Synthesis of 2-and 4-hydroxymethyl Loratadine, usual impurities in Loratadine syrup formulations

The synthesis of two contaminants of Loratadine, generated when the product is formulated as a syrup, is described. The products, identified as 2-and 4-hydroxymethyl derivatives of the starting compounds, are obtained by the corresponding substitution of the pyridine moiety of Loratadine.


Introduction
Loratadine, 1, is [4-(8-chloro-5,6-dihydrobenzo [5,6]cyclohepta [1,2-b]pyridin-11-ylidene)piperidine -1-carboxylic acid ethyl ester].It is a non-sedating anthistamine, 1 marketed, inter alia, as a syrup.The formation of the 2-and 4-hydroxymethyl derivatives 2,3 (Figure 1) on the pyridine ring has been described, which result from a redox process of the drug with other formulation components. 2,3Accelerated degradation experiments showed the formation of 0.5% of both contaminants in the syrup, dependent on the presence of air, and eventually related to the in situ generation of formaldehyde. 3The preparation of both contaminants has been necessary to prepare references for quality control of drug formulations, and a scheme has been developed starting from the parent Loratadine 1.

Results and Discussion
The substitution of the pyridine moiety has been performed using the strategy of Okamota and Tani, 4 and Feely and Beavers-Tani, 5 as a crucial step (Scheme 1), by cyanide nucleophilic substitution of the corresponding 1-methoxypyridinium salts.The starting Loratadine 1 was converted into the N-oxide 4, and then into the N-methoxypyridinium salt 5.The attack of cyanide ion produced a mixture of the corresponding nitriles 6 and 7, in which the 2-isomer predominated (4:1).Both products were separated by chromatography, and used to prepare the final compounds.A more selective approach to 6 was performed by bromination of the N-oxide 4, in the presence of Br 3 PO, by adapting the process described by Jung et al., 6 which allowed the preparation of 8.An alternative chlorination with Cl 3 PO, always produced smaller yields.Then, treatment of 8 with CuCN produced 6. Extensive deacylation of the piperidine nitrogen was produced in both steps, and was the cause of the observed reduction of yields.
The process for obtaining 2 is indicated in Scheme 2, in which a classical Pinner process converted 6 into the ester 9. Finally, the best results in the reduction step were obtained with DIBAL-H, which produced the hydroxymethyl derivative 2 in small yield.A similar approach was applied to 7, going to the ester 10, which, on reduction, produced the hydroxymethyl derivative 3 (Scheme 3) also, in small yield.

Scheme 3
Identification of the products in the reduction steps 9-2 and 10-3, was performed by HPLC-MS of the crude mixture obtained in the process.The acid 11 was detected in the mixture used to obtain 2, with a yield of 43 %, while 12 was detected in the mixture used to obtain 3, with a yield of 48 % (Figure 2).Compound 4 (17g, 42.7 mmol) dissolved in acetone (500 mL), stirring at 60 ºC had dimethyl sulfate (4.05 mL, 42.7 mmol) added dropwise.The reaction mixture was stirred at the same temperature for 6 hours further.The solvent was evaporated to give 19.86g of the pyridinium salt 5 as a brown oil.This was used in the next step without further purification.Then, KCN (8.2g, 0.13 mol) was dissolved in water (100 mL) and 5 (19.86g, 0.15 mol) dissolved in water (200 mL) was added slowly.The reaction mixture was stirred at RT for 10 min, then was extracted with diethyl ether (3x100 mL).The organic layer was separated and a solid formed.This solid was filtered and characterized as compound 6.The filtrate was washed with HCl 10% (2x50 mL), the aqueous layer neutralized with saturated aq.Na 2 CO 3 and extracted with diethyl ether.The organic layer was dried over Na 2 SO 4 , filtered, concentrated to dryness, and the crude mixture purified by flash chromatography (SiO  (7 mL) and methanol (7 mL).The mixture was cooled at 0 ºC and HCl gas bubbled through it for 5 hours, then it was stirred at RT for 15h.The solvent was evaporated to dryness and the residue washed with water (50 mL), and extracted with CH 2 Cl 2 (3x50 mL).The organic layer was separated, dried over Na 2 SO 4 , filtered and concentrated to dryness.The residue was purified by flash chromatography (SiO 2 , hexane/AcOEt 2:1) to give 9 (0.32g, 75%) as a yellow solid.Mp 145-148 ºC.IR (KBr, cm

12 Figure 2 Issue in Honor of Prof. J. Elguero and P. Molina ARKIVOC 2005 (ix) 200-206 ISSN 1424-6376 Page 203 © ARKAT USA, Inc Experimental Section General Procedures.
1ll melting points were measured in capillary tubes and are uncorrected.IR spectra were determined on KBr disks using a Nicolet Impact 410 spectrophotometer.1HNMR spectra were obtained at 200 or 300 MHz on VARIAN GEMINI or UNITY apparatus.Chemical shifts (δ) were determined using TMS as internal standard, and multiplicity (s, singlet; d, doublet; dd, double-doublet; t, triplet; q, quartet; m, multiplet) is indicated for every signal.HPLC-MS analyses were performed on an Agilent 1100 apparatus.A chromatographic column Luna C18 (150 × 4.6 mm) 5 µm Phenomenex, was used, with a mobile phase formed by a triple gradient of 4% aq.formic acid (A), water (B), and acetonitrile (C).The gradient started as A (2.5%), B (93%) and C (4.5%), and in 30 min.reached A (2.5%), B (4.5%) and C (93%).In the Mass detector, the fragmenter operated at 70 eV.HRMS was performed on an Applied Biosystems 4700 spectrometer.Elemental analysis was performed on a LECO CHNS-932 instrument.All reactions were carried under Ar using solvents dried by routine procedures.