DESCRIPTION
The present invention relates to a new process for obtaining 5-cyanophthalide, which is an intermediate used for the synthesis of citalopram and its active enantiomer S(+) citalopram, both of which are known active ingredients commonly used for treating depression.
The process provides for starting from 5-carboxyphthalide which, in its acyl chloride form, is reacted with hydroxylamine to give the corresponding hydroxamyl phthalide which is subsequently subjected to a dehydration reaction to give 5-cyanophthalide.
Field of the invention
Citalopram is a drug which has been known for some time for the treatment of depression. Because it has a chiral centre, citalopram is normally produced and marketed in the form of a racemic mixture.
The S(+) enantiomer, better known as escitalopram, is responsible for almost all of the pharmacological activity of the citalopram racemate. The preparation of citalopram is described, for example, in European patent application EP1032566 while that of its enantiomer, escitalopram, is described, for example, in European patent application EP347066, both of which applications are mentioned here by way of reference; both of the above-mentioned methods provide for starting from a common intermediate, 5-cyanophthalide, whose structural formula is indicated below.
NCL
(Figure Remove)
O
CqH5N02 159.14
Numerous publications describe the preparation of 5-cyanophthalide. One method for the preparation of 5-cyanophthalide was originally mentioned and proposed by Levy and Stephen J.Chem.Soc. 1931, 867; that method provides for starting from

5-aminophthalide which is converted into 5-cyanophthalide by means of a diazotization reaction followed by a reaction with CuCN. Other methods have been described over the years.
For example, EP1140886 describes a method for the synthesis of 5-cyanophthalide starting from 5-carboxyphthalide. The method provides for reaction between 5-carboxyphthalide and a chlorinating agent, such as thionyl chloride, to give the chlorocarbonyl derivative which is then reacted with alkylamines or ammonia to give the corresponding carbamyl derivatives which, when subjected to a dehydration reaction, give 5-cyanophthalide; the yields of 5-cyanophthalide starting from 5-carboxyphthalide reported in that document are of the order of 68%.
EP 1254129, on the other hand, provides for the synthesis of 5-cyanophthalide by reacting a thiazolyl intermediate and an oxazolidine derivative of 5-carboxyphthalide and subsequently dehydrating to give the cyanophthalide. All of the methods mentioned above describe processes in which it is necessary to isolate the reaction intermediates and/or to use potentially dangerous reagents, such as ammonia or alkylamines.
Description of the invention
A one-pot process which enables 5-cyanophthalide to be obtained directly from 5-carboxyphthalide has now surprisingly been found and forms the main subject-matter of the present invention; the method in question provides for the transformation of 5-carboxyphthalide into 5-chlorocarbonyl phthalide; preferably, this intermediate is not isolated and, by reaction with hydroxylamine, it is converted into 5-hydroxamyl phthalide, whose structural formula is indicated below,
(Figure Remove)

C9H7NO4 193.16
with optimum reaction yields and a high degree of purity.

This compound is then subjected to dehydration by means of suitable dehydrating agents, such as thionyl chloride or phosphorus oxychloride, to give 5-cyanophthalide obtained with yields and a high standard of purity; the entire sequence of the process is shown in Figure 1.
The present invention therefore relates to a process for the production of 5-cyanophthalide comprising:
(a) the conversion of 5-carboxyphthalide into 5-halocarbonyl phthalide;
(b) the subsequent conversion of the 5-halocarbonyl phthalide into 5-
hydroxamyl phthalide;
(c) the subsequent dehydration of the 5-hydroxamyl phthalide.
According to one aspect of the invention, the 5-halocarbonyl phthalide
corresponds to 5-chorocarbonyl phthalide; the latter is obtained by reacting 5-
carboxyphthalide with a chlorinating agent, preferably selected from thionyl
chloride, phosphorus pentachloride, sulphuryl chloride or mixtures thereof.
The above-mentioned reaction is carried out in the presence of an aprotic, polar,
organic solvent, preferably at reflux temperature; this solvent is preferably
selected from DMF, DMSO, or mixtures thereof, and also performs the function
of catalyzing the reaction.
According to a further aspect of the invention, the 5-halocarbonyl phthalide is not
isolated or purified.
The 5-hydroxamyl phthalide is then obtained by reacting 5-halocarbonyl
phthalide with hydroxylamine. This reaction is readily carried out in an aprotic
organic solvent, preferably selected from THF, toluene, or mixtures thereof; the
reaction temperature is preferably from 0 to + 20 °C, even more preferably from
+5to+15°C.
The conversion of 5-hydroxamyl phthalide into 5-cyanophthalide is carried out in
the presence of dehydrating agents, preferably selected from thionyl chloride,
phosphorus oxychloride, sulphuryl chloride or mixtures thereof. According to one
aspect of the invention, the dehydrating agent is used as a solvent for the reaction
which is preferably carried out at the reflux temperature of the solvent.
As will be appreciated from the following Examples, which are purely illustrative
and non-limiting with respect to the invention, the present process permits the

