The present invention relates to a process for the preparation of thiazepine derivatives and, in particular, to the preparation of 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine and salts thereof.
The compound, 11-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine (Formula I)
(Formula Removed)
exhibits useful antidopaminergic activity and may be used, for example, as an antipsychotic agent with a substantial reduction in the potential to cause side effects such as acute dystonia, acute dyskinesia, pseudo-Parkinsonism and tardive dyskinesia.
The compound of formula I is described in granted European Patent EP 240,228. This patent describes the properties of the compound of formula I and its synthesis from dibenzo[b,f][l,4]thiazepine-l l(10-H)-one. In this synthetic route it is necessary to prepare and purify the compound 2-(2-hydroxyethoxy)ethyl-l-piperazine (HEEP).
Granted European Patent EP 282,236 describes an improved process for the preparation of the compound of formula I which obviates the need to prepare and purify the compound 2-(2-hydroxyethoxy)ethyl)-l-piperazine since this improved process does not use 2-(2-hydroxyethoxy)ethyl-l-piperazine. It also obviates the need to use carboxyethyl piperazine which is used to prepare 2-(2-hydroxyethoxy)ethyl-l-piperazine.
Many Pharmaceuticals are developed as salts of pharmacologically acceptable acids or bases. This is usually done if the biologically active substance itself has a physical form which makes it unsuitable to handle in manufacturing processes. Most manufacturing processes involve materials handling in mixing and formulation which is facilitated by the active materials being either a liquid or free-flowing high melting solids. Although salts can be made with suitable acids or bases these often add nothing to the therapeutic benefit of the pharmaceutical and are therefore redundant biologically. It would be better if the
pharmaceutical could be manufactured as the pure active substance.
The reported synthesis of 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo[b,f]|l,4]thiazepine provides 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo[b,f][l,41ithiazepine as a fumarate salt since it has been necessary to prepare the salt to
efficiently obtain a sufficiently pure product. Moreover, to prepare the fumarate salt it has
been necessary to first prepare the hydrogen fumarate salt and subsequently convert it to the
fumarate.
The present invention is based, at least in part, on an improved method of purifying
the compound of formula 1, and in particular on a method of purifying the compound of
formula 1 such that the compound of formula I is obtained in a crystalline form.
According to the present invention there is provided crystalline 11 -(4-[2-(2-
hydroxyethoxy )ethyl |-1 -piperazinyl)-dibenzo[b,fj[l ,4]thiazepine.
The crystalline 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo[b,f|| 1,4]thiazepine may be converted into one of its pharmaceutically acceptable
salts and so the present invention also provides crystalline 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-
1 -piperazinyl)-dibenzo[b,f][ 1,4]thiazepine or a pharmaceutically acceptable salt prepared
therefrom.
The crystalline 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo|b,f][ 1,4]thiazepine is generally provided in a substantially pure form. It is generally
preferred that the crystalline 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo|b,f|[ 1,4]thiazepine is greater than 90% pure, more preferably 99% or greater than
9<>% pure.
According to the present invention there is also provided a process for preparing
crystalline 1 l-(4-[2-(2-hydroxyethoxy)ethylJ-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine or a
pharmaceutically acceptable salt thereof which comprises crystallising 1l-(4-[2-(2-
hydroxyethoxy)ethyl|-l-piperazinyl)-dibenzo[b,fj[l,4]thiazepine from a non-aromatic solvent;
and whereafter, when a pharmaceutically acceptable salt is required, reacting 11-(4-[2-(2-
hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,fj[l,4]thiazepine with an acid which affords a
pharmaceutically acceptable anion.
According to the present invention there is also provided a process for preparing
crystalline 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,fj[l,4]thiazepine or a
pharmaceutically acceptable salt thereof which comprises crystallising 1l-(4-[2-(2-
hydroxyethoxy)ethyl |-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine from a non-aromatic solvent
substantially in the absence of water;
and whereafter, when a pharmaceutically acceptable salt is required, reacting 11-(4-[2-(2-
hydroxyethoxy)ethyl|-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine with an acid which affords a
pharmaceutically acceptable anion.
The crystallisation may be initiated with the aid of a seed crystal.
The salts of 1 l-(4-|2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo[b,f]| 1,4]thiazepine will generally comprise acid-addition salts. Convenient salts may
be selected from those pharmaceutically acceptable salts known in the art. These may be
obtained by any conventional salt preparation method known in the art. For example, salts
may be obtained by reacting 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo(b,f][ 1,4]thia/,epine with a convenient acid, such as, hydrochloric acid, maleic acid,
fumaric acid, citric acid, phosphonic acid, methanesulphonic acid and sulphuric acid.
