&bgr;-lactam production

Details &bgr;-lactam production &bgr;-lactam production

2001-10-11

2003-04-22

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

Reexamination Certificate

active

06552186

ABSTRACT:

The present invention relates to the production of &bgr;-lactams, such as pharmaceutically active &bgr;-lactams, e.g. cephalosporins, such as ceftriaxone or similar compounds.
In one aspect the present invention provides a process for the production of a compound of formula
wherein X and R
1
are substituents useful in cephalosporin chemistry and R
E
is hydrogen, a negative charge or together with the COO— group to which R
E
is attached is an ester, e.g. ceftriaxone or cefotaxime; comprising
i) reacting a compound of formula
 wherein R is hydrogen or silyl, R′
E
is silyl or together with the COO— group to which R
E
is attached is an ester; and X is as defined above, with a compound of formula
 wherein Y is halogen, Y′ is a group which forms a basis that a compound of formula III is in a reactive form; and R
1
is as defined above, to obtain a compound of formula
 wherein Y, X, R′
E
and R
1
are as defined above;
ii) reacting a compound of formula II wherein X, Y, R′
E
and R
1
are as defined above, with a compound of formula
 wherein R′ is hydrogen or silyl and R″ is silyl; to obtain a compound of formula
 wherein X, R
1
, R′ and R′
E
are as defined above, and desilylating a compound of formula VI to obtain a compound of formula I; or
ii′) desilylating a compound of formula II wherein Y, X, R′
E
and R
1
are as defined above, and reacting a desilylated compound of formula II with thiourea in a solvent system containing organic solvent and water; e.g. and an alcohol; to obtain a compound of formula I;
e.g. a compound of formula I in free form; e.g. or a compound of formula I in the form of a solvate, or in the form of an ester or in the form of a salt, or in the form of an ester or in the form of a salt, and in the form of a solvate.
In another aspect the present invention provides a process for the production of a compound of formula I, wherein X, R
1
and R
E
are as defined above, e.g. ceftriaxone or cefotaxime; comprising reacting a compound of formula II, wherein Y, X, R′
E
and R
1
are as defined above, with a compound of formula V wherein R′ and R″ are as defined above according to step ii) as defined above; or
desilylating a compound of formula II, wherein Y, X, R′
E
and R
1
are as defined above, and reacting a desilylated compound of formula II with thiourea according to step ii′) as defined above, to obtain a compound of formula I;
e.g. a compound of formula I in free form; e.g. or a compound of formula I in the form of a solvate, or in the form of an ester or in the form of a salt; or in the form of an ester or in the form of a salt, and in the form of a solvate.
A compound of formula I in free form, in the form of an ester and in the form of a salt; e.g. and in the form of a solvate; e.g. or in the form of a non-solvate, may be obtained.
A compound of formula I in free form, e.g. and in the form of a solvate or in the form of a non-solvate; may be converted in the form of an ester or in the form of a salt; e.g. and in the form of a solvate, or in the form of a non-solvate; and vice versa. A compound of formula I in the form of a solvate may be converted into a compound of formula I in the form of a non-solvate and vice versa. Conversion may be carried out according to a method as conventional, e.g. including a method as conventional.
It is one advantage of the present invention that a compound of formula II needs not to be isolated in the course of the reaction. It is another advantage of the present invention that a process of the present invention may be a one-pot process.
In a compound of formula I,
