JPH0948782A - New production of 4-desoxy-4'-demethyl-4-epipodophyllotoxin derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially advantageously obtain a compound useful as an antitumor agent with less by-product, free from problem on the safety and sanitation, and without restriction of raw materials by reacting a specific aldehyde compound with an amine in the presence of a specific reductant. SOLUTION: This compound is expressed by formula II and obtained by reacting (a) a compound of formula I (R is H or an OH-protecting group) with (b) a compound of the formula: HN(CH3 )(CH2 )n NR1 R2 (R1 and R2 are each H or a lower alkyl; (n) is 2-6) in the presence of (c) a compound of the formula: H3 B.X [X is a (substituted) monocyclic heterocycle or a group of the formula: NR3 R4 R5 (R3 , R4 and R5 are each H, a lower alkyl or phenyl)].

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 4-desoxy-
Regarding a novel method for producing a 4'-demethyl-4-epipodophyllotoxin derivative, more specifically, 4-desoxy-4'-demethyl described in International Patent Publication No. 92/12982, which is useful as an antitumor agent. -4-A novel method for producing an epipodophyllotoxin derivative.

[0002]

2. Description of the Related Art General formula (4)

[0003]

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[In the formula, R represents a hydrogen atom or a hydroxyl-protecting group, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group, and n represents an integer of 2 to 6. ]
As a method for producing the 4-desoxy-4′-demethyl-4-epipodophyllotoxin derivative represented by, for example, the following method is described in International Patent Publication No. 92/12982.

[0005]

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[Wherein R ₁ , R ₂ and n have the same meanings as described above,
R'is a methyl group, a benzyloxycarbonyl group, a lower alkanoyl group which may have a halogen atom, or -Si.
(Rx) (Ry) (Rz) group (wherein Rx, Ry and Rz are the same or different and are lower alkyl groups or phenyl groups). That is, in the above method, the compound represented by the general formula (5) is reacted with the amine represented by the general formula (2) in the presence of sodium borohydride or sodium cyanoborohydride in an inert solvent. A method of obtaining a compound represented by the general formula (6), and further deprotecting it if necessary to obtain a compound represented by the general formula (4) in which R is a hydrogen atom.

[0007]

In the above method, sodium borohydride is used. This use has problems in the following points, and there is a point to be improved as an industrial production method. 1) Since sodium borohydride may generate a highly poisonous hydrogen cyanide, there is a problem in industrial safety in terms of occupational safety and health, and its use should be avoided. 2) It is difficult to obtain sodium borohydride on an industrial scale.

Further, sodium borohydride is practically difficult to use for the following reasons. 1) Since sodium borohydride is a strong alkali and easily produces decomposition products, it is necessary to add an acid to the reaction solution in advance. At that time, sodium borohydride is decomposed by the acid, and thus the reaction is completely completed. A theoretical amount of sodium borohydride or more is required to proceed. In addition, hydrogen gas is generated due to decomposition, and a very large amount of heat is generated, which is very dangerous. 2) In addition, when the reaction is performed by the method of 1), the amount of by-products produced increases.

[0009]

[Means for Solving the Problems] The present inventors have earnestly studied a method for industrially producing a compound represented by the above general formula (4), which has no problems in occupational safety and health and is not restricted by raw materials. As a result of examination, the present invention has been completed. That is, the present invention has the general formula (1)

[0010]

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[In the formula, R represents a hydrogen atom or a hydroxyl-protecting group. 4-desoxy-4'-demethyl-4-formylmethyl-4-epipodophyllotoxin derivative represented by] the general formula _{(2) HN (CH 3)} (CH 2) n NR 1 R 2 (2) [In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group, and n represents an integer of 2 to 6. The amine represented by the formula is represented by the general formula (3) H ₃ B · X (3) [wherein, X is a heterocyclic ring which coordinates with a hetero atom, and which may have a substituent or NR. ₃ R ₄ R ₅ (where R ₃ ,
R ₄ and R ₅ are the same or different and each represents a hydrogen atom, a lower alkyl group or a phenyl group. ). ] It reacts in presence of the reducing agent represented by these, General formula (4)

[0012]

[Chemical 6]