Preferred salts include fumarate salts and in particular the hemi-fumarate salt. It is
generally preferred that the fumerate salt of 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo[b,f]| 1,4 |thiazepine is bis-[l l-(4-[2-(2-hydroxyethoxy)ethyl]-l -piperazinyl)-
dibenzo[b,f]| 1,4jthia/.epine] fumarate.
It is generally preferred, for example, that the solvent is dry. It is further preferred that
the I l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine is also dry so
that the solution formed on dissolving 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo|b,f][ 1,4 jthiazepine in the solvent is substantially free from water. More especially,
the solution formed in the crystallisation process should be free from water.
Thus, in a preferred embodiment there is provided a process for preparing 11 -(4-[2-(2-
hydroxyethoxy)ethyl j-1 -piperazinyl)-dibenzo[b,f][l,4]thiazepine, or a pharmaceuticallyacceptable
salt thereof, which comprises crystallising 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-lpiperazinyl)-
dibenzo| b,l][ 1,4|thiazepine from a solution of 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-
1 -piperazinyl)-dibenzo[b,f]| 1,4]thiazepine in a non-aromatic solvent which is free from water.
The crystalline 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine
may, if desired, be converted to a pharmaceutically-acceptable salt, as mentioned above.
Examples of suitable solvents include, for example, esters such as those of formula
R'CO2R2 wherein R1 and R2 are alkyl groups; ethers of formula R3OR4 wherein R3 and R4 are
alkyl groups; and ketones of formula R5COR6 wherein R5and R6 are alkyl groups.
Particular values of R1, R2, R-', R4, R5 and R6 include, for example, (l-6C)alkyl such as
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl and hexyl.
Conveniently, R1, R2. R1 and R4 are selected from (l-4C)alkyl.
Specific examples of suitable solvents include, for example, ethyl acetate, isobutyl
acetate, methyl iso-butylketone and methyl tert-butyl ether.
Solvents of particular interest include, for example, ethers. Thus, a solvent of
particular interest is methyl tert-butyl ether.
The temperature of the solution containing 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-lpiperazinyl)-
dibenzo[b,f][ 1,4]thiazepirie may be decreased during the crystallisation. In
general, the temperature will be decreased to about O C. Conveniently, the temperature is
decreased gradually over a period of time. Thus, in a specific example, the temperature is
decreased to ambient temperature (about 25 C) and then further decreased to about O C over a
period greater than 1 hour and generally greater than 2 hours. In particular, the temperature is
decreased from ambient temperature to 0 C over a period of about 2 to 4 hours, preferably
about 3 hours. Where a seed crystal is used it will generally be added to the crystallisation
mixture when that mixture is at ambient temperature. In the case where the temperature is
decreased, the seed crystal will, in general, be added just before the temperature is decreased
(from ambient temperature).
The quantity of solvent employed to crystallise 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-lpiperazinyl)-
dibenzofb,f][l,4]thiazepine will vary according to the precise solvent selected.
In particular the quantity of solvent is that which, when 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-lpiperazinyl)-
dibenzo[b,f][ 1,4]thiazepine is dissolved in it, gives a concentration (before
crystallisation) of about 120 to 160mg/ml, more particularly 130 to 150mg/ml. It is generally
preferred that the quantity of solvent is that which gives a concentration (before
crystallisation) of about 135 to 145mg/ml.
In a particular embodiment of the present invention there is provided a method of
purifying 11 -(4-[2-(2-hydroxyethoxy)ethyl]-l -piperazinyl)-dibenzo[b,f][l,4]thiazepine
comprising crystallising 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo|b,f][ l,4]thia/epme from methyl tert-butylether in the absence of water.
Preferred, particular and specific conditions include those mentioned above.
As mentioned above, the crystalline product may, if desired, be converted to a
pharmaceutically acceptable salt.
In a further embodiment of the present invention there is provided a method of
preparing the fumarate salt of 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo[b,f|[l,4]thiazepine, which method comprises reacting crystalline 11-(4-[2-(2-
hydroxyethoxy)ethyl)-l-piperazinyl)-dibenzo[b,i][l,4]thiazepine with fumaric acid.
The crystalline 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo[b,f][l,4]thiazepine will generally be prepared as herein before defined.
