INTERMEDIATE IN THE PREPARATION OF CYCLOPROPYLCARBOXYLATE ESTERS AND PROCESS FOR ITS MANUFACTURE

NOVEL INTERMEDIATE IN THE PREPARATION OF CYCLOPROPYLCARBOXYLATE ESTERS AND PROCESS FOR ITS MANUFACTURE The invention relates to a compound which is a useful intermediate in the preparation of cyclopropylcarboxylate esters. The invention also relates to a process for the preparation of the compound.

The cyclopropylcarboxylate esters are insecticidally-active compounds known as "pyrethroids" and as they comhine exceptionally good insecticidal properties with a very low mammalian toxicity, they are of considerable interest to the agrochemical industry and much effort has been expended in finding economic routes to them and to their principal intermediates.

The general formula of one class of these pyrethroid compounds may be represented as follows:- IK VCH=CX2 (I) where each asterisk denotes an asymmetric carbon atom; each X is a halogen atom; and R is a member of a group of radicals known to impart insecticidal activity to the molecule, e.g. 3-phenoxybenzyl or alpha-cyano-3-phenoxybenzyl. It is known that the stereo- isomeric form of the acid portion of the ester of formula I should be in the (1R, cis) form for maximum insecticidal activity, i.e.

the absolute configuration at carbon atom 1 io R and the two hydrogen atoms on carbon atoms 1 and 3 are in a cis relationship.

ii±£252 This nomenclature is known as the Elliott nomenclature and is defined in M. Elliott, A.W. Farnham, N.F. James, P.M. Needham and D.A. Pullman, Nature, 1974, 248, 710.

It follows, therefore, that if these stexeoisomeric esters of formula I are to be prepared, either a stereospecific chemical route is required or the desired stereo-isomer must be obtained from a racemic form by physical separa¬ tion techniques. The latter are expensive and laborious and not readily employed on an industrial scale. The Applicant has found a stereospecific route which uses as starting material the naturally-occurring substance 0)-3-carene whose formula is as follows:- (ID This compound is an inexpensive readily-available natural terpens and in our copending Canadian application 316,588 is disclosed a route to the (1R, cis)~ acid portion of the pyrethroid ester of formula I starting from (+)-3-carene and proceeding via the novel cyclopropane compound according to the invention.

The present invention provides 3-.formyl-2,2-dimethyl-cyclopropane- carbaldehyde dimethyl acetal whose formula is : - CHO /0-CH3 (III) Preferably the compound of formula III is in the same stereoisomeric form as that of the cyclopropane ring of (+)-3-carene because this leads to compounds "O i 111325» of general formula I (R=H) in the (1R, cis) form; such compounds generate opti¬ mum levels of insecticidal activity in the pyrethroid end-product.

The compound III or its preferred stereoisomeric form may be prepared by methods known per se, for example by oxidising the corresponding alcohol to the desired aldehyde (see "Methoden der Organischen Chemie" (Houben Weyl), Volume VII, Part 1 (1954) 159-192 and J. Org. Chem. 35 (1970) No. 11, 4000- 4002) . It has been found that the compound may be conveniently prepared by a method which is characterised in that 3-hydroxymethyl-2,2-dimethylcyclopropane- carbaldehyde dimethyl acetal of formula:- H / CH20H /\ /0-CH3 CHZ -V- CH CIV) y \ o-CH3 is subjected to the action of an oxidising agent capable of oxidising a primary alcohol to an aldehyde, e.g. a chromium trioxide-pyridine complex. Preferably compound IV is employed in the same stereoisomeric form as that of the cyclo¬ propane ring of (+)-3-carene.

As has been indicated above a multi-stage process for the preparation of insecticidally active compounds, starting with (+)-3-carene and in which the compound according to the invention is employed as intermediate, is described in Canadian patent application 316,588.

The following Example further illustrates the invention. Yields and 20. purities were determined by means of gas-liquid chromatography and nuclear magnetic resonance (NMR) spectroscopy. The NMR data quoted were recorded at 90 MHz using solutions of the compounds in deuterochloroform.

lltZ25Z Example - Preparation of a stereoisomer of g-formyl-2,2-diHiethylcyclopropane- carbaldehyde dimethyl acetal (compound III) (a) Preparation of a stereoisomer of 1-(2,2-diniethoxyethyl~2,2-dimethyl-3-(2- oxo-propyl)cyclopropane (compound A) A flask was charged with (+)-3-carene (375 mmol) and water-free methanol (150 ml) and kept at a temperature of -60oC. Then, a mixture of ozone and oxygen was passed through the liquid in the flask at a rate of 70 1/h (corresponding to 75 mmol of ozone per hour until the (+)-3-carene was fully converted (5 hours).

