Method for synthesis of 4beta-amino-4'-demethyl-4-desoxypodophyllotoxin

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 4β-amino-4'-demetyl-4-desoxypodophyllotoxin of formula (1), involving the following steps: a) reaction of thiourea and 4β-halogenoacetamido-4'-demethyl-4-desoxypodophyllotoxin in a medium of a weak pure acid or mixture of acid, water an organic solvent without using any other solvent at temperature higher than ambient temperature; b) extraction of 4β-amino-4'-demethyl-4- desoxypodophyllotoxin.

EFFECT: compound is an intermediate product in synthesis of anti-cancer compounds.

22 cl, 1 tbl, 1 ex

The technical field to which the invention relates.

The present invention relates to a method for producing 4β-amino-4'-demethyl-4-methoxymethylethoxy formula 1 of 4β-halogenoacetyl-4 demethyl-4-methoxymethylethoxy formula 3 (X=Cl, Br or I) splitting in the presence of thiourea and acid. In particular, the invention concerns a method of obtaining 4β-amino-4'-demethyl-4-methoxymethylethoxy formula 1 of 4'-demethylepipodophyllotoxin formulas 2 through 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy formula 3 (X=Cl, Br or I).

The level of technology

4β-amino-4'-demethyl-4-methoxymethylethoxy is a synthetic intermediate compound used in the production of anti-cancer compounds (application for French patent No. 0404053).

Technology of production of this intermediate compound is based on the conversion of 4'-demethylepipodophyllotoxin (formula 2) 4β-azido-4'-demethyl-4-methoxymethylethoxy formula 4, followed by catalytic oxidation of this derived azide to amine derivative of formula 1. The problem with this transformation is the lack of stereoselectivity conversion of the activated derivative at position 4 (pasilabinimo), providing a mixture of azides α and β of formula 4. This problem is partially solved through the use of sodium azide and triperoxonane acid, see J. Med. Chem. 1991, No. 34, str. However, you need to clean the intermediate connection azide of formula 4 using chromatography, and the product by catalytic reduction, i.e. amine of formula 1. Another method disclosed in Chinese Chemical Letters, 1993, No. 4 (4), str. These authors use the method with the use of azide by reaction between the nitrogen-hydrogen acid HN₃(prepared in situ) in the presence of epirate BF₃at -10~-15°C. Obtained by these authors, the results indicate a high stereoselectivity transformation ratio output not less than 80%. The method of conversion of the azide of formula 4 in the amine of formula 1 is described in Tet. Let., 1999, No. 40, str and Tet. Let., 2000, str. These authors applied the samarium iodide in t-BuOH and THF (tetrahydrofuran) or in a double connection FeSO₄·7H₂O/NH₃. Recently, a confirmation message prompts you to clean chromatography, Bioorg. Med. Chem., 2003, No. 11, str. The authors have obtained amine of formula 1 when the yield factor of 70%.

However, these methods create two problems: 1) the use of hazardous derived azide, which is potentially explosive, especially when used in large mass is Taba in industrial production of medicaments; 2) the need for one or even two stages chromatography to obtain compound "Amin" formula 1 high quality to produce the target product, namely anti-cancer drug, which are costly steps in industrial scale production.

Disclosure of inventions

The present invention is to solve both of these problems, i.e. removal of hazardous or explosive compounds and stages of purification by chromatography.

4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy, which is an intermediate compound of formula 3, is a known compound (application for French patent No. 0404053, WO 2004/073375). Also known transition of the compounds of formula 2 to the compound of formula 3 (application for French patent 0404053). Therefore, an object of the invention is the method of synthesis of compounds of formula 1 from the compound of formula 3.

In traditional organic synthesis splitting chloracetamide to obtain amines are produced by processing the derived chloracetamide tertiary amide-thiourea in ethanol in the presence of acetic acid at the optimum ratio of 5:1 (A.Jirgensons and other Synthesis, 2000, str). When this reaction is applied ethanol and acetic acid does not contain water. This method has never been used for a number of podophylla oxine and for this it is not suitable. Indeed, as applied in the case of the compound of formula 3, this method results in 10 hours at reflux distilled to convert less than 10% of the source material (the compound of formula 3), and the reaction intermediate compound (X=S - isothiouronium in the form of chloride) is no longer reacts (see comparative example). A longer reaction time is unfavorable from the viewpoint of purity, which is so formed as secondary products.