Crystalline 11 -(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo[b,fj[l,4]thiazepine will generally be reacted with the fumaric acid in a solvent such as
an alcohol. Examples of suitable alcohols will include methanol and ethanol. A particularly
suitable solvent is ethanol which may convenienetly be in the form of industrial methylated
spirits (IMS).
The present invention also provides a method of preparing crystallinel l-(4-[2-(2-
hydroxyethoxy)ethyl|-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine, or a pharmaceutically
acceptable salt thereof, from a solution of I l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo[b,f][l,4]thiazepine in an aromatic solvent which process comprises:
a) adding water and an acid to the solution of 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-lpiperazinyl)-
dibenzo|b,f]| 1,4]thiazepme in the aromatic solvent;
b) separating the aqueous and organic phases;
c) adding a non-aromatic solvent and a base to the aqueous phase;
d) separating the aqueous and the non-aromatic solvent phases;
e) drying the non-aromatic solvent phase;
f) crystallising 1 l-(4-|2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo[b,f][l,4]thiazepine from the non-aromatic solvent; and
whereafter, if a pharmaceutically acceptable salt is desired, reacting the 1l-(4-[2-(2-
hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine with an acid which affords a
pharmaceutically acceptable anion.
Particular, preferred and specific values include the values mentioned above.
The aromatic solvent is preferably toluene.
It will be appreciated that the amount/strength of acid added in step (a) will be such
that the aqueous phase is made acidic and the amount/strength of base added in step ((c) will
be such that the aqueous phase is made basic.
The compound of this invention is a central nervous system depressant and may be
used as a tranquilizer for the relief of hyperactivity states, for example, in mice, cats, rats,
dogs and other mammalian species, and additionally for the management of psychotic states
in man, in the same manner as chlorpromazine. For this purpose thel 1 -(4-[2-(2-
hydroxyethoxy)ethyl |-1 -piperazinyl)-dibenzo[b,i][l,4]thiazepine, or physiologically
acceptable acid addition salt thereof, may be administered orally or parenterally in a
conventional dosage form such as tablets, pill, capsule, injectable or the like. The dosage in
mg/kg of body weight of a compound of the present invention in mammals will vary
according to the size of the animal and particularly with respect to the brain/body weight ratio.
In general, a higher mg/kg dosage for a small animal such as a dog will have the same effect
as a lower mg/kg dosage in an adult human. A minimum effective dosage for the compound
of formula I will be at least about l.Omg/kg of body weight per day for mammals with a
maximum dosage for a small mammal such as a dog, of about 200mg/kg per day. For
humans, a dosage of about 1.0 to 40mg/kg per day will be effective, for example, about 50 to
2()00mg/day for an average person weighing 50 kg. The dosage can be given once daily or in
divided doses, for example, 2 to 4 doses daily. The dose may be conventionally formulated in
an oral or parenteral dosage form by compounding about 25 to 500mg per unit of dosage of
conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like as called for
by accepted pharmaceutical practice, for example, as described in US Patent 3,755,340. The
compound of formula I (or salt) may be used in pharmaceutical compositions as previously
described or be contained in or co-administered with one or more known drugs.
Thus, according to the present invention there is also provided a pharmaceutical
composition comprising crystalline 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo[b,f][ 1,4]thiazepine, or a pharmaceutically acceptable salt prepared therefrom,
together with a pharmaceutically acceptable diluent or carrier.
In particular, there is provided a pharmaceutical composition comprising
crystallinel 1 -(4-|2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4|thiazepine and a
pharmaceutically acceptable diluent or carrier.
The present invention also provides a method of treating neuropsychiatic disorders (in
particular, a method of treating psychoses, more particularly schizophrenia) using
crystallinel l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine, or a
pharmaceutically acceptable salt prepared therefrom
In particular, the present invention provides a method of treating
neuropsychiatic disorders, comprising administering an effective amount of crystallinel l-(4-
[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine to a warm-blooded
mammal such as man. In particular, the present invention provides a method of treating
psychoses, more particularly schizophrenia.
The present invention also provides the use of crystalline 1l-(4-[2-(2-
hydroxyethoxy)ethyl|-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine in the manufacture of a
medicament for treating neuropsychiatric disorders and in particular psychoses such as
schizophrenia.
As mentioned above, the present invention offers advantages over known methods of
preparing 1 l-(4-f2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f)[l,4]thiazepine and its
salts.
