Development of a practical and scalable synthetic route to YM758 monophosphate, a novel If channel inhibitor

Article abstract of DOI:10.1021/op5002885

A novel, practical, and efficient synthesis of (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide monophosphate (YM758 monophosphate, (R)-1·H₃PO₄ (Figure 1) is described. The

Full text of DOI:10.1021/op5002885

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Full Paper
Development of a Practical and Scalable Synthetic Route
to YM758 monophosphate, a Novel If Channel Inhibitor
Shinya Yoshida, Kiyotaka Marumo, Kazuhiro Takeguchi, Takumi Takahashi, and Toshiyasu Mase
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op5002885 • Publication Date (Web): 17 Oct 2014
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Development of a Practical and Scalable Synthetic
Route to YM758 monophosphate, a Novel If Channel
Inhibitor
Shinya Yoshida,*,† Kiyotaka Marumo,‡, Kazuhiro Takeguchi,† Takumi Takahashi§ and Toshiyasu Mase†
† Process Chemistry Labs., Astellas Pharma Inc., 160ꢀ2 Akahama, Takahagiꢀshi, Ibaraki 318ꢀ0001, Japan
‡ Astellas Pharma Tech Co., Ltd., 160ꢀ2 Akahama, Takahagiꢀshi, Ibaraki 318ꢀ0001, Japan
§Technology Product Management, Astellas Pharma Inc., 2ꢀ5ꢀ1, NihonbashiꢀHoncho, Chuoꢀku, Tokyo, 103ꢀ
8411, Japan
Abstract
A
novel, practical, and efficient synthesis of (ꢀ)ꢀNꢀ{2ꢀ[(R)ꢀ3ꢀ(6,7ꢀdimethoxyꢀ1,2,3,4ꢀ
tetrahydroisoquinolineꢀ2ꢀcarbonyl)piperidino]ethyl}ꢀ4ꢀfluorobenzamide monophosphate (YM758
monophosphate, (R)-1·H3PO4 (Figure 1) is described. The target molecule (R)ꢀ1 has a potent If current
channel inhibitor. Medicinal chemistry synthetic routes were very long and suffered from extensive use
of chlorinated solvents and silicaꢀgel column chromatography. A number of steps in the medicinal
chemistry route were also unattractive for largeꢀscale synthesis due to some reasons for example the use
of unstable intermediates. An important objective of a new synthetic route was avoidance of such a use
of unstable intermediate, and it was achieved by the discovery of an important 4,5ꢀdihydrooxazole
intermediate 19 and ringꢀopening Nꢀalkylation of chiral amine with 19 under acidic condition. The new
procedure does not require any purification by column chromatography for all steps. Overall yield was
significantly improved from 14 or 34% to 49% compared to that of the medicinal synthetic routes. This
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highly efficient process was successfully demonstrated at a pilotꢀscale operation, yielding 36.5kg of (R)-
1·H3PO4.
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Introduction
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YM758 monophosphate (R)-1·H3PO4 has an inhibitory action for If current and shows a strong and
specific activity selectively lowering a heart beat and decreasing oxygen consumption of heart muscle in
a selective manner whereby it is useful as a preventive and / or treating agent for diseases of circulatory
system such as ischemic heart diseases (e.g., angina pectoris and myocardial infarction), congestive
heart failure, arrhythmia, etc.1 Herein, we describe our efforts to develop a practical, scalable approach
to (R)-1·H3PO4 which was demonstrated in a largeꢀscale synthesis for the first GMP delivery. 1g, 1h
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. H3PO4
YM758 monophosphate
(R)-1.H3PO4
Figure 1. Structure of (R)-1·H3PO4
Medicinal Chemistry Synthetic Route A
The synthetic route to (R)-1·H3PO4 used in Medicinal Chemistry Synthetic Route A was long, linear
1g,1h
and involved unstable intermediates (Scheme 1).
described below.
These issues for a largeꢀscale synthesis are
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a
Scheme 1. Medicinal Chemistry synthetic Route A for (R)-1·H3PO4
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L-tartaric acid
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(R)-4.HCl
c
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b
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(R)-5
7
e
d
(R)-6
(R)-8
(R)-9
HCl
10.HCl
Crude (R)-1.H3PO4
(R)-1.H3PO4
f
h
g
(R)-1
a Reagents and conditions: (a) Boc2O, NaHCO3, EtOAcꢀwater, 50%; (b) aq. KOH, CHCl3, then 3, K2CO3, CH3CN, 84%; (c)
(1) 4M HCl/EtOAc, EtOH, (2) aq. KOH, CHCl3, quantitative yield; (d) 7, THF, CHCl3, SiO2 column chromatography, 57%;
(e) (1) aq. NaOH, EtOH, (2) aq. HCl; (f) (1) 10·HCl, aq. KOH, CHCl3, (2) EDCꢁHCl, HOBt, DMF; (g) aq. H3PO4, EtOH,
93% in three steps; (h) recrystallization with EtOH/water, 74%. Overall yield: 16%.
