Process Development of an Efficient and Cost-Effective Telescoping Route to a Key Synthetic Precursor for the Preparation of a Renin Inhibitor

Article abstract of DOI:10.1021/acs.oprd.8b00414

Here, we describe an efficient and cost-effective telescoping route to the pharmacologically active form (2), which is a key manufacturing precursor to a novel renin inhibitor for the treatment of hypertension. An efficient synthetic route to the target compound was established with 64% overall yield over nine steps with three isolations.

Full text of DOI:10.1021/acs.oprd.8b00414

Article
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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Process Development of an Efficient and Cost-Effective Telescoping
Route to a Key Synthetic Precursor for the Preparation of a Renin
Inhibitor
Akihito Nonoyama,*,† Yoshio Nakai,‡ Shoukou Lee,‡ Satoshi Suzuki,§ Takeya Ando,†
Nobuhisa Fukuda,‡ Hiroaki Tanaka,† and Kazuhiko Takahashi¶
†Process Chemistry Research and Development Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka
3-chome, Konohana-ku, Osaka 554-0022, Japan
‡Chemistry Research Unit Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka 3-chome,
Konohana-ku, Osaka 554-0022, Japan
§Formulation Research and Development Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 13-1, Kyobashi 1-chome, Chuo-ku,
Tokyo 104-8356, Japan
¶Technology Research and Development Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka
564-0053, Japan
S
* Supporting Information
ABSTRACT: Here, we describe an efficient and cost-effective telescoping route to the pharmacologically active form (2),
which is a key manufacturing precursor to a novel renin inhibitor for the treatment of hypertension. An efficient synthetic route
to the target compound was established with 64% overall yield over nine steps with three isolations.
KEYWORDS: renin inhibitor, prodrug, telescoping, C−N coupling, N/O chemoselectivity, oxazinone
condition led to a tetra-substituted benzoic acid derivative 6.
Condensation with 14 gave 7 in 87% yield. Reduction of the
nitro group and removal of the benzyl group on 7 was carried
out simultaneously by hydrogenation in excellent yield.
Subsequent amidation of 8 with 15 and intramolecular
cyclization in the presence of cesium carbonate provided 10,
which required purification by silica-gel chromatography
(overall yield over two steps, 47%). N-Alkylation of 10 with
16, followed by deprotection of the Cbz group by hydro-
genation and N-acylation with propionyl chloride, afforded 13
(overall yield over two steps, 66%). Finally, acid-mediated
removal of the Boc group and purification by silica-gel
chromatography delivered 2 in quantitative yield. The overall
yield of the process to 2 was 10%. A 50 g synthesis of API was
accomplished for the toxicity test through this synthetic route.
First- and Second-Generation Process Routes. The
discovery route described above is not particularly attractive
for large-scale manufacturing because of: (i) the requirement
of several rounds of silica-gel column chromatography; (ii) a
potentially explosive nitration reaction; (iii) a long linear route.
We focused on these issues and planned the convergent route
shown in Scheme 3.
INTRODUCTION
■
Plasma renin activity1 (PRA) plays an important role in the
pathogenesis of hypertension (elevated blood pressure). In
addition, high PRA is known to be a risk factor for myocardial
infarction (heart attack) in patients suffering from hyper-
tension.
During our screening study, the oxazinone derivative (2)
was identified as a potential renin inhibitor. However, a parallel
artificial membrane permeability assay showed that improve-
ment in membrane permeability was required. Therefore, the
medicinal team designed 1 as an optimized prodrug of 2, which
possessed immediate absorption and suitable physicochemical
properties. 1 was transformed to its active metabolite 2
immediately in the body and showed powerful inhibition of
PRA activity in human plasma (half-maximal inhibitory
concentration (IC50) = 0.73 nM).
The retrosynthetic pathway of 1 (Scheme 1) shows that 1
was derived from 2 and the prodrug2 part (double esters;3 3).
Establishment of an efficient synthetic route for the structurally
complex 2 will be essential for future commercial production.
Here, we describe the history of synthetic development and
present an efficient, cost-effective telescoping route to 2.
We considered that 2 would be condensed between the
corresponding carboxylic acid 29 and a secondary amine. We
planned to introduce the carboxylic acid unit of 29 by Friedel−
Crafts acylation of 26, which would be prepared from the
RESULTS AND DISCUSSION
■
Discovery Route. The discovery route4 to 2 used by the
medicinal chemistry team is described in Scheme 2. Tetra-
substituted benzene 4 was prepared from a commercially
available derivative of benzoic acid over two steps in 41% yield
in which only low regioselectivity was observed in nitration.5
Benzylation of 4 and subsequent hydrolysis of 5 under a basic
Special Issue: Japanese Society for Process Chemistry
Received: November 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.8b00414
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Scheme 1. Retrosynthetic Pathway of 1
Scheme 2. Discovery Route of 2
Scheme 3. Retrosynthesis Analyses of 2
Scheme 4. Route Selection to 20
B
DOI: 10.1021/acs.oprd.8b00414
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Scheme 5. O-Alkylation and Byproduct via Smiles Rearrangement
Table 1. Examination of C−N Coupling
a
a
a
a
entry
Pd cat.
mol %
base
solvent
temp [°C]
24 [%]
26 [%]
25 [%]
27 [%]
b
1
2
3
4
5
6
7
8
Pd(PtBu3)2
Pd(PtBu3)2
Pd(PtBu3)2
Pd(PtBu3)2
Pd(PtBu3)2
Pd(PtBu3)2
Pd(PPh3)4
10
10
10
2.5
2.5
2.5
2.5
2.5
K2CO3
K3PO4
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
NMP
toluene
DMF
DMF
DMF
150
150
150
150
150
110
150
150
140
Nd
Nd
Nd
Nd
3
79
10
Nd
Nd
88 (69)
78
60
98 (70)
19
18
1
52
92 (75)
3
9
22
40
0.6
Nd
Nd
Nd
Nd
4.8
Nd
Nd
0.4
50
Nd
44
32
Nd
b
c
NHC-Pd 1
Pd(PtBu3)2
d
b
9
5
a
b
c
d
HPLC area%. Isolated yield. NHC-Pd 1: allychloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-idinylidene]palladium(II). Manufacturing
condition for first-process generation route.
intramolecular C−N coupling of 24. The latter would be
synthesized via O-alkylation between the corresponding phenol
23 and diamide 20, which would be prepared from the mono-
Boc ethylenediamine 17.
provide 20 in high yield with >99% purity through
crystallization.
