DE2301014A1 - NEW INTERMEDIATE PRODUCTS FOR THE MANUFACTURE OF SEMI-SYNTHETIC PENICILLINS AND CEPHALOSPORINS AND METHODS FOR THEIR MANUFACTURING - Google Patents

Description

"New intermediates for the manufacture of semi-synthetic Penicillins and cephalosporins and processes for their preparation "

The invention relates to new phosphorylated penicillin and cephalosporin derivatives and processes relating to their production and use in the production of semi-synthetic penicillins and cephalosporins.

In its broadest sense, the invention encompasses compounds of the following structure:

3 0 9 8 2 9/1 U 1

AHP-5753

Y-N-O =

CH

-N-

^CH 3 O

and

C-O-P-Z

CH ₂ R

Ζ ¹ —Ρ— (R ³ )

t Z

In these formulas, Z and Z each represent an organic radical and they can be linked to one another so that they can be linked to the Phosphorus atom form a heterocyclic ring; Y denotes hydrogen or an acyl radical. These compounds are suitable as intermediates for the production of non-toxic cephalosporins and penicillins which have gram-positive and / or gram-negative activity against microorganisms.

In its narrower sense, the invention relates to compounds of the formulas:

HR ⁵ -N-

0 =

.KL

3 0 R

If ¹

(A)

CH ₂ -R

P- (R ³ )

- 2 - 309829 / IHI

(B)

^ AHP-5753

23010U

where R is hydrogen, (lower) alkanoyloxy having 2 to 8 carbon atoms (e.g. acetoxy, propionoyloxy, butanoyloxy, etc.), aryloxy or a quaternary ammonium radical (e.g. pyridinium, quinolinium, picolinium radical, etc.); Vr represents oxygen (= 0) when the phosphorus atom is pentavalent;

5
R is hydrogen or an organic acyl group; R ¹ and R ² for (lower) -alkoxy, (lower) -alkylthio, aryloxy, arylthio, aryl- (lower) -aLkyloxy, aryl- (lower) -alkylthio, halogen, (lower) -alkyl, aryl, aryl- (lower) -alkyl, halo- (lower) -alkyloxy, halo- (lower) -alkyl or represent a radical of the following structure:

Η ^ Γ_ ^

-N-

^H 3 CH:

or

CH 2 -R

309829 / IUI

⁷ AHP-5753

The radicals R and R are preferably linked to one another so that they form the following rings with the phosphorus atom:

-joder R '

in which η is an integer from zero to 1 and m is an integer are from 1 to 6; X stands for sulfur, oxygen or methylenej R is selected from hydrogen and 1 to 3 (Lower) alkyl radicals; X preferably represents oxygen.

The term "(lower) alkyl" as used herein alone or in conjunction used with otherwise designated groups is intended to include straight or branched chain alkyl groups consisting of 1 to 6 carbon atoms (e.g. methyl, ethyl, propyl, Butyl, isobutyl, hexyl, 2-ethylpropyl, etc.).

The term "(lower) alkoxy" as used herein alone or in connection with groups with other names is intended straight-chain or branched alkoxy groups with 1 to 6 carbon atoms (e.g. methoxy, propoxy, butoxy, isobutoxy, Pentoxy, 1,1-dimethylbutoxy). The term used here "Halogen" is intended to include chlorine, bromine, iodine and fluorine. The term "aryloxy" includes phenoxy, naphthoxy and unsaturated ones heterocyclic rings which contain 5 to 7 ring members and 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. The term "aryl (lower) alkyloxy" includes an aryl nucleus, which has a ring carbon atom with a (Lower) alkyloxy group is connected. Examples of aryl (lower) alkyloxy radicals are benzyloxy, phenethyloxy, etc. The

309829/1 U1

S AHP-5753

The term "aryl" is illustrated by phenyl and naphthyl and the term ⁿ aryl (lower) alkyl "is illustrated by benzyl, phenethyl, etc. Examples of (lower) alkylthio radicals are thiomethyl, thiobutyl, thioisopropyl, etc. Examples of "Arylthio radicals ¹¹ 'are phenylthio, chlorophenylthio, methylphenylthio, methoxyphenylthio, etc. Examples of ^w aryl (lower) alkylthio radicals ¹¹ are benzylthio, phenethylthio, chlorophenethylthio etc.

The acyl group defined by R is derived from an organic one Carboxylic acid or an organic sulfonic acid or a suitable reactive functional derivative thereof away.

The preferred acyl groups defined by R are listed under selected from the groups of the following formulas, those having a free amino group in the form of an acid addition salt present, which can then be converted into the free base.

3 0 9 8 2 9/1 U 1

CH-

—C-

Il ο

₆ AHP-5753

C— >

Ο — CH-C

CH-C -

I Il

NH ₂ O

KH ' «ίο

C -

CH-

—-C—

HN C-IJ-C-1, w ₂

NH

-NH,

Ii

H — C-

HN-C — N — C-NH,

Il O

You

2 - 6 -

309829/1141

AHP-5753

In the structural formulas above: R and R ^{7 represent} hydrogen or (lower) alkoxy; R ^{8 represents} hydrogen, (lower) alkyl or phenyl; R ^ and R for hydrogen or halogen; R ¹¹ and R ^{12 represent} hydrogen, halogen, (lower) alkyl, (lower) alkoxy, phenyl or phenoxy; R ^{15 represents} hydrogen, (lower) alkyl or aryl;

a for an integer from zero to 1; b for an integer from zero to 5 »

£ for an integer from zero to 2; d is an integer from 1 to 3, but when a is zero, d is greater than 1, and when j * is 1, d is less than 3.

