DE3121510A1 - 6-Alkyl-2-subst. penems and process for their preparation - Google Patents

Abstract

The invention relates to compounds having good antibacterial activity, which correspond to the following general formula (1) <IMAGE> in which R denotes a hydrogen atom, a lower alkyl, trichloroethyl, benzyl, p-nitrobenzyl, acetoxymethyl, pivaloxymethyl or phthalidyl group; X denotes a hydrogen atom or a hydroxy group which is free or protected as an acetate and one of the substituents R' and R'' denotes a hydrogen atom and the other denotes an alkyl group. The invention furthermore relates to a process for their preparation.

Description

Description

The invention relates to compounds having good antibacterial activity represented by the following general formula (1) correspond, where R is a hydrogen atom. denotes a lower alkyl, trichloroethyl, benzyl, p-nitrobenzyl, acetoxymethyl, pivaloxymethyl or phthalidyl group; X denotes a hydrogen atom or a free or acetate-protected hydroxyl group and one of the substituents R 'and R "denotes a hydrogen atom and the other an alkyl group.

The invention also relates to a method for their production.

A thioenol ether is reacted with chlorosulfonyl isocyanate and that 4-thio-subst. thus obtained. -azetidinon is used according to an alternative method either converted into 4-chloroazetidin-2-one or into azetidinyl sulfone. Both of these intermediates when they are substituted with an appropriately substituted thioacid in the presence of a Base treated, converted into an acylthioazetidin-2-one, which by condensation with a suitable glyoxylic acid derivative, a mixture of diastereoisomeric carbinols results. The subsequent chlorination of the mixture gives the corresponding chlorides, which are converted into their phosphorylids by means of triphenylphosphine. By heating of the ylid in an inert solvent at a temperature of Finally, from 50 to 140 ° C., the compounds of the formula (1) are obtained.

The invention relates to 6-alkyl-2-functionalized penems and processes for their preparation. The invention relates to the synthesis of compounds of the general formula (1) wherein R is a hydrogen atom, a lower alkyl, trichloroethyl, benzyl, p-nitrobenzyl, acetoxymethyl, pivaloxymethyl or phthalidyl group; X denotes a hydrogen atom, a lower alkyl or a free or acetate-protected hydroxyl group and one of the substituents R 'and R ″ denotes hydrogen and the other denotes lower alkyl.

These compounds are penems which are used and potentially used in the pharmaceutical field. The synthesis of the compounds (1) according to the invention can be carried out according to a number of reaction stages, as explained below.

In the above reaction scheme, the symbols all have those previously given Definitions.

The starting material for the first reaction stage shown is a thioenol ether (2) with chlorosulfonyl isocyanate in a manner known per se to form the B-lactam (3), which is a 4-thio-substituted azetidinone The ß-lactam (3) can be converted into the corresponding 4-acylthioazetidin-2-one (6) one of two alternative methods. With the first it will ß-Lactam (3) with chlorine in an organic solvent to form 4-chloroazetidin-2-one (4) treated as a cis-trans mixture. Suitable solvents are CH2Cl2, CHCl3 and CCl4, and the methods are known per se [for example by J.C. Sheehan, Dr Ben-Ishai and J.U. Piper, J.Amer.

Chem. Soc., 95, 3064 (1979)]. The second of the alternative methods comprises the initial oxidation of the β-lactam (3) using an oxidizing agent, like KMnO4 or NaC04, with formation of azetidinyl sulfone (5). The techniques will by J.C. Sheehan and C.A.Panetta in J.Org.Chem. 38, 940 (1973).

Since both the Chlorazetidin-2-one (4) and the Azetidinyi sulfon (5) Having a good leaving group at the 4-position results in treating both of these intermediates with a suitably substituted thioacid in the presence a base such as sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, Potassium hydroxide or triethylamine, in a suitable solvent; like water, Tetrahydrofuran, dimethylformamide, acetone, hexamethylene phosphoramide, or a mixture from two or more the 4-acylthioazetidin-2-.one (6).

The compound (6) obtained in this way can be converted into the corresponding diastereoisomeric carbonyl (7) by condensation with a suitable G, lyokylsäurederivate CHCOOR are converted, where R is the definition given above possesses, either at a temperature of 40 to 1000C or at ambient temperature in the presence of a base, such as triethylamine or pyridine, and a drying agent, like a molecular sieve.

