CA1041996A - Process for producing penicillins and cephalosporins - Google Patents

Abstract

Title of Invention:
A PROCESS FOR PRODUCING ANTIBIOTIC SUBSTANCE

ABSTRACT OF THE DISCLOSURE

Penicillins and cephalosporins are prepared, with advantages from industrial viewpoint, by reacting 6-aminopenicillanic acid or 7-aminocephalosporanic acids with three valency phosphorus compounds to form a protecting group, then reacting the above-obtained product with the reactive deriva-tives of carboxylic acid, and then solvolyzing the product to remove the protective group to form penicillins and cephalosporins, respectively.

Description

104~9~
This invention relates to an improved process for pro-ducing an antibiotic substance, and more particularly to a novel process for producing penicillins and cephalosporins.
The compounds to be produced by the process of this invention are shown by the following general formula (I), R - (C)n - CONH ~ S~y (I) COOH
wherein Y signifies C CcH3 or CH2 ~ --C}12R
R signifies a hydrogen atom, halogen atom, azido, acyloxy, alkoxy, aryloxy or S-R' group (R' signifies an alkyl, aryl or heterocyclic group) each of Rl and R2 signifies a hydrogen atom or a substituted or unsubstituted alkyl, aryl, aralkyl, arylo::y, cycloalkane or heterocyclic group, or Rl and R may jointly form a ring, R3 signifies a hydrogen atom, halogen atom, hydroxyl, am ~ alkylamino, azid'o, cyano alkyloxy, alkylthio, ; ~ .

aryloxycarbonyl, aralkyloxycarbonyl or alkoxycarbonyl group, and ~:
n signifies numeral 0 or 1.

The compounds shown by Y being~ C -CH3 f those of the above general formula (I) are penicillins of the following formula (I-l), .

R - (C)n - CONH J ~ S ~, ( I-l) wherein the symbols are the same as mentioned above.
These penicillins such as, for example ~-phenoxyethyl-penicillin, ~-phenoxypropylpenicillin, methylphenylisoxazolyl-penicillin, methylchlorophenylisoxazolylpenicillin~ methyl~i-iI` ~

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ci~loro~h~nylis-~x~olfll~nicillin,~-amil~obenzyl~enicillin~ ~-amino-~-(L~-hydr~xyBcnzyl)penicillin, ~-carboxylbcnzylpenicillin,

2,6-dir.lethoxyph~n~lpenicillin, aminocyclohexylpenicillin, etc., show strong antibacterial properties against Gram-positive bac- i terias and Gram-negative bacterias, and are extremely superior as a medicine against the diseases of the human being and animal.
The compounds shown by Y being -CH2 ~ ~CH2R

of those of the above general formula (I) are cephalosporins of 1.0 ', the following formula ( I-2 ), I

R - (C) - CONH ~S ~ (I-2) R O'--N ~/LCH2R
COOEI -whe~ein the symbols are the same as mentioned above.
~ These cephalosporins such as, for example, 7-(2-thienyl-acetamido)-3-acetoxymethyl- 3-cephem-4-carboxylic acid, 7-(~.-aminophenyl~c~tamido)-3-acetoxymethyl-3-cephem-4-car-boxylic acid, 7-(~-aminophenylacetamido)-3-methyl-3-cephem-4-carboxylic acid, 7-(-aminophenylacetamido)-3-methoxymethyl-3-_O
cephem-4-carboxylic acid, 7-(a-aminophenylacetamido)-3-methyl-thior.lcthyl-3-cephem-4-carboxylic acid, 7-[1-(1H)-tetrazolylace-tamido]-3-[2-(5:methyl-1,3,4-thiadiazolyl)-thiomethyl]-3-cephem-4-carboxylic acid, 7-[-amino-p-hydroxyphenyl)-acetamido]-3-methyl-3-cephem-4-carboxylic acid, etc., show strong antibac-terial properties against Gram-positive and Gram-negative bacterias, and are extremely superior as a medicine against the diseases of the human being and animal.
}leretofore, it is known that there are processes for preparing these penicillins or cephalosporins such as, for ~0 exar~lple, Schotten Baumann process which dissolves alkali metal salt of 6-aminopenicillanic acid or 7-aminocephalosporanic I,l ~
.

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acids of the formula (II), H2N I ~S ~ (II) ~ ~COOH s wherein the symbol is the same as mentioned above, into water, and reacts acid halides therewith, or a process which dlssolves trialkylamine salt of the general formula (II) into an organic solvent, and reacts the reactive derivatives of carboxylic acid in the presence of acid-binding agent.
However, in the former method, since the reaction is generally carried out under alkaline conditions, the cleavage of unstable ~-lactam ring in a molecule of the compound of the formula (II) is incorporated so that the purity of the resultant compound of the formula (I) becomes extremely bad and its yield is also low. In the latter method, despite the reaction is carried out in non-aqueous solvent and is homogeneous, its yield is low and the cleavage of ~-lactam ring is incorporated, and accordingly complicated steps are necessary for the separation and refining of the resultant objective product, and it is very difficult to perform these methods from an industrial viewpoint.
Then, there was found out a method for obtaining the compound of the formula (I) by dissolving the compound of the formula (II) into non-aqueous solvent with other method without using trialkylamine salt and by acylating so as to prevent the cleavage of ~-lactam ring of the compound of the formula (II) in a good yield. Several reports have, heretofore, been published concerning this method. There have been reported a process for protecting carboxylic group of 6-aminopenicillanic acid with trialkylsilyl group [Ann. 673, 166-170(1964)]; a process for protecting carboxylic group and amino group of 6-aminopenicil-lanic acid together with trialkylsilyl group [Japanese Patent Publication No. 4064/65, and No. 8353/65, Belg. Patent No.

