PROCESS FOR THE PREPARATION OF 1-(3-TRIFLUOROMETHYLPHENYL)-2- (2-BENZOYLOXYETHYLAMINO)-PROPANE

METHODE DE PREPARATION DU 1-(3- TRIFLUOROMETHYLPHENYL)-2-(2- BENZOYLOXYETHYLAMINO)-PROPANE

English Abstract

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TITLE OF THE INVENTION
"PROCESS FOR THE PREPARATION OF 1-(3-TRIFLUOROMETHYLPHENYL)-
2-(2-BENZOYLOXYETHYLAMINO)-PROPANE"
ABSTRACT OF THE DISCLOSURE
The invention relates to a process for preparing 1-(3-tri-
fluoromethylphenyl)-2-(2-benzoyloxyethylamino)propane by cata-
lytic debenzylation of 1-(3-trifluoromethylphenyl)-2-[N-(2-
benzoyloxyethyl)-N-benzylamino]propane.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for the preparation of 1(3-trifluoromethyl-
phenyl)-2-(2-benzoyloxyethylamino)propane, the formula of
which is CH3
<IMG> (I)
where Ar represents a 3-trifluoromethylphenyl residue,
characterized in that l-(3-trifluoro-methylphenyl)-2-
[N-(2-benzoyloxyethyl)-N-benzylamino]-propane, of the formula
VII, is catalytically debenzylated according to the following
reaction scheme:
<IMG> (I)
(VII)
where Ar has the same meaning as above.
2. A process as claimed in claim 1, characterized in
that the debenzylation reaction is catalyzed by palladium.
3. A process as claimed in claim 1, characterized in
that l-(3-trifluoromethylphenyl)-2-[N-(2-benzoyloxyethyl)-
N-benzylamino]-propane is prepared according to the
following synthetic pathway:

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<IMG>
(VI)
<IMG> <IMG>
(V) (VI)
<IMG>
(VII)
where Ar has the same meaning as above.
4. A process as claimed in claim 3 characterized in that
the reduction with NaBH4 is performed directly on the crude
reaction product from (3-trifluoromethylphenyl)acetone and
benzylamine, without isolation of the Schiff base (IV).

Description

This invention relates to a new process for the synthe~is
of 1-(3-trifluoromet.hylphenyl)-2-(2-benzoyloxyethylamina~pro-
pane, of -the ~ormula (I)
CH3
Ar-CH2-CH-NH-CH2-CH2-O-C-C6H5 (I)
O
where Ar ,represents a 3-tri~luoromethylphenyl re~idue.
Compound (I) is well-know *or its interesting hypolipaemi-
zing activity.
¦ According to the prior art (F2P 1517 587) said substance is
preparod~by a benzoylation reaction of 1-(3-trifluoromethylphe
¦ nyl)-2-(2-hydroxyethyl-amino~propane, as shown in the -~ollowin~
scheme: CH
3 C H -COCl
Ar-CH2-CH-NH-CH2-CH20H 6 5 _ ~ (I)
` (II)
where Ar has the same meaning as aboveO
~hi~ reaction is characterized by a low y~d~owing to the
l competitive benzoylation at the N-atomO Moreo~er, the starting
¦ compound (II) can be obtained only through the reaction of the
co~re~ponding primary amine (III) with ethylene oxide-
CH3 C ~ ~ /CH2 CH3
Ar-CH2-CH-NH2 -- ~ Ar-CH2-CH-NH-CH2-CH20H
(III) (II)

4~
where Ar has the same meaning as above.
This reaction shows a highly unsatisfactory course
hecause, even in the presence of an understoichiometric of
ethylene oxide, a great amount of the bis-hydroxyethyl
derivative is produced.
This by-product must be separated from (II) by a distil-
lation under reduced pressure which is accompanied by some
drawbacks.
The amine (III) itself is prepared from (3-trifluoro-
. methylphenyl)acetone, for example through the oxime, whichis reduced catalytically. Only poor yields are obtained.
The low transformation yield in the final steps of the
synthesis greatly affect the economy of the process leading
to (I)-
This is particularly true because the above side reactionsdestroy the trifluoromethyl-substituted moiety of the mole-
cule, that is of the more expensive component.
It has been found that the above described drawbacks can
be overcome by employing for the preparation of ~I) a new
synthesis procedure, characterized in that 1-(3-trifluoro-
methylphenyl)-2-[N-(2-benzoyloxyethyl)-N-benzylamino]-propane,
of the formula VII, is catalytically debenzylated according
to the following ireaction scheme:
CH3
I ~2
Ar-cH2-cH-N-cH2-cH2-o U C6 5 (I)
CH~2-C~H.5 0
(VII)
where Ar has the same meaning as aboveO
The reaction scheme can be more specifically set out as
follows:

3 -
CH CH
1 3 C6H5-~12NH2 1 3 NaB H
Ar~CH2~C= ~ Ar-CH2-C=N~CH2-C6H5 ~ ?
(IV)
f H3 C ~ - CH2 f H3
Ar~cH2-cH-NH-c~I2-c6H5 Q ~ Ar-CH2-CH~I-CH2-CH20H
(V) CH2-C~H5
l (~1)
¦ C6H5~ cl ~aH2 cH I~ ~H2 cH2 0 e C6 5 ~ (I)
CH2-C6H5
l (VII)
~where Ar has the same meaning as above.
I The preparation of the ~ohif~ base (IV) can be acoomplished
Ireadily and the expected product is obtained in nearly quanti-
¦tative yield. The same applies for the reduction of the N-be_
¦zylderivati~e (~ In practi~e, it is suitable to bring about ~:
¦the reduction of (IV) ~ith a boro~ydride withou~b isolation of
¦the said Schiff base,
¦ ~he h~ro~-;yethylation rsaction of 1-(3-trifluoromethylphe-
¦nyl)-2-(2-N benzylamin~-propane (V) occurs smoothly and affo~s
¦high yields of compound ~VI) which is practically free from
¦by-products~ Owing to the lack of hydrogen atoms on the amine
¦nitrogen the~ subs~quent benzoylation step i5 also univocal and
¦can be brought about directly with benzoyl chloride? without
¦any addition of acid acceptors~ Finally, the catalytic debenzy~

