A highly efficient synthesis of a naphthalenoid histamine-3 antagonist

Article abstract of DOI:10.1002/adsc.200900162

A highly efficient synthesis of the potent and selective histamine-3 receptor antagonist 1A was accomplished in four chemical steps and a salt formation step in 36% overall yield from 6-bromo-2naphthalenol 9. The key features are a regioselective Suzuki coupling protocol for selective vinylation of 12 with potassium vinyltrifluoroborate in high yield (92%) with excellent regioselectivity (90:2) and a base-catalyzed hydroamination reaction of 11 in an anti-Markovnikov fashion under mild reaction conditions. An optimized copper-catalyzed cross coupling reaction is used to incorporate the pyridazinone 4.

Full text of DOI:10.1002/adsc.200900162

FULL PAPERS
DOI: 10.1002/adsc.200900162
A Highly Efficient Synthesis of a Naphthalenoid Histamine-3
Antagonist
Yi-Yin Ku,a,* Tim Grieme,a Yu-Ming Pu,a and Ashok V. Bhatiaa
a
R450, Process Research and Development, Global Pharmaceutical Research and Development, Abbott Laboratories,
North Chicago, IL 60064-4000, USA
Fax : (+1)-847-938-5932; phone: (+1)-847-937-4843; e-mail: yiyin.ku@abbott.com
Received: March 12, 2009; Revised: May 11, 2009; Published online: July 7, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900162.
Abstract: A highly efficient synthesis of the potent base-catalyzed hydroamination reaction of 11 in an
and selective histamine-3 receptor antagonist 1A was anti-Markovnikov fashion under mild reaction condi-
accomplished in four chemical steps and a salt for- tions. An optimized copper-catalyzed cross coupling
mation step in 36% overall yield from 6-bromo-2- reaction is used to incorporate the pyridazinone 4.
naphthalenol 9. The key features are a regioselective
Suzuki coupling protocol for selective vinylation of Keywords: copper-catalyzed cross coupling; hista-
12 with potassium vinyltrifluoroborate in high yield mine-3 antagonist; hydroamination; pyridazinone;
(92%) with excellent regioselectivity (90:2) and a regioselective Suzuki vinylation
Introduction
Results and Discusstion
Histamine-3 receptor antagonists modulate the re- Compound 1 was initially assembled via three key
lease of a variety of neurotransmitters.[1] Hence hist- components: 2-(R)-methylpyrrolidine 2, naphthalene
ACHTUNGTRENNUNGamine-3 antagonists may have greater efficacy and alcohol 3 and pyridazinone 4 as summarized in
broader scope than drugs targeting a single neuro- Scheme 1. Although the early work allowed use of 2
transmitter and offer therapeutic benefits in disorders and 4 in bulk quantities, the preparation of 3 required
of cognition.[2] Several new classes of high-potency five chemical transformations starting from 6-bromo-
non-imidazole-based histamine-3 antagonists have 2-napthoic acid methyl ester 5.[3c] The lengthy synthe-
been described recently.[3] Compound 1,[3b] a member sis and the high cost of 5 necessitated a more efficient
of new class of naphthalene-based histamine-3 antag- process for 1. The ready availability of 6-bromo-2-
onists, has been reported.[3] In order to further evalu- naphthalenol 9 in bulk quantities and its low cost led
ate this compound we needed to develop a more effi- us to investigate the use of 9 as a starting material.
cient and scalable synthesis. In the present report, we
Retrosynthetically, 1 can be envisioned from a
describe a highly efficient and practical process for cross-coupling reaction of 10 with pyridazinone 4. The
the synthesis of 1A involving new protocols of a re- b-arylethylamine 10 could arise from the hydroamina-
gioselective Suzuki coupling for selective vinylation of tion reaction of 11. Subsequently, the vinylnaphtha-
ther triflate group vs. bromide, and a base-catalyzed lene 11 could be derived from a selective vinylation
hydroamination in an anti-Markovnikov fashion reaction of 12 which could be prepared from the com-
under mild reaction conditions.
mercially available 6-bromo 2-naphthalenol
(Scheme 2).
