DE1185190B - Process for the production of penicillins - Google Patents

Description

GERMAN

PATENT OFFICE

EDITORIAL

German class: 12 ρ -4/01

Number:
File number:
Registration date:
Display day:

1185 190
S76179IVd / 12p October 7, 1961 January 14, 1965

The invention relates to a method for the production of new penicillins, the valuable chemotherapeutic Activity, especially antimicrobial properties. The connections show especially a high degree of antimicrobial effect on against Micrococcus pyrogenes, Proteus vulgaris and Diplococcus pneumoniae. In addition, they show an extended shelf life and produce high serum titers. There are few side efects. Certain of these compounds also have antimicrobial activity against microorganisms that are different from the known penicillins as like penicillin-resistant strains of Staphylococcus aureus.

The products of the process are therefore useful for the treatment of various microbial infections and result in a safe and effective therapy with at most extremely few side effects associated therewith. The administration of these compounds can be in any conventional form, e.g. B. as solutions, suspensions, creams, ointments, tablets or capsules, and they are suitable for oral, parenteral or topical application, depending on the nature of the infection in question.

The compounds obtained according to the process are represented by the general formula I:

Process for the production of penicillins

Applicant:

Smith Kline & French Laboratories, Philadelphia, Pa. (V. St: A.)

Representative:

Dr. H.-H. Willrath and Dipl.-Ing. H. Roever, Patent attorneys, Wiesbaden, Hildastr. 18th

Named as inventor:

John Rüssel Eugene Hoover, Glenside, Pa .; Alfred Wen-Jen Chow, Merchantville, N.J. (V. St. A.)

Claimed priority:

V. St. v. America of October 13, 1960 (62 333), March 23, 1961 (97 749)

-j- (CH ₂ ) "- C - NH-

NH-O =

CH-HC C-CH ₃

= C N CHCOOM

Here, M denotes a hydrogen atom or a physiologically acceptable cation, Z is an oxygen or sulfur atom, and η denotes the number 0 or 1.

The production of non-toxic salts of the corresponding salts is therefore also within the scope of the invention Carboxylic acids. Those contained in these salts and denoted by M in the general formula I. Cations can e.g. B. the alkali ions, such as the sodium ion or potassium ion or the calcium ion, and organic amine cations, e.g. B. lower alkylammonium groups, like triethylammonium.

The process according to the invention for the preparation of penicillins of the general formula I consists in that, in a manner known per se, an aqueous solution of 6-aminopenicillanic acid or a salt the same with a compound of the general formula II

- | - (CH ₂ ) _n -C -Y

is treated, where Y is a radical O

Il

- Ο - C - O - alkyl

or a chlorine atom, and that then optionally a compound of the general Formula I, in which M is a hydrogen atom

409 768/383

Reaction with a base is converted into its non-toxic salt, in which M is a cation.

Several of the required thionaphthenecarboxylic acids and benzofurancarboxylic acids used as the starting material are readily available. Those that are not out of the appropriate Thionaphthene or benzofuran prepared by methods analogous to those of a known type can be described below, without for this method of preparation protection is sought for the starting materials.

To prove the superior effectiveness of the

IO process products a process product is compared with penicillin G and α-aminobenzylpenicillin. These compounds were administered subcutaneously to groups of mice (weighing 18-20 g) intravenously infected with a strain of benzylpenicillin-resistant Staphylococcus aureus (No. 24,390). The subject compounds were administered in a saline solution at doses of 20, 40, 80 and 100 mg / kg to each group once a day for 2 days. The results of these experiments during 7 days after infection are recorded in Table I.

Table I.

link

number

the

animals

Dose mg / kg% surviving animals

I. day

2 day

3 day

4th day

5th day

day

7th day

6- [Thionaphthenyl- (3 ') -acetamido] -penicillanic acid

Penicillin G.

α-aminobenzyl penicillin

10
10
10
10

10
10
10
10

10
10
10
10

20th

40

80

100

20th

40

80

100

20th

40

80

100

90
100
100
100

90
80
90
90

100

100

100

80

70
90
90
90

80
50
70
80

80
70
60
70

30th
40
60
50

60
20th
20th
30th

40
20th
30th
40

20th
40
50
40

20th

10

10

20th

10

10

10
10
50
30th

10

20th

10

10

In Table II, the dilution test method found lowest growth inhibitors of Staphylococcus aureus No. 20,390 Concentrations of four process products and a comparison substance compared.

