Note: Descriptions are shown in the official language in which they were submitted.
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 1 -
A PROCESS FOR THE PREPARATION OF FROVATRIPTAN AND FROVATRIPTAN
SUCCINATE AND THEIR SYNTHETIC INTERMEDIATES
Field of the invention
The present invention relates to the active pharmaceutical ingredient
frovatriptan and
pharmaceutically acceptable salts thereof. In particular, it relates to
efficient processes for
the preparation of frovatriptan and its synthetic intermediates, which are
amenable to large
scale commercial production and provide the required products with improved
yield and
purity.
Background of the invention
Frovatrip tan (I), chemically named R-(+)-6-carboxamido-3-methylamino-1,2,3,4
tetrahydrocarbazole, is currently marketed as the monosuccinate salt
monohydrate (II) for
the treatment of migraine.
0
H3C-- NH2
110
(1)
0
T T3C¨ NT T2
= CO2H
1110 = Hp
C0,14
(11)
Various processes for the preparation of frovatriptan base are disclosed in
the prior art but,
as discussed below, these processes are neither particularly suitable nor
convenient for large
scale commercial production.
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
-2-
0
-N
11101 +
= 0 acc tic acid
0
0 CN
NHNI-12 HC1 N
110
1111
Ts0 CN
(i) Na0I I
(ii) tosyl chloride, pyridine
411110/ 110 methyl amine
0 \/---
H3C--
4110/ di-tert-butyl dicarbonate H3C--N
CN
4110/ =
0
(i) NaNO2, 1-I22 1-3c-"N NH2
(ii) sodium metabisulphite-
1110
I i
Scheme 1
The process for obtaining frovatriptan base and pharmaceutically acceptable
salts thereof
disclosed in -LIS 5616603 is shown in Scheme 1. The first step involves
tetrahvdrocarbazole
ring formation, via a Fischer Indole synthesis, involving the reaction of 4-
cyanophenylhydrazine hydrochloride and 4-benzyloxy-cyclohexanone in acetic
acid to
afford 3-benzyloxy-6-cyano-1,2,3,4-tetrahydrocarbazole, which was isolated
after column
/0 chromatography. This product was hydrolysed with sodium hydroxide to
give 3-hydroxy-6-
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 3 -
cyano-1,2,3,4-tetrahydrocarbazole, which was further treated with tosyl
chloride in the
presence of pyridine to yield 3-tosyloxy-6-cyano-1,2,3,4-tetrahydrocathazole.
The tosyloxy
group was removed by treatment with methyl amine in a scaled tube at 100 C to
yield 3-
met hyl am no- 6- cyano-1,2,3,4-tetrahyd rocarbazo I e, which was isolated
after column
chromatography. The 3-methylamino-6-cyano-1,2,3,4-tetrahydrocarba2ole was N-
protected
to afford 3-tert-butyloxycarbonylmethylamino-6-cyano-1,2,3,4-
tetrahydrocarbazole,
oxidised with hydrogen peroxide and further treated with sodium metabisulphite
to afford
racemic frovatriptan, which was isolated after column Chromatography in an
overall yield
of 6.1%.
However, the process disclosed in US 5616603 has several limitations with
respect to
preparing commercial quantities. In particular, several steps require column
chromatography; the process involves several protection and deprotection
steps; the
isolated yields are very low and the transformation of 3-tosyloxy-6-cyano-
1,2,3,4-
tetrahydrocarbazole to 3-methylamino-6-cyano-1,2,3,4-tetrahydrocarbazole
requires heating
the mixture in a scaled tube.
Another process for the preparation of frovatriptan is described in US 6359146
and is
illustrated in Scheme 2. 4-Methylamino-cydohexanone(2,2'-
dimethvltrimethylene)ketal
hydrochloride was prepared by reaction of 1,4-cyclohexanedione(mono-2,2'-
dimethyltrimethylene)ketal and methyl amine in the presence of molecular
sieves to form a
Schiff's base intermediate which was hydrogenated using palladium on carbon as
a catalyst
to afford 4-methylamino-cydohexanone(2,2'-dimethyltrimethylene)ketal. The 4-
methylamino-cyclohcxanone(2,2'-dirncthyltrimethylenc)ketal hydrochloride was
obtained
after treatment with hydrochloric acid and this product was reacted with 4-
cyanophenylhydrazine via Fisher Indole cyclisation to yield 3-methylarnino-6-
cyano-1,2,3,4-
tetrahydrocarbazole. The racemic 3-methvlamino-6-cyano-1,2,3,4-
tetrahydrocarbazole was
resolved by formation of a diastereomeric salt using L-pyroglutamic acid and
the optically
pure diastereomeric salt was further treated with boron-trifluoride-acetic
acid complex to
afford frovatriptan. The reaction mixture was basified with sodium hydroxide
solution and
extracted with n-butanol to give frovatriptan free base, which was further
treated with
succinic acid to afford the monosuccinate salt monohydrate.
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 4 -
o C,
(i) ___________ methyl amine, MS 4A,
ilL<"1 H31= HO
0 NC
1111
NHNH2 . HO
0 0 (ii) Pd-C, H2 0 hydrochloric acid
(iii) HO
L7s) 0
H H
rI3C-"N (.N
H3C-1\' CN
= # (i) L-pyrc.Elutamic acid.
4111k110 . 000,H
(it) crystalltsatton N
N H
H H
=
H
(1) I3F3 . AcOH II3C--N NI I2
b succinic acid
ase ______________
410/ 10 .
N
H (I)
0
H
113C-- NI12
CO,H
= 110 = c = 1120
CO2H
H
(II)
Scheme 2
However the procedure disclosed in US 6359146 has several limitations. In
particular, the
trans formation of R-(1-)-3-methylamino- 6-cya no-1,2,3,4-te
trahydrocarbaz ole L-
pyroglutamic acid salt with boton-itifluoride-acetic acid complex to
frovairiptan generates
indole carboxylic acid as a side product, resulting in a very low yield. Hence
this
transformation is not suitable for large scale production. In addition, the
work-up step
involves basification with sodium hydroxide solution and this is
unsatisfactory as it may
lcad to hydrolysis of the amidc group to the corresponding carboxylic acid.
Moreover,
frovatriptan is isolated by extraction with ii-butatiol, a water wash and cot
iceiltratioll to
obtain frovatriptan. However, n-butanol as well as frovatriptan free base have
significant
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 5 -
solubility in water and consequently complete removal of frcc basicity (due to
sodium
hydroxide solution) from n-butanol extracts is a time consuming process.