The subsequent chlorination of the resulting diastereoisomeric carbinols (7), preferably using thionyl chloride and a base such as pyridine, or polymeric bases at a temperature of -78 ° to -00 ° C., gives the chlorides (8), which is converted into the phosphorylid (9) by means of triphenylphosphine and a base, such as Pyridine, 2,6-lutidine or polymeric bases, for example at a temperature of 25 to 50 ° C9 Finally, the compound (1) is easily obtained, by the ylid (9) preferably at a temperature of 50 to 1400C in a Inert solvents, such as benzene, toluene or xylene, heated preferred solvents according to the invention Compounds are # -trans-6-ethyl-2-methyl-2-penem-3-carboxylic acid (1a: R¹-ethyl; R "m Xm R = H); # -trans-6-ethyl-2-acethoxymethyl-2-penem-3-carboxylic acid (1b: R¹ = ethyl; X = OCOCH3; R "= R = H).

The in vitro activities [minimum inhibitory concentration (µg / ml)] of the compounds 1a and ib are in the following.

Table 1 in comparison with cefoxitin.

Table 1 Comparison of the in vitro activities of racemic 1a (R '= Et; R ", X, R = H) and 1b (R' = Et; X = OAc; R", R = H) with cefoxitin Microorganism Minimum inhibitory concentration (µg / ml) Cefoxitin 1a 1b Staphylocaccus aureus Smith ... 1 2 0: 5 Staphylocaccus aureus 39/2 .... 2 4 1: Diplococcus pneumoniac ATTC 6301 .... 0.25 1 0.25 Streptococccus pyogenes C 203 .... 0.25 1 0.25 Streptococcus agalactiac B 77 .... 1 2 1 Streptococcus jaecalls ATCC 6057 .... 64 64 128 Escherichia cali G ..... 8 32 64 Escherichia cali TEM. ..... 8 32 64 Escherichia cali 1507 E. .... 8 32 64 Klebsiella pneumoniae ATTC 10031 .... 0.5 32 8 Klebsiella aerogenes 1082 E .... 2 32 64 Klebsiella aerogenes 1522 E. .... 4 32 32 Enterobacter aerogenes ATCC 8308 .... 8 64 128 Enterobacter cloacae P 99 ... ... 128 64 128 Enterobacter clocae 1321 E .... 16 64 64 Salmonella typhi Watson .... 2 16 16 Salmonella dublin ISM ....... 2 32 64 Shigella sonnel ATCC 11060 .... 16 32 128 Pasteurella multocida 985 A .... - 8 4 Proteus vulgaris X 20 ... ... ... 2 64 32 """inoculo hasso .... 2 64 16 Proteus mirabllis ATCC 9921 .. ... ... 2 32 8 Pseudomonas aeruginosa ATCC 9027 ... 128 128 128 Pseudomonas aeruginosa G ............... - 256 128 The following examples of the individual reaction steps illustrate the invention.

For example 1 1 1- (p-Toluolthio) -1-butene, 2- (R '= Et; R "= H) These Connection is obtained by using the method described by G. Modena et al. for similar products method described is used [Boll. Sci. Fac. Chim. Ind. Bologna, 18, 66 (1960)].

12.42 g (0.1 mol) p.thiocresol and 7.21 g (0.1 mol) butyric aldehyde are dissolved in anhydrous CHCl3, cooled to -5 ° C and saturated with dry HCl. The water formed is separated off, excess HCl is under a no-strobe, Stripped off and the solution is treated with (CH3CH2) 3N (0.2 mol) and overnight heated to reflux.

The cooled reaction mixture is in a mixture of 150 g of ice and Poured 150 ml of conc HCl solution and extracted with 4 x 100 ml of CHCl3. The United Extracts are washed with water until neutral; dried over Na2S04 and concentrated in vacuo; a residue is obtained which is distilled. Man obtains 2 (R "= H, R '= CH3); b.p. 106-108 ° C at 1.5 torr (9.5 g; 0.053 mol; 53%).

NMR (cis / trans mixture 35/65): 1.04 (3H, T, J = 8 HZ), 2.22 (2H, M), 2.31 (3H, S), 5.65-6.30 (2H, M), 6.15 (4H, M).

