JPH0616600A - Production of phenoxyethylamine - Google Patents

Abstract

PURPOSE:To obtain in an industrially advantageous way a phenoxyethylamine useful as an intermediate for medicines and pesticides, esp. insecticides using inexpensive materials by reaction of a specific phenolic compound with a specific 2-oxazolidone compound in the presence of a base. CONSTITUTION:The compound of formula III [e.g. 2-(2,3-dimethylphenoxy) ethylamine] important as a raw material for medicines and pesticides, esp. insecticides, can be obtained in high yield by reaction of (A) a phenolic compound of formula I (R<1> to R<5> are each H, alkyl, aralkyl, alkoxy, alkoxyalkyl, halogen or dialkylamino) (e.g. 2,3-xylenol) with (B) a 2-oxazolidone compound of formula II (R<6> to R<9> are each H or alkyl; R<10> is H, alkyl, aryl or aralkyl) (e.g. 2-oxazolidone) in the presence of a base (e.g. sodium methoxide) in a solvent (e.g. butanol) at 120 deg.C for 4hr.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for producing phenoxyethylamines, which is useful as a raw material for producing medical and agricultural chemicals.

[0002]

2. Description of the Prior Art Phenoxyethylamines have been known to be important as raw materials for the production of pharmaceuticals and agricultural chemicals, especially as a raw material for the production of insecticides (JP-A-59-3666).
No. 7, JP-A-62-67, etc.), it is known that they can be produced by the methods shown in the following reaction formulas (wherein Ar represents an aryl group; R and R ′ are Represents an alkyl group; X represents a halogen atom).

(1) ArOCH ₂ CH ₂ Br + NH
₃ → ArOCH ₂ CH ₂ NH ₂ Chem. B
er. , 70 (1937) p. 979 (2) ArOK + ClCH ₂ CH ₂ NH ₂ →
ArOCH ₂ CH ₂ NH ₂ · J. Pharm. Soc.
Japan, 63 (1943), page 546 (3) ArOCH ₂ CONH ₂ + LiAlH ₄ →
_{ArOCH 2 CH 2 NH 2 · Helv} . Chemica
Acta. , 31 (1948), page 1397 (4) ArOCH ₂ CH ₂ Br + potassium phthalimide → → → ArOCH ₂ CH ₂ NH ₂ · J. Chem. Soc. , (1933) p. 270 US Pat. No. 3,474,134 (5) ArOH + ethyleneimine → ArO
CH ₂ CH ₂ NH ₂ · J. Amer. Chem, So
c. , 73 (1951), page 2584 (6) ArOCH ₂ CH ₂ Br + hexamethylenetetramine → ArOCH ₂ CH ₂ NH ₂ · Roczniki Chem. , 661 (1958
Year) ・ C. A. (1961) 2537 pages

(7) ArX + NH ₂ CH ₂ CH ₂ O
K → ArOCH ₂ CH ₂ NH ₂ · Khim. Prom-St. , Ser; Reakt.
Osobo Christ. Ves Chestva
(2) 1-3 ・ C. A. 92 (3) 22184q (8) RCH ₂ NHOH + R'X → RCH ₂
NHOR '→ RCH = NR' → R'NH ₂ · Chem. Letter, vol. 10, p. 1057 (9) ArSO ₂ NHCH ₂ CH ₂ OH + NaOH
→ ArOCH ₂ CH ₂ NH ₂ Tetrahedron Lett. , Vol. 26, 228
Page 9 (10) ArOCH ₂ CN + LiAlH ₄ →
ArOCH ₂ CH ₂ NH ₂ · J. Amer. Chem.
Soc. , Volume 109 (1987) pp. 4036 to ₍₁₁₎ ArOCH 2 CH = NOH are reduced in the presence of a catalyst, a method of manufacturing a ArOCH ₂ CH ₂ NH _2. JP-A-2-62841 (12) A method of producing secondary alkylamines by reducing ArOCH ₂ CR = NOH in the presence of a catalyst.・ DE-A-1,934,014