[In the formula, R ₁ , R ₂ , n and R have the same meanings as described above. ] 4-desoxy-4'-demethyl-4- represented by
The present invention provides a method for producing an epipodophyllotoxin derivative. According to the present invention, the compound represented by the general formula (4) can be produced without using a raw material having a problem in occupational safety and health, which is a great advantage as an industrial production method.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION In the compound of the general formula (1) of the present invention, the protecting group for the hydroxyl group represented by R is such that the reagent used in the present invention does not react with the hydroxyl group under the reaction of the present invention. The group is not particularly limited as long as it can be protected and can be removed after the reaction.
Specifically, acyl groups such as acetyl, benzoyl and pivaloyl groups; methoxycarbonyl, ethoxycarbonyl,
Alkoxycarbonyl group such as benzyloxycarbonyl group; aryloxycarbonyl group such as phenoxycarbonyl group; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t
ert-butyl, pentyl, neopentyl, hexyl and other linear or branched alkyl groups having 1 to 6 carbon atoms;
Examples thereof include aralkyl groups such as benzyl and trityl groups.
Further, these protecting groups may be further substituted with a substituent such as a halogen atom, a nitro group, an aryloxy group, an alkoxy group and the like. Among the above, preferred examples of the hydroxyl-protecting group that can be used in the present invention include an alkoxycarbonyl group which may be substituted with a halogen atom, and specific examples include methoxycarbonyl, ethoxycarbonyl and benzyloxy. Carbonyl, chloromethoxycarbonyl, dichloromethoxycarbonyl, trichloromethoxycarbonyl, fluoromethoxycarbonyl, bromomethoxycarbonyl, iodomethoxycarbonyl,
Examples thereof include 2-iodoethoxycarbonyl, 2,2-dichloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2,2,2-tribromoethoxycarbonyl groups.

In the compound of the general formula (2) of the present invention, the lower alkyl group represented by R ₁ and R ₂ is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Butyl, ter
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as t-butyl, pentyl, neopentyl and hexyl groups. Examples of the compound of the general formula (2) include N,
N-diethyl-N'-methylethylenediamine, N,
N, N'-trimethylethylenediamine, N, N, N '
-Trimethylpropylenediamine, N, N, N'-trimethyl-1,6-hexanediamine and the like can be mentioned. Among them, N, N, N'-trimethylethylenediamine is preferable.

In the compound of the general formula (3) of the present invention,
The monocyclic heterocycle represented by X is preferably a 5- or 6-membered heterocycle having 1 to 3 nitrogen atom, oxygen atom or sulfur atom as a hetero atom, and examples thereof include pyridine, pyridazine, pyrimidine, pyrazine and pyrrole. , Imidazole,
Examples thereof include piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran and oxathian. Among them, pyridine, piperidine, piperazine, morpholine, tetrahydrofuran, oxathian and the like are preferable, and pyridine is more preferable. Examples of the substituent which these monocyclic heterocycles may have include a lower alkyl group, a di-lower alkylamino group and a phenyl group. Examples of the lower alkyl group include R ₁ and R ₂ . Examples thereof include lower alkyl groups, and examples of di-lower alkylamino groups include dimethylamino, diethylamino, dipropylamino, dibutylamino, dimethylethylamino, dimethylpropylamino and diethylpropylamino groups. Further, in the compound of the general formula (3), R ₃
Examples of the lower alkyl group represented by R ₅ to R ₅ include the same as the above lower alkyl groups.

X in the compound represented by the general formula (3)
Specific examples of N, N-diethylaniline, pyridine, 4-dimethylaminopyridine, 2,6-lutidine,
Piperidine, piperazine, morpholine, 4-methylmorpholine, 4-ethylmorpholine, 4-phenylmorpholine, 1,4-oxathiane, etc .; and ammonia, ter
t-butylamine, dimethylamine, diethylamine,
Examples include trimethylamine, triethylamine, N, N-diisopropylethylamine and the like. Of these, pyridine, trimethylamine or triethylamine is preferable.

The compound of the general formula (1) in the present invention is
For example, it can be obtained by the method described in International Patent Publication No. 92/12982. Further, as the compound of the general formula (3), those which are generally commercially available can be used, and even compounds other than the commercially available products can be used, for example, J. Am. Che.
m. Soc., 81, 4791 (1959) or Organic Reaction vol.5
5 It can be produced by the method described in p30. That is,
The compound of the general formula (3) and the borane-amine complex are amine compounds corresponding to the borane-amine complex to be obtained, a metal boron compound (as a metal, sodium, lithium, etc.) and an acid (a mineral acid or a Lewis acid) by the above-mentioned known method. )
Can be easily manufactured.

