DE2145354C3 - Thioesters and process for their preparation - Google Patents

Description

The invention relates to new thioesters and a process for their preparation.

The invention relates in particular to the thioesters according to the main claim.

Preferred thioesters according to the invention are defined in claims 2 and 3.

The thioesters of the invention are intermediates that work in a very simple and smooth manner Cephalosporin derivatives can be converted. This is of considerable importance as it is constantly large Efforts are being made to make the representatives of the penicillin and cephalosporin antibiotics chemically and thus to modify their pharmacological behavior. This can be done very easily with the help of the claimed thioesters can be achieved.

DE-OS 20 06 689 clarifies between .r the single-stage Conversion of penicillin sulfoxide esters into deacetylcephalosporic acid esters, but does not lead to the Biologically extremely valuable end products that are obtained via the thioesters according to the invention with high yields are accessible.

Treatment of the thioesters according to the invention with an oxidizing agent leads to 3-hydroxy-3-methylcephalosporins the general formula

/
A-CH-CH

CH ₂

O = C

OH

CH.,

R '

wherein A and R 'have the meanings given above. These 3-Hydroxycephalosporins can too the 3-unsaturated compounds are dehydrated.

It should also be noted that the thioesters in which the group R 'is a carboxyl group, have weak gram-positive antibacterial activity.

The invention also relates to a process for the preparation of the thioesters according to the invention according to claim 4.

The penicillin sulfoxide used as the starting material for this process can be any appropriate Method for the preparation of penicillin sulfoxides can be obtained, for example according to the in the U.S. Patent 3,197,466. The carboxyl group of the penicillin sulfoxide used is preferably esterified to protect this group during the rearrangement reaction. Penicillin esters are well known to those skilled in the art. The preferred ester groups are those that «, I for regeneration the free acid can be easily removed. Typical examples of such groups are tert-butyl, Benzyl, methoxybenzyl, nitrobenzyl, benzhydryl, trichloroethyl and phenacyl radicals. For examples of other ester groups that can be used in the process of the invention include the methyl, ethyl, 4-methyl-3-butenyl and 3-methyl-3-butynyl radical.

From the formulas it can be seen that R denotes the remainder of an acyl group which is attached to the 6-amino group of the Penicillin is bound. This is preferably a group that is produced by fermentation can be generated, for example the benzyl or phenoxy methyl group. The acylation of the 6-amino group of penicillin, however, is well known Examples of R include methyl, cyclohexyl, α-aminobenzyl, methoxybenzyl, a-hydroxybenzyl, p-Cyanophenylethyl, phenylthiomethyl, m-hydroxybenzyl, p-nitrophenoxymethyl, p-chlorobenzyloxyethyl, Hydroxyhexyl and allyl radicals

Typical examples of groups R 'are alkoxymethyl, Alkanoyloxymethyl or carboxamido groups. Individual examples of R 'include the hydroxymethyl, Ethoxymethyl, acetoxymethyl, benzoyloxymethyl, p-hydroxybenzoyloxymethyl, N-phenylcarboxamido, N-Cyclohexylcarboxamido-, N-Octylcarboxamido-, Methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trichloroethoxycarbonyl or p-Methoxybenzyloxycarbonyirest The most common penicillins are those in which R ' an ester group of the type specified is typical for easily cleavable esters are the tert-butyl, benzyl, Benzhydryl, trichloroethyl, p-nitrobenzyl and p-methoxybenzyl esters.

The W substituent in the thioester produced is derived from that used in the reaction Acid anhydride. A limitation of the invention to any theoretical explanation, such as the implementation is not intended, however, it appears that a sulfhydryl compound is formed as an intermediate and esterified by the acid anhydride. W therefore means the methyl radical when acetic anhydride is used the ethyl radical if propionic anhydride is used, the propyl radical if butyric anhydride is used, and the phenyl radical when benzoic anhydride is used.

Typical starting materials for the process according to the invention are the following penicillin sulfoxides:

Trichloroethyl ester of penicillin V sulfoxide,
p-nitrobenzyl ester of penicillin G sulfoxide,
Methyl-6- (m-chlorophenylacetamido) penam-

3-carboxylate-1-oxide,
S-hydroxymethyl-e-icyclohexylcarboxamido) -

penam-1-oxide,

3- acetoxymethyl-6- (capramido) -penam-1 -o> .id,
3-butoxymethyl-6- (p-nitrophenoxyacetamido) -

penam-1-oxide,

N-methylamide of penicillin V-sulfoxide,
3-hydroxymethyl-6- (almondamido) -penam-1 -oxide, S-benzyloxymethyl-o-acetamidopenam-l-oxide,
3-Benzyloxymethyl-6- (phenoxyacetamido) -

penam-1-oxide.

