March 2008
Notes
Chem. Pharm. Bull. 56(3) 383—384 (2008)
383
Unusual Detritylation of Tritylated Tetrazole in Sartan Molecules
Sankareswaran SRIMURUGAN, Paulsamy SURESH, Balaji BABU, Salmara Ganeshbhat HIRIYANNA, and
*
Hari Narayan PATI
Department of Process Chemistry, Advinus Therapeutics; Bangalore-560058, India.
Received October 4, 2007; accepted December 11, 2007; published online December 14, 2007
Tritylated tetrazole of 2a underwent unusual detritylation under basic reaction condition during the synthe-
sis of methyl ether of olmesartan medoxomil 1. The unusual detritylation was found to be a common feature in
the case of all tetrazole containing Sartan molecules (3—7).
Key words tritylamine; deprotection; detritylation; sartan molecule; tetrazole
Triphenylmethyl (Trityl) and related groups have been
used extensively for N- and O-protection, where detritylation
is accomplished employing acidic conditions, either with
protonic acids1) (e.g., hydrochloric acid, acetic acid, CF3COOH)
or lewis acids2) (e.g.
,
ZnBr2, diisopropyl aluminium chloride,
Yb(OTf)3). Other methods reported for removal of trityl
groups involve reductive protocols (e.g., Li powder and a cat-
alytic amount of naphthalene).3) Trityl protected alcohols and
amines are reported to exhibit good stability under basic re-
action conditions and this property is made use in the total
synthesis of various natural products and oligonucleotides.
Sartans are a class of drugs that are effective in treating
Chart 1
tion to 2 in 92% yield as shown in Chart 1.
The unusual detritylation was interesting which prompted
hypertension and heart failure. These drugs block the renin- us to screen all the tetrazole containing sartan drugs. Accord-
angiotensin system and represent one of the most significant ingly, olmesartan medoxomil (3) was tritylated by the usual
therapeutic interventions available for the treatment of hyper- method and the tritylated olmesartan medoxomil (3a) was
tension.4—6) There are about seven sartans in clinical practice, subjected to similar reaction condition as indicated in Chart
of which five of them possess a tetrazole moiety in their 1. As expected, detritylation was effected forming 3 in 90%
structure. The protection and deprotection of the N-atom of yield along with little hydrolysed product. In a similar way
the tetrazole moiety becomes essential during the synthesis tritylated losartan (4a), valsartan (5a), candesartan (6a) and
of these sartan drugs. Olmesartan medoxomil (3) is a newest irbesartan (7a) were synthesized and subjected to deprotec-
addition to the family of sartan drugs.7,8) The multigram syn- tion using aqueous NaOH as shown in Chart 2. The results
thesis of (3) is always accompanied by the formation of cor- obtained are shown in Table 1.
responding methyl ether (1) as an impurity. For impurity pro-
filing of an active pharmaceutical ingredient (API) we have were isolated without any side reactions in 84—90% yield.
synthesized and characterized this potential impurity (1). Heterocyclic tritylamines other than sartan molecules were
The reaction times were around 2—3 h and the products
During the synthesis, it was observed that the tritylated tetra- examined under same reaction condition to have a better in-
zole unusually underwent detritylation under basic reaction sight on detritylation reaction. Simple tritylated pyrazole,
condition.9)
imidazole and imidazole derivative 8 were found to be stable
under basic reaction condition both at ambient temperature
and also at reflux temperature. No detritylation however was
observed in all the cases.
In this communication, we have generalized this unusual
detritylation under basic condition as a common feature in
the case of tetrazole containing sartan molecules (3—7).
Results and Discussion
The tetrazole was protected with trityl group during the
synthesis of 1 while the other protecting groups (e.g., N-Boc) Conclusion
were unsuccessful. The synthetic route involves the hydroly-
An unusual N-detritylation in sartan molecules under basic
sis of ethyl ester of 2a under basic condition. On treatment of condition was identified and explored. This can be regarded
2a with saturated NaOH solution in aqueous methanol, unex- as an exclusive method of detritylation for sartan molecules
pectedly hydrolysis of ester was accompanied by detrityla- and not for other heterocyclic compounds. This should be a
∗ To whom correspondence should be addressed. e-mail: hari.pati@advinus.com
© 2008 Pharmaceutical Society of Japan