Process for preparing 3-substituted-methyl-3-cephem derivatives

Various 7-amino-3-substituted-methyl-3-cephem-4-carboxylic acids and lower alkylsilyl derivatives such as 7-amino-3-(2,3-cyclopenteno-1-pyridiniomethyl)-3-cephem-4-carboxylic acid iodide and trimethylsilyl 7-trimethyl-silylamino-3-(5,6,7,8-tetrahydro-2-isoquinoliniomethyl)-3-ceph em-4-carboxylate iodide are valuable intermediates in the preparation of new and novel antibacterial agents. A new process for the preparation of these acids and the derivatives has been devised.

BACKGROUND OF THE INVENTION 
1. Field of the invention 
This invention relates to chemical compounds useful as chemical 
intermediates in the preparation of valuable antibiotic substances. 
2. Description of the prior art 
There exists a need to provide alternate and more efficient methods of 
producing key intermediates necessary for the preparation of new and 
valuable antibacterial agents. The new intermediate compounds and process 
for their preparation were heretofor unknown. 
DETAILED EXPLANATION OF THE INVENTION 
Compounds having the formula 
##STR1## 
wherein -.sup..sym. A represents 
##STR2## 
(wherein R.sup.2 is a hydrogen atom or an amino group, and n is an integer 
of 1 to 2); Y.sup..crclbar. represents an anion; and R.sup.1 represents a 
lower alkyl group; are prepared by a process which comprises reacting 
7-amino-3-halogenomethyl-3-cephem-4-carboxylic acid of the formula 
##STR3## 
(wherein X is a halogen atom) with (tri-loweralkylsilyl)trifluoroacetamide 
of the formula 
##STR4## 
(wherein R.sup.1 is as defined above) and a pyridine compound of the 
formula (IV) 
##STR5## 
(wherein R.sup.2 and n are as defined above). 
If necessary, by releasing the protective groups [namely, (R.sup.1).sub.3 
Si-], 7-amino-3-substituted-methyl-3-cephem-4-carboxylic acid (or 
carboxylate) of the formula 
##STR6## 
are prepared. 
Schematically, the reaction sequence may be illustrated as below. 
##STR7## 
(wherein X is a halogen atom) 
##STR8## 
(wherein R.sup.2 is a hydrogen atom or an amino group, and n is an integer 
of 1 to 2); Y.sup..crclbar. represents an anion; and R.sup.1 represents a 
lower alkyl group; 
##STR9## 
This invention relates mostly to novel compounds and the process therefor. 
More particularly, this invention relates to novel compounds which are 
useful as intermediates in the preparation of therapeutically active 
cephalosporins, and to the processes for preparing such compounds. 
It is an object of the present invention to provide chemical intermediates 
which can easily converted to cephalosprins and other therapeutically 
useful substances. It is another object of the present invention to 
provide a novel process for the preparation of these compounds. 
The main objective of the present invention is the synthesis of valuable 
key intermediates in the ultimate synthesis of particular final compounds, 
i.e. cephalosporins having a substituted pyridinio group at the 
3-position. 
The primary objective of the present invention is to prepare intermediates 
that are readily converted into compounds disclosed in the inventors' 
co-pending patent applications such as U.S. patent application Ser. No. 
656,162 and European Patent Application No. 84 306967.5. 
The present invention is explained in more detail below. 
Examples of the pyridine compounds used for the reaction of the present 
invention are pyridine, 4-aminopyridine, 3-aminopyridine, 2-aminopyridine, 
2,3-cyclopentenopyridine, 5,6,7,8-tetrahydroquinoline, 
3,4-cyclopentenopyridine, 5,6,7,8-tetrayhydroisoquinoline, etc. 
Examples of the group represented by -.sup..sym. A are pyridinium, 
aminopyridinium 
##STR10## 
2,3-cyclopenteno-1-pyridinium 
##STR11## 
5,6,7,8-tetrahydro-1-quinolinium 
##STR12## 
3,4-cyclopenteno-1-pyridinium 
##STR13## 
5,6,7,8-tetrahydro-2-isoquinolinium 
##STR14## 
etc. 
