.5 mol.

Alcohols usable as solvents include methanol, ethanol, isopropyl alcohol, t-
Examples thereof include aliphatic alcohols such as butyl alcohol, ethylene glycol, and ethylene glycol monomethyl ether. Preferred solvents are methanol, ethanol, and isopropyl alcohol, and methanol or ethanol is more preferred. Here, alcohols containing no water are preferred. The absence of water is preferred because the reaction activity can be kept high. The amount of the alcohol used is an amount capable of dissolving the reaction components, and specifically, 0.3 to 100 in weight ratio to the α-dialkylaminoacetic acid ester compound.
Times, preferably 0.5-20 times, more preferably 0.1 times.
5 to 5 times.

Examples of the type of chlorine used in the reaction include simple alkali metals or hydrides, oxides and hydroxides thereof. Preferred bases are hydrides and hydroxides of sodium and potassium, and sodium and potassium. Is more preferred. The reaction is usually 20 to 10
It is carried out in the range of 0 ° C., preferably 40-90 ° C.
More preferably, it is carried out in the range of 60 to 80 ° C. The reaction time varies depending on the charged amount, the reaction temperature, etc.
6 hours.

By carrying out the reaction according to the method of the present invention described above, the reaction is accelerated to a level that can be carried out industrially, and an undesirable hydrolysis reaction is largely suppressed. Using other bases, specifically sodium hydroxide, potassium hydroxide, or organic bases such as triethylamine, pyridine, the reaction is significantly slower or does not proceed at all. In order to prevent the by-product of N, N-dialkylglycine which is a hydrolyzate, for example, N, N-dimethylglycine, a solvent system containing no water is preferable.

[0019]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. Example 1 7.9 g of scandium trifluoromethanesulfonate was dissolved in methanol (30 ml), and further dissolved in 25.1 g of N-methylhydroxylamine hydrochloride and 57.9 g of a 28% methanol solution of sodium methoxide. -27.5 ml of dimethylglycine ethyl ester were added. When the reaction mixture was stirred under heating at reflux (80 ° C.) for 5 hours, the raw material residual ratio by gas chromatography became 22.4%, and the by-product ratio of N, N-dimethylglycine became 0.62% or less. After cooling the reaction mixture to room temperature, the target substance was extracted with acetonitrile from the residue obtained by concentration under reduced pressure. The acetonitrile extract was concentrated, acetonitrile was added to the residue, and the mixture was shaken sufficiently. Then, insolubles were removed by filtration. The filtrate was concentrated and the residue was recrystallized from ethyl acetate to give 13.5 g of pure N-methyl-α-dimethylaminoacetohydroxamic acid.
(50% yield). The physical data of this product are as follows. Melting point 100-101 ° C (superscript: 1) H-NMR measurement value (CDCl (subscript: 3)
Medium, δ value with TMS as standard) 2.38 (s, 6H), 3.25 (s, 2H), 3.31 (s, 3H), 10.28 (s, H) Gas chromatograph used for reaction analysis and product purity test The graphing conditions are as follows. Column: 50% (cyanopropylphenyl) methylpolysiloxane 0.53 mm × 30 m Carrier gas: helium Flow rate: 33.9 ml Detection: FID Column temperature: 100 ° C → 200 ° C (heating 10 ° C / min)

Example 2 In 60 ml of an ethanol solvent to which 2.45 g of anhydrous zinc chloride was added,
Example 1 except that the reaction was carried out using 19.5 g of N-ethylhydroxylamine hydrochloride, 13.6 g of sodium ethoxide and 21.1 g of N, N-dimethylglycine methyl ester.
16.9 g (yield 64%) of pure N-ethyl-α-dimethylaminoacetohydroxamic acid was obtained in exactly the same manner as described above.
Melting point 71 ° C-74 ° C

Example 3 Ethanol solvent 9 to which 2.45 g of anhydrous aluminum chloride was added
In 5 ml, N-methylhydroxylamine hydrogen sulfate 31.8
g, 15.0 g of sodium ethoxide and 23.4 g of N, N-dimethylglycine methyl ester in the same manner as in Example 1 except that pure N-methyl-α was used.
17.2 g of dimethylaminoacetohydroxamic acid (yield 65
%). The physical properties of this product were the same as in Example 1.

Comparative Example 1 A solution of 91.9 g of N-methylhydroxylamine hydrochloride in methanol (200 ml) was added to 212.2 g of a 28% methanol solution of sodium methoxide while cooling with ice. After the cloudy reaction mixture was stirred under ice cooling for 30 minutes, 117.2 g of N, N-dimethylglycine methyl ester was added. When the reaction mixture was stirred at 50 ° C. for a total of 9 days, the raw material remaining rate was 44.7%, and the by-product rate of N, N-dimethylglycine was 0.35 in gas chromatography.
% Or less. Most of the solvent was distilled off under reduced pressure, methanol was added to the residue, and the mixture was thoroughly shaken. Then, insolubles were removed by filtration. The filtrate was concentrated to obtain a paste-like substance.
This was analyzed by gas chromatography and found to be
Since 28% of N, N-dimethylglycine methyl ester was contaminated, it was purified by silica gel column chromatography. Elution with chloroform / methanol (9/1) yielded 33.6 g of a solid. Recrystallize from acetone, 3
1.1 g (yield 24%) of the first crystal was obtained. The solid obtained from the filtrate was also recrystallized from acetone in the same manner to obtain 1.1.
A second crystal of g was obtained. The pure N-methyl-
α-Dimethylaminoacetohydroxamic acid was 32.2 g (yield 24%).

Comparing the results of the Examples and Comparative Examples, the Examples show that the reaction time is shorter, the amount of unreacted substances is less, the yield of the desired product is better, and the production process can be simplified. I understand.

[0024]

According to the method of the present invention, an N-methyl-α-dialkylaminoacetohydroxamic acid compound useful as a deacylating agent can be efficiently produced. Also, since the method of the present invention comprises a reaction under non-aqueous conditions,
The solvent can be easily removed from the system after the reaction.

Claims (3)

[Claims] 1. General formula (1): [In the formula, R ¹ , R ² and R ³ each represent an alkyl group which may be the same or different. Α
A dialkylaminoacetic acid ester compound is reacted with a base and N-alkylhydroxylamine to give a compound of the general formula (2): [Wherein, R ¹ and R ² have the same meanings as described above, and R ⁴ represents an alkyl group. In producing an N-alkyl-α-dialkylaminoacetohydroxamic acid compound represented by the formula:
The method is carried out in an alcoholic solvent in the presence of at least one metal selected from the group consisting of Group IIB and IIB to IVB metals or metal compounds thereof. 2. The method according to claim 1, wherein the metal compound is a scandium salt, a lanthanium salt, a zinc salt or an aluminum salt. 3. The amount of metal or metal compound per mole of α-dialkylaminoacetic acid ester compound is from 0.01 to 0.01.
3. The composition according to claim 1, wherein the amount is 0.50 mol.
The method described in.