Process for the preparation of cyclopropane carboxylic acids

Details Process for the preparation of cyclopropane carboxylic acids Process for the preparation of cyclopropane carboxylic acids

2000-08-17

2001-04-10

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Carboxylic acids and salts thereof

C562S510000

Reexamination Certificate

active

06215023

ABSTRACT:

The present invention relates to processes for the preparation of compounds usable as intermediates in the preparation of cyclopropane carboxylic esters.
Cyclopropane carboxylic esters are insecticidally active compounds which are known as “pyrethroids”, and since they combine exceptionally good insecticidal properties with very low toxicity to mammals they are of considerable interest. Therefore, much effort has been made in order to find economically favourable routes for preparing them and their most important intermediates.
A selection of these pyrethroid compounds showing a remarkably high activity can be prepared from acids of the general formula II, where the carbon atoms marked 1 and 3 are asymmetrical carbon atoms and where the geometry in the cyclopropane ring is 1R,cis, i.e., the absolute configuration at carbon atom 1 is R and the two hydrogen atoms at carbon atoms 1 and 3 are in cis-position. The compounds II can be prepared from the compounds I. R
1
represents a halogen atom (e.g., Cl or Br) or haloalkyl (e.g., CF
3
). X
1
and X
2
represents halogen atoms (e.g., Cl or Br). R
1
, X
1
and X
2
may be the same or different.
The superscripts
1,2 etc.
in the following description refer to the list of references stated at the end of the present description.
It is known
1,2,3
that the acid II should have the geometry 1R,cis in order that pyrethroids derived therefrom can obtain maximum insecticidal activity. If R
1
and X
2
are CF
3
and Cl, respectively, it is further more known that the chlorine atom and cyclopropane group should be at the same side of the carbon-carbon double bond, Z configuration, in order to obtain maximum insecticidal activity, which is shown in Scheme 1.
Therefore, it is of great importance to be able to prepare the exact isomer of II which provides the most active pyrethroids in a technically as well as economically attractive manner in order to minimize in this way the applied amount of active substance (insecticide) in the treatment of agricultural crops, habitations and the like.
The preparation of II of the desired 1R,cis configuration takes place from the intermediate I where the configuration is already present. In addition to the asymmetric centres at positions 1 and 5, the intermediate I has an asymmetric carbon atom at position 4, which means that I can occur in the two configurations 1R,4R,5S and 1R,4S,5S where, however, the synthesis of I preferably leads to 1R,4R,5S. In the further reaction of I both configurations lead to II.
The desired configuration of I at carbon atoms 1 and 5 is obtained through known synthetic steps from the natural product &Dgr;-3-carene
4,5,6,7
which in the terminology of chiral chemistry is said to belong to “the chiral pool”, i.e. the collection of relatively inexpensive and readily available natural substances of a described configuration among which one can find starting materials of a particular, desired configuration.
It is known
6,7
that the reduction I→II can be carried out by metallic zinc or other metals (e.g., magnesium). Reactions corresponding to the transformation I→II are called “elimination of &bgr;-halo esters” and can be carried out under different conditions
10
. A comprehensive review work
10
discusses several possible sets of conditions for carrying out such reactions, inter alia, reaction with Zn and electrolysis. Reactants equal or analogous to those used in the present invention are not mentioned.
Apparently, previously described
8
trans-&bgr;-bromo-acetoxy elimination reactions are only practicable on systems wherein bromine is further activated by an ester group, since experiments under the conditions described (NaHSO
3
, Na
2
SO
3
) gave, for the starting compound I (R
1
=X
1
=X
2
=Br), only a little II (R
1
=X
2
=Br) and more III (R
2
=X
2
=Br) (see Scheme 2) together with unreacted starting compound. Experiments under the conditions described (NaHSO
3
, NaHCO
3
) gave no reaction for I (R
1
=CF
3
; X
1
=X
2
=Cl), not even in the presence of a catalyst (Pt).
However, it has unexpectedly been found that just the halolactone I in the presence of metal catalysts (e.g., Pt, Pd, Ni, Rh, or Os) can be reduced to the cyclopropane carboxylic acid II by using formate (HCOO
−
), hypophosphite (H
2
PO
2
−
), phosphite (HPO
3
2−
) or hydrogen (H
2
), respectively, as reducing agent.
Simultaneously, it has unexpectedly been found that if R
1
=CF
3
and X
1
=X
2
=Cl, the product II consists predominantly of the desired Z-isomer.
This synthetic route is totally specific in respect of the stereoisomerism of the products so that the geometry of I can be found again in the product II. In this way costly racemate resolutions as well as yield losses to useless isomers are avoided.
Previous attempts
9
to reduce similar halolactone systems with hydrogen in the presence of a metal catalyst [Pd(C)5%] resulted in simple dehalogenation only, with the lactone ring being maintained.
Here is described a number of new synthetic methods for the preparation of the (1R,cis)-acid moiety of the pyrethroid esters of formula II from the halolactone I. These synthetic methods can be used in the same way to prepare the racemic (1RS,cis)-acid moiety of the pyrethroid esters from racemic halolactones which in turn are synthesized from racemic Biocartol.
In accordance with the above the invention relates to a process for the preparation of cyclopropane carboxylic acids of the general formula II, wherein the substituent R
1
represents a halogen atom, preferably Cl or Br, or haloalkyl (halo in haloalkyl being, e.g., fluoro, chloro or bromo, and alkyl in haloalkyl being suitably a lower alkyl such as alkyl having 1-3 carbon atoms), preferably CF
3
, and the substituent X
2
represents a halogen atom, preferably Cl or Br, where R
1
and X
2
may be the same or different, and wherein the configuration of II predominantly is Z for R
1
=CF
3
and X
2
=Cl, which process is characterized by reacting, in the presence of a catalyst, a compound of the general formula I, wherein the substituents R
1
and X
2
are as defined above, and the substituent X
1
represents a halogen atom, preferably Cl or Br, where R
1
, X
1
and X
2
may be the same or different, with a compound which is a hydrogen donor.
A great advantage of the present invention is that the use of expensive reducing agents such as Zn or other metals can be avoided and that, e.g., hydrogen can be used instead.
A further advantage of the present invention is that, as by-products, carbon dioxide (CO
2
)+sodium chloride (NaCl), phosphorous acid (H
3
PO
3
)+sodium chloride (NaCl), phosphoric acid (H
3
PO
4
)+sodium chloride (NaCl) or hydrochloric acid (HCl), respectively, are obtained instead of zinc ions or other metal ions.
Zinc is an element for which maximum concentrations have been set, if it is to be discharged with wastewater or spread with sludge from a purification plant. This means that a production using zinc in major amounts will have to incorporate an expenditure demanding step for recovering the applied zinc. The same conditions apply to other metals.
Use can be made of various appropriate embodiments of the process of the invention as stated in claims
2
-
7
.
The process of the invention and its various embodiments are caracteristic by being ideal and not previously described for the preparation of II from I.
By suitably selecting solvent, temperature, calatyst and pH level in the reaction mixture, it is possible to minimize the occurrence of undesirable by-products of the general formulae III, IV and/or V:
R
2
represents hydrogen (H), a halogen atom (e.g., Cl or Br) or haloalkyl (e.g., CF
3
). X
1
represents a halogen atom (e.g., Cl or Br). R
2
and X
1
may be the same or different.
By selecting solvent, temperature, catalyst and pH level in the reaction mixture it is likewise possible to control the reaction to preferably give the desired Z- or E-isomer of II.
NMR and HPLC analyses of

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