Example 2 3-Ethyl-4- (p-toluolthio) -azetidin-2-one, 3- (R '= Et; R "= H) To a stirred mixture of 28.30 g (0.2 mol) of chlorosulfonyl isocyanate in 80 ml anhydrous, peroxide-free (CH3CH2) 20, which is cooled to -300 C, is given 30.30 g (0.17 mole) 1- (p-toluene thio) -1-butene 2 (Y = H; R '= CH3) over 30 minutes After 4 hours of additional stirring at -300C, the reaction mixture is slowly poured into a stirred suspension of 50 g NaHCO3, 35 g Na2S03.7H20, 500 g ice and 500 ml water poured. Stir until the organic layer reacts neutrally. The products will then extracted three times with (CH3CH2) 20. The combined extracts become saturated with. NaCl solution, dried over Na2S04 overnight and evaporated in vacuo. A residue is obtained which can be determined by column chromatography is cleaned on silica gel. Elution with C6H6 gives disulfide 5 (12.05 g; 0.049 Mole).

NMR: 2.27 (3H, S), 7.33 (4H, center of an AB-Q, J = 8 Hz); MS: 246 (M +); 123 (CH3-C6H4-S +); 108 (C6H4S +).

Elution with 95: 5 C6H6 / CH3COOC2H5 gives the azetidinone 3 (11 g, 0.051 Mol, 30%) as a solid, m.p. 70 to 72 ° C.

NMR (cis / trans mixture 1: 9, trans isomer): 1.00 (3H, T, J = 8 Hz), 1.78 (2H, M, J = 8 Hz, J1 = 6 Hz), 2.33 (3H, S), 3.00 (1H, dT, J1 = 6 Hz, Jvic = 2 Hz), 4.45 (In ,, D, Jvic = 2Hz), 7.00 (1H, br.S), 7.26 (4H, center of an AB-Q, J3 = 9 Hz); IR: 3330, 1765.

For example 3 3-Ethyl-4-chloroazetidin-2-one, 4 (R '= Et; R "= H) To a solution of 221 mg (1 mmol) 3-ethyl-4- (p-tolylthio) -azetidin-2-one, 3 (Y = H; R '= CH3) in 10 ml of CCl4, 141 mg (2 mmol) of Cl2 in 1.8 ml of CCl4 are added at 0 ° C. while stirring. After half an hour, additional stirring, the solvent is in vacuo in the Evaporated cold, and oily, crude chlorides are obtained as a 70:30 trans-cis mixture.

NMR (CDCl3, #) trans isomer: 1.00 (3H, T, J = 7.0 Hz), 1.77 (2H, M, J = 7.0 Hz, J1 = 7.0 Hz), 3.50 (1H, dT, J1 = 7.0 Hz, J2 = # 2.0 Hz), 5.27 (1H, D, J2 = # 2.0 Hz), 7.00 (1H, br.) #Max (CHCL3, cm-1): 1785.

Example 4 3-Ethyl-4- (p-toluothio) -azetidin-2-one-S, S-dioxide, 5 (R '= Et; R "= H) (A) To a solution of 6.20 g (0.028 mol of 3-ethyl-4- (p-tolu6lthio) -azetidin-2-one a solution of 8.80 g (0.056 Mol) KMnO4 in 100 ml of water in the course of 20 min Stir the excess of KMnO4 by slowly adding a 30% solution of H202 destroyed until the color of the reaction mixture fades.

Most of the product is obtained by diluting it with water Crystals precipitate and the supernatant solution is extracted well with CH2CL2. The combined extracts are washed with water, with saturated NaHCO3 solution and again washed with water until they react neutral and dried over Na2S04. Evaporate the solvent gives further product as a white solid; Total yield 6.25 g (0.024 mol, 86%), m.p. 131-132 ° C.

NMR (cis / trans mixture 1: 9, trans isomer): 0.94 (3H, T, J = 7 Hz), 1.78 (2H, M, J = 7 Hz, J1 = 8 Hz), 2.50 (3H, S), 3.40 (1H, dT, J1 = 8 Hz, Jvic = 2 Hz), 4.56 (1H, D, Jvic = 2 Hz), 7.00 (1H, br.), 7.65 (4H, center of an AB-Q, J3 = 9 Hz); IR: 3330, 1785.

(B) The crude product, which, as described above, by reaction of 30.30 g (0.17 mol) 1- (p-toluene thio) -1-butene and 28.30 g (0.2 mol) chlorosulfonyl isocyanate is obtained is dissolved in 80% aqueous CH3COOH solution (400 ml).

The solution is washed with 3 x 100 ml portions of hexane and then with a solution of KMnO4 (18 g, 0.114 mol) in 250 ml of water treated according to the same, The process described under A gives 11.6 g (0.045 mol; 26.4) of the sulfone 5.

