Ortho-metalation process for the synthesis of...

Details Ortho-metalation process for the synthesis of... Ortho-metalation process for the synthesis of...

2000-04-27

2001-08-07

Powers, Fiona T. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C548S250000, C548S252000, C548S253000

Reexamination Certificate

active

06271375

ABSTRACT:

The present invention relates to a process useful for the synthesis of 2-substituted-1-(tetrazol-5-yl)benzenes and, more particularly, it relates to a process of direct ortho-metalation of (tetrazol-5-yl)benzene useful for the preparation of 2-substituted-1-(tetrazol-5-yl)benzenes, well-known intermediates for angiotensin II antagonists. The angiotensin II antagonists constitute a new therapeutic class, whose parent compound losartan (INN) has been recently launched on the pharmaceutical market as drub useful for the treatment of hypertension, anxiety, glaucoma, heart attack. Most of the compounds belonging to the class of angiotensin II antagonists has a common biphenyltetrazolyl moiety.
Compounds such as the already mentioned losartan, candesartan, irbesartan, tasosartan and valsartan, to list the most known compounds of this therapeutic class, are all represented by the following general formula
in which A is an optionally substituted nitrogen containing heterocycle or an open amide residue
In particular the A residue has the following meanings, for the different previously identified angiotensin II antagonists:
losartan-A=2-butyl-4-chloro-5-hydroxymethyl-imidazol-1-yl
candesartan-A=2-ethoxy-7-carboxy-1H-benzimidazol-1-yl
irbesartan-A=2-butyl-1,3-diaza-spiro[4.4]non-1-en-4-on-3-yl
tasosartan-A=2,4-dimethyl -5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-on-8-yl
valsartan-A=(S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoylamino
It is evident that one of the key intermediates useful in the synthesis of the compounds of formula I is represented by 2-substituted phenyltetrazole derivatives of formula
in which R is a hydrogen atom, a protective group or a salifying group and X is a halogen atom selected among chlorine, bromine and iodine.
The intermediates of formula II are used in a cross-coupling reaction with a suitable substituted phenyl derivative to obtain the biphenyl portion of the compounds of formula I.
In our knowledge, among the literature methods for the preparation of the compounds of formula II, only one method that involves a direct metalation, that is an exchange reaction between a hydrogen atom and a metal, is reported. In particular this method is described in the U.S. Pat. No. 5,039,814 (Merck & Co. Inc.) and, in effect, it involves the ortho-lithiation of phenyltetrazole followed by a transmetalation reaction.
A disadvantage of this process is represented by the necessity to use organolithium compounds that require particular safety procedures to be used on a large scale, because of their high inflammability and reactivity.
The most common alternative to the direct metalation of phenyltetrazoles is the metalation of the corresponding 2-halo-substituted derivative, that is an exchange reaction between a halogen atom and a metal, as described, for example, in the European patent applications No. 550313 (Synthelabo) and No. 539086 (American Home Products Corp.).
It would be advantageous to prepare the phenyltetrazoles of formula II by direct metalation, avoiding the use of compounds that require particular safety procedures such as organolithium compounds.
Some methods for the direct metalation of activated organic compounds that do not involve lithium derivatives are well-known from the literature. Von Adrian Marxer et al. in Helvetica Chimica Acta, 57(7), 1988-2000 (1974) describe the use of ethylmagnesium bromide for the direct ortho-metalation of phenylpyrazoles with very good results.
Philip E. Eaton et al. in J. Am. Chem. Soc., 111(20), 8016-8018 (1989) reported the direct ortho-metalation of cubanes and of aromatic substrates by using an excess of a Hauser base, that is of a compound of formula R
2
NMgBr. Nevertheless our attempts to carry out the direct ortho-metalation of a phenyltetrazole to obtain a compound of formula II, following the methods described in the literature, were quite disappointing. In particular, using ethylmagnesium bromide no ortho-metalated product was formed whereas using a strong excess of a Hauser base the conversion was so low to make the process not practicable. Now we have found that the compounds of formula II can be prepared by direct ortho-metalation of the corresponding phenyltetrazole without using organolithium compounds.