With a synthesis of 20 secured, the final assembly was
pursued. O-Alkylation of 23 was conducted with 20 by
addition of tBuOK in THF (Scheme 5). The aniline
compound (25) was formed as a byproduct that increased
over time via Smiles rearrangement.8 The aniline 25 was
removed completely by crystallization to give the crystalline 24
in 79% isolated yield in 98% HPLC.
First, we evaluated the order of N-acylation for the synthesis
of 20 from 17 (Scheme 4). The mono-Boc-protected 17 was
prepared from the reaction between Boc anhydride and an
excess amount of ethylenediamine6 in 74% yield. In the first
instance, N-acylation of 17 with propionyl chloride and
subsequent deprotection of the Boc group were done in one
pot to yield noncrystalline 19 in good yield.7 Without further
purification, secondary N-acylation of 19 with acyl chloride
derived from 15 presented 20 in 38% isolated yield. The
hydroscopic property of 19 led to degradation of the acid
anhydride form of 15 to give the low yield. In the alternate
sequence, amide 21 resulting from 17 and 15 could be isolated
by crystallization from CHCl3/n-heptane as white crystals in
94% yield with >98% high-performance liquid chromatography
(HPLC) purity. One-pot Boc deprotection followed by the
second N-acylation with propionyl chloride proceeded to
Formation of the benzoxazine core via intermolecular Pd-
catalyzed carbon−nitrogen coupling reaction9,10 was inves-
tigated (Table 1). The reaction proceeded with 10 mol %
11
Pd(PtBu3)2 and K2CO3 in DMF at 150 °C in 69% isolated
yield in 98% HPLC purity (entry 1). When using a stronger
base such as K3PO4 or Cs2CO3, larger amounts of 25 or 27 via
Smiles rearrangement were formed (entry 2, 3) as byproducts.
A smaller amount of catalyst also showed excellent reactivity
(entry 4). Employing this reaction in other solvents such as
NMP or toluene did not elicit better results (entry 5, 6). Using
other Pd catalysts such as Pd(PPh3)4 or Pd N-heterocyclic
carbene catalysts such as NHC-Pd 112 gave lower or moderate
C
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Scheme 6. Friedel−Crafts Acylation to 29 and Conversion to 2
yields (entry 7, 8). Consequently, Pd(PtBu3)2 and K2CO3 in
DMF appeared to be the suitable condition for the reaction.
Typically, this reaction consumed the starting material;
however, when a different lot of Pd(PtBu3)2 was used in a
kilogram-scale synthesis, the starting material was not
consumed and a larger amount of byproducts were observed.
This suggests that different lots of catalyst perform differently.
In order to prepare needed material, 5 mol % of Pd(PtBu3)2
was used for the kilogram-scale campaign, and the reaction
proceeded smoothly. Celite filtration, extraction with toluene/
MTBE, and solvent switching to AcOEt were carried out.
Crystallization from AcOEt/heptane delivered 6.4 kg of 26 in
75% yield with >99% HPLC purity as brown crystals.
Construction of the tetra-substituted benzene 29 was
achieved through a Friedel−Crafts reaction (Scheme 6). The
reaction required an excess amount of AlCl3, (COCl)2, and
quenching with 1 N HCl aq. to provide 29. During quenching,
a considerable exothermic reaction (243 kcal/mol measured by
super CRC) was observed. A slow addition of 1 N HCl over 3
h and a large amount of reaction solvent were therefore
required. However, this led to low productive efficiency in the
reaction (∼17 g of target compound per L). After completion
of quenching, 1-BuOH was added and the phases were allowed
to separate. Insufficient water washing led to formation of the
butyl ester of 29 in the crystallization step. Thus, the organic
layer was washed until the pH of the water layer was above 2.5.
Then, 6.8 kg of 29 was isolated by crystallization from 1-BuOH
in 92% yield with >99% HPLC purity as white crystals. Acyl
chloride formation was achieved by treating 29 with 1.9 equiv
of SOCl2 at 50 °C, followed by removal of excess SOCl2 and
gas under reduced pressure. Addition of a mixture of 14 and
N,N-dicyclohexylmethylamine (DCHMA) at 50 °C afforded
13. Importantly, the acid anhydride 30 (Figure 1) was
generated readily in the presence of even small amounts of
water. Thus, 14 and DCHMA were dried via a water−toluene
azeotrope before being used. Variations in the reaction time
and color (which required decoloration with active carbon) in
the acyl chlorination step were observed, but 8 kg of amide 13
was delivered in 74% isolated yield with >99% HPLC purity.
Finally, removal of the Boc group in 13 and desalting with
NaOH aq. gave 6 kg of 2 in 96% yield. The overall yield of the
entire process from ethylenediamine to 2 was 24%, and 5.9 kg
of API by this first-generation process route was delivered for
the preclinical and clinical test.
Further scale-up for the next campaign required minor
optimization in each step (second-generation process route in
Scheme 7). In the first-generation process route, generation of
the impurity 25 was the cause of the lower yield in the O-
alkylation step. We found that using tBuONa as a base and
toluene/1-BuOH = 3/1 (w/w) as a solvent could suppress
generation of this impurity. This optimized condition gave
target compound 24 in 88% yield and >98% HPLC purity. The
next stage of the synthesis was intermolecular carbon−nitrogen
coupling in 24. Through the previous campaign, variation of
the catalytic activity between lots of Pd(PtBu3)2 was observed.
Thus, in situ preparation of the catalyst was investigated, and it
was achieved with 2 mol % Pd(OAc)2 and 6 mol % PtBu313 in
xylene, which provided 26 in 96% yield and >99% HPLC
purity. Use of excess AlCl3 and (COCl)2 resulted in
considerable time for quenching, low production efficiency,
and generation of hazardous CO, but reduction of these
reagents or adaptation of another method was not found.
