Synthesis of N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)-isoquinoline-3-[11C]ca rboxamide ([11C-carbonyl]PK11195) and some analogues using [11C]carbon monoxide and 1-(2-chlorophenyl)isoquinolin-3-yl triflate

Article abstract of DOI:10.1039/b205838c

The benzodiazepine receptor ligand, N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide (PK11195), and five structurally related analogues were ¹¹C-labelled via a palladium-mediated carbonylation using [¹¹C]carbon monoxide, 1-(2-chlorophenyl)isoquinolin-3-yl trifluoromethanesulfonate and various amines. The ¹¹C-labelled products were obtained with decay-corrected radiochemical yields in the range of 10-55% and with high specific radioactivity (e.g. 200-900 GBq μmol^-1). The radiochemical purity of the final products exceeded 98%. In a typical experiment starting with 3.75 GBq [¹¹C]carbon monoxide, 0.57 GBq of LC-purified products were obtained within 35 min of the start of the carbonylation reaction. For confirmation of the labelling position, N-(1-methylethyl)-1-(2-chlorophenyl)-isoquinoline-3-(¹³C)carboxamide was prepared and analysed by NMR. The precursor 1-(2-chlorophenyl)isoquinolin-3-yl trifluoromethanesulfonate was synthesised in five steps starting from 2-chlorobenzophenone. The precursor N-methyl-sec-butylamine was prepared from sec-butylamine by the reaction with ethyl chloroformate followed by reduction with LiAlH₄. The non-radioactive reference compounds for the analogues were synthesised from 1-(2-chlorophenyl)isoquinoline-3-carboxylic acid and the appropriate amines.

Full text of DOI:10.1039/b205838c

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Synthesis of N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)-
isoquinoline-3-[11C]carboxamide ([11C-carbonyl]PK11195)
and some analogues using [11C]carbon monoxide and
1-(2-chlorophenyl)isoquinolin-3-yl triflate
1
Obaidur Rahman,a Tor Kihlberga,b and Bengt Långströma,b
a Department of Organic Chemistry, Institute of Chemistry, Uppsala University, Box 531,
S-751 21 Uppsala, Sweden
b Uppsala University PET Centre, UAS, S-751 85 Uppsala, Sweden.
E-mail: bengt.langstrom@pet.uu.se
Received (in Cambridge, UK) 25th June 2002, Accepted 9th October 2002
First published as an Advance Article on the web 5th November 2002
The benzodiazepine receptor ligand, N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide
(PK11195), and five structurally related analogues were 11C-labelled via a palladium-mediated carbonylation using
[11C]carbon monoxide, 1-(2-chlorophenyl)isoquinolin-3-yl trifluoromethanesulfonate and various amines. The
11C-labelled products were obtained with decay-corrected radiochemical yields in the range of 10–55% and with
high specific radioactivity (e.g. 200–900 GBq µmolϪ1). The radiochemical purity of the final products exceeded
98%. In a typical experiment starting with 3.75 GBq [11C]carbon monoxide, 0.57 GBq of LC-purified products
were obtained within 35 min of the start of the carbonylation reaction. For confirmation of the labelling position,
N-(1-methylethyl)-1-(2-chlorophenyl)-isoquinoline-3-(13C)carboxamide was prepared and analysed by NMR. The
precursor 1-(2-chlorophenyl)isoquinolin-3-yl trifluoromethanesulfonate was synthesised in five steps starting from
2-chlorobenzophenone. The precursor N-methyl-sec-butylamine was prepared from sec-butylamine by the reaction
with ethyl chloroformate followed by reduction with LiAlH4. The non-radioactive reference compounds for the
analogues were synthesised from 1-(2-chlorophenyl)isoquinoline-3-carboxylic acid and the appropriate amines.
with [11C]carbon monoxide and an aryl triflate.† It should be
Introduction
pointed out that the analogues of PK11195 presented in this
paper could not be labelled with [11C]methyl iodide. A prelimin-
ary account of this work has been reported previously10 as a
conference abstract. This paper describes the results in detail.
The “peripheral-type” benzodiazepine receptor, also named the
ω3 receptor,1a has been found in high concentrations in organs
such as kidney, heart, adrenal cortex and testis, although
its concentration in the brain is expected to be low.1 The physio-
logical role of the ω3 receptor is still unclear and intensive
research is focused on mapping the binding site of this receptor.
