Y. Sawai et al. / Tetrahedron 70 (2014) 2370e2377
2375
the case of morpholine, regioisomer 10 was generated in 1:13 ratio
to 2c by HPLC analysis and pure 2c was obtained in 79% yield by
a successive one-pot hydrolysis. When the secondary amine was
switched to piperidine, regioselectivity was improved to 1:28 and
the yield of pure 2c was also increased to 90%. The result was
comparable to that of a reported procedure using the BF4 salt 4a
(87%).4
Anal. Calcd for C10H22N3Cl3$H2O: C, 38.91; H, 7.84; N, 13.61; Cl,
34.36. Found: C, 38.56; H, 8.21; N, 13.63; Cl, 34.58.
4.3. Synthesis of 2-iminiomethylvinamidinium trihalide
(5, as Br containing salt)
To a solution of 2-bromoacetic acid (49.5 kg, 356 mol) in DMF
(155.7 kg, 2130 mol) was added dropwise phosphoryl chloride
(217.9 kg, 1421 mol) at 0 ꢁC. The mixture was stirred at 80 ꢁC for 1 h,
at 95 ꢁC for 1 h and at 105 ꢁC for 1 h. 48% Aqueous HBr (119.7 kg,
710 mol) and THF (877 kg) were successively added dropwise to the
mixture. After stirring for 2 h, the resultant precipitate was col-
lected by dry N2 pressure filtration, washed with THF (439 kg)/
EtOH (78 kg), and dried by through-flow drying with warmed dry
N2 at 60 ꢁC to give 5 (84.1 kg, 263 mol, 74% yield, H2O: 5.3 w/w%) as
3. Conclusion
2-Iminiomethylvinamidinium trihalide
5 was isolated as
crystals for the first time. A noteworthy feature of 5 is its non-
deliquescent nature in air, whereas the dihalide 4b/4e is deliques-
cent to give a decomposed material. This feature makes it attractive
as a synthetic reagent to serve as a triformylmethane synthon.
Through intensive scale-up studies, an industrially feasible
manufacturing process of 5 has been successfully developed. As
a synthetic application of the air stable vinamidinium trihalide,
we have also established an efficient and scalable synthesis of the 7-
acylamino-3-formy-8-methylquinoline 2b, a versatile intermediate
leading to MCHR1 antagonists 1. The key to the successful quinoline
annulation was an in situ aminal protection of the aldehyde moiety
with a secondary amine, which effectively inhibited the problem-
atic side reaction that gave imine 7 and tarry by-product, with
good water tolerance. Moreover we demonstrated that the
reaction protocol was effective at providing a common substrate 2c.
Another type of synthetic application of 5 is the focus of ongoing
research.
white crystals. 1H NMR (300 MHz, DMSO-d6)
9H), 6.86 (br s, 3H), 8.87 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
43.77, 48.88, 91.45, 165.24.
d 3.48 (s, 9H), 3.59 (s,
d
4.4. Conversion of 5 to 2-iminiomethylvinamidinium diha-
lide (4e)
2-Iminiomethylvinamidinium trihalide 5 (50.0 g) was humidi-
fied by through-flow with air (approximately 50% RH) at room
temperature for 9 h to give 4e (45.9 g) as a brown solid.26 1H NMR
(300 MHz, DMSO-d6)
d
3.48 (s, 9H), 3.59 (s, 9H), 3.65 (br s, 2H), 8.91
43.81, 48.86, 91.44, 165.20.
(s, 3H); 13C NMR (75 MHz, DMSO-d6)
d
4.5. Synthesis of N-(3-amino-2-methylphenyl)-4-(cyclo-
4. Experimental section
4.1. General
propylmethoxy)benzamide (3b)
To a solution of ethyl 4-hydroxybenzoate (24.6 kg, 148 mol) in
20% NaOEt/EtOH (55.3 kg, 163 mol) was added (bromomethyl)cy-
clopropane (30 kg, 222 mol). The mixture was refluxed 3 h and then
refluxed with 3 N aq NaOH (73.9 kg, 222 mol) for 2 h. After acidified
with concd HCl (59 kg), the mixture was cooled to room temper-
ature. The resultant precipitate was collected by filtration, washed
with water/EtOH (2:1, 46 kg), and dried in vacuo to give 4-(cyclo-
propylmethoxy)-benzoic acid (26.6 kg, 138 mol, 93% yield) as white
All materials were purchased from commercial suppliers and
used without further purification. Melting points were recorded on
€
a Buchi B-540 micromelting apparatus and were uncorrected. NMR
spectra were run at 300 MHz (1H) and 75 MHz (13C) on a Bruker
DPX-300 spectrometer. Chemical shifts are reported as
d values
using tetramethylsilane as an internal standard and coupling con-
stants (J) are given in hertz (Hz). The following abbreviations are
used: s¼singlet, d¼doublet, t¼triplet, m¼multiplet, and br¼broad.
