JPH1045686A - Production of optically active 1-phenyl-ethylamines - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compounds useful as an intermediate for the synthesis of an active compound having bactericidal/fungicidal characteristics or a pharmacological property by treating a racemic 1-phenyl-ethylamine with an optically active lactic acid N-phenylcarbamate under a specific condition. SOLUTION: The method for producing optically active 1-phenyl-ethylamines of formula III is to treat a solution of a racemic 1-phenyl-ethylamine of formula I [X is a halogen; (n) is 0, 1, 2] in an alkanol with an optically active lactic acid N-phenylcarbamate of formula II at 70-100 deg.C. On reacting the compounds in 0.4-0.5 molar ratio of the latter/the former, the produced crystalline salt is separated and then treated with an aqueous alkali metal hydroxide solution in the presence of an organic solvent having a suitably and slightly miscible property with water.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel process for the preparation of known optically active 1-phenyl-ethylamines which can be used as intermediates for the synthesis of active compounds having fungicidal or fungicidal properties.

A solution of racemic 1- (4-chloro-phenyl) -ethylamine in ethanol and lactic acid (S)-(-)
6-N-phenylcarbamate solution in ethanol
By combining at a temperature between 0 ° C and 70 ° C, filtering the resulting crystal slurry with suction and treating the product with aqueous sodium hydroxide in the presence of methylene chloride,
It has already been disclosed that -1- (4-chloro-phenyl) -ethylamine can be prepared (EP-A 0 341).
475). A disadvantage of this method is that the desired enantiomer is obtained with sufficiently high optical purity only after repeated racemic resolution. Another disadvantage is that (R) -1-
In order to isolate (4-chloro-phenyl) -ethylamine with the required purity, a relatively large amount of lactic acid (S)-(-)
-N-phenyl carbamate is required.
Finally, this separation method is also limited by the fact that the crystallization is slow and the resulting salts are difficult to filter.

[0003] This time, a) equation

[0004]

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Wherein X represents a halogen and n represents a number 0, 1 or 2; a formula R-OH (II) of a racemic 1-phenyl-ethylamine wherein R represents 1 carbon atom; A alkanol of the formula (II) in an alkanol of the formula (II) at a temperature between 70 ° C and 100 ° C, optionally in the presence of an alkanol of the formula (II)

[0006]

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The optically active lactate N-phenyl carbamate of formula (I) wherein the ratio of reactants is 0.4 to 0.5 mole of formula (III) per mole of racemic 1-phenyl-ethylamine of formula (I) *) Such that the optically active lactate N-phenyl carbamate is present, then b) separating the resulting crystalline salt and optionally in the presence of an organic solvent that is sparingly miscible with water When treating with an alkali metal hydroxide aqueous solution, the formula

[0008]

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It has been found that optically active 1-phenyl-ethylamines of the formula wherein X and n have the above-mentioned meanings are obtained.

In order to label optically active compounds, the chiral centers in the above formula and in the following are marked in each case with (*).

It should be considered very surprising that the optically active 1-phenyl-ethylamines of the formula (I *) can be prepared with very high yields and excellent optical purity by the process according to the invention. . The reason is that there was no indication in the prior art that this particular method of bringing the reactants together resulted in a dramatic improvement in this result.

The method according to the invention is characterized by several advantages. For example, as described above, it enables the production of optically active 1-phenyl-ethylamine with very high yields and significant optical purity. Another advantage is that significantly less optically active lactate N-phenyl carbamate is required for racemic resolution than in the corresponding prior art methods. Another advantageous aspect is that only a relatively short time is required to crystallize each salt and the salts can be easily filtered. Furthermore, the process according to the invention is suitable for preparing both (R) and (S) enantiomers of the 1-phenyl-ethylamines of formula (I *).

A solution of one mole of lactic acid (S)-(-)-N-phenylcarbamate in isopropanol is added to a refluxing solution of two moles of racemic 1- (4-chloro-phenyl) -ethylamine in isopropanol, The resulting crystalline product is then filtered off with cooling, if the filter cake is washed successively with isopropanol and toluene and subsequently treated with aqueous sodium hydroxide solution and extracted with toluene, the steps of the process according to the invention Can be represented by the following reaction formula.

[0014]

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In the above formulas and in the following, the configuration with respect to the chiral center is in each case the symbols (S) and (R)
Indicated by.

Formula (I) gives a general definition of the racemic 1-phenyl-ethylamines required as starting materials for carrying out the process according to the invention. In this equation,
X preferably represents fluorine, chlorine or bromine, and n represents the number 0, 1 or 2.

