CA1040192A - Intermediates for producing semi-synthetic penicillins and methods of production - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Phosphorylated derivatives of 6-APA, 7-ACA, and 7-ADCA derivatives are described which are intermediates in the preparation of semi-synthetic penicillins and cephalosporins.
The compounds are prepared by the reaction of 6-APA, 7-ACA, 7-ADCA or a salt thereof with a phosphorus halide in the presence of an acid acceptor. The phosphorylated derivatives may be acylated to form phosphorylated acylated derivates which upon hydrolysis with water split off the protective group(s) to provide the corresponding semi-synthetic penicillin or cephalo-sporin having useful antibacterial activity.

Description

The present invention relates to phosphorylated 6-APA, 7-ACA, and 7-ADCA derivatives and the process for their produc-tion.
In a broad aspect, the present invention is concerned with the production of semi-synthetic penicillins and cephalo-sporins in high yields from compounds such as 6-amino penicillanic acid, 7-amino cephalosporanic acid, and 7-amino-3-desacetoxy cephalosporanic acid.

Copending application serial number 156,109 filed l97~
November 9, ~ thus discloses compounds having the following structure:

Acyl ~ - ~ ~ CH3 o~ I L C - o - ~ -R6 A

and Acyl ~ ~ ~ B

~ ~--~ CH2R4 1 ,~R5 O--C O--P~

wherein: Acyl is an organic acyl radical; R4 is a member selected from the class consisting of hydrogen, (lower)alkanoyloxy con-taining 2 to 8 carbon atoms, and a quaternary ammonium radical.
R and R6 are eaeh selected from the class eonsisting of (lower) alkyl, phenyl, phenyl(lower)alkyl, and naphthyl(lower)alkyl; and R5 and R6 may be joined together to form with phosphorus, the ring CH2)m --X or wherein X is selected from the class consistin~ of oxygen, methylene and sul~ur; m is an integer from 1 to 6; R7 is hydrogen or (lower)alkyl.
The preferred compounds of the invention of copending application number 156,109 are those having the following formulae: I/ S \ CH3 Acyl - N r ~H3 O ~ o--p\~
and Acyl ~J CH2R4 o=c-o-P,~l wherein: Acyl is as above; R is selected from the class con-sisting of hydrogen and acetoxy.
The term "(lower)alkyl`' as employed herein alone or in conjunction with other designated groups is intended to encompass straight chain or branch chain alkyl groups consisting of from one through six carbon atoms, e.g. methyl, ethyl, propvl, butyl, isobutyl, hexyl and 2-ethylpropyl. The term "phenyl(lower)alkyl"
is illustrated by benzyl, phenethyl, etc.
The term "(lower)alkanoyloxy" is illustrated by acetoxy, propionoyloxy and butanolyloxy. The term "quaternary ammonium"
is illustrated by pyridinium, quinolinium and picolinum. The term "tertiary amine" is illustrated by any of -the well-known radicals such as triethylamine, tribenzylamine, N-ethylpiperidine which are described in the penicillin and cephalosporin art as capable of forming an amine salt with the carboxyl group.

The acyl grou~ is derived from an organic carboxylic acid or a suitable functional reactive derivative thereof. The preferred acyl radicals are selected from groups having the following formulae:

R8 ~ 8 (CH2)a~

O -CH- C ---- ~ CH - C--Rll R12 --~(C~H ) ><(CH2) --C-- ~ C----R13~/ (CH2) a~

Rl ~1 ( C~l 2 ) d O \ ` --,~ (7H C
H C HN--C -N--C--NH

2 11 O IIH 2 ,~
CH - C --.. . . .

wherein: R3 is selected from the class consisting of hydrogen, (lower)alkyl and phenyl; R8 and R9 are selected from the group consisting of hydroyen and (lower)alkoxy; R10 is selected from the class consisting of hydrogen, (lower)alkyl and phenyl; Rll and R12 are selected from the class consisting of hydrogen and halogen; R13 and R14 are selected from the class consisting of hydrogen, halogen, (lower)alkyl, (lower)alkoxy, phenyl and phenoxy;
a is an integer from 0 to 1; _ is an integer from 0 through 5;
c is an integer from 0 through 2; d is an integer from 1 through

3, with the proviso that when a is 0, d is greater than 1, and when a is 1, d is less than 3.
The compounds of copending application number 156,109 are interemdiates in the preparation of semi-synthetic penicillins and cephalosporins which are produced by hydrolysis of these compounds.
The compounds of copending application number 156,109 are prepared by acylation of the corresponding phosphorylated 6-amino-penicillanic acids, 7-amino-cephalosporanic acids and 7-amino-3-desacetoxy cephalosporanic acids in the absence of an acid acceptor.
The present invention provides said corresponding phosphorylated compounds.
According to the present invention therefore, there is provided compounds selected from the group consisting of those having the following formula O - ~ - O-- P R