The process according to the invention can be illustrated by the following reaction scheme;

309829/1 UI

15 ° '

rl L -j

CH

-N-

CH-

C-OM

+ Halogen PR '
·. (R ³ )

co
ο
CD
co I. Γ 0R ^a
n ¹⁵ cj ■ CH ₃ R ¹
I. to 03 •
H-halogen SCHj
0
Il ■ 0 — P— I. n— η (R ³ ) - * ■

II

Acid acceptor

solvent

.15 »

RtZ-C-N-

halogen

Acid acceptor
R ^a -0H

0 =

0 =

III

CH,

.N.

R ^x

-0-P-R * »3.

Acid halide

CH,

"3 0 R ^A

"I ₂

.N 1 C-O-P-R *

(R ³ )

GO O

IV

0R

H-halogen

co

0 =

N-

CH ₃

^CH

hydrolysis

Halo

H ₃ N ¹

0-

3 O

■ C-0 - Ρ— R '

(R ³ )

VI

Acylating agents

and

Acid acceptor

Acyl '

H N '

0 =

N -

VIII

I ₃

2 Il

hydrolysis

.C-OH

Acyl

H
-ti

.N.

, CH,
CH,

• C — 0 — P — R,

(R ³ )

VII

CaI

AHP-5753

In the above reaction sequence, M stands for hydrogen, Alkali metal (e.g. Na, K etc.) or a tertiary amine (e.g. triethylamine, dimethyl aniline) and R - * stands for one Substituents selected from those contained in natural and synthetic penicillins. This here The term "natural penicillins" used includes those which are produced by fermentation, as well as those the biosynthetic by adding certain precursors to the fermentation broth getting produced. Examples of such penicillins are:

Penicillin S (R ⁵ stands for -chlorocrotyl mercaptomethyl); Penicillin V (R ¹⁵ stands for phenoxymethyl); Penicillin G (R ¹⁵ stands for benzyl);
Penicillin F (R ¹⁵ stands for 2-pentyl); Penicillin K (R ¹⁵ stands for 2-heptyl); Penicillin X (R ¹⁵ stands for p-hydroxybenzyl); Dihydropenicillin F (R ¹⁵ stands for amyl); Penicillin T (R ⁵ stands for p-aminobenzyl); Penicillin O (R: ^Ό stands for allyl mercaptomethyl); Penicillin N (R ^ stands for 4-amino-4-carboxybutyl). Although a natural penicillin is preferably used as the starting material of the formula I for the reaction with a phosphorus halide of the formula II, the feasibility of the process is not limited to these starting materials and also works when a synthetic penicillin falling under the formula I is used as a reactant.

Examples of special phosphorus halides falling under the formula II are. Phosphorus oxychloride, phosphorus trichloride, diphenylphosphorochloridate, Phosphorochloridate, phenyl phosphorus dichloridate, ethyl phosphorus dichloridate, cyclic ethylene phosphorochloridate, Diethyl phosphorochloridate, diethyl phosphorochloridite, Ethyl phosphorus dichloridite, cyclic ethylene phosphorus chloridite (2-chloro-1,3,2-dioxaphospholane), cyclic

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ff

AHP-5753

Propylene phosphorochloridite (2-chloro-1,3,2-dioxaphosphorinane), Etc.

The reaction of a compound of the formula I with a compound of the formula II is preferably carried out in the presence of an anhydrous, inert aprotic solvent and in the presence of an acid-binding agent. This reaction is conducted at a temperature ranging from about -40 ° to about + 1O ⁰ C, preferably at -1O ° C to about +10 ⁰ C is performed. The molar ratio of a compound of the formula I to a compound of the formula II is about 0.5: 1 to 3: 1, preferably about 1: 1. If "the molar ratio is greater than 1: 1

1 2 and at least one of the radicals R or R halogen, dimers or trimers can be obtained, as in the following Formulas illustrated is:

and

3
CH.

V ⁸ N

Q-C

ο η> n O ΰ — 0 — Ρ— Ο— C

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AHP-5753

Suitable acid-binding agents are tertiary amines, such as triethylamine, Dimethylaniline, quinoline, pyridine, lutidine; Alkali metal carbonates; Alkaline earth metal carbonates or other acid scavengers known in the art. The preferred one acid binding agent is a weak tertiary afflin. With "strong amines" are meant here that by

-3-6

Dissociation constants in the range from 10 to 10 are indicated are or have a comparable basicity, in contrast to "weak amines", which by dissociation

—8 —11 constants ranging from 10 "to 10 ~ are labeled.

