Thioester derivatives of thiazolyl acetic acid and their use...

Details Thioester derivatives of thiazolyl acetic acid and their use... Thioester derivatives of thiazolyl acetic acid and their use...

2002-01-04

2003-08-26

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C540S225000, C540S227000, C540S228000, C544S182000

Reexamination Certificate

active

06610845

ABSTRACT:

FIELD OF INVENTION
The present invention relates to novel thioester derivatives of thiazolyl acetic acid of the general formula (I), useful as an intermediate for the preparation of cephalosporin antibiotics having the general 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
2
(R
a
and R
b
independently of one another represent hydrogen or methyl and R
2
represents H or C
1
-C
4
alkyl).
BACKGROUND OF THE INVENTION
Use of 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 involving stringent conditions 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) has 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 is then reacted with cephem moiety to prepare cephalosporin antibiotics, but the processes are time consuming accompanied 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 7-amino-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3yl) thiomethyl]-3-cephem-4-carboxylic acid (7-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 antibiotics 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 2-mercaptobenzothiazole (MBT) is also produced as a byproduct [Chemical Abstracts, 111, p.19243 (1989)], which is difficult to remove.
Thus, it is evident that the procedures described in the prior art for the preparation of these cephalosporin antibiotics are complex, involving protection, deprotection and also associated with generation of toxic byproduct. 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, without producing this toxic byproduct. 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 same thioester is exploited in U.S. Pat. No. 5,869,649 for making three more important cephalosporin antibiotics.
OBJECTIVES OF THE INVENTION
In the co pending application U.S. application Ser. No. 09/754,302, U.S. Pat. No. 6,388,070 the Applicant has disclosed another novel thioester derivative of thiazole acetic acid & its use in the synthesis of various ceplalosporin antibiotics. In continuation of search for more such derivatives, the Applicant observed that the title compound (I) works equally well and also has the similar advantages as described in the aforementioned US application.
The primary objective of this invention is to prepare a new thioester derivative of thiazolyl acetic acid of the formula (I), which would be better than the earlier reactive derivatives and also 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 derivative of formula (I) from thiazolyl acetic acid of the formula (IV) and 1,2,5,6 tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-thiol (VI).
Yet another objective of the present invention is to provide a process for the preparation of cephalosporin antibiotics of the general formula (II) at low temperature, which will be simple and cost effective.
Still another objective of the present invention is to produce cephalosporin antibiotics that are high purity 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 a new thioester derivatives of thiazolyl acetic acid of formula (I) and also provides a method by which the said thioester derivatives can be prepared by reacting thiazolyl acetic acid of the general formula (IV) with the commercially available 1,2,5,6 tetrahydro-2-methyl-5,6 dioxo-1,2,4-triazin-3-thiol (VI) using Vilsmeier reagent (V) as a condensing agent. (Ber. 60B, 119 (1927). The thioester derivatives thus obtained are reacted with 7-amino-cephem carboxylic acids of the general formula (III) to produce cephalosporin antibiotic compounds of the general formula (II), as described above. The cephalosporin antibiotics obtained are of high purity (95-99%). The method is workable at commercial scale without necessitating for the protection of the amino group of the acylating agents, and avoiding the generation of the toxic byproduct 2-mercaptobenzothiazole.
DETAILED DESCRTIPTION OF THE INVENTION
1. The present invention provides a process for the preparation of a new thioester of the formula (I), as mentioned earlier. The said process comprises condensation of thiazolylacetic acid represented by formula (IV)
wherein, R
1
represents H, trityl, CH
3
, CR
a
R
b
COOR
2
(R
a
and R
b
independently of one another represents hydrogen or methyl and R
2
represents H or C
1
-C
4
alkyl).
with 1,2,5,6 tetrahdro-2-methyl-5,6 dioxo-1,2,4-triazin-3-thiol of formula (VI)
In presence of Vilsmeier reagent of the formula (V) in an organic solvent.
at temperature being maintained in the range −10° C. to +30° C.
The thioester of general Formula (I) thus 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 the general formula (II).
wherein, in formula (I), R
1
represents H, trityl, CH
3
, CR
a
R
b
COOR
2
(R
a
and R
b
independently of one another represents hydrogen or methyl and R
2
represents H or C
1
-C
4
alkyl).
In formula (III) R
3
represents CH
3
, —CH═CH
2
, CH
2
OCH
3
, CH
2
OCOCH
3
,
R
4
is hydrogen, salt, carboxylic protecting group or an inner salt.
R
5
is hydrogen or trialkylsilyl.
wherein formula (II), R
1
, R
3
and R
4
are as defined above.
Another embodiment of the present invention provides a method by which cephalosporin antibiotics are obtained in high purity and excellent yield without the necessity for protecting the amino group of the acylating agents and avoiding the production of toxic byproduct namely 2-mercaptobenzothiazole(MBT).
In one another embodiment of the present invention, the substituent R
3
in cephem compound (II) and (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-carbonylthiol. In general, R
3
represents —CH
2
—X wherein X is a residue of any organic or inorganic nucleophilic compound, e.g., halogen, hydroxy,

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