The reaction in the method of the present invention is preferably carried out in a suitable solvent. The solvent is not limited as long as it does not affect the reaction, for example, methanol, ethanol, alcohols such as isopropanol, dichloromethane, halogenated hydrocarbons such as dichloroethane, acetonitrile, water, acetic acid, formic acid and the like alone or It can be mixed and used.

The amount of the compound represented by the general formula (2) used may be 1 equivalent or more, preferably 1 to 1.5 equivalents, relative to the compound of the general formula (1). The amount of the reducing agent represented by the general formula (3) used is 0.3 to 3 equivalents, preferably 0.5 to 1 equivalents, relative to the compound of the general formula (1). The reaction temperature is 0 to 60 ° C., preferably 10 to 5
0 ° C. The reaction time varies depending on the reaction temperature, the reaction reagent, etc., but is generally several hours to 48 hours.

It is also possible to allow an organic acid or a mineral acid to coexist in the reaction solution. Examples of the organic acid include acetic acid and formic acid, and examples of the mineral acid include hydrochloric acid and sulfuric acid. further,
The compound of the general formula (4) obtained in the present invention can be obtained as a hydrochloride salt crystal by dissolving in a suitable solvent and adding hydrochloric acid or blowing hydrogen chloride gas. As a solvent for this reaction, alcohols such as methanol, ethanol and isopropanol, halogenated hydrocarbons such as dichloromethane and dichloroethane, ketones such as acetone and methyl ethyl ketone, acetonitrile and water may be used alone or in combination. it can.

When R is a hydroxyl-protecting group in the compound of formula (4), the protecting group can be removed by a method known in the art depending on the kind of the protecting group. For example, when the protecting group is a benzyloxycarbonyl group or a benzyl group, an inert solvent (eg ethyl acetate,
The deprotected compound can be obtained by catalytic reduction in the presence of a catalyst in methanol, tetrahydrofuran, acetonitrile or the like (single or mixed solvent). The inert solvent is not particularly limited as long as it does not participate in the reaction. As the catalyst, for example, palladium black, platinum or the like can be used. At that time, the hydrogen pressure is preferably atmospheric pressure to 3 atm, more preferably atmospheric pressure to 2 atm, and the reaction temperature is preferably 0 to 40 ° C., more preferably room temperature.

The compound obtained by the production method of the present invention can be easily purified by conventional purification methods such as concentration, extraction, crystallization and recrystallization.

[0024]

EXAMPLES The present invention will be described in detail below with reference to examples. Example 1 Synthesis of 4-desoxy-4'-demethyl-4- (2- (2-dimethylaminoethyl) methylaminoethyl) -4-epipodophyllotoxin 4-desoxy-4'-demethyl-4-formyl Methyl-
1.0 g of 4-epipodophyllotoxin (2.34 mmo
99% Formic acid (0.5 ml) was added to a suspension of l) in methanol (25 ml), and the mixture was cooled to about 5 ° C. N, N,
240 mg of N'-trimethylethylenediamine (2.3
A solution of 5 mmol) in methanol (5 ml) and 205 mg (2.81 mmol) of trimethylamine borane were added, and the mixture was reacted at about 40 ° C. for 24 hours.

The reaction mixture was concentrated under reduced pressure and the residue obtained was diluted with water 2.
0 ml and 10 ml of ethyl acetate were added and stirred for 30 minutes. The aqueous layer was separated, 10 ml of ethyl acetate was added, and the mixture was stirred for 30 minutes. The resulting aqueous layer was separated and cooled to about 5 ° C.
The N-sodium hydroxide aqueous solution was stirred while being added dropwise until the pH became 8.9. Then, 4-desoxy-4′-demethyl-4- (2- (2-dimethylaminoethyl) methylaminoethyl) -4-epipodophyllotoxin 50 m
g was added as a seed crystal, and the mixture was stirred at about 5 ° C for 1 hour. The precipitated crystals were collected by filtration, washed with water (5 ml x 3), and then washed at about 40 ° C.
And dried under reduced pressure with 4-desoxy-4'-demethyl-4-.
(2- (2-Dimethylaminoethyl) methylaminoethyl) -4-epipodophyllotoxin 0.91 g (yield 7
5.8%) was obtained as a white powder.

