DE1445807A1 - Process for the preparation of 2-dehydroemetine - Google Patents

Description

DR. F. ZUMSTEIN - DR. E. ASSMANN - DR. R. KOENIQSBERQER

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Emetine 16

GLAXO LABOEATOHIES LIMITED Greenford, Middlesex, England

Process for the preparation of 2-dehydroemetine

The invention relates to new compounds for the production of 2-dehydroemetine and related compounds are suitable.

The. Patent specification patent application

G 32344 describes the preparation of compounds of the following Skeletal formula:

-C0.E

N-E "

where E and S mean "aliphatic, araliphatic? or aryl groups, such as alkyl groups or arylmethyl groups, as intermediates in the synthesis of-" emetine and its derivatives such a group can generally be removed by hydrogenolysis without attack taking place at other points of the molecule, free secondary bases being obtained which are analogs of emetine. R " kaiai

I8 5Q / 146 8. ^

preferably also one. Be an alkyl group which may be substituted, for example by hydroxy, oxo or acyl oxy groups, since certain of these groups contribute desirable properties when they are in the 2'-position of (-) - emetine and 2-dehydroemetine · Such alkyl groups preferably have 1-7 carbon atoms, ^V BOTB generally have ~ 1-4 carbon atoms. Therefore, the ketones of Formula Γ can be used as intermediates in the manufacture of 2-dehydroemetine and related compounds.

It has now been found that the above-mentioned 2-dehydro- emetine and analogous compounds can advantageously be prepared from compounds of the formula I via intermediates the skeletal formula;

II

-GH-R ¹

OR ⁵

-R ¹

wherein R has the meaning given above, R ^{1 is} an aliphatic, araliphatic or aromatic carbon-hydrogen group and Έ. mean an acyl group, since it has been found that the allyl acid function of such compounds can be reduced very easily by metal-ammonia and metal-priraaros amine reduction systems

According to the invention there is therefore a method for production of compounds of the skeletal formula:

9098 50/146 8

III

in that a compound of the skeletal formula II is reduced with a metal-ammonia or metal-primary amine reduction system, where E *, B ¹ and B have the meaning given above.

Compounds of the skeletal formula II, in which B ¹ , B ¹ and E have the above meanings, are new and form a feature of the present invention. B is preferably an alkyl group, in particular a methyl group, since the reaction leads to products with a 3-alkyl group, for example an ethyl group as in emetine. B ^ is preferably a lower aliphatic acyl or aroyl group, preferably an acetyl group, since such groups lead to a particularly simple reduction

As indicated above, B 'is preferably an aryl-methyl group, such as a benzyl group, since it is inert and can be easily removed. It can easily be removed by hydrogenolysis after the metal-ammonia beduction. B ¹ can also preferably be an alkyl group with 1-7, preferably 1-4, carbon atoms, which optionally carry substituents such as hydroxyl or acyloxy groups.

For example, the present method can be used to induce compounds that are described in the hritiaihca patent application G 50 014 and the skeletal

^föriiel! 909850/1468 /

IV

-COR ¹

N-GH ₂ CH ₂ CO-R

have, wherein R is aliphatic or araliphatic Denotes a hydrocarbon group and R denotes the above Has meaning because after the reduction of the ketone groups to hydroxyl groups and the esterification the allyl oxygen puncture can be selectively reduced without a substantial Attack on the saturated oxygen function takes place · Therefore the intermediate products of the skeletal formula are:. ·

..CH-R ¹
OR ⁵

N-OH ₂ CH ₂ -CH-R ' ΟΈ?

where R, R and Br have the meaning given above, for the preparation of 2 ¹ -substituted dehydroemetine derivatives suitable .__ - _ ^ ■ "■■ - ■ - -". ■■ - · '. "-. ' ^ -

The connections can be in the 3 ', 4'

6V, 7 «,

8th",

6, 7, 8, 9, 10 and 11 positions, e.g. by aliphatic, aromatic or araliphatic hydrocarbons, ether or thioether groups or tertiary Amino groups, which preferably have 1-4 carbon atoms, e.g. methyl, ethyl, propyl, butyl, amyl, benzyl,

909850/1468

BATH

Phenyl, methoxy, ethoxy, propoxy, butoxy, amyloxy, benzyloxy, phenoxy, dialkylamino groups, etc. The groups can also have more than one position, e.g. in methylenedioxy groups. According to one feature of the invention the 6 ', 7', 9 and 10 positions preferably carry lethoxy groups and the remaining positions are unsubstituted.

