The subject of the present invention is novel process for the preparation of the [4-
(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-thiazolo-2-yl]-[2-cyclopropyl-l-(3-
fluoro-4-methylphenyl)-ethyl]-amine of formula (I)

and the new intermediates of the preparation process.
The compound of formula (I) is the key intermediate to the preparation of the [4-(2-
chloro-4-methoxy-5-methylphenyl)-Af-propynyl-5-methyl-thiazolo-2-yl]-[2-
cyclopropyl-1 -(3-fluoro-4-methylphenyl)-ethyl]-amine of formula (VI)

- which is a known CRF1 (corticrotropin releasing factor 1) receptor antagonist
with potential antidepressant and / or anxiolytic effect.

The thiazolamine of formula (I) is presently prepared in several steps, utilizing the
Hantzsch synthesis (WO2001005776 Sanofi-Aventis).
The preparation process used so far (WO2001005776 Sanofi-Aventis) starts from
the compound of the general formula (II)

- where X means halogen atom. This compound, however, easily decomposes, it is
irritative, its quality is hard to reproduce, its isolation and treatment involves
difficulties.
Our aim was to find a starting material for the preparation of the compound of
formula (I) which is well characterized, easy to treat, which is well crystallizable,
and can be prepared conveniently, in high yield. To our surprise, we found that the
2-thiocyanato-l-(2-chloro-4-methoxy-5-methylphenyl)-propan- 1-one of formula

is a starting material which fulfills all our needs. A further advantage of applying
the compound of formula (III) is that under specific conditions, i.e. in the presence
of a phase transfer catalyst, it can be prepared easily in aqueous medium, from the
previously used compound of general formula (II). This new process according to
our invention is environment friendly, since only aqueous effluent is formed, the
amount of the used organic solvents is small and the solvents can be re-used, the

process can be performed in industrial scale and it results high purity product in
high yield.
The preparation of the ketone derivative (III) in aqueous conditions is surprising,
since the thiocyanate group is sensitive to water, it can easily transform into
isothiocyanate, or it can suffer hydrolysis. Therefore, in the state of art, it is
prepared either in ionic liquid (Tetrahedron Letters 46 (2005) 1489-1491) or in
alcoholic medium (J. Indian Chem. Soc, 81 (2004) 786-788), but in any case in the
absence of water.
The subject of the invention is novel process for the preparation of [4-(2-chloro-4-
methoxy-5-methylphenyl)-5-methyl-thiazolo-2-yl]-[2-cyclopropyl-l-(3-fluoro-4-
methylphenyl)-ethyl]-amine of formula (I)

wherein
a.) the 2-halogeno-l-(2-chloro-4-methoxy-5-methylphenyl)-propan-l-one of the
general formula (II)

where X means halogen, is reacted with an alkali metal-thiocyanate, in the presence
of a phase-transfer catalyst, and
b.) the thus obtained 2-thiocyanato-l-(2-chloro-4-methoxy-5-methylphenyl>
propan-1 -one of formula (III)


or a tautomeric form of it is reacted with the 2-cyclopropyl-l-(3-fluoro-4-
methylphenyl)-ethyl-amine

of formula (IV).
To prepare the appropriate optically active isomer of the compound of formula (I)
we have to start from the respective optically active amine of formula (IV).
In one embodiment of the process according to the invention, in step a.) the reaction
is performed in the binary system consisting of an aprotic solvent and water.
In one alternative of the process according to the invention, the compound of the
general formula (II) - where X favourably means chloro or bromo group,
preferably bromo group, - is dissolved in an aprotic organic solvent and reacted
with the aqueous solution of an alkali metal-thiocyanate - preferably potassium-
thiocyanate - in the presence of a phase transfer catalyst - preferably TBAB
(tetrabutyl-ammonium bromide). The reaction mixture is worked-up by separation
of the organic phase after dilution of the mixture with water. In a given case after

