US3120528A - Derivatives of 17-ketoyohimbane alkaloids and process therefor - Google Patents

Derivatives of 17-ketoyohimbane alkaloids and process therefor Download PDF

Info

Publication number
US3120528A
US3120528A US88306A US8830661A US3120528A US 3120528 A US3120528 A US 3120528A US 88306 A US88306 A US 88306A US 8830661 A US8830661 A US 8830661A US 3120528 A US3120528 A US 3120528A
Authority
US
United States
Prior art keywords
acyl
solution
derivatives
acid
mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US88306A
Inventor
Jr John Shavel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Pharmaceutical Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner Lambert Pharmaceutical Co filed Critical Warner Lambert Pharmaceutical Co
Priority to US88306A priority Critical patent/US3120528A/en
Application granted granted Critical
Publication of US3120528A publication Critical patent/US3120528A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D459/00Heterocyclic compounds containing benz [g] indolo [2, 3-a] quinolizine ring systems, e.g. yohimbine; 16, 18-lactones thereof, e.g. reserpic acid lactone

Definitions

  • the present invention relates to new and novel derivatives of 17-ketoyohimbane alkaloids of the formulae:
  • a I B C N wherein R is the acyl radical of an aliphatic carboxylic acid containing 1 to 6 carbon atoms and R is hydrogen or R and to the pharmaceutically acceptable non-toxic acid addition and quaternary ammonium salts thereof.
  • This invention also relates to a new and novel method of preparing these compounds from 17-ketoyohimbane alkaloids.
  • the compounds of this invention are I0-acyl-17-keto or l0-acyl-l7,17-diacyloxy or 17,17-diacyloxy derivatives of the ring system comprised of the rings denoted by A, B, C, D and E of the above formulae.
  • A, B, C, D and E of the above formulae.
  • four different compounds are possible in this ring system.
  • the D and E rings are transfused, thetwo compounds difiering by reason of different configurations of the hydrogen atom at the 3-position.
  • the D and E rings are cisfused, the two compounds again differing from each other by reason of different configurations of the hydrogen atom at the 3- position.
  • the present invention includes within its scope 10-acyl-17-keto, 10-acyl-17,17-diacyloxy, and 17,17-diacyloxy derivatives of yohimbane, 3-epiyohimbane, alloyhimbane and 3-epialloyohimbane.
  • These new compounds are all prepared from 17-ketoyohimbane alkaloids, specifically from yohimbone, 3-epiyohimbone, alloyohimbone and 3-epialloyhimbone by the procedure to be de scribed hereinafter.
  • lO-acetylyohimbone 10-acetyl-l7,17-di acetoxyyohimbane, IO-propionylyohimbone, 10-propionyl- 17,17-dipropionoxyyohimbane, 10-acetyl-3epiyohimbone, 10 acetylalloyohimbone, 10 acetyl-3epialloyohimbone, 10 acetyl-17,l7-diacetoxy-3epiyohimbane, 10-acetyl-17,
  • the new and novel compounds of this invention have interesting pharmacological activity with minimal toxicity and are useful as analgesics, tranquilizers and hypotensive agents. They are also valuable intermediates in the production of other alkaloids of the yohimbane series.
  • the 10-acyl-17,17-diacyloxy derivatives are valuable intermediates in the production of the corresponding IO-acyl-17-keto derivatives by the method to be described hereinafter.
  • the new and novel compounds of this invention may be prepared by the reaction of a 17-ketoyohimbane alkaloid, that is yohimbone, 3- epiyohimbone, alloyohimbone or 3-epialloyohimbone with an acid anhydride or an acyl halide having R acyl groups at a temperature between +25 C. and 50 C. for between 5 minutes and 4 hours in the presence of a Friedel- Crafts catalyst.
  • this reaction is carried out within a temperature range +25 C. and '40 C. for '30 minutes to 4 hours, the reaction mixture contains largely the 10-acyl-17,17-diacyloxy and 10-acyl-17-keto derivatives, of the formulae:
  • R is an acyl radical of an aliphatic carboxylic acid containing 1 to 6 carbon atoms. Reaction conditions of 40 to 50 C. for 5 to 30 minutes favor the production of the 17,17-diacyloxy derivative of the formula:
  • a Friedel-Crafts catalyst is employed in the reaction, for example boron trifiuoride, aluminum chloride, aluminum bromide, stannic chloride, ferric chloride, ferric bromide, hydrofluoric acid, polyphosphoric acid, titanium tetrachloride, sulfuric acid and the like. It has been found that boron trifluoride is a particularly effective catalyst in the production of the compounds of this invention.
  • the reaction is carried out in the liquid phase under anhydrous conditions.
  • the reaction mixture may also contain a carboxylic acid or ester thereof corresponding to the acid anhydride or acid halide, that is a carboxylic acid of the formula R OH or an ester of the formula R OR wherein R is a lower alkyl'group of 1 to 6 carbon atoms.
  • the acylating agent (acid anhydride or acyl halide), either with or Without the corresponding acid or ester, is initially saturated with catalyst, preferably at a temperature within the range of 20 C. to +10 C.
  • the temperature of the resulting mixture is then adjusted to the desired reaction temperature and the 17-ketoyohimbane alkaloid starting material is added, either as a solid or as a solution in the acylating agent or in an inert organic solvent, such as methylene chloride, dioxan, tetra hydrofuran and the like.
  • the reaction mixture is then stirred at the reaction temperature to completion.
  • the reaction mixture is poured onto ice at the conclusion of the reaction, the resulting mixture is made alkaline and is then extracted with such organic solvents as ethylene dichloride and chloroform. The product is recovered from the extract by crystallization.
  • reaction mixture is poured onto ice at the conclusion of the reaction, the resulting mixture made alkaline and then extracted with organic solvents.
  • the products may be separated and recovered by fractional crystallization and may be further purified by crystallization and chromatography.
  • the 10-acyl-17,17-diacyloxy derivatives may be converted to the 10-acyl-17-keto derivatives by treatment with an aqueous mineral acid or alkali metal hydroxide solution, or by treatment with an alcohol solution of an alkali metal alkoxide.
  • the oil remaining after the above described extraction may be treated with acid, base or alkali metal alkoxide to convert any of the 10-acyl-17,17-diacyloxy derivative therein to the corresponding 10-acyl-17-keto derivative which is then recovered and purified by crystallization.
  • non-toxic acid addition salts are those formed with maleic, fumaric, benzoic, ascorbic, succinic, bismethylenesalicylic, methylsulfonic, ethane-disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, stearic palmitic, itaconic, glycolic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, sulfamic phosphoric and nitric acids.
  • the acid addition salts may be prepared in the conventional manner, for example, by treating a solution or suspension of the free base in an organic solvent with the desired acid, and then recovering the salt which forms by crystallization techniques.
  • the quaternary salts are prepared by heating a suspension of the base in a suitable solvent with a reactive alkyl halide such as methyl iodide, ethyl bromide, n-hexyl bromide, benzyl chloride or a reactive ester such as methyl sulfate, ethyl sulfate or methyl p-toluene sulfonate.
  • the new and novel compounds of this invention may be formulated with conventional pharmaceutical carriers into dosage unit forms, such as tablets, capsules, elixirs, suppositories, solutions, suspensions and the like.
  • Example I A mixture of 25 ml. glacial acetic acid in 400 ml. acetic anhydride is saturated with boron trifiuoride at 0 C. by passing boron trifluoride into the solution for 15 minutes. The resulting solution is cooled to -20 C. and 50 g. yohimbone are added. The reaction mix ture is agitated for 2 hours and is then poured onto crushed ice. The suspension is made basic with ammonium hydroxide and extracted with chloroform. The extract is dried over sodium sulfate, filtered and evaporated to yield an oil which on crystallization from acetonitrile yields 25.8 g. crystals (fraction A) and a mother liquor (fraction ML).
  • Example 11 A solution of ml. glacial acetic acid and 1400 ml. acetic anhydride is saturated with boron trifluoride as described in Example I and to the mixture is added a solution