CH627149A5 - Process for the preparation of lower alkyl esters of racemic cis- or trans-3-formyl-2,2-disubstituted-1-cyclopropanecarboxylic acids - Google Patents

Description

The subject of the present invention is a process for the preparation of lower alkyl esters of 2,2- disubstituted racemic eis- or trans-3-formyl-cyclopropane-1-carboxylic acids of general formula:

0

HORN

CHO

in which R represents an alkyl radical comprising from 1 to 6 carbon atoms and X represents an alkyl radical comprising from 1 to 6 carbon atoms, or else the two radicals X represent together, with the carbon atom to which they are bonded, a cycloalkyl radical comprising from 3 to 7 carbon atoms, characterized in that one reacts a lower alkyl hemi-ester of eis- or transcyclopropane 1,3-dicarboxylic 2,2-disubstituted racemic of general formula :

-GOLD

X

X

■ C-OH

in which X and R retain the abovementioned meanings, with a reducing agent chosen from the group consisting of diborane and alkaline hydroborides and subjects the lower alkyl ester of cis-outrans-3-hydroxymethylcyclopropane-1-carboxylic acid 2 , 2-racemic disubstituted resulting from general formula:

:-GOLD

to oxidation by means of an oxidizing agent or an oxidizing system, chosen from the group consisting of chromic acid in the presence of pyridine, lead tetracetate in the presence of pyridine, manganese dioxide, chlorosuccinimide with action dimethyl sulfide, dimethyl sulfoxide after esterification of the alcohol function with a sulfonic acid.

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627149

This process is illustrated by diagram I.

In the general formula I, R represents a methyl, ethyl, propyl, linear or branched, butyl, linear or branched, pentyl, linear or branched, hexyl, linear or branched radical, and X represents in particular a methyl radical, an ethyl radical, a propyl radical, linear or branched, a butyl radical, linear or branched, a pentyl radical, linear or branched, a hexyl radical, linear or branched, or else the two radicals X represent together, with the carbon atom to which they are linked, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radical.

The reduction by diborane of compounds II to compounds III is advantageously carried out in a solvent constituted by an etheroxide.

This solvent is preferably tetrahydrofuran.

This solvent can also be dimethylsulfide.

The reduction with diborane is advantageously carried out with an excess of reagent. Advantageously, 4 to 6 mol of diborane are used per 1 mol of diacid II monoester.

To effect the reduction of compounds II into compounds III, it is advantageous to use, as alkaline hydroboride, sodium hydroboride or potassium hydroboride.

The reduction with alkaline hydroborides is preferably carried out in a solvent consisting of an etheroxide, and in particular in tetrahydrofuran.

As the alkaline hydroboride, sodium hydroboride is preferably used.

The reduction by hydroboride is advantageously carried out with an excess of this reagent, preferably of the order of 2 mol per 1 mol of acid-ester II.

An advantageous procedure consists in introducing the solution of the acid-ester II into the hydroboride solution.

The oxidation by chromic acid in the presence of pyridine of the compounds III into compounds I is carried out, preferably, within methylene chloride.

The oxidation with chromic acid in the presence of pyridine is advantageously carried out using an excess of oxidizing agent corresponding to approximately 1.5 mol per 1 mol of compound III.

The oxidation of alcohols III to aldehydes I by lead tetracetate in the presence of pyridine is advantageously carried out in an excess of pyridine.

The oxidation of alcohols III to aldehydes I can also be carried out either by the action of manganese dioxide, or by the action of chlorosuccinimide, then dimethylsulfide.

It is also possible to carry out the passage of alcohols III to aldehydes I by preparing a sulfonate, in particular a paratoluene sulfonate of alcohol III, which is then subjected to the action of dimethylsulfoxide, in a basic hot medium.

The compounds of general formula II, of structure eis or of structure trans, used at the start of the process of the invention, for which X represents a methyl radical, are described in the literature, as well in series eis as in series trans.

The compounds of general formula II of trans structure, for which X is different from methyl, are easily obtained by monosaponification of the corresponding 2,2-disubstituted transcyclopropane-1-carboxylic acid diesters (1) according to the scheme:

0 11

•HORN

X

"" H

trans (A)

X

HORN

1 basic equivalent

GOLD

X

trans (II)

X

'C-OH

Examples of these preparations are given in the experimental part, in the case where X represents either a methyl radical or an ethyl radical, or in the case where the two substituents X represent, with the carbon atom to which they are linked, a cyclohexyl radical or a cyclopentyl radical.

The trans diesters (A) themselves can be obtained by total synthesis in a single step by condensation of a fumarate or an alkyl maleate and a suitable triphenylphosphonium halide, according to the process of the patent application. French title "Process for the preparation of lower alkyl esters of racemic transcyclopropane-1,3-dicarboxylic acids 2,2-disubstituted and new esters of said acids", filed on December 30, 1976 by the licensee under the number 76.39532.

Examples of preparation of diesters (A) are given in the experimental part.