Friedel−Crafts acylation was conducted without optimization,
which resulted in 32 kg of 29 in 91% yield and >99% HPLC
purity. This campaign revealed that further scale-up would be
inadvisable because quenching with 1 N HCl led to
considerable safety concerns for further scale-up. Acyl
chlorination of 29 was accomplished with SOCl2 in a previous
manufacturing process, but variation in the reaction time and
brown coloration of the target compound were noted.
Through screening of acyl chlorination reagents, 1-chloro-
N,N-2-trimethyl-1-propenylamine (CTPA)14 was found to be
suitable for the reaction, and this reagent can be obtained in
bulk quantity at reasonable cost. Compared with SOCl2, acyl
chlorination with CTPA did not require removal of excess
reagents and/or decoloration with activated carbon. The
optimized procedure was scaled up to 1200 L, whereby 28 kg
of 13 was prepared in 86% yield and >99% HPLC purity as
white crystals. The final stage of the synthesis was scaled up
Figure 1. Structure of the acid anhydride 30.
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Scheme 7. Second-Generation Process Route of 2
Scheme 8. Third-Generation Process Route of 2
Scheme 9. Fate Analysis on O-Alkylated Byproduct 37
without optimization, which delivered 22 kg of 2. In this
campaign, the overall yield from ethylenediamine to 2 was
37%.
quantity from suppliers at reasonable cost. Hence, Friedel−
Crafts acylation could be avoided, and the synthetic route was
shortened.
Third-Generation Process Route. We achieved kilogram-
scale synthesis of 2 through the second-generation process
route. However, inherent issues in Friedel−Crafts acylation
and modest overall yield were important bottlenecks in terms
of a cost-effective, efficient commercial manufacturing route.
Thus, we attempted to find an alternate route for the synthesis
of 2. Intensive survey of materials revealed that the tetra-
substituted benzene derivative 30 could be obtained in bulk
The nitro compound 30 was reduced to the corresponding
amine 31 by hydrogenation in the presence of Pd/C in
quantitative yield (Scheme 8). After removal of Pd/C through
filtration, treatment of 31 with acyl chloride derived from 15
gave amide 32. The latter was extracted with AcOiPr, and the
solvent exchanged into DMF in preparation for the next step.
The solution was heated to 80 °C in the presence of potassium
carbonate to afford 33, which was isolated by crystallization
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from DMF/water and resulted in preparation of a three-step
telescoped approach in 76% overall yield. Treatment of 33
with 36 in the presence of cesium carbonate as a base in DMF
was converted to 34 contaminated with ca. 10% of the O-
alkylated compound 37 as a major byproduct.15 Then, 34 was
extracted with CHCl3 and reacted with 5 equivalents of
methanesulfonic acid to prompt deprotection of the Boc
group. Subsequent N-acylation with propionyl chloride in the
presence of triethylamine was carried out in one pot to
produce 35. After washing with water, CHCl3 was displaced to
1-BuOH, hydrolysis was carried out in two phases, and 29 was
isolated by crystallization from 1-BuOH. Although crystalline
29 had >98% purity, it contained 1.4% of 38 derived from 3716
(Scheme 9). This amount of 38 was too high to permit
isolation of acceptable API. Therefore, further purification of
29 by recrystallization was required, which reduced impurities
to an acceptable level (<0.3%). The four-step telescoped
synthesis and single recrystallization from 33 to 29 led to a
yield of 65%. Conversion to 2 through 13 was achieved by the
same manner as the second-generation process route. The
overall yield to 2 was improved to 41% over nine steps.
Fourth-Generation Process Route. The following three
issues still remained in the third generation synthesis: (i) there
are a high number of intermediates isolated, which causes
product loss and poor process efficiency; (ii) there is a high
formation of impurities, which causes poor yield; (iii) un-
desirable solvents such as CHCl3 and DMF needed to be
avoided considering the environmental, toxicological, and
quality concerns. We began to explore a more efficient
synthetic route by improving the third generation process
route. Analysis of 32 revealed that the N,O-bisacyl compound
39 (HPLC area%: 1.1%) was a major byproduct (Figure 2). By
crystallization from NMP/water with >99% purity. This
optimized processes increased the yield from 76% to 87%
over the initial three steps.
As mentioned above, contamination of 38 into 29 derived
from the O-alkylated compound 37 required recrystallizations
to gain 29 with satisfactory purity in the third-generation
process route. To ameliorate this situation, we scrutinized the
reaction conditions from 33 to 34 closely (Table 2). Less
expensive K3PO4 and less toxic DMA showed almost identical
reactivity and N/O selectivity compared with the original
procedure (entries 1 and 2). Heating to 70 °C increased
reactivity, although regioselectivity was decreased slightly
(entry 3). No reaction took place with K2HPO4 or Li3PO4
(entries 4 and 5). K2CO3 elicited lower reactivity and
selectivity (entry 6). Tertiary alkoxides such as tBuOK,
tBuONa, or tBuOLi presented higher selectivity, but a larger
amount of starting material remained unreacted (entries 7, 8,
and 9). Other solvents such as THF or acetonitrile did not give
satisfactory results (entries 10 and 11). Consequently, the less
expensive K3PO4 and less toxic DMA at 70 °C was chosen as
the best condition (entry 2) from the perspective of reactivity
and selectivity.
To improve purity, undissolved salt was removed through
filtration, and then, toluene (instead of CHCl3) was used for
extraction at 70 °C to afford 34 in toluene solution. Treatment
of 34 with methanesulfonic acid resulted in a Boc-deprotected
methanesulfonic acid salt 43, but the O-alkylated compound
37 was transformed to 33 (Scheme 10). The latter remained in
the organic layer of combined solvents (toluene/THF = 9/1)
efficiently, but additional extraction with toluene ensured that
the methanesulfonic acid salt 43 was extracted into the water
layer exclusively. An aqueous solution of sodium hydroxide was
added in the presence of propionic anhydride in two phases to
invoke neutralization and N-acylation consecutively. Subse-
quent hydrolysis of 35 gave 29 after crystallization from 1-
BuOH, which provided the compound in >99.5% purity
without further purification. The yield from 33 to 29 was
increased from 65% to 80% over four steps.
