GB1596030A

GB1596030A - Esters of formyl cyclopropane carboxylic acids

Info

Publication number: GB1596030A
Application number: GB5417877A
Authority: GB
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1976-12-30
Filing date: 1977-12-29
Publication date: 1981-08-19
Also published as: JPS5384947A; CH627149A5; FR2376120B1; JPS623141B2; BE862461A; JPS61171453A; FR2376120A1

Abstract

Lower alkyl esters of racemic cis- or trans-3-formyl-2,2-disubstituted-1-cyclopropanecarboxylic acids are prepared by reduction of a lower alkyl hemiester of racemic cis- or trans-2,2-disubstituted-1,3-cyclopropanedicarboxylic acid followed by oxidation of the ester of cis- or trans-3-hydroxymethyl-1-cyclopropanecarboxylic acid obtained. The said derivatives are advantageous intermediates in the synthesis of esters of pyrethrinoid type.

Description

(54) ESTERS OF FORMYL CYCLOPROPANE CARBOXYLIC ACIDS (71) We, ROUSSEL UCLAF, a French Body Corporate of 35 Boulevard des Invalides, Paris 7eye, France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates inter alia to a process for the preparation of lower alkyl esters of racemic 2,2-disubstituted cis- and trans-3-formyl-cyclopropane-1-carboxylic acids.

According to the present invention there is provided a process for the preparation of cis or trans compounds of general formula I,

(wherein R represents an alkyl radical containing from 1 to 6 carbon atoms and either X represents an alkyl radical containing from 1 to 6 carbon atoms or the two radicals X, together with the carbon atom to which they are attached, represent a cycloalkyl radical containing from 3 to 7 carbon atoms) which comprises oxidising an appropriate cis or trans compound of formula II,

(wherein X and R are as defined above) by means of chromic acid in the presence of pyridine, lead tetraacetate in the presence of pyridine, manganese dioxide, chloro succmimlde with subsequent treatment with dimethylsulphide or by esterification of the alcohol function with a sulphonic acid followed by treatment with dimethylsulphoxide, whereby the desired compound of formula I is obtained.

Oxidation with chromic acid in the presence of pyridine is preferably effected also in the presence of methylene chloride and preferably using about 1.5 moles of chromic acid per mole of the compound of formula II. Oxidation with lead tetracetate in the presence of pyridine is preferably effected with excess pyridine. Oxidation may also, if desired, be effected by treatment with manganese dioxide or by reaction with chloro succinimide followed by treatment with dimethylsulphide. Alternatively oxidation may be effected by converting the alcohol of formula II into a sulphonate by reaction with a sulphonic acid e.g. p-toluenesulphonic acid and then subjecting the sulphonate thus formed to the action of dimethylsulpoxide, preferably with heating and in the presence of a base.

The compounds of general formula II may, for example, be obtained by reduction of an appropriate cis or trans compound of formula III,

(wherein R and X are as hereinbefore defined) by means of diborane or an alkali metal borohydride. The reduction is preferably effected in the presence of an ether oxide e.g. tetrahydrofuran as solvent. When reduction is effected by means of diborane, dimethylsulphide may alternatively, be used as solvent if desired. The reduction is preferably effected with an excess of the diborane or alkali metal borchydride e.g. from 4 to 6 moles of diborane or about 2 moles of alkali metal borohydride per mole of the compound of formula III. When the reduction is effected by means of an alkali metal borohydride then preferably this will be potassium or, more preferably, sodium boron hydride. According to a preferred method, reduction is effected by introduction of a solution of the compound of formula III into a solution of an alkali metal borohydride.

The cis and trans compounds of general formula III wherein X represents a methyl radical are known from the literature.

Compounds of general formula III having the trans configuration may be obtained by monosaponification of the corresponding 2,2-disubstituted-trans-cyclopropane-1- carboxylic acid of formula IV i.e.:

o ? 1-OR -OR X > < z/H ~ 1 molar equivalent X of base I I --OH /OOR O (IV) (III) (wherein R is as hereinbefore defined).

Such mcnosaponifications are illustrated hereinafter in the Examples.

Ccmpounds of general formula III having the cis configuration may also be obtained, if desired, from a compound of formula IV. Thus, for example, a compound of formula IV as hereinbefore defined may be treated with at least 2 equivalents of a base and then acidified to give a compound of formula V,

(wherein X is as hereinbefore defined). Said compound of formula V may subsequently be heated with acetic anhydride than hydrolysed to effect isomerisation and thus yield a compound of formula VI,

(wherein X is as hereinbefore defined). The compound of formula VI may be reacted with acetyl chloride to form a compound of formula VII,

(wherein X is as hereinbefore defined), which compound of formula VII may then be treated with an alcohol of formula R-OH (wherein R is as hereinbefore defined) in the presence of pyridine to give the desired cis compound of formula III. If desired, the stages involving the compound of formula VI may be omitted since these merely constitute a purification procedure.