R ~ N. ..
O _1 ~ R5 O-- C --O ~ - R6 wherein: R4 is a member selec~ed from the class consisting of hydrogen, (lower)alkanoyloxy containing 2 to 8 carbon atoms, and a quaternary ammonium radical; R5 and R6 are each selected from the class consisting of (lower)alkyl, phenyl, naphthyl, phenyl(lower) alkyl and naphthyl(lower) alkyl; and R5 and R6 when joined together with the phosphorus atom form the ring;

(CH2)m \ R7` ~ ~ \

wherein: X is selected from the class consisting of oxygen, methylene and sulfur; m is an integer from 1 to 6; R7 is selected from the class consisting of hydrogen and (lower) alkyl.
The present invention also provides a process for the production oE the phosphorylated compounds oE the present invention which comprises reacting a compound of the formula:
/s~
H2N' I

~ ~L'CH2R4 o = C--oR2 or ~ / CH3 H N ~ ~ CH3 30O ~ C - oR2 -wherein R is selected from the class consistlng of hydrogen, alkali metal and tertiary amine; R4 is selected from the class consisting of hydrogen, (lower)alkanoyloxy containing 2 to 8 carbon atoms, and a quaternary ammonium radical; with a phosphorylating agent of the formula:

halogen IR ~6 wherein: R5 and R6 are each selected from the class consisting of (lower)alkyl, phenyl, naphthyl, phenyl(lower)alkyl and naphthyl(lower)alkyl; R5 and R6 when joined together with the phosphorus atom form the ring:

C~2 X ~J\

(CH2)m X /

X is selected from the class consisting of oxygen, methylene and sulfur; m is an integer from 1 to 6; and R7 is selected from the class consisting of hydrogen and (lower)alkyl the molar ratio of the phosphorylating agent to starting penicillin or cephalosporin being at least 1:1.
- In general, the semi-synthetic penicillins and cephalo-sporin~.may be prepared according to the following flow diagrams, using 6-APA and 7-ACA respectively, as illustrative starting materials.

z u~ l ~ o u~ ~ ~ ... I
=u ~r~ \/
~ ~ 0 \~ U O =l ) ~ ; ~
-~_______~_1 7 r ---1; H
H F~ ~ X O
__ H
l r~
X-~7 l ) I ~
~1 \ ~
~ ~ In I
S~ ~
~0 ~ O

O ~ ~~ 0=~
~ ~ r~

H r~ O >
a ~ H

r-l H I l O H 5~Z O
U~
r ;l O ~ r-l +

o ~ o El H

; O

` . .

;

2 1 ~ 1 ~ ~ I

o o ~ ~ ~

O ~ H

~--~; O H
u~ H iY--~D ,0 _ ~ ~ \ ~1 ~ <~

H
~Z; O
aJ ~q ~ a O H C~
~, ~ .
+ _ t .
~ . ~
0~ ~ ~ .
o~ b m x~

p~ X

Z o N ~--Z; O
m z In the foregoing process, and in particular in accordance with the process of the present invention the starting material e.g. 6-APA, 7-ACA or 7-ADCA which may be obtained by any number of procedures described in the art (2. g. see U.S. Patents 3,499,909 and 2,941,995) is reacted with a phosphorus halide of formula II in the presence of inert organic solvent and an acid acceptor to form a compound of formula III or VII respec-tively. This reaction is preferably carried out at a tempera-ture above -10C and not higher than about 25C. The molar ratio of an acid binding agent to a starting material such as 6-APA is about 0.75:2 and the molar ratio of acid binding agent to a compound of formula II is 1:1.
Suitable acid binding agents are tertiary amines such as triethyl amine, dimethylaniline, quinoline, pyridine, lutidine, alkali metal carbonates; alkaline earth carbonates or other acid binding agents known in the art. The preferred acid binding agent is a strong tertiary amine.As used herein "strong amines"
are those characterized by having dissociation constants in the range of from 10 3 to 10 6 or having comparable basicity, às distinguished from "weak amines" which are characterized by having dissociation constants in the range of from 10 8 to 10 11.
A wide range of anhydrous non-hydroxylic organic sol-vents are useful in the reaction of 6-APA or 7-ACA with a phosphorylating agentincluding hydrocarbons such as benzene and toluene; chlorinated solvents such as methylene chloride, chloroform and chlorobenzene; ethers such as diethyl ether, dioxane, tetrahydrofuran and other conventional solvents such as methylisobutylketone, dimethylformamide, ethyl acetate, acetoni-trile, etc.
The reaction between 6-APA, 7-ACA, or 7-ADCA and a phosphorus halide is carried out preferably at a temperature at which the reaction proceeds to completion in a reasonably short time period, i.e. between -10C and +10C.
A compound of formula III and VII prepared according to the present invention can be isolated by removing the hydro-halide base by filtration and distillation of the solvent, or if the intermediate is to be converted at once to a penicillin or caphalosporin, the reaction mixture can be acylated directly without filtration or concentration.
The prodcut or products obtained from the reaction of a compound of formula I or VI with a phosphorylating agent is dependent on the molar ratio of the reactants as to whether an anhydride of the penicillanic acid is formed. Thus, if the molar ratio of a compound of formula II to formula I is greater than 1:1, the predominant material obtained is a compound of formula III, particularly as the molar ratio increases to about 2:1 and higher. Where the molar ratio is 1:1 or less (e.g. 0.5:1)~ the predominant compound is 6 IR ~ ~ ~ CH