However, these (1) to (12)
The manufacturing method described in [1] has the following problems. In (1), (4) and (6), ArOCH ₂ CH ₂ B is used.
There are many by-products during the synthesis of r, and the yield is poor. Further, since there are halogen substituents, there are many restrictions on the method of introducing a substituent into Ar, and it is very difficult to produce the target compound. In (2) and (5), the yield is very poor. In (3) and (10), since LiAlH _{4 as} a manufacturing raw material is expensive, there is a cost problem in industrial production. In (7), metal potassium as a manufacturing raw material is expensive, and further, there is a danger in handling it. In (8), since the manufacturing raw material is very expensive, there is a cost problem in industrial production. In (9), there is a problem that the reaction does not proceed unless the substituent is such as p-nitro. In (11) and (12), since the reduction reaction is a high-pressure reaction, there are large restrictions on the apparatus and there is a cost problem as an industrial manufacturing method.

Therefore, from the above problems, it has been desired to develop a method capable of industrially producing the target compound easily and at low cost under mild conditions by using a cheaper raw material than the conventional one. .

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel method for producing phenoxyethylamines, which is useful as a raw material for producing medical and agricultural chemicals.

[0008]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that phenols and 2-oxazolidones are reacted in the presence of a base under mild conditions. The inventors have found a novel method for producing phenoxyethylamines in high yield and completed the present invention.

That is, the present invention is as follows. Formula (I):

[0010]

[Chemical 4]

(In the formula, R ^{1 to} R ⁵ may be the same or different and each represents a hydrogen atom, an alkyl group, an aralkyl group, an alkoxy group, an alkoxyalkyl group, a halogen atom or a dialkylamino group). Phenols and the following formula (II):

[0012]

[Chemical 5]

(In the formula, R ^{6 to} R ⁹ may be the same or different and each represents a hydrogen atom or an alkyl group; R ¹⁰ represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group). 2-oxazolidones are reacted in the presence of a base, represented by the following formula (III):

[0014]

[Chemical 6]

The present invention relates to a method for producing phenoxyethylamines represented by the formula (wherein R ^{1 to} R ¹⁰ are as defined above). Hereinafter, the present invention will be described in detail. Each compound represented by the above formulas (I) to (III) [hereinafter referred to as compound (I) to (III), respectively]. ], The symbol (A used in the target compound [compound (III)] and its manufacturing raw materials [(I), (II)]
r, R ^{1 to} R ¹⁰ ) are as follows.

Examples of R ^{1 to} R ⁵ include the same or different hydrogen atom, alkyl group, aralkyl group, alkoxy group, alkoxyalkyl group, halogen atom, dialkylamino group and the like; alkyl group Is preferably a linear or branched alkyl group having 1 to 5 carbon atoms; the aralkyl group is preferably a linear or branched aralkyl group having 7 to 10 carbon atoms; and the alkoxy group is , A straight-chain or branched alkoxy group having 1 to 5 carbon atoms is preferable; an alkoxyalkyl group is a straight-chain or branched alkoxy group having 1 to 5 carbon atoms, or a straight-chain or branched alkoxy group having 1 to 5 carbon atoms. A chain or branched alkyl substituent is preferred; a halogen atom is preferably a chlorine atom, a fluorine atom, etc .; and a dialkylamino group is preferred. Preferred substituents are straight-chain or branched alkyl having 1 to 5 carbon atoms.

Examples of R ^{6 to} R ⁹ include a hydrogen atom and an alkyl group which may be the same or different; the alkyl group may be a straight or branched chain having 1 to 5 carbon atoms. Alkyl groups are preferred.

R ¹⁰ is a hydrogen atom, an alkyl group,
Aryl group, aralkyl group, etc. can be mentioned;
As the alkyl group, a linear or branched alkyl group having 1 to 5 carbon atoms is preferable; as the aralkyl group,
A linear or branched aralkyl group having 7 to 10 carbon atoms is preferable.