Moreover, the
distillation of n-butanol requires considerable amounts of energy and it is
not a cost
effective method for the preparation of the free base. In order to obtain the
pharmaceutically acceptable purity of the monosuccinate monohydrate (II)
extensive
crystallisation is required which results in low yields. Hence, the overall
yield of frovatriptan
mottos uccinate monohydrate is 3.7%.
A method for the preparation of 4-hydrazino-benzamide hydrochloride, which has
been
16 used as a starting material for the preparation of frovatriptan, has
been disclosed in US
5616603. 4-Amino-benzamide was treated with sodium nitrite under acidic
conditions to
form the diazonium salt which was reduced with sodium sulphite to afford 4-
hydrazino-
benzamide hydrochloride (Scheme 3).
= NH2 0 N1-12
(i) NaNO2, HC1
(ii) N a2S03
11101
NH2 NHNH2 . HG!
Scheme 3
The 4-hydra7ino-benzamide hydrochloride was further treated with 4-methylamino-
cyclohexanone(2,2'-dimethyltrimethylene)ketal under acidic conditions and
after
basification and work-up, the racemic base was obtained in 63% yield. However
the
resolution of racemic compound was done by formation of a diastereotneric salt
using
optically pure (1S)-(+)-10-camphorsulphonic acid and recrystallised 10 times
in methanol
to give the optically pure salt with 99% e.e, with a very low yield (Scheme
4).
This method has severe disadvantages as the recrystallisation of the
diastereomcric salt
requires 10 crystallisations and consequently this process is not suitable for
scale-up and
preparation of commercial quantities of frovatriptan.
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 6 -
0 H3C,
) methyl amine, MS 4A. NH . HCI
(i
H2N = NHNH2 . HO
0 0 (ii) Pd-C, H2
0 0
Ls's/KJ HCI
X hydrochloric acid
0
I
H3C¨N NH,
1S-(+)-10-camphorsulphonic acid
(ii) crystallisation
0
HC ¨ NH2
1110
=
SO3H
Scheme 4
Another method for the preparation of optically pure frovatriptan, disclosed
in WO
94/14772, involves formation of a derivative of racemic frovatriptan free base
to obtain the
corresponding enantiomer after separation by chiral HPLC. The racernic free
base was
treated with benzyl chloroformate or di-tert-butyl dicarbonate in basic medium
to give the
N-protected mtrahydrocarbazole. The protected optically pure enantiomer was
separated
by chiral HPLC and subsequently deprotected typically by hydrogenation in the
presence of
catalytic amounts of Pd-carbon or under acidic conditions respectively to
afford thc
required optically pure base and hydrochloride salt. However, the above method
involves
the separation of compounds with chiral HPLC which is not an economical method
for
scale-up and commercial production.
Another approach for the preparation of frovatriptan has also been disclosed
in WO
94/14772 (Scheme 5). 4-Hydrazino-benzamide hydrochloride (prepared according
to
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- -
Scheme 3) was rcfluxcd with 4-phthalimido-cydohcxanonc in acetic acid to form
carboxamido-3-philialimido-1,2,3,4-tetrahydrocarbazole via a Fisher Indole
cyclisation
reaction. After column chromatography, 6-carboxamido-3-phthalimido-1,2,3,4-
tetrahydrocarbazole was isolated in 46% molar yield. This phthalimido-
protected carbazole
was further treated with hydrazine hydrate in the presence of potassium
carbonate to
afford raccmic 3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazolc in 64% molar
yield.
The resolution of the racemic amine was effected by diastereomeric salt
formation using
optically pure 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid (DIKGA) in
methanol.
Two crystallisations of the diastereomeric salt in methanol afforded the
product in 25%
molar yield and with an optical purity of more than 98% e.e. The optically
pure
diastereomeric salt was treated with potassium carbonate solution to give N-
desmethyl-
ftwatriptan. However, in order to achieve methylation of this product, to
obtain
frovatriptan, the optically pure amine has to he protected in order to avoid
side reactions
such as dimethylation. Therefore, the amine was reacted with benzaldehyde in
the presence
of sodium cyanoborohydride to yield (+)-3-benzylamino-6-carboxamido-1,2,3,4-
tctrahydrocarbazole as an intermediate which was reacted with formaldehyde to
give (+)-3-
N -ben zyl carbox amid o-3-m ethyl am i no-1,2,3,4-tetrah yd rocarbaz ol e.
After column
chromatography, the resultant product was isolated in 57.5% molar yield as a
foam with
purity >98%. However this quality of product is not suitable for the
commercial
preparation of frovatriptan. The deprotection of the benzyl group was
performed by
hydrogenolysis in the presence of catalytic amounts of Pd-activated carbon and
1
equivalent of succinic acid to yield the final compound (II) with an optical
purity of 99.5%
and a chemical purity of 96-98%. It has been observed that after several
crystallisation of
the crude frovatriptan, prepared according to the above method, in a range of
solvents
such as methanol, ethanol, isopropanol, n-butanol, acetone or tert-butyl
methyl ether, a
commercially acceptable purity of frovatriptan cannot be obtained.
CA 02756876 2011-09-27
WO 2010/122343
PCT/GB2010/050658
- 8 -
NH2
(i)4-phthalimido-cyclohexanone NH,
(ii)
NHNH, HC1
1-1
H2NH,
41110/
hydrazine hydrate 1110 DIKGA
0
OC\r
112 NH,
fe..c r5/ K,CO3
/ = 0
=
11
= CH;
1.42 NH2 (i) ben zaldchyck, PhCHr" NH2
sodium cyanoborohydride.
.1(ii) formaldehyde
( =
i) Pd-C, TI2 HC ¨ N112
ii succinic acid
4111t 110 = CO2H = H20
CO,H
(11)
Scheme 5
An alky, lation method for the preparation of frovatrip tan is disclosed in US
5616603
(Scheme 6). (+)-3-Amino-6-carboxamido-1,2,3,4-tetrahydrocarhazole was treated
with
carbon disulphide in the presence of dicyclohexylcarbodiimide pcc and pyridine
to yield
the intermediate compound 6-carboxamido-3-isothiocpnato-1,2,3,4-
tetrahydrocarbazole,
which was reduced with sodium borohydride to afford frovatriptan, which was
isolated
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 9 -
after column chromatography in 4-6% yield. However, this process has major
disadvantages
as carbon disulphide is a well known toxic compound and, moreover, column
chromatography is not suitable for scalc-up and commercial scale production.