¹ H-NMR (DMSO-d ₆ ; TMS): δ 6.86 (1H, s), 6.42 (1H, s), 6.20 (2H, s), 5.96 (1
H, d, J = 0.7Hz), 5.95 (1H, d, J = 0.7Hz), 4.41 (1H, d,
J = 5.6Hz), 4.35 (1H, t, J = 8Hz), 4.07 (1H, dd, J = 8,1
1Hz), 3.62 (6H, s), 3.09 to 3.19 (2H, m), 2.87 (1H,
m), 2.26 ~ 2.48 (6H, m), 2.18 (3H, s), 2.06 (6H,
s), 1.90 ~ 2.06 (1H, m), 1.45 ~ 1.52 (1H, m)

Next, the obtained 4-desoxy-4'-demethyl-4- (2- (2-dimethylaminoethyl) methylaminoethyl) -4-epipodophyllotoxin 700 was obtained.
mg (1.37 mmol) was dissolved in 6.6 ml of acetone and 0.4 ml of water, insoluble matter was removed by filtration, and further washed with 4.95 ml of acetone and 0.3 ml of water,
The filtrate and washings were combined and cooled to about 5 ° C. 6N for cooling liquid
-Add 0.46 ml (2.76 mmol) of hydrochloric acid water dropwise,
The mixture was stirred at about 5 ° C for 1 hour. The crystals are collected by filtration and acetone 14
After washing with ml, the residue was dried under reduced pressure at about 40 ° C. to obtain 562 mg (yield 70.6%) of the hydrochloride of the title compound as white crystals.

¹ H-NMR (DMSO-d ₆ ; TMS): δ 7.05 (1H, s), 6.46 (1H, s), 6.20 (2H, s), 5.98 (2
H, d), 4.45 (1H, d), 4.37 (1H, t), 4.18 (1H, m), 3.
62 (6H, s), 3.38 ~ 3.58 (6H, br), 3.13 ~ 3.20 (2H,
m), 2.94 (1H, m), 2.83 (6H, s), 2.81 (3H, s), 2.33
(1H, m), 1.91 (1H, m)

Example 2 Synthesis of 4-desoxy-4'-demethyl-4- (2- (2-dimethylaminoethyl) methylaminoethyl) -4-epipodophyllotoxin 4-desoxy-4'-demethyl- 4-formylmethyl-
1.0 g of 4-epipodophyllotoxin (2.34 mmo
99% Formic acid (0.5 ml) was added to a suspension of l) in methanol (25 ml), and the mixture was cooled to about 5 ° C. N, N,
240 mg of N'-trimethylethylenediamine (2.3
A solution of 5 mmol) of methanol (3 ml) and a solution of 323 mg (2.80 mmol) of triethylamine borane in methanol (3 ml) were added, and the mixture was reacted at about 20 ° C. for 24 hours.

The reaction mixture was concentrated under reduced pressure, and the residue obtained was mixed with water (2).
0 ml and 10 ml of ethyl acetate were added and stirred for 30 minutes. The aqueous layer was separated, 10 ml of ethyl acetate was added, and the mixture was stirred for 30 minutes. The resulting aqueous layer was separated and cooled to about 5 ° C.
The aqueous solution of N-sodium hydroxide was stirred while dropping to pH 8.9 and stirred at about 5 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with water (5 ml × 3), dried under reduced pressure at about 40 ° C., and 4-desoxy-4′-demethyl-4- (2-
(2-Dimethylaminoethyl) methylaminoethyl)-
0.75 g of 4-epipodophyllotoxin (yield 62.5
%) As a white powder. The NMR values were in agreement with those obtained in Example 1.

Example 3 Synthesis of 4-desoxy-4'-demethyl-4- (2- (2-dimethylaminoethyl) methylaminoethyl) -4-epipodophyllotoxin 4-desoxy-4'-demethyl- 4-formylmethyl-
1.0 g of 4-epipodophyllotoxin (2.34 mmo
99% Formic acid (0.5 ml) was added to a suspension of l) in methanol (25 ml), and the mixture was cooled to about 5 ° C. N, N,
240 mg of N'-trimethylethylenediamine (2.3
A solution of 5 mmol) of methanol (3 ml) and a solution of 260 mg (2.80 mmol) of pyridineborane in methanol (3 ml) were added, and the mixture was reacted at about 20 ° C. for 24 hours.

