Synthesis of a cis 2,5-disubstituted morpholine by de-epimerization: Application to the multigram scale synthesis of a mineralocorticoid antagonist

Article abstract of DOI:10.1021/op400101p

A convergent route to multigram quantities of a mineralocorticoid antagonist 3 is described. Starting from (R)-phenylglycinol, the synthesis of cis 2,5-morpholine 2 is accomplished utilizing a de-epimerization to install the second stereogenic center. The multigram synthesis of 3 was completed through a sequence of an S_NAr reaction, Dakin oxidation, alkylation, and cyclization to provide a crystalline solid.

Full text of DOI:10.1021/op400101p

Article
pubs.acs.org/OPRD
Synthesis of a cis 2,5-Disubstituted Morpholine by De-epimerization:
Application to the Multigram Scale Synthesis of a Mineralocorticoid
Antagonist
Matthew Sammons, Sandra M. Jennings, Michael Herr, Catherine A. Hulford, Liuqing Wei,
James F. Hallissey, E. Jason Kiser, Stephen W. Wright, and David W. Piotrowski*
Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: A convergent route to multigram quantities of a mineralocorticoid antagonist 3 is described. Starting from (R)-
phenylglycinol, the synthesis of cis 2,5-morpholine 2 is accomplished utilizing a de-epimerization to install the second stereogenic
center. The multigram synthesis of 3 was completed through a sequence of an SNAr reaction, Dakin oxidation, alkylation, and
cyclization to provide a crystalline solid.
INTRODUCTION
DISCUSSION AND RESULTS
■
■
Abnormal activation of the mineralocorticoid receptor (MR) by
elevated levels of the endogenous agonist aldosterone leads to a
salt imbalance causing hypertension, detrimental effects to the
cardiovascular system, and chronic kidney diseases. The
marketed agent, Eplerenone, is a steroidal MR antagonist
used for lowering blood pressure in hypertensive patients but is
contraindicated in diabetic patients (Figure 1).1 Previous
Our favored retrosynthetic disconnection for 3 was to break the
C−N bond between the morpholine 2 and the pyridooxazinone
moiety. This option afforded the opportunity to independently
develop a route to 2, an intermediate that contains two
stereogenic centers, allowed for the preparation of medicinal
chemistry analogs using other amines, and could lead to a
convergent route suitable for scale-up. With this disconnection
in mind, an efficient route to 2 was sought.
Several routes to access 2,5-disubstituted morpholinones
have been reported, but most of these suffer from the lack of
stereocontrol, the use of protecting groups, or the paucity of
disclosed characterization data to allow for assessment of the
stereochemistry of the products.3,4 The use of a commercially
available chiral pool starting material, namely (R)-2-phenyl-
glycinol 4, would allow for installation of the defined C5
stereocenter and could be further manipulated into 2. In this
case, the use of racemic 2-chloropropanoyl chloride for the
acylation and cyclization could provide a 50:50 mixture of
diastereomers that could be separated or, as inferred from a few
reports, lead to some level of stereocontrol (Scheme 1).3
Acylation of 4 with racemic 2-chloropropanoyl chloride
provided 5 in 97% yield. The diastereomeric mixture 5 was
treated with NaH in THF to affect the SN2 cyclization to the
morpholinones 6 and 7. Analysis of the crude reaction mixture
by 1H NMR revealed one predominant diastereomer,
suggesting that considerable diastereomeric enrichment had
occurred. After a difficult separation of 6 and 7 by
chromatography, 1H NMR studies indicated that morpholinone
7 with the desired cis stereochemistry, was the major product.
Specifically, the strong NOESY cross peak observed between
H2″ and H6 and the weak correlation between H2′ and H6
support the axial orientation of H2″ and H6. The observation of
a cross peak between aromatic H12/H8 and CH3 supports the
cis orientation of the phenyl and methyl groups. Finally,
Figure 1. Steroidal and nonsteroidal MR antagonists.
reports from the Pfizer laboratories disclosed two different
compounds, 1 and PF-03882845, from the pyrazoline chemo-
type that were investigated as part of a program to discover
nonsteroidal MR antagonists for treatment of hypertension and
diabetic nephropathy.2 An alternative morpholine-based series
that was a potent MR antagonist with different physicochemical
properties was also discovered. Herein, we describe the
enantiospecific synthesis of cis 2,5-disubstituted morpholine 2
and its use in a scalable synthesis of 3, for which multigram
quantities were required to support preclinical toxicology
studies.
