PROCESS FOR THE PREPARATION OF 2-(CYCLOHEXYLMETHYL)-W-{2-[(2S)-1-
METHYLPYRROLIDIN-2-YL]ETHYL}-1,2,3,4-TETRAHYDROISOQUINOLINE-7-
SULFONAMIDE
FIELD OF THE INVENTION
The present invention relates to processes for preparing 2-(cycIohexylmethyl)-/V-{2-
[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide, various
intermediates thereto and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
The histamine H3 receptors are found in the central and peripheral nervous systems.
The administration of histamine H3 receptor ligands may influence the secretion of
neurotransmitters in the brain and the periphery and thus can be useful in the treatment
of several disorders, including Alzheimer's disease and other dementias, obesity,
central nervous system disorders such as vigilance and sleep disorders, narcolepsy,
Parkinson's disease, attention-deficit hyperactivity disorder, memory and learning
disorders, epilepsy, schizophrenia, moderate cognitive disorders, depression, anxiety,
cardiovascular disorders, and gastrointestinal disorders.
To illustrate, a number of studies in the literature have demonstrated the cognitive
enhancing properties of histamine H3 receptors antagonists in rodent models (See, e.g.,
Giovanni et al., Behav. Brain Res., 1999, 104, 147- 55). These reports further suggest
that antagonists and/or inverse agonists could be useful for the treatment of cognitive
impairments in neurological diseases such as Alzheimer's disease and related
neurodegenerative disorders. Alzheimer's disease is the most common cause of
dementia in the elderly, and is often characterized with one or more symptoms such as
memory loss, confusion, irritability and aggression, mood swings, language breakdown,
long-term memory loss, withdrawal of the sufferer, and loss of motor control.
2-(Cyclohexylmethyl)-/V-{2-[(2S)-1 -methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide, which has the structure of Formula (I):
is a potent histamine H3 receptor antagonist with inverse agonist properties. The
preparation, physical properties and beneficial pharmacological properties of 2-
(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide are described in, for example, WO2005/1 18547
(also US2007/01 05834).
WO2005/1 18547 describes a general method of synthesis which is difficult to transpose
to the industrial scale for production in large quantities. This method of synthesis entails
reacting 2-(2,2,2-trifluoroacetyl)-1 ,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride with
(+/-)-2-(2-aminoethyl)-1-methylpyrrolidine, which product is deprotected in methanol and
hydrochloric acid. The enantiomers are next separated by chiral chromatography. The
resulting /V-{2-[(2S)-1 -methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-
sulfonamide undergoes reductive amination with cyclohexanecarboxaldehyde in the
presence of a palladium catalyst. 2-(Cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-
yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide is isolated as the free base and
converted to a salt.
The present invention makes it possible to optimize the synthesis of 2-
(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide for industrial use by avoiding the chiral
chromatographic separation of the enantiomers of (+/-)-A/-[2-(1-methylpyrrolidin-2-
yl)ethyl]-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide and by providing a more direct
synthesis.
BRIEF SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for producing
(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide and salts thereof, of high purity and in a relativ
high yield suitable for use on an industrial scale.
The present invention is also directed to synthetic intermediates, for example 2-
cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride HX, a compound of
Formula (II) given below, that are useful in the preparation of the 2-(cyclohexylmethyl)-
A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide
and salts thereof. The compound of Formula (II) is surprisingly stable as this compound
contains a tertiary amine on the same molecule as a sulfonyl chloride substituent.