The main reason for isolation of 13 was to remove 44
(Figure 4), and therefore, it was thought that control of 44
would allow for one less isolation. To suppress this formation
of 44, initially, we attempted an inverse addition such that the
acid chloride 28 solution was added dropwise to a mixture of
amine 14 and DCHMA. This inverse addition could reduce
formation of dimer 44 from 4.2% to 0.5%, but the acid chloride
28 solution in toluene was supersaturated, and the precipitated
acyl chloride was clogged during transfer. However, it was
proposed that precipitation of the acid chloride 28 reduced its
concentration in the supernatant, which could lead to
suppression of dimer formation. This was explored by
modifying the temperature described in Table 3. Addition of
the amine 14 into acid chloride 28 without precipitation of 28
Figure 2. Structure of the bisacyl 39.
secondary addition of N-methyl moropholine (NMM) and
heating the reaction mixture to 45 °C in the step, the impurity
39 was reacted with the substrate 31 to give target compound
32.
In the next intramolecular O-alkylation, DMF-derived
byproduct 40 and intermolecular alkylation reaction-derived
byproducts 41 and 42 were identified (Figure 3). Hanging the
solvent from DMF to NMP and dilute conditions could
suppress formation of these byproducts, and 33 was isolated by
Figure 3. Structure of impurities in the intramolecular O-alkylation.
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Table 2. Optimization of the Reaction Condition for N-Alkylation
a
a
entry
base
solvent
temp [°C]
34/(34 + 33) [%]
34/37
1
2
3
4
5
6
7
8
Cs2CO3
K3PO4
K3PO4
K2HPO4
Li3PO4
K2CO3
tBuOK
tBuONa
tBuOLi
K3PO4
K3PO4
DMF
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
THF
50
50
70
70
70
70
70
70
70
70
70
96.8
92.2
98.9
NR
12.1/1
12.7/1
11.6/1
NR
NR
NR
60.5
92.3
81.1
74.4
28.8
82.4
10.9/1
17.4/1
15.7/1
19.5/1
11.8/1
14.5/1
9
10
11
CH3CN
a
Calculated on the basis of HPLC area%.
Scheme 10. Removal of the O-Alkylated Byproduct
of the fourth-generation process route was 64% over nine steps
(Scheme 11).
SUMMARY
■
We developed an efficient and cost-effective telescoping route
to 2, which is the key precursor for a novel renin inhibitor (1).
In the first steps, optimization of the reaction and workup
condition in each step through the physicochemical properties
of impurities and development of a telescoped process were
accomplished. For the following four steps and final two steps,
we developed telescoped processes to avoid the isolation of
intermediates. The overall yield to 2 approached 64% over
nine steps. The route comparison is shown in Table 4.
Compared with the discovery route, the number of steps and
isolations improved from 12 to 9 and 12 to 3, respectively, and
the overall yield increased from 10% to 64%.
Figure 4. Structure of dimer 44.
provided 4.2% of dimer 44 at 40 °C (entry 1). A lower
temperature enabled suppression of the amount of dimer 44
(entries 2 and 3) due to the precipitated acid chloride 28
(0.33% and 0.22%, respectively). Eventually, the equivalent of
amine 14 could be decreased to 1.05 equiv without extension
of the reaction time (entry 4).
Final acid-mediated deprotection of the Boc group in 13
gave 2 in excellent yield. For expediency, the chemistry
mentioned above was telescoped such that 13 was not isolated
but instead was converted directly to 2, which resulted in 92%
yield with >99% HPLC purity over two steps. The overall yield
EXPERIMENTAL SECTION
■
1
General. H and 13C NMR spectra were recorded on a
Bruker Ultrashield 400 Plus spectrometer at 400 and 100.6
MHz, respectively. Chemical shifts (δ) are given in parts per
million, and tetramethylsilane was used as the internal standard
for spectra obtained in DMSO-d6, Methanol-d4 and CDCl3.
High-resolution mass spectra were measured on a Thermo
Fisher Scientific LTQ Orbitrap Discovery. HPLC was
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Table 3. Temperature Examination during Amidation
a
a
a
entry
temp [°C]
acyl chloride precipitate
time [h]
29 [%]
13 [%]
44 [%]
1
2
3
40
30
20
25
−
+
+
+
3
3
4
4
0.09
0.18
0.41
0.50
90.32
96.29
96.22
95.59
4.21
0.33
0.22
0.42
b
4
a
b
HPLC area%. 1.05 eq. of 14 was used.
Scheme 11. Fourth-Generation Process Route
Second Generation Process Route (Scheme 7).
Table 4. Comparison of Synthetic Route
discovery
route
second
generation
third
fourth
route
generation generation
number of reaction
12
12
10
9
10
5
9
3
a
steps
number of
isolations
8
a
a
overall yield (%)
37
41
64
c
c
c
manufacturing
100
31
19
b
tert-Butyl (2-(1-bromocyclobutane-1-carboxamido)-
ethyl)carbamate (21). To a solution of 15 (28.0 kg, 156.4
mol, 1.0 equiv) dissolved in CHCl3 (269.0 kg) and DMF (2.8
kg) was added thionyl chloride (22.3 kg, 187.4 mol, 1.2 equiv)
dropwise over 1 h at 50 °C under a nitrogen atmosphere. The
reaction was monitored by HPLC until completion (10 h) at
the same temperature to give a solution of carboxylic acid
chloride.