Received: April 18, 2013
© XXXX American Chemical Society
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Scheme 1. Initial synthetic route to 2
Scheme 2. Cyclization reaction of the discrete diastereomers 8 and 9
Scheme 3. Improved synthetic route to 2
reduction of 7 with LAH provided 2 in a quantitative yield.
This route was adequate for initial supplies of 2, only requiring
chromatography to separate 6 and 7, and allowing for gram
scale-up under these conditions.
stoichiometric KOt-Bu (potassium tert-butoxide, 0.5 equiv)
resulted in mixtures of 8 and 9 along with varying amounts of 7
in the isolated crude reaction mixture. Thus, under the
cyclization conditions epimerization of the methyl group is
occurring resulting in rapid interconversion between the
diastereomers. The presence of the amide in the chain enforces
either a half-chair or a boat conformation for the SN2
displacement that occurs during ether bond formation. In this
case, the (R,S)-diastereomer 8 can adopt the lower energy half-
chair in the transition state resulting in a faster rate of
cyclization to provide the kinetic reaction product 7 as the
major product.6
With a reasonable understanding of the selective formation
of 7 in hand, the synthetic route to 2 was adapted to allow for
safe scale-up. The improved route is shown in Scheme 3.
Concerns over the use of sodium hydride on a large scale
prompted a change to the more scale amenable KOt-Bu. As
described above, stopping the cyclization reaction promptly
upon completion (∼1 h) afforded morpholinone 7 as the
predominant product. These modified reaction conditions
resulted in a cleaner crude reaction profile enabling the
crystallization of 7 from the crude reaction mixture and
The preferential formation of the cis morpholinone 7 was
intriguing. This appears to be an example of dynamic kinetic
asymmetric transformation type III where de-epimerization of a
diastereomeric mixture of enantiomeric pairs is taking place.5
Our preliminary observations indicated that the reaction time
was a key parameter for controlling the ratio of 7:6. If the
reaction was stopped within 1 h, 1H NMR analysis showed that
morpholinone 7 was the major product with only a trace of 6
observed (96:4, 7:6). If the mixture was reacted overnight at
ambient temperature the ratio of 7:6 in the crude reaction was
about 90:10. This suggests that morpholinone 7 is the kinetic
product. To confirm this assertion, morpholinone 7 was
exposed to the cyclization conditions at reflux for 2 d. A 50:50
mixture of morpholinone diastereomers 6 and 7 was obtained.
When individual diastereomer 8 or 9 was reacted under the
cyclization conditions for about 1 h, only morpholinone 7 was
obtained (Scheme 2). Experiments in which 8 or 9 was
individually exposed to the reaction conditions with sub-
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eliminating the need for chromatography. The use of LAH in
the reduction to morpholine 2 was replaced by the more scale-
up friendly Vitride. This improved route enabled preparation of
2 on >40 g scale.
3). Decreasing the equivalents of UHP led to incomplete
conversion of the starting material.
Two side products were identified from these oxidation
reactions by analysis of the crude reaction mixtures by LCMS:
amino aldehyde 15 and morpholine 12. The formation of 15
can be explained by base hydrolysis of the pivaloyl group, which
is part of a vinylogous imide. The formation of 15 was observed
in control reactions with no oxidant added. The formation of
12 was observed only in the presence of oxidant. We postulate
that it could arise from overoxidation of 14 to form a quinone
iminium species, followed by hydrolysis to liberate 12. No
pyridine N-oxides or other products derived from the pyridine
moiety of 14 were observed.
