Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
0
1 This invention relates to a process for preparing a
1,2-propylene glycol solvate compound of an ~ntibiotic 7-[D-a-
amino-~-(p-hydroxyphenyl)acetamido]-3-(1,2,3-triazol 5-ylthio-
methyl~-3-cephem-4-carboxylic acid.
More specifically, ~his lnvention relates to a process
for preparing a 1,2-propylene glycol solvat:e compound of 7-[D-a-
amino-~-(p-hydroxyphenyl)acetamido~-3-~1,2,3-triazol-5-ylthio-
methyl)-3-cephem-4-carboxylic acid which comprises dissolving
7-~D-a-amino-a-~p-hydroxyphenyl)acetamido]-3-(1,2,3-triazol-5-
1~ ylthiomethyl)-3-cephem-~-carboxylic acid or a solvate compound
thereof in an acidic 1,2-propylene glycol under substantially
anhydrous condition, and neutralizing the xesulting solution to
precipitate a crystalline 1,2-propylene glycol solvate compound `!
o~ 7-[D-~amino-~-(p-hydroxyphenyl)acetamido]-3-~1,2~3-triazol-
5-ylthiomethyl)-3~cephem-4-carboxylic acid.
7-[D-~-amino-a-(p-hydroxyphenyl)acetamido]-3-tl,2,3-
triaZol-5-ylthiomethyl)-3-cephem-4-carboxylic acid is also called
as cefatrizine and a process for the preparation thereof is
disclosed in Japanese Patent Publication (Unexamined) Nos.
.
31689/74 and 94696/74. The present compound disclosed in the
above publications is either in an amorphous form or in ~a
crystalline methanol solvate compound and, therefore, the compound
cannot be used as a pharmaceutical in view of contamination with
impurities or the toxicity of methanol present in the solvate
compound.
~- Further, Japanese Patent Publication (Unexamined) No.
105813/75 discloses processes for converting the above amorphous
compound or the crystalline methanol solvate compound in-to a
. ,~
non-toxic 1,2-propylene glycol solvate compound. The processes
disclosed therein are the following two alternative pxocedures
'
34`~
O leadin~ to crystalline 1,2-propylene ~lycol solvate compounds
1) a process comprising clissolving 7-~D-~-amino-~-~p-hyclroxy-
phenyl)acetamido}-3-(1,2,3-trizol-5-ylthiomethylj-3-cephem-4-
carboxylic acid or a sol~ate compound in aqueous l,2-propylene
glycol undex acidlc conditions and neutra].izing the resulting
solution to obtain crystalline 1,2-propylene glycol solvate
compound, and
2) a process comprising dissolving 7-[D-a-amino-~-~p-hydroxy-
phenyl)acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-
: 10 carboxylic acid or a solvate compound thereof in an aqueous
solution containing a water-soluble organic compound having a
~: ketone functional group and, after neutralizing the resulting
solution, diluting the solution with 1,2-propylene glycol to
obtain a crystalline 1,2-propy].ene glycol solvate cc~pound.
However, either of these conventional processes is
not satisfactory in conducting the process on an industrial .
scale since it requires complicated operations within a relatively
,, :
short period of time in an aqueous solvent under strongly acidic
conditions, but, the preparation o~ a uniform solution required in
these conventional processes generally takes a prolonged time and
thus the starting material tends to be decomposed during the :
preparation of the solution.
As a result of extensive studies for solving the above
problems, the present inventors have found a process which can
:, -
easily provide the desired l,2-propylene glycol solvate compound
of 7-[D-a-amino-~-(p-hydroxyphenyl)acetamido]-3-(1.,2,3-triazol-5- ~ .
ylthiomethyl)-3-cephem-4-carboxylic acid in high yield and in
high purity. .
More specifically, the present inventors have found
~ 30 that 7-[D-~-amino-a-[p-hydroxyphenyl)acetamido]-3-(1,2,3-triazol-
: -2-
5-ylthiomethyl)-3-cephem-4-carboxylic acid or a solvate compound ~ ~:
per _ is sparingly solu~le in 1,2-propylene glycol but it can
be easily dissolved in 1,2-propylene glycol by converting the
cephem compound or its solvate described above into an acid salt
thereof and further found that a 1,2-propylene glycol solvate
compound of 7 [D-~-amino-~ (p-hydroxyphenyl)acetamido]-3-tl,2,3-
triazol-5-ylthiomethyl)-3~cephem-4-carboxylic acid can be
precipitated in high yield by making the above solution of the
acid salt in 1,2-propylene glycol neutral.