9
Preparation of triflate 12 was straightforward under
biphasic reaction conditions (toluene and 30%
K3PO4) using triflic anhydride at 08C [Eq. (1)].[4] Tri-
flate 12 was isolated in good yield (87%) and high
purity (>97%), and was used in the next step without
further processing.
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A Highly Efficient Synthesis of a Naphthalenoid Histamine-3 Antagonist
FULL PAPERS
Scheme 1. The initial eight-step process.
Scheme 2. Retrosynthesis of 1.
tin by-product. Although several boronic vinyl deriva-
tives have been used for the vinylation of triflates or
bromides,[7] achieving high regioselectivity could be
challenging. The similar reactivity of bromide and tri-
flate groups under palladium-catalyzed cross-coupling
conditions often produced mixed results. For example,
the regioselective Suzuki coupling favoring the bro-
mide over triflate group was reported,[8a,b,c] while the
A regioselective vinylation of the triflate group of opposite selectivity was also reported for Kumada
12 was necessary due to the inability to cross-couple and Stille couplings.[8d,e] To the best of our knowledge,
the triflate group with pyridazinone 4. Of the com- no information about the selectivity of vinylation of a
monly used coupling reactions for vinylation are the triflate group in the presence of a bromide was avail-
Stille coupling[5] with vinyltin reagents and the Suzuki able. In order to achieve the necessary selective vinyl-
coupling[6] with vinylboron derivatives. Our efforts ation of 12, a number of reaction conditions were in-
were focused on a regioselective vinylation of triflate vestigated. Several commercially available vinylboron
12 with vinylboron derivatives to avoid producing a reagents (vinylboronate pinacol ester,[7a] trivinylcyclo-
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Table 1. Selected results of the vinylation reaction.
Reaction Conditions[a]
Yield [%][b]
11A
12
11
11B
1
2
3
4
5
PdCl
Pd(OAc)2/P
Pd(PPh3)4/Et3N (1.0 equiv.)/n-PrOH/958C/15 h
Pd(PPh3)4/Et3N (2.0 equiv.)/Cs2CO3 (2.0 equiv., 1M)/EtOH/458C/15 h
Pd(PPh3)4/Cs2CO3 (2 equiv., 1M)/EtOH/458C/15 h
G
1
1
5
0
53
1
52
90
77
4
59
4
2
5
6
9
9
0
0
G
E
N
G
17
[a]
[b]
2 mol% of Pd catalysts were used.
The HPLC assay yields of the reaction mixture were determined using quantitative HPLC analysis by comparison to a
known amount of analytical pure reference standards.
triboroxane,[7c] potassium vinyltrifluoroborate[7d]) were the reaction mixture allowed for milder reaction con-
evaluated under the established protocols.[7] From ditions, which contributed to the improved regioselec-
these studies, potassium vinyltrifluoroborate was tivity and reduced oligomerization, and thus subse-
found to produce the best overall results in respect to quently resulted in the yield improvement. Interest-
the yield and selectivity and was selected for the fur- ingly, when Et3N was omitted from the optimized re-
ther optimization. Under the established protocol action conditions, the reaction was slower and failed
using potassium vinyltrifluoroborate [PdCl2ACTHNUGRTENUNG(dppf)· to go to completion (Table 1, entry 5). This combina-
CH2Cl2/Et3N/n-PrOH/reflux],[7d] the desired product tion of an organic base and an aqueous inorganic
was obtained in 53% yield (Table 1, entry 1). The low base to accelerate the vinylation reaction might be ap-
yield is presumably due to the product oligomeriza- plicable to other Suzuki cross-coupling reactions. The
tion under the reaction conditions. Other commonly coupling product 11 is a highly crystalline solid and
used palladium systems were then investigated can be easily isolated in high purity by a simple pre-
A
R
E
N