A wide variety of anhydrous, non-hydroxylic organic Solvent is suitable for reacting a compound of the formula I with a phosphorylating agent for this purpose include hydrocarbons such as toluene; chlorinated solvents such as methylene chloride, chloroform and chlorobenzene; Ether, such as diethyl ether, tetrahydrofuran; and other common solvents such as methyl isobutyl ketone, dimethylformamide, ethyl acetate, Acetonitrile etc. The preferred solvents are the chlorinated solvents

The penicillin of the formula III protected on the carboxyl group is converted into the corresponding imino halide of the formula IV by reaction with an acid chloride in the presence of an acid acceptor. Examples of suitable acid halides include phosphorus pentachloride, phosgene, phosphorus oxychloride, oxalyl chloride, p-toluenesulfonic acid chloride, phosphorus pentabromide, etc. The acid acceptor is an acid binding agent which is any of the previously described in connection with the reaction of a compound of formula I with a compound of Formula II described can act. The formation of the Iminohalogenidverbindung is under anhydrous conditions at temperatures below ⁰ C, preferably at temperatures between -10 ° C and -65 ° C carried out. An inert or-

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309829/114 1

■ η

ΑΗΡ-5753 23010U

General solvents such as methylene chloride, dichloroethane, chloroform, diethyl ether or one of the other solvents described above is present in the reaction. Since it is not necessary to isolate the intermediate of the formula III (but it can also be carried out), the solvent used in the reaction of a compound of the formula I with a compound of the formula II is present when a compound of the formula III is reacted with an acid halide will. A slight excess of acid halide, no more than about 10 %, is employed in preparing a compound of Formula IV.

The Iminohalogenidverbindung of formula IV is prepared by reacting the Iminohalogenides under anhydrous conditions with a primary or secondary alcohol (R ^a OH) at temperatures below about -1O ° C, preferably at temperatures between about -30 ° C and -6O ° C, in the Iminoether hydrohalide of formula V converted. At these temperatures, the group protecting the carboxyl group is resistant to cleavage. Examples of R ^a are lower alkyl, hydroxy (lower) alkyl, phenyl (lower) alkyl, cycloalkyl with k to 8 carbon atoms, (lower) alkoxy (lower) alkyl, aryloxy (lower) alkyl, etc. .

Examples of suitable primary and secondary R ^a OH compounds are methanol, ethanol, n-butanol, isopropanol, amyl alcohol, benzyl alcohol, 2-phenylethanol-1, cyclohexyl alcohol, 1,6-He; candiol, 2-methoxyethanol, 2-isopropoxyethanol, 2-butoxyethanol, 2-p-chlorophenoxyethanol, 2- (p-methoxybenzyloxy) -ethanol, diglycol etc.

The imino ether bond is cleaved without the carboxyl protecting group being removed. This is ater preferably achieved by hydrolysis with V / at a temperature below -2O ° C, at a temperature between -30 ⁰ C and -60 ° C.

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309829/1 141

AKP-5753

After the formation of a compound of the formula VI, the acylation is carried out at a temperature between -60 ° C. and room temperature, preferably below ⁰ ° C., in the presence of an acid-binding agent, which can be one of the materials described above, to form a compound of the formula VII carried out. The acid binding agent is preferably a weak amine. So much acid-binding agent must be used that the hydrogen halide is removed from a compound of the formula VI and immediate acylation of the 6-amino group is made possible. When carrying out this reaction, an excess of acylating agent over the acid acceptor is used.

Suitable acylating agents include carboxylic acid halides, carboxylic acid anhydrides, mixed anhydrides with others Carboxylic acids or inorganic acids; Esters such as thiol esters and phenol esters; Lactones; and carboxylic acids with carbodiimides or N, N -carboxylic diimidazoles.

Examples of some specific preferred acylating agents are phenoxyacetyl chloride, 2,6-dimethoxybenzoyl chloride, benzenesulfonyl chloride, 2-phenoxypropionyl chloride, 2-phenoxybutyryl chloride, D (-) - Phenylglyeylchlorid «HCl, 1-aminocyclopentanecarboxylic acid chlori d HCl, 1-aminocyclohexanecarboxylic acid chloride HCl, 2-Amino-2-carboxyindanoic acid chloride · HCl, 2-ethoxynaphthoyl bromide and 3- (2,6-dichlorophenyl) -5-methyl-isoxazole-4-carbonyl chloride, etc.

The acylated penicillin of the formula VII is obtained as the hydrohalide salt, when the acyl radical is an α- or ß-amino group contains. This intermediate of formula VII is by Hydrolysis converted into a semisynthetic penicillin compound of formula VIII, with the carboxyl protecting group Will get removed. If this product is in the form of a hydrohalide salt, it can be easily obtained using known ones

- 14 309829/1 U 1

* f ΑΗΡ-5753

Convert the neutralization process into its corresponding basic form. For example, the hydrohalide salt is used for briefly with water, which is a base such as triethylamine, Contains sodium bicarbonate or the like, preferably treated in the presence of a water-miscible solvent.

If the final penicillin to be obtained is an alpha-aminobenzylpenicillin (ampicillin), it has been found to be Proven advantageous that halide in an aryl sulfonic acid salt to convert the aminopenicillin, either by adding a suitable sulfonic acid to the reaction mixture, the the selected organic solvent and water contains, or by adding to the aqueous extracts that - like described immediately before - have been separated. In this context one advantageously uses one 25% excess of the sulfonic acid in the preparation of the corresponding ampicillin salt.

