Organic Process Research & Development
ARTICLE
aqueous layer was then acidified by HOAc to pH = 4-5 to
generate a slurry. The slurry was extracted with EtOAc (3 ꢀ
400 mL). The organic layers were combined, dried over Na2SO4,
filtered, and concentrated to afford 18 g (78%) of 1 as a pale
yellow solid. After being dried under vacuum overnight, 1H NMR
showed that the product was an acetate salt (0.8 equiv by NMR
2 h. To the reaction mixture was added 1.5 L water, and lots of
solids were precipitated out. The solids were collected by filtration,
triturated with a mixture of EOAc (50 mL) and saturated aq
NaHCO3 (50 mL), filtered, washed with water and EtOAc, and
dried to afford 12.5 g (84%) of 4b as a white solid. LC-MS (APCI,
Mþ þ 1) 378.0; 1H NMR (400 MHz, DMSO-d6) 3.47-3.59 (m,
4 H) 3.72-3.83 (m, 4 H) 3.85 (s, 3 H) 7.06 (dd, J = 8.56, 2.52 Hz,
1 H) 7.22 (d, J = 2.52 Hz, 1H) 7.36 (d, J = 8.56 Hz, 1 H).
3-(2-Chloro-4-methoxy-phenyl)-4-cyano-5-morpholin-4-
yl-thiophene-2-carboxylic Acid [2-methyl-prop-(E)-ylide-
ne]amide (14b). A brown slurry of 3-(2-chloro-4-methoxy-
phenyl)-4-cyano-5-morpholin-4-yl-thiophene-2-carboxylic acid
amide (4b) (12.5 g, 33.1 mmol) in 80 mL of DMF-DMA was
heated to reflux at 110 °C for 1.5 h to form a yellow slurry.
MeOH was generated as the reaction proceeded. After cooling,
the solvent was removed under reduced pressure. The sticky
residue was triturated with MeOH and dried under vacuum to
afford 14.0 g (95%) of 14b as a white solid. LC-MS (APCI, Mþ
þ 1) 433.0; 1H NMR (400 MHz, DMSO-d6) 2.75 (s, 3 H) 3.07
(s, 3 H) 3.51-3.60 (m, 4 H) 3.74-3.80 (m, 4 H) 3.81 (s, 3 H)
6.94 (dd, J = 8.56, 2.52 Hz,1 H) 7.08 (d, J = 2.52 Hz, 1 H) 7.19 (d,
J = 8.31 Hz, 1 H) 8.31 (s, 1 H).
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integration). LC-MS (APCI, Mþ þ 1) 406.0; H NMR
(400 MHz, DMSO-d6) of its HOAc salt: 1.91 (s, 3H from
acetate salt), 3.49-3.58 (m, 4 H) 3.75-3.84 (m, 4 H) 7.37-7.44
(m, 1 H) 7.46-7.51 (m, 1 H) 7.72 (d, J = 2.01 Hz, 1 H) 8.42 (s,
1 H), triazole N-H protons were missing due to deuterium
exchange; 13C NMR (100 MHz, DMSO-d6) 50.2, 65.2, 88.8,
115.9, 127.2, 128.8, 132.6, 133.0, 133.8, 134.2, 134.5, 144.0,
155.5, 165.1, one triazole carbon missing due to overlap; IR
(neat, cm-1) 3054, 2900, 2207, 1597, 1508; HRMS Calcd for
C17H13Cl2N5OS: 405.0219. Found: 405.0218.
3-(2-Chloro-4-methoxy-phenyl)-4-cyano-5-morpholin-4-
yl-thiophene-2-carboxylic Acid Ethyl Ester (5b). A mixture
of 4-cyano-3-iodo-5-morpholin-4-yl-thiophene-2-carboxylic acid
ethyl ester (6) (18 g, 46 mmol, 1.0 equiv), 2-chloro-4-methoxy
phenylboronic acid (10.3 g, 55.1 mmol, 1.2 equiv), Pd(PtBu3)2
(1.17 g, 2.3 mmol, 0.05 equiv), CsF (21.1 g, 138 mmol, 3.0 equiv),
dioxane (200 mL), toluene (12 mL) and water (50 mL) was
flushed with N2 and stirred at 85 °C. After being stirred at 85 °C
for 12 h, the reaction was judged complete by LC-MS. To the
reaction mixture was added Si-thiol (15 g), and the mixture was
stirred at 25 °C for 2 h to remove the Pd catalyst. The resulting
mixture was then diluted with EtOAc and filtered through Celite.