To a solution of 17 (27.6 kg, 172.3 mol, 1.1 equiv) dissolved
in CHCl3 (89.1 kg) and N-methyl morpholine (NMM) (34.8
kg, 344.0 mol, 2.2 equiv) was added the solution of carboxylic
acid chloride over 2 h at −5 °C, and the reaction was
monitored by HPLC until completion (1 h). To the mixture
was added water (280.0 kg) and CHCl3 (168.0 kg), followed
by warming to 25 °C and stirring for 15 min. The separated
cost
a
b
From SM to 2. Manufacturing cost is calculated on the basis of
c
variable cost and fixed for the synthetic route from SM to 1. Relative
cost when the 2nd generation process route is set to 100.
performed on a Shimazu LC-20A; Sumipax ODS C-217
column (4.6 mm i.d. × 150 mm, 5 μm); eluent: (a) 0.1% TFA
aq. and (b) MeOH; flow rate = 1.0 mL/min; temperature: 30
°C; UV detection at 220 nm; gradient: (b/a) 50/50 (0 min)−
90/10 (0−30 min)−90/10 (30−35 min)−10/90 (35.01
min)−10/90 (35.1−45 min). The purity listed is determined
by area %. All reactions were carried out under nitrogen unless
otherwise mentioned. Reagents and solvents were used as
obtained from commercial suppliers without further purifica-
tion.
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organic phase was washed with water (280.0 kg) with stirring
for 15 min, and the organic phase obtained was concentrated
by evaporation to give a suspension (164.0 kg). To this
suspension was added CHCl3 (61.2 kg), followed by heating to
50 °C to give a solution, and n-heptane (87.9 kg) was added
dropwise over 40 min. The mixture was cooled to 43 °C; then,
a precipitate was observed. After heating to 50 °C, n-heptane
(87.9 kg) was added, and the mixture was cooled to 0 °C over
4 h; the precipitate obtained was filtered, washed with a
mixture of CHCl3 and n-heptane, and dried to give 21 (47.1
kg, 146.7 mol, 93.8% yield) as a white solid.
1 - ( 2 - C h l o r o - 5 - m e t h y l p h e n o x y ) - N - ( 2 -
propionamidoethyl)cyclobutane-1-carboxamide (24).
To a solution of tBuONa (14.2 kg, 147.3 mol, 1.2 equiv) in
toluene (523.0 kg) and 1-BuOH (187.0 kg) was added 26
(17.5 kg, 122.7 mol, 1.0 equiv) with stirring under a nitrogen
atmosphere. The mixture was stirred at 20 °C for 1 h. To the
mixture was added 20 (34.0 kg, 122.7 mol, 1.0 equiv) over 40
min and stirred at the same temperature. The mixture was
heated to 45 °C, and the reaction was monitored by HPLC
until completion (2.5 h). After cooling to 25 °C, water (250.0
kg) was added with stirring for 15 min. The separated organic
phase was washed with water (84.0 kg) and concentrated to
give a suspension (245.0 kg). The suspension was heated to 45
°C and stirred at the same temperature for 30 min and then
cooled to 0 °C over 2 h. n-Heptane (84.0 kg) was added
dropwise to the cooled suspension, and the resulting
suspension was stirred at the same temperature for 2.5 h.
The precipitate was filtered, washed with a mixture of toluene
and n-heptane twice, and dried to give 24 (36.4 kg, 107.6 mol,
87.6% yield) as a white solid.
White solid; 1H NMR (400 MHz, CDCl3) δ 6.94 (brs, 1H),
5.00 (brs, 1H), 3.37−3.31 (m, 2H), 3.30−3.23 (m, 2H), 2.97−
2.88 (m, 2H), 2.57−2.48 (m, 2H), 2.28−2.16 (m, 1H), 1.95−
1.84 (m, 1H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
171.9, 156.8, 79.7, 59.5, 41.5, 39.7, 37.8 (2C), 28.3 (3C), 16.9;
HRMS (ESI) calcd. for C12H21BrN2O3 m/z 321.0808 [M +
H]+, found 321.0811.
White solid; 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.0
Hz, 1H), 6.71 (d, J = 8.0, 1.2 Hz, 1H), 6.59 (t, J = 5.6 Hz, 1H),
6.29 (d, J = 1.2 Hz, 1H), 5.81 (t, J = 5.6 Hz, 1H), 3.47−3.31
(m, 2H), 3. 25−3.19 (m, 2H), 2.73−2.65 (m, 2H), 2.41−2.32
(m, 2H), 2.21 (s, 3H), 2.03 (q, J = 8.0 Hz, 2H), 2.00−1.84 (m,
2H), 1.03 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
174.2, 173.8, 150.1, 137.8, 130.2, 123.3, 120.7, 116.5, 81.9,
40.0, 39.1, 31.7 (2C), 29.4, 21.3, 13.7, 9.7; HRMS (ESI) calcd.
for C17H23ClN2O3 m/z 339.1470 [M + H]+, found 339.1471.
1-Bromo-N-(2-propionamidoethyl)cyclobutane-1-
carboxamide (20). To a solution of 21 (47.1 kg, 146.6 mol,
1.0 equiv) in CHCl3 (462.0 kg) was added methanesulfonic
acid (21.1 kg, 220.0 mol, 1.5 equiv) over 15 min at 50 °C. The
reaction was monitored by HPLC until completion (2 h), and
the mixture was cooled to 25 °C. After addition of
triethylamine (40.1 kg, 395.9 mol, 2.7 equiv) over 1 h at the
same temperature, propionyl chloride (14.9 kg, 161.3 mol, 1.1
equiv) was added dropwise over 1 h at the same temperature.
The reaction was monitored by HPLC until completion (1 h
10 min); then, water (236.0 kg) was added. A separated
aqueous phase was extracted with CHCl3 (405.0 kg) with
stirring for 15 min. Combined organic phases were
concentrated by evaporation to give a suspension in CHCl3
(150.0 kg). To this suspension was added CHCl3 (134.0 kg),
followed by heating to 50 °C to give a solution, and n-heptane
(91.4 kg) was added dropwise over 30 min. After cooling to 43
°C over 15 min, a precipitate was observed. The suspension
was heated to 50 °C, and n-heptane (91.4 kg) was added over
20 min at the same temperature. After cooling to 0 °C over 3 h
30 min, the precipitate obtained was filtered, washed with a
mixture of CHCl3 and n-heptane, and dried to give 20 (34.0
kg, 122.8 mol, 83.8% yield) as a white solid.