Table II

link

α-furylpenicillin

6- [thionaphthenyl- (3 ') - acetamido] -

penicillanic acid

6- [thionaphthenyl- (2 ') - carbamido] -

penicillanic acid

6-rhionaphthenyl- (2 ') - acetamido] -

penicillanic acid

6- [benzofuryl- (3 ') - carbamido] -

penicillanic acid

Lowest
inhibiting
concentration
((ig / ml)

45

1.8

0.02

0.09

0.016

0.055

55

The following examples serve to further illustrate the invention.

example 1

a) 270 g (2.02 mol) of anhydrous aluminum chloride are added to 1.8 l of carbon disulfide. The suspension is cooled to 5 ° C and a mixture of 210 g (1.57 mol) of thionaphthene, 107 g (1.36 mol) of acetyl chloride and 200 ml of carbon disulfide are added dropwise at such a rate that the temperature is kept below 10 ° C will. When the addition is complete, the reaction mixture is left to stand for 2 hours and 10% strength hydrochloric acid is then added to decompose the reaction mixture. The layers that form are then separated. The aqueous layer is extracted three times with ether and these essential extracts are combined with the organic layer. This solution is dried over magnesium sulfate. The solvents are removed in vacuo and the residue obtained in this way is fractionally distilled in order to obtain 3-acetylthionaphthene (b.p. ₃ = 135 to 137 ° C.).

A solution of 34 g (0.825 mol) of sodium hydroxide in 280 ml of water is cooled to 0 ⁰ C, and to the solution are 48.0 g (154 ml, 0.3 mol) of bromine was added dropwise at such a rate that the temperature drops below 10 ⁰ C is held. The solution is cooled again to 0 ⁰ C and treated dropwise with 17.6 g (0.1 mol) of 3-Acetylthionaphthen, keeping the temperature at 0 ° C. After decolorization, the reaction mixture is stirred for a further 3 hours and, after this time has elapsed, distilled with steam in order to remove the bromoform and carbon tetrabromide. The residue is then ^{cooled to 50 °} C. and acidified by adding 40 ml of concentrated sulfuric acid. The solid thus formed is filtered off, washed with water and recrystallized from hexane to give thionaphthenic (3) carboxylic acid.

A solution of 12.3 g (0.086 mol) Thionaphthen- (3) -carboxylic acid in 200 ml of acetone is cooled in an ice bath to 0 ⁰ C. The cooled solution will

10.2 g (0.1 mol) of triethylamine in 100 ml of acetone are added. The temperature of the reaction mixture is cooled to - 10 ⁰ C and held added dropwise a solution of 12.5 g (0.11 mol) of ethyl chloroformate in 50 ml of acetone was added with stirring, so that finally a reaction temperature of -5 ° C is maintained. A solution of 23.8 g (0.1 mol) of 6-aminopenicillanic acid in 40 ml of water and 15 ml of triethylamine is then slowly added to this mixture with stirring. When the addition is complete, the mixture is stirred and allowed to come to room temperature. Then it is stirred for another half hour. The mixture is extracted with three portions of 300 ml of ether and the resulting aqueous solution is adjusted to pH 2.0 with 6 η-sulfuric acid, while the temperature is kept at less than 10 ^° C. At pH 2, the solution is extracted with 250 ml of butyl acetate and then twice with 75 ml of butyl acetate each time.

250 ml of water are added to the combined butyl acetate extracts and the pH is adjusted to 8.0 by adding solid potassium bicarbonate while stirring. The layers are separated and the aqueous layer is adjusted to pH 2.0 by addition of 6 N sulfuric acid at less than 1O ⁰ C. This acidic aqueous mixture is then extracted with 200 ml of butyl acetate and the organic extract is then washed once with water and dried over sodium sulfate. A solution of potassium hydroxide in n-butanol (40 g / l) is added to the butyl acetate solution with vigorous stirring until the reaction mixture has reached pH 8.4. The mixture is cooled until crystallization occurs. The crystals are then centrifuged off, washed with a small amount of acetone and dried. The dried crystals are recrystallized from butanol and dried to obtain the potassium salt of 6- [thionaphthenyl- (3 ') - carbamidoj-penicillanic acid.