Examples of the anion of the formula Y.sup..crclbar. are inorganic anions 
such as a halogen anion (Cl.sup..crclbar., I.sup..crclbar., etc.), and a 
sulfonate anion (HSO.sub.4.sup..crclbar., SO.sub.4.sup..crclbar..crclbar., 
etc.); and organic anions such as a benzenesulfonate anion (C.sub.6 
H.sub.5 SO.sub.3.sup..crclbar.), an acetate anion (CH.sub.3 
COO.sup..crclbar.), a fumarate anion (HOOC--CH.dbd.CH--COO.sup..crclbar.), 
a citrate anion 
##STR15## 
etc. 
Examples of "Halogen" in the foregoing definition are chlorine, bromine, 
iodine and fluorine. 
Examples of "lower alkyl" are methyl, ethyl, propyl, butyl, iso-butyl, etc. 
Thus, typical lower alkyl is straight or branched carbon chain alkyl 
having 1 to 5 carbon atoms. 
The compounds (prepared by the process of this invention) of the formula 
(I.sub.1) are novel compounds. And, the compounds (prepared by the process 
of this invention) of the formula (I.sub.2) except 
7-amino-3-pyridiniomethyl-3-cephem-4carboxylate (namely, 
##STR16## 
are also novel compounds. 
A known process for producing the above known compound (namely, 
7-amino-3-pyridiniomethyl-3-cephem-4-carboxylate) are disclosed in 
unexamined Japanese patent application laid-open under the laying-open No. 
Sho. 56-12397, and the known process comprises hydrolysing cefaloridin 
which is known as a valuable antibacterial compound. However, this known 
process is not economical, and is not suitable for the practical 
production of the compound. 
The process of the present invention is entirely different from the known 
process, and has a characteristic in that 7-amino-3-halogenomethyl 
cephalosporanic acid (II), which is easily available, is used as starting 
material. Further, the loweralkylsilyl compounds of this invention are 
easily soluble in organic solvents, and side reactions such as 
rearrangement of double bond at the 2-position of the cephalorsporin 
nucleus (.DELTA..sup.3 .fwdarw..DELTA..sup.2 rearrangement) do not occur 
in the process of this invention even when reacting nucleophilic reagent 
such as pyridine compounds. Thus, the process of this invention exhibits 
high yield and high purity. 
So, the process of this invention is excellent in case of industrial 
manufacturing of cephalosporin compounds. 
In the process of this invention, 
7-amino-3-halogenomethyl-3-cephem-4-carboxylic acid (II) or a salt thereof 
is reacted with (tri-loweralkylsilyl)trifluoroacetamide (III.sub.1 or 
III.sub.2) and pyridine compound (IV) in an organic solvent which is inert 
for the reaction. 
As (tri-loweralkylsilyl)trifluoroacetamide, is used 
O,N-bis(tri-loweralkylsilyl)trifluoroacetamide (III.sub.1) or 
N-methyl-N-tri-loweralkylsilyltrifluoroacetamide (III.sub.2). Preferable 
examples of the compounds (III.sub.1) and (III.sub.2) are 
O,N-bis(trimethylsilyl)trifluoroacetamide 
##STR17## 
N-methyl-N-trimethylsilyltrifluoroacetamide 
##STR18## 
When reacting 7-amino-3-halogenomethyl-3-cephem-4-carboxyl acid with 
(tri-loweralkylsilyl)trifluroacetamide (III.sub.1 or III.sub.2) and 
pyridine compound (IV), it is preferred that 
7-amino-3-halogenomethyl-3-cephem-4-carboxylic acid is, first, reacted 
with (tri-loweralkylsilyl)trifluoroacetamide (III.sub.1 or III.sub.2), and 
then with pyridine compound (IV) (that is, 2 step reaction). However, 
(Tri-loweralkylsilyl)trifluoroacetamide (III.sub.1 or III.sub.2) and 
pyridine compound (IV) can be reacted simultaneously with 
7-amino-3halogenomethyl-3-cephem-4-carboxylic acid. 
