Development of Large-Scale Synthesis using a Palladium-Catalyzed Cross-Coupling Reaction for an Isoquinolone Derivative as a Potent DPP-4 Inhibitor

Article abstract of DOI:10.1021/op5000072

An efficient large-scale synthesis of a novel DPP-4 inhibitor 1, an isoquinolone derivative bearing an aminomethyl group at the 3-position and carbamoylmethoxy group at the 6-position, is described. We have developed an effective and convenient synthetic

Full text of DOI:10.1021/op5000072

Article
pubs.acs.org/OPRD
Development of Large-Scale Synthesis using a Palladium-Catalyzed
Cross-Coupling Reaction for an Isoquinolone Derivative as a Potent
DPP‑4 Inhibitor
Misayo Sera,* Makoto Yamashita, Yuujirou Ono, Takashi Tabata, Eigo Muto, Takashi Ouchi,
and Hiroyuki Tawada
Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome,
Yodogawa-ku, Osaka 532-8686, Japan
ABSTRACT: An efficient large-scale synthesis of a novel DPP-4 inhibitor 1, an isoquinolone derivative bearing an aminomethyl
group at the 3-position and carbamoylmethoxy group at the 6-position, is described. We have developed an effective and
convenient synthetic method utilizing a key intermediate possessing a cyano group at the 3-position and a halogen atom at the 6-
position. The key reaction, the insertion of an oxygen atom at the 6-position of isoquinolone was achieved by a cross-coupling
reaction using 6-bromoisoquinolone and sodium tert-butoxide (tBuONa) in the presence of Pd(OAc)2 and rac-BINAP as a
catalyst to afford 6-tert-butoxyisoquinolone in good yield. The cyano group at the 3-position was hydrogenated in the presence of
Raney nickel to give the aminomethyl moiety of compound 1. The synthetic route has been successfully applied to
multikilogram-scale preparations in good yield and high quality.
INTRODUCTION
■
Dipeptidyl peptidase-4 (DPP-4) inhibitors have been used as a
new class of antidiabetic drugs.1 DPP-4 is an enzyme that
inactivates incretin hormones, such as glucagon-like peptide 1
(GLP-1) which stimulates insulin secretion. Therefore, the
inhibition of DPP-4 leads to increase insulin secretion from the
pancreas.
Figure 2. Isoquinolone derivatives as drug candidates.
Compound 12 has been developed as a candidate for a DPP-4
inhibitor and is an isoquinolone derivative bearing an amino-
methyl group at the 3-position and a carbamoylmethoxy group at
the 6-position (Figure 1). The 6-position oxygen substituted
and noncommercially available starting material 4 for the
manufacturing process, (2) a linear route using a tedious
protection−deprotection process in 16 steps and poor overall
yield (5%), with an especially low yield for the final step, (3)
several preparations requiring column chromatography. In this
manuscript, we describe an alternative effective synthetic route
that was developed for the large-scale manufacturing process.
Our retrosynthetic approach to 1 identified the isoquinolone
derivative 12 as the key intermediate, containing a cyano group as
a precursor of the aminomethyl group at the 3-position and a
hydroxyl group or halogen at the 6-position (Scheme 2). It was
assumed that 12 would be obtained by cyclization of 13. When R
Figure 1. DPP-4 inhibitor 1.
was halogen, investigation of a C−O bond formation reaction
between an arylhalide and an alcohol would be required to
introduce an oxygen atom at the 6-position.
isoquinolone structure has been reported as a useful skeleton for
several kinds of biologically active compounds. For example 2,3
RESULTS AND DISCUSSION
Synthesis of Isoquinolone Derivatives by Ortho-
as a potassium channel inhibitor, and 3,4 as a Rho-kinase
inhibitor, have been researched for the treatments of cardiac
diseases (Figure 2). Therefore, it is important to establish an
efficient synthesis for the 6-position oxygen substituted
isoquinolone derivatives.
The compound 1 was initially synthesized by the complicated
route to introduce an aminomethyl group at the 3-position and a
■
Lithiation. First, we investigated the synthesis of the 2-
benzoylbenzoic acid derivative 15 utilizing ortho-lithiation,5 as
shown in Scheme 3. Commercially available benzoic acid 14 was
treated with 2 equiv of LiTMP (lithium 2,2,6,6-tetramethylpi-
peridide)5b at −78 °C followed by reaction with methyl
carbamoylmethoxy group at the 6-position of an isoquinolone
ring, as shown in Scheme 1. However, this route had the
following severe issues for a scale-up synthesis: (1) an expensive
Received: January 9, 2014
Published: February 17, 2014
© 2014 American Chemical Society
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Scheme 1. Medicinal chemistry route
Scheme 2. Retrosynthetic analysis of 1
benzoate, but the benzoylated compound 15 was not obtained
(Scheme 3). Next, o-lithiation of amide 165d was investigated.