~ OH

with the amount of a compound of formula III becoming smaller as the molar ratio of a compound of formula II is decreased in re-lation to the amount of 6-APA.
The molar ratio of phosphorylating agent to the starting material such as a compound of formula I or VI to produce the compounds of the present invention is greater than 1:1, prefer-ably at least 2:1.
The fact that mixtures of phosphorylated compounds can be produced under certain reaction conditions does not interfere with the process of acylation and subsequent formation of the aesired semi-synthetic penicillin or cephalosporin.
The phosphorylated acylated compounds of formula A and B
may be prepared in accordance with copending application number 156,109 by the acylation of a compound of formula III or VII of the present invention in accordance with the reaction sequence shown above in diagrams A and B, respectively.
Suitable acylating agents include carboxylic acid halide5, carboxylic acid anhydrides, mixed anhydrides with other carboxylic or inorganic acids; esters such as thiol esters and phenol esters;
lactones; and carboxylic acids with carbodiimides or N,Nl-carboxyl-diimidazoles.
Illustrative of some specific preferred acylating a~ents are phenoxyacetyl chloride, 2,6-dimethoxybenzoyl chloride, benzene sulfonyl chloride, 2-phenoxypropionyl chloride, 2-phenoxy-butyl chloride, D(-)phenylglycyl chloride HCl, l-aminocyclopentane-carboxylic acid chloride HCl, l-aminocyclohexanecarboxylic acid chloride HCl, 2-amino-2-carboxyindane acid chloride HCl, 2-ethoxy naphthoyl bromide and 3-(2,6-dichlorophenyl)-5-methyl-isoxazole carbonyl chloride, etc.
In carrying out the acylation step, it has been sur-prisingly found that an acid acceptor need not be present during the reaction. Heretofore such a reagent was deemed essential for successfully carrying out the acylation procedure as illustrated by U.S. Patents 3,595,855; 3,249,622. In addition, where a strong amine is used in reacting a compound of formula I with a compound of formula II, it is desirable to avoid the presence of any excess strong amine because the strong amine has a deleterious effect on the yield of semi-synthetic penicillin produced. The acylation process is carried out in the presence of an inert anhydrous organic solvent. Suitable solvents may be the same as earlier exemplified for the reaction producing the phosphorylated deri vatives of 6-APA, 7-ACA, 7-ADCA, etc.
The acylated penicillins and cephalosporins of formulae IV and IX are readily hydrolyzed by treating with water, to split off the protective group from the amino group and the carboxyl group to form a semi-synthetic penicillin or cephalosporin embraced by formulae V and X, respectively.
The acylation of a compound of formula III or VII first results in the formation of an intermediate of formula IV(a) or VIII, respectively. These intermediates rapidly convert to a compound of formula IV and IX, respectively as a reuslt of expulsion of R6~ _ ~ _ halogen from the nitrogen atom. This expulsion is due to the presence of an anion (e.g. Cl-) upon formation of the intermediate of formula IV(a~ or VIII, respectively, which attacks the phosphorus atom linked to the nitrogen. It is possible that the presence of a weak base during the acylation would bind the anion and thereby avoid the expulsion of R ~ - halogen. In the latter case hydrolysis of a compound of formula IV(a) or VIII, respectively, would result in direct formation of a compound of formula V or X, rather than intermediate IV or IX.
The hydrolysis is carried out at a pH between 0.5 and 2 at a tempearture below about 15, preferably between 0 and 5C.
The hydrolysis is carried out by treatment with water.
Where the acylating agent used is in the form of an acid addition salt, the penicillin or cephalosporin of formula V
or X is recovered upon hydrolysis as an acid addition salt (e.g.
chloride) which may then be converted to the free base by methods well known in the art. In the event the ultimate penicillin to be obtained is ~-aminobenzyl penicillin (ampicillin), it has been "3~
found advantageous to change the chloride to an aryl sulfonic aci~ salt o~ the aminopenicillin either by adding an appropriate sulfonic acid to the reaction mixture comprising the selected organic solvent and water, or to the aqueous extrac~s separated as described immediately above. In this connection, a 25~
excess of the sulonic acid has been used to advantage in pre-paring the corresponding salt of ampicillin.
The aryl sulfonic salt of the ~-aminobenzyl penicillin may then be converted to the penicillin per se by reaction with a base such as triethylamine or diethylamine in approximately 85%
isopropanol. In the case of ampicillin specifically, the sulfonic acid salt, wet with water and ethyl acetate, may be added to isopropanol containing a molar equivalent of triethylamine at 75-80C whereby the anhydrous form of ampicillin described and claimed in U.S. Patent 3,144,445 is formed and collected by fil-tration from the hot mixture.
Alternatively, the corresponding penicillin may be obtained, but in hydrated form, by raising the pH of the aqueous reaction mixture containing the hydrochloride salt of said penicillin to the iso-electric point.
The starting materials defined by formula II may be prepared by procedures described in the literature. For example, the preparation of 2-chloro-1,3,2-dioxaphospholane is described by Lucas et al, J. Am. Chem. Soc. 72, 5491-5497 (1950). Other compounds within the scope of formula II may be prepared by the procedures described by srown et al, J. Chem Soc. 878-881 (1970).
The following exmples are given by way of illustration and are not to be construed as limitations of this invention.