b) On the other hand, 3.5 g (0.02 mol) of thionaphthene (3) carboxylic acid are allowed to react with 11 ml of thionyl chloride at room temperature overnight. The resulting solution is ^{evaporated at 35 °} C. in vacuo, and the oil obtained in this way is mixed with 25 ml of benzene, whereupon the mixture is evaporated again. After adding a further 25 ml of benzene and repeating the procedure, the remaining oil is kept under vacuum to remove any trace of thionyl chloride; then 4 g of the oil are dissolved in 50 ml of anhydrous Acton. This solution is slowly added, with stirring, to 4.3 g of 6-aminopenicillanic acid in 190 ml of 3% strength aqueous sodium bicarbonate and 120 ml of acetone. The reaction mixture is kept l ^x / 2 hours at 25 ° C., extracted twice with 150 ml of ether and the remaining aqueous solution is treated with 40 ml of butyl acetate; this mixture is ^{cooled to below 10 °} C., adjusted to pH 2.4 with 20% phosphoric acid, and the phases are then separated. The aqueous phase is extracted with 15 ml of butyl acetate, and the combined butyl acetate extracts are washed with 10 ml of water which has been adjusted to pH 3. The washed organic solution is then dried over magnesium sulfate and filtered, and 9.6 ml of 30% strength potassium 2-ethyl caproate in isopropanol are added to the filtrate. 1 part by volume ether wi ^r d then added with stirring, and the forming, after cooling, crystals are filtered, washed with ether-butyl acetate (1: 1) and then washed with ether and finally dried to give the potassium salt of 6- [Thionaphthenyl- (3 ') -carbamidoj-penicillanic acid. Decomposition point: 129 to 145 ° C. Yield 70% of theory.

Treatment of the potassium salt with hydrochloric acid and extraction with ether then gives the free 6- [thionaphthenyl- ^ O-carbamidol-penicillanic acid.

Example 2

To a boiling solution of 152.5 g (1 mol) of 2-chlorobenzaldehyde in 700 ml of ethanol is added dropwise with stirring a molten mixture of 120 g sodium sulfide and 16 g sulfur in the course of 2 hours. The mixture is then cooled and with a solution of 60 g Potassium hydroxide and 60 g of sodium sulfide combined in 300 ml of water. The mixture is 15 minutes heated and brought to the boil. A solution of 140 g is then added to this mixture with stirring Chloroacetic acid in 250 ml of water which has been neutralized by adding sodium bicarbonate. the The mixture is left to stand for 15 hours. At the end of this period a crystalline one forms Dimensions. This is collected by filtration and dissolved in dilute aqueous sodium hydroxide solution. After acidification, a solid is formed which is filtered off, dried and recrystallized from hexane to give thionaphthenic (2) carboxylic acid.

This compound is then reacted analogously to the process of Example 1 in place of thionaphthen (3) carboxylic acid. The potassium salt of 6 - [thionaphthenyl - (2 ') - carbamido] - penicillanic acid is obtained in this way. Decomposition point: 183 to 185 ^° C. Yield: 70% of theory.

B ei s-p i e 1 3

A cooled solution of 29.5 g (0.217 MpI) of n-butyl bromide in 40 ml of anhydrous ether is dropwise to a chilled suspension of 3.6 g (0.535 mol) of finely cut lithium wire in Given 70 ml of anhydrous ether. During the addition, the reaction mixture is placed in an ice bath cooled and, after the addition was complete, heated with stirring and reflux for 1 hour. Then the reaction mixture filtered and chilled in an ice bath. 19.3 g (0.144 mol) of thionaphthene are then added Add 30 ml of anhydrous ether. When the addition is complete, the mixture is refluxed for 45 hours heated.

150 g (5.0 mol) of formaldehyde are slowly added to this ethereal solution of thionaphthenelithium in 500 ml of chilled anhydrous ether. The mixture is refluxed for 1 hour heated and then poured into 5 l of ice water, which would be saturated with ammonium chloride. The organic Layer is then separated and the aqueous layer extracted three times with ether. The United organic layers are dried over sodium carbonate and vacuum distilled to give 2- (oxymethyl) thionaphthene to surrender.

A mixture of 32.8 g (0.20 moles) of 2- (oxymethyl) thionaphthene and 29.7 g (0.25 mol) of thionyl chloride are refluxed U / 2 hours. The mixture is then distilled and recrystallized from hexane to give 2- (chloromethyl) thionaphthene to surrender.

