Note: Descriptions are shown in the official language in which they were submitted.
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A PROCESS FOR THE MANUFACTURE OF IDALOPIRDINE
FIELD OF THE INVENTION
The present invention relates to the preparation of N-(2-(6-fluoro-1H-indo1-3-
y1)-ethyl)-
3-(2,2,3,3-tetrafluoropropoxy)-benzylamine, INN-name idalopirdine, and
pharmaceutically
acceptable salts thereof.
BACKGROUND ART
N-(2-(6-fluoro-1H-indo1-3-y1)-ethyl)-3-(2,2,3,3-tetrafluoropropoxy)-
benzylamine is a potent and
selective 5-HT6 receptor antagonist which is currently in clinical
development. Its chemical
structure is depicted below as Compound (I).
HN
F
11 0 F
F 1.1 N\ F
H
Compound (I)
The synthesis of N-(2-(6-fluoro-1H-indo1-3-y1)-ethyl-(2,2,3,3-
tetrafluoropropoxy)-benzylamine, its
use for the treatment of disorders such as cognitive dysfunction disorders,
and pharmaceutical
compositions comprising this substance are disclosed in U.S. Patent No.
7,157,488 ("the '488
patent"). The '488 patent further describes the preparation of the
corresponding monohydro-
chloride salt.
Although the synthetic methods disclosed in the above-identified reference
suffices to prepare
small quantities of material, it suffers from a variety of safety issues, low
yields or processes that
are not amendable to large scale synthesis.
A method of manufacture useful for the production of kilogram quantities of
material for
preclinical, clinical and commercial use is disclosed in international patent
application No.
W02011/076212.
The method of manufacture as disclosed in W02011/076212 starts from
commercially available
6-fluoroindole and is outlined in Scheme A.
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Scheme A
/
N CN
\ _______ Ism
F Step 1 - \ \ Step 2
_____________________________________________________ 10- \
= N
H F 1.1 N F
H H
Compound (X) Compound (II) Compound (III)
Step 3
HN NH2
F
\ . 0\ F _...., Step 4 \
F 40 N F F = N
H H
Compound (I) Compound (IV)
This method of manufacture comprises the steps of
1) reacting 6-fluoroindole with an iminium ion species generated in-situ
from formaldehyde
and dimethylamine in the presence of an acidic aqueous solution to produce
Compound (II)
/
N\
\
F N
H
Compound (II) ;
2) reacting Compound(II) with KCN in the presence of DMF-water to produce
Compound
(III);
CN
F 1\\I
H
Compound (III) ;
3) hydrogenation of Compound (III) in the presence of NH3 using Raney
nickel (RaNi) to
produce Compound (IV);
NH2
F 1\\I
H
Compound (IV) ;
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4) and reacting Compound (IV) with 3-(2,2,3,3-tetrafluoropropoxy)-benzaldehyde
(Compound (IX)) in the presence of a solvent followed by the addition of
reducing agent.
The hydrogenation of (6-fluoro-1H-indo1-3-yl)acetonitrile (Compound (III)) to
2-(6-fluoro-
1H-indo1-3-ypethylamine (Compound (IV)) disclosed in W02011/076212 comprises
more
specifically the steps of:
(a) mixing (6-fluoro-1H-indo1-3-yOacetonitrile, aq. ammonia and a
RaNi catalyst in an
alcoholic solvent; and
(b) hydrogenating the mixture with H2.
The synthesis of Compound (IX) can convinently be carried out as illustrated
in Scheme B.
Scheme B
F Step 1 F Step 2 F
_________________________ 710- _____________________ 110- 0 0
F X OH F X OTs F 0
F F F F F F
Compound (VIII) Compound (IX)
The synthesis of Compound (IX) comprises the following steps:
1) Subjecting 2,2,3,3-tetrafluoro- 1 -propanol to tosylation to yield Compound
(VIII);
2) and reacting Compound (VIII) in a displacement reaction with 3-
hydroxybenzaldehyde in
the presence of a base to yield Compound (IX).
W02011/076212 further discloses 2-(6-fluoro-1H-indo1-3-ypethylamine hydrogen L-
(+)-tartrate (the
1:1 salt of 2-(6-fluoro-1H-indo1-3-ypethylamine and L-(+)-tartaric acid) as
well as a process for
the purification of 2-(6-fluoro-1H-indo1-3-ypethylamine comprising the steps
of:
(a) dissolving 2-(6-fluoro-1H-indo1-3-ypethylamine in methanol;
(b) adding a solution of L-(+)-tartaric acid in methanol; and
(c) filtering off the tartaric acid salt precipitate.
The use of Raney Nickel in an industrial production is, however, problematic
as it easily ignites if
it becomes dry during storage, use or as waste. Hence, an alternative cost
effective and selective
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method for the synthesis of N-(2-(6-fluoro-1H-indo1-3-y1)-ethyl)-3-(2,2,3,3-
tetrafluoropropoxy)-
benzylamine is desirable, which avoids the use of Raney Nickel without any
significant loss in
yield. Such a method has been found and is disclosed in this patent
application.
A synthetic route for the starting material 6-fluoroindole (Compound (X)) is
via the classical
Leimgruber-Batcho indole synthesis. However, as previously reported (Gillmore,
A. T. et al., Org.
Proc. Res. Dev. 2012, 16, 1897-1904; Boini, S. etal., Org. Proc. Res. Dev.
2006, 10, 1205-1211),
isolation and handling of the enamine intermediate, e.g. Compound (XII), is
often problematic due
to thermal instability. Therefore, a modified Leimgruber-Batcho indole
synthesis has been
developed and is disclosed herein.
SUMMARY OF THE INVENTION
In one embodiment of the invention is disclosed a process for the preparation
of Compound (IV)
NH2
0 \
F N
H
Compound (IV)
comprising the steps of:
(a) mixing Compound (III), (6-fluoro-1H-indo1-3-yOacetonitrile, NH3 in
water and a
supported nickel catalyst in a solvent; and
(b) hydrogenating the mixture with hydrogen.
In another embodiment of the invention is disclosed a process for the
preparation of Compound (I)
HN
F
. 0
0 \
_____________________________________________________ F
F N F
H
Compound (I)
comprising the above mentioned steps of the process for the preparation of
Compound (IV).
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In another embodiment of the invention is disclosed a process for the
preparation of Compound
(X)
\
F N
H
Compound (X)
via a modified Leimgruber-Batcho indole synthesis. This new synthetic route of
Compound (X)
5 avoids the need to isolate Compound (XII) as illustrated in Scheme C:
Scheme C
H ?
