Note: Descriptions are shown in the official language in which they were submitted.
2116~6~
The present invention relates to a process for
the preparation of dextrorotatory 2-(3,4-dichloro-
phenyl)-4-hydroxybutylamine of the formula
o~ (+) HocH2~H2~H~H2NH2
Cl
The compound (I), which is described in the
patent applications EP-A-0 428 434, EP-A-0 474 561, EP-
A-0 515 240 and EP-A-0 559 538, is a key intermediate
in the synthesis of tachykinin antagonists.
According to the above documents, the compound
(I) is prepared by resolving the racemate via its
D-(-)-tartrate.
It has now been found that treating racemic 3-
cyano-3-(3,4-dichlorophenyl)propionic acid with D-(-)-
N-methylglucamine effects a second-order asymmetric
conversion to give (-)-3-cyano-3-(3,4-dichlorophenyl)-
propionic acid, which, on enantioconservative reduction
with a borane, gives the compound of formula (I).
It has also been found, surprisingly, that the
compound of formula (I) can be obtained from 3,4-
dichlorophenylacetonitrile by reaction with an alkalimetal halogenoacetate, preferably sodium chloroacetate,
resolution of the 3-cyano-3-(3,4-dichlorophenyl)pro-
pionic acid in situ and enantioconservative reduction
as indicated above.
Thus, according to one of its features, the
present invention relates to a process for the pre-
paration of (+)-2-(3,4-dichlorophenyl)-4-hydroxybutyl-
amine of formula (I), which comprises
(a) treating 3,4-dichlorophenylacetonitrile of formula
(II):
-
2Il-6464
Cl ~ CH2CN (II)
05 with an alkali metal halogenoacetate in liquid ammonia
or in a polar aprotic solvent, in the presence of a
strong base, at a temperature of -40~C to +25 C;
(b) treating the resulting racemic 3-cyano-3-t3,4-
dichlorophenyl)propionic acid of formula (III):
CN
a~ ~ C ,~CH~H2-COOH (III)
with D-(-)-N-methylglucamine in order to crystallize
all the acid (III) in the form of the D-(-)-N-methyl-
glucamine salt of the levorotatory acid;
(c) treating said salt with a strong acid; and
(d) subjecting the freed (-)-3-cyano-3-(3,4-dichloro-
phenyl)propionic acid of formula (IV):
CN
(-) a ~ CH-CH2-COOH (IV)
to enantioconservative reduction with a borane
to give the derivative (I).
More particularly, step (a) is carried out
using an alkali metal halogenoacetate such as sodium or
potassium chloroacetate or sodium or potassium bromo-
acetate, in the presence of a strong base such as
sodium amide, sodium tert-butylate or sodium ethylate.
Solvents which can be used are liquid ammonia at low
-
21164fi4
temperature (-40~C to -30~C) or a polar aprotic solvent
which is inert under the reaction conditions, such as
dimethyl sulfoxide or N,N-dimethylformamide. The
cyanoacid of formula (III) thus obtained after a reac-
05 tion time of 4-5 hours is isolated by treatment with
water or mixtures of water with an ether, for example
isopropyl ether. It can be converted to one of its
salts.
Step (b) can be carried out on the isolated
cyanoacid (III) or else in situ directly after step (a)
in a solvent such as an alcohol, preferably ethanol.
The D-(-)-glucamine salt of (-)-3-cyano-3-(3,4-di-
chlorophenyl)propionic acid crystallizes directly and
can be isolated.
The levorotatory acid is freed from its salt by
treatment with a strong acid, according to step (c),
and isolated by extraction with an appropriate solvent
such as dichloromethane, dichloroethane or 1,1,1-tri-
chloroethane. The acid (IV) can be converted to one of
its salts.
In step (d), theenantioconservative reductiOn
with a borane such as BH3 or B2H~, optionally in the
form of a complex with tetrahydrofuran or dimethyl
sulfide, is carried out at room temperature in a
solvent of the ether type, such as dioxane or tetra-
hydrofuran. After the excess borane has been destroyed
and the solvent has been evaporated off, the amino-
alcohol (I) is isolated by removal of the by-products
using successive treatments with an acid and then with
a base, followed by extraction with an appropriate
solvent such as dichloromethane, dichloroethane or
1,1,1-trichloroethane.