Bocꢀprotected bromoethylamine compound 3 was an unstable compound therefore it was easily
decomposed during storage even at 5 °C in a labꢀscale. Furthermore, as primary amine compound (R)-
6
was also an unstable compound, selfꢀcondensation occurred and an impurity was observed during
vacuum concentration in a labꢀscale. Additionally, protection and deprotection steps were inefficient
way in a largeꢀscale synthesis. Needless to say, it was an impractical manner that needed many steps to
prepare (R)-1·H3PO4 (total eight steps) and the overall yield was low (16%). Finally, the use of
chlorinated solvents for extraction steps and purifying steps in SiO2 column chromatography should be
avoided from the point of view of environment as well.
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Scheme 2. Medicinal Chemistry synthetic Route B for (R)-1·H3PO4
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HCl
L-tartaric acid
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10.HCl
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(R)-13
(R)-4.HCl
(R)-11
(R)-12
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f
(R)-16
(R)-17
(R)-14
(R)-1.H3PO4
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Crude (R)-1.H3PO4
g
h
i
(R)-1
a Reagents and conditions: (a) (1) aq. NaOH, (2) Boc2O, 1,4ꢀdioxane; (b) (1) aq. NaOH, EtOH, (2) aq. HCl, CHCl3, 96% in
two steps; (c) 10·HCl, EDCꢁHCl, HOBt, Et3N, THF, CHCl3, SiO2 column chromatography, quantitative yield; (d) (1) 4M
HCl/EtOAc, (2) aq. NaOH, CHCl3, 77%; (e) 15, K2CO3, CH3CN, CHCl3, SiO2 column chromatography, 92%; (f) 40%
MeNH2/MeOH, CHCl3, SiO2 column chromatography, 84%; (g) 7, CH3CN, CHCl3, SiO2 column chromatography then
Al2O3 column chromatography; (h) aq. H3PO4, EtOH; (i) recrystallization with EtOH/water, 60% in three steps. Overall
yield: 34%.
Some issues of Medicinal Chemistry Route B (Scheme 2) for a largeꢀscale synthesis are described
below. First, a protection of (R)ꢀ4 and a deprotection of (R)ꢀ13 were inefficient ways for a largeꢀscale
synthesis. Furthermore, since a waste product is resulted by deprotection, the use of phthalimide alkyl
bromide 15 was an unattractive manner to install an amino unit. Second, since Boc protected amino acid
(R)ꢀ12 was a fragile compound, it was easily decomposed during storage even at 5 °C in a labꢀscale.
Third, a diacylated impurity was produced in the final benzoylation step and was difficult to purge into
mother liquor. Finally, the use of chlorinated solvents for extraction step and purifying step in SiO2
column chromatography should be avoided from the point of view of environment as well. Needless to
say, it was not a practical way that needed many steps to prepare (R)-1·H3PO4 (nine steps), the overall
yield was low (34%). Against this background, we experienced strong demand for the development of a
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scalable production process for (R)-1 with a higher overall yield that does not require column
chromatography purification and unstable intermediates. To that end, we started to look for an
alternative synthetic route of (R)-1 and developed a new synthetic route for a firstꢀscale up synthesis. In
following sections, we describe details of our achievements.
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Results and Discussion
Our synthetic strategy
A new synthetic strategy was designed to improve some issues of Medicinal Chemistry routes (Scheme
3). Our new strategy is to introduce (R)ꢀ1ꢀ{2ꢀ[(4ꢀfluorobenzoyl)amino]ethyl}piperidineꢀ3ꢀcarboxylate
(R)-8 as an intermediate via Nꢀalkylation of (R)-4 with bromide 18b without protection and
deprotection.
Scheme 3. New Synthetic Strategy for (R)-1 a
Amidation
10
(R)-1
(R)-9
Hydrolysis
N
-Alkylation
(R)-4
18
(R)-8
Benzoylation
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Synthesis of Bromo compound (18)
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First, to prepare the benzoylated bromoethylamine compound 18, some typical reaction conditions
were investigated. As results, the use of organic base for example pyridine or Et3N in organic solvent
such as THF or CH3CN gave poor conversion due to a poor solubility of 2ꢀbromoethylamine
hydrobromide in the organic solvents. Therefore, we attempted this reaction under SchottenꢀBaumann
like conditions (Table 1). 2 As results, EtOAc gave the best HPLC yield of 18 (entry 1) in comparison
with other solvents such as toluene, CH3CN, MTBE and MIBK (entries 2 ꢀ 5).
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Table 1. Synthesis of Bromo compound 18a
entry
solvents
HPLC yield of 18 b
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5
98%
93%
95%
91%
88%
EtOAc
Toluene
CH3CN
MTBE
MIBK
–
water
water
–
–
water
–
water
–
water
a K2CO3:7 × 2mol., 2 :× 1.0 mol., reaction temp.:0 °C,
b:determined by HPLC method A (see Experimental Section).
Synthesis of (R)-8 (N-alkylation of (R)-4 with 18)
Next, Nꢀalkylation reaction of (R)-4 with 18 was investigated in various basic conditions, for example
potassium carbonate, sodium hydroxide, sodium hydride, Et3N, DBU and so on. As results, in many
cases, 18 was converted to another compound smoothly, however, the desired alkylated compound (R)-
8 was not detected by LCꢀMS analysis. After NMR and Mass spectrum studies of this major product,
we assigned that the structure of major product was 2ꢀ(4ꢀfluorophenyl)ꢀ4,5ꢀdihydrooxazole 19 as shown
Scheme 4. 3
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Scheme 4. Main product of Nꢀalkylation of (R)-4 with 18 in a basic condition
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(R)-4
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base
(R)-8
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?