It took the adaptation and improvement of methods to achieve the required conversion. Unexpectedly, the inventors have established a method for the synthesis of the compounds of formula 1 from the compound of formula 3, which allows to obtain the compound of formula 1 with a high degree of purity without additional purification steps (in particular, chromatography).

The object of the invention is a method for the synthesis of 4β-amino-4'-dimethyl-4-methoxymethylethoxy formula 1:

characterized in that it comprises the following successive stages:

a) carrying out the reaction in an environment of weak net acid without another solvent at a temperature above ambient temperature, between thiourea and 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy formula 3:

where: X represents a halogen atom selected the CSOs from the group consisting of chlorine, bromine and iodine, preferably chlorine;

b) removing 4β-amino-4'-demethyl-4-methoxymethylethoxy.

In respect of the method of splitting chloracetamide described in the prior art (A.Jirgensons etc., Synthesis, 2000, str), it was found that this operation can be carried out in a pure weak acid, i.e. without the presence of water or an organic solvent. In the sense of the present invention the use of the term "acid" goes back to its definition on Bronsted (Bronsted), namely it is a chemical substance that can lose a proton H⁺. A weak acid is an acid, which is in contrast to the strong acid is not dissociated completely in the water.

A weak acid is characterized mainly by the pH value from 4 to 6 at 25°C. In particular, a weak acid is predominantly carboxylic acid of formula 5, R-COOH, where R is a hydrogen atom or an alkyl radical with 1 or 2 carbon atoms. More severe acid now not used as a solvent, they do not have acceptable pouchetii (in particular, butyric acid). In particular, the weak acid is selected from the group consisting of formic, acetic or propionic acid, preferably acetic acid.

The following relations between the different compounds correspond to sootnosheniyami, used for these compounds, unless otherwise specified.

In the framework of the present invention, the expression "pure weak acid" means that the acid is glacial, i.e. not containing water. The expression "without another solvent" means that the reaction medium in step a) contains only pure weak acid, the compound of formula 3 and thiourea, therefore, it does not contain water or another solvent, such as alcohol or an organic solvent.

At the step a) reaction medium is preferably heated to temperatures above 60°C, more preferably to a temperature of from 60 to 100°C. Another characteristic of the invention is that used pure weak acid serves as a solvent during the reaction. The molar ratio between 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy and a weak acid is not less than 0.5.

The molar ratio between 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy and thiourea is preferably from 0.5 to 1. According to the optimal execution of the invention in step a) 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy lead in contact with a pure weak acid before the addition of thiourea. Another, better option 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy and pure weak acid is that are in contact with one another, and 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy is preferably in suspension in pure weak acid, and the reaction medium is heated to the desired temperature before the addition of thiourea at this temperature.

The duration of the reaction in stage a) is preferably from 1 to 3 hours. In case of use of pure acetic acid duration of the reaction in step a) is about 2 hours.

At the end of step a) target product formula 1 precipitates in the reaction medium. It is extracted in the step (b) any known to the average expert way, in particular, a simple filtration and drying by conventional methods are sufficient.

After filtering and drying in the usual way compound of formula 1 in the form of hydrochloride, bromhidrosis or hodgert get with an average molar yield of over 85%, preferably more than 90% of the molar amount of the compounds of formula 3. In case of use of pure acetic acid compound of formula 1 in the form of hydrochloride, bromhidrosis or hodgert get with an average molar yield of 93% of the molar amount of the compounds of formula 3.

The compound of formula 1 is preferably obtained when the degree of purity of more than 90%, more preferably 95% or more.

The compound of formula 1 obtained in the form of hydrochloride, bromhidrosis or is oggidata, is clean and does not require an additional step of purification by chromatography. It can be directly used in the subsequent steps of the synthesis, which is a significant advantage from the standpoint of cost-effective production on an industrial scale.

The object of the present invention is also a method for the synthesis of 4β-amino-4'-demethyl-4-methoxymethylethoxy formula 1:

characterized in that it comprises the following successive stages:

i) carrying out the reaction in a mixture of acid, water and an organic solvent at a temperature above the ambient temperature between thiourea and 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy formula 3:

where X means a halogen atom selected from the group consisting of chlorine, bromine and iodine, preferably chlorine;

ii) removing 4β-amino-4'-demethyl-4-methoxymethylethoxy.