The above series of reactions is illustrated hereinafter in the Examples.

The compounds of general formula IV may be prepared, for example, according to the process described and claimed in our co-pending British Patent Application No. 54177/77 (Serial No. 1,596,029) of even date herewith. According to the abovementioned application the compounds of general formula IV may be prepared by reaction of an appropriate alkyl fumarate or maleate with an appropriate triphenyl phosphonium halide. Such a process is illustrated in the Examples.

The process of the present invention is of particular advantage in that it enables the compounds of general formula I to be prepared in a reasonably small number of stages and under conditions which are easily industralised. The compounds of general formula I are of considerable importance in that they may be converted using a Wittig reaction with an appropriate phosphonium salt of phosphorane, into esters of cyclopropane carboxylic acid having good insecticidal properties. Thus, the process according to the invention allows cis and trans cyclopropane carboxylic acid derivatives to be prepared by a totally synthetic route. This route is illustrated in the accompanying drawings.

The compounds of general formula I wherein X is other than a methyl radical are novel compounds forming a further feature of the present invention. Specific novel compounds of formula I which may be mentioned are: racemic trans methyl spiro - [2,4] - heptane - 2 - formyl - 1 - carboxylate, racemic trans ethyl 2,2 - diethyl - 3 - formyl - cyclo - propane - 1 - carboxylate, racemic trans ethyl spiro - [2,5] - octane - 2 - formyl - 1 - carboxylate, racemic cis methyl 2,2 - diethyl - 3 - formyl - cyclo - propane - 1 - carboxylate and racemic cis methyl spiro - [2,5] - octane - 2 - formyl - I - carboxylate.

The following non-limiting Examples serve to illustrate the present invention. In the Examples X + X = cyclopentyl or cyclohexyl indicates that the two symbols X in formula I, together with the carbon atom to which they are attached, represent a cyclopentyl or cyclohexyl radical respectively.

Example 1.

Lower alkyl esters of racemic 2,2-disubsituted-trans-3-hydroxymethyl-cyclopropane-1 carboxylic acids (Tans compound of formula II).

Into 4 cm3 of tetrahydrofuran are introduced 10-3 mole of a lower alkyl monoester cf racemic 2,2-disubstituted-trans-cyclopropane-1,3-dicarboxylic acid (compound of formula III), followed, drop by drop under nitrogen, by 4 x 10-3 mole of diborane in solution in tetrahydrofuran (i.e. 4 cm of a 1N solution of diborane). The mixture obtained is agitated and concentrated to dryness under reduced pressure. 2 cm3 of water are added to the residue and the resultant mixture is extracted with ether. The ethereal phases are washed with water then with a saturated aqueous solution of sodium chloride, dried and concentrated to dryness. The residue is purified by chromatography on silica gel eluting with ether.

The experimental results obtained are summarised in the following Table: Trans compounds of formula II

X X R Yield Physical constants (A) methyl methyl ethyl 70% B.Pt. = 95 C under 0.1 mm of mercury (B) cyclopentyl methyl 81% B.Pt. - 120 C under 0.2 mm of mercury (C) ethyl | ethyl ethyl 94% B.Pt. = 1300C under 0.2 mm of mercury (D) cyclohexyl ethyl 79% B.Pt. 1250C under 0.1- mm of mercury (A) racemic trans ethyl 2,2-dimethyl-3-hydroxymethylcyclopropane 1-carboxylate, (B) racemic trans methyl spiro-[2,4]-heptane-2-hydroxymethyl 1-carboxylate, (C) racemic trans ethyl 2,2-diethyl-3-hydroxymethylcy olopropane- 1-carboxylate.

(D) racemic trans ethyl spiro-C2,Sl-octane-2-hydroxymethyl- 1-carboxylate.

The lower alkyl monoesters of racemic 2,2 - disubstituted - trans - cyclopropane1,3 - dicarboxylic acids (trans compounds of general formula III) can be prepared in the following manner: To 10-2 mole of racemic 2,2 - disubstituted - trans - cyclopropane - 1,3 - dicarboxylic acid diester (trans compound of formula IV) are added, drop by drop, 1.3 X 10-2 moles of potassium hydroxide in solution in 6 cm3 of alcohol (alcohol esterifying the acid functions of the compound of formula IV). The mixture obtained is reflexed for 3 hours, then the alcohol is eliminated. 5 cm3 of water are added and the resultant mixture is extracted with ether. The aqueous phase is acidified to pH 1 and extracted with ether. The ethereal phase is washed with water then with a saturated solution of sodium chloride, dried and concentrated to dryness. The residue is purified by chromatography on silica gel eluating with a mixture (50:50) of ether and petroleum ether (B.Pt.=35-750 C).