When n-BuLi (2 equiv) was added to a solution of 16 in THF at
−50 °C and quenched with D2O, the deuterated derivative 20
was obtained in 24% yield. On the other hand, treatment of 16
with n-BuLi at 0 °C followed by reaction with D2O gave
compound 20 in quantitative yield (Scheme 4). The o-lithiated
compound of amide 16 was stable, and the subsequent addition
of methyl benzoate gave benzophenone 17. However, alkylation
of 17 with bromoacetonitrile failed to give 18 (Scheme 3).
Synthesis of 6-Haloisoquinolone Derivatives. Since the
o-lithiation approach proved unsuccessful and the appropriate
starting materials to synthesize 6-hydroxyisoquinolone are
difficult to purchase, we designed an alternative synthetic route
via a 6-haloisoquinolone (Scheme 5). Friedel−Crafts reaction of
the commercially available acid anhydride 21 with benzene6 in
the presence of anhydrous aluminum chloride in o-dichlor-
obenzene afforded 4-bromobenzophenone 22. The selectivity
for the desired regioisomer was 2:1 (4-bromoisomer 22a:5-
bromoisomer 22b) ratio, but the isomer 22a was easily purified
by crystallization from ethyl acetate and toluene in 47% yield in
high quality (HPLC area % >99%). On the other hand, Grignard
reaction of anhydride 21 with phenylmagnesium bromide7
afforded a 1:1 ratio of regioisomer mixtures (22a, 22b).
Compound 25 was synthesized from 22a by amidation and
cyclization in excellent yield using the known procedures.6c On
the basis of these results, the route B using Friedel−Crafts
reaction was adopted to obtain the key intermediate 25 in 35%
overall yield over two steps. Next, the key reaction to introduce
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Scheme 3. Synthesis of isoquinolone derivatives (Route A)
Scheme 4. Deuteration study of 16
Scheme 5. Synthesis of isoquinolone derivatives (Route B)
an oxygen atom at the 6-position of the isoquinolone ring was
examined.
C−O Bond Formation by a Palladium-Catalyzed Cross-
Coupling Reaction. Although several methods for C−O bond
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formation with an aromatic ring have been reported, such as
direct nucleophilic substitution reactions,8 and copper-9 or
palladium-catalyzed10 cross-coupling reactions, we first inves-
tigated palladium-catalyzed C−O bond formation of aryl halides
with alcohols (alkoxides), as reported by Buchwald et al. and
Hartwig et al. They reported that this C−O bond formation is a
useful and powerful method for obtaining aryl ethers and also
oxygen-containing heterocycles via intramolecular C−O bond
formation, whereas it was not well-known to apply this method
to heterocyclic compounds except halopyridines.11
Table 2. Optimization of the coupling reaction in the presence
of Pd(OAc)2 and BINAP
a
In order to apply palladium-catalyzed C−O bond formation
reaction to bromoisoquinolone 25, suitable conditions for the
reaction of 25 with tBuONa were investigated because the tert-
butoxy group as an oxygen source could be easily used to give the
hydroxyl group. To establish an appropriate catalyst system for
this substrate, first, several ligands were screened in the presence
of Pd(OAc)2 as a catalyst (Table 1). The desired product 26 was
not obtained using monophosphines (runs 1−5). Biphenyl-
based electron-rich bulky monophosphine ligands (runs 6, 7)
displayed moderate efficiency, and bis(phosphine), especially
BINAP (run 8) was found to be the best ligand, giving 26 in
nearly quantitative yield.12
c
Pd(OAc)2
(mol %)
ligand
tBuOH
(equiv)
time
(h)
conversion
run
1
(mol %)
(26, %)
1.0
1.0
1.0
1.0
1.0
0.5
0.4
0.2
(R)-BINAP
(3.0)
2.0
2.0
2.0
2.0
−
4
23
8
94
76
20
98
97
98
60
16
2
3
(R)-BINAP
(2.0)
(R)-BINAP
(1.2)
b
4
rac-BINAP
(3.0)
2
b
5
rac-BINAP
(3.0)
2
b
6
rac-BINAP
(1.5)
−
24
24
b
7
rac-BINAP
(1.2)
−
a
Table 1. Screening of ligands
b
8
rac-BINAP
(0.6)
−
24
a
b
Conditions; tBuONa (1.5 equiv), toluene, 100 °C. Recrystallized 25
c
was used. Determined by HPLC (condition 1)
was the most favorable reaction condition (run 6). Further
lowering of catalyst loading decreased conversion (runs 7, 8), so
the run 6 condition was selected as the optimum condition.
