Organic Process Research & Development
Communication
next challenge was to show the advantage in the terms of the
effluent load generated per kilogram of the intermediate (1)
produced by the current process. This comparison was very
much required for making any commercial decision. In order to
have an idea of the effluent load, all four processes (references 4
(q, 2H, J = 8), 1.2 (t, 3H, J = 8). IR (KBr): 3349 (alcoholic
OH), 2663 (aromatic C−H), 1037 (C−O)
5-Ethyl 2-Vinyl Pyridine (3). Fifty grams of 2-(5-ethyl-
pyridine-2-yl)ethanol (1) and 37g (1.1 mol equiv) of
triethylamine were dissolved in toluene and p-toluenesulfonyl
chloride (42 g, 1.1 mol equiv) was added slowly at 0−5 °C for
about 2−4 h. After that the reaction mass was maintained at 0−
5 °C for 30−60 min. The progress of the reaction was
monitored by TLC. After the completion of the reaction, the
precipitated triethylamine hydrochloride was filtered off to give
toluene-4-sulfonic acid-2-(5-ethyl-pyridin-2-yl)ethylester (7).
This was followed by addition of K CO and toluene, and
5, with and without recovery, and the current process) were
compared for the waste generated per kilogram of (1), and data
are captured in Table 6. Total effluent generated by the present
4
route (route-3) is 75% less than route-1 , 59% less than route-
5
5
2
and 8% less than route-2r.
CONCLUSIONS
2
3
■
the reaction mass was refluxed for 10 h. The progress of the
reaction was monitored by TLC. After the completion of the
reaction, salts were filtered, organic layer washed with 25 mL
water and the organic layer concentrated under reduced
The present article describes the development of a process for
the manufacturing of 2-(5-ethylpyridin-2-yl)ethan-1-ol. The
process was improved by exploiting the physical characteristics
of the aqueous formaldehyde which allowed us to perform the
reaction in the aqueous formaldehyde itself without using any
other organic cosolvent. Recovering and recycling of unreacted
starting material (2) enabled us to increase the efficiency
further with decreased effluent load. The current process
enabled us to increase the overall productivity by 27%.
pressure to obtain the title compound (3) in 100% yield.
1
Mass found (M + H): 134; H NMR: (CDCl , 200 MHz): δ
3
=
=
7.1−8.4 (m, 3H), 6.8 (dd,1H, J = 13.2), 5.6 and 6.1 (dd, 2H, J
12), 2.6 (q, 2H, J = 7.6), 1.2 (t, 3H, J = 7.6). IR (KBr): 2663
(
aromatic C−H), 2966.6 (C−H, aliphatic).
-(5-Ethylpyridin-2-yl)prop-2-en-1-ol (4). Fifty grams of
-(5-ethyl-pyridine-2-yl)propane-1,3-diol (5) in 85 g (3 mol
2
Experimental Section. Chemicals and solvents used were
purchased either from Fluka or Merck. All the reagents were of
analytical grade. Thin layer chromatography (TLC) was
performed on E-Merck AL silica gel 60 F254 plates and
visualized under UV light. IR spectra were recorded as KBr
pellet with Perkin-Elmer Spectrum GX FTIR instrument, and
2
equiv) of Ac O was refluxed for 6 h. The progress of the
2
reaction was monitored by TLC. After the completion of the
reaction, Ac O was removed under vacuum using a closely
2
packed Fenske-type packing column to give 2-(2-pyridinyl)-3-
1
acetoxypropene (6). A solution of (6) and K CO in ethanol
only diagnostic and/or intense peaks are reported. H NMR
2 3
was refluxed for 15 h. The progress of the reaction was
monitored by TLC. After the completion of the reaction, the
reaction mass was concentrated, the resulting solid was
spectra were recorded in CDCl with a Varian Mercury plus
3
2
00 MHz instrument. Signals due to the solvent served as the
internal standard. All the chemical shifts were reported in δ
ppm) using TMS as an internal standard. Mass spectra were
recorded with a PE Sciex model API 3000 instrument.