Example 1 D(~ aminobenzylpenicillin 6-Aminopenicillanic acid (10.81 g, 0.05 mole) is stirred for 1/2 hr. in 100 ml. of dichloromethane at 0-5C
containing 13.85 ml. of triethylamine. At 0-5C, a solution of 12.65 g 10.1 mole) of 2-chloro-1,3,2-dioxphospholane in 50 ml. of dichloromethane is added over 1 hr., and the mixture is stirred an additional 1/2 hr. at 0-5C. The resulting product is 6-(1,3,2-dioxaphospholane-2-yl amino)penicillanic acid, 1,3,2-dioxaphospholan-2-yl ester. D-(-)phenylglycyl chloride hydrochloride (10.63 g., 0.05 mole) is added to the stirred mixture over 2 min., and stirring is continued for 1/2 hr. at 0-5C under nitrogen. The cooling bath is removed and the temperature is allowed to go to 17C and held at this temperature for a total acylation time of 3 hr. The resulting acylated product is 6-(2-amino-2-phenylacetamido)-penicillanic acid, 1,3,2-dioxaphospholan-2-yl ester. The mixture is poured into 300 ml. of water at 0-5C and stirred for 15 min., with the pH
going to 0.7. Celite is added, the mixture is filtered, and the fi~trate is separated and the water layer (340 ml.) is bioassayed vis. S. Lutea. The addition of 5 ml. of this solution to 2a5 ml. of 1~ pH 6 buffer gives an assay value of 700 r/ml. of ampicillin.
The ~-naphthalene sulfonic acid salt is prepared from the 340 ml. of solution by adding ethyl acetate (40 ml.) and cooling to 0-1-C followed by addition of 29.4 g of a 37.68%
solution of ~-naphthalene sulfonic acid over 10 min. and holding the pH at 1.5 to 1.7 with the addition of 5N sodium hydroxide.
This mixture is stirred overnight at 5~ (filtered, stirred in 60 ml. of ~k `~

ethyl acetate for 5 min., filtered and sucked dry, giving 27.3 g.
the ~-naphthalene sulfonic acid salt of D(-)~-aminobenzylpenicillin.
It was bioassayed vsO S. Lutea presence of 560 y/mg. of ampicillin.

10, .