The reaction mixture formed was allowed to adopt a temperature of 20oC, dimethyl sulphide (750 mmol) and p-toluene-sulphonic acid (1.74 mmol) were added and the mixture formed was stirred for four days at 20oC. At the end of this period the (+)-3-carene was fully converted into compound A. Methanol and dimethyl sulphide were evaporated from the reaction mixture, at a pressure of 24 mbar (40oC), diethyl ether (150 ml) was added to the residue obtained, the solution formed was washed with a 5%w aqueous solution of sodium hydrogen carbonate (30 ml), with four 30 ml portions of water, the washed solution was dried over anhydrous magnesium sulphate and the solvent was evaporated from the dried li¬ quid at a temperature of 30oC and a pressure of 24 mbar to give a residue (68.9g). This residue was distilled at 830C/1 mbar to give a fraction consist- ing of the cis isomer, compound A, yield 73.5%.

(b) Preparation of a stereoisomer of 2-(2,2-dimethoxyethyl)-3,5-dimethylcyclo- propylmethyl acetate (compound B) The contents of a flask charged with compound A (200 mmol) prepared as in (a) in this Example, chloroform (300 ml) and 3-chloroperbenzoic acid (384 mmol) were stirred at 20oC for 24 hours. The precipitate formed was separated by filtration, the filtered precipitate was mixed with n-pentane (150 ml), the mixture was separated by filtration, the combined filtrates were "O washed with two 50 ml portions of a 5% solution of sodium carbonate in wator and with two 50 ml portions of water, the washed liquid was dried over anhydrous magnesium sulphate and the solvent was evaporated from the dried liquid at a temperature of 90°C and a pressure of 20 mbar to give a residue containing compound B in a yield of 97%. The content of compound B in the residue was 92%, only the cis isomer had been formed.

(c) Preparation of a stereoisomer of 2,2-dimethyl3(2-formyl-methyl)cyclo- propyl methyl acetate (compound C) The contents of a flask charged with compound B. (218 mmol) in the residue prepared as described in (b), acetic acid (40 ml) and water (20 ml) were stirred at 60oC during 2.5 hours. The •,4 a- solvent was evaporated from the reaction mixture at a temperature of 5 C and a pressure of 2k mbar, the residue obtained was taken up in diethyl ether (150 ml), the solution obtained was washed with two 50 ml portions of a 5#w solution of sodium hydrogen carbonate in water and with two 50 ml portions of water, the washed solution was dried over anhydrous ma,gnesium sulphate and the.solvent was evaporated from the dried liquid at a temperature of 30OC and a pressure of 2k mbar to give a residue containing compound C in a yield of 80%; the content of compound C in the residue was 85%. Only the cis isomer had been formed, (d) Preparation of a stereoisomer of 2-(3-acetoxymethyl-g1g- aimethylcyclopropyl)vinyl acetate (compound D) The contents of a flask charged with compound C (175 mmol) in the residue prepared as described in (c), triethylamine (386 mmol) and acetic anhydride (350 ml) were stirred at 20 C for 18 hours. The solvent was evaporated from the reaction mixture at a temperature of 70 C and a pressure of 20 mbar, the residue obtained was washed with five Uo ml portions of water, the washed solution was dried over anhydrous magnesium sulphate and the solvent was evaporated from the dried liquid at a temperature of U0OC and a pressure of 20 mbar to give a residue containing compound D in quantitative yield. The content of compound D in.the residue was 88.k%; 6k% of compound D had the cis structure, 36% the trans structure of the carbon-carbon double bond. The orientation to the cyclopropane ring was still cis.

(e) Preparation of a stereoisomer of 3-acetoxymethyl-2,2-dimethyl- cyclopropanecarbaldehyde dimethyl acetal (compound B) A flask was charged with compound D (175 mmol) present in the residue obtained in d, water-free methanol (200 ml) and p-toluenesulphonic acid (1.16 mmol) and kept at a temperature of -650C. Then, a mixture of ozone and oxygen was passed through the liquid in the flask at a rate of 60 l/h (corresponding to 70 mmol of ozone per hour) until compound D was fully converted (2.5 hours). The reaction mixture formed was allowed to adopt a temperature of 20OC, dimethyl sulphide (350 mmol) was A.jJjLAà'i'' added and the mixture formed -was stirred for 17 hours at 20 C.