3-Cyano-3-(3,4-dichlorophenyl)propionic acid
(III) is prepared by reacting sodium chloroacetate with
3,4-dichlorophenylacetonitrile (II), for example in
2136g6~
liquid ammonia in the presence of sodium amide accor-
ding to the technique of A.G. CHIGAREV and D.V. IOFFE,
Zh. Org. Khim. 3, 85-8 (1967), or in the presence of
another very strong base such as sodium or potassium
05 tert-butylate in liquid ammonia at -33~C or in anhy-
drous dimethyl sulfoxide at room temperature. The
yield of 3-cyano-3-(3,4-dichlorophenyl)propionic acid
isolated is 74 to 78%, but it is even better if the
product is not isolated, because it suffices to react
it with D-(-)-N-methylglucamine, an inexpensive indus-
trial product obtained from D-glucose and methylamine
(KARRER, HERKENRATH - Helv. Chim. Acta, 20, 37 (1937)),
in order to crystallize all the racemic cyanoacid (III)
in the form of the salt of the levorotatory acid. The
yield is excellent, being 190% based on the levorota-
tory enantiomer contained in the racemate (III). The
crystallization solvent can be methanol, ethanol,
Cellosolve~ or any other suitable solvent. The reso-
lution temperature is between the boiling point of the
solvent and 0~C. The N-methylglucamine must be present
in at least the stoichiometric amount. It is pre-
ferably used in slight excess.
After the 3-cyano-3-(3,4-dichlorophenyl)pro-
pionic acid has been freed from its D-(-)-N-methyl-
glucamine salt by reaction with a strong acid such as
hydrochloric acid, oxalic acid or an ion exchange resin
of the sulfonic acid type, it is reduced in an enantio-
conservative manner (enantiomeric purity: 99%)
with borane.
The yield of this double reduction is at least
70%.
The borane can be used in the form of its
dimer, B2H~, but is preferably used in a more manipula-
ble form such as the complex form with tetrahydrofuran
or dimethyl sulfide, the latter complex being marketed
- ~1646g
as BMS.
~ 3 \ S / 3
05 BH3 BH3
The second-order asymmetric conversion according to
step (b) of the process of the present invention is
surprising and constitutes a further subject of the
present invention, which thus relates, according to
another of its features, to a process for the prepara-
tion of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic
acid, which comprises treating racemic 3-cyano-3-(3,4-
dichlorophenyl)propionic acid with D-(-)-N-methyl-
glucamine and treating the resulting D-(-)-N-methyl-
glucamine salt of (-)-3-cyano-3-(3,4-dichlorophenyl)-
propionic acid with a strong acid.
3-Cyano-3-(3,4-dichlorophenyl)propionic acid
(III) and its salts, and its (-) isomer of formula (IV)
and its salts, are novel products and represent a
further feature of the present invention.
More particularly, the D-(-)-N-methylglucamine
salt of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic
acid constitutes another feature of the present inven-
tion.
The compound (I) as obtained by the processaccording to the invention may advantageously be used
for the stereoselective synthesis of optically pure
arylalkylamines ,which are antagonists of neurokinin
receptors.
Particularly, the compound (I) may be used for
the preparation of the arylalkylamines described in the
patent applications EP-A-0 428 434, EP-A-0 474 561,
EP-A-0 515 240 and EP-A-0 559 538 according to the
general synthesis scheme illustrated below in Scheme 1,
in which the substituents B an~ ~ represent all the
substituents of the aminated ring of the
arylalkylamines disclosed in the EP patent applications
referred above, W, T and Z are as described in said
05 patent applications, and Ar' is a dichlorophenyl group.
SCHEME 1
OH-(CH2) 2 - * IcH CH2 NH2
Ar'
Cl-CO-Z ou W=C=N-Z
OH-(CH2) 2 - * CH-CH2-NH-T - Z
Ar'
CH3S02Cl
CH3SO2- O - (CH2) 2 ICH CH2 NH T
Ar' ~
B - D NH
B - D Ar'
The sign "*" means that the carbon atom
identified by this symbol has the defined configuration
(+) or (-).