A mixture of 13.8 g (0.076 mol) 2- (chloromethyl) thionaphthene, 7.8 g (0.12 mol) potassium

cyanide, 125 ml of dioxane and 65 ml of water is stirred under reflux for 3 hours. Then the mixture cooled, admixed with additional water and separated the organic layer. The aqueous layer is then extracted three times with benzene, and these benzene extracts are then combined with the organic Layer united. The combined organic solutions are then washed, dried and the The solvent is then removed under reduced pressure. The residue is distilled in vacuo, to give 2- (cyanomethyl) thionaphthene.

A mixture of 13.8 g (0.08 mol) of 2- (cyanomethyl) thionaphthene, 10 g of sodium hydroxide (0.25 mol), 50 ml of water and 50 ml of ethanol is refluxed for 18 hours. Then the Mix cooled and slow with about

17 ml of concentrated hydrochloric acid are added until the mixture only reacts slightly basic. she is then filtered and the filtrate boiled to remove excess ethanol. Then it becomes water added and the aqueous basic solution washed with ether. The washed solution is first Clarified with activated charcoal, filtered and the filtrate acidified. The solid substance that forms becomes filtered off, dried and recrystallized from carbon tetrachloride to give thionaphthenyl (2) acetic acid result.

Thionapthenyl (2) acetic acid is then reacted analogously to Example 1 in accordance with the process. Here receives the potassium salt of 6 - [- thionaphthenyl- (2 ') - acetamido] -penicillanic acid. Decomposition point: 231 to 237 ° C. Yield: 75% of theory.

Example 4

A stream of hydrogen chloride is passed through a solution of 372 g (4.6 mol) of 37% strength aqueous formaldehyde, 153 ml (4.2 mol) of concentrated hydrochloric acid and 500 g of thionaphthene until the solution is saturated with hydrogen chloride. During this time, the temperature rises to approximately 85 ^° C. and is held at this level for 1 hour while hydrogen chloride continues to be slowly passed through. At the end of this time, the mixture is cooled and poured into 350 ml of ice water. The mixture is then extracted with benzene and the benzene extracts are washed with water, 10% aqueous sodium bicarbonate solution and finally again with water. This washed benzene solution is then dried and the solvents are removed under reduced pressure. The residue is distilled in vacuo to give 3- (chloromethyl) thionaphthene.

13.9 grams (0.076 moles) of 3-chloromethylthionaphthene are combined with 7.8 g (0.12 mol) of potassium cyanide, 125 ml of dioxane and 65 ml of water. This mixture is stirred under reflux for 3 hours and then cooled. The organic layer is separated and the aqueous layer extracted three times with benzene. These benzene extracts are then with the organic layer and then washed with water, dried, and the solvents are stripped off under reduced pressure. The residue is distilled in vacuo to give 3- (cyanomethyl) thionaphthene to surrender.

A mixture of 13.7 g (0.08 mol) of 3- (cyanomethyl) thionaphthene, 10 g of sodium hydroxide (0.25 mol), 50 ml of water and 50 ml of ethanol

Heated under reflux for 18 hours. Then the

The mixture is cooled and approximately 17 ml of concentrated hydrochloric acid are slowly added until the mixture is mixed is only weakly basic. It is then filtered and used to remove excess alcohol cooked. Then water is added to the aqueous basic solution and this dilute solution with Ether washed and clarified with decolorizing charcoal. After filtration, the filtrate is acidified and the solid substance that forms is again filtered off,

ίο dried and recrystallized from carbon tetrachloride to give thionaphthenyl (3) acetic acid. If an equivalent amount of (3-thionaphthenyl) acetic acid is used instead of thionaphthen (3) carboxylic acid in the procedure of Example 1, the potassium salt of 6- | thionaphthenyl (3 ') - acetamido] penicillanic acid is obtained. Decomposition point: 228 ^° C. Yield: 80% of theory.