With a reliable means to access a 3-hydroxypyridine
precursor from aldehyde 11 in place, the scale-up of 3
commenced. The key starting material for the scale-up, 11, was
prepared from 16 by a modification of the previously published
method.11 The use 2.5 M n-BuLi at −40 °C and N-
formylmorpholine for the metalation/formylation step followed
by 3 N HCl for the workup simplified processing and increased
Several attempts to prepare 3 directly from morpholine 2
were made. Attempts to prepare 3 from bromopyridine 10 (or
its fluoropyridine analog) via an an SNAr process were
unsuccessful. The addition of 2 to an activated pyridine N-
oxide7 or copper catalyzed couplings were also attempted, but
these approaches failed to provide any product. After several
ligand/base combinations were evaluated, conditions were
found to accomplish the one-step Buchwald−Hartwig amina-
tion of bromopyridine 10 with morpholine 2 permitting
preparation of 3 on ∼50 mg scale (Scheme 4). However, the
low yield and difficult purification associated with this coupling
made the use of these amination conditions for larger scale
preparation of 3 unattractive.8
Scheme 4. Buchwald−Hartwig amination conditions
throughput. Treatment of 11 with morpholine 2 and Hunig’s
̈
base in DMF gave a quantitative yield of 17, which was then
subjected to the Dakin oxidation using UHP and NaOH at 0
°C. Conducting the oxidation at this temperature not only
effectively doubled the reaction time from 18 to 36 h compared
to the reaction at ambient temperature but also minimized the
formation of side products, resulting in a slightly higher yield of
18. Alkylation of hydroxypyridine 18 proceeded uneventfully
on scale to provide ester 19 in high yield. During the
deprotection and cyclization of 19 in refluxing 1 N aq HCl, 3
precipitated from the reaction solution. Filtration of the desired
product from the reaction mixture resulted in an excellent yield
of 3 as a fully crystalline solid with >99.5% purity (HPLC).
Scheme 7 depicts the final route used to prepare >35 g of 3 in a
single run. The steps to prepare 17, 18, and 19 were telescoped
(largest single run preparation of 110 g, 43 and 59 g,
respectively), but each of these intermediates was purified by
filtration through silica gel. If larger quantities of 3 were needed,
additional optimization of the Dakin oxidation step and workup
modification to remove the concentrations to dryness could
potentially improve the synthesis and render a multikilogram
process.
While considering ways to activate the pyridine for
nucleophilic substitution, we were drawn to the possibility of
using a para carbonyl group that could facilitate the desired
SNAr reaction and be subsequently converted into the required
3-hydroxypridine by a Baeyer−Villiger type9,10 oxidative
cleavage (Scheme 5). These disconnections had the added
benefit that the potential starting material, pyridine 11, was
known and had been previously synthesized on a large scale.11
At this point it was not immediately clear how efficient the
new SNAr/oxidative cleavage route would be, so we opted to
conduct several early experiments with a model system using
commercially available morpholine 12 (Scheme 6). Oxidation
of aromatic aldehydes to give phenols under Baeyer−Villiger or
Dakin conditions is usually restricted to aldehydes containing
electron-donating groups.12 The combination of the electron-
deficient pyridine substituted with electron-donating amines
thus presented an uncertain outcome. Treatment of chloropyr-
idine 11 with 12 uneventfully provided access to aldehyde
substrate 13. A series of oxidation conditions were assessed
(Table 1). Substantial conversion to the desired hydroxypyr-
idine was observed using basic H2O2 (as a 30 wt % aq. solution)
in MeOH (Dakin oxidation, entry 2). The use of an excess of
urea-hydrogen peroxide complex (UHP) as a safe alternative to
CONCLUSIONS AND SUMMARY
■
As a result of the optimization work described herein, a
convergent route was developed to enable the preparation >35
g of 3 in a single run for preclinical toxicology studies. The
route to morpholine 2 started from (R)-phenylglycinol and
featured the installation of the second stereogenic center via de-
epimerization. The synthesis was completed through a
sequence of SNAr, Dakin oxidation, alkylation, and cyclization
to provide crystalline 3.