0 0
H2N NI-I2 (i) CS2, DCC
I NIL,
(ii) pyridine
411It N aBH4 4110/
3
Scheme 6
As discussed above, all the processes disclosed in the prior art for the
preparation of
frovatriptan and its salts suffer from serious disadvantages with respect to
commercial
production.
Considering the importance gained by frovatriptan for the treatment of
migraine there is a
great need for developing simple, inexpensive, good yielding and commercially
feasible
processes for the manufacture of high quality frovatriptan and its
pharmaceutically
acceptable salts.
Object of the invention
Therefore, there is a need for improved processes for the synthesis of
frovatriptan,
pharmaceutically acceptable salts thereof and synthetic intermediates thereof,
which
provide commercial products conveniently with acceptable yield and purity.
A further object of the present invention is to provide high quality
frovatriptan and
pharmaceutically acceptable salts and/or solvates or hydrates thereof which
are necessary
for pharmaceutical compositions for usc in the manufacture of medicaments, in
particular
for the treatment of migraine.
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 10 -
Summary of the invention
The tcrm frovatriptan as uscd herein throughout thc description and claims
means
frovatriptan and/or any salt, solvate or hydrate thereof unless specified
otherwise. The
3 intermediates named can be racemates or single enantiomers unless
specified otherwise.
The processes of thc present invention can bc used to prepare frovatriptan,
its antipode S-
, (+6-carboxamido-3-methylarnino-1,2,3,4 tetrahydrocarbuole, or racemic
frovatriptan.
A first aspect of the present invention provides a process for the preparation
of 6-
/0 carboxarnido-3-phthalimido-1,2,3,4-tetrahydrocarbazole comprising the
following steps:
(a) reaction of 4-aminobenzamide with a nitrite ion in the presence of a
mineral acid
and a sulphonic acid;
(b) reduction of the diazonium salt formed; and
(c) addition of 4-phthalimido-cyclohexanone or a protected form thereof.
Preferably, in the process according to the first aspect of the present
invention, the
reduction of step (b) is carried out with a dithionite ion, a sulphite ion or
stannous chloride,
which is preferably sodium sulphite or sodium dithionite, and most preferably
sodium
sulphite.
Preferably, in the process according to the first aspect of the present
invention, the reaction
of step (a) is carried out at a temperature below 5 C.
Preferably, in the process according to the first aspect of the present
invention, the nitrite
ion used in step (a) is from a metal nitrite, preferably an alkaline earth or
alkali metal nitrite,
preferably an alkali metal nitrite such as sodium nitrite or potassium
nitrite. Preferably, in
the process according to the first aspect of the present invention, the
nitrite ion is from
sodium nitrite.
Preferably, in the process according to the first aspect of the present
invention, the mineral
acid used in step (a) is hydrochloric acid or hy-drobromic acid, preferably
hydrochloric acid.
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 11 -
Preferably, in thc process according to thc first aspect of the present
invention, the
sulphonic acid used in step (a) is p-toluene sulphonic acid, benzene sulphonic
acid,
methane sulphonic acid or ethane sulphonic acid. Most preferably, the
sulphonic acid is p-
toluene sulphonic acid.
Optionally, in step (c) of the process according to the first aspect of the
present invention,
the 4-plithalimido-cydohexanone can be used in a protected form such as in the
form of
an acetal, such as a dialk-yl acetal. Preferably, the acetal is the dimethyl
acetal.
io Preferably, in the process according to the first aspect of the present
invention, the 6-
carboximido-3-phthalimido-1,2,3,4-tetrahydrocarbazole is prepared in a 'one-
pot' process
from 4-aminobenzamide, which means that all steps (a) to (c) in the process
according to
the first aspect of the present invention are carried out without purifying
any intermediates,
preferably without purifying or isolating any intermediates, preferably in one
reaction
vessel.
A second aspect of the present invention provides a process for the
preparation of
frovatriptan comprising a process according to the first aspect of the present
invention.
A third aspect of the present invention provides a pmcess for the preparation
of 3-amino-
6-carboxamido-1,2,3,4-tetrahydrocarbazole comprising deprotection of 6-
carboxamido-3-
phthalimido-1,2,3,4-tetrahydrocarbazole with hydrazine in the presence of
another organic
base. Preferably, the another organic base is a trialkyl amine, most
preferably triethyl amine.
A fourth aspect of the present invention provides a process for the
preparation of
frovatriptan comprising a process according to the third aspect of the present
invention.
A fifth aspect of the present invention provides a process for the preparation
of 3-N -
benzy1-6-carboxamido-3-methylamino-1,2,3,4-tetrahydrocarbazole comprising
reductive
amination of 3-amino-6-carboxamiclo-1,2,3,4-tetrahydrocarbazolc with
benzaldehyde and
formaldehyde at pH 4-6. Preferably, the reductive amination is carried out
stepwise, adding
benzaldehyde first and then formaldehyde. Preferably, the reducing agent is
sodium
cyanohorohydride. Preferably, the reductive amination is carried out in the
presence of an
CA 02756876 2011-09-27
WO 2010/122343 PUT/GB2010/050658
- 12 -
acid, such as acetic acid, a mineral acid like hydrochloric acid or
hydrobromic acid, or a
silphonic acid like p-toluene sulphonic acid. Preferably, the reductive
amination is carried
out in the presence of acetic acid.
A sixth aspect of the present invention provides a process for the preparation
of
frovatriptan comprising a process according to the fifth aspect of the present
invention.
A seventh aspect of the present invention provides a process for the
preparation of
frovatriptan (preferably frovatriptan free base) comprising catalytic
hydrogenolysis of 3-N-
benzy1-6-carboxatnido-3-methylamino-1,2,3,4-tetralaydrocarbazole. Preferably,
the catalyst
is Pd on charcoal, more preferably 20% Pd on charcoal. Preferably, the
reaction solvent for
the catalytic hydrogenolysis is a C" alcohol (such as methanol or ethanol),
acetic acid, or a
mixture thereof. Preferably, the reaction solvent for the catalytic
hydrogenolysis is
methanol.
Optionally, any one of the processes of the first seven aspects of the present
invention can
include a further step for the purification of frovatriptan by crystallising
from one or more
organic solvents selected from acetates such as ethyl acetate, methyl acetate,
isopropyl
acetate; chlorinated hydrocarbon solvents such as dichloromethane, chloroform,
dichloroethane; ethers such as diethyl ether, tert-hutyl methyl ether,
diisopropyl ether;
ketonic solvents such as acetone, methyl ethyl ketone, diethyl ketone, methyl
isopropyl
ketone and other higher ketones; alcoholic solvents such as methanol, ethanol,
n-propanol,
t-butanol, pentanols and higher alcohols; and mixtures thereof.