For this purpose different types of ligands have been developed.
One important class of ligands for the ω3 receptor are benz-
oxazepine and benzothiazepine derivatives.2 The first non-
benzodiazepine ligand found to bind to the ω3 receptor at a
nanomolar concentration level was PK11195.3 The 3H-labelled
PK11195 was used to investigate the subcellular localisation of
the ω3 receptor in adrenal gland of rats.4 It was also used to
measure the spatial changes in glial fibrillary acidic protein
messenger RNA levels in the hippocampus following transient
global forebrain ischemia in rats.5 Methyl[11C]-labelled PK11195
is now being used as a tracer in various PET applications.6
Although carbon monoxide is a versatile reagent for the
synthesis of carbonyl compounds,7 [11C]carbon monoxide has
until recently8 rarely been applied as a precursor in labeling
chemistry. The main reason for this has been the problem of
trapping [11C]carbon monoxide in the reaction medium.7 To
overcome this, a method was developed that made it possible
to concentrate and enclose small amounts (<50 nmol) of [11C]-
carbon monoxide in small volumes, typically 200 µL. This
method has been recently applied to the synthesis of a wide
range of 11C-labelled carbonyl compounds, e.g. 11C-labelled
amides and imides using organohalides.9 In the present report,
the versatility of the method is further explored by the altern-
ative 11C-labelling of PK11195 and the synthesis of some
11C-analogues using a palladium mediated carbonylation
Results and discussion
The 11C-labelled 1-(2-chlorophenyl)-N-methyl-N-(1-methyl-
propyl)isoquinoline-3-carboxamide 7a and five analogues
7b–f were synthesised in a 200 µL micro-autoclave using tetra-
kis(triphenylphosphine)palladium(), the triflate 6, amines,
lithium bromide and [11C]carbon monoxide at a conc. of
around 10Ϫ4 M (see Scheme 2). In the syntheses, the [11C]-
carbon monoxide and the reaction mixture were transferred
into the micro-autoclave at ambient temperature and then
placed in a heated oil bath for 5 min. The micro-autoclave
reached the set temperature within 5 min as determined by
independent measurement. The conversion of [11C]carbon
monoxide to products (trapping efficiency) was up to 97%
(Table 1) and the decay-corrected radiochemical yields of
LC-purified products, calculated from [11C]carbon monoxide,
were 10 to 55% (Table 1). The specific radioactivity of
LC-purified products, using irradiation of 10 µA h, was 248
to 976 GBq µmolϪ1 (Table 1) as determined by LC-MS. The
radiochemical purity exceeded 98%. In a typical experiment
starting with 3.35 GBq of [11C]carbon monoxide, 0.57 GBq of
purified product was obtained within 35 min from the start of
the carbonylation reaction. The identities of the 11C-labelled
products were confirmed by LC-MS. Preliminary identification
† The IUPAC name for triflate is trifluoromethanesulfonate.
DOI: 10.1039/b205838c
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This journal is © The Royal Society of Chemistry 2002
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Table 1 Radiochemical yields and specific radioactivity for the 11C-labelled PK11195 and some analogues
Amount of
amine/µmol
Trapping
Specific Radioactivity/
Entry
Amine
Product
efficiency (%)a
RCY b, c
GBq µmolϪ1
1
2
3
4
5
6
N-Methyl-sec-butylamine
sec-Butylamine
Isopropylamine
N,N-Dipropylamine
N,N-Diallylamine
Aniline
7a
7b
7c
7d
7e
7f
120
143
175
142
160
164
95
97
97
93
80
91
1
2
2
2
5
2
55 1 (3)
45 1 (3)
47 2 (3)
35 1 (2)
26 1 (2)
10 1 (2)
393
431
248
336
535
976
a Decay-corrected, the fraction of radioactivity left in the crude product after purging with nitrogen. b RCY= radiochemical yield; decay-corrected,
calculated from the amount of radioactivity in the crude product before purg ing with nitrogen, and the radioactivity of the LC purified product.
c Values in parentheses shows the number of runs.
was performed using analytical LC with co-injection of non-
radioactive materials. The labelling position for compound 7c
was confirmed by comparison of the 13C NMR spectra of the
13C-substituted product with that of the non-radioactive refer-
ence compound 12a. The 13C-compound was prepared using
(13C)carbon monoxide, triflate and amine under the similar
conditions to those used for the preparation of 11C-compounds.