DETAILED DESCRIPTION OF THE INVENTION
Definitions and Abbreviations
As used above, and throughout the description of the invention, the following
abbreviations, unless otherwise indicated, shall be understood to have the following
meanings:
EtOAc ethyl acetate
g gram
kg kilogram
L liter
mL milliliter
MTBE methyl i-butyl ether
NaBH(OAc)3 sodium triacetoxyborohydride
As used above, and throughout the description of the invention, the following terms,
unless otherwise indicated, shall be understood to have the following meanings:
The term "2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride HX salt"
refers to the salt of 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride
formed after the reaction of 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline with
excess chlorosulfonic acid. The 2-cyclohexylmethyI-1 ,2,3,4-tetrahydroisoquinoline-7-
sulfonyl chloride HX salt may be a mixture of salts. For calculation purposes, one
skilled in the art may regard the HX salt as an HCI salt.
The term "pharmaceutically acceptable" refers to those compounds, materials,
compositions, carrier agents, bulking agents, solvents, diluents and other
excipients which are, within the scope of sound medicinal judgment, suitable for
contact with humans or other mammals without undue toxicity, irritation, allergic
response and the like, commensurate with a reasonable benefit/risk ratio.
A process of the invention for preparing 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-
methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide, or a
pharmaceutically acceptable salt thereof, or a solvate or hydrate of a pharmaceutically
acceptable salt comprises:
a) reductively aminating 1,2,3,4-tetrahydroisoquinoline, or a salt thereof, with
cyclohexanecarboxaldehyde to give 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline,
or a salt thereof;
b) reacting 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline, or a salt thereof,
with excess chlorosulfonic acid to give 2-cyclohexylmethyl-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonyl chloride HX salt, and optionally recrystallizing the 2-
cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride HX salt;
c) coupling 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride
HX salt with (-)-2-(2-aminoethyl)-1-methylpyrrolidine to form 2-(cyclohexylmethyl)-/V-{2-
[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
d) optionally reacting 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-
yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide with a stoichiometric amount or
an excess of a salt-forming acid in a solvent to form a salt or a hydrate or solvate
thereof; and
e) optionally recrystallizing the product of step d).
In one aspect of the invention, processes for preparing the 2-(cyclohexylmethyl)-A/-{2-
[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide or a
pharmaceutically acceptable salt thereof, or a solvate or hydrate of a pharmaceutically
acceptable salt as well as intermediates that are useful for preparing such compounds
are outlined in Scheme :
Scheme :
(la)
(salt)
The processes for preparing 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-
yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide, or a pharmaceutically acceptable
salt thereof, or a solvate or hydrate of a pharmaceutically acceptable salt, as outlined in
Scheme 1 comprise:
a) reductively aminating 1,2,3,4-tetrahydroisoquinoline with
cyclohexanecarboxaldehyde to give the compound of formula (III), 2-cyclohexylmethyl-
1,2,3,4-tetrahydroisoquinoline, or a salt thereof;
b) reacting the compound of formula (III) with chlorosulfonic acid to give a
compound of formula (II), 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl
chloride HX salt, and optionally recrystallizing the compound of formula (II);
c) coupling the compound of formula (II) with (-)-2-(2-aminoethyl)-1-
methylpyrrolidine to form a compound of formula (I), 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-
methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
d) optionally reacting the compound of formula (I) with a stoichiometric amount
or an excess of a salt-forming acid in a solvent to form a salt or a hydrate or solvate
thereof, of Formula (la), 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide acid addition salt; and
e) optionally recrystallizing the product of step d).
A particular process of the invention for preparing 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-
methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide, or a
pharmaceutically acceptable salt thereof, or a solvate or hydrate of a pharmaceutically
acceptable salt, comprises:
a) reductively aminating 1,2,3,4-tetrahydroisoquinoline, or a salt thereof, with
cyclohexanecarboxaldehyde in the presence of a reducing agent and in an organic
solvent to give 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline, or a salt thereof;
b) reacting 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline, or a salt thereof,
with excess chlorosulfonic acid optionally in the presence of a co-solvent to give 2-
cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride HX salt, and
optionally recrystallizing the 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-
sulfonyl chloride HX salt;
c) coupling 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride
HX salt with (-)-2-(2-aminoethyl)-1 -methylpyrrolidine in an organic solvent to form 2-
(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide;
d) optionally reacting 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-
yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide, with a stoichiometric amount or
an excess of a salt-forming acid in a solvent to form a salt or a hydrate or solvate
thereof; and
e) optionally recrystallizing the product of step d).