Optionally, any one of the processes of the first seven aspects of the present
invention can
include a further step for the preparation of a pharmaceutically acceptable
salt and/or
solvate or hydrate of frovatriptan. A preferred salt of frovatriptan is the
succinate salt.
Preferably any one of the processes of the first seven aspects of the present
invention is
carried out on a commercial scale, preferably to prepare frovatriptan or a
salt, solvate or
hydrate thereof or a process intermediate thereof (such as 6-carboxamido-3-
plithalimido-
1,2,3,4-tetrahydrocarbazole, 3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole
or 3-N-
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 13 -
benzy1-6-carboxamiclo-3-methylamino-1,2,3,4-tetrahydrocarbazole) in batches of
50g, 100g,
500g, lkg, 5kg, 10kg, 20kg, 50kg or more.
An eighth aspect of the present invention provides frovatriptan or
frovatriptan succinate
prepared by a process according to one or more of the first seven aspects of
the present
invention. Preferably, the frovatriptan and frovatriptan succinatc arc
suitable for treating or
preventing migraine.
A ninth aspect of the present invention provides a pharmaceutical composition
comprising
frovatriptan or frovatriptan succinate prepared by a process according to one
or more of
the first seven aspects of the present invention, and one or more
pharmaceutically
acceptable diluents or carriers. Preferably, the pharmaceutical composition is
suitable for
treating or preventing migraine.
A tenth aspect of the present invention provides the use of frovatriptan or
frovatriptan
succinate prepared by a process according to one or more of the first seven
aspects of the
present invention, in the preparation of a medicament for the treatment or
prevention of
migraine.
An eleventh aspect of the present invention provides a method of treating or
preventing
migraine, comprising administering to a patient in need thereof a
therapeutically or
prophylactically effective amount of frovatriptan or frovatriptan succinate
prepared by a
process according to one or more of the first seven aspects of the present
invention.
Preferably the patient is a mammal, preferably a human.
A twelfth aspect of the present invention provides frovatriptan with a
chemical purity of
greater than 99%, more preferably greater than 99.5%, even more preferably
greater than
99.8% and most preferably greater than 99.9% (as measured by HPLC).
A thirteenth aspect of the present invention provides frovatriptan with an
optical purity of
greater than 99%, more preferably greater than 99.3%, even more preferably
greater than
99.8% and most preferably greater than 99.9% (as measured by chiral HPLC).
CA 02756876 2011-09-27
WO 2010/122343 PCT/G112010/050658
- 14 -
A fourteenth aspect of the present invention provides frovatriptan succinatc
with a
chemical purity of greater Ian 99.5%, more preferably greater than 99.8% and
most
preferably greater than 99.9% (as measured by HPLC).
A fifteenth aspect of the present invention provides frovatriptan succinate
with an optical
purity of greater than 99.5%, more preferably greater than 99.8% and most
preferably
greater than 99.9% (as measured by chiral HPLC).
The terms "optical purity" and "chiral HPLC purity" are used interchangeably
herein
throughout the description and claims, and mean the percentage of the desired
enantiomer
in a given mixture.
Detailed description of the invention
The present invention provides improved processes for the preparation of
highly pure
frovatriptan. The improved processes arc simple, inexpensive, good yielding
and can be
easily adopted for commercial production with a high degree of consistency and
reproducibility. In addition, the present invention provides improved
processes for the
synthesis of frovatriptan intermediates. Intermediate 6-carboxamido-3-
phthalimido-1,2,3,4-
tetrahydrocarbazole CIV) is preferably prepared in a 'one-pot' synthesis
without the need to
isolate the intermediate 4-hydrazino-benzamide hydrochloride.
The frovatriptan free base prepared by the improved processes according to the
present
invention can be easily converted into any suitable pharmaceutically
acceptable salt, such as
the succinate, benzoate, oxalate, hydrochloride, hydrobromide, acetate,
propionate,
maleate, formate or a sulphonate. Most preferably the salt is the succinate
salt.
The processes of the present invention comprise improved and defined process
parameters
for the manufacturing of frovatriptan wherein formation of degradation
impurities is
precisely controlled and minimized.
In addition, the processes of the present invention offer simple work-up
procedures with
optimum conditions for improved yield and quality with minimum contamination
with
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 15 -
process impurities. The improved proccsscs can bc easily adapted on commercial
scale as
efficient and convenient processes.
The processes of the present invention preferably avoid column chromatography
purification technique for isolation, thereby making the processes simpler and
more
adaptable for large scale commercial production.
Optionally, the present invention can include a further step for the
purification of
frovatriptan by crystallising from one or more organic solvents selected from
acetates such
as ethyl acetate, methyl acetate, isopropyl acetate; chlorinated hydrocarbon
solvents such as
dichloromethane, chloroform, dichloroethane; ethers such as diethyl ether,
tert-butyl
methyl ether, diisopropyl ether; ketonic solvents such as acetone, methyl
ethyl ketone,
diethyl ketone, methyl isopropyl ketone and other higher ketones; alcoholic
solvents such
as methanol, ethanol, n-propanol, t-butanol, pentanols and higher alcohols;
and mixtures
thereof.
Optionally, the 4-phthalimido-cyclohexanone can be used in the form of an
acetal, such as
a diaLkyl acetal. Most preferably, the acetal is the &methyl acetal.
Optionally, the first seven aspects of the present invention can include a
further step for
the preparation of a pharmaceutically acceptable salt and/or solvate or
hydrate of
frovatriptan.
Further aspects of the invention provide frovatriptan and frovatriptan
succinate of greater
than 99% chemical purity (as measured by HPLC). Preferably the frovatriptan
and
frovatriptan succinate of the present invention have a chemical purity of
greater than
99.5%, more preferably greater than 99.8% and most preferably greater than
99.9%.
Further aspects of the invention provide frovatriptan and frovatriptan
succinate of greater
than 99% optical purity (as measured by chiral HPI,C). Preferably the
frovatriptan and
frovatriptan succinate of the present invention have an optical purity of
greater than 99.5%,
more preferably greater than 99.8% and most preferably greater than 99.9%.