The coupling product 26 was used without purification after
extraction. Deprotection of the tert-butyl group with trifluoro-
acetic acid13 in acetonitrile afforded 27 in excellent yield over two
steps. Compound 27 was then reacted with chloroacetamide in
the presence of potassium carbonate as a base in N,N-
dimethylformamide (DMF) to give 28 in excellent yield
(Scheme 6).
Preparation of 1 through Reduction of Nitrile. The
reduction of a cyano group to an aminomethyl group was also an
important point for this strategy. Hydrogenation in the presence
of Raney nickel14 is a practical method for nitrile hydrogenation.
It was found to be a valuable method for this compound (Table
3). Comparison of solvents tetrahydrofuran (THF) and N,N-
dimethylacetamide (DMAC), showed that 28 dissolved easily in
DMAC, and the reduction worked well under 0.6−0.8 MPa
hydrogen atmosphere at 50 °C (run 4). The reduction under low
hydrogen pressure (0.2 MPa) proceeded within 24 h (run 5). In
general, it is well-known that dimer products are produced in the
reduction of nitriles,14b and ammonia solution is often used to
prevent the production of dimers. Therefore, we added ammonia
solution to the reaction mixture (runs 1−5). Our project
schedule required a manufacturing-scale synthesis at this point so
that the reaction conditions of run 4 were used, as shown in the
Experimental Section. However, it was found that the addition of
ammonia was not necessary for the reduction of this compound
(run 6), presumably due to the bulky group (isobutyl and
phenyl) adjacent to the nitrile, inhibiting the dimerization by
steric hindrance. After the reaction was completed, the amine was
extracted to the aqueous layer with hydrogen chloride, and then
b
run
ligand
conversion (26, %)
1
2
triphenylphosphine
0
5
tri-tert-butylphosphine
tri-o-tolylphosphine
3
0
4
tris(2-furyl)phosphine
tris(4-methoxyphenyl)phosphine
2-(di-tert-butylphosphino)biphenyl
2-(dicyclohexylphosphino)biphenyl
(R)-BINAP
0
5
0
6
60
44
94
0
7
8
9
1,2-bis(diphenylphosphino)ethane
Pd(PPh3)4
10
0
a
Conditions; 25 (1.0 equiv), Pd(OAc)2 (2.0 mol %), ligand (4.0 mol
%), BuOH (2.0 equiv), BuONa (1.5 equiv), toluene (10 v/w), 100
t
t
b
°C, 2−4 h. Determined by HPLC (condition 1)
Next, the coupling reaction conditions of Pd(OAc)2 and
BINAP were optimized further (Table 2). A 1:3 ratio of catalyst
to ligand was the most effective (run 1), and it was found that rac-
BINAP could be used in place of (R)-BINAP. We also found that
the reaction rate was improved using recrystallized 25 (runs 1 vs
4). Our project schedule required a manufacturing-scale
synthesis at this point, so the coupling reaction conditions of
run 4 were used, as shown in the Experimental Section, but
further optimization was continued as shown in runs 5−8.
Generally, alcohols were used for the oxygen sources. The fact
that the reaction proceeded without addition of tert-butanol (run
5) revealed that tBuONa worked as both a base and an oxygen
source. In addition, we also evaluated this reaction using low
catalyst loadings in order to improve the cost effectiveness (runs
6−8) and showed that Pd(OAc)2/rac-BINAP = 0.5:1.5 (mol %)
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Scheme 6. Process route of 1
neutralization of the aqueous layer gave the free base 1 as crystals
in high yield and high quality (80% yield, 99% HPLC area%).
Design of Quality Control for API. The quality of final
product 1 using the improved manufacturing process was
evaluated. The residual metals such as palladium and nickel were
extremely low, less than 0.1 ppm in the API. The final compound
had four polymorphs, which were two hydrates and two free
bases. The free bases were hygroscopic, and the monohydrate
form A was dehydrated above 50 °C in vacuo. The monohydrate
form B was selected as the development form because of its
stability. As a result of our detailed study, it was found that the
different monohydrate forms A and B could be selectively
produced, depending on the temperature at crystallization. The
pure monohydrate form B was constantly obtained by the
recrystallization from aqueous ethanol above 50 °C.