The reaction proceeds easily at room temperature. When performing the 
reaction in 2 steps, the 1st step may be performed at room temperature and 
the 2nd step may be performed under heating or cooling at a temperature 
from -20.degree. C. to 40.degree. C. Examples of the inert organic solvent 
usually used are dichlromethane, acetone, acetonitrile, tetrahydrofuran, 
and chloroform. 
In the process of invention, tri-loweralkylsilyl compounds (I.sub.1) are 
produced. The compounds (I.sub.1) can be used, as it is, as starting 
materials for various cephalosporin compounds which may be valuable 
antibacterial agents. That is, the compounds (I.sub.1) can be subjected 
directly to the next reaction for producing the valuable cephalosporin 
compounds. However, the compounds (I.sub.2) obtained after releasing the 
tri-loweralkylsilyl groups (protective groups) can be used as staring 
materials for producing the valuable cephalosporin compounds, if 
necessary. 
The removal of the protective groups for the reaction product is easily 
performed, by treatment with water or alcohol-solvent. Examples of alcohol 
are mono-OH alcohol (such as methanol, ethanol, propanol) and di-OH 
alcohol (such as 1,2-ethanediol, 1,3-propanediol, 1,3-butanediol). It is 
preferred to use 1,3-butanediol, in view of the ease of separation and 
purification of the formed compounds. 
The manufacturing process and the process of this invention will be further 
explained by the following Reference-Examples and -Explanation and 
Examples. Reference explanation and Reference Examples show the 
manufacturing process for producing 7-substituted aminocephalosporin 
compounds by introducing a substituent at 7-amino position of the 
cephalosporin nucleus of the compounds of this invention. 
Reference Explanation: 
Cephalosporin derivatives claimed in the inventors' co-pending applications 
(U.S. patent application Ser. No. 656,162 and European Patent Application 
No. 84 306967.5) are prepared from the compounds of this invention by 
amidation (acylation) at the 7-amino group position in the compounds of 
this invention by using suitable acylating agents. This amidation reaction 
is explained below. 
##STR19## 
In the above formulae, .circle.P is a hydrogen atom or a protective 
group for an amino group, .circle.P' is a hydrogen atom or a 
tri-loweralkylsilyl group; and .circle.Q is a hydrogen atom or a 
tri-loweralkylsilyl group; -A.sup..sym. is as defined above. 
Compounds I (valuable cephalosporin compounds) can thus be produced by 
reacting substituted oxyiminothiazolylacetic acid derivative or reactive 
derivative thereof with 7-amino-3-cephem derivative (I.sub.1 and I.sub.2) 
and then, if necessary, releasing any protective group(s). 
In this case the protective group for an amino group may be one usually 
used in the field of peptide chemistry and practical examples are acyl 
groups such as a formyl group, an acetyl group, a propionyl group, a 
tert-butoxycarbonyl group, a methoxyacetyl group, a methoxypropionyl 
group, a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group; 
tri-loweralkylsilyl groups such as a trimethylsilyl group; and aralkyl 
groups such as a benzyl group, a benzhydryl group (diphenylmethyl group), 
a trityl group. 
The reaction is usually performed in a solvent under cooling at room 
temperature or below. Any solvents which do not take part in the reaction 
can be used. Examples of the solvent usually used are organic solvents 
such as dioxane, tetrahydrofuran, ether, acetone, ethyl methyl ketone, 
chloroform, dichloromethane, dichloroethane, methanol, ethanol, 
acetonitrile, ethyl acetate, ethyl formate, dimethylformamide dimethyl 
sulfoxide; these solvents may be used alone or in appropriate combination. 
The acylating agent may be a free carboxylic acid or a reactive derivative 
thereof. Suitable examples of the compound are mixed acid anhydrides, acid 
anhydrides, acid halides, active esters, active amides, acid azides. When 
using the compound in the form of a free carboxylic acid, it is preferred 
to use a condensing agent such as N,N'-dicyclo-hexylcarbodiimide or 
N,N'-diethylcarbodiimide. 
