DE2145354A1 - Thioesters and process for their preparation - Google Patents

Description

PATENT LAWYERS

D R. I. M A A S

DR. W. PFEIFFER

DRF. VOITHENLEITNER

β MUNICH 23
UNGERERSTR. 25 - TEL. 39 0236

OL 85 407

Eil Lilly and Company, Indianapolis, Indiana, V.Sb.A.

Thioesters and process for their preparation

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

The invention relates to thioesters of the formula

A-CH-CH-S-C-W

I I

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

R ¹ CH ₃

0 where £

A is the remainder I ¹ I ^N or RC-NH,

Il

2Ö9Ö12 / 1800

2 U 5 3 5 A

R is a C -C -alkyl radical, Cg-Cg cycloalkyl radical or C ₂ alkenyl radical, which is optionally substituted with hydroxy, mercapto, C ₁ -C alkoxy, C -C alkylthio or cyano, a hydrogen atom, a carbethoxy group, a residue

> —CH- or

Q Y

CH-

/ W-o-c-,

Q " ^v 'CH,

Q is a hydrogen atom, a hydroxyl group, a mercapto group, a chlorine atom, a bromine atom, a C -C_ -alkyl radical, a C -C ^ -alkoxy group, a C.-C-j-alkylthio group, a Nitro group or a cyano group, X an oxygen atom, a sulfur atom, or a carbon-carbon bond,

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2U535A

Y is a hydroxy group, a mercapto group or a Araino group,

m is an integer from 0-2,
η is an integer from 1 to 2,
R ^{1 is} a radical -CH ₂ OZ,

0
-CH ₂ OCZ,

Il

-C-NHZ or

0
-COR ";

R "is a Cj-C ^ -alkyl radical, C.-Cg-tert.-alkyl radical, Cg-Cg-tert.-alkenyl radical, C ^ -Cg-tert.-alkynyl radical, Benzyl radical, methoxybenzyl radical / nitrobenzyl radical, Benzhydryl radical, phthalimidomethyl radical, succinimidomethyl radical, phenacyl radical or trichloroethyl radical,

Z is a hydrogen atom, a Cj-Cg-alkyl radical, C ₃ -Cg -cycloalkyl _{radical or C 2} -Cg-alkenyl radical, which is optionally hydroxy, mercapto, C.-C ^ alkoxy, C ₁ -C ₃ -alkylthio or is cyano-substituted, or a phenyl or phenyl-C -Chalkyl radical, which is optionally hydroxy, mercapto, chlorine, bromine, C ₁ -C ₃ alkyl, C -Cg alkoxy, C ₁ -C ₃ - BIkYItMo-, nitro- or cyano-substituted, and

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2H5354

a methyl, ethyl, propyl or phenyl radical

means.

The invention also relates to a process for the preparation of a thioester of the formula

0 A-CH-CH-S-C-W

I I

O = C-N-CH-C = CH ₂

in which a penicillin sulfoxide of the formula

A-CH-CH

O = C-N-

CH.

"CH.

-CH-R ¹

with a triphenylphosphine or a trialkylphosphite In Presence of acetic anhydride, propionic anhydride, butyric anhydride or benzoic anhydride is reacted at a temperature of 40 to 125 degrees C. Suitable trialkyl phosphites are those in which the alkyl groups contain 1 to 4 carbon atoms. In the above formulas means

209812 / 18ÖÖ

a rest

O or R-C-NH

a C -Cg -alkyl radical, C ₃ -Cg -cycloalkyl radical or C ^ -Cg-alkenyl radical, which is optionally substituted with hydroxy, mercapto, C -C.alkoxy, Cj-Cj-alkylthio or cyane, a hydrogen atom, a carbethoxy group, a residue