Since the above procedures are carried out under
substantially anhydrous conditions, undesirable side reactions
such as a hydrolysis reaction of the ~-lactam ring can be prevented
anda pure crystalline product can be obtained in high yield.
~ s described above, 7-~D-~-amino-~-(p~hydroxyphenyl)~
acetamino]~3-(1,2,3-trizol-5-ylthiomethyl)-3-cephem-4-carboxylic
acid or a solvate compound thereof per se is sparingly soluble
in substantially anhydrous 1,2-propylene glycol, but when an acid ~
is added to the above mixture, a clean solution can be easily ~`
obtained.
Generally, in the process of this invention,. it is not
necessary to isolate the acidic salt of 7-[D-~-amino-~-(p-
hydroxyphenyl)acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)-3-
cephem-4-carboxylic acid, but if desired, the aeidic salt may.
be isolated and thereafter can be dissolved in 1,2-propylene
glycol. Examples of acids which can be used for forming acidic
1,2-propylene glycol are hydrogen chloride gas, sulfuric acid,
phosphoric acid, and the compounds which are capable of generating
the above acids during the procedures according to the process
of this in~ention, for example, trimethylsilyl chloride,
phosphorus trichloride, thionyl chloride and the like, but hydro-
g~n chloride gas is particularly preferred for ease in operation.
~3-
4~
1 The ~.erm "a solvate compound of 7-[D-~-amino-~-
(p-hydroxyphenyl)acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)-
3-cephem-~-carbo~ylic acid" used in the present invention means
a hydrate or a solvate compound wi-th an oryanic solvent. The
hydrate can be an amorphous form as disclosed in Japanese Patent
Publication (Une~amined) Nos. 31689/74 and 94696/74r or a
sesqui-hydrate or a monohydrate. Also, the solvate compound with
an organic solvent can generally be a methanol solvate compound.
The clean solution thus obtained is then neutralized with an
organic base whereby the desired 1,2-propylene glycol solvate
compound of 7-[D-~-amino-~-(p-hydroxyphenyl)acetamido~-3-
(1,2,3-triazol-5-ylmethylthio)-3-cephem-4-carboxylic acid can
; be precipitated as crystals. Generally, the crystals precipitate
slowly and, therefore, a small amount o~ the authentic 1,2-
propylene glycol solvate compound can be added to the solution
in order to promote the crystallization, if desired.
Examples of organic bases which can be used ~or ~ ;
neutralization are triethylaminetpyridine~ dimethylaniline,
diethylamine, ammonia and the like. The salts formed with these
oxganic bases are generally easily soluble in 1,2-propy].ene
glycol and therefore contamination of the salt described above
to the desired crystals can be avoided.
The separation o~ the'desired crystals from the
1,2~propylene glycol solution can generally be perormed by ~ '
filtration, but since 1,2-propyle~e glycol per se is highly
;~ viscous, it is advantageous to dilute the reaction mixture with
a solvent which is soluble in 1,2-propylene glycol prior to the
filtration operation whereby separation can be conducted more
easily. Also, the content of 1,2-propylene glycol in the
desired crystalline solvate compound can be ~ontrolled to a
4~ :
desired level by controlling the amoun-t of the above-described
solvent. Examples of solvents which can be used for this :
purpose are ethanol, acetonitrile, acetone, water and the like.
The crystalline 1,2~propylene glycol solvate compound
obtained in accordance with the process of this invention is .
extremely stable and when the crystals are dispersed in water,
no deterioration in the physiological activities of the comp~und
occurs withou-t causing any adverse affects on crystallinity and
uniform dispersibility of the crystals and without forming any
: 10 oily, lumpy and viscous materials.
The invention of this applicatinn will be described
in detail by referrin~ to the following Examples, but these
Examples are given for illustrative purpose only and are not to
be construed as limiting the present invention. Unless otherwise : :
. indicated, all parts, percents and ratios are by weight.
Example 1
: 7-[D~ mino-a-(p-hydroxyphenyl)acetamido]-3-(1,2,3-
. triazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid monomethano- ~
late (1.0 g) was dissolved it room temperature in a dried 1% - ~;
hydrochloric ~cid-1,2-propylene glycol solution (8 ml). Vpon
addition of pyridine (0.32 ml) to the resulting mixture while
stirring, the light yellow color of the reaction mixture . .