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615344(1962), ~.S. Patent No. 3, 249,622(1966)]; and a process for protectinq 7-aminocephalosporanic acids with trialkylsilyl group [British Patent No. 1,073,530(1967) and C.A. 68,12984].
According to these processes, the compound of the formula (II) protected by the trialkylsilyl group has good solubility against various solvents, and the removal of the protecting group after the acylation is very easy and the yield of the objective product is also excellent.
However, these conventional processes known per se require to react with excessive trialkylsilylchloride, N-tri-methylsilyldiethylamine, hexamethyldisilazane, etc., in the state of cooperative solvent at a temperature of 60 to 90C.
or above for long time against the compound of the formula (II) in order to prepare trialkylsilyl derivatives of the compound of the formula (II), and the yield of the product is low, and yet the compound of the formula (II) is decomposed by heating with the result that these processes are nothing but dangerous process from the industrial viewpoint.
Furthermore, the method for protecting the carboxylic group of 6-aminopenicillanic acid with dihalogenosilane deriva-tives was published [~est Germany Patent Disclosure No.
1,923,642(1969)].
However, since the method does not always give a satisfied yield and also the handling of the dihalogenosilane derivatives is troublesome because of its skin-toxity, it is disadvantageous from a industiral viewpoint.
As a result of a number of researches on the pro-tecting group which enables the compound of the formula (II) to be dissolved readily into non-aqueous solvent, and which is easy to prepare and yet readily for the acylation and removal of the protecting group thereafter, the present inventors have found out that the protecting groups which are easily prepared I`

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by reacting the compound of the formula (II) with the three valency phosphorus compounds of the general formula (III), RS > P - X (III) wherein R signifies an alkyl, haloalkyl, aryl, aralkyl, alkyl-oxy, haloalkyloxy, aryloxy, aralkyloxy or dialkylamino group, R5 signifies an alkyl, haloalkyl, aryl, aralkyl, alkyloxy, aryloxy, haloalkyloxy, aralkyloxy, dialkylamino group or halogen atom, or R and R5 may jointly form a ring, X signifies a halogen atom, is an extremely superior protecting group.
It is, therefore, an object of this invention to provide an improved process for producing penicillins and cephalosporins.
It is, another object of this invention to provide a process for the acylation of 6-aminopenicillanic acid or 7-aminocephalosporanic acids to produce penicillins and cephal-osporins from the industrially advantageous point.
It is a further object of this invention to provide a process which comprises reacting the compound of the formula (II) with the three valency phosphorus compounds of the formula ~III) to form a protecting group, and then acylating the reaction products followed by removing the protective group to obtain penicillins and cephalosporins, respectively.
These and further object will become more apparent when consideration is given to the following detail disclosure.
According to the process of this invention, each of the penicillins and the cephalosporins is produced by reacting the salts of 6-aminopenicillanic acid or 7-aminocephalosporanic acids of the formula (II) with three valency phosphorus com-pounds of the formula (III), and then reacting the productobtained above with reactive derivatives of carboxylic acid of the following general formula (IV), 1 ' Ii`

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R
)n (IV) wherein the symbols are the same as mentioned above, and then solvolyzing the product.
The salt of the compound of the formula (II) used in this invention includes, for example, an alkali metal salt such as sodium,potassium etc., secondary amine salt such as diethyl-amine, piperidine, morphine, pyrrolidine, etc., or tertiary amine salt such as trialkylamine, N-alkylpiperidine, N-alkyl-morpholine, etc.
The three valency phosphorus compounds of the formula (III) include the following compound, CH3PC12, C2H5PC12, C H PBr /C4HgPC121 C6HsPC12/C6HsP~r2~ 6 S 2 2 3 C H ~ PCl, C H ~PCl, (C6H5)2Cl' CH3PC12~ C2H5opcl2~ C3H70pC12, 4 9 2~ ClCH2CH20PC12, C6H50PC12, Cl ~ OPC12' C6H5CH20PC12' ClCH2CH2CH20PC12, ClCH2CHCH20PC12, CH3CHCH20PC12, CH30CH2CH20PC12, Cl Cl 2 5 2 2 2' (CH30)2PCl, (C2H50)2PCl, (ClCH2CH 0) PCl (C6H50)2pcl~ (C6H5cH20)2Pcl~ ( ~ C H5 ~ PCl, C2H5 ~ PCl, (CH3)2N > PCl, (CH3)2N-PC12~ Co> PCl~ CH3 rO ~PCl, ClCH ~ o ~ PCl, CH30CH2 ~ o ~ , CH3 T ~ PCl C o~ PCl, ~ ~ PCl.

Examples of the carboxylic acids of the general formula (IV) include, for example, phenyl acetic acid, a-phenoxyacetic acid, ~-phenoxypropiOnic acid, a-phenoxybutyric acid, diphenoxy-acetic acid, diphenylacetic acid, naphtylacetic acid, napthoxy-acetic acid, a-aminophenylacetic acid, a-chlorophenylacetic acid, ... .
; 5 I~ -~ . . . ..

-' ~04199~i a-bromophenylacetic acid, a-azido-phenylacetic acid,mandelic acid, a-methylthiophenylacetic acid, -ethoxycarbonylphenylacetic acid, thienylacetic acid, tetrazolylacetic acid, l-aminocyclo-hexanecarboxylic acid, 2,6-dimethoxybenzoic acid, a-benzyloxy-carbonylphenylacetic acid, a-amino-(4-hydroxyphenyl)acetic acid, a-amino-(3,5-dichloro-4-hydroxyphenyl)acetic acid, a-amino-(3-chloro-4-hydroxyphenyl)acetic acid, a-amino-(4-nitrophenyl) acetic acid, a-amino-(4-chlorophenyl)acetic acid, a-amino-(4-methoxyphenyl)-acetic acid, a-amino-(4-methylthiophenyl)acetic acid, a-amino-(4-acetamidophenyl)acetic acid, a-amino-cyclohexa-dienylacetic acid, a-aminocyclohexylacetic acid, a-amino-thienyl-acetic acid, cyanoacetic acid, 4-pyridylthioacetic acid, 3-phenyl-5-methyl-4-isoxazolylcarboxylic acid, 3-(2-chlorophenyl)-5-methyl-4-isoxazolylcarboxylic acid, 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolylcarboxylic acid, 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolylcarboxylic acid, 3-phenyl-5-methyl-4-isothia-zolylcarboxylic acid, a-amino-(substituted or unsubstituted-thiazolyl)acetic acid, etc. These reactive derivatives include acid halide, acid anhydride, mixed acid anhydride with organic or inorganic acid, active ester, acid azide, acid cyanide, active acid amide, etc., particularly preferably acid chloride, mixed acid anhydride, or active acid amide. The mixed acid anhydrides with substituted acetate, alkyl carbonate, aryl car-bonate, or aralkyl carbonate. The active esters include, for example cyanomethyl ester, substituted phenyl ester, substituted benzyl ester, substituted thiophenyl ester, etc. The active acid amide includes, for example, N-acylsaccharin, N-acylimi-dazole, N-acylbenzoylamide, N,N-dicyclohexyl-N-acylurea, N-acylsulfonamide, etc. When the compound of the formula (IV) is a-amino acid, the objective product may be produced in a high yield to react it as cyclic anhydride such as oxazolidine-2,5-dion; mixed acid anhydrides in which amino group is protected Il .. - . . ... . .

