Efficient and viable synthesis
development for Tiaprofenic Acid in pharmaceutical
industries
Raghubabu K.1*,
Mohan N.1, Kalyanaramu B.2, Ramadas C.3 Narayanarao
M.3
1Department
of Engineering Chemistry, AU College of Engineering (A), Andhra University, Visakhapatnam-530003,
AP (India)
2Department
of Chemistry, Maharajah’s College (Aided & Autonomous),
Vizianagaram-535002, AP (India).
3Tyche Industries
Limited, 11-15-28, Siris Complex, Doctors Colony, L B Nagar, Hyderabad-500074, India
ABSTRACT:
An
industrially efficient method was developed to synthesize of tiaprofenic acid (5-benzoyl-alpha-methyl-2-thiopheneacetic
acid) (1) which is a very important
pharmaceutical compound having anti-inflammatory and analgesic activity. Sodium
salt of propionitrile is reacted with
5-benzoyl-2-bromothiophene (4) to
yield nitrile crude (5) and further hydrolysis to give tiaprofenic
acid (5-benzoyl-alpha-methyl-2-thiopheneacetic acid) (1).
KEYWORDS: Sodamide, Propionitrile,
Anti-inflammatory, Tiaprofenic acid, NSAID
INTRODUCTION:
Tiaprofenic
Acid (1) is NSAID (non-steroidal
anti-inflammatory drug), similar to ibuprofen. It reduces inflammation and
fever and relieves pain. Tiaprofenic Acid (1) is also used in the treatment of
arthritis, headaches and menstrual cramps. Several processes for the
preparation of the alpha-methyl-2-thiopheneacetic acid (2) derivatives are known.
All
the known processes1-4 (Scheme-1) use the
alpha-methyl-2-thiopheneaceticacid (2)
as intermediate product.
The
preparation of said intermediate shows several drawbacks being based on very
laborious and low yield processes contemplating very expensive or very
dangerous reactants such as sodium cyanide. We wish to report to use sodamide
as base, which is easy to handle even at
the production scale and the room temperature is sufficient for reaction takes
place. We present an economically and industrially viable synthesis of
5-benzoyl-alpha-methyl-2-thiopheneacetic acid, which is obtained from propionitrile (3)
and 5-benzoyl-2-bromothiophene (4)
in two steps by employing commercially available, less expensive, nontoxic raw
materials by simplified experimental conditions and isolation procedures.
Sodium salt of propionitrile is reacted with
5-benzoyl-2-bromothiophene to yield nitrile crude (5) and further hydrolysis to give tiaprofenic acid (-benzoyl-alpha-methyl-2-thiopheneacetic
acid) (1) (Scheme-2)
Preparation of 5-benzoyl-alpha-methyl-2-thiopheneacetic acid (1):
Propionitrile (10 grams, 0.1818 mol) are slowly added while maintaining the
temperature between 0 and 50C to a suspension of sodamide
(5 grams, 0.1282 mol) in 15ml of THF. At the end the mixture is stirred for 2
hrs at 00C. A solution separately prepared dissolving (20grms, 0.0749 mol) of 5-benzoyl–2-bromothiophene in 40ml THF is
slowly added at 0-50C. The mixture was refluxed for 3 hrs and then quenched
with 2 M HCl (200 ml), extracted two times with methylene dichloride (300 ml), and washed with brine (50
ml). After drying over MgSO4, the solution was filtered,
concentrated by rotary evaporation to yield crude nitrile.
Charged 10% aq. NaOH solution (100 ml) and maintain 90-950C for 2 hrs and
washed two times with MDC (300 ml) collected aq. layer and acidified with con HCl and stir for 3 hrs at room temperature and then filter
and wash with water (100 ml). (Yield: 10.7 g, 55%, HPLC purity 98%; mp 95-970C).
1H NMR (300 MHz, CDCl3) : 1.67 (d, 3H); 4.12 (m, 1H); 7.05 (d, 1H);
7.45-7.60 (m, 4H); 7.85 (d, 2H);
This paper describes the synthesis of tiaprofenic
acid (5-benzoy-alph-methyl-2-thiopheneacetic acid) and the reagents used in the
proposed synthesis are normal cost and readily available in all chemical
laboratories and small scale pharmaceutical industries.
Acknowledgement:
The
authors are thankful to Tyche Industries Limited for
their continuous cooperation in this work.
REFERENCES:
1. Bercot–Vatteroni M.; Moreau et R.C.; Reynaud. P.; Soc. Chem. Bull.; Fr. 1961: 1820;
2. French Patent Application
N.2398068; Canadian Patent N.1201442).
3. Armitage B.J.;
Jeffery J.E.; Nicholson J.S.; US Pat.3959364
(Chem. Abstr., 1976; 117:131048d)
4. Frisell C, Lawesson S. O. Organic Syntheses, 1973; 5: 642
Received on 19.10.2012
Modified on 23.10.2012
Accepted on 25.10.2012
© A&V Publication all right reserved
Research Journal of Pharmaceutical Dosage
Forms and Technology. 4(6): November–December, 2012, 318-319