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 16 -
The high quality frovatriptan and pharmaceutically acceptable salts and/or
solvates or
hydrates thereof prepared by the present invention are used for the
preparation of
pharmaceutical compositions to use in the manufacture of medicaments for the
treatment
or prevention of migraine.
A preferred process for the preparation of frovatriptan and its succinatc salt
incorporating
preferred embodiments of the first seven aspects of the present invention is
outlined in
Scheme 7.
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 17 -
0 NH2
ii
(i) NaN0,, HCI, PTSA
(iii) 0
(E) Na2S63
(i 4-phtlialimido-cyclohexanone
N
41 10
0
NH2
NH2 N (IV)
H
0
H2N NIT,
hyerayine hydrate = DIKOA
N (V)
H
I10= 0
..
0
H NH, 0 F 0>
1-12- ' NH2
K2CO3
N N
II H
(VII)
(vr)
i
CH3 o
(i) benzaldehyde, phulr-N NII2Pd-C, Hz
sodium cyanohorohyd ride.-
(ii) formaldehyde 41111t 110
N
H
(VIII)
0 0
H H
1-13C' NH, H3C--- NH2
. (CO 2H
= 1110 succinic acid
41111t 110 . Hp
N(I) N CO2H
H
H
(11)
Scheme 7
5 The preferred embodiment involves the treatment of 4-aminobenzamide with
sodium
nitrite in the presence of hydrochloric acid and p-toluene sulphonic acid at a
temperature
of -5 C to -10 C to afford a diazonium salt. It is necessary to keep the
temperature of the
reaction mixture below 5 C, preferably between -5 C to -10 C, to avoid
decomposition of
the diazonium salt.
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 18 -
Reduction of die diazonium intermediate can be earned out by using any
suitable reducing
agent. Preferred rcducing agents arc sodium dithionitc, stannous chloride or
sodium
sulphite. Most preferably, the reducing agent is sodium sulphite. The sodium
sulphite can
be dissolved in water to obtain a clear solution and added to the diazonium
salt mixture,
keeping the temperature of the reaction mixture between -5 C to -10 C. It has
been
observed that the addition of sodium sulphite is an extremely exothermic
reaction and it is
important to maintain the required temperature, otherwise the addition of the
diazonium
salt into the sodium sulphite solution was not able to give the improved yield
and purity of
the product (IV).
After complete addition of the sodium sulphite solution, preferably the
temperature of the
reaction mixture is allowed to rise and preferably the reaction mixture is
stirred for around
12 hours at 25-30 C until complete conversion to the corresponding hydrazine
salt.
Preferably 4-phthalimido-cyclohexanone is added portionwise at a temperature
of 40-45 C
and preferably the temperature of the reaction mixture is raised to 70-75 C in
order to
complete the reaction. Preferably the 4-phthalimicio-cyclohexanone is added at
40-50 C
and preferably cyclisation reaction, via Fisher Indole reaction, is carried
out in a
methanol/water mixture at 70-75 C or an isopropanol/water mixture at 70-80 C.
Preferably the product, 6-carboxamido-3-phthalimido-1,2,3,4-
tetrahydrocarbazole (IV), is
filtered, neutralised, washed with water and optionally purified by reflux in
dichloromethane to give yields greater than 90%.
WO 94/14772 discloses a similar process for the preparation of 6-carboxamido-3-
phthalimido-1,2,3,4-tetrahydrocarbazole (IV) via a Fisher Indole cyc1isation
reaction by
reacting 4-hydrazino-benzamide hydrochloride and 4-phthalimido-cyclohexanone
in acetic
acid (Scheme 5). The product was isolated by column chromatography to afford
only 46%
yield. However, the present inventors have surprisingly found that the use of
p-toluene
sulphonic acid (PTSA) enhanced the Fisher Indolc cyclisation reaction to a
great extent and
gave much higher yields (>90%) with an HPLC purity of more than 98% without
any
purification.
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 19 -
Preferably thc dcprotection of the phthalimido moiety from 6-carboxamido-3-
phthalimido-
1,2,3,4-teu:ahydrocarbazole is performed using hydrazine (e.g. hydrazine
hydrate) in
isopropanol and tricthyl amine as a base. Preferably the mixture is heated to
80-85 C and
stirred for 3 hours to achieve complete deprotection of the phthalimido
moiety. Preferably
3 the work-up is done by removing the solvent under reduced
pressure and preferably the
concentrated mass is treated with potassium carbonate solution and triethyl
amine.
Preferably the crystallised ( )-3-atnino-6-carboxamido-1,2,3,4-
tetrahydrocarbazole is
filtered and washed with water to afford a >90% yield. The deprotection
reaction can also
be carried out using hydrazine hydrate (3 eq.) in ethanol (10 volumes) as
solvent without
the triethyl amine. Preferably the mixture is heated to 60-65 C for 4-5 hours
to achieve
complete deprotection of the phthalimido moiety. Preferably the reaction
mixture is filtered
and the solvent is removed to afford the ( )-3-amino-6-carboxamido-1,2,3,4-
tetrahydrocarbazole in 50% molar yield. Therefore deprotection of the
phthalimido moiety
in compound (IV) using hydrazine hydrate and another organic base, such as
triethvl
amine, leads unexpectedly to dramatic enhancements of the yield. The product
obtained by
the process of the present invention is easily isolated by filtration in a
molar yield of 92%
= with an HPI .0 purity of more than 98% which can be further used without
purification.
Resolution of ( )-3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole can be
carried out
using 1 equivalent of 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid in
methanol.
Preferably, after 1 hour of reflux, the reaction mixture is gradually allowed
to reach ambient
temperature and is further cooled to 5-10 C and stirred for 1 hour. Preferably
the
crystallised diastereomeric salt is filtered and washed with cooled methanol.
Preferably the
diastcrcomcric enriched salt is rcerystallised two times under identical
conditions in
methanol (10 volumes for crystallisation + 2 volumes for washing the solid) to
afford 24%
of compound (VI) with a chiral IIPLC purity of >99.8%. The volume of solvent
and
temperature play a significant role in deciding the yields and optical purity
of the
diastereotneric salt (VI). Preferably the optically pure salt is dissolved
into water (5
volumes) and treated with 2 equivalents of potassium carbonate solution to
afford (+)-3-
amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole after filtration and washing
with water
and isopropanol.
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 20 -
The temperature range for thc filtration of the DIKGA salt formation and
subsequent
crystallisation of the optically enriched diastereomeric salt (VI) is 5-10 C.
