CA1276015C - Process for producing etoposide - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:
The present invention relates to a process for producing etoposide by reacting a 4'-halogenoacetyl-4'-demethylepipodo-phyllotoxin-.beta.-D-2,3-di-0-halogenoacetyl-4,6-0-ethylideneglucoside represented by the general formula:

Description

~.~7~

BACKGROUND OF THE INVENTION:
: A process for producing etoposide represented by -the formula:
C 3 ~ o i (O ~ ~/o (I) : H3CO ~ OCH3 H
~ .
'~ comprisi~g the following steps (1) and (2) is already known ., (see Canadian Patent No. 956939):
~ ..

C33~o O ~ (1) removal of A
< ~ ~ (2) removal of B
~
CH30 ~ OCH3 (II)OB

: whereln A represents formyl or acetyl, and B
represents benzyloxycarbonyl.

`~

7Çi(~ ~

owever, the above process haq drawbacks that two steps, i.e., a sfep of removing A and a subsequent step of removing B, are necessary, the removal of A is time-consuming (for example, the reaction can not be completed even after 20 to 30 hours) and, because of the increased production of by-products such as colored products, the quality of the produced etoposide is poor and its yield is low.
DETAILED DESCRIPTION OF THE INVENTION:
As a result of a variety of studies about a novel process for producing etoposide, the inventors of the present invention have found that by using a compound represented by formula ~III):

: ~ C~3 ~

[ O (III) H3CO~ocx3 OR

wherein Rl and R2, which may be the same or different, represent each -COCHX2 or -COCX3, wherein X represents a halogen atom, ' ~.2761J15 obtaine by utilizinq a di- or tri-haloqenoacetyl halide as a starting material, and reacting this compound with an alcohol, an amine and/or ammonia, Rl and R2 can be removed simultaneously to obtain etoposide and that the obtained etoposide is low in an impurity content so that it can be easily purified.
The present invention has been completed on the basis : of the above finding.
,~ The present invention will now be described in more detail. As examples of X in Rl and R2 of a compound of formula (III) used as a starting material in the present invention, fluorine, chlorine, bromine, and iodine can be mentioned, among which chlorine or bromine is particularly desirable.
As examples of Rl and R2, difluoroacetyl, dichloroacetyl, dibromoacetyl, diiodoacetyl, trifluoroacetyl, trichloroacetyl, tribromoacetyl, and triiodoacetyl can be mentioned.
As examples of the alcohols which can be used in this invention, there can be mentioned lower (Cl - C4) alcohols having l to 3 hydroxyl groups and lower amino alcohols having l to 3 lower hydroxyalkyl groups on the nitrogen atom, and more particularly, lower monohydric alcohols such as methanol, ethanol, propanol, and butanol; lower polyhydric alcohols such as ethylene glycol and glycerine; and lower (Cl - C4) amino alcohols such as monoethanolamine, dimethanolamine, and tripropanolamine, among which lower monohydric alcohols such as methanol and ethanol are desirable. It is desirable to use these alcohols as solvents for the present reaction, but I Z76(~15 alcohols other than these may be used. In this case, it is suitable that the alcohol is used usually in an amount at least equivalent to that of compound (III).
As the amines which can be used in the present invention, there can be mentioned Cl - C6 aliphatic primary amines such as methylamine, ethylamine, n-propylamine, and n~butylaminei Cl - C6 aliphatic secondary amines such as dimethylamine, diethylamine, di-n-propylamine, di-n-butylamine, and di-n-hexylamine; C4 - C5 cyclic amines which may contain oxygen atoms, such as pyrrolidine, piperidine, and morpholine, and aliphatic diamines such as ethylenediamine, among which the lower alkyl primary and secondary amines such as methylamine and diethylamine are desirable. When these amines and/or ammonia are usad, these may be used as solvents, but it is usually desirable to use some other solvents.
In this case, its amount is usually at least equivalent or preferably l to 3 equlvalents per equivalent of compound (III).
Although it is of course possible to add an amine or ammonia as such to the reaction system, it is also possible that an acetate or hydrochloride of an amine and/or ammonia is added in the presence of a base, ~or example, pyridine or triethylamine to the reaction system and to effect the reaction with the free amine and/or ammonia prepared in situ.
In the present invention, said alcohols, amines, or ammonia may be used alone or as a mixture of at least two of them. ~Oen they are used ir~ the form of a mixture, it is _5_ I ~ Z~6Q~5 desirable that an alcohol is used as the solvent. In this case, it is suitable that an amine or ammonia is used in an amount of about 1 to 1CJ equivalents, preferably about 1 to 3 equivalents per equivalent of compound (III).
~ he use of compounds other than the alcohols, amines, and ammonia as the solvent is not particularly limited so ~ar as they do not adversely affect the reaction and, as examples of these compounds, chloroform, ether, 1,2-dichloroethylene, dimethylformamide, and pyridine can be mentioned.
The reaction of the present invention, especially the reaction with an alcohol can proceed smoothly when a lower tertiary alkylamine such as trimethylamine or triethylami.ne, a pyridine such as pyridine or a lower-alkyl-substituted pyridine, or an organic carboxylic acid salt is added as a catalyst to the reaction system. As the organic carboxylic acid salts, the~re can be mentioned (1) metal salts ~r ammonium salts of an at least monobasla aliphatic carboxylic acids, for example, sodium acetate,potassium acetate, magnesium acetate, sodium propionatej sodium succinate, ammonium formate, ~:
ammonium acetate, ammonium malonate, ammonium succinate, and alkylammonium acetate, (2) metal salts ~alkali metal salts or alkaline earth metal salts~ or ammonium salts of aromatic carboxylic acids, for example, sodium benzoate, ammonium isonicotinate, ammonium benzoate, ammonium anthranilate, and alkylammonium benzoate, and (3) ammonium salt- or metal salt-form.
(alkali metal saIt-form or alkaline earth metal salt-form) :~
- 6 - :