Expression

[0018]

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And

[0020]

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[0021] 1-phenyl-ethylamines of the formula wherein X represents fluorine, chlorine or bromine are particularly preferred.

Racemic 1-phenyl-ethylamines of the formula (I) have already been disclosed (EP-A 0 341).
475).

Formula (II) provides a general definition of the alkanols required as solvents for carrying out the process according to the invention. In this formula, R is preferably methyl, ethyl,
represents n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or 2,2-dimethyl-propyl.

Isopropanol is particularly preferred.

Formula (III *) provides a definition of the optically active lactate N-phenyl carbamates required as reactants to carry out the process according to the invention. They are, in particular, lactic acid
(S)-(-)-N-phenyl carbamate and lactic acid (R)
-(+)-N-phenyl carbamate. Optically active lactate N-phenyl carbamates are also known.

The alkali metal hydroxide solution suitable for releasing optically active 1-phenyl-ethylamines is preferably an aqueous solution of sodium hydroxide or potassium hydroxide. Aqueous sodium hydroxide is particularly preferred.

Suitable organic solvents in each case for extracting the optically active 1-phenylethylamine are preferably methylene chloride, tert-butyl methyl ether or toluene. Toluene is particularly preferred.

When carrying out the process according to the invention, the reaction temperatures can be varied within a certain range. In general, the process is carried out at a temperature between 70 and 100 ° C., preferably at the reflux temperature of the mixture of 1-phenyl-ethylamine and alkanol, unless the temperature exceeds 100 ° C. When low-boiling alkanols are used,
The process is carried out at a pressure slightly above atmospheric to obtain the desired temperature range.

In carrying out the process according to the invention, the amount of reactants is 1 mol of the racemic 1-phenyl-formula (I).
It is selected so that 0.4 to 0.5 mol of optically active lactate N-phenylcarbamate of formula (III *) is present per ethylamine. However, higher amounts of optically active lactate N-phenylcarbamate can also be used.

When carrying out the process according to the invention, the time period during which the optically active lactate N-phenylcarbamate is added to the solution of 1-phenylethylamine in the alkanol can be varied within a substantial range. In general, metering is carried out in such a way that 1 mol of optically active N-phenylcarbamate is added to the corresponding amount of 1-phenyl-ethylamine over a period of 1 to 5 hours. Preferably,
As soon as the crystalline product has precipitated from the alcoholic solution of the amine, the process is carried out such that the addition of the optically active N-phenylcarbamate is interrupted for 5 to 60 minutes.

Generally, the process according to the invention is carried out at atmospheric pressure. However, if low-boiling alcohols are used, the process may be carried out under pressure, or if high-boiling alcohols are used,
It can also be carried out under reduced pressure.

When carrying out the process according to the invention, the detailed steps are necessary after adding an alcoholic solution of the racemic 1-phenyl-ethylamine of the formula (I) into a reaction vessel and heating it to the desired temperature. Adding an appropriate amount of the optically active lactate N-phenylcarbamate of formula (III *) within a selected time period. The optically active lactate N-phenylcarbamate may be added in solid form or as a solution in an alkanol of formula (II).

After the addition has ended, preferably after precooling, the reaction mixture is filtered off with suction and the product is washed with alcohol or toluene. The enantiomer of 1-phenyl-ethylamine contained in the filtrate and not reacting with the optically active lactate N-phenylcarbamate may be isolated or may be subjected to racemization and recycled. The filter residue may be treated with an aqueous alkali metal hydroxide solution after it has been wetted with a solvent or after previously dried, and the treatment using the aqueous alkali metal hydroxide solution is performed at room temperature. It is preferred to use a small excess of aqueous alkali metal hydroxide to keep the pH of the mixture in the alkaline range, for example 12-13.

The subsequent processing is performed by a general method. In general, the steps of repeatedly extracting the mixture with an organic solvent that is slightly miscible with water, concentrating the combined organic phases under reduced pressure, and distilling the remaining residue are performed.

The aqueous phase essentially comprises the optically active lactate N-phenyl-carbamate used in the form of an alkali metal salt. The free acid may be recovered by precipitating and acidifying the mixture.

When carrying out the process according to the invention, lactic acid
If (S)-(-)-N-phenylcarbamate is used, this is a reaction of the 1-phenyl-ethylamine used.
(R) Form salts with enantiomers. The resulting product is thus the (R) enantiomer of this amine. In a similar way,
Of 1-phenyl-ethylamine used by using lactic acid (R)-(+)-N-phenylcarbamate
The (S) enantiomer is obtained.

