This invention relates to an improved process for the preparation of 4'-demethyl-epipodophyllotoxin. 4'-Demethylepipodophyllotoxin of the formula II of the drawing accompanying this specification is an important precursor for the anticancer drugs like etoposide and teniposide. Etoposide (VP-16) is one of the most widely used and largest selling drug amongst the anticancer agents. Etoposide is a semisynthetic derivative of podophyllotoxin (a naturally occurring lignan lactone extracted from the roots and rhizomes of podophyllum peltatum and podophyllum embodi and is currently used in the treatment of small-cell lung cancer, testicular cancer, malignant lymphoma and other types of tumour. The precursor of etoposide 4'-demethylepipodophyllotoxin has been prepared in the literature by passing hydrogen bromide gas at 0°C and stirring at this temperature for 48 hrs followed by hydrolysis (as described by M. Kuhn, C. Keller-Juslen and A. Von Wartburg, Helvetica chemica Acta 1969, 52, 944). This is the only procedure known in the literature. The known process has many drawbacks such as the desired compound II is not only obtained in low yields but there are difficulties in the purification process as large number of side products are obtained in this reaction.
Therefore, the objective of the present invention is to provide an improved process for the preparation of 4'-demethylepipodophylltoxin (II) with improved yields. The present method is more simple and convenient as it is devoid of the generation of hydrogen bromide gas. Further this method offers the desired product in high yield (>75%), hence, this is an economically and practically attractive process.
Accordingly, the present invention provides an improved process for the preparation of 4'-demethylepipodophyllotoxin (II) which comprises reacting Podophyllotoxin of formula (I) of the drawing accompanying this specification with demethylating and iodinating agent other than hydrogen bromide in aprotic solvent between 0-40°C for a period in the range of 2 to 5 hours, subjecting to in situ hydrolysis in presence of a mild inorganic known base between 20 to 40°C for a period in the range of 1 to 3 hours, recovering and purifying the the 4'-demethylepipodophyllotoxin by known solvent extraction methods.
Statement of invention
In one of the embodiment of the present invention podophyllotoxin used is naturally occurring which is purified by column chromatography. In another embodiment of the invention the podophyllotoxin reacted with various demethylation or iodinating reagent systems such as chlorotrimethylsilane - sodium iodide, hexamethyldisiloxane -aluminium iodide, phenyltrimethylsilane - iodine and allyltrimethylsilane - iodine. In still another embodiment of the invention aprotic solvent used may be such as acetonitrile, dichloromethane, carbontetrachloride. In yet still another embodiment of the invention the base used may be such as BaCO3. CsCO3, K2CO3, Na2CO3 „
The process of the present invention is as illustrated in scheme I which comprise.
i) Isolating podophyllotoxin from the roots and rhizomes of Podophyllum peltatum
and Podophyllum embodi.
ii) Purification of podophyllotoxin using resin as adsorbent by column
chromatography.
iii) Reaction of podophyllotoxin by various demetylating and iodinating reagents to
form the 4-iodo-4'-demethylpodophylloioxin.
iv) Using various aprotic solvents for the simultaneous iodination and regioselective
demethylation such as acetonitrile, dichloromethane, carbontetrachloride etc.
v) Stirring the reaction mixture between 0°C to 40° C for 2 to 5 hrs
vi) In situ hydrolysis of the 4-iodo-4'-demethylpodophyllotoxin by bases likeBaCO3
or CsCO3 or K2CO3 to afford 4'-demethylepipodophyllotoxin.
vii) Stirring this reaction mixture between 20° to 40°C for 1 to 3 hrs
viii) Purification of (II) by recrystalisation using EtOAc/hexane.
The process of this invention is illustrated by the following examples. However, this should not limit the scope of this invention.