The compounds of general formula II of structure eis, for which X is other than methyl, are obtained by the following reactions given below:

HORN

trans (A)

HORN

base (2 or more equivalents, then acidification)

C-OH

trans (2)

C-OH

(AC) 20 heating, then hydrolysis b-OH

eis (3)

C-OH

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627149

4

V

acetyl chloride

0 II

Passage through eis (3) acids can be avoided. It constitutes a stage of purification.

Examples of these preparations are given in the experimental part, in the cases where X represents a methyl radical, an ethyl radical, or in the case where the two substituents X represent, with the carbon atom to which they are bonded, a radical cyclopentyle or cyclohexyle.

The advantage of the process of the invention lies in that it makes it possible to prepare aldehydes I, of eis or trans structure, in a limited number of steps, under conditions which are easy to industrialize. These aldehydes I have great industrial utility, because they lead, by Wittig reaction with phosphonium salts or suitable phosphoranes, to obtaining cyclopropane-carboxylic acids of very diverse structures, then to esters of these gifted acids insecticide properties.

As indicated above, the starting compounds II, both in series and in series, can be obtained conveniently from the corresponding diesters (A) which, themselves, can be prepared in a single step by synthesis total.

Finally, the process of the invention appears as an essential step allowing the obtaining, by total synthesis, of cyclopropanecarboxylic acids eis or trans of very diverse structures.

Scheme II annexed summarizes all the reactions allowing the production of these cyclopropanecarboxylic acids by synthesis

Compounds tra total and shows the interest of the process of the invention in this reaction chain.

The compounds of general formula I, as defined above,

in which X is different from methyl, are new.

s Among these compounds, special mention will be made of those whose names follow:

racemic methyl transspiro- [2,4] -heptane 2-formyl 1-carboxylate;

racemic ethyl 2,2-diethyl 3-formylcyclopropane 1-carboxylate io;

racemic ethyl transspiro- [2,5] -octane 2-formyl 1-carboxylate;

racemic methyl 2,2-diethyl 3-formylcyclopropane 1-carboxylate;

racemic methyl cisspiro- [2,5] -octane 2-formyl 1-carboxylate iî.

The intermediaries whose names follow are also new:

racemic methyl transspiro- [2,4] -heptane 2-hydroxymethyl 1-carboxylate;

Racemic ethyl 2,2,2-diethyl 3-hydroxymethylcyclopropane 1-carboxylate;

racemic ethyl transspiro- [2,5] -octane 2-hydroxymethyl 1-carboxylate;

racemic methyl 2,2-dimethyl 3-hydroxymethylcyclopropane 1-carboxylate;

racemic methyl 2,2-diethyl 3-hydroxymethylcyclopropane 1-carboxylate;

the racemic transspiro- [2,4] -heptane 1,2-dicarboxylic acid monomethyl ester;

30 the monoethyl ester of transspiro [2,5] octane acid

1.2-racemic dicarboxylic;

2,2-diethylcyclopropane eis acid monomethyl ester

1.3-racemic dicarboxylic;

the racemic cisspiro- [2,5] -octane 1,2-dicarboxylic acid monomethyl ester.

The following examples illustrate the invention.

In these examples, the indication X + X = cyclopentyl or cyclohexyl means that X + X with the carbon to which they are linked represent a cyclopentyl or cyclohexyl radical.

-40 Example 1:

Lower alkyl esters of trans 3-hydroxymethylcyclopropane 1-carboxylic 2,2-disubstituted racemic acids (trans compound of general formula III).

10-3 mol of 45 lower alkyl monoester of transcyclopropane 1,3-di-2,2-disubstituted racemic acid (compound of general formula II) are added to 4 cm 3 of tetrahydrofuran, added dropwise under nitrogen atmosphere,

4 x 10-3 mol of diborane in solution in tetrahydrofuran,

or 4 cm3 of a solution N of diborane, stirred, concentrated to dryness under reduced pressure, add 2 cm3 of water to the residue, extract with ether, wash the ethereal phases with water, with a saturated aqueous solution sodium chloride, dried, concentrated to dryness, purified by chromatography on silica gel, eluting with ether.

The experimental results obtained are summarized in the following table is of formula III

X

X

R

Yield

Physical constants a) methyl methyl

ethyl

70

Eb. = 95 ° C under 0.1 mm of mercury b) methyl cyclopentyl

81

Eb. = 120 ° C under 0.2 mm of mercury c) ethyl

ethyl

ethyl

94

Eb. = 130 ° C under 0.2 mm of mercury d) cyclohexyl

ethyl

79

Eb. = 125 ° C under 0.1 mm of mercury a) Trans 2,2-dimethyl 3-hydroxymethylcyclopropane I-racemic ethyl carboxylate.

b) Racemic methyl transspiro / 2,4 / heptane 2-hydroxymethyl 1-carboxylate.

c) Trans 2,2-diethyl 3-hydroxymethylcyclopropane 1-racemic ethylcarboxylate.

d) Racemic ethyl transspiro / 2.5 / octane 2-hydroxymethyl 1-carboxylate.