For Scheme 1:
Step a) entails the formation of 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline, or a
salt thereof, by reacting 1,2,3,4-tetrahydroisoquinoline and cyclohexanecarboxaldehyde,
in the presence of a reducing agent, such as formic acid, sodium triacetoxyborohydride,
sodium borohydride, hydrogen with a catalyst, such as palladium on carbon, and the
like, in a suitable organic solvent, such as methyl f-butyl ether, ,2-dichloroethane,
dichloromethane, or acetonitrile. This reaction is preferably performed at temperatures
between about 8°C and about 25°C when the reducing agent is sodium
triacetoxyborohydride, and at about 55°C when the reducing agent is formic acid in
methyl f-butyl ether. In one aspect, the 2-cyclohexylmethyl-1 ,2,3,4-
tetrahydroisoquinoline is isolated as an acid addition salt, for example a hydrochloride
salt.
2-Cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride HX salt is
prepared in step b) by reacting 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline, or a
salt thereof, with excess chlorosulfonic acid, optionally in the presence of a co-solvent
such as an aprotic, acid stable solvent, for example a halogenated solvent such as
dichloromethane, chloroform, 1,2-dichloroethane, and the like; at temperatures
preferably between about 2°C and about 35°C. The product of this reaction is optionally
recrystallized to remove positional isomers. Recrystallization solvents include, for
example, acetonitrile with sulfuric acid.
Accordingly, one embodiment of the invention is the process for preparing 2-
cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride HX salt by reacting
2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline with excess chlorosulfonic acid.
Another embodiment of the invention is the process for preparing 2-(cyclohexylmethyl)-
A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide
comprising the step of reacting 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline with
excess chlorosulfonic acid. Another embodiment of the invention comprises optionally
recrystallizing the product of the reaction between 2-cycIohexylmethyl-1 ,2,3,4-
tetrahydroisoquinoline and excess chlorosulfonic acid. A particular embodiment is the
product prepared by reacting 2-cyclohexylmethyl-1 ,2 3,4-tetrahydroisoquinoline with
excess chlorosulfonic acid.
The coupling of 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride
HX and (-)-2-(2-aminoethyl)-1-methylpyrrolidine to prepare 2-(cyclohexylmethyl)-/V-{2-
[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide in step
c) is carried out in an organic solvent, for example dichloromethane, chloroform, 1,2-
dichloroethane, methyl f-butyl ether, and toluene, and at a temperature between about
0°C and about 35°C.
Therefore, one embodiment of the invention is the process for preparing 2-
(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide by coupling 2-cyclohexylmethyl-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonyl chloride HX salt with (-)-2-(2-aminoethyl)-1-
methylpyrrolidine. In one aspect, the coupling is carried out in an organic solvent.
Pharmaceutically acceptable salts of 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-
2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide, and hydrates and solvates
thereof, include conventional, non-toxic salts of 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-
methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide, which can be
formed with either inorganic acids such as hydrochloric acid, or organic acids such as
benzoic acid, fumaric acid, oxalic acid and L-tartaric acid. A pharmaceutically
acceptable salt can be obtained using standard procedures well known in the art, such
as by reacting the compound of Formula (I) with stoichiometric amounts or with an
excess of the desired salt-forming acid in a suitable solvent or various combinations of
solvents. For example, an oxalate salt can be made by dissolving the compound of
Formula (I) in ethanol and adding about 1. 1 equivalents of oxalic acid, and allowing the
salt to form. In one aspect of the invention, a fumarate salt is obtained. In a preferred
aspect, the fumarate salt is a difumarate monohydrate salt.