The 13C NMR analysis of the product gave only one peak
(from carbonyl carbon at 163.95 ppm) which matched the
carbonyl peak in the 13C NMR spectrum of the reference
compound 12a.
In initial experiments, the hydrochloride salt of the amine 10
was used. The tetrahydrofuran (THF) solution of the free base
was prepared by treatment with 2,2,6,6-tetramethylpiperidine
(TMP) followed by separation of the TMP–hydrochloride.
Under these conditions, both the trapping efficiency (52%) and
the radiochemical yield (27%) were low. One reason for this was
the relatively low concentration of the amine (0.23 µM).
Another reason could be the residual TMP which could affect
the reaction rate and result in side-products. By using the free
amine at higher concentrations (0.48 µM), the possible negative
effect of TMP was avoided. In this case both the trapping
efficiency (95%) and the radiochemical yield (55%) were
improved.
The lead compound PK11195 has previously been labelled
with 11C in the N-methyl group using [11C]methyl iodide.11 The
carbonylation method may have advantages over the former
method for the following reasons. (i) Due to minimal isotopic
dilution9a in the precursor production, the specific radioactivity
of the product is high (e.g. 393 GBq µmolϪ1 for 7a) compared to
the corresponding values described elsewhere11 for the same
compound 11C-labelled at the methyl position (20–96 GBq
µmolϪ1. (ii) The approach allows the possibility of readily
preparing a broad range of 11C-labelled analogues of PK11195
by simply employing different amines including structures that
are difficult to 11C-label using previously available strategies.
(iii) The labelled target compounds are easily separated from
labelled side products and precursors by preparative LC. (iv)
From a biological point of view, labelling a carbonyl group
can be advantageous in cases where there are differences in
metabolic stability.
Scheme 1
The triflate 6 was prepared according to Scheme 1. A one-pot,
reductive amination12 of ketone 1 in the presence of TiCl4, NH3
(g) and NaCNBH3 gave amine 3 via imine 2. The reduction
of imine 2 was pH dependent and an optimum was found
at around pH = 4. The pH was adjusted by the addition of
methanolic HCl. The amide 4 was obtained from amine 3 by
the reaction with ethyl diethoxyacetate. Reactions between
amines and esters are usually sluggish and for this reason the
amine was activated by conversion to the aluminium amide by
treatment with trimethylaluminium.13 The aluminium amide
reacted with ethyl diethoxyacetate at ambient temperature to
form 4. Cyclisation of 4 in the presence of conc. H2SO4 at
ambient temperature14 gave alcohol 5. Finally, alcohol 5 was
treated with trifluoromethanesulfonic anhydride at ambient
Scheme 2
temperature15 to give triflate 6. Triflate 6 was then used to
prepare labelled compounds 7a–f (Scheme 2).
Amine 10 was prepared from commercially available
sec-butylamine 8 by a reaction with ethyl chloroformate
followed by reduction with LiAlH4 (Scheme 3).16 After work-up,
the amine 10 was obtained as the hydrochloride salt. The free
base was liberated with KOH, extracted with diethyl ether and
then carefully distilled.
The reference materials for the lead compound PK11195 and
one of the analogues 7b are commercially available. The refer-
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containing nitrogen (AGA, Nitrogen 6.0) and 0.1% oxygen
(AGA, Oxygen 4.8) bombarded with 17 MeV protons to give
[11C]carbon dioxide. [11C]Carbon monoxide was produced from
[11C]carbon dioxide by a process described previously.21
Liquid chromatographic analysis (LC) was performed with
a Beckman 126 gradient pump and a Beckman 166 variable
wavelength UV-detector in series with a βϩ-flow detector. The
following mobile phases were used: 0.05 M ammonium
formate, pH 3.5 (A) and acetonitrile–H2O, 50 : 7 (B). For
analytical LC, a Jones Chromatography Genesis C18 (4 µm,
250 × 4.6 mm id) column was used with a flow of 1.5 mL minϪ1
.