The compound (III) can be obtained in high yield by reacting the compound (I) with the compound (II) in the presence of a base or in the presence or absence of a solvent. As the base, an alkali metal lower alkoxide (eg, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium propoxide,
Potassium propoxide, sodium isopropoxide,
Potassium isopropoxide, sodium butoxide, potassium butoxide, etc.), alkali hydroxide (eg, sodium hydroxide, potassium hydroxide, etc.) can be mentioned; when alkali hydroxide is used, it reacts with phenols In order to avoid the influence of the water generated in this way, it is preferable to previously react the alkali metal phenoxide obtained by reacting the phenol with the alkali hydroxide with the 2-oxazolidone.

The solvent is not particularly limited as long as it does not directly participate in this reaction, and examples thereof include alcohols (methanol, ethanol, isopropanol, butanol, cyclohexanol, amyl alcohol, ethylene glycol, ethylene glycol monomethyl ether,
Ethylene glycol monoethyl ether, diethylene glycol, propylene glycol, etc.), ethers (dioxane, tetrahydrofuran, diethyl ether, dibutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, dimethoxyethane, etc.), aprotic polar solvents (dimethylformamide, dimethylacetamide, Examples thereof include dimethyl sulfoxide, N, N-dimethylimidazolidone, acetonitrile, etc., aromatic compounds (benzene, toluene, xylene, methylnaphthalene, petroleum ether, ligroin, hexane, chlorobenzene, dichlorobenzene, etc.). Preferably alcohols, ethers and aprotic polar solvents; more preferably those The points 80 ° C. good at is one or more [e.g., alcohols having a boiling point above butanol, ethers (diethylene glycol dimethyl ether, diethylene glycol diethyl ether), such as a non-protonic polar solvents].

The amount of the solvent used is such that the concentration of the compound (I) is 5.
-50% by weight, preferably 10-40% by weight. The amount of the raw material used is usually 1.0 to 5.0 mol, preferably 1.0, of the compound (II) per 1 mol of the compound (I).
It is recommended to use ~ 2.0 mol. The amount of the base used is usually 0.8 to 2.0 mol, preferably 0.9 to 1.5 mol, per 1 mol of compound (I).
The reaction temperature is 80 ° C. or higher, but considering the thermal stability of the raw materials and products, it is preferably 80 to 200 ° C., more preferably 90 to 150 ° C. The reaction time varies depending on the above-mentioned concentration, temperature and raw material, but is usually 2 to 100 hours.

In the reaction, it is preferable that the compound (I) is reacted with a base to generate a phenoxide, and the compound (II) is added thereto. When an alkali hydroxide is used as the base, the phenoxide obtained by reacting the compound (I) with the base is preferably dried and reacted with the compound (II).

The compound (I) can be easily obtained as a commercial product or by synthesizing by a conventional method. Examples of the compound (I) include the compounds having the substituents of R ^{1 to} R ⁵ described above; preferably phenols optionally having a substituent stable to a base (for example, , Phenol, cresol, xylenols,
(Methoxyphenol, fluorophenol, chlorophenol, benzyloxyphenol, methoxyethylphenol, ethoxyethylphenol, ethoxyethyldimethylphenol, dimethylaminophenol, etc.)
Is good. The compound (I) also includes positional isomers of the respective substituents of R ^{1 to} R ⁵ and compounds in which the substituents are duplicated.

