PROCEDE DE PREPARATION D'UN COMPOSE THERAPEUTIQUE ACTIF

PROCESS FOR PREPARATION OF A THERAPEUTICALLY ACTIVE COMPOUND

Abrégé anglais

Abstract:
A process for preparing therapeutically active compounds
comprising preparation of a Wittig reagent and employing
it in a reaction according to the reaction scheme:
NaOCH3
<IMG> <IMG>
Ph3PO
<IMG>

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparation of a therapeutically active compound
of the formula
VI
<IMG>
wherein R is methyl or hydrogen, a geometrical isomer thereof or a
therapeutically acceptable salt of said compound or geometrical isomer
in any degree of hydration, characterized in that a Wittig reagent is
prepared according to the following reaction scheme:
<IMG> <IMG>
<IMG>
<IMG>
<IMG>
(IV)
wherein Ph denotes a phenyl group, X represents Br or OPh and R is as
defined above; and either the Wittig reagent of formula IV is reacted
with 4-bromophenyl-3-pyridyl-ketone in the presence of sodium methylate
according to the following reaction scheme:

<IMG> Br? + NaOCH3 + <IMG>
(V)
NaBr + CH3OH + <IMG> + PH3PO
(VI)
or the Wittig reagent of formula IV is reacted with a base to form a
Wittig reagent of the formula
<IMG>
which is reacted with 4-bromophenyl-3-pyridyl-ketone.
2. A process according to claim 1 wherein X is a bromine atom.
3. A process according to claim 1 wherein X is a phenoxy group.
4. A process according to claim 1 wherein the Wittig reagent of
formula IV is reacted with sodium methylate to form a Wittig reagent of
the formula
<IMG>
11

which is then reacted with 4-bromophenyl-3-pyridyl-ketone.
5. A process according to claim 1, 3 or 4 wherein the reaction
between the Wittig reagent and 4-bromophenyl-3-pyridyl-ketone is carried
out in an organic solvent.
6. A process according to claim 1, 3 or 4 wherein the reaction
between the Wittig reagent and 4-bromophenyl-3-pyridyl-ketone is carried
out in dimethyl formamide, hexamethylphosphornstriamide or dimethylsul-
foxide.
12

Description

108219B
Astra Lakemedel AB
Sodertalje/SWEDEN
Inventor: P Bamberg
KA 541-1
78 06 16
RN/ACE
A novel process for preparation of a therapeutically active
compound
Description
Techn_cal Field
The present invention is related to a novel process for pre-
5 paration of a therapeutically active compound.
.
An object of the invention is to provide a process enabling
improved economy of production and avoiding use of chemicals
that are difficult to handle.
Background Art
Swedish Patent 361 663 discloses i.a. a compound of the
formula
'~
_ I _
..

1~8Zl~
Br
CH
~H2
N(CH3)2
10 believed to be useful as an anti-depressive agent, and a
method for preparation thereof, comprising dehydration of an
intermediate of the formula
~r ~ ~ II
CH2 OH
I H2
/ ~
CH3 CH3
.,,. ' ' '
25 The main disadvantages of the known method is that the pre-
: paration of the intermediate is complicated, involving
- chemicals which are difficult to handle, such as butyl lithium,
and that only a low overall yield may be obtained.
30 Belgian Patent 835 802 discloses a related therapeutically
; active compound having the formula
- . . , .: . . : .
.
',: ' . ' . :.. ~ :

1~8~8
J~ 111
CH
CH2
The present invention provides a process for preparation of a
therapeutically active compaund of the formula
Br
VI
~CH
H2
. CH3 R
-, wherein R is methyl or hydrogen, a geometrical isomer thereof or a
therspcutically acceptable salt of said compound or geometrical isomer
in any degree of hydration, characterized in that a Wittig reagent is :-
prepared according to the following reaction scheme:
Ph3P * BrCH2CH2X ) ~Ph3 ~CH2CH2X ~ Br~3
~h3P CH2CH2X~ B ~ 1 2 HN \ 3
.
rPh3P~3CH2CH2 ~ ~ 3 ~ CH ~ 2
(IV)
: . ,
.
.. . . '

--` 10~ 8
Wherein Ph denotes a phenyl group, X represents Br or OPh and R is
as defined above; and either the Wittig reagent of formula IV is
reacted with 4-bromophenyl-3-pyridyl-ketone in the presence of sodium
methylate according to the following reaction scheme:
3PCH2CH2N ~ ~ B ~ ~ NaOCH3 ~ ~ C
O
(IV) (V)
Br
NaBr I CH30H + ~ C ~ ~ Ph3PO
CH
CH2N ~ 3
:, ,
CVI)
or the Wittig reagent of formula IV is reacted with a base to form a
Wittig reagent of the formula
: CH
Ph3P CH C 2N \
R
: which is reacted with 4-bromophenyl-3-pyridyl-ketone.
In-oné embodiment the present invention provides a process
for preparation of a compound of formula I or III characterized in that
a Wittig reagent is prepared according to the following reaction scheme: .
?~
- , , , ~
., . , : . . :- ~ . :
. ~ .. . .. . .
:: : .: : ,,,
:, ,'',," ' '': ' ' , . .' ~ ' ' ~ ':