.Z76~!15 weakly idic cation exchange resins having carboxyl grcups as exchangeable groups. Among them ammonium salts, desirably Cl - C3 saturated fatty acid ammonium salts, more desirably, ammonium acetate and ammonium formate are preferred, and the amount of these compounds are about 5 - 100 w/w ~, more desirably about 30 - 50 w/w ~, based on the compound of the general formula (III).
The temperature in the present invention varies with a solvent or catalyst used, but it is usually -10 to 100C, 1Q desirably 0 to 90C, especially 20 to 70C, and the reaction is brought to completion within about 0.1 to 7 hours.
: The compound of formula (III) which is used as a ~; starting material in the present invention is a novel substance :~ . not described in literature, and it can be synthesiz~d by : using well-known 4'-demethyIepipodophyllotoxin (IV) (see U.S. Patent No. 3524844) as.,a starting material, and reacting this through, for example, the following reaction : routes:
~ .
~ H H
' (0~ ~0~
0~ ,~ o ~V""~
f~l ~o H H3CO ~ OCH3 (IV) (V) :~

~ ~ ~ ,0~: C 33 ~ ~

:~ ~
' H3Co O OCH3 ~ - R2 (III) wherein Rl and R2 are as defined above.
~Namely, the compound (I)~can~be obtained by~reacting 4'-demethylepipodophyllotoxin (I~) with a dihalogeno- or trihalogeno-acetyl chloride (R2Cl) ln an lnert solvent and condensing the resulting 4'-halogenoacetyl-4'-demethyl-epipodophyllotoxin (V) wLth a 4,6-0-ethylidene-2,3-di-0- -halogenoacetyI-~-D-glucopyranose (VI) at a temperature lower ~than 0C Ln~an inert solvent in the presence of boron trifluoride ethyl etherate. It is suitable that the glucopyranose of the yeneral formula (IV) is used in an amount of at least one equivalent per equivalent of the compound of the general formula ~V).
Here, the compound (VI) is a novel one, and can be synthesized by using a well-known 4,6-~-ethylidene-1-0-benzyloxycarbonyl-~-D-glucopyranose (VII) as a starting material througll 'or exam~le, the following r~aFtion outes:

7 ~ ~t~

3 ~ ~ O ~ COCH2 ~ lCl (VII) H

3 ~ ~ 11 hydrogenolysis ~ O- COCH2 ~ - ~ (VI) (VIII) wherein Rl is as defined above.
Namely, the compound (VI) can be obtained by reacting 4,6-O-ethylidene~ benzyloxycarbonyl-~-D-glucopyranose (VII) with a dihalogeno- or trihalogeno-acetyl chloride in an lnert solvent and subjecting the resulting 4,6-0-ethylidene-1 O-benzyloxycarbonyl-2,3-di-0-halogeno-acetyl-~-D-glucopyranose tVIII) to~hydrogenolysis. Here, although the formation of a small amount of an a-isomer is not avoidable in the hydrogenolysis, the compound (VI) has such a property that the separation o~
an a-isomer from a ~-isomer is easy because only the ~-isomer is crystallized selectively ~rom the reaction solution.
Further, the ~-isomer of the compound (VI) has good stability, and undergoes substantially no isomerization into the a-isomer, 80 tha~ t aan be stored for e long time.

_g_' ::

6~5 According to the present invention, the removal of the halogenoacetyl groups can be effected under a gentle condition, for example, at 25C or room temperature, within a short time, so that the formation of by-products such as colored products is little and it is possible to obtain etoposide from compound ~III) in high yields. Therefore, puriication after the reaction such as removal of colored products is easy and, for example, pure etoposide can be obtained by adding a hydrophobic solvent such as chloroform to the reac-tion solution, washing the solution with water, distilling off the solvent and recrystallizing the residue from a solvent.
The resulting etoposide has such an extremely low inorganic content that its ignition residue (a residue left after ignition of etoposide) is 0.1 ~ by weight or below. Further, when an alcohol is reacted in the presence of an ammonium salt of a lower fatty acid, such as ammonium acetate, or a tertiary amine, or when an alcohol is used in combination with an amine or ammonia in the present invention, the reaction lS brought to completion within a~short time at room temperature, and etoposide can be recovered merely by concentrating the reaction solution, so that the reaction operation and the after-treatment subsequent to the reaction are easy, and the process is extremely advantageous as an industrial production process. Particularly, in the latter case, the reaction can be brought to completion within a short time.

.

i~ - 10 -6~5 The present invention will now be described in detail with reference to examples.
Example 1 1 g of 4'-dichloroacetyl-4'-demethylepipodophyllotoxin-~-D-2,3-di-O-dichloroacetyl-4,6-0-ethylideneglucoside (III) ~Rl, R2 = -COCHC12) and l g of ammonium acetate were dissolved in 20 ml of methanol, and the solution was stirred at 25C for 1.5 hours. After completion of the reaction, the methanol was concentrated to 10 ml and the resulting solution was cooled to obtain 0.55 g (yield: 86.1 ~) of etoposide.
The Rf value of TLC (silica gel, developer, chloroform:methanol (1:1)), IR, NMR, and optical rotation of the obtained crystal were identical to those of the substance obtained by the process of Canadian Patent No. 956939.
~ ::
m.p. 259 - 260C, Rf = 0.44 Examples 2 to 9 l g of compound (III)(Rl, R2 = -COCHC12) was~reacted under conditions shown in the following table, and the reaction solution was treated in the same manner as in Example l to obtain etoposide.

IL~ '1 Z7~Q~S

q~ ~_ d~ ~ ~_ ~
O~1 u~ oo ~r u~ CO
~ O ~D I_ ~ ~ ~ ~
~ o~ ~ ~o o~ C~ CO

E
~ ~ ~ ~ S ~ ~
.~ O S~ ,1 ~ 1~ ~r ~r er ~ o ~ o a) ~ a~ L~ = =
~0~1 ~ ~

~ ~ o o o o o o : ~ 3~ ~ ~ ~ ~ ~
~ .___ .
~ ~ ~ ~ ~ . ~ ~ ,., : , ~ ~ .
~ : :
~:: ~ ::
~ ~r ~ ~r ~ J~ N ~ i~
N N N ~ 3 ~3 ~ 3 Q~ ~ _ ~ 11 1`' Ir I

1 276Q~5 o- o' co r~
P~ ~

a~ ~1 h ~
~1 o 'S~
rl h rl a) ~ ~ c~
~ ~ ~ o :
1~ ~ H
0-1 _ t) ~ 3~ ~ ~ ~, : ~ . ~
~`: ~ ~
.
, ~ --__ C~ ~ ~
X
.

