JPS61215384A - Production of deoxypodophyllotoxin intermediate - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a stereoselective synthetic raw material for a compound suitable as an anticancer only by heating under reflux advantageously, by reacting a specific compound such as an easily obtainable o-hydroxymethylbenzylsilane compound as a raw material with maleic anhydride. CONSTITUTION:A compound (e.g., o-hydroxymethylbenzylsilane compound) shown by the formula I (R is lower alkyl; X and Y are lower alkyl, or X and Y are bonded to form lower alkylene; Ar is 3,4,5-trimethoxyphenyl, 3,4- dimethoxyphenyl, etc., with the proviso that X and Y are lower alkyl when Ar is 3,4-methylenedioxyphenyl) is reacted with maleic anhydride in a solvent (preferably benzene) under reflux, to give a compound shown by the formula II. The compound shown by the formula I is obtained by reducing piperonal with sodium borohydride and from synthesis through several processes such as a reaction with thionyl chloride, etc.

Description

[Detailed Description of the Invention] [Industrial Application Field] This invention relates to a method for producing a deoxypodophyllotoxin intermediate, and more specifically, it relates to a method for producing a deoxypodophyllotoxin intermediate (+) having anticancer properties.
- A method for producing a deoxypodophyllotoxin intermediate, which is a useful raw material for stereoselectively synthesizing deoxypodophyllotoxin and its analogous compounds.

The present invention relates to a method for producing an intermediate.

[Prior art and its problems] Conventionally, deoxypodophyllotoxin has been used as an anticancer substance in the treatment of cancer.

There are studies on the synthesis of deoxypodophyllotoxin (for example, Dhi Rajapaksa et al., The Journal of the American Chemical Society, Vol. 1).
Volume 03, page 6208 (1981) [D
, Rajapaksa et al., J.
+ Am.

Chew, S oc,, 1038208 (19
81)], all of which are racemic syntheses of deoxypodophyllotoxins, and it is difficult to stereoselectively synthesize only compounds having the stereochemistry necessary for anticancer properties.

This invention was made based on the above-mentioned circumstances, and uses deoxypod, which is a useful raw material for stereoselectively synthesizing (+)-deoxypodophyllotoxin, which is an anticancer substance, and its analogous compounds. The object of the present invention is to provide a method for producing a phyllotoxin intermediate.

[Means for solving the above problems 1 The outline of this invention for solving the above problems is as follows.

General formula [I] (wherein, R represents a lower alkyl group, X and Y each represent a lower alkyl group or combine with each other to represent a lower alkylene group, and Ar is 3,4.5-trimethoxy Indicates either a phenyl group, 3,4-dimethoxyphenyl group, or 3,4-methylenedioxyphenyl group, provided that
When Ar is a 3,4-methylenedioxyphenyl group, X and Y each represent a lower alkyl group) and maleic anhydride are reacted to form the compound of the general formula [II] (wherein, This is a method for producing a deoxypodophyllotoxin intermediate, which is characterized by producing a compound represented by

Among the compounds represented by the general formula [11 (hereinafter referred to as silylmethyl derivatives), it is preferable that the R is a methyl group, and the X and Y are methyl groups, or It is an oxy group.

Next, the method of the present invention will be explained with reference to a typical example shown in FIG.

The silylmethyl derivative, such as the 0-hydroxymethylbenzylsilane compound [compound (1), see Figure 1], is produced by reducing piperonal with sodium polyhydride and then converting it into 3,4-methylene with onyl chloride, as shown in Figure 1. Wurtz (W) using benzyl dioxychloride followed by magnesium pieces and trimethylsilyl chloride.
urtz) type coupling reaction to synthesize 3,4-methylenedioxybenzyltrimethylsilane [compound (2), see Figure 1]. Next, this compound (2) was mixed with methylene chloride in the presence of aqueous sodium bicarbonate. A bromine compound [compound (3)] is obtained by bromination in
This compound (3) can be obtained by reacting with, for example, 3,4.5-)rimethoxybenzaldehyde using n-butyllithium.

Compound (1) and maleic anhydride are reacted under reflux in a solvent.

As the solvent, aromatic solvents such as benzene and toluene can be used, but it is better to use benzene than the toluene. This is because the reaction can be completed with

It is preferable that the maleic anhydride is reacted in an amount 5 times or more equivalent to that of the compound (1).