production of 5-cyanophthalide starting from 5-carboxyphthalide with yields of 80%; that is to say, with yields approximately 18% higher than those reported in EP1140886; in addition, the use of hydroxylamine instead of ammonia is an improvement in terms of the scalability and danger of the process.
Example 1; synthesis of 5-chlorocarbonyl phthalide
There are introduced into a flask, in an inert nitrogen atmosphere: 5-carboxyphthalide (50 g, 0.2806 mole), thionyl chloride (125 ml, 1.71 mole), and dimethylformamide (0.5 ml). The system is heated under reflux (60°C) for 5 hours.
The system is returned to ambient temperature and evaporated under vacuum to leave a residue. Toluene (3 x 100 ml) is introduced and a solid is obtained which is taken up with tetrahydrofuran (500 ml). A solution containing 5-chlorocarbonyl phthalide (purity HPLC (A%) 98%) 50 g (titrated in solution, molar yield 91%) is obtained.
Example 2: synthesis of cvanophthalide starting from 5-hydroxamyl phthalide
Hydroxylamine HC1 (8.86 g, 0.1275 mole), triethylamine (12.9 g, 0.1275 mole)
and tetrahydrofuran (30 ml) are introduced into a flask. The system is brought to
10°C. A solution of 5-chlorocarbonyl phthalide (100 ml corresponding to
approximately 11 g of 5-chlorocarbonyl phthalide 0.056 mole) is added dropwise
over a period of 1 hour.
The whole is left under agitation for 1 hour and is then evaporated under vacuum.
The appearance of a solid is observed and 5-hydroxamyl phthalide 10 g (molar
yield 92% P%=99.16%) is filtered off.
1HNMR (DMSO-d6 400MHz) 5.45(2H,s), 7.87(lHs), 7.91(lH,s), 7.98(lH,s).
9.30 (lH,s), 11.52(lH,s)
2 g of 5-hydroxamyl phthalide (0.01 mole) are introduced into a flask to which
thionyl chloride (15 ml) is added, and the whole is heated under reflux (80°C) to
give, after 6 hours, a light yellow solution.