18
base
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4,5-dihydrooxazole
At that time, we predicted that the ring opening Nꢀalkylation of the 4,5ꢀdihydrooxazole 19 in acidic
condition would be able to work (Scheme 5).4 It means that after protonation of nitrogen, αꢀposition of
oxygen was attacked by nucleophile, in this case (R)-4.
Scheme 5. Plausible mechanism of ringꢀopening Nꢀalkylation in acidic conditions
19
(R)-8
Under this hypothesis, we conducted reactions of 4,5ꢀdihydrooxazole 19 and (R)-4 under various
acidic conditions. These results are shown in Table 2.
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Table 2. Acid and solvent screening for ringꢀopening Nꢀalkylationa
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entry
conditions
19 : 8b
62 : 38
<1 : >99
88 : 12
<1 : >99
12 : 88
11 : 89
64 : 36
(R)-8 : (S)-8c
4M HClꢀEtOAc (1.05 eq.) / toluene, 1 day
pꢀTsOH monohydrate (1.05 eq) / toluene, 1 day
AcOH (1.05 eq.) / toluene, 2 days
ꢀ
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99.3 : 0.7
ꢀ
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PPTS (1.05 eq.) / toluene, 2 days
96.5 : 3.5
MeSO3H (1.05 eq.) / toluene, 2 days
TFA (1.05 eq.) / toluene, 2 days
99.3 : 0.7
97.3 : 2.7
pꢀTsOH monohydrate (1.05 eq.) / EtOAc, 2 days
pꢀTsOH monohydrate (1.05 eq.) / CH3CN, 2 days
ꢀ
ꢀ
69 : 31
a
b
Temperature: reflux of solvent, (R)-4: 1.2 equiv (>99.5% ee), determined by HPLC method A (see
experimental Section), c (S)-8 : enamtiomer of (R)-8, determined by HPLC method B (see experimental Section).
A starting material (R)-4 was purchased from supplier as a free base and its enantiopurity was more
than 99.5% ee. As shown in Table 2, pꢀTsOH monohydrate gave the best yield in this reaction in
comparison with any other acids (entry 2). Another sulfonic acid such as MeSO3H gave low yields of
product due to the poor solubility of the methane sulfonic acid salt of (R)-4 in toluene (entry 5). In
contrast, the use of weak acid such as PPTS gave a fullꢀconversion, however racemization occurred
during the reaction and more than 3% of enantiomer (S)-8 was observed by HPLC analysis (entry 4).
Furthermore, AcOH did not give a fullꢀconversion. As a solvent, toluene was the best because of the
low-polarity and high boiling point, the reaction proceeded smoothly at approximately 110 °C. Other
solvents such as EtOAc or CH3CN gave a long reaction time due to a lower boiling point. Additionally
we assigned two major impurities 20 and 21 in this reaction (Figure 2). Since the percentage of these
impurities in a reaction mixture was less than 1% each other on HPLC, there was no critical issue to
meet the desired purity of the final product.
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Di-alkylated impurity
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Hydrolysis impurity
20
Figure 2. Structures of major impurities during Nꢀalkylation
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As described above, we developed a ringꢀopening Nꢀalkylation condition. However, it was an
imperfect way to prevent the racemization during the reaction to meet the desired quality (> 99.0% ee).
To overcome the issue, understanding the cause of the racemization mechanism was necessary.
Eventually, we considered that the main reason of racemization would be caused by the selfꢀbasicity of
(R)-4 under heating conditions. Therefore, to minimize racemization and accelerate the desired reaction
rate, optimization of reaction conditions study was conducted as shown in Table 3.
Table 3. Optimization for Nꢀalkylation a
pꢀTsOH
monohydrate
(equiv)
19 : 8b
(R)-8 : (S)-8c
time
(R)-4
entry
(equiv)
1.5
(h)
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8
0.5
0.5 : 99.5
3 : 97
67.8 : 32.2
99.3 : 0.7
94.6 : 5.4
90.8 : 9.2
89.0 : 11.0
99.0 : 1.0
99.3 : 0.7
99.5 : 0.5
1.1
0.7
0.5
0.3
1.2
1.1
1.05
1.2
1.2
1.2
1.2
1.2
1.1
1.2
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32
1.0 : 99
0.4 : 99.6
ND : 100
10 : 90
9 : 91
4 : 96
a reaction temperature: 110 °C, b determined by HPLC method A (see experimental Section), c determined by
HPLC method B (see experimental Section).
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To understand the reason of racemization, excess amount of (R)-4 was used for this reaction (entry 1).