Example 5 3-Ethyl-4-acetylthio-azetidin-2-one, 6 (R '= Et; R "= H; X = H) A mixture of 4.56 g (18 mmol) 3-ethyl-4- (p-toluolthio) -azetidin-2-one-S, S-dioxide, and 1.52 g (20 mmol) thiolacetic acid in 160 ml (CH3) 2CO and 80 ml water becomes 2 Stirred continuously at pH 9 (NaOH) for up to 3 h. The reaction mixture is with NaCl saturated and extracted with 3 x 75 ml CH2C12. The combined extracts are up to Washed with water to neutrality, dried over Na2SO4 and evaporated in vacuo. An oil is obtained which is filtered through a short column of silica gel.

Elution with 97: 3 C6H6 / CH3COOC2H5 gives the azetidinyl thioester in Form of white crystals (948 mg; 5.55 mmol; 30.8%).

NMR (trans isomer, 95%): 1.04 (8Z, T, J = 8 Hz), 1.84 (2H, M, J = 8 Hz, J1 = 8 Hz), 2.40 (3H, S), 3.18 (In, dT, J1 = 8 Hz, Jvic = 2.5 Hz), 5.04 (In, D, Jvic = 2, 5 Hz), 6.85 (1H, br.); IR: 3330, 1770, 1695.

Example 6 3-Ethyl-4-acetoxyacetylthio-azetidin-2-one, 6 (R '= Et; R "= H); X = OAc) A mixture of 16.5 g (65 mmol) of 3-ethyl-4- (p-toluolthio) -azetidin-2-one-S, S-dioxide, and 26.8 g (200 mmol) acetoxythiolacetic acid in 300 ml (CH3) 2CO becomes 3 Stirred continuously at pH 7.5 (NaOH) h '. 100 ml of saturated NaCl solution are used and extracted the mixture with 3 x 100 ml CH2C12. The combined extracts are Washed with water until neutral, dried over Na2SO4 and evaporated in vacuo. An oil is obtained which is purified by column chromatography on silica gel. Elution with 80:20 C6H6 / CH3COOO2H5 gives the azetidinyl thioester (1.5 g; 6.5 mmol; 15%).

NMR (trans isomer> 95%): 1.08 (3n, T, J = 8 Hz), 1.83 (2H, M, J = 8 Hz), 2.18 (3H, S), 3.15 (1H, dT, J1 = 8 Hz, Jvic = 2 Hz), 4.70 (2H; S), 4.98 (1H, D, Jvic = 2 Hz), 6.95 (1H, br.); IR: 3450, 1780, 1730, 1690.

B e i s p i-e 1 7 p-nitrobenzyl-2- (3'-ethyl-4'-acetylthio-2'-oxo-azetidin-1'-yl) -2-hydroxy-acetate, 7 (R '= et; R "= X = H; a mixture of 3.47 g (20 mmol) of 3-ethyl-4-acetylthioazetidin-2-one and 9.10 g of p-nitrobenzyl glyoxylate in 200 ml of anhydrous benzene is 4 h with a Dean-Stark water collector heated to reflux. The cooled reaction mixture is eluted through a short column of silica gel. Further elution with 98: 2 C6H6 / CH3COOC2H5 gives the carbonylamides in the form of a white foam contaminated with p-nitrobenzyl glyoxylate (6.40 g).

IR: 3400, 1765; 1740, 1695.

B e i s p i e l 8 p-Nitrobenzyl-2- (3'-ethyl-4'-acetylthio-2'-oxo-azetidin-1'-yl) -triphenylphosphoranylidene acetate, 9 (R '= et; R "= X = H; R = PNB) To a solution of 6.40 g of carbinolamide in 200 ml of anhydrous TnF, cooled to -20 ° C and under N2, are added 3.16 g of pyridine followed by 4.60 g g thionyl chloride.

The resulting mixture is 30 min at -200C and a further 30 min at 00C stirred. After filtering the suspension, the solution is in vacuo at room temperature evaporated; a residue is obtained which is taken up in C6H6 and twice im The crude chlorides 8 (R '= CH3; Y = X = H; Y = X = H; R = PNR) are dissolved in anhydrous CH2C12 (100 ml) and overnight at room temperature stirred under N2 with 9 g triphenylphosphine.

The solvent is evaporated in vacuo and the residue on chromatographed on a silica gel column. Elution with C66 gives the unreacted Triphenylphosphine and elution with 9: 1.C6H6 / CH3COOC2H5 the phosphorane in the form of a Foam (4.06g; 6.5mmol; 82%, based on 6).

IR: 1755.