13
H2O2 gave a small, but appreciable, increase in yield (entry
Scheme 5. Retrosynthesis of 3
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Scheme 6. Chloropyridine SNAr reaction and oxidation to 14
Synthesis of 2-Chloro-N-((R)-2-hydroxy-1-phenyl-
ethyl)-propionamide (5).14 (R)-Phenylglycinol (4) (75.5 g,
552 mmol) was dissolved in 2-methyltetrahydrofuran (2-
MeTHF) (1130 mL) and stirred under N2. Triethylamine
(90 mL, 623 mmol) was added, and the clear solution was
cooled to 5 °C. A solution of 2-chloropropionyl chloride (54
mL, 552 mmol) in 2-MeTHF (150 mL) was added over 50
min. Solids appeared in the reaction mixture as the addition was
done (triethylamine HCl) and the internal temperature
increased from 4 to 12 °C. After the addition was complete
the mixture was warmed to rt. After 2 h, water (750 mL) was
added, the mixture was stirred for 15 min, and the layers were
separated. The organic layer was washed with brine (450 mL),
dried over Na2SO4, and filtered. The residue was rinsed with
ethyl acetate (∼100 mL) and concentrated to yield 122.1 g
Table 1. Oxidative cleavage of 13 to 14
entry
oxidant (equiv)
base (equiv)
solvent
yield (%)
1
2
3
4
5
m-CPBA (1.1)
H2O2 (5)
−
CH2Cl2
MeOH
MeOH
CH2Cl2
MeOH
10
NaOH (5)
NaOH (4)
K3PO4 (3)
K2CO3 (4)
42
UHP (4)
52
UHP/Ac2O (3)
UHP (4)
−
trace
EXPERIMENTAL SECTION
General. The progress of reactions and chemical purity
■
were assessed by the analytical methods listed. Analytical LC-
MS/UV-ELSD Method: Phenomenex Gemini-NX C18 column
(4.6 mm × 50 mm, 3 μm); mobile phase A: 0.1% formic acid in
water (v/v); mobile phase B: 0.1% formic acid in acetonitrile
(v/v); UV detection at 220 nm; flow rate 1.5 mL/min; column
temperature 60 °C; gradient: initial conditions: A-95%:B-5%;
linear ramp from 0.0 to 1.90 min; hold from 1.90 to 2.25 min;
return to initial conditions 2.25−2.50 min. ELS detection was
performed using a Polymer Laboratories (Varian) 2100 ELS
detector. Purities are reported as ELSD area percent. Analytical
UPLC Method: BEH C8 column (2.1 mm × 100 mm, 1.7 μm);
mobile phase A: 50 mM NaClO4/0.1% H3PO4; mobile phase
B: acetonitrile; UV detection at 210 nm; flow rate 0.5 mL/min;
gradient: initial conditions: A-95%:B-5%; linear ramp from 0.25
to 6.25 min; hold from 6.25 to 6.75 min; return to initial
conditions 6.85−9.50 min. High resolution mass spectroscopy
(HRMS) was performed on a LC-MS TOF using a C18 2.5 μm
3.0 mm × 5.0 mm column at 60 °C; ammonium formate: water
as mobile phase A and 50:50 methanol/acetonitrile as mobile
phase B. Optical rotations were obtained on a polarimeter at
589 nm. Infrared spectra (FT-IR) were collected of neat liquids
or solids on the ZnSe surface. The terms “concentrated” and
“evaporated” refer to the removal of solvent at reduced pressure
on a rotary evaporator with a bath temperature of less than 60
°C.
1
(97%) of a white solid as a mixture of diastereomers. H NMR
(400 MHz, CDCl3) 7.40−7.27 (5H, m), 5.07−5.01 (1H,
overlapping dt), 4.47 and 4.43 (1H, overlapping q), 3.92−3.89
(2H, overlapping m), 1.77 and 1.72 (3H, d). m/z = 228.0/
230.0 (M+H)+. The discrete diastereomers were prepared in an
analogous manner.
Data for (2S,5R)-2-Chloro-N-(2-hydroxy-1-phenyl-
ethyl)propanamide (8). 1H NMR (400 MHz, CDCl3)
7.40−7.28 (5H, m), 5.05 (1H, dt, J = 7.3, 4.7 Hz), 4.43 (1H,
q, J = 6.9 Hz), 3.91 (2H, d, J = 4.7 Hz), 2.13 (1H, m), 1.77
(3H, d, J = 6.9 Hz); 13C NMR (125 MHz, CDCl3) 169.9,
138.3, 129.0, 128.1, 126.6, 66.3, 56.0, 55.9, 22.8; FTIR (cm−1)
1656.4 (s); HRMS Calcd for C11H15ClNO2 (M+H)+ 228.0786;
Found 228.0781.