ACHTUNGRTEN(NGNU dba)2, cipitation procedure with water. This material was
C
Pd(PPh3)4,
E
Pd
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
sults being listed in Table 1. The introduction of the 2-(R)-methylpyrrolidine 2
Of the screened catalysts, PdACHUTNTGERN(NGNU PPh3)4 produced com- via a hydroamination reaction of 11 in an anti-Mar-
parable results (Table 1, entry 3) to PdCl2 kovnikov fashion was the next challenging step. The
(dppf)·CH2Cl2 and was used for further optimization. transition metal-catalyzed hydroamination of styrenes
It is interesting that with Pd(OAc)2/P(o-tolyl)3, the vi- leading to b-arylethylamines has been reported in sev-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
nylation took place preferentially at the bromide eral recent studies,[9] since this class of amines is prev-
(Table 1, entry 2). Solvent screening (THF, DMA, alent in many biologically important compounds.[10]
DMF, NMP, dioxane, i-PrOH, toluene, EtOH and n- Hydroamination of styrenes is an elegant and simple
PrOH) indicated that the alcoholic solvents, n-PrOH method to prepare b-arylethylamines due to its high
and EtOH were optimal. No noticeable difference atom-efficiency. We were particularly interested in
was observed when other organic bases including i- the base-catalyzed hydroamination for its simplicity.
Pr2NH, n-Pr2NH, i-Pr2NEt, morpholine, and piperi- Although the methodology has been reported,[11] it
dine were used in the place of Et3N. However, a sub- has been restricted to simple styrenes and not been
stantial rate acceleration was observed when widely used for the molecules containing additional
2.0 equivalents of Cs2CO3 (1.0M) aqueous solution functional groups. This is perhaps due to the incom-
was added to the reaction mixture of 12 (1.0 equiv.)/ patibility of the harsh reaction conditions with mole-
PdACHTUNGTRENNUNG(PPh3)4 (2 mol%)/Et3N (2.0 equiv.)/EtOH. The re- cules containing functional groups. When we carried
action could then be carried out at a lower tempera- out the initial hydroamination under the “typical” re-
ture (458C instead of 978C), which consequently led action conditions[11c] using one equivalent of 2-(R)-
to considerable yield increase to 92% (Table 1, methylpyrrolidine 2 and 10 mol% of n-BuLi in THF
entry 4), with no hydrolysis of the triflate group and at 1208C under pressure, a very complex reaction
less than 2% of the bromo-coupling regioisomer mixture was obtained and no desired product was de-
formed. Addition of an aqueous Cs2CO3 solution to tected. When n-BuLi was increased to a stoichiomet-
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A Highly Efficient Synthesis of a Naphthalenoid Histamine-3 Antagonist
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amine 2 under a slow addition (~15 min) of vinyl-
naphthalene to the amide, the desired product can be
obtained in 65% yield. Use of less than 0.5 equiv. of
n-BuLi and less than 1.5 equiv. of amine 2 resulted in
incomplete conversion. When the reaction was carried
out at lower temperatures (below À258C) or at
higher temperatures (above 08C), inferior results
were produced. Among of the solvents (THF, MTBE,
DME) evaluated, THF was the solvent of choice.
Also, reverse addition of 2-(R)-methylpyrrolidine
amide to the vinylnaphthalene resulted in low yield.
The above results suggest that facilitating protona-
tion of the carboanion 10A with an excess of amine 2
improves the reaction yield. It was then attempted to
use different external secondary amines as the proton
source for this improvement provided these amines
would not to undergo addition to the olefin. When
diisopropylamine or tetramethylpiperidine (TMP)
Scheme 3. Proposed hydroamination pathway.