Scheme 3
For semi-preparative LC, a Jones Chromatography Genesis C18
(4 µm, 250 × 10 mm id) column was used with a flow of 4 mL
minϪ1. Synthia, an automated synthesis system,22 was used for
LC injection and fraction collection. Data collection and LC
control were performed using a Beckman System Gold chrom-
atography software package.
All quantitative radioactivity measurements were performed
using an ion chamber (Veenstra Instrumenten bv, VDC-202).
For rough estimations of radioactivity during production, a
portable dose-rate meter was used (Långenäs eltekniska AB).
In the analysis of 7, the unlabelled reference substance was
used in the LC runs. The identities of synthesised materials
were determined using 1H and 13C NMR, GC-MS and LC-MS.
NMR spectra were recorded on a Varian Gemini-200 (200
MHz), a Varian XL 300 (300 MHz) and a Varian Unity-400
(400 MHz) NMR spectrometers. Tetramethylsilane or chloro-
form-d1 was used as the internal standard. LC-MS was per-
formed using a Fisons VG Platform mass spectrometer with
electrospray ionisation. A Beckman 126 pump, a CMA 240
autosampler and a Beckman Ultrasphere ODS C18 (5 µm,
100 × 4.6 mm id) column were used for LC-MS separation.
Mobile phases were A and B. GC-MS was performed with
a Finnigan GCQ mass spectrometer coupled to a Finnigan
Q-GC. Melting points were determined using a Büchi melting
point apparatus.
2-Chlorobenzophenone, titanium tetrachloride, sodium
cyanoborohydride, trimethylaluminium, ethyl diethoxyacetate,
trifluoromethanesulfonic anhydride, pyridine, THF, sec-
butylamine, ethyl chloroformate, triethylamine, lithium-
aluminium hydride, lithium chloride, lithium bromide, conc.
sulfuric acid and tetrakis(triphenylphosphine)palladium()
were obtained from Aldrich. Ammonia was obtained from
Skoghalsverken AB, Sweden. The reference substances
PK11195 and N-sec-butyl-1-(2-chlorophenyl)isoquinoline-3-
carboxamide (nor-PK11195) were obtained from Sigma RBI.
THF was distilled from sodium–benzophenone under
nitrogen. Pyridine was distilled from CaH2 under nitrogen.
Scheme 4
ence compounds for the other four analogues were synthesised
from different amines and carboxylic acid 11 (Scheme 4). The
acid 1-(2-chlorophenyl)isoquinoline-3-carboxylic acid was
synthesised in three steps starting with o-chlorobenzoyl chlor-
ide and glycine. o-Chlorobenzoyl chloride was reacted with
glycine in a basic medium17 to give 2-chlorohippuric acid
(2-chlorobenzamidoacetic acid) which was then treated with
benzaldehyde in the presence of sodium acetate and acetic
anhydride to form 2-(2-chlorophenyl)-4-benzylidene-5(4H )-
oxazolone. This oxazolone was aromatized to 1-(2-chloro-
phenyl)isoquinoline-3-carboxylic acid 11 in the presence of a
Lewis acid (AlCl3) and HCl.18 Finally the carboxylic acid was
converted to an amide by reacting with oxalyl chloride followed
by the appropriate amines.19
All of the compounds (labelled and unlabelled), except for 3,
7a and 10, presented in this paper are novel. The syntheses
of unlabelled compounds 320 and 1016b have been reported
previously but were prepared by different methods. Compound
3 was reported20a to be an oil (bp20 Torr 186–188 ЊC) whereas we
obtained it as a white solid (mp 42 ЊC). The labelled compound
7a was reported previously to be 11C-labelled at the N-methyl
position. The report presented here describes the 11C-labelling
of this compound at the carbonyl position.
Synthesis of precursor
ꢀ-(2-Chlorophenyl)phenylmethylamine 3. Titanium tetra-
chloride (8.0 mL, 13.8 g, 0.073 mol) was added to a solution
of 2-chlorobenzophenone (10.8 g, 0.05 mol) in dry toluene
(300 mL). The reddish-brown solution was cooled to 0–5 ЊC
and purged with NH3 (g) for 20 min. The mixture was allowed
to warm to room temperature and stirred overnight. The
reaction was carefully quenched with a methanolic solution
of NaCNBH3 (9.0 g, 0.15 mol in 100 mL of methanol). The
mixture was acidified (pH ∼ 4) with methanolic HCl and stirred
at ambient temperature for 2 h. The solvent was removed under
reduced pressure, water (300 mL) and ether (300 mL) were
added and made basic (pH ∼ 12) with solid KOH. The white
precipitate was filtered off and the organic layer was separated,
acidified (pH ∼ 2) with conc. HCl and extracted with water.