/ \\ - (CH ₂ ) _m -X- (CH ₂ ) _n -,

H-

or

-C-

209812/1800

- 6 - 2.U535A

Q is a hydrogen atom, a hydroxyl group, a mercapto group, a chlorine atom, a bromine atom, a C -C -alkyl radical, a C3 ^ C ₃ -alkoxy group, a C.-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 hydroxyl group, a mercapto group or an amino group,

m is an integer from 0 to 2,
η is an integer from 1 to 2,

R 'a remainder -

-CH ₂ OCZ,

-C-NHZ or

0
-COR ",

R "is a C ₁ -C ₄ -A ^ y! Radical, C ^ Cg-tert.-alkyl radical, C ₅ -Cg-

tert-alkenyl radical, Cc-Co-tert-alkynyl radical, * benzyl radical,

;> ο

Methoxybenzyl, nitrobenzyl, benzhydryl, Phthalimidomethyl radical, succinimidomethyl radical, phenacyl radical or trichloroethyl radical,

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2U535A

Z is a hydrogen atom, a C ^ Cg-alkyl radical, C ₃ -C ₃ -cycloalkyl radical or C ^ -Cg-alkenyl radical, which is optionally hydroxy, mercapto, C -C ₃ -alkoxy, C -Cg-alkylthio or is cyan-substituted, or a phenyl or phenyl-C -C ^ -alkyl radical, which is optionally hydroxy, mercapto, chlorine, bromine, C -C ^ -alkyl-, C.-C ₃ -alkoxy-, C - C ^ alkylthio, nitro or cyane substituted, and

W is a methyl, ethyl, propyl or phenyl radical.

That used as the starting material for this process Penicillin sulfoxide can be obtained by any convenient method for the preparation of penicillin sulfoxides, for example, by the method described in U.S. Patent 3,197,466. The carboxyl group of the one used Penicillin sulfoxide is preferably esterified to protect this group during the migration reaction. Penicillin esters are well known to those skilled in the art. The preferred ester groups are those used to regenerate the Allow free acid to be easily removed. Typical examples of such groups are tert-butyl, benzyl, methoxybenzyl, Nitrobenzyl, benzhydryl, trichloroethyl and Phenacyl radical. For examples of other ester groups which are used in the context of the process according to the invention can include the methyl, ethyl, 3-methyl-3-butenyl and 3-methyl-3-butynyl radical.

From the formulas it can be seen that R is the remainder of an acyl group referred to, which is attached to the 6-amino group of penicillin. This is preferably one Group that can be produced by fermentation, for example the benzyl or phenoxymethyl group. The acylation however, the 6-amino group of penicillin is generally known, so that it can be obtained by introducing other acyl groups

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-s- 2H535A

into the penicillins is made possible by chemical methods that R is from any of those acyl groups which can be linked to the penicillin system. Literally thousands of such groups are known. "Examples of R include methyl, cyclohexyl, alpha-aminobenzyl, methoxybenzyl, alpha-hydroxybenzyl, para-cyanophenylethyl, phenylthiomethyl, meta-hydroxybenzyl, para-nitrophenoxymethyl, para-chlorobenzyloxyethyl, Hydroxyhexyl and allyl radical. The meanings given for R in the above formulas are therefore fc are just examples of this large number of groups, and other equivalent groups will be apparent to those skilled in the art.

R ¹ can represent any group which can be in the 3-position of the penicillin ring. Typical examples of such groups are described in connection with the formulas. Thus, R ¹ can mean an alkoxymethyl, alkanoyloxymethyl, carboxamido or ester group. Individual examples of R ¹ include hydroxymethyl, ethoxymethyl, acetoxymethyl, benzoyloxymethyl, para-hydroxybenzoyloxymethyl, N-phenylcarboxamido, N-cyclohexylcarboxamido, N-octylcarboxamido, methoxycarbonyl, "tert-butoxycarbonyl," Benzyloxycarbonyl, para-nitrobenzyloxycarbonyl, trichloroethoxycarbonyl or para-methoxybenzyloxycarbonyl radical .. The most common penicillins are those in which R 'is an ester group. The preferred esters are those which can be easily cleaved to regenerate the free carboxyl group. Typical of these Easily cleavable esters are the tert-butyl, benzyl, benzhydryl, trichloroethyl, para-nitrobenzyl and para-methoxybenzyl esters.