ric amount at 228C, the desired product was formed were used under the optimized conditions using 1.0
in 14% yield. With further reducing the reaction tem- equiv. of amine 2, the desired product was obtained in
perature to 08C, the product was obtained in 34% ~65% yield. No by-products resulting from the addi-
yield, although it was not necessary to use a stoichio- tion of amides (i-Pr2NLi and TMPLi) to the double
metric amount of n-BuLi according to the reaction bond were detected. This result is comparable with
mechanism (Scheme 3). Aryl bromides are known to the reaction using excess of 2-(R)-methylpyrrolidine 2
form benzyne intermediates with strong bases,[12] and and this protocol should be more useful when it is un-
likewise the presence of the bromo group in the mole- desirable to use an excess of a valuable amine. These
cule could generate benzyne intermediates, which results demonstrate the synthetic utility of base-cata-
could subsequently react with the amine 2 leading to lyzed hydroamination reaction under mild conditions
the by-products. This coupled with the polymerization using functionalized vinyl aromatics, thus expanding
could be the main reason for the low yield and the the scope of this methodology.
need to use more than a catalytic amount of n-BuLi.
A simple and efficient purification procedure for 10
To improve the reaction yield, an excess amount of was developed. The HCl salt of the desired product
amine 2 was added to facilitate the protonation of the 10 was found to have very low solubility in aqueous
initial formed carbanion 10A and drive the reaction solution and even lower in a brine solution, and it was
to the desired pathway. When more than 5 equiv. of 2 easily crystallized from the aqueous solution leaving
was used at 08C with 1.0 equiv. of n-BuLi, the reac- all the HCl salts of impurities in the solution. The
tion yield was increased to 55%. Further optimization final incorporation of the pyridazinone 4 was accom-
of the reaction conditions revealed that when less n- plished with an optimized copper-catalyzed coupling
BuLi (0.5 equiv.) was used at the temperature range reaction.[3c] After screening a variety of ligands and
of À158C to À208C with a minimum of 1.5 equiv. of solvents, it was found that use of 8-hydroxyquinoline
Scheme 4. The new four-step process.
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Yi-Yin Ku et al.
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sulfonic anhydride (171.7 g, 0.609 mol) dropwise keeping the
temperature below 58C within 0.5 h. The resulting mixture
was stirred at 58C for 1 h. The aqueous layer was separated
and the organic layer was washed with 5% NaHCO3
(1200 mL), 20% brine (800 mLꢁ2) and dried over Na2SO4.
The organic solution was concentrated to ~200 mL volume
under reduced pressure, and azeotroped with heptane
(500 mLꢁ2) to ~200 mL volume. The slurry was diluted
with heptane (300 mL) and cooled to À108C, and mixed for
3 h. The product was collected by filtration, and dried under
vacuum to afford 145.0 g of the title compound as an off-
white solid (the product was analyzed against pure reference
standard and determined to have a 96% w/w potency, result-
ing in a 87% potency adjusted isolated yield). The crude
product is used in the next step without further purification.
A small pure reference sample was obtained by column
chromatography purification to obtain the pure product as a
as ligand in DMF gave the best result producing the
desired product in 84% yield (Scheme 4). The crude
coupling product was further purified by an extractive
work-up procedure, salt formation and crystallization
of its bis-citrate salt 1A to high purity (>99%).
Conclusions
In summary, we have developed a highly efficient and
practical process for the synthesis of 1A with an over-
all yield of 36%. The process is highlighted by the de-
velopment of a regioselective Suzuki coupling proto-
col for the selective vinylation of 12 using potassium
vinyltrifluoroborate in high yield 92% and excellent
regioselectivity (90:2). The successful hydroamination
of 6-bromovinylnaphthalene 11 was achieved under
mild reaction conditions. In addition, an efficient
cross-coupling reaction between the bromide 10 and
pyridazinone 4 was accomplished with the optimized
copper-catalyzed reaction using 8-hydroxyquinoline as
ligand. This column chromatography-free process in-
volving several simple work-up and purification pro-
cedures is amendable to the large-scale preparation of
1A
1
solid: mp 54–558C. H NMR (CDCl3): d=8.04 (s, 1H), 7.82
(d, J=9.1 Hz, 1H), 7.62–7.66 (dd, J=8.8, 1.9 Hz, 1H), 7.39
(dd,
J=9.1,
2.5 Hz,
1H);
DCI-MS:
m/z=356
[M+NH4ÀH2O]+.