.~ - 13 -~.~7~ 5 Example 10 `` 1 g of 4'-dichloroacetyl-4'-demethylepipodophyllo-toxin-~-D-2,3-di-O-dichloroacetyl-4,6-O-ethylideneglucoside (III) (Rl, R2 = -COCHC12) and 1 g of magnesium acetate were refluxed for 4 hours in 20 ml of methanol. After completion of the reaction, the methanol was distilled off and, after adding 30 ml of chloroform, the residue was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuum, and the residue was recrystallized from methanol to obtain 0.49 g (yield: 76.7 %) of etoposide crystals.
Example 11 4.75 g (yield: 64.6 %) of etoposide crystals were obtained by the same reaction as in Example 1 except that com-pound (III)(Rl, R2 = -COCHC12) used in Example 1 was replaced ; with 4'~dibromoacetyl-4'-demçthylepipodophyll~otoxin-~-D-2,3-di-O-dibromoacetyl-4,6-O-ethylideneglucoside (III) ~Rl, R2 =
-COCHBr2 ) .
Example 12 l 20 1 g of compound (III) (Rl, R2 = -COCHC12) was dissolved in 20 ml of methanol and after adding 0.64 g of diethylamine, the solution was stirred at 25C for 10 minutes. After completion of the reaction, the solvent was distilled off in vacuum. After adding 20 ml of chloroform, the residue was neutralized with 2N hydrochloric acid, washed with water, and dried over anhydrous magnesium sulfate. The solution was ' ~.Z~6~S

concentrated in ~7acuum to a volume of 10 ml to obtain 0.53 g (yield: 83.1 ~) of etoposide crystals.
Example 13 0.51 g (yield: 80.0 %) of etoposide crystals were obtained by the same reaction as in Example 12 except that diethylamine usecl in Example 12 was replaced with 0.~8 g of di-n-propylamine.
Example 14 1 g of compound (III) (Rl, R2 = -COCHC12) was added to 20 ml of methanol in which 0.15 y of ammonia gas had been ~ dissolved, and the mixture was stirred at 25C for 30 minutes.
;~ After completion of the reaction, the solvent was distilled off in vacuum. After aading 10 ml of chloroform, the residue was recrystallized to obtain 0.54 g (yield: 84.7 ~) of etoposide crystals.
~`~ Example 15 0.40 g (yield: 62.7 %) of etoposide crystals were obtained by the same reaction as in Example 12 except that methanoI used in Example 12 was replaced with 20 ml of diethyl-amine.
Likewise, the reaction was effected by replacing methanol used in Example 12 with 20 ml of pyridine.
Example 16 Production of 4'-dichloroacetyl 4'-demethylepipodo-phyllotoxin- ~-D-2,3-di-O-dichloroacetyl-4,6-O-ethylideneglucoside (III~ (R1, R2 = -COCHC12) ~Z~