Step 1 Step 2 \ N.NNH2
IP- 0
H
F 1 Kir,2 ms-, F NO2 NO ________ F NO2
Compound (XI)
Compound (XIII) Compound (XII)
Not isolated
Step 3
F H
= NI\
Compound (X)
The synthesis of Compound (X) comprises the following steps:
10 (a) Reacting Compound (XIII) with pyrrolidine and an acetal of DMF in a
solvent, and
subsequently treating the obtained mixture with semicarbazide hydrochloride to
obtain
solid Compound (XI),
(b) subjecting Compound (XI) to a reduction step with a catalyst and a
reductant to yield
Compound (X).
15 DETAILED DESCRIPTION OF THE INVENTION
The following are definitions for various abbreviations as used throughout the
description and
claims:
"DEM" is diethoxymethane.
"DMF" is N,AT-dimethylformamide.
20 "Me0H" is methanol.
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"THF" is tetrahydrofuran.
"TCE" is 2,2,2-trichloroethanol.
"i-PrOH" is 2-propanol (isopropyl alcohol).
"OTs" is p-toluensulfonate
"RaNi"/"Raney nickel" is an activated nickel catalyst which is optionally
doped with another metal
and that comes in different particle sizes and forms
"Cyanide source" is KCN, NaCN, or other agents which release the CN- anion.
"aq" is aqueous.
"DI" is distilled or ultra-pure.
"rt" is room temperature.
"approx." is approximately
"mm" is minutes
"h" is hours
"eq" is equivalents.
"g" is grams.
"mL" is milliliter.
"L" is liter.
"kg" is kilogram.
"M" is molar.
"w/w" is weight per weight.
"v/v" is volume per volume.
"HPLC" is high pressure liquid chromatography.
"LC-MS" is liquid chromatography-mass spectrometry
"Pd/C" is palladium on charcoal.
"Pt/C" is platinum on charcoal.
"Rh/C" is rhodium on charcoal.
"Rh/Alumina" is rhodium on aluminium oxide.
"Ni/Silica-alumina" is nickel on a mixture of silicon oxide and aluminium
oxide
"PRICATTm" is the trademark for a series of supported nickel catalysts on
silica with/without
added promotors, from Johnson Matthey Process Technologies.
"NMP" is N-methylpyrrolidinone.
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"DMF-DMA" is N,N-dimethylformamide dimethyl acetal.
"EDG" is ethylene glycol.
Throughout the description and claims the term "nickel catalyst" refers to
catalysts comprising
nickel or nickel oxides or mixtures thereof.
In one embodiment of the invention is disclosed a process for the preparation
of Compound (1V)
NH2
0 \
F N
H
Compound (IV)
comprising the steps of:
(a) mixing (6-fluoro-1H-indo1-3-yOacetonitrile, NH3 in water and a
supported nickel catalyst
in a solvent; and
(b) hydrogenating the mixture with hydrogen.
In a first particular embodiment the solvent is an alcoholic solvent
In a second particular embodiment the nickel catalyst is supported on silica
or alumina.
In a third particular embodiment of any of the preceeding embodiments the
supported nickel
catalyst is selected from the group comprising PRICAT 55/5P and PRICAT 62/15P.
In a fourth particular embodiment of any of the preceeding embodiments the
alcoholic solvent is
methanol, ethanol or 2-propanol.
In a fifth particular embodiment of any of the preceeding embodiments the
hydrogenation is run at
a pressure from approx. 2 to approx. 10 bar, more particularly from approx. 2
to approx. 6 bar and
most particularly from approx. 2 to approx. 4 bar.
In a sixth particular embodiment of any of the preceeding embodiments the
hydrogenation is run at
a temperature from about 40 C to about 70 C, more particularly from about 50
C to about 60 C.
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In a seventh particular embodiment of any of the preceeding embodiments the
hydrogenation is run
with a loading from about 8 % to about 31 % (w/w) supported nickel catalyst
relative to (6-fluoro-
1H- indo1-3 -yOacetonitrile.
In another embodiment of the invention is disclosed a process for the
preparation of Compound (I)
HN
F
. 0
0 \
_____________________________________________________ F
F N F
H
Compound (I)
comprising the steps of any of the above mentioned embodiments of the process
for the preparation
of Compound (IV).
In a particular embodiment Compound (IV) is reacted with Compound (IX) in a
solvent followed
by reduction to give yield Compound (I).
In a more particular embodiment sodium borohydride is used as the reducing
agent for the
reduction to Compound I.
In another embodimemt of the invention is disclosed a process for the
preparation of Compound
(X)
lel \
F N
H
Compound (X)
Comprising the steps of:
(c) Reacting Compound (XIII) with pyrrolidine and an acetal of DMF in a
solvent, and
subsequently treating the obtained mixture with semicarbazide hydrochloride to
obtain
solid Compound (XI),
(d) subjecting Compound (XI) to a reduction step with a catalyst and a
reductant to yield
Compound (X).
In a particular embodiment Compound (XIII) is reacted in DMF or NMP as
solvent.
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In a more particular embodiment Compound (XIII) is converted to Compound (XI)
using DMF-
DMA.
In a particular embodiment Compound (XI) is reduced to Compound (X) using
Raney nickel or
palladium on charcoal as catalyst.
In a more particular Compound (XI) is reduced to Compound (X) using hydrazine
or hydrogen
as reductant.
Compound (I) forms pharmaceutically acceptable acid addition salts with a wide
variety of organic
and inorganic acids and include the physiologically acceptable salts which are
often used in
pharmaceutical chemistry. Such salts are also part of this invention. Such
salts include the
pharmaceutically acceptable salts listed in Berge, S. M.et at., J. Phann. Sci.
1977, 66, 1-19 which
are known to the skilled artisan. Typical inorganic acids used to form such
salts include
hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric,
hypophosphoric,
metaphosphoric, pyrophosphoric, and the like. Salts derived from organic
acids, such as aliphatic
mono and dicarboxylic acids, phenyl substituted alkanoic acids,
hydroxyalkanoic and
hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic
acids, may also be used.
Such pharmaceutically acceptable salts thus include chloride, bromide, iodide,
nitrate, acetate,
phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate,
chlorobenzoate, dinitrobenzoate,
hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate,
isobutyrate,
phenylbutyrate, a-hydroxybutyrate, butyne-1,4-dicarboxylate, hexyne-1, 4-
dicarboxylate, caprate,
caprylate, cinnamate, citrate, formate, fumarate, glycollate, heptarioate,
hippurate, lactate, malate,
maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate,
isonicotinate, oxalate,
phthalate, teraphthalate, propiolate, propionate, phenylpropionate,
salicylate, sebacate, succinate,
suberate, benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate,
ethylsulfonate,
2-hydroxyethylsulfonate, methylsulfonate, naphthalene-l-sulfonate, naphthalene-
2-sulfonate,
naphthalene-1,5-sulfonate, p-toluenesulfonate, xylenesulfonate, tartrate, and
the like.