As we expected, more than thirty percent of (S)-8 enantiomer was observed on HPLC analysis. It means
that the racemization might be happened by the selfꢀbasicity of (R)-4. To prevent the racemization, 1.1
equiv. of pꢀTsOH was charged in the reaction as a counter acid (entry 2). As a result, the racemization
was improved at the level of <1%, however reaction rate was very slow, 3% of starting material 19 was
remained even after 36ꢀhours reaction. From these results, we considered that catalytic amount of acid
might be better to accelerate the reaction rate. It was considered that the amine might be blocked by
large amount of acids and the desired reaction would be prevented. Based on the hypothesis, catalytic
amount of acid was used for this alkylation reaction as shown entries 3ꢀ5. As expected, the desired
reaction was accelerated, in contrast, an unacceptable level of enantiomer (S)-8 was observed. From
these results, we could understand that the balance between amount of acid and reaction rate is clearly
important for the scaleꢀup synthesis. To solve these issues, we optimized the reaction conditions (entries
6ꢀ8). From these findings, we selected the condition of entry 8 as an optimal reaction condition for the
first scaleꢀup synthesis. Finally, we developed the practical procedure to afford desired (R)-8. 4,5ꢀ
dihydrooxazole 19 was used in alkylation step without isolation and purification because it had enough
quality after the phase separation (see experimental section).
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End game
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Scheme 6. Completion of synthesis
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. HCl
10.HCl
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hydrolysis
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R
( )-1
R
( )-9
R
( )-8
The procedure of hydrolysis of ethyl ester (R)-8 was modified of original medicinal chemistry method.
After the hydrolysis of ethyl ester with NaOH in aqueous ethanol and neutralized with aqueous HCl,
several amide coupling agents with commercially available 6,7ꢀdimethoxyꢀ1,2,3,4ꢀ
tetrahydroisoquinoline monohydrochloride (10ꢁHCl) were screened for amidation. Some results of the
screening are described in Table 4. From these findings, EDCꢁHCl/HOBt in DMF with Et3N gave the
best reaction profile (entry 1). In contrast, CDI gave the poor conversion and racemization, unacceptable
levels of enantiomer (S)-1 was observed in the reaction mixture (entry 2). Furthermore, DPPA in the
presence of Et3N 5 gave clean reaction profile, however an enantiomer (S)-1 was detected approximately
5% on HPLC analysis (entry 3). Finally, SOCl2 (acid chloride method) gave a poor reaction profile by
HPLC analysis (entry 4). In this case, the mild and waterꢀresistant coupling reagent EDCꢁHCl gave the
best yield without racemization.
Table 4. Amide formation a
entry
conditions
(R)-9:(R)-1 b
(S)-1 (%) c
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2
3
EDCꢁHCl (1.2 eq.), HOBt (0.3 equiv), Et3N (1.0 equiv) / DMF
CDI (1.2 equiv), Et3N (2.7 equiv) / DMF
0.06 : 96.1
31.1 :67.8
0.1 : 95.8
0.4
7
DPPA (1.2 equiv), Et3N (2.7 equiv) / DMF
5
SOCl2 (1.0 equiv) / then added to Et3N (2.0 equiv),
4
multi peaks d
and 10: 1 equiv/CH3CN
reaction was carried out at 0 °C and then 25 ºC, 10: 1 equiv. b The ratio was determined by HPLC method C. (S)-1:
enamtiomer of (R)-1, determined by HPLC method D, d multi peaks were observed on HPLC analysis.
a
c
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After the amidation, a free base (R)-1 was converted to the monophosphate with 85 wt% phosphoric
acid in aqueous ethanol (Scheme 7). The detailed salt formation procedure is described in the
experimental section. Through the synthetic process for drug substance (R)-1·H3PO4, just final product
was isolated as crystals. Any other intermediates were not isolated and not purified in this process. It
means that we could well optimize the reaction conditions in every step for the preparation of the free
base (R)-1 and the final crystallization step has a robust purification method that could control the
quality of final product. Though 0.4% of enantiomer (S)-1 was detected in the free base (R)-1, it was
well purged into the mother liquor and only 0.02% of (S)-1 was observed in the drug substance (HPLC
method D). In conclusion, we could prepare the high quality drug substance (R)-1·H3PO4 in a first sale
up synthesis (Scheme 8).
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Scheme 7. Salt formation
. H3PO4
85%H3PO4
EtOH -H2O
(R)-1.H3PO4
(R)-1
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Scheme 8. Summary of the new synthetic routea
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.HBr
2
NH2
O
NH
Br
Cl
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)-4
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H
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N
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)-9
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NH.
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10.HCl
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e
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F
YM758 monophosphate
R
(
)-1
.
R
(
)-1 H3PO4
a Reagents and conditions: (a) K2CO3, EtOAcꢀwater, 5ºC then 50ºC; (b) pꢀTsOHꢁH2O, toluene, reflux; (c) aq.NaOH, EtOH,
water, < 25 °C; (d) EDCꢁHCl, HOBt, Et3N, DMF, ꢀ4 to 4 °C; (e) aq. H3PO4, EtOHꢀwater, 49% yield from 7.