-(5-Ethylpyridin-2-yl)ethan-1-ol (1). To 1000 mL steel
autoclave was added an aqueous solution of formaldehyde
86.73 g on 100% basis) and 5-ethyl-2-methylpyridine (200 g)
extracted with CH Cl , the solvent was removed under vacuum,
(
2
2
and the resulting oil was distilled under reduced pressure (<10
mmHg at 165−170 °C) to obtain the title compound (4) in
2
7
1% yield.
1
Mass found (M + H): 162, H NMR: (CDCl , 200 MHz): δ
(
3
=
7−8.3 (m, 3H), 5.6 and 5.3 (s, 2H), 2.6 (q, 2H, J = 7.2), 1.2
at room temperature. The temperature was raised to 155 °C
over a period of one hour. The resultant reaction mass was
maintained at the same temperature for 3 h. The reaction mass
was cooled to room temperature, and the contents were
transferred into a fractional distillation setup fitted with a
closely packed Fenske-type column. Three factions were
collected under reduced pressure using the PIG adapter. 5-
Ethyl-2-methylpyridine (102 g) was collected as fraction-1
below 110 °C (15 Torr), 5-ethyl-2-vinylpyridine (3−4 g), as
fraction-2 between 110 and 130 °C (15 Torr), and 2-(5-
ethylpyridin-2-yl)ethan-1-ol (70 g) as fraction-3 below 160 °C
(
t, 3H, J = 8). IR (KBr): 3399 (alcoholic OH), 2856 (aromatic
C−H), 1031 (C−O), 2925.6 (C−H, aliphatic).
AUTHOR INFORMATION
■
Notes
†
Dr. Reddy’s Communication No. IPDO IPM-IPDO IPM-
00374.
The authors declare no competing financial interest.
(
10 Torr).
1
Found mass (M + H): 152, H NMR (CDCl , 200 MHz): δ
ACKNOWLEDGMENTS
3
■
=
=
8.3−7.0 (m, 3H), 4.5 (s, 1H), 4.0 (t, 2H, J = 5.6), 3.0 (t, 2H, J
We are grateful to the management of Dr. Reddy’s Laboratories
Limited for giving support to carry out this work. We are also
appreciative to the colleagues of analytical, PR&D, and process
engineering departments for their cooperation, especially Dr.
Amarendra Bhattacharya, Sandeep Reddy, and Alikepally
Srinivasa Reddy, for helpful considerations.
5.6), 2.6 (q, 2H, J = 7.8), 1.2 (t, 3H, J = 7.6). IR (KBr): 3349
(
OH), 2663 (aromatic C−H), 1037 (C−O).
2
-(5-Ethyl-pyridin-2-yl)-1-propan-1,3-diol (5). To a
1
3
1
000 mL steel autoclave was added 50 g of (2) and 202 g of
7% aqueous formaldehyde, and the temperature was raised to
70−175 °C; the resultant reaction mass was maintained at that
temperature for about 10 h. Excess formaldehyde was removed
under reduced pressure; crude reaction mixture was dissolved
in methanol (∼200 mL), and solvent was removed under
vacuum. Chromatography with AcOEt/MeOH 9:1 to 8:2
REFERENCES
■
(
1) (a) Sohda, T.; Momose, Y.; Meguro, K.; Suiyama, Y.; Ikeda, H.
Arzneim. Forsch. 1990, 40, 37. (b) Sohda, T.; Ikeda, H.; Meguro, K.
Chem. Pharm. Bull. 1995, 43, 2169. (c) Gillies, P. S.; Dunn, Ch. J.
Drugs 2000, 60, 333.
furnished (5) as a white solid, with a yield of 20−27%.
1
Mass found (M + H): 182, H NMR: (CDCl , 200 MHz): δ
(2) Tanis, S. P.; Parker, T. T.; Cocla, J. R.; Fischer, R. M.; Kletzein, R.
3
7−8.3 (m, 3H), 4.1 (s, 2H), 4 (m, 4H), 3 (t, 2H, J = 5.6), 2.6
F. J. Med. Chem. 1996, 39, 5053.
1
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dx.doi.org/10.1021/op400196y | Org. Process Res. Dev. 2014, 18, 168−173