Organic Process Research & Development
Communication
EXPERIMENTAL SECTION
44.2 (s, 1C), 43.1 (s, 1C), 40.9 (s, 2C), 35.9 (s, 1C), 23.8 (s,
C), 14.6 (s, 1C). HRMS (ESI) m/z calcd for C27H34F2NO4
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2
General Information. All solvents and reagents were
obtained from commercial sources and used as they were
received. The melting point was measured in a Mettler Toledo
MP 90 Melting Point System at a 3 °C/min ramp, and the
+
(
free base MH ), 474.2450; found, 474.2449.
Method B. Ligand-Free Heck Reaction (Scheme 4). A
mixture of (R)-1-(5-bromo-2,3-difluorophenoxy)-3-((1-(2,3-
dihydro-1H-inden-2-yl)-2-methylpropan-2-yl)amino)propan-
1
13
result was not corrected. H and C NMR spectra were
recorded on a Bruker 400 MHz spectrometer, and chemical
shifts (δ) are reported in parts per million (ppm), with
multiplicities abbreviated as follows: s = singlet, d = doublet, t
2
-ol hydrochloride (1) (1.0 g, 2.04 mmol), NMP (4.0 mL),
and sodium acetate (0.2 g, 2.44 mmol) was stirred at 20 °C
and degassed by slowly bubbling nitrogen for 5 min. Ethyl
acrylate (carcinogenic! 0.27 mL, 2.44 mmol) was added,
=
triplet, m = multiplet, dd = doublet of doublets. Residual
followed by Pd(OAc) (0.23 mg, 0.0010 mmol, charged by
2
solvent signals were used as references. HRMS (m/z) was
measured using a LTQ Discovery Orbitrap (Thermo) mass
spectrometer equipped with a heated electrospray ionization
HESI) ion source.
R,E)-Ethyl 3-(3-(3-((1-(2,3-Dihydro-1H-inden-2-yl)-2-
methylpropan-2-yl)amino)-2-hydroxypropoxy)-4,5-difluoro-
phenyl)acrylate Hydrochloride (2). Method A (Schemes 1
and 3). Heck Reaction with Ligand P(o-tol) . A mixture of
R)-1-(5-bromo-2,3-difluorophenoxy)-3-((1-(2,3-dihydro-1H-
inden-2-yl)-2-methylpropan-2-yl)amino)propan-2-ol hydro-
taking 0.5 mL of a premade solution of Pd(OAc) in NMP
2
with 0.46 mg/mL concentration). The reaction was slowly
heated to 140 °C and stirred for 2.5 h, and a sample was taken
for HPLC to monitor the reaction progress. The reaction was
then cooled to room temperature, filtered through filter paper,
and washed with 3 mL of EtOAc. The resulting solution was
analyzed for the solution yield.
(
(
3
Study of the Oxidation of P(o-tol) with NMP-5-OOH
3
(
Presented in NMP (Table 1); the Amounts of Solvents and
P(o-tol)3 Charged Were Calculated Based on a Heck
Reaction for 2 g of 1 (Scheme 1). To four vials each
containing a stir bar were charged toluene (6 mL), NMP with
different levels of NMP-5-OOH (1.5 mL, except in the fourth
chloride (1) (150.0 kg, 305.6 mol), toluene (450 L), NMP
(
7
113 L), and N,N-diisopropylethylamine (DIPEA) (99.0 kg,
64.0 mol) was stirred at 20 °C and degassed by bubbling
nitrogen through for at least 1 h. Tri(o-tolyl)phosphine (1.395
vial no NMP was added), and P(o-tol) (18.6 mg). Each
3
kg, 4.58 mol) and Pd(OAc) (0.343 kg, 1.53 mol) were added.
2
reaction was bubbled with N for 5 min at room temperature,
2
The headspace of the reactor was degassed by evacuating and
refilling with nitrogen for three cycles. Ethyl acrylate
carcinogenic! 42.8 kg, 427.8 mol) was added followed by
and then capped and heated to 98 °C. Samples were taken for
HPLC testing after 2.5 h.