solvent exchange, the compound of the formula (III) can be well crystallized, in
high yield.
In one variant of step b.) the compound of formula (III) is added to the compound
of formula (IV), to obtain the desired product with a favourable impurity profile and
in high yield.
To achieve the best yield the addition period lasts for at least one hour.
In step b.) favourably an apolar aprotic solvent is applied, preferably methyl-
cyclohexane or toluene. Step b.) is preferably performed at a temperature range
between 25°C and reflux temperature, most preferably at reflux temperature.
The compounds of the general formula (II) and the amine of formula (IV), as well
as their preparation are known from the patent application of publication number
WO2001005776 .
A further subject of the invention is the new compound of formula (III) and its
tautomers, as well as their preparation.
Of the tautomers of compound (III), the 5-(2-chloro-4-methoxy-5-rnethylphenyl)-4-
methyl-[1.3]-oxathioI-2-ylideneamine of formula (V)

is also the subject of the invention.
Further details of our process are demonstrated in the following examples without
limiting the claims to the examples.

EXAMPLES
Example 1. Preparation of compound (III) from compound (II) in
dichloromethane (PCM)
291.5g 2-bromo-l-(2-chloro-4-methoxy-5-methylphenyl)-propan-l-one (II) is
dissolved in
291g DCM,
5.3g TBAB (tetrabutyl-ammoniura-bromide) catalyst is added to it.
167g KSCN is dissolved in
83.6g water. The aqueous solution is added to the DCM solution.
The resulting binary system is heated to 40°C (reflux) and is stirred
for 3-4 hours.
The reaction is accompanied by salt precipitation. Water is added to
the mixture until the salt dissolves. The lower, aqueous phase is
separated, the upper, organic phase is evaporated, while
870ml methanol (MeOH) is added to it.
From the methanol solution compound (III) crystallizes on cooling.
The crystals are filtered off, washed several times with MeOH.
Yield: 90-95%
Melting point: 75°C (MeOH)
IR-spectrum: 2158 cm"1 (CN), 1664 cm"1 (C=O)
'H-spectrum (DMSO-d6, TMS): 7.73 (1H, s), 7.14 (1H, s), 5.28 (1H,
q, J= 7,2Hz), 3.89 (3H, s), 2.16 (3H, s), 1.60 (3H, d, J= 7.2Hz)
13C-NMR-spectrum: 194.7, 160.9, 132.6, 131.5, 126.3, 125.5, 113.5,
111.4, 56.7, 49.4, 18.8, 15.8
Example 2. Preparation of compound (III) from compound (II) in
methyl-cyclohexane (MCH)

The preparation procedure is as described in Example 1, but MCH is
used as solvent, instead of DCM. The product is crystallized from
MCH on cooling.
Yield: 60%
Example 3. Preparation of compound (V) from compound (III) in an apolar
solvent in the presence of an amine
26.4g compound (III) (prepared as described in example 1. or 2.) is
suspended in
52 ml MCH.
In stoichiometric amount an amine (preferably benzylamine) is added
to the mixture.
The mixture is stirred for 0.5-1 hour (the structure of the amine
influences the reaction time). Thick precipitate is obtained, it is
filtered off and washed several times with methyl-cyclohexane.
Yield: 85%.
Example 4. Preparation of compound (V) from compound (HI) in a tertiary
amine as solvent
The preparation procedure is as described in Example 3, with the
difference that compound (III) is suspended in triethyl-amine as
solvent, instead of MCH, and no other amine is added to the mixture.
Yield: 85%.
Melting point: 106°C (EtOH)
IR-spectrum: 3253 cm'1 (NH), 1679 cm"1 (C=N)
'H-spectrum (DMSO-d6, TMS): 7.30 (1H, s), 7.14 (1H, s), 3.86 (3H,
s), 2.14 (3H, s), 1.88 (3H,s)
l 3C-NMR-spectrum: 163.1 (s), 158.9 (s), 138.9 (d), 133.0 (s), 131.4
(s), 125.3 (s), H8.3(s), 111.8(d), 111.5 (s), 56.0 (t), 15.3 (t), 11.6(t)

