Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-05
2002-05-14
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S222000, C540S225000, C540S228000, C548S144000
Reexamination Certificate
active
06388070
ABSTRACT:
FIELD OF INVENTION
The present invention relates to novel thioester derivatives of thiazolyl acetic acid of the general formula (I). The invention also relates to a novel process for preparation of the thioester derivatives. The reactive thioester derivatives are useful as intermediate for the preparation of cephalosporin antibiotics having the formula (II). In addition, the present invention also relates to a process for preparation of cephalosporin antibiotics using the said thioester derivatives.
wherein, R
1
represents H, trityl, CH
3
, CR
a
R
b
COOR
3
(R
a
and R
b
independently of one another represents hydrogen or methyl and R
3
represents H or C
1
-C
7
alkyl).
R
2
represents C
1
-C
4
alkyl or phenyl.
BACKGROUND OF THE INVENTION
Acid chlorides, anhydrides, esters, amide etc. are reported in the chemical literature for activation of carboxylic acid of formula (IV). Activation in the form of acid chloride required protection and deprotection of NH
2
group.
Activation of acid (IV) is reported by SO
2
Cl
2
,/DMF in U.S. Pat. No. 5,856,502 and SOCl
2
/DMF in U.S. Pat. No. 5,037,988. These processes suffer the limitation of using harmful and pungent smelling chemicals like SOCl
2
, SO
2
Cl
2
along with solvents like benzene, toluene, etc. and stringent conditions required for carrying out the reactions at commercial scale.
In U.S. Pat. Nos. 4,576,749 and 4,548,748 the acid of formula (IV) have also been activated by reacting with 1-hydroxybenzotriazole (HOBT) or 2-mercaptobenzothiazole (MBT) in the presence of dicyclohexylcarbodiimide (DCC) to produce reactive ester of the acid (IV) which then reacted to cephem moiety to prepare cephem antibiotics, but the processes are time consuming and with low yields, hence not suitable.
U.S. Pat. No. 4,767,852 discloses a process for production of cephems by acylating 7-amino-3-cephem-4-carboxylic acid with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (MAEM). Similarly, U.S. Pat. No. 5,026,843 (1991) disclosed a process for preparing ceftriaxone disodium hemiheptahydrate by acylation of ACT by using MAEM as acylating agents in good yield and quality. Thus MAEM has become the standard acylating agent for the preparation of cephalosporins having an oximino group and a 2-aminothiazolyl group in 7-position of cephem compounds.
However, the synthesis of MAEM from acid (III) and 2,2′-dithio-bis-benzothiazole involves use of costly condensing agent triphenylphosphine (TPP). Moreover, during condensation of MAEM with 7-amino-3-cephem-4-carboxylic acid compound (III), a toxic compound MBT is also produced as a byproduct, see e.g., Chemical Abstracts, 111, 19243
P
(1989) which is difficult to remove completely.
Thus it is evident that the procedures described in the prior art for preparation of these antibiotics are complex, involving protection, deprotection and are associated with toxic byproduct generation. Hence there is a need to develop new acylating agents which are capable of transferring the 2-aminothiazolyl moiety to cephem compounds of formula (III) in good yield but without producing this toxic by product. On the similar lines, a new thioester was reported by D. G. Walker, Tet. Lett. 1990, 31, 6481 to, acylate the cephem moiety to get cefepime sulfate but yields obtained by using this thioester were in the range of 54-73% which cannot be considered as good yield to operate a process at commercial scale. The use of this thioester was reported in the Tet. Lett. 1990, 31, 6481 only for cefepime and not for other cephalosporins. This thioester was exploited in U.S. Pat. No. 5,869,649 for making three other important cephem antibiotics.
OBJECTIVES OF THE INVENTION
The primary objective of the invention is to prepare novel thioester derivatives of thiazolyl acetic acid of the general formula (I), which would be better than the existing reactive derivatives and suitable for being used in the manufacture of cephalosporin antibiotics.