N-(2-(7-Methyl-3-oxospiro[benzo[b][1,4]oxazine-2,1′-
cyclobutan]-4(3H)-yl)ethyl)propionamide (26). To a
suspension of Pd(OAc)2 (482.0 g, 2.15 mol, 0.02 equiv),
potassium carbonate (297.0 kg, 2.15 mol, 0.02 equiv), and
xylene (313.0 kg) was added PtBu3 50% toluene solution (2.5
kg, 6.5 mol, 0.06 equiv) at 25 °C under nitrogen atmosphere.
The mixture was heated to 80 °C and stirred for 1 h at the
same temperature. After cooling to 40 °C, potassium carbonate
(29.4 kg, 212.7 mol, 2.0 equiv) and 24 (36.4 kg, 107.4 mol, 1.0
equiv) were added, and the mixture was heated to 130 °C. The
reaction was monitored by HPLC until completion (3 h), and
the reaction mixture was cooled to 45 °C. THF (72.8 kg) and
water (182.0 kg) were added, and the separated organic phase
was washed with water (72.8 kg) and concentrated to give a
suspension (178.0 kg). The suspension was heated to 75 °C to
give a clear solution. After cooling to 0 °C over 8 h, the
precipitate was filtered, washed with a mixture of toluene and
White solid; 1H NMR (400 MHz, CDCl3) δ 6.94 (brs, 1H),
6.17 (brs, 1H), 3.43−3.38 (m, 4H), 2.97−2.88 (m, 2H), 2.60−
2.51 (m, 2H), 2.20 (q, J = 7.2 Hz, 2H), 2.30−2.19 (m, 1H),
1.96−1.85 (m, 1H), 1.12 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 175.0, 172.5, 59.4, 40.8, 39.6, 37.8 (2C), 29.6,
16.9, 9.8; HRMS (ESI) calcd. for C10H17BrN2O2 m/z
277.0546 [M + H]+, found 277.0548.
I
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n-heptane twice, and dried to give 26 (31.2 kg, 103.3 mol,
96.1% yield) as a white solid.
White solid; 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J = 8.8
Hz, 1H), 6.83−6.78 (m, 2H), 6.12 (brs, 1H), 4.04 (t, J = 6.4
Hz, 2H), 3.51 (dd, J = 6.8, 6.4 Hz, 2H), 2.58−2.49 (m, 2H),
2.31−2.21 (m, 2H), 2.26 (s, 3H), 2.16 (q, J = 8.0 Hz, 2H),
2.01−1.82 (m, 2H), 1.10 (t, J = 8.0 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 174.4, 168.4, 143.2, 134.1, 126.4, 123.5, 118.5,
114.4, 79.4, 40.8, 38.3, 31.3 (2C), 29.5, 20.7, 13.2, 9.6; HRMS
(ESI) calcd. for C17H22N2O3 m/z 303.1703 [M + H]+, found
303.1704.
tert-Butyl (R)-3-(N-Isopropyl-7-methyl-3-oxo-4-(2-
propionamidoethyl)-3,4-dihydrospiro[benzo[b][1,4]-
oxazine-2,1′-cyclobutane]-6-carboxamido)piperidine-
1-carboxylate (13). To a solution of 29 (20.0 kg, 57.7 mol,
1.0 equiv) in toluene (160.0 kg) was added 1-chloro-N,N-2-
trimethyl-1-propenylamine (CTPA) (9.3 kg, 69.3 mol, 1.2
equiv) at 60 °C, and the mixture was stirred. The reaction was
monitored by HPLC until completion (2 h). After cooling to
40 °C, to the mixture was added a mixture of 14 (16.8 kg, 69.3
mol, 1.2 equiv) and N,N-dicyclohexylmethylamine (DCHMA)
(13.5 kg, 69.3 mol, 1.2 equiv) in toluene (77.1 kg) over 40
min, and the reaction mixture was stirred at the same
temperature. The reaction was monitored by HPLC until
completion (2 h). After cooling to 20 °C, 3.65% AcOH aq.
(171.2 kg) was added. The separated organic phase was
washed with 3.65% AcOH aq. (171.2 kg) and water (25.6 kg)
and then concentrated to give a suspension (97.0 kg). Toluene
(17.0 kg) was added, and the suspension was heated to 60 °C
to give a clear solution. n-Heptane (81.4 kg) was added, and a
tiny amount of 13 was added. After cooling to 0 °C over 4 h,
the precipitate was filtered, washed with a mixture of toluene
and n-heptane, and dried to give 13 (28.2 kg, 49.4 mol, 85.5%
yield) as a white solid.
7-Methyl-3-oxo-4-(4-oxohexyl)-3,4-dihydrospiro-
[benzo[b][1,4]oxazine-2,1′-cyclobutane]-6-carboxylic
Acid (29). To a suspension of AlCl3 (68.8 kg, 516.3 mol, 5.0
equiv) and oxalyl chloride (39.3 kg, 309.8 mol, 3.0 equiv) in
CH2Cl2 (306.9 kg) was added 26 (31.2 kg, 103.3 mol, 1.0
equiv) in CH2Cl2 (306.9 kg) at −5 °C over 2.5 h. The reaction
mixture was stirred for 2.5 h at the same temperature, allowed
to warm to 25 °C, and stirred for 1 h at the same temperature.
The reaction mixture was cooled to −5 °C. 1 N HCl aq. (466.8
kg) was added over 4 h with maintenance of the internal
temperature below 25 °C, and the mixture was stirred for 10 h
at the same temperature.