Table 3. Reduction of nitrile to aminomethyl
H2
a
solvent
(v/w)
aq NH3 temperature time pressure
conversion
run
1
(v/w)
(°C)
(h)
(Mpa)
(1, %)
THF
0.15
70
70
70
50
70
70
4
1
96.4
96.7
97.3
97.8
95.3
96.9
(15)
2
3
4
5
6
DMAC
(5)
0.15
0.15
0.15
0.15
−
4
5
1
DMAC
(4.5)
0.6−0.8
0.6−0.8
0.2
CONCLUSIONS
■
DMAC
(4.5)
7
In summary, we have developed an efficient and convenient
manufacturing process for the DPP-4 inhibitor 1, giving a large-
scale preparation in short steps using a palladium-catalyzed cross-
DMAC
(4.5)
24
4
DMAC
(4)
1
t
coupling reaction of bromoisoquinolone 25 with BuONa as a
key reaction and avoiding column chromatography. In addition,
the reduction of a cyano group to an aminomethyl group by
hydrogenation in the presence of Raney nickel as the catalyst
gave 1 in good yield and high quality. We have also achieved good
a
Determined by HPLC (condition 2).
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quality control of the API. Our improved method enabled the
synthesis of 1 in only seven steps and 22% overall yield (Scheme
6), and we have successfully applied the established manufactur-
ing method to multikilogram-scale preparations.
(2.92 kg, 24.54 mol) was added to a mixture of 22a (6.24 kg,
20.45 mol), N,N-dimethylformamide (125 mL, 1.62 mol), and
toluene (81.1 L) under nitrogen atmosphere. The mixture was
stirred at 50 °C for 1.5 h. The mixture was concentrated in vacuo.
Toluene (32.1 L) was added to the residue and concentrated in
vacuo again. The residue was dissolved at 90 °C in toluene (12.5
L) under nitrogen atmosphere. N-Ethyldiisopropylamine (3.96
kg, 30.64 mol) was added to the mixture and stirred at 90 °C for 5
min. Then 23 (3.81 kg, 33.97 mol) was added to the mixture and
stirred at 90 °C for 3 h. After cooling to room temperature, 1
mol/L aq HCl (62.4 L) was added, and the organic layer was
separated. The organic layer was washed with 10% aq NaCl (62.4
L) and concentrated in vacuo. Acetonitrile (31.2 L) was added to
the residue and concentrated in vacuo again. Ethanol (18.7 L)
was added to the mixture. After heating to 40 °C, acetic
anhydride (2.51 kg, 24.59 mol) and 1,8-diazabicyclo[5.4.0]-
undec-7-ene (6.23 kg, 40.92 mol) were added successively. The
mixture was stirred at 50 °C for 1 h. After cooling to room
temperature, water (15.6 L) was added, and the mixture was
stirred at room temperature for a further 1 h. The resulting
precipitate was collected by filtration, washed with 70% aq
ethanol (25 L) and dried in vacuo at 50 °C to give the title
compound (5.97 kg). A suspension of crude 25 in THF (59.7 L)
was heated to 55 °C. Activated carbon (Shirasagi A) (0.3 kg) was
added to the solution and stirred at 55 °C for 10 min. Activated
carbon was filtered off and washed with THF (17.9 L). The
filtrate was concentrated in vacuo until the weight of the mixture
reached 17.2 kg. The mixture was stirred at 45 °C, and heptane
(59.7 L) was added to the mixture. The whole mixture was stirred
at 40−45 °C for 30 min and then at 0−10 °C for 1 h. The
precipitate was collected by filtration, washed with cooled THF/
heptane (1:5, 6.0 L), and dried in vacuo at 50 °C to give the title
compound (5.88 kg, 75.4% yield) as white crystals. (HPLC area
EXPERIMENTAL SECTION
General. Melting points were determined by using the
■
capillary method on a Buchi 535 apparatus and were uncorrected.
̈
1H NMR and 13C NMR spectra were determined in CDCl3 or
DMSO-d6 on a Bruker DPX-300 or Bruker Avance 500 and
reported in δ ppm using tetramethylsilanes as the internal
standard. The following abbreviations were used: s = singlet, d =
doublet, t = triplet, m = multiplet, dd = doublets of doublet, br =
broad. Elemental analyses were carried out by Takeda Analytical
Laboratories Ltd. The purities of the products were assessed by
HPLC analyses using a YMC column ODS-A A-302 (4.6 mm ×
150 mm) at 25 °C with UV detection at 254 nm. Elution was
conducted at 1.0 mL/min using condition 1: 0.05 mol/L
KH2PO4/CH3CN = 3:7, and condition 2; 0.05 mol/L KH2PO4/
CH3CN = 6:4.