Another objective of the present invention is to provide a process for the synthesis of thioester derivatives of formula (I) from thiazolyl acetic acid of the general formula (IV) and thio-oxadiazoles of the general formula (VI).
Yet another objective of the present invention is to provide a simple, high yielding and cost-effective process for the preparation of cephalosporin antibiotics of the general formula (II).
Still another objective of the present invention is to produce cephalosporin antibiotics that are highly pure and free from toxic byproducts.
One more objective of the present invention is to provide a process for the preparation of cephalosporin antibiotics of the general formula (II) from the said novel thioester derivatives.
SUMMARY OF THE INVENTION
The present invention provides novel thioester derivatives of thiazolyl acetic acid of the general formula (I). The invention also provides a method by which, the said thioester derivatives can be prepared. The thioester derivatives so obtained are reacted with 7-amino-cephem carboxylic acids of the general formula (III) to produce cephalosporin antibiotic compounds having the general formula (II).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides new thioesters of the general formula (I) that are prepared by a novel method which has not been reported in the prior art. The use of these compounds in the process for preparing cephem derivatives renders the process entirely new and different from others. The novel derivative of thiazolyl acetic acid is represented by the formula (I)
wherein, R
1
represents H, trityl, CH
3
, CR
a
R
b
COOR
3
(R
a
and R
b
independently of one another represents hydrogen or methyl and R
3
represents H or C
1
-C
7
alkyl).
R
2
represents C
1
-C
4
alkyl or phenyl
The synthesis of compound (I) is achieved by reacting thiazolyl acetic acid of the general formula (IV) with thio-oxadiazoles of the general formula (VI) in organic solvent in presence of an organic base. The condensation is done with the help of a condensation agent of the formula (V). When the above reaction is carried out, the temperature is maintained between −10° and +30° C.
wherein, R
1
represents H, trityl, CH
3
, CR
a
R
b
COOR
3
(R
a
and R
b
independently of one another represents hydrogen or methyl and R
3
represents H or C
1
-C
7
alkyl).
R
2
represents C
1
-C
4
alkyl or phenyl
wherein R
4
is CH
3
, —CH═CH
2
, CH
2
OCH
3
, CH
2
OCOCH
3
,
or a standard cephalosporin substituent.
R
5
is hydrogen, salt or carboxylic protecting group.
R
6
is hydrogen or silyl.
In an embodiment the organic solvent is selected from the group comprising dichloromethane, tetrahydrofuran, dioxane, N,N-dimethylformamide, acetone, carbon tetrachloride and mixtures thereof.
In another embodiment the condensation agent is bis-(2-oxo-oxazolidinyl) phosphinic chloride.
In still another embodiment the organic base is selected from triethylamine diethylamine, tributylamine, pyridine, N-alkylanilines, 1,8-diazabicyclo[5.4.2]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, N-methylmorpholine and mixtures thereof.
The compound (I) so obtained is reacted with 7-amino cephem carboxylic acids of the general formula (III) in organic solvent in presence of organic base to obtain cephalosporin antibiotics of general formula (II).
For protection of carboxylic group as ester, following group can be used which are easily converted into free carboxylic acid, e.g. p-methoxybenzyl, p-nitrobenzyl, diphenyl methyl, phenacyl trimethylsilyl.
wherein, R
1
, R
2
R
4
, R
5
, & R
6
are as defined above.
The present invention provides a method by which cephalosporin antibiotics are obtained in high purity (95-99%) and excellent yield (79-95%) without the necessity for protecting the amino group of the acylating agents and the production of toxic byproduct namely 2-mercaptobenzothiazole is avoided.
The substituent R
4
in cephem compound (III) represents methyl, acetyloxymethyl, methoxymethyl, vinyl, pyridylmethyl, propenyl, 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-thiol, furanyl-2-
Deshpande Pandurang Balwant
Luthra Parven Kumar
Berch Mark L.
Orchid Chemicals & Pharmaceuticals Ltd.
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