Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-02-12
2004-09-07
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S195000
Reexamination Certificate
active
06787649
ABSTRACT:
The present invention relates to &bgr;-lactams, more specifically to cephalosporins e.g. cefotiam, such as of formula
see e.g. Merck, 12
th
edition, item 1985.
An oral form of cefotiam for administration may contain cefotiam in the form of cefotiam hexetil, i.e. (6R,7R)-[1-(cyclohexyloxycarbonyloxy)ethyl]-7-[2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate; e.g. in the form of a dihydrochloride. A parenteral form may e.g. contain cefotiam in the form of a dihydrochloride.
Cefotiam, e.g. in the form of a dihydrochloride, which may be used as an intermediate in the production of cefotiam hexetil, may e.g. be produced by acylation of the amine group in (6R,7R) 7-amino-3-[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl]-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (7-ACMT) of formula
with 4-chloro-3-oxobutyryl chloride, followed by ring formation with thio urea to obtain the aminothiazolyl ring in the side chain attached to the amine group in position 7 of the ring structure.
We have found surprisingly a novel and simple process for the production of cefotiam.
In one aspect the present invention provides a process for the production of cefotiam, e.g. a compound of formula III, comprising
(i) acylating a compound of formula II; e.g. in the form of a salt, e.g. a salt with an halogenic acid, such as hydrochlorid acid, hydrobromic acid; e.g. a mono- or dihydrochloride; or a mono- or dihydrobromide; or a salt with tetrahydroboric acid; with a compound of formula
in an activated form; to obtain a compound of formula
e.g. in free form or in the form of a salt, e.g. an alkali metal salt, or a salt with an amidine, a guanidine, ammonia or an amine; preferably in the form of a salt with an amine; and
(ii) deformylating a compound of formula I to obtain a compound of formula III, e.g. in the form of a hydrochloride, such as a dihydrochloride.
Alkali includes e.g. sodium, potassium. An amidine includes e.g. DBU (1,8-diazabicyclo(5,4,0)undec-7-ene) and DBN (1,5-diazabicyclo(4,3,0)non-5-ene). A guanidine includes tetramethylguanidine. An amine includes an amine of formula NR
1
R
2
R
3
, wherein R
1
, R
2
, and R
3
independently of each other are hydrogen, alkyl, or aryl; or R
2
and R
3
together with the nitrogen atom to which they are attached denote heterocyclyl and R
1
is hydrogen, alkyl, aryl or represents an additional bond to form a double bond to R
2
or to R
3
. Preferably an amine includes e.g. tertiary amines, e.g. aliphatic, such as triethylamine, tributylamine, ethyldiisopropylamine; secondary amines, such as dibutylamine and primary amines, e.g. tert. octylamine (2,2,4-trimethylpentaneamine). If R
2
and R
3
together with the nitrogen atom to which they are attached are heterocyclyl, an amine includes cyclic unsaturated or saturated amines, such as N-methylpyrrolidine, N-ethylpiperidine, pyridine, chinoline. An amine may be unsubstituted or substituted; substituents include e.g. halogen, alkyl, e.g. (C
1-4
)alkyl; nitro, alkoxy, e.g. (C
1-4
)alkoxy. Preferably an amine is tributylamine. If not otherwise defined herein, alkyl includes (C
1-8
)alkyl, such as (C
1-4
)alkyl; and aryl includes phenyl, naphthyl, preferably phenyl. Heterocyclyl includes a saturated or unsaturated ring system; e.g. aliphatic or aromatic; e.g. having 5 to 7 ring members; e.g. being anelled to a further ring (system); e.g. of 4 to 12 ring members. Heterocyclyl may contain one or more, e.g. 1 to 4 hetero atoms; e.g. selected from O, S, N.
A solvent or a solvent system includes one single solvent and a mixture of two or more individual solvents.
A compound of formula I, e.g. in free form and in the form of a salt, is new.