In the process of the invention, the penicillin sulfoxide is at least one equivalent a trialkyl phosphite in which the alkyl groups contain 1 to 4 carbon atoms, at a temperature im Range from 40 to 125 ° C in the presence of at least one equivalent of acetic anhydride, propionic anhydride, Butyric anhydride or benzoic anhydride implemented. The trialkyl phosphite can for example Trimethyl phosphite, triethyl phosphite, tripropyl phosphite or tri-n-butyl phosphite. Trimethyl phosphite and Triethyl phosphite are preferred because of their ease of separation after the reaction has ended preferred temperature range for the reaction is 50 to 120 ° C. The reaction is preferably carried out in an inert solvent, for example in carbon

Hydrogen such as benzene or toluene or ethers such as dioxane or ethylene glycol dimethyl ether carried out

It should be noted that hydroxyl, mercapto and amino groups in the penicillin sulfoxide used be protected by known measures during implementation. For example, hydroxy and Mercapto groups in general by conversion into an easily cleavable ester or thioester, for For example the formate, acetate or trifluoroacetate, amino groups are protected by substitution with an easily removable group, for example triphenymethyl, trimethylsilyl, tert-butyloxycarbonyl, Trichloräthoxycarbonyl-, Benzyloxycarbonyl-, a lower alkanoyl or the benzoyl radical or protected by formation of the enamine with methylacetatoacetate. The protective group used in each case has for the purposes of the invention are not of critical importance.

The preparation of the thioesters is further illustrated by the following examples.

example 1

A solution of 5.0 g of penicillin V sulfoxide 2,2,2-trichloroethyl ester, 1.1 ml of acetic anhydride and 5 ml of trimethyl phosphite in 100 ml of toluene is ^{heated to 95 to 96 °} C. for 14 hours. Thin layer chromatography with silica gel / ether shows two main components with Rr values of 0.65 and 0.78. The spot with the Rr value 0.78 corresponds to the thiazoline formed as a by-product, and the zone with the FV value δ.65 corresponds to the desired thioacetate. The reaction mixture is concentrated in vacuo and the semi-solid residue is triturated with isopropyl alcohol. The white solid substance obtained (2.10 g) is recrystallized from 25 ml of isopropyl alcohol, whereby 1.75 g of the thiazoline formed as a by-product and having a melting point of 138 to 140 ^° C. are obtained. The structure is confirmed by the IR, NMR and UV spectra, which are identical to those of an authentic sample previously prepared by reacting penicillin V sulfoxide trichloroethyl ester with trimethyl phosphite in the absence of acetic anhydride. The isopropyl alcohol from the triturated residue is concentrated in vacuo and leaves 2.75 g of a pale yellow semi-solid substance. This material is dissolved in carbon tetrachloride and again concentrated in vacuo. This procedure is repeated twice to remove the last traces of isopropyl alcohol. Finally, after complete removal of carbon tetrachloride in vacuo, 2.50 g of the thioacetate (R = phenoxymethyl, R '= trichloroethoxycarbonyl and W = methyl) remain. The IR, NMR and UV and mass spectrum confirm the assigned structure.

If the molar ratio of acetic anhydride to penicillin sulfoxide ester is increased to 10: 1, the Amount of thioester too.

Example 2 Example 3

A solution of 5 g of penicillin V-sulfoxidtrichloroethyl ester, 2.5 ml of trimethyl phosphite and 2 ml of acetic anhydride in 50 ml of dioxane are refluxed for 7 hours The solvent is removed in vacuo, the residue is dissolved in ethyl acetate *, and the Solution is washed well with water. The ethyl acetate solution is dried over magnesium sulfate, and the solvent is removed in vacuo to give a pale yellow foamy substance. the Treatment of this foamy substance with methanol yields 1.8 g of crystals which act as the thiazoline product be detected. The mother liquor turns into a pale yellow foamy substance in vacuo concentrated The NMR spectrum shows that it is the same thioacetate as in Example 1 is somewhat contaminated with further thiazoline. The structure ascribed is also confirmed by the IR spectrum

Example 4

The procedure of Example 3 is repeated with the exception that 3.5 ml of trimethyl phosphite and 5 ml of acetic anhydride can be used. As a product; 857 mg of the thiazoline and 3.9 g of the thioacetate obtain. The IR spectrum confirms the assigned structure.