4-Bromo-2-(phenylcarbonyl)benzoic Acid (22a). A
suspension of benzene (5.16 kg, 66.06 mol) and anhydrous
aluminum chloride (11.8 kg, 88.50 mol) in o-dichlorobenzene
(40 L) was cooled to 0 °C. 5-Bromo-2-benzofuran-1,3-dione 21
(10.0 kg, 44.05 mol) was added to the mixture portionwise under
10 °C. After addition, the mixture was stirred at room
temperature for 1 h and 80 °C for 1 h. After cooling to 5 °C,
ethyl acetate (80 L) was added to the mixture. Water (40 L) was
then added carefully, keeping the temperature under 40 °C. The
organic layer was separated and washed with 4 mol/L aq HCl (40
L) and water (40 L) successively. The organic layer was
concentrated in vacuo. Toluene (50 L) was added to the residue,
and the organic layer was concentrated in vacuo again. Toluene
(60 L) and ethyl acetate (6 L) were added to the residue, and the
solids were dissolved at 80 °C. The mixture was cooled to room
temperature and stirred at room temperature for 1 h. The
resulting precipitate was collected by filtration and washed with
toluene (12 L). The crude crystals were dissolved in toluene (60
L) and ethyl acetate (3 L) at 95 °C. The mixture was cooled to 5
°C and stirred at 5 °C for 1 h. The resulting precipitate was
collected by filtration, washed with toluene (12 L), and dried in
vacuo at 50 °C to give the title compound (6.34 kg, 47.2% yield)
as white crystals. (HPLC area % 99%, condition 2); mp 195−198
1
% 99.9%, condition 2); mp 206.5−208.9 °C. H NMR (300
MHz, CDCl3): δ 1.04 (d, J = 6.7 Hz, 6H), 2.30−2.39 (m, 1H),
4.15 (d, J = 7.5 Hz, 2H), 7.39−7.44 (m, 3H), 7.55−7.60 (m, 3H),
7.76 (dd, J = 8.6, 1.9 Hz, 1H), 8.39 (d, J = 8.6 Hz, 1H). 13C NMR
(126 MHz, CDCl3): δ 19.93, 28.41, 54.55, 113.01, 116.70,
126.11, 128.28, 129.03, 129.21, 129.33, 129.51, 129.65, 130.27,
130.28, 133.10, 136.35, 160.28. Anal. Calcd for C20H17N2OBr: C,
63.00; H, 4.49; N, 7.35; Br, 20.96. Found: C, 62.96; H, 4.41; N,
7.36; Br, 20.86.
6-tert-Butoxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-
3-isoquinolinecarbonitrile (26).15 A suspension of Pd(OAc)2
(34.7 g, 0.15 mol) and rac-BINAP (288.7 g, 0.46 mol) in toluene
(56.1 L) was stirred at 40 °C for 30 min under nitrogen
atmosphere. The mixture was cooled to 25 °C, and 25 (5.90 kg,
15.47 mol), tert-butanol (2.92 L, 30.94 mol), tBuONa (2.23 kg,
23.2 mol), and toluene (2.95 L) were added. After stirring at 25
°C for 20 min, the solution was heated at 95−100 °C for 2.5 h.
Then the mixture was cooled to 15 °C, diluted with 0.5 mol/L aq
HCl (29.5 L), and stirred at 25 °C for 30 min. After dissolution
with toluene (17.7 L), the organic layer was separated and
washed with water (29.5 L) twice. The organic layer was
concentrated in vacuo, and acetonitrile (29.5 L) was added to the
residue. The mixture was concentrated in vacuo again.
Acetonitrile (29.5 L) was added to the residue and concentrated
in vacuo until the weight of the mixture reached 14.8 kg. The
residual solution was used in the next reaction without further
purification. (HPLC area % 95.9%, condition 1); 1H NMR (300
MHz, CDCl3): δ 1.03 (s, 3H), 1.05 (s, 3H), 1.33 (s, 9H), 2.30−
2.39 (m, 1H), 4.14 (d, J = 7.5 Hz, 2H), 6.78−6.79 (m, 1H),
1
°C. H NMR (300 MHz, CDCl3): δ 7.44 (t, J = 7.8 Hz, 2H),
7.53−7.60 (m, 2H), 7.71 (m, 4H), 7.94 (d, J = 8.3 Hz, 1H). 13C
NMR (126 MHz, DMSO-d6): δ 126.88, 129.17, 129.43, 129.64,
130.52, 132.39, 133.19, 133.75, 136.99, 143.83, 166.62, 195.11.
Anal. Calcd for C14H9O3Br: C, 55.11; H, 2.97; Br, 26.19. Found:
C, 55.01; H, 2.98; Br, 26.13.
[(2-Methylpropyl)amino]acetonitrile (23). A mixture of
isobutylamine (6.75 kg, 92.29 mol) and triethylamine (10.30 kg,
101.79 mol) in ethyl acetate (33.8 L) was cooled to 5 °C.
Bromoacetonitrile (11.10 kg, 92.54 mol) was added dropwise
under 30 °C over 2 h. After addition, the mixture was stirred at 25
°C for 3 h, and then water (33.8 L) was added. The organic layer
was separated and washed with 10% aq NaCl (33.8 L). The
organic layer was concentrated in vacuo, and purified by
distillation under 10 mmHg/82 °C to give the title compound
1
(5.99 kg, 57.9% yield) as a yellow oil.; H NMR (300 MHz,
CDCl3): δ 0.94 (d, J = 6.6 Hz, 6H), 1.17 (br, 1H), 1.74 (m, 1H),
2.54 (d, J = 6.6 Hz, 2H), 3.59 (s, 2H).