104199~

by diphenyl methyl ~roup, trityl group, bis~p-methoxyphenyl~;
methyl group, bis(p-methoxyphenyl)-phenylmethyl group, trifluoro-acetyl group, salicylidene group, benzylidene group, p-nitro-benzylidene group or enamine with ~-diketones or ~-keto-acid derivatives such as, for example, enamine with acetoacetic acid ester, acetoacetamides, acetylacetone, benzoylacetone, ~-formyl-propionic acid ester, ~-acetylcyclopentanone, ~-acetylcyclohexa-none, etc.; or hydrochloride of acid chloride.
In carrying out the present process, the salt of the compound of the formula (II) is dissolved or suspended in a proper solvent such as, for example, methylene chloride, chloro-form, carbon tetrachloride, ethylene chloride, trichloroethane, trichlene(trilene), acetnitrile, acetone, tetrahydrofuran, diox-ane, ethyleneglycoldimethyl ether, formamide, dimethylformamide, dimethylacetamide, or the like, and this is added to the solu-tion containing the compound of the formula (III). Alternatively, the compound of the formula (III) is added to the salt of the compound of the formula (II). These are reacted below room temperature and preferably at a temperature of -50 to 0C.
Preferred mol ratio of the compounds (II) and (III) i9 1: O. 5 to 1:2. It is preferred that the reaction is conducted in the presence of an acid-binding agent, so that slightly excessive amount of an acid-binding agent against the compound of the formula (II) is added into the solution containing the compound of the formula (III).
The acid-binding agent includes trialkylamine, N,N-dialkyl aniline, pyridine and its homologs, quinoline and its homologs, N-alkylmorpholine, N-alkylpiperidine, etc., and particularly pyridine, picolines, lutidines, collidines, N,N-dimethylaniline, etc. are preferred. As the solvent of thecompound of the formula (III), there may be used benzene, tolu-ene, xylene, ethyl acetate, etc. in addition to the aforemen-tioned solvents.

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The reaction proceeds rapidly and the reaction so;lution become chlorless or pale yellow.
Then, to the reaction mixture at a temperature of -50 to 50C are added reactive derivatives of the compound of the -formula (IV) to be reacted sufficiently. The reaction is com-pleted for 30 minutes to 2 hours at the same temperature. This reaction is preferable to be conducted in the presence of an acid-binding agent, but in the process of this invention since the acid-binding agent is generally added sufficiently in the initial step, it is not always necessary to add the acid-binding agent in the final step.
Then, to the reaction solution water and/or alcohols such as, for example, methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, etc., so that the phosphorus derivatives are decomposed. This solvolysis is ordinarily cond~cted at room temperature or while being slightly cooled.
As mentioned above in detail, the present invention has succeeded to obtain the penicillins and cephalosporins by the acylation of the compound of the formula (II) protected by the novel three valency phosphorus derivatives which are simply prepared and easily removed. Therefore, according to the pre-sent invention, the objective product of high purity may be obtained in high yield with simple operation.
The following Examples are given by way of illustra-tion only and are not to be construed as limiting.
Example 1 0.46 g. of 2-chloro-4-methyl-1,3,2-dioxaphospholane was dissolved in 7 ml. of methylene chloride, and 0.8 g. of N,N-dimethylaniline was added thereto while being cooled in ice.
To the mixture was added the solution of 1 g. of triethylamine salt of 6-aminopenicillanic acid and 0.4 g. of N,N-dimethylaniline in 7 ml. of methylene chloride at 0C. After the mixture was g _ ,.

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reacted for 10 min~tes, to the reaction mixture was added drop-wise the solution of 0.63 g. of ~-phenoxypropionylchloride in

3 ml. of methylene chloride. After the reaction mixture was raised to room temperature over a period of approximately 30 minutes and was further reacted for 30 minutes, the mixture was poured into 10 ml. of water. After stirring for 20 minutes, the organic layer was collected, washed with water and evaporated -under reduced pressure. The residue was dissolved in 3 ml. of butyl acetate, and to the mixture was added concentrated aqueous solution of 0.32 g. of potassium acetate, and the mixture was stirred to deposit white crystals. The deposited crystals were filtered, and washed with acetone. There was obtained 1.24 g.
(98%) of a potassium salt of phenoxyethylpenicillin. When this was recrystallized from aqueous acetone, there was obtained 1.2 g. (95%) of crystals showing a decomposition point of 220C.
The infrared absorption spectrum of the product was identical with that of the standard sample.
~xample 2 The procedure of ExaMple 1 was repeated under the same reaction conditions, except tnat 0.49 g. of 2-chloro-1,3,2-dioxaphospholane was used instead of 2-chloro-4-methyl-1,3,2-dioxaphospholane and there was obtained 1.24 g. (98%) of crude crystals of potassium salt of phenoxyethylpenicillin.
Example 3 0.94 g. of triethylamine was added to the suspension of 1 g. of 6-aminopenicillanic acid in 7 ml of methylene chloride, and the mixture was reacted at room temperature for 30 minutes to become transparent solution, and then to the mixture was added 0.5 g. of dimethylchlorophosphite, and the mixture was reacted for 30 ~inutes. The deposited triethylamine hydrochloride was filtered, and the filtrate was evaporated under reduced pressure. The residue was dissolved in the solution of 1.1 g.

