GB1596033A

GB1596033A - (-)-(2-methoxyphenyl) ethylamine

Info

Publication number: GB1596033A
Application number: GB16197/78A
Authority: GB
Original assignee: Boots Co PLC
Current assignee: Boots Co PLC
Priority date: 1978-04-25
Filing date: 1978-04-25
Publication date: 1981-08-19
Also published as: JPS54154724A

Description

(54) (-)-a-(2-METHOXYPHENYL)ETHYLAMINE (71) We, THE BOOTS COMPANY LIMITED, a British Company of 1 Thane Road West, Nottingham, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to a novel optical base.

In our cognate U.K. Application 9697/77; 1946/78 (Serial No. 1596032) we have described a process of asymmetric transformation of a 2-arylpropionic acid in which a salt of the acid with a chiral organic nitrogenous base is heated under specified conditions.

We have found that when racemic 2-(2-fluoro-4-biphenylyl)propionic acid is to be converted to acid containing a preponderance of the (+)-isomer better results are achieved when heating the salt formed from (-)-a-(2-methoxyphenyl)ethylamine than when using the salt formed from any other chiral base. This isomer is a novel compound.

Accordingly the invention provides (- )-a-(2-methoxyphenyl)ethylamine.

The invention also provides a process for preparing (-)-a-(2-methoxyphenyl)ethylamine which comprises resolving the racemic base by crystallisation of its salt formed with (+)-mandelic acid.

We have found this acid will give optically pure (-)--(2-methoxyphenyl)ethylamine with two crystallisations of the salt. When using (+)-tartaric acid no resolution occurred and using (+)-O,O'-dibenzoyltartaric acid four crystallisations were required to obtain almost optically pure base but the base recovered had + rotation.

The invention is illustrated in the following Examples in which specific rotations were measured at room temperature and in ethanol at a concentration of 1% w/v (except in the case of the free base where the rotation was measured using the neat compound).

Example 1 A warm solution of a-(2-methoxyphenyl)ethylamine (16.1 g. 0.107 mole) and (+)mandelic acid (16.1 g.. 0.107 mole) in industrial methylated spirit (50 ml) was allowed to stand at room temperature overnight. The crystalline salt was collected. washed with cold industrial methylated spirit and the salt was then dried in vacuo. A portion of this was converted into the free base and characterized as the N-isobutyryl derivative which had [a]D = -92.0". The remainder of the salt was recrystallized from industrial methylated spirit (35 ml) to give pure (-)-a-(2-methoxyphenyl)ethylammonium (+)-mandelate. This was dissolved in aqueous sodium hydroxide (20 ml. 1N) and the free base was isolated in ether. The ether extract was washed with water, dried over anhydrous magnesium sulphate, evaporated and distilled to give (-)-a-(2-methoxyphenyl)ethylamine, b.p. 125-127"C/ 25mm, [a]D = -55.6". The N-isobutyryl derivative had [a]D = -99.3".

Example 2 The salt formed from (-)-a-(2-methoxyphenyl)ethylamine and 2-(2-fluoro-4biphenylyl)propionic acid was mixed with a petroleum fraction having initial b.p. 112"C and the mixture heated at 1150C for 72 hours. The quantity of petrol was such as to dissolve 10% of the salt at 115"C. On completion of the heating the hot mixture was filtered through a steam heated Buchner funnel, the salt washed with hot petrol and dried in vacuo, to give 80.1% yield of salt. This was acidified and the acid mixture extracted with ether. The ether extract was washed with water, dried over magnesium sulphate and evaporated to give 2-(2-fluoro-4-biphenylyl)ropionic acid having a] D +42.10.

Optically pure (+)-2-(2-fluoro-4-biphenylyl)propionic acid has [a]D to44.7", and acid having an optical purity of 94.0% can be obtained with one recrystallisation of the acid from this Example.

For the purposes of comparison replacing the base of the invention with the following bases gave the following results: Yield of [a]D of acid Base salt (%) recovered ( ) (-)-(a)-methylbenzylamine 80.0 +31.3 (- )-(ct)-(4-isopropylphenyl)ethylamine 61.2 +34.2 (+)-a-cyclohexylethylamine 61.3 +29.3 (-)-a-(3-chlorophenyl)ethylamine 49.0 +37.0 )-a-(4-fluorophenyl)ethylamine 64.0 +37.3 )-a-(3-fluorophenyl)ethylamine 58.0 +34.9 (- )-a-(2-chlorophenyl)ethylamine 57.6 +37.6 It will be seen that the chiral base of the invention gives higher yields of salt from which acid of higher specific rotation is recovered than when using any of the other chiral bases above.

In addition, it is necessary to recrystallise the salts formed from these bases at least once, to obtain salt which would yield 2-(2-fluoro-4-biphenylyl)propionic acid of similar optical purity to that obtained using the base of the invention. Such further recrystallisation will obviously reduce the yield still further apart from being an undesirable further processing step.

WHAT WE CLAIM IS: 1. (-)-a-(2-Methoxyphenyl)ethylamine 2. A process for preparing (- )-a-(2-methoxyphenyl)ethylamine which comprises resolving the racemic base by crystallisation of its salt formed with (+)-mandelic acid.

3. (-)-a-(2-Methoxyphenyl)ethylamine when obtained by the process claimed in claim 2.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. the mixture heated at 1150C for 72 hours. The quantity of petrol was such as to dissolve 10% of the salt at 115"C. On completion of the heating the hot mixture was filtered through a steam heated Buchner funnel, the salt washed with hot petrol and dried in vacuo, to give 80.1% yield of salt. This was acidified and the acid mixture extracted with ether. The ether extract was washed with water, dried over magnesium sulphate and evaporated to give 2-(2-fluoro-4-biphenylyl)ropionic acid having a] D +42.10. Optically pure (+)-2-(2-fluoro-4-biphenylyl)propionic acid has [a]D to44.7", and acid having an optical purity of 94.0% can be obtained with one recrystallisation of the acid from this Example. For the purposes of comparison replacing the base of the invention with the following bases gave the following results: Yield of [a]D of acid Base salt (%) recovered ( ) (-)-(a)-methylbenzylamine 80.0 +31.3 (- )-(ct)-(4-isopropylphenyl)ethylamine 61.2 +34.2 (+)-a-cyclohexylethylamine 61.3 +29.3 (-)-a-(3-chlorophenyl)ethylamine 49.0 +37.0 )-a-(4-fluorophenyl)ethylamine 64.0 +37.3 )-a-(3-fluorophenyl)ethylamine 58.0 +34.9 (- )-a-(2-chlorophenyl)ethylamine 57.6 +37.6 It will be seen that the chiral base of the invention gives higher yields of salt from which acid of higher specific rotation is recovered than when using any of the other chiral bases above. In addition, it is necessary to recrystallise the salts formed from these bases at least once, to obtain salt which would yield 2-(2-fluoro-4-biphenylyl)propionic acid of similar optical purity to that obtained using the base of the invention. Such further recrystallisation will obviously reduce the yield still further apart from being an undesirable further processing step. WHAT WE CLAIM IS:

1. (-)-a-(2-Methoxyphenyl)ethylamine

2. A process for preparing (- )-a-(2-methoxyphenyl)ethylamine which comprises resolving the racemic base by crystallisation of its salt formed with (+)-mandelic acid.