The filtrate was washed with brine, dried over Na2SO4, filtered,
and concentrated to afford 19 g (100% yield) 5b as a pale yellow
solid with over 85% purity, which was used in the subsequent
hydrolysis step without further purification. LC-MS (APCI, Mþ
4-(2-Chloro-4-methoxy-phenyl)-2-morpholin-4-yl-5-(2H-
[1,2,4]triazol-3-yl)-thiophene-3-carbonitrile (2). To a slurry
of 3-(2-chloro-4-methoxy-phenyl)-4-cyano-5-morpholin-4-yl-
thiophene-2-carboxylic acid [2-methyl-prop-(E)-ylidene]-amide
(14b) (14 g, 32 mmol, 1.0 equiv) in HOAc (20 mL) and EtOH
(100 mL) was added dropwise NH2NH2 H2O (10.7 mL, 323
3
mmol, 10 equiv) whilst maintaining the reaction mixture tem-
perature at -10-0 °C with stirring. Upon the completion of
addition, the reaction was slowly warmed to 60 °C and allowed
to stir at this temperature for 1.5 h to reach completion. The
resulting yellow slurry was cooled to 25 °C, diluted with water
(500 mL), and extracted with EtOAc (500 mL). The separated
organic layer was treated with 1.0 M NaOH (500 mL) and the
desired triazole product was taken into aqueous solution. The
aqueous solution was separated and further washed with EtOAc
(2 ꢀ 200 mL) to remove all other organic impurities. The
aqueous layer was then acidified by HOAc to pH = 4-5 to
generate a slurry. The slurry was extracted with EtOAc (3 ꢀ
200 mL). The organic layers were combined, dried over Na2SO4,
filtered, and concentrated to afford 8.0 g (55%) of 2 as a white
1
þ 1) 407.0; H NMR (400 MHz, DMSO-d6) 0.99-1.05 (m,
3 H) 3.58-3.65 (m, 4 H) 3.75-3.81 (m, 4 H) 3.83 (s, 3 H)
3.98-4.08 (m, 2 H) 6.98 (dd, J = 8.56, 2.52 Hz, 1 H) 7.14 (d, J =
2.52 Hz, 1 H) 7.25 (d, J = 8.56 Hz, 1 H).
3-(2-Chloro-4-methoxy-phenyl)-4-cyano-5-morpholin-4-
yl-thiophene-2-carboxylic Acid (13b). To a suspension of
3-(2-chloro-4-methoxy-phenyl)-4-cyano-5-morpholin-4-yl-thio-
phene-2-carboxylic acid ethyl ester (5b) (19.0 g, 47 mmol,
1.0 equiv) in MeOH (200 mL) and THF (50 mL) was added a
solution of LiOH (5.59 g, 233 mmol, 5 equiv) in water (50 mL)
at 25 °C. The resulting clear-orange solution was stirred at 25 °C
for 12 h to reach completion. The volatiles were removed under
reduced pressure. The remaining aqueous solution was solidified
during concentration. This slurry was diluted with water and
acidified to pH ≈ 3 with 2 N HCl. The resulting solids were
filtered, washed with water and a minimal amount of MeOH, and
dried under vacuum at 50 °C for 7 h to afford 16 g (90%) of 13b
as a pale-yellow solid. LC-MS (APCI, Mþ þ 1) 379.0; 1H NMR
(400 MHz, DMSO-d6) 3.54-3.63 (m, 4 H) 3.74-3.81 (m, 4 H)
3.83 (s, 3 H) 6.97 (dd, J = 8.56, 2.52 Hz, 1 H) 7.12 (d, J = 2.52 Hz,
1H) 7.25 (d, J = 8.56 Hz, 1 H).
3-(2-Chloro-4-methoxy-phenyl)-4-cyano-5-morpholin-4-
yl-thiophene-2-carboxylic Acid Amide (4b). To a solution of
3-(2-chloro-4-methoxy-phenyl)-4-cyano-5-morpholin-4-yl-thio-
phene-2-carboxylic acid (13b) (15.0 g, 40 mmol, 1.0 equiv)
in DMF (500 mL) was added CDMT (8.51 g, 47.5 mmol,
1.2 equiv) and NMM (9.2 mL, 83.4 mmol, 2.0 equiv). The
resulting mixture was stirred at 25 °C for 1 h to form a transparent
solution. Ammonia gas was bubbled through the mixture for
30 min, and the reaction was then allowed to stir at 25 °C for
1
solid. After being dried under vacuum overnight, the H NMR
showed that the product was an acetate salt (0.75 equiv). LC-
1
MS (APCI, Mþ þ 1) 402.0; H NMR (400 MHz, DMSO-d6)
1.91 (s, 3 H from HOAc salts) 3.49-3.56 (m, 4 H) 3.76-3.83
(m, 4 H) 3.84 (s, 3 H) 6.96 (dd, J = 8.69, 2.64 Hz, 1 H) 7.11 (d,
J = 2.52 Hz, 1H) 7.27 (d, J = 8.56 Hz, 1 H) 8.41 (s, 1 H), triazole
N-H protons were missing due to deuterium exchange; 13C
NMR (100 MHz, DMSO-d6) 50.2, 55.3, 65.2, 88.9, 113.0, 114.3,
116.1, 125.3, 132.3, 133.7, 135.7, 144.0, 155.5, 160.8, 164.9, one
triazole carbon missing due to overlap; IR (neat, cm-1) 3239,
2902, 2205, 1606, 1503; HRMS Calcd for C18H16ClN5O2S:
401.0708. Found: 401.0713.
Ethyl 4-cyano-3-(4-cyano-2-fluorophenyl)-5-morpholi-
nothiophene-2-carboxylate (5c). A slurry of ethyl 4-cyano-3-
iodo-5-morpholinothiophene-2-carboxylate (6) (250.0 g, 637 mmol)
and 4-cyano-2-fluorophenylboronic acid (126.2 g, 765 mmol,
1.2 equiv) in a mixture of toluene (188 mL) and 1,4-dioxane
(3 L) was charged a with premade solution of CsF (290.5 g,
1.91 mol, 3 equiv) in water (750 mL) in a jacketed reactor. The
resulting slurry was purged with N2 for 20 min and charged with
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dx.doi.org/10.1021/op100286g |Org. Process Res. Dev. 2011, 15, 556–564