CA1101840A

CA1101840A - Process for preparing cephalosporin compounds

Info

Publication number: CA1101840A
Application number: CA318,788A
Authority: CA
Inventors: Masataka Fukumura; Hisao Tobiki
Original assignee: Sumitomo Chemical Co Ltd
Current assignee: Sumitomo Chemical Co Ltd
Priority date: 1977-12-30
Filing date: 1978-12-28
Publication date: 1981-05-26
Also published as: IT7852465A0; MX5389E; JPS5495589A; IT1109398B; ES476196A1

Abstract

ABSTRACT OF THE DISCLOSURE
A process for preparing a 1,2-propylene glycol solvate com-pound of 7-[D-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid which comprises dissolving 7-[D-.alpha.-amino-.alpha.-(p-hydroxyphenyl)-acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid or a solvate compound thereof in an acidic 1,2-propylene glycol under substan-tially anhydrous condition, and neutralizing the resulting solution to precipitate a crystalline 1,2-propylene glycol solvate compound of 7-[D-.alpha.-amino-.alpha.(p-hydroxyphenyl)acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.

Description

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.

~' .

' ' 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.

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Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a 1,2-propylene glycol solvate compound of 7-[D-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid which comprises dissolving 7-[D-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid or a solvate compound thereof in an acidic 1,2-propylene glycol under sub-stantially anhydrous condition, and neutralizing the resulting solution to precipitate a crystalline 1,2-propylene glycol solvate compound of 7-[D-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetamido]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.