The water extract was made basic (pH ∼ 12) with solid KOH,
saturated with NaCl and extracted with diethyl ether (2 × 200
mL). The ether extract was dried over MgSO4 and concentrated
under reduced pressure to give the title compound as a white
solid (6.4 g, 59%), mp 42 ЊC (lit. oil, bp20 Torr 186–188 ЊC).
Experimental
General
[11C]Carbon dioxide was prepared using the Scanditronix
MC-17 cyclotron at the Uppsala University PET Centre. The
14N(p,α)11C reaction was performed in a gas target chamber
J. Chem. Soc., Perkin Trans. 1, 2002, 2699–2703
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δH (200 MHz, CDCl3): 7.6 (1H, dd), 7.1–7.5 (8H, m), 5.7
(1H, s), 1.8 (2H, br s). δC (50 MHZ, CDCl3): 144.0, 142.0, 133.0,
129.5, 128.2, 128.1, 127.9, 127.0, 126.9, 126.8, 55.1. GC-MS:
m/z 217, 201, 180, 165, 140, 106, 77.
water (15 mL). The precipitate was filtered off and the filtrate
was made acidic (pH ∼ 2) with conc. HCl. The solvent was
removed under reduced pressure and the residue was dissolved
in water and extracted with diethyl ether. The aqueous extract
was concentrated under reduced pressure (assisted with the
addition of ethanol) to give the amine as the hydrochloride salt
(0.72 g, 85%), mp 120 ЊC (lit. 120–122 ЊC).
δH (300 MHz, CDCl3): 9.2 (2H, br s) 3.0 (1H, m), 2.5 (3H, t),
1.9 (1H, m), 1.7 (1H, m), 1.3 (3H, d), 0.9 (3H, t). δC (75 MHz,
CDCl3): 56.7, 29.6, 25.6, 15.2, 9.8.
N-[ꢀ-(2-Chlorophenyl)phenylmethyl]-2,2-diethoxyacetamide
4. A solution of the amine 3 (0.88 g, 4 mmol) in dry CH2Cl2
(15 mL) was carefully treated with trimethylaluminium (2.0 mL
of a 2 M solution in hexane) and the mixture was stirred at
room temperature for 15 min under argon. Ethyl diethoxy-
acetate (0.8 mL, 0.7 g, 4 mmol) was added and the reaction
mixture was stirred under argon at 25 ЊC for 20 h. The reaction
was carefully quenched with 1 M HCl and extracted with
CH2Cl2. The organic phase was dried over MgSO4 and con-
centrated under reduced pressure to afford the title compound
as a colourless oil. Yield 66% (calculated from the integral
values of the proton spectrum).
δH (200 MHz, CDCl3): 7.1–7.4 (9H, m), 6.6 (1H, d), 5.2
(1H, s), 4.8 (1H, s), 3.5–3.8 (4H, m), 1.1–1.2 (6H, m). δC (50 MHz,
CDCl3): 167, 140, 138, 133, 131, 128.8, 128.7, 126, 127.4, 127,
126.9, 98, 63, 54, 15. GC-MS: m/z 348, 312, 266, 256, 238, 216,
201, 165, 138, 103, 77, 75, 57.
Synthesis of reference compounds
General procedure. 1-(2-Chlorophenyl)isoquinoline-3-carb-
oxylic acid 11 (300 mg, 1.06 mmol) was suspended in dry
CH2Cl2 (10 mL) and oxalyl chloride (185 µL, 2.12 mmol) was
added followed by 2 drops of DMF. The mixture was stirred at
25 ЊC for 2 h. The solvent was removed under reduced pressure
and traces of oxalyl chloride were removed by the addition and
subsequent evaporation of toluene (2 × 3 mL). The residue was
dissolved in dry THF (10 mL) and added to an ice cold solution
of the amine (1.5 mmol) and pyridine (86 µL, 1.06 mmol) in
THF (10 mL). The mixture was stirred at 25 ЊC for another
2 h, concentrated under reduced pressure and the residue was
partitioned between ethyl acetate (50 mL) and water (50 mL).