Example 9 Acetonyl 2- (3'-ethyl-4'-acetoxyacetylthio-2'-oxo-azetidin-1'-yl) -2-triphenylphosphoranylidene acetate, 9 (R '= Et; R "= H; X = OAc; R = CH2COCH3) A mixture of 3.40 g (14.8 mmol) of 3-ethyl-4-acetoxyacetylthio-azetidin-2-one and 4.2 g of distilled acetonyl glyoxylate in 200 ml of anhydrous benzene is means a Dean-Stark water collector heated to reflux for 4 h. The reaction mixture is evaporated almost to dryness in vacuo (1 torr) at 800C. The residue will dissolved in 100 ml CH3COOC2H5 and used to remove excess acetonyl glyoxylate washed with 5 x 50 ml of water. The resulting crude carbinolamides (5.3 g) will be dissolved in 200 ml of anhydrous THF, cooled to -200C under N2, with 3.0 g of pyridine treated and finally treated dropwise with 4.1 g of thionyl chloride.

The reaction mixture is 30 min at -20 ° C and a further 30 min at 09C stirred. After filtering the suspension, the solution is in vacuo at room temperature evaporated.

A residue is obtained which is taken up in C6H6 and im Vacuum is evaporated at room temperature.

The crude chlorides 8 (R '= CH3; Y = H; X = OAc; R = CH2COCH3) are in 100 ml of anhydrous CH2Cl2 dissolved. and overnight under N2 at room temperature 7 g triphenylphosphine stirred. The solvent is evaporated in vacuo and the residue was chromatographed on a silica gel column.

Elution with C6H6 results in unreacted PPh3 and elution with 8: 2 C6H6 / CH3COOC2H5 gives the phosphorane in the form of a foam (2.5 g; 4.13 mmol; 28%, based on 7).

IR: 1755.

Example 10 (#) - trans-6-Ethyl-2-methyl-2-penem-3-carboxylic acid-p-nitro benzyl ester, 1 (R '= Et; R "= X = H; R = PNB) A catalytic amount of p-hydroxyquinone becomes a solution of phosphorane 9 (R '= CH3; Y = X = H; R = PNB) (1.0 g; 1.60 mmol), dissolved in 150 ml of toluene, and the mixture is heated for 40 h at 800 C under N2. The cooled reaction mixture is poured onto the top of a silica gel column and elution is carried out with 95: 5 toluene / CH3COOC2H5. The product is obtained in one 61% yield (340 mg; 0.98 mmol).

NMR: 1.07 (3H, T, J = 7 Hz), 1.91 (2H, M, J = 7 Hz, J = 7 Hz), 2.36 (3H, S), 3.69 (In, M, J1 = 7 Hz, Jvic = 2 Hz), 5.34 82H, dD, Jgem = 14 Hz), 5.36 (1H, D, Jvic = 2 Hz), 7.36 (2H, D, J2 = 8 Hz), 8.22 (2H, D, J2 = 8 Hz); IR: 1790, 1710; UV: 264, 310.

Example 11 (#) - trans-6-ethyl-2-acetoxymethyl-2-penem-3-carboxylic acid acetonyl ester, 1 (R '= Et; R "= H; X = OAc; R = CH2COCH3) A solution of the phosphorane 9 (R' = CH3; Y = H; X = OAc; R = CH2COCH3) (1.12 g, 1.85 mmol), dissolved in 180 ml of toluene, is left under for 26 h N2 heated to 800C. The cooled reaction mixture is poured onto the top of a Poured silica gel column and eluting with 95: 5 toluene / CH3COOC2H5. Man the product is obtained in a yield of 77% (464 mg; 1.42 mmol).

NMR: 1.03 (3H, T, J = 7 Hz), 1.94 (2H, M, 5 = 7 Hz, J1 = 8 Hz), Z.06 (3H, S), 2.16 (3H, S), 3.67 (1H, dT, J1 = 8 Hz, Jvic = 2 Hz), 4.67 (2H, S), 5.17 (2H, center an AB-Q, Jgem = 15 Hz), 5.30 (1H, D, Jvic = 2 Hz); IR: 1790, 1745, 1715; UV: 323.