The pharmaceutically acceptable salt of 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-
methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide, or hydrate or
solvate thereof, is optionally recrystallized. Suitable recrystallization solvents include,
for example isopropanol or ethanol in the presence of an anti-solvent such as toluene or
acetone.
Another aspect of the invention are the processes described above further comprising
the step of formulating 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide or a pharmaceutically acceptable salt
thereof, or a solvate or hydrate of a pharmaceutically acceptable salt, with one or more
pharmaceutically acceptable carrier agents, bulking agents, solvents, diluents and
other excipients. In one aspect, the process comprises the step of formulating 2-
(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate with one or more
pharmaceutically acceptable carrier agents, bulking agents, solvents, diluents and
other excipients.
The compound of Formula (IV), (-)-2-(2-aminoethyl)-1-methylpyrrolidine, may be
prepared as outlined in Scheme 2.
Scheme 2
According to Scheme 2 , step 1), racemic 2-(2-aminoethyl)-1-methylpyrrolidine is
resolved by combining 2-(2-aminoethyl)-1-methylpyrrolidine with a chiral resolving
agent, such as di-p-toluoyl-D-tartaric acid, in an alcohol, such as ethanol, methanol,
isopropanol, and the like and combinations thereof including combinations with water.
Preferably, the solvent is a combination of ethanol and water. The reaction is preferably
performed at temperatures between about 0°C and about the reflux temperature of the
mixture, and more preferably, below about 100°C.
Racemic 2-(2-aminoethyl)-1-methylpyrrolidine starting material is commercially available
(for example from Anichem LLC, American Custom Chemicals Inc., Acros, or Aldrich) or
otherwise may be prepared according to procedures well know to those skilled in the
art. (See, e.g., Turner, S.C.; Esbenshade, T.A.; Bennani, Y.L.; Hancock, A.A. Bioorg.
Med. Chem. Lett. 2003, 13, 2131-2135).
Step 2) involves removing the resolving agent by dissolving the product of step 1), for
example, (-)-2-(2-aminoethyl)-1-methylpyrrolidine, 0,0'di-p-toluoyl-D-tartaric acid salt, in
a two-phase mixture of a strong acid, such as concentrated HCI, HBr, H2SO , H3PO4,
and a non-polar solvent, such as f-butyl methyl ether, isopropyl acetate, and the like, at
temperatures between about room temperature and about 100°C. The desired product
may be isolated by removing the acid, such as the tartaric acid, with a non-polar
solvent, such as f-butyl methyl ether or isopropylacetate. In one aspect, (-)-2-(2-
aminoethyl)-1-methylpyrrolidine is isolated in aqueous solution as a salt. In another
aspect, the acidic solution of (-)-2-(2-aminoethyl)-1-methylpyrrolidine salt is basified by
the addition of a concentrated, strong base, such as sodium hydroxide, allowing the
isolation of (-)-2-(2-aminoethyl)-1-methylpyrrolidine as the distillable free base.
The following examples present typical syntheses as described in Schemes 1 and 2.
These examples are understood to be illustrative only and are not intended to limit the
scope of the present invention in any way.
Example 1
Preparation of (-)-2-(2-Aminoethyl)-1-methylpyrrolidine, 0,0 -Di-p-toluoyl-D-tartaric acid
salt
A stock solution of aqueous ethanol was prepared by mixing ethanol (10370 mL) and
water (2080 mL). A mixture of O,O'-di-p-tolouyl-D-tartaric acid (1624 g , 4.203 mol) and
a portion of the above described stock solution of aqueous ethanol (9050 mL) was
stirred at around 65°C under a nitrogen atmosphere. Separately, racemic 2-(2-
aminoethyl)-1-methylpyrrolidine (700 g, 5.35 mol) was dissolved in a portion of the
aqueous ethanol stock solution (3400 mL). The amine solution was then added dropwise
to the tartaric acid solution so that the temperature was maintained at about 65°C
and no solids formed during the addition. The reaction was held at about 65°C for no
less than 30 min before being cooled to about 0°C. The precipitate was collected by
filtration. A stream of nitrogen was pulled through the collected solid until no longer wet.