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EXPERIMENTAL SECTION
General experimental
Unless otherwise stated, all reactions were carried out under nitrogen.
Reactions were monitored
by LC-MS. All reagents were purchased and used without further purification.
NMR spectra
5 were recorded at 500 or 600 MHz (1H NMR), and calibrated to the residual
solvent peak. The
following abbreviations are used for NMR data: s, singlet; d, doublet; t,
triplet; m, multiplet.
Coupling constants are rounded to nearest 0.5 Hz.
LC-MS method:
Acquity UPLC BEH C18 1.7 gm column; 2.1 x 50 mm operating at 60 C with flow
12 mL/min of a
10 binary gradient consisting of water + 0.1 % formic acid (A) and
acetonitrile + 5% water + 0.1 % formic
acid (B). UV detection at 254 nm.
HPLC method:
Xterra RP18 column (100 mm x 4.6 mm, 3.5 gm), mobile phase: 10 mM Ammonium
carbonate
(pH 8.5)/Acetonitrile, 86/14 to 14/86 (v/v, %), flow rate: 2 mL/min, column
temperature: about
45 C, detection: UV at 280 nm.
Compound list:
(1): N-(2-(6-Fluoro-1H-indo1-3-y1)-ethyl-(2,2,3,3-tetrafluoropropoxy)-
benzylamine
(II): (6-Fluoro-1H-indo1-3-ylmethyl)-dimethylamine
(III): 2-(6-Fluoro-1H-indo1-3-yOacetonitrile
(IV): 2-(6-Fluoro-1H-indo1-3-yOethylamine
(V): 2-(6-Fluoro-1H-indo1-3-yOethylamine hydrogen L-(+)-tartrate
(VI): 2-(1H-Indo1-3-yOethylamine
(VII): Bis(2-(6-Fluoro-1H-indo1-3-ypethyl)amine
(VIII): 2,2,3,3-Tetrafluoropropylp-toluenesulfonate
(IX): 3-(2,2,3,3-Tetrafluoropropoxy)benzaldehyde
(X): 6-Fluoroindole
(XI): (E)-2-(4-fluoro-2-nitrostyryl)hydrazine -1 -carboxamide
(XII): (E) - 1-(4-fluoro-2-nitrostyryl)pyrrolidine
(XIII): 4 -flu oro -1 -methyl-2-nitrobenzene
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Example 1: Synthesis of Compound (XI)
Scheme I
-----\
NH 0 =HCI
---../ r----\ H2N,NANH2 H ?
DMF-DMA 0 \ IV/ H
lei \ NI,N2.NH2
lo H
F NO2 NMP, 50 C)IP F NO2 HCI (aq), rt F NO2
Compound (XIII) Compound (XII) Compound
(XI)
Compound (XIII) (5.0 g, 32.2 mmol) is dissolved in NMP (10 mL). DMF-DMA (4.8
g, 40.3
mmol) and pyrrolidine (3.0 g, 42.0 mmol) is added and the reaction is warmed
to 50 C and
stirred for 18 h. The resulting solution is then added to a stirred 50 C warm
solution of
semicarbazide hydrochloride (4.7 g, 41.9 mmol) and aq. HC1 (36% w/w, 2 mL) in
water (40 mL)
and stirred for 2 h. The reaction mixture is cooled to 20 C and the formed
orange solid is filtered
off, washed with water and dried under vacuum at 50 C for 18 h to yield
Compound (XI) (6.4 g,
83%) with >95% purity according to 1H NMR analysis.
Example 2: Synthesis of Compound (X)
Scheme II
H 011 Hydrogen (1 bar)
0 1
\ NI.NNH2 Pd/C (1 mol %) H 1 VP-
Ethanol, 50 C F \ .1 N
F NO2 H
Compound (XI) Compound (X)
A mixture of Compound (XI) (7.50 g, 31.2 mmol) and palladium on carbon (5% Pd
loading,
Johnson Matthey type 338, 59.4% w/w water) (1.64 g, 0.312 mmol) in ethanol (75
ml) was
hydrogenated at 50 C and 1.2 bar hydrogen for 3 h.
The reaction mixture was filtered, and the filtrate was evaporated to dryness.
The solid residue
was heated with ethanol (50 mL) at 50 C to yield a homogeneous solution. Water
(50 mL) was
then added dropwise at 50 C with vigorous stiffing. The resulting mixture was
concentrated on
the rotary evaporator in vacuum at 40 C to approx. 1/2 volume. The resulting
suspension was
filtered, and the precipitate was washed with water and dried in vacuum at 40
C to Compound
(X) (3.58 g, 85%) as an off-white solid, with 100% UV purity according to LC-
MS analysis.
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Example 3: Synthesis of Compound (II)
Details of the synthesis of Compound (II) from commercially available 6-
fluoroindole are provided
below. The procedure outlined in Scheme III uses diethoxymethane and
dimethylamine to generate
the "iminium ion species". An alternative procedure using formaldehyde in
place of
diethoxymethane is also provided below.
Scheme III
1. (Et0)2CH2, H20, HCO2H
1.1 \ 2. AcOH, H20, Me2NH
3. 3M NaOH
011.'
\
¨95%
Compound (X) Compound (II)
Procedure using diethoxymethane
To reactor A were charged diethoxymethane (DEM) (65 mL, 0.52 mol), water (50
mL) and formic
acid (39 mL, 1.02 mol)). The mixture was heated at approx. 80 C (reflux) for
approx. 2 h and then
cooled to approx. 20 C. To reactor B were charged 6-fluoroindole (50 g, 0.37
mol) and 80% acetic
acid (66 mL, 1.17 mol). The suspension was cooled to 2-5 C. 40% Aq.
dimethylamine (103 mL,
2.04 mol) was added dropwise to reactor B keeping the temperature below
approx. 15 C. The
reaction mixture was stirred for approx. 20 min and at the same time the
temperature was adjusted
to 2-4 C.
The mixture from reactor A (DEM, water, formic acid, formaldehyde and ethanol
at about 20 C)
was added drop-wise to reactor B while keeping the temperature at 2-8 C. The
reaction mixture
was stirred for additional 10 min at 2-8 C. The reaction mixture was slowly
warmed to approx.