Compound (II) can be obtained, for example, from US Pat.
437388, U.S. Pat. No. 2,437,389, U.S. Pat. No. 2,437,390, and JP-A-59-222481), and can be easily obtained by reacting a carbonic acid diester with a corresponding amino alcohol. Examples of the compound (II) include R described above.
Examples thereof include compounds having a substituent of ^{6 to} R ¹⁰ ; preferably 2-oxazolidone, 3-methyl-2.
-Oxazolidone, 3-phenyl-2-oxazolidone, 3-ethyl-2-oxazolidone, 4-methyl-2
-Oxazolidone, 4-ethyl-2-oxazolidone,
4,4-dimethyl-2-oxazolidone, 5-methyl-
2-oxazolidone, 5-ethyl-2-oxazolidone, 4,5-dimethyl-2-oxazolidone, 3,4-
Dimethyl-2-oxazolidone, 3,5-dimethyl-2
-Oxazolidone and the like are preferred.

After the completion of the reaction, the desired compound (III) produced as described above can be added with an acid to carry out operations such as liquid separation and filtration to obtain salts of phenoxyamines. The liberated compound (III) can be isolated by putting it in an aqueous alkali metal hydroxide solution to decompose it and performing operations such as solvent extraction and liquid separation. Then, it can be further purified by a purification operation such as distillation. The acid used here is
Mineral acids (hydrochloric acid, sulfuric acid, phosphoric acid, etc.) and organic acids (acetic acid, formic acid, toluenesulfonic acid, etc.) can be mentioned.
These acid decomposition reactions are normally completed in 0.1 to 1 hour at room temperature.

Examples of the compound (III) include compounds having the substituents R ^{1 to} R ¹⁰ described above corresponding to the compounds (I) and (II) as the raw materials used in the above production. Preferably; 2-phenoxyethylamine, 2- (4-methylphenoxy) ethylamine, 2- (2,3-dimethylphenoxy) ethylamine, 2- (3-methoxyphenoxy) ethylamine, 2
-(4-fluorophenoxy) ethylamine, 2- (4
-Chlorophenoxy) ethylamine, 2- (4-bromophenoxy) ethylamine, 2- (4-benzyloxyphenoxy) ethylamine, 2- [4- (2-methoxyethyl) phenoxy] ethylamine, 2- [4- (2-
Ethoxyethyl) phenoxy] ethylamine, 2- [4
-(2-Ethoxyethyl) -2,3-dimethylphenoxy] ethylamine, 2- (4-dimethylaminophenoxy) ethylamine, N-methyl-2-phenoxyethylamine, N-ethyl-2-phenoxyethylamine, N
-Phenyl-2-phenoxyethylamine, N-methyl-2- (4-methylphenoxy) ethylamine, N-methyl-2- (3-methoxyphenoxy) ethylamine,
N-methyl-2- (2,3-dimethylphenoxy) ethylamine, N-phenyl-2- (2,3-dimethylphenoxy) ethylamine, N-methyl-2- (4-fluorophenoxy) ethylamine, N-methyl- 2- [4-
(2-Methoxyethyl) phenoxy] ethylamine, N
-Methyl-2- [4- (2-ethoxyethyl) phenoxy] ethylamine, N-methyl-2- [4- (2-ethoxyethyl) -2,3-dimethylphenoxy] ethylamine, N-ethyl-2-phenoxy Ethylamine, N-
Ethyl-2- (2,3-dimethylphenoxy) ethylamine, N-ethyl-2- [4- (2-ethoxyethyl)
Phenoxy] ethylamine, N-ethyl-2- [4-
(2-Ethoxyethyl) -2,3-dimethylphenoxy] ethylamine and the like are preferable. The compound (I) also includes positional isomers of the respective substituents of R ^{1 to} R ¹⁰ and compounds in which the substituents are duplicated.