The mechanism of the reaction between compound (1) and maleic anhydride is not necessarily clear, but as shown in Figure 1, the reaction between compound (1) and maleic anhydride produces a Hafester compound [compound (4)]. This forms an acidic unit, which acts as a catalyst and promotes the elimination reaction, and the eliminated maleic acid easily releases water and becomes neutral maleic anhydride again.

The compound (4) becomes an O-quinodimethane compound [compound (7)] via compound (5) and compound (8), and this compound (7) reacts with maleic anhydride, which functions as a genophile, to form deoxy It is estimated that a podophyllotoxin intermediate [compound (8)] is produced.

According to the method of the present invention, the deoxypodophyllotoxin intermediate represented by the general formula [11] can be obtained in high yield.

The resulting deoxypodophyllotoxin intermediate can be isolated from the reaction product solution by a conventional separation operation, and purified by a conventional method to obtain a pure product.

The deoxypodophyllotoxin intermediate obtained by the method of the present invention is derived into deoxypodophyllotoxin, which is an anticancer agent, and its analogous compounds by the following synthetic method.

That is, as shown in FIG. 2, when a deoxypodophyllotoxin intermediate such as compound (8) is refluxed with a lower alcohol such as methyl alcohol, it becomes a Hafester compound [compound (8)], and this compound (9) is
When heated under reflux in methyl alcohol in the presence of 2 equivalents of sodium methoxide, it is converted to a 1,2-cis-2,3-trans-Hafester compound [Compound (1G)]. Subsequently, this compound (10) was purified by Gaig
) et al. (H. J. Geis et al., Angewande Hiemi English International Edition, Vol. 23, p. 142 (1984) [H, J, G.
-ais et al, Angew, Ch.
em, Int, Ed, Engl.

When reduced with lithium triethylporohydride according to Trans., 142 (1984)], IS, the ester moiety in compound (10) is selectively reduced to obtain a carboxylic acid alcohol compound [compound (11)]. Next, when this compound (11) is heated under reflux in an aromatic solvent such as benzene in the presence of P-toluenesulfonic acid, deoxypodophyllotoxin [compound (12)] can be obtained in high yield. Compounds similar to deoxypodophyllotoxin can also be easily obtained in the same manner.

[Effects of the Invention] The deoxypodophyllotoxin intermediate obtained by the method of the present invention is produced by using a compound that can be easily synthesized from easily available basic raw materials as a raw material, and by combining maleic anhydride and the aforementioned raw materials. It can be easily produced by simply heating and refluxing. Further, the method of the present invention can produce a deoxypodophyllotoxin intermediate as a raw material for stereoselectively synthesizing (+)-deoxypodophyllotoxin and its analogous compounds, which are useful as anticancer agents.

[Example 1 Next, examples and reference examples of this invention will be shown.

(Reference Example 1) 6-((3,4,5-1rimethoxyphenyl)hydroxymethyl)-3,4-methylenedioxybenzyltrimethylsilane (in formula I1, R is a methyl group, ,
Y is bonded to a 3,4-methylenedioxy group, and Ar
is a 3.4.5-trimethoxyphenyl group) 40 g of piperonyl alcohol (0.26 m
o l) in methylene chloride solution at 0°C under an argon stream.
20 ml (0.27 mol) of thionyl chloride was added dropwise thereto, and the mixture was stirred for 1.5 hours. The solvent was distilled off under reduced pressure, and benzene was added to the resulting residue. This penzene mixture was washed successively with water, a saturated aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous sodium sulfate. After this,
The solvent was distilled off under reduced pressure, and the resulting residue was vacuum distilled to obtain piperonyl chloride as a colorless oil.

5.8 g (0.25 no l) of magnesium ribbon and a catalytic amount of iodine were added to 200 ml of a solution of 34 g (0.20 no l) of this piperonyl chloride in tetrahydrofuran (THF), and 30 m I of trimethylsilyl chloride was added at 0°C under an argon stream. C0,24no l)
was dripped. The mixture was stirred at the same temperature for 30 minutes, then stirred at room temperature for 30 minutes, and heated under reflux for an additional 30 minutes. A saturated aqueous ammonium chloride solution was added at 0°C, and the mixture was filtered through Celite. The filtrate was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting oil was subjected to vacuum distillation to obtain 3,4-methylenedioxybenzyltrimethylsilane [compound (2) in Figure 1].