Preferably, the compound (I) as obtained by the
process of the invention will be used for the
preparation of optically pure arylalkylamines of
formula (VI)
21164fi~
A
Y N - (CH2)2*C - CH2 NH-T-Z
Ar' (VI)
in which:
05 - Y represents - either a group Cy-N in which
. Cy represents a phenyl, unsubstituted or
substituted one or more times with one of the
substituents selected from:
hydrogen, a halogen atom, a hydroxyl, a C1-C4 alkoxy,
a C1-C4 alkyl, a trifluoromethyl, the said
substituents being the same or different; a C3-C7
cycloalkyl group; a pyrimidinyl group or a pyridyl
group;
X
I
- or a group Ar-(CH2)x-C in which
. Ar represents a phenyl, unsubstituted or
substituted one or more times with one of the
substituents selected from:
hydrogen, a halogen atom, a hydroxyl, a C1-C4 alkoxy,
a C1-C4 alkyl, a trifluoromethyl, the said
substituents being the same or different; a pyridyl
group; a thienyl group;
. x is O or 1;
. X represents a hydroxyl,a C1-C4 alkoxy; a
hydroxyalkyl in which the alkyl group is a C1-C3
alkyl group; a C1-C4 acyloxy; a phenacyloxy; a
carboxyl, a C1-C4 carbalkoxy; a cyano; an
aminoalkylene in which the alkylene is a C1-C3 group;
a group -N-(X1)2 in which the groups X1 independently
represent hydrogen, a C1-C4 alkyl; a group -NH-CO-Alk
in which Alk represents a C1-C6 alkyl;
a group Alkl-NH-CO-Alk'1 in which Alkl is a Cl-C3
82~6~fi4
alkylene and Alk'1 is a C1-C3 alkyl; a C1-C4 acyl; a
group -S-X2 in which X2 represents hydrogen or a C1-
C4 alkyl group;
or alternatively, X forms a double bond with the
05 carbon atom to which it is linked and with the
adjacent carbon atom in the heterocycle;
- Ar' represents a dichlorophenyl group;
- R represents hydrogen;
- T represents a group selected from
~0~ 1
-C- and -C-NH-
W being an oxygen or a sulphur atom, and
- Z represents either hydrogen, or M or OM when
01~5 T represents a -C- group, or M when T represents a
W
group -C-NH; M represents a C1-C6 alkyl; a phenylalkyl
in which the alkyl is a C1-C3 group, optionally
substituted on the aromatic ring with a halogen, a
trifluoromethyl, a C1-C4 alkyl, a hydroxyl, a C1-C4
alkoxy; a pyridylalkyl in which the alkyl is a C1-C3
group; a naphthylalkyl group, optionally substituted on
the naphthyl ring with a halogen, a trifluoromethyl, a
C1-C4 alkyl, a hydroxyl, a C1-C4 alkoxy; a
pyridylthioalkyl in which the alkyl is a C1-C3 group;a
styryl; an optionally substituted mono-, di- or
tricyclic aromatic or heteroaromatic group;
or of one its salts with inorganic or organic acids.
The compounds of formula (VI), which are
described in the patent application EP-A-O 474 561, are
prepared according to the above Scheme 1, in which B-D<
is represented in formula (VI) by Y.
The compound of formula (I) obtained by
the process according to the invention is
, particularly suitable for the preparation of
- 9 - 21164fi~
the (-)-N-methyl-N-[4-(4-phenyl-4-acetylamino-
piperidyl)-2-(3,4-dichlorophenyl)butyl]benzamide
hydrochloride or methanesulfonate.
The compound of formula (I) as obtained
05 according to the process of the invention may also be
used for the preparation of optically pure quaternary
basic amides of formula (VII)
Arl Tl CO--N--CH2--*ICH--(CH2)2--Am ~ , A ~ (VII)
Ar'
in which
- Arl is an optionally substituted mono-, di- or tri-
cyclic aromatic or heteroaromatic group;
- T1 is a direct bond, a hydroxymethylene group, an
alkoxymethylene group in which the alkoxy group is
Cl-C4, or a C1-Cs alkylene group;
- Ar' is a dichlorophenyl group;
- R is hydrogen;
- Am ~ is the radical
X - N~
X3
in which X1, X2 and X3, together with the nitrogen
atom to which they are bonded, form an azabicyclic or
azatricyclic system optionally substituted by a
phenyl group; and
- A ~ is a pharmaceutically acceptable anion.