Example 5

The procedure of Example 3 is repeated with 2.5 ml of trimethyl phosphite and 10 ml of acetic anhydride. 1 g of the thiazoline and 3.86 g of the thioacetate are obtained. The IR spectrum confirms the ascribed Structure.

In Examples 3 to 5, the molar ratio of acetic anhydride to penicillin sulfoxide is 2: 1.5: 1 and 10: 1, respectively. The higher molar ratio results in the formation of smaller amounts of the thiazoline product and larger amounts of the desired thioester. However, increasing the molar ratio from 5: 1 to 10: 1 does not significantly change the product distribution. _D. ■, _c example 6

A solution of 5 g of phthalimidopenicillin sulfoxide trichloroethyl ester, 2 ml of trimethyl phosphite and 5 ml of acetic anhydride in benzene is refluxed for 24 hours. The reaction mixture is washed six times with 100 ml of water each time, dried over magnesium sulfate and freed from the solvent in vacuo, giving 4.5 g of a white foamy substance. Thin layer chromatography only shows one product that is less polar than the starting material. By NMR spectroscopy is demonstrated that this product has the SS, ^ unsaturated isomers of the desired thioacetate. Treatment of this product with triethylamine gives the <x-, ^ -unsaturated isomer.

Analysis for C ₂ OHi ₇ N ₂ O ₆ Cl ₃ S:

The procedure of Example 1 is carried out with the p-nitrobenzyl ester instead of the trichloroethyl ester repeated The corresponding thioacetate is obtained as the product of the reaction, in which R is the Phenoxymethyl group, R 'the p-nitrobenzyloxycarbonyl group and W the methyl group. That NMR spectrum confirms the assigned structure.

Calculated: C 46.22, H 330, N 5.39; found:

fty isomer: C 45.97, H 3.56, N 5.12; found:

«, JS isomer: C 46.20, H 3.51, N 5.19.

\ oi \ o (dioxane) jS.y-Isomeres = -144 ° and α, / Msomeres = -33 °

Example 7

A solution of 50 g penicillin V suIfoxidtrichloräthylester, 25 ml of trimethyl phosphite and 55 ml of acetic anhydride in 300 ml of toluene is heated for 16 hours at 100 ⁰ C. The cooled solution is washed well with water and the solvent is removed in vacuo to give an oil. It is demonstrated by NMR spectroscopy that this oil consists of a mixture of the oc, β- and ^, ^ - unsaturated isomers of the desired thioacetate. By treating the mixture with 1 ml of triethylamine in benzene, the ß.y-isomer is converted into the a, J? -Isomer, which is obtained as a pale yellow foamy substance.

As can be seen from Examples 5 and 6, the treatment of the / ^ - unsaturated isomer of the invention results available thioester with a base under mild conditions for isomerization of the double bond in the side chain with a shift to the «, ^ position. So this isomer has the formula

Il

A-CH-CH-S-C-W

O = C-

-NC = C-CH ₃
R 'CH ₃

wherein A, R 'and W are as defined above. This shift of the double bond takes place in the presence of a base with a dissociation constant of greater than about 10- ¹⁰ at a temperature in the range of 0 to 50 ⁰ C and preferably in the range of 20 to 30 ° C for a period of not more than about 30 minutes Instead of the base can serve as the solvent for this isomerization, or an inert solvent can be used, for example methanol, ethanol, tetrahydrofuran, dioxane or dimethylformamide. This base can be an organic or inorganic base, for example sodium hydroxide, sodium carbonate, sodium methylate, potassium ethylate, trimethylamine, Ν, Ν-dimethylaniline, pyridine, dimethylamine, methylamine, piperidine or ammonia. About one equivalent of base should be used per mole of thioester.

Example 8

A solution of 1 g of phthalimidopenicillin sulfoxide trichloroethyl ester is heated, 0.5 ml of trimethyl phosphite and 1.6 ml of isobutyric anhydride in 30 ml of dioxane reflux for 20 hours. The product is purified by preparative thin layer chromatography and receives 689 mg of a white foam. The white foam persists, as does the NMR spectrum shows from the /J.y- isomer of the desired thiobutyric acid ester. By reacting this product with triethylamine, a light yellow foam is obtained, which can be identified via the NMR spectrum as the «^ -unsaturated isomer. The NMR spectrum of the fty isomer shows bands at 108,116,139,141,293, 349,378 and 472 Hz.