40 C over a 1 h period. The reaction mixture was stirred at approx. 40 C for
an additional 1 h.
The reaction mixture was cooled to about 20 C.
To reactor C was charged aq. NaOH (800 mL, 2.40 mol, 3 M) and the solution was
cooled to about
10 C. The reaction mixture from reactor B was added dropwise to the NaOH
solution in reactor C
while keeping the temperature at 10-15 C (pH > 14). The suspension was
stirred for 40 min at
5-20 C (pH >14). The product was collected by filtration and the filter-cake
was washed twice
with water (2 x 250 mL). The product was dried at approx. 60 C under vacuum
for 16 h to yield
Compound (II) (67.6 g, 95%) with 98% UV purity in HPLC analysis.
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Procedure using formaldehyde:
A 250 L reactor was charged with approx. 40% aq. dimethylamine (35.7 kg, 317
mol) at approx.
17 C under an inert atmosphere. The mixture was cooled to approx. 4.5 C and
glacial acetic acid
(43.4 kg, 723 mol) was added dropwise over 140 min while maintaining the
temperature at approx.
15 C. After stirring for 20 min at about 3 C, 37% aqueous formaldehyde (25.9
kg, 319 mol) was
slowly added over about 20 min while keeping the temperature between approx. 0
C to approx.
C. 6-Fluoroindole (39.2 kg, 290 mol) was added. The reaction was exothermic
and reached a
final temperature of approx. 40 C, and it was then cooled down to approx. 20
C. The reaction
solution was slowly added to a 650 L reactor previously charged with aq. NaOH
(3 M) over a
10 period of approx. 40 min. The formed suspension was stirred for approx.
40 min while keeping the
temperature between 5 to 20 C. The precipitate was filtered from solution,
washed with water on
the filter, and dried at approx. 50 C to afford Compound (II) (45.4 kg, 81%).
Example 4: Synthesis of Compound (III)
A detailed synthesis of Compound (III) from Compound (II) is provided below in
Scheme IV.
Scheme IV
/
N CN
\ KCN
F N DMF/H20, Reflux F N
H H
¨90%
Compound (II) Compound (III)
Step-wise procedure:
(6-Fluoro-1H-indo1-3-ylmethyl)-dimethylamine (II) (65 g, 0.338 mol), KCN (31
g, 0.476 mol),
DMF (195 mL) and water (104 mL) were charged to the reactor. The reaction
mixture was heated
to about 100-105 C (strong reflux) for about 5-8 h. The reaction mixture was
cooled to 20-25 C.
Water (780 mL) and toluene (435 mL) were charged to the reactor and the
mixture was stirred
vigorously for >2 h. The organic and aqueous layers were separated. The
organic layer was washed
with 5% NaHCO3 (6 x 260 mL), aq. HC1 (260 mL, 2 M), 5% NaHCO3 (260 mL) and 5%
NaC1
(260 mL), respectively. The organic layer was filtered and concentrated to
dryness. Me0H (260
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mL) was added and the solution was concentrated to dryness to yield Compound
(III) as a brown
oil (53.0 g, 90%) with 95% UV purity according to HPLC analysis.
Example 5: Screening of palladium catalysts:
To a solution of Compound (III) (200 mg, 1.15 mmol) in Et0H (2.0 mL) was added
additive and
Pd/C catalyst at rt. The mixture was hydrogenated at 4 bar at the specified
temperature for the
specified time. The reaction mixture was analysed directly by LC-MS. The
results are listed in
Table 1.
,
CN
NH2 N
H
\ _,..... la
N IS F
F0 il F N
H +
FS N
H H
Compound (III) Compound (IV) Compound (VII)
Pd/C catalyst2 % Cat.4 Temp .1 C Time/h Additive
III/%3 VII/%3 IV/%3
A102023-5 5 70 20 5 eq. CHC13 5 9 70
A102023-5 5 70 2.5 Seq. H2SO4 0 28 56
A102023-5 5 60 20 5 eq. NH3 in Me0H (7 M) 0 22 2
A102023-5 2 70 24 1 eq. Aq. HC1 (12 M) 10 14 49
A102023-5 2 50 24 Seq. CHC13 28 10 53
A102023-5 2 70 48 None 2 20 1
A102023-5 2 70 1 Ms0H 0 30 31
A102023-5 2 100 48 Seq. CHC13 0 44 8
A102023-5 2 70 48 5 eq. Aq. HC1 (12 M) 10 13 36
A102023-5 2 70 48 Ac20 ND ND 32
A102023-5 2 70 1 5 eq. CHC13, 5 eq. DMF- 43 8 38
DMA
A102023-5 2 70 48 Boc20 0 ND 24
A102023-5 2 70 48 Seq. HC1 ND ND 10
A102023-5 2 70 64 Seq. CHC13 25 18 39
A102023-5 5 70 19 Seq. CHC13 7 10 64
A102023-5 5 70 19 Seq. C2C16 2 2 30
A102023-5 5 70 19 5 eq. Cl3CCH3 2 2 45
A102023-5 5 70 19 Seq. TCE 2 5 48
331 2 70 24 Seq. CHC13 62 8 21
331 2 50 24 Seq. CHC13 60 6 26
331 2 70 64 Seq. CHC13 60 9 19
338 2 70 24 Seq. CHC13 56 11 20
338 2 50 24 Seq. CHC13 59 9 26
338 2 70 64 Seq. CHC13 74 6 11
394 5 70 20 Seq. CHC13 14 14 54
394 5 70 2.5 Seq. H2SO4 0 20 51
394 5 60 20 5 eq. NH3 in Me0H (7 M) 0 35 3
A503038-5 2 70 24 Seq. CHC13 38 13 35
A503038-5 2 50 24 5 eq. CHC13 33 10 50
39 2 70 64 5 eq. CHC13 52 10 26
39 5 70 19 Seq. CHC13 5 14 61
39 5 70 19 Seq. C2C16 2 2 21
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39 5 70 19 5 eq. Cl3CCH3 5 13 52
39 5 70 19 5 eq. TCE 5 13 48
38H 2 70 64 Seq. CHC13 41 14 30
87L 2 70 64 Seq. CHC13 11 51 23
424 2 70 64 Seq. CHC13 46 13 27
440 2 70 64 Seq. CHC13 36 15 22
Table 1. Screening of heterogeneous palladium catalystsi
1. Reaction conditions according to the general method.
2. Catalysts obtained from Johnson Matthey Process Technology.
3. UV-area percentage in LC-MS.
5 4. Loading of catalyst in mol% catalyst relative to Compound (III).
