A Simple and convenient synthesis of triprolidine

Full text of DOI:10.1080/00304940902802370

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5. H. Loo, A. Hale and H. D’haenen, Int. Clin. Psychopharmacol., 17, 239 (2002).
6. C. Mentzer and C. Beaudet, Compt. Rend., 234, 1692 (1952).
7. H. M. C. Ferraz and L. F. Silva, Jr., Tetrahedron, 57, 9939 (2001).
8. L. Wu, H. Ye and D. Xiao, Zhongguo Yiyao Gongye Zazhi, 35, 67 (2004); Chem. Abstr., 144,
212431 (2004).
Organic Preparations and Procedures International, 41:168–171, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940902802370
A Simple and Convenient Synthesis of Triprolidine
G. Venkateswara Rao, B. Narayana Swamy,
P. Hareesh Kumar, and G. Chandrasekara Reddy
Vittal Mallya Scientific Research Foundation, Bangalore, India
Triprolidine (3)1 is an anti-histamine drug belonging to 1,1-diaryl-2-propyleneamine class1
having trade names ActidilTM and MyodilTM. It is a very popular first-generation anti-
histamine used for coughs and colds. In combination with pseudo-ephedrine, it is being sold
under the brand name ActifedTM. Recently Bolser,2 Pratter, and Abouzgheib3 reported that
for coughs associated with the common cold, first-generation anti-histamine decongestants
would be more effective than newer nonsedative antihistamines. This observation together
with continuous demand for first-generation anti-histamines prompted us to search for
nonhazardous commercially viable alternate synthesis of triprolidine.
The carbon-carbon double bond in propyleneamines such as Acrivastine,4–7 Pyrrobu-
tamine,8,9 Triprolidine, Zimeldine10 have been built by dehydration of corresponding
alcohols11–14 or by the Wittig method.15 n-Butyllithium has been employed in both the Wit-
tig condensation and in the preparation of the tertiary alcohol (Scheme 1) at around −70◦C.
However, large-scale preparations of these compounds employ the dehydration method
rather than the Wittig method because no efficient method was available for preparation of
the intermediates such as 2-(N,N-dialkylaminoethyl)triphenylphosphonium bromides and
2-aroylpyridines. Having developed commercially viable methods for the preparation of
2-(p-toloyl)pyridine (1)16 and 2-(N-pyrrolidinoethyl)triphenylphosphonium bromide (2)17
we now report the preparation of triprolidine (3) without the use of n-butyllithium.
The existing industrial scale preparation of triprolidine11–14 involves the con-
densation of 2-bromopyridine with β-pyrrolidino-4-methylpropiophenone using alkyl-
lithium at around −70◦C followed by dehydration using sulfuric acid between 140
Submitted August 29, 2008.
Address correspondence to G. Chandrasekara Reddy, P. O. Box 406, K. R. Road, Bangalore
560004, India. E-mail: gcreddy@vmsrf.org

A Simple and Convenient Synthesis of Triprolidine
169
Scheme 1
and 160◦C to give thermally more stable E-isomer. The disadvantages of this method
are poor yields (about 30% overall yield from bromopyridine), use of alkyllithium
at low temperatures (−70◦C) and the use of large amounts of sulfuric acid (five
volumes). The present method for the preparation of triprolidine involves the Wit-
tig condensation of compound 1 with compound 2 using potassium t-butoxide in
methylene dichloride (MDC) at around 10◦C followed by isomerisation with methane-
sulfonic acid (Scheme 2). The Wittig condensation of compounds 1 and 2 had
been performed using bases such as t-BuOK, sodium hydride, and sodamide in
various solvents such as hexane, toluene, dimethylformamide, dichloromethane, etc.
(Table 1). Combinations such as t-BuOK and MDC, NaH and DMF gave better results
while all other combinations result in formation of either traces of product or no product at
all. However, the relative ease of handling t-BuOK compared to NaH prompted us to use
the first combination for the scale-up.
Scheme 2
The Wittig condensation led to a mixture of E,Z-isomers in a 1:2 ratio and simple
heating of this mixture at 200◦C for several hours did not alter the isomeric ratio. The
existing dehydration and isomerization step using sulfuric acid is temperature-sensitive and
gave inconsistent results. In contrast, replacement of sulfuric acid with methanesulfonic
acid in the isomerization step did not affect the yield of the product or its purity even at a
temperature of about 200◦C. The crude E-isomer thus obtained was purified as its oxalate
and then converted into triprolidine hydrochloride using a saturated solution of HCl gas in
isopropanol.
In conclusion, we have developed a new, simple, and cost-effective route for the
preparation of triprolidine using intermediates 1 and 2. These intermediates are in turn
prepared using cheaper and commercially available raw materials. Thus this method is
not only commercially viable but also eliminates the use of hazardous n-butyllithium. We