B e i s p i e 1 12 (#) - trans-6-ethyl-2-methyl-2-penem-3-carboxylic acid, 1a (R '= Et; R "= X = R = H) 340 mg (0.98 mmol) (#) - trans-6-ethyl-2-methyl-2-penem-3-carboxylic acid p-nitrobenzyl ester are dissolved in 20 ml of CH3COOC2H5 and with 15 ml of a 0.2 M aqueous NanCO3 solution and 500 mg of 10% Pd / C mixed. The resulting mixture is in a hydrogen atmosphere stirred until the absorption of hydrogen ceases. The catalyst is filtered off (Celite) and washed with NaHCO3 solution and CH3COOC2H5. The filtrate and wash solutions are united. The organic phase is separated off and the aqueous phase twice washed with more Cn2Cl2.

Acidification (5% aqueous citric acid) of the aqueous phase, subsequent Extraction with CH2C12, drying over Na2S04 and evaporation of the solvent in Vacuum gives the acid as a yellowish solid.

IR: 1785, 1670, 1590 W: 302.

Example 13 (+) - trans-6-ethyl-2-acetoxymethyl-2-penem-3-carboxylic acid, 1b (R '= Et; R "= R = H; X = OAc) 190 mg (0.58 mmol) (t) -trans-6-ethyl-2-acetoxymethyl-2-penem-3-carboxylic acid acetonyl ester are dissolved in 28 ml of THF and 9 ml of water (at 0 ° C). Add to the stirred solution man 5.9 ml of a 0.1 M aqueous NaOH solution in the course of 20 minutes. One stirs more 10 min at 0 ° C and wash the mixture with cold CH2CL2, add another 70 ml cold CH2C12 and then 2.4 ml of cold 20% aqueous citric acid solution. The organic phase is separated off and the aqueous phase with 2 × 20 ml of CH2C12 extracted. The combined extracts are dried over Na 2 SO 4 and the solvent is removed in vacuo. A residue is obtained which is chromatographed on silica gel will. Elution with 9: 1 CH2C1 / CH3COOH yields 40 mg of the acid as a light yellow solid.

NMR: 1.1.0 (3H, T, J = 7 Hz), 2.0 (2H, M, J = 7 Hz, J1 = 8 Hz), 2.11 (3H, S), 3.82 (1H, dT, J1 = 8 Hz, Jvic = 2 Hz), 5.19 (2H, center of an AB-Q, Jgem = 16 Hz), 5.35 (1H, D, Jvic = 2 Hz), 9.16 (1H, be, exchange with D2O); IR: 1785, 1750, 1670, 1590 UV: 254, 314.

End of description.

Claims (1)

6-alkyl-2-substituted penems and process for their preparation P.a t e n t a n s p r ü e. h e 1. # -trans-6-ethyl-2-methyl-2-penem-3-carboxylic acid 2. # -trans-6.ethyl-2-acethoxymethyl-2-pene, -3-carboxylic acid. 3 Process for the preparation of compounds of the general formula wherein R is a hydrogen atom ,. X is a lower alkyl, trichloroethyl, benzyl, p-nitrobenzyl, acetoxymethyl, pivaloxymethyl or phthalidyl group. denotes a hydrogen atom, a lower alkyl or a hydroxyl group, namely a free hydroxyl group or a hydroxyl group protected as an acetate, and one of the substituents R't denotes a hydrogen atom and the other denotes lower alkyl, characterized in that a thioenol ether of the general formula (2) wherein R 'and R "have the definitions given above, with chlorosulfonyl isocyanate to form a compound of the general formula (3) wherein R 'and R "have the definitions given above, which reacts (a) with chlorine in a solvent to form a compound of the general formula (4) is reacted, wherein R 'and R "have the meanings given above, which with a thioacid of the general formula wherein X has the meaning given above, in a solvent in the presence of a base to form a compound of the general formula (6) is reacted, wherein, R¹ and R "have the meanings given above; or (b) with an oxidizing agent to form a compound of the general formula (5) is reacted, wherein R¹ and R "have the meanings given above, this compound with a thioacid of the general formula wherein X has the meaning given above, in a solvent in the presence of a base to form a compound of the general formula (6) is implemented; the compound of the general formula (6) with a compound of the general formula CHOCO OR wherein R has the meaning given above, with formation of a compound of the general formula (7) is condensed, wherein R, X, R 'and R "have the meanings given above, with thionyl chloride in the presence of a base to form a compound of the general formula (8) wherein X, R, R 'and R "have the definitions given above, is reacted, which with triphenylphosphine in the presence of a base to form a compound of the general formula (9) is reacted in which X, R, R¹ and Rh have the definitions given above and Ph is a phenyl group, this compound being heated to a temperature of 50 to 1400C in an inert solvent to form a compound of the general formula (1) as defined above , is implemented.