Example 2 l-aminocyclohexane penicillin 6-Aminopenicillanic acid (43.25 gO, 0.7 mole) is stirred in dichloromethane (400 ml.) containing triethylamine (55.6 ml., 0.4 mole) at room temperature until solution is complete. The temperature is lowered to 0-5C, and 50.6 g. (0.4 mole) 2-chloro-1,3~2-dioxophospholane in 200 ml. of dichloromethane is added over 1 hr., and stirring is continued at 0-5C for 1/2 hr.
l-aminocyclohexanecarboxylic acid chloride hydrochloride (40 g., 0.2 mole) is added, and the mixture is stirred while the internal temperature is allowed to slowly go to 10C over 1/2 hr., and the reaction is continued for an additional 2 1/2 hr. at 10C. The mixture is poured into 200 ml. of cold (0-5C) water and the mixture is stirred in an ice bath for 15 min. Isopropanol (160 ml.) and celite (15 g.) are added, the mixture is filtered by suction, and the cake is washed with 40 ml. of isopropanol.
The two-phase filtrate is poured into a 2 liter round bottom 3-neck flask, and while stirring at 15-20C, the pH is raised to 5.4-5.5 with 5N NaOH, giving white crystals of dihydrate of the above titled compound.
Example 3 D(-)-~-aminobenzylpenicillin 6-Aminopenicillanic acid (43.25 g., 0.2 mole) is stirred in dichloromethane (400 ml.) containing triethylamine (55.6 ml., 0.4 mole) at room temperature until solution is complete. The temperature is lowered to 0-5C, and 50.6 g.
(0.4 mole) 2-chloro-1,3,2-dioxophospholane in 200 ml. of di-chloromethane is added over 1 hr., and continue to stir at 0-5C
for 1/2 hr. D(-)phenylglycyl chloride hydrochloride (43.6 g., 0.2 mole) is added over about 1 min., and the mixture is stirred at 0-5C for 3/4 hr. The ice bath is lowered so that only the lower 1-2 cm. of the flask is in the ice water, and the internal temperature is allowed to slowly (about 25 min.) go to 10C, and then held at this point fo~ a total temperature raising time and reaction time of 2 hr. The mixture is poured into 800 ml.
of room temperature water, and the flask is rinsed with 200 ml.
of water. The mixture is stirred with the vessel in an ice bath for 15 min., Super Cel (a trademark) is added, the mixture is filtered by suction, and the cake is washed with 200 ml. water.
The layers are separated, and the aqueous phase is placed in a 2 liter round bottom flask containing 200 ml. ethyl acetate. The internal temperature is lowered to 0-10C and the pH is adjusted to 2 by the addition of 5N sodium hydroxide. Then 100 ml. of a 37.7~ ~-naphthalene sulfonic acid solution is added in about 10 minutes while keeping the pH at 1.5 to 1.7 with 5N NaOE. After stirring 6 hr. at 0-5C, and no stirring for 12 hr., the mixture is filtered, and the cake is washed with about 100 ml. of cold pH 2 water. After sucking as dry as possible the cake is stirred in 250 ml. of ethyl acetate for 5 minutes, the mixture is filtered, and the cake is washed with 2 x 50 ml. ethyl acetate, giving 137 g. of the above titled product. A portion of the sample is dried indicating 53.5% NVM with a corresponding yield of 66%, but bioassay vs. S. Lutea indicates 380 ~/mg. with a corresponding yield of 75%. This material is converted to anhydrous ampicillin in 80% yield by the standard isopropanol/triethylamine procedure as described in U.S. Patent 3,487,073.
Example 4 D(~ -aminobenzylcephalosporin In a manner similar to the process for preparation of ampicillin in Example 1, but using 7-amino-cephalosporanic acid (54.6 g., 0.2 mole) instead of 6-aminopenicillanic acid, D(-)-~-aminobenzylcephalosporin is isolated by adjusting the pH of the aqueous phase, obtained after filtration, to about 5.75.

Example 5 naphtha1ene sulfonic acid salt of D(~ -aminobenzylpeni _llin 6-Aminopenicillanic acid (21.7 g., 0.1 mole) is stirred in dichloromethane (200 ml.) at 0-5C, and 14.0 ml. (0.1 mole) of triethylamine is added, and the mixture is stirred for 1/2 hr.
At 0-5C, a solution is aripped in of 2-chloro-1,3,2-dioxophos-pholane (12.7 g., 0.1 mole) in dichloromethane (100 ml.) over a 1 hr. period and stirring is continued at 0-5C for 1/2 hr.
D-(-)-phenylglycyl chloride hydrochloride (21.3 g., 0.1 mole) is added all at once and the mixture is stirred at 0-5C for 30 min.
The ice bath is lowered so that only the lower 1-2 cm. of the flask is in the ice water, and the internal temperature is allowed to slowly go to 10C over about 2 hr., and the mixture is poured into 450 ml. of room temperature water, and the flask is rinsed with 60 ml. of water. The mixture is stirred with the vessel in an ice bath for 15 min., Super Cell (a trademark) is added, the mixture is filtered by suction, and the cake is washed with 100 ml. of water. The layers are separated, and the aqueous phase is placed in a 1 liter round bottom flask containing 100 ml. of ethylacetate. The internal temperature is lowered to 0-10C and the pH is raised to 2 by the addition of 5N NaOh. Then 60 g. of a 37~ ~-naphthalene sulfonic acid solution is added within 5 to 10 min. while keeping the pH at 1.5 to 1.7 with 5N NaOh. After stirring overnight at 0-5C the mixture is filtered, and the cake is washed with cold pH2 water (30ml.). After sucking as dry as possible the cake is stirred in 125 ml. of ethyl acetate for 5 min., the mixture is filtered, and the cake washed twice with ethyl acetate, giving 38.2 g. of the ~-naphthalene sulfonic acid salt of D(-)-~-aminobenzylpenicillin. A portion of the sample is dried indicating the presence of 6.36 g. of NVM, with a corres-ponding 44~ yield of the above titled product.

