GB2246774A - Preparation of enantiomers of 1-(2,6-dimethylphenoxy)-2-aminopropane and N-acyl derivatives thereof - Google Patents
Preparation of enantiomers of 1-(2,6-dimethylphenoxy)-2-aminopropane and N-acyl derivatives thereof Download PDFInfo
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Abstract
A process for the preparation of 1-(2,6-dimethylphenoxy)-2-aminopropane predominantly in the form of the S enantiomer and/or N-acyl-1-(2,6-dimethylphenoxy)-2-aminopropane predominantly in the form of the R enantiomer, which process comprises supplying N-acyl-1-(2,6-dimethylphenoxy)-2-aminopropane to a biocatalyst capable of stereoselectively hydrolysing the N-acyl group of the S enantiomer to 1-(2,6-dimethylphenoxy)-2-aminopropane and recovering the 1-(2,6-dimethylphenoxy-2-aminopropane predominantly in the form of the S enantiomer and/or N-acyl-1-(2,6-dimethylphenoxy)-2-aminopropane predominantly in the form of the R enantiomer. Optionally, the N-acyl-1-(2,6-dimethylphenoxy)-2-aminopropane recovered predominantly in the form of the R enantiomer, may be converted to (R)-1-(2,6-dimethylphenoxy)-2-aminopropane.
Description
PREPARATION OF ENANTIOMERS OF l-(2,6-DIMETHYLPHENOXY)-2-AMINOPROPANE The present invention relates to a process for the stereoselective preparation of enantiomers of l-(2,6-dimethylphenoxy)-2-aminopropane.
l-(2,6-dimethylphenoxy)-2-aminopropane, more commonly referred to as Mexiletine, is active as a pharmaceutical, in particular as an antiarrhythmic agent.
US Patent No. 3,954,872 (US-A-3,954,872) discloses compounds of the formula
wherein R is hydrogen or alkyl of 1 to 3 carbon atoms, and R1 is hydrogen or methyl, and non-toxic, pharmacologically acceptable acid salts thereof. When
R and R1, are both hydrogen, formula I represents l-(2,6-dimethylphenoxy)-2-aminopropane.
In common with a number of pharmaceutically active compounds, the two enantiomers of 1- (2, 6-dimethyiphenoxy) -2-aminopropane exhibit differing levels of pharmacological activity. It follows that a preferred process for the preparation of l-(2,6-dimethylphenoxy)-2-aminopropane is one which stereoselectively yields the compound predominantly in one enantiomeric form.
US-A-3,954,872 discloses three methods for the preparation of compounds of formula I starting from an
N-protected form of the compounds of formula I, from 2,6-dimethylphenol or its metal salt, or from the imines or N-substituted imines corresponding to the compounds of formula I. However, none of the three methods disclosed are tailoredd to producing the compound of formula I predominantly in the form of one enantiomer. Instead, in US-A-3,954,872 it is suggested that the racemic mixtures of the compound of formula I may be divided into their optically active antipode components by conventional methods, for example by salt formation with optically active acids such as D-3-bromocamphor-8-sulfonic acid or dibenzoyl-D-tartaric acid.Alternatively, it is suggested that an optical antipode can be obtained by starting with an optically active antipode of the
N-protected form of the compound of formula I. There is no disclosure in US-A-3,954,872 of a method for preparing optically active antipodes of the
N-protected forms of the compounds of formula I.
A number of studies into the pharmokinetic and pharmacological performance of l-(2,6-dimethylphenoxy)-2-aminopropane have been conducted.
Grech-Belanger, O.; Turgeon, J. and Gilbert, M.;
Br. J. clin. Pharmac. (1986), 21, 481-487 investigated the pharmokinetics of S-(+)- and R-(-)- mexiletine (1(2, 6-dimethylphenoxy) -2-aminopropane) and of the corresponding conjugates after administration of a dose of racemic mexiletine (l-(2,6-dimethylphenoxy)2-aminopropane) to volunteers.
McErlane, K.M. and Igwemeziel, L.; Journal of
Chromatography, 415 (1987) 335-346, Biomedical
Applications, developed a sensitive, stereoselective high-performance liquid chromatographic assay for the resolution of enantiomers of mexiletine (1- (2, 6-dimethylphenoxy) -2-aminopropane) as their 2-naphthoyl derivatives and conducted a study of the stereoselective disposition of the enantiomers in man.