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of dimethylaniline in 10 ml. of methylene chloride, and to ~the solution was added dropwise the solution of 1 g. of ~-phenoxy-butyryl chloride in 3 ml. of methylene chloride. After reacted for 1 hour, the reaction mixture was poured into 10 ml. of water and was hydrolized at a pH of 1.0 for 15 minutes. The organic layer was collected, washed with water and evaporated under reduced pressure. This was dissolved by adding 3 ml. of butyl acetate and 1 ml. of acetone thereto. To the mixture was added 0.45 g. of fine powder of potassium acetate, to gradually deposit white crystals after once dissolved. The deposited crystals were filtered and washed with acetone, and there was obtained 1.65 g. (85.5~) of potassium salt of phenoxypropylpeni-cillin.
When this was recrystallized from aqueous acetone, there was obtained white crystals showing a decomposition point of 215C.
The infrared absorption spectrum of the product was identical with that of the standard sample Example 4 The procedure of Example 3 was repeated under the same reaction conditions, except that 0.34 g. of dimethylphos-phinouschloride instead of dimethylchlorophosphite, and there was obtained 1.6 g. (82.7%) of potassium salt of phenoxypropyl-penicillin.
Example 5 .
0.46 g. of 2-chloro-4-methyl-1,3,2-dioxaphospholane was dissolved in 7 ml. of methylene chloride, and 0.8 g. of N,N-dimethylaniline was added thereto while being cooled in ice.
To this solution was added a mixture of 1 g. of triethylamine salt of 6-aminopenicillanic acid and 0.4 g. of N,N-dimethylaniline in 7 ml. of methylene chloride at 0C. After reacted for 10 minutes, to the reaction mixture was added dropwise the solution ' 1 ,, f ~0419~
of 0.77 g. of 3-phenyl-S-methyl-~-isoxazolylcarbonylchloride in 3 ml. of methylene chloride. The reaction r,1ixture was raised to room temperature over a period of approximately 30 minutes, and was reacted for 30 minutes. After the reaction mixture was poured into 10 ml. of water and stirred for 15 minutes, the organic layer was collected, washed with water and evaporated under reduced pressure. The residue was dissolved by adding 3 ml. of ~utyl acetate, 1 ml. of acetone and one droplet of water. When finely pulverized sodium acetate was added thereto, it was once dissolved therein and then deposited crystals. The crystals were filtered and washed sufficiently with acetone, and there was obtained 1.15 ~. (87.5~) of white crystals of sodium salt of Methylphenylisoxazolylpenicillin.
When this was recrystallized from aqueous acetone, there was obtained white crystals showing a decomposition point of 188 to 190C.
The infrared absorption spectrum of the product was identical with that of the standard sample.
Example 6 0.46 g. of 2-chloro-4-methyl-1,3,2-dioxaphospholane was dissolved in 7 ml of methylene chloride, and 0.8 g. of N,N-dimethylaniline was added thereto. To the solution was added a mixture solution of 1 g. of triethylamine salt of 6-aminopenicil-lanic acid and 0.4 g. of N,N-dimethylaniline in 7 ml. of meth-ylene chloride at 0C. After reacted for 10 minutes, to the reaction mixture was added dropwise the solution of 1.0 g. of 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolylcarbonylchloride in 3 ml. of methylene chloride. After the reaction mixture was raised to room temperature over a period of approximately 30 minutes and was further reacted for 30 minutes, the mixture was poured into 10 ml. of water. After stirring for 20 minutes, the organic layer was collected, washed with water and evaporated I',`
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under reduced pressure. To the residue was added ~ropwise~3 ml. of butyl acetate, 1 ml. of acetone and one droplet of water, and to the mixture was added 0.27 g. of finely pulverized sodium acetate, and there was deposited white crystals after once dissolved. The deposited crystals were filtered and washed with acetone, and there was obtained 1.4 g. (87.5%) of sodium salt of methyldichlorophenylisoxazolylpenicillin.
When this was recrystallized from aqueous acetone, there was obtained 1.25 g. of white crystals showing a decompo-sition point of 220 to 222C.
Example 7 0.4 g. of 2-chloro-1,3,2-dioxaphospholane was dissolved in 5 ml. of dioxane, and 0.8 g. of N,N-dimethylaniline was added thereto. To the mixture was added the solution of 1 g.
of triethylamine salt of 6-aminopenicillanic acid and 0.4 g.
of N,N-dimethylaniline in 5 ml. of dioxane of 10C. After reacted for 10 minutes, to the reaction mixture was added drop-wise the solution of 1.0 g. of 3-(2,6-dichlorophenyl)-5-methyl-

4-isoxazolylcarbonylchloride in 2 ml. of dioxane. After the reaction mixture was raised to room temperature over a period of approximately 30 minutes and was further reacted for 30 minutes, the mixture was poured into 20 ml. of water. After stirring for 20 minutes, the deposited jelly crystals were dissolved in 3 ml. of butyl acetate and 1 ml. of acetone and to the mixture was added 0.27 g. of finely pulverized sodium acetate, to deposit white crystals after once dissolved. The deposited crystals were filtered and washed with acetone, and there was obtained 1.3 g. (81.4~) of sodium salt of methyl-dichlorophenylisoxazolylpenicillin.
When this was recrystallized from aqueous acetone, there was obtained 1.2 g. of white crystals showing a decompo-sition point of 220 to 222C.

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10419~i Examyle 8 0.92 g. of 2-chloro-4-methyl-1~3~2-dioxaphospholane was dissolved in 10 ml of methylene chloride, and 1.6 g. of N,N-diemthylaniline was added thereto. This mixture was cooled to -40C., and to the mixture was added the solution of 2 g.
of triethylamine salt of 6-aminopenicillanic acid and 0.8 g.
of N,N-dimethylaniline in 10 ml. of methylene chloride, and the mixture was reacted for 1 hour. On the other hand, after 1 g.
of potassium N-(N', N'-dimethylaminocarbonylpropen-2-yl)-~-amino-phenylacetate was suspended in 10 ml of methylene chloride andcooled to -40C., two droplets of N-methylmorpholine were added thereto, and the solution of 0.84 g. of ethyl chlorocarbonate in 2 ml. of methylene chloride was added dropwise thereto. The resultant mixture was stirred at the same temperature for 90 minutes, to obtain a mixed anhydride. This was added at once to the solution previously prepared, and reacted at -40C. for 1 hour, and was then raised to 0C. over a period of 1 hour.
The reaction solution was filtered, the filtrate was concentrated at low temperature under reduced pressure. The residue was dissolved in 5 ml. of water and 20 ml. of methyliso-butylketone, and the solution was adjusted to a pH of 2.5 with dilute hydrochloric acid while being stirred and allowed to stand for 15 minutes. The water layer was collected, and was adjusted to a pH of 5.2 with triethylamine, to deposit the crystals. The deposited crystals were filtered, and washed sufficiently with cold water, and there was obtained white cry-stals of D-(~ aminobenzylpenicillin trihydrate.
When this was recrystallized by the conventional method, there was obtained 1.9 g. (74%) of white crystals.
Example 9 2 g. of triethylamine salt of 6-aminopenicillanic acid and 1.6 g. of N,N-dimethylaniline were mixed with 15 ml.

