Method for the synthesis of irinotecan

Abstract

The present invention relates to a method for the synthesis of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (i.e. iriniotecan), comprising: (a) preparing 10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptotecin; and (b) selectively ethylating the compound of step (a) at the 7-position, thus resulting in the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin. The present invention is further directed to the use of 10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (i.e. 7-des-ethyl-irinotecan) as intermediate in a method for the synthesis of irinotecan as described.

Claims

1. A method for the synthesis of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin having the structure according to Formula (1), the method comprising: ##STR00006## (a) preparing 10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin by contacting 10-hydroxycamptothecin with chlorocarbonyl-4-piperidinopiperidine hydrochloride; and (b) selectively ethylating the compound obtained in step (a) at the 7-position, thus resulting in the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin.

2. The method of claim 1, wherein step (a) is performed in acetonitrile in the presence of at least one alkali metal carbonate or of a strong organic base.

3. The method of claim 2, wherein step (a) is performed in the presence of an alkali metal carbonate selected from the group consisting of Na.sub.2CO.sub.3, K.sub.2CO.sub.3, Rb.sub.2CO.sub.3, and Cs.sub.2CO.sub.3.

4. The method of claim 2, wherein step (a) is performed in the presence of a strong organic base and wherein said strong organic base is triethylamine.

5. The method of claim 1, wherein step (a) is performed at a temperature in the range between 20° C. and 80° C.

6. The method of claim 1, wherein step (b) is performed in the presence of ferrous sulfate, hydrogen peroxide, and propionic aldehyde.

7. The method of claim 5, wherein step (a) is performed at a temperature of 60° C.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1: Schematic representation of an established synthesis route for the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin that uses camptothecin as starting material and 10-hydroxycamptothecin as intermediate.

(2) FIG. 2: Schematic representation of an alternative established synthesis route for the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin that uses camptothecin as starting material and 7-ethylcamptothecin as intermediate.

(3) FIG. 3: Schematic representation of the synthesis route according to the presently claimed subject matter that uses 10-hydroxycamptothecin as starting material and 10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin as intermediate.

DETAILED DESCRIPTION OF THE INVENTION

(4) The present invention is related to the unexpected finding that 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonylcamptothcin (i.e., irinotecan) can be produced in high overall yield of more than 90% and virtually without contaminating by-products. The synthesis pathway is characterized by the use of 10-hydroxycamptothecin as starting material and 10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptotecin (i.e., 7-des-ethyl-irinotecan) as intermediate product for performing selective ethylation at the 7-position, thus interfering with the respective production of 11-ethyl-irinotecan and 7-ethyl-10-hydroxycamptothecin as adverse by-products.

(5) The present invention will be described in the following with respect to particular embodiments and with reference to certain drawings but the invention is to be understood as not limited thereto but only by the appended claims. The drawings described are only schematic and are to be considered non-limiting.

(6) Where the term “comprising” is used in the present description and claims, it does not exclude other elements or steps. For the purposes of the present invention, the term “consisting of” is considered to be a preferred embodiment of the term “comprising”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also to be understood to disclose a group, which preferably consists only of these embodiments.

(7) Where an indefinite or definite article is used when referring to a singular noun e.g. “a”, “an” or “the”, this includes a plural of that noun unless specifically stated otherwise.

(8) In case, numerical values are indicated in the context of the present invention the skilled person will understand that the technical effect of the feature in question is ensured within an interval of accuracy, which typically encompasses a deviation of the numerical value given of ±10%, and preferably of ±5%.

(9) Furthermore, the terms first, second, third, (a), (b), (c), and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.

(10) Further definitions of term will be given in the following in the context of which the terms are used. The following terms or definitions are provided solely to aid in the understanding of the invention. These definitions should not be construed to have a scope less than understood by a person of ordinary skill in the art.

(11) In one aspect, the present invention relates to a method for the synthesis of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin having the structure according to Formula 1, the method comprising:

(12) ##STR00005## (a) preparing 10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin; and (b) selectively ethylating the compound of step (a) at the 7-position, thus resulting in the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin.

(13) The overall reaction scheme of the method of the present invention is schematically illustrated in FIG. 3.