Data for (2R,5R)-2-Chloro-N-(2-hydroxy-1-phenyl-
ethyl)propanamide (9). 1H NMR (400 MHz, CDCl3)
7.40−7.28 (5H, m), 5.05 (1H, dt, J = 7.3, 4.7 Hz), 4.48 (1H,
q, J = 6.9 Hz), 3.91 (2H, d, J = 4.6 Hz), 2.25 (1H, m), 1.72
(3H, d, J = 7.1 Hz); 13C NMR (125 MHz, CDCl3) 169.8,
138.3, 129.0, 128.0, 126.5, 66.2, 55.84, 55.80, 22.5; FTIR
Scheme 7. Scale-up route for the preparation of 3
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(cm−1) 1655.6 (s); HRMS Calcd for C11H15ClNO2 (M+H)+
228.0786; Found 228.0777.
layers were dried over MgSO4, filtered, and concentrated to
give the crude product. The crude product was taken up in
MTBE (375 mL) until a slurry formed. The solids were filtered,
washed successively with MTBE (100 mL) and 1:1 MTBE/
heptane (200 mL), and dried under vacuum to provide 40.7 g
(54%) of 11 as a yellow solid. H NMR (400 MHz, CDCl3)
10.83 (br s, 1H), 9.89 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.18 (d,
J = 8.0 Hz, 1H), 1.35 (s, 9H).
Synthesis of (2R,5R)-2-Methyl-5-phenylmorpholin-3-
one (7). A solution of 5 (60 g, 260 mmol) in t-BuOH (tert-
butanol) (540 mL) was added to a stirred suspension of KOt-
Bu (59.1 g, 527 mmol) in t-BuOH (920 mL) at rt. The reaction
mixture was stirred for 1 h. The pH of the reaction mixture was
adjusted to pH 4 by adding aq 1 N HCl (140 mL). The mixture
was concentrated to remove the t-BuOH. Ethyl acetate (1000
mL) and water (500 mL) were then added. After the layers
were separated, the organic layer was washed with brine (250
mL), dried over Na2SO4, filtered, and concentrated to provide a
solid. The solid was completely dissolved in hot heptane/ethyl
acetate. After cooling to ambient temperature overnight, the
solid was filtered and dried to afford 33.8 g (67%). Mp 97.4−
1
Synthesis of N-(3-Formyl-6-((2R,5R)-2-methyl-5-
phenylmorpholino)pyridin-2-yl)pivalamide (17). A mix-
ture of 2 (53 g, 300 mmol), 11 (75.6 g, 314 mmol), DMF (150
mL), and diisopropylethylamine (Hunig’s base) (53 mL, 300
̈
mmol) was stirred at 100 °C for 18 h. The mixture was cooled
to rt and concentrated. The residue was dissolved in ethyl
acetate (1 L), and water was added (600 mL). The layers were
then separated. The organic layer was washed with aq 1 N HCl
(500 mL), dried over Na2SO4, filtered, and concentrated. The
residue was dissolved in CH2Cl2 and filtered through silica gel,
which was eluted with 50% ethyl acetate in heptane (3 L)
followed by 100% ethyl acetate (500 mL) to provide 116.5 g
1
98.0 °C (heptane); H NMR (400 MHz, CDCl3) 7.34 (5H,
m), 4.62 (1H, m), 4.34 (1H, q, J = 7.0 Hz), 4.00 (1H, dd, J =
11.9, 4.1 Hz), 3.84 (1H, ddd, J = 11.9, 4.5, 0.8 Hz), 1.54 (3H, d,
J = 7.0 Hz); 13C NMR (101 MHz, CDCl3) 172.0, 139.4, 128.8,
128.3, 126.5, 73.6, 67.6, 56.5, 17.3; FTIR (cm−1) 1662.0 (s);
HRMS Calcd for C11H14NO2 (M+H)+ 192.1019; Found
1
(>100%) of the desired product 17. H NMR (400 MHz,
20
192.1019; [α]D −29.6 (c 0.530, MeOH).
CDCl3) 11.58 (1H, br s), 9.52 (1H, m), 7.60 (1H, d, J = 8.8
Hz), 7.26 (4H, m), 6.24 (1H, d, J = 9.0 Hz), 4.45 (1H, dd, J =
12.1, 1.6 Hz), 4.04 (1H, dd, J = 12.0, 3.8 Hz), 3.75 (1H, m),
3.04 (1H, dd, J = 13.6, 11.0 Hz), 1.36 (9H, s), 1.28 (3H, d, J =
6.2 Hz). LCMS: tR = 1.46 min, m/z = 380.2 (M-H)−, ELSD
purity 100%.