In respect of the method of splitting chloracetamide disclosed in the prior art (A.Jirgensons etc., Synthesis, 2000, str), it was found that adding water to the reaction environment contributes to the reaction, accompanied by complete consumption of starting material without the formation of degradation products.

Preferably, the reaction medium did not contain any other solvent and reagent. In phase i), the reaction medium is preferably heated to a temperature above 60°C, more preferably to a temperature of from 60 to 100°C. the Molar ratio of 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy and timesaving is preferably from 0.5 to 1. In phase i) 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy preferably brought into contact with a mixture of acid, water and an organic solvent before the addition of thiourea. More optimally, when 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy and a mixture of acid, water and an organic solvent will result in contact between them, while preferably, 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy were suspended in the above-mentioned mixture, and the reaction medium is heated to the desired temperature before the addition of thiourea at this temperature.

Preferably, the organic solvent used in the second method according to the invention, represented a water-soluble organic solvent, more preferably, to be selected from the group consisting of cyclic ethers, in particular dioxane, alcohols, in particular methanol, ethanol, propanol and isopropanol, and N,N-dimethylacetamide, dimethylformamide and N-methylpyrrolidone.

In the first preferred embodiment of the second method according to the invention the organic solvent is an alcohol, preferably ethanol.

Under this first option, the acid is preferably a strong acid, in particular selected from the group consisting of hydrochloric, sulfuric and phosphoric acids. The volume ratio of alcohol/water + strong acid) is preferably 2-5:0.5 to 2, more preferably of 2.5:1, with a strong acid has a normality of from 1 to 2. The compound of formula 1 is preferably obtained with a molar yield of over 80%, more preferably more than 85%, in particular 90%. The duration of the reaction is preferably more than 8 hours but less than 10 hours, more preferably about 9 hours.

The compound of formula 1 also preferably be obtained with purity of over 90%, in particular 95%.

Alternatively, in the first option, preferably use a weak acid, in particular carboxylic acid of formula 5, R-COOH, where R is a hydrogen atom or alkylpyridine with 1-2 carbon atoms. More severe acid now not used as solvents and do not have acceptable properties pouchetti (in particular, butyric acid). In particular, the weak acid is selected from the group consisting of formic, acetic or propionic acid, preferably acetic acid. The volume ratio of alcohol/water/weak acid is preferably 2-10:0.5 to 2:0.5 to 2, more preferably 5:1:1. In particular, the volume ratio of ethanol/water/acetic acid is preferably 5:1:1.

The compound of formula 1 are preferably in a molar yield of more than 55%, preferably 60%. The duration of the reaction is preferably more than 8 hours but less than 11 hours, more preferably about 10 hours.

The compound of formula 1 are preferably in a purity of more than 90%, in particular 95%.

In the second preferred embodiment of the second method according to the invention the organic solvent is a cyclic simple ether, in particular dioxane, N,N-dimethylacetamide, dimethylformamide and N-organic.

The volume ratio of the cyclic simple ether (dioxane) or N,N-dimethylacetamide, dimethylformamide and N-organic/water/weak acid (acetic acid) is preferably 2-10:0.5 to 2:0.5 to 2, more preferably 5:1:1. The volumetric ratio of dioxane or N,N-dimethylacetamide dimethylformamide and N-organic/water/acetic acid is preferably 5:1:1. The compound of formula 1 is preferably obtained when the molecular output of more than 60%, more preferably more than 65%, in particular 70%. The duration of the reaction was preferably more than 4 hours but less than 10 hours, more preferably about 5-6 hours.

The compound of formula 1 is preferably obtained with a purity of more than 90%, preferably 95%.

In the studied cases, the desired product precipitated in the reaction medium. It was removed in step b) by any known to the average expert way, in particular, a simple filtration and drying by known methods are sufficient.

The obtained compound of formula 1 in the form of hydrochloride, bromhidrosis or hodgert was clean and did not require additional purification step chromatography. It can be used directly in the subsequent steps of the synthesis, providing a significant advantage from the standpoint of cost-effective production on an industrial scale.