IR spectra were recorded on a Horiba FT-210 spectrophotometer.
The mass spectral analyses, microanalyses, and ion chromatogra-
phy analyses were carried out at Takeda Analytical Research
Laboratories, Ltd. HPLC analyses were performed with a Hitachi L-
7000. Detection was performed with an ultraviolet absorption
photometer (wavelength 254 nm). Purity was determined by HPLC
and presented as the area percentage of the compound peak rela-
tive to the total area of all the peaks integrated. Water content was
determined by Hiranuma AQV-7 Karl Fisher volumetric titrator.
crystals. Mp 180 ꢁC; 1H NMR (300 MHz, CDCl3)
d 0.35e0.40 (m, 2H),
0.64e0.70 (m, 2H), 1.27e1.31 (m, 1H), 3.88 (d, J¼6.9 Hz, 2H),
6.91e6.96 (m, 2H), 8.03e8.08 (m, 2H); 13C NMR (75 MHz, CDCl3)
d
3.23, 10.08, 72.96, 114.27, 121.48, 132.34, 163.54, 171.67; IR (KBr) n
3084, 1675 cmꢀ1; MS (FAB) m/z 193 (MH)þ. Anal. Calcd for
C11H12O3: C, 68.74; H, 6.29. Found: C, 68.48; H, 6.20.
To
a suspension of 4-(cyclopropylmethoxy)benzoic acid
(25.0 kg, 130 mol) in toluene (217 kg) were added DMF (0.5 kg) and
thionyl chloride (18.6 kg, 156 mol). The mixture was stirred at
40e50 ꢁC for 1 h. The acid chloride solution was added to a sus-
pension of 2,6-diaminotoluene (3a, 23.8 kg, 195 mol) and TEA
(35.5 kg, 351 mol) in toluene/THF (5:3, 350 kg) below 0 ꢁC. The
mixture was stirred at the same temperature for 0.5 h and then at
room temperature for 2 h. After adding acetone (791 kg) and water
(200 kg), the layers were separated. The separated organic layer
was washed with 5% aq NaHCO3 (205 kg) and water (200 kg) and
then the solvent was switched to EtOH (198 kg) via vacuum con-
centration. After stirring the slurry at room temperature for 1 h, the
resultant precipitate was collected by filtration, washed with EtOH
(237 kg), and dried in vacuo to give 3b (35.4 kg, 119 mol, 92% yield)
as white crystals. Mp 202 ꢁC; 1H NMR (300 MHz, DMSO-d6)
4.2. Synthesis of 2-iminiomethylvinamidinium trichloride (5,
as Br free salt)
To a solution of 2-chloroacetic acid (2.00 g, 21.2 mmol) in DMF
(18.6 g, 254 mmol) was added dropwise phosphoryl chloride
(26.0 g, 170 mmol) at 0 ꢁC. The mixture was stirred at 80 ꢁC for 1 h,
at 95 ꢁC for 1 h, and at 105 ꢁC for 1 h. After concd HCl (4.29 g,
42.4 mmol) and THF (120 mL) were successively added at room
temperature, the mixture was stirred for 0.5 h. The resultant pre-
cipitate was collected by dry N2 pressure filtration, washed with
THF (40 mL), and dried by through-flow drying to give 5 (5.10 g,
16.5 mmol, 78% yield, as monohydrate) as white crystals.
d
0.33e0.37 (m, 2H), 0.56e0.62 (m, 2H), 1.21e1.27 (m, 1H), 1.91 (s,
3H), 3.89 (d, J¼6.9 Hz, 2H), 4.86 (s, 2H), 6.49e6.57 (m, 2H),
6.86e6.93 (m, 1H), 6.96e7.07 (m, 2H), 7.89e7.99 (m, 2H), 9.62 (s,
Mp 129e131 ꢁC; 1H NMR (300 MHz, DMSO-d6)
(s, 9H), 6.95 (br s, 3H), 8.93 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
43.78, 48.80, 91.43, 165.24; IR (ATR)
1619, 1453, 1417, 1319 cmꢀ1
d
3.48 (s, 9H), 3.59
1H); 13C NMR (75 MHz, DMSO-d6)
d
3.98, 10.93, 13.05, 73.12, 112.94,
114.87, 116.04, 118.90, 126.30, 127.58, 130.28, 137.68, 148.10, 161.97,
165.55; IR (KBr)
3419, 3313, 1644 cmꢀ1; MS (FAB) m/z 297 (MH)þ.
d
n
.
n