2′-halobiphenyl-4-yl intermediates in the synthesis of angiotensin II antagonists

#This is a National Stage entry of International Application No. PCT/EP2009/053267, filed Mar. 19, 2009, the contents of the prior application are hereby incorporated herein in their entirety by reference.

#The present invention relates in general to the field of organic chemistry and in particular to the preparation of substituted biphenyls, in particular to 4-halomethyl-2′-halobiphenyl and their use as intermediates in preparation of angiotensin II antagonists. The invention also relates to halo and organometal intermediates for preparing telmisartan. Further the invention relates to use of in line analytics. In addition, the invention relates to the process for preparing pharmaceutical composition and/or dosage form comprising the process for preparing said biphenyls or intermediates. The embodiments of the present invention can be beneficially applied also for preparing a medicament.

#Angiotensin II antagonists (“sartans”) are efficient active compounds with biological activity which has proved useful for the treatment of hypertension. Most of commercially available sartans contain biphenyl moiety substituted with 5-tetrazolyl or carboxy group on the position 2′ (Formula 1, X is COOH or 5-tetrazolyl).

#Surprisingly it has been found that 2′-halo-4-methylbiphenyls can be obtained in a simple one-pot two-step technical process, in yields that are industrially applicable and competitive in which a 4-halotoluene is reacted with a 1,2-dihalobenzene in the presence of magnesium, lithium, zinc, cobalt or copper, and optionally a catalyst selected from a transition metal compound, preferably a manganese, cobalt or copper compound, wherein less than 1, particularly less than 0.9 molar, particularly less than 0.2 molar excess of 4-halotoluene with regard to 1,2-dihalobenzene is used, that for each mol of 1,2-dihalobenzene, from 1.0 to 1.9, particularly from 1.0 to 1.2 mol 4-halotoluene is used, more particularly from 1.05 to 1.15 mol, and arisen organometal intermediates are quenched proportionally for each 1 mol of 1,2-dihalobenzene by less than 2.9 mol, particularly 1-2 mol, about 1 mol of elemental halogen.

#The catalyst optionally used can be a palladium, copper, manganese, ruthenium, chromium, nickel compound, or the like.

#Suprisingly it was noted that when the molar excess of 4-halotoluene with regard to 1,2-dihalobenzene is less than 1, preferably less than 0.9, more preferably less than 0.2, it significantly improves the reaction yield. The reason might be that the organometal reaction is a complex reaction and its yield depends on the ratio of reactants. In the case of the prior art ratio, when it was for 1,2-dihalobenzene to 4-halotoluene 1:2, the high excess of starting reactants like 4-halotoluene could induce transmetalation. Metalated 1,2-dihalobenzene could produce symmetric dimeric products in one side while liberated 4-halotoluene could consume more metal or produce symmetric dimeric products with prepared 4-metalated toluene on the other side. Such side reaction may considerably reduce yield and quality. Thus, reducing the molar excess of the 4-halotoluene in the metalo reaction surprisingly improved utility of the reaction in the industry. Further, it was unexpectedly observed that less halogen is needed to sufficiently quench the reaction, when the ratio of the starting reagents is changed.