The organic extract was washed with water (2 × 50 mL) and
dried over MgSO4. The solvent was removed under reduced
pressure to give the crude product. The crude product was
purified by flash chromatography using ethyl acetate–pentane
(1 : 1) as the eluent. The compound 12d was purified by
recrystallization from absolute ethanol.
N-(1-Methylethyl)-1-(2-chlorophenyl)isoquinoline-3-carb-
oxamide 12a. Yield 75%, mp 148 ЊC. δH (400 MHz, CDCl3): 8.6
(1H, s), 8.1 (2H, m), 7.6 (2H, m), 7.5 (2H, m), 7.4 (3H, m), 4.3
(1H, m), 1.2 (6H, m). δC (100 MHz, CDCl3): 163.8, 157.3, 142.9,
137.8, 136.6, 133.4, 131.5, 130.7, 130.1, 129.8, 128.8, 128.5,
128.2, 127.2, 126.8, 120.2, 41.4, 22.86, 22.84. GC-MS: m/z 324,
309, 281, 266, 241, 239, 220, 203, 176, 150, 139, 120, 102, 88, 87,
58.
1-(2-Chlorophenyl)isoquinolin-3-ol 5. A solution of amide
4 (0.93 g in 15 mL of CH2Cl2) was added slowly with ice cold
conc. H2SO4 (15 mL) and the mixture was stirred overnight at
ambient temperature. The reaction mixture was poured onto ice
and carefully neutralised with 20% NH3 solution. The product
was extracted with CH2Cl2 (2 × 150 mL), dried over MgSO4
and concentrated to give the crude product. The crude product
was purified by flash chromatography using pentane–diethyl
ether (1 : 1) as the eluent (Rf = 0.4) to give the product as a
bright yellow solid (0.42 g, 60%), mp 223 ЊC.
δH (300 MHz, DMSO): 10.8 (1H, br s), 7.8 (1H, d), 7.4–7.6
(5H, m), 7.2–7.3 (2H, m), 7.0 (1H, s). δC (75 MHz, DMSO):
159.5, 139.9, 137.5, 132.0, 131.3, 130.3, 129.3, 127.1, 126.4,
125.7, 124.0, 122.0, 100.3. GC-MS: m/z 255, 227, 192, 165, 137,
113, 95, 81, 63.
N,N-Dipropyl-1-(2-chlorophenyl)isoquinoline-3-carboxamide
12b. Yield 55%, mp 104 ЊC. δH (400 MHz, CDCl3): 8.0 (1H, s),
7.9 (1H, d), 7.7 (1H, t), 7.6–7.5 (3H, m), 7.4–7.3 (3H, m), 3.5–
3.4 (3H, m), 3.3 (1H, m), 1.7 (2H, m), 1.6 (1H, m), 0.9 (3H, t),
0.6 (3H, t). δC (100 MHz, CDCl3): 169.0, 157.4, 148.2, 138.1,
136.6, 133.3, 131.3, 130.6, 130.0, 129.7, 128.3, 127.8, 127.2,
127.1, 126.8, 120.9, 51.0, 48.3, 22.3, 21.02, 11.7, 11.1. GC-MS:
m/z 366, 337, 309, 281, 266, 242, 239, 203, 176, 128, 101, 58.
N,N-Diallyl-1-(2-chlorophenyl)isoquinoline-3-carboxamide
12c. Yield 50%, mp 120 ЊC. δH (400 MHz, CDCl3): 8.1 (1H, s),
7.9 (1H, d), 7.7 (1H, t), 7.6 (1H, d), 7.5 (2H, m), 7.4 (3H, m), 5.9
(2H, m), 5.2 (2H, m), 5.0 (2H, m), 4.1 (3H, m), 4.0 (1H, m).
δC (100 MHz, CDCl3): 169.1, 157.5, 147.3, 137.8, 136.5, 134.1,
133.3, 133.0, 131.3, 130.7, 130.0, 129.7, 128.5, 127.8, 127.4,
127.2, 126.8, 121.3, 117.8, 117.7, 51.0, 47.8. GC-MS: m/z 362,
334, 327, 321, 293, 284, 267, 266, 253, 239, 204, 176, 151, 128,
97, 68.