A process for the
preparation of optically pure amine (VII) from (VI) preferably involves
treatment with an
inorganic base, for example 2 equivalents of potassium carbonate to yield >95%
of pure
amine (VII). The chemical purity is >99.7% (determined by I IPLC) and optical
purity 99.8-
100% (determined by chiral HPLC).
Preferably the optically pure amine (VII) is reacted with 1.3 equivalents of
benzaldehyde in
the presence of 3.0 equivalents of sodium cyanoborohydricie in methanol to
yield (+)-3-
benzylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole as an intermediate.
Preferably the
temperature of the reaction mixture is -5 C to -10 C and preferably glacial
acetic acid is
used to maintain the reaction mixture at pH 4-6. Alternatively, when the
reaction is carried
out in the absence of acetic acid, the reaction does not go to completion and
side products
are formed. Preferably, after completion of the reaction, formaldehyde
(preferably as a
formalin solution) is added and stirred for 6 hours. The time of stirring is
necessary to
complete the reaction. Preferably 1-2 equivalents of formaldehyde can be used
and the
temperature is preferably at -10 C to 0 C. After completion of the reaction,
preferably the
solvent is removed under reduced pressure. To the concentrated mass,
preferably 20-30
volumes of water are added and stirred for 1 hour. Preferably the pH of the
reaction
mixture is adjusted to ¨11 by addition of 30% potassium carbonate (aq)
solution at 25-
C. Preferably the product is extracted in ethyl acetate and mixed with water
and
acidified with hydrochloric acid whilst maintaining the temperature at 25-30 C
to obtain
pH 2. Preferably the mixture is stirred for 1 hour and the organic layer is
separated.
Preferably the reaction mixture is extracted with ethyl acetate to remove the
side products
25 and impurities. Preferably the aqueous layer is basifiecl to about pH 11
using 30%
potassium carbonate (aq) solution. Preferably ethyl acetate and isopropanol
are added to
the reaction mixture and preferably the reaction mixture is then cooled and
filtered to give
compound (VIII) as a solid. The acid and base treatment can be repeated a
second time if
necessary. The preferred temperature range for the filtration of crystallised
(VIII) is 0-5 C.
30 Alternatively, the N-benzylatcd intermediate can be isolated if required
and used for the
subsequent transformation.
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 21 -
The inventors have observed that thc purity of compound (VIII) is surprisingly
very
important with respect to the purity of any frovairipian which is derived from
it., as the
main impurity generated during the preparation of (VIII) is difficult to
remove in
subsequent transformations. However, the procedure according to the present
invention,
wherein the reductive amination with sodium cyanoborohydride is carried out
using
intermediate (VII) and benzaldehyde in the presence of glacial acetic acid at
pH 4-6,
significantly enhances the purity and yield of intermediate (VIII). Preferably
the product is
isolated by simple filtration to afford a free flowing powder in 85% yield
with an HPLC
purity of more than 99.5%. Therefore, this transformation can be achieved in
high yield
with a very pure product without the need for column chromatography.
Alternative reducing agents for the reductive amination are sodium
borohydride, Pd-
carbon/hydrogen, sodium triacetoxyborohydride, decaborane, triethyl
silane/iridium
complex, zinc/acetic acid, sodium borohydride/magnesium chlorate, zinc
borohydride/zinc chloride, silica gel/zinc borohydride, nickel chloride/sodium
borolaydride, Pd/formic acid, Ti(01304/NaBH4, Bu,SnH, Bu2SnC1H, Bu2SnIH,
Et,SiH-
tritluoroacetic acid, Ti((YPr),-polymethylhydrosiloxane, PhSiF1,-Bu,SnClõ
Picoline-borane
or Zr(BH4)2C1,(dabco)2.
Preferably the deprotection of 3-N-benzy1-6-carboxamiclo-3-methylamino-1,2,3,4-
tetrahydrocarbazole is carried out by catalytic hydrogenolysis using 20% Pd on
activated
charcoal in methanol (preferably around 10 volumes) at 25-30 C. Preferably,
after
completion of the reaction, the work-up is done by filtering the reaction
mixture through a
Celite bed and washing with methanol. Preferably the combined mother liquors
arc distilled
under reduced pressure and recrystallised in isopropanol to afford
frovatriptan free base (I).
Alternative catalysts for the catalytic hydrogenolysis are 5 or 10% Pd/C,
PdBa.SOõ 20% Pd
hydroxide on carbon, Pd black, ammonium formate and formic acid.
Alternative solvents for the catalytic hydrogcnolysis can be ethanol, tri
fluoroethanol, ethyl
acetate or acetic acid.
CA 02756876 2011-09-27
WO 20101122343 PCT/GB2010/050658
- 22 -
WO 94/14772 discloses a process for the preparation of (+)-6-carboxamido-3-
me thylainino-1,2,3,4- Le trail ydrocarbazole monosuccinale monohydrate
(II) by
hydrogcnolysis of (VIII) using Pearlman catalyst in the presence of sucdnic
acid. (+)-6-
Carboxam id o- 3-methyl ami no-1,2,3,4- tetra hyd rocarba7o1 e monosucci nate
mono hydrate (II)
has a very low solubility in organic solvent and consequently isolation of
(II) in the
presence of a Pearlman catalyst is troublesome, because the product is
contaminated with
catalyst. Furthermore, the procedure disclosed in WO 94/14772 could not afford
a product
with a satisfactory impurity profile as required by the ICH guidelines, even
after
recrystallisation using solvents such as methanol/water. However, the present
invention
surprisingly provides a simple process involving catalytic hydrogenolysis of
intermediate
(VIII) with Pd/C to afford highly pure frovatriptan base which can be
optionally further
purified with an alcohol, such as isopropanol, to afford a satisfactory
impurity profile in
57.5% yield with an I IPLC purity of more than 99.8%.
A preferred process for the recrystallisation of frovatriptan free base (I)
comprises
treatment with activated carbon in hot isopropanol (preferably 13 volumes).
Preferably,
crude free base (I) is treated with 5% of activated carbon (w/w) at 80-85 C
and the
product filtered when hot and the mother liquor cooled to 25-30 C. The
preferred
temperature range for the filtration of crystallised frovatriptan (I) is 25-30
C. The chemical
purity of product (I) is >99.85% (as measured by HPLC). The optical purity of
product (I)
is >99.9% (as determined by chiral HPLC).
The highly pure frovatrip tan base can then be converted into the required
salt, such as the
monosuccinate monohydratc in 91% yield with a chemical purity of >99.9% and an
optical
purity of >99.90/fl.