The arylsulfonic acid salt of the α-aminobenzylpenicillin can then be converted to the penicillin per so by reaction with a base such as triethylamine or diethylamine in approximately 85% isopropanol. Especially in the case of ampicillin, the wetted with water and ethyl acetate sulfonic acid salt to isopropanol at 75 to 80 ⁰ C are added, which contains a molar equivalent of triethylamine, thereby forming the anhydrous Ampicillinform v / ill be described in U.S. Patent 3,144,445, which is isolated from the hot mixture by filtration.

Alternatively, the appropriate penicillin can be obtained by increasing the pH of the aqueous reaction mixture containing the hydrochloride salt of penicillin, up to the isoelectric point, but in hydrated form.

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309829/114

4§ AHP-5753

23010H

Instead of a penicillin of form I, a cephalosporin of the following formula can be used to make semi-synthetic cephalosporins:

O = C-OM

wherein R and M have the same meaning as previously defined, and R is one of those in natural and represents synthetic cephalosporins occurring substituents, There are numerous examples of this in the prior art. Examples of substituents from natural cephalosporins are 2-thienylmethyl, (cephalothin); A-amino- ^ carboxy-n-butyl, (Cephalothin C); other cephalosprin compounds are those described in U.S. Patents 3,499,909, 3,093,638, and 3,270,755.

The natural or synthetic penicillins and cephalosporins, used as starting materials are commercially available or described in the literature. as well the phosphorus halides of the formula II are commercially available or, in cases where they are not available, they can can be easily prepared by standard organic processes that are described in the chemical literature and known to those skilled in the art are known.

The following examples serve to illustrate some embodiments of the invention.

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309829/1141

AHP-5753

example 1

D (-) - g-aminobenzylpenicillin

Potassium penicillin G (75 g, 0.2 mol) and N, N-dimethylaniline (DMA) (53 ml, 0.418 mol) are stirred in 300 ml of dichloromethane at 10 ⁰ C to give 2-chloro-1,3,2 -dioxaphospholane (27 ml, 0.3 mol) be added over 20 minutes. The resulting product is δ-phenylacetamido-penicillanic acid 1,3,2-dioxaphospholan-2-yl ester. After additional 1/2 hour of stirring at 10 ⁰ C, the temperature at -55 ° C is lowered, and powdered PCl ₅ (45 g, 0.216 mol) was added at once. With constant cooling in an acetone / dry ice bath, the temperature rises to about -45 ° C and the mixture is stirred at -40 ° C for 2 hours. The product obtained from this reaction is ^t 6 - [- (a-chlorophenethylidene) -amino] -penicillanic acid-1, S ^ -dioxaphospholan ^ -yl-ester. The temperature is ^{lowered again to -6O 0} C and 67 ml of absolute alcohol are added at the highest permissible rate, so that the temperature can be kept below -40 ° C, with 6 - [- (a-Äthoxyphenäthyliden) -amino] - penicillanic acid 1,3,2-dioxaphospholan-2-yl ester is formed. After 2 1/2 hours of stirring at -40 ° C the temperature at -50 ⁰ C is lowered, and is added dropwise in 52.5 ml of water, to let go, without the temperature above -40 ° C, so that the hydrochloride salt of the 6 Aminopenicillanic acid 1,3,2-dioxaphospholan-2-yl ester is formed. After stirring overnight (about 18 hours) at -40 ° C, the flask is fitted with a dropping funnel containing 112 ml of dimethylaniline and a 250 ml Erlenmeyer flask containing 52.5 g of D (-) - phenylglycyl chloride- contains hydrochloride, is connected with a Gooch pipe.

About 1/6 of the acid chloride is added and dimethylaniline is slowly added dropwise. At this point the tempera-

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Safe...

ΑΗΡ-5753

door to -25 ° C. The two substances are added simultaneously so that all of the acid chloride is added over the course of 30 minutes and the dimethylaniline is added over the course of 40 minutes, with the aim of always having more acid chloride in the mixture than dimethylaniline. After another 40 minutes, the reaction mixture is almost clear, the hydrochloride salt of the D (-) - a-aminophenylacetamidopenicillanic acid 1,3,2-dioxaphospholan-2-yl ester is poured into 700 ml of water and the flask is rinsed with 100 ml of water , The hydrochloride salt of D (-) - a-aminobenzylpenicillin is formed. The aqueous mixture is stirred rapidly in an ice bath for 15 minutes. Super-Cell is added, the mixture is filtered and the cake is washed with 200 ml of water. After the layers have separated, the aqueous phase is placed in a 2 liter four-necked flask and 150 ml of ethyl acetate are added. The mixture is cooled to 0 to 10 ⁰ C, the pH is adjusted with 5N sodium hydroxide to 1.7, and outputs 105 ml of 37% naphthalenesulfonic acid over a period of about 10 minutes at 0 to 10 ° C added, the pH with 5N sodium hydroxide is held at 1.5 to 1.7. During the addition of the naphthalenesulfonic acid, a few seed crystals of the naphthalenesulfonic acid salt of D (-) - a-aminobenzylpenicillin are added and the flask is scratched in order to accelerate the crystallization. Stirring is continued for 6 hours at 0 to 10 ^° C., the naphthalenesulfonic acid salt of D (-) - oc-aminobenzylpenicillin is filtered off. It is stirred in 250 ml of cold water of pH 1.5 to 1.7 for 5 minutes and then filtered. The cake is squeezed out and sucked fairly dry and then stirred in 250 ml of ethyl acetate for 5 minutes. The slurry is filtered and the cake washed twice with ethyl acetate to give 109 g of naphthalenesulfonic acid salt of D (-) - a-aminobenzylpenicillin, non-volatile material ("NVM") = 54.5 % t corresponds to 53 % yield of naphthalenesulfonic acid salt of D (-) - a-aminobenzylpenicillin. This salt is prepared according to the standard described in U.S. Patent 3,487,073

