DE2145354B2 - 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 the one-step conversion of penicillin sulfoxide esters into deacetylcephaiosporic acid esters, but does not lead to the Biologically extremely valuable end products, which 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 of the general formula

/ A-CH-CH

CH ₂

OH

25th

JO

O = C N C

\ / \ C CH ₃

/ \ MR'

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 are used 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 _T which can be generated by fermentation, for example the benzyl or phenoxymethyl group. However, the acylation of the 6-amino group of penicillin is well known. Examples of R include methyl, cyclohexyl,-aminobenzyl, methoxybenzyl,-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 hydroxymeünyl, ethoxymethyl, acetoxymethyl, benzoyloxymethyl, p-hydroxybenzoyloxymethyl, N-phenylcarboxamido, N-cyclohexylcarboxamido, N-octylcarboxamido, methoxycarbonyl, tert-butoxycarbonyl Benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trichloroethoxycarbonyl or p-methoxybenzyloxycarbonyl radicals 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 means hence the methyl radical if 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 C sulfoxide, Methyl-e-fm-chlorophenylacetamidojpenam-

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

penam-1-oxide,

3-acetoxymethyl-6- (capramido) -penam-l-oxide, 3-butoxymethyl-6- (p-nitrophenoxyacetamido) -

penam-l-oxide,

N-methylamide vow penicillin V-sulfoxide, 3-hydroxymethyl-6- (almondamido) -penam-l-oxide, S-benzyloxymethyl-e-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. Of the 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 Example the formate acetate or trifluoroacetate, amino groups are protected by substitution with an easily removable group, for example triphenyunethyl, 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 stretch with the Rr value 0.78 corresponds to the thiazoline formed as a by-product, and the zone with the Rr value 0.65 corresponds to the desired thioacetate. The reaction mixture is concentrated in vacuo and the semi-solid residue is treated with isopropyl alcohol! rubbed in. 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 with 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

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 V represent the methyl group. The NMR spectrum confirms the assigned structure.

Example 3

A solution of 5 g of penicillin V sulfoxide trichloroethyl ester, 2.5 ml of trimethylphosphate 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

lu the solvent is removed in vacuo, whereby a pale yellow foamy substance is obtained. 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 deals with something 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. The product is 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 with 23 ml Trimethyl phosphite and 10 ml of acetic anhydride repeated. There are 1 g of the thiazoline and 3.86 g of the thioacetate obtain. The IR spectrum confirms the assigned structure.

In Examples 3 to 5 the molar ratio of acetic anhydride to penicillin sulfoxide is 2: 1, 5: 1 and 10: 1. The higher molar ratio has the formation of lesser amounts of the thiazoline product and greater Amounts of the desired thioester result. By increasing the molar ratio from 5: 1 to 10: 1, However, the product distribution does not change significantly.

^dert · 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 are refluxed for 24 hours warmed up. The reaction mixture is washed six times with 100 ml of water each time, over magnesium sulfate dried and freed from the solvent in vacuo, leaving 4.5 g of a white foamy substance can be obtained. Thin layer chromatography only shows one product that is less polar. as the The starting material is. It is demonstrated by NMR spectroscopy that this product is dao /? -, y-unsaturated Is isomers of the desired thioacetate. Treatment of this product with triethylamine provides the ä-, ^ -unsaturated isomers.

Analysis for C ₂₀ H ₁₇ N ₂ O ₆ CI ₃ S:

Calculated: C 46.22, H 330. N 5.39;

found:

jS.y-Isomeres: C 45.97, H 3.56, N 5.12:

found:

«, ^ - Isomer: C 46.20, H 331, N 5.19.