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627149

The lower alkyl monoesters of transcyclopropane acids eliminate the alcohol, add 5 cm3 of water, extract with ether, acidify the phase.

1,3-dicarboxyls 2,2-racemic disubstituted, aqueous trans compounds at pH 1, extract the aqueous phase with ether, wash the phase of general formula II, can be prepared as follows: ethereal with water, with a saturated solution of sodium chloride,

AIO-2 mol of dry transcyclopropane acid diester, concentrated to dryness, purified by chromatography on silica gel, 1,3-dicarboxylic 2,2-disubstituted racemic (trans compound of s eluting with a mixture (50/50) ether / petroleum ether (Eb. =

formula (A)) 1.3 x 10-2 mol of potash 35-75 ° C are added dropwise.

dissolved in 6 cm3 of alcohol (alcohol esterifying the acid functions The experimental results obtained are summarized in the table of diester I), brings the reaction mixture to reflux for 3 h, as follows:

Trans compounds of formula II

X

X

R

Yield

Physical constants e) methyl methyl

ethyl

72

M.p. = 57 ° C (starting from compound a)

f) methyl cyclopentyl

65

M.p. = 96 ° C (starting from compound y)

g) cyclohexyl

ethyl

84

M.p. = 76 ° C (starting from compound Sx)

h) ethyl

ethyl

ethyl

75

(from compound ßj)

e) monoethyl ester of racemic 2,2-dimethylcyclopropane 1,3-dicarboxylic acid (used to prepare compound a).

f) Monomethyl ester of racemic transspiro / 2,4 / heptane 1,2-dicarboxylic acid (used to prepare compound b).

g) Monoethyl ester of racemic transspiro / 2.5 / octane 1,2-dicarboxylic acid (used to prepare compound d).

h) Monoethyl ester of racemic 2,2-diethylcyclopropane 1,3-dicarboxylic acid (used to prepare compound c).

Example 2:

Eis 3-hydroxymethyl 2,2-dimethylcyclopropane 1-carboxylic acid racemic methyl ester (compound of general formula III, with structure eis) by reduction of the anhydride of the corresponding diacid by sodium hydroboride. 3S

In 0.5 cm3 of tetrahydrofuran, 2 mmol of sodium hydroboride (0.28 g) is suspended, cooled to 0 ° C., gradually adding a solution of 1 mmol of acid anishydride 2.2 -dimethylcyclopropane 1,3-dicarboxylic racemic, in solution in 2 cm3 of tetrahydrofuran, leaves to cool to 20 ° C, stirred 40 for 1 h at this temperature, cools to 0 ° C, slowly acidifies to pH 3-4, with a solution aqueous with 10% hydrochloric acid,

extract with ether, combine the ethereal fractions, dry them, concentrate to dryness, add to the residue diazomethane until a persistent yellow color, remove the solvent by distillation under reduced pressure, 45 purify the residue by chromatography on silica gel eluting with a mixture of 95% benzene and 5% ethyl acetate and obtains the methyl ester of racemic eis 3-hydroxymethyl 2,2-dimethylcyclopropane 1-carboxylic acid. Yield = 67.5%.

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NMR spectrum:

8 = 1.20-1.60 ppm (2 H multiplet);

S = 1.20 ppm (6 H singlet);

S = 3.60 ppm (3 H singlet);

8 = 3.80-3.86 ppm (2 H doublet);

8 = 3.52 ppm (1 H, alcohol).

Example 3:

Methyl esters of isis 3-hydroxymethylcyclopropane 1-carboxylic 2,2-disubstituted racemates (compound of general formula III of structure eis) by reduction using diborane.

In z cm3 of tetrahydrofuran, there are introduced y mmol (or xg) of monomethyl ester of the ciscyclopropane 1,3-dicarboxylic acid 2,2-disubstituted racemates of formula II, slowly adding, at 0 ° C, r mmol (or s cm3 ) of a solution of diborane in tetrahydrofuran or in methyl disulfide, stirred for 2 h at 25 ° C., eliminates the diborane by distillation under reduced pressure, adds 10 cm3 of water, extracted with ether, combines the organic phases, washing them with water, drying them, concentrating them to dryness by distillation, purifying the residue on silica gel, eluting with ether.