(a) 4'-dichloroacetyl-4'-demethylepipodophyllotoxin (V) (R2 = -COCHC12 ) . 8 g of 4'-demethylepipodophyllotoxin (IV) was dissolved in 160 ml of acetone and, after 3.2 g of pyridine, the solution was cooled to -5 to -10C. To this solution, 4.1 g of dichloroacetyl chloride was added dropwise over a period of 1.5 hours, and the solution was further stirred for 0.5 hour.
The acetone was distilled off in vacuum, and the obtained solid was dissolved in 160 ml of 1,2-dichloroethane and washed with water. The 1,2-dichloroethane solution was dried over anhydrous .~ magnesium sulfate, and then concentrated in vacuum to obtain ~ 9.5 g (yield: 93.4 ~) of compound (V) (R2 = -COCHC12).
: m.p. 207 - 208C
IR vKBr 3540, 1775, 1600, 1485, 1235, 1130 cm 1 (b) 4,6-O-ethylidene-l-O-benzyloxycarbonyl-2,3-di-O-dichloro-: acetyl-~-D-glucopyranose (VIII) (Rl = -COCHC12) 34.0 g of 4,6-O-ethylidene-l-O-benzyloxycarbonyl-~-D-glucopyranose (VII) was suspended in 340 ml of 1,2-dichloroethane and, after adding 23.7 g of pyrïdine, the suspension was cooled ~ 20: to 0 to 5C. To this suspension, 32.4 g of dichloroacetyl ~ chloride was added dropwise over a period of about one hour and further stirred for 0.5 hour. The reaction solution was washed with water, and the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuum to obtain 51.0 g (yield: 90 %) of compound (VIII) (Rl = -COCHC12).
m.p. 150 - 151C
.~ IR vKBax 1770, 1255, 1100, 820 cm 1 ~`

~ - 16 -Il ~1 2~ 5 (c) 4,6-O-ethylidene-2,3-di-O-dichloroacetyl-~-D-glucopyranose (VI) (Rl = -COC~C12) 10.0 g of compound (VIII) (Rl = -COCHC12) was dissolved in 50 ml of acet.one and, after adding l.0 g of palladium black, the solution was subjected to hydrogenolysis at -5 to -10C and an elevated pressure. After completion of the reaction, the catalyst was filtered off, and the solvent was distilled off in vacuum. 17 ml of diisopropyl ether was added to the r~sidue, and the mixture was cooled to 0C and filtered by suction to obtain 7.3 g (yield: 95.9 ~) of compound (VI) (Rl = -COCHC12) m.p. 133 - 135C
IR vmax 3445, 1775, 1305, 1165, 1095, 1005, 815 cm 1 (d) 4'-dichloroacetyl-4'-demethylepipoaophyllotoxin-~-D-2,3-di-0-dichloroacetyl-4,6-O-ethylideneglucoside (III) (Rl, R2 =

-COCHC12) 3.0 g of compound ~V) (R2 = -COCHCl2) was dissolved ; in 60 ml of 1,2-dichloroethane and, after adding 2.5 g of compound (VI) (Rl = -COCHCl2), the solution was cooled to -10C.
l.l g of boron trifluoride ethyl etherate was added thereto dropwise over a period of about 1.5 hour, and, after completion of the addition, the reaction mixture was further stirred for 0.5 hour. 0.8 g of pyridine was added thereto dropwise while the internal temperature was being kept at -5 to -10C, and the reaction mixture was washed with water. ~he organic layer w dried over anhydrous ma~nesium sulfate and c~ncentrated 6Q~L~

in vacuum, and the residue was recrystallized from methanol to obtain 4.4 g (yield: 81.4 %) of compound (III) (Rl, R2 =
-COCHC12).
m.p. 207 - 208C
IR vmB~ 1880, 1610, 1490, 1240, 1130, 935, 820 cm 1 Further, compound (III) was obtained from 105 g of compound (V) and 5.0 g of compound (VI) by the same reaction and treatment as those described above.
Example 17 4'-Dibromoacetyl-4'-demethylepipodophyllotoxin-:~ ~-D-2,3-di-O-dibromoacetyl-4,6-O-ethylideneglucoside (III) (Rl, R2 = -COCHBr2) (a) 4'-dibromoacetyl-4'-demethyleplpodophyllotoxin (V~

2 = ~CC~Br2 ) :
: 5.0~g of 4'-demethylepipodophyllotoxin was dissolved ~: in 150 ml of 1,2-dichloroethane. After adding 1.. 5 g of : pyridine, the solution was cooled to -5 to 10C. To this :
~: solution, 3.8 g of dibromoacetyl chloride was added dropwise ~ over a period of about 1.5 hours, and the mixture was further :~ 20 stirred for 0.5 hour. The reaction solution was washed with : water, and the organic layer was dried over anhydrous magnesium : sulfate and concentrated in vacu~m to a volume of 50 ml to obtain a 1,2-dichloroethane solution of compound (V) (R2 =
-COCHBr2 ) .
(b) 4,6-O-ethylidene-l-O~benzyloxycarbonyl-2,3-di-O-dibromo-: acetyl-~-D-glucopyranose (VIII) (R2= -COCHBr2) 11 ._ ..

