Process for making camptothecin derivatives

Details Process for making camptothecin derivatives Process for making camptothecin derivatives

2003-07-25

2004-04-20

Aulakh, Charanjit S. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S048000

Reexamination Certificate

active

06723849

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a process for making certain camptothecin derivatives and will have application to a semi-synthetic process for making large quantities of highly lipophilic camptothecins that include one or more silicon atoms in the structure.
BACKGROUND OF THE INVENTION
Highly lipophilic camptothecin derivatives (HLCDs), particularly those containing silicon-based moieties, are effective anticancer drugs. One of the most noted of the silicon-containing HLCDs has the IUPAC name (4S)-4-ethyl-4-hydroxy-11-[2-(trimethylsilyl)ethyl]-1H-pyrano[3′:4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione, and has also referred to as 7-(2′-trimethylsilyl)ethyl camptothecin (also known as Karenitecin™ and BNP1350), currently in human clinical trials in the United States and internationally. U.S. Pat. No. 5,910,491 and others describe the compositions, formulations, and processes for making Karenitecin™ and other related HLCDs.
The currently known most preferred process for making Karenitecin™ is described and claimed in U.S. Pat. No. 6,194,579 (the '579 patent), incorporated herein by reference. In the '579 patent, Karenitecin™ and other silicon-containing HLCDs are manufactured by reacting camptothecin with a TMS-aldehyde and a strong oxidizing agent (hydrogen peroxide is preferred) in the presence of a metal sulfate to effect a Minisci-type alkylation. As described in the '579 patent, the resulting alkylation moiety contained one less carbon atom than the TMS-aldehyde, a typical characteristic of the Minisci alkylation.
The prior process for synthesizing Karenitecin was efficient in small-scale (gram) production, but improvements were necessary to enable efficient larger scale production. Improvements were needed primarily to boost yields (and accordingly reduce impurities), and to simplify the purification process. The prior process resulted in 50%-60% yields and had to be purified by column chromatography.
Other prior processes for synthesizing HLCDs can be found in U.S. Pat. No. 6,150,343 and others. These prior processes utilize a total synthesis route to synthesize the camptothecin skeleton. Due to the low yields and higher costs of these methods, they are considered impractical and inefficient for conducting large-scale synthetic operations.
SUMMARY OF THE INVENTION
The synthetic process of this invention is adapted to produce HLCDs having the following structure I:
wherein
A is —(CH
2
)
n
— where n is 1 to 6;
and R
1
, R
2
, and R
3
are individually lower alkyl or aryl.
The process is essentially a one-step process for synthesizing the preferred compounds from camptothecin. As is well known, camptothecin can be isolated from the bark of the
Camptotheca accuminata
tree, which grows primarily in Asia. The active form of camptothecin is the (S)-stereoisomer shown above, which can be purchased as a commercial product in substantially pure form from any of a number of commercial sources in China and India.
In the process of this invention, camptothecin is dissolved in a strong acid. Oxidizing agent is added to this solution, which is then added to the solubilized aldehyde reagent/metal sulfate solution. The aldehyde is dissolved in a nonpolar aprotic solvent, which both enhances the solubility of the aldehyde and minimizes the possibility of solvent reaction with the camptothecin.
Further, the mode of addition of reagents has been altered from the previous method. 30% sulfuric acid is utilized initially to solubilize the camptothecin, rather than being added to the camptothecin/aldehyde solution. This change limits the exothermic changes of the prior process, which decreases the possibility of polymerization of the aldehyde. Yields and purity are highly improved over prior processes for synthesizing Karenitecin.
Finally, extraction and other final processing steps were improved, and allow the process to be scaled up to make larger quantities (>50 g) of Karenitecin. The preferred process calls for extraction with dichloromethane, followed by washing of the extract, then recrystallizing the crude product from the extract using dimethyl formamide (DMF).
DETAILED DESCRIPTION OF THE INVENTION
The preferred embodiments depicted below are not intended to be exhaustive or to limit the invention to the precise forms disclosed. They have been chosen and described to explain the principles of the invention, and its application and practical use to thereby enable others skilled in the art to understand its teachings.
In this application, the term “lower alkyl” means a straight or branched chain hydrocarbon containing from one to six total carbon atoms. “Aryl means an aromatic ring system, fused or unfused, preferably from one to three total rings, with the ring elements consisting entirely of carbon atoms.
The process of this invention is employed to synthesize compounds of formula I, shown above. Preferred compounds synthesized by the process include those compounds where n is 1, 2 or 3, and R
1
, R
2
and R
3
are methyl, tert-butyl or phenyl. The process is depicted in the following Schemes.
Scheme 1 illustrates the recrystallization of camptothecin from its natural product. The recrystallization is preferably carried out at elevated temperatures, in any organic solution that will dissolve camptothecin, most preferably N,N-dimethyl formamide. The end product is substantially pure (preferably no less than 90%, most preferably no less than 98%) S-camptothecin.
Scheme 2 illustrates the preparation of the aldehyde reactant by oxidation from the corresponding alcohol. In the Scheme, m is 0 to 5 and the alkylene chain linking the terminal silane to the alcohol (aldehyde) may be straight-chain or branched-chain, as desired. Preferably, m is 1 to 3, most preferably 1, and the most preferred end product is 3-trimethylsilyl-1-propanal.
The process shown in Scheme 2 is preferably a one-step, single pot process. The alcohol is generally available from commercial sources, as are the reagents. As shown, the alcohol is reacted with one or more oxidizing agents, such as sodium hypochlorite, hydrogen peroxide, and others, in the presence of a catalyst, such as 2,2,5,5-tetramethyl piperidino-1-oxo (TEMPO). The reaction is carried out at room temperature and generates highly pure (90%+) concentrations of the desired end product.
Scheme 3 illustrates the conversion of (S)-camptothecin to the desired formula I compound. The conversion is preferably achieved through a modified Minisci-type alkylation reaction. A Minisci-type alkylation utilizes aldehyde in the presence of hydrogen peroxide and metal sulfate to effect an alkylation that is one carbon atom fewer than the aldehyde.
In the process of this invention, as depicted in Scheme 3, the modified Minisci-type alkylation provides for first mixing the aldehyde and the metal sulfate reagents in a strong acid solution, and agitating to produce a homogenous solution. To the mixture is added a nonpolar, aprotic co-solvent, preferably an ether or diether, most preferably 1,2-dimethoxy ethane (Monoglyme®). The cosolvent is preferably non-reactive with the other reagents and inhibits the formation of undesired side products often found in a Minisci-type alkylation reaction. In the prior processes to synthesize formula I compounds, the major undesired side product included the N-oxide form of camptothecin, and resulted in low yields and purity.
After premixing the aldehyde and metal sulfate, camptothecin from Scheme 1 is dissolved in a strong acid, and a strong oxidizing agent, preferably hydrogen peroxide. The camptothecin solution is then slowly added to the aldehyde/metal sulfate solution, and the temperature controlled. Preferred addition times depend upon the amount, generally between 10 mL/min to 2000 mL/min, most preferably between 25 mL/min to 500 mL/min. The temperature is controlled by conventional means, and is preferably kept below about 50° C., most preferably below 40° C. Additional oxidizing agent is preferably added to the mixture after the initia

Affiliated with

Also associated with

Rating

Process for making camptothecin derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for making camptothecin derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for making camptothecin derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3188296