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of methylene chlori~e, and to the mixture was added dropwise 0.92 g. of 2-chloro-4-methyl-1,3,2-dioxaphospholane at -20C., and the mixture was reacted at the same temperature of 30 min-utes. Then, to the reaction mixture was added 1.3 g. of D(-)-~-aminophenylacetylchloride hydrochloride, and the mixture was reacted at 20C. for 1.5 hour. After the reaction mixture was poured into 250 ml. of water and stirred for 10 minutes, the water layer was collected. Further, 10 ml. of water was added to the organic layer so as to extract the resultant product.
These water layers were combined and 10 ml of ethyl acetate was added thereto, and the mixture was then adjusted to a pH of 5.5 with 10%-sodium hydroxide. The water layer was collected, and 12 g. of ar.lmonium sulfate was added thereto so as to deposit crystals. Thedeposited crystals were filtered, and there was obtained 2.5 g. (98.4%) of crude crystals of D(-)-~-aminobenzyl-penicillin trihydrate.
When this was recrystallized by the conventional method, 2.15 g. (84.6%) of objective product was obtained.
The results of the case that other three valency phos-phorus compounds were used similarly are as follows;

Three Valency Phosphorus Mol Ratio Yield (%) Compounds ~o L o~PCl 1.05 82.6 CH3OPC12 0.6 74.2 (CH30)2PC1 1.05 76.8 (ClCH2CH2O)2PC1 1.05 78.6 (C6H5O)2PC1 1.05 73.0 (C6H5)2PC1 1.05 63.0 Example 10 2 g. of triethylamine salt of 6-aminopenicillanic Il `

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acid and 0.8 g. of!N,N-dimethylaniline were mixed with 10 ~1.
of methylene chloride, and to the mixture was added dropwise 0.92 g. of 2-chloro-4-methyl-1,3,2-dioxaphospholane at -40C., and the mixture was then reacted at the same temperature for 30 minutes. On the other hand, 1 g. of sodium Dt-)-N(N',N'-dimethyl-aminocarbonylpropen-2-yl)-~-amino-(p-hydroxyphenyl) acetate was suspended in 10 ml. of methylene chloride, and two droplets of N-methylmorpholine were added thereto at -40C. and the solution of 0.~4 g. of ethyl chlorocarbonate in 2 ml. of meth-ylene chloride was further added dropwise thereto, and themixture was then reacted at the same temperature for 90 r~linutes to produce a mixed anhydride. This was added at once to the solution previously prepared, and reacted at -40C for 1 hour, the resulting mixture was raised to 0C. over a period of 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Then, the residue was dissolved in 10 ml. of water and 20 ml. of methylisobutylketone, and the solution was adjusted to a pH of 2.5 with dilute hydro-chloric acid while being stirred, and allowed to stand for 15 minutes. The water layer was collected, and was adjusted to a pH of 5.2 with 10%-sodium hydroxide so as to deposit crystals.
The deposited crystals were filtered, and washed with cold water, and there were obtained 2.94 g. (70~) of crystals of 6-[D(-)-~-amino-(p-hydroxyphenyl)-acetamido]penicillanic acid trihydrate.
The infrared absorption spectrum and thin layer chroma-togram of the product were identical with those of the standard sample.
Example 11 2.72 g. of 7-amino-3-acetoxymethyl-3-cephem-4-carbox-ylic acid was suspended in 20 ml. of methylene chloride, 2 g. of triethylamine was added thereto to be dissolved transparently, ,li :

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and then to the mixture were added the solution of 2.4 g. of N,~-dimethylaniline and 1.7 g. of N,N-dimethylaniline hydro-chloride in 7 ml. of methylene chloride. This mixture was cooled to -20C., and to the mixture was added dropwise 1.4 g.
of 2-chloro-1,3,2-dioxaphospholane. After reacted at the same temperature for 30 minutes, to the reaction mixture was added dropwise the solution of 1.9 g. of thienylacetyl chloride in 5 ml. of methylene chloride. After the reaction mixture was raised to 20C. and reacted for 2 hours, the mixture was poured into 20 ml. of water and stirred for 15 minutes, the organic layer was collected, washed with water, and evaporated under reduced pressure. The residue was dissolved in butyl acetate, and to the solution was added concentrated aqueous solution of 0.9 g. of sodium acetate and stirred, to deposit the crystals.
The crystals were filtered, and washed with butyl acetate and then with acetone, and there was obtained 3.6 g. of crystals of sodium salt of 7-(2-thienylacetamido)-3-acetoxy-methyl-3-cephem-4-carboxylic acid.
The infrared absorption spectrum and thin layer chromatogram of the product were identical with those of the standard sample.
Example 12 The procedure of Example 11 was repeated under the same reaction conditions, except that 1.5 g. of 2-chloro-1,3,2-dioxaphosphorinan was used instead of 2-chloro-1,3,2-dioxaphos-pholane,and there was obtained 3.5 g. of crystals of sodium salt of 7-(2-thienylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid.
Example 13 30 - The procedure of Example 11 was repeated under the same reaction conditions, except that 1.7 g. of diethylchloro-phosphite was used instead of 2-chloro-1,3,2-dioxaphosphoran, I!

- 10~199~
and ~here was obtained 3.2 g. of crystals of sodium salt of 7-(2-thienylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid.
Example 14 2.72 g. of 7-amino-3-acetoxymethyl-3-cephem-4-carbox-ylic acid was suspended in 20 ml. of methylene chloride, and to the mixture was added 2 9. of tirethylamine to be dissolved transparently. Then, to the mixture was added the solution of 2.4 g. of N,N-dimethylaniline and 1.7 g. of N,N-dimethylaniline hydrochloride in 7 ml. of methylene chloride. After the mixture was cooled to -30C. and 1.5 g. of 2-chloro-4-methyl-1,3,2-dio-xaphospholane wasadded dropwise thereto, the mixture was reacted at the same temperature for 30 minutes. On the other hand, 3.5 g. of sodium N-(N',N'-dimethylaminocarbonylpropen-2-yl)-D(-)-~-aminophenylacetate was suspended in 30 ml. of methylene chloride, and two droplets of N-methylmorpholine was added dropwise there-to, and cooled to -30C., and the solution of 1.2 g. of ethyl chlorocarbonate in 3 ml. of methylene chloride was added drop-wise thereto, and reacted at the same temperature for 2 hours.
This mixture was added at once to the solution previously prepared, and reacted at -30C. for 1 hour and then raised to 0C. over a period of 1 hour. After the reaction, insoluble matters were filtered, and the filtrate was concentrated under reduced pressure, and to the residue were added ln ml. of water and 25 ml. of methylisobutylketone to be dissolved, and adjusted to a pH of 2.5 with dilute hydrochloric acid while being stirred, and allowed to stand for 15 minutes. When the water layer was collected and was adjusted to a pH of 5.5 with triethylamine, there was obtained 2.9 y. of crystals of 7-(~<-aminophenylace-tamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid dihydrate.
The infrared absorption spectrum and thin layer chroma-togram of the product was identical with those of the standard sample.