Methanol and dimethyl sulphide were evaporated from the reaction mixture, at a pressure of 16 nibar, diethyl ether (50 ml) vas added to the residue obtained and so much of a saturated aqueous solution of sodium "bicarbonate was added to the mixture that the pH reached a value of 7. Then, the mixture was washed with three 50 ml portions of water, the washed liquid was dried over anhydrous magnesiimi sulphate and the solvent was evaporated from the dried liquid at a temperature of lt-0 C and a pressure of 2k nibar to give a residue (29.6 g) containing compound E (yield between 78$). Only the cis isomer had been formed. The IIMR spectrum of compound E showed the following absorptions:- 6 = 3.38 ppm (singlet, C-O-CH ) 6= 1.18 ppm (singlet, H-C-CH Ô = U.2 ppm (multiplet, H-C-O-CH )<5 = 1.1 ppm (multiplet, H-C-CHg) Ô = 1.2 ppm (multiplet, H-C-C(H)-«5= \.2 ppm (multiplet, H-C-CHg) (0CH3)2) 6 = 1.18 ppm (singlet H3C-C-CH3) 6= 2.1 ppm (singlet, H3C-C(0)-0-) (f) Preparation of a stereoisomer of 3-hydroxymethyl-2.2-dimethyl- cyclopropanecarbaldehyde dimethyl acetal (compound F) A flask was charged with all of the residue obtained in (e), water (75 ml), sodium hydroxide (150 ramol) and acetone (25 ml) and the liquid obtained was kept under reflux (60 C) for three hours. Then, the acetone and part of the water were evaporated at a pressure of 16 mbar, the residue obtained was extracted with five 50 ml portions of diethyl ether (during the last two extractions so much sodium chloride was added that the aqueous phase was saturated with this salt), the combined five extract phases were dried over anhydrous magnesium sulphate and the solvent was evaporated from the dried liquid at a temperature of ho C and a pressure of 2U mbar to give a residue containing compound III in a yield of 51$» calculated on starting compound D. This cis content was 70%.

The ÏÏMR spectrum of the cis isomer of compound F showed the following absorptions:- XÏXZZSZ & = 3.32 ppm (singlet, C-O-CH ) 5= 1.05 ppm (singlet, H-C-CHg) 6 = U.83 ppm (singlet, H-C-0-CH,)6= 1.2 ppm (multiplet, H-C-CH2) « = 1.53 ppm (doublet, H-C-C(H)- 5= 3.8 ppm (doublet, jC-OH) (0CH3)2) 6 = 1.05 ppm (singlet, H3C-C-CH3)& = U.3 ppm (singlet, HgC-OH) 6 = 1.53 ppm (doublet, H-C-C(H)- 5= 3.8 ppm (doublet, HgC-OH) (0CH3)2) &= 1.05 ppm (single't, "H C-C-CH ) à = h.3 ppm (singlet, HgC-OH) (g) Preparation of a stereoisomer of 3-formyl-2,2- amethylcyclo- pfopanecarbaldehyde dimethyl acetal (compound III) A flask was charged with a mixture of pyridine (120 mmol) and methylene chloride (150 ml) and then with chromium trioxide (60 mmol), at a temperature of 20OC. The contents of the flask were stirred for 15 minutes. Then, a solution of 1.lh g of the ..residue obtained in (f) - which containsd6.39 mmol of compound F - in methylene chloride (5 ml) was added to the contents of the flask and stirring was continued for 20 minutes. The precipitate in the flask was allowed to settle, the liquid in the flask was decanted, the precipitate was washed with three ml portions of diethyl ether, the three washings were filtered over a bed of 2 cm Florisil (trade mark), the combined three filtrates were washed with two 20 ml portions of a 5#v aqueous solution of sodium hydroxide and then with two 20 ml portions of water and the combined washed ethereal liquids were added to the decanted liquid. The liquid thus obtained was dried over anhydrous magnesium sulphate and the solvent was evaporated from the dried liquid at a pressure of 16 mbar to give a residue containing compound III in a yield of 59$> calculated on starting compound III. The content of the compound III in the residue was h6.5%. The cis content of compound III was 10%.

The MR spectrum of the cis isomer of compound G showed the following absorptions :

6 = 3.30 ppm (singlet, C-O-CH) 6 = 1,8 ppm (doublet, H-C-C(O)H) 6 = k.Q ppm (doublet, H-C-O-CH S = 9,6 ppm (doublet, H-C=0) 6 =. 1.2 ppm (multiplet, H-C-C(H)~ (0CH3)2) 6 = 1 .22 ppm (singlet, H-C-C-CH-) 6= 1.37 ppm (singlet, H C-C-CH ) The stereoisomer of compound III was converted into a stereoisomer of 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropyl- carboxylic acid (Formula I: R=H : X=Cl) and it was found that its stereoisomeric form was the same as the (IB, cis) form of the acid, the known active acid portion of certain pyrethroid esters.

-* 52 PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS; 1. 3-Formyl-2J2-dimethylcyclopropanecarbaldehyde dimethyl acetal.

2. Compound according to claim 1 in the same stereoisomeric form as that of the cyclopropane ring of (+)-3-carene.

3. A process for preparing the compound claimed in claim 1 characterised in that 3-hydroxymethyl-2,2-diinethylcyclopropanecarhaldehyde dimethyl acetal is subjected to the action of an oxidising agent.

4. A process according to claim 3 characterised in that 3-hydroxymethyl- 2,2-dimethylcyclopropanecarbaldehyde dimethyl acetal is employed in the same stereoisomeric form as the cyclopropane ring of (+)-3-carene.

5. a process according to claim 3 or 4 characterised in that the oxidis¬ ing agent is a chromium trioxide pyridine complex.

SMART § BIGGAR OTTAWA, CANADA PATENT AGENTS tir