Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2001-01-08
2002-04-02
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C540S579000
Reexamination Certificate
active
06365735
ABSTRACT:
SUMMARY
The invention relates to a new process for preparing vinca alkaloids by reacting a product of catharanthine and vindoline type, characterised in that the reaction conditions are chosen so that vindoline is oxidised.
The invention relates to a process for preparing vinca alkaloids of the general formula (I)
in which:
R′
1
represents a hydrogen atom or an alkoxy, acyl, formyl or halogenoacyl group,
R′
2
represents a hydrogen atom or an alkyl group,
R′
3
and R″
3
are identical or different and each independently represents a hydrogen atom or a hydroxyl or alkanoyloxyl group, or else R′
3
and R″
3
together form a carbonyl group or else R′
3
and R′
5
together form an epoxy bridge or a double bond,
R′
4
represents a hydrogen atom or an alkyloxycarbonyl, hydroxymethyl or alkanoyloxymethyl group, preferably an alkyloxycarbonyl group,
R′
5
and R″
5
are identical or different and each independently represents a hydrogen atom or a hydroxyl, alkanoyloxyl, ethyl or 2-hydroxyethyl group,
R′
6
represents a hydrogen atom or an ethyl, 2-hydroxyethyl or acetyl group,
R′
7
represents a hydrogen atom or a cyanide group,
R
1
represents a hydrogen atom or an alkyl, formyl or acyl group, preferably hydrogen or an alkyl group,
R
2
represents a hydrogen atom or an alkoxy group,
R
3
represents a hydrogen atom or a hydroxyl or alkanoyloxyl group, or else R
3
and R
4
together form an epoxy bridge or a double bond,
R
4
represents a hydrogen atom or a hydroxyl or alkanoyloxyl group, or else R
4
and R
5
together form an epoxy bridge,
R
6
represents an alkyloxycarbonyl, hydrazido, acetamido, hydroxymethyl or alkanoyloxymethyl group,
R
5
and R
7
represent a hydrogen atom or a hydroxyl or alkanoyloxyl group, as well as their addition salts with acids and their quaternary ammonium salts.
Some derivatives of the formula (I) are known as being intermediates in the preparation of anti-tumor medicaments such as vinblastine, vincristine and vinorelbine.
R=CH
3
, vinblastine
R=CHO, vincristine
n=2, anhydrovinblastine
n=1, vinorelbine
The remarkable anti-tumor properties of these complex natural molecules, extracted from the Madagascar periwinkle,
Carantheus roseus
, are known and they are already used in anti-cancer treatment. Vinblastine and vincristine are “spindle poisons” which oppose the formation of the mitotic spindle during cellular division, thus preventing cellular proliferation.
Vincristine and vinblastine are active agents in the treatment of leukemia, lymphosarcoma and solid tumors. Vinblastine is also used in the treatment of Hodgkin's disease.
Vinorelbine is currently used in the treatment of the most widespread form of cancer of the lungs, that is lung cancer of non-small cells. It is also used in the treatment of metastasic cancers of the breast.
The methods currently used for preparing vinblastine and vincristine involve extraction of these molecules from plants. The plants have to be crushed and dried before these substances can be extracted. The extraction process is long and costly, given that the extract obtained is very complex, containing at least 200 different alkaloids. The yields are also very low; 5 to 10 g of vinoblastine are obtained per ton of dried plant material, and 0.5 to 1 g of vincristine per ton of dried plant material.
Many research groups have thus tried to achieve synthesis of these molecules by using more efficient procedures which enable better yields and which make use of derivatives with interesting anti-tumor properties but which are endowed with lower levels of toxicity.
The patent FI 882 755, filed by the HUATAN-MAKI Oy Company, relates to the formation of vinblastine and vincristine by irradiation of catharanthine and of vindoline with UV radiation in an acidic aqueous solution, under an atmosphere of oxygen or an inert gas. The yields obtained in these reactions are extremely low.
Furthermore, other processes are known which make use of anhydrovinblastine which is an intermediate in the synthesis of vinblastine, vincristine and also of vinorelbine.
Anhydrovinblastine is thus a key chemical intermediate which enables access to all alkaloids of the vinblastine type. This intermediate is synthesised by coupling catharanthine and vindoline.
The latter two alkaloids are also extracted from the Madagascar periwinkle but, in contrast to vincristine and vinblastine, they represent the main constituents of the extract obtained. In fact, 400 g of catharanthine per ton of dried plant material and 800 g of vindoline per ton of dried plant material are obtained.
The preparation of anhydrovinblastine by coupling catharanthine and vindoline is therefore a favoured route for synthesising this intermediate product.
There are several methods for preparing anhydrovinblastine from catharanthine and vindoline.
The patent FR 2 296 418 filed by ANVAR describes a process during the course of which the N-oxide of catharanthine is coupled to vindoline in the presence of trifluoroacetic anhydride.
When this process is performed at ambient temperature only the inactive 16′-R epimer of anhydrovinblastine is obtained. The naturally occurring active 16′-S epimer is obtained as the major product when this reaction is performed at a temperature which is at least 50° C. lower and under an inert gas. Nevertheless, even at low temperature, 10% of the 16′-R epimer of anhydrovinblastine is still produced.
This process has several disadvantages. The operating conditions are extremely restrictive due to the use of anhydrous solvents, the low temperature and the atmosphere of inert gas. The product obtained has to be subjected to a purification procedure due to the presence of 10% of the 16′-R epimer of anhydrovinblastine. The yield of isolated anhydrovinblastine is low, of the order of 35%.
A second process, suggested by VUKOVIC et al. in the review “Tetrahedron” (1998, volume 44, pages 325-331) describes a coupling reaction between catharanthine and vindoline initiated by ferric ions. Catharanthine is also oxidised in this reaction. The yield of anhydrovinblastine is of the order of 69% when the reaction is performed under an atmosphere of inert gas. However, this process has the major disadvantage that it leads to many secondary products. These are impurities resulting from further oxidation of the dimeric alkaloids formed, whatever the chosen operating conditions. This makes the purification stage difficult and delicate.
An improved process was suggested in the patent U.S. Pat. No. 5,037,977 and this increases the yield of anhydrovinblastine to 89%. However, this improvement is described only for very small amounts of reagents and its extension to the industrial scale seems to be difficult. In any case, these processes based on ferric ions lead in all cases to many secondary products due to the fact that these ions are responsible for parasitic reactions.
A third process described by GUNIC et al. in “Journal of the Chemical Society Chemical Communications” (1993), volume 19, pages 1496-1497, and by Tabakovic et al. in “Journal of Organic Chemistry” (1997), volume 62, pages 947-953, describes a coupling reaction between catharanthine and vindoline as a result of anodic oxidation of catharanthine. However, this process also suffers from disadvantages which, on the one hand, are due to the requirement for an inert atmosphere and, on the other hand, are connected with the nature of the electrochemical process itself, involving wear of the electrodes, difficulty in controlling the reproducibility and the cost of electrolytes. And, as in all the preceding methods, the anhydrovinblastine is contaminated with about 10% of the 16′-R epimer of anhydrovinblastine.
It should be noted that all the processes disclosed hitherto, without exception, involve splitting open the catharanthine molecule, this being induced by oxidation or activation of the latter. These processes are performed under restrictive conditions and do not permit satisfactor
Balasubramanian Venkataraman
Henderson & Sturm LLP
Raymond Richard L.
Roowin S.A.
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