Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-09-30
1998-11-24
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D49122
Patent
active
058408991
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a new process for the preparation of 9-amino-20(S)-camptothecin of formula (I) ##STR4## which is a known antitumor agent: Wani et al., J. Med. Chem. 1987, 30, 1774-1779; Hsiang et al., Cancer Res. 49, 4385-4389, Aug. 15, 1989; Cancer Res. 49, 1465-1469, Mar. 15, 1989.
BACKGROUND OF THE INVENTION
In our patent application filed on Aug. 6, 1993 in the United Kingdom as UK 93 16352.5, a method for the preparation of 9-amino camptothecin comprising the steps illustrated in the below Scheme A was disclosed. ##STR5## wherein X is a group which can be removed reductively.
When the reduction of a compound of formula (d) wherein X is halogen is carried out in a single step by using, to catalyze this reaction, for example, palladium supported on Carbon (Pd/C), the desired product is obtained with an impurity of halo-amino derivative which is difficult to separate and consequently, it is a problem to isolate 9-amino camptothecin in pure form without affecting the overall yields.
We have found a new process which eliminates or minimises the presence of the undesired by-product and in the meantime permits the use not only of a 12-halogen, but also of a 10-halogen derivative as a substrate of the reductive reactions which lead to the 9-amino camptothecin.
Accordingly, the present invention provides a new process for preparing 9-amino camptothecin of formula (I) starting from a compound of formula (II), according to the steps illustrated in Scheme I below: ##STR6## wherein Hal is 10- or 12-halogen.
The process comprises the reductive transformation of a 10- or 12-halogen derivative of formula (II) either in a single step, or alternatively, in two steps reducing first a compound of formula (II) to the compound of formula (III) and, further, reducing the compound of formula (III) to the compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparing 9-amino camptothecin of formula (I) ##STR7## which comprises:
1) reducing a compound of formula (II) ##STR8## wherein Hal is 10- or 12-halogen, in a single step to the 9-amino camptothecin of formula (I) or, alternatively, 2a) reductively removing the Hal group from a compound of formula (II) so obtaining the compound of formula (III) ##STR9## and
2b) reducing the compound of formula (III) so obtaining the 9-amino camptothecin of formula (I); the said steps. 1) and 2a) and, optionally, step 2b) each being carried out in the presence of a catalytic amount of a compound of formula PdL.sub.2 wherein L is acetate (--COO--CH.sub.3) or halogen and, additionally, in the presence of an ammonium formate as a hydrogen source.
In the formulae of the present specification, a dotted line ( . . . ) indicates a substituent below the plane of the ring; a wedged line (z,1 ) indicates a substituent above the plane of the ring.
Preferably the halogen Hal is Br or Cl.
Preferably PdL.sub.2 is Pd(OOC--CH.sub.3).sub.2 or PdCl.sub.2.
The reductions under steps 1), 2a) and, optionally, 2b) may each be carried out in the presence of a catalytic amount, for example from 0.01% to 0.2% by weight of a compound of formula PdL.sub.2 wherein L is acetate or halogen and, additionally, in the presence of, for example, from 1 to 10 molar equivalents of a suitable ammonium formate such as ammonium formate or triethylammonium formate (which may be also prepared in situ). The reductions may be performed in a suitable solvent such as dimethylformamide (DMF), MeOH, CHCl.sub.3, dioxane or mixture thereof. They are typically carried out at a temperature of from room temperature to about 150.degree. C., preferably from about 40.degree. C. to about 100.degree. C. The reductions can each be carried out for a time which may vary from, for example, few minutes to one day, preferably from about 5 minutes to about 12 hours.
The reduction in step 1) may be carried out in the presence of, e.g., from 4 to 6 molar equivalents of an ammonium formate. Suitable ammonium formates are, for example, ammonium formate and t
REFERENCES:
patent: 5106742 (1992-04-01), Wall et al.
patent: 5225404 (1993-07-01), Giovanella et al.
patent: 5602141 (1997-02-01), Bedeschi
patent: 5614628 (1997-03-01), Cabri et al.
Bedeschi Angelo
Cabri Walter
Candiani Ilaria
Zarini Franco
Daus Donald G.
Pharmacia S.p.A.
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