Hanon, D.W.G.; Grech-Belanger, O.; Turgeon, J.
and Uprichard A.C.G.; Fed. Am. Soc. Exp. Biol. J.
(1988), 2, abstract 1813, investigated the antiarrhythmic potency of the enantiomers of mexiletine (1(2, 6-dimethylphenoxy) -2-aminopropane), which indicated antiarrhythmic differences between the enantiomers and the racemate.
Finally, Igwemezie, L.; Kerr, C.R. and McErlane,
K.M.; Xenobiotica, (1989), vol. 19, No. 6, 677-682, further investigated the pharmokinetics of mexiletine (1- (2, 6-dimethylphenoxy) -2-aminopropane) in man using the hplc assay developed by McErlane, et al, discussed above.
Given the differences in activity between the enantiomers, it can be seen that there is a need for a simple process capable of stereoselectively preparing an enantiomer of l-(2,6-dimethylphenoxy)-2-aminopropane operable on a commercial scale.
Most surprisingly, a novel and advantageous process has now been found for preparing (S)-1-(2,6- dimethylphenoxy)-2-aminopropane, and/or (R) -1- (2, 6-dimethylphenoxy) -2-aminopropane, which involves the use of a biocatalyst.
Accordingly, the present invention provides a process for the preparation of l-(2,6-dimethylphenoxy)-2-aminopropane predominantly in the form of the S enantiomer, and/or N-acyl-l- (2, 6-dimethyl- phenoxy)-2-aminopropane predominantly in the form of the R enantiomer, which process comprises supplying N-acyl-1- (2, 6-dimethylphenoxy) -2-aminopropane to a biocatalyst capable of stereoselectively hydrolysing the N-acyl group of the S enantiomer to 1-(2,6- dimethylphenoxy)-2-aminopropane and recovering the 1(2, 6-dimethylphenoxy) -2-aminopropane predominantly in the form of the S enantiomer and/or N-acyl-1-(2,6dimethylphenoxy)-2-aminopropane predominantly in the form of the R enantiomer.
It has been found that (S)-l-(2,6-dimethyl- phenoxy-2-aminopropane and (R) -N-acyl-l- (2, 6-di- methylphenoxy)-2-aminopropane having an enantiomeric purity in excess of 99% may be prepared in high yield by the process according to the present invention.
Enantiomeric purity is defined as 100% x [S enantiomerl/(R enantiomer]+[S enantiomer)) in the case of the S enantiomer and 100% x (R enantiomer)/((R enantiomer]+[S enantiomer]) in the case of R enantiomer for each compound.
The N-acyl-1- (2, 6-dimethylphenoxy) -2-aminopropane is preferably supplied to the biocatalyst in the form of a racemic mixture, although other mixtures of the R and S enantiomers of the N-acyl derivative are suitable as starting materials for the process.
The acyl group in the N-acyl-1-(2,6-dimethyl phenoxy)-2-aminopropane is preferably an aliphatic acyl group, more preferably an alkanoyl group, alkoxycarbonyl group or formyl. Alkanoyl groups preferably have from 2 to 6 carbon atoms, more preferably from 2 to 4 carbon atoms, with acetyl being especially preferred. Alkoxycarbonyl groups preferably have from 2 to 6 carbon atoms, more preferably from 2 to 4 carbon atoms, with methoxycarbonyl being especially preferred. The acyl group is most preferably acetyl.
The biocatalyst may be a microorganism, in particular a bacterium, fungus or yeast, or a plant or animal cell, or an extract thereof, or an enzyme.
Preferably, the biocatalyst is a microorganism, an extract thereof, or an enzyme. More preferably the biocatalyst is a microorganism selected from the genera Rhodococcus, Bacillus, Arthrobacter and
Corynebacterium. The microorganism is most preferably of the genus Arthrobacter. A specific example of a microorganism useful as a biocatalyst in the process of the present invention is Arthrobacter sp NCIMB 40140 deposited on 9th May 1989, at the National
Collections of Industrial and Marine Bacteria Ltd.,
Torry Research Station, PO Box 31, 135 Abbey Road,
Aberdeen, ABO 8DG, United Kingdom.
Microorganisms suitable for use in the process according to the invention have been isolated from soil samples by a selection procedure which identifies those microorganisms that are capable of growing on acetamides, for example N-sec-butyl-acetamide.
When a microorganism is used as the biocatalyst, it may be in a growing or non-growing state.
While the hydrolysis of N-acyl-l-(2,6-dimethyl- phenoxy)-2-aminopropane is usually carried out in the presence of whole microorganism cells, the hydrolytic enzyme system may have been completely or partly extracted from the microorganism prior to carrying out the hydrolysis. To avoid unnecessary separation, enzyme purification and enzyme immobilisation procedures, the enzyme is usually present with at least some of the cell components. When in association with the cells, these may be live or dead, intact, treated in some way or themselves immobilised and optionally homogenised, so long as the enzyme component itself is retained in an active and stable form to allow the hydrolysis to proceed.
Immobilisation of the enzyme or the cells may be by any of the methods known in the art so long as the enzyme hydrolysing activity is retained intact.
The microorganisms are preferably cultured prior to use for the hydrolysis for about 1 to 10 days, whereafter the cells are suspended in a liquid salts medium, preferably a minimal liquid nutrient medium, and N-acyl-1- (2, 6-dimethylphenoxy) -2-aminopropane is subjected to the action of the cells.To grow the microorganism used for the hydrolysis, ordinary culture media containing an assimilable carbon source, for example glucose, glycerol, lactate and/or sucrose, a nitrogen source, for example ammonium sulphate, ammonium nitrate and/or ammonium chloride, together with an agent for an organic nutrient source, for example yeast extract, malt extract peptone and/or meat extract, and an inorganic nutrient source, for example phosphate, magnesium, potassium, zinc, iron and other metals in trace amounts, may be used, along with an acetamide inducer such as acetamide or an
N-alkyl acetamide, for example N-sec-butylacetamide or acetanilide, or a thiocetamide such as thioacetanilide, as necessary. As an alternative culture medium, a medium containing salts plus an acetamide, for example N-sec-butylacetamide or acetanilide, or thioacetamide is used.
A temperature between 0 and 450C and a pH between 3.5 and 8 is maintained during the growth of the microorganism.
Preferably the microorganisms are grown at a temperature between 20 and 370C and at a pH between 4 and 8.
During the hydroysis of N-acyl-l-(2,6-dimethyl- phenoxy)-2-aminopropane, an ordinary culture medium may be used containing an assimilable carbon source when required, for example glucose, lactate, sucrose, fructose and/or glycerol, a nitrogen source when required, for example ammonium sulphate, ammonium nitrate and/or ammonium chloride, with an agent for an organic nutrient source when required, for example yeast extract, salt extract, peptone and/or meat extract, and an inorganic nutrient source when required, for example phosphate, magnesium, potassium, zinc, iron and other metals in trace amounts.
Preferably during the hydrolysis of N-acyl-1-(2,6dimethylphenoxy)-2-aminopropane the microorganisms are held in a substantially non-growing state using a minimal culture medium. The microorganism can be used in the non-growing state for example under exclusion of the nitrogen source in an aqueous medium containing salts, for example sodium chloride and/or potassium phosphate, or in water alone. A temperature of between 0 and 450C and a pH between 3.5 and 9 is maintained during this stage. Preferably the microorganisms are kept at a temperature between 20 and 370C and a pH between 4 and 8.
The N-acyl-l- (2, 6-dimethylphenoxy) -2-aminopropane can conveniently be supplied to the biocatalyst at concentrations of from 1 to 200 g/l, preferably at a concentration of at least 5 g/l.
The 1(2, 6-dimethylphenoxy) -2-aminopropane predominantly in the form of the S enantiomer produced during the process of the present invention can be recovered and purified according to any of the procedures known per se for such products. Suitable recovery and purification procedures include fractional crystallisation from the broth or differential acid/base/solvent extraction.
The S enantiomer of 1-(2,6-dimethylphenoxy)-2aminopropane may, if required, be converted into a pharmaceutically acceptable salt thereof, such as the hydrochloride, by conventional methods, for example by treatment with hydrochloric acid to afford the hydrochloride salt.
In addition to, or as an alternative to, preparing (S) -1- (2, 6-dimethyl-phenoxy) -2-aminopropane, the process of the present invention may also be used to prepare the R enantiomer of the N-acyl-1-(2,6-dimethylphenoxy)-2-aminopropane starting material, which product may, if required, be converted into ()-1- (2,6-dimethylphenoxy)-2-aminopropane. The biocatalyst used in the process/hydrolyses the S enantiomer of the N-acyl-l- (2, 6-dimethylphenoxy-2-aminopropane) starting material to yield the amine, whilst leaving the R enantiomer of the starting material substantially unreacted. The R enantiomer of the starting material may then be recovered if required. Recovery and purification of the R enantiomer may be carried out using any of the procedures known per se for such products.
(R) -N-acyl-1- (2, 6-dimethylphenoxy) -2-aminopropane may be converted into ()-l-(2,6-dimethylphenoxy)-2- aminopropane by standard methods known in the art, for example by hydrolysis either with a base, such as an alkali metal hydroxide, for example sodium hydroxide, or an acid, such as an inorganic acid, for example, hydrochloric acid or sulphuric acid. The hydrolysis is effected in the presence of water, conveniently at a temperature of from 50 0C up to the reflux temperature of the reaction mixture.
(R) -1- (2, 6-dimethyiphenoxy) -2-aminopropane may be converted, if desired, into a pharmaceutically acceptable salt thereof, such as the hydrochloride, by conventional methods, for example by treatment with hydrochloric acid to afford the hydrochloride salt.
The N-acyl-1-(2,6-dimethylphenoxy)-2-aminopropane starting material for use in the process of the present invention may be readily prepared by acylating 1- (2, 6-dimethylphenoxy) -2-aminopropane using conventional techniques, for example by reacting the amine with an appropriate acyl halide or acid anhydride. The 1-(2,6-dimethylphenoxy)-2-amino- propane to be acylated may be prepared using standard synthesis routes known in the art, for example one of the methods disclosed and exemplified in US-A-3 ,954,872.
The following examples illustrate the invention.
The medium used was as follows:
PSX
Quantities in g/l KH PO 8.92
2 4
Na2HPO4 2.84 (NH4)2HPO4 1.0 (NH4)2SO4 0.2
KC1 0.2
Trisodium citrate 0.294 CaS04.7H2O 0.005 MgSO4.7H20 0.2 ZnSO4. 7H2 0 0.0005 MnC12.4H2O 0.003 CUSO4. 5H2O 0.00015 H3BO3 0.00005 Na2MoO4.2H2O 0.000055
KI 0.0001 (NH4)2SO4.FeSO4 .6H2O 0.0025 pH adjusted to 7.0
Example 1
Preparation of (S) -1(2 ,6-dimethylphenoxy) -2-amino- propane and (R) -N-acetyl-l- (2 ,6-dimethylphenoxy) - 2-aminopropane using Arthrobacter sp NCIMB 40140
Arthrobacter sp NCIMB 40140 was stored on nutrient agar slopes at 4 0C. A slope was used to inoculate ten 250 ml conical flasks each containing 100 ml sterile PSX medium and 5 g/l
N-sec-butylacetamide. The flasks were incubated in an orbital incubator to maintain aerobic conditions for 72 hours at 300C.
The cells from each flask were then harvested by centrifugation at 6000 g for 20 min at 10 0C. The cell pellets were resuspended in 0.1 M potassium phosphate buffer, pH 7, and combined to give a total volume of 200 ml. The cell suspension was added to a 2 1 conical flask and incubated with 20 g/l (RS)-N-acetyl-1-(2,6-dimethylphenoxy)-2-aminopropane for 23 h at 30 0C in an orbital incubator. During this time the conversion of N-acetyl-1-(2,6-dimethylphenoxy)-2-aminopropane to 1(2, 6-dimethylphenoxy) -2- aminopropane was monitored by gas chromatographic analysis under the following conditions:
Instrument : Varian 3500 gc
Column : DB-1, 4 m x 0.32 mm i.d.
(supplied by Varian Associates,
Walton-on-Thames, Surrey, UK)
Carrier gas : He at 2.7 ml/min
Column temperature : 160 0C Retention times : l-(2,6-dimethylphenoxy)-2
aminopropane 0.6 min N-acetyl-l- (2, 6-dimethyl- phenoxy)-2-aminopropane 2.6 min
After 23 hours, the following procedures were used to extract the l-(2,6-dimethylphenoxy)-2-aminopropane and N-acetyl-l- (2, 6-dimethylphenoxy) -2-amino- propane: (a) N-acetyl-l- (2 ,6-dimethylphenoxv) -2-aminopropane The transformation mixture was titrated to pH 2 with 4 M sulphuric acid. The acidic solution was washed with 100 ml volumes of dichloromethane until gas chromatograph analysis showed no further extraction of N-acetyl-1- (2, 6-dimethylphenoxy) -2- aminopropane.The combined dichloromethane extracts were washed twice with 100 ml 4 M sulphuric acid to remove residual amine. The dichloromethane was dried using anhydrous sodium sulphate and then evaporated to dryness under reduced pressure to yield the N-acetyl-1- (2, 6-dimethylphenoxy) -2-aminopropane.
(b) 1- (2 ,6-dimethylphenoxy) -2-aminopropane The acidic aqueous phase from the first extraction was titrated to pH 12 with 4 M NaOH and washed with 100 ml volumes of dichloromethane until gas chromatograph analysis showed no further amine extraction. The combined dichloromethane extracts were dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to yield the l-(2,6-dimethylphenoxy)-2-aminopropane as an oil.
The enantiomeric composition of the 1-(2,6-dimethylphenoxy)-2-aminopropane was determined by preparing the 2-naphthoyl derivative of the amine as described by K.M. McErlane and L. Igwemezie (Journal of Chromatography 415 (1987) 335-346. 0.5 mg 1- (2, 6-dimethylphenoxy) -2-aminopropane was dissolved in 0.4 ml 1 M NaOH. To this was added 15 p1 of a 1 mg/ml solution of 2-naphthoyl chloride in dichloromethane. The reaction mixture was vortex mixed for 2 min. The derivatives were then extracted into 0.6 ml mobile phase and 20 p1 injected onto the following high performance liquid chromatography (hplc) column:
Column : covalently bound D-phenylglycine
("Pirkle column"), 250 x 4.6 mm
(Hichrom, Reading, Berkshire, UK)
Mobile phase : 5.5% v/v propan-2-ol in hexane at
1.4 ml/min.
Detection : uv absorbance at 254 nm
Retention times : (R)-l-(2,6-dimethylphenoxy)-2
aminopropane 25 min (S) -1(2, 6-dimethylphenoxy) -2- aminopropane 27 min
The elution order of the enantiomers (R) before (S) is stated in the aforementioned paper by McErlane and Igwemezie.
When the 2-naphthoyl derivative of 1- (2, 6-di-methylphenoxy) -2-aminopropane produced by
Arthrobacter sp NCIMB 40140 was analysed in the same way, only the peak corresponding to the S enantiomer was seen. This indicates that the amine contained at least 99% of the S enantiomer.
Further evidence for a single enantiomer of 1- (2, 6-dimethylphenoxy) -2-aminopropane being present was obtained by analysing the underivatised amine on a second chiral hplc column:
Column : Chiracel OD 250 x 4.6 mm i.d.
(supplied by Hichrom, Reading,
Berkshire, UK)
Mobile phase : hexane/propan-2-ol/diethylamine in
the ratio 970/30/1 by volume at a
flow rate of 1.5 ml/min
Detection : u.v. at 254 nm
According to this method (RS)-1-(2,6-dimethylphenoxy)-2-aminopropane was resolved into two equal size peaks running at 9 and 10 min corresponding to the R and S enantiomers respectively. By contrast the microbially-derived 1- (2, 6-dimethylphenoxy) -2-amino- propane produced only one peak at 10 min. No trace of the other enantiomer was detected.
The enantiomeric composition of the N-acetyl-l (2, 6-dimethylphenoxy) -2-aminopropane extracted at the end of the incubation was also investigated by chiral hplc:
Column: Chiralcel OD (250 x 4.6 mm i.d)
Mobile Phase: hexane/propan-2-ol/diethylamine in
the ratio 800/200/1 by volume at a
flow rate of 2 ml/min
Detection: u.v. at 254 nm
Using this method, racemic N-acetyl-1-(2,6-dimethylphenoxy)-2-aminopropane was resolved into two peaks of equal area with retention times of 2.9 and 4.8 min. By contrast, the microbially-derived N-acetyl-l- (2, 6-dimethylphenoxy) -2-aminopropane exhibited two peaks in the ratio 86:14.Since the product of the microbial hydrolysis was (S)-1-(2,6- dimethylphenoxy)-2-aminopropane, it was concluded that the remaining N-acetyl-1- (2, 6-dimethylphenoxy) -2- aminopropane was enriched in the R enantiomer. In conclusion, 86% R and 14% S N-acetyl-1-(2,6-dimethylphenoxy)-2-aminopropane was present in the sample.
Example 2
Preparation of (R) -N-acetyl-l- (2 ,6-dimethvlphenoxy) -2- aminopropane and (S) -1- (2 ,6-dimethylphenoxy) -2 -amino- propane from (RS)-N-acetyl-l-(2, 6-dimethylphenoxy) -2- aminopropane using Arthrobacter sp NCIMB 40140
The organism was grown and harvested as generally described in Example 1, with the following variations in the method. A single flask of culture was prepared (100 ml culture). The cells were resuspended in 0.1 M potassium phosphate pH 7 to a final volume of 20 ml.
The suspension was added to a 250 ml conical flask, together with 5 g/l (RS)-N-acetyl-l-(2,6-dimethylphenoxy)-2-aminopropane. This was incubated in an orbital shaker at 300C. Periodically 0.25 ml samples were removed from the flask, 10 p1 2 M NaOH added and shaken with 0.25 ml dichloromethane. The dichloromethane layer was decanted and 1 p1 was analysed for- N-acetyl-l- (2, 6-dimethylphenoxy) -2-aminopropane and 1- (2, 6-dimethylphenoxy) -2-aminopropane using gas chromatography as described in Example 1.
The remaining dichloromethane was evaporated using a flow of nitrogen gas and the residue redissolved in hexane/propan-2-ol/diethylamine in the ratio 970:30:1 by volume. The enantiomeric compositions of the l-(2,6-dimethylphenoxy)-2-amino propane and remaining N-acetyl-l- (2, 6-dimethyl- phenoxy)-2-aminopropane were investigated by chiral hplc analysis of 20 1 of this solution:
Column : Chiracel OD (250 x 4.6 mm i.d.)
Mobile phase : hexane/propan-2-ol/diethylamine in
the ratio 970/30/1 by vol. at a
flow rate of 1.5 ml/min.
Retention times : 1-(2,6-dimethylphenoxy)-2-
aminopropane, 9 min and 10 min R
and S enantiomers respectively.
N-acetyl-1-(2,6-dimethylphenoxy)-
2-aminopropane, 14 and 26 min R
and S enantiomers respectively.
Using these analyses the data represented in
Table 1 were obtained for the biotransformation.
I I Incubation time I Amidel I Amine2 (h) I g/l %R3 I g/l 1 1 2.91 72 1 0.88 > 99 2 1 2.38 81 1 1.22 > 99 4 1 2.24 > 99 1 1.87 > 99 6 1 2.21 > 99 1 2.09 98 24 1 2.28 > 99 1 2.19 90 TABLE 1 1Amide: N-acetyl-1-(2,6-dimethylphenoxy)-2-amino- propane 2Amine: 1- (2 ,6-dimethylphenoxy) -2-aminopropane 3Enantiomeric purity of the amide
= 100% x [R amide]/([R amide] + [S amide]) 4Enantiomeric purity of the amine
= 100% x (S amine)/((S amine] + tR amine))
The data represented in Table 1 show that both (S)-1-(2,6-dimethylphenoxy)-2-aminopropane and (R)-1(2,6-dimethylphenoxy)-2-aminopropane can be prepared in excellent yields and to a high degree of purity using Arthrobacter sp NCIMB 40140.
Claims (15)
1. A process for the preparation of 1- (2, 6-dimethylphenoxy) -2-aminopropane predominantly in the form of the S enantiomer
and/or N-acyl-1-(2,6-dimethylphenoxy)-2-
aminopropane predominantly in the form of the R
enantiomer, which process comprises supplying N-acyl-1- (2, 6-dimethylphenoxy) -2-aminopropane to
a biocatalyst capable of stereoselectively
hydrolysing the N-acyl group of the S enantiomer
to 1- (2, 6-dimethylphenoxy) -2-aminopropane and
recovering the 1(2, 6-dimethylphenoxy) -2-amino- propane predominantly in the form of the S
enantiomer and/or N-acyl-1- (2, 6-dimethyl- phenoxy)-2-aminopropane predominantly in the form
of the R enantiomer.
2. A process according to claim 1, in which the
N-acyl-1-(2,6-dimethylphenoxy)-2-aminopropane is
supplied in racemic form.
3. A process according to claim 1 or 2, in which the
N-acyl group is an aliphatic acyl group.
4. A process according to claim 3, in which the
N-acyl group is a C(2-6) alkanoyl, C(2-6)
alkoxylcarbonyl group or formyl.
5. A process according to claim 4, in which the
N-acyl group is acetyl.
6. A process according to any preceding claim, in
which the biocatalyst is a microorganism, an
extract of a microorganism or an enzyme.
7. A process according to claim 6, in which the
biocatalyst is a microorganism selected from the
genus Rhodococcus, Bacillus, Arthrobacter and Corvnebacterium.
8. A process according to claim 7, in which the
biocatalyst is a microorganism of the genus
Arthrobacter.
9. A process according to any of claims 6 to 8, in
which the microorganism has been grown in the
presence of an acetamide or a thioacetamide.
10. A process according to claim 9, in which the
microorganism has been grown in the presence of
N-sec-butylacetamide, acetanilide or
thioacetanilide.
11. A process according to any preceding claim in
which the R enantiomer of the N-acyl-1-(2,6
dimethylphenoxy)-2-aminopropane is recovered, the
process further comprising the step of converting
the R enantiomer of the N-acyl-l-(2,6-dimethyl
phenoxy)-2-aminopropane into (R)-1-(2,6-dimethyl- phenoxy)-2-aminopropane, a salt thereof or an
N-protected form thereof.
12. A process substantially as hereinbefore described
having reference to either of Examples 1 and 2.
13. (S) -1- (2, 6-dimethylphenoxy) -2-aminopropane when
prepared by a process according to any preceding
claim.
14. (R) -N-acyl-1- (2, 6-dimethylphenoxy) -2-aminopropane when prepared by a process according to any of
claims 1 to 12.
15. (R) -1- (2, 6-dimethylphenoxy) -2-aminopropane, a
salt thereof or an N-protected form thereof, when
prepared by a process according to claim 11.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9017315A GB2246774A (en) | 1990-08-07 | 1990-08-07 | Preparation of enantiomers of 1-(2,6-dimethylphenoxy)-2-aminopropane and N-acyl derivatives thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9017315A GB2246774A (en) | 1990-08-07 | 1990-08-07 | Preparation of enantiomers of 1-(2,6-dimethylphenoxy)-2-aminopropane and N-acyl derivatives thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9017315D0 GB9017315D0 (en) | 1990-09-19 |
| GB2246774A true GB2246774A (en) | 1992-02-12 |
Family
ID=10680304
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9017315A Withdrawn GB2246774A (en) | 1990-08-07 | 1990-08-07 | Preparation of enantiomers of 1-(2,6-dimethylphenoxy)-2-aminopropane and N-acyl derivatives thereof |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2246774A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997041214A1 (en) * | 1996-04-25 | 1997-11-06 | Novartis Ag | Biocatalysts with amine acylase activity |
| WO1997046698A1 (en) * | 1996-05-30 | 1997-12-11 | Bayer Aktiengesellschaft | Process for producing optically active amines |
| US5985933A (en) * | 1997-01-24 | 1999-11-16 | Celgene Corporation | Methods for treating central and peripheral nerve pain |
-
1990
- 1990-08-07 GB GB9017315A patent/GB2246774A/en not_active Withdrawn
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997041214A1 (en) * | 1996-04-25 | 1997-11-06 | Novartis Ag | Biocatalysts with amine acylase activity |
| US6235516B1 (en) | 1996-04-25 | 2001-05-22 | Novartis Ag | Biocatalysts with amine acylase activity |
| EP1889903A1 (en) * | 1996-04-25 | 2008-02-20 | Novartis AG | Biocatalysts with amine acylase activity |
| WO1997046698A1 (en) * | 1996-05-30 | 1997-12-11 | Bayer Aktiengesellschaft | Process for producing optically active amines |
| US6187582B1 (en) | 1996-05-30 | 2001-02-13 | Bayer Aktiengesellschaft | Process for producing optically active amines |
| US5985933A (en) * | 1997-01-24 | 1999-11-16 | Celgene Corporation | Methods for treating central and peripheral nerve pain |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9017315D0 (en) | 1990-09-19 |
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