The experimental results obtained are summarized in the following table:

Eis ii diacid monomethyl ester

THF

b2h6

THF

b2h (

(CH3) 2s

Methyl ester of alcoholic acids eis iii

X

X

xg y mmol zcm3

rmmol s cm3

rmmol s cm3

Yield

NMR spectrum

methyl (Comp methyl osécj)

0.344

2.0

8

8

8

94.5% (m)

8 = 1.2-1.6 ppm (m, 2H); 1.2 ppm (s, 6H); 2.8 ppm (1H, alcohol); 3.60 ppm (s, 3H); 3.80-3.86 ppm (d, 2H).

cyclohexyle (Compound and)

0.540

2.54

8

10.14

10.14

77% (n)

S = 1.04-1.84 ppm (m, 12H);

2.66 ppm (1H, alcohol); 3.66 ppm (s, 2H); 3.85-3.93 ppm (d, 2H)

627149

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Eis II diacid monomethyl ester

THF

b2he

THF

b2h6

(CH3) 2S

Eis III alcoholic methyl ester

X X

xg y mmol zcm3

rmmol s cm3

rmmol s cm3

Yield

NMR spectrum

methyl | methyl (Compound Cj)

0.258

1.5

6

6.0

0.57

86% (o)

S = 1.20-1.60 ppm (m, 12H); 1.20 ppm (s, 6H); 2.26 ppm (1H, alcohol); 3.60 ppm (s, 3H); 3.80-3.86 ppm (d, 2H)

ethyl | ethyl (Composed of ^

0.320

1.6

8

6.4

0.61

65% (P)

8 = 0.72-1.12 ppm (m, 6H); 1.12-1.92 ppm (m, 2 + 4H); 3.14 ppm (1H, alcohol); 3.62 ppm (s, 3H); 3.84-3.90 ppm (d, 2H)

cyclohexyle (Compound e ^

0.318

1.5

6

6.0

0.57

91.5%

(q)

8 = 1.08-1.84 ppm (m, 12H);

2.54 ppm (1H, alcohol); 3.72 ppm (1.3H); 3.92-4.00 ppm (d, 2H)

m = multiplet; s = singlet; d = doublet.

m) Cis 2,2-dimethyl 3-hydroxymethylcyclopropane 1-racemic methyl carboxylate.

n) Cisspiro / 2,5 / octane 2-hydroxymethyl 1-racemic methyl carboxylate.

o) Cis 2,2-dimethyl 3-hydroxymethylcyclopropane 1-racemic methyl carboxylate (same compound as m), p) Cis 2,2-diethyl 3-hydroxymethylcyclopropane 1-racemic methyl carboxylate.

q) Cisspiro / 2,5 / octane 2-hydroxymethyl 1-racemic methyl carboxylate (same compound as n).

The monomethyl esters of the cis cyclopropane 1,3-dicarboxylic 2,2-disubstituted racemic diacids of formula II, used starting from the process of Example 3, can be prepared as follows:

Stage A:

Preparation of racemic 1,3-dicarboxylic 2,2-disubstituted transcyclopropane diacids (compounds (2).

In a nitrogen atmosphere, reflux is carried out for 2 h a

30 mixture of x mmol (yg) of diesters of transcyclopropane 1,3-dicarboxylic acids 2,2-disubstituted racemates (trans compound of general formula A), r mmol (sg) of potash and t cm3 of methanol (or ethanol), remove the alcohol by distillation, extract the reaction mixture with water, extract with ether, acidify with hydrochloric acid, extract the acidic aqueous phases with ether, wash the ethereal phase with a saturated aqueous solution of sodium chloride, dries it and concentrates to dryness under reduced pressure.

The experimental results obtained are as follows:

Starting trans diester (A)

Potash

Methanol or ethanol

Trans Diacid (2)

X

X

R

xmmol yg rmmol sg tcm3

P.F.

Yield

NMR spectrum

methyl (Com]

methyl methyl a)

ethyl

74.8

16.0

224.4

12.6

28 (ethanol)

212 ° C

90% (r)

8 = 1.26 ppm (s, 6H); 1.96 ppm (s, 2H); broad acid band at ± 10 ppm (2H)

ethyl | ethyl (Compound ß)

methyl

11.15

2.7

33.45

1.88

4.3 (ethanol)

246 ° C

94.5% (s)

8 = 0.70-1.10 ppm (t, 6H); 1.10-1.90 ppm (m, 4H) 2.0 ppm (s, 6H); broad acid band (2H) 3-5 ppm.

cyclohexyl (Compound 8)

methyl

38

9.1

114

6.4

14.3 (methanol)

248 ° C

65% (t)

8 = 1.2-1.8 ppm (m, 10H);

1.92 ppm (s, 2H) broad acid band (2H) 8 = ± 10 ppm cyclopentyl (Compound y)

methyl

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10.0

141

7.9

25.0 (methanol)

207-208 ° C

96% (u)

8 = 1.40-1.96 ppm (m, 8H); 2.09 ppm (s, 2H); acid band (2H) at 4.89 ppm s = singlet; t = triplet; m = multiplet.

r) Racemic 2,2-dimethylcyclopropane 1,3-dicarboxylic acid; s) Racemic 2,2-diethylcyclopropane 1,3-dicarboxylic acid; t) Racemic transspiro / 2,5 / octane 1,2-dicarboxylic acid;

u) Racemic transspiro / 2,4 / heptane 1,2-dicarboxylic acid.