Data for the minor isomer (2S,5R)-2-methyl-5-phenyl-
morpholin-3-one (6). Spectroscopic data are in agreement
3
1
with reported data. Mp 93.7−93.8 °C (heptane); H NMR
(400 MHz, CDCl3) 7.49−7.31 (m, 5H), 6.00 (br s, 1H), 4.84
(dd, J = 4.5, 10.3 Hz, 1H), 4.30 (q, J = 7.0 Hz, 1H), 4.09 (dd, J
= 4.3, 11.7 Hz, 1H), 3.56 (t, J = 11.1 Hz, 1H), 1.57 (d, J = 7.0
Hz, 3H); 13C NMR (101 MHz, CDCl3) 171.6, 137.1, 129.1,
128.9, 126.6, 74.2, 70.4, 57.7, 17.5; FTIR (cm−1) 1670; HRMS
Calcd for C11H14NO2 (M+H)+ 192.1019; Found 192.1019;
Synthesis of N-(3-Hydroxy-6-((2R,5R)-2-methyl-5-
phenylmorpholino)pyridin-2-yl)pivalamide (18). To a 0
°C solution of 17 (88.8 g, 232.9 mmol) in MeOH (300 mL)
were added UHP (87.66 g, 931.9 mmol) and NaOH in MeOH
(1 M, 930 mL, 930 mmol). The reaction mixture was stirred at
0 °C for 42 h. Na2SO3 (100 g) was added, and the mixture was
stirred at 0 °C for 30 min. The reaction mixture was then
concentrated. The residue was dissolved in water (1 L) and
ethyl acetate (500 mL). The layers were separated, and the
aqueous layer was extracted with ethyl acetate (2 × 300 mL).
The combined organic layers were washed with brine (300
mL), dried over MgSO4, filtered, and concentrated. The crude
product was filtered through silica gel (500 g), eluting with
CH2Cl2 (5 L). The filtrate was concentrated to provide 42.7 g
(49%) of the desired product 18. 1H NMR (400 MHz, CDCl3)
9.46 (1H, s), 7.76 (1H, br s), 7.16−7.32 (6H, m), 6.37 (1H, d, J
= 8.8 Hz), 5.13 (1H, m), 4.40 (1H, dd, J = 11.7, 1.6 Hz), 4.05
(1H, m), 3.87 (1H, m), 3.74 (1H, m), 2.93 (1H, m), 1.35 (9H,
s), 1.24 (3H, d, J = 6.2 Hz). LCMS: tR = 1.46 min, m/z = 371.5
(M+H)+, ELSD purity 100%.
20
[α]D −88.5 (c 0.92, CH3CN).
Synthesis of (2R,5R)-2-Methyl-5-phenylmorpholine
(2). A solution of 7 (32 g, 167.3 mmol) in toluene (600 mL)
was added to an ice cooled solution of sodium bis(2-
methoxyethoxy)aluminum hydride (Vitride, 65 wt % in toluene,
300 mL, 1000 mmol). The reaction mixture was stirred at 5 °C
for 1 h and stirred at rt overnight. Aq 2 M NaOH (700 mL,
1390 mmol) was added to the reaction mixture, allowing the
temperature to rise to 45 °C. The solution was diluted with
toluene (100 mL), and the layers were separated. The organic
layer was washed with aq K2CO3 (10%, 100 mL), dried over
Na2SO4, filtered, and concentrated to afford 31.0 g (100%) of
1
the desired product 2 as an oil. H NMR (400 MHz, CDCl3)
7.52 (2H, d, J = 7.4 Hz), 7.43−7.34 (2H, m), 7.33−7.27 (1H,
m), 4.14−3.72 (4H, m), 2.86−2.71 (m, J = 6.0, 12.0 Hz, 1H),
1.88 (1H, br s), 1.34 (3H, d, J = 6.4 Hz); 13C NMR (101 MHz,
CDCl3) 141.5, 128.4, 127.7, 127.3, 70.7, 68.0, 57.3, 48.4, 17.4;
FTIR (cm−1) 3317 (w); HRMS Calcd for C11H15NO (M+H)+
Synthesis of Ethyl 2-(6-((2R,5R)-2-Methyl-5-phenyl-
morpholino)-2-pivalamidopyridin-3-yloxy)acetate (19).