X is a substituent useful in cephalosporin chemistry. A substituent useful in cephalosporin chemistry includes e.g. a substituent according to a substituent conventional in cephalosporin chemistry, e.g. including a substituent conventional in cephalosporin chemistry. A substituent useful in cephalosporin chemistry includes a substitutent which is useful in pharmaceutically active cephalosporins; and a substituent which is useful in intermediates for the production of pharmaceutically active cephalosporins. Preferably X is alkyl or alkenyl, more preferably methyl or ethenyl; e.g. including unsubstituted or substituted alkyl and alkenyl; e.g. unsubstituted alkyl and alkenyl, and alkyl and alkenyl substituted by alkoxy, heterocylcylthio, heterocycylcarbonylthio; alkylcarbonyloxy, preferably methylcarbonyloxy, heterocycly;
R
1
is a substituent useful in cephalosporin chemistry. Preferably R
1
is unsubstituted or substituted alkyl, e.g. unsubstituted alkyl, or alkyl substituted by carboxyl. More preferably R
1
is methyl; carboxymethyl; or a group of formula —C(CH
3
)
2
COOH.
R
E
is hydrogen, a negative charge or is, together with the COO— group to which R
E
is attached, an ester group; e.g. an ester group useful in cephalosporin chemistry.
If R
E
is a negative charge, the group X may contain a positive charge; e.g. in the form of a positively charged amine.
If R
E
together with the COO— group to which R
E
is attached is an ester group R
E
preferably forms with the COO— group a physiologically hydrolysable and acceptable ester, e.g. R
E
is a substituent useful in cephalosporin chemistry.
A compound of formula I may thus be in the form of a physiologically-hydrolysable and -acceptable ester. By physiologically-hydrolysable and -acceptable esters as used herein is meant an ester in which the COO— group together with R
E
forms an ester which is hydrolysable under physiological conditions to yield an acid which is itself physilogically tolerable at dosages to be administered. The term “R
E
together with the COO— group to which R
E
is attached is an ester group” is thus to be understood as defining regular pro-drug forms of a compound of formula I. A group —OR
E
may be preferably a group which is easily hydrolysable under physiological conditions. Such esters may be administered preferably orally, since hydrolysis usually takes place under the influence of the digestive enzymes. Parenteral administration may be indicated if the ester per se is an active compound or, if hydrolysis occurs in the blood.
If not otherwise defined herein heterocyclyl includes e.g. 5 or 6 membered heterocyclyl; e.g. including a bicyclic ring system, e.g. of 10 to 12 carbon atoms; e.g. hetrocyclyl having 1 to 4 heteroatoms; e.g. selected from N,O or S; e.g. including unsubstituted heterocyclyl or substituted heterocyclyl, e.g. unsubstituted heterocyclyl or heterocyclyl substituted; e.g. by one or more substituents; e.g. by a substituent useful in cephalosporin chemistry; e.g. heterocyclyl substituted by alkyl e.g. including (C
1-4
)alkyl; carboxyalkyl; carbonyl. Alkyl includes (C
1-4
)alkyl. Alkenyl includes (C
2-4
)alkenyl. Alkoxy includes (C
1-4
)alkoxy. Silyl includes trialkylsilyl, e.g. trimethylsilyl. Halogen (halo-) includes bromide, chloride, iodide.
A solvent system or solvent (system) includes one or more individual solvents.
Preferably a compound of formula I is cefdinir (see e.g. Merck Index, 12
th
edition, item 1971), cefditoren (see e.g. Merck Index, 12
th
edition, item 1972), cefepime (see e.g. Merck Index, 12
th
edition, item 1973), cefetamet (see e.g. Merck Index, 12
th
edition, item 1974), cefixime (see e.g. Merck Index, 12
th
edition, item 1975), cefmenoxime (see e.g. Merck Index, 12
th
edition, item 1976), cefodizime (see e.g. Merck Index, 12
th
edition, item 1979), cefotaxime (see e.g. Merck Index, 12
th
edition, item 1983), cefpirome (see e.g. Merck Index, 12
th
edition, item 1990), cefpodoxime and cefpodoxime proxetil (see e.g. Merck Index, 12
th
edition, item 1991), ceftazidime (see e.g. Merck Index, 12
th
edition, item 191995), cefteram (see e.g. Merck Index, 12
th
edition, item 1996), ceftiofur (see e.g. Merck Index, 12
th
edition, item 1999), ceftiaxone (see e.g. Merck Index, 12
th
edition, item 2001), cefuzonam (see e.g. Merck Index, 12
th
edition, item 2003); more preferably a compound of formula I is ceftriaxone or

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