[0027]

[Boiling point 150 ° C / 4 mmHg: Kugelrohr]

Example 2 2-Fluorophenol (2.8 g) and sodium methoxide (28% methanol solution) (4.9 g) were mixed under a nitrogen atmosphere, and the mixture was stirred at 50 ° C. and then butanol (10 ml) was added. added. The reaction system was depressurized to remove methanol, and 2-oxazolidone (2.6 g) was added to 1
The mixture was stirred at 20 ° C (bath temperature) for 8 hours. The reaction mixture was cooled, 1N hydrochloric acid (50 ml) was added, this was filtered,
After liquid separation, the aqueous layer was added with 4N-NaOH until the pH became 11 or more to release organic substances. Next, this organic matter is extracted with methylene chloride, and then separated, dried and concentrated to obtain crude 2- (4-fluorophenoxy) ethylamine, which is further distilled to obtain a highly purified target compound of 0. 0.9 g was obtained (yield 23%). [Boiling point 135 ° C./3 mmHg: Kugelrohr] ¹ H-NMR (CDCl ₃ ) (δppm): 1.42
(S, 2H, NH ₂ ), 3.08 (t, 2H, C
_{H 2), 3.96 (t,} 2H, CH 2), 6.79~
7.02 (m, 4H, phenyl proton)

Example 3 4-Bromophenol (0.87 g), potassium methoxide (0.36 g) and butanol (10 ml) were mixed under a nitrogen atmosphere and the reaction system was decompressed to remove butanol. 2-Oxazolidone (1.22 g) and butanol (10 ml) were added thereto, and the mixture was heated under reflux for 3 days.
The reaction mixture was cooled, 6N-hydrochloric acid (15 ml) and methylene chloride (15 ml) were added, and the mixture was stirred for 30 minutes.
After 10N-NaOH (15 ml) and methylene chloride (15 ml) were added to this mixture for partitioning, the organic layer was washed with 1
It was washed with N-NaOH (10 ml), dried and concentrated. The obtained residue was subjected to column chromatography (Wako Gel Q C200, n-hexane: ethyl acetate = 1: 1.
1, and then 0.23 g of 2- (4-bromophenoxy) ethylamine was obtained by purification with methylene chloride: methanol = 10: 1.
%). ¹ H-NMR (CDCl ₃ ) (δ ppm): 1.86
(Brs, 2H, NH ₂ ), 3,07 (t, 2H, CH
_{2), 3.96 (t, 2H} , CH 2), 6.72~6.
84 (m, 4H, phenyl proton), 7.30-7.
41 (m, 4H, phenyl proton)

Example 4 2,3-xylenol (1.22 g), potassium methoxide (0.71 g) and butanol (10 ml) were mixed under a nitrogen atmosphere and the reaction system was depressurized to remove butanol. 3-methyl-2-oxazolidone (1.
52 g) and butanol (5 ml) were added and the mixture was heated under reflux for 10 hours. The reaction mixture was cooled to 6N hydrochloric acid (1
0 ml) and methylene chloride (15 ml) were added and the mixture was stirred for 30 minutes. 10N-NaOH (12 m
l) and methylene chloride (15 ml) were added for liquid separation, and the organic layer was washed with 1N-NaOH (10 ml), dried and concentrated. The obtained residue was subjected to column chromatography (Wako Gel Q C200, n-hexane: ethyl acetate = 1: 1, and then methylene chloride: methanol = 1.
N-methyl-
1.37 g of 2- (2,3-dimethylphenoxy) ethylamine was obtained (yield 77%). ¹ H-NMR (CDCl ₃ ) (δppm): 1.76
(Brs, 1H, NH), 2.14 (s, 3H, C
_{H 3), 2.27 (s,} 3H, CH 3), 2.97
(S, 3H, CH ₃ ), 2.29 (t, 2H, C
H ₂ ), 4.06 (t, 2H, CH ₂ ), 6.71
(D, 1H, phenyl proton), 6.77 (d, 1
H, phenyl proton), 7.03 (dd, 1H, phenyl proton)

Example 5 N-methyl-2- (3-methoxyphenoxy) ethylamine was added in the same manner as in Example 4 except that m-methoxyphenol (1.24 g) was used instead of 2,3-xylenol. 0.26 g was obtained (yield 75%). ¹ H-NMR (CDCl ₃ ) (δppm): 1.76
(Brs, 1H, NH), 2.50 (s, 3H, C
_{H 3), 2.97 (s,} 3H, CH 3), 3.78
(S, 3H, OCH ₃ ), 4.05 (t, 2H, C
H ₂ ), 6.46 to 6.66 (m, 3H, phenyl proton), 7.12 to 7.28 (m, 1H, phenyl proton)