Conclusions
In summary, a new practical synthetic route has been developed for largeꢀscale synthesis of the (R)-
1·H3PO4 drug substance. Undesirable features of the Medicinal chemistry synthetic routes were
conveniently avoided by employing a ringꢀopening Nꢀalkylation of 4,5ꢀdifydrooxazole 19 with (R)ꢀethyl
nipecotate (R)-4. In addition, an Nꢀalkylation reaction between 4,5ꢀdifydrooxazoles and amines under
acidic condition should be quite important methodology and suitable for largeꢀscale synthesis. The
original Medicinal Chemistry synthesis A and B were significantly shortened from nine synthetic steps
to five and the overall yield was also considerably improved from 16% or 34% to 49%. Finally, the use
of chlorinated solvents was eliminated, and no chromatographic purification was required for any of the
stages. In a first scaleꢀup synthesis campaign, we prepared the 36.5 kg of (R)-1·H3PO4 under GMP
conditions.
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Experimental Section
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GENERAL.
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Starting materials, reagents and solvents were obtained from commercial suppliers and used without
further purification. 1H and 13C NMR spectra were recorded in the specified deuterated solvent.
Chemical shifts of 1H NMR spectra are reported in parts per million (ppm) on the δ scale from an
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internal standard of residual solvent (CHCl3 7.26 ppm; DMSOꢀd6 2.50 ppm) or TMS. Data are reported
as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet
and br = broad), coupling constant (Hz) and integration. Chemical shifts of protonꢀdecoupled 13C NMR
spectra are reported in ppm from the central peak of CDCl3 (77.0 ppm), DMSOꢀd6 (39.5 ppm) on the δ
scale. IR spectra was performed KBr disk method (JP16). HPLC was performed using HITACHI Dꢀ
2500 or Dꢀ7500 system. HPLC Methods were described below.
HPLC Methods.
Method A.
YMCꢀPack ODSꢀA, 5ꢂm, 4.6 mm × 150 mm column, elution 0.01M K2HPO4 (adjust pH 7.0 by aq.
H3PO4)/CH3CN = 6/4 ,over 60 min., 1.0mL/min., at 25 °C, with UV detection at 254 nm.
7: 23 min., 18: 5.5 min., 19: 6.2 min., (R)-8: 7.3 min., pꢀTsOH: 1.5 min., toluene: 20 min., (R)-9： 1.6
min.
Method B.
DAICEL CHIRALCEL ODꢀH, 5 ꢂm, 4.6 mm × 250 mm column, elution nꢀhexane/EtOH / Et2NH =
90/10/0.1, over 60 min., 0.5 mL/min., at 25 °C, with UV detection at 254 nm.
(R)-8: 11.3 min., (S)-8: 12.6 min.
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Method C.
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YMCꢀPack ODSꢀA, 5 ꢂm, 4.6 mm × 150 mm column, elution 0.1 M potassium hexafluorophosphate
(adjust pH 2.0 by aq. H3PO4)/CH3CN = 6/4 ,over 60 min., 1.0mL/min., at 25 °C, with UV detection at
254 nm.
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DMF： 1.7 min., HOBt： 1.9 min., 10: 2.7 min., (R)ꢀ9: 3.3 min., (R)-1: 9 min., toluene:20 min.
Method D.
DAICEL CHIRALPAK ADꢀRH, 5 ꢂm, 4.6 mm × 150 mm column,
elution 20 mM Na2HPO4 ꢀNaH2PO4 (pH7.0)/MeOH = 1 / 50, over 30 min., 1.0 mL/min., at 40 °C, with
UV detection at 254 nm.
(R)-1: 6.6 min., (S)-1: 3.8 min.
N-(2-bromoethyl)-4-fluorobenzamide (18)
To a solution comprising water (110 L) and potassium carbonate (36.8 kg, 266.3 mol) was added 2ꢀ
bromoethylamine monohydrobromide 2 (27.3 kg, 133.2 mol) below –5 °C. To the reaction mixture was
added EtOAc (100 L) followed by 4ꢀfluorobenzoyl chloride 7 (21.1 kg, 133.1 mol) at 5 °C or lower
temperature. The reaction mixture was agitated for 1 h; HPLC analysis subsequently indicated that <
1% of 7 remained (HPLC method A), and afforded 18 having a purity of 85.2% (HPLC method A). The
reaction mixture was used next step without quenching. Analytical pure 18 was obtained by
concentration in Labs.
1H NMR (400 MHz, DMSOꢀd6): δ 8.78 (1H, br), 8.05 – 8.10 (1H, m), 7.90 – 7.95 (1H, m), 7.45 – 7.51
13
(1H, m), 7.29 – 7.34 (1H, m), 4.84 (1H, t, J = 9.7 Hz), 4.13 (1H, t, J = 9.7 Hz), 3.48ꢀ3.68 (2H, m), C
NMR (100 MHz, DMSOꢀd6): δ 165.2, 163.9 (d, JCF = 248.3 Hz), 129.9, 129.8, 116.8 (d, JCF = 22.4 Hz),
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115.3, 115.1, 41.3, 31.9, ESIꢀMS m/z: 246.1 (M++1), IR (KBr) /cmꢀ1: 3305, 3097, 2972, 2900, 1640,
1506, 599.
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The reaction mixture of 18 was heated at 45 to 52 °C and agitated for 4 h; HPLC analysis subsequently
indicated that < 1% of 18 remained (HPLC method A). To the reaction mixture was added toluene (40
L). After the phase separation at 35 °C, the organic layer was washed with water (80 L) afforded 19
having purity 98% (HPLC method A) as a solution of toluene–EtOAc. The solution was used next step.