The experimental results obtained are summarised in the following Table: Trans compounds of formula III

X x R Yield Physical constants (E) methyl methyl ethyl 72% M.Pt. -- 570C [starting with compound (i)l (F) cyclopentyl methyl 65% M.Pt. - 960C [starting with compound (ii)l (G) cyclohexyl ethyl 84% M:Pt. -- 760C [starting with compound (iii)1 (H) ethyl ethyl ethyl 75% [starting with compound (iv)] (E) mono ethyl ester of racemic-trans-2,2-dimethylcyclopropane 1,3-dicarboxylic acid (used to prepare compound A), (F) mono methyl ester of racemic-trans-spiro-[2,4]-heptane-1 2 dicarboxylic acid (used to prepare compound B), (G) mono ethyl ester of racemic-trans-spirb-[2,5]-octane-1,2- dicarboxylic acid (used to prepare compound D), (H) mono ethyl ester of racemic-trans-2,2-diethylcyclopropane- 1,3-dicarboxylic acid (used to prepare compound C.

Example 2.

Methyl racemic cis-3 -hydroxymethyl-2,2-dimethyl-cyclopropane l-carboxylate (compound of formula II of cis configuration) by reduction of the corresponding cis diacid anhydride with sodium borohydride.

2 millimoles of sodium borohydride (0.28 g) are suspended in 0.5 cm3 of tetra hydrofuran, cooled to 0 C and a solution of 1 millimole of racemic ds-2,2-dimethyl- cyclopropane-1,3-dicarboxylic acid anhydride in solution in 2 cm3 of tetrahydrofuran, is gradually added thereto. The mixture obtained is allowed to cool to 200 C, agitated for 1 hour at this temperature, then cooled to 0 C and acidified slowly to pH 3-4 with an aqueous solution containing 100/c hydrochloric acid. The resultant mixture is extracted with ether. The ethereal fractions are combined, dried and concentrated to dryness. Diazomethane is added to the residue until a peristent yellow colouration occurs. The solvent is then eliminated by distillation under reduced precsure. The residue is purified by chromatography on silica gel eluting with a mixture of 95% benzene and 5% ethyl acetate. Methyl racemic cis-3-hydroxymethyl-2,2-dimethylcyclopropane-l-carboxylic is obtained. Yield 67.5%.

N.M.R. Spectrum.

#=1.20-1.60 p.p.m. (multiplet 2 H), #=1.20 p.p.m. (singlet 6 H), #=3.60 p.p.m. (singlet 3 H), #=3.80-3.86 p.p.m. (doublet 2 H), #=3.52 p.p.m. (1 H, alcohol), Example 3.

Methyl esters of racemic 2,2 - disubstituted - cis - 3 - hydroxy - methyl - cyclopropane - 1 - carboxylic acids (compounds of general formula II of cis configuration) by reduction with diborane.

Into z cm3 of tetrahydrofuran are introduced y millimoles (that is x grams) of the mono methyl ester of racemic 2,2-disubstituted-cis-cyclopropane-1,3-dicarboxylic acids of formula II and slowly, at 0 C, r millimoles (that is s cm3) of a solution of diborane in tetrahydrofuran or in dimethylsulphide) are added thereto. The mixture obtained is agitated for 2 hours 30 minutes at 250 C and then the diborane is eliminated by distillation under reduced pressure. 10 cm3 of water are added to the residue and the resultant mixture is extracted with ether. The organic phases are combined, washed with water, dried and concentrated to dryness by distillation. The residue is purified on silica gel eluting with ether.

The experimental results obtained are summarised in the following Table:

Mono methyl ester of cis compound of Methyl ester of cis compound formula ill THF B2H6 THF B2H (CH3)2S of formula ii y m r m , r m x x x g moles z om3 moles 5 cm moles 5 Cm3 Yield N.M.R. Spectrum W~ methyl 0.344 2.0 t cz CS , ~ iDn t ces ,mro :^ e 8 = e z e e C1) (lH v v ., ppm (5, 311); 3.80-3.86 .ppm (d, 2H). v 0.540 2.54 8 10.14 10.14 I i 77 N a 1.04 - 1.84ppm ~ 0 o o (N) 2.66 ppm (111 p alcohol; 3.66 .ppm E) (s, 2ff); 3.85 3.93 ppm (d, 211) "E methyl 0.258 1.5 6 -. - 6.0 0.57 86 % =1.20-1A'0ppm Lt"E I (0) (s, 611); 2.26 ppm o (111, alcohol); C1) 3.60 ppm (s, 311) 3.80-3.86 ppm (d, 211) ethyl ethyl 0.320 1.6 8 - - 6.4 0.61 65 % a 0.72-1.12 ppm (m. 611); 1.12 (Compound E O 1.92 Oo o I L .14ppm (111 alcohol); 3.62 ppm (5, 311); 3.84-3.90 ppm o oc oc o > E > cs ~ o E me e OO es m = multiplet s = singlet d = doublet

Mono methyl ester of cis compound of Methyl ester of cis compound formula III THF B2H6 THF B2H6 (CH3)2S of formula II y m. r m. r m.