6-Bromo-2-(2-methylpropyl)-1-oxo-4-phenyl-1,2-di-
hydroisoquinoline-3-carbonitrile (25). Thionyl chloride
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7.23−7.24 (m, 1H), 7.39−7.43 (m, 2H), 7.52−7.57 (m, 3H),
8.42 (d, J = 8.8 Hz, 1H).
filtration, washed with 10% aq ethanol (1.58 L) and ethyl acetate
(1.05 L) and dried in vacuo at 60 °C to give the title compound
(856.9 g, 80.7% yield) as white crystals. (HPLC area % 99.4%,
condition 2.) A suspension of crude 1 (1.12 kg) in 90% aq
ethanol (3.36 L) was heated at 60−65 °C. The resulting solution
was filtered through DISPOSABLE FILTER ASSEMBLY
HDCII (1.2 μm, DFA3201 J012P) and washed with warmed
90% aq ethanol (1.12 L). The solution was heated at 60−65 °C,
water (6.72 L) was added while keeping at 60−65 °C, and
monohydrate form B (1.12 g) was added as the crystal seed.
Then water (8.96 L) was added to the mixture while keeping at
60−65 °C, and the whole mixture was stirred at 60−65 °C for 1 h
and then at 20−30 °C for 1 h. The precipitate was collected by
filtration, washed with 20% aq ethanol (1.68 L), and dried in
vacuo at 60 °C to give the title compound (1.12 kg, 95.1% yield)
as white crystals. (HPLC area % 99.7%, condition 2); mp 172−
175 °C. 1H NMR (300 MHz, CDCl3): δ 0.99 (s, 3H), 1.01 (s,
3H), 1.26 (br s, 2H), 2.21−2.30 (m, 1H), 3.66 (s, 2H), 4.18−
4.21 (m, 2H), 4.32 (s, 2H), 6.04 (br s, 1H), 6.31−6.32 (m, 1H),
6.54 (br s, 1H), 7.01−7.05 (m, 1H), 7.26−7.28 (m, 2H), 7.45−
7.54 (m, 3H), 8.43 (d, J = 8.8 Hz, 1H). 13C NMR (126 MHz,
CDCl3): δ 20.25, 28.86, 40.91, 50.52, 66.70, 108.03, 115.40,
118.50, 119.93, 128.15, 129.11, 130.52, 130.64, 136.65, 139.39,
141.69, 159.85, 162.51, 170.44. Anal. Calcd for C22H26N3O5: C,
66.48; H, 6.85; N, 10.57. Found: C, 66.46; H, 7.02; N, 10.45.
6-Hydroxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-
isoquinolinecarbonitrile (27). Trifluoroacetic acid (2.30 L,
30.96 mol) was added to the solution of 26 described above, and
the mixture was stirred at 55−65 °C for 5 h. After cooling to 20
°C, the reaction mixture was diluted with water (29.5 L) and
ethyl acetate (70.8 L). The organic layer was separated, washed
with water (29.5 L), and concentrated in vacuo until the weight
of the mixture reached 18.9 kg. Heptane (35.4 L) was added to
the residue at 20−30 °C, and the mixture was stirred at 0−5 °C
for 1 h. The resulting precipitate was collected by filtration,
washed with cooled ethyl acetate/heptane (1:3, 8.9 L), and dried
in vacuo at 50 °C to give the title compound (4.34 kg, 88.1% yield
for two steps) as yellow crystals. (HPLC area % 99.2%, condition
1
1); mp 258−262 °C. H NMR (300 MHz, CDCl3): δ 1.00 (s,
3H), 1.01 (s, 3H), 2.26−2.35 (m, 1H), 4.11 (d, J = 7.4 Hz, 2H),
6.72−6.73 (m, 1H), 7.16−7.23 (m, 1H), 7.37−7.40 (m, 2H),
7.48−7.51 (m, 3H), 8.35 (d, J = 8.8 Hz, 1H). 13C NMR (126
MHz, DMSO-d6): δ 20.28, 28.54, 53.91, 110.67, 114.05, 115.88,
119.70, 119.99, 129.37, 129.51, 129.62, 130.75, 130.83, 134.10,
137.10, 160.11, 162.06. Anal. Calcd for C20H18N2O2: C, 75.45;
H, 5.70; N, 8.80. Found: C, 75.38; H, 5.87; N, 8.75.