White solid; [α]2D2 = −33.1 (c 1.02, CHCl3); 1H NMR (400
MHz, CDCl3, major rotamer) δ 6.83 (s, 1H), 6.81 (s, 1H),
6.12−5.92 (m, 1H), 4.23−3.81 (m, 5H), 3.80−3.63 (m, 1H),
3.62−3.34 (m, 2H), 3.11−2.94 (m, 1H), 2.93−2.79 (m, 1H),
2.79−2.58 (m, 1H), 2.48−2.36 (m, 1H), 2.37−2.17 (m, 5H),
2.15 (q, J = 7.2 Hz, 2H), 2.03−1.65 (m, 4H), 1.62−1.47 (m,
1H), 1.45 (s, 9H), 1.41−1.27 (m, 1H), 1.14−1.20 (m, 3H),
1.10 (d, J = 8.0 Hz, 3H), 1.08 (d, J = 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3, major rotamer) δ 174.2, 170.3, 167.9,
154.7, 143.0, 132.5, 129.8, 129.4, 126.7, 119.6, 111.0, 79.3,
51.8, 51.2, 43.6, 41.0, 37.6 (2C), 31.7, 30.8, 29.2, 28.3 (3C),
27.3, 25.5, 20.7, 20.3, 18.2, 13.0, 9.5; HRMS (ESI) calcd. for
C31H46N4O6 m/z 571.3490 [M + H]+, found 571.3492.
1-BuOH (624.0 kg) was added, and the separated organic
phase was washed with water (446.0 kg). The separated
organic phase was washed with water (112.0 kg) and
concentrated to give a suspension (129.0 kg). 1-BuOH (14.2
kg) was added, and the suspension was heated to 110 °C to
give a clear solution. After cooling to 0 °C over 18 h, the
precipitate was filtered, washed with a mixture of 1-BuOH and
n-heptane twice, and dried to give 29 (32.5 kg, 93.7 mol, 90.7%
yield) as a white solid.
(R)-N-Isopropyl-7-methyl-3-oxo-N-(piperidin-3-yl)-4-
(2-propionamidoethyl)-3,4-dihydrospiro[benzo[b][1,4]-
oxazine-2,1′-cyclobutane]-6-carboxamide (2). To a
suspension of 13 (27.9 kg, 48.9 mol, 1.0 equiv) in toluene
(55.9 kg) and water (28.0 kg) was added 35% HCl aq. (40.3
kg, 391.9 mol, 8.0 equiv) at 10 °C. The reaction was
monitored by HPLC until completion (3 h), and the separated
organic phase was extracted with water (10.3 kg). Toluene
(336.0 kg) was added to the collected aqueous phase, and 24%
NaOH aq. (65.1 kg, 391.9 mol, 8.0 equiv) was added at 10 °C.
After heating to 75 °C, the organic phase was separated and
1
White solid; H NMR (400 MHz, DMSO-d6) δ 12.76 (s,
1H), 7.96 (t, J = 6.0 Hz, 1H), 7.64 (s, 1H), 6.97 (s, 1H), 3.93
(t, J = 6.0 Hz, 2H), 3.29 (q, J = 6.0 Hz, 2H), 2.57−2.49 (m,
2H), 2.46 (s, 3H), 2.27−2.17 (m, 2H), 1.99 (q, J = 7.6 Hz,
2H), 1.95−1.85 (m, 1H), 1.83−1.70 (m, 1H), 0.92 (t, J = 7.6
Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ 173.4, 168.0,
166.2, 145.5, 135.8, 126.9, 124.9, 120.3, 117.2, 79.1, 41.3, 36.2,
31.0 (2C), 28.6, 20.9, 12.8, 9.8; HRMS (ESI) calcd. for
C18H22N2O5 m/z 347.1601 [M + H]+, found 347.1600.
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washed with water (28.9 kg). The organic phase obtained was
concentrated, and the suspension was heated to 80 °C,
followed by addition of n-heptane (76.9 kg) over 1 h. After
addition of a tiny amount of 2, the mixture was cooled to 15
°C over 5 h. The precipitate was collected, washed with a
mixture of toluene and n-heptane, and dried to give 2 (22.4 kg,
47.6 mmol, 97.3% yield) as a white solid.
mixture was heated to 80 °C under nitrogen atmosphere. The
reaction was monitored by HPLC until completion (3 h); the
mixture was cooled to 50 °C. Water (169.73 g) was added over
1 h, and the mixture was stirred for 1 h. The resulting
suspension was cooled to 25 °C over 2 h, and the precipitate
was filtered. The filter cake was washed with water (46.29 g)
twice and dried to give 33 as a white solid (10.27 g, 39.3 mmol,
87.2% yield in 3 steps based on 15).
White solid; [α]2D2 = −4.63 (c 1.08, CHCl3); 1H NMR (400
MHz, CDCl3, major rotamer) δ 6.82 (s, 1H), 6.78 (s, 1H),
6.11−5.97 (m, 1H), 4.10−4.02 (m, 1H), 3.98−3.92 (m, 1H),
3.89−3.75 (m, 1H), 3.75−3.65 (m, 1H), 3.52−3.40 (m, 2H),
3.18−3.06 (m, 1H), 2.98−2.90 (m, 1H), 2.89−2.59 (m, 3H),
2.44−2.24 (m, 3H), 2.20 (s, 3H), 2.14 (q, J = 7.6 Hz, 2H),
2.01−1.64 (m, 5H), 1.60−1.48 (m, 3H), 1.32−1.20 (m, 1H),
1.10 (d, J = 7.6 Hz, 3H), 1.07 (d, J = 8.0 Hz, 3H); 13C NMR
(100 MHz, CD3OD, measured at 328 K, major rotamer) δ
177.1, 172.6, 169.0, 144.8, 133.8, 130.9, 128.5, 120.7, 112.7,
80.8, 54.4, 53.0, 46.4, 42.1, 37.7 (2C), 32.4, 31.8, 30.1, 28.9,
27.8, 20.9 (2C), 18.5, 13.9, 10.2; HRMS (ESI) calcd. for
C26H38N4O4 m/z 471.2966 [M + H]+, found 471.2964.
Fourth Generation Process Route (Scheme 11).
1
White solid; H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H),
7.47 (s, 1H), 6.86 (s, 1H), 3.87 (s, 3H), 2.73−2.62 (m, 2H),
2.55 (s, 3H), 2.35 (q, J = 9.2 Hz, 2H), 2.08−1.91 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 168.5, 167.0, 145.5, 137.4, 124.4,
123.4, 120.3, 118.0, 80.1, 51.8, 31.8 (2C), 21.6, 13.3; HRMS
(ESI) calcd. for C14H15NO4 m/z 262.1074 [M + H]+, found
262.1075.