Within the first or second method according to the invention 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy formula 3 receive preferably the reaction between the 4'-demethylepipodophyllotoxin formula 2:

and halogenoacetyl formula 6 X-CH₂- C≡N, where X means a halogen atom selected from the group consisting of chlorine is, bromine and iodine, in an acidic environment. This is followed by a Ritter reaction for the direct capture of 4β-chloroacetamido-4'-demethyl-4-methoxymethylethoxy crystallization at the end of the reaction when the ratio of the output preferably more than 80%, more preferably more than 90%.

This intermediate compound possesses exclusively the β stereochemistry on the carbon atom in position 4. At this stage the problem of stereochemistry. Purity specified intermediate compounds is that this connection can be used without additional purification phase splitting to receive 4β-amino-4'-demethyl-methoxymethylethoxy formula 1.

4'-demethylepipodophyllotoxin formula 2 (obtained by the method described in French patent No. 2742439) is preferably treated with chloroacetonitrile, regular and cheap reagent, together with sulfuric acid. Therefore, 4β-chloroacetamido-4'-demethyl-4-detoxicification preferably obtained when the ratio of the yield of 93%.

After filtering and drying in the usual way compound of formula 1 in the form of hydrochloride, bromhidrosis or hodgert receive as a result of applying ice pure acetic acid (without water and other organic solvent, the first method according to the invention) with an average molar yield of 86% of the molar amount of 4β-demethylepipodophyllotoxin is a (formula 2), i.e. in two stages (from compounds of formula 2 to the compound of formula 3, then from the compounds of formula 3 to the compound of formula 1).

The implementation of the invention

The following examples show methods used.

Example 1. Getting 4β-chloroacetamido-4'-demethyl-4-methoxymethylethoxy (formula 3)

In a suspension of 30 g (0,075 mol) of 4'-demethylepipodophyllotoxin 47.5 ml of 0.75 mole) of chloroacetonitrile add drops of 0.5 ml of concentrated sulfuric acid at ambient temperature. Shaken for one hour at the same temperature, while watching the dissolution and re-precipitation. Add 300 ml of 2-propanol. The precipitate is filtered, washed with 200 ml of 2-propanol and water until pH 7. The obtained solid white dried in vacuum at 40°C and received from 32.9 g of compound chloracetamide formula 3. The molar yield was 93%.

Melting point F 240°C.

The NMR analysis of the proton:¹N Yarm (DMSO) δ 8,65 (d, 1H, J=7 Hz, NH), compared to 8.26 (s, 1H, 4'-OH), 6,78 (s, 1H, H₅), is 6.54 (s, 1H, H₈), 6,24 (s, 2H, H_2'N_6'), of 5.99 (d, 2H, J=11.3 Hz, OCH₂O)to 5.17 (dd, 1H, J=4,56 and 7 Hz, H₄), 4,51 (d, 1H, J=5,2 Hz, H₁), the 4.29 (t, 1H, J=8 Hz, H_11a), 4,10 (s, 2H, CH₂Cl), of 3.97 (m, 1H, H₃), of 3.78 (dd, 1H, J=8 Hz and 10 Hz, H_11b), 3,63 (s, 6H, 2×och₃)and 3.15 (dd, 1H, J=5,2 and 14 Hz, H₂).

Other halogenoacetyl (X=Br, I) can be the ü obtained similarly using bromoacetonitrile or idatetime.

Comparative example. Getting 4-amino-4'-demethyl-4-methoxymethylethoxy (formula 1). Method using ethanol/acetic acid 5:1 (Synthesis, 2000, str).

Table 1: experiment 1.

A suspension of 0.5 g (1.05 mmole) 4β-chloroacetamido-4'-demethyl-4-methoxymethylethoxy obtained in example 1 in a mixture of 2.5 ml of ethanol and 0.5 ml of glacial acetic acid is brought to 80°C with shaking. Once imposed 0.12 g (of 1.57 mmole) of thiourea. Shaken at this temperature for 10 hours. Analysis of the reaction medium thin-layer chromatography showed the presence of only less than 10% of the desired product 4β-amino-4'-demethylepipodophyllotoxin (formula 1) from the present intermediate isothiouronium (X=S-isothiouronium), which is entered into the reaction, and the products of decomposition.

Example 2. Getting 4β-amino-4'-demethyl-4-methoxymethylethoxy (formula 1). Method with the use of pure glacial acetic acid, the first method according to the invention.

Table 1: experiment 2.