The residue obtained by concentrating the reaction solution under reduced pressure was diluted with water 2.
0 ml and 10 ml of ethyl acetate were added and stirred for 30 minutes. The aqueous layer was separated, ethyl acetate (10 ml) was added, and the mixture was added to 3
Stir for 0 minutes. The aqueous layer obtained by separating the layers was cooled to about 5 ° C., and the mixture was stirred while dropping a 2N-sodium hydroxide aqueous solution until the pH reached 8.9, and stirred at about 5 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with water (5 ml x 3), and then washed with about 4
After drying under reduced pressure at 0 ° C., 4-desoxy-4′-demethyl-4
1.02 g (yield 84.8%) of-(2- (2-dimethylaminoethyl) methylaminoethyl) -4-epipodophyllotoxin was obtained as a white powder. The NMR values were in agreement with those obtained in Example 1.

Example 4 Synthesis of 4-desoxy-4'-demethyl-4- (2- (2-dimethylaminoethyl) methylaminoethyl) -4-epipodophyllotoxin 4-desoxy-4'-demethyl- 4-formylmethyl-
40.0 g of 4-epipodophyllotoxin (93.8 mm
ol) in methanol (200 ml) and 90% formic acid (4.0 ml) at about 25 ° C. in N, N, N′-trimethylethylenediamine 10.7 g (103.1 mmo).
1) in methanol (120 ml) and pyridine borane (4.5 g, 47.0 mmol) in methanol (80 m).
1) The solution was added and the reaction was carried out at about 25 ° C. for 3 to 5 hours.

After the reaction, 12.3 ml of formalin was added,
After stirring at about 23 ° C. for 1 hour, the reaction mixture was concentrated under reduced pressure, 400 ml of 1M aqueous formic acid was added to the obtained residue, and the mixture was left at room temperature overnight. 400 ml of ethyl acetate was added and the mixture was stirred for 30 minutes, the aqueous layer was separated, 400 ml of ethyl acetate was further added, and the mixture was stirred for 30 minutes. Water layer obtained by layer separation is about 5 ℃
And cooled to 2N-sodium hydroxide aqueous solution to a pH of about 8.
The mixture was stirred until it reached 0, and then 400 mg of 4-desoxy-4′-demethyl-4 (2- (2-dimethylaminoethyl) methylaminoethyl) -4-epipodophyllotoxin was added as a seed crystal. Then, the mixture was stirred while adding a 2N-sodium hydroxide aqueous solution dropwise until the pH reached about 8.9. The mixture was stirred at about 5 ° C for 1 hour. The precipitated crystals were collected by filtration, washed with water (200 ml × 3), dried under reduced pressure at about 40 ° C., and then 4-desoxy-4′-demethyl-4- (2
-(2-Dimethylaminoethyl) methylaminoethyl)
-4-Epipodophyllotoxin 44.3 g (yield 85.
9%) as a white powder. The NMR values were in agreement with those obtained in Example 1.

Claims (5)

[Claims] 1. A compound represented by the general formula (1): [In the formula, R represents a hydrogen atom or a protective group for a hydroxyl group. 4-desoxy-4'-demethyl-4-formylmethyl-4-epipodophyllotoxin derivative represented by] the general formula _{(2) HN (CH 3)} (CH 2) n NR 1 R 2 (2) [In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group, and n represents an integer of 2 to 6. And an amine represented by the general formula (3) H ₃ B · X (3) [wherein, X is a heterocyclic ring optionally coordinated with a hetero atom or NR ₃ R ₄ R ₅ (where R ₃ ,
R ₄ and R ₅ are the same or different and each represents a hydrogen atom, a lower alkyl group or a phenyl group. ). ] The reaction is carried out in the presence of a reducing agent represented by the general formula (4): [In the formula, R ₁ , R ₂ , n and R are as defined above. ] The manufacturing method of the 4-desoxy-4'-demethyl-4-epipodophyllotoxin derivative represented by these. 2. The production method according to claim 1, wherein R is a hydrogen atom. 3. The amine represented by the general formula (2) is N,
2. N, N'-trimethylethylenediamine.
Or the manufacturing method according to 2. 4. The production method according to claim 1, wherein the monocyclic heterocycle of X is pyridine. 5. The production method according to claim 1, wherein X is trimethylamine, triethylamine or pyridine.