Process for the preparation of substituted...

Details Process for the preparation of substituted... Process for the preparation of substituted...

2000-05-30

2001-11-13

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S124000, C546S132000

Reexamination Certificate

active

06316624

ABSTRACT:

CROSS-REFERENCE
This application is a 371 of PCT/GB98/03635 filed Dec. 27, 1998.
The present invention concerns a process for preparing 3-cyano-8-substituted-8-azabicyclo[3.2.1]octanes. 3-Cyano-8-substituted-8-azabicyclo[3.2.1]octanes are useful as intermediates for certain insecticides (see, for example, WO 96/37494).
The present invention provides a process for preparing a compound of formula (IV), wherein R
1
is C
1-4
alkyl, C
1-4
haloalkyl, benzyl, C
3-6
alkenyl or C
3-6
alkynyl (provided that the &agr;-carbon atom of R
1
is neither unsaturated nor substituted with halogen), which comprises reacting a compound of formula (III) with a source of hydroxylamine in the presence of an acid. A preferred source of hydroxylamine is hydroxylamine hydrochloride or hydroxylamine itself. Suitable acids that can be used for this reaction include organic acids (such as formic acid or acetic acid) or mineral acids (such as hydrochloric acid, nitric acid or sulphuric acid).
In one particular aspect the present invention provides a process for preparing a compound of formula (IV), wherein R
1
is as defined above, comprising the steps:
i. ring opening a compound of formula (II) to give a compound of formula (III); and,
ii. reacting a compound of formula (III) with a source of hydroxylamine in the presence of an acid.
It is preferred that the ring opening of a compound of formula (II) is by reacting it with a strong organic acid (such as trifluoroacetic acid).
In another aspect the present invention provides a process for preparing a compound of formula (IV), wherein R
1
is as defined above, comprising the steps:
i. converting a compound of formula (I) to a compound of formula (II) by a methylene insertion reaction;
ii. ring opening a compound of formula (II) to give a compound of formula (III); and,
iii. reacting a compound of formula (III) with a source of hydroxylamine in the presence of an acid.
It is preferred that the compound of formula (I) is converted to a compound of formula (II) by reacting it with a suitable sulphur ylid (such as that generated by reacting trimethylsulphoxonium iodide and an alkali metal hydride (for example sodium hydride)).
Alkyl groups may be straight or branch chains are, for example, methyl ethyl, n-propyl or iso-propyl.
Haloalkyl is preferably alkyl optionally substituted with chlorine or fluorine and is, for example, 2,2,2-trifluoroethyl or 2,2-difluoroethyl.
Alkenyl and alkynyl groups are, for example, allyl or propargyl.
A compound of formula (II) can be prepared by adding a compound of formula (I) to a sulphur ylid (such as the ylid formed by the reaction of sodium hydride with trimethylsulphoxonium iodide), the reaction being carried out in a suitable solvent (such as tetrahydrofuran) and at a suitably elevated temperature (preferably in the range 50-100° C., such as at the boiling point of the solvent used).
A compound of formula (III) can be prepared by ring opening a compound of formula of formula (II) under acidic conditions (such as with an organic acid (preferably acetic acid or, especially, trifluoroacetic acid) or a suitable ion exchange resin (for example an Amberlyst® resin)) in a suitable solvent (such as toluene) and at a suitably elevated temperature (such as between 50° C. and the boiling point of the solvent used).
A compound of formula (IV) can be prepared by reacting a compound of formula (III) with hydroxylamine hydrochloride in the presence of an acid, which may also act as a solvent (such as formic acid) at a suitably elevated temperature (such as between 50° C. and the boiling point of the solvent used).
In another aspect the present invention provides a process for preparing a compound of formula (IV) which comprises the steps:
i. reacting a compound of formula (I) with a sulphur ylid (preferably formed by the reaction of sodium hydride with trimethylsulphoxonium iodide) at 50-100° C. to give a compound of formula (II);
ii. ring opening a compound of formula (II) under acidic conditions and at a temperature in the range 50-120° C. to give a compound of formula (III); and,
iii. reacting a compound of formula (III) with hydroxylamine hydrochloride in the presence of an acid and at a temperature in the range 50-120° C.
A compound of formula (A) can be prepared by reacting a compound of formula (IV) with a compound R
2
L, wherein R
2
is pyridyl optionally substituted with halogen, C
1-4
alkyl, C
1-4
alkoxy, cyano, C
2-4
alkenyl or C
2-4
alkynyl, and L is a suitable leaving group (such as halogen or mesylate). Thus, in a further aspect the present invention provides a compound of formula (A) when made by reacting a compound of formula (IV) (as prepared by a process as hereinbefore described) with a compound R
2
L.
A compound of formula (A), wherein R
1
is C
1-4
alkyl, C
1-4
haloalkyl, benzyl, C
3-6
alkenyl or C
3-6
alkynyl (provided that the &bgr;-carbon atom of R
1
is neither unsaturated nor substituted with halogen), and R
2
is pyridyl optionally substituted with halogen, C
1-4
alkyl, C
1-4
alkoxy, cyano, C
2-4
alkenyl or C
2-4
alkynyl, when prepared by a process comprising the steps:
i. reacting a compound of formula (III) with a source of hydroxylamine in the presence of an acid to provide a compound of formula (IV); and,
ii. reacting a compound of formula (IV) with a compound R
2
L, wherein L is a suitable leaving group (such as halogen or mesylate).
In a further aspect the present invention provides a compound of formula (II) wherein R
1
is CH
2
CHF
2
or CH
2
CF
3
.
In a still further aspect the present invention provides a compound of formula (III) wherein R
1
is CH
2
CHF
2
or CH
2
CF
3
.
The following Example illustrate the invention. Selected NMR data and mass spectral data are presented in the Examples. For NMR data, no attempt has been made to list very absorption. The following abbreviations are used throughout the Examples:
m =
multiplet
ppm =
parts per million
THF =
tetrahydrofuran
q =
quartet
s =
singlet


REFERENCES:
patent: 3120537 (1964-02-01), Archer et al.
patent: 96/37494 (1996-11-01), None
patent: 97/13770 (1997-04-01), None
patent: 97/43286 (1997-11-01), None
G.A. Olah, Synthetic Methods and Reactions; 60′. Improved One-Step Conversion of Aldehydes into Nitriles with Hydroxylamine in Formic Acid Solution, Synthesis, 112-113 (1979).
M. Fishman et al., Studies in Alkylation, 5 J.Heterocyclic Chem., 467-469 (Aug. 1968).
P. Bartlett et al., Chorismate Mutase Inhibitors: Synthesis and Evaluation of Some Potential Transition-State Analogues, 53 J. Org. Chem., 3195-3210 (1988).
Paquette, L., Encyclopedia of Reagents for Organic Synthesis, 2792 (1995).
Houben-Weyl, Methoden der Organischen Chemie, G. Thieme, 1339-1346 (1988).
Houben-Weyl, Methoden der Organischen Chemie, G. Thieme, 549-555 (1983).

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