7-Methyl-3-oxo-4-(4-oxohexyl)-3,4-dihydrospiro-
[benzo[b][1,4]oxazine-2,1′-cyclobutane]-6-carboxylic
acid (29). To a solution of 33 (10.00 g, 38.3 mmol) in DMA
(50.00 g) was added tripotassium phosphate (12.19 g, 57.4
mmol) and 36 (9.44 g, 42.1 mmol) under nitrogen
atmosphere. The mixture was heated to 70 °C and stirred at
the same temperature. The reaction was monitored by HPLC
until completion (6 h); then, the mixture was cooled to 30 °C.
The suspension was filtered to remove an undissolved
inorganic substance, and the filter cake was washed with
DMA (15.00 g). The filtrate was heated to 70 °C; toluene
(200.00 g) and water (70.00 g) were added, and separated
organic phase was washed with water (70.00 g). The toluene
solution was used for the following reaction without isolation.
To the 34 solution in toluene was added methanesulfonic
acid (18.39 g, 191.4 mmol). The reaction was monitored by
HPLC until completion (4 h). After addition of water (60.00
g), the separated aqueous phase was washed with toluene
(50.00 g), and water (10.00 g) was added to give a 34 solution
in water. The solution was used for the following reaction
without isolation.
1-Bromo-N-(2-propionamidoethyl)cyclobutane-1-car-
boxamide (33). To a solution of 30 (10.0 g, 47.4 mmol) in
THF (80.0 g) was added 10% Pd/C (50% wet, 0.5 g), and the
mixture was stirred at 30 °C under hydrogen atmosphere. The
reaction was monitored by HPLC until completion (6 h);
then, the suspension was filtered to give 31 solution in THF.
The solution was used for the following reaction without
isolation.
To a solution of 15 (8.07 g, 45.1 mmol) in AcOiPr (48.4 g)
was added DMF (0.81 g), and the mixture was heated to 60
°C. Thionyl chloride (6.17 g, 51.9 mmol) was added at the
same temperature, and the reaction was monitored by HPLC
until completion (1 h). The mixture was cooled to 20 °C and
added to a solution of 31 and NMM (10.95 g, 108.2 mmol)
over 2 h at 2 °C. Secondary NMM (10.95 g, 108.2 mmol) was
added, and the reaction mixture was heated to 45 °C to
transform 39 to 32. After addition of water (40.37 g),
separated organic phase was washed with 7.2% HCl aq. (40.37
g) and water (40.37 g) twice. The solvent was displaced with
NMP (123.46 g) to give a 32 solution in NMP. The solution
was used for the following reaction without isolation.
To the 43 solution in water was added 1-BuOH (120.00 g),
and the mixture was cooled to 5 °C. Propionic anhydride (7.47
g, 57.4 mmol) was added at the same temperature; then, 24%
NaOH aq. (41.46 g, 248.8 mmol) was added at the same
temperature. The reaction was monitored by HPLC until
completion (1 h). The aqueous phase was separated to give a
35 solution in 1-BuOH. The solution was used for the
following reaction without isolation.
To the solution of 32 in NMP was added potassium
carbonate (6.86 g, 49.6 mmol) and water (6.17 g), and the
K
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To the 35 solution in 1-BuOH was added 1-BuOH (60.0 g),
and the mixture was heated to 55 °C.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.8b00414.
■
S
24% NaOH aq. (19.14 g, 114.8 mmol) was added, and the
reaction mixture was stirred at the same temperature. The
reaction was monitored by HPLC until completion (3 h). After
cooling to 20 °C, 35% HCl aq. (15.97 g, 153.1 mmol) was
added, and the separated organic phase was washed with water
(50.00 g) repeatedly until pH of the aqueous phase was 2.5 or
more. The obtained organic phase was concentrated to give
the suspension (47.70 g). After heating to 110 °C, the mixture
was cooled to 0 °C over 6 h. The precipitate was collected and
washed with 1-BuOH twice and dried to give 29 (10.61 g, 30.6
mmol, 80.0% yield in 4 steps) as a white solid.
NMR spectra for compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: akihito-nonoyama@ds-pharma.co.jp.
ORCID
Akihito Nonoyama: 0000-0001-5411-3076
Notes
The authors declare no competing financial interest.
■
REFERENCES
■
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(R)-N-Isopropyl-7-methyl-3-oxo-N-(piperidin-3-yl)-4-
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oxazine-2,1′-cyclobutane]-6-carboxamide (2). To a
solution of 29 (24.02 g, 69.4 mmol, 1.0 equiv) in toluene
(192.20 g) was added CTPA (11.12 g, 83.2 mmol, 1.2 equiv),
and the mixture was stirred at 60 °C. The reaction was
monitored by HPLC until completion (2 h). After cooling to
25 °C, the mixture of 14 (17.65 g, 72.8 mmol, 1.05 equiv) and
DCHMA (16.26 g, 83.2 mmol, 1.2 equiv) in toluene (114.71
g) was added over 1 h at the same temperature. The reaction
was monitored by HPLC until completion (4 h). After
addition of 3.65% AcOH aq. (205.39 g), the separated organic
phase was washed with 3.65% AcOH aq. (205.39 g) and water
(30.75 g) and then concentrated to give a toluene solution
(369.42 g). The solution was used for the following reaction
without isolation.
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(44.61 g) at 10 °C. The reaction was monitored by HPLC
until completion (2 h). After addition of water (43.37 g), the
separated organic phase was extracted with water (43.37 g).
Toluene (451.20 g) was added to the collected aqueous phase,
and 24% NaOH aq. (71.37 g) was added at 10 °C. After
heating to 75 °C, the organic phase was separated and washed
with water (38.78 g). The organic phase obtained was
concentrated, and the suspension was heated to 80 °C,
followed by addition of n-heptane (103.37 g) over 1 h. After
addition of a tiny amount of 2, the mixture was cooled to 15
°C over 5 h. The precipitate was collected, washed with a
mixture of toluene and n-heptane, and dried to give 2 (29.88 g,
63.5 mmol, 91.6% yield in 2 steps) as a white solid.
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