In another aspect the present invention provides a compound of formula I, e.g. in free form or in the form of a salt; e.g. an alkali metal salt, or a salt with an amidine, a guanidine, ammonia or an amine, such as in the form of a salt with tributylamine, e.g. tri-n-butylamine.
In another aspect the present invention provides a process for the production of a compound of formula III, comprising deformylating a compound of formula I, e.g. in free form or in the form of a salt; e.g. an alkali metal salt, or a salt with an amidine, a guanidine, ammonia or an amine; to obtain a compound of formula III, e.g. in free form or in the form of a salt; e.g. a hydrochloride, such as a dihydrochloride; and isolating a compound of formula III.
A compound of formula I may e.g. be obtained by reaction of a compound of formula IV in an activated form, with a compound of formula II.
In another aspect the present invention provides a process for the production of a compound of formula I, comprising reacting a compound of formula IV in an activated form with a compound of formula II; and isolation of a compound of formula I.
A process according to the present invention may be carried out as follows:
A compound of formula II, in free form or in the form of an acid addition salt; e.g. an acid addition salt with hydrochloric acid, tetrafluoroboric acid; is dissolved in a solvent; e.g. an organic solvent; in the presence of a base; e.g. including ammonia, amines, amidines, guanidines; and is reacted with a compound of formula IV in an activated form. A compound of formula I is obtained in the form of a salt with
an amidine, e.g. if an amidine is used as a base;
a guanidine, e.g. if a guanidine is used as a base;
ammonia, e.g. if ammonia is used as a base;
an amine, e.g. if an amine is used as a base.
A compound of formula I, e.g. in the form of a salt, may be obtained in crystalline form. E.g. a compound of formula II in a solvent system is treated with a base and a compound of formula IV in an activated form; and a compound of formula I in the form of a salt may precipitate; e.g. on addition of an anti-solvent to the reaction mixture. An anti-solvent includes organic solvent which lowers the solubility product of a compound of formula I in a solvent on addition to said solvent.
A compound of formula I in free form may be obtained by treatment of a compound of formula I in the form of a salt, e.g. a salt with an amidine, a guanidine, ammonia or or an amine; with an acid; e.g. including a strong acid, e.g. a mineralic acid, such as hydrochloric acid, hydrobromic acid, hydrosulphuric acid; or mixtures of individual acids; e.g. in the presence of organic solvent and optionally in the presence of water.
A compound of formula I in the form of an alkali metal salt, e.g. including sodium and potassium, may be obtained, e.g. by treating a compound of formula I in free form with an alkali source, e.g. an alkali salt, e.g. a sodium or potassium salt, such as an alkali metal salt of a carboxylic acid, e.g. an alkali acetate, hexanoate; e.g. in the presence of an alcohol.
A solvent system includes e.g. halogenated, such as chlorinated, hydrocarbons, e.g. dichloromethane; nitriles, e.g. acetonitrile; ketones, e.g. acetone, methylethylketone, methylisobutylketone; ethers, e.g. tetrahydrofurane; esters, e.g. (C
1-3
)carboxylic acid (C
1-4
)esters; and mixtures of individual solvent, e.g. as described above. Anti-solvent includes solvent (system) as described above; water and alcohols, e.g. including(C
1-4
)alcohols.
In a preferred process of the present invention tributylamine, e.g. tri-n-butylamine, is used as a base; a compound of formula II is preferably in the form of a salt with hydrochloric acid or tetrafluoroboric acid; a preferred solvent includes acetonitrile.
The amount of the base used is not ciritcal; per equivalent of a compound of formula II one equivalent of a base may be used; or an higher amount of a base; e.g. 2 to 3 equivalents.
An additional amount of a base may preferably be used, e.g. 2 to 8 equivalents, e.g.
in the case that a compound of formula II is used in the form of an acid addition salt, e.g. a corresponding additional amount which is necessary to neutralize the acid which is set free durin
Kremminger Peter
Ludescher Johannes
Wolf Siegfried
Berch Mark L.
Furman Diane E.
Sandoz GmbH
Thallemer John D.
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