2-[(3-Cyano-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-
isoquinolinyl)oxo]acetamide (28). A suspension of 27 (4.30
kg, 13.51 mol), 2-chloroacetamide (1.52 kg, 16.25 mol) and
potassium carbonate (2.24 kg, 16.21 mol) in N,N-dimethylfor-
mamide (21.5 L) was stirred at 75−85 °C for 3 h. After cooling to
25 °C, acetonitrile (21.5 L) was added to the mixture. The pH of
whole mixture was adjusted to 5−6 at 15−25 °C with 1 mol/L aq
HCl, and water (28.0 L) was added. Then the mixture was stirred
at 20−30 °C for 1 h. The precipitate was collected by filtration,
washed with acetonitrile/water (1:3, 8.6 L) twice, and dried in
vacuo at 50 °C to give the title compound (4.64 kg, 91.5% yield)
as yellow crystals. (HPLC area % 99.2%, condition 1); mp 198−
200 °C. 1H NMR (300 MHz, CDCl3): δ 1.02 (s, 3H), 1.05 (s,
3H), 2.30−2.39 (m, 1H), 4.14 (d, J = 7.5 Hz, 2H), 4.41 (s, 2H),
5.78 (br s, 1H), 6.46 (br s, 1H), 6.67−6.68 (m, 1H), 7.22−7.25
(m, 1H), 7.38−7.42 (m, 2H), 7.54−7.58 (m, 3H), 8.51 (d, J = 8.9
Hz, 1H). 13C NMR (126 MHz, DMSO-d6): δ 20.26, 28.53,
54.05, 67.07, 110.53, 113.99, 116.27, 118.69, 121.26, 129.43,
129.46, 129.77, 130.65, 130.84, 133.64, 136.67, 159.99, 161.66,
169.36. Anal. Calcd for C22H21N3O3: C, 70.38; H, 5.64; N, 11.19.
Found: C, 70.35; H, 5.80; N, 11.08.
AUTHOR INFORMATION
Corresponding Author
*Telephone: +81-6-6300-6552. FAX:+ 81-6-6300-6251. E-mail:
misayo.sera@takeda.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Mr. Kokichi Yoshida and Dr. Kiminori Tomimatsu for
their helpful discussion, and Dr. David Cork and Mr. Tsuneo
Yasuma for their advice on the manuscript.
REFERENCES
■
(1) (a) Weber, A. E. J. Med. Chem. 2004, 47, 4135. (b) Deacon, C. F.;
Ahren, B.; Holst, J. J. Expert Opin. Investig. Drugs 2004, 13, 1091.
(2) (a) Oi, S.; Ikedou, K.; Takeuchi, K.; Ogino, M.; Banno, Y.; Tawada,
H.; Yamane, T. WO/2002/062764, 2002. (b) Banno, Y.; Miyamoto, Y.;
Sasaki, M.; Oi, S.; Asakawa, T.; Kataoka, O.; Takeuchi, K.; Suzuki, N.;
Ikedo, K.; Kosaka, T.; Tsubotani, S.; Tani, A.; Funami, M.; Tawada, M.;
Yamamoto, Y.; Aertgeerts, K.; Yano, J.; Maezaki, H. Bioorg. Med. Chem.
2011, 19, 4953. (c) Maezaki, H.; Banno, Y.; Miyamoto, Y.; Moritou, Y.;
Asakawa, T.; Kataoka, O.; Takeuchi, K.; Suzuki, N.; Ikedo, K.; Kosaka,
T.; Sasaki, M.; Tsubotani, S.; Tani, A.; Funami, M.; Yamamoto, Y.;
Tawada, M.; Aertgeerts, K.; Yano, J.; Oi, S. Bioorg. Med. Chem. 2011, 19,
4482.
2-{[3-(Aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-
dihydro-6-isoquinolinyl]oxy}acetamide Hydrate (1).16
A
suspension of 28 (1.05 kg, 2.80 mol) and 25% ammonium
hydroxide (158 mL) in N,N-dimethylacetamide (4.73 L) was
hydrogenated in the presence of Raney nickel (NDHT-90, 265
mL) under 0.6−0.8 MPa hydrogen atmosphere at 50 °C for 5.5
h. After cooling to 25 °C, Raney nickel was filtered off and
washed with N,N-dimethylacetamide (1.58 L). The combined
filtrate was diluted with ethyl acetate (5.25 L) and 1 mol/L aq
HCl (6.3 L). The organic layer was separated and extracted with
0.2 mol/L aq HCl (2.1 L). The aqueous layer was combined and
washed with ethyl acetate (3.15 L). Activated carbon (Shirasagi
A) (52.5 g) was added to the aqueous layer, and the mixture was
stirred at room temperature for 15 min. Activated carbon was
filtered off and washed with 0.1 mol/L aq HCl (2.1 L). The pH of
the combined aqueous layer was adjusted to 8.3−8.7 at 30 °C
with 5% ammonium hydroxide (2.75 L), and diluted with water
(2.5 L). The whole mixture was stirred at 20−30 °C for 30 min
and at 0−10 °C for 1 h. The precipitate was collected by
(3) Trotter, B. W.; Claiborne, C.; Ponticello, G. S.; Mcintyre, C. J.;
Liverton, N.; Claremon, D. A. WO/2005/030791, 2005.