According to the kind of reactive derivative of carboxylic acid used, it 
may be preferred for smooth reaction to operate in the presence of a base. 
Examples of such a base are inorganic bases such as sodium 
hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, 
potassium carbonate; and organic bases such as trimethylamine, 
triethylamine, dimethylaniline, pyridine.

EXAMPLE 1 
##STR20## 
In 10 ml of dichloromethane was suspended 680 mg of 
7-amino-3-iodomethyl-3-cephem-4-carboxylic acid and after adding thereto 
1.2 ml of O,N-bis(trimethylsilyl)trifluoroacetamide, the mixture was 
stirred for 30 minutes at room temperature to form a clear solution. The 
solution was cooled to 5.degree. to 6.degree. C., and 316 mg of pyridine 
was added thereto. After stirring the solution for 4 hours at the same 
temperature, 1.6 ml of 1,3-butanediol was added thereto. Precipitates thus 
formed were collected by filtration, washed with 30 ml of dichloromethane, 
and dried to provide 730 mg of 
7-amino-3-(1-pyridiniomethyl)-3-cephem-4-carboxylic acid iodide. 
##STR21## 
Using the compound of Example 1 as a starting material, the following 
compound was obtained. 
Reference Example 1 
##STR22## 
(i) In 10 ml of dichloromethane was suspended 419 mg of 
7-amino-3-(1-pyridiniomethyl)-3-cephem-4-carboxylic acid iodide and after 
adding thereto 0.9 ml of O,N-bis(trimethylsilyl)trifluoroacetamide, the 
mixture was stirred for 30 minutes to form a clear solution. The solution 
was cooled to -40.degree. C., and 0.5 ml of pyridine was added thereto. 
(The solution thus formed is hereafter referred to as "Solution A".) 
In 10 ml of dichloromethane was suspended 738 mg of 
(Z)-.alpha.-(2-tritylamino-4-thiazolyl)-.alpha.-[(2-tritylamino-4-thiazoly 
l)methoxyimino]acetic acid and after cooling the suspension to 3.degree. to 
4.degree. C., 208 mg of phosphorus pentachloride was added thereto, and 
the mixture was stirred for 15 minutes at 3.degree.-4.degree. C. (The 
solution thus formed is hereafter referred to as "Solution B".) 
Solution B was added dropwise to solution A and the temperature of the 
reaction mixture was elevated to -10.degree. C. over 15 minutes. After 
adding to the reaction mixture 1 ml of water, 1 ml of tetrahydrofuran and 
3 ml of 1N-hydrochloric acid, the mixture was stirred for 10 minutes at 
-10.degree.-0.degree. C. The reaction mixture was distilled under reduced 
pressure to remove dichloromethane and tetrahydrofuran and after adding to 
the residue obtained 50 ml of water, precipitates (powder) thus formed 
were collected by filtration, washed with water, and dried to provide 0.91 
g of a crude product (a compound having protective groups). 
(ii) After adding to the crude product obtained as above 20 ml of 
trifluoroacetic acid and 6 ml of water under ice-cooling, the mixture was 
stirred for 1 hour at room temperature. Insoluble materials were removed 
by filtration, and the filtrate was concentrated under reduced pressure. 
To the residue was added 20 ml of ether, and the powder thus formed was 
collected by filtration to provide 0.45 g of a crude product. The crude 
product was suspended in 50 ml of water and after adding 2 ml of 
1N-hydrochloric acid, the formed solution was subjected to column 
chromatography on Diaioh HP-20 and the product was eluted first with water 
and then with mixtures of water-methanol of successively changing mixing 
ratio. The fractions containing the desired product were concentrated, and 
lyophilized to provide 80 mg of 
(Z)-7-{.alpha.-(2-amino-4-thiazolyl)-.alpha.-[(2-amino-4-thiazolyl)methoxy 
imino]acetamido}-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate. 