The formula (I) which can be prepared by the process according to the invention
*) Optically active 1-phenyl-ethylamines are valuable intermediates for the synthesis of active compounds with fungicidal or fungicidal properties or pharmacological properties (EP-A03).
41 475 and EP-A0 300 313).
Therefore, the expression

[0038]

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And

[0040]

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N- (R)-[1- (4-Chloro-phenyl) -ethyl]-(1R) -2,2-dichloro-1-ethyl-3t-methyl-1r-cyclopropanecarboxamide and N- Fungicidal / fungicidal diastereomer of (R)-[1- (4-chloro-phenyl) -ethyl]-(1S) -2,2-dichloro-1-ethyl-3t-methyl-1r-cyclopropanecarboxamide The mixture has the formula

[0042]

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(1R) -2,2-Dichloro-1-ethyl-3t-methyl-1r-cyclopropanecarbonyl chloride and (1S) -2,2-dichloro-1-ethyl-
A 1: 1 mixture of 3t-methyl-1r-cyclopropanecarbonyl chloride is prepared in the presence of a diluent, for example, methyl chloride, and an acid-binding agent, for example, triethylamine.

[0044]

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By reacting with R-1- (4-chloro-phenyl) -ethylamine.

The method according to the invention is further illustrated by the following examples.

[0047]

EXAMPLES Preparation Example Example 1

[0048]

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205 g (0.98 mol) of lactic acid (S)-
(-)-N-phenylcarbamate (R: S ratio = 2: 9
A solution of 8) in 585 g of isopropanol is prepared by heating the mixture to 40 ° C. 120 g of this solution are added dropwise over 20 minutes to a refluxing solution of 320 g (2.06 mol) of racemic 1- (4-chloro-phenyl) -ethylamine in 350 g of isopropanol. The mixture is first refluxed for 30 minutes without further addition, and the remainder of the solution of lactic acid (S)-(-)-N-phenylcarbamate in isopropanol is then added dropwise over 90 minutes to the refluxing reaction mixture. The reaction mixture is then
C. and filtered with suction through a pressure filter,
In this case, the filter is subjected to a pressure of 0.5 bar over atmospheric pressure. The collected amount of filtrate was 6 after 2.5 minutes.
Reaches 00 g and after 9 minutes reaches 870 g. The filter cake is washed successively with isopropanol and toluene. The filter cake is subsequently suspended in water, aqueous sodium hydroxide solution is added until a pH of 12.5 is reached, and the mixture is stirred at room temperature for 5 minutes and extracted repeatedly with toluene. The organic phase is concentrated under reduced pressure. In this way, 130 g (8 of theory)
1.2%) of (R) -1- (4-chloro-phenyl) -ethylamine (R: S ratio = 98.6: 1.4) are obtained.

Comparative Example A

[0051]

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205 g (0.98 mol) of lactic acid (S)-
(-)-N-phenylcarbamate (R: S ratio = 2: 9
A solution of 8) in 585 g of isopropanol is prepared by heating the mixture to 40 ° C. Add this solution to 6
Dropwise, a solution of 320 g (2.06 mol) of racemic 1- (4-chloro-phenyl) -ethylamine in 350 ml of isopropanol kept at 0 ° C. is stirred. The reaction mixture is then cooled to 5 ° C. and filtered off with suction through a pressure filter, the latter being at a pressure of 0.5 bar above atmospheric pressure. The collected amount of filtrate reaches 600 g after 15 minutes. Even after extended suction filtration, 870 g of filtrate are not obtained. The still wet filter cake is suspended in water, aqueous sodium hydroxide solution is added until a pH of 12.5 is reached, and the mixture is stirred at room temperature for 5 minutes and extracted repeatedly with toluene. The organic phase is concentrated under reduced pressure.
In this way, 137 g (85.6% of theory) of (R)-
1- (4-Chloro-phenyl) -ethylamine (R: S ratio = 94.3: 5.7) is obtained.

Comparative Example B

[0054]

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91 g both heated to 60-70 ° C.
(0.587 mol) of racemic 1- (4-chloro-phenyl) -ethylamine in 300 ml of isopropanol and 122 g (0.583 mol) of lactic acid (S)-
The solution of (-)-N-phenylcarbamate in 800 ml of isopropanol is combined and left at room temperature for 16 hours. The resulting crystal slurry is filtered off with suction and then treated with a mixture of 200 ml of a 10% strength aqueous sodium hydroxide solution and 300 ml of methylene chloride. The organic phase is separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. In this way, 44.
5 g of (R) -1- (4-chloro-phenyl) -ethylamine having an optical purity of 89.4% ee are obtained.

