JPS5998098A - Novel method for preparing 4'-demethyl- epipodophyllotoxin-beta-d-ethylidene glucoside and acyl derivative thereof - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a carcinostatic agent in high purity and yield, by reacting a halogenoacetyldemethyl-epipodophyllotoxin-beta- D-di-O-halogeno-O-ethylidene glucoside with an amine or ammonia. CONSTITUTION:A 4'-halogenoacetyl-4'-demethyl-epipodophyllotoxin-beta-D-2,3-di- O-halogenoacetyl-4,6-O-ethylidene glucoside expressed by formula I [R is halogenoacetyl expressed by the formula -COCH2X (X is halogen)] is reacted with an amine, e.g. ethylamine, and/or ammonia in a molar amount of preferably 3- 10 times of that of the compound expressed by formula I in a solvent, e.g. pyridine, preferably at 0-70 deg.C for 0.5-5hr to afford the aimed compound expressed by formula II. EFFECT:The purification after completing the reaction is easily carried out, and the method is advantageous as an industrial method.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 4'-halogenoacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3-di-0-halogenoacetyl-4,6-0-ethylidene gluco7 Do (1
) with an amine and/or ammonia to remove the halogenoacetyl group, and a method for producing 4'-demethyl-epipodophyllotoxin-β-ethylatene glucoside (Co., Ltd.), which is characterized by removing the halogenoacetyl group by reacting the acyl The present invention relates to compound (1).

[In the formula, R represents a no-lognoacetyl group represented by -COCH2X (in the formula, X represents a halogen)] The above formula (
The compound represented by 6) is called VP16-213, which exhibits antitumor activity and is a useful substance as a precancer agent.

The method for producing the compound (ill) is described in Japanese Patent Publication No. 45-382
No. 58 and Japanese Patent Publication No. 46-37837 are known. However, in these methods, since the protecting groups of the aglycone and those of the sugar are different, their removal requires two steps. That is, palladium-
Hydrogenolysis is carried out using carbon as a catalyst, and zinc acetate is used to remove acetyl or formyl groups, which are sugar protecting groups. In particular, the removal of sugar protecting groups requires high temperatures and long periods of time; for example, the reaction is not completed even after 20 to 30 hours of reaction, and further reaction increases by-products, resulting in lower yields and lower industrial performance. This is not a good manufacturing method.

Therefore, the present inventors conducted various studies in order to overcome the above-mentioned drawbacks, and found that by reacting Compound 5 with amine and /''!, or A = = A at room temperature for several hours. , the halogenoacetyl group 1, which is a protective group at the 4'-position of the aglycone and the 2- and 3-positions of the sugar, can be removed all at once and safely, and a highly purified compound (J, 1) can be obtained in high yield. They found this and completed the present invention.

In the present invention, the 4' position of the aglycone and the 2 and 3 positions of the sugar
The no-lognoacetyl groups R at the positions may be the same or different. The norogen of X is chlorine,
Examples include bromine.

The amines used in the present invention include aliphatic amines such as methylamine/ethylamine, n-propylamine, and n-butylamine; fatty amines such as dimethylamine, diethylamine, di-n-propylamine, and dilopylamine; Examples include group secondary amines, cyclic amines such as pyrrolidine, piperidine, and morpholine, and aliphatic diamines such as ethylenediamine. These amines and/or
Alternatively, when using ammonia, it is of course possible to add it to the reaction system as it is, but for example, add amine and/or ammonia acetate, hydrochloride, etc. in the presence of a base such as pyridine or triethylamine. Free amine and/or ammonia may be prepared and reacted in-system. The amount used is the compound Th(I)KJt L
A suitable amount is 3 to 10 moles.

The reaction temperature varies depending on the type of amine.
00°C is preferred, and 0-70°C is particularly suitable. The time required for the reaction varies depending on the type of amine and the reaction temperature, but is usually 0.5 to 5 hours.

The solvent to be used is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include chloroform, ethylene chloride, methanol, echnol, and pyridine.