Example 6 2,3-xylenol (1.22 g), potassium methoxide (0.71 g) and butanol (10 ml) were mixed and stirred under a nitrogen atmosphere to obtain a homogeneous solution, and then the reaction system was obtained. Was reduced to remove butanol. Butanol (5 ml) was added to the obtained potassium-2,3-xylenoxide.
And further added 3-phenyl-2-oxazolidone [Ber. Deutsch Chem. GeS. , 55
Page (manufactured according to 1966, melting point 120 ° C.) (2.4
5 g) was added and the mixture was heated under reflux for 15 hours. The reaction mixture was cooled, 6N-hydrochloric acid (20 ml) and methylene chloride (20 ml) were added, and the mixture was stirred for 1 hr. 1 for this mixture
0N-NaOH (20 ml) and methylene chloride (20 m
l) was added and the layers were separated, and then the organic layer was washed with 1N-NaOH.
It was washed 3 times (20 ml), dried and concentrated. The obtained concentrated liquid was subjected to column chromatography (Wako Gel Q
C200, eluted with n-hexane: ethyl acetate = 3: 1)
N-phenyl-2- (2,3
2.27 g of -dimethylphenoxy) ethylamine was obtained (yield 94%). ¹ H-NMR (CDCl ₃ ) (δppm): 2.15
_{(S, 3H, CH 3)} , 2.27 (s, 3H, C
H ₃ ), 3.53 (t, 2H, CH ₂ ), 4.14
(T, 2H, CH ₂ ), 6.60 to 7.27 (m, 8
H, phenyl proton)

Example 7 4- (2-Ethoxyethyl) -2,3-dimethylphenol (1.9 g) and sodium methoxide (28% methanol solution) (2 g) were mixed under a nitrogen atmosphere to give 50.
Stir at ℃. After a uniform solution was obtained, the reaction system was depressurized to remove methanol to obtain sodium 4- (2-ethoxyethyl) -2,3-dimethylphenoxide. Butanol (10 ml) was added thereto, 2-oxazolidone (1 g) was further added, and the mixture was stirred at 120 ° C. (bath temperature) for 4 hours to precipitate a colorless solid. The reaction mixture was cooled, 1N-hydrochloric acid (40 ml) was added, this was filtered, the obtained solid and the aqueous layer were mixed, and 4N-Na was added.
OH was added until the pH was above 11 to liberate organics. Next, this organic matter was extracted with methylene chloride, and then separated, dried and concentrated to obtain crude 2- [4- (2-ethoxyethyl) -2,3-dimethylphenoxy] ethylamine, which was further distilled. 1.1 g of the target compound purified with high purity was obtained (yield: 47%). [Boiling point 210 ° C./4 mmHg: Kugelrohr]

[0034]

According to the novel production method of the present invention, it is possible to produce phenoxyethylamines, which are useful as a raw material for producing pharmaceuticals and agricultural chemicals, in a high yield under moderate reaction conditions using inexpensive raw material compounds. it can.

Claims (1)

[Claims] 1. The following formula: (In the formula, R ^{1 to} R ⁵ may be the same or different and each represents a hydrogen atom, an alkyl group, an aralkyl group, an alkoxy group, an alkoxyalkyl group, a halogen atom or a dialkylamino group.) The following formula: (In the formula, R ^{6 to} R ⁹ may be the same or different and each represents a hydrogen atom or an alkyl group; R ¹⁰ represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group.) 2-oxazolidone With a group in the presence of a base, represented by the following formula: (In the formula, R ^{1 to} R ¹⁰ have the same meanings as described above.) The method for producing phenoxyethylamines.