A mixture of 18 (61.5 g, 166.4 mmol), NaI (5.0 g, 33.4
mmol), acetone (475 mL), powdered K2CO3 (34.5 g, 250
mmol), and ethyl bromoacetate (18.4 mL, 166 mmol) was
stirred at reflux overnight. The mixture was then cooled to
ambient temperature, filtered, and concentrated. The residue
was dissolved in CH2Cl2 and filtered through silica gel (400 g)
eluting with 10:1 CH2Cl2/ethyl acetate and 1:1 CH2Cl2/ethyl
acetate. The filtrate was concentrated to provide 58.9 g (78%)
20
178.1226; Found 178.1232; [α]D 3.1 (c 1.01, MeOH).
Synthesis of N-(6-Chloro-3-formyl-pyridin-2-yl)-2,2-
dimethyl-propionamide (11). Spectroscopic data are in
agreement with reported data.11 To a solution of 16 (66.4 g,
312 mmol) and TMEDA (47 mL, 312 mmol) in 2-MeTHF
(660 mL) at −40 °C under N2 was added n-BuLi (2.5 M in
hexane, 312 mL, 781 mmol) at <−25 °C. After 1 h, N-
formylmorpholine (108 g, 937 mmol) was added while
maintaining the temperature between −15 and 15 °C. After
1.5 h, the mixture was cooled to 4 °C and treated with 3 N HCl
(550 mL) and stirred overnight. The solution was diluted with
2-MeTHF (600 mL), and the layers were separated. The
organic layer was washed with brine (200 mL). The aqueous
layer was extracted with 2-MeTHF. The combined organic
1
of the desired product 19. H NMR (400 MHz, CDCl3) 8.64
(1H, s), 7.42 (2H, m), 7.21 (3H, m), 7.01 (1H, m), 6.08 (1H,
d, J = 8.8 Hz), 5.20 (1H, m), 4.51 (2H, s), 4.34 (1H, m), 4.22
(2H, q, J = 7.2 Hz), 4.09 (2H, m), 3.75 (1H, m), 3.00 (1H, m),
1.35 (9H, s), 1.24 (6H, m). LCMS: tR = 1.48 min, m/z = 456.6
(M+H)+, ELSD purity 100%.
E
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Organic Process Research & Development
Article
Synthesis of 6-((2R,5R)-2-Methyl-5-phenyl-
morpholino)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (3).
Aq. 1 N HCl (560 mL, 560 mmol) and 19 (51.4 g, 113
mmol) were stirred at reflux 4 h. The reaction mixture was
cooled to rt, followed by cooling in an ice/water bath. The
precipitate was filtered and rinsed with water. The solid was
dried in a vacuum oven at 50 °C overnight to provide 36.4 g
(99%) of 3 as a white crystalline solid. Mp 203.8−204.7 °C; 1H
NMR (400 MHz, CDCl3) 7.65 (1H, br s), 7.18−7.33 (5H, m),
7.08 (1H, m), 6.11 (1H, d, J = 8.8 Hz), 5.16 (1H, m), 4.52 (2H,
s), 4.39 (1H, dd, J = 11.7, 1.6 Hz), 4.04 (1H, dd, J = 11.8, 3.8
Hz), 3.89 (1H, dd, J = 13.1, 3.1 Hz), 3.73 (1H, m), 2.97 (1H,
dd, J = 13.1, 10.7 Hz), 1.25 (3H, d, J = 6.2 Hz); 13C NMR (125
MHz, CDCl3) 166.4, 153.3, 139.8, 138.2, 130.8, 128.7, 128.0,
127.2, 126.7, 101.3, 72.3, 70.5, 67.8, 54.0, 47.4, 19.3; FTIR
(cm−1) 1701.4 (s); HRMS Calcd for C18H19N3O3 (M+H)+
326.1505; Found 326.1498; UPLC: tR = 3.937 min, 99.75%.
Anal. Calcd for C18H19N3O3: C, 66.45; H, 5.89; N, 12.91.