lo - - 2 ~ ~ ~ 4 6 ~
The compounds of formula (VII) are prepared by
a process consisting essentially in:
- reacting a compound of formula (I) as obtained by the
process of the invention with a ~v,..~ound of formula
Arl-Tl-CO-OH
in which Tl and Arl are as defined above, and
- reacting the compound thus obtA~e~ , of formula
Ar~ T1 CO NH ~H2 -*ICH-(CH2 ~ OH
in which Ar' is as defined-above, with a ~u...~ound of
formula G-Cl, in which G is a leaving group such as
mesyl or benzene sulfonyl, then
- reacting the resulting cG...~ound, of formula
Ar~ Tl CO-NH - CH2- *CIH-(CH2 ~ O - G
with a tertiary amine of formula
X2
X3
in which Xl, X2 and X3 are as defined above, in an
organic solvent at a temperature between ambient and
120-C, and
- isolating the resulting product or else, if
a~ro~.iate, exchAnging the methane sulfonate anion of
2116964
the resulting quaternary salt with another
pharmaceutically acceptable anion.
The compound of formula (I) as obtained
according to the process of the invention is
~5 particularly suitable for the preparation of the
(+)-1-[2-[3-(3,4-dichlorophenyl)-1-[(3-
isopropoxyphenyl)-acetyl]piperidyn-3-yl]ethyl]-4-
phenyl-1-azoniabicyclo-[2.2.2]octane chloride.
The Examples which follow illustrate the
invention without however implying a limitation.
EXAMPLE 1
(+)-3-Cyano-3-(3,4-dichlorophenyl)propionic
acid (III)
A mixture of 18.6 g (0.10 mol) of 3,4-dichloro-
phenylacetonitrile and 12 g (1.03 mol) of dry sodiumchloroacetate is reacted for 5 hours at room tempera-
ture in 150 ml of dry dimethyl sulfoxide, in the pre-
sence of 10.5 g (1.05 mol) of sodium tert-butylate.
After the reaction, the reaction mixture is poured into
2~ 1 liter of iced water and acidified to pH < 3 with
hydrochloric acid. The cyanoacid is extracted with
ethyl acetate, which is washed to pH > 3, dried over
magnesium sulfate and concentrated to dryness. Tne
residue is solidified in 1,2-dichloroethane to give
16.1 g of the expected compound (III), which is charac-
terized by proton NMR.
EXAMPLE 2
(+)-3-Cyano-3-(3,4-dichlorophenyl)propionic
acid (III)
A mixture of 93 g (0.50 mol) of 3,4-dichloro-
phenylacetonitrile and 64 g (0.55 mol) of sodium
chloroacetate is reacted for 4 hours at -33 C in 500 ml
of liquid ammonia, in the presence of 21 g (0.54 mol)
of sodium amide. After evaporation of the ammonia, the
- 12 - ~ 6 ~
residue is taken up with water and then with isopropyl
ether and is acidified to pH < 3 with hydrochloric
acid. The organic phase is washed with water to
pH ~ 3, separated off by decantation, dried over
05 magnesium sulfate and concentrated to dryness. The
residue is solidified in toluene and characterized by
proton NMR. M.p. = 106 C.
EXAMPLE 3
(+)-3-Cyano-3-(3,4-dichlorophenyl)propionic
acid (III)
A mixture of 186 g (1.00 mol) of 3,g-dichloro-
phenylacetonitrile and 126 g (1.05 mol)ofsodium chloro-
nitrile~and 105 g (1.05 mol) of sodium tert-butylate
i8 reacted for 4 h~urs at -33 C in 1 liter of
liquid ammonia. After the reaction, the ammonia is
evaporated off and the residue is taken up with 500 ml
of iced water and then with 500 ml of isopropyl ether
and is acidified to pH < 3 with hydrochloric acid. The
aqueous phase is ~i~c~rded and the organic phase is
washed with water to pH ~ 3, separated off by decanta-
tion, dried over magnesium sulfate and concentrated
under vacuum. The residue is solidified in 250 ml of
toluene and the cyanoacid is filtered off and dried at
50 C under a vane pump vacuum to give 190 g (yield:
78%) of the expected (+)-3-cyano-3-(3,4-dichloro-
phenyl)propionic acid. M.p. = 104 C.