Example 5. Preparation of compound (I) from compound (HI) in methyl-
cyclohexane (MCH)
26.3g isolated product (III) is dissolved in
52 ml MCH.
The reaction mixture is heated to 85-90 °C and is added to the 85-90
°C solution of
19.2 g amine (IV) in MCH (20%). The addition period is 2-4 hours. After the
addition, the reaction mixture is stirred at 85-90 °C for one hour. The
MCH solution of the crude product (I) is cooled and the precipitated
crystals are filtered off. The crystalline product is covered with a
small amount of MCH.
Yield: 80%.
Example 6. Preparation of compound (I) from compound (III) in MCH and
MeOH
The preparation procedure is as described in Example 5, but product
(I) is crystallized from MeOH, instead of MCH, after solvent
exchange.
Yield: 90%
Example 7. Preparation of compound (I) from compound (V)
The preparation procedure is as described in Examples 5 and 6, but
instead of compound (III), compound (V) is used, in the same amount.
Yield: 85%

Claims
characterized in that
a.) the compound of the general formula (II)

1. Process for the preparation of the [4-(2-chloro-4-methoxy-5-methylphenyl)-
5-methyI-thiazolo-2-yl]-[2-cyclopropyl-l-(3-fluoro-4-methyIphenyl)-ethyl]-amine
of formula (I)

- where X means halogen - is reacted with an alkali metal-thiocyanate, in the
presence of a phase transfer catalyst,
and
b.) the thus obtained 2-thioyanato-l-(2-chloro-4-metoxy-5-methylphenyl)-propan-
1-one of formula (III)


or a tautomeric form of it is reacted with the 2-cyclopropyl-l-(3-fluoro-4-
methylphenyl)-ethyl-amine

of formula (IV).
2. The process as defined in claim 1., characterized in that,
in step b.) the ketone of formula (III) is added to the amine of formula (IV).
3. The process as defined in claim 2., characterized in that,
the addition of the ketone of formula (III) to the amine of formula (IV) takes at
least 1 hour,
4. The process as defined in any of claims 1-3., characterized in
that, in step a.) the reaction is performed in a binary system consisting of an
aprotic solvent and water,
5. The process as defined in any of claims 1-4., characterized in
that step b.) is carried out in an apolar aprotic solvent.

6. The process as defined in claim 5., characterized in
t h a t the apolar aprotic solvent applied in step b.) is methyl-cyclohexane or
toluene.
7. The process as defined in any of claims 1-6., characterized in
t h a t step b.) is carried out at a temperature between 25 °C and reflux
temperature.
8. The process as defined in claim 7., characterized in
that step b.) is carried out at reflux temperature.
9. The process as defined in any of claims 1-8., characterized by
that in the general formula (II) X means bromo group.
10. The 2-thiocyanato-l-(2-chloro-4-methoxy-5-methylphenyl)-propan-l-one

of formula (III) and its tautomers.
11. Of the tautomers of the compound of formula (III) according to claim 10.,
the 5-(2-chloro-4-methoxy-5-methylphenyl)-4-methyl-[1.3]-oxathiol-2-ylidene-
amine of formula (V).




12. Process for the preparation of the 2-thiocyanato-l-(2-chloro-4-methoxy-5-
methylphenyl)-propan-l-one of formula (III)
- where X means halogen - is reacted with an alkali metal-thiocyanate, in the
presence of a phase transfer catalyst.
13. Process for the preparation of the [4-(2-chloro-4-methoxy-5-methylphenyl)-
5-methyl-thiazol-2-yl]-[2-cyclopropyl-l-(3-fIuoro-4-methyl-phenyl)-ethyl]-amine
of formula (I)


characterized by that the 2-thiocyanato-l-(2-chloro-4-methoxy-5-methyl-
phenyl)-propan-l-one of formula (III)

is reacted with the 2-cyclopropyl-l-(3-fluoro-4-methylphenyl)-ethyl-amine of
formula (IV)

in a way that the ketone of formula (III) is added to the amine of formula (IV).

ABSTRACT

The subject of the present invention is a novel process for the preparation of the [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-thiazolo-2-yl]-[2-cyclopropyl- l-(3-fluoro-4-methylphenyl)-ethyl]-amine of formula (I) and the new intermediates
of the preparation process.