##STR23## 
EXAMPLE 2 
##STR24## 
In 50 ml of dichloromethane was suspended 1.7 g of 
7-amino-3-iodomethyl-3-cephem-4-carboxylic acid and after adding thereto 
2.8 ml of O,N-bis(trimethylsilyl)trifluoroacetamide, the mixture was 
stirred for 30 minutes at room temperature to form a clear solution. After 
adding thereto 654 mg of 2,3-cyclopentenopyridine, the solution was 
stirred for 4 hours at room temperature to provide trimethylsilyl 
7-trimethylsilylamino-3-(2,3-cyclopenteno-1-pyridiniomethyl)-3-cephem-4-ca 
rboxylate iodide. After adding thereto first 4 ml of 1,3-butanediol, and 
then adding 150 ml of ether, precipitates thus formed were collected by 
filtration, washed with 50 ml of ether, and dried to provide 1.8 g of 
7-amino-3-(2,3-cyclopenteno-1-pyridiniomethyl)-3-cephem-4-carboxylic acid 
iodide. 
##STR25## 
Using, as a starting material, trimethylsilyl 
7-trimethylsilylamino-3-(2,3-cyclopenteno-1-pyridiniomethyl)-3-cephem-4-ca 
rboxylate iodide obtained in the reaction course of Example 2, the 
following compound was obtained. 
Reference Example 2 
##STR26## 
In 25 ml of dichloromethane was suspended 3.92 g of 
(Z)-.alpha.-(2-tritylamino-4-thiazolyl)-.alpha.-[(2-tritylamino-4-thiazoly 
l)methoxyimino]acetic acid and after cooling the suspension to 3.degree. to 
4.degree. C. and then adding thereto 1.04 g of phosphorus pentachloride, 
the mixture was stirred for 15 minutes at 3.degree.-4.degree. C. (The 
solution thus formed is hereafter referred to as "Solution A".) 
A solution containing trimethylsilyl 
7-trimethylsilylamino-3-(2,3-cyclopenteno-1-pyridiniomethyl)-3-cephem-4-ca 
rboxylate iodide obtained in the reaction course of Example 2 was cooled to 
-50.degree. C., and 2.2 ml of pyridine was added thereto. (The solution 
thus formed is hereafter referred to as "Solution B".) 
Solution A was added dropwise to solution B, and the temperature of the 
reaction mixture was increased to -15.degree. C. over 15 minutes. After 
adding thereto 5 ml of water, 10 ml of tetrahydrofuran, and 10 ml of 
1N-hydrochloric acid, the resultant solution was stirred for 10 minutes 
under ice-cooling. The reaction mixture was distilled under reduced 
pressure to remove dichloromethane and tetrahydrofuran and after adding to 
the residue obtained 200 ml of water, precipitates thus formed were 
collected by filtration. The precipitates obtained was washed with water, 
and dried to provide 5.5 g of a crude product (a compound having 
protective groups). After adding to the crude product 60 ml of 
trifluoroacetic acid and 12 ml of water under ice-cooling, the mixture was 
stirred for 1 hour at room temperature. Insoluble materials were removed 
by filtration, and the filtrate was concentrated under reduced pressure. 
To the residue was added 150 ml of ether to form a powder, and the powder 
was collected by filtration to provide 2.7 g of a crude product. The crude 
product was suspended in 200 ml of water and after adding thereto 4 ml of 
1N-hydrochloric acid, the formed solution was subjected to column 
chromatography on Diaion HP-20 and the product was eluted first with water 
and then mixtures of water and methanol of successively changing mixing 
ratio (water:methanol from 10:1 to 10:6). The fractions containing the 
desired product were concentrated, and lyophilized to provide 275 mg of 
(Z)-7-{.alpha.-(2-amino-4-thiazolyl)-.alpha.-[(2-amino-4-thiazolyl)methoxy 
imino]acetamido}-3-(2,3-cyclopenteno-1-pyridinyl)-3-cephem-4-carboxylate. 