The metal-ammonia reduction system can, for example an alkali metal or alkaline earth metal, preferably lithium or calcium and liquid ammonia. Its cheap, if an inert solvent is present, which serves as a solubilizer for the substance to be reduced, e.g. a Ethers such as tetrahydrofuran, dimethoxyethane, diethyl ether, etc. In the metal primary amine system, the amine is usually a lower alkylamine such as ethylamine or a diamine such as Ethylenediamine. Care must be taken, however, that the aromatic rings do not occur when such a system is used to be attacked.

When reducing compounds of the skeletal formula V, where 'S? represents an acyl group, the non-allylic acyloxy group is not reduced, but is still usually hydrolyzed to provide the corresponding hydroxy compound. If this hydrolysis does not proceed completely, a special hydrolysis step can also be switched on, for example using aqueous alkali, preferably in the presence of a solvent such as an alkanol, for example methanol or ethanol, in order to make the compound soluble. If 2-dehydroemetine compounds are to be prepared which are not substituted on the 2'-nitrogen atom, it is possible to oxidize the hydroxyalkyl side chain to the corresponding oxoalkyl side chain, which is then oxidized by treatment with hydrazine or a base, e.g. an alkali such as an alkali metal hydroxide etc. or an organic base

909850 / U68

U45807

the spontaneous removal of Öxo-AllQrl-Kette'bei her, ^ _AEK. ^ education. Also, in using such a strong _w,: possible alkaline conditions, as Äusgangsmaterial - ,, incompletely hydrolyzed acyl derivatives to use of compounds of the skeleton of formula III wherein R is a 3 'hydroxy-butyl group, without the above- mentioned separate hydrolysis step Sodium t-butoxide or, more commonly, potassium t-butoxide and benzophenone in t-butanol / benzene are used as preferred Oppenauer reagents

"'-" ³ S · "Compounds of the skeletal formula II or V, in which R- is an acyl radical, can be prepared by reacting the corresponding -.- ■ -alcohols (R ^» H) with acylating agents such as the appropriate acid anhydrides, preferably in the presence an acid, for example perchloric acid, sulfuric acid, acetic acid or p-toluenesulfonic acid, or a base, such as an alkali metal carbonate or acetate or pyridine. Acetic acid halides and other acylating agents can also be used with advantage. Acetic acid anhydride derivatives are particularly preferred the means of choice.

The starting alcohols (skeletal formulas II and 7; R ⁵ = H) can be prepared from the ketones of the skeletal formulas I or IV by reduction, for example with a metal hydride as the reducing agent, for example a borohydride or aluminum hydride of an alkali metal or alkaline earth metal. An inert solvent is preferably present. In the case of sodium or potassium hydride, the solvent is preferably an alcohol such as methanol, ethanol, etc., optionally in the presence of a hydrocarbon as solvent, such as benzene, toluene, etc. If lithium borohydride or lithium aluminum hydride are used, the inert solvent is preferably an ethereal solvent, such as Tetrahydrofuran or diethyl ether. .

It must be noted that the reduction in Keto groups in the compounds of the formulas I and IV are further

909850/1468

introduces asymmetric centers and therefore possibly Sterioisomers supplies. However, these are removed in the subsequent reactions according to the invention and it can therefore be preferable to use the mixture of isomers without separation

You compounds of counter skeletal formulas have in the 11b-1 and ^{the 1-position} asymmetric centers which lead to a variety of stereoisomeric therefore forms. The! Configuration of the hydrogen atoms in the 11B and 1 ^f-positions of natural emetine and 2-Dehydroemetin is the same as in the below reaction sequence for the preparation of 2-Dehydroemetin, namely, the 11b and 1 'are hydrogen atoms in the alpha configuration the various formulas listed here and therefore this stereoisomeric form is preferred

For a better understanding of the invention, the following are made Examples are given for illustration only. The reactions explained in Examples 1-5 are given below Reaction scheme, which is also used to identify those in the Examples of compounds used, shown schematically »

909850 / U68

-GO-GH,

-GH ₂ -GH,

'N-CHpGHp- OH- OH, OH.

-GH ₂ GH ₅

W- H

OH

H-GH ₂ GH ₂ GH-GH ₃ ^: OH

OAc

N-GH ₂ GH ₂ CH-GH ₃

"OAa

GOGH

-GH ₂ PiI ^;

9: 850/1488

example 1

Reduction of 3-aoetyl-i _f 4 »6,7-tetrahydrQ ~ 9,10-dimethoxy- 2- [i ', 2', 3 ', ^' - tetrahydro-S ', 7'-dimethoxy-2' - (3 "-oxobutyl) isoohinol-1 '~ ylj-methyl-11b jjfl-benzo-ja] -quinollzine (YI) with sodium borohydride

7 grams of sodium borohydride in 60 ml of water became 20 grams of the diketone (VI) in 250 ml of methanol at 15-20 ° and 30 ml of benzene. added. After 30 minutes the Organic solvent removed in vacuo, the residue diluted with water and the mixture with concentrated Hydrochloric acid (24 ml) acidified. Then the solution was neutralized with 2N sodium hydroxide and the basic product extracted three times with 00 ml of benzene each time. After three times Washed with 50 ml of water, the combined benzene extracts were dried over MgSO 4, and made a slurry evaporated. When ether was added, the diol (VII) was a white crystalline solid mass (13.93 grams) F = 128 ° obtained with prior softening.

Example 2,.
Preparation of the diol diacetate (VIII)

(a) 12.5 grams of the diol (VII) in 100 ml of benzene were added 10 ml of acetic anhydride, which contained 3 drops of 60 # aqueous perchloric acid, heated to reflux for 1 1/2 hours. The basic product was extracted from the solution with 20 ml of 2N hydrochloric acid .und 2 × 20 ml of water and the combined aqueous acidic extracts were acidified with sodium bicarbonate neutralized in the presence of 40 ml of chloroform. Then the layers were separated and the aqueous phase 2 χ extracted with 40 ml of chloroform. By evaporation of the Solvent from the washed and dried chloroform extracts gave 12.04 grams of diol diacetate (VIII) in the form of a light yellow foam, which occurs in thin-layer chromatography was homogeneous.

9G9850 / U6 8

- "- 10 ---

(b) 20 grams of diketone (VI) were made with sodium borohydride reduced and the basic product as indicated in 1 above, extracted into benzene. The benzene solution was up e ^ n volume of about 150 ml concentrated and 20 ml of vinegar; Acid anhydride and 3 drops of sulfuric acid were added. " The acetylation and work-up as in example (a) provided the diol diacetate in the form of a crude rubbery one Dimensions. This was triturated with ether and 2.43 grams of insoluble solids removed. Evaporation of the ethereal solution provided 18.7 grams of diol diacetate (VIII) in the form a homogeneous light yellow foam.

Example 3

(*) N-03-Hydroxybutyi) dehydroemetin

12.87 grams of diol diacetate (VIII) in 100 ml of tetraurane was used within 10 minutes to 0.7 grams of lithium in 300 ml of liquid Ammonia added. After 5 minutes, 2 ml of acetone were added to make the blue color disappear and then the solvents were evaporated. The residue was diluted with water and extracted 3 χ with 50 ml Benaol. The combined extracts were washed 3 with 50 ml of water and the solvent removed in vacuo. 10.87 grams were obtained of a light foam.

8 grams of crude product were exposed to 400 grams of aluminum oxide (grade H) absorbed in benzene and with 1 1 50 $ strength ethyl acetate-benzene and 2.5 liters of ethyl acetate eluted. By evaporation of the eluates 6.12 grams of N- (3-hydroxybutyl) dehydroemetine were obtained in the form of a foam. . '"

Example 4

(i) dehydroemetine hydrochloride

(a) 5 »79 grams of (i) N- (3-hydroxybutyl) dehydrpenietin were added in 80 ml of t-butanol, the potassium t-butoxide (from 2.4 grams of potassium) Contained 19 grams of benzophenone and 45 ml of benzene, 16 hours ■ heated to reflux under nitrogen. The mixture was then

909850 / I46B

cooled, acidified with concentrated hydrochloric acid and the solvent removed in vacuo. The residue was in Added water and extracted 3 times with 50 ml of benzene. The aqueous acidic layer was neutralized with 2N sodium hydroxide solution and the basic product extracted 4 χ with 30 ml of ether. Obtained by evaporation of the washed essential extracts man (ί) dehydroemetin in the form of a light foam that through Dissolve in 25 ml of methanol and acidify with methanolisoher Hydrochloric acid was fed into the hydrochloric jib · 4.49 grams Hydrochloride precipitated as white crystals, F, 242-244 ° (Decomposition).