Example 6: Screening of homogenous catalysts:
To a solid mixture of metal complex and any ligand was added solvent (1.0 mL).
The mixture
was stirred for 30 min, and added to a mixture of additive (10 mol %) and
Compound (III) (200
mg, 1.15 mmol) in solvent (1.0 mL).
10 The mixture was hydrogenated at 4 bar and at the specified temperature
for the specified time.
The reaction mixture was analysed directly by LC-MS.
rCN :
.====
NH N =
H
= .===
=
=
\ / .
F)[i -"- FJ - N. + le N N =F 1
H H F
H H
Compound (III) Compound (IV) Compound (VII) .
Metal complex Ligand % Cat.9 Temp/ C Time/h Additive Solvent 111/%2
VII/ IV/
%2 %2
[(Me-ally1)(COD)Ru]23 DPPE4 1 110 16 KOtBu PhMe 25 0 49
[(Me-ally1)(COD)Rul23 - 1 110 16 KOtBu PhMe 84 0 0
(PPh3)3RuC125 - 1 110 16 KOtBu PhMe 75 0 4
(PPh3)3RhH(C0)6 - 1 110 16 KOtBu PhMe 78 0 0
(MesRuC1)22 PPh3 1 110 16 KOtBu PhMe 79 0 0
R.19-cymene)RuC12]28 DPPB9 2 120 2.5 NaOH 2- 72 0 11
butanol
Table 2. Screening of homogeneous catalystsi
1. Reaction conditions according to the general method.
15 2. UV-area percentage in LC-MS.
3. Bis(2-methylally1)(1,5-cyclooctadiene)ruthenium(11), cas number
12289-94-0.
4. DPPF: 1,1'-Bis(diphenylphosphino)ferrocene, cas number: 12150-46-8.
S. Tris(triphenylphosphine)ruthenium(II) dichloride, cas number 15529-
49-4.
6. Tris(triphenylphosphine)rhodium(I) carbonyl hydride, cas number
17185-29-4.
7. Dichloro(mesitylene)ruthenium(ll) dimer, cas number 52462-31-4.
8. Dichloro(p-cymene)ruthenium(II) dimer, cas number 52462-29-0.
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9. Loading of catalyst in mol% catalyst relative to Compound (III).
Example 7: Screening of rhodium, platinum and nickel catalysts
To a solution of Compound (III) (200 mg, 1.15 mmol) in solvent was added
additive and catalyst
at rt. The mixture was hydrogenated at 4 bar at the specified temperature for
the specified time.
The reaction mixture was analysed directly by LC-MS.
CN
NH2 11 NH2
010 \
F N lk
F O Ersi\ + FO N\ µ/N + N\
H H H H
Compound (III) Compound IV) Compound (VII) Compound No
Catalyst2 % Cat4 Temp/ Time/ Additive Sol- III/% VII/ VI/%
IV/%
C h vent 3 0/03 3
3
Rh/C (JM 20A) 1 rt 25 Aq. NH3 (32%) - 24 8 0 45
(29 eq. NH3)
Rh/C (JM 20A) 1 40 25 Aq. NH3 (32%) - 21 4 0 63
(29 eq. NH3)
Rh/C (JM 20A) 1 60 25 Aq. NH3 (32%) - 0 4 0 82
(29 eq. NH3)
Rh/C (JM 20A) 1 60 2.1 NH3 (7 M) (12 Me0 0 17 0 71
eq. NH3) H
Rh/C (JM 20A) 1 40 4 NH3 (7 M) (12 Me0 0 21 0 69
eq. NH3) H
Rh/C (JM 20A) 1 rt 4 NH3 (7 M) (12 Me0 0 24 0 67
eq. NH3) H
Rh/C (JM 20A) 1 rt 22 5 eq. Ms0H Et0H 0 6 0 69
Rh/C (JM 20A) 1 rt 22 5 eq. H2SO4 Et0H 0 8 0 51
Rh/C (JM 20A) 0.4 68 22 83% v/v aq. Et0H 0 8 0 60
NH3 (32%) (24
eq.NH3)
Rh/C (JM 20A) 0.4 60 15 10 mol % LiOH Et0H 0 30 1 65
Rh/C (JM 20A) 0.4 60 20 40% v/v aq. Et0H 0 10 <5 61
NH3 (32%) (12
eq.NH3)
Rh/C (JM 20A) 0.4 70 20 40% v/v aq. Et0H 0 11 <5 57
NH3 (32%) (12
eq.NH3)
Rh/C (JM 20A) 0.4 50 20 40% v/v aq. Me0 0 17 0 72
NH3 (32%) (12 H
eq.NH3)
Rh/C (JM 20A) 0.4 60 20 40% v/v aq. Me0 0 12 <5 59
NH3 (32%) (12 H
eq.NH3)
Rh/C (JM 20A) 0.4 60 20 40% v/v aq. IPA 0 11 0 73
NH3 (32%) (12
eq.NH3)
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Rh/C (JIM 20A) 0.4 70 20 40% v/v aq. IPA 0 11
0 68
NH3 (32%) (12
eq.NH3)
Rh/C 1 60 10 40% v/v aq. Et0H 0 13 0 70
(JM C101023-5) NH3 (32%) (12
eq.NH3)
Rh/Alumina 1 60 24 40% v/v aq. Et0H 0 16 0 80
(JIM 526) NH3 (32%) (12
eq.NH3)
Rh/Alumina 1 60 24 40% v/v aq. Et0H 0 17 0 79
(JM C301011-5) NH3 (32%) (12
eq.NH3)
Rh/Alumina 1 60 24 40% v/v aq. Et0H 0 16 0 82
(JIM 524) NH3 (32%) (12
eq.NH3)
Rh/Alumina 1 60 10 61% v/v aq. Me0 0 24 0 70
(JIM 524) NH3 (32%) (15 H
eq.NH3)
Rh/Alumina 1 60 10 67% v/v aq. Me0 0 17 0 79
(JIM 524) NH3 (32%) (27 H
eq.NH3)
Rh/Alumina 1 60 10 68% v/v aq. Me0 0 15 0 79
(JIM 524) NH3 (32%) (35 H
eq.NH3)
Rh/Alumina 1 50 24 68% v/v aq. Me0 0 17 0 79
(JIM 524) NH3 (32%) (35 H
eq.NH3)
Rh/Alumina 1 60 10 68% v/v aq. Et0H 0 11 0 75
(JM 524) NH3 (32%) (35
eq.NH3)
Rh/Alumina 0.5 60 24 68% v/v aq. Me0 0 19 0 56
(JIM 524) NH3 (32%) (35 H
eq.NH3)
Rh/Alumina 0.25 60 36 68% v/v aq. Me0 0 17 0 38
(JIM 524) NH3 (32%) (35 H