Example 9

A solution of 1 g of phthalimidopenicillin su! Foxidtrichloräthylester is heated, 0.5 ml trimethyl phosphite and 1 ml of a mixed formic acid / acetic acid

Anhydride in 20 ml of dioxane for 20 hours at reflux. After cleaning through Preparative thin-layer chromatography gives 639 g of a white foam which can be determined from the NMR spectrum than the /J.y- unacidified isomer of the desired Thioacetic acid ester can be identified. Obtained by treating this product with thioethylamine one the «, ^ isomers. The NMR spectrum of the α, j3 isomer has bands at 130, 134,136, 293, 346, 352,377, 383 and 441 Hz. The spectrum of the / 2, y-isomer shows corresponding bands, which are predominantly about in Are shifted towards the weaker field.

Example 10

A) Conversion of
Ampicillin in N-acetylampicillin sulfoxide

The pH of a suspension of 10 g of ampicillin trihydrate in 86 ml of water is brought to a value of 6.9 at room temperature by adding disodium hydrogen phosphate. 8.0 ml of acetic anhydride are then added at the same time as additional disodium hydrogen phosphate in order to keep the pH above 6.0. After adding 4.5 g of disodium hydrogen phosphate (which is washed in together with 14 ml of water), the remaining acetic anhydride is added in one portion. After about 5 minutes, a cloudy solution with a pH of 3.7 is obtained. After 15 minutes, this suspension cooled to 5 ° C and added slowly 4.30 ml of 40% peracetic acid to while cooling to maintain the temperature below 10 ⁰ C. In the course of 15 minutes after the addition is complete, the clear reaction mixture is heated to 20 ^° C. and the pH is then brought to 1.9 by adding 70% methanesulfonic acid. When reducing the pH, seed crystals are added at a pH of 2.5, which causes rapid crystallization. After stirring for 15 minutes at a pH of 1.9, the product is filtered off and washed well with water. Drying in vacuo at 50 ^° C. gives 8.55 g of a white product which increases in weight when left to stand over the weekend, so that in the end 8.80 g are obtained. This indicates the formation of the monohydrate. The melting point of the material is 172 ° C (with decomposition). The NMR spectrum confirms that the product is N-acetyl-ampicillin sulfoxide

B) Manufacture of

A solution of 4.25 g of the product of Example 1 in 60 ml of dry tetrahydrofuran is stirred 30 minutes in the presence of 6 g of a molecular sieve (type 4A). The mixture is filtered and washed Residue with 20 ml of dry tetrahydrofuran and combine the washing liquids with the filtrate

1.40 ml of triethylamine are then added to this combined solution to form a solution of the triethylammonium salt. The salt solution is added in one portion to a at - held 10 ⁰ C solution of 1.21 g pivaloyl chloride in 50 ml dry tetrahydro- 'ran. The resulting solution is stirred for 30 minutes under a dry nitrogen atmosphere to complete the formation of the mixed anhydride. Then are added at - 10 ⁰ C 1.5 ml of anhydrous dimethylaniline in one portion to the mixture and stirred for 30 minutes at a temperature

between - 10 ° C and 0 ° C. The mixture is then poured over 150 g of crushed ice to form the product to fail. However, since the product proves to be soluble, the mixture is in vacuo on a Rotary evaporator evaporated. A solution of the oily residue is prepared in 100 ml of cold Water. By acidifying with a 70% aqueous methanesulfonic acid solution to a pH of 2 there is no starting acid. The aqueous solution is saturated with sodium chloride and extracted twice with 100 ml of ethyl acetate. The extracts are combined, dried over sodium sulfate and concentrated on a rotary evaporator to a syrup. By triturating the residue with 100 ml of ether a white, granular solid is obtained, which is filtered off, washed with ether and dried, whereby one 2.33 g of the product is obtained. The NMR spectrum confirms the presence of the desired product and shows that the product contains pivalic acid. Attempts to remove the pivalic acid by refluxing eliminating in 100 ml of ether have proven unsuccessful. After drying, one obtains the desired product melting at 145-147 ° C with a yield of 2.21 g. The material is in the used in the following stage.