[*] o (dioxane) / ?, y-isomeres = - 144 ° and
λ, 8- isomer = -33 "

Example 7

A Lu> ung of 50 g penicillin V sulfoxidtrichloräthylester, 25 ml of trimethyl phosphite and 55 ml of acetic anhydride in 300 ml of toluene, 16 hours is heated to 100 ⁰ C. The cooled solution is washed well with water and the solvent is removed in vacuo to give an oil. It is shown by NMR spectroscopy that this oil consists of a mixture of the x, ji and j, y-unsaturated isomers of the desired thioacetate. By treating the mixture with 1 ml of triethylamine in benzene, the ^, y isomer is converted into the «. ^ 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 inven uungigcinäu ei "Mdmiuieii Tiiiuf sier with a base underneath mild conditions for isomerizing the double bond in the side chain with a shift in the x / J position. So this isomer has the formula

A - CII CH-S-C-W

I I

O = C N-C = C-CH.,

I I

R 'CHj

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 more than about 10 ^-10 at a temperature in the range of from 50 ° C to 50 ° C and preferably in the range of 20 to 30 ° C for a time of no more than about 30 minutes . 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

One heats a reading of 1 g of phthalimidopenicillin sulfoxide trichloroethylacetate, 0.5 ml of trimethyl phosphite and 1.6 ml of isobutyric anhydride in 30 ml of dioxane for 20 hours at reflux. Man Purifies the product by preparative thin layer chromatography and receives 689 mg of a white foam. As the NMR spectrum shows, the white foam consists of the / ty-isomereji of the desired thiobutyric acid ester. By reacting this product with triethylamine, a light yellow foam is obtained, which on the NMR spectrum as the ct ^? - unsaturated Isomers can be identified. The NMR spectrum of the ^, / - isomer shows bands at 108,116,139,141,293, 349,378 and 472 Hz.

Example 9

A solution of 1 g of phthalimidopenicillin sulfoxide trichloroethyl ester is heated, 0.5 ml of trimethyl phosphite and 1 ml of a mixed formic acid / acetic acid anhydride in 20 ml of dioxane to reflux for 20 hours. After cleaning through preparative thin-layer chromatography gives 639 g of a white foam which, via the NMR spectrum

· -> trum as the ß.y-unsaturated isomer of the aimed Thioacetic acid ester can be identified. Obtained by treating this product with thioethylamine one the Λ, / msomere. The NMR spectrum of the «^ isomer has bands at 130, 134, 136, 293, 346, 352, 377,

κι 383 and 441 Hz. The range of / ?, ylsomcren shows corresponding bands that are predominantly shifted approximately in the direction of the weaker field.

Example 10

A) Conversion of
Ampicillin in N-acetylampicillin sulfoxide

Bring the pH of a suspension of 10 g of ampicillin trihydrate in 86 ml of water at room temperature

J (I door by adding disodium hydrogen phosphate a value of 6.9. 8.0 ml of acetic anhydride are then added at the same time with additional disodium hydrogen phosphate. around the pH value above 6.0 / u keep. After adding 4.5 g of disodium hydrogen

2 \ phosphate (which is washed together with 14 ml of water), the remaining acetic anhydride is placed in a po. iion to. After about 5 minutes, a cloudy solution with a pH of 3.7 is obtained. After 15 minutes, this suspension is cooled to 5 ° C. and added

Slowly 4.30 ml of 40% peracetic acid / u, cooling to keep the temperature below 0 ^° C. In the course of 15 minutes after the addition is complete, the clear reaction mixture is warmed to 20 ° C. and then brought to pH by adding

j-. 70% methanesulfonic acid to a value of 1.9. at the reduction in pH is added at a pH of 2.5 crystal nuclei, whereby a rapid crystallization is caused. After stirring for 15 minutes at pH 1.9 the product is filtered off and washed well with water. By drying in vacuo at 50 ° C 8.55 g of a white product is obtained, which increases in weight when left standing over the weekend, so that you ultimately get 8.80 g. This indicates the

4ϊ Formation of the monohydrais. The melting point of the Materials is 172 ° C (with decomposition). The NMR spectrum confirms that it is the product is N-acetyl-ampicillin sulfoxide.

B) Manufacture of
N-acetyl-ampicillin-NN-dimethylamide sulfoxide

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 solution of 1 ^ 21 g of pivaloyl chloride in 50 ml of dry tetrahydrofuran. The resulting solution is stirred for 30 minutes under a dry nitrogen atmosphere, to complete the formation of the mixed anhydride. Then 13 ml of anhydrous are added at -10 ° C Add dimethylaniline in one portion to the mixture and stir for 30 minutes at one temperature

C _h H ₅ ~ CH - CONH

CH ₁ CNH

ΊΙ ο

S - CCH.,

= Y-- N

CH,

IL "

