TFAA-H₃PO₄ mediated rapid and single-step synthesis of mutual prodrugs of paracetamol and NSAIDs

Figures & data

short-legendScheme 1. TFAA-H3PO4 mediated esterification of paracetamol (1) with NSAIDs (2).

Table 1. Effect of solvents on the reaction of paracetamol (1) and aspirin (2a).^a

Entry	Solvent	Time (h)	Yield^b (%)
1	Benzene	48	22
2	Chloroform	48	25
3	Acetone	48	25
4	Acetonitrile	6	75
5	Acetonitrile	14	77
6	Acetonitrile	9	82^c
^aAll the reactions were carried out using 1 (1.0 mmol), 2a (1.0 mmol), 85% H3PO4 (1.0 mmol), TFAA (4.0 mmol) in a solvent (5 mL).
^bIsolated yield.
^cThe reaction was carried out at 60°C.

Table 2. Preparation of ester (3) via the reaction of paracetamol (1) with NSAIDs (2).^a

Entry	Ar =	ArCO2H 2 (NSAID)	Esters 3	Reaction at RT		Reaction at 60°C
				Time (h)	Yield^b (%)	Time (h)	Yield^b (%)
1		2a (Aspirin)	3a	14	77	9	82
2		2b (Indomethacin)	3b	10	70	3	85
3		2c (Naproxen)	3c	14	95	5	98
4		2d (Ibuprofen)	3d	10	16	5	96
^aAll the reactions were carried out using 1 (1.0 mmol), 2 (1.0 mmol), 85% H3PO4 (1.0 mmol), TFAA (4.0 mmol) either under neat conditions or in acetonitrile (5 mL).
^bIsolated yield.

Figure 1.  ¹H NMR spectra of compound 3a.

Figure 2.  ¹H NMR spectra of compound 4.

Figure 3.  ¹³C NMR spectra of compound 4.

short-legendScheme 2. TFAA-H3PO4 mediated reaction of 1 with dichlofenec (2e).

short-legendScheme 3. Preparation of compound 3e using chloroformate method 10 .

short-legendScheme 4. Reported two-step process for the preparation of mutual prodrugs 10 15.

Table 3. A comparison between the TFAA-H₃PO₄ mediated esterification of 1 and 2 with conventional two-step methods.

Entry	NSAIDs (2)	Products (3)	TFAA-H3PO4 mediated method		Acid chloride method		Mixed anhydride method^a
			Time (h)	Yield (%)	Time^b (h)	Yield (%)	Time (h)	Yield (%)
1	2a	3a	9	82	13	77	Overnight	77
2	2b	3b	3	85	10	75	Overnight	70
3	2c	3c	5	98	13	95	Overnight	95
4	2d	3d	5	96	13	90	Overnight	90
5	2e	3e (ester)^c and/or 4	1	95^d	13	77^e	Overnight	55^f
^aResults are summarized from 10.
^bTotal time taken.
^cExpected ester.
^dYield of compound 4 only.
^eCombined yield of 3e and 4.
^fYield of compound 3e.

Fadl , T.A. Omar , F.A. Inflammopharmacology 1998 , 6 , 143 – 157 .

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Wechter , W.J. ; Schwartz , E.B. ; World Patent Application No WO/2004/032845 .

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