A suspension of 17 g (0,0358 mole) 4β-chloroacetamido-4'-demethyl-4-methoxymethylethoxy obtained in example 1 in 75 ml of glacial acetic acid is heated to 80°C with shaking. Add once 4,2 g (0,0537 mole) of thiourea. At this temperature, shaken for 1.5 hours, while watching the dissolution and re-precipitation. R is the promotional environment is filtered in the hot state, washed with 75 ml of glacial acetic acid and diisopropyl ether. The obtained solid white dried in vacuum at 40°C. the Obtained 14.6 g of the compounds of formula 1 in the form of a hydrochloride in a molar yield of 93%.

Melting point F was more than 260°C.

The NMR analysis of the proton:¹N Yarm (DMSO) δ 8,63 (m, 2H), 8,32 (m, 1H), 7.23 percent (s, 1H, H₅), 6,60 (s, 1H, H₈), 6,18 (s, 2H, H_2'N_6'), equal to 6.05 (d, 2H, J=2.1 Hz, och₂About), to 4.73 (d, 1H, J=4.5 Hz, H₄), 4,56 (d, 1H, J=5,2 Hz, H₁), 4,34 (m, 2H, H_11aand H_11b), the 3.65 (dd, 1H, J=5,2 Hz, H₂), 3,62 (s, 6H, 2×och₃), 3,06 (m, 1H, H₃).

Example 3. Getting 4β-amino-4'-demethyl-4-methoxymethylethoxy (formula 1). Method using ethanol and hydrochloric acid 1N, the second method according to the invention, the first option, the first alternative.

Table 1: experiment 3.

A suspension of 0.5 g (1.05 mmole) 4β-chloroacetamido-4'-demethyl-4-methoxymethylethoxy obtained in example 1 in a mixture of 2.5 ml of ethanol and 1 ml of 1N hydrochloric acid is heated to 80°C with shaking. Once added 0.12 g (of 1.57 mmole) of thiourea. When the specified temperature is shaken for 9 hours to see the dissolution and re-precipitation. The cooled reaction medium is filtered, washed with ethanol and diisopropyl ether. The obtained solid white dried in vacuum at 40°C. the Obtained 0.4 g of the compound is ormula 1 in the form of a hydrochloride in a molar yield of 90%.

Melting point F amounted to over 260°C.

Example 4. Getting 4β-amino-4'-demethyl-4-methoxymethylethoxy (formula 1). Method using ethanol/water/acetic acid (5:1:1), the second method according to the invention, the first option, the second option.

Table 1: experiment 4.

A suspension of 0.5 g (1.05 mmole) 4β-chloroacetamido-4'-demethyl-4-methoxymethylethoxy obtained in example 1 in a mixture of 2.5 ml of ethanol, 0.5 to water and 0.5 glacial acetic acid is heated to 80°C with shaking. Once added 0.12 g (of 1.57 mmole) of thiourea. At the same temperature was shaken for 10 hours, while watching the dissolution and re-precipitation. The cooled reaction medium is filtered, washed with ethanol and diisopropyl ether. The obtained solid white dried in vacuum at 40°C. the Obtained 0.27 g of the compound of formula 1 in the form of a hydrochloride in a molar yield of 60%.

Melting point F amounted to over 260°C.

Example 5. Getting 4β-amino-4'-demethyl-4-methoxymethylethoxy (formula 1). Method using solvent (N,N-dimethylacetamide, dioxane)/water/acetic acid, the second method according to the invention, the second option.

Table 1: experiment 5.

A suspension of 0.5 g (1.05 mmole) 4β-chloroacetamido-4'-demethyl-4-methoxymethylethoxy obtained in example 1 in a mixture of 2.5 ml of dioxane or N,N, 0.5 ml water and 0.5 ml of glacial acetic acid is heated to 80°C with shaking. Once added 0.12 g (of 1.57 mmole) of thiourea. When the specified temperature is shaken for 5-6 hours, while watching the dissolution and re-precipitation. The cooled reaction medium is filtered, washed with 2-propanol and diisopropyl ether. The obtained solid white dried in vacuum at 40°C. the Obtained 0.31 g of compounds of formula 1 in the form of a hydrochloride in a molar yield of 70%.

Melting point F amounted to over 260°C.

The results of the experiments obtained in the comparative example and in examples 2-5, presented in the following table 1.