(14) In a first step, the method of the present invention comprises the preparation of 10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin, that is, 7-des-ethyl-irinotecan.

(15) In a specific embodiment, 10-hydroxycamptothecin is used as starting material for the preparation of 7-des-ethyl-irinotecan. 10-hydroxycamptothecin is an intermediate or byproduct in several other synthesis schemes, for example in the pathway illustrated in FIG. 1, and thus readily available. However, the use of other starting materials is possible as well, for example, the employment of camptothecin.

(16) Subsequently, a [4-(1-piperidino)-1-piperidino]carbonyl substituent is attached to the hydroxyl group at the 10-position of 10-hydroxycamptothecin in order to obtain 7-des-ethyl-irinotecan.

(17) In a preferred embodiment, this reaction step (i.e., when using 10-hydroxycamptothecin as starting material) is performed in acetonitrile in the presence of anhydrous carbonates of alkali metals or of a strong organic base. Any anhydrous carbonates of alkali metals or any strong organic base such as triethylamine, 4-dimethyl-aminopyridine, or ethyldiisopropylamine may be employed. Particularly preferably, the anhydrous carbonates of alkali metals are selected from the group consisting of Na.sub.2CO.sub.3, K.sub.2CO.sub.3, Rb.sub.2CO.sub.3, and Cs.sub.2CO.sub.3; and the strong organic base is triethylamine.

(18) In another preferred embodiment, the attachment of the [4-(1-piperidino)-1-piperidino]carbonyl substituent is performed at a temperature in the range between 20° C. and 80° C., particularly preferably at a reaction temperature of 60° C.

(19) The attachment of attachment of the [4-(1-piperidino)-1-piperidino]carbonyl substituent is a characterizing step of the method of the present invention with respect to an improvement of the selectivity for ethylation only occurring at the 7-position.

(20) The presence of the bulky carboxy-piperidino-piperidine group in 7-des-ethyl-irinotecan interferes with or even completely blocks an unwanted ethylation at the 11-position (commonly also referred to as “known effect of ortho-position”), resulting in the undesired byproduct 11-ethyl-irinotecan which is produced in significant amounts in the synthesis pathways for irinotecan that are established in the art, which, in turn, requires the implementation of additional reaction steps in order to remove the byproduct.

(21) It has also been found that 7-des-ethyl-irinotecan has a significantly better solubility as compared to camptothecin and 10-hydroxycamptothecin, respectively, which results in a reduction in the reaction volume required for performing the ethylation step. Finally, the carboxy-piperidino-piperidine group neutralizes the functionality of the 10-hydroxyl group as a trap for radicals which, in turn, would interfere with the subsequent ethylation at the 7-position.

(22) In a second step, the method of the present invention comprises the selective ethylation of 1-des-ethyl-irinotecan at the 7-position, thus resulting in the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, that is, irinotecan.

(23) In a particular preferred embodiment, the ethylation reaction is performed in the presence of ferrous sulfate, hydrogen peroxide, and propionic aldehyde, that is, through classical Fenton's chemistry (Fenton, H. J. H. (1894) J. Chem. Soc. Trans. 65, 899-911) being well established in the art.

(24) In a further particular preferred embodiment, the ethylation reaction is preceded by an esterification reaction at the C9-position in order to sterically interfere with an ethylation at the 11-position.

(25) The method of the present invention results in an increase in overall yield of irinotecan of up to 90-92% (as compared to the starting material) as well as a significantly improved selectivity of the ethylation reaction, thus resulting in the virtual absence of the unwanted byproduct 11-ethyl irinotecan which is very difficult to separate in order to increase the purity of the irinotecan preparation.

(26) In another aspect, the present invention is directed to the use of 10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin as intermediate in a method for the synthesis of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin as described herein.

(27) The invention is further described by the figures and the following examples, which are solely for the purpose of illustrating specific embodiments of this invention, and are not to be construed as limiting the claimed subject matter in any way.