170
Rao et al.
Table 1
Wittig Condensation of 1 and 2 under Different Conditions
Yield of
S. No
Base
Solvent
Product
E/Z Ratio
1
2
3
4
5
6
Sodamide
t-BuOK
t-BuOK
t-BuOK
NaH
THF, Toluene
DMF
THF, Toluene
MDC
THF, Toluene
DMF
Nil
Nil
Traces
71%
Traces
70%
—
—
—
1:2
—
NaH
1:2
believe that this method would also be useful for the preparation of compounds related to
triprolidine.
Experimental Section
All chemicals and solvents are LR grade and were used as obtained. Crystallizations were
performed in 2-butanone and ethyl acetate. The melting point was determined on Acro
melting point apparatus and are uncorrected. The IR Spectrum was recorded on a Thermo
Nicolet FT-IR instrument in KBr discs. 1H NMR and 13C NMR spectra were recorded on a
Bruker 200 MHz instrument. Chemical shifts are reported in δ units downfield from TMS as
an internal standard in the case of CDCl3 and DSS in the case of D2O. Mass spectrum was
recorded on a Q-TOF microTM instrument with AMPS MAX 10/6A system. The HPLC
analysis was performed using a Shimadzu CLASS VP using column conditions: RP18
column, 5 microns, 250 × 0.46 mm; mobile phase-acetonitrile: 0.1 M phosphate buffer of
pH 3.0 (7:3); detection 210 nm; flow rate 1 mL/min.
Preparation of 1-(4-Methylphenyl)-1-(2-pyridyl)-3-pyrrolidino-prop-1-ene E/Z Mixture
To a stirred solution of 1 (40 g, 0.2 mol) and 2 (104 g, 0.23 mol) in CH2Cl2 (400 mL) at
10◦C was added potassium t-butoxide as a solid (52 g, 0.46 mol) over a period of 1 hour.
After the complete addition of t-BuOK, the reaction mixture was stirred using a magnetic
stirrer at room temperature for 2 hours and then quenched in 500 mL of water. The layers
were separated and the product from the organic layer was extracted into aqueous oxalic
acid solution (25 g, in 250 mL of water), which was basified to pH 9.0 using 10% aqueous
NaOH solution and re-extracted into toluene (2 × 100 mL). The toluene layer was then
dried over anhydrous Na2SO4 and evaporated to give a reddish brown oil (40 g, 71% yield)
consisting of about two parts of Z and one part of E isomers of compound 3.
Isomerization of E and Z Mixture of 1-(4-Methylphenyl)-1-(2-pyridyl)-3-pyrrolidino-
prop-1-ene into Triprolidine (3)
The isomeric mixture of compound 3 (40 g) was heated with methanesulfonic acid (80 mL)
at 190◦C for 6 hours. The reaction mass was cooled to 10◦C and the pH adjusted to 8.0 using