1-(2-Chlorophenyl)isoquinolin-3-yl trifluoromethanesulfonate
6. A suspension of 5 (0.37 g) in dry pyridine (10 mL) was cooled
to 0 ЊC and carefully treated with trifluoromethanesulfonic
anhydride (0.4 mL, 0.68 g, 2.3 mmol). The mixture was allowed
to warm to room temperature and stirred over night. The
solvent was removed under reduced pressure and the residue
was partitioned between water and diethyl ether. The ether
extract was washed with water and brine, dried over MgSO4
and concentrated under reduced pressure. The crude product
was purified by flash chromatography using hexane–diethyl
ether (1 : 1) as the eluent (Rf=0.6) to afford the product as a
yellow solid (0.40 g, 71%), mp 72 ЊC.
δH (200 MHz, CDCl3): 7.95–7.99 (1H, d), 7.71–7.81 (2H, m),
7.66 (1H, s), 7.44–7.63 (5H, m). δC (50 MHz, CDCl3): 158.9,
151.0, 138.9, 136.2, 133.2, 131.6, 131.3, 130.5, 129.8, 128.3,
127.6, 127.2, 126.8, 110.8, 109–128 (q, ϪCF3). GC-MS: m/z
387, 359, 254, 236, 228, 226, 202, 191, 164.
N-Phenyl-1-(2-chlorophenyl)isoquinoline-3-carboxamide 12d.
Yield 40%, mp 159 ЊC. δH (400 MHz, CDCl3): 10.1 (1H, br s),
8.7 (1H, s), 8.1 (1H, d), 7.7–7.8 (4H, m), 7.6 (2H, m), 7.5 (3H,
m), 7.3–7.4 (2H, m), 7.1 (1H, t). δC (100 MHz, CDCl3): 162.6,
157.5, 142.6, 137.9, 137.6, 136.8, 133.5, 131.5, 131.1, 130.3,
130.0, 129.3, 129.0, 128.7, 128.5, 127.5, 126.9, 124.3, 120.8,
119.9. GC-MS: m/z 358, 329, 281, 265, 256, 239, 225, 203, 176,
152, 135, 88, 73.
N-Methyl-sec-butylamine 10. A solution of sec-butylamine
(1.0 g, 13.7 mmol) in dry diethyl ether (15 mL) was cooled to
0 ЊC and treated with triethylamine (1.9 mL, 1.41 g, 14 mmol).
Ethyl chloroformate (1.3 mL, 1.49 g, 13.7 mmol) was added
dropwise and the mixture was stirred at room temperature for
1 h under nitrogen. Water (20 mL) was added and the product
was extracted with diethyl ether (3 × 15 mL). The ether extract
was dried over MgSO4 and concentrated under reduced
pressure to give the carbamate 9 as a colourless oil (1.73 g,
87%). A solution of carbamate 9 (1.0 g, 6.9 mmol) in dry THF
(10 mL) was treated carefully with LiAlH4 (10 mL of a 1 M
solution in THF) and the mixture was refluxed for 4 h under
argon. The excess hydride was decomposed by slow addition of
Synthesis of N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)-
isoquinoline-3-[11C]carboxamide and analogues
General procedure. The triflate 6 (6.2 mg, 16.0 µmol),
tetrakis(triphenylphosphine)palladium (4.6 mg, 4.2 µmol) and
2702
J. Chem. Soc., Perkin Trans. 1, 2002, 2699–2703

View Article Online
T. Matsui, K. Hayashida, M. Takamura, K. Yamada, S. Tou and
LiBr (2.0 mg, 23 µmol) were placed in a vial (1 mL). The vial
was flushed with nitrogen and the contents were dissolved in
THF (250 µL). The mixture was shaken until the solution was
homogeneous. Amine (143 µmol) was added and the resulting
mixture was transferred under pressure (35 MPa) to the micro-
autoclave (200 µl), pre-charged with [11C]carbon monoxide in
helium. The micro-autoclave was heated at 180 ЊC for 5 min.