X X x g moles z cm moles s cm moles s cm Yield N.M.R. Spectrum cyclohexyl 0.318 1.5 6 - - 6.0 0.57 91.5% # = 1.08-1.84 ppm (m, 12H); (Compound E1) (Q) 2.54 ppm (1H, alcohol); 3.72 ppm (1.3H); 3.92 4.00 ppm (d, 2H) (M) racemic cis methyl 2,2-dimethyl-3-hydroxymethylcyclopropane-1-carboxylate, (N) racemic cis methyl spiro-[2,5]-octane-2-hydroxymethyl-1-carboxylate, (O) racemic cis methyl 2,2-dimethyl-3-hydroxymethylcyclopropane-1-carboxylate [same compound as (M)], (P) racemic cis methyl 2,2-diethyl-3-hydroxymethylcyclopropane-1-carboxylate, (Q) racemic cis methyl spiro-[2,5]-octane-2-hydroxymethyl-1-carboxylate [same compound as (N)]. m = multiplet s = singlet d = doublet The mono esters of the racemic 2,2-disubstituted-cis-cyclopropane-1,3-dicarboxylic acids of formula III, used at the start of the process of Example 3, can be prepared in the following manner: Stage A: Preparation of the racemic 2,2 - disubstituted - trans - cyclopropane - 1,3dicarboxylic acids [compounds of general formula V]: Under nitrogen, a mixture of x millimoles (y grams) of racemic 2,2-disubstituted-trans-cyclopropane-1,3-dicarboxylic acid diester (compound of formula IV), r millimoles (s grams) of potassium hydroxide and t cm of methanol (or ethanol) is refluxed for 2 hours and then the alcohol is eliminated by distillation. The mixture obtained is extracted with water. The aqueous extract is extracted with ether then acidified with hydrochloric acid. The aqueous acidic phases are finally extracted with ether. The ethereal phase is washed with a saturated aqueous solution of sodium chloride, dried and concentrated to dryness under reduced pressure.

The experimental results obtained are as follows:

Potassium Methanol Compound of formula IV hydroxide or ethanol Compound of formula V x m. r m.

X X R moles y g moles s g t cm P.F. Yield N.M.R. Spectrum methyl methyl ethyl 74.8 16.0 224.4 12.6 28 212 C 90 % # = 1.26 ppm (s, 6H); 1.96 ppm [Compound (ethanol) (R) (s, 2H); wide (i)] acidic band at # 10 ppm (2H) ethyl ethyl methyl 11.15 2.7 33.45 1.88 4.3 246 C 94.5% # = 0.70-1.10 ppm (t, 6H); 1.10-1.90 [Compound (ethanol) (S) ppm (m, 4H) (v)] 2.0 ppm (s, 6H); wide acidic band (2H) 3-5 ppm cyclohexyl methyl 38 9.1 114 6.4 14.3 248 C 65 % # = 1.2-1.8 ppm (m, 10H); [Compound (methanol) (T) 1.92 ppm (s, 2H) (vi)] wide acidic band (2H) # = # 10 ppm cyclopentyl methyl 47 10.0 141 7.9 25.0 207 - 96 % # = 1,40-1.96 ppm 208 C (m, 8H); 2.09 ppm [Compound (methanol) (U) (s, 2H); acidic (ii)] band (2H) at 4.89 ppm (R) racemic trans 2,2-dimethyl-cyclopropane-1,3-dicarboxylic acid, (S) racemic trans 2,2-diethyl-cyclopropane-1,3-dicarboxylic acid, (T) racemic trans spiro-[2,5]-octane-1,2-dicarboxylic acid, (U) racemic trans spiro-[2,4]-heptane-1,2-dicarboxylic acid. s = singlet t = triplet m = multiplet The compounds of general formula IV used in the Table above and in the Table for preparing the trans compounds of formula III in Example 1, can be prepared in the following manner: Preparation of racemic trans ethyl 2,2-dimethyl-cyclopropane-1,3-dicarboxylate (com pound of formula IV with X=methyl and R=ethyl): Into 15 crit, of dimethoxyethane are introduced under nitrogen, 0.576 g of triphenyl isopropyl phosphonium bromide, followed slowly at 0 C by 0.090 g of butyl lithium in solution in 0.7 cm3 of pentane. The mixture obtained is agitated for 30 minutes at 0 C and then 0.156 g of methyl fumarate in solution in 5 cm3 of dimethoxyethane are introduced therein. The resultant mixture is agitated for 15 minutes at 0 C, the temperature is allowed to rise again to 20 C and agitation is continued until discolouration takes place (about 2 hours). Water is then added and the mixture obtained is agitated, then extracted with ether. The ethereal extracts are washed with water, then with a saturated aqueous solution of sodium chloride, dried and concentrated to dryness. The residue is rectified under reduced pressure. 0.108 g of racemic trans ethyl 2,2-dimethyl-cyclopropane-1,3-dicarboxylate are obtained. B.Pt.=820 C under 0.7 mm of mercury [called compound (i)].