The W substituent in the thioester produced is derived from the acid anhydride used in the reaction. One limitation

2 0 9 8 1 2/1800

_ ₉ _ · 2U535A

the invention on any theoretical explanation of how to implement it is not intended, apparently however, a sulfhydryl compound is used as an intermediate formed and esterified by the acid anhydride. W therefore means 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 G sulfoxide

Methyl 6- (meta-chlorophenylacetamido) penam-3-carboxylate-1-oxide,

3-hydroxymethyl-6- (cyclohexylcarboxamido) penam-1-oxide,

3-acetoxymethyl-6- (capramido) penam-1-oxide,

3-butoxymethyl-6- (para-nitrophenoxyacetamido) -penam-1-oxide,

N-methylamide of penicillin V-sulfoxide, 3-hydroxymethyl-6- (mandelamido) -penam-1-oxide, S-benzyloxymethyl-ö-acetamidopenam-l-oxide,

3-Benzoyloxymethyl-6- (phenoxyacetamido) penam-1-oxide.

20981 2/1800

2U5354

It is apparent to those skilled in the penicillin field that R, R ¹ , R ″ and Z can represent other radicals equivalent to those mentioned. The essential feature of the starting material is the penam sulfoxide base system.

In the process according to the invention, the penicillin sulfoxide is mixed with at least one equivalent of triphenylphosphine or a trialkyl phosphite at a temperature in the range from 40 to 125 degrees C in the presence of at least one equivalent Acetic anhydride, propionic anhydride, butyric anhydride or Benzoic anhydride implemented. The trialkyl phosphite to be used is one in which the alkyl groups contain 1 to 4 carbon atoms. 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. The preferred temperature range for the reaction is 50 to 120 degrees C. The reaction is preferably carried out in an inert solvent, for example carried out in hydrocarbons such as benzene or toluene or ethers such as dioxane or ethylene glycol dimethyl ether.

It should be noted that hydroxyl, mercapto and amino groups in the penicillin sulfoxide used during the reaction be protected by known measures. For example, hydroxy and mercapto groups are generally characterized by Conversion into an easily cleavable ester or thioester, for example formate, acetate or trifluoroacetate, protected. Amino groups are created by substitution with an easily removable group, for example triphenylmethyl, Trimethylsilyl, tert-butyloxycarbonyl, trichloroethoxycarbonyl, Benzyloxycarbonyl, a lower alkanoyl or the benzoyl radical or by forming the Enamine protected with methyl acetoacetate. The respectively

209812/1800

_β ι ι ^ _-

2U5354

has used protecting group for the purposes of the invention no 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 ICX) ml of toluene is heated to 95 to 96 degrees C. for 14 hours. Thin layer chromatography with silica gel / ether shows two main components with R _f values of 0.65 and 0.78. The spot with the R _f value 0.78 corresponds to the thiazoline formed as a by-product, and the zone with the R _f value 0.65 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 degrees 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, the

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2U535A

Vacuum 2.50 g of the thioacetate (R = phenoxymethyl, R ¹ = trichloroethoxycarbonyl and W = methyl). The IR, NMR, UV and mass spectrum confirm the assigned structure. . "

When the molar ratio of acetic anhydride to penicillin sulfoxide ester is increased to 10: 1, the amount increases Thioester too.

Example 2

The procedure of Example 1 is repeated with the para-nitrobenzyl ester instead of the trichloroethyl ester. The corresponding thioacetate is obtained as the product of the reaction, in which R = phenoxymethyl, R ¹ = para-nitrobenzyloxycarbonyl and W = methyl.

Example 3

A solution of 5 g of penicillin V-sulfoxide trichloroethyl 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 good with it Water washed. The ethyl acetate solution is over magnesium sulfate dried, and the solvent is removed in vacuo, leaving a pale yellow foamy substance is obtained. Treatment of this foamy substance with methanol gives 1.8 g of crystals, which as the thiazoline product can be detected. The mother liquor turns into a pale yellow foamy substance in vacuo constricted. The NMR spectrum shows that it is the same thioacetate as in Example 1, which is somewhat contaminated with more thiazoline.

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Example 4

The procedure of Example 3 is with the exception repeated / that 3/5 ml of trimethyl phosphite and 5 ml of acetic anhydride be used. The product obtained is 857 mg of the thiazoline and 3.9 g of the thioacetate.

Example 5

The procedure of Example 3 is carried out with 2.5 ml of trimethyl phosphite and 10 ml of acetic anhydride repeatedly. 1 g of the thiazoline and 3.86 g of the thioacetate are obtained.