; disappeared and, immediately thereafter, colorless crystals began
to precipitate. After stirring for one hour at room temperature,
. acetonitrile (100 ml) was added to the mixture and the precipitated
crystals were separa~ed by filtra~ion. The crystals were then
.; dried in vacuo at 40 to 50C to ob~ain a 1,2-propylene glycol
:; solvate compound (1.02 g). The crystals thus obtained were :
found to be a composite combined with 1 mol of 1,2-~ropylene
glycol by NMR spectral analysis.
_5_
~ :
- :
1 Example 2
7-lD-~-Amino-a-(p-hydroxyphenyl)acetamido]-3~ 2,3-
triazol-5~ylthiomethyl)-3-cephem-4-carboxylic acid monohydrate
(1.0 g) was dissolved a-t room temperature in a dried 0.5
hydrochloric acid-1,2-propylene glycol solution (14 ml). Upon
addition of pyridine (0.3 ml) to the resulting mixture while
stirring, the light yellow color of the reaction mixture dis-
appeared and, about 1 minute thereafter, colorless rystals
beyan to precipitate. After stirring for 2 hours at room
temperature, 100 ml of acetonitrile was added to the mixture and
the precipitated crystals were separated by filtration. The
crystals were then dried in vacuo at 40 to 50C to obtain a ;
1,2-propylene glycol solvate compound (0.98 g). The crystals
thus obtained were found to be a composite combined with 1 mol
of l,2-propylene glycol by NMR spectral analysis.
E
7-[D-a-Amino-~-(p-hydroxyphenyl)acetamido]-3-(1,2,3-
triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid monomethan-
olate (1.0 g) was dissolved at room temperature in a dried 0.5%
hydrochloric acid-1,2-propylene glycol solu-tion (15 ml). Upon
dropwise addition of triethylamine (0.25 ml) to the resulting
mixture while stirring, the light yellow color of the reaction
mixture disappeared and, about 1 minute thereafter, colorless
crystals began to precipitate. After stirring for 2 hours at
room temperature, acetonitrile (100 ml) was addad to the mixture
followed by working up in the same manner as described in
Example 2 to obtain a 1,2-propylene glycol solva-te compound
(0.89 g). The crystals thus obtained were found to be a
; composite combined with 1 mol of 1,2-propylene glycol by NMR
spectral analysis.
~'
.
' '
433
Example 4
The reaction was conduc-ted in the same manner as
described in Example 3, but usiny ethanol (100 ml) in place o~
ace-tonitrile after crystals precipita-ted. The crystals thus
obtained were separated by ~iltration to obtain a l,2-propylene
glycol solvat~ compound (0.77 g). The crystals thus obtained ~ ;
were formed to be a composite combined with 1 mol of 1,2-propylene
~lycol by NMR spectral analysis.
Example 5
7-[D-~-Amino-N-(p-hydroxyphenyl)acetamido3-3-(1,2,3-
triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid monomethano-
late (0.50 g) was dissolved at room temperature in a 1% sulfuric
acid-1,2-propylene glycol solution (4 ml). Upon dropwise
addition of pyridine (0.35 ml) to the resulting mixture while
stirring, the light yellow color oE the reaction mixture
disappeared and, about one minute thereafter, colorless crystals
; began to precipitate. After stirring for one hour at room
temperature, acetonitrile (50 ml) was added to the mixture and
the precipitated crystals were separated by filtration. The
.o crystals were then dried in vacuo at 40 to 50~C to obtain a
1,2-propylene glycol solvate compound (0.52 g). The crystals ;~
thus obtained were found to be a composite combined with 1 mol
of 1,2-propylene glycol by NMR spectral analysis.
Example 6
7-~D-a-Amino-a-(p-hydroxyphenyl)acetamido]-3-(1 t 2,3-
triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (1.0 g~ was
suspended in 1,2-propylene glycol (20 ml) at room temperature~
Trimethylsilyl chloride (0.66 g) was added with stirring, when a
clean solution was obtained. Upon dropwise addition of pyridine
~ 30 (0.82 ml) to the resulting mixture while stirring, colorless
.:
.
crystals began -to precipit~te. ~fter stirring for one hour at
room temperature, aeetonitrile (50 ml) was added to the mixture
and the precipitated crystals were separated by filtration. The
erystals were then dried in vaeuo at 40 to 50C to obtain a
1,2-propylene glycol solvate compound ~0.88 g). The erystals
thus obtained were found to be a eomposite eombined with 1~3 mol
of l,2-propylene glycol by NMR speetral analysis.
,~
1 0 ' ''
': ';::
,: . -
. I
~. .
` ~:.