44 g (0.28 mol) of (R) -1 formed
150 ml of-(4-chloro-phenyl) -ethylamine
Solution in ethanol at 60 ° C. and
59 g (0.282 mol) of lactic acid (S) heated to 0 ° C
Combine with a solution of-(-)-N-phenylcarbamate in 400 ml of ethanol and leave at room temperature for 16 hours. The resulting crystal slurry is filtered off with suction and then treated with a mixture of 200 ml of a 10% strength aqueous sodium hydroxide solution and 300 ml of methylene chloride.
The organic phase is separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. In this way, 40.4 g
(88.8% of theory) with an optical purity of 97.4% ee
(R) -1- (4-Chloro-phenyl) -ethylamine is obtained.

The main features and aspects of the present invention are as follows.

1.a) Equation

[0059]

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Wherein X represents a halogen and n represents a number 0, 1 or 2. Formula R-OH (II) of a racemic 1-phenyl-ethylamine wherein R represents 1 carbon atom A alkanol of the formula (II) in an alkanol of the formula (II), optionally at a temperature of between 70 ° C and 100 ° C.

[0061]

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Treated with the optically active lactate N-phenylcarbamate wherein the ratio of reactants is 0.4-0.5 mol of formula (III) per mole of racemic 1-phenyl-ethylamine of formula (I) *) Such that the optically active lactate N-phenylcarbamate is present, then b) separating the resulting crystalline salt and, optionally, in the presence of an organic solvent which is slightly miscible with water, with an alkali metal Formula characterized by treating with an aqueous oxide solution

[0063]

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Wherein X and n have the above-mentioned meanings.

2. The racemic 1-phenyl-ethylamines used have the formula

[0066]

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The method according to the above-mentioned item 1, which is a compound of the formula: wherein X is fluorine, chlorine or bromine.

3. The racemic 1-phenyl-ethylamines used have the formula

[0069]

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Wherein X is fluorine, chlorine or bromine, or

[0071]

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The method according to the above 1, wherein the compound is

4. The racemic 1-phenyl-ethylamine used has the formula

[0074]

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The method according to 1 above, wherein the compound is

5. The racemic 1-phenyl-ethylamine used has the formula

[0077]

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The method according to the above 1, wherein the compound is

6. formula

[0080]

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1- (4-chlorophenyl) -ethylamine of the formula

[0082]

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(1) The method according to the above (1), wherein lactic acid (S)-(-)-N-phenylcarbamate is used.

7. When the solvent used is a compound in which R is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.
-Butyl, tert-butyl or 2,2-dimethyl-
The method according to 1 above, wherein the alkanol is alkanol of formula (II) representing propyl.

8. The method according to claim 1, wherein the solvent used is isopropanol.

9. The method according to claim 1, wherein the alkali metal hydroxide solution used is a sodium hydroxide solution or a potassium hydroxide solution.

10. The process of claim 1 wherein the organic solvent used that is slightly miscible with water is toluene.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Ud Kraz Germany

Claims (3)

[Claims] 1. a) Formula: ## STR1 ## Wherein X represents a halogen and n represents the number 0, 1 or 2 of the formula R-OH (II) of the racemic 1-phenyl-ethylamine, wherein R is 1 to 5 carbon atoms. A alkanol of the formula [II] at a temperature between 70 ° C and 100 ° C, optionally in the presence of an alkanol of the formula (II). Of the optically active lactate N-phenylcarbamate, wherein the ratio of the reactants is from 0.4 to 0.5 mole of the formula (III) per mole of racemic 1-phenyl-ethylamine of the formula (I)
*) Such that the optically active lactate N-phenylcarbamate is present, then b) separating the resulting crystalline salt and, optionally, in the presence of an organic solvent which is slightly miscible with water, with an alkali metal A formula characterized by treating with an aqueous oxide solution Wherein X and n have the above-mentioned meanings. 2. The racemic 1-phenyl-ethylamine used has the formula ## STR4 ## The method according to claim 1, which is a compound of the formula: 3. The racemic 1-phenyl-ethylamine used has the formula ## STR5 ## The method according to claim 1, which is a compound of the formula: