CA1182827A - Intermediates for the production of picropodophyllin and processes for the preparation and use thereof - Google Patents
Intermediates for the production of picropodophyllin and processes for the preparation and use thereofInfo
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- CA1182827A CA1182827A CA000432955A CA432955A CA1182827A CA 1182827 A CA1182827 A CA 1182827A CA 000432955 A CA000432955 A CA 000432955A CA 432955 A CA432955 A CA 432955A CA 1182827 A CA1182827 A CA 1182827A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
ABSTRACT OF THE DISCLOSURE
The present invention provides compounds useful as intermediates in the preparation of antineoplastic agents, having the structure:
VI
wherein R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl, aralkyl, or R1 and R2 taken together represent the group -O-CH2-O-, R3 repre-sents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group; and X represents Cl, Br or I.
The present invention also provides a process for preparation of compounds VI in a single step wherein X and Y are the same and represent Cl, Br, or I, and R3 is as previously defined except that in this instance, it does not represent a protecting group.
The present invention provides compounds useful as intermediates in the preparation of antineoplastic agents, having the structure:
VI
wherein R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl, aralkyl, or R1 and R2 taken together represent the group -O-CH2-O-, R3 repre-sents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group; and X represents Cl, Br or I.
The present invention also provides a process for preparation of compounds VI in a single step wherein X and Y are the same and represent Cl, Br, or I, and R3 is as previously defined except that in this instance, it does not represent a protecting group.
Description
INTERMEDIATES FOR THE PRODUCTION OF
l~ICROPODOPHYLLIN AND PROCESSE5 FOR
THE PREPARATION THEREO:F
The present invention is directed to intermediates which can be converted into podophyllotoxin and rela-ted compounds, which are known antineoplastic agents. Addition-ally, the present invention provides processes for the preparation of such intermediates, and processes for the conversion of the intermediates into known intermediates which are readily converted into podophyllotoxin and related compounds.
This application is a division of copending Canadian patent application Serial No. 372,161 filed March 3, 1~81.
Podophyllotoxin (I~ a known lignan lactone isolated from several species of Podophyllum, is a potent cytotoxic agent. Numerous other related compounds having the characteristic axyltetralin ring structure, either naturally occurring or derived from some naturally occur-ring compounds are known. Some of these compounds possess antineoplastic activity while others are useful for conver-sion to compouncls having such activity. Podophyllotoxin has the structure shown below:
OtI
//~/
C:EI3 C) o~
OC~I 3 Podophyllo~oxin (I) Podophyllotoxin has also been prepared synthe-tically~ The synthesis involves the production of picropodophyllin (II), shown below:
~l~iZ~
<0_~ ' ~3 ~ OCH3 oc~3 Picropodophyllin (II~
Picropodophyllin is the cis-lactone isomer of podophyllotoxin II~, and can be epimerized into podophyllotoxin (I3 accor-ding to the procedure of Gensler et al, described inJ. Org. Chem., 31, 404-8 (1966). The epimerization is accomplished by preparing the O-tetrahydropyranyl derivative of picropodophyllin, converting it to the sodium enolate by treatment with triphenylmethylsodium, and quenching the enolate with excess acetic acid.
In J. Am. Chem. Soc., 82, 1714-1727 (1960), Gensler et al report the total synthesis of picropodophyllin (II) by a lengthy procedure involving 14 steps and a low overall yield.
~ore recently, in U.S. Patent No. 4,122,092 to Andrew S. Kende and Peter S. Rutledge, there has been described a simpler, more dire~t route for the production of picropodophyllin (II) involving, as an intermediate, a tetralone of formula III, (their XV), shown below.
< ~Ç~<COOR2 C$3 ~\~C~3 III
~L61Z~7 wherein R2 is alkyl and R is methyl or hydrogen. Compound III is produced by a four~step proceduxe utilizing 2-~3,4-methylenedioxyphenyl)ethyl mesylate as a starting material, wherein the immediate precursor to the tetralone III is the corresponding tetralin. However, oxidation of the tetralin to the tetralone III cannot readily be achieved on a larger than 0.2 g scale and thus presents a volume~ric limitation to the synthesis. Conversion of the tetralone III to picropodophyllin (II) is thereafter readily accumplished by the four-step procedure disclosed in the above-cited Kende et al patent.
U.S. Patent No. 3,524,844 to Keller Juslen et al discloses 4'-demethylepipodophyllotoxin-B -D(substi-tuted) glucosides of the formula:
Rl R2~o o O
~ ~ \
~0 ~0 <o ~
~
rvc~3 OCH3 0~
wherein, inter alia, Rl is hydrogen and R2 is an a].kyl or a 2-thienyl moiety. These compounds are prepared from 4'-demethylepipodophyllotoxin V shown below:
~æ~7 o~
<~ r ~
- O
30~oc~3 OEI
which, in turn, is prepared from podophyllotoxin. Both of the latter conversions are described in U.Su 3,524,844.
The 4'-demethylepipodophylloto~in -~ -D(substituted)-gluco-sides are antineoplastic agents.
The present invention provides compounds having the structure:
oR3 R
V~
wherein R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl, aralkyl, or Rl and R2 taken together represent the group -0-CH2-0-, R3 repre-sellts hydrogen~ alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group; and ~ represents C1, Br or I, whenever prepared by the process described below, or by an obvious chemical equivalent thereof.
The protecting group R3 may be any conventional protecting group which is stable to anhydrous base. Such protecting groups are well known to those skilled in the art and include moieties such as tetrahydropyranyl, trialkyl silyl, methoxymethyl, ~-ethoxye-thyl and the like. Other suitable protecting groups are disclosed in: PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, McOmie lPlenum Press, 1973), Chapter 3. Suitable leaving groups consti-tuting Y are are well ]cnown to those skilled in the artand include, for example, tosylate, brosylate, nosylate, mesylate, triflate, nonaflate, tresylate, etc~; and X represents Cl, Br or I, preferably Br or I.
In a preferred embodiment of the present invention, there are provided compounds of the formula:
~Rb ~ X
a wherein Rl, R2 and X are as previously defined, and R4 is the same as R3 except that R4 cannot be a protecting group. Thus R4 represents hydrogen, alkyl, aralkyl or acyl. It is also preferred that X represent Br. Addition-ally, it is preferred that R4 represent lower alkyl, i.e., a group containing l to 6 carbon atoms, and most preferably methyl. Furthermore, it is preferred that Rl and R2, both represent methoxy, or taken together, represent the group -O-CH2-0-. Most preferably Rl and R taken together represent the group -O-CH2-0-.
Preparation of compounds VI may be accomplished in any suitable manner. Pre~erably, compounds VI-a are prepared in a single step from the corresponding (substituted) styrene by treating the styrene with any source of electro-philic bromine~ iodine, or chlorine, together with R40H
wherein R4 is as previous]y defined, i.e., hydrogen, alkyl, aralkyl or acyl. The preparation of compounds VI~a is shown below:
l~ICROPODOPHYLLIN AND PROCESSE5 FOR
THE PREPARATION THEREO:F
The present invention is directed to intermediates which can be converted into podophyllotoxin and rela-ted compounds, which are known antineoplastic agents. Addition-ally, the present invention provides processes for the preparation of such intermediates, and processes for the conversion of the intermediates into known intermediates which are readily converted into podophyllotoxin and related compounds.
This application is a division of copending Canadian patent application Serial No. 372,161 filed March 3, 1~81.
Podophyllotoxin (I~ a known lignan lactone isolated from several species of Podophyllum, is a potent cytotoxic agent. Numerous other related compounds having the characteristic axyltetralin ring structure, either naturally occurring or derived from some naturally occur-ring compounds are known. Some of these compounds possess antineoplastic activity while others are useful for conver-sion to compouncls having such activity. Podophyllotoxin has the structure shown below:
OtI
//~/
C:EI3 C) o~
OC~I 3 Podophyllo~oxin (I) Podophyllotoxin has also been prepared synthe-tically~ The synthesis involves the production of picropodophyllin (II), shown below:
~l~iZ~
<0_~ ' ~3 ~ OCH3 oc~3 Picropodophyllin (II~
Picropodophyllin is the cis-lactone isomer of podophyllotoxin II~, and can be epimerized into podophyllotoxin (I3 accor-ding to the procedure of Gensler et al, described inJ. Org. Chem., 31, 404-8 (1966). The epimerization is accomplished by preparing the O-tetrahydropyranyl derivative of picropodophyllin, converting it to the sodium enolate by treatment with triphenylmethylsodium, and quenching the enolate with excess acetic acid.
In J. Am. Chem. Soc., 82, 1714-1727 (1960), Gensler et al report the total synthesis of picropodophyllin (II) by a lengthy procedure involving 14 steps and a low overall yield.
~ore recently, in U.S. Patent No. 4,122,092 to Andrew S. Kende and Peter S. Rutledge, there has been described a simpler, more dire~t route for the production of picropodophyllin (II) involving, as an intermediate, a tetralone of formula III, (their XV), shown below.
< ~Ç~<COOR2 C$3 ~\~C~3 III
~L61Z~7 wherein R2 is alkyl and R is methyl or hydrogen. Compound III is produced by a four~step proceduxe utilizing 2-~3,4-methylenedioxyphenyl)ethyl mesylate as a starting material, wherein the immediate precursor to the tetralone III is the corresponding tetralin. However, oxidation of the tetralin to the tetralone III cannot readily be achieved on a larger than 0.2 g scale and thus presents a volume~ric limitation to the synthesis. Conversion of the tetralone III to picropodophyllin (II) is thereafter readily accumplished by the four-step procedure disclosed in the above-cited Kende et al patent.
U.S. Patent No. 3,524,844 to Keller Juslen et al discloses 4'-demethylepipodophyllotoxin-B -D(substi-tuted) glucosides of the formula:
Rl R2~o o O
~ ~ \
~0 ~0 <o ~
~
rvc~3 OCH3 0~
wherein, inter alia, Rl is hydrogen and R2 is an a].kyl or a 2-thienyl moiety. These compounds are prepared from 4'-demethylepipodophyllotoxin V shown below:
~æ~7 o~
<~ r ~
- O
30~oc~3 OEI
which, in turn, is prepared from podophyllotoxin. Both of the latter conversions are described in U.Su 3,524,844.
The 4'-demethylepipodophylloto~in -~ -D(substituted)-gluco-sides are antineoplastic agents.
The present invention provides compounds having the structure:
oR3 R
V~
wherein R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl, aralkyl, or Rl and R2 taken together represent the group -0-CH2-0-, R3 repre-sellts hydrogen~ alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group; and ~ represents C1, Br or I, whenever prepared by the process described below, or by an obvious chemical equivalent thereof.
The protecting group R3 may be any conventional protecting group which is stable to anhydrous base. Such protecting groups are well known to those skilled in the art and include moieties such as tetrahydropyranyl, trialkyl silyl, methoxymethyl, ~-ethoxye-thyl and the like. Other suitable protecting groups are disclosed in: PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, McOmie lPlenum Press, 1973), Chapter 3. Suitable leaving groups consti-tuting Y are are well ]cnown to those skilled in the artand include, for example, tosylate, brosylate, nosylate, mesylate, triflate, nonaflate, tresylate, etc~; and X represents Cl, Br or I, preferably Br or I.
In a preferred embodiment of the present invention, there are provided compounds of the formula:
~Rb ~ X
a wherein Rl, R2 and X are as previously defined, and R4 is the same as R3 except that R4 cannot be a protecting group. Thus R4 represents hydrogen, alkyl, aralkyl or acyl. It is also preferred that X represent Br. Addition-ally, it is preferred that R4 represent lower alkyl, i.e., a group containing l to 6 carbon atoms, and most preferably methyl. Furthermore, it is preferred that Rl and R2, both represent methoxy, or taken together, represent the group -O-CH2-0-. Most preferably Rl and R taken together represent the group -O-CH2-0-.
Preparation of compounds VI may be accomplished in any suitable manner. Pre~erably, compounds VI-a are prepared in a single step from the corresponding (substituted) styrene by treating the styrene with any source of electro-philic bromine~ iodine, or chlorine, together with R40H
wherein R4 is as previous]y defined, i.e., hydrogen, alkyl, aralkyl or acyl. The preparation of compounds VI~a is shown below:
2~
OR~
Ra~ ~> Rl~ X
XI ~I a Sources of electrophilic halogens include:
in the case of bromine, elemental bromine, and N-bromoamides such as N-bromosuccinlmide or N-bromoacetamide; in the case of chlorine, elemen-tal chlorine, and N~chloroamides;
and in the case of iod~ine, a solution of iodine with an oxidizing agent such as HgO, HI03, etc.
When R4QH is an alcohol, i.e., when R4 is alkyl or aralkyl, the alcohol is also the solvent. When R40H
is water or a carboxylic acid, a co-solvent such as acetone, dimethylsulfoxide, or dioxane, preferably acetone, should be utilized. Additionally when R40H is water or a carboxylic acid, an alkali salt of a carboxy]ic acid is preferably utilized. Thus~ for instance, when R40H is water or acetic acid, the reaction is preferably conducted in the presence of bodium acetate. When the acid is other than acetic acid, the corresponding acid salt is preferably utilized.
The above reaction is conveniently carried out at a temperature of between about -20C, and about ~30C, preferably at about room temperature, i.e., 23C.
In a preferred embodiment, the source of electrophilic halogen will comprise elemental bromine and R40H will comprise a (lower) alkyl, i.e., 1-6 carbon atoms, alcohol such as methanol, ethanol, isopropanol, t-butyl alcohol, etc, most preferably methanol.
If desired, compounds VI may be provided by a step-wise procedure by, for instance, halogenating a (substituted) benza~dehyde to provide the ortho~halo(sub-stituted)benzaldehyde, converting the o-halo(substitu-ted) benzaldehyde to ~he corresponding styrene, and treating the styrene with a source of electrophilic halogen, ~1~%~
which may be the same or different halogen as the ring halogen, together with R4OH. Thus, for instance, 3,4 methylenedioxybenzaldehyde (piperonal~ ~ay be treated with iodine and a silver salt to provide 3,4~methylene-dioxy-6-iodobenzaldehyde, The latter is converted to the corresponding s~yrene by ~reatment with (methyl) triphenylphosphonium bromide and a suitable base such as potassium carbonate or n-butyl lithium, according to the Wittig reaction to provide the ortho-iodo(substi tu;ted)styrene. The styrene is treated with bromine or chlorine in a simple alcohol, i.e., methanol, ethanol, etc., to provide compound VI wherein Y is bromine or chlorine and X is iodine. Compounds VI or VI-a may, if desired, be treated to convert the side chain halogen -to another leaving group, and/or to con~ert R3 or R4 to any of the previously enumerated pro~ecting groups by means known to those skilled in the art.
Compounds VI and VI-a may be used to form compounds VII-a and VII-b, shown below:
R2 ~[ C ~<z 2 R~ ~ R9 OR~
VII-a; j=l VII-b; ~=0 wherein Rl, R2 and R3 are as previously defined, j is an integer having a value of 0 or 1, zl represents a conventional non~reacting electron withdrawing group.
Non-reacting electron withdrawing groups are well known to ~ose skilled in the art and include, for example, COO(alkyl)~ COO(aryl)~ COO(aralkyl), substituted ketones such as CO(alkyl), CO(aryl) and CO(aralkyl) and amides such as, CONH2r etc. z2 represents a conventional non-reac~ing electron withdrawing group or hydrogen. Preferred electron withdrawing groups are those which can readily be converted to a carboxyl group. It is also preferred that both ~1 and z2 represent electron withdrawing groups.
R8 and R9 are the same or different and represent hydrogen, alkyl, aralkyl, alkoxy, aralkoxy, or acyl and R7 represents hydrogen, alkyl, aralkyl or acyl. 1 5 In a preferred embodiment Z represents COOR
and z2 represents COOR6, wherein R5 and R6 are the same or different and represent alkyl, or aralkyl, and j repre sents the integer 1. Preferably R5 and R6 are the same and represent lower alkyl, most preferably, ethyl. Addi-tionally, it is preferred -that R3 represent lower alkyl and that Rl and R2 represent methoxy or, taken together, represent the group -0-CH2-0-. R8 and R9 are preferably lower alkoxy, most preferably methoxy while R7 is preferably lower alkyl or aralkyl, most preferably methyl or benzyl.
Compounds VII-a and VII-b can be prepared from compounds VL and VI-b (shown below) through the process of "insertion~cyclization". The insertion-cyclization reaction, as u~ilized herein, is shown below:
~ '--R ~
30 R2 ~ X kyl llthiun ~¦ R2 Li J
YI; j=l XII
VI-b; j~
XII+ ~C ~ \Z~
R.l XIII XIV
:,, 21~
1 2 R3 zl z2 y X and j are as previously defined; Rl represents hydrogen, alkyl, aryl, substituted aryl, or aralkyl.
The reaction proceeds most readily when X repre-sents I or Br. The alkyl lithium utilized may be anyprimary, secondary, or tertiary alkyl lithium. When X represents I, a primary alkyl lithium is preferred because of cost. When X represents Br, it is preferred that the alkyl lithium utilized be a secondary or tertiary alkyl lithium and when X represents Cl, it is preferred that ~he alkyl lithium be a tertiary alkyl lithium. Any inert solvent which is liquid at reaction temperatures may be utilized. A preferred solvent constitutes a mixture of diethyl ethex and tetrahydrofuran.
The insertion-cyclization reaction sequence shown above should be initiated at a temperature of less than -40C, preferably at a temperature of less than -78C, most preferably at a temperature of about -100C.
The reaction is initiated by adding the alkyl li-thium to compound VI or VI-b to provide lithium-haloyen exchange thus forming compound XII as an unisolated intermediate.
The exchange proceeds most readily when t-butyllithium is used and has been found to be completed within ten minutes when the ring halogen, i.e., X, is Br or I. Complete-ness of the exchange can readily be determined by NMRexamination of an aliquot the ~eaction mixture after quenching with water.
Upon completion of the exchange, compound XIII
is slo~ly added to the reaction mixture followed by agitation for a short period of time, i.e., up to about an hour.
The mixture is thereafter slowly warmed to a temperature of between about 0C and about 120C, preferably between about 40C and 90C, and stirred or refluxed to complete the ring closure. It has been found that xing closure 3s proceeds slowly at lower temperatures, e.g., several days at about 20C, and rapidly at higher temperatures, e.g.~ an hour at 85C.
In order to reflux the mixture at the preferred elevated temperatures, it may be necessary to remove ~28Z~
the lower boiling solvent and replace the same with a higher boiling inert solvent, such as an ether or benzene.
A preferred inert solvent is 1,2-dimethoxyethane which has a boiling point of 83C. Completion of ring closure can be determined by NMR examination of the reaction product.
- Compounds XIII are readily available via the Knoevenagel condensation of a di(electron wi~hdrawing group) methane with an aldehyde. The Knoevenagel reaction is well known and forms no part of the present invention.
A detailed discussion of the reaction may be found in:
ADVANCED ORGANIC CHEMISTRY, 2nd ~d., March (McGraw-Hill, 1977) pages 854-859.
It is preferred that R10 represent the radical:
R~ ~ R9 ~herein R7, R8 and R9 are as previously defined. Addition-ally, it is preferred that zl represent CoOR5 and z2 represent COOR6 ~herein R5 and R6 are as previously defined.
Most preferably, the reaction is carried out wherein j represents the integer 1 and R5 and R6 represent the same or different lower alkyl, most preferably ethyl.
Additionally, it is preferred that R3 represent lower alkyl and that RL and R2 each represent methoxy or, taken together, represent -0-CH2-O-. R8 and R9 are preferably lower alkoxy, most preferably methoxy, while R7 is prefera-bly lower alkyl or aralkyl, most preferably methyL or benzyl.
Compounds VII-a may be converted to the corres-ponding tetralone III-a as shown below:
o~3 Rl ~ ~ zl 2. Jones Reagent VII-a ~2 ~ z2 ~9~ ~ R9 oR7 III-a l R2 R3 R7 R8 R9, zl, z2 are as previously defined. Thus, compounds VII-a are treated with an aqueous mineral acid such as H2SO~, HCl, HBr, etc., pre~erably HCl, to effect hydrolysis and to thus provide the corres-ponding alcohol at C-4, and the alcohol is oxidized to the ketone III-a, by the Jones oxidation.
The hydrolysis is conducted at a temperature of about -20C to about 40C, preferably about 0C, in any polar solvent, preferably acetone. The hydrolysis is continued until disappearance of the starting material at which point Jones reagent may be added. The Jones Oxidation and Jones reagent are well known to those skilled in the art. The same are discussed in Bowden et al, J. Chem. Soc. 39 (1946) and Bowers et al, J. Chem. Soc.
2548 (1953). Upon completion of the Jones oxidationt the reaction is quenched, e.g., with methanol, to provide the tetralone III-a.
Certain of the compounds III--a, i.e., when zl and Z are each COO(lower alkyl), R8 and R9 are each methoxy and R7 is methyl, designated tetralone III-b, can be readily converted into picropodophyllin (II) and ~13æb);~7 picrosikkimotoxin (VIII), shown below:
-~3~0 _. O
CH3 ~ 'OC~i3 oc~3 Picrosikkimotoxin (VIII) through the procedures disclosed in U.S. Patent No. 4,122,092to Kende ~t al~ at column 7, line 36 through column 8, line 17. If tetralone III-a is in a form other than that of tetralone III-b, it is convert~d into tetralone III-b by means known to those skilled in the art. There-after, tetralone III-b can be converted to the above-stated compounds by the process disclosed in U.S. Patent No. 4,122~092 to Kende e,t al.
The latter, i.e., compounds II and VIII, are readily converted into antineoplastic agents podophyllotoxin (I) and sikkimotoxin ~I~), shown below:
0}~
C~ O ~ _ ~
CH/O ~ OC~ 3 OC~ 3 Sikkimotoxin (IX~
through the Gensler enolate quenching procedure previously described. Podophyllotoxin is converted into the antineo-plastic agents, 4'-demethylepipodophyllotoxin- ~ -D-subs-ti-tu~ed)glucosides ~IV3, by the procedure of U.S. Patent No. 3~524,844.
Overall) the present invention provides a simple straightforward procedure for preparing known antineoplas-tic agents. Use of the intermediates and processes of the present invention avoids the volumetrically limiting tetralin to ~etralone oxidation step of the prior art.
Additionally, the intermediates of the present invention can be readily prepared from less complex, and often commercially available starting materials such as piperonal.
With regard to previous references to lower alkyl and lower alkoxy groups, for the purposes of the present disclosure the term, lower alkyl, is intended to mean a straight or branched chain alkyl moiety containing 1 to 6 carbon atoms and the term, lower alkoxy, is intended to mean a straight or branched chain alkoxy moiety having ~0 1 to 6 carbon atoms.
A particularly preferred reaction sequence is shown below:
< ~ Wit~ig Reaction <
O
XI-a C~3GH > <O ~ ~r VI-c "C' ; ~ < ~O~cooca2c~3 ca o ~\ ocx ~ 3 ~3 1 O(~I3 ~X~3 O
< ~ ~ COOC~2C~
COOCH2c~3 2~ Jones Reagen~
~3 I OCH3 OC~ 3 I Pr~cedure of ~ . 4,122,092 > Picropodophyllin I
Podaphyllo toxin Quenc~h 5 ~1 ~8~2~
The following examples serve to illustrate the intermediates and processes of the present invention.
E~am~le 1 2-Methoxy~2(6-bromo-3~4-methylenedioxyphenyl)~l~bromoethane (VI-a; where X=Br, Rl and R2=0-CH~-0, R4=CH3) (a) Preparation of Starting Material: 3,4 Methylenedioxystyrene To a stirred suspension of (methyl)triphenyl-phosphonium bromide (17.1 g, 48 mmol) and potassium carbon-a~e ~6.63 g, 48 mmol) in THF (200 ml) were added piperonal (6.0 g, 40 mmDl) and 18-crown-6 (120 mg, 0.46 mmol).
The mixture was heated to reflux under nitrogen and refluxed for 36 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate evaporated to dryness at 15C. The resulting solid was stirred in 100 ml cold diethylether to dissolve the desired product, then filtered to remove inorganic salts, and the filtrate evaporated at 15C~ This process was repeated a second time. The product was filtered through 60 g basic alumina (pentane/ether, 24/1) and the solvent removed as beore to give 5.36 g 189~) of the liquid styrene. NMR (CDC13) ~
6.89 (lH, singlet), 6.70-~.74 (2H, 2 overlapping singlets), 6.43-6.7 ~lH, partially obscured doublet)~ 5.84 (2H, singlet), 5.50 (lH, doublet), 5.06 (lH, doublet).
(b) Preparation of Title Compound:
Bromine (3.15 ml, 61.4 mmol) was added dropwise to a stirred solution of 3,4-methylenedioxystyrene (3.0 g, 20.0 mmol) in dry methanol (60 ml) undex nitroyen at 0C. The resulting solution was stirred at 0C for 15 minutes, then at room temperature for 36 hours, at which point a white precipitate had appeared, and the reaction was complete by TLC (ether/cyclohexane, 1/1).
The reaction mixture was cooled to 0C and filtered, and the product was washed with cold methanol, yielding 4.07 g. The mother liquors were evaporated, and the residue poured into water containing several spatula tips of sodium bisulfite. This was extracted with methylene chloride three times, and the combined extracts were washed with water, saturated sodium bicarbonate and satura-;~82~Z7 16ated sodium ~hlor~de, filtered throu~h sodium sulfate, and evaporated. The resulting offYwhite solid was recrystal-lized twice from methanol, to give an additional 0.67 g of the title compound. Total yield: 5.34 g (79%);
m.p. 87-88.5C, NMR (CDC13)~ 6.92 (lH, singlet), 6.38 (lH, singlet), 5.94 (2H, singlet), 4.68 (lHr doublet),
OR~
Ra~ ~> Rl~ X
XI ~I a Sources of electrophilic halogens include:
in the case of bromine, elemental bromine, and N-bromoamides such as N-bromosuccinlmide or N-bromoacetamide; in the case of chlorine, elemen-tal chlorine, and N~chloroamides;
and in the case of iod~ine, a solution of iodine with an oxidizing agent such as HgO, HI03, etc.
When R4QH is an alcohol, i.e., when R4 is alkyl or aralkyl, the alcohol is also the solvent. When R40H
is water or a carboxylic acid, a co-solvent such as acetone, dimethylsulfoxide, or dioxane, preferably acetone, should be utilized. Additionally when R40H is water or a carboxylic acid, an alkali salt of a carboxy]ic acid is preferably utilized. Thus~ for instance, when R40H is water or acetic acid, the reaction is preferably conducted in the presence of bodium acetate. When the acid is other than acetic acid, the corresponding acid salt is preferably utilized.
The above reaction is conveniently carried out at a temperature of between about -20C, and about ~30C, preferably at about room temperature, i.e., 23C.
In a preferred embodiment, the source of electrophilic halogen will comprise elemental bromine and R40H will comprise a (lower) alkyl, i.e., 1-6 carbon atoms, alcohol such as methanol, ethanol, isopropanol, t-butyl alcohol, etc, most preferably methanol.
If desired, compounds VI may be provided by a step-wise procedure by, for instance, halogenating a (substituted) benza~dehyde to provide the ortho~halo(sub-stituted)benzaldehyde, converting the o-halo(substitu-ted) benzaldehyde to ~he corresponding styrene, and treating the styrene with a source of electrophilic halogen, ~1~%~
which may be the same or different halogen as the ring halogen, together with R4OH. Thus, for instance, 3,4 methylenedioxybenzaldehyde (piperonal~ ~ay be treated with iodine and a silver salt to provide 3,4~methylene-dioxy-6-iodobenzaldehyde, The latter is converted to the corresponding s~yrene by ~reatment with (methyl) triphenylphosphonium bromide and a suitable base such as potassium carbonate or n-butyl lithium, according to the Wittig reaction to provide the ortho-iodo(substi tu;ted)styrene. The styrene is treated with bromine or chlorine in a simple alcohol, i.e., methanol, ethanol, etc., to provide compound VI wherein Y is bromine or chlorine and X is iodine. Compounds VI or VI-a may, if desired, be treated to convert the side chain halogen -to another leaving group, and/or to con~ert R3 or R4 to any of the previously enumerated pro~ecting groups by means known to those skilled in the art.
Compounds VI and VI-a may be used to form compounds VII-a and VII-b, shown below:
R2 ~[ C ~<z 2 R~ ~ R9 OR~
VII-a; j=l VII-b; ~=0 wherein Rl, R2 and R3 are as previously defined, j is an integer having a value of 0 or 1, zl represents a conventional non~reacting electron withdrawing group.
Non-reacting electron withdrawing groups are well known to ~ose skilled in the art and include, for example, COO(alkyl)~ COO(aryl)~ COO(aralkyl), substituted ketones such as CO(alkyl), CO(aryl) and CO(aralkyl) and amides such as, CONH2r etc. z2 represents a conventional non-reac~ing electron withdrawing group or hydrogen. Preferred electron withdrawing groups are those which can readily be converted to a carboxyl group. It is also preferred that both ~1 and z2 represent electron withdrawing groups.
R8 and R9 are the same or different and represent hydrogen, alkyl, aralkyl, alkoxy, aralkoxy, or acyl and R7 represents hydrogen, alkyl, aralkyl or acyl. 1 5 In a preferred embodiment Z represents COOR
and z2 represents COOR6, wherein R5 and R6 are the same or different and represent alkyl, or aralkyl, and j repre sents the integer 1. Preferably R5 and R6 are the same and represent lower alkyl, most preferably, ethyl. Addi-tionally, it is preferred -that R3 represent lower alkyl and that Rl and R2 represent methoxy or, taken together, represent the group -0-CH2-0-. R8 and R9 are preferably lower alkoxy, most preferably methoxy while R7 is preferably lower alkyl or aralkyl, most preferably methyl or benzyl.
Compounds VII-a and VII-b can be prepared from compounds VL and VI-b (shown below) through the process of "insertion~cyclization". The insertion-cyclization reaction, as u~ilized herein, is shown below:
~ '--R ~
30 R2 ~ X kyl llthiun ~¦ R2 Li J
YI; j=l XII
VI-b; j~
XII+ ~C ~ \Z~
R.l XIII XIV
:,, 21~
1 2 R3 zl z2 y X and j are as previously defined; Rl represents hydrogen, alkyl, aryl, substituted aryl, or aralkyl.
The reaction proceeds most readily when X repre-sents I or Br. The alkyl lithium utilized may be anyprimary, secondary, or tertiary alkyl lithium. When X represents I, a primary alkyl lithium is preferred because of cost. When X represents Br, it is preferred that the alkyl lithium utilized be a secondary or tertiary alkyl lithium and when X represents Cl, it is preferred that ~he alkyl lithium be a tertiary alkyl lithium. Any inert solvent which is liquid at reaction temperatures may be utilized. A preferred solvent constitutes a mixture of diethyl ethex and tetrahydrofuran.
The insertion-cyclization reaction sequence shown above should be initiated at a temperature of less than -40C, preferably at a temperature of less than -78C, most preferably at a temperature of about -100C.
The reaction is initiated by adding the alkyl li-thium to compound VI or VI-b to provide lithium-haloyen exchange thus forming compound XII as an unisolated intermediate.
The exchange proceeds most readily when t-butyllithium is used and has been found to be completed within ten minutes when the ring halogen, i.e., X, is Br or I. Complete-ness of the exchange can readily be determined by NMRexamination of an aliquot the ~eaction mixture after quenching with water.
Upon completion of the exchange, compound XIII
is slo~ly added to the reaction mixture followed by agitation for a short period of time, i.e., up to about an hour.
The mixture is thereafter slowly warmed to a temperature of between about 0C and about 120C, preferably between about 40C and 90C, and stirred or refluxed to complete the ring closure. It has been found that xing closure 3s proceeds slowly at lower temperatures, e.g., several days at about 20C, and rapidly at higher temperatures, e.g.~ an hour at 85C.
In order to reflux the mixture at the preferred elevated temperatures, it may be necessary to remove ~28Z~
the lower boiling solvent and replace the same with a higher boiling inert solvent, such as an ether or benzene.
A preferred inert solvent is 1,2-dimethoxyethane which has a boiling point of 83C. Completion of ring closure can be determined by NMR examination of the reaction product.
- Compounds XIII are readily available via the Knoevenagel condensation of a di(electron wi~hdrawing group) methane with an aldehyde. The Knoevenagel reaction is well known and forms no part of the present invention.
A detailed discussion of the reaction may be found in:
ADVANCED ORGANIC CHEMISTRY, 2nd ~d., March (McGraw-Hill, 1977) pages 854-859.
It is preferred that R10 represent the radical:
R~ ~ R9 ~herein R7, R8 and R9 are as previously defined. Addition-ally, it is preferred that zl represent CoOR5 and z2 represent COOR6 ~herein R5 and R6 are as previously defined.
Most preferably, the reaction is carried out wherein j represents the integer 1 and R5 and R6 represent the same or different lower alkyl, most preferably ethyl.
Additionally, it is preferred that R3 represent lower alkyl and that RL and R2 each represent methoxy or, taken together, represent -0-CH2-O-. R8 and R9 are preferably lower alkoxy, most preferably methoxy, while R7 is prefera-bly lower alkyl or aralkyl, most preferably methyL or benzyl.
Compounds VII-a may be converted to the corres-ponding tetralone III-a as shown below:
o~3 Rl ~ ~ zl 2. Jones Reagent VII-a ~2 ~ z2 ~9~ ~ R9 oR7 III-a l R2 R3 R7 R8 R9, zl, z2 are as previously defined. Thus, compounds VII-a are treated with an aqueous mineral acid such as H2SO~, HCl, HBr, etc., pre~erably HCl, to effect hydrolysis and to thus provide the corres-ponding alcohol at C-4, and the alcohol is oxidized to the ketone III-a, by the Jones oxidation.
The hydrolysis is conducted at a temperature of about -20C to about 40C, preferably about 0C, in any polar solvent, preferably acetone. The hydrolysis is continued until disappearance of the starting material at which point Jones reagent may be added. The Jones Oxidation and Jones reagent are well known to those skilled in the art. The same are discussed in Bowden et al, J. Chem. Soc. 39 (1946) and Bowers et al, J. Chem. Soc.
2548 (1953). Upon completion of the Jones oxidationt the reaction is quenched, e.g., with methanol, to provide the tetralone III-a.
Certain of the compounds III--a, i.e., when zl and Z are each COO(lower alkyl), R8 and R9 are each methoxy and R7 is methyl, designated tetralone III-b, can be readily converted into picropodophyllin (II) and ~13æb);~7 picrosikkimotoxin (VIII), shown below:
-~3~0 _. O
CH3 ~ 'OC~i3 oc~3 Picrosikkimotoxin (VIII) through the procedures disclosed in U.S. Patent No. 4,122,092to Kende ~t al~ at column 7, line 36 through column 8, line 17. If tetralone III-a is in a form other than that of tetralone III-b, it is convert~d into tetralone III-b by means known to those skilled in the art. There-after, tetralone III-b can be converted to the above-stated compounds by the process disclosed in U.S. Patent No. 4,122~092 to Kende e,t al.
The latter, i.e., compounds II and VIII, are readily converted into antineoplastic agents podophyllotoxin (I) and sikkimotoxin ~I~), shown below:
0}~
C~ O ~ _ ~
CH/O ~ OC~ 3 OC~ 3 Sikkimotoxin (IX~
through the Gensler enolate quenching procedure previously described. Podophyllotoxin is converted into the antineo-plastic agents, 4'-demethylepipodophyllotoxin- ~ -D-subs-ti-tu~ed)glucosides ~IV3, by the procedure of U.S. Patent No. 3~524,844.
Overall) the present invention provides a simple straightforward procedure for preparing known antineoplas-tic agents. Use of the intermediates and processes of the present invention avoids the volumetrically limiting tetralin to ~etralone oxidation step of the prior art.
Additionally, the intermediates of the present invention can be readily prepared from less complex, and often commercially available starting materials such as piperonal.
With regard to previous references to lower alkyl and lower alkoxy groups, for the purposes of the present disclosure the term, lower alkyl, is intended to mean a straight or branched chain alkyl moiety containing 1 to 6 carbon atoms and the term, lower alkoxy, is intended to mean a straight or branched chain alkoxy moiety having ~0 1 to 6 carbon atoms.
A particularly preferred reaction sequence is shown below:
< ~ Wit~ig Reaction <
O
XI-a C~3GH > <O ~ ~r VI-c "C' ; ~ < ~O~cooca2c~3 ca o ~\ ocx ~ 3 ~3 1 O(~I3 ~X~3 O
< ~ ~ COOC~2C~
COOCH2c~3 2~ Jones Reagen~
~3 I OCH3 OC~ 3 I Pr~cedure of ~ . 4,122,092 > Picropodophyllin I
Podaphyllo toxin Quenc~h 5 ~1 ~8~2~
The following examples serve to illustrate the intermediates and processes of the present invention.
E~am~le 1 2-Methoxy~2(6-bromo-3~4-methylenedioxyphenyl)~l~bromoethane (VI-a; where X=Br, Rl and R2=0-CH~-0, R4=CH3) (a) Preparation of Starting Material: 3,4 Methylenedioxystyrene To a stirred suspension of (methyl)triphenyl-phosphonium bromide (17.1 g, 48 mmol) and potassium carbon-a~e ~6.63 g, 48 mmol) in THF (200 ml) were added piperonal (6.0 g, 40 mmDl) and 18-crown-6 (120 mg, 0.46 mmol).
The mixture was heated to reflux under nitrogen and refluxed for 36 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate evaporated to dryness at 15C. The resulting solid was stirred in 100 ml cold diethylether to dissolve the desired product, then filtered to remove inorganic salts, and the filtrate evaporated at 15C~ This process was repeated a second time. The product was filtered through 60 g basic alumina (pentane/ether, 24/1) and the solvent removed as beore to give 5.36 g 189~) of the liquid styrene. NMR (CDC13) ~
6.89 (lH, singlet), 6.70-~.74 (2H, 2 overlapping singlets), 6.43-6.7 ~lH, partially obscured doublet)~ 5.84 (2H, singlet), 5.50 (lH, doublet), 5.06 (lH, doublet).
(b) Preparation of Title Compound:
Bromine (3.15 ml, 61.4 mmol) was added dropwise to a stirred solution of 3,4-methylenedioxystyrene (3.0 g, 20.0 mmol) in dry methanol (60 ml) undex nitroyen at 0C. The resulting solution was stirred at 0C for 15 minutes, then at room temperature for 36 hours, at which point a white precipitate had appeared, and the reaction was complete by TLC (ether/cyclohexane, 1/1).
The reaction mixture was cooled to 0C and filtered, and the product was washed with cold methanol, yielding 4.07 g. The mother liquors were evaporated, and the residue poured into water containing several spatula tips of sodium bisulfite. This was extracted with methylene chloride three times, and the combined extracts were washed with water, saturated sodium bicarbonate and satura-;~82~Z7 16ated sodium ~hlor~de, filtered throu~h sodium sulfate, and evaporated. The resulting offYwhite solid was recrystal-lized twice from methanol, to give an additional 0.67 g of the title compound. Total yield: 5.34 g (79%);
m.p. 87-88.5C, NMR (CDC13)~ 6.92 (lH, singlet), 6.38 (lH, singlet), 5.94 (2H, singlet), 4.68 (lHr doublet),
3.44 (2H, multiplet), 3.29 (3H singlet) t Mass Spec.
340,338,336 (M+).
Example 2
340,338,336 (M+).
Example 2
4-Methoxy-2~2-dicarbethoxy-6,7~methylenedioxy-1-(3',4',5'-trimethoxyphenyl)~etralin, (VII-a; where R1 and R
O-CH2-O, ~3 = CH3, zl, z = COOC2H5, R7 - CH3, R , R
= OCH3) To a solution o~ the methoxydibromide prepared in Example 1 (490 mg, 1.45 mmol) in ether (8 ml) ak ~100C
(ether/liquid nitrogen) under nitrogen was added t-butylli~h-ium (0.98 ml, 1.52 mmol, 1.55 M in pentane) dropwise via syringe. The reaction mixture was stirred for 30 minutes at -100C, and then diethyl(3,4,5-trimethoxyphenyl) methylenemalonate (490 mg, 1.45 mmol) [prepared by the method o~ Papadakis et al, J. Org. Chem, 21, 593 (1956)]
in tetrahydrofuran (1.5 ml) was added slowly via syringe.
The reaction was maintained at -100C for 1 hour and then allowed to come slowly to room temperature and stirred ~or 16 hours. The ether and THF were removed with a nitrogen stream and 1,2-dimethoxyethane (8 ml) was distilled into the reaction vessel. The solution was refluxed for 1 hour under nitrogen, poured into dilute ammonium chloride, and extracted with methylene chloride. The organic layer was washed with water and saturated sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure to give 730 mg of crude title product as a 3/2 mixture of diastereomers by NMR. A
small portion (78 mg) was purified by separative thin layer chromatography (ether/cyclohexane, 1/1) to give 27 mg of the less polar diastereomer~ NMR (CDC13) ~ 6.87 (lH, singlet), 6.37 (lH, singlet), 6.25 (2Hr singlet3,
O-CH2-O, ~3 = CH3, zl, z = COOC2H5, R7 - CH3, R , R
= OCH3) To a solution o~ the methoxydibromide prepared in Example 1 (490 mg, 1.45 mmol) in ether (8 ml) ak ~100C
(ether/liquid nitrogen) under nitrogen was added t-butylli~h-ium (0.98 ml, 1.52 mmol, 1.55 M in pentane) dropwise via syringe. The reaction mixture was stirred for 30 minutes at -100C, and then diethyl(3,4,5-trimethoxyphenyl) methylenemalonate (490 mg, 1.45 mmol) [prepared by the method o~ Papadakis et al, J. Org. Chem, 21, 593 (1956)]
in tetrahydrofuran (1.5 ml) was added slowly via syringe.
The reaction was maintained at -100C for 1 hour and then allowed to come slowly to room temperature and stirred ~or 16 hours. The ether and THF were removed with a nitrogen stream and 1,2-dimethoxyethane (8 ml) was distilled into the reaction vessel. The solution was refluxed for 1 hour under nitrogen, poured into dilute ammonium chloride, and extracted with methylene chloride. The organic layer was washed with water and saturated sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure to give 730 mg of crude title product as a 3/2 mixture of diastereomers by NMR. A
small portion (78 mg) was purified by separative thin layer chromatography (ether/cyclohexane, 1/1) to give 27 mg of the less polar diastereomer~ NMR (CDC13) ~ 6.87 (lH, singlet), 6.37 (lH, singlet), 6.25 (2Hr singlet3,
5.84 (2H, singlet), 4.74 (lH, singlet), 4.16 (5H, multiplet3, 3.78 (3H, singlet), 3.73 (6H, singlet), 3.58 (3H, singlet~, ~32~7 2.3~2.7 ~2H, multiplet)~ 1.20 (6H, two overlapping triplets);
~assSpec., 516 [M+), and 39 mg of the more polar diastereomer;
NMR (CDC13)~ 6077~1H~ singlet), 6.46 (lH, singlet), 6.17 (2H, singlet)) 5~90l2HJ doublet~, 4.87(1H~ singlet), 402 (5HJ multiplet), 3.84(3H, singlet), 3~81(6H, singlet) J
3.54(3H, singlet), 2.90(lH, broad doublet), 2~52(lH~
doublet), 1.20(6H~ two overlapping triplets), Mass Spec.
516 (M~)~ Total yield: 117 mg (85%). The crude mixture was used directly for the oxidation (Example 5).
Example 3 4-Methoxy-2,~-dicarbethoxy~ 3',5'-dimethoxy-4'-benzyloxyphenyl) 6,7-methylenedioxytetralin (VII-a; where Rl and R = O-CH2-0, R = CH3, T T ~ ~ T T
~ , ~ - ~vv~2n5, ~ ~6rl5 2' R , R = OCH3) The reaction was run as in Example 2 using the methoxy dibromide of Example 1 (136 mg., 0.402 mmol), t butyllithium (0.267 ml, 0.422 mmoli 1.58M
in pentane), ether l6 ml), THF (1 ml), 1,2-dimethoxyethane (6 ml) and diethyl(3,5 dimethoxy-4-benzyloxyphenyl)methylene malonate (172 mg., 0~402 mmols.) Workup gave 219 mg of crude product, which was purified by preparative TLC
(acetone/ether/hexanes, 1~1/3) to give 95 mg of the more polar diastereomer; NMR (CDC13),~ 7.2-7.5 (5H, multiplet),
~assSpec., 516 [M+), and 39 mg of the more polar diastereomer;
NMR (CDC13)~ 6077~1H~ singlet), 6.46 (lH, singlet), 6.17 (2H, singlet)) 5~90l2HJ doublet~, 4.87(1H~ singlet), 402 (5HJ multiplet), 3.84(3H, singlet), 3~81(6H, singlet) J
3.54(3H, singlet), 2.90(lH, broad doublet), 2~52(lH~
doublet), 1.20(6H~ two overlapping triplets), Mass Spec.
516 (M~)~ Total yield: 117 mg (85%). The crude mixture was used directly for the oxidation (Example 5).
Example 3 4-Methoxy-2,~-dicarbethoxy~ 3',5'-dimethoxy-4'-benzyloxyphenyl) 6,7-methylenedioxytetralin (VII-a; where Rl and R = O-CH2-0, R = CH3, T T ~ ~ T T
~ , ~ - ~vv~2n5, ~ ~6rl5 2' R , R = OCH3) The reaction was run as in Example 2 using the methoxy dibromide of Example 1 (136 mg., 0.402 mmol), t butyllithium (0.267 ml, 0.422 mmoli 1.58M
in pentane), ether l6 ml), THF (1 ml), 1,2-dimethoxyethane (6 ml) and diethyl(3,5 dimethoxy-4-benzyloxyphenyl)methylene malonate (172 mg., 0~402 mmols.) Workup gave 219 mg of crude product, which was purified by preparative TLC
(acetone/ether/hexanes, 1~1/3) to give 95 mg of the more polar diastereomer; NMR (CDC13),~ 7.2-7.5 (5H, multiplet),
6.71 (lH, singlet), 6.42 (lH, singlet), 6.12 (2H, single~, 5.84 (lH, singlet), 5.80 (lH, singlet), 4.88 t2H~ singlet), 4.78 (lH, singlet), 3.44-4.28 (5H, multiplet), 3.62 (6H, singlet), 3.35 (3H, singlet), 2.78 (lH, broad doublet), 2.36 (lH, doublet~, 1.10 (6H, two overlapping triplets);
and 63 mg of the less polar diastereomer; NMR (CDC13) ~
and 63 mg of the less polar diastereomer; NMR (CDC13) ~
7.20-7.52 (5H, multiplet), 6.91 (lH, singlet), 6.40 (lH, singlet), 6.28 (2H, singlet), 5085 (2H, singlet), 4.91 (2H, singlet), 4.73 (lH, singlet), 3.68 -4.50 (5H, multiple^t), 3.67 (6H, singlet), 3.52 (3H, singlet), 2.76 (lH, doublet), 2.31 (lH, doublet), 1.13 (6H, two overlapping triplets).
Total yield: 158 mg (67%).
Example 4 2,2,-Dicarbethoxy~ 3',4',5'-trime-thoxy phenyl~-5,6-methylenedioxyindan ~VII-b; where Rl and R O~CH2-O_, zl and z2 = COOC2H5, R7-CH3, R8, R9 = OCH33 6-bromo-3,4-methy]enedioxybenzyl chloride (364 mg, 1.45 mmol) is reacted as in Example 2 with t-butyllithium (0.98 ml, 1.5 mmol, 1.55 M in pentane) and diethyl (3,4,5 trimethoxyphenyl)methylenemaionate (490 mg, 1.45 mmol) to provide the title compound (551 mg, 8]~ yield).
xam~le 5 2,2-Dicarbethoxy-1-(3',4',5'-trimethoxyphenyl)-6,7-methylene-dioxytetralone (III-b; where Rl and R2 = O-CEI2-O, zl, Z = COOC2H5, R7 - CH3, R , R = OCH3) To the crude methoxy diester of Example 2 (37 mg) in acetone (1.5 ml) at 0C was added 6 N HCl (1.5 ml)O After the reaction had been stirred 5 hours at 0C, TLC (ether/cyclohexane, 1/1) indicated the complete disappearance of the starting material. Jones reagent (20 drops of 2M, excess was then added, and the reaction was stirred 40 minutes at 0C and quenched with methanol (0.5 ml). The mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water and saturated sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure to give 28 mg l75%) pure title compound: m.p. 152.5-153C, IR(CHC13) 1730, 1690 cm 1; NMR (CDC13) ~ 7.51 (lH, singlet), 6.65 (lH, singlet) 6.25 (2H, singlet~, 6.06 (2H, singlet), 5.08 (lH, singlet), 414 (4H~ two overlapping quadruplets~, 3.82 (3H, singlet), 3.75 ~6H, singlet), 3.25 (2H, singlet), 1.16 (6H, two overlapping triplets);
Mass Spec. 500 (M~). Anal: Calculated for C26H32Olo:
C,62.39, H, 5.64. Found: C,62.42; H,5.66.
Although the invention has been described in considerable detail with particular reference to certain preferred embodiments thereof, variations and modifications can be effected within the spirit and scope o-f the inven-tion as described hereinbefore, and as defined in the appended claims.
Total yield: 158 mg (67%).
Example 4 2,2,-Dicarbethoxy~ 3',4',5'-trime-thoxy phenyl~-5,6-methylenedioxyindan ~VII-b; where Rl and R O~CH2-O_, zl and z2 = COOC2H5, R7-CH3, R8, R9 = OCH33 6-bromo-3,4-methy]enedioxybenzyl chloride (364 mg, 1.45 mmol) is reacted as in Example 2 with t-butyllithium (0.98 ml, 1.5 mmol, 1.55 M in pentane) and diethyl (3,4,5 trimethoxyphenyl)methylenemaionate (490 mg, 1.45 mmol) to provide the title compound (551 mg, 8]~ yield).
xam~le 5 2,2-Dicarbethoxy-1-(3',4',5'-trimethoxyphenyl)-6,7-methylene-dioxytetralone (III-b; where Rl and R2 = O-CEI2-O, zl, Z = COOC2H5, R7 - CH3, R , R = OCH3) To the crude methoxy diester of Example 2 (37 mg) in acetone (1.5 ml) at 0C was added 6 N HCl (1.5 ml)O After the reaction had been stirred 5 hours at 0C, TLC (ether/cyclohexane, 1/1) indicated the complete disappearance of the starting material. Jones reagent (20 drops of 2M, excess was then added, and the reaction was stirred 40 minutes at 0C and quenched with methanol (0.5 ml). The mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water and saturated sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure to give 28 mg l75%) pure title compound: m.p. 152.5-153C, IR(CHC13) 1730, 1690 cm 1; NMR (CDC13) ~ 7.51 (lH, singlet), 6.65 (lH, singlet) 6.25 (2H, singlet~, 6.06 (2H, singlet), 5.08 (lH, singlet), 414 (4H~ two overlapping quadruplets~, 3.82 (3H, singlet), 3.75 ~6H, singlet), 3.25 (2H, singlet), 1.16 (6H, two overlapping triplets);
Mass Spec. 500 (M~). Anal: Calculated for C26H32Olo:
C,62.39, H, 5.64. Found: C,62.42; H,5.66.
Although the invention has been described in considerable detail with particular reference to certain preferred embodiments thereof, variations and modifications can be effected within the spirit and scope o-f the inven-tion as described hereinbefore, and as defined in the appended claims.
Claims (25)
1. A process for the preparation of a compound having the structure:
(VI) wherein R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl, aralkyl, or R1 and R2 taken together represent the group -O-CH2-O-, R3 repre-sents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br, or I, which comprises:
treating a compound of the structure:
(XI) wherein R1 and R2 are as defined above, with a source of electrophilic chlorine, bromine iddine and a compound of the formula R4OH in which R4 is hydrogen alkyl, aralkyl or acyl to form a compound of the formula:
and, if necessary, converting R4 to a protecting group and/or converting the side chain X to a leaving group.
(VI) wherein R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl, aralkyl, or R1 and R2 taken together represent the group -O-CH2-O-, R3 repre-sents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br, or I, which comprises:
treating a compound of the structure:
(XI) wherein R1 and R2 are as defined above, with a source of electrophilic chlorine, bromine iddine and a compound of the formula R4OH in which R4 is hydrogen alkyl, aralkyl or acyl to form a compound of the formula:
and, if necessary, converting R4 to a protecting group and/or converting the side chain X to a leaving group.
2. The process of claim 1 wherein said source of electrophilic bromine comprises Br2.
3. The process of claim 1 wherein R1 represents methoxy,
4. The process of claim 3 wherein R2 represents methoxy.
5. The process of claim 1 wherein R1 and R2 taken together represent -O-CH2-O-.
6. The process of claim 1 wherein R3 represents lower alkyl.
7. The process of claim 6 wherein R3 represents methyl.
8. The process of claim 7 wherein R1 represents methoxy.
9. The process of claim 6 wherein R1 and R2 taken together represent the group -O-CH2-O-.
10. The process of claim 1 wherein X and Y each represent Br.
11. The process of claim 1 wherein X
represents I.
represents I.
12. The process of claim 6 wherein X and Y each repre-sent Br.
13. The process of claim 9 wherein X and Y each represent Br.
14. A compound of the formula:
wherein:
R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, or R1 and R2 taken together represent the group -O-CH2-O-, R3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br or I, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
wherein:
R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, or R1 and R2 taken together represent the group -O-CH2-O-, R3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br or I, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
15. A compound of the formula:
wherein:
R1 represents methoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, R3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br or I, whenever prepared by the process of claim 3, or by an obvious chemical equivalent thereof.
wherein:
R1 represents methoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, R3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br or I, whenever prepared by the process of claim 3, or by an obvious chemical equivalent thereof.
16. A compound of the formula:
wherein:
R1 represents methoxy, R2 represents methoxy, R3 represents hydrogan, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br or I, whenever prepared by the process of claim 4, or by an obvious chemical equivalent thereof:
wherein:
R1 represents methoxy, R2 represents methoxy, R3 represents hydrogan, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br or I, whenever prepared by the process of claim 4, or by an obvious chemical equivalent thereof:
17. A compound of the formula:
wherein:
R1 and R2 taken together represent the group -O-CH2-O-, R3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents C1, Br, I or a leaving group, and X represents C1, Br or I, whenever prepared by the process of claim 5, or by an obvious chemical equivalent thereof.
wherein:
R1 and R2 taken together represent the group -O-CH2-O-, R3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents C1, Br, I or a leaving group, and X represents C1, Br or I, whenever prepared by the process of claim 5, or by an obvious chemical equivalent thereof.
18. A compound of the formula:
wherein:
R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, or R1 and R2 taken together represent the group -O-CH2-O-, R3 represents lower alkyl, Y represents C1, Br, I or a leaving group, and X represents C1, Br or I, whenever prepared by the process of claim 6, or by an obvious chemical equivalent thereof.
wherein:
R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, or R1 and R2 taken together represent the group -O-CH2-O-, R3 represents lower alkyl, Y represents C1, Br, I or a leaving group, and X represents C1, Br or I, whenever prepared by the process of claim 6, or by an obvious chemical equivalent thereof.
19. A compound of the formula:
wherein:
R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, or R1 and R2 taken toyether represent the group -O-CH2-O-, R3 represents methyl, Y represents C1, Br, I or a leaving group, and X represents Cl, Br or I, whenever prepared by the process of claim 7, or by an obvious chemical equivalent thereof.
wherein:
R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, or R1 and R2 taken toyether represent the group -O-CH2-O-, R3 represents methyl, Y represents C1, Br, I or a leaving group, and X represents Cl, Br or I, whenever prepared by the process of claim 7, or by an obvious chemical equivalent thereof.
20. A compound of the formula:
wherein:
R1 represents methoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, R3 represents methyl, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br or I, whenever prepared by the process of claim 8, or by an obvious chemical equivalent thereof.
wherein:
R1 represents methoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, R3 represents methyl, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br or I, whenever prepared by the process of claim 8, or by an obvious chemical equivalent thereof.
21. A compound of the formula:
wherein R1 and R2 taken together represent the group -O-CH2-O-, R3 represents lower alkyl, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br or I, whenever prepared by the process of claim 9, or by an obvious chemical equivalent thereof.
wherein R1 and R2 taken together represent the group -O-CH2-O-, R3 represents lower alkyl, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br or I, whenever prepared by the process of claim 9, or by an obvious chemical equivalent thereof.
22. A compound of the formula:
wherein:
R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, or R1 and R2 taken together represent the group -O-CH2-O-, R3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Br, and X represents Br, whenever prepared by the process of claim 10, or by an obvious chemical equivalent thereof.
wherein:
R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, or R1 and R2 taken together represent the group -O-CH2-O-, R3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Br, and X represents Br, whenever prepared by the process of claim 10, or by an obvious chemical equivalent thereof.
23. A compound of the formula:
wherein:
R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, or R1 and R2 taken together represent the group -O-CH2-O-, R3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group, and X represents I, whenever prepared by the process of claim 11, or by an ob-vious chemical equivalent thereof.
wherein:
R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, or R1 and R2 taken together represent the group -O-CH2-O-, R3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group, and X represents I, whenever prepared by the process of claim 11, or by an ob-vious chemical equivalent thereof.
24. A compound of the formula:
wherein:
R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, or Rl and R2 taken together represent the group -O-CH2-O-, R3 represents lower alkyl Y represents Br, and X represents Br, whenever prepared by the process of claim 12, or by an obvious chemical equivalent thereof.
wherein:
R1 represents alkoxy or aralkoxy, R2 represents hydrogen, alkoxy, aralkoxy, alkyl or aralkyl, or Rl and R2 taken together represent the group -O-CH2-O-, R3 represents lower alkyl Y represents Br, and X represents Br, whenever prepared by the process of claim 12, or by an obvious chemical equivalent thereof.
25. A compound of the formula:
wherein:
R1 and R2 taken together represent the group -O-CH2-O-, R3 represents lower alkyl, Y represents Br, and X represents Br, whenever prepared by the process of claim 13, or by an obvious chemical equivalent thereof.
wherein:
R1 and R2 taken together represent the group -O-CH2-O-, R3 represents lower alkyl, Y represents Br, and X represents Br, whenever prepared by the process of claim 13, or by an obvious chemical equivalent thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA000432955A CA1182827A (en) | 1980-03-05 | 1983-07-21 | Intermediates for the production of picropodophyllin and processes for the preparation and use thereof |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/127,436 US4294763A (en) | 1980-03-05 | 1980-03-05 | Intermediates for the production of picropodophyllin and related compounds and processes for the preparation and use thereof |
US127,436 | 1980-03-05 | ||
CA000372161A CA1181083A (en) | 1980-03-05 | 1981-03-03 | Intermediates for the production of picropodophyllin and related compounds and process for the preparation and use thereof |
CA000432955A CA1182827A (en) | 1980-03-05 | 1983-07-21 | Intermediates for the production of picropodophyllin and processes for the preparation and use thereof |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000372161A Division CA1181083A (en) | 1980-03-05 | 1981-03-03 | Intermediates for the production of picropodophyllin and related compounds and process for the preparation and use thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1182827A true CA1182827A (en) | 1985-02-19 |
Family
ID=27166985
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000432955A Expired CA1182827A (en) | 1980-03-05 | 1983-07-21 | Intermediates for the production of picropodophyllin and processes for the preparation and use thereof |
Country Status (1)
Country | Link |
---|---|
CA (1) | CA1182827A (en) |
-
1983
- 1983-07-21 CA CA000432955A patent/CA1182827A/en not_active Expired
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