Analytical pure 19 was obtained by concentration in Labs.
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1H NMR (400 MHz, DMSOꢀd6): δ 7.89 – 7.95 (2H, m), 7.28 – 7.34 (2H, m), 4.41 (2H, t, J = 9.4 Hz),
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3.96 (2H, t, J = 9.4 Hz), C NMR (100 MHz, DMSOꢀd6): δ 163.8 (d, JCF = 249.0 Hz), 162.0, 130.2,
130.1, 124.1 (d, JCF = 3.0 Hz), 115.7, 115.5, 67.5, 54.4, FABꢀMS m/z: 166 (M++1), IR (KBr) /cmꢀ1:
3059, 2983, 2912, 1652, 1510, 1353, 1066, Anal. calcd for C9H8FNO: C,65.45; H,4.88; N,8.48; F,11.50,
Found: C,65.27; H,4.79; N,8.33; F,11.29.
(R)-1-{2-[(4- fluorobenzoyl)amino]ethyl}piperidine-3-carboxylate ((R)ꢀ8)
To the tolueneꢀEtOAc solution of 19 were added toluene (440 L), ethyl (R)ꢀpiperidineꢀ3ꢀcarboxylate
(R)-4 (25.1 kg, 159.7 mol) and pꢀtoluenesulfonic acid monohydrate (26.6 kg, 139.8 mol), and the
mixture was heated and the solvent was distilled at atmospheric pressure to evaporate 260 L and
agitated under refluxing for approximately 32 h; HPLC analysis subsequently indicated that < 5% of 19
remained (HPLC method A). After the reaction mixture was cooled, EtOAc (260 L) and 4% (w/v)
aqueous solution of NaHCO3 (180 L) were added. After phase separation at 30 ºC, the organic layer was
washed with a 4% (w / v) aqueous solution of NaHCO3 (180 L) twice. The organic layer was
concentrated in vacuo to give (R)ꢀ8 having a purity of 86.7% (HPLC method A). This product was used
next step without purification and isolation.
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Analytical pure was obtained by crystallization as a following procedure. The solution of 61 g of crude
product (R)ꢀ8 in EtOAc (100 mL) was concentrated. To the residue were added diisopropyl ether (120
mL) and nꢀheptane (120 mL). The batch was heated and the resulted solution was cooled to – 4 ºC. The
resulting slurry was aged for 12 h and then filtered, washed with a mixed solution of diisopropyl ether
with nꢀheptane, and dried in vacuo at 40 °C to afford 53.31g of (R)ꢀ8 (87.4% overall yield from 4ꢀ
fluorobenzoyl chloride 7). Enantiomer (S)ꢀ8 was observed 0.6% by Chiral HPLC analysis (method B).
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1H NMR (400 MHz, DMSOꢀd6): δ 8.35 – 8.40 (1H, m), 7.85 – 7.95 (2H, m), 7.25 – 7.33 (2H, m), 4.05
(2H, q, J = 7.1 Hz), 3.35 (2H, dd, J = 13.3 Hz, 6.7 Hz), 2.85ꢀ2.90 (1H, m), 2.65ꢀ2.70 (1H, m), 2.45 –
2.51 (3H, m), 2.20 – 2.26 (1H, m), 2.05 – 2.10 (1H, m), 1.75 – 1.80 (1H, m), 1.60 – 1.65 (1H, m), 1.35 –
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1.50 (2H, m), 1.16 (3H, t, J = 7.1 Hz), C NMR (100 MHz, DMSOꢀd6): δ 173.3, 165.0, 162.5, 131.0,
130.9, 129.7 (d, JCF = 9.0 Hz), 115.2, 115.0, 59.7, 57.0, 55.0, 53.2, 41.0, 36.9, 26.4, 23.9, 14.0, FABꢀMS
m/z: 323 (M++1), IR (KBr) /cmꢀ1: 3344, 3060, 2952, 2813, 1733, 1683, 1548, 1503, 1291, 1228.
(R)-1-{2-[(4-fluorobenzoyl)amino]ethyl}piperidine-3- carboxylic acid ((R)ꢀ9)
To a solution of (R)ꢀ8 in EtOH (260 L) was added water (64 L). After cooling, an aqueous of NaOH
(8.0 kg of NaOH, 200 mol/ 90 L of water) was added to the batch and agitated at < 25 °C for 2 h; HPLC
analysis subsequently indicated that < 1% of (R)ꢀ8 remained (HPLC method A). Then the batch was
added conc. hydrochloric acid (38 wt%) and pH was adjusted to pH 3.06. This solution was
concentrated in vacuo. And the resulting residue was added toluene (190 L) and the mixture was
concentrated in vacuo. To the residue was added toluene (190 L) followed by concentrating in vacuo.
To the residue was added toluene (190 L) followed by concentrating in vacuo to give (R)ꢀ9 having a
purity of 90.4% (HPLC method A). Analytical pure (R)ꢀ9 was obtained by concentration in Labs.