The solid was recrystallized from ethanol (15950 mL)/water (2457 mL) affording the
desired product as a colorless solid: 1322.4 g (44%), >99.5% ee.
Example 2
Preparation of (-)-2-(2-Aminoethyl)-1-methylpyrrolidine
A solution of HCI (296 mL, 3.55 mol) and water (517 mL) was added to a mixture of (-)-
2-(2-aminoethyl)-1-methylpyrrolidine, 0,0 -di-p-toluoyl-D-tartaric acid salt (900 g , 1.75
mol) and MTBE (3.2 L). After stirring for 45 minutes, the layers were separated.
Additional MTBE (1 .6 L) was added to the aqueous layer. After stirring for about 10
minutes, the layers were separated. With stirring, 50% aqueous NaOH (476 mL, 9.19
mol) was added to the aqueous acid layer over about 35 minutes. The mixture was
stirred for about 35 minutes, then cooled to 10°C. The organic layer was separated and
distilled at reduced pressure to provided 206 g (92%) of (-)-2-(2-Aminoethyl)-1-
methylpyrrolidine.
Example 3
Preparation of a Compound of Formula (III): 2-Cyclohexylmethyl-1 ,2,3,4-
tetrahydroisoquinoline HCI
A mixture of 1,2,3,4-tetrahydroisoquinoline (359.6 g , from Fluka), NaBH(OAc)3 (686.7 g)
and MTBE (5.4 L) was cooled and stirred as cyclohexanecarboxaldehyde (328.8 g , from
Aldrich) was added over an approximately 30 minute period, maintaining the
temperature of the reaction between about 8.8 and 2 1.1°C over the course of the
addition. The reaction was stirred at 20°C for about 2 hours. A solution prepared from
50% aqueous NaOH (259 g) diluted to 1.1 L with H2O was added with cooling, keeping
the temperature at about 20°C. The reaction was stirred for 30 minutes, until no further
hydrogen release was observed. The layers were separated, and the organic layer was
washed with H2O (2 x 2L). The organic layer was dried with MgS0 4, and the drying
agent was removed by filtration.
While stirring and maintaining the temperature at about 20°C, HCI gas (103 g) was
bubbled into the solution, causing a precipitation of the hydrochloride salt. The salt was
collected by filtration, washed with MTBE (4 L), and dried to provide 1637 g of the
desired product.
Example 4
Preparation of a Compound of Formula (II): 2-(Cyclohexylmethyl)-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonyl chloride HX
Chlorosulfonic acid (2.48 L) was added to a reactor containing 2-cyclohexylmethyl-
1,2,3,4-tetrahydroisoquinoline HCI ( 1 .10 kg) and CH2CI2 (5.5 L) over a period of about
one hour, while maintaining the temperature between - 1.8°C and 2.8°C with cooling.
Following the addition of the chlorosulfonic acid, the reaction was allowed to warm to
10°C, where it was held for approximately 2.5 hours. The reaction was warmed to 35°C
over 2 hours, then was held at 35°C for 1 hour. The reaction was then maintained at
20°C overnight. The CH2CI2 was removed by distillation until the pot temperature
reached 65°C. The reaction vessel was maintained at room temperature overnight.
The mixture was slowly added to a suspension of MTBE ( 6.5 L) and seed crystals of 2-
(cyclohexylmethyl)-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride HX (10 g), keeping
the temperature between 20 to 25°C. After about 30 minutes, the product was collected
by filtration affording an off-white solid. To isolate the desired product, the solid was
mixed with acetonitrile (6.5 L) and concentrated H2SO4 (32 mL), and the mixture was
heated to 70°C. The resulting solution was slowly cooled. A solid was isolated by
filtration, rinsed with acetonitrile (2 L) and dried to provide 863.7 g of the desired
product.