In the above reaction the ethyl fumarate may be replaced by ethyl maleate to obtain the compound (i) with the same yield and the same quality.

Preparation of racemic trans methyl 2,2-diethyl-cyclopropane-1,3-dicarboxylate (com pound of formula IV with X=ethyl and R=methyl): Int 1300 cm3 of dimethoxyethane are introduced, under nitrogen, 55 g of tri phenyl 3-pentyl phosphonium iodide followed slowly at 0 C by 55 cm3 of a 2.1 N solution of butyl lithium in pentane. The mixture obtained is agitated for 30 minutes at 25 C, cooled to 0 C and then, very slowly, 14.4 g dimethyl fumarate (or 14.4 g of dimethyl maleate) are introduced therein. The resultant mixture is agitated at 25 C until discolouration of the reaction mixture takes place (about 5 hours). Water is then added and the mixture obtained is extracted with ether. The ethereal extracts are washed with a saturated aqueous solution of sodium chloride, dried and concentrated to dryness. The residue is rectified under reduced pressure. 6 g of racemic trans methyl 2,2-diethyl-cyclopropane-1,3-dicarboxylate are obtained. B.Pt.=65 C under 0.1 mm of mercury. M.Pt.=25 to 30 C. [called compound (v)].

N.M.R. Spectrum (carbon tetrachloride).

#=0.76-1.08 p.p.m. (t, 6H), #=1.24-2.92 p.p.m. (m, 4H), 3=2.08 p.p.m. (s, 2H), 3=3.63 p.p.m. (s, 6H).

In a similar manner, starting with ethyl fumarate and 3-pentyl triphenyl phos phonium iodide, racemic trans ethyl 2,2-diethyl-cyclopropane-1,3-dicarboxylate may be obtained.

(Compound of formula IV with Methyl and R= ethyl).

B.Pt=8385 C under 0.5 mm of mercury [Compound (iv)].

Preparation of racemic trans methyl 2,2-diethyl-cyclopropane-1,3 -dicarboxylate (Com pound of formula IV with X=ethyl and R=methyl): Into 15 cni, of dimethoxyethane are introduced, under nitrogen, 0.688 g of triphenyl 3-pentyl phosphonium iodide followed slowly at 0 C by 0.05 g of butyl lithium in solution in 0.7 cm, of pentane. The mixture obtained is agitated for 30 minutes at 0 C and then 0.128 g of dimethyl fumarate in solution 5 cm of dimethoxyethane, are introduced therein. The resultant mixture is agitated for 15 minutes at 0 C, the temperature is then allowed to rise again to 200 C and agitation is continued until discolouration takes place (about 2 hours). Water is then added and the mixture obtained is agitated then treated as in Example 1. The residue is chromatographed on silica gel eluting with a mixture of benzene containing 3% of ethyl aectate. 0.150 g of racemic trans methyl 2,2-diethyl-cyclopropane- 1,3 -dicarboxylate are obtained [called compound (v)].

Preparation of racemic trans methyl spiro-[2,4] heptane-1-dicarboxylate (Compound of formula IV with X+X=cyclot?enty1 and R=methyl): Into 4300 cmS of dlmetnoxyethane are introduced, under nitrogen, 160 g of triphenyl cyclopentyl phosphonium bromide, followed slowly at 0 C by 160 cm3 of a 2.1 N solution of butyl lithium in pentane. The mixture obtained is agitated for 30 minutes at 250 C, cooled to 0 C and, very slowly, 43.2 g of dimethyl fumarate are introduced therein. The resultant mixture is agitated at 25 C until discolouration of the reaction mixture occurs (about 5 hours). Water is then added and the mixture obtained is extracted with ether. The extract is treated as in Example 2. 15.2 g of racemic trans methyl spiro-[2,4]-heptane-1,2-dicarboxylic are obtained. B.Pt=890 C under 0.08 mm of mercury [called compound (n)].

N.M.R Spectrum (dimethylsulphoxide).

=1.40--1.80 p.p.m. (m, 8H), 0=2.22 p.p.m. (s, 2H), 3=3.64 p.p.m. (s, 6H).

Preparation of racemic trans methyl spiro-[2,5]-octane-1,2-dicarboxylate (Compound of formula of formula IV with X+X=cyclohexyl and R=methyl): Into 3200 cm3 of dimethoxyethane are introduced, under nitrogen, 115 g of triphenyl cyclohexyl phosphonium bromide, followed slowly at 0 C by 112 cm3 of a 2.1 N solution of butyl lithium in pentane. The mixture obtained is agitated for 30 minutes at 250 C, cooled and then, very slowly 32.5 g of dimethyl fumarate are introduced therein. The resultant mixture is agitated at 250 C until discolouration takes place (about 5 hours). Water is then added thereto and the mixture thus formed is extracted with ether. The ethereal extracts are washed with a saturated aqueous solution of sodium chloride, dried and concentrated to dryness. The residue is rectified under reduced pressure, 20.4 g of racemic trans methyl spiro-[2,5]-octane-1,2-di carboxylate are obtained. B.Pt.=133-138 C under 0.5 mm of mercury [called compound (vi)]: N.M.R Spectrum (dimethylsulphoxide).

