Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
1999-02-17
2001-05-01
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
active
06225469
ABSTRACT:
The present invention relates to an improved process for the preparation of certain 1,2,4-triazolo[1,5a]pyrimidines which are useful in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, head injuries and haemorrhage.
Compounds of Formula A
in which R, represents H or optionally substituted alkyl, alkoxy or alkanoyl; R
2
and R
3
independently represent H or optionally substituted alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl or sulphonyl; R
4
and R
5
independently represent H, alkyl or together with the carbon atom to which they are attached represent optionally substituted cycloalkylidene; and R
6
, R
7
and R
8
independently represent H, halo hydroxy, mercapto, cyano or optionally substituted alkyl, alkanoyl, alkoxy, alkoxycarbonyl, carboxy, alkanoyloxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, sulphamoyl, carbamoyl, alkylcarbanoyl or alkanoylamino; processes for their preparation, and their use in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, head injuries and haemorrmage are described in WO95/10521 (Knoll AG).
In WO95/10521, there is a disclosure of the preparation of compounds of formula A by coupling alcohols of formula B
with phenols of formula C
in the presence of a redox coupling agent which, for example, in the “Mitsunobu” reaction is diethyl azodicarboxylate with triphenylphosphine. This reaction leads to the production of triphenylphosphine oxide which is separated from the compound of formula A by flash column chromatography on silica gel.
The “Mitsunobu” reaction using a redox couple, in which the reducing agent is triphenylphosphine, is a very good method for producing chiral compounds of formula A because it results in generally good yields with high stereoselectivity (inversion) and is relatively simple to carry out since the alcohol activation and displacement reactions take place in a single transformation—usually at room temperature. However, the resultant formation of triphenylphosphine oxide is a disadvantage because it is difficult to remove from the desired product. Flash column chromatography is an acceptable laboratory-scale solution to this problem, but is not practicable on an industrial scale in terms of cost, time efficiency and ease of handling.
One solution to the problem is to use for example a basic phosphine, such as diphenyl(2-pyridyl)phosphine or (4dimethylamirophenyl)diphenylphosphine, as the reducing agent in the redox couple. This facilitates product isolation since the resulting phosphine oxide is removed by aqueous acid washing. However, these basic phosphines may not be suitable for chiral compounds of formula A since the acid washing may cause racemisation of the chiral centre, and some compounds of formula A are soluble in strong acid so that separation from the phosphine oxide would not be achieved by acid washing. Furthermore, use of these basic phosphines is not commercially viable on a production scale. In addition, the yield can be substantially reduced by using a reducing agent other than triphenylphosphine. Polymer-bound phosphines may also be used to avoid the formation of triphenylphosphine oxide. However, these phosphines are expensive and the reaction is significantly slower so that time and cost efficiency are compromised.
Surprisingly, we have now found a means of reducing the level of triphenylphosphine oxide from the desired compound of formula A which is inexpensive, quick, requires mild conditions and neutral pH, and is very easy to carry out both on a laboratory scale and on a production scale. This new process enables the use of triphenylphosphine in the redox couple (thus resulting in good stereospecificity and yield) and the efficient removal of the unwanted triphenylphosphine oxide. The process can also be applied to other tri-substituted phosphine redox couples if desired, since it is effective at reducing the levels of other phosphine oxides. Other elements of group V of the periodic table, such as arsenic and antimony, are also able to form tri-substituted compounds (arsines and stibines) which may be used as reducing agents. The process of the present invention may also be applied to reducing the level of the oxides of such compounds.
It will be understood that for the remainder of this document, the term “tri-substituted phosphine, arsine and/or stibine” refers to tri-substituted phosphine, arsine and/or stibine in which the substituents are organic moieties.
The present invention comprises a process for the preparation of compounds of formula I
including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof in which:
R
1
represents H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C
1-6
alkyl, C
1-6
alkoxy or C
1-6
alkanoyl;
R
2
and R
3
independently represent H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkanoyl, C
1-6
alkylthio, C
1-6
alkylsulphinyl or C
1-6
alkylsulphonyl;
R
4
and R
5
independently represent H, C
1-6
alkyl or R
4
and R
5
combined together with the carbon atom to which they are attached represent C
3-6
cycloalkylidene (each alkyl or cydoalkylidene being optionally substituted with one or more of halo, cyano, hydroxy, amino or C
1-6
-alkyl); and
R
6
, R
7
and R
8
independently represent H, halo, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino; and any nitrogen atom being optionally substituted with one or more C
1-6
alkyl): C
1-6
alkyl, C
1-6
alkanoyl, C
1-7
alkoxy, C
2-6
alkoxycarbonyl, carboxy, C
1-6
alkanoyloxy, C
1-6
alkyfthio, C
1-6
alkylsulphinyl, C
1-6
alkylsulphonyl, C
1-6
alkyl-sulphonylamino, sulphamoyl, carbamoyl, C
2-6
ikylcarbamoyl or C
1-6
alkanoylamino; said process comprising the reaction involving an alcohol of formula II
in which R
1
, R
2
, R
3
, R
4
and R
5
are as defined above, with a phenol of formula III
in which R
6
, R
7
and R
8
are as defined above, in the presence of an inert diluent and at least one redox couple comprising an oxidising agent and a reducing agent which is selected from a tri-substituted phosphine, arsine or stibine wherein the reducing agent becomes oxidised; wherein
a) a metal salt is added to form a complex or complexes with the oxidised reducing agent or agents produced in the process, and
b) the resultant complex or complexes is/are separated from the desired product.
It will be understood that the oxidising agent becomes reduced during the process, and that the reduced oxidising agent may be removed from the desired product either before or after steps a) and b) are carried out. Preferably, the reduced oxidising agent is removed from the desired product after steps a) and b) are carried out.
It will be understood that any group mentioned herein which contains a chain of three or more atoms signifies a group in which the chain may be straight or branched. For example, an alkyl group may comprise propyl which includes n-propyl and isopropyl and butyl which includes n-butyl, sec-butyl, isobutyl and tert-butyl. The total number of carbon atoms is specified herein for certain substituents, for example C
1-6
alkyl signifies an alkyl group having from 1 to 6 carbon atoms. The term ‘halo’ as used herein signifies fluoro, chloro, bromo and iodo. The term ‘halide’ as used herein signifies fluoride, chloride, bromide or iodide. The term ‘optionally substituted’ as used herein, unless immediately followed by a list of one or more substituent group or groups, means optionally substituted with one or more of halo, cyano, hydroxy, amino or C
1-6
alkyl. When the phenyl ring substituents R
6
, R
7
and R
8
are other than H, the substituent may replace any H a
Holman Nicholas John
Koser Stefan
Balasubramanian Venkataraman
Keil & Weinkauf
Knoll Aktiengesellschaft
Raymond Richard L.
LandOfFree
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