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309829/1141

ft AHP-5753

Isopropanol process converted into the anhydrous ampicillin.

example

q-aminobenzyl penicillin

Following the procedure of Example 1, but using 31 ml (0.3 mol) of 2-chloro-1,3,2-dioxaphosphorinane and 45 ml of water, the naphthalenesulfonic acid salt of 6-α-aminobenzylpenieillin is isolated in 56 % yield.

example

Potassium penicillin G (75 g, 0.2 mol) and N, N-dimethylaniline (DMA) (53 ml, 0.418 mol) are stirred in 300 ml dichloromethane at 0 ⁰ C, and phosphorus trichloride (8.8 ml, 0.1 mol ) can be added in the course of 10 minutes. After stirring for a further 1/2 hour at 0 ° C., the temperature is lowered to -55 ° C. and powdered PCl ₅ (45 g, 0.216 mol) is added all at once. With continued cooling in an acetone / dry ice bath, the temperature rises to about -45 ° C and the mixture is stirred at -40 ° C for 2 hours. The temperature is again lowered to ⁰ C and -6O Priority 72j8 ml absolute alcohol 12.7 ml (0.1 mol) of DMA by weight with the maximum permissible speed so added that the temperature can be kept below -40 ⁰ C. . After 2 1/2 hours of stirring at -40 ⁰ C to -50 ° C, the temperature is lowered, and 45 ml of water are added dropwise, without allowing the temperature to about -40 ° C to go. The reaction is then continued and worked up as in Example 1, the naphthalenesulfonic acid salt of 6-α-aminobenzylpenicillin being obtained in 57% yield.

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23010U

The following example 4 Ms 8 illustrate specific ones the carboxyl group-protected penicillins and cephalosporins which are produced by the process according to the invention can.

- 20 -

309829/1 141

AHP-5753

Example 4

\ rn

H C — C — NH-

NH

• ^

HCl

CH ₃

^CH 3 R ¹

.1 .

where R, R, R, R + R and n mean the following:

OCH ₃
0-φ Ο-Ο ^ -φ

^OC 2 ^H 5

Cl OCH.

0-ψ Cl

0-ψ O-CH -φ

R = 0

= 0 2 R + R

Ό-

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309829/1141

AHP-3753

Example 5

HCl NH

! -NH-

, ^0H 3 ^RJ
3—0—]

wherein R ¹ , R, R ³ , R ¹ ^ -R and n are as follows:

Br
Cl
0-ψ
Cl

^O0 2 ^H 5

R.
Br

°° 2 ^Η 5

Cl

^ΟΟ 2 ^Η 5

O-CH ₂ - ((>

R = 0

= 0 rV

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AHF-5753 23010H

Example 6

H ₂ OCOCH.

where R, R, R, R + R and n mean the following:

R. R. R. Cl Cl = 0 OC ₂ H ₅ 0C ₀ H
2 5 = 0 Cl ο-φ = 0 Cl ^0O 2 ^H 5 Cl = 0 ο-φ ο-ό = 0

n_

1 1 O 1 1 O

- 23 309829 / 1U1

JIt

Example l

! -NH-

O = I

-N-

^X 3

ncH.

• 0—]

-R '

12 3 12
where R, R, R, R + R and n mean the following:

R ²

Cl

s ³

= 0

2

R H-R

OCH
0-φ
Cl

OCH,

OCH

= 0

OC ₀ H
0-CH ₉ - (J)

Cl

= 0

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AHP-5753

Example 8

OCHoQ-NH-1

ι 2 3 1 2 where R, R, R, R + R and n mean the following:

0-φ

R.
Cl

^OC 2 ^H 5
Cl

ο-φ ο-φ

Br

R = 0

= 0

2

R + R

= 0

OCOCH,

= 0

η_ 1

1 0 1 0 0 0

309829/1141

46 AHP-.5753

The following tables illustrate other representative compounds obtained by the method according to the invention can be.

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309829/1 1 4 1

TABLE I.

Source material

Phosphorylating link

Iminohalide derivative of the formula IV

Imino ether derivative
of Formula V

Hydrochloride salt of the 6-APA derivative of formula VI

O CO CO IO CO

IV)

2-pentenyl penicillin

n-heptylpenicillin

2-chloro-1,3,2-, dioxaphospholane

Diethylphosphorochloridate

3,5-diphenyl 4-isoxazolyl penicillin

Methylphosphoric dichloridite

6-C- (1-bromo-3-

hexenylijden) -amino J-

penicillanic acid

ί, 3,2-dioxaphospholan

2-yl ester

6 - [- (1-Chloro ctylidene) amino] -ρ eni cillanic acid monoanhydride with phosphoric acid diethyl ester

6- [chloro (3,5-diphenyl-4-isoxazolylmethylene) amino] penicillanic acid monoanhydride with monochlorophosphorous acid methyl ester