(4) Plettenburg, O.; Lorenz, K.; Loehn, M.; Weston, J.; Kleemann, H.-
W. WO/2009/156099, 2009.
(5) (a) Parham, W. E.; Sayed, Y. A. J. Org. Chem. 1974, 39, 2051.
(b) Nguyen, T. H.; Chau, N. T. T.; Castanet, A. S.; Nguyen, K. P. P.;
Mortier, J. J. Org. Chem. 2007, 72, 3419. (c) Parham, W. E.; Bradsher, C.
K.; Edgar, K. J. J. Org. Chem. 1981, 46, 1057. (d) Beak, P.; Brown, R. A. J.
Org. Chem. 1982, 47, 34.
(6) (a) Stephens, H. N. J. Am. Chem. Soc. 1921, 43, 1950. (b) Asano, Y.;
Kitamura, S.; Ohra, T.; Aso, K.; Igata, H.; Tamura, T.; Kawamoto, T.;
Tanaka, T.; Sogabe, S.; Matsumoto, S.; Yamaguchi, M.; Kimura, H.;
Itoh, F. Bioorg. Med. Chem. 2008, 16, 4715. (c) Itoh, F.; Kimura, H.;
Igata, H.; Kawamoto, T.; Sasaki, M.; Kitamura, S. EP 1484320 A1, 2004.
452
dx.doi.org/10.1021/op5000072 | Org. Process Res. Dev. 2014, 18, 446−453

Organic Process Research & Development
Article
(7) Rahman, M. T.; Nahar, S. K. J. Organomet. Chem. 1992, 425, 201.
(8) (a) DeVries, V. G.; Moran, D. B.; Allen, G. R.; Riggi, S. J. J. Med.
Chem. 1976, 19, 946. (b) Pearson, A. J.; Gelormini, A. M. J. Org. Chem.
1994, 59, 4561. (c) Woiwode, T. F.; Rose, C.; Wandless, T. J. J. Org.
Chem. 1998, 63, 9594.
(9) (a) Lindley, J. Tetrahedron 1984, 40, 1433. (b) Aalten, H. L.; van
Koten, G.; Grove, D. M.; Kuilman, T.; Piekstra, O. G.; Hulshof, L. A.;
Sheldon, R. A. Tetrahedron 1989, 45, 5565. (c) Keegstra, M. A.; Petters,
T. H. A.; Brandsma, L. Tetrahedron 1992, 48, 3633. (d) Fagan, P. J.;
Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem. Soc. 2000, 122,
5043.
(10) (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 10333. (b) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 3395. (c) Torraca, K. E.; Kuwabe, S. I.; Buchwald,
S. L. J. Am. Chem. Soc. 2000, 122, 12907. (d) Parrish, C. A.; Buchwald, S.
L. J. Org. Chem. 2001, 66, 2498. (e) Kuwabe, S. I.; Torraca, K. E.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 12202. (f) Mann, G.;
Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 122,
3224. (g) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org.
Chem. 2002, 67, 5553.
(11) Watanabe, M.; Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1999, 40,
8837.
(12) Tawada, H.; Yamashita, M.; Sera, M.; Ouchi, T. JP 2005-35933A,
2005.
(13) (a) Lee, J. A.; Kim, H. O.; Tosh, D. K.; Moon, H. R.; Kim, S.;
Jeong, L. S. Org. Lett. 2006, 8, 5081. (b) Jeong, L. S.; Lee, J. A.; Kim, H.
O.; Tosh, D. K.; Moon, H. R.; Lee, S. J.; Lee, K. M.; Sheen, Y. Y.; Chun,
M. W. Nucleosides, Nucleotides, Nucleic Acids 2007, 26, 1021.
(14) (a) Nishimura, S.; Ikeda, S.; Kinoshita, K.; Kawashima, M. Bull.
Chem. Soc. Jpn. 1985, 58, 391. (b) Juday, R.; Adkins, H. J. Am. Chem. Soc.
1955, 77, 4559.
(15) Subsequent optimization of the manufacturing process showed
that tBuOH was not necessary and a lower catalyst loading of Pd(OAc)2
0.5 mol% and rac-BINAP 1.5 mol% could be used.
(16) Subsequent optimization of the manufacturing process showed
that the ammonia solution could be omitted.
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