~4~ Z
Example 6 Following the procedure of Example 1, a series of phosphorylated penicillin compounds are prepared by reacting 2 moles of a phosphorylating agent of formula C with one mole of 6-APA to produce a compound of formula D.

.~ R

C o I ~ I c_ O _ P - R6 .. .
R5 R6 X _5r R6, (a) C~3 CH3 Cl CH3 C-H3 (b) ~ ~ Cl (c) CH2~ CH2~ Br CH2~ CH

L> Cl ¦ ~ = S>

(e ) C2H5 C2H5 Cl 1 C2H5 C2H5 ~ Cl ~ ~

! ICH \ Cl ~ CH

_ . . ... 1. . . . ~ i ~ 18 -'.'~ ~

z Example 7 Following the procedure of Example 4, a series of phosphorylated penicillin compounds are prepared by reacting 2 moles of a phosphorylating agent of formula C with one mole of 7-ACA or 7-ADCA to produce a compound of formula E.

.. ..... .. . .. .. ... _ . ........ ... .. , .. _ _ _ . .. _ . _ _ _, _ _ _ _ 6 ~5 75 S

R _ _ p _ x = ~N ~H2R
o= c -~ o- P---R6 ~ C E

.. _ _____ . _ .... . . . .. .. . _. . . _ . ..... ... _ _5, R , X R2 R5 _6, X
(a) CH3 CH3 Cl H CH3CH3 Cl [__~O ~ Br ~ H r O

(C) 0 ~ F H 0 ~ F ¦(d) CH2~ CH20 Cl O CH2~ C~12~ Cl ~ '(e) ~-- -O ~ Cl 0~ L_~o o Cl I

~. o, -,,~ - 19 -z Example 8 Following the procedure of Example 1, a series of phosphorylated penicillin compounds are prepared by reacting 0.5 mole of a phosphorylating agent of formula C with one mole of 6-APA to produce a compound of formula F.

~ p - X R6~ 3 . ._ (a) CH3 CH3 Cl CH3 CH3 (b) ~ ~ Cl (c)CH2~ CH2~ Br CH2~ CH

(d)~ S Cl ~ S/

( )2 5 C2H5 Cl C2H5 C2H5 (f)~ / ~ Cl ~ O \

_ __ ....

Example 9 Following the procedure of Example 4 a series of phosphorylated cephalosporin compounds are prepared by re~cting 0.5 mole of a phosphorylating agent of formula C with one mole of 7-ACA or 7-ADCA to produce a compound of formula G.

C G O=C- OH

R5 R6 X ~2 R5 R6 (a) CH3 CH3 Cl H CH3 CH3 (b) ~ O\ Br H C \

(c) ~ ~ F H
(d) CH2~ CH2~ Cl ~ 2~ 2 . _ O CH3 , Example 10 Following the procedure of ~xamp]e 1, the following ac~lating agents are used in place of D (-) phenyl glycine chloride hydrochloride to obtain the following acylated phosphorylated penicillin derivatives. Those having an amino group are obtained as the hydrochloride salt.

. .

R - ~ ~ C~3 acylating agent R

hydrochloride salt of l-aminocyclo- ~ ~ _ pentane carboxylic acid chloride hydrochloride salt of l-aminocyclo-2-hexene-l-carboxylic acid chloride hydrochloride salt of l-amino-1-indane carboxylic acid chloride ~ ~

hydrochloride salt of l-amino-1,2,3,4- r ~ _ C -tetrahydronaphthoic acid chloride ~

~\~
hydrochloride salt of l-amino-7-ethoxy- ~ ~ 2 -1,2,3,4,-tetrahydro-1-naphthoic acid chloride / <

hydrochloride salt of 2-amino-2-indane- ~ NH
carboxylic acid chloride Example 10 (continued~
acylating agent R

hydrochloride salt of 2-amino~
phenoxy-2-indane carboxylic acid ~ i chlorlde hydrochloride salt of l-amino-1,2,3,4- ~ ~ C _ tetrahydro-3,6-dimethyl-1-naphthoic acid chloride hydrochloride salt of 1-amino-3- 3 1 -- ~ 7H C
cyclopentene-l-carboxylic acid ¦ ~ .
chloride f 3-(phenyl)-5-methyl-4-isoxazole- ~
carbonyl chloride \=~