Example 5

A solution of 15.2 g (0.086 mol) of benzofuryl-2-acetic acid in 200 ml of acetone is cooled ^{to 0 ° C. in an ice bath.} The cooled solution is mixed with 10.2 g (0.1 mol) of triethylamine in 100 ml of acetone. The temperature of the reaction mixture is cooled to - held for 10 ⁰ C and is added dropwise with stirring a solution of 12.5 g (0.11 mol) of ethyl chloroformate in 45 ml of acetone to such that the final reaction temperature is maintained at -5 ° C . A solution of 23.8 g (0.1 mol) of 6-aminopenicillanic acid in 40 ml of water and 15 ml of triethylamine is slowly added to this mixture with stirring. When the addition is complete, the mixture is stirred and allowed to come to room temperature, whereupon it is stirred for a further half an hour. The mixture is extracted with three portions of 300 ml of ether and the resulting aqueous solution is adjusted to pH 2.0 with 6 η-sulfuric acid, while a temperature below 10 ^° C. is maintained. At pH 2, the solution is extracted with 250 ml of butyl acetate and then twice with 74 ml of butyl acetate.

The combined butyl acetate extracts are mixed with 250 ml of water and by adding solid Potassium bicarbonate adjusted to pH 8.0 with stirring. The layers are separated, and the aqueous Layer is adjusted to pH 2.0 by adding 6N sulfuric acid at less than 10 ° C. This sour aqueous mixture is then extracted with 200 ml of butyl acetate and this extract once with water washed and then dried over sodium sulfate. To the butyl acetate solution is added vigorously Stir a solution of potassium hydroxide in n-butanol (40 g / l) until the reaction mixture is pH 8.4 has reached. It is then cooled until crystallization occurs. The crystals are through Collected by centrifugation, washed with a small amount of acetone and dried. The dried ones Crystals are recrystallized from butanol and dried to give the potassium salt of 6- [benzofury1- (2 ') -acetamido-penicillanic acid to obtain. Decomposition point: 219 to 222 ° C. Yield: 95% of theory.

Example 6

11 ml of thionyl chloride are mixed with 3.24 g (0.02 mol) Benzofuran-3-carboxylic acid are combined and the mixture is left at room temperature overnight ditched. The resulting solution is evaporated in vacuo at 35 ° C, and the so obtained

oil is mixed with 25 ml of benzene, whereupon the mixture is evaporated again. After adding a further 25 ml of benzene and repeating the procedure, the remaining oil is kept under vacuum to remove any trace of thionyl chloride. 4 g of the oil thus obtained are dissolved in 50 ml of dried acetone and this solution is added, with stirring, to 4.3 g of 6-aminopenicillanic acid in 190 ml of a 3% strength aqueous sodium bicarbonate solution and 120 ml of acetone. The reaction mixture is kept at 25 ⁰ C IV2 hours, extracted twice with 150 ml of ether and added to the remaining aqueous solution with 40 ml of butyl acetate. This mixture is ^{cooled to below 10 °} C., adjusted to pH 2.4 with 20% strength phosphoric acid, and the phases are separated. The aqueous phase is extracted with 15 ml of butyl acetate and the combined butyl

acetate extract washed with 10 ml of water and adjusted to pH 3. The washed organic solution is then dried over magnesium sulfate, filtered and the filtrate with 9.6 ml of 30% potassium 2-ethylcaproate added in isopropanol. Then 1 part by volume of ether is added with stirring; which Crystals which form after cooling are filtered off, with ether-butyl acetate (1: 1) and then washed with ether and finally dried to give the potassium salt of 6- [benzofuryl- (3 ') - carbamidoj-penicillanic acid to obtain. Decomposition point: 216 to 218 ° C. Yield: 80% of theory.

Claims (1)

Claim: Process for the preparation of penicillins of the general formula I. / S \ / CH3 j - (CH ₂ VC -NH-CH-HC-CH ₃ C O = C N CH-COOM where Z is an oxygen or sulfur atom, M is a hydrogen atom or a physiologically acceptable cation and η is the number 0 or 1, characterized in that in a known manner an aqueous solution of 6-aminopenicillanic acid or a salt thereof with a compound of the general formula II Il '* - C- 35 II treated, where Y is a remainder
O Il - O - C - O - alkyl or a chlorine atom, and that then optionally a compound of the general Formula I, in which M is a hydrogen atom, by reaction with a base in whose nontoxic salt is converted, wherein M is a cation. Considered publications:
Notice of publication of the Belgian patent No. 569 728. When the announcement was made, two priority documents and a transfer declaration were displayed. ♦ 09 7H / 3I3 1. »5 Q Bundeidruckerei Berlin