Loratadina

Issue in Honor of Prof. J. Elguero and P. Molina

ARKIVOC 2005 (ix) 200-206

Synthesis of 2- and 4-hydroxymethyl Loratadine, usual impurities in Loratadine syrup formulations
Verónica Cerrada, M. Paz Matía-Martín, J. Luis Novella, and Julio Alvarez-Builla* Planta Piloto de Química Fina, Universidad de Alcalá. 28871 Alcalá de Henares, Madrid, Spain E-mail: julio.alvarez@uah.es Dedicated toProf. José Elguero (received 31 Dec 04; accepted 21 Mar 05; published on the web 25 Mar 05) Abstract 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. Keywords:Fused pyridines, pharmaceuticals, Loratadine, synthesis, contaminants

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.2,3 Accelerated 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. 3 The preparation of both contaminants has been necessary to prepare references for quality control of drugformulations, and a scheme has been developed starting from the parent Loratadine 1.
O N 1 Loratadine R1 = R2 = H 2 R1= CH2OH; R2 = H 3 R1 = H; R2 = CH2OH O CH3

N Cl R2

R1

Figure 1
ISSN 1424-6376 Page 200
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Issue in Honor of Prof. J. Elguero and P. Molina

ARKIVOC 2005 (ix) 200-206

Results and Discussion
The substitution of the pyridine moiety has been performedusing 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-isomerpredominated (4:1). Both products were separated by chromatography, and used to prepare the final compounds.
O N MCPBA N Cl 1 (87%) Cl 4 Br3OP (30%) O N O CH3 CuCN N Cl 8 Br (40%) N Cl 6 O N O CH3 O N O + N (CH3O)2SO2 (85%) Cl 5 KCN (60%) O CH3 (14%) O N O CH3 O CH3 O N CH3 O + N _ CH3O-SO3 O CH3

CN Cl

N

CN 7

Scheme 1 A more selective approach to 6 was performed by bromination of theN-oxide 4, in the presence of Br3PO, by adapting the process described by Jung et al.,6 which allowed the preparation of 8. An alternative chlorination with Cl3PO, 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 isindicated 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.

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O N HCl CN MeOH N (75%) 6 Cl 9 O CH3 O N O O CH3 DIBAL-H O CH3ARKIVOC 2005 (ix) 200-206

O N

O

CH3

N Cl

N (12%) Cl 2

OH

Scheme 2 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.
O N HCl MeOH (48%) Cl CN 7 10 O O CH3 O N O CH3 O N DIBAL-H (12%) Cl O CH3 3 OH O CH3

N Cl

N

N

Scheme 3 Identification of the products in the...