3-(2',6'-dichlorophenyl)-5-methyl- ~

4-isoxazole-carbonyl chloride Cl ~ ~ - -2,6-dimethoxy-benzoic acid chloride $ C --2-ethoxy-1-naphthoyl chloride ~

~-phenoxy butyric acid chloride CH ~ o - CH C -lH2 ~`~

Example 11 Following the procedure of Example 4, the acylating agents identified below are used to obtain the following acylated phosphorylated cephalosporins. Those having the amino group are obtained as the hydrochloride salt.

. .. .~

R ~

acylating agent \ O--. . . I - R2 D(-)phenyl glycine chloride, ~/ ~ ~ CH C H
hydrochloride \

20 ~2-thi nylacetic acid chloride ~ N

D(-)phenyl glycine chloride, fi~ O-C-CH
hydrochloride ~ ~ fH-C ~ 3 phenoxyacetic acid chloride ~ _ ~ O~CH2-C~ O-C-CH3 . .

It is to be understood that the only lim~tation on the acyl radical of the synthetic penicillins and cephalosporins is that they be essentially non-toxic upon in vitro or in vivo application.
The synthetic penicillins and cephalosporins prepared from the intermediates of the present invention have activity against gram positive and/or gram negative bacteria and may be utilized in pharmacological compositions in association with pharmacologically acceptable carrier, e.g. in suitable injectable forms, including solutions and suspensions; or orally as tablets, capsules, and the like, utilizing conventional solvents, suspen-soids, excipients, and the like. These compounds may be admin-istered orally or parenterally. Naturally, the dosage of these compounds will vary somewhat with the form of administration and the particular compound chosen. Further, it will vary with the particular subject under treatment.

Supplementary Disclosure The 6-(1,3,2-dioxaphospholan-2-yl amino) penicillanic acid 1,3,2-dioxaphospholan-2-yl ester produced in Example 1 displayed the following physical characteristics: IR 5.57 (~-lactam), 5.74 (CO2P ), 10.15 P-O-C); NMR (CDC13) S 1.38 (d,6, CH3CH), 1.56 (S,3,CH3), 1.6 (S,3,CH3), 3.22-5.32 (m,9, remaining protons except 6-CH), 5.4 (d,1,6-CH).
The phosphorylated penicillin compound (b) in the Table of Example 6 had the following physical characteristics:
10 IR 5.56 (~-lactam), 5.71 (C02P ); NMR (CDC13) ~.15 (broad singlet, 6,CH3-C-CH3), 4.15-6.25 (m,4,remaining protons except aromatic), 7.35 (m,20,aromatic).
The phosphorylated penicillin compound (b) in the Table of Example 7 had the following physical characteristics:
IR (film) 5.60 u (C--O), 5.85 (C=0); NMR (CDC13) ~ 1.10-1.67 (m,CH3CH), 2.17 (S, CH3), 2.8-5.33 (m,remaining protons).
The phosphorylated penicillin compound (e) had the following characteristics: IR (film) 5.59 u (C=O), 5.75 (C=O);
NMR (CDC13) ~ 1.1-1.67 (m,CH3CH); 2.05 (S,CH3CO); 3.3~5.4 (m, remaining protons).

~ r 26 -

Claims (16)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method for the production of a compound selected from the group consisting of those having the following formula wherein: R4 is a member selected from the class consisting of hydrogen, (lower) alkanoyloxy containing 2 to 8 carbon atoms and a quaternary ammonium radical; R5 and R6 are each selected from the class consisting of (lower)alkyl, phenyl, naphthyl, phenyl(lower) alkyl and naphthyl(lower) alkyl; and R5 and R6 when joined together with the phosphorus atom form the ring:

or wherein: X is selected from the class consisting of oxygen, methylene and sulfur; m is an integer from 1 to 6; R7 is selected from the class consisting of hydrogen and (lower) alkyl which comprises reacting a compound of the formula:
wherein R2 is selected from the class consisting of hydrogen, alkali metal and tertiary amine; R4 is selected from the class consisting of hydrogen, (lower)alkanoyloxy containing 2 to 8 carbon atoms, and a quaternary ammonium radical; with a phos-phorylating agent of the formula:

wherein: R5 and R6 are each selected from the class consisting of (lower)alkyl, phenyl, naphthyl, phenyl(lower)alkyl and naphthyl(lower)alkyl; R5 and R6 when joined together with the phosphorus atom form the ring:

or X is selected from the class consisting of oxygen, methylene and sulfur; m is an integer from 1 to 6, and R7 is selected from the class consisting of hydrogen and (lower)alkyl, the molar ratio of the phosphorylating agent to starting penicillin or cephalosporin being at least 1:1.