Seed crystals of 2-(cyclohexylmethyl)-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride
HX can be obtained following general procedures known to those skilled in the art in
view of the above-described procedure. Alternatively, 2-(cyclohexylmethyl)-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonyl chloride HX can be readily prepared as described
above without the use of seed crystals.
Example 5
Preparation of a Compound of Formula (I): 2-(Cyclohexylmethyl)-/V-{2-[(2S)-1-
methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide
A slurry of 2-(cyclohexylmethyl)-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride HX
(477.7 g) and CH2CI2 (4.78 L) was cooled to about 5°C. A solution (-)-2-(2-aminoethyl)-
1-methylpyrrolidine ( 85.1 g) in CH2CI2 (370 mL) was added at a rate that kept the
temperature below 9°C. Upon completion of the addition, the reaction was warmed to
25°C. After about 4 hours, the solvent was removed at reduced pressure, leaving a
viscous oil. After standing over the weekend under N2 atmosphere in a cold room at
4°C, the oil was treated with a solution of K2C0 3 (452 g) in water (2.8 L) followed by
EtOAc (6.5 L). The two-phase mixture was stirred for 30 minutes, before the aqueous
layer was removed. The organic layer was washed with water (3 x 3L). The solvent
was evaporated at reduced pressure leaving 488.5 g of 2-(cyclohexylmethyl)-/V-{2-[(2S)-
1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide as a viscous
oil.
Example 6
Preparation of a Compound of Formula (la): 2-(Cyclohexylmethyl )-N -{2-[(2S)-1-
methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate
monohydrate
A solution of 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide (532 g , 1.27 mol) in SDA 3C ethanol (1056 ml_)
was added to a suspension of fumaric acid (302 g , 2.60 mol) in water (624 ml_). The
resulting solution was diluted with acetone (4 L) then cooled and seeded with milled 2-
(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate (4.2 g). After seeding,
the mixture was stirred to allow crystal growth then further diluted with acetone (1990
ml_). After cooling, the product was collected by filtration and washed with acetone
( 1.500 L). Filtration was conducted by portionwise loading of acetone into the filterdryer.
After loading of each portion of acetone ( 1 .5L) stirring was turned on at 2.6 rpm
to ensure good contact between product and acetone. The product was dried in a
vacuum oven at 40°C with nitrogen purge and vacuum (residual pressure 400 mBar)
then allowed to re-hydrate at room temperature in the air to yield 684.7 g (85.8 %) of 2-
(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.
Seed crystals of 2-(cyclohexylmethyl)-W-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate can be obtained
following general procedures known to those skilled in the art. Alternatively, 2-
(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate can readily be prepared
as described above without the use of seed crystals.
CLAIMS
What is claimed is:
1. A process for preparing 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-
yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide, or a pharmaceutically acceptable
salt thereof, or a solvate or hydrate of a pharmaceutically acceptable salt comprising:
a) reductively aminating ,2,3,4-tetrahydroisoquinoline, or a salt thereof, with
cyclohexanecarboxaldehyde to give 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline,
or a salt thereof;
b) reacting 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline, or a salt thereof,
with excess chlorosulfonic acid to give 2-cyclohexylmethyl-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonyl chloride HX salt, and optionally recrystallizing the 2-
cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride HX salt;
c) coupling 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride
HX salt with (-)-2-(2-aminoethyl)-1-methylpyrrolidine to form 2-(cyclohexylmethyl)-/V-{2-
[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
d) optionally reacting 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-
yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide with a stoichiometric amount or
an excess of a salt-forming acid in a solvent to form a salt or a hydrate or solvate
thereof; and
e) optionally recrystallizing the product of step d).
2 . The process according to claim 1, wherein the reductive amination of step a) is
performed in an organic solvent in the presence of a reducing agent.