2-Bromo-6-vinylnaphthalene (11)
A mixture of trifluoromethanesulfonic acid 6-bromonaph-
thalen-2-yl ester (12) (96.0 g, 96 w/w% potency, 260 mmol),
potassium vinyltrifluoroborate (42.6 g, 318 mmol) in EtOH
(2.6 L) and a 1.0M aqueous solution of cesium carbonate
(530 mL) was purged with nitrogen, to the mixture was then
added
tetrakis(triphenylphosphine)palladium
(3.1 g,
Experimental Section
3 mmol) followed by triethylamine (74 mL, 530 mmol). The
mixture was heated to 458C for 15 h under nitrogen (HPLC
indicated complete consumption of the starting material)
and cooled to room temperature. To the mixture was added
H2O (1.5 L), the resulting suspension was stirred at room
temperature for 2 h and filtered. The wet-cake was washed
with H2O (500 mL) and dried in the vacuum oven at 458C
for 48 hour to give the product as a beige solid; yield: 61.3 g
(the product was analyzed against pure reference standard
and determined to have a 91% w/w potency, resulting in a
90% potency adjusted isolated yield).
The NMR spectra were recorded at a Varian 400 MHz in-
1
strument at 400 MHz for H and 100 MHz for 13C. The elec-
trospray ionization (ESI) and atmospheric pressure chemical
ionization (APCI) mass spectra were obtained using a Hew-
lett Packard 1100, LC-MS, HPLC-mass spectrometer and
fast atom bombardment (FAB) mass spectra were obtained
using a JEOL SX102A spectrometer. All the reactions were
performed under a positive pressure of nitrogen. Commer-
cial grade anhydrous solvents and reagents were used with-
out further purification. All reactions were monitored by
HPLC (Zorbax SB-C8, 4.6 mmꢁ25 cm column) with purities
being determined by peak area % at the UV detector wave-
lengths of 215 and 230 nm and NMR analysis. The HPLC
assay yields of the reaction mixture were determined using
quantitative HPLC analysis by comparison to a know
amount of analytical pure reference standards and potency
refers to a wt% assay by HPLC versus a purified standard.
The enantiomeric purity of the product was determined by
the chiral HPLC analysis using a Chiral Pak-AD column,
10 mm, 250 mmꢁ4.6 mm (Chiralcel Technologies) at the UV
detector wavelength of 223 nm. The elemental analysis was
performed by Quantitative Technologies Inc.
The crude product is used in the next step without further
purification. A small pure reference sample was obtained by
column chromatography purification to obtain the pure
1
product as a solid: H NMR (CDCl3): d=7.86 (d, J=2.0 Hz,
1H), 7.54–7.61 (m, 4H), 7.42–7.44 (dd, J=8.7, 2.0 Hz, 1H),
6.73–6.80 (dd, J=17.5, 11.0 Hz, 1H), 5.79 (d, J=17.5 Hz,
1H), 5.28 (d, J=11.0 Hz, 1H); 13C NMR (CDCl3): d=
136.18, 135.12, 133.77, 131.62, 129.42, 129.32, 129.29, 126.93,
125.84, 124.00, 119.55, 114.54; GC-MS (DEI): MW=232:
anal. calcd. for C12H9Br: C 61.83, H 3.89, Br 34.28; found:
C 61.76, H 3.69, Br 34.25.