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The diesters of racemic 1,3-dicarboxylic acids 2,2-disubstituted transcyclopropane of formula A, used at the start of stage A, are described in the French patent application entitled “Process for the preparation of lower alkyl esters of transcyclopropane 1,3-dicarboxylic acids 2,2-disubstituted racemates and new esters of said acids ", deposited on December 30, 1976 by the licensee under No. 76.39532.

The compounds of formula A, used in the preceding table and in the table for the preparation of trans compounds of formula II, appearing in preparation in Example 1, can be prepared in the following manner:

Preparation of racemic ethyl trans-2,2-dimethylcyclopropane 1,3-dicarboxylate (compound A with X = methyl and R = ethyl).

0.576 g of triphenylisopropylphosphonium bromide is introduced into 15 cm3 of dimethoxyethane under a nitrogen atmosphere, introduced slowly at 0 ° C. 0.090 g of butyllithium dissolved in 0.7 cm3 of pentane, stirred for 30 min at 0 ° C, introduced 0.156 g of diethyl ester of fumaric acid dissolved in 5 cm3 of dimethoxyethane, stirred for 15 min at 0 ° C, allowed the temperature to rise to 20 ° C and stirred until discolored, that is to say for about 2 hours, add water, stir, extract with ether, wash the ethereal extracts with water, then, with a saturated aqueous solution of sodium chloride, dry, concentrate to dryness, rectify under reduced pressure and obtains 0.108 g of racemic ethyl 2,2-dimethylcyclopropane 1,3-dicarboxylate. Eb. = 82 ° C under 0.7 mm of mercury (called compound a).

To carry out this reaction, ethyl fumarate can be replaced by ethyl maleate, obtaining compound a with the same yield and the same quality.

Preparation of the racemic methyl 2,2,2-diethylcyclopropane 1,3-dicarboxylate (compound A with X = ethyl and R = methyl).

In 1300 cm3 of dimethoxyethane, 55 g of triphenyl 3-pentylphosphonium iodide are introduced under nitrogen, slowly added at 0 ° C. 55 cm3 of butyllithium 2, IN solution in pentane, stirred for 30 min at 25 ° C, cooled at 0 ° C, very slowly introduced 14.4 g of dimethyl ester of fumaric acid (or 14.4 g of dimethyl ester of maleic acid), stirred at 25 ° C until discoloration of the reaction mixture , which requires approximately 5 h, add water, extract with ether, wash the ether extracts with a saturated aqueous solution of sodium chloride, dry, concentrate to dry, rectify the residue under reduced pressure and obtain 6 g of racemic methyl 2,2-diethylcyclopropane 1,3-dicarboxylate. Eb. = 65 ° C under 0.1 mm of mercury. Mp 25 to 30 ° C (called compound ß).

NMR spectrum (carbon tetrachloride):

S = 0.76-1.08 ppm (t, 6H);

S = 1.24-2.92 ppm (m, 4H);

8 = 2.08 ppm (s, 2H);

S = 3.63 ppm (s, 6 H).

Similarly, starting from ethyl fumarate and 3-pentyltriphenylphosphonium iodide, the racemic ethyl 2,2-diethylcyclopropane 1,3-dicarboxylate is obtained (compound A with X = ethyl and R = ethyl) . Eb. = 83-85 ° C under 0.5 mm of mercury (compound ßt).

Preparation of the racemic methyl 2,2,2-diethylcyclopropane 1,3-dicarboxylate (compound A with X = ethyl and R - methyl).

In 15 cm3 of dimethoxyethane, 0.688 g of triphenyl 3-pentylphosphonium iodide is introduced under nitrogen, slowly added at 0 ° C 0.05 g of butyllithium dissolved in 0.7 cm3 of pentane, stirred for 30 min at 0 ° C, introduced 0.128 g of dimethyl ester of fumaric acid dissolved in 5 cm3 of dimethoxyethane, stirred for 15 min at 0 ° C, introduced 0.128 g of dimethyl ester of fumaric acid dissolved in 5 cm3 of dimethoxyethane, stirred for 15 min at 0 ° C, allowed the temperature to rise to 20 ° C, stirred until discolored, that is to say for approximately 2 h, added water, stirred, treated as in l Example 1, chromatograph residue 5 on silica gel, eluting with a mixture of benzene with 3% ethyl acetate and obtain 0.150 g of racemic methyl 2,2,2-diethylcyclopropane 1,3-dicarboxylate (called compound ß).

Preparation of racemic methyl trans-spiro [2,4J-heptane 1,2-dicarboxylate (compound A with X + X = cyclopentyl and R = methyl).