3. The process according to claim 2 , wherein the reducing agent is selected from
the group consisting of sodium triacetoxyborohydride, sodium borohydride, formic acid,
and hydrogen with a catalyst.
4 . The process according to claim 1 wherein the reaction of step b) is performed in
the presence of a co-solvent.
5. The process according to claim 4 , wherein the co-solvent is selected from the
group consisting of dichloromethane, chloroform, and 1,2-dichloroethane.
6. The process according to claim 1, wherein step c) is performed in the presence
of an organic solvent.
7 . The process according to claim 6, wherein the organic solvent is selected from
the group consisting of dichloromethane, chloroform, ,2-dichloroethane, methyl f-butyl
ether, and toluene.
8. The process according to claim 1, wherein the salt formed in step d) is a
pharmaceutically acceptable salt.
9 . The process according to claim 1, further comprising formulating 2-
(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide or a pharmaceutically acceptable salt thereof, or a
solvate or hydrate of a pharmaceutically acceptable salt, with one or more
pharmaceutically acceptable carrier agents, bulking agents, solvents, diluents and
other excipients.
10 . The process according to claim 1, wherein the salt-forming acid in step d) is
fumaric acid to provide 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-
,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.
11. The process according to claim 10 , further comprising formulating 2-
(cyclohexylmethyl)-N -{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate with one or more
pharmaceutically acceptable carrier agents, bulking agents, solvents, diluents and
other excipients.
12. The process according to claim , comprising
a) reductively aminating 1,2,3,4-tetrahydroisoquinoline, or a salt thereof, with
cyclohexanecarboxaldehyde in the presence of a reducing agent and in an organic
solvent to give 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline, or a salt thereof;
b) reacting 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline, or a salt thereof,
with excess chlorosulfonic acid optionally in the presence of a co-solvent to give 2-
cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride HX salt, and
optionally recrystallizing the 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-
sulfonyl chloride HX salt;
c) coupling 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride
HX salt with (-)-2-(2-aminoethyl)-1-methylpyrrolidine in an organic solvent to form 2-
(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide;
d) optionally reacting 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-
yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide with a stoichiometric amount or
an excess of a salt-forming acid in a solvent to form a pharmaceutically acceptable salt
or a hydrate or solvate thereof; and
e) optionally recrystallizing the product of step d).
13. The process according to claim 12, further comprising formulating 2-
(cyclohexylmethyl)-/\/-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide or a pharmaceutically acceptable salt thereof, or a
solvate or hydrate of a pharmaceutically acceptable salt, with one or more
pharmaceutically acceptable carrier agents, bulking agents, solvents, diluents and
other excipients.
14. The process according to claim 12 , wherein the salt-forming acid in step d)
is fumaric acid to provide 2-(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-
yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.
15 . The process according to claim 14, further comprising formulating 2-
(cyclohexylmethyl)-/V-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1 ,2,3,4-
tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate with one or more
pharmaceutically acceptable carrier agents, bulking agents, solvents, diluents and
other excipients.
16. A process for preparing 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-
sulfonyl chloride HX salt by reacting 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline
with excess chlorosulfonic acid.
17. A process for preparing 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-
yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide comprising the step of reacting 2-
cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline with excess chlorosulfonic acid.
18. The process according to claim 17 wherein the reaction is performed in the
presence of a co-solvent.
19. A process for preparing 2-(cyclohexylmethyl)-A/-{2-[(2S)-1-methylpyrrolidin-2-
yl]ethyl}-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonamide by coupling 2-cyclohexylmethyl-
1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride HX salt with (-)-2-(2-aminoethyl)-1-
methylpyrrolidine.
20. The product prepared by reacting 2-cyclohexylmethyl-1 ,2,3,4-
tetrahydroisoquinoline with excess chlorosulfonic acid.
2 1. The compound 2-cyclohexylmethyl-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl
chloride HX salt.