2. A compound selected from the group consisting of those having the following formula wherein: R4 is a member selected from the class consisting of hydrogen, (lower) alkanoyloxy containing 2 to 8 carbon atoms, and a quaternary ammonium radical; R5 and R6 are each selected from the class consisting of (lower)alkyl, phenyl, naphthyl, phenyl(lower) alkyl and naphthyl(lower) alkyl; and R5 and R6 when joined together with the phosphorus atom form the ring:

or wherein: X is selected from the class consisting of oxygen, methylene and sulfur; m is an integer from 1 to 6; R7 is selected from the class consisting of hydrogen and (lower) alkyl.
when prepared by the process as claimed in claim 1 or an obvious chemical equivalent thereof.

3. A process as claimed in claim 1, in which the reactant compound has the formula wherein R2 is as in claim 1.

4. A compound having the formula:

wherein: R5 and R6 are selected from the class consisting of (lower)alkyl, phenyl, naphthyl phenyl(lower)alkyl and naphthyl (lower)alkyl; and R5 and R6 when joined together with phosphorous form the ring ; or wherein: X is selected from the class consisting of oxygen, CH2 and sulfur; R7 is selected from the class consisting of hydrogen and (lower) alkyl; and m is an integer from 1 to 6 when prepared by the process as claimed in claim 3 or an obvious chemical equivalent thereof.

CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE

5. A process as claimed in claim 3, in which in the reactants R5 and R6 are formed together to form said ring with said phosphorus atom and wherein X is oxygen and m is 1.

6. A compound according to claim 4, wherein R5 and R6 are joined together to form said ring with said phosphorus atom and wherein X is oxygen and m is 1 when prepared by the process as claimed in claim 5 or an obvious chemical equivalent thereof.

7. A process as claimed in claim 3, in which in the reactants R5 and R6 together with the phosphorus atom forms the group

8. A compound which is:

when prepared by the process as claimed in claim 7 or an obvious chemical equivalent thereof.

9. A method as claimed in claim 1, which comprises reacting a compound of the formula:

wherein R2 is selected from the class consisting of hydrogen, alkali metal and tertiary amine, R4 is selected from the class consisting of hydrogen, (lower)alkanoyloxy containing 2 to 8 carbon atoms, and a quaternary ammonium radical; with a phosphory-lating agent of the formula:

wherein: R5 and R6 are each selected from the class consisting of (lower)alkyl, phenyl, naphthyl, phenyl(lower)alkyl and naphthyl(lower)alkyl; R5 and R6 when joined together with the phosphorus atom form the ring:

; or X is selected from the class consisting of oxygen, methylene and sulfur; m is an integer from 1 to 6; and R7 is selected from the class consisting of hydrogen and (lower)alkyl.

10. A compound of the formula:

wherein: R4 is selected from the class consisting of hydrogen, (lower)alkanoyloxy containing 2 to 8 carbon atoms, and a quaternary ammonium radical; R5 and R6 are selected from the class consisting of (lower)alkyl, phenyl, naphthyl, phenyl(lower alkyl) and naphthyl(lower) alkyl; and R5 and R6 when joined together with the phosphorus atom form the ring ; or R7 is selected from the class consisting of hydrogen and (lower)-alkyl; m is an integer from 1 to 6; and X is selected from the class consisting of oxygen, methylene and sulfur when prepared by the process as claimed in claim 9 or an obvious chemical equivalent thereof.

11. A process according to claim 9, wherein R5 and R6 are joined together with the phosphorus atom to form the ring:

wherein X is oxygen and m is one.

12. A process as claimed in claim 11, in which R4 is hydrogen.

13. A process as claimed in claim 11, in which R4 is acetoxy.

14. A compound which is:

when prepared by the process as claimed in claim 13 or an obvious chemical equivalent thereof.

15. A compound which is:

when prepared by the process as claimed in claim 12 or an obvious chemical equivalent thereof.

16. A process according to claim 9, which comprises reacting a cephalosporin selected from the class consisting of 7-amino-cephalosporanic acid and 7-amino-3-desacetoxy cephalospor-anic acid under anhydrous conditions and in the presence of an acid binding agent with a 2-halo-1,3,2-dioxaphospholane or a lower alkyl substituted derivative thereof at a temperature between about -10°C and +25°C, the molar ratio of said 2-halo-1,3,2-dioxaphospholane or lower alkyl derivative thereto to said cephalosporin being at least 1:1.