(b) 9 grams of diol acetate in 60 ml of tetrahydrofuran were reduced with 0.485 grams of lithium in 200 ml of liquid ammonia as described in Example 3 above, 7 »32 grams of crude (*) N- (3-hydroxybtttyl) dehydroemetine was not chromatographed purified, but oxidized to crude ("L) dehydroemetine according to the Oppenauer process described in Example (a) above. This was obtained in the form of a light foam (5.16 grams) which was taken up in 25 ml of methanol and treated with methanolic hydrochloric acid The pure (t) dehydroemetine hydrochloride was obtained in the form of pale crystals (4.0 grams), mp 247-249 ° (decomposition).

Example 5 Editing of Dloldiaoetat (YI) with calcium in liquid

ammonia

5 grams of diacetate in 60 ml of dry tetrahydrofuran were added added dropwise over 25 minutes to a solution of 1 gram calcium in 200 ml refluxed ammonia. To 40 minutes was acetone to remove the blue color and then added 5 ml of ethanol. Then the Removed ammonia and the residue 10 minutes with 2N sodium hydroxide solution heated to 100 ° »Then 200 ml of chloroform were added and the emulsion was clarified by filtering through kieselguhr · The alkaline layer was 2 χ with 50 ml of chloroform extracted and the combined organic extracts were

909850/1468

Washed 3 times with 300 ml of water and dried over Mg So. Evaporation of the solvent gave 3.75 grams. crude (t) -N - ('3-HydiOX # butyl) dehydroemetin in the form of a light foam. The ppenau oxidation of part of this Substance as in example 4 provided crude (*) dehydroemetin, from which one after Uia crystallization from methanol the pure Hydrochloride. M.p. 244-247 ° (decomposition).

Example 6

A solution of 9 grams of sodium borohydride in 25 ml of water was added to a solution of 25 grams of the diketone (VI) in 150 ml of methanol and 25 ml of benzene, which was kept at 0 °, and the mixture was stirred for a further 55 minutes. The mixture was then acidified with 23 ml of hydrochloric acid and evaporated to dryness in vacuo. The residue was taken up in 100 ml of 2N sodium hydroxide solution and extracted 1 with 100 ml and 2 with 25 ml of chloroform and the extracts were washed 2 with 50 ml of water. The chloroform solution was evaporated to give 26.92 grams of a foam. This was taken up in 250 ml of benzene, the solution was azeotropically dried and 5 grams of anhydrous potassium carbonate and 10 ml of acetic anhydride were added. This mixture was refluxed overnight, filtered off and evaporated to a foam. This was treated with 100 ml of ether and the solution filtered and evaporated again to give 28 grams of diol diacetate (VIII) in the form of a foam. This was dissolved in 300 ml of dry ether and this solution was added to 600 ml of redistilled ammonia. About 2 grams of lithium was then added in small portions until a permanent blue color appeared, followed by stirring for 5 minutes, and then ammonium chloride was added to destroy excess lithium. The solvents were evaporated and the residue was dissolved in 200 ml of benzene and 50 ml of water and separated. The benzene solution was washed with water and the combined aqueous washings extracted with 25 ml of benzene. The benzene solutions were evaporated to dryness leaving 25 grams of a foam.

8AD ORIGINAL

This was overnight with a solution of 4.75 grams Potassium in 112 ml of t-butanol, 25 grams of benzophenone and 50 ml Benzene heated to reflux. The following day the mixture was acidified with 20 ml of hydrochloric acid and evaporated, leaving a gummy mass. Then 200 ml Benzene and 200 ml barrel added, separated and the benzene layer extracted with 200 ml »/ anser. The combined aqueous Extracts were washed with iither and with 2η sodium hydroxide solution made alkaline and extracted 4 x with 100 ml of ether. The essential extracts were washed with sodium sulfate dried and evaporated and the residue in 40 ml of methanol • Taken on its own and acidified with methanol, SaIa is more likely to be acidic, -Ui'.n thus received 14.02 grams of dehydroemetine dihydrochloride in Form of white crystals ff. 246-249 ° (decomposition).

Example 7

10 grams of diketone (VI) were treated as in Example 6, only <* as lithium was replaced by 4.5 grams of sodium. 2.2 grams of dehydroemetine hydrochloride were obtained.

Example 8

100 grams of diketone (TI) were treated as in Example 6, but the ether used as a solvent in the ammonia reduction was replaced by dimethoxyethane. One received so finally 45 grams of dehydroemetine hydrochloride.