5.1 g of 4,6-O-ethylidene-l-O-benzyloxycarbonyl-~D-glucopyranose (VII) was suspended in 51 ml of 1,2-dichloroethane.
After adding 3.6 g of pyridine, the suspension was cooled to 0 to 5C. To this suspension, 7.8 g of dlbromoacetyl chloride was added dropwise over a period of about one hour, and the mixture was further stirred for 30 minutes. Then, the reaction ~ solution was washed with water, and the organic layer was ; dried over anhydrous magnesium sulfate and concentrated in vacuum to a volume of 25 ml to obtain a 1,2-dichloroethane solution of compound (VIII) (Rl = -COCHBr2).
(c) 4,6-O-ethylidene-2,3-di-O-dibromoacetyl-~-D-glucopyranose (VI) (Rl = -COCHBr2) 0.4 g of palladium black was added to 25 ml of the 1,2-dichloroethane solution of compound (VIII) (Rl = -COCHBr2) : of (b), and the solution was hydrogenated at -10 to -5C and ~: an elevated pressure. After completion of the reaction, the cata7yst was filtered off to obtain a 1,2-dichloroethane solu-tion of compound (VI) (Rl = -COCHBr2).
.; (d) 4l-dibromoacetyl-4'-demethylepipodophyllotoxin-~-D-2,3-2:0 ~ di-O-dibromoacetyl-4,6-O-ethylideneglucoside (III) (Rl, R2 =

~ -coc~Br2) : 25 ml of a 1,2-dichloroethane solution of compound (V) (R2 = -COCHBr2) was combined with 50 ml of a 1,2-: dichloroethane solution of compound (VI) tRl = -COCHBr2), and the combined solution was cooled to 10C. 2.8 g of boron : trifluoride ethyl etherate was added thereto dropwise over , - 19 -, 76~

a period of aboul: 1.5 hours. After completion of the addition, the reaction mixture was further s~irred for 30 minutes. 2.0 g of pyridine was added thereto dropwise while the internal temperature was being kept at -5 to ~'0C, and the reaction mixture was washed with water. The organic layer was concen-trated in vacuum/ and the residue was recrystallized from methanol to obtain compound (III) (Rl, R2 = -COCHBr2).
Example 18 4'-DichLoroacetyl-4'-demethylepipodiphyllotoxin-~-D-2,3-di-O-trichloroacetyl-4,6-O-ethylideneglucoside (III) (Rl = -COCC13, R2 = -COCHC12) (a) 4,6-O-ethylidene-l-O-benzyloxycarbonyl-2,3-di-O-trichloroacetyl-~-D-glucopyranose (VIII) ~Rl = -COCC13) 25 ml of 1,2-dichloroethane solution of compound (VIII) (Rl = -COCC13) was obtained by the same reaction as in Example 17 except that dibromoacetyl chloride was replaced with trichloroacetyl chloride.
(b) 4,6-O-ethylidene-2,3-di-O-trichloroacetyl-~-D-glucopyranose (VI) (Rl = -COCC13) : 20 25 ml of a 1,2-dichloroethane solution of compound (VI) (Rl = -COCC13) was obtained by the same reaction as in Example 17 (c) by using 25 ml of the solution obtained in (a).
(c) 4'-dichloroacetyl-4'-demethylepipodophyllotoxin-~-D-2,3-di-O-trichloroacetyl-4,6-O-ethylideneglucoside (III) (Rl =
-COCC13, R2 = -COCHC12) ,, , ~ ~7~5 Compound ~III) IRl = -COCC13, R2 = -COCHC12) was obtained by reacting 25 ml of the solution obtained in (b) with 50 ml of a 1,2-dichloroethane solution containing compound (V) : (R2 = -COCHC12) obtained in Example 16 (a) in the same : manner as in Example 16 (d).