- 104199~
Example 15 2.72 g. of 7-amino-3-acetoxymethyl-3-cephem-4-carbox-ylic acid was suspended in 20 ml of methylene chloride, and to the mixture was added 2 g. of triethylamine to be dissolved.
Then, to the mixture was added the solution of 2.4 g. of N,N-dimethylaniline and 1.7 g. of N,N-dimethylaniline hydrochloride in 7 ml. of methylene chloride. After this mixture was cooled to -20C. and 1.5 g. of 2-chloro-4-methyl-1,3,2-dioxaphospholane was added dropwise thereto, the mixture was reacted at the same temperature for 30 minutes. To the reaction mixture was added 2.1 g. of D(~ -aminophenylacetylchloride hydrochloride, and raised to 20C. and reacted for 2 hours. After the reaction, to the reaction mixture was added 50 ml. of water and stirred for 10 minutes, and then adjusted to a pH of 5.2 with 10%-sodium hydroxide so as to deposit crystals. The deposited crystals were filtered and washed with water, and there was obtained 3.97 g. (90%) of crystals of 7-[D(-)--aminophenylacetamido]-3-ace-toxymethyl-3-cephem-4-carboxylic acid dihydrate.
The results of the case that other three valency phos-20 phorus compounds were used similarly are as follows:

Three valency Phosphorus Mol Ratio Yield (%) Compounds C ~PCl 1.05 88 O
(CH30)2PC1 1.05 80.5 (cl-cH2cH2o)2pcl1.05 83.9 (C6H5O)2PC1 1.05 74 (C6H5)2Pcl 0 05 65.1 3_ Example 16 2.86 g. of diethylamine salt of 7-amino-3-methyl-3-cephem-4-carboxylic acid and 1.2 g. of N,N-dimethylaniline were i . Il `

.. .. .

199~
mixed with 25 ml. of methylene chloride, and 1.5 g. of 2-chloro-4-methyl-1,3,2-dioxaphospholane was added dropwise thereto at -20C. for 15 minutes, and then reacted at the same temperature for 30 minutes. To the reaction mixture was added 2.1 g. of D(-)-a-aminophenylacetylchloride hydrochloride, and raised to 20C. and reacted for 2 hours. After the reaction, to the reaction mixture was added 50 ml. of methanol and adjusted to a pH of 1.0 with 10%-hydrochloric acid. Insoluble matters were filtered, and then the filtrate was adjusted to a pH of 5.2 with triethylamine and stirred for 15 minutes. After the deposited matters were filtered, the filtrate was concentrated to one-third of the original amount under reduced pressure, and the residue was diluted with 50 ml. of acetone so as to deposit crystals. The deposited crystals were filtered, and there was obtained 2.7 g. (73.5%) of crystals of 7-[D(-)-a-aminophenylace-tamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate.
The infrared absorption spectrum and thin layer chromatogram of the product were identical with those of the standard sample.
Example 17 2.36 g. of sodium salt of 7-amino-3-methyl-3-cephem-4-carboxylic acid was suspended in 25 ml. of methylene chloride, and to the mixture was added 1.2 g. of N,N-dimethylaniline, and raised to 20C. and to the mixture was added dropwise 1.5 g. of 2-chloro-4-methyl-1,3,2-dioxaphosphorlane for 15 minutes. After .
the mixture was reacted at the same temperature for 1 hour, to the mixture was added 2.1 g. of D(-)-a-aminophenylacetylchloride hydrochloride, and reacted at 20C. for 2 hours. After the reaction, to the reaction mixture was added 50 ml. of methanol, and the mixture was adjusted to a pH of 5.2 with 10~-hydrochloric acid. After the insoluble matters were filtered, the filtrate was adjusted to a pH of 5.2 with triethylamine, and stirred for rl .

,- . - ~ . ~ . ...

- 109~99,~
15 minutes. After the deposited matters were filtered, the filtrate was concentrated to one-third of the original amount under reduced pressure, and the residue was diluted with 50 ml.
of acetone, and there was obtained 2.6 g. (71%) of crystals of 7-[D(-)-a-aminophenylacetamide]-3-methyl-3-cephem-4-carboxylic a~id monohydrate.

SUPPLEMENT~RY DISCLOS~-RE
Example 18 In 25 ml of methylene chloride was suspended 2 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid, and 1.36 g. of diethylamine was added thereto to form a clear solution. Fur-ther, 2.6 g. of triethylamine and 1.13 g of N,N-dimethylaniline were added to form a solution. The reaction liquid was cooled to -15C, and 2.6 g of 2-chloro-4-methyl-1,3,2-dioxaphospholane was added dropwise thereto over 15 minutes, and at said tempera-ture, reaction was effected for 30 min., after which 2.12 g. of D(-)-a-aminophenylacetylchloride hydrochloride was added thereto.
The temperature of the resulting solution was elevated to 20C, and at said temperature, reaction was contined for 1.5 hours, after which 0.8 g. of n-butanol was added dropwise to the reaction solution at 0C, and the solution was subjected to alco-holysis for 20 minutes. Ten milliliters of water was added to the solution while controlling the temperature so as not to ex-ceed 10C, and extraction was effected for 10 minutes. The aqueous layer was separated and 40 ml. of acetone was added to the layer. Triethylamine was thereafter added to the resulting solution to adjust the pH thereof to 5.5. The solution was stirred at 0-5C for 15 hours, and the thus precipitated cry-stals were collected by filtration to obtain 2.4 g. of 7-[D(-)-a-aminophenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate (75.3~).
The IR spectrum and thin layer chromatogram of the cry-stals agreed with those of the standard sample.

~ Il . .

Claims (29)

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

1. A process for producing penicillins and cephalosporins of the general formula wherein > Y represents or R represents a hydrogen atom, halogen atom, azido, acyloxy, alkoxy, aryloxy or S-R' group, R' representing an alkyl, aryl, or heterocyclic group; each of R1 and R2 represents a hydrogen atom or an alkyl, aryl, hydroxy substituted aryl, aralkyl, aryloxy, cycloalkyl or heterocyclic group or heterocyclic group substituted by methyl and phenyl or by a halosubstituted-phenyl group, or and R2 may jointly form a ring; R3 represents a hydrogen atom, halogen atom, hydroxyl, amino, protected-amino, alkylamino, azido, cyano, alkyloxy, alkylthio, aryloxycarbonyl, aralkyloxycarbonyl or alkoxycarbonyl group; and n represents 0 or 1, comprising reacting a salt of 6-aminopenicillanic acid or 7-aminocephalospor-anic acid of the general formula wherein ? Y has the above meanings, with a trivalent phosphorus compound of the following general formula wherein R4 represents an alkyl, haloalkyl, aryl, aralkyl, alkyl-oxy, haloalkyloxy, aryloxy, aralkyloxy or dialkylamino group;
R5 represents an alkyl, haloalkyl, alkyloxy, aryloxy, haloalkyl-oxy, aryl, aralkyl, aralkyloxy or dialkylamino group or a halo-gen atom, or R4 and R5 may jointly form a ring; and X represents a halogen atom, to form a protecting group; reacting the product thus obtained with a reactive derivative of a carboxylic acid of the general formula wherein R1, R2, R3 and n have the above meanings and then solvolyzing the product to remove the protecting group.