#=1.20-1.80 p.p.m. (m, 10H), #=2.12 p.p.m. (s,2H), s=3.68 p.p.m. (s, 6H).

In a similar manner, starting with cyclohexyl triphenyl phosphonium bromide and ethyl fumarate, trans ethyl spiro-[2,5]-octane 1,2 dicarboxylate is obtained (compound of formula IV with X+X=cyclohexyl and R=ethyl). B.Pt=90-103 C under 0.8 mm of mercury [Compound (iii)].

Stage B: Preparation of racemic 2,2-disubstituted cis-cyclopropane- 1,3-dicarboxylic diacids (compounds of general formula VI).

In a sealed tube under vacuum, a mixture of x grams of a trans diacid and 3x grams of acetic anhydride are heated for 6 hours at 220 C. The mixture is then allowed to cool and the excess acetic anhydride and the acetic add formed are eliminated. To the mixture thus obtained is added 50 cm:l of water and 1 g of active charcoal.

The resultant mixture is heated to 1200 C for 2 hours 30 minutes and then

Trans diacid of formula V Weight of acid Weight of acetic Cis diacids of formula VI in grams anhydride X X (x) in grams (3x) M.Pt. Yield N.M.R. Spectrum methyl methyl 10.3 30.9 79 % # = 1.16 p.p.m. (s, 3H) ; # = 1.34 p.p.m. (s, 3H) ; (Compound R) (V) # = 1.80 p.p.m. (s, 2H) ; wide acidic band (2H) at about # 9 - 10 p.p.m. ethyl ethyl 5.42 16.26 180 C 71.5% # = 0.40 - 1.10 p.p.m. (t, 6H) ; # = 1.10 - 1.60 p.p.m. and 1.60 (Compound S) (W) 2.00 p.p.m. (m, 5H) ; wide acidic band at 4:48 p.p.m.

(2H) cyclohexyl 7.59 22.77 210 - 75 % # = 1.00 - 2.00 p.p.m. (m, 12H) ; 212 C wide acidic band (2H) at about (Compound T) (X) 9.60 p.p.m. cyclopentyl 1.00 3.00 185 C 72 % # = 1.40 -3.30 p.p.m. (m, 10H) ; wide acidic band (2H) at about (Compound U) (Y) 4:51 p.p.m.

(V) racemic cis 2,2-dimethyl-cyclopropane-1,3-dicarboxylic acid, (W) racemic cis 2,2-diethyl-cyclopropane-1,3-dicarboxylic acid, (X) racemic cis spiro-[2,5]-octane-1,2-dicarboxylic acid, (Y) racemic cis spiro-[2,4]-heptane-1,2-dicarboxylic acid. s = singlet t = triplet m = multiplet Stage C: Preparation of racemic 2,2-disubstituted cis cyclopropane-1,3-dicarboxylic diacid anhydrides (compounds of general formula VII): A mixture of x millimoles (that is y grams) of a cis diacid and r m moles (s grams or tcm ) of acetyl chloride is heated to 40 for 2 hours, then cooled and the excess acetyl chloride and the acetic acid formed are eliminated by distillation under vacuum to obtain the desired cis anhydride.

The experimental results obtained are as follows:

Cis diacid of formula VI Acetyl chloride Cis diacid anhydride of formula VII X X x m. moles y g x m. moles s g t cm M.Pt. Yield N.M.R. Spectrum methyl methyl 49.0 7.72 98.0 7.7 7.0 55 C 96 %* # = 1.20 - 1.60 p.p.m.

(d, 6H) ; 2.55 p.p.m.

(Compound V) (Z) (s, 2H) ethyl ethyl 17.7 3.3 35.4 2.8 2.5 100 % # = 0.70 - 1.24 p.p.m.

(m, 6H) ; (Compound W) (A1) # = 1.32 - 2.84 p.p.m.

(m, 4H) ; # = 2.56 p.p.m. (s, 2H) cyclohexyl 28.4 5.6 56.8 4:45 4.0 100 C 95.5%* # = 1.30 - 1.80 p.p.m.

(m, 10H) ; (Compound X) (B1) # = 2.46 p.p.m. (s, 2H).

* After purification in ether.