Claims (14)

1. A process for producing etoposide represented by the formula (I):

(I) which comprises reacting a 4'-halogenoacetyl-4'-demethyl-epipodophyllotoxin-.beta.-D-2,3-di-0-halogenoacetyl-4,6-0-ethylideneglucoside represented by thç general formula:

(III) wherein R1 and R2 , which may be the same or different, represent each -COCHX2 or -COCX3, wherein X represents a halogen atom, with an alcohol, an amine, and/or ammonia to remove the halogenoacetyl groups.

2. A process according to claim 1, wherein a compound of general formula (III) is reacted with a C1 - C4 lower alcohol having 1 - 3 hydroxyl groups, a lower amino alcohol having 1 - 3 lower hydroxyalkyl group on the nitrogen atom, a mono- or di-(C1 - C6 alkyl)amine, a C4 -C5 cyclic amine, morpholine, and/or ammonia.

3. A process according to claim 1, wherein the reaction with an alcohol is effected in the presence of a lower tertiary alkylamine, a pyridine or an organic carboxylic acid salt.

4. A process according to claim 3, wherein said organic carboxylic acid salt is (1) an alkali metal salt, alkaline earth metal salt or ammonium salt of a C1 - C4 aliphatic carboxylic acid, (2) a metal salt or ammonium salt of an aromatic carboxylic acid, or (3) an ammonium salt- or metal salt-form weakly acidic cation exchange resin having carboxyl groups as exchangeable groups.

5. A process according to claim 4, wherein said organic carboxylic acid salt is an ammonium salt of a C1 - C3 saturated fatty acid.

6. A process according to claim 3, wherein said alcohol is methanol or ethanol.

7. A process according to claim 1, wherein at least one equivalent of said alcohol or 1 to 3 equivalents of said amine or ammonia is used per equivalent of compound (III).

8. A process according to claim 1, wherein said alcohol is used in combination with said amine or ammonia.

9. A process according to claim 4, wherein the amount of said organic carboxylic acid salt is 5 to 100 w/w %, based on the compound of the general formula (III).

10. A process for producing etoposide, which comprises reacting a 4'-halogenoacetyl-4'-demethylepipodophyllotoxin-.beta.-D-2,3-di-0-halogenoacetyl-4,6-0-ethylideneglucoside represented by the general formula:

wherein R1 and R2, which may be the same or different, represent each -COCHX2 or -COCX3, wherein X represents a halogen atom, with methanol or ethanol in the presence of ammonium acetate or ammonium formate to remove the halogenoacetyl groups.

11. A 4'-halogenoacetyl-4'-demethylepipodophyllotoxin-.beta.-D-2,3-di-0-halogenoacetyl-4,6-0-ethylideneglucoside represented by the general formula:

wherein R1 and R2, which may be the same or different, represent each -COCHX2 or -COCX3, wherein X represents a halogen atom.

12. A process for producing etoposide represented by the formula (I):

(I) which comprises reacting a 4'-halogenoacetyl-4'-demethyle-pipodophyllotoxin- -D-2,3-di-0-halogenoacetyl-4,6-0-ethyl-ideneglucoside represented by the formula:

(III) wherein R1 and R2, which may be the same or different, represent -COCHX2 or -COCX3, wherein X represents a chlorine atom, with lower C1-C4 alcohols having 1 to 3 hydroxyl groups in the presence of ammomium salt of an organic carboxylic acid to remove the halogenoacetyl groups at a temperature of -10 to 100°C.

13. A process according to claim 12, wherein at least one equivalent of said alcohol is used per equivalent of compound (III).

14. A process according to claim 12, wherein the amount of ammonium salt of an organic carboxylic acid is 5 to 100 w/w%, based on the compound of the general formula (III).