Example 1
Procedure : A solution of naturally occurring podophyllotoxin (2.0 mmol) in acetonitrile (95 ml) was added to the stirred suspension of sodium iodide (4.4 mmol) and chlorotrimethylsilane (4.4 mmol) in acetonitrile (20 ml). This reaction mixture was continued stirring for 4 hrs. After the formation of the intermediate as indicated by TLC, CsCO3 (4.8 mmol) and water (4 ml) was added subsequently to the reaction mixture and stirred for further 3 hrs. After the completion of the reaction as indicated by TLC, the reaction mixture was quenched with saturated sodium thiosulphate solution. Then the reaction mixture was diluted with ethyl acetate and organic layer was separated. This organic layer was washed with brine solution, dried over anhydrous Na2SO4 and evaporated under vacuum to give crude product. This is recrystallized from ethylacetate-hexane to give pure 4'-demethyl epipodophyllotoxin (75% yield). This is further purified for analytical purpose by column chromatography employing ethylacetate-hexane solvent system, m.p. 230-232°C. 'HNMR (DMSO-d6): 8.25 (1H, s), 6.97 ( H, s), 6.51 ( 1H, s ), 6.25 (2 H, s), 6.01 (2 H, s), 5.43 (1 H, d, J=6 Hz), 4.63-4.85 (1 H , m), 4.10-4.60 (3 H), 3.64 (6 H,s); IR(Nujol): 3410, 1750, 1618, 1520, 1508, 1490 cm"1 MS : 402 (M+, 20)
Example 2
Procedure : A solution of naturally occurring podophyllotoxin (2.0 mmol) in acetonitrile (95 ml) was added to the stirred suspension of iodine (4.4 mmol) and allyltrimethylsilane (4.4 mmol) in acetonitrile (20 ml). This reaction mixture was continued stirring for 4 hrs.
After the formation of the intermediate as indicated by TLC, CsCO3(4.8 mmol) and water (4 ml) was added subsequently to the reaction mixture and stirred for further 3 hrs. After the completion of the reaction as indicated by TLC, the reaction mixture was quenched with saturated sodium thiosulphate solution. Then the reaction mixture was diluted with ethyl acetate and organic layer was separated. This organic layer was washed with brine solution, dried over anhydrous Na2SO4 and evaporated under vacuum to give crude product. This is recrystallized from ethylacetate-hexane to give pure 4'-demethyl epipodophyllotoxin (75% yield). This is further purified for analytical purpose by column chromatography employing ethylacetate-hexane solvent system.

We claim:
1) An improved process for the preparation 4'-demethylepipodophyllotoxin of the
fonnula II of the drawing accompanied which comprises: reacting
podophyllotoxin with iodinating and demethylating agents other than hydrogen
bromide in aprotic solvent between 0-40°C for a period in the range of 2 to 5 hrs,
subjecting to in situ hydrolysis with a mild inorganic known base between 20-
40°C for a period in the range of 1 to 3 hrs, recovering and purifying the 4'-
demethylepipodophyllotoxin by known solvent extraction methods.
2) A process as claimed in claim 1, wherein iodinating and demethylating agents
selected from chlorotrimethylsilane-sodium iodide, phenylmethylsilane-iodide,
hexamethyldisiloxane-aluminium iodide, hexamethyldisilane-iodine and
allyltrimethylsilane-iodine.
3) A process as claimed in claims 1-2, wherein aprotic solvent used is such as
acetonitrile, dichloromethane. carbon tetrachloride.
4) A process as claimed in claims 1-3, wherein the base used is such as BaCO3
K2C03 CsC03, Na2C03.
5) A process as claimed in claims 1-5, wherein recovering is effected by extraction
the reaction mixture with solvents such as ethylacetate, chloroform,
dichloromethane and benzene.
6) A process as claimed in claims 1-6, wherein purification is effected by
recrystalisation using ethylacetate-hexane solvent system.
7) A process for the preparation of 4'-demethylepipodophyllotoxin of formula II
substantially as here in described with reference to the examples.