The crude product was transferred to a pre-evacuated, septum-
fitted vial (5 mL). The micro-autoclave was washed with THF
(200 µL) which was emptied into the same collection vial.
The radioactivity was measured before and after the vial was
purged with nitrogen. The solvent volume was reduced to less
than 0.2 mL by heating at 50 ЊC and purging with nitrogen.
Acetonitrile–water (1 : 1, 2 mL) was added and the resulting
solution was injected onto the semi-preparative LC. Solvent
A–B (50 : 50), linear gradient to 0 : 100 within 8 min, flow 4 mL
minϪ1, tR= 12.5, 12.6, 11.9, 12.8, 11.8 and 13.5 min for products
7a, 7b, 7c, 7d, 7e and 7f respectively. The identity and radio-
chemical purity of the collected fractions were assessed by
analytical LC: solvent A–B (70 : 30), linear gradient to 0 : 100
within 10 min, flow 1.5 mL minϪ1, wavelength 254 nm, tR = 9.3,
11.3, 10.5, 11.8, 11.1 and 12.6 min for products 7a, 7b, 7c, 7d, 7e
and 7f respectively. LC-MS: m/z 353, 339, 325, 367, 363 and 359
(Mϩ ϩ 1) for products 7a, 7b, 7c, 7d, 7e and 7f respectively.
M. Kawamura, J. Biochem. (Tokyo), 1989, 106, 1026.
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(b) T. Kihlberg, F. Karimi and B. Långström, J. Labelled Compd.
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B. Långström, J. Chem. Soc., Perkin Trans 1, 2001, 1528; (d )
T. Kihlberg, G. Antoni, M. Björkman, F. Karimi, O. Rahman,
M. Ögren and B. Långström, [11C]Carbon monoxide has become a
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Synthesis of N-(1-methylethyl)1-(2-chlorophenyl)-isoquin-
oline-3-(13C)carboxamide (13C-7c). Tetrakis(triphenylphos-
phine)palladium (9.6 mg, 8.8 µmol), triflate 6 (15.5 mg,
40 µmol) and LiBr (4.3 mg, 49.4 µmol) were put in a vial (1 mL).
The vial was flushed with nitrogen and the contents were
dissolved in THF (250 µL). Isopropylamine (20 µL, 234 µmol)
was added and the resulting homogeneous mixture and
(13C)carbon monoxide were transferred under pressure
(35 MPa) to the micro-autoclave (200 µL). The micro-autoclave
was heated (180 ЊC) for 10 min. The crude product was
transferred to a pre-evacuated, septum-fitted vial (5 mL). The
solvent was evaporated by purging with nitrogen at 50 ЊC. A
sufficient quantity of the corresponding 11C-labelled compound
was added to the crude product and purified by semipreparative
LC using the same chromatographic method as described
for the 11C-labelled compound. The radioactive fraction was
collected and evaporated under reduced pressure to yield the
title compound (4.0 mg, 32% calculated from 6). δC (100 MHz,
CDCl3): 163.95 (carbonyl carbon).
10 O. Rahman, T. Kihlberg and B. Långström, J. Labelled Compd.
Radiopharm., 2001, 44, S997.
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Acknowledgements
19 Y. Hamuro, S. J. Geib and A. D. Hamilton, J. Am. Chem. Soc., 1997,
119, 10587.
We would like to thank Professor Wyn Brown for linguistic
corrections. The Swedish Nature Research Council is
acknowledged for its support by grant K3464 (B.L.).
20 (a) S. Rossi, O. Pirola, A. Groppetti, F. Selva and M. L. Zappia,
Farmaco Ed. Sci. IT, 1965, 20, 25; (b) A. Sasse, H. Stark,
X. Ligneau, S. Elz, S. Reidemeister, C. R. Ganellin, J.-C. Schwartz
and W. Schunack, Bioorg. Med. Chem., 2000, 8, 1139.
21 P. Lidström, T. Kihlberg and B. Långström, J. Chem. Soc., Perkin
Trans. 1, 1997, 2701.
22 P. Bjurling, R. Reineck, G. Westerberg, A. D. Gee, J. Sutcliffe and
B. Långström, Proceedings of the VIth workshop on tragetry
and target chemistry, TRIUMF, Vancouver, Canada, 1995,
pp. 282–284.
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