A solution of 5 g (24 mmol I) of this 3.4-methylenedioxybenzyltrimethylsilane in methylene chloride 70
ml sodium bicarbonate 1, 10 g and water 48 ml
1 was added, and 30 ml of a methylene chloride solution containing 1.3 ml (25 mmol) of bromine was added dropwise at 0°C over 1 hour. After the dropwise addition, the mixture was stirred at the same temperature for 30 minutes, the methylene chloride layer was separated, and water The layer was extracted with methylene chloride. The methylene chloride taken out in 0 minutes and the extracted methylene chloride were combined, washed successively with a 10% aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure, and the resulting oil was vacuum distilled to obtain 6.5 g (yield: 94.3%) of (6-bromo-3,4-methylenedioxybenzyl)trimethylsilane. Ta.

2.9 g (lo, 1 mmol) of this (6-bromo-3,4-methylenedioxybenzyl)trimethylsilane
of THF solution (0.2M) under a stream of argon.
n-Butyllithium (10.1 mmol) was added dropwise at ℃ and stirred at the same temperature for 15 minutes, then 3 at -78℃.
．． 4.5-) Rimethoxybenzaldehyde 2.0g (
10.2 mmol) of THF solution* (LM) was added dropwise,
The mixture was stirred at the same temperature until the reaction was completed. Water was added at room temperature and the THF layer was separated. The aqueous layer was extracted with ether, and the ether layer and THF layer were combined and washed successively with water and saturated brine. Then, after drying with anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography to obtain 6-((3,4,5-trimethoxyphenyl)hydroxymethyl)-3,4-methylenedioxybenzyltrimethylsilane 3. .8 g (yield 92.1%) was obtained. The identification data is shown below.

Melting point 95-97℃ Engineering temperature 3500 cm'ax NMR (CDCl2) δ 0.05 (9H, s), 2.03 (IH, br
o,).

2, IQ (2H, s), 3.75 (3H, s), 3
．． 77 (6H, s), 5.75 (IH, s).

5J2 (2H, S”), 6.44 (LM, 5).

6.51 (2H, ri, 6.73 (IH, ri MSm/
e404CM)283
(100%) MSm/e Calculated value as C21H280BSi; 4
04.1654 (M) Measured value: 404.1669
(M) (Reference Example 2) 6-((3,4-dimethoxyphenyl)hydroxymethyl)-3,4-methylenedioxybenzyltrimethylsilane (in formula 11, R is a methyl group, X and Y
is bonded to form a methylenedioxy group, 1, and Ar is 3.4
-Synthesis of a starting compound (which is a dimethoxyphenyl group).

Obtained in the same manner as in Reference Example 1 (6-bromo-3,4-
methylenedioxybenzyl)trimethylsilane 1 g
(3,5 mmol) and 0.58 g of veratrumaldehyde instead of 3.4.5-)rimethoxybenzaldehyde.
(3.5 mmol) was used, except that the reference example 1 was
940 mg of 6-((3,4-dimethoxyphenyl)hydroxymethyl)-3,4-methylenedioxybenzyltrimethylsilane (yield 71.
8%).

The identification data is shown below.

IR Nuji"3500cm' a x NMR (CDCl2) δ 0.03 (9H, s), 2.07 (IH, br,,
), 2.10 (2H, S), 3.83 (6H, Ri,
5.57 (I H, br, ), 5.83 (2
H, s), 6.43 (LH, S), 6.73-6.9
7 (4H.

m) MSm/e 374 (M ) 253.
149 (M) MSm/e Calculated value as C2oH2805Si; 3
74.1550 CM) measured value, 374.155
1 CM”) (Reference Example 3) 6-r(3,4,5-trimethoxyphenyl)hydroxymethyl)-3,4-dimethoxybenzyltrimethylsilane (In formula [I], R, X, and Y are methyl A
(6-bromo-3,
1 g (3.3 mmol) of 6-bromo-3,4-dimethoxybenzyltrimethylsilane and 3°4.5-4-methylenedioxybenzyltrimethylsilane instead of 4-methylenedioxybenzyl)trimethylsilane.
Trimethoxybenzaldehyde 0.85g (3.3mm
1.15 g of 6-(hydroxy(3°4.5-)dimethoxyphenyl)methyl)-3°4-dimethoxybenzyltrimethylsilane (yield) was prepared in the same manner as in Reference Example 1 except that 82.9%) was obtained.