1-[2-(6-Bromonaphthalen-2-yl)-ethyl]-2-methyl-
pyrrolidine (10)
To a cooled solution of 2-(R)-methylpyrrolidine (9.53 g,
112 mmol) in THF (200 mL) at À158C was added n-BuLi
(1.6m in hexane, 23 mL, 37 mmol) dropwise keeping the
temperature below À108C. The resulting mixture was stirred
at À158C for 10 min. To the cooled solution was added a so-
lution of 2-bromo-6-vinylnaphthalene (11) (17.5 g, 91 w/w%
potency, 68.3 mmol) in THF (200 mL) dropwise keeping the
Trifluoromethanesulfonic Acid 6-Bromonaphthalen-2-
yl Ester (12)[4]
To a mixture of 6-bromonaphthalen-2-ol 9 (100 g, 0.448
mol) in toluene (1200 mL) was added a solution of potassi-
um phosphate (300 g) in H2O (700 mL). The mixture was
cooled to 08C, to the mixture was added trifluoromethane-
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A Highly Efficient Synthesis of a Naphthalenoid Histamine-3 Antagonist
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temperature below À158C (this took about 30 min). After
addition, the resulting mixture was stirred at À158C for
10 min and quenched with H2O (5 mL) and allowed to
warm to room temperature. The organic solution was fil-
tered through a pad of Celite to remove some solid. The fil-
trate was concentrated to about 30 mL volume, EtOAc
(200 mL) was added followed by 5% NaHCO3 (150 mL).
The organic layer was separated, washed with 5% NaHCO3
(2ꢁ150 mL), and extracted with 2N HCl (3ꢁ150 mL). The
HCl salt of the desired product slowly precipitated out from
the aqueous solution upon addition of brine (150 mL). The
resulting suspension was cooled to 08C, stirred at 08C for 1
hour and filtered. The product was dried in a vacuum oven
at 508C for 24 hour to obtain the product as an HCl salt;
yield: 18.1 g (the product was analyzed against pure refer-
ence standard and determined to have a 87% w/w potency,
resulting in a 65% potency adjusted isolated yield).
The crude product is used in the next step without further
purification. A small pure reference sample was obtained by
recrytallization to obtain the pure product as a solid. The
NMR spectra were taken using the free base obtained from
the purified HCl salt. 1H NMR (CDCl3): d=7.95 (d, J=
1.8 Hz, 1H), 7.63–7.68 (m, 3H), 7.49–7.51 (dd, J=8.6,
1.9 Hz, 1H), 7.36–7.38 (dd, J=8.3, 1.8 Hz, 1H), 3.36–3.41
(m, 1H), 3.16–3.23 (m, 1H), 3.01–3.07 (m, 2H), 2.47–2.58
(m, 2H), 2.40 (m, 1H), 1.98–2.05 (m, 1H), 1.87–1.93 (m,
1H), 1.76–1.82 (m, 1H), 1.52–1.61 (m, 1H), 1.21 (d, J=
6.2 Hz, 3H); 13C NMR (CDCl3): d=137.69, 132.86, 131.66,
129.34, 129.04, 128.82, 128.10, 126.84, 126.54, 118.93, 60.78,
55.37, 53.62, 34.80, 32.58, 21.88, 18.24; APCI-MS: m/z=319
(M+H)+; anal. calcd. for C17H21BrClN: C 57.56, H 5.97, N,
3.95; found: C 57.54, H 5.98, N 3.91.
lution was charged into the mixture until the pH of the mix-
ture is ~13. The upper organic phase was separated, and the
lower aqueous solution was extracted once with isopropyl
acetate (50 mL). The combined organic solution was washed
with 5% NaHCO3 (250 mL x2), and 25% brine (200 mL),
dried over Na2SO4, and filtered. The filtrate was concentrat-
ed to dryness, and ethyl acetate (170 mL) was added. The
resulting solution was heated to 408C, and salicylic acid
(4.80 g, 34.7 mmol) was added. The solution was stirred at
408C for 2 h, and cooled to 208C. The slurry was mixed for
2 h, filtered, washed with ethyl acetate (50 mL), dried under
vacuum at 558C overnight to afford 12.7 g of the salicylate.