A preferred process for the preparation of frovatriptan succinate salt (II)
from free base (I)
and succinic acid comprises using 15 volumes of methanol and 1 volume of water
(based
on the quantity of free base) as solvents. The optimum temperature range for
the filtration
of crystallised frovatriptan succinate salt (II) is -10 C to -15 C. The
chemical purity of
product (II) obtained is >99.9% (as measured by HPLC) and the optical purity
is >99.9%
(as determined by chiral HPLC).
CA 02756876 2011-09-27
WO 2010/122343 PUT/GB2010/050658
- 23 -
Further details of the invention arc illustrated below in the following non-
limiting
examples.
Examples
( )-6-Carboxamiclo-3-phthalimiclo-12,3,4-tetrahydrocarbazolc (IV)
Hydrochloric acid (35%) (3.2 L) was added to a cooled solution of 4-
aminobenzamide (2.0
Kg, 14.69 mol) in water (14 L, 7 volumes) at 5-10 C. Then p-toluene sulphonic
acid (10.1
Kg, 3.44 mol) was added to the reaction mixture and further cooled to -5 C to -
10 C.
Sodium nitrite (1.76 Kg, 25.7 mol) was dissolved into water (4 L, 2 volumes)
and added to
the cooled reaction mixture over a period of 2.5 hours at -5 C to -10 C and
further stirred
for 4 hours. Sodium sulphite (5.6 Kg, 44.4 mol) was dissolved into water (16
L, 8 volumes)
and added dropwise to the diazonium salt over a period of 3 hours at a
temperature of
-5 C to -10 C. After stirring for 2 hours, the temperature of the reaction
mixture was
allowed to rise to ambient and stirred for 12 hours. The reaction was
monitored by TLC.
Methanol (16 L, 8 volumes) was added to the yellow suspension and 4-
phthalimido-
cyclohexanone (4.64 Kg, 19.07 mol) was added portionwise at a temperature of
40-45 C.
After maintaining the reaction mixture at 40-45 C for 30 minutes, the
temperature of the
reaction mixture was raised to 70-75 C and maintained for 8 hours. After
completion of
the reaction, the mixture was cooled to 25-30 C, filtered and washed with
water (40 L). The
wet cake was mixed with water (40 L) and the pH adjusted to 7-8 using 10%
potassium
carbonate (acj) solution, and the slurry was filtered and washed with water
(40 1). The
product was dried under vacuum at 60-65 C. The crude product was purified by
reflux in
dichloromcthanc (30 L) and dried to afford the title compound (3.70 Kg).
Molar yield: 70%
I IPLC purity: 98.06%
( )-3-Amino-6-carboxamido-1.2.3.4-tetrahydrocarba2ole
Hydrazine hydrate (906 g, 18.12 mol) was added to a stirred suspension of ( )-
6-
carboxamido-3-phthalimido-1,2,3,4-tetrahydroc.arbazole (IV) (2.43 Kg, 6.76
mol) in
isopropanol (24.3 L, 10 volumes) at 25-30 C over a period of 30 minutes and
then triethyl
amine (1.36 Kg, 13.44 mol) was added. The mixture was heated to 80-85 C and
stirred for
3 hours to achieve complete deprotection of the phthalimido moiety. The work-
up was
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 24 -
done by removing thc solvent under reduced pressure and the concentrated mass
was
treated with potassium carbonate solution (2.92 Kg in 48.6 L water) and
triethyl amine (680
g, 6.73 mol) at 25-30 C and stirred for 1 hour. The mixture was cooled to 5-10
C and
further stirred for 1 hour. The crystallised product was filtered, the cake
was washed with
3 water (7.29 L, 3 volumes) and isopropanol (7.29 L, 3 volumes). The
product was dried
under reduced pressure at 55-60 C for 5 hours to afford the title compound
(1.53 Kg).
Molar yield: 92%
HPLC purity: >98%
(+) -3- Amino-6- carb oxamido-1 .2.3.4 - tetr ally dr ocarbazole (VII)
A solution of 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid (DIKGA) (1.95
Kg, 6.67
mol) in methanol (3.75 L) was added to a stirred solution of ( )-3-amino-6-
carboxamido-
1,2,3,4-tetrahydrocarbazole (V) (1.5 Kg, 6.54 mol) in methanol (11.25 L) at 40-
45 C and
further heated to 55-60 C. After 1 hour of reflux, the reaction mixture was
gradually
allowed to reach ambient temperature and further cooled to 5-10 C and stirred
for 1 hour.
The crystallised diastcrcomcric salt was filtered and the cake washed with
cooled methanol
(3 I., 2 volumes). The solid was dried at 55-60 C for 5 hours. The
diastereonneric enriched
salt was recrystallised two times under identical conditions in methanol (10
volumes for
crystallisation + 2 volumes for washing the solid) to afford recrystallised
diastereomeric salt
(VI) as a white amorphous solid (1.04 Kg).
Molar yield: 24%
HPLC purity: >99.9%
Chiral HPLC purity: >99.8%
The optically pure amine (VII) was prepared by addition of a potassium
carbonate solution
(546.5 g dissolved in 2060 nil water) to a clear solution of the
diastereotneric salt (1030 g
dissolved in 5150 ml water) at 0-5 C and further stirred for 1 hour. The
crystallised (+)-3-
amino-6-carboxamido-1,2,3,4-tetrahvdrocarbazole (VII) was filtered and the
solid was
washed with water (2080 ml, 2 volumes) and finally with isopropanol. The
product was
dried under reduced pressure at 50-55 C for 6 hours to obtain the title
compound as a
white powder (468.5 g) .
Molar yield: >96%
HPLC purity: >99.79/a
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 25 -
Chiral HPLC purity: >99.85%
3-N-Benzy1-6-carboxamido-3-mcthylamino-1,2.3.4-tetrahydrocarbazole (VIII)
Benzaldehyde (147 nil, 1.43 mol) was added to a stirred solution of (j-3-amino-
6-
carboxamido-1,2,3,4-tetrahydrocarbazole (VII) (250 g, 1.09 mol) in methanol
(5000 ml, 20
volumes) at 25-30 C. The reaction mixture was stirred for 2 hours at 25-30 C.