According to the method of the present invention, the halogenoacetyl group R can be easily removed in a short time and under mild conditions, and Compound I can be obtained from Compound (1) in high yield. Therefore, purification after the reaction is completed is easy, for example, by washing the reaction solution with water,
This method is extremely advantageous as an industrial production method because a pure compound can be obtained by simply performing recrystallization.

The compound of formula (1) used as a starting material in the method of the present invention is derived from the plant Podophyllum emodi
Using 4'-demethyl-epipodophyllotoxin (III) obtained from the antitumor active substance podophyllotoxin produced by Wall (see Japanese Patent Publication No. 43-6469) as a raw material, it is synthesized, for example, through the following reaction route. be done.

[In the formula, R is the same as above]

Sochi, 4'-temethyl-epipodophyllotoxin (m)
In an inert solvent, 4'-nigenoacetyl-4'-demethyl-epipodophyllotoxin (IV) obtained by reacting 4'-logenoacetyl chloride with 4'-logenoacetyl chloride in an inert solvent,
4.6-0-ethylidene-2,3-diO-no. in the presence of boron trifluoride ethyl etherate at a temperature below 0°C.
Compound (I) is obtained by condensation with logonoacetyl-β-D-glucobylanose M. Here, compound M is a new compound, 4.6-0-ethylidene-1-
It is synthesized using 0-benzyloxycarbonyl-β-D-glucobylanose (Vl) as a raw material, for example, through the following reaction route.

[The formula is the same as above]

That is, 4,6-0-ethylidene obtained by reacting 4,6-0-ethylidene-1-0-benzyloxycarbonyl-β-D-glucobylanose (Vl) with halogenoacetyl chloride in an inert solvent. /-1-0-benzyloxycarbonyl-2,3-di-O-halogenoacetyl-
Compound M is obtained by hydrogenolyzing β-D-glucobylanose (1).

The present invention will be specifically explained below with reference to Examples and Reference Examples.

Example 1゜4'-temethyl-evibodophyllotoxin-β-1)-
Preparation of ethylidene glucoside I 4'-lyloloacetyl-4'-f methyl-epipodophyllotoxin-β-D-2,3-cy0-chloroacetyl-11,6-0-ethylidene glucoside (I) (It-
,-(,'0C11□C1) 8.2 P 75
Dissolve in 0 ml and cool to 0°C. Add 4.5 l of 70% ethylamine and stir at 0°C for 1 hour.

After the reaction is completed, 200 ml of chloroborum is added, neutralized with 2N hydrochloric acid, washed with water, and dried over anhydrous sodium sulfate. The crude crystals obtained by distilling off the solvent under reduced pressure were recrystallized from chloroform to obtain 4.9 fI- crystals. (Yield 83.1%) The TLC of the crystal obtained here was 1 (, f value (silica gel,
Developing solvent chloroform: methanol-921), I
R.

The NMR and optical rotation were the same as those of the material obtained by the method of Japanese Patent Publication No. 46-37837.

m, P, 259 to 262°C ．．
When the reaction was carried out in the same manner as in Example 1 using 5 g, 4.6 p of the compound ([) was obtained. (Yield 78.0%) Example 3 Process for producing 4'-demethyl-evidophyllotoxin-β-ethylidene glucoside (II) In Example 1, 98% ethylenediamine 2,0? When the reaction was carried out in the same manner as in Example 1 using
Compound (1,1) /1.9 y: If2.
(Yield 483 l dab) Example 4'-temethyl-epipodophyllotoxin-β-1)-
Process for manufacturing ethylidene glucoside (Compound (1)) (I
(,--COCI-12CI) 8.2 P is dissolved in a mixed solvent of 15 Oml of chloroform and 50 ml of methanol, 6.6y- of diethylamine is added, and the mixture is stirred at room temperature for 4 hours. After the reaction was completed, the same treatment as in Example 1 was carried out to obtain compound (11) 3.6P. (Yield 61.0%) Example 5 4'-demethyl-epipodophyllotoxin-β-1)-
Preparation method of Ethylidene Glucoside Co., Ltd. Compound (11 (I = COCl-12C'l) 8.2 P in 150 ml of methanol) is suspended, 10 ml of pyridine and 50 ml of ammonium acetate are added, and the mixture is refluxed for 1 hour. After methanol was distilled off under reduced pressure, the residue was treated in the same manner as in Example 1 to obtain compound (11) 4.59-. (yield 763%)
Example 6 11'-demethyl-epipodophyllotoxin-β-I)
-Production method of ethylidene glucoside ()) (
J(--COCII2 C1) 8.21 was dissolved in a mixed core medium of 150 ml of chloroform and 50 ml of methanol, 10 m/4 of triethylamine and 35 y of ammonium chloride were added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, 4.9 g of compound (II) was obtained by the same treatment as in Example 1.
-I got it. (Yield 83.1%) Example 7 Process for producing 4'-demethyl-epipodophyllotoxin-β-ri-ethylidene glucoside (Compound) In Example 6, compound (1) (I(, = -COCI- 12CI) 4'-bromoacetyl-4'-demethyl-epipodophyllotoxin-β-D-2.3-di-0-bromoacetyl-4,6-0-ethylidene glucoside (i) ( R
--COCI-12Br) 9.59- was carried out in the same manner as in Example 6, and compound (II) was obtained.
48g was obtained. (Yield 81.8%) Example A 4'-chloroacetyl-4'-demethyl-epibotophyllotoxin-β-D-2,3-diO-chloror]acetyl-4,6'-0- Ethylidene glucoside (it(1)
The method for producing 4'-lyloloacetyl-4'-demethyl-ebipotophyllotquinone (IV) (J(=-COCI-12CI) 4)
'-Demethyl-epipodophyllotoxin (III) 40
01 was suspended in 750 ml of anhydrous ethylene chloride, 11.954 ml of anhydrous pyridine was added, and the mixture was cooled to -20°G. Add 15.4P of mono-loacetyl chloride to this solution.
The mixture was added dropwise over 1 hour and stirred for an additional 5 hours. After the reaction is completed, the reaction solution is washed with water and the 41st layer is dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was recrystallized from methanol to obtain compound (IV)'(l(,-
-COCH2C1) 434g- was obtained. (Yield 91.1
%) m, P, 238-240°C IJr 11 also ν 3550. '1783.1765 (sb)
.

+11iJX 1480.1230,1130C17 "1 (bl 4
．． (5-O-ethylidene-1-0-benzyloxycarbonyl-2,3-di-O-taloloacetyl-β-1)
-Glucobylanose (Vll) (R〆0CI-12(
1) Production method 4, 6-0-ethylidene-1-0-benzyloxycarbonyl-β-〇-glucobylanose (Vl) 51, O
g- to anhydrous OO form (500 mtV) 8),
Add anhydrous pyridine 3561 and cool to -CO°C. 11 g of 42.8 P of 95% chloroacetyl chloride was added to this solution over 1 hour, and the mixture was stirred at room temperature for 0.5 hour. After the reaction is completed, the reaction solution is washed with water and the organic layer is dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was recrystallized from isopropyl ether to obtain compound (VJI).
(1t--COCH2C1) 66.6'P was obtained. (Yield 9o, 1%) m, P-130~131°C IILν"B'-1765,1255,1098,70
0C#, ax (c) 4,6-0-ethylidene-2,3-diO-
Chloroacetyl-β-1)-glucobylanose (2(+
1=-coco□CI) Compound (■) (l is also --COCH□CI) 493 P
l',! (: Dissolve in 500% acetone, add 10% para-7um carbon and heat at -10 to -15°C.
Hydrogenation is performed at +'+ pressure. After the reaction, separate the catalyst θ・i'it2: After washing with dry acetone l'oome,
The solvent was concentrated under reduced pressure at a bath temperature of 30°C, and the residue was evaporated under high vacuum for 30°C.
1:1 dried shite compound (V+ (++--cocI) at °C
-■2c+) 35.6 y was obtained as a white nail-like substance. (Yield 99.2%) 11mo・C11CI・3600
．． 1765,1282,1130°+11; IX ■, -095Crn-1 kl) 4'-chloroacetyl-4'-demethyl-epipotophyllotoquinone-β-D -2,3-di-0-taloloacetyl-4,6- 0-ethylidene glucoside (1
) (I also = -COCH2C1) manufacturing process compound CIV)
(R=-COCI-12C+) 11.9 P is dissolved in 150 m/ of anhydrous 1;=i ethylene, and then the compound (■(1 is also one=-COCII,, CI) 9.9 P
and cooled to -20°C. Trifluoride 1+: IIj
After adding 71 i'ii of 15.37 ml of Echetyl Niteller, the mixture was stirred at -20°C for 05 hours.

After completion of the reaction, pyridine:y4.09- was added dropwise, and the reaction solution was mixed with water (k), and then the organic layer was dried over anhydrous sodium sulfate.

(The crude product obtained by distilling the solvent under reduced pressure was distilled from methanol to give compound (I).
-COC11□C+)16 II g was 4I. (Yield 80.3, %) m, P, 244-246°C IRvl (Br1775, 1601, 1483, 123
2° Mouth 1a rtney COCl-12Br) (a) 4'-bromoacetyl-4'-demethyl-epipodophyllotoxin G
V) Preparation Example A of (R2COClI213r) -
The crude product obtained in (a) using 98% bromoacetyl chloride 20.99- in place of chloroacetyl chloride was recrystallized from benzene to form compound (IV) (R-=-
COCI-12Br) 47.09- was obtained.

(Yield 90.2%) m, P, 22 Q ~ 222°C Br 11 (ν 3540.1782.1765.160
1゜1ax 1483.1232,1124Cn+-(b) 4,
6-0-ethylidene-1-0-benzyloxycarbonyl-2,3-di-0-bromoacetyl-β-1)-glucobylanose (Vll) (R=-C0C1121Jr
) Preparation Example A -(+)) 98% bromoacetyl chloride 53.0y-ite compound (Vll) <■ also--COCI-12Br) in place of chloroacetyl chloride
76.2! i"i was obtained. (yield 87.3%) +11.I'・140~14'2°C I3r [1 also ν 1770, 1760, 1
243.1122cm-+11; JX (c) II, 6-0-ethylidene-2,3-diO
-bromoacetyl-β-■)-glucobylanose (v)
(R,,=--COCI21.3r) In Example A-(c), compound (■) ('R--COC1
l. CI) instead of compound (■) (R--COCI-
1□'Br)-58,25t'i using compound M(I also --COCI-12Br)l! 4.11 was obtained as white claws. (Yield 98.9%) - 11 is also (II(cyto 3575,1758.□275
．． □□25゜111; 1)
Manufacturing method example A of (R--COCI-12Br,) -
In (d) compound (IV) (I also --COCFI
Compound (IV) (I also - COCH2 instead of 2C)
13r) 13.0P, compound M(I(,=-C
Compound M (R--COCI(
2Br) 12.41 to form compound (J) (R--
COCI-12Br) 18.8 f was obtained.

(Yield 79.1%) m, P, 201-2036C ■■ also vKBr max 1770.1763 (sh), 1603゜1
483, 1232, 1120Cnr Patent applicant Nippon Kayaku Co., Ltd.

Claims (1)

[Scope of Claims] A 4'-halogen compound represented by the formula 1 [wherein I represents a halogenoacetyl group represented by the formula -○○Cl-l2X (wherein X represents a halogen]] Acetyl-4'-demethyl-epipodophyllotoxin-β-1) -2,3-
4'-demethyl-epipodophyllo of the formula characterized in that the halogenoacetyl group is removed by reacting di-O-halogenoacetyl-4,6-o-ethylidene curcoside with an amine and/or ammonia. Method for producing toxin-β-D-ethyritene glucoside. 4'-halogenoacetyl-4'-demethyl- represented by the formula 2 [wherein I represents a halogenoacetyl group represented by the formula -COCI-12X (in the formula, X does not represent a halogen)]
Epipodophyllotoxin-β-D-2,3-di0-
Halogenoacetyl-4,6-0-ethylidene glucoside.