160 g of triphenylcyclopentyl-5 phosphonium bromide are introduced into 4300 cm3 of dimethoxyethane under a nitrogen atmosphere, slowly introduced at 0 ° C. 160 cm3 of butyllithium 2, IN solution in pentane, stirred for 30 min at 25 ° C. , cools to 0 ° C, very slowly introduces 43.2 g of dimethyl ester of fumaric acid, stirred at 25 ° C until discoloration of the reaction mixture, which requires approximately 5 h, adds water, extracted with ether, treated as in Example 2 and obtained 15.2 g of racemic methyl transspiro- [2,4] -heptane 1,2-dicarboxylate. Eb. = 89 ° C under 0.08 mm of mercury (called compound y).

NMR spectrum (dimethyl sulfoxide):

S = 1.40-1.80 ppm (m, 8 H); 8 = 2.22 ppm (s, 2H);

8 = 3.64 ppm (s, 6 H).

30 . Preparation of racemic methyl transspiro- [2,5] -octane 1,2-dicarboxylate (compound A with X + X = cyclohexyl and R = methyl).

In 3200 cm3 of dimethoxyethane, 115 g of triphenylcyclohexylphosphonium bromide are introduced under a nitrogen atmosphere, 35 introduced slowly at 0 ° C. 112 cm3 of butyllithium 2, IN solution in pentane, stirred for 30 min at 25 ° C., cooled to 0 ° C, very slowly introduced 32.5 g of dimethyl ester of fumaric acid, stirred at 25 ° C until discoloration of the reaction mixture, which requires approximately 5 h, adds water, extracted with water. ether, washing the ether extracts with a saturated aqueous sodium chloride solution, drying, concentrating to dryness, rectifying the residue under reduced pressure and obtaining 20.4 g of transspiro- [2,5] -octane 1,2- racemic methyl dicarboxylate. Eb. = 133-138 ° C under 0.5 mm of mercury (called compound 8).

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NMR spectrum (dimethyl sulfoxide):

8 = 1.20-1.80 ppm (m, 10 H);

8 = 2.12 ppm (s, 2H);

n / a 8 = 3.68 ppm (s, 6 H).

Similarly, starting from cyclohexyl-triphenylphosphonium bromide and ethyl fumarate, ethyl transspiro- [2,5] -octane 1,2-dicarboxylate is obtained (compound A with X + X = cyclohexyl and R = ethyl). Eb. = 90-103 ° C under 0.8 mm 55 of mercury (compound Sj).

Stage B:

60 Preparation of ciscyclopropane 1,3-dicarboxylic 2,2-disubstituted racemic acids (3).

In a vacuum-sealed tube, a mixture of x g of trans diacids and 3 x g of acetic anhydride is heated for 6 h at 220 ° C.

leaves to cool, removes excess acetic anhydride and acetic acid-65 as formed, adds 50 cm3 of water, 1 g of activated carbon, heats at 120 ° C for 214 h, filters hot, then eliminates l 'water by distillation under reduced pressure; the remaining solid is pure cis diacid.

The experimental results obtained are as follows:

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Trans diacids (2)

Acid weight in grams

(x)

Weight of acetic anhydride in grams (3x)

Diacids cis (3)

X X

P.F.

Yield

NMR spectrum

methyl methyl (Compound r)

10.3

30.9

79% (v)

S = 1.16 ppm (s, 3H); S = 1.34 ppm (s, 3H);

8 = 1.80 ppm (s, 2H);

broad acid band (2H) around ± 9-10 ppm

ethyl j ethyl (Compound s)

5.42

16.26

180 ° C

71.5% (w)

8 = 0.40-1.10 ppm (t, 6H); 8 = 1.10-1.60 ppm and 1.60-2.00 ppm (m, 5H);

broad acid band at 4.48 ppm (2H)

cyclohexyl (Compound t)

7.59

22.77

210-212 ° C

75% (x)

8 = 1.00-2.00 ppm (m, 12H); broad acid band (2H) 9.60 ppm cyclopentyl (Compound u)

3.00

I85 ° C

72%

(y)

8 = 1.40-3.30 ppm (m, 10H); broad3 acid band (2H) around 4.51 ppm v) Cis 2,2-dimethylcyclopropane 1,3-dicarboxylic acid racemic. w) Racemic cis 2,2-diethylcyclopropane 1,3-dicarboxylic acid. x) Racemic cisspiro / 2,5 / octane 1,2-dicarboxylic acid.

y) Racemic cisspiro / 2,4 / heptane 1,2-dicarboxylic acid.

Stage C:

of diacid eis and r mmol (s g or t cm3) of acetyl chloride, Preparation of the anhydrides of the diacids ciscyclopropane cools, eliminates excess acetyl chloride and acetic acid

Racemic 2,2-disubstituted 1,3-dicarboxylics (4). formed by vacuum distillation and obtains the desired cis anhydride.

A mixture of x mmol (i.e. y g) is heated at 40 ° C. for 2 hours. The experimental results obtained are as follows:

Diacids cis (3)

Acetyl chloride

Diacid cis anhydride (4)

X

X

xmmoles yg xmmoles sg tcm3

P.F.