O ¹

9 0 9.8 5 0 / U 6 8

Claims (28)

A η s ρ r ü c h / e: 1. Process for the preparation of "compounds of the skeletal formula: III GH ₂ R ¹ wherein R ^{f is} a substituted or unsubstituted aliphatic, araliphatic or aromatic G group and 1 '
wherein R is a substituted or unsubstituted aliphatic, araliphatic or aromatic group, characterized in that an ester of the skeletal formula GH - R ¹
ι -ζ.
OR ° - - R ' IT wherein R and R ^{1 have} the meaning given above and R ^{J is} an acyl- ^ G group, is reduced with a metal / ammonia or metal / primary amine reduction system. 2 .. Terfahren according to claim 1, characterized in that dai3 9 0 9 8 5 0/1468 the metal of the reduction system is an alkali or alkaline earth metal. 3. Procedure according to. Claim 2, characterized in that the metal used is lithium or calcium. 4. The method according to claim 1-3, characterized in that an inert solvent for in the reaction medium
the ester is included. 5. The method according to claim 4, characterized in that the solvent is an ether. 6. The method according to claim 5, characterized in that the solvent tetrahydrofuran, dirnethoxyethane or Diethyl ether is. 7. The method according to claim 1-6, characterized in that
is. 3
that R ^ is a lower aliphatic acyl or aroyl group 8. The method according to claim 7, characterized in that
that R ^{5 is} an acetyl group. 9. The method according to claim 1-8, characterized in that R ^{1 is} an arylmethyl group. 10. The method according to claim 9, characterized in that R ^{1 is} a benzyl group. 11. The method according to claim 1-8, characterized in that R ^{1 is} a substituted or unsubstituted alkyl group having 1-7 carbon atoms. 12. The method according to claim 11, characterized in that R ^{1 is} a 3-acyloxy alley! Group. 9 0 9 8 5 0 / U 6 8 - ID - 13, the method according to spoke 1 - 12, characterized in that that the initial connection of formula II by reduction a connection of the skeletal formula GO-R ¹ If- -R «. in which R has the meaning given in claim 1 and R "denotes a substituted or unsubstituted. aliphatic, araliphatic © or aromatic hydrocarbon group, with a reagent which is used to reduce an Oxp-G group to a hydroxy 1- Group serves and implementation of the reduction product with an acylation agent, h; created vrird. "- -. .... ,: .. - ^Λ _ .. · ■ .-; . _; . - _ 14. The method according to "claim 1-3, characterized. That a MetallhydrM is used as a reducing agent. 15. The method according to claim 14, characterized in that as a reagent, a borohydride or aluminum hydride Alkali or alkaline earth metal is used. . · 16. The method according to claim 15, characterized in ^^, that the reduction in an inert. Solvent out- * will lead. ; 17. The method according to claim 16, characterized in that that "when using τοη lithium aluminum hydride or borohydride an ether is used as the inert solvent. 90985Q / U8 8 18. The method according to claim 16, characterized in that if sodium or potassium borohydride is used as the solvent, an alkanol is used, 19. The method according to claim 13-18, characterized in that that as acylating agent an anhydride or acid halide is used. 20. The method according to claim 19, characterized in that acetic anhydride is used as acylating agent. 21. The method according to claim 13-20, characterized in that the G group R "is a 3-ketoalkyl group of the general formula -CH ₂ -CH ₂ -OO-R ² , wherein R ^{2 is} an aliphatic or araliphatic hydrocarbon- Group means. 22. The method according to claim 21, characterized in that ρ
R is a methyl group. 23. The method according to claim ^{1-22, characterized in that R 1 is} a 3-acyloxyalkyl group, the group R in the reduced product is a 3-hydpoxyalkyl or 3-acyloxyalkyl group, which is then oxidized under the conditions of the Oppenauer reaction Will get removed. 24. The method according to claim 23 »characterized in that the reduced product with an alkali metal t-butoxide is oxidized in the presence of an aromatic ketone. 25. The method according to claim 1-24, characterized in that the hydrogen atoms in positions 11b and 1 ¹ in the formulas given in claim 1 possess alpha configuration. 26. The method according to claim 1-25, characterized in that that the starting compounds in the benzene rings with > one or more aliphatic, araliphatic or aromatic hydrocarbon, ether or thioether groups or tertiary amino groups are substituted. 9098 50/146 8 - ₁₈ - 14458Q7 27. The method according to claim. 1 - 26, characterized, that the starting compounds have one or more alkoxy-Ö groups with 1-4 carbon atoms on the benzene rings. 28. The method according to claim 27, characterized in that the starting connections in positions 6 ¹ , 7 ¹ , 9 and 10 carry methoxyl groups. 909 850714 68