Toluene (20 ml) is introduced. The whole is evaporated under vacuum to leave a residue which is taken up with toluene (20 ml). The whole is heated under reflux and precipitation is awaited. Filtration is carried out to give 5-cyanophthalide 1.5 g (molar yield 91%) (purity HPLC (A%) 99%). 1HNMR (DMSO-d6 400MHz) 5.45(2H,s), 7.87(lHs), 7.91(lH,s), 7.98(1 H,s)
Example 3: one-pot synthesis of cyanophthalide starting from 5-carboxyphthalide
There are introduced into a flask in an inert nitrogen atmosphere: 5-
carboxyphthalide (50 g, 0.2806 mole), thionyl chloride (125 ml, 1.71 mole), and
dimethylformamide (0.5 ml). The system is heated under reflux (60°C) for 3
hours.
The system is returned to ambient temperature. The system is evaporated under
vacuum to leave a residue, and toluene (3 x 100 ml) is introduced; a solid is
obtained which is taken up with tetrahydrofuran (500 ml). A solution containing
5-chlorocarbonyl phthalide (purity HPLC (A%) 98%) 50 g (titrated in solution,
molar yield 91%) is obtained.
An aqueous hydroxylamine solution (18 ml, 12.5 g, 0.378 mole) is introduced into
a flask. The system is brought to 10°C. A chlorocarbonyl phthalide solution (100
ml corresponding to approximately 11 g of chlorocarbonyl phthalide 0.056 mole)
is introduced (period of introduction 1 hour). The appearance of a solid is
observed during the dropwise addition. The whole is left under agitation overnight
and then filtered.
The solid is washed with water (100 ml) and 5-hydroxamyl phthalide 10.5 g
(molar yield 92% P%=99.%) is obtained.
1HNMR (DMSO-d6 400MHz) 5.45(2H,s), 7.87(lHs), 7.91 (lH,s), 7.98(1 H,s),9.30
(lH,s), 11.52(lH,s)
2 g of 5-hydroxamyl phthalide (0.01 mole) are introduced into a flask to which
thionyl chloride (15 ml) is added and the whole is heated under reflux (80°C) to
give, after 6 hours, a light yellow solution.
Toluene (20 ml) is introduced. The whole is evaporated under vacuum to leave a
residue which is taken up with toluene (20 ml). The whole is heated under reflux

and precipitation is awaited. Filtration is carried out and cyanophthalide 1.5 g
(molar yield 91%) (purity HPLC (A%) 99%) is obtained.
1HNMR (DMSO-d6 400MHz) 5.45(2H,s), 7.87(lHs), 7.91(lH,s), 7.98(1 H,s)

1. A process for the production of 5-cyanophthalide comprising: (a) the
conversion of 5-carboxyphthalide into 5-halocarbonyl phthalide; (b) the
subsequent conversion of the 5-halocarbonyl phthalide into 5-hydroxamyl
phthalide; (c) the subsequent dehydration of the 5-hydroxamyl phthalide.
2. A process according to claim 1, characterized in that the 5-halocarbonyl
phthalide is 5-chlorocarbonyl phthalide.
3. A process according to claim 2, characterized in that step (a) is carried out by
reacting 5-carboxyphthalide with a chlorinating agent, preferably selected
from thionyl chloride, phosphorus pentachloride and/or sulphuryl chloride.
4. A process according to any one of the preceding claims, characterized in that
step (a) is carried out in the presence of an aprotic, polar, organic solvent,
preferably at reflux temperature.
5. A process according to claim 4, characterized in that the aprotic, polar,
organic solvent is selected from DMF and/or DMSO.
6. A process according to any one of the preceding claims, characterized in that
the 5-halocarbonyl phthalide is not isolated or purified.
7. A process according to any one of the preceding claims, characterized in that
step (b) is carried out by reacting the 5-halocarbonyl phthalide with
hydroxylamine.
8. A process according to any one of the preceding claims, characterized in that
step (b) is carried out in an aprotic organic solvent.
9. A process according to claim 8, characterized in that the organic solvent is
selected from THF and/or toluene.
10. A process according to any one of the preceding claims, characterized in that
step (b) is carried out at a temperature of from 0 to + 20 °C, preferably from
+5to+15°C.
11. A process according to any one of the preceding claims, characterized in that
step (c) is carried out in the presence of dehydrating agents, preferably
selected from thionyl chloride, phosphorus oxychloride and/or sulphuryl
chloride.

12. A process according to claim 11, characterized in that the dehydrating agent
is used as a reaction solvent.
13. A process according to claim 12, characterized in that step (c) is carried out
at the reflux temperature of the solvent.
14. A process for the preparation of citalopram or escitalopram comprising a
process for the production of 5-cyanophthalide according to any one of the
preceding claims.

15. A process for the production of 5-cyanophthalide
substantially as herein described with reference to the
foregoing description, examples and the accompanying
drawing.