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1H NMR (400 MHz, DMSOꢀd6, VT 90 °C): δ 8.74 (1H, br), 7.95 – 8.03 (2H, m), 7.20ꢀ7.27 (2H, m),
3.68 (2H, q, J = 5.9 Hz), 3.50 – 3.60 (1H, m), 3.41 – 3.49 (1H, m), 3.25 (1H, t, J = 6.0 Hz), 2.85 – 3.05
(4H, m), 1.79 – 2.05 (3H, m), 1.46 – 1.60 (1H, m), 13C NMR (100 MHz, DMSOꢀd6, VT 90 °C): δ 172.1,
165.2, 163.6 (d, JCF = 247.8 Hz), 130.2, 129.5 (d, JCF = 6.6 Hz), 114.8 (d, JCF = 22.1 Hz), 114.4, 114.1,
55.5, 54.9, 52.2, 51.3, 33.7, 24.4, 20.9, FABꢀMS m/z: 295 (M++1), IR (KBr) /cmꢀ1: 3330, 3070, 2958,
2582, 1726, 1649, 1543, 1506.
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(-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-
fluorobenzamide ((R)ꢀ1)
To a solution of (R)ꢀ9 in DMF (200 L), 6,7ꢀdimethoxyꢀ1,2,3,4ꢀtetrahydroisoquinoline
monohydrochloride 10·HCl (23.0 kg, 100.1 mol) was added. After cooling to 5 °C, triethylamine (10.1
kg, 99.8 mol) was added at <10 °C followed by the addition of HOBt (4.0 kg, 29.6 mol) and EDCꢁHCl
(23.0 kg, 120.0 mol). The batch was agitated at –4 to 4 °C for one night (14 h); HPLC analysis
subsequently indicated that < 2% of 10 remained (HPLC method C). To the batch were added water (64
L), EtOAc (380 L), and a 8%(w/v) aqueous solution of NaOH (105 L). After the phase separation,
aqueous layer was extracted with EtOAc (190 L). The collected organic layer was washed with a
8%(w/v) aqueous solution of NaOH (130 L) two times and water (57 L). The resulting organic layer
was washed with water (170 L) and the batch was concentrated in vacuo to afford (R)ꢀ1 having a purity
of 79% (HPLC method C). The resulting batch was added EtOH (140 L) and the resulting solution was
used next step without purification. Analytical pure (R)ꢀ1 was obtained by concentration in Labs.
1H NMR (500 MHz, CDCl3): δ 7.77 – 7.88 (2H, m), 7.11 (2H, t, J = 8.7 Hz), 6.95 (1H, br), 6.55 – 6.65
(2H, m), 4.62 (1H, br), 4.59 (1H, br), 3.85 (3H, s), 3.84 (3H, s), 3.75ꢀ3.82 (1H, m), 3.70 (1H, t, J = 5.8
Hz), 3.45ꢀ3.63 (2H, m), 2.85ꢀ2.95 (1H, m), 2.81 (1H, t, J = 5.8 Hz), 2.75 (1H, t, J = 5.8 Hz), 2.55ꢀ2.65
(2H, m) , 2.32ꢀ2.40 (1H, m), 2,18ꢀ2.25 (2H, m), 2.08ꢀ2.15 (1H, m), 1.75ꢀ1.87 (2H, m), 1.54ꢀ1.68 (2H,
m), 13C NMR (125 MHz, CDCl3): δ 2 rotamers (172.9, 172.7), 166.4, 164.7 (d, JCF = 253Hz), 2 carbons
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(148.1, 148.0, 147.7), 130.9, 129.4, 129.3, 2 carbons (127.0, 125.6, 125.3, 124.3), 115.6, 115.4, 2
rotamers (111.8, 111.3), 2 rotamers (109.5, 108.9), 56.9, 2 carbons (56.0), 2 rotamers (55.9, 55.7), 53.6,
2 rotamers (47.1 ,44.1), 2 rotamers (43.3, 40.0), 2 rotamers (39.8, 39.5), 36.7, 2 rotamers (29.4, 27.9), 2
rotamers (27.6, 27.4), 24.9, HRMS (FABꢀMS [M+H]+ , m/z), calcd for C26H32FN3O4 470.2455, found
470.2459, IR (KBr) /cmꢀ1: 3366, 2939, 1640, 1518, 1503, 1226, 1160.
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(-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-
carbonyl)piperidino]ethyl}-4-
fluorobenzamide monophosphate (YM758 monophosphate, (R)-1·H3PO4)
To the ethanolic solution of (R)-1 was added EtOH (330 L). Then to the batch was added 85 wt%
phosphoric acid (11.5 kg, 99.7 mol) and water (52 L) followed by heating. The resulting solution was
filtered via a 1 µm filter, into another vessel. The filtrate was heated with stirring to 65 – 75 °C and
cooled. The solution was added 30 g of (R)-1·H3PO4 as seed crystals at 50 – 60 °C followed by cooling.
And the resulting slurry was aged for 12 h at 0 – 5 ºC, filtered, washed with EtOH, dried in vacuo at 60
°C to afford 36.51 kg of (R)-1·H3PO4 having a purity of 98.9% (HPLC method C). Optical isomer (S)-1
was observed 0.02% by Chiral HPLC analysis (HPLC method D). Overall yield was 49% from 4ꢀ
fluorobenzoyl chloride 7.