A Simple and Convenient Synthesis of Triprolidine
171
conc. ammonia solution. The solid product was extracted into hexane (3 × 150 mL) and the
hexane layer was dried over anhydrous sodium sulfate and evaporated to afford triprolidine
(35 g, 87% yield). The free base thus obtained was dissolved in 175 mL of 2-butanone,
12 g of oxalic acid was added and then the mixture was stirred at room temperature for 2
hours. The solid product obtained was collected and dried to yield the E-isomer (99% pure
by HPLC, 38.0 g, 75% yield). The pure E-isomer of triprolidine oxalate was dissolved in
100 mL of water and 7 mL of conc. ammonia was added to yield triprolidine free base as a
solid (28 g). The solid obtained was dissolved in 150 mL of ethyl acetate, and 10% gaseous
HCl in isopropanol (37 mL) was added to afford triprolidine hydrochloride (29.0 g, 67%
yield) as a white solid, mp. 117–118◦C, lit.18 mp.116–118◦C.
IR(KBr): 3402, 3251, 2885, 2611, 2499, 1631, 1581, 1512, 1461, 1427, 991 cm−1. 1H
NMR (D2O, 200 MHz): δ 2.05 (brs, 4 H), 2.43 (s, 3 H), 3.34 (brs, 4 H), 3.97 (d, 2 H, J =
7.2 Hz), 6.55 (t, 1 H, J = 7.2 Hz), 7.13 (d, 2 H, J = 7.8 Hz), 7.25 (d, 1 H, J = 7.8 Hz), 7.37
(d, 2 H, J = 7.8 Hz), 7.43 (m, 1 H), 7.80 (t, 1 H, J = 7.8 Hz), 8.53 (d, 1 H, J = 4.4 Hz). 13C
NMR (CDCl3, 50 MHz) δ 21.1, 23.3, 52.3, 119.0, 123.0, 129.1, 129.6, 133.1, 136.5, 138.3,
148.1, 149.2, 156.2; TOF-MS (ES+) m/z: 279(M+H)+, 208 (100%).
References
1. S. A. Benezra and Yang Chen-Hwa, Analytical Profiles of Drug Substances, 8, 509 (1979).
2. D. C. Bolser, Chest, 129, 238 (2006).
3. M. R. Pratter and W. Abouzgheib, Chest, 129, 1121 (2006).
4. T. O. V. Rydh and C. B. J. Uttf, BE 842368 (1976); Chem. Abstr., 87, 102173 (1977).
5. J. E. Baeckvall, R. E. Nordberg, J. E Nystroem, T. Hoegberg and B. Ulff, J. Org. Chem., 46, 3479
(1981).
6. T. Hoegberg, B. Ulff, A. L. Renyi and S. B. Ross, J. Med. Chem., 24, 1499 (1981).
7. T. Hoegberg and C. B. J. Ulff, EP 52588 (1982); Chem. Abstr., 97, 127511 (1982).
8. R. N. Brogden and D. Mctavish, Drugs, 41, 927 (1991).
9. J. W. A. Findlay and G. G. Coker, EP 85959 (1983); Chem. Abstr., 100, 6345 (1984).
10. J. Mills, US Patent, 2655509 (1953); Chem. Abstr., 48, 77749 (1954).
11. D. W. Adamson, US Patent 2,712,020 (1955); Chem. Abstr., 49, 4026 (1955).
12. D. W. Adamson, US Patent 2,712,023 (1955); Chem. Abstr., 49, 10377 (1955).
13. D. W. Adamson, J. Chem. Soc., 312 (1958).
14. D. W. Adamson, DE 1227464 (1966); Chem. Abstr., 66, 37780 (1967).
15. G. G. Coker and J. W. A. Findlay, US Patent, 4,639,459 (1987); Chem. Abstr., 106, 196267
(1987).
16. G. V. Rao, B. N. Swamy, P. H. Kumar, and G. C. Reddy, Synth. Commun., 39, 1 (2009).
17. G. V. Rao and G. C. Reddy, Tetrahedron Lett., 49, 824 (2008).
18. The Merck Index, 12th Edition, (1996).