(Z) racemic cis 2,2-dimethyl-cyclopropane-1,3-dicarboxylic acid anhydride, (A1) racemic cis 2,2-diethyl-cyclopropane-1,3-dicarboxylic acid anhydride, (B1) racemic cis spiro-[3,5]-octane-1,2-dicarboxylic acid anhydride. d = doublet s = singlet m = multiplet Stage D: Preparation of the mono methyl esters of racemic 2,2-disubstituted ciscyclopropane-1,3-dicarboxylic diacids (compounds of general formula III) of cis structure): Into / cm of methanol are introduced y millimoles (that is x grams) of a cis diacid anhydride followed by 5 drops of pyridine. The mixture obtained is agitated for 16 hours at 20 C and then excess methanol is eliminated by distillation. The residue is purified by chromatography on silica gel eluting with ether to yield the desired cis diacid mono methyl ester.

The experimental results obtained are as follows:

Cis anhydride of formula VII Cis acid ester of formula III X X x grams y m. moles M. Pt. Yield N.M.R. Spectrum methyl methyl 0.35 2.5 107 C 100%* # = 1.28 - 1.40 p.p.m. (d, 6H) ; # = 1.97 p.p.m. (s, 2H) ; (Compound Z) (C1) # = 3.76 p.p.m. (s, 3H) ; # = 10.96 p.p.m. (1H, acid) ethyl ethyl 0.76 4.5 76 C 84% # = 0.84 - 1.20 p.p.m. (t, 6H) ; # = 1.30 - 2.10 p.p.m. (m, 6H) ; (Compound A1) (D1) # = 3.72 p.p.m. (s, 3H) ; # = 10.34 p.p.m. (1H, acid) cyclohexyl 0.72 4.0 91 C 84% # = 1.20 - 2.10 p.p.m. (m, 12H) with 1s (2H) # = 1.92 p.p.m.

(Compound B1) (E1) # = 10.92 p.p.m. (1H, acid) * Unpurified (C1) mono methyl ester racemic cis 2,2-dimethyl-cyclopropane1,3-dicarboxylic acid, (d1) mono methyl ester of racemic cis 2,2-diethyl-cyclopropane1,3-dicarboxylic acid, (E1) mono methyl ester of racemic cis spiro-[2,5]-octane-1,2-dicarboxylic acid. d = doublet s = singlet t = triplet m = multiplet Example 4.

Lower alkyl esters of racemic 2,2-disubstituted-trans-3-formyl-cyclopropane-1carboxylic acids (trans compounds of general formula I).

Into 4 cm of dichloroethane are introduced, under nitrogen, 1.5 X 10-3 mole of a CrO3/pyridine complex. The mixture obtained is added, drop by drop, to a suspension of 10-3 mole of a lower alkyl ester of 2,2-disubstituted trans 3-hydroxymethyl-cyclopropane-1-carboxylic acid (trans compound of formula II), obtained according to Example 1, in 1 cm of methylene chloride. The resultant mixture is agitated for 2 hours and then ether is added thereto. Insoluble substances are removed from the resultant mixture, by filtration, then the filtrate is concentrated to dryness by distillation under reduced pressure. The residue is purified by chromatography on silica gel eluting with ether.

The experimental results obtained are as follows: Trans -Compound of formula I

X X R Yield Physical constants methy methyl ethyl 66% B.Pt. = 65 C under 0.1 mm of mercury (I) cyclopentyl methyl 64% B.Pt. =- 850C under 0.4'mm of mercury (J) ethyl ethyl ethyl 77% B.Pt. = 88 C under 0.5 mm of mercury (K) cyclohexyl ethyl 70% B.Pt. 850C under 0.5 mm of mercury (L) (l) racemic trans -e thy l 2,2-dime thyl-3-formy l-cyclopropane-1-carboxylate, obtained starting with compound (A) of Example 1, (J) racemic trans methyl spiro-[2,4}heptane-2-formyl-1-carboxylate, obtained starting with compound (B) of Example 1, (K) racemi d trans ethyl 2,2-diethyl-3-formyl-cyclopropane-1-carboxylate obtained starting with compound (C) of Example 1, (L) racemic trans ethyl spiro-[2,5]-octane-2-formyl-1-carboxylate, obtained starting with compound (D) of Example 1.

Example 5.

Methyl esters of racemic 2,2-disubstituted-cis-3-formyl-cydopropane-1-carboxylic acids by oxidation with a chromic anhydride/pyridine hydrochloride complex (cis compounds of general formula I).

Into a solution of x millimoles (y grams) of a chromic anhydride/pyridine hydrochloride complex in methylene chloride are added slowly r millimoles (s grams) of a methyl ester of 2,2-disubstituted-cis-3-hydroxymethylcyclopropane-1- carboxylic acid. The mixture obtained is agitated for 2 hours at 20 C and then filtered. The filtrate is concentrated to dryness and the residue is purified by chromatography on silica gel eluting with ether.