2. A process according to claim 1, wherein in the reactants Y is ; R1 and R2 each represents a hydrogen atom or an alkyl, aryl, aralkyl, aryloxy, cycloalkyl or hetero-cyclic group or heterocyclic group substituted by methyl and phenyl or by a halo-substituted-phenyl group, or R1 and R2 may jointly form a ring; R3 represents a hydrogen atom, halogen atom, hydroxyl, amino, alkyl-amino, protected-amino, azido, cyano, alkyloxy, alkylthio, aryloxycarbonyl, aralkyloxycarbonyl or alkoxycarbonyl group; and n represents 0 to 1.

3. A process according to claim 1, wherein the salt of 6-aminopenicillanic acid or 7-aminocephalosporanic acid is selected from the group consisting of an alkali metal salt, a secondary amine salt and a tertiary amine salt.

4. A process according to claim 1, wherein the three valency phosphorus compound is selected from the group consisting of (CH3)2PCl, (C6H5)2PCl, CH3OPCl2, (CH3O)2PCl, (C2H5O)2PCl, (C6H5O)2PCl, (ClCH2CH2O)2PCl, , and .

5. A process according to claim 1, wherein the carboxylic acid is selected from the group consisting of .alpha.-phenoxypropionic acid, thienylacetic acid, .alpha.-aminophenylacetic acid, 3-phenyl-5-methyl-4-isoxazolylcarboxylic acid, 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolylcarboxylic acid, N-(N',N'-dimethylaminocarbonylpropen-2-yl)-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetic acid, and N-(N',N'-dimethyl-amino-carbonylpropen-2-yl)-.alpha.-aminophenylacetic acid.

6. A process according to claim 1, wherein the reaction between the 6-aminopenicillanic acid or 7-aminocephalo-sporanic acid and the three valency phosphorus compound is carried out in the presence of an acid-binding agent at a temp-erature of -50 to 0°C.

7. A process according to claim 6, wherein the acid-binding agent is N,N-dimethylaniline.

8. A process according to claim 1, wherein the reaction between the 6-aminopenicillanic acid or 7-aminocephalo-sporanic acid protected with the three valency phosphorus com-pound and the reactive derivatives of carboxylic acid is carried out at a temperature of -50 to 50°C.

9. A process according to claim 1, wherein the solvolysis is carried out by the addition of at least one of water and alcohol to the penicillin or cephalosporin protected with the three valency phosphorus compound.

10. A process according to claim 1 or 9, wherein the solvolysis is carried out at room temperature or with slight cooling.

11. A process according to claim l, wherein 6-amino-penicillanic acid is reacted with 2-chloro-4-methyl-1,3,2-dioxa-phospholane, and the resulting product is reacted with .alpha.-phenoxy-propionyl chloride, and then solvolyzed and reacted with potas-sium acetate to yield the potassium salt of phenoxyethylpenicillin.

12. A process according to claim 1, wherein 6-amino-penicillanic acid is reacted with 2-chloro-1,3,2-dioxaphospholane and the resulting product is reacted with .alpha.-phenoxypropionyl chloride, and then solvolyzed and reacted with potassium acetate to yield the potassium salt of phenoxyethylpenicillin.

13. A process according to claim 1, wherein 6-amino-penicillanic acid is reacted with triethylamine and then with dimethylchlorophosphite or dimethylphosphinous chloride, the resulting product is reacted with .alpha.-phenoxybutyryl chloride, and then solvolyzed and reacted with potassium acetate to produce the potas-sium salt of phenoxypropylpenicillin.

14. A process according to claim 1, wherein 6-aminopenicil-lanic acid is reacted with 2-chloro-4-methyl-1,3,2-dioxaphosphoran;
and the resulting product is reacted with 4-isoxazolylcarbonyl chloride, and then solvolyzed and reacted with sodium acetate to produce the sodium salt of methylphenylisoxazolylpenicillin.

15. A process according to claim 1, wherein 6-amino-penicillanic acid is reacted with 2-chloro-4-methyl-1,3,2-dioxa-phosphoran; and the resulting product is reacted with 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolylcarbonyl chloride, and then solvolyzed and reacted with sodium acetate to produce the sodium salt of methyldichlorophenylisoxazolylpenicillin.

16. A process according to claim 1, wherein the tri-ethylamine salt of 6-aminopenicillanic acid is reacted with 2-chlo-ro-1,3,2-dioxaphosphoran; and the resulting product is reacted with 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolylcarbonyl chloride, and then solvolyzed and reacted with sodium acetate to produce the sodium salt of methyldichlorophenylisoxazolylpenicillin.

17. A process according to claim 1, wherein the triethyl-amine salt of 6-aminopenicillanic acid is reacted with 2-chloro-4--methyl-1,3,2-dioxaphosphoran; the resulting product is reacted with potassium N-(N',N'-dimethylaminocarboxylpropen-2-yl)-.alpha.-amino-phenylacetate and solvolyzed to yield D(-)-.alpha.-aminobenzylpenicillin trihydrate.

18. A process according to claim 1, wherein the triethyl-amine salt of 6-aminopenicillanic acid is reacted with 2-chloro-4-methyl-1,3,2-dioxaphosphoran; and the resulting product is reacted with D(-)-.alpha.-aminophenylacetylchloride hydrochloride and solvolyzed to yield D(-)-.alpha.-aminobenzylpenicillin trihydrate.

19. A process according to claim 1, wherein the triethyl-amine salt of 6-aminopenicillanic acid is reacted with 2-chloro-4-methyl-1,3,2-dioxaphosphoran; and the resulting product is reacted with sodium D(-)-N-(N',N'-dimethylaminocarbonylpropen-2-yl)-.alpha.-amino-(p-hydroxyphenyl)acetate and solvolyzed to yield 6-[D(-)-.alpha.-amino-(p-hydroxyphenyl)-acetamido] penicillanic acid trihydrate.