6 - [- (1-Phenoxy-3- 6-aminopenicillanhexenylidene) acid-1,3,2-dioxaamino j-penicillan-phospholan-2-ylic acid-1,3,2-dioxaester phospholan- »2-yl ester

6 - [- (1-Äthoxyoctyliden) -amino] -ρenicillanic anhydride with
Phosphoric acid diethyl ester

6 - [- (a-Ethoxy) -3,5-diphenyl-4-isoxazolylmethy-1en) -amino] -penicillanic acid monoanhydride with
Mono chlorophosphorous acid methyl ester

6-aminopenicillanic anhydride with Pho sphorsäurediethylester

6-aminopenicillanic acid monoanhydride with monochlorophosphorus acid methyl ester

τ

55 * -

VJl

TABLE I continued ;

I. Starting
material Pho.sporylating
link no
ω
I. Benzyl
penicillin Diethylpho spho r-
chloridite co
σ
co 829 / ct-phenoxy-
ethyl-
penicillin Phenylpho sphor-
dichloridate -F- • 2-ethoxy
naphthyl
penicillin 2-chloro-1,3,2-
dioxapho sphorinan Cephalothin Dibenzyl phosphorus
chloridate

Iminohalide iminoether derivative derivative of the formula IV of the formula V

6 - [- (α-Bromophenethylidene) amino] penicillanic acid monoanhydride with phosphoric acid diethyl ester

6 - [- (1-chloro-2-

phenoxypropylidene) -

amino] -penicillan-

acid monoanhydride

with monochlorophosphorus

phosphoric acid phenyl

6 - [- [chloro- (2-ethoxy
naphthyl) -methylene] -amino] -penicillanic acid e-1,3,2-dioxaphosphorinan-2-yl ester

7 [[l (
thienyl) -äthyli den] -cephalosporansäuremonoanhydrid with
Phosphoric acid dibenzyl ester

6 - [- (α-Benzyloxyphenethylidene) amino] penicillanic acid monoanhydride with phosphoric acid diethyl ester

6 - [- (1-Methoxy-2-phenoxypropylidene) amino] penicillanic acid monoanhydride with phenyl monochlorophosphorate

6 - [- (Ethoxy- (2-ethoxynaphthyl) methylene; -amino] -penicillanic acid 1,3,2-dioxaphosphorin-2-yl ester

7 - [- (Ethoxy-2- (2-thienyl) -ethylidene) -amino] -cepha-Io sporic acid monoanhydride with phosphoric acid dibenzyl ester

Hydrochloride salt of the 6-APA or 7-ACA derivative

6-aminopenicillanic acid monoanhydride with phosphoric acid diethyl ester

6-aminopenicillanic acid monoanhydride with monochloropho phenyl sulfate.

6-aminopenicillanic acid-1,3,2-dioxapho sphorinan-2-yl ester

7-Amino cephalo sporanic acid mono anhydride with phosphoric acid dibenzyl ester

TABLE II

Hydrochioridsalζ des 6-APA or 7-ACA derivatives

Acylating agent Acylated penicillin
or cephalosporin

Finished penicillin or cephalosporin

CJ O CO OO

^ f

6-aminopenicillanic acid 1,3,2-dioxaphospholan-2-yl ester

6-aminopenicillanic acid monoanhydride with phosphoric acid diethyl ester

β-aminopenicillanic acid monoanhydride with monophosphorous acid methyl ester

Benzenesulfonyl chloride

N-carbon xy anhydride of 2-amino-2-phenoxy-2-indanecarboxylic acid

Furan-2-carboxylic acid chloride • 6- (benzenesulphonamido) ^{-penicillansäure-1,3,2-1} -dioxapho spholan-2-yl ester

6- (2-amino-2-phenoxy-2-indan-carboxamido) -penicillanic acid monoanhydride with phosphoric acid diethyl ester

6- (2-furancarboxamido) penicillanic acid monoanhydride with monochlorophosphorous acid methyl ester

6- (Benzenesulfonamido) -penicillanic acid

6- (2-Amino-3-phenoxy-2-indancarboxamido) penicillanic acid

6- (2-furancarboxamido) penicillanic acid

6-aminopenicillanic acid e-mono anhydride with phosphoric acid diethyl ester

N-carboxyanhydride of 2-amino-2-phenoxy-2-indanecarboxylic acid β- (2-Amino-3-phenoxy-2-indane-carboxamido) -penicillanic acid monoanhydride with phosphoric acid diethyl ester

β- (2-Amino-3-phenoxy-2-indane-carboxamido) -penicillanic acid

TABLE II continued:

HydroChloride Salζ des
6-APA or 7-ACA derivatives

Acylating agents

Acylated penicillin or cephalosporin

Finished penicillin or cephalosporin

CD
CO
CO

6-aminopenicillanic acid mono anhydride d
with monochlorophosphoric acid phenyl
ester

6-aminopenicillanic acid-1,3,2-dioxapho spholan-2-ylester

N-carboxyanhydride of 1-aminocyclopentanecarboxylic acid

D (-) - Phenylglycylchl ο ri d- hydrochloride

6- (1-aminocyclopentane "carboxamido ) -p eni cillanic acid monoanhydride with monochlorophosphoric acid phenyl ester