(
setting the reactor’s nitrogen flow to 1−2 SCFM for at least 5
min. The reaction was slowly heated to 94−99 °C and stirred
for 2 h. After the reaction was deemed complete by HPLC
ASSOCIATED CONTENT
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*
sı Supporting Information
monitoring, the mixture was cooled to 50−60 °C, and H O
2
(
375 L) was added. After being stirred for 15 min, the mixture
was filtered through Celite and washed with 50 °C toluene
225 L). The layers were separated, and 15% w/w aqueous
HCl (450 L) was added slowly to the organic layer at 45−55
C. The layers were separated after stirring for 15 min, and
H O (22.5 L) was added slowly to the organic layer at 45−55
1
13
1
Copies of H and C NMR spectra for 1; H NMR
monitoring of NMP-5-OOH generated by bubbling air
through NMP; LCMS detection of NMP-5-OOH
(
°
2
°C. The reaction mixture was cooled slowly to 20−40 °C and
aged for 30 min after crystallization began. The resulting slurry
was cooled slowly to 5−10 °C, and filtered and washed with
cold TBME (450 L). To the wet cake was then added EtOH
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Corresponding Author
(
375 L). The mixture was heated to 25−60 °C to dissolve the
solid and then charged with H O (300 L) while maintaining
2
the solution temperature at 40−45 °C. The reaction mixture
was cooled to 30−35 °C, seeded with 2 (15.0 g), and aged for
3
3
0 min after the solid began to form. The slurry was cooled to
−7 °C, filtered, and washed with TBME (450 L). The
Author
product was dried under vacuum at 40−45 °C to afford 2
Hayao Matsuhashi − Chemical Development,
GlaxoSmithKline, Collegeville, Pennsylvania 19426, United
States
(
138.5 kg, 271.8 mol, 89% yield) as a white solid: mp. 156.4
1
°C. H NMR (400 MHz, DMSO-d6) δ (ppm): 8.93 (m, 1H),
8
.58 (m, 1H), 7.60 (d, J = 16.1 Hz, 1H), 7.50−7.52 (m, 2H),
.18 (m, 2H), 7.10 (m, 2H), 6.78 (d, J = 16.1 Hz, 1H), 5.97
7
(
(
(
d, J = 4.5 Hz, 1H), 4.20−4.29 (m, 5H), 3.20 (m, 1H), 3.09
dd, J = 14.3, 7.0 Hz, 2H), 2.98 (m, 1H), 2.60 (m, 1H), 2.56
m, 1H), 1.97 (d, J = 5.5 Hz, 2H), 1.40 (s, 6H), 1.26 (t, J = 7.1
Notes
The authors declare no competing financial interest.
1
3
Hz, 3H). C NMR (100 MHz, DMSO-d6) δ (ppm): 166.4 (s,
C), 150.6 (dd, J = 244.5, 11.1 Hz, 1C), 148.4 (dd, J = 8.0, 4.0
Hz, 1C), 143.2 (s, 2C), 143.2 (s, 1C), 141.5 (dd, J = 250.5,
1
ACKNOWLEDGMENTS
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1
4.1 Hz, 1C), 131.1 (dd, J = 9.1, 5.0 Hz, 1C), 126.6 (s, 2C),
24.4 (s, 2C), 120.3 (s, 1C), 111.0 (s, 1C), 109.9 (d, J = 18.1
The authors thank Mark Bokhart for HRMS determination,
Alan Freyer for NMR analysis, and Michael Liangmin Wu
(deceased) for LCMS determination.
1
Hz, 1C), 71.8 (s, 1C), 65.8 (s, 1C), 60.6 (s, 1C), 60.1 (s, 1C),
D
Org. Process Res. Dev. XXXX, XXX, XXX−XXX