C) Manufacture of the
Thioacetate of the following formula

C ₆ H ₅ -CH - CONH

CH ₃ CNH
O

O = *

A solution of 1.0 g of the amide obtained in step B, 1.0 ml of trimethyl phosphite and 2 ml is heated Acetic anhydride in 20 ml of dry dioxane for 2.5 hours under a dry nitrogen atmosphere to reflux (104 ° C). The dioxane is drawn off in vacuo using a rotary evaporator and rub the residue several times with 50 ml of ether. Removal of the solvent gives 0.56 g of a light yellow oil. By narrowing the

In ether extracts, 0.82 g of a light yellow oil is obtained. Both samples smell of phosphite. The thin-layer chromatographic analysis of these products shows that they contain essentially the same product. The NMR spectrum of in an amount of 0.56 g of the sample obtained confirms the stated structure. This results from the following findings:

A) The signals of the geminal methyl groups of the starting material are not related to the end product available;

B) acetyl signals occur as a result of the acetamide groups and the thioacetate groups;

C) at 1.85ό the broad methyl signal of the following occurs Group on:

—C — CH ₃

D) the Ν, Ν-dimethyl signals remain at around 3.0ö exist; and

35 E) also the /? - lactam signals at 5.4 to 6.4 (5 are contained in the end product as well as in the starting material CON (CH ₃ J ₂ material.

CCH ₃

Claims (4)

Patent claims:
L thioester of the form .;] Il A-CH - CH - S - C-W O = C N-CH - C = CH, R 'CH ₃ wherein A a remainder N— or O
R — C— NH- a Ci-C ₈ -alkyl, Cj-Cg-cycloalkyl or C2-Ce-alkenyl radical, which can optionally be hydroxy-, mercapto-, Ci-Cralkoxy-, Ci-C ₃ -alkylthio- or cyano-substituted, a hydrogen atom, a carethoxy group or a residue .-X- (CH ₁ ), - or Q is a hydrogen atom, a hydroxyl group, a mercapto group, a chlorine atom, a bromine atom, a Ci - C3-alkyl radical, a Q - Cr alkoxy group, a Ci-C ₃ -alkylthio group, a nitro group or a cyano group, X is an oxygen atom, a sulfur atom or a carbon-carbon bond, Y is a hydroxy, mercapto or amino group, m is an integer from 0 to 2, η is an integer from 1 to 2, R 'a remainder -CH ₂ OZ or -CH ₂ OCZ
O Il —C — NHZ
O Il —C — O — R " R "is a Ci - C ₄ -alkyl, C ₄ - Ce-tert-alkyl-, C ₅ - C ₈ -tert-alkenyl-, Cs-Ce-terL-alkynyl-, benzyl-, methoxybenzyl-, nitrobenzyl -, benzhydryl, phthalimidomethyl, succinimidomethyl, phenacyl or trichloroethyl radical, Z is a hydrogen atom, a Ci - Cs-alkyl, C ₃ -C ₈ -cycloalkyl or C ₃ -Ce-alkenyl radical, which is optionally hydroxy, mercapto, QC ₃ -alkoxy, Cj - C ₃ -alkylthio or can be cyan-substituted, or a phenyl or phenyl-Ci-Cj-alkyl radical, which is optionally hydroxy, mercapto, chlorine, bromine, Ci-C ₃ alkyl, Ci-C ₃ alkoxy, Ci -Cj -alkoxy-, Ci -Qj-alkylthio-, nitro- or cyano-substituted can be, and W denotes a methyl, ethyl, propyl or phenyl radical. 2. thioester according to claim 1, characterized in that A is a radical R — C — NH- R is a phenoxymethyl radical, R 'is a radical CO ₂ R "and W is a methyl radical. 3. thioester according to claim 1, characterized in that A is a radical Il R — C —NH- R is a benzyl radical, R 'is a radical CO ₂ R "and W is a methyl radical. 4. Process for the preparation of the compounds according to claim 1, characterized in that one a penicillin sulfoxide of the general formula t
S. A-CH-CH CH ₃ CH ₃ O = C- -N- -CH-R ' in which A and R 'have the meanings given in claim 1, with at least one equivalent a trialkyl phosphite wherein the alkyl groups contain 1 to 4 carbon atoms, at one Temperature in the range from 40 to 125 ° C in the presence of at least one equivalent of acetic anhydride, Reacts propionic anhydride, butyric anhydride or benzoic anhydride.