Table 1 shows a significant advantage, and it does so in the case of use of pure glacial acetic acid at 80°C during the short duration of the reaction, 2 h, to obtain the desired product with excellent yield coefficient with providing very satisfactory purity for subsequent use in the synthesis of anticancer compounds.

1. The method of synthesis of 4β-amino-4'-demethyl-4-methoxymethylethoxy formula 1

includes the following successive stages:
a) carrying out the reaction in pure weak acid without another solvent at a temperature above the temperature which tours the environment between thiourea and 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy formula 3

where X means a halogen atom selected from the group consisting of chlorine, bromine or iodine, preferably chlorine;
b) removing 4β-amino-4'-demethyl-4-methoxymethylethoxy.

2. The method according to claim 1, in which the pure weak acid is a carboxylic acid of formula 5 R-COOOH, where R is a halogen atom or an alkyl radical with 1 to 2 carbon atoms, in particular acetic acid.

3. The method according to claim 1 or 2, wherein in step a) the reaction medium is heated to a temperature of from 60 to 100°C.

4. The method according to claim 1 or 2, in which step a) 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy lead in contact with a pure weak acid before the addition of thiourea.

5. The method according to claim 3, in which step a) 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy lead in contact with a pure weak acid before the addition of thiourea.

6. The method according to claims 1, 2 or 5, in which the duration of the reaction in step a) is from 1 to 3 p.m.

7. The method according to claim 3, in which the duration of the reaction in step a) is from 1 to 3 p.m.

8. The method according to claim 4, in which the duration of the reaction in step a) is from 1 to 3 p.m.

9. The method of synthesis of 4β-amino-4'-demethyl-4-methoxymethylethoxy formula 1

includes the following successive stages:
i) carrying out the reaction in a mixture of acid in the water and organic solvent at a temperature above the ambient temperature between thiourea and 4β-halogenoacetyl-4'-demethyl-methoxymethylethoxy formula 3

where X is a halogen atom selected from the group consisting of chlorine, bromine and iodine, preferably chlorine;
ii) removing 4β-amino-4'-demethylepipodophyllotoxin.

10. The method according to claim 9, in which step (i) reaction medium is heated to a temperature of 60-100°C.

11. The method according to claim 9 or 10, in which in step i) 4β-halogenoacetyl-4'-demethyl-methoxymethylethoxy brought into contact with a mixture of acid, water and an organic solvent before the addition of thiourea.

12. The method according to claim 9 or 10, in which the organic solvent is a water-soluble organic solvent, preferably selected from the group consisting of cyclic ethers, in particular dioxane, alcohols, in particular ethanol, and N,N-dimethylacetamide, dimethylformamide, N-methylpyrrolidone.

13. The method according to claim 11, in which the organic solvent is a water-soluble organic solvent, preferably selected from the group consisting of cyclic ethers, in particular dioxane, alcohols, in particular ethanol, and N,N-dimethylacetamide, dimethylformamide, N-methylpyrrolidone.

14. The method according to any of p, 10, or 13, in which the solvent is ethanol.

15. The method according to claim 11, in which the solvent is ethanol.

16. The method according to item 12, in which the solvent is ethanol.

17. The method according to 14, in which the acid is a strong acid, selected in particular from the group consisting of hydrochloric, sulfuric and phosphoric acids.

18. The method according to item 15 or 16 in which the acid is a strong acid, selected in particular from the group consisting of hydrochloric, sulfuric and phosphoric acids.

19. The method according to claim 9, in which the acid is a weak acid, in particular, carboxylic acid of formula 5, R-COOH, where R means a hydrogen atom, an alkyl radical with 1 to 2 carbon atoms, preferably acetic acid.

20. The method according to claim 20, in which the volumetric ratio of ethanol or dioxin or N,N-dimethylacetamide, dimethylformamide, N-organic : water : acetic acid is 5:1:1.

21. The method according to claim 1 or 9, in which the molar ratio between 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy and thiourea is 0.5-1.

22. The method according to claim 1 or 9, in which 4β-halogenoacetyl-4'-demethyl-4-methoxymethylethoxy formula 3 is obtained by reaction between 4'-demethylepipodophyllotoxin formula 2

and halogenoacetyl formula 6X-CH₂- =M, where X means a halogen atom selected from the group consisting of chlorine, bromine and iodine, in an acidic environment.