CH,

between - IO ° C and 0 ⁰ C. the mixture is poured over 150 g of crushed ice then to precipitate the product. However, since the product is found to be soluble, the mixture is evaporated in vacuo on a rotary evaporator. A solution of the oily residue is prepared in 100 ml of cold water. Acidification with a 70% aqueous M- hansulfonsäurelösung to a pH value of 2 arises no starting acid. The aqueous solution is saturated with sodium chloride and extracted twice with 100 ml of ethyl acetate. Ma.ι combines the extracts, dries them over sodium sulfate and concentrates them on a rotary evaporator to form a syrup. Trituration of the residue with 100 ml of ether gives a white, granular solid which is filtered off, washed with ether and dried to give 2.33 g of the product. The NMR spectrum confirms the presence of the desired product

. _ir > A -. »:» » Λ ~ η Λ ~ - η λ.λ. * η: ι: - - —.L..ι.

iitita fv-ΐβΐ, UUL * UUJ I IUUUIM II railll3llUI t. UtIlIItIfI.

Attempts to remove the pivalic acid by refluxing in 100 ml of ether have turned out to be no proven successful. After drying, the desired product is obtained, which melts at 145 to 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

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 > Sphere to reflux (104 ° C). One pulls that Dioxane is removed in vacuo with the aid of a rotary evaporator and the residue is triturated several times with 50 ml Ether. Removal of the solvent gives 0.56 g of a light yellow oil. By narrowing the

ίο ether extracts you get 0.82 g of a light yellow oil. 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

r, 0.56 g of the obtained sample confirms the stated structure. This results from the following findings:

ri j u *! C ^ rignSiC uCF gCtitiriaiCn mCitiyigrUpjjCfi uC5 starting material are not available with end product;

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

C) at 1.85 (5 occurs the broad methyl signal of the following Group on:

C-CH.,

CON (CHO ₂

D) the N, N-dimethyl signals at around 3.0 (5 persist; and

j-, E) also the 0-lactam signals at 5.4 to 6.4 (5 are im Included in the end product as well as in the starting material.

Claims (4)

Claims:! .Thioester of the formula Il A-CH-CH-S-C-W I I O = C N-CH-C = CH, R 'CH ₃ A a remainder to 15th 20th N— or Il R — C — NH- 30th R is a Ci-C ₈ -alkyl-, d-Ce-cycloalkyl- or C ₂ -Ce-alkenyl radical, which can optionally be hydroxy-, mercapto-, Ci-Cj-alkoxy-, Ci-C ₃ -alkylthio- or ryane-substituted , a hydrogen atom, a carethoxy group or a radical . X (CH ₂ ) " or CH ₁ CH ₃ 45 50 Q is a hydrogen atom, a hydroxyl group, a mercapto group, a chlorine atom, a bromine atom, a Ci- Cs-alkyl radical, a Ci-Cj-alkoxy group, a Ci-Cj-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, π is an integer from I to 2, R 'a remainder 55 or ! I -CH ₂ OCZ
O Il —C — NHZ Il —C — O — R " R "is a Ci-C ₄ -alkyl, C ₄ -C ₆ -th-alkyl, C ₅ -C ₈ -terL-alkenyl, C ₅ - Cg-tert-alkynyl, benzyl, methoxybenzyl, Nitrobenzyl, benzhydryl, phthalimidomethyl, succinimidomethyl, phenacyl or trichloroethyl radicals, Z is a hydrogen atom, a Ci-Ce-alkyl, C ₃ -C ₈ -cycloalkyl or Cj-Ce-alkenyl radical, which is optionally hydroxy, mercapto, Ci-C ₃ alkoxy, Ci C3-alkylthio or can be cyan-substituted, or a phenyl or phenyl-Ci - C ₃ -alkyl radical, which is optionally hydroxy, mercapto, chlorine, bromine, Ci -C ₃ -alkyI-, Ci-C ₃ -alkoxy, Ci - C ₃ alkoxy, Ci - C ₃ alkylthio, nitro or cyano substituted, and W denotes a methyl, ethyl, propyl or phenyl radical. 2. thioester according to claim 1, characterized in that that A has a remainder Il R — C — NH- R is a phenoxymethyl radical, R 'is a radical CO2R "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 CH ₃ A-CH-CH O = C- -N- CH ₃ 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. CH ₂ OZ