eq.NH3)
Rh/Alumina 1 60 10 74% v/v aq. IPA 0 15 0 80
(JIM 524) NH3 (32%) (30
eq.NH3)
Rh/Alumina 1 60 10 77% v/v aq. IPA 0 13 0 84
(JIM 524) NH3 (32%) (44
eq.NH3)
Rh/Alumina 1 70 10 77% v/v aq. IPA 0 10 0 78
(JIM 524) NH3 (32%) (44
eq.NH3)
Rh/Alumina 1 80 10 77% v/v aq. IPA 3 8 0 64
(JIM 524) NH3 (32%) (44
eq.NH3)
Rh/Alumina 1 90 8 77% v/v aq. IPA 2 7 0 71
(JIM 524) NH3 (32%) (44
eq.NH3)
Rh/Alumina 0.5 80 15 77% v/v aq. IPA 15 4 0 61
(JIM 524) NH3 (32%) (44
eq.NH3)
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Rh/Alumina 0.25 80 19 77% v/v aq. IPA 39 2 0 39
(JM 524) NH3 (32%) (44
eq.NH3)
Rh/Alumina 1 60 10 77% v/v aq. IPA 0 11 0 85
(JM 524) NH3 (32%) (44
eq.NH3)
Rh/Alumina 1 60 10 77% v/v aq. Et0H 0 8 0 73
(JM 524) NH3 (32%) (44
eq.NH3)
Rh/Alumina 2 60 6 77% v/v aq. IPA 0 12 0 79
(JM 524) NH3 (32%) (44
eq.NH3)
Rh/Alumina 3 60 5 77% v/v aq. IPA 0 <1 0 82
(JM 524) NH3 (32%) (44
eq.NH3)
Rh/Alumina 0.5 60 21 77% v/v aq. IPA 11 7 0 74
(JM 524) NH3 (32%) (44
eq.NH3)
Rh/Alumina 5 rt 14 50% v/v aq. Et0H 0 21 10 69
(S-A) NH3 (32%) (15
eq.NH3)
Rh/Alumina 5 40 14 50% v/v aq. Et0H 0 17 7 73
(S-A) NH3 (32%) (15
eq.NH3)
Rh/Alumina 5 60 14 50% v/v aq. Et0H 0 10 26 64
(S-A) NH3 (32%) (15
eq.NH3)
Rh/Alumina 1 60 14 40% v/v aq. Et0H 0 11 0 85
(S-A) NH3 (32%) (12
eq.NH3)
Rh/Alumina 1 70 14 40% v/v aq. Et0H 0 11 0 84
(S-A) NH3 (32%) (12
eq.NH3)
Rh/Alumina 1 60 24 40% v/v aq. IPA 0 9 0 83
(S-A) NH3 (32%) (12
eq.NH3)
Rh/Alumina 1 60 24 40% v/v aq. Me0 0 13 <5 66
(S-A) NH3 (32%) (12 H
eq.NH3)
Rh/Alumina 1 60 24 40% v/v aq. Et0H 0 9 <5 71
(S-A) NH3 (32%) (12
eq.NH3)
Rh/Alumina 1 60 24 40% v/v aq. EDG 0 11 0 75
(S-A) NH3 (32%) (12
eq.NH3)
Rh/Alumina 1 60 10 77% v/v aq. IPA 0 9 0 88
(S-A) NH3 (32%) (44
eq.NH3)
Pt/C (JM 117) 1 60 24 40% v/v aq. Et0H 62
14 <5 11
NH3 (32%)
Table 3. Screening of rhodium and platinum catalysts'
1. Reaction conditions according to the general method.
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2. Catalysts obtained from Johnson Matthey Process Technology (designation:
JM) or Sigma-Aldrich A/S
(designation: S-A).
3. UV-area percentage in LC-MS.
4. Loading of catalyst in mol% catalyst relative to Compound (III).
CN
NH2
F N F N
H FNNF
Compound OM COpOnd Compound ono
Catalyst2 % Cat Temp/ Time/ Additive
Solvent III/% VII/ IV/%
(w/w) C h 3 %3 3
Ni/silica- 11 60 10 40% v/v aq. NH3 Et0H 46 <4 37
alumina (32%) (12 eq.NH3)
(Aldrich)
PRICAT 12 60 10 40% v/v aq. NH3 Et0H 29 <2 49
55/5P (32%) (12 eq.NH3)
PRICAT 12 60 10 40% v/v aq. NH3 Et0H 50 3 36
62/15P (32%) (12 eq.NH3)
PRICAT 29 50 20 79% v/v aq. NH3 Et0H 0 <0.6 91
62/15P (32%) (44 eq. NH3)
PRICAT 31 50 21 40% v/v aq. NH3 Et0H 0 13 81
55/5P (32%) (12 eq.NH3)
PRICAT 31 50 9 79% v/v aq. NH3 Et0H 0 <0.6 96
55/5P (32%) (44 eq. NH3)
PRICAT 31 60 6 79% v/v aq. NH3 Et0H 0 <0.6 92
55/5P (32%) (44 eq. NH3)
PRICAT 31 50 8 79% v/v aq. NH3 IPA 0 <0.6 95
55/5P (32%) (44 eq. NH3)
PRICAT 31 50 9.5 79% v/v aq. NH3 Me0H 0 <0.6 94
55/5P (32%) (44 eq. NH3)
PRICAT 31 50 20 79% v/v aq. NH3 Et0H 0 <0.6 91
55/5P (32%) (44 eq. NH3)
PRICAT 31 50 10 65% v/v aq. NH3 IPA 0 <0.6 94
55/5P (32%) (15 eq. NH3)
PRICAT 31 50 10 67% v/v aq. NH3 IPA 0 <0.6 93
55/5P (32%) (23 eq. NH3)
PRICAT 31 50 10 75% v/v aq. NH3 IPA 0 <0.6 95
55/5P (32%) (35 eq. NH3)
PRICAT 24 50 15 65% v/v aq. NH3 IPA 0 <0.6 93
55/5P (32%) (15 eq. NH3)
PRICAT 24 50 15 67% v/v aq. NH3 IPA 0 <0.6 93
55/5P (32%) (23 eq. NH3)
PRICAT 24 50 15 75% v/v aq. NH3 IPA 0 <0.6 95
55/5P (32%) (35 eq. NH3)
PRICAT 24 50 12 65% v/v aq. NH3 IPA 0 <0.6 92
55/5P (32%) (15 eq. NH3)
PRICAT 20 50 17 65% v/v aq. NH3 IPA 0 <0.6 86
55/5P (32%) (15 eq. NH3)
PRICAT 16 50 20 65% v/v aq. NH3 IPA 0 <0.6 88
55/5P (32%) (15 eq. NH3)
PRICAT 12 50 30 65% v/v aq. NH3 IPA 0 <0.6 89
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PRICAT 8 50 40 65% v/v aq. NH3 IPA 0 <0.6 81
55/5P (32%) (15 eq. NH3)
Table 4. Screening of Nickel catalystsi
1. Reaction conditions according to the general method.
2. Catalysts obtained from Johnson Matthey Process Technology, except for the
first which was obtained
from Sigma-Aldrich.