##STR27## 
EXAMPLE 3 
##STR28## 
In 50 ml of dichloromethane was suspended 1.7 g of 
7-amino-3-iodomethyl-3-cephem-4-carboxylic acid and after adding thereto 
2.8 ml of O,N-bis(trimethylsilyl)trifluoroacetamide, the mixture was 
stirred for 30 minutes at room temperature to form a clear solution. After 
adding thereto 665 mg of 5,6,7,8-tetrahydroisoquinoline, the solution was 
stirred for 4 hours at room temperature to provide trimethylsilyl 
7-trimethylsilylamino-3-(5,6,7,8-tetrahydro-2-isoquinoliniomethyl)-3-cephe 
m-4-carboxylate iodide. After adding thereto first 4 ml of 1,3-butanediol, 
and then adding 150 ml of ether, precipitates thus formed were collected 
by filtration, washed with 50 ml of ether, and dried to provide 2 g of 
7-amino-3-(5,6,7,8-tetrahydro-2-isoquinoliniomethyl)-3-cephem-4-carboxylic 
acid iodide. 
##STR29## 
Using, as a starting material, trimethylsilyl 
7-trimethylsilylamino-3-(5,6,7,8-tetrahydro-2-isoquinoliniomethyl)-3-cephe 
m-4-carboxylate iodide obtained in the course of the reaction of Example 3, 
the following compound was produced. 
Reference Example 3 
##STR30## 
In 25 ml of dichloromethane was suspended 3.92 g of 
(Z)-.alpha.-(2-tritylamino-4-thiazolyl)-.alpha.-[(2-tritylamino-4-thiazoly 
l)methoxyimino]acetic acid and after cooling the suspension to 3.degree. to 
4.degree. C. and then adding thereto 1.04 g of phosphorus pentachloride, 
the mixture was stirred for 15 minutes at 3.degree.-4.degree. C. (The 
solution thus formed is hereafter referred to as "Solution A".) 
A solution containing trimethylsilyl 
7-trimethylsilylamino-3-(5,6,7,8-tetrahydro-2-isoquinoliniomethyl)-3-cephe 
m-4-carboxylate iodide in the reaction course of Example 3 was cooled to 
-50.degree. C., and 2.2 ml of pyridine was added thereto. (The solution 
thus foremd is hereafter referred to as "Solution B".) 
Solution A was added dropwise to solution B, and the temperature of the 
reaction mixture was increased to -15.degree. C. over 15 minutes. After 
adding thereto 5 ml of water, 15 ml of 1N-hydrochloric acid, and 10 ml of 
tetrahydrofuran, the resultant solution was stirred for 10 minutes under 
ice-cooling. The reaction mixture was distilled under reduced pressure to 
remove dichloromethane and tetrahydrofuran and after adding to the residue 
obtained 200 ml of water, precipitates thus formed were collected by 
filtration to provide 10 g of a crude product containing water (a compound 
having protective groups). After adding to the crude product 70 ml of 
trifluoroacetic acid and 14 ml of water under ice-cooling, the mixture was 
stirred for 1 hour at room temperature. Insoluble materials were removed 
by filtration, and the filtrate was concentrated under reduced pressure. 
To the residue was added 200 ml of ether to form a powder, and the power 
was collected by filtration to provide 4 g of a crude product. The crude 
product was suspended in 300 ml of water and after adding 6 ml of 
1N-hydrochloric acid, the formed solution was subjected to column 
chromatography on Diaion HP-20 and the product was eluted first with water 
and then mixtures of water and methanol of successively changing mixing 
ratio (water:methanol from 10:1 to 10:7). The fractions containing the 
desried product were concentrated, and lyophilized to provide 393 mg of 
(Z)-7-{.alpha.-(2-amino-4-thiazolyl)-.alpha.-[(2-amino-4-thiazolyl)methoxy 
imino]acetamido}-3-(5,6,7,8-tetrahydro-2-isoquinoliniomethyl)-3-cephem-4-ca 
rboxylate.