1H NMR (500 MHz, DMSOꢀd6): δ 8.70 (1H, br), 7.88 – 8.00 (2H, m), 7.27 (2H, t, J = 8.3 Hz), 6.86,
6.77 (1H, s in combination), 6.72 (1H, s), 4.63 (1H, ABq, J=16.0Hz)*, 4.50 (1H, ABq, J=16.8Hz) *,
3.71 (6H, s), 3.60 – 3.70 (2H, m), 3.40 – 3.57 (2H, m), 3.04 – 3.20 (3H, m), 2.60 – 2.82 (4H, m), 2.25 –
2.48 (2H, m), 1.60 – 1.85 (3H, m), 1.30 – 1.50 (1H, m), 13C NMR (125 MHz, DMSOꢀd6,): δ 2 rotamers
(171.2, 171.1), 165.1, 163.8 (d, JCF = 248 Hz), 147.4, 147.3, 130.6, 129.9, 129.8, 2 rotamers (126.2,
125.9), 125.0, 115.2, 115.0, 2 rotamers (111.9, 111.8), 2 rotamers (110.0, 109.9), 56.4, 55.5, 55.4, 2
rotamers (54.6, 54.4), 2 rotamers (52.6 ,52.5), 2 rotamers (46.1, 43.3), 2 rotamers (42.6, 39.4), 2
rotamers (37.3, 37.0), 35.5, 2 rotamers (28.6, 27.2), 2 rotamers (26.3, 26.1), 22.8, IR (KBr) /cmꢀ1: 3316,
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3295, 3075, 2951, 2843, 2350, 1648, 1521, 1502, 1225, 1021, 1114, 962, 863, HRMS (FABꢀMS
[M+H]+ , m/z), calcd for C26H32 FN3O4 (free base) 470.2455, found 470.2440, [α]D20: ꢀ20.8° (solvent:
water, 0.25 g/25 mL, 100 mm cell), Mp:206.7 °C (by DSC), Anal. calcd for C26H32N3O4FꢁH3PO4: C,
55.02; H, 6.22; N, 7.40; F, 3.35; P, 5.46, Found: C, 55.01; H, 6.15; N, 7.43; F, 3.29; P, 5.44.
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*It is made two protons in total integration.
AUTHOR INFORMATION
Corresponding Author
shinya.yoshida@astellas.com
NOTES
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful to Dr. Toshihiro Watanabe and Dr. Akio Kakefuda for helpful discussions about
medicinal synthetic methods for (R)-1. And we thank Mr. Sou Yamaguchi for analytical study.
REFERENCES
(1)
(a) Kakefuda, A.; Watanabe, T.; Taguchi, Y;Masuda, N; Tanaka, A; Yanagisawa, I Chem. Pharm. Bull.
2003, 51, 390.
(b) Kakefuda, A.; Watanabe, T.; Takahashi, T.; Sakamoto, S.; Tsukamoto, S. Synth. Commun. 2001, 31,
401.
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(c) Watanabe, T.; Kakefuda, A.; Okazaki, T.; Masuda, N. Jpn. Kokai Tokkyo Koho, 2000, JP
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(d) Kakefuda, A.; Watanabe, T.; Kubota, H.; Masuda, N. Jpn. Kokai Tokkyo Koho, 1999, JP11189593.
(e) Watanabe, T.; Kakefuda, A.; Masuda, N. WO9813364.
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(f) Watanabe, T.; Kakefuda, A.; Masuda, N. WO00/75133.
(g) Yoshida, S.; Watanebe, T.; Marumo K,; Kakefuda, A. WO2004058710.
(h) Yoshida, S.; Watanebe, T.; Marumo K.; Yamguchi, S. WO2004089933.
(2)
(a) Herz, W.; Tocker, S. J. Am. Chem. Soc. 1955, 77, 3554.
(b) Fisher, L. E.; Caroon, J. M.; Jahangir; Stabler, S. R. ; Lundberg, S.; Muchowski, J. M. J. Org. Chem.
1993, 58, 3643.
(c) Cortés, E. C.; Romero, E. C.; Ramírez, F. G. J. Heterocycl. Chem. 1994, 31, 1425.
(3)
(a) Kashima, C.; Arao, H. Synthesis 1989, 11, 873.
(b) Inoue, M.; Yamashita, M. Jpn. Kokai Tokkyo Koho, 2008088128.
(4)
(a) Arai, I.; Yamamoto, T.; Naora, H. WO98/45264.
(b) Coutts, L. D.; Meckler, H.; Popp, K.F. Synth. Commun. 2004, 34 (15), 2697.
(c) Gabriel, S.; Elfeldt, P. Chem. Ber. 1891, 24, 3213.
(d) Goldberg, A.; Kelly, W. J. Chem. Soc. 1948, 1919. (e) Fry, E. M. J. Org. Chem. 1950, 15, 802.
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(a) Shioiri, T.; Yamada, S. Chem. Pharm. Bull. 1974, 22, 849.
(b) Shioiri, T.; Yamada, S. Org. Synth. 1984, 62, 187.
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Synopsis of TOC
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O
NH
NH2
Br
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O
+
O
H+
O
O
+
+
N
H
N
N
O
H
F
F
F
Cl
F
O
O
N
N
H
O
F
. H3PO4
O
O
O
N
N
N
H
O
F
YM758 monophosphate
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