5 3. UV-area percentage in LC-MS.
4. Loading of catalyst in weight % catalyst relative to Compound (III).
Example 8: Synthesis of 2-(6-Fluoro-1H-indo1-3-371)ethylamine hydrogen L-(+)-
tartrate (V)
To a solution of Compound (III) (10.0 g, 57.4 mmol, 96% UV purity in LC-MS) in
aqueous
ammonia (59.2 g, 65.0 mL, 834 mmol, 24% w/w) and IPA (35.0 mL) was added
PRICAT type
10 55/5P catalyst (3.0 g) at rt. The mixture was transferred to a steel
autoclave and hydrogenated at
4 bar hydrogen for 23 h at 50 C. The mixture was cooled and filtered through
a glass micro fibre
filter (Whatman GF/A) using additional IPA (35 mL). The filtrate was
concentrated by
evaporation in vacuo to approx. 1/3 volume. IPA (70 mL) was added, and the
mixture was again
concentrated to approx. 1/3 volume. The IPA addition and evaporation sequence
was repeated
15 twice. The last time the mixture was evaporated to dryness in vacuo.
The residue was dissolved in IPA (200 mL) and water (10 mL) was added. The
solution was
heated to reflux. Then a solution of L-(+)-Tartaric acid (8.62 g, 57.4 mmol)
in water (30 mL)
was slowly added over a period of 10 min to the stirred solution at reflux.
The resulting solution
was slowly cooled to rt with stirring. The formed suspension was filtered and
the precipitate was
20 washed with cold IPA (50 mL) and dried in vacuo to yield Compound (V)
(14.5 g, 77% yield) as
a white powder with >99.9% UV purity in LC-MS analysis.
Analytical data for Compound (V): 1H NMR (600 MHz, CDC13) 6H 2.96 (t, J = 7.5
Hz, 2H), 3.05
(t, J= 7.5 Hz, 2H), 6.87 (dt, J= 2.0, 10 Hz, 1H), 7.14 (dd, J= 2.0, 10 Hz,
1H), 7.54 (dd, J= 5.5,
10.0 Hz, 1H), 11.1 (br s, 1H); 13C NMR (150 MHz, DMSO-d6) 6c 23.6, 39.7, 72.4
(tartrate), 97.9
(d, J= 25.5 Hz), 107.4 (d, J= 24.5 Hz), 110.4, 119.6 (d, J= 10.0 Hz), 124.0,
124.5, 136.6 (d, J =
12.5 Hz), 159.4 (d, J = 232.5 Hz), 175.2 (tartrate); LC-MS (APPI): m/e calc.
for C10H12FN2
[M+H]+ 179.10, found 179.2 (free base).
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Example 9: Large scale synthesis of 2-(6-fluoro-1H-indo1-3-yl)ethylamine
hydrogen
L-tartrate (V)
Hydrogenation
PRICAT type 55/5P catalyst (14.0 kg) was charged to a reactor followed by
charging of a
solution of Compound (III) (46.3 kg, 266 mol) in isopropanol (76.4 kg). Then
isopropanol (106
L) and aq. ammonia (302 L, 25%) was charged. The mixture was transferred to a
steel autoclave
under nitrogen, using extra isopropanol (92 L) for washing of reactor. The
autoclave was
evacuated and then pressurized with hydrogen gas to 3 bar. The content was
heated to 55 C and
hydrogenated at 3 bar hydrogen for 48 h. The content was cooled to 25 C, and
the autoclave was
purged with nitrogen gas, and the content filtered on a pressure nutsch
filter. The filter was
washed with isopropanol (2 x 145 L). This yielded a solution of Compound (IV).
Precipitation
The amount of solution of Compound (IV) from two hydrogenations of the above
size was
concentrated by vacuum destillation to smallest possible volume, diluted with
IPA (486 L) and
again concentrated by vacuum destillation. This was repeated twice with two
batches of
isopropanol (285 L and then 306 L). Then isopropanol (930 L) and ethyl acetate
(450 kg) was
added, and the mixture was heated to 60 C. A solution of L-(+)-tartaric acid
(39.9 kg, 26.6 mol)
in water (85 L) and isopropanol (280 L) was added slowly over a period of
approx. 30 min to the
solution. The formed suspension was stirred at 60 C for 3 h, and cooled over
a period of 3 h to
C. The suspension was filtered on a pressure nutsch filter, and the filter
cake was washed
twice with a mixture of isopropanol (170 L), ethyl acetate (78 kg) and water
(17 L). The filter
cake was broken up and dried on trays in a vacuum oven at 60 C for 5 days to
yield Compound
(V) (163 kg, 94%) as an off-white solid.
Example 10: Precipitation of 2-(6-fluoro-1H-indo1-3-yl)ethylamine hydrogen L-
(+)-tartrate
(V)
Compound (IV) (5.4 g, 30.3 mmol) was dissolved in isopropyl alcohol (60 mL)
and was heated
to 60 C. A solution of L-(+)-tartaric acid (4.55 g, 30.3 mmol) in water (12
mL) was prepared,
and approx. one third of this solution was added dropwise over 5 min, and the
solution was
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allowed to stir for a further 10 min prior to seeding. Precipitation was
observed. A further one
third of this solution was added dropwise, and after 10 min the remainder of
the aqueous solution
was added dropwise. The suspension was allowed to stir at 60 C for 30 min,
and then was
allowed to cool to 50 C, and was stirred at that temperature for 1 h. The
suspension was then
allowed to cool to room temperature (approx. 22 C) overnight (approx.16 h).
The suspension
was filtered, and the residue was dried under vaccum to give Compound (V) (7.7
g, 77% yield)
as a solid.