6- (α-Aminophenylacetamido) -penicillanic acid-1,3,2-dioxaphospholan-2-yl-ester

6- (1-aminocyclopentane

carboxamido; -penicillan-

acid

6- (α-aminophenylacetamido) penicillanic acid

7- Aminocephalo sporanic acid inonoanhydride with phosphoric acid dibenzyl ester

N-carboxyanhydride of 1-aminocyclohexanecarboxylic acid 7- (1-aminocyclohexanecarboxamidoj-cephalosporanic acid monoanhydride with phosphoric acid dibenzyl ester

7- (1-Amino cyclohexane acetamido) cephalosporanic acid

Claims (17)

2381014 AHP-5753 PATENT CLAIMS: νΐ. Hydrohalide salt of a compound of the formulas: , CH ₃ LJ-O -BR ² (R ³ ), or CH ₂ R - 31 - 309829/1 141 AHP-5753 wherein R is hydrogen (lower) alkanoyloxy having 2 to 8 carbon atoms, Aryloxy or a quaternary ammonium radical; R ^ is oxygen (= 0);
η represents an integer from zero to 1; R and R (lower) alkoxy, (lower) alkylthio, aryl, aryloxy, arylthio, aryl (lower) alkyl, aryl (lower) alkylthio, halogen, lower alkyl, halo (lower) alkyl, halo - (Lower) alkyloxy, a radical of the formula III: 0 = , CH,
-CH, .N. (III) when the hydrohalogenide salt is a compound of the formula I, or a radical of the formula IV: (IV) CH ₂ R when the hydrohalide salt is a compound of the formula II, 1 2
mean and wherein R and R when linked together - 32 - 309829/1 UI 23010U * »AHP-5753 form the following rings with the phosphorus atom: CH ₂ - or R P- wherein X is oxygen, sulfur or methylene; R denotes hydrogen or (lower) alkyl and m denotes a is an integer from 1 to 6. 2. Hydrohalide salt of a compound of the formula: CH ₃ te YY- where R is hydrogen or lower alkyl and m is an integer from 1 to 6. 3. The compound of claim 2 which is the hydrochloride salt of 6-aminopenicillanic acid 1,3,2-dioxaphospholan-2-yl ester. 4. The compound of claim 2 which is the hydrochloride salt of 6-aminopenicillanic acid 1,3,2-dioxaphosphorinan-2-yl ester. 5. The compound of claim 1 which is the hydrochloride salt of 6-aminopenicillanic acid anhydride with dichlorophosphorus acid. - 33 - 309829/1141 3H AHP-5753 6. Process for the production of semi-synthetic penicillins or semi-synthetic cephalosporins, characterized in that that a hydrohalide salt of a compound of the formulas: or C = O 1 I 3
R ¹ -P- (R ³ ) k ² wherein R, R,, 4 R is the linked radicals R and R, R, X, η and in each have the same meaning as in claim 1 to have; with an acylating agent which is an organic carboxylic acid or a reactive derivative thereof acts, is reacted in the presence of an acid acceptor and then treated the resulting product with water becomes an acid addition salt of a compound of the formulas: 309829/1 TA 1 SS AHP-5753 Acyl H or acyl-Ä C-OH 0 = to manufacture. 7. The method according to claim 6, characterized in that the acid addition salt to be acylated is a Compound of the following formula is used: -o-pCL 8. The method according to claim 7, characterized in that the acylating agent DC-J-phenylglycyl chloride hydrochloride; 1-amino cyclohexanecarboxylic acid chloride hydrochloride; 3- (2,6-dichlorophenyl) -5-methyl-isoxazole-4-carboxyl chloride; 2-amino-2-carboxyindanoic acid chloride hydrochloride; 2-phenoxybutyryl chloride; 2-phenoxypropionyl chloride or 1-aminocyclopentanecarboxylic acid chloride hydrochloride is used. 9. Process for the preparation of the hydrohalide salt of ö-ta-aminophenylacetamidoJ-penicillanic acid, characterized in that that a hydrohalide salt of 6-aminopenicillanic acid-1,3,2-dioxaphospholan-2-yl ester with phenylglycyl chloride - 35 - 309829/1141 23010H # ΑΗΡ- 5753 hydrochloride is reacted in the presence of a tertiary amine and a non-aqueous solvent at a temperature of about 0 ° to -60 ⁰ C and the resulting product is treated with water to produce the hydrohalide salt of 6- (a-aminophenylacetamido) -penicillanic acid. 10. A process for the production of semi-synthetic penicillins or semi-synthetic cephalosporins, characterized in that that (a) a combination of the formulas: CH ₃ Rl5 -. , ol- i UC-OM or with a phosphorylating agent of the formula: R ¹ • ρ Halogen - P - R in the presence of an acid acceptor and an inert organic solvent at a temperature between about -40 ° - 36 3 0 9 8 2 9 / 1U1 AHP-5753. and about + 1O ⁰ C is reacted to obtain a compound of the formulas : -C-N or - O - P - R ² to. (b) (a) the compound obtained in the presence of an acid acceptor is reacted at a temperature below 0 ⁰ C, to form the corresponding iminohalide produce an acid halide in a stage; (c) the Iminohalogenidverbindung is reacted with an alcohol at a temperature below about -10 ⁰ C to the Iminohalogenidverbindung in the Hydrohalogenidsalζ the corresponding Iminoätherverbindung convert; (d) the imino ether compound by hydrolysis at a temperature below about -20 ° C to the hydrohalide salt of a compound of the formulas: - 37 - 309 8 29/1 14 1 AHP-5753 H ₂ N- CH ₃ • C ■ - O - R ^x PR ² 'η or H ₂ N- O = K ^ -CH ₂ R -f - (* ³ ) η