The reaction
mixture was then cooled to 0-10 C and sodium cyanoborohydride (206 g, 3.27
mol) was
added portionwise over a period of 1.5 hours before glacial acetic acid (138
g, 2.18 mol)
was added dropwise at a temperature of -5 C to -10 C to obtain a pH of 4-6 and
further
stirred for 6 hours. Formaldehyde solution (37%) (133 ml, 1.64 mol) was added
dropwise at
a temperature of 0 C to -10 C. The reaction mixture was further stirred for 6
hours. The
reaction was monitored by HPLC as well as TLC. Then the temperature of the
reaction
mixture was allowed to reach ambient conditions. The solvent was removed under
reduced
pressure. Water (500 ml, 20 volumes) was added to the concentrated mass and
stirred. The
pH of the reaction mixture was adjusted to ¨11 by addition of 30% potassium
carbonate
(aq) solution at 25-30 C. The reaction mixture was extracted with ethyl
acetate (1 x 2500 ml
and 2 x 1250 ml). The combined organic extracts were washed with water (1250
ml, 5
volumes) and brine solution (1250 ml, 5 volumes). The combined organic
extracts were
mixed with water (5000 ml, 20 volumes) and acidified with hydrochloric acid
(35%) (250
nil) maintaining the temperature at 25-30 C to obtain pH 2. The mixture was
stirred for 1
hour and the organic laver was separated. The reaction mixture was extracted
with ethyl
acetate (1 x 2500 ml and 2 x 1250 ml). The aqueous layer was basified to pH
¨11 using
30% potassium carbonate (aq) solution at 25-35 C. The reaction mixture was
further
extracted with ethyl acetate (1 x 2500 ml and 2 x 1250 m1). The combined
organic extracts
were washed with water (1250 ml, 5 volumes) and bone solution (1250 ml, 5
volumes). The
combined organic extracts were again mixed with water (5000 ml, 20 volumes)
and
acidified with hydrochloric acid (35%) (250 ml) maintaining the temperature at
25-30 C to
obtain pH 2. The mixture was stirred for 1 hour and the organic layer was
separated. The
reaction mixture was extracted with ethyl acetate (1 x 2500 ml and 2 x 1250
ml). The
aqueous layer was cooled to 0-5 C, basified to pH ¨11 using 30% potassium
carbonate
(aq) solution at 0-5 C. Then ethyl acetate (750 ml, 3 volumes) and isopropanol
(250 ml
water, 1 volume) were added and the mixture was stirred for 5 hours at 0-5 C.
The
CA 02756876 2011-09-27
WO 2010/122343 PCT/GB2010/050658
- 26 -
resulting mixture was filtered and the solid was washed with ethyl acetate
(500 ml, 2
volumes) to yield die tide compound (310g).
Molar yield: 859/0
HPI E purity: >99.5%
(+)-6-Carboxamiclo-3-methylamino-1,2,3,4-tctrahydrocarbazole (Froyatriptan, I)
3-N-Benzyl-6-carboxamido-3-methylamino-1,2,3,4-tetrahydrocarbazole (VIII) (250
g, 0.75
mol) was dissolved in methanol (1250 ml, 5 volumes) at 25-30 C. 20% Pd on
activated
charcoal (20 g) was mixed with methanol (1230 ml, 5 volumes) at 25-30 C and
added to the
clear solution of 3-N-benzy1-6-carboxarnido-3-methylamino-1,2,3,4-
tetrahydrocarbazole
(VIII) under a nitrogen atmosphere. Hydrogen gas was bubbled through the
solution at 25-
30 C until complete deprotection of the benzyl moiety. The excess of hydrogen
gas was
removed from the solution by bubbling nitrogen in the reaction mixture for 15
minutes.
Work-up was done by filtering the reaction mixture through a Celite bed and
washing with
methanol (500 ml, 2 volumes). The combined mother liquors were distilled under
reduced
pressure at 50-55 C, vacuum 200-250 mbar to yield a slurry mass. Thcn
stripping was done
using isopropanol (3 x 250 ml) and the isopropanol was distilled to remove the
traces of
methanol present in the reaction mixture. To the reaction mixture isopropanol
(250 ml, 1
volume) was added and the mixture was slowly chilled to -10 C to -12 C. After
stirring for
2 hours, the product was isolated by filtration and washed with isopropanol
(250 nil, 1
volume). The crude product was dried at 50-55 C for 6 hours to obtain the
title compound
as a white powder (144 g). The product was further purified by
recrystallisation using
isopropanol (1872 ml, 13 volumes). The reaction mixture was heated to reflux
and the clear
solution was treated with activated carbon (Norit Supra 13 activated charcoal,
7.2 g, 5%
w/w) for 15 minutes. The reaction mixture was filtered through a Cclite bed
under hot
conditions and the Cate bed was washed with isopropanol (288 ml, 2 volumes).
The
combined mother liquors were concentrated under reduced pressure at 25-30 C
and the
concentrated mass was cooled to 25-30 C and stirred for 2 hours. The product
was easily
isolated by filtration and washed with isopropanol (144 ml, 1 volume). The
product was
dried under reduced pressure at 50-55 C for 6 hours to afford the title
compound as a
white powder (105 g).
Molar yield: 57.5%
HPLC purity: >99.8%
CA 02756876 2011-09-27
WO 2010/122343 PCT/G82010/050658
- 27 -
Chiral HPLC purity: >99.9%
Frovatriptan monosuccinatc monohydratc (II)
(+)-6-Carboxamido-3-methylamino-1,2,3,4,-tetrahydrocarbazole (I) (90 g, 0.37
rnol) was
dissolved into methanol (450 ml, 5 volumes), the solution was filtered and
washed with
methanol (90 ml) to obtain a clear solution and to the mother liquor water (90
ml) was
added. In another flask succinic acid (45 g, 0.38 mol) was dissolved into
methanol (720 ml,
9 volumes) and filtered to remove the extraneous material and obtain a clear
solution. The
clear solution of succinic acid was added into the solution of (1) at 25-30 C
over a period of
15 minutes and further stirred for 3 hours. The reaction mixture was chilled
to -10 C to
-12 C and further stirred for 2 hours. The product was isolated by filtration
and the cake
washed with methanol (180 ml, 2 volumes). The product was dried at 45-50 C for
10 hours
to obtain the title compound as a white powder (127.5 g).
Molar yield: 91%
HPLC purity: >99.9%
Chiral HPLC purity: >99.9%
It will be understood that the present invention has been described above by
way of
example only. The examples are not intended to limit the scope of the
invention. Various
modifications and embodiments can be made without departing from the scope and
spirit
of the invention, which is defined by the following claims only.