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 smaller amounts of the thiazoline product and larger amounts of the desired Thioesters result. The product distribution is increased by increasing the molar ratio from 5: 1 to 10: 1 but not significantly changed.

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 The reaction mixture is washed six times with 100 ml of water each time, dried over magnesium sulfate and im The solvent was removed in vacuo to give 4.5 g of a white foamy substance. Thin layer chromatography shows only-a product that is less polar

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2U5354

than is the starting material. It is demonstrated by NMR spectroscopy that this product is the beta-gamma unsaturated one Is isomers of the desired thioacetate. Treatment of this product with triethylamine provides the alpha-beta unsaturated isomer.

Analysis: Calculated for C ₂₀ H ₁₇ N ₂ OgCl ₃ S: C, 46.22; H 3.30; N 5.39;

found:

beta, gamma: C, 45.97; H 3.56; N 5.12

found:

alpha, beta: C, 46.20; H 3.51; N 5.19

/ alpha_ / _n (dioxane) beta, gamma isomer = -144 and

alpha, beta isomer = -33 °.

⁵ Example 7

A solution of 50 g of penicillin V-sulfoxide trichloroethyl ester, 25 ml methyl phosphite and 55 ml acetic anhydride in 300 ml ^ toluene is heated to 100 degrees C for 16 hours. The cooled The solution is washed well with water and the solvent is removed in vacuo to give an oil. By NMR spectroscopy shows that this oil consists of a mixture of alpha-beta and beta-gamma-unsaturated Isomers of the desired thioacetate. By treating the mixture with 1 ml of triethylamine in benzene the beta-gamma isomer becomes the alpha-beta isomer converted, which is obtained as a pale yellow foamy substance.

As can be seen from Examples 5 and 6, the treatment of the beta-gamma-unsaturated isomer of according to the invention obtainable thioester with base under

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2H535A

mild conditions for isomerizing the double bond in the side chain with a shift in the alpha, beta position. So this isomer has the formula

A-CH-CH-S-C-W

O = C-NC = C-CH ₃

R ¹ CH ₃

wherein A, R ¹ and W are as defined above. This shift of the double bond takes place in the presence of a base having a dissociation constant above about 10 at a temperature in the range of 0 to 50 degrees C and preferably in the range of 20 to 30 degrees 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. The base can be an organic or inorganic base, for example sodium hydroxide, sodium carbonate, sodium methoxide, potassium methoxide, trimethylamine, Ν, Ν-dimethylaniline, pyridine, dimethylamine, methylamine, piperidine or ammonia. About one equivalent of base should be used per mole of thioester.

The thioesters in which R 'is a carboxyl group, show weak gram positive aritibacterial activity. The most significant advantages of those obtainable according to the invention Thioesters, however, lie in their use as intermediates in the manufacture of cephalosporin antibiotics. By treatment with an oxidizing agent, these thioesters are converted into a 3-hydroxy-3-methy! Cephalosporin formula

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214 5 3 5

A-CH-CH ^X \ CH ₂ OH O = C -N c CH ₃

HR ¹

converted, wherein A and R ^{1 are} as defined above. Such a 3-hydroxycephalosporin can be dehydrated to the 3-unsaturated compound.

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Claims (6)