EXAMPLES

Example 1

(28) 20 g of 10-hydroxycamptothecin are dissolved in 100 ml of acetonitrile, before adding 30 g of anhydrous K.sub.2CO.sub.3. Subsequently, a solution of 17.6 g of 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride is added to 300 ml of acetonitrile under stirring. Stirring is continued for about 6 hours at 60° C.

(29) Acetonitrile is evaporated, and the dry residue is dissolved in 200 ml dichloromethane. The organic layer is rinsed with 4×100 ml distilled water in order to remove non-organic impurities, and the solvent is evaporated. 400 ml of 40% H.sub.2SO.sub.4 are added to the dry residue at 20° C. After dissolution, 10.5 g of FeSO.sub.4×7 H.sub.2O is added, cooled to −10° C. and mixed with 10 ml of propionic aldehyde.

(30) The resulting solution of H.sub.2O.sub.2 and propionic aldehyde is cooled to 0° C. (75 ml of distilled water are cooled to 0° C. and 3.3 ml of 32% H.sub.2O.sub.2 and 5 ml of propionic aldehyde are added) and incubated in a smooth flowing manner for 150 min. The reaction product (i.e. irinotecan) is diluted with water to a volume of 3 l and transferred to chromatographic purification (Diaion sorbent resin).

Example 2

(31) 20 g of 10-hydroxycamptothecin are dissolved in 300 ml of acetonitrile. 20 ml of triethylamine are added along with 17.6 g of 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride. Stirring is continued for about 2 hours at 60° C.

(32) The reaction mass is evaporated to dryness. 300 ml of H.sub.2O are added and again evaporated. An aqueous solution of sulfuric acid (400 ml of 40% H.sub.2SO.sub.4) is added into the dry residue.

(33) Then, 10.5 g of FeSO.sub.4*7H.sub.2O are added at 20° C., cooled to −10° C. before propionic aldehyde is added (10 ml).

(34) The resulting solution of H.sub.2O.sub.2 and propionic aldehyde cooled to 0° C. (75 ml of distilled water are cooled to 0° C. and 3.3 ml of 32% H.sub.2O.sub.2 and 5 ml of propionic aldehyde are added) and incubated in a smooth flowing manner for 150 min. The reaction product (i.e. irinotecan) is diluted with water to a volume of 3 l and transferred to chromatographic purification (Diaion sorbent resin).

Example 3

(35) 20 g of Irinotecan are diluted in aqueous solution of sulfuric acid (400 ml of 40% H.sub.2SO.sub.4). FeSO.sub.4×7H.sub.2O (10.5 g) is added at 20° C., and the solution is cooled to −10° C. C before propionic aldehyde is added (10 ml). The resulting solution of H.sub.2O.sub.2 and propionic aldehyde cooled to 0° C. (75 ml of distilled water are cooled to 0° C. and 3.3 ml of 32% H.sub.2O.sub.2 and 5 ml of propionic aldehyde are added) and incubated in a smooth flowing manner for 150 min. 11-ethyl-irinotecan is not detected during analysis of the reaction product by means of HPLC.

Example 4

(36) When comparing the method of the present invention as illustrated in FIG. 3 with two methods for the synthesis of irinotecan that are established in the art (illustrated in FIG. 1 and FIG. 2, respectively) with respect to the numbers and types of unwanted reaction products it becomes immediately evident that the method of the present invention provides for superior results. The findings are summarized in the following table.

(37) TABLE-US-00001 Function in the process according to Compound name FIG. 1 FIG. 2 FIG. 3 10-hydroxycamptothecin intermediate virtually absent starting material irinotecan enantiomer by-product by-product by-product 7-des-ethyl irinotecan by-product by-product intermediate 7-ethyl-10-hydroxycamptothecin virtually absent intermediate virtually absent 11-ethyl irinotecan by-product by-product virtually absent 7-ethyl-camptothecin virtually absent intermediate virtually absent 7,11-diethyl-10- by-product by-product virtually absent hydroxycamptothecin camptothecin starting material starting material virtually absent

(38) The present invention illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising”, “including”, “containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by embodiments and optional features, modifications and variations of the inventions embodied therein may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.

(39) The invention has been described broadly and generically herein. Each of the narrower species and sub-generic groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

(40) Other embodiments are within the following claims. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.