Yield

NMR spectrum

methyl | methyl (Compound v)

49.0

7.72

98.0

7.7

7.0

55 ° C

96% *

(z)

8 = 1.20-1.60 ppm (d, 6H); 2.55 ppm (s, 2H)

ethyl | ethyl (Compound w)

17.7

3.3

35.4

2.8

2.5

100% (a0

8 = 0.70-1.24 ppm (m, 6H); 8 = 1.32-2.84 ppm (m, 4H); 8 = 2.56 ppm (s, 2H)

cyclohexyl (Compound x)

28.4

5.6

56.8

4.45

4.0

100 ° C

95.5% * (bt)

8 = 1.30-1.80 ppm (m, 10H);

8 = 2.46 ppm (s, 2H)

* After purification in ether.

d = doublet; s = singlet; m = multiplet.

z Cis 2,2-dimethylcyclopropane 1,3-dicarboxylic acid anhydride racemic; at! Racemic cis 2,2-diethylcyclopropane 1,3-dicarboxylic acid anhydride; b! Racemic cisspiro / 3,5 / octane 1,2-dicarboxylic anhydride.

Stage D:

55 of diacid cis anhydride, add 5 drops of pyridine, stir

Preparation of the monomethyl esters of the diacids cis- for 16 h at 20 ° C., eliminates the excess methanol by distillation,

racemic 1,3-dicarboxylic 2,2-disubstituted racemic (compo- purifies the residue by chromatography on silica gel, eluting with

s of general formula II of cis structure). ether and obtain the desired cis diacid monomethyl ester. Y mmol (i.e. x g) are introduced into 5 cm 3 of methanol. The experimental results obtained are as follows:

Cis anhydride (4)

Eis (II) ester acids

X

X

xg y mmol

P.F.

Yield

NMR spectrum

methyl (Com]

methyl joséz)

0.35

2.5

107 ° C

100% * (c,)

8 = 1.28-1.40 ppm (d, 6H); 8 = 1.97 ppm (s, 2H); 8 = 3.76 ppm (s, 3H); 8 = 10.96 ppm (1H, acid)

9

627,149

I

Cis anhydride (4)

Eis ester acids (U)

X

X

xg y mmol

P.F.

Yield

NMR spectrum

ethyl (Comp

daring ethyl a!)

0.76

4.5

76 ° C

84% (d,)

8 = 0.84-1.20 ppm (t, 6H); 8 = 1.30-2.10 ppm (m, 6H); S = 3.72 ppm (s, 3H); 8 = 10.34 ppm (1H, acid)

cyclohexyle (Compound bi)

0.72

4.0

91 ° C

84% (ei)

8 = 1.20-2.10 ppm (m, 12H) with ls (2H) at 1.92 ppm 8 = 10.92 ppm (1H, acid)

♦ Not purified.

d - doublet; s = singlet; t = triplet; m = multiplet.

e, Cis 2,2-dimethylcyclopropane 1,3-dicarboxylic acid monomethyl ester;

d! Racemic cis 2,2-diethylcyclopropane 1,3-dicarboxylic acid monomethyl ester;

ej Cisspiro / 2,5 / 1,2-octane 1,2-dicarboxylic acid monomethyl ester.

Example 4:

\ trans 3-hydroxymethylcyclopropane 1-carboxylic 2,2-disubstituted

Lower alkyl esters of trans 3-formylcyclopropane acids (trans compound of general formula III) obtained in Example 1, in

1-carboxylic 2,2-racemic disubstituted (trans compound of formula solution in j ^ of methylene chloride, stirred for 2 h, general I). add ether, remove, by filtration, the insoluble material formed, concentrate

Into 4 cm 3 of dichloroethane are introduced, under a dry atmosphere by distillation under reduced pressure, purified by chromatography.

of nitrogen, 1.5 x 10-3 mol of Cr03pyridine complex, added dropwise to 25% on silica gel, eluting with ether.

drop in suspension IO-3 mol of lower alkyl ester of acid The experimental results obtained are the following:

Trans compound of general formula I

X

X

R

Yield

Physical constants methyl

(i)

methyl

ethyl

66

Eb. = 65 ° C under 0.1 mm of cyclopentyl mercury

0)

methyl

64

Eb. = 85 ° C under 0.4 mm of mercury

ethyl

(k)

ethyl

ethyl

77

Eb. = 88 ° C under 0.5 mm of cyclohexyl mercury

(1)

ethyl

70

Eb. = 85 ° C under 0.5 mm of mercury i) Trans 2,2-dimethyl 3-formylcyclopropane 1-racemic ethyl carboxylate, obtained from compound a of example 1.

j) Racemic methyl transspiro / 2,4 / heptane 2-formyl 1-carboxylate, obtained from compound b of Example 1.

k) Trans 2,2-diethyl 3-formylcyclopropane 1-racemic ethyl carboxylate, obtained from compound c of Example 1.

1) Transspiro / 2.5 / octane 2-formyl 1-racemic ethyl carboxylate, obtained starting from compound d of Example 1.