ACKNOWLEDGMENTS
We thank Brian Samas and Ivan Samardjiev for the X-ray crystal
structure of 3. We thank Andy Butler for NMR analysis of 7.
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REFERENCES
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Found: C, 66.26; H, 5.62; N, 12.75. [α]D −224.5 (c 0.392,
MeOH).
N-[3-Formyl-6-((R)-3-phenyl-morpholin-4-yl)-pyridin-
2-yl]-2,2-dimethylpropionamide (13). Compound 13 was
prepared according to the procedure described for 17. 1H NMR
(400 MHz, CDCl3) 11.63 (br. s., 1H), 9.57 (s, 1H), 7.65 (d, J =
8.6 Hz, 1H), 7.48 (d, J = 7.8 Hz, 2H), 7.40−7.23 (m, 3H), 6.28
(d, J = 9.0 Hz, 1H), 5.58−5.33 (m, 1H), 4.73−4.55 (m, 1H),
4.45 (d, J = 12.1 Hz, 1H), 4.10 (dd, J = 3.5, 11.7 Hz, 1H), 4.03
(dd, J = 3.9, 12.1 Hz, 1H), 3.77 (d, J = 3.1 Hz, 1H), 3.54 (d, J =
3.9 Hz, 1H), 1.40 (s, 9H); 13C NMR (101 MHz, CDCl3) 190.1,
177.1, 159.8, 153.3, 145.0, 128.7, 127.6, 127,5, 108.0, 99.8, 69.8,
67.1, 54.9, 40.9, 40.8, 27.56; FTIR (cm−1) 1619 (s), 1556 (m),
1509 (s), 1385 (m); HRMS Calcd for C21H26N3O3 (M+H)+
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368.1969; Found 368.1967; [α]D −338.8 (c 0.747, CH3CN).
N-[3-Hydroxy-6-((R)-3-phenyl-morpholin-4-yl)-pyri-
din-2-yl]-2,2-dimethylpropionamide (14). Compound 14
1
was prepared according to the procedure described for 18. H
NMR (400 MHz, CDCl3) 9.68 (s, 1H), 7.84−7.57 (br, 1H),
7.35−7.05 (m, 6H), 6.41 (d, J = 8.8 Hz, 1H), 4.78 (t, 1H),
4.07−3.92 (m, 3H), 3.86 (m, 1H), 3.62−3.47 (m, 2H), 1.34 (s,
9H); 13C NMR (125 MHz, CDCl3) 179.1, 151.8, 139.9, 136.7,
136.1, 130.6, 128.4, 127.5, 127.0, 109.0, 71.6, 67.1, 57.5, 45.6,
39.4, 27.6; FTIR (cm−1) 1463 (s), 1290 (w), 1267 (m); HRMS
Calcd for C20H26N3O3 (M+H)+ 356.1969; Found 356.1967;
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B.; Waldo, M.; Chen, M. H.; Mennen, K. E. Org. Process Res. Dev.
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4750.
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[α]D −120.2 (c 1.213, CH3CN).
(12) (a) Roy, A.; Reddy, K. R.; Mohanta, P. K.; Ila, H.; Junjappat, H.
Synth. Commun. 1999, 29, 3781−3791. (b) Chen, S.; Hossain, M. S.;
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ASSOCIATED CONTENT
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S
* Supporting Information
(13) Cooper, M. S.; Heaney, H.; Newbold, A. J.; Sanderson, W. R.
Synlett 1990, 533−535.
1
Copies of H and 13C NMR spectra for compounds 2, 3, 5−9,
13, 14, 17−19; the HPLC purity assessment; single crystal X-
ray structure; crystallographic information file (cif); powder X-
ray diffractogram; and COSY, HMBC, HSQC, and NOESY
spectra for compound 3 are included. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) Kissane, M.; Lawrence, S. E.; Maguire, A. R. Tetrahedron:
Asymmetry 2010, 21, 871−884.
AUTHOR INFORMATION
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Corresponding Author
*Telephone: (860) 686-0271. E-mail: david.w.piotrowski@
pfizer.com.
Notes
The authors declare no competing financial interest.
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dx.doi.org/10.1021/op400101p | Org. Process Res. Dev. XXXX, XXX, XXX−XXX