The product is characterized by proton NMR at
200 MHz in DMS0:
- unresolved signals between 2.85 and 3.1 ppm, 2
protons: -CH~-
- complex signal at 4.5 ppm, 1 proton: -CH-
- aromatic protons between 7.4 and 7.75 ppm, 3 protons
- one acidic proton at 12.8 ppm
EXAMPLE 4 211b~6~
(-)-3-Cyano-3-(3,4-dichlorophenyl)propionic
acid (IV)
A mixture of 186 g (1.00 mol) of 3,4-dichloro-
05 phenylacetonitrile, 126 g (1.05 mol) of sodium chloro-
acetate and 105 g (1.05 mol) of sodium tert-butylate is
reacted for 4 hours at -33 C in 1 liter of liquid
ammonla .
After the reaction, the ammonia is evaporated
off and the residue is taken up with 500 ml of iced
water and then with 500 ml of isopropyl ether and is
acidified to pH < 3 with hydrochloric acid. The
aqueous phase is discarded and the organic phase is
washed with water to pH > 3, separated off by decanta-
tion, dried over magnesium sulfate and concentrated
under vacuum. The concentrate is redissolved in 2
liters of absolute ethanol, the solution is heated and
292 g of D-(-)-N-methylglucamine are added. After
crystallization, the product is filtered off, rinsed
with ethanol and dried under vacuum to give 396 g of
the N-methylglucamine salt of (-)-3-cyano-3-(3,4-
dichlorophenyl)propionic acid.
[~]D25 = -14.7 (C = 1, CH30H).
The yield is 91% based on the 3,4-dichloro-
phenylacetonitrile.
The salt obtained is dissolved in 900 ml of 1 Nhydrochloric acid and extracted with 2 liters of di-
chloromethane. The organic phase is washed with water,
separated off by decantation, dried over sodium sulfate
and concentrated. The product is solidified in 500 ml
of cyclohexane to give 187 g of the expected product.
The yield is 76.5% based on the 3,4-dichlorophenyl-
acetonitrile. M.p. = 98 C.
[~] 25 = -8.6~ (C = 1, CH30H).
Enantiomeric purity by HPLC: 99%.
Proton NMR at 200 MHz in DMS0: same spectrum as the
racemate.
1r ~ 4 6 ~
EXAMPLE 5
(+)~2-(3,4-dichlorophenyl)-4-hydroxy-butylamine
(I)
350 ml of a l molar solution of BH, in THF are
05 added to a solution of 244 g (1 mol) of (-)-3-cyano-3-
(3,4-dichlorophenyl)propionic acid in 500 ml of THF,
cooled to O-C. When the evolution of hydrogen has
ceased, 650 ml of the borane solution are added at
20-C, followed by 1000 ml at 40-C. When the reaction
is complete, the excess borane is destroyed by the
addition of methanol and the reaction mixture is con-
centrated to dryness. The concentrate is dissolved in
500 ml of water, acidified with hydrochloric acid and
washed twice with 250 ml of toluene. The a~ueous phase
~5 is rendered alkaline with sodium hydroxide and extrac-
ted with twice 400 ml of dichloromethane. The organic
phase is washed with water, separated off by decanta-
tion, dried over magnesium sulfate and concentrated
under vacuum to give 159 g (yield: 68%) of the expected
product. Chiral purity by HPLC: 99%.
The product is characterized by proton NMR in
CDCl3 at 200 MHz:
- unresolved signals at 1.8 ppm, 2H
- one singlet at 2.4 ppm, 3H
- unresolved signals between 2.65 and 2.9 ppm, 3H
- unresolved signals between 3.35 and 3.6 ppm, 2H
- aromatic protons between 6.95 and 7.35 ppm, 3H
[~] 2~ = +9.8- (C = 1, MeOH).
M.p. = 80-81 C.
30- EXAMPLE 6
(+)-2-(3,4-Dichlorophenyl)-4-hydroxybutylamine
(I)
The pror~ re of EXAMPLE 5 is followed except
that borane dimethyl sulfidë is used, dilution is
carried out with 750 ml of tetrahydrofuran and the
operating temperatures are 20-C and then 50 C. The
same product is obtained wi~th the same yield and the
same characteristics.
'