The identification data is shown below.

IR' Dial 3500cm-1 a x NMR (CDCl2) δ 0.03 (9H,S), 2.13 (2H,S)
, 2.27 (IH, br.), 3.78.3.80
．． 3.83 (15H, s), 5.87 (IH, br
,,s) ,6.52 (LH,s),6.57
(2H, s) 6.99 (I H, s) MSm/e 420 (M
)299 (100%) MSm/e Calculated value as C22H3208Si;
420.1966 (M) Measured value, 420.195
4(M) (Reference Example 4) 6-((3,4-dimethoxyphenyl)hydroxymethyl)-3,4-dimethoxybenzyltrimethylsilane (
[In formula 11, R, X, and Y are methyl groups, and Ar is 3
, 4-dimethoxyphenyl group) (Reference Example 4) 6-((3,4-dimethoxyphenyl)hydroxymethyl)-3,4-dimethoxybenzyltrimethylsilane (
In the mth formula, R, X, and Y are methyl groups, and Ar is 3.4
-Dimethoxyphenyl group) Synthesis of 6-bromo-3,4-dimethoxybenzyltrimethylsilane instead of (6-bromo-3,4-methylenedioxybenzyl)trimethylsilane in Reference Example 1.
0g (9.9mmol) and 1.4.4.5-1 veratrumaldehyde instead of 5-1rimethoxybenzaldehyde.
Except for using 85 g (9,9 mm o l),
6-((3,4-
dimethoxyphenyl)hydroxymethyl)-3,4-dimethoxybenzyltrimethylsilane 3.3 g (yield 85
．． 3%).

The identification data is shown below.

ZR'di'3500cm-'max NMR (CDCl2) δ 0.03 (9H, s), 2.10 (2B
, s) , 2.13 (IH, br, s),
3.78 (3H, s).

:182 (3H, s), 3.84 (6H,
s) , 5.88 (l H, br, , s),
6.51 (IH, s) 6.77~7, (15
(4H, m) MS m/e 390 (M”)2
70 (100%) MSm/e Calculated value as C21H3oO5Si; 39
0.1861 (M+) Measured value; 390.1839 (M) (Reference Example 5) 6-((3,4-methylenedioxyphenyl)hydroxymethyl)-3,4-dimethoxybenzyltrimethylsilane (No. [I] In the formula, R, X, and Y are methyl groups,
A is a 3,4-methylenedioxyphenyl group.)
Synthesis of 6-bromo-3,4-dimethoxybenzyltrimethylsilane l in place of (6-bromo-3,4-methylenedioxybenzyl)trimethylsilane in Reference Example 1
, 5 g (4,95 mmo 1) and 0.75 biperonal instead of 3.4.5-trimethoxybenzaldehyde.
6-((3,4-methylenedioxyphenyl)hydroxymethyl)-3,4-dimethoxybenzyltrimethylsilane 1 was prepared in the same manner as in Reference Example 1 except that g (5,0 mmol) was used. .50g (yield 80.
9%).

The identification data is shown below.

IR' layer 3500cm" a x NMR (CDCl2) δ 0.03 (9H,!ri, 2.03 (2H, s), 2
．． 21 (I H, br, , 3.79 (3H, s
), 3.82 (3H, s), 5.83 (LH, br
,,s), 5.88 (2H,S), 6.48 (
IH, s), 6.76 (3H, br,, s), 6.9
4 (IH,s)MSm/e 374
(M) 150.44 (100%) MSm/e Calculated value as C2oH2B05Si; 3
74.1548 (M) Measured value: 374.152
0 (M) (hereinafter, blank space) (Example 1) 6.7-methylenedioxy-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-2
, 3-naphthalene dicarboxylic anhydride ((111), where X and Y are methylenedioxy groups bonded to each other,
At is 3,4,5-) Synthesis of deoxypodophyllotoxin intermediate) which is U methoxyphenyl group 5-((3,4,5-trimethoxyphenyl)hydroxymethyl)- obtained in Reference Example 1 above 3,4-methylenedioxybenzyltrimethylsilane 2g (4,θmmol
) and 2.4 g (24.5 mmol) of anhydrous leic acid were heated under reflux in toluene under an argon stream for 24 hours. Thereafter, it was allowed to cool and purified by column chromatography to obtain the title compound (1.45 g, yield 71
．． 8%), the identification data of which are shown below.

Melting point 182.5-183.5℃ IR Nuji''1845.1770cm-1m a X NMR (CDCl2) δ 3.00-3.30 (2H, m), 3.53
~3.75 (2H, m), 3.80 (6H1s
), 3.85 (3H, s), 4.30 (LH, d.

J=5.5Hz), 5.92 (2H, s).

6.50 (2H, !9), 6.62 (LH, s
), 6.75 (IH, s) M S m / e + 412 (M, 100%), 384,339° (Example 2) 1-(3,4-dimethoxyphenyl)-6,7-methylenedi Oxy-1,2,3,4-tetrahydro-2,3-
Naphthalene dicarboxylic anhydride (in formula [111, X,
Synthesis of Deoxypodophyllotoxin Intermediate (6-<(3,4-dimethoxyphenyl) obtained in Reference Example 2) where Y is a methylenedioxy group bonded to each other and Ar is a 3,4-dimethoxyphenyl group
The title compound was prepared in the same manner as in Example 1 above, except that 7250 mg (0,87 mmo+) of hydroxymethyl)-3,4-methylenedioxybenzyltrimethylsila and 330 mg (3,37 mm, ol) of maleic anhydride were used. (160 mg, yield 62.5%), the identification data of which are shown below.

IR Nuji"'1850.1780cm' a x NMR (CDCl2) δ 2.85-3.10 (2H, m), 3.43-3.70 (2H, m), 3.80 (3H
1s), 3.86 (3H, s), 4.32 (IH,
d.

J = 5.5Hz), 5-90 (2H, s)
, 6.80-6.76 (5H, m), MS m/e + 382 (M, 100%) (Example 3) 6.7-Simethoxy1-(3,4,5-)dimethoxyphenyl) -1,2,3,4-tetrahydro-2,3-
Naphthalene dicarboxylic anhydride (in the formula [II], X and Y are each a methyl group, and Ar is a 3,4.5-
150 mg of 6-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-3,4-dimethoxybenzyltrimethylsilane obtained in Reference Example 3. The title compound was obtained in the same manner as in Example 1 (117 mg, yield 71.8%), except that 188 mg (1.92 mmol) of maleic anhydride was used, and its identification data is shown below.

IR'ji"-"1850.1780cm-'a
x NMR (CDCl2) δ 3.10-3.35 (21(, m), 3.50-3.
70 (2H, m), 3.73 (6H1S), 3°8
0 (6H, s), 3.85 (3H.

s), 4.37 (IH, d, J=5.5Hz),
6.37 (2H, 5), 6.83 (IH, S)
, 6.73 (IH, S) MSm/e + 428 (M, 100%), 300M5m/e
Calculated value as C23H2408 428.147
1 (M') Measured value 428.1461 CM
) (Example 4) 1-(3,4-dimethoxyphenyl)-6,7-simethoxy 1.2,3.4-tetrahydro-93-naphthalene dicarboxylic anhydride (in formula [II], X, Y is a methyl group and Ar is a 3,4-dimethoxyphenyl group Synthesis of 6-((3,4-dimethoxyphenyl) obtained in Reference Example 4)
hydroxymethyl)-3,4-dimethoxybenzyltrimethylsilane 200mg (0,51m mo I
) and 251 mg of maleic anhydride (2,56 mmo I
) The title compound was obtained in the same manner as in Example 1 (134 mg, yield 65.9%), and its identification data are shown below.

IR Nujol 1850.1780cm-1a x NMR (CDCl2) δ 2.85-3.35 (2H, m), 3.47-3.77 (2H, m), 3.80 (3H
1s), 3.87 (3H, s), 3.88 (3H,
! 3.93 (3H, s), 6.83-6.90 (5H, m) Ms m/e 398 (M, 100%) Ms m/e Calculated value as C22H2207
398.1364 CM) Measured value 398°1
358(M+) (Example 5) 6.7-Simethoxy1-(3,4-methylenedioxyphenyl)-1,2,3,4-tetrahydro-2,3-
Naphthalene dicarboxylic anhydride (in the formula III, X,
Deoxypodophyllotoxin intermediate in which Y is a methyl group and Ar is a 3,4-methylenedioxyphenyl group]
Synthesis of 300 mg (0.8 m
mol) and maleic anhydride 392 mg (4.0 mm
o l) was heated under reflux in toluene under an argon atmosphere for 24 hours. Thereafter, it was allowed to cool and purified by column chromatography to obtain the title compound (205 m
g, yield 67.1%).

The identification data is shown below.

Melting point 174-175℃ IR Nuji'"1860.1795cm" a
x NMR (CDCl2) δ 3.00 ~ 3.27 (2H, m), 3.50
~3.73 (2H, m), 3.78 (3H
1s), 3.97 (3H,s), 4.25
(11(, d.

J = 5.5Hz), 6.80 (2H,
s), 6.45-6.87 (5H, m) M S m / e 382 (M, 100%), 253 M S m /
e Calculated value as C21H1a O-t 38
2.1051 (M+) measurement value 382.1039
CM) (Reference Example 6) Deoxypodophyllotoxin [Compound (12
)] Synthesis of 6,7-methylenedioxy-1-(
3,4,5-trimethoxyphenyl)-1,2,3,4
500 ml of a methyl alcohol solution containing 5 g (12.1 mmol) of -tetrahydro-2,3-naphthalene dicarboxylic anhydride was heated under reflux for 12 hours under an argon stream. The solvent methyl alcohol is distilled off under reduced pressure,
The colorless crystals obtained are recrystallized with methyl alcohol,
A colorless acicular Hafester compound [compound (9)] was obtained.

3.5 g (7.9 mmol) of this Hafestel body
To 70 ml of a methyl alcohol solution was added 851 mg (15.8 mmol) of sodium methoxide, and the mixture was heated to reflux under an argon atmosphere. The solvent methyl alcohol was distilled off under reduced pressure, and methylene chloride was added to the resulting residue, which was washed successively with a 10% aqueous hydrochloric acid solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.

A 1,2-cis-2,3-trans hafester compound [compound (10)] was obtained.

A THF solution of 1.0 g (2.25 mmol) of this 1,2-cis-2,3-transhafester 12 ml
4.5 ml of lithium triethylporohydride (THF solution of LM) was added to 1 at -20°C under an argon stream,
The mixture was stirred at the same temperature for 30 minutes and further stirred at room temperature for 1 hour. Thereafter, a 10% aqueous hydrochloric acid solution was added, and the T)IF layer was separated. The aqueous layer was extracted with ether, and the THF layer and the extracted ether layer were combined, washed with a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a colorless powdery hydroxycarboxylic acid [compound (11)].

To a solution of 750 mg of the hydroxycarboxylic acid in 10 ml of benzene solution, 21 mg of p-)luenesulfonic acid was added.
was added, and the mixture was heated under reflux for 10 minutes under an argon atmosphere. After cooling, the mixture was washed successively with saturated sodium hydrogen carbonate and saturated saline solution, and dried over anhydrous magnesium sulfate. The pale yellow crystals obtained by distilling off the solvent under reduced pressure were recrystallized from ethyl alcohol to obtain colorless acicular deoxypodophyllotoxin (645 mg), the identification data of which are shown below.

Melting point 234-236℃ IR Nujo" 1765cm-1a x NMR (CDCl2) δ 2.58-3.34 (4H, m), 3.73
(6H, s), 3.79 (3H, s),
3.80~4-10 (IH, m), 4.30~
4.71 (2H, m), 5.92 (2H,
s), 6.32 (2H, s), 6.51
(LH,s), 6.87 (IH,s)M
S m / e + 398 (M, 100%) Elemental analysis calculation value C; 66.32, H, 5,57 analysis value
C; 66.23, H; 5.34 Various spectral data and behavior on silica gel thin layer chromatography of the deoxypodophyllotoxin thus synthesized were all consistent with that of the natural product.

[Brief explanation of drawings]

The first r11 is a reaction route diagram of the method of this invention, and the second
The figure is a reaction route diagram for synthesizing deoxypodophyllotoxin from the deoxypodophyllotoxin intermediate obtained according to the present invention.

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents a lower alkyl group, and Ar represents either a 3,4,5-trimethoxyphenyl group, a 3,4-dimethoxyphenyl group, or a 3,4-methylenedioxyphenyl group.However,
When Ar is a 3,4-methylenedioxyphenyl group, X and Y each represent a lower alkyl group. ) is reacted with maleic anhydride to form a compound represented by the general formula, ▲Mathematical formula, chemical formula, table, etc.▼ (In the formula, X, Y, Ar are the same as above.) A method for producing a deoxypodophyllotoxin intermediate.