Example 11: Precipitation of 2-(6-fluoro-1H-indo1-3-yl)ethylamine hydrogen L-
(+)-tartrate
(I) from crude 2-(6-fluoro-1H-indo1-3-ypethyl-1-amine (III) after
hydrogenation
Crude Compound (1V) (329 g, 1.8 mol) was dissolved in isopropanol (660 mL) and
the solution
was warmed to 50 C. This was transferred to a 10 L flask, and more
isopropanol (2.3 L) was
added. The resultant solution was then heated to and maintained at 60 C using
a
thermostatically-controlled heating mantle. Separately, a solution of L-(+)-
tartaric acid (246 g,
1.6 mol) in water (650 mL) was prepared, total volume 800 mL. A portion of
this aqueous
solution (266 mL) was added to the solution of the amine at a rate of 25
mL/min. After
approximately 80 mL of the solution was added, precipitation was observed. A
further 130 mL
of the solution was added at a rate of 2 mL/min. The remainder of the solution
was then added at
a rate of 6 mL/min. The heating mantle was then turned off, and the suspension
was allowed to
cool overnight to 23 C (approx. 17 h). The suspension was then cooled to 20
C using a water
bath, and filtered. The filter cake was broken up and dried under vacuum at 50
C to give
Compound (V) (443 g, 73%) as a solid.
Example 12: Synthesis of Compound (IX)
Scheme V
0, lel
OH
TsCI
F NaOH F K2CO3 F
_________________________ YIP- _____________________ III0- el 0
F F F F F F OH H20, 50 C F )0Ts NMP, 100
C F )
F0
Compound (VIII) Compound (IX)
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To p-toluenesulfonyl chloride (140 g, 0.734 mol) was added 2,2,3,3-tetrafluoro-
1-propanol (100
g, 0.757 mol) followed by water (440 mL). The mixture was stirred while aq.
NaOH (100 mL,
27.7% w/w) was added slowly. The mixture was heated to 50 C and maintained at
that
temperature for 5 h. The mixture was cooled to rt, and toluene (700 mL) was
added. The mixture
was stirred for 15 min, and the phases were separated. The organic phase was
washed with aq.
ammonia (250 mL, 5% w/w), brine (200 mL, 5% w/w) twice and finally filtered
and evaporated
to dryness to yield Compound (IX) (183 g, 87%) as a colorless oil.
Crude Compound (VIII) (45.8 g, 0.160 mol) from above was mixed with potassium
carbonate
(32.2 g, 0.233 mol) and 3-hydroxybenzaldehyde (25.0 g, 0.205 mol) in N-
methylpyrrolidinone
(137 mL). The mixture was stirred at 90 C for 1 h, and then at 100 C for 3 h.
The mixture was
cooled to 50 C, and water (220 mL) was added. The resulting mixture was added
to a mixture of
toluene (400 mL), brine (75 mL, 15% w/w), water (200 mL) and aq. NaOH (60 mL,
27.7%
w/w). The mixture was stirred briefly and the phases were separated. The
organic phase was
washed sequentially with aq. NaOH (230 mL, 2 M) twice, aq. HC1 (150 mL, 2M),
aq. NaHCO3
(150 mL, 5% w/w), and lastly with brine (50 mL, 5% w/w). The organic phase was
filtered and
evaporated to dryness in vacuo. The resulting oil was stripped twice with
isopropanol (100 mL)
to yield Compound (IX) (34.4 g, 91%) as an oil.
Example 13: Synthesis of Compound (I) as HC1-salt
Scheme VI
1. NaOH aq, toluene, THF
H¨CI
NH2 OHC HN
2.
OH 0 , i-PrOH
\ HOL
OH (IX) F F
3. NaBH4, i-PrOH 401
0 OH
4. Toluene, CH3CN, aq. HCI
5. Acetone, aq. HCI
Compound (V) as Compound (I) as HCI-
salt
L-(+)-tartaric acid salt Yield: ¨80%.
Procedure:
Compound (V) (49.3 g, 0.150 mol) was stirred in a mixture of toluene (270 mL),
THF (100 mL),
aq. NaOH (200 mL, 2 M) and aq. NaC1 (65 mL, 15% w/w). The phases were
separated. The
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organic phase was washed with aq. NaCl (200 mL, 5% w/w). The organic phase was
concentrated
under reduced pressure to dryness and the residue dissolved in isopropanol
(400 mL).
Compound (IX) (39.0 g, 0.165 mol) and isopropanol (200 mL) were charged to the
reaction
mixture. The reaction mixture was heated at 60 C for 2.5 h and then cooled to
about 55 C. To the
hot reaction mixture was charged a suspension of NaBH4 (7.4 g, 0.196 mol) in
isopropanol (100
and 50 mL). The reaction mixture was heated at 55 C for 2.5 h and then cooled
to about 15-20 C.
Aq. HC1 (80 mL, 2 M) was added dropwise over a period of about 30 min. Aq. HC1
(140 mL, 2 M)
was added over a period of 15 min. The mixture was stirred vigorously for 15
min. The mixture
was concentrated to half volume followed by addition of aq. NaOH (83 mL, 6 M)
to pH? 14.
Toluene (400 mL) was added. The phases were separated and the organic phase
was washed with
aq. NaOH (200 mL, 2 M), aq. NH4C1 (200 mL, 3% w/w) and water (200 mL),
respectively. The
organic phase was filtered and concentrated to dryness. The residue was
dissolved in toluene
(550 mL) and acetonitrile (50 mL). Aq. HC1 (33 mL, 6 M) was added drop-wise.
The resulting
suspension was stirred for 2-4 hours and then filtered. The filter-cake was
washed with
toluene:acetonitrile mixture (9:1, 2 x 75 mL) and aq. HC1 (2 x 75 mL, 0.1 M),
respectively. The
crude HC1 salt of Compound (I) was dried under vacuum at about 45 C for about
16 h.
Final purification of the HC1 salt of Compound (I) was performed by first
dissolving the isolated
salt in acetone (300 mL). The solution was filtered and concentrated to a
volume of about 90-120
mL. Filtered aq. HC1 (1900 mL, 0.1 M) was added dropwise over 30 min. The
resulting
suspension was stirred at 20-25 C for 16 h and then filtered. The filtercake
was washed with
filtered HC1 (200 mL, 0.1 M) and filtered water (150 mL), respectively. The
purified HC1 salt of
Compound (I) (52.2 g, 80%) was dried at 40 C under vacuum for about 16 h and
isolated as a
white solid with >99.5% UV purity in HPLC analysis.
