Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-30
2001-11-27
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S124000
Reexamination Certificate
active
06323343
ABSTRACT:
CROSS-REFERENCE
This application is a 371 of PCT/GB98/03633 filed Dec. 7, 1998.
The present invention concerns a process for preparing 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, CH
2
(C
1-3
haloalkyl), benzyl, CH
2
(C
2-5
alkenyl) or CH
2
(C
2-5
alkynyl), which comprises reducing a compound of formula (III). It is preferred that the reduction is effected using a mixture of an alcohol (preferably methanol) and a suitable metal (such as magnesium); by using a borohydride (such as an alkali metal borohydride, for example lithium or sodium borohydride) in an alcohol (preferably methanol) and, optionally, in the presence of a suitable amine (such as pyridine); or by catalytic hydrogenation (for example using a catalyst comprising palladium at a suitable pressure).
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. dehydrating a compound of formula (II) to give a compound of formula (III); and,
ii. reducing a compound of formula (III).
For example, a compound of formula (II) can be dehydrated by the use of a suitable acid chloride (such as thionyl chloride, phosphorus oxychoride, sulphuryl chloride or phosgene), in the presence of a suitable amine having a pKa in the range 3-11 (especially 4-6) [such as a tri(C
1-4
alkyl)amine (such as triethylamine or diisopropylethylamine), pyridine, a (C
1-4
alkyl)pyridine (such as (&agr;-picoline, &bgr;-picoline or &ggr;-picoline), a di(C
1-4
alkyl)-aminopyridine (such as 4-dimethylaminopyridine), quinoline, isoquinoline or a di(C
1-4
alkyl)aniline (such as N,N-dimethylaniline)], optionally in a solvent [such as an excess of amine, or an aprotic or polar aprotic solvent for example an aromatic hydrocarbon (especially toluene, a xylene, fluorobenzene or chlorobenzene), acetonitrile, an ether (especially tetrahydrofuran or dioxan) or a chlorinated aliphatic solvent (especially dichloroethane)], at a suitable temperature in the range 0-110° C. (especially 10-40° C.).
It is preferred that a compound of formula (II) is dehydrated by the use of a suitable acid chloride (such as thionyl chloride or phosphorus oxychoride) in the presence of a suitable amine (preferably pyridine).
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. cyanating a compound of formula (I) to give a compound of formula (II);
ii. dehydrating a compound of formula (II) to give a compound of formula (III); and,
iii. reducing a compound of formula (III).
It is preferred that the compound of formula (I) is cyanated by reacting it with hydrogen cyanide in the presence of a suitable base. It is preferred that the hydrogen cyanide is prepared in situ (for example by the reaction of an inorganic cyanide (such as an alkali metal cyanide, for example sodium cyanide or potassium cyanide) with an acid (such as an organic acid (for example acetic acid) or a strong mineral acid (for example hydrochloric acid)). Suitable bases include the cyanide anion (for example from the presence of an inorganic cyanide (such as an alkali metal cyanide, for example sodium cyanide or potassium cyanide)). The cyanation reaction may be carried out in the presence of ammonium chloride.
It is preferred that the cyanation of the compound of formula (I) is carried out in the presence of a solvent or mixture of solvents. A preferred solvent is water, and preferred mixtures of solvents include mixtures of water with an ether (such as diethyl ether or methyl tert-butyl ether), an alcohol (such as methanol or n-butanol) or an aromatic solvent (such as toluene).
Alkyl groups of R
1
may be straight or branch chains are, for example, methyl, ethyl, n-propyl or iso-propyl.
The haloalkyl moiety of the group CH
2
(C
1-3
haloalkyl) is preferably alkyl optionally substituted with chlorine or fluorine and is, for example, 2,2,2-trifluoromethyl or 2,2-difluoromethyl. (Thus, CH
2
(C
1-3
haloalkyl) is, for example, 2,2,2-trifluoroethyl or 2,2-difluoroethyl.)
Alkenyl and alkynyl groups are, for example, vinyl, allyl or propargyl.
A compound of formula (II) can be prepared by adding a suitable inorganic cyanide (preferably potassium cyanide) to a mixture of a compound of formula (I) and a suitable mineral acid (preferably hydrochloric acid or sulphuric acid) and, optionally, ammonium chloride, at a suitable temperature (preferably in the range −20-20° C., such as at about 0° C.) and allowing the reaction to take place at this temperature. Suitable solvents for this reaction include water or a mixture of water and an organic solvent (such as an ether (for example diethyl ether)).
In one aspect a compound of formula (II) can be prepared from a compound of formula (I) by the method described above wherein an excess of hydrogen cyanide is used for the preparation. The excess may be achieved by using an excess (such as between 1 and 2 (especially 1.1-1.8) equivalents) of acid and an excess (such as between 1 and 2 (especially 1.1-1.6) equivalents) of inorganic cyanide. In another aspect all the inorganic cyanide is added at the beginning of the preparation and the acid is added over a period of time during the course of the preparation. It is preferred that the acid is a strong mineral acid (especially hydrochloric acid or sulphuric acid) and that the inorganic cyanide is sodium cyanide or potassium cyanide.
In a further and preferred aspect a compound of formula (II) can be prepared by using an excess (such as 1-10, especially 2-7 equivalents) of a strong mineral acid (especially hydrochloric acid or sulphuric acid) and an excess (such as 1-12, especially 3-8 equivalents) of alkali metal cyanide (for example sodium cyanide or potassium cyanide) relative to the compound of formula (I). It is preferred that the process is operated at a temperature in the range −20-20° C., such as at about 0° C.
In another aspect, a mixture of a compound of formula (I) with a suitable mineral acid (preferably hydrochloric acid or sulphuric acid) in a suitable solvent (preferably water) is added over a period of time to an inorganic cyanide (for example sodium cyanide or potassium cyanide) during the course of the preparation of a compound of formula (II) at a suitable temperature (for example in the range −20-20° C., such as at about 0° C.).
Compounds of formula (II) can degrade over time. Degradation can be minimised by isolating the compound of formula (II) in a suitable organic solvent (such as an ether (for example diethyl ether or methyl tert-butyl ether) or an alcohol (for example methanol or n-butanol), and such solution can be used in the processing of a compound of formula (II) to a compound of formula (III). Alternatively, degradation can be minimised by adding a suitable stabilising agent (such as a small amount of concentrated sulphuric acid) to the compound of formula (II) prior to its isolation.
A compound of formula (III) can be prepared by adding a compound of formula of formula (II) to a mixture of phosphorus oxychloride and a suitable amine (such as pyridine) in a suitable solvent (which may be an excess of phosphorus oxychloride, or, when the amine is a liquid, may be an excess of the amine) and allowing the reaction to proceed at a suitably elevated temperature (such as between 50° C. and the boiling point of the solvent used).
For the dehydration of a compound of formula (II) it is preferred that an acid chloride is added to a mixture of a compound of formula (II) and an amine, preferably as <20° C.
A compound of formula (IV) can be prepared by adding a compound of formula (III) to a mixture of an alcohol (preferably methanol) and, optionally, a suitable amine (such as pyridine), and then adding a suitable borohydride (especially sodium borohydride) to
Bowden Martin Charles
Brown Stephen Martin
Perrior Trevor Robert
Smith Douglas John
Hale and Dorr LLP
Rotman Alan L.
Syngenta Limited
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