Claims 1. Thioesters of the formula Ä-CH-CH-S-C-W O = C-N -CH-C = CH ₂ I .1 R ¹ CH- where Ä is a remainder a Cj-Cg-alkyl, Cg-Cg-cycloalkyl or ^C ₂ -Cg-alkenyl radical, which is optionally hydroxy, mercapto, C _{-C 3} alkoxy, Cj ^ -C ^^ - alkylthio or cyano-substituted can be a hydrogen atom, a carbethoxy group or a radical '-CH- or ^{Q CM} 3 "209812/1800 2H5354 Q is a hydrogen atom, a hydroxyl group, a mercapto group, a chlorine atom, a bromine atom, a C .- * C ₃ -alkyl radical, a C.-Cj -alkoxy group, a C.-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, η is an integer from 1 to 2, R ^f a remainder -CH ₂ OZ, 0
-CH ₂ OCZ, -C-NHZ or 0
-COR ", R "is a C -C.-alkyl, C.-C ^ -tert.-alkyl-, 0, .- C ₀ -tert.-alkenyl-, C _g -Co-tert.-alkynyl-, benzyl-, Methoxybenzyl, nitrobenzyl, benzhydryl, phthalimidomethyl, succinimidomethyl, phenacyl or trichloroethyl radical, Z is a hydrogen atom, a C 1 _{-C 6 -alkyl, C 3} -C 6 -CyClQ-alkyl or C 1 -C 6 alkenyl radical, which optionally 209612/1 2H535A - ■ 19 - hydroxy-, mercapto-, C - C_-alkoxy-, C ^ -C ^ j thio- or cyano-substituted, or 'a phenyl or phenyl-C -C ^ -alkyl radical, which is optionally hydroxy-, mercapto-, chlorine, bromine, C ₁ -C ₃ -alkyl, C ^ Cg-alkoxy, C ^ -C ^ -alkylthio, nitro- or cyano-substituted, and W is a methyl, ethyl, propy1 or phenyl radical mean. 2. thioester according to claim 1, characterized in that that A has a remainder R-C-NH, R is a phenoxymethyl ^{radical, R 1 is} a radical CO _? R "and W denote a methyl radical. 3. thioester according to claim 1, characterized in that A is a radical 0 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 a thioester of the formula 0 A-CH-CH-S-C-W I I O = C -N-CH-CH = CH ₂ , Il R ¹ CH, 209812/1800 -20- 2U535A characterized in that one uses a penicillin sulfoxide the formula f
S, S " CH- A-CH-CH C " \ CH ₃ O = C -N - - - - - CH-R ' with at least one equivalent of triphenylphosphine or a trialkylphosphite, in which the alkyl groups are 1 to Containing 4 carbon atoms at a temperature im Range from 40 to 125 degrees C in the presence of at least one equivalent of acetic anhydride, propionic anhydride, Converts butyric anhydride or benzoic anhydride, where in the formulas mean Il 0 A is a residue · - _N or RC a C -CG-alkyl, C, -CG-cycloalkyl or C ₂ -CG-alkenyl, optionally substituted hydroxy, mercapto, C ₁ ~ C ₃ alkoxy, C ₁ -C ₃ alkylthio or cyansubstituiert can be a hydrogen atom, a carbethoxy group or a radical 209812/1800 - (CH ₂ ) _m -X- ^) - CH- or Y Q Q is a hydrogen atom, a hydroxyl group, a mercapto group, a chlorine atom, a bromine atom, a C.-C ~ -alkyl radical, a C.-C ₃ -alkoxy group, a CC - 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, 2 0981271800 R * a remainder -CH "OZ, CH ₂ OCZ, C-NHZ Or O
-COR " R "is a C ₁ -C ₄ -AlkYl-, C ^ Cg-tert» -alkyl-, ^C 5 ~ ^C 8 ~ tert, - alkenyl-, Cg-Cg-tert-alkynyl-, benzyl-, methoxybenzyl-, Nitrobenzyl, benzhydryl, phthalimidomethyl, succiniraidomethyl, phenacyl or trichloroethyl radical, Z is a hydrogen atom, a C ^ -Cg-alkyl, C_-Cg-cycloalkyl or C ₂ -Cg-alkenyl radical, which is optionally hydroxy, mercapto, C.-C ₃ alkoxy, C ₁ -C ₃ - may be alkylthio- or cyano-substituted, or a phenyl or phenyl-Cj-C ^ alkyl radical, which may optionally be hydroxy, mercapto, chlorine, bromine, C -C ₃ -alkyl, C -C ^ -alkoxy, C -C - can be alkylthio-, nitro- or cyane-substituted, and W is a methyl, ethyl, propyl or phenyl radical. 209812/1800 5. The method according to claim 4, characterized in that that A has a remainder R-C-NH, R is a phenoxymethyl radical, R 'is a radical CO ₂ R "and W is a methyl radical. 6. The method according to claim 4, characterized in that that A has a remainder R-C-NH, R is a benzyl radical, R ^{1 is} a radical CO-R "and W is a methyl radical. 209812/1800