PROCEDE DE PRODUCTION DE PENICILLINES ET DE CEPHALOSPORINES

PROCESS FOR PRODUCING PENICILLINS AND CEPHALOSPORINS

Abrégé anglais

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.

Revendications

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
<IMG>
wherein > Y represents <IMG> or <IMG>
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
<IMG>
wherein ? Y has the above meanings, with a trivalent phosphorus
compound of the following general formula
22

<IMG>
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
<IMG>
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 <IMG> ; 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.
23

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, <IMG> , <IMG> and <IMG> .
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.
24

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-
26

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-
27

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.
28

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.
29

26. A process for producing penicillins of the
formula
<IMG>
wherein R6 represents an organic acyl group of the formula
<IMG>
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
<IMG>
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
<IMG>
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

<IMG>
wherein R6 represents an organic acyl group of the formula
<IMG>
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
<IMG>
wherein R" is as defined above with an organo phosphorus
(III) monohalide of the formula
<IMG>
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
31

<IMG>
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
<IMG>
wherein R6 represents an organic acyl group of the formula
<IMG>
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
<IMG>
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
32

(2) actylating the phosphorylated product of step (1)
with a reactive derivative of carboxylic acid of the general
formula
<IMG>
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
<IMG>
wherein R represents an organic acyl group of the formula
<IMG>
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,
33

<IMG>
wherein R' is as defined above, with an organophosphorus
monohalide or dihalide of the formula
<IMG>
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
<IMG>
wherein R1, R2, R3 and n have the above meanings and then sol-
volyzing the acylated product to remove the phosphorus pro-
tecting group.
34

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), .
R3
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-
-- 1 --
iI` ~
.

04199~
.f ~.~
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
R3
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 ~
.

1~4~9~
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.
-- 3 --
~, .
.` .LI `
. . .

~.04~9~
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
-- 4 --
I`
.~ . . .

10~199~.
by reacting the compound of the formula (II) with the three
valency phosphorus compounds of the general formula (III),
R4
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),
-- 5 --
1 '
Ii`

10419~
R
)n (IV)
R2
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
-- 7
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.
Il `

- 104~99f~
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 _
,.
.
. ~ . . ... .

~04199~
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.
-- 10 --
I
.

~ 04199/~
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
-- 11 --
' 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
- 12 -
I',`
,
: . .

- ~04199~ ~
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.
- 13 -
., ~ ',~

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.
- 14 -
Il, .
.

~.04~99',i
.
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
- 15 -
Il `

109~199~
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,
- 16 -
,li :
, . . . . .

1C~419Y~
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,
- 17 -
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.
- 18 -

- 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
-- 19 --
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
- 20 -
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.
- 21 -
~ Il
. .