The experimental results obtained are summarised in the following Table:

Pyridine hydrochloride/ Cis alcohol ester of formula II CrO3 complex Cis aldehyde ester of formula I X X r m.moles s g x m.moles y g Yield N.M.R. Spectrum methyl methyl 1.45 0.23 2.18 0.47 69% # = 1.32 - 1.56 p.p.m. (d, 6H); (Compound M) (F1) # = 1.60 - 2.12 p.p.m. (m, 2H); # = 3.72 p.p.m. (s, 3H); # = 9.64 - 9.72 p.p.m. (d, 1H) ethyl ethyl 0.825 0.153 1.24 0.248 73% # = 0.80 - 1.16 p.p.m. (t, 6H); # = 1.16 - 2.20 p.p.m. (m, 6H); (Compound P) (G1) # = 3.72 p.p.m. (s, 3H); # = 9.68 - 9.74 p.p.m. (d, 1H). cyclohexyl 1.31 0.260 1.96 0.425 78% # = 1.20 - 2.20 p.p.m. (m, 12H); # = 3.72 p.p.m. (s, 3H); (Compound N) (H1) # = 9.67 - 9.72 p.p.m. (d, 1H). d = doublet, m = multiplet, s = singlet, t = triplet.

(F1) Methyl ester of racemic cis 2,2-dimethyl-3-formyl-cyclopropane-1-carboxylic acid, (G1) Methyl ester of racemic cis 2,2-diethyl 3-formyl-cyclopropane-1-carboxylic acid, (H1) Methyl ester of racemic cis spiro-[2,5]-octane-2-formyl-1-carboxylic acid.

Claims

WHAT WE CLAIM IS:1. A process for the preparation of cis or trans compounds of general formula I,

(wherein R represents an alkyl radical containing from 1 to 6 carbon atoms and either X represents an alkyl radical containing from 1 to 6 carbon atoms or the two radicals X, together with the carbon atom to which they are attached, represent a cycloalkyl radical containing from 3 to 7 carbon atoms) which comprises oxidising an appropriate cis or trans compound of formula II,

(wherein X and R are as defined above) by means of chromic acid in the presence of pyridine, lead tetraacetate in the presence of pyridine, manganese dioxide, chlorosuccinimide with subsequent treatment with dimethylsulphide or by esterification of the alcohol function with a sulphonic acid followed by treatment with dimethylsulphoxide, whereby the desired compound of formula I is obtained.
2. A process as claimed in claim 1 wherein oxidation is effected by means of chromic acid in the presence of pyridine and of methylene chloride.
3. A process as claimed in claim 1 or claim 2 wherein oxidation is effected by means of chromic acid in the presence of pyridine and about 1.5 moles of chromic acid are used per mole of the compound of formula II.
4. A process as claimed in claim 1 wherein oxidation is effected by means of lead tetraacetate in the presence of an excess of pyridine.
5. A process as claimed in any of the preceding claims wherein the compound of formula II is obtained by reduction of an appropriate cis or trans compound of formula III,

(wherein R and X are as defined in claim 1) by means of diborane or an alkali metal borohydride.
6. A process as claimed in claim 5 wherein the reduction is effected in the presence of an ether oxide as solvent
7. A process as claimed in claim 6 wherein the ether oxide is tetrahydrofuran.
8. A process as claimed in claim 5 wherein reduction is effected by means of diborane and in the presence of dimethylsulphide as solvent.
9. A process as claimed in any of claims 5 to 8 wherein the reduction is effected with an excess of the diborane or alkali metal borohydride as compared with the compound of formula III.
10. A process as claimed in claim 9 wherein, to effect reduction, from 4 to 6 moles of diborane are used per mole of the compound of formula III.
11. A process as claimed in claim 9 wherein, to effect reduction, about 2 moles of alkali metal borohydride are used per mole of the compound of formula III.
12. A process as claimed in any of claims 5 to 7, 9 and 11 wherein reduction is effected by means of sodium or potassium borohydride.
13. A process as claimed in any of claims 1 to 12 for the preparation of compounds of general formula I having the trans structure.
14. A process as claimed in any of claims 1 to 12 for the preparation of compounds of general formula I having the cis structure.
15. A process for the preparation of compounds of general formula I as defined in claim 1 substantially as herein described.
16. A process for the preparation of compounds of general formula I as defined in claim 1 substantially as herein described with reference to the Examples.
17. Compounds of general formula I as defined in claim 1 whenever prepared by a process as claimed in any of claims 1 to 16.
18. Compounds of general formula I as defined in claim 1 wherein X is other than a methyl radical.
19. Racemic trans methyl spiro-[2,4]-heptane-2-formyl-1-carboxylate.
20. Racemic trans ethyl 2,2-dimethyl-3-formyl-cyclopropane-1-carboxylate.
21. Racemic trans ethyl spira-r2,51 -octane-2-formyl-l-carboxylate.
22. Racemic cis methyl 2,2-diethyl-3-formyl-cyclopropane-1-carboxylate,
23. Racemic cis methyl spiro-[2,5]-octane-2-formyl-1-carboxylate.