20. A process according to claim 1, wherein 2-chloro-1, 3,2-dioxaphosphoran or 2-chloro-1,3,2-dioxaphosphorinan or diethylchlorophosphite is reacted with 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid, and the resulting product is reacted with thienylacetyl chloride, and then solvolyzed and reacted with sodium acetate to produce the sodium salt of 7-(2-thienylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid.

21. A process according to claim 1, wherein 4-methyl-2-chloro-1,3,2-dioxaphosphoran is reacted with 7-amino-3-acetoxy-methyl-3-cephem-4-carboxylic acid; and the resulting product is reacted with sodium N-(N',N'-dimethylaminocarbonylpropen-2-yl)-D(-)-.alpha.-aminophenylacetate, and solvolyzed to yield 7-(.alpha.-amino-phenylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylid acid dihydate.

22. A process according to claim 1, wherein 4-methyl-2-chloro-1,3,2-dioxaphosphoran is reacted with 7-amino-3-acetoxy-methyl-3-cephem-4-carboxylic acid; and the resulting product is reacted with D(-)-.alpha.-aminophenylacetylchloride hydrochloride and solvolyzed to yield 7-[D(-)-.alpha.-aminophenyl-acetamido]-3-aceto-xymethyl-3-cephem-4-carboxylic dihydrate.

23. A process according to claim 1, wherein 4-methyl-2-chloro-1,3,2-dioxaphosphoran is reacted with 7-amino-3-methyl-3-cephem-4-carboxylic acid; and the resulting product is reacted with D(-)-.alpha.-aminophenylacetylchloride hydrochloride and solvolyzed to yield 7-[D(-)-.alpha.-aminophenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate.

24. A process according to claim 1, wherein 4-methyl-2-chloro-1,3,2-dioxophosphoran is reacted with the sodium salt of 7-amino-3-methyl-3-cephem-4-carboxylic acid; and the resulting product is reacted with D(-)-.alpha.-aminophenylacetylchloride hydro-chloride and solvolyzed to yield 7-[D(-)-.alpha.-aminopneylyacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate.

25. A process according to claim 1 which comprises reacting 7-amino-3-methyl-3-cephem-4-carboxylic acid with diethyl-amine in methylenechloride, reacting the salt obtained in situ and in the presence of triethyl amine and N,N-dimethylaniline with 4-methyl-2-chloro-1,3,2-dioxaphospholane and then with D(-)-.alpha.-aminophenylacetylchloride and treating the solution so obtained with n-butanol.

26. A process for producing penicillins of the formula wherein R6 represents an organic acyl group of the formula wherein R1, R2, R3 and n are as in claim 1, which comprises:
(1) reacting 6-aminopenicillanic acid with an organo phosphorus (III) monohalide of the formula wherein R4 represents an alkyl, haloalkyl, aryl, aralkyl, alkyloxy, haloalkyloxy, aryloxy, aralkyloxy or dialkylamino group;
R5 represents an alkyl, haloalkyl, alkyloxy, aryloxy, haloalkyloxy, aryl, aralkyl, aralkyloxy or dialkylamino group and X represents a halogen atom(2) acylating the phosphorylated product of step (1) with a carboxylic acid of the general formula wherein R1, R2, R3 and n have the above meanings and then solvolyzing the acylated product to remove the phosphorus protecting group.

27. A process for producing cephalosporins of the formula wherein R6 represents an organic acyl group of the formula wherein R1, R2, R3 and n are as in claim 1 and R' represents hydrogen, lower alkanoyloxy containing 2 to 8 carbon atoms and a quaternary ammonium radical which comprises:
(1) reacting 7-aminocephalosporanic acid of the formula wherein R" is as defined above with an organo phosphorus (III) monohalide of the formula wherein R4 represents an alkyl, haloalkyl, aryl, aralkyl, alkyloxy, haloalkyloxy, aryloxy, aralkyloxy, or dialkylamino group; R5 represents an alkyl, haloalkyl, alkyloxy, aryloxy, haloalkloxy, aryl, aralkyl, aralkyloxy or dialkylamino group and X
represents a halogen atom (2) acylating the phosphorylated product of step (1) with a carboxylic acid of the general formula wherein R1, R2, R3 and n have the above meanings and then solvolyzing the acylated product to remove the phosphorus pro-tecting group.

28. A process for producing penicillins of the formula wherein R6 represents an organic acyl group of the formula wherein R1, R2, R3 and n are as in claim 1 which comprises:
(1) reacting a salt selected from the group consisting of the alkali metal salt, secondary amine salt, and tertiary amine salt of 6-aminopenicillanic acid, with an organo phosphorus monohalide or dihalide of the formula wherein R4 represents an alkyl, haloalkyl, aryl, aralkyl, alkyloxy, haloalkyloxy, aryloxy, aralkyloxy or dialkylamino group; R5 represents an alkyl, haloalkyl, alkyloxy, aryloxy, haloalkyloxy, aryl, aralkyl, aralkyloxy or dialkylamino group or a halogen atom and X represents a halogen atom in the presence of an acid-binding agent and (2) actylating the phosphorylated product of step (1) with a reactive derivative of carboxylic acid of the general formula wherein R1, R2, R3 and n have the above meanings and then solvolyzing the acylated product to remove the phosphorus protecting group.

29. A process for producing cephalosporins of the formula wherein R represents an organic acyl group of the formula wherein R1, R2, R3 and n are as in claim 1 and R" represents a hydrogen atom, a halogen atom, or an azido, acyloxy, alkoxy, aryloxy, or S-R"' group where R"' represents an alkyl, aryl, or heterocyclic group, which comprises:
(1) reacting a salt selected from the group consisting of an alkali metal salt, secondary amine salt, and tertiary amine salt of 7-aminocephalosporanic acid of the formula, wherein R' is as defined above, with an organophosphorus monohalide or dihalide of the formula wherein R4 represents an alkyl, haloalkyl, aryl, aralkyl, alkyloxy, haloalkoxy, arloxy, aralkyloxy, or dialkylamino group; R5 represents an alkyl, haloalkyl, alkyloxy, aryloxy, haloalkyloxy, aryl, aralkyl, aralkyloxy, or dialkylamino group or a halogen atom and X represents a halogen atom in the presence of an acid-binding agent and (2) acylating the phosphorylated product of step (1) with a reactive derivative of carboxylic acid of the formula wherein R1, R2, R3 and n have the above meanings and then sol-volyzing the acylated product to remove the phosphorus pro-tecting group.