This salt was then freed up in a mixture ethyl acetate
(150 mL) and 10% Na2CO3 aqueous solution (100 mL). The
organic solution was washed with 20% brine (150 mLꢁ2),
dried over Na2SO4, filtered. The filtrate was concentrated to
dryness, and azeotroped with absolute ethanol (100 mL) to
dryness. The residue was dissolved in absolute ethanol
(200 mL), and the solution was heated to 408C. Anhydrous
citric acid (18.1 g, 94.3 mmol) was added all at once, and the
solution seeded with small amount of bis-citrate salt. The so-
lution was mixed at 408C for 5 h, and the slurry was cooled
to 258C, and mixed for 2 h. The product was isolated by fil-
tration, washed with absolute ethanol (100 mL), dried under
vacuum at 508C overnight to give the bis-citrate salt as an
off-white solid; yield: 18.4 g (70% overall); mp 150–1528C.
1HNMR (DMSO-d6): d=8.12 (d, J=1.7 Hz, 1H), 8.10 (dd,
J=3.8, 1.5 Hz), 7.98 (d, J=8.4 Hz, 1H), 7.96 (d, J=8.9 Hz,
1H), 7.90 (s, 1H), 7.68 (dd, J=8.6, 2.1 Hz, 1H), 7.55 (dd,
J=8.4, 1.4 Hz, 1H), 7.52 (dd, J=9.6, 3.8 Hz, 1H), 7.11 (dd,
J=9.5, 1.6 Hz, 1H), 3.60 (m, 2H), 3.47 (m, 1H), 3.21 (m,
4H), 2.67 (d, J=15.3 Hz, 4H), 2.58 (d, J=15.3 Hz, 4H),
2.18 (m, 1H), 1.95 (m, 2H), 1.62 (m, 1H), 1.35 (d, J=
6.5 Hz, 3H); 13C NMR (DMSO-d6): d=175.89, 171.36,
159.50, 138.90, 137.68, 135.80, 132.51, 132.12, 131.53, 130.71,
128.51, 128.02, 127.75, 126.91, 124.17, 123.85, 71.91, 63.16,
52.58, 43.59, 31.31, 30.90, 21.08, 15.58; APCI-MS (ESI):
m/z=334 (M+1); anal. calcd. for C33H39N3O15: C 55.23, H
5.48, N 5.86; found: C 55.26, H 5.31, N 5.87; Pd=8 ppm,
Cu=3 ppm.
2-{6-[2-(Methyl-1-pyrrolidin-1-yl)-ethyl]-2-
naphthalen-2-yl}-2H-pyridazin-3-one (1A)[3c]
To a reaction vessel were charged 1-[2-(6-bromonaphthalen-
2-yl)-ethyl]-2(R)-methylpyrrolidine
(12.5 g, 87 w/w% potency, 36.8 mmol), CuCl (174 mg,
1.75 mmol, 5 mol%), 8-hydroxyquinoline (514 mg,
hydrochloride
(10)
3.54 mmol, 10 mol%), K2CO3 powder (12.19 g, 88.0 mmol),
2H-pyridazin-3-one (4) (5.06 g, 52.7 mmol), and DMF
(57 mL). The reaction vessel was evacuated, and backfilled References
with N2 (repeated 3 times). The reaction vessel was then
pressurized with N2 to 5 psi, and the mixture was heated to
1408C, and maintained for 18 h (HPLC indicated complete
consumption of the starting material) (Caution: the internal
pressure will rise, and must be vented as needed). The reac-
tion mixture was cooled to 208C, and isopropyl acetate
(200 mL), 30% NH4OH (100 mL), 4% Na2EDTA-23%
NaCl solution (100 mL) were added. The mixture was agi-
tated for 0.5 h, filtered through a pad of filter aid, rinsed
with isopropyl acetate (20 mL). The lower aqueous solution
was extracted with isopropyl acetate (50 mL). The combined
organic layers were washed with 4% Na2EDTA-23%NaCl
solution (250 mLꢁ3) and analyzed against reference stan-
dard to contain 9.80 g of the free base of 1 (84% assayed
yield). It was then concentrated to ~200 mL volume and ex-
tracted with a mixture of H2O:CH3SO3H:NMP (70:10:20 by
volume) (150 mL followed by 50 mL). Isopropyl acetate
(200 mL) was added to the combined aqueous extract, and
the mixture was cooled to <108C. 50% NaOH aqueous so-
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