- ~0821~8
Ph3P + BrCH2CH2Br~~~~~ ~ Ph3 ~CH2CH2Br3 B ~ ;
[Ph3 ~CH2CH2B~ B~ + 2HN 3 ~ ~Ph3P CH2CH2N H3 ] B ~ +
CH ~ H
3 \N / B ~ (IV)
R/ \ H
wherein Ph denotes phenyl and R denotes CH3 or H, and reacted with 4-
bromophenyl-3-pyridylketone in the presence of sodium methylate according
: to the following scheme:
[Ph3PCH2CH2N ~ 3] B ~ + NaOCH3 + ~ / ~ N
, lCI -:
(IV)
(V)
Br
Na~r ~ CH~OH t ~ ~ I ph~rO
; H
: ¦ ~ CH
CH2N;\ 3
R
; (VI)
The last reaction step is suitably carried out in a solvent
such as dimethylformamide, hexamethylphosphorus-~riamide or di-
methylsulfoxide. The new manner of preparing the Wittig reagent has
surprisingly been found to be operable and is technically advantageous.
A further advantage of the new process is that the simple reactant sodium
methylate may be used as a base instead of butyl lithium often used in
.
... -, - 5-
,.~.,~
.,
. . . - . .: .
.. .. : ,: . . ' -
, ~ . . : , . . . .
.

- 108Z198
similar reactions. Butyl lithium is, as mentioned, difficult to
handle and should if possible be avoided in production on a technical
scale because of its strong reactivity, which i.a. may lead to self-
ignition.
The therapeutically active end compound VI exists in two
stereoisomeric forms, a Z-form and an E-form according to the IUPAC
nomenclature. The preferred isomer is the Z-isomer, having the
configuration.
\ /
CH3
H ~ R
The preferred isomer may be obtained by isolation from an isomeric
mixture of the end compound VI.
In another embodiment of the invention the Wittig reagent of
formuls IV is prepared by the following reaction
~Ph3P-CH2CH20P ~ 3 ~ HN ~ ~ ~ h3P -CH-CH2N 3 ~ Br~
It is reacted with a base to form a Wittig reagent of formula
Ph3P = CH-CH2N \ 3
which is then reacted with 4-bromophenyl-3-pyridyl ketone in accordance
with the following reaction scheme
B - 6 ~
, . .: . . .... . - : . . :
. .: .
.: - . . .. . , : -.
... ,.. ,
.. . . , . ., ~ .
- - .. . .. .

108Z1~8
IV CH3
base Ph P=CH-CH N
_ _ __ ~ 32 \ R
Ph3P=CH-CH N / 3 3r Vl I Ph3P0
lCI
:. O
,~ (V) .
wherein R represents methyl or hydrogen.
; The base with which the Wittig reagent of formula IV is reacted
is preferably sodium methylate but this is not essential as other bases
can be used.
Again the last reaction step, i.e. the reaction between the
- Wittig reagent and the 4-bromophenyl-3-pyrityl-~etone, is carried out in
a solvent such as dimethylformamide, hexamethylphosphorus-triamide or
dimethylsulfoxide.
10The invention is further illustrated by the following example:
Step 1. Preparation of[Ph3~CH2CH2Br] BrG~
A mixture of triphenylphosphine (26.2 g, 0.1 mole) and 1,2-di-
bromoethane (18.8 g, 0.1 m~le) in xylene (40 ml) was boiled gently for
about 2.5 hours. A precipitate formed during this time. After cooling
to ambient temperature the mixture was filtered and the crystals were
washed with xylene yielding 29.2 g (65%) of product.
Step 2. Preparation of[m3PCH2CH2NMe2] B ~
;
A solution of 2-bromoethylenetriphenylphosphonium bromide
(13.5 g, 0.03 mole) in acetonitrile (200 ml) was treated in the cold
20with dimethylamine (20 g, 0.44 mole) in 50 ml of acetonitrile. The
. .
,:

108~
mixture was kept at ambient temperature over night and filtered. The
crystals were washed with acetone yielding the product, mp 200-203C.
Step 3. N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allyl-
amine-dihydrochloride
.
To 0.14 g (2.5 mmol) of sodium methylate in 1 ml of dimethyl-
formamide was added a suspension of 1,4 g t2.5 mmol) dimethylamino
ethyltriphenyl-phosphonium bromide in 2 ml of dimethylformamide. After
a few minutes stirring 0.66 g (2.5 mmol) 3-pyridyl-4-bromophenylketone
was added in 2 ml of dimethylformamide. A brown solution was formed.
lOj The mixture was stirred at room temperature overnight and thereafter
poured into ice water. The oily precipitate was extracted with ether.
The ether phase was washed with water and evaporated. The residue
was stirred with ether/petroleum ether 1:2, whereby triphenyl-
phospineoxide crystallized. The crystals were filtered off and the mother
lye was evaporated. The residue was extracted with hexane (2 x 10 ml),
and to the hexane solution was added l ml of concentrated hydrochloric
acid. Two phases were formed. A mixture of ethanol/ether 1:1 was dropped
in until one homogenous phase was obtained. The product then crystallized,
and after cooling 0.3 g (ca 30~) thereof was isolated. M.p. 178-
-192C. This product gave no depression of the melting point on
admixture with an authentic sample. The MMR-spectrum was identical to
that of an authentic sample.
While being advantageous over previously known processes for
preparing the compound of formula VI the modified processes above do
not have all the advantages of the original process of the present
invention.
.

18~19~3
Industrial Applicability
The compound and the methods of the invention are useful in
the pharmaceutical industry, especially in preparation of a compound
of formula VI above in a technical scale.
,~ _ g_
- . . .
. '. ' . ~ :