Note: Descriptions are shown in the official language in which they were submitted.
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-- 1 -
5 Process for preparing 4-aryl-piperidine derivatives
The present invention relates to a novel process for preparing 4-aryl-
piperidine derivatives.
US Patent No. 4,007,196 describes certain compounds which are
described as possessing anti-depressant activity.
The compounds of that invention relates to 3-substituted 4-aryl-piperidi-
15 nes of the general formula A:
~ (A)
25 wherein R' represents hydrogen, alkyl having 1-4 carbon atoms and F
may be in any of the available positions.
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US Patent No. 4,585,777 and US Patent No. 4,593,036 describes a
compound of the following formula B:
,1~
OCH3
~ ~J ( B )
1 O CH3
The compounds of formula A and B are described as inhibitors of reup-
take of 5-hydroxytryptamine (5-HT~ which induces a potentiation of 5-
HT induced neurotransmission. [D. R. Thomas, D. R. Nelson, and A. M.
Johnson, Neuropsychopharmacol. 93: 193-200 (1987)]. Since several
disorders is thought to be caused by an imbalance in 5-HT levels the
compounds could be used as pharmaceutical agents for the treatment of
central and peripheral diseases.
One particular compound disclosed in US Patent No. 4,007,196 has
been found to be of special value especially in the treatment of depres-
sions. This compound is known as paroxetine and has the following
formula C:
F
2~ c~\ ~ J~~' (C)
H Paroxetine
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-- 3 -
Paroxetine, which is the pure enantiomer (3S,4R)-4-(4-fluorophenyl)-3-
(3,4-methylenedioxyphenoxymethyl)piperidine has been found to be a
potent inhibitor of serotonin reuptake and to be an effective antide-
pressant in man [ S. M. Holliday and G. L. Plosker, Drugs ~nd ,4ging 3:
278-299 (1993)]. The pharmacological activity resides in this isomer and
the corresponding stereoisomer is considerably less potent with respect
to inhibition of 5-HT uptake in vitro ~P. Plenge, E. T. Mellerup, T. Honoré,
and P. L. Honoré, J. Ph~rm Pharmacol. 39: 877-882 (1987)].
Several methods for the synthesis of analogues of Paroxetine have been
described. The pivotal component in the synthesis is the 3-hydroxy-
methyl-1-methyl-4-phenylpiperidine (D1), which in several steps can be
transformed into the desired compounds as described in USP 4,007,196,
USP 4,585,777,USP 4,593,036, and J. A. Christensen, M. Engelstoft,
K. Schaumbaurg, H. Schou, and F. Watjen, Tet. Lett. 24 ,5151-4
(1983)]:
20 ~ /Z
1~ Dl ~ D2
CH3 CE3
The synthesis of intermediate D1 has been described in several publica-
tions. In one method (Scheme E) arecoline, by a Grignard reaction is
transformed into a mixture of the four different isomers of methyl 4-
phenyl-nipecotinic acid (E2), which by reduction can be transformed into
(E3) [USP 4,007,196]:
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-- 4 --
~ ~ o'CH3 ~ o,C~
CH3 CH N
El 3 E2 CK3 E3
The Grignard reaction involves the use of ether solvents and is further-
more complicated by the use of the toxic starting material arecoline.
In another method (USP 4,902,801 and W0 94/21609) the intermediary
15 D1 is prepared by reduction of the imide (F2), prepared from
benzaldehyde and methyl N-methylamidomalonate. The reduction
involves the use of lithium aluminium hydride, aluminium hydride or
diborane using ether solvents like diethyl ether, tetrahydrofurane and
dimethoxyethane, scheme F:
X
J CO~Me O~0~ Re:Zuctio~
F 1 CH3 CH3
F2 F3
In another method (USP 2,748,140, USP 4,007,196; USP 4,593,036;
USP 4,585,777J the intermediate D1 is prepared by reacting
methylamine, formaldehyde and a-methylstyrene (G1). Intermediates in
this synthesis is the oxazine derivative (G2) and the potent neurotoxic
,
¦ CA 02220963 l997-ll-l3
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compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [USP
;2,748,140, C. J. Schmidle and R. C. Mansfield, J. Am. Chem. Soc. 77
5698-5700 (1955); C. J. Schmidle and R. C. Mansfield, J. Am. Chem.
Soc. 78 425-428 (1956); C. J. Schmidle and R. C. Mansfield, J. Am.
Chem. Soc. 78 1702-1705 (1956);P. Sohar, J. Lazar, and G. Bernath,
Chem. Ber., 118, 551-559, (1985)].
MPTP has in primates and in humans been found to cause anatomical
and behavioral changes analogous to those of Parkinson's disease [M.
Gerlach, P. Riederer, H. Przuntek, and M. B. H. Youdin, EUR. J. Pharma-
col. Mol. Pharm, 208, 273-286, (1991); S. P. Markey and N. R.
Schnuff, MedicinalRes. Rev.6.386, (1986)].1t is known that the
1-methyl group causes MPTP to be toxic and that substitution of the
methyl group with longer alkyl groups will abolish the toxicity [S. K.
Youngster, P. K. Sonsalla, and R. E. Heikkila, J. Neurochem. 48, 929-
934, (1987)], scheme G:
x G2 X G3
_1 ~ IJ~
H3C X3C
- ~ X=H: MPTP
X X
~3 G4 ~3 G5
¦ Red
OH ~ ~OH
X3 C CH3
=
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Since Paroxetine is one of four possible isomers, the use of the practi-
cally and economically best procedure for the isolation of this isomer is
of high importance. The procedure will involve the use of the appropriate
isomer of D1 in combination with the use of the right conditions for
5 reaction as well as separations by recrystallizations using optically active
acids, e.g. mandelic acid, tartaric acid, and dibenzoyltartaric acid. These
transformations have been described using 3-hydroxymethyl-1-methyl-4-
phenylpiperidine and the corresponding 4-fluorophenyl-analog.
10 By the present invention easily available starting materials, by a pro-
cedure which is carried out in aqueous medium, are reacted to give a
compound of formula Vlll, wherein R1 can be C2 5-alkyl, phenyl-C, 5-alkyl,
or substituted phenyl-C1 5-alkyl, preferentially ethyl. Using this method
the intermediary 1 -alkyl- 1 ,2,3, 6-tetrahydro-4-phenylpyridine will in
15 comparison with MPTP be non-toxic as described in:S. K. Youngster, P.
K. Sonsalla, and R. E. Heikkila, J. Neurochem 48, 929-934, ~1987).
Furthermore in the present invention by separating the racemic tetrahy-
dropyridine (Ill~ derivative into the pure enantiomers which are
subsequently reduced either catalytically or by LiAlH4 to give the entio-
20 meric pure (+)-cis- (Vll) and (-)-trans 1-alkyl-4-phenyl-3-hydroxymethylpi-
peridine (Vl) derivatives, which both are transformed to pure (-)-trans-1-
alkyl-4-phenyl-3-(3,4-methylenedioxyphenoxymethyl)-piperidine deriva-
tives (Vlll), an economically route for the synthesis of a compound of
formula IX, using both possible enatiomers, is obtained.
The transformation of either Vll or Vl to pure Vlll is described in J. A.
Christensen, M. Engelstoft, K. Schaumbaurg, H. Schou, and F. Wàtjen,
Tet. Lett. 24,5151-4 (1983)].
30 Accordingly, the present invention provides a process for the preparation
of a compound of formula Vlll,
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( VI I I )
Rl
wherein R1 is C2 5-alkyl, phenyl-C, 5-alkyl, or substituted phenyl-C, 5-alkyl,
10 by
a) reacting an primary amine of formula ~I)
R'-NH2 (1)
1 5
wherein Rl is C2 5-alkyl, phenyl-C, 5-alkyl, or substituted phenyl-C, 5-alkyl,
with a compound of formula (Il)
~\
~J (II)
,,~
25 wherein X is halogen, preferably F, to form a compound of formula lll
X
~ (III)
~OH
N
1 1
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- 8 -
wherein X and R' are as defined above, and
b) by crystallizing the salt of a mixture of a compound of formula lll
and a suitable optically active acid, preferably (-)~O,O-ditoluoyltartaric
~ 5 acid to form, upon purification of the basic component, an optically
~ active compound of formula IV,
~ (IV)
'\ OH
N
1 1
which is able to rotate the plane of polarized light clockwise, and a
mother liquid containing an optically active compound which upon
crystallization in the presence of a suitable optically active acid, prefer-
ably ( + )-O,O-ditoluoyl tartaric acid, and purification of the basic compo-
20 nent, forms a compound of formula V, which is able to rotate the planeof polarized light counterclockwise:
~ (V)
~ ~--OE
N
1 1
wherein R' and X are as defined above,
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_ 9 _
c) by treatment of a compound of formula lV, wherein R' and X are
as defined above with metal hydrides, preferably LiAlH4 or NaAlH4, to
form a compound of formula Vl,
X
(VI )
~ OH
wherein R1 and X are as defined above,
15 dJ by treatment of a compound of formula V, wherein R' and X are
as defined above with hydrogen in the presence of a suitable metal
catalyst, preferably palladium on carbon to give a compound of formula
Vll,
X
l (VII )
J OH
N
l1
wherein R' and X are as defined above.
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- 10 -
e) by treatment of a compound of formula Vl,
S ~ (VI)
"~'~OH
N
Rl
with benzene sulfonylchloride, or another suitable reagent, which reacts
with the hydroxy group to transform it into a leaving group, which
subsequently can be removed by treatment with 3,4-methylenedioxyphe-
nolate, prepared by treatment of 3,4-methylenedioxyphenol with a base,
15 preferably sodium methanolate, to give a compound of formula Vlll
1~3 ~ (VIII )
""~o_~ o>
N
R
25 wherein R1 and X are defined as above,
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f) by trea~ment of a compound of formula Vll,
~ (VII)
~~ OH
wherein R' and X are as defined above, with benzene sulfonylchloride, or
another suitable reagent, which reacts with the hydroxy group to trans-
form it into a leaving group, which subsequently can be removed by
treatment with 3,4-methylene dioxyphenolate, prepared by treatment of
15 3,4-methylenedioxyphenol with a base, preferably sodium methanolate
to give a compound of formula Vlll,
~ ~0 (VIII)
wherein R1 and X are as defined above,
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g) by treatment of a compound of formula Vlll,
~ (VIII)
o~ ~
N
R
wherein R' and X are as defined above with chlorethylchloroformate or
another similar reagent, followed by decomposition of the intermediary
carbamate by methanol to form a compound of formula IX,
1 5 ~
~ o ( IX)
NX
wherein X is as defined above.
25 The present invention is illustrated by the following examples:
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EXAMPLE 1
( + ,-)-1-Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyri-
5 dine hydrochloride
Ethylamine hydrochloride (132.2 9) was dissolved in formaldehyde (500
ml, 37 ~/0) and the mixture heated to 70~C. 1-methyl-4'-fluorostyrene
(200 ml) was added over 1 hour keeping the temperature about 70~C.
After the styrene was added the mixture was refluxed at 96~C for 4
hours. The reaction mixture was cooled down to 80~C and extracted
with toluene (100 ml). The aqueous phase was evaporated at atmos-
pheric pressure until the bottom temperature reached 100~C, and then
hydrochloric acid was added (135 ml) and the reaction mixture refluxed
for 20 hours. Toluene was added (120 ml) and aqueous ammonia (25 %)
until pH = 5.5. The phases were separated and the aqueous phase
extracted with more toluene (240 ml) and made pH = 9.3 with aqueous
ammonia. The phases were separated and the toluene phase extracted
with hydrochloric acid (16 times 100 ml, 0.5 M). According to analysis
on HPLC (Column: RP18; Eluent: methanol, water: 90,10 (triethylamine,
phosphoric acid until pH = 7); Flow: 0.9 ml/min; Detector: UV 220 nm;
RT = 3.22 min) the fractions 3 to 15 were pooled, treated with filter
aid, made pH= 9.0 with sodium hydroxide and extracted twice with
toluene (200 ml and 100 ml). The toluene phases were pooled and
evaporated to an oil (164 g). The oil was dissolved in 2-propanol (300
ml) and the hydrochloride of the title compound precipitated with con-
centrated hydrochloric acid.
Yield 86.4 g ( 24.8 %), M.p. 192~C. The product was identified by 'H-
NMR and elemental analysis.
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- 14-
EXAMPLE 2
(-)-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine
( + ,-)-1-Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyri-
dine hydrochloride (84.6 g) was dissolved in a mixture of water (100 ml)
and toluene (250 ml) and the aqueous phase made pH = 10 with
sodium hydroxide. The toluene phase was separated. The aqueous phase
extracted with another portion of toluene (50 ml). The combined toluene
phase was dried over potassium carbonate and evaporated to an oil
(76.5 g). The oil (72 g) was dissolved in acetone (900 ml) with (-)-0,0'-
ditoluoyltartaric acid (59 g) at 50-60~C. Formic acid (7.1 g) was added
to the mixture. The mixture was cooled down to room temperature and
the precipitate filtered off.
Yield 47.3 g of (-)-1-Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-
tetrahydropyridine hemi-(-)-0,0'-ditoluoyltartrate M.p. 149-151 ~C.
The free base was liberated from the 0,0'-ditoluoyltartrate by dissolving
in a mixture of toluene (100 ml) and water (100 ml), made pH = 11
with sodium hydroxide. The aqueous phase was extracted with another
portion of toluene (50 ml). The combined toluene extract was washed
with water (50 ml), dried over potassium carbonate and evaporated.
Yield 24.9 g, M.p. 70-75~C, [ ~ ]20D = -127.2~ (c = 1 % in methanol).
The identity was confirmed by 'H-NMR and elemental analysis. The
enantiomeric purity was confirmed by Chiral HPLC to be better than
99 %. Chiral HPLC: (Column: Cycloband 1 2000-SN (Astec); Eluent:
acetonitrile, methanol, acetic acid, triethylamine: 100, 5, 0.3, 0.2; Flow:
0.8 ml/min, Detector: UV 240 nm, RT((+)-isomer) = 11.5 min, RT((-)-
isomer) = 10.1 min).
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- 15-
EXAMPLE 3
a ( + )-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyri-
_ ~ 5 dlne,
The mother liquor from precipitation of (-)-1-ethyl-3-hydroxymethyl-4-(4-
fuorophenyl)-1,2,3,6-tetrahydropyridine hemi-(-)-0,0'-ditoluoyltartrate
was evaporated and dissolved in a mixture of toluene (200 ml) water
(100 ml) and sodium hydroxide added until pH = 10. The aqueous
phase was separated and extracted with another portion of toluene (100
ml). The combined toluene phase was dried over potassium carbonate
and evaporated to an oil (47 9). The oil was dissolved in acetone (900
ml) with ( ~)-0,0'-ditoluoyltartaric acid (59 g). Formic acid ( 2.2 g) was
added and the mixture stirred until next day.
The precipitate was filtered off, washed with acetone and dried.
Yield 52.8 g of (~)-1-ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-
tetrahydropyridine hemi-( + )-0,0'-ditoluoyltartrate, M.p. 146-147~C.
The free base was liberated from the ( + )-0,0 '-ditoluoyltartrate by
dissolving in a mixture of toluene (100 ml), water (100 ml) and sodium
hydroxide at pH = 11. The aqueous phase was extracted with another
portion of toluene (50 ml), v~ashed with water (50 ml) and evaporated.
Yield 3~.4 g, M.p. 55-70~C, [~]D20 = 104.1~ (c = 1 % in methanol).
The identity was confirmed by 'H-NMR and elemental analysis.
The enantiomeric purity was determined by Chiral HPLC to be 97.5 %
Chiral HPLC: (Column: Cycloband 1 2000-SN ( Astec); Eluent:
acetonitrile, methanol, acetic acid, triethylamine: 100, 5, 0.3, 0.2; Flow:
0.8 ml/min, Detector: UV 240 nm, RT((+)-isomer) = 11.5 min, RT((-)-
isomer) = 10.1 min).
-
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- 16 -
EXAMPLE 4
( + )-cis-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-piperidine
hydrochloride
(-)-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine
(24.9 g) was dissolved in a mixture of ethanol (100 ml), acetic acid
(12.7 ml) and water (50 ml). Palladium on carbon ~2 9, 10 % Pd, 50 %
10 wet) was added and the mixture hydrogenated at atmospheric pressure
at room temperature for 28 hours. Toluene ( 200 ml) was added and
sodium hydroxide added until pH = 12. The toluene phase was sepa-
rated, the aqueous phase extracted with another portion of toluene (50
ml). The combined toluene phase was dried over potassium carbonate
15 and evaporated. The oil was dissolved in acetone (70 ml) and the
hydrochloride of the title compound precipitated with concentrated
hydrochloric acid (10 ml) (18.4 9). Evaporation of the mother liquor and
crystallisation from ethanol gave another crop of crystals (3.1 g).
Yield 21.5 g, M.p. 215-217~C, [a]D20 = 82.1 ~ (c = 1 ~/0, abs. ethanol)
The identity of the product was confirmed by 'H- and '3C-NMR and
elemental analysis.
The enantiomeric purity of the product was verified by Chiral HPLC to be
better than 99 %.
Chiral HPLC: Column: Chiradex,~-Cyclodextrin ( Merck); Eluent: metha-
nol, buffer: 15, 85 (10 mM (disodiumhydrogenphosphate/sodiumdihydro-
genphosphate, pH = 6)); Flow: 1.0 ml/min. Detector: UV 215 or 270
nm; RT((-)-trans-isomer)) = 9.1 min, RT((+)-trans-isomer)) = 11.5 min,
RT((-)-cis-isomer)) = 13.5 min, RT((+)-cis-isomer)) = 15.8 min.
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EXAMPLE 5
( + )-trans-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-piperidine
Lithium aluminium hydride (3 9) and sodium hydride 60 % (3 g) was
dispersed in dry tetrahydrofuran (80 ml). The mixture was heated at
60~C for 1 hour and then cooled to 20~C. To this mixture was added a
solution of (+)-1-ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-
10 tetrahydropyridine (Z0 g) in tetrahydrofuran (40 ml) over 1 hour. Themixture was stirred at 50~C for 1 hour. The mixture was then added to
a solution of (+)-tartaric acid (24 9) and sodium hydroxide (20 g) in
water (100 ml) at a temperature below 25~C. The mixture was
extracted twice with toluene (100 ml and 50 ml). The extract was dried
15 over potassium carbonate and evaporated ( 21 g). The crude, slightly
sticky, product was recrystallized from heptane (40 ml) and a little ethyl
acetate .
Yield 14.8 9, M.p. 75-85~C, [a]D20 = 29.9 ~ ( c = 1 %, abs. ethanol)
The identity was confirmed by 'H-NMR and elemental analysis. The
enantiomeric purity was controlled by Chiral HPLC to be better than 99.8
%.
25 Chiral HPLC: Column: Chiradex ,B-Cyclodextrin ( Merck); Eluent: metha-
nol, buffer: 15, 85 (10 mM (disodium hydrogen phosphate/sodium
dihydrogen phosphate, pH = 6)); Flow: 1.0 ml/min. Detector: UV 215 or
270 nm; RT((-)-trans-isomer)) = 9.1 min, RT((~)-trans-isomer)) = 11.5
min, RT((-)-cis-isomer)) = 13.5 min, RT((+)-cis-isomer)) = 15.8 min.
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EXAMPLE 6
(-)-trans-1 -Ethyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxyme-
thyl)-piperidine hydrochloride
( + )-cis-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-piperidine
hydrochloride (21 9) was dissolved in a mixture of toluene (50 ml), water
(50 ml) and sodium hydroxide (7 ml, 32.5 %). The aqueous phase was
separated and extracted with another portion of toluene (30 ml). The
combined toluene extract was dried over potassium carbonate and
evaporated to an oil (17.2 g). The oil was dissolved in toluene (86 ml)
and sodium hydroxide (17.2 9, 32.5 %) was added. Benzene sulfonyl-
chloride (16.6 9) was added over 1 hour keeping the temperature
between 20 and 30~C with external cooling with ice and water. After
the addition the reaction mixture was stirred at ambient temperature for
3 hours. Water was added (50 ml) and the toluene phase was separated.
A solution of 3,4-methylenedioxyphenol (17 9) in methylisobutylcarbinol
(4-methyl-2-pentanol) (90 ml) was added to the toluene phase together
with sodium hydroxide (17.2 9, 32.5 %). The mixture was refluxed for 4
hours and stirred overnight at ambient temperature. Water was added
(50 ml), the organic phase separated and evaporated to a viscous oil
(29.5 9). The oil was dissolved in acetone (100 ml) and precipitated as
the hydrochloride salt of the title compound with concentrated hydro-
chloric acid (10 ml). Yield 16.4 9, M.p. 244-246~C, [a]D20 = 72.8 ~ (c
= 1 %, abs. ethanol).
The identity was confirmed by 1H-NMR and elemental analysis.
The enantiomeric purity was established by Chiral HPLC to better than
99.5 %. Chiral HPLC: Column:,~-Cyclodextrin, Chiradex (Merck); Eluent: -
methanol,buffer: 46, 60 (1% triethylamine pH =4.1 adjusted with acetic
acid); Detector; UV 290 nm; RT ((+)-trans-isomer) = 10.2 min; RT ((-)-
trans-isomer) = 1Z.0 min.
,
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- 19 -
EXAMPLE 7
(-)-trans-1 -Ethyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxyme-
thyl)-piperidine hydrochloride
( + )-trans-1 -Ethyl-3-hydroxymethyl-4-(4-fluorophenyl)-piperidine (14.4 g)
and triethylamine (14.4 ml) was dissolved in dichloromethane (26 ml).
The solution was cooled to between -10 to 5~C and benzenesulfonyl
chloride (14.1 9) was added over 2 hours keeping the stated temperature
during the addition. The temperature was raised to 10~C over 15 min.
and water was added (40 ml) and the mixture stirred for 15 min. The
organic phase was separated and the aqueous phase was extracted with
dichloromethane (30 ml). The combined extract was dried over mag-
15 nesium sulfate and evaporated to an oil.
The oil was dissolved in dimethylformamide (60 ml) together with 3,4-
methylenedioxyphenol (10 9) and the solution was heated to 45~C. A
solution of sodium methanolate (prepared from 2.3 9 sodium dissolved in
20 30 ml methanol evaporated to dryness) in dimethylformamide (30 ml)
was added over 15 min to the solution of sulfoester and phenol. The
reaction mixture was stirred for 2 hours at 45~C. Water was added (200
ml) and the mixture extracted twice with toluene ~100 ml and ~0 ml) .
The extract was evaporated to a viscous oil (25.8 9).
The oil (20.8 g) was dissolved in acetone (66 ml) and the hydrochloride
of the title compound crystallized with concentrated hydrochloric acid
(6.6 ml). Yield 19.9 9, M.p. 242-243~C, [~] = - 72.2 ~ ( c = 1 %, abs.
ethanol) .
30 The identity was confirmed by 'H-NMR and elemental analysis.
The enantiomeric purity was verified by Chiral HPLC
Chiral HPLC: Column:,~-Cyclodextrin, Chiradex (Merck); Eluent: metha-
nol, buffer: 46, 60 ( 1% triethylamine pH = 4.1 adjusted with acetic
,
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- 20 -
acid); Flow: 1.0 ml/min; Detector; UV 290 nm; RT ((+)-trans-isomer) =
10.2 min; RT ((-)-trans-isomer) = 12.0 min.
EXAMPLE 8
(-)-trans-4-(4-Fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-
piperidine hydrochloride
(-)-trans-1-Ethyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxyme-
thyl)-piperidine hydrochioride (15.4 g) was dissolved in a mixture of
toluene (100 ml), water (50 ml) and sodium hydroxide (3.5 ml, 32.5 %).
The toluene phase was separated. The aqueous phase extracted with
another portion of toluene (50 ml). The extracts was combined and dried
15 over potassium carbonate. The dry toluene solution was evaporated to
give an oil (11.5 9). The oil (4.75 9) was redissolved in dry toluene (50
ml), cooled to -10~C. 1-Chloroethylchloroformate (2.85 9) in dry toluene
(20 ml) was added over 15 min.àt-10~C. The mixture was heated
slowly to reflux and refluxed for 1 hour. The reaction mixture was
evaporated to an oil, dissolved in methanol (50 ml) and refluxed for 1
hour. The mixture was evaporated to an oil and dissolved in a mixture of
toluene (30 ml) and water (20 ml) and sodium hydroxide (32 %) was
added until pH = 11. The phases were separated and the aqueous phase
extracted with another portion of toluene (30 ml). The combined toluene
25 extract was dried over potassium carbonate and evaporated to an oil.
(5.2 9). The oil was dissolved in ethanol (15 ml) with L(+)-tartaric acid
(2.37 9). The tartrate of the title compound was crystallized by cooling
and could be filtered off and dried. Yield 6.2 9, M.p. 174-176~C.
30 The identity was confirmed by 'H-NMR and elemental analysis.
The enantiomeric purity was verified by Chiral HPLC to be better than
99.5 %.
CA 02220963 l997-ll-13
WO 96/36636 PCT/DK96/00185
- 21 -
Chiral HPLC: Column: Chiral-AGP (Chromtech); Eluent: 2-propanol:buffer,5:95 (10 mM sodium acetate, pH = 5.2); Flow: 1.0 ml/min, Detector:
UV 290 nm; RT((+)-isomer) = 8.7 min and RT((-)-isomer) = 12.5 min.
1CI
1';
~'5
:30