gz
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lation of compound (VI-L) affords the expected product (I) in
high yield and great purity.
Accordingly9 the new process has to be considered a great
improvement with re~pect to the prior art.
The following example i~ illustrative rather than limitati-
ve of the present invention,
E~AMP~E
a) 1-(3-TrifluoromethylphenYl)-2-b~n~ a=~g~LLL~
A solution of 101 g (0.5 mole) of (3-trifluoromethylphenyl`
acetone and 53 g (0 5 mole) of benzylamine in 500 ml of benze-
ne i~ refluxed in an apparatus which allow~ ~ continuosly re-
move the reaction water (a suitable apparatu~ is for example
a Marcu~son'~ device).
When no more water is evolved~ the benzene is e~aporated un
der diminished pressure, at last ~ith a rotating evaporator.
~ he residue? w~ich is formed mainly by the Schiff base (IV),
weigh~ !147 g; it is dissolved in ethanol (500 ml) and the
resulting solution is 910wly added with stirring to a suspensi n
f 7 5 g (0.2 mole) of NaB~4 in 200 ml o.f ethanol. During the
addition the temperature iæ kept at 15~20C by external coolin .
When the addition is complete~ the mi~ture is stirred for
10 hours at room temperature and then most of the ethanol is
distilled (finally under diminished pressure), After diluition
with 400 ml of ~ater, the reaction mixture is acidified with
2N EIC The emall a ount of unreaoted Xe-tone ia extracted with

llZ~9,~
CH cl2, the aqueous ~eyer is basified with 15~0 NaOH and the
¦organic base is extracted with CH2C12, After drying of the
¦organic layer with K2C03, the solvent is removed and the resi-
¦due is distilled under diminished pressure. The yield of the
!product is 129 g9 bop. 0 5 = 130-133C. The yield on the star-
¦ting ketone is 88%.
¦AnalYSis for C17 18 3
reg~ ~ C=69.62; H-6.14; N=4~77
l found ~o C=69.83; H=6~11; N=4.64
¦ ~he spectral data (IR and NMR) are in agreement with the
¦expected structure.
b) 1-(3-~rifluorometh~lphenyl)-2- ~ ?-h~drox~ethyl)-~-benæ~
amino7-pro~e.
I
~o 58.6 g (0.2 mole) of the prod~ct obtained as described
~in a) is added 1 ml of water and the mixture is cooled -to
1-10C in an autoclave. 16 g (0.36 mole) of liqui-fied ethylene
¦oxide (-10C) are then added.
l The reaction mixture is heated to 100-115C ~or 8 hours,
¦cooled down and taken up with 300 ml of toluene~ It is washed
¦with 2 x 200 ml of water and dried on Na2SQ4~ ~he solvent is
¦eliminated under diminished pressure. 60~6 g (90~o of the theo
¦retical amount) of the product are obtained as a colourless
~ uid~ b.p. 0 5= 140-~4C.
¦Analysis for ClgH220NF3
rei.~ C=67.65; H=6.52; N=4.15

C1 4~Z
il - 6 -
found % C=67.81; H=6.54; N=4.23
The IR and NMR spectra are in agreement with the expected
structure.
c) 1-(3-Trifl rometh~phenyl)-2-/N-(2-benzoyloxye~-
z,ylaminQ7~propaneO
A mixture of 50.5 g(0.15 mole) of 1-(3-trifluoromethylphe-
nyl)-2-~(2-hydroxyethyl)-N-benzylamin~7-propane and 22,4 g
(0.16 mole) oE benzoyl chloride in 200 ml of anhydrous toluene
are heated f`or 6 hours under stirring at 70-80C.After cooling
the hydrochloride of the benzoylation product separates out an~
is filtered with suc tion, thoroughly washed with toluene a~d
dried.M.p. 141C.Yield 58.6 g(82% of the theoretical amount),
Analy~iS for C26H26N2F3Cl
req.~ C=65.40; H~5.66; Cl=7,44;N=2.93
found 7~o C=65.52~ H=5.68; Cl=7,63;N=2.98
The spectral data(IR and NMR~are in agreement with the ex-
pected ones,
d)1-(3-Trifluoromethylphenyl)-2-(2-benzoyloxyeth~lamino)proparE
A solution of 47.7 g (0,1 mole) OI -the hydrochloride descri
bed under c) in 400 ml of ethanol is hydrogenated in the pre-
~ence of 2~5 g of 510 palladium on carbon, at room temperature
and pressure. During 1.5 hour 0.1 mole oE hydrogen are consu-
med. The catalyst is Eiltered out and the solvent removed un-
der diminished pressure. The residue is -taken up in 150 ml of
ethy scetate, filtered with suction snd the crystalline pro-

492
duct is washed with a little-ethyl acetate.
The hydrochloride o~ 1-(3-trifluoromethylphenyl)-2-(2-ben
zoyloxyethylamino)-propane obtained shows a m.p. of 160-161C.
A mi~ture with a product prepared according to Fr.P. 1.517.587
: does not show any lowering o~ the m.p.
~he yield o~ the debenzylation 9tep is o~er 951~.