RS is converted; (e) a ^{compound formed in step (d 1} ) with an acylation agent, which is an organic carboxylic acid or a functional reactive derivative of such an acid, is reacted in the presence of an acid acceptor to achieve acylation of the amino group , and (f) the acylated compound is treated with enough water to give a compound of the following formulas: Acyl-N- O = -N- CH ο C-OH or acyl-1 O = ^ Λ N. ^ J-CH ₂ R C = O OH - 38 - 309829 / IUI ΑΗΡ-5753 in the form of the free base or as the corresponding acid addition salt - where there is a free amino group on the acyl radical - is obtained; , The symbols used in the above formulas have the following meanings:
M stands for hydrogen, an alkali metal or a tertiary 15th
R is a substituent found in natural or semi-synthetic penicillins; 16
'R is a substituent found in natural and semi-synthetic cephalosporins; 12 ^ i. 1 R, R, R, R, R, X, the linked radicals R and R, η and m have the same meaning as in claim 1 11. The method according to claim 10, characterized 15 16 net that the substituents R and R are occurring in natural penicillins and natural cephalosporins Substituents acts. 12. The method according to claim 11, characterized in that a compound of the phosphorylating agent following formulas: ρ — halo or (OH,)- c m Halo is used, where R and m are those mentioned in claim 1 Have meanings. 13. The method according to claim 12, characterized in that that the acyl radical is chosen from the radicals of the following formulas: - 39 - 309 8 29 / TU 1 IHP-5753 O-CH- C- NH ₂ O (CH ₂ ) b c— CH2) ^ y * ^H 2 (CH ₂ ^ t ~ J / Ii HC-.
HN C-Ν-C-NH HN-C ί — C — NH- L ² / ti η — g— NH, -HO- 309829/1 UI 23010H AHP-5753 ß 7
■ where R and R are hydrogen or (lower) alkoxy; R is hydrogen, (lower) alkyl or phenyl; R and R represent hydrogen or halogen; R ¹¹ and R ^{12 are} hydrogen, halogen, (lower) alkyl, (lower) alkoxy, phenyl or phenoxy; R ^{D is} hydrogen, (lower) alkyl or aryl; a is an integer from zero to 1; b is an integer from zero to 5; c. is an integer from zero to 2 and d is an integer from 1 to 3, but when a is zero, d is greater than 1 and when a is 1, d is less than 3. 14. Process for the production of semi-synthetic penicillins, characterized in that (a) a 'penicillin compound of the formula: O = ι ι » N 1— η - OM with a phosphorylating agent of the formula: CH -0- ^ P-HaIo is implemented, where a compound of the formula: UH ₂ ^ O (CH ₂ ), - 41 - 309829 / IUI 23Q10U AHP-5753 is formed and the reaction is carried out under anhydrous conditions in the presence of an organic solvent and an acid acceptor at a temperature in the range from about -40 ⁰ C to about +10 ⁰ C, the molar ratio of the penicillin compound to the phosphorylating agent about 0.5: 1 to is about 3: 1; (b) the compound obtained in step (a) is reacted with an acid chloride in the presence of an acid acceptor at a temperature between about -10 ⁰ C and -65 ⁰ C to produce a iminochloride compound of the formula: _R 15 "J ¹ CH ₃ to build; (c) the iminochloride is reacted with an alcohol at a temperature below about -10 ⁰ C- to form an imino ether of the formula: HCl ^CH 3 ^ O- A t-c - ο - to build; (d) reacting the imino ether with water at a temperature below about -20 ⁰ C and the resulting compound is treated with a reactive derivative of an organic carboxylic acid in the presence of an acid acceptor at a temperature between about 0 ⁰ C and -60 ⁰ C to a compound of the formula: - 42 309829/1 141 AHP-5753 Acyl III ^Y N -O- to build; and ie) the resulting acylated product is hydrolyzed to remove the group protecting the carboxyl group and obtain a semisynthetic penicillin; The symbols used in the above formulas have the following meanings: M represents hydrogen, an alkali metal or a tertiary area; * 1S
R is phenoxymethyl or benzyl; R represents hydrogen or lower alkyl; R ^a represents lower alkyl, hydroxy (lower) alkyl, phenyl (lower) alkyl, cycloalkyl, aryloxy (lower) alkyl, (lower) alkoxy (lower) alkyl; and m is an integer from 1 to 6. 15. The method according to claim 14, characterized in that that as a phosphorylating agent 2-chloro-1,3,2-dioxaphospholane or 2-chloro-1,3,2-dioxaphosphorinane is used. 16. The method according to claim 15, characterized in that that as acylating agent D (-) - Phenylglycylchloridhydrochlbrid is used 4 17. The method according to claim 11, characterized in that phosphorus trichloride is used as the phosphorylating agent will. 309829 / IUI