Example 5:

Methyl esters of cis 3-formylcyclopropane 1-carboxylic acids 2,2-disubstituted racemic by oxidation by the chromic anhydride / pyridine hydrochloride complex (compound of general formula I, of cis structure).

In a solution of x mmol (yg) of chromic anhydride / pyridine hydrochloride complex in methylene chloride, r mmol (sg) of the cis-3-hydroxymethylcyclopropane 1-carboxylic acid methyl ester is slowly added 2.2 -disubstituted, stirred for 2 h at 20 ° C., filtered, concentrated to dryness, purifies the residue by chromatography on silica gel, eluting with ether.

The experimental results obtained are summarized in the following table:

Eis ester alcohol (III)

Pyridine hydrochloride complex Cr03

Eis aldehyde ester (I)

X

X

rmmol sg xmmol yg

Yield

NMR spectrum

methyl (Comp methyl dare m)

1.45

0.23

2.18

0.47

69%

(f,)

8 = 1.32-1.56 ppm (d, 6H); 8 = 1.60-2.12 ppm (m, 2H); 8 = 3.72 ppm (s, 3H); 8 = 9.64-9.72 ppm (d, 1H)

627149

10

Eis ester alcohol (III)

CrOj pyridine hydrochloride complex

Eis aldehyde ester (I)

X X

rmmol sg x mmol yg

Yield

NMR spectrum

ethyl ethyl (Compound p)

0.825

0.153

1.24

0.248

73% (gi)

8 = 0.80-1.16 ppm (t, 6H); 8 = 1.16-2.20 ppm (m, 6H); 8 = 3.72 ppm (s, 3H); S = 9.68-9.74 ppm (d, 1H)

cyclohexyl (Compound n)

1.31

0.260

1.96

0.425

78% (hi)

8 = 1.20-2.20 ppm (m, 12H); 8 = 3.72 ppm (s, 3H); 8 = 9.67-9.72 ppm (d, 1H)

d = doublet; m = multiplet; s - singlet; t = triplet.

fj Racemic cis 2,2-dimethyl 3-formylcyclopropane 1-carboxylic acid methyl ester. g! Racem cis 2,2-diethyl 3-formylcyclopropane 1-carboxylic acid methyl ester. hj Racemic cisspiro / 2,5 / octane 2-formyl 1-carboxylic acid methyl ester.

Diagram I

O

11

Diagram II

627

© Q

jY-P = ((|)) 3, Hai

X '

based

0

627149

12

Schemall (continued)

X X

cis (II)

cyclopropanecarboxylic acid ester with Z of variable structure, for example 2'-methyl-propenyl, cyclopentylidenemethyl, etc.

R

Claims (9)

627149 1. Process for the preparation of lower alkyl esters of cis-or trans-3-formylcyclopropane I-2,2-disubstituted ra-cemic carboxylic acids of general formula: GOLD X LHO X H in which R represents an alkyl radical comprising from 1 to 6 carbon atoms and X represents an alkyl radical comprising from 1 to 6 carbon atoms, or else the two radicals X represent together, with the carbon atom to which they are bonded, a cycloalkyl radical comprising from 3 to 7 carbon atoms, process characterized in that a lower alkyl hemi-ester of eis- or transcyclopropane 1,3-dicarboxylic 2,2-disubstituted racemic compound of formula is reacted general: (II) HORN X -OH X in which X and R retain the abovementioned meanings with a reducing agent chosen from the group consisting of diborane and alkaline hydroborides and subjects the lower alkyl ester of cis-or trans-3-hydroxymethylcyclopropane 1-carboxylic acid 2, 2-racemic disubstituted resulting from general formula: .HORN to oxidation by means of an oxidizing agent or an oxidizing system chosen from the group consisting of chromic acid in the presence of Pyridine, lead tetracetate in the presence of pyridine, manganese dioxide, chlorosuccinimide with subsequent action dimethyl sulfide, dimethyl sulfoxide after esterification of the alcohol function with a sulfonic acid. 2. Method according to claim 1, characterized in that the solvent, within which the reduction is carried out with diborane, is an etheroxide. 2 3. Method according to claim 2, characterized in that the ether oxide is tetrahydrofuran. 4. Method according to claim 1, characterized in that the solvent, within which the reduction is carried out with diborane, is dimethylsulfide. 5. Method according to claim 1, characterized in that the reduction by alkaline hydroboride is carried out within an etheroxide. 6. Method according to claim 5, characterized in that this etheroxide is tetrahydrofuran. 7. Method according to one of claims 1, 5 and 6, characterized in that the alkaline hydroboride is sodium hydroboride. 8. Method according to claim 1, characterized in that the oxidation of a compound III to compound I, by chromic acid in the presence of pyridine, is carried out in methylene chloride. 9. Method according to claim 1, characterized in that the oxidation of a compound III to compound I, by lead tetracetate in the presence of pyridine, is carried out in an excess of pyridine.