Firstly, the present invention provides crystallinel l-(4-[2-(2-hydroxyethoxy)ethyl]-lpiperazmyl)-
dibenzo[b,f][ 1,4]thiazepine. In particular the invention provides proceses for the
preparation crystalline 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo[b,f|[ 1,4]thiazepine which is of high purity. In general, the crystalline material had a
high melting point consistent with a crystalline solid of high purity and good quality.
Previously, pure 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo[b,f][ 1,4|thiazepine has been obtained by provision of a purified salt, the fumarate.
This has necessitated preparation of the hydrogen fumarate salt followed by subsequent
conversion to the fumarale salt. This conversion is a relatively low output process which
requires the use of relatively dilute reaction mixtures to ensure the formation of the desired
liimarate salt rather than a mixture of hydrogen fumarate and fumarate salt forms.
By utilising purified crystalline! l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo|'b,f]| 1,4 jthia/epme, the fumarate salt may be prepared in a relatively high output
process since the difficulties associated with obtaining the correct salt form are minimised.
The present invention also provides processes for the preparation of 11 -(4-[2-(2-
hydroxyethoxy)ethyl|-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine and its salts in a more
productive manner than previously reported which uses plant and/or materials such as
solvents more efficiently.
The invention will now be illustrated by the following non-limiting examples in
which, unless stated otherwise:
(i) temperature are given in degrees Celsius (C);
operations were carried out at room or ambient temperature, that is, at a temperature in the
range of 18-25'C.
( i i ) evaporation of solvent was carried out using a rotary evaporator under reduced
pressure (600-4000 pascals; 4.5-30 mmHg) with a bath temperature of up to 60 C;
( i i i ) in general, the course of reactions was followed by TLC and/or HPLC and reaction
times are given for illustration only;
( i v ) melting points are uncorrected and (dec) indicates decomposition; the melting points
given are those obtained for the materials prepared as described; polymorphism may result in
isolation oi"materials with different melting points in some preparations;
( v ) all final products were essentially pure by TLC and/or HPLC and had satisfactory nuclear
magnetic resonance (NMR) spectra and microanalytical data;
( v i ) yields are given for illustration only;
(vii) reduced pressures are given as absolute pressures in pascals (Pa); other pressures are
given as gauge pressures in bars;
(viii) chemical symbols have their usual meanings; the following abbreviations have also
been used: v(volume), w(weight), mp (melting point), L (liters), ml (milliliters), g (grams),
mmol (millimoles), mg (milligrams), min (minutes), h (hours), IMS(industrial methylated
spirits); and
The 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine was
prepared as described in granted European Patent No. EP 282,236. This compound may also
be prepared as described in granted European Patent No. 240,228.
Example 1
(a) Water (106ml) was added to a stirred mixture of 11 -(4-[2-(2-hydroxyethoxy)ethyl]-lpiperazinyl)-
dibenzo|b,f|[l,4]thiazepine (59g) in toluene at 40°C. Concentrated hydrochloric
acid (21.4ml) was added to the mixture and the mixture was stirred vigorously for 15 minutes
at 40 C. The phases were separated.
Methyl tert-butyl ether (256ml) was added to the aqueous phase. Aqueous sodium
hydroxide solution (15.4ml. density 1.5g/cm3) was added and the mixture was warmed to
45 C and stirred vigorously for 15 minutes. The mixture was allowed to settle and the phases
were separated. The organic phase was washed with water (2 x 25ml) at 45 C and then dried
by distillation at 55 C using a Dean and Stark separator. The dried mixture was allowed to
cool to 25 C, seeded and stirred overnight to give a solid. The mixture was cooled to 0 C, and
maintained at 0 C for 4 hours. The solid was collected by filtration, washed with methyl tertbutyl
ether and dried in a vacuum oven at 50 C overnight.
There was thus obtained 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-
dibenzo[b,f][l,4]thia/epine (46.7g) as a white crystalline solid, m.p, 82-84 C.
(b) IMS (35ml) was added to free base (30.Og) and the stirred mixture was heated at 60 C
in a 100ml flask to give a solution. This solution was transferred to a 500ml reactor vessel via
a sinter. The 100ml flask was washed with warm (60°C) IMS (10ml) and the washings added
to the reactor vessel. The mixture in the reactor vessel was warmed to 60 C with stirring.
Fumaric acid (4.65g) and IMS (60ml) were added to the 100ml flask. The mixture
was heated to 60 C with stirring to give a solution which contained a small number of solid
lumps of material. The mixture was added to the reaction vessel via the sinter so as to filter
the mixture and remove the lumps. The resulting mixture in the reaction vessel was stirred to
give crystalline material.
IMS (1 Oml) was added to the 100ml flask, warmed to 60°C and transferred to the
reaction vessel. The thick crystalline mass in the reaction vessel was heated to reflux and then
allowed to cool to ambient temperature, to give a solid. The stirred mixture was cooled to 0 C
and the temperature of the mixture maintained at this temperature for 1 hour. The solid was
collected by filtration and washed with cool (0 to 5 C) IMS (30ml). This IMS had been used
to wash the reaction vessel out. The solid was dried in a vacuum oven at 55 C overnight to
give bis-[1 l-(4-|2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine|
fumarate as a white crystalline solid (32.7g); 94.4% yield).
Example 2
Using a similar method to that described in Example 1, 11-(4-[2-(2-
hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine was crystallised from the
solvents listed below in place of methyl tert-butylether.
Solvent __ Strength (%) Yield (%} M.P. ("Q
Kthyl acetate '"
iso-butyl acetate
Methyl iso-butylketone
Methyl iso-butylketone1 '!
Methyl tert-butyiether
Methyl tert-butylether
(Table Removed)
1 1 1 crystallised from previously isolated 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-
pipera/inyl)-diben/o[b,f][1,4]thiazepine
|2| good solid
131 80% charge
Strength is a measure of purity
Example 3
The following illustrate representative pharmaceutical dosage forms containing a
compound of 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine
and salts thereof, for example as illustrated in any of the previous Examples, (hereafter
referred to as "compound X"), for therapeutic or prophylactic use in humans:
(a)Tablet
mg/tablet
Compound X... 50.0
Mannitol, USP 223.75
Croscarmellose sodium..,. 6.0
Maize starch 15.0
Hydroxypropylmethylcellulose (HPMC), 2.25
Magnesium stearate.. 3.0
(b)Capsule
Compound X 10.0
Mannitol, USP 488.5
Croscarmellose sodium 15.0
Magnesium stearate 1.5
The above formulations may be obtained by conventional procedures well
known in the pharmaceutical art. The tablets may be enteric coated by conventional means,
for example to provide a coating of cellulose acetate phthalate.

WE CLAIM
1. A process for preparing crystalline11-(4-[2-(2-hydroxycthoxy)ethyl]-l-piperazinyl-dibenzo[b,f][l,4]thiazepine which comprises crystallising 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]jthiazepine from a solution of 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperuinyl)-dibenzo[b,f][l,4]thiazepine in a solvent which is an ester of formula R1COR2 wherein R1 and R2 are (1-4C) alkyl groups; an ether of formula R3OR4 wherein R3 and R4 are (1-4C)alkyl groups; or a ketone of formula R5COR6 wherein R5 and R6 are (l-4C)alkyl groups; and in which the solution is substantially free from water.
2. A process as claimed in claim 1 wherein the solvent is selected from ethyl acetate, isobutyl acetate, methyl iso-butylke-tone and methyl tert-butyl ether.
3. A process as claimed in claim 2 wherein the solvent is methyl tert-butyl ether.
4. A process as claimed in any one of claims 1 to 3 wherein the 11-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibcazo [b,f][l,4]thiazepine and the solvent are heated to give a solution and the temperature of the solution containing the 11 -(4-[2-(2-hydroxyethoxy)ethyl]-l-piperaziny-dibenzo[b,f][l,4]thiazepine is decreased to ambient temperature and then further decreased to about 0 °C over a period greater than 1 hour.
5. A process as claimed in claim 4 wherein the temperature is decreased from ambient temperature to 0 °C over a period of about 2 to 4 hours.
6. A process as claimed in claim 4 or 5 wherein the temperature is decreased from ambient temperature to 0°C over a period of about 3 hours.
7. A process as claimed in any one of claims ito 6 wherein the quantity of the solvent is that which, when 11-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperuinyl)-dibenzo[b,f][l,4]thiazepine is dissolved in it, gives a concentration (before crystallisation) of about 120 to 160 mg/ml.
8. A process as claimed in claim 7 wherein the quantity of solvent gives a concentration (before crystallisation) of 135 to 145 mg/ml.
9. A process as claimed in any one of claims 1 to 8 which comprises reacting crystalline 11 -(4-[2-(2-hydroxyethoxy) ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine with fumaric acid to
give the fumarate salt of 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b-f][l,4]thiazepine.