Therefore, object of the present invention is a process of direct ortho-metalation for the preparation of compounds of formula
in which
R is a hydrogen atom, a protective group or a salifying group and X is a halogen atom selected among chlorine, bromine and iodine, that involves the treatment of a compound of formula
 in which R has the above reported meanings, with a Grignard compound of formula
R
1
-MgX  (IV)
 in which X has the above reported meanings and R
1
is a straight or branched C
1
-C
6
alkyl group or a benzyl group; in the presence of a catalytic amount of a secondary amine of formula
R
2
-NH-R
3
  (V)
 in which R
2
and R
3
, the same or different, are branched or cyclic C
3
-C
6
alkyl groups or trialkylsilyl groups having from 1 to 3 carbon atoms in the alkyl moiety or R
2
and R
3
together with the NH group form an optionally substituted cyclic amine. The process object of the present invention is useful for the preparation of intermediates for the synthesis of angiotensin II antagonists.
The protective groups of the tetrazole moiety are those commonly used in the known syntheses of angiotensin II antagonists and they mainly consist of straight or branched C
1
-C
6
alkyl groups, optionally mono or poly substituted with aryl groups such as phenyl or pyridyl or with arylalkoxy groups, and of C
1
-C
3
alkoxy or alkylthio groups.
In the process object of the present invention the preferred protective group is tertbutyl.
Sodium and potassium ions are preferably used as salifying groups. The alkyimagnesium halides of formula IV are well-known compounds. Generally they are prepared from the corresponding alkyl halides by treatment with magnesium.
Preferably an ethylmagnesium halide prepared in situ, more preferably ethylmagnesium bromide, is used.
Generally the amount of the Grignard compound of formula IV is at least stoichiometric, preferably in slight excess compared to the phenyltetrazole of formula II, but amounts even lower then the stoichiometric one are successfully used.
Therefore the molar ratio compound IV: compound III is generally between 1:1 and 1.5:1 more preferably between 1.05:1 and 1.3:1.
The secondary amine of formula V usually has very bulky substituents linked to the NH group.
The amines of formula V are preferably those in which R
2
and R
3
are branched or cyclic C
3
-C
6
alkyl groups or R
2
and R
3
together with the NH group form an optionally substituted cyclic amine.
Specific examples of amines having branched or cyclic C
3
-C
6
alkyl groups as R
2
and R
3
substituents are diisopropylamine, di-tert-butylamine, di-sec-butylamine, tert-butyl-iso-propylamine, di-cyclopentylamine and di-cyclohexylamine.
Preferred examples of amines of formula V wherein R
2
and R
3
together with the NH group form an optionally substituted cyclic amine comprises pyrrolidines, piperidines and morpholines, which are tetra-substituted at the two vicinal positions to the nitrogen, such as 2,2,6,6-tetramethylpiperidine and 2,2,5,5-tetramethylpyrrolidine. In particular the piperidine derivatives, in turn, can be further substituted at the 4 position by alkyl and alkoxy groups or by an oxo group protected as acetal. Particularly preferred amines of formula V are 2,2,6,6-tetramethylpiperidine and diisopropylamine.
The amines of formula V are used in catalytic amount compared to the Grignard compound IV, that is in a molar amount smaller than the stoichiometric one. Generally the molar ratio compound V: compound IV is between 0.01:1 and 0.5:1, more preferably between 0.05:1 and 0.2:1.
The direct ortho-metalation, object of the present invention, is carried out in a suitable solvent, usually ethers and their mixtures with aliphatic or aromatic hydrocarbons. Preferably tetrahydrofuran, optionally in ad

Affiliated with

Also associated with

Rating

Ortho-metalation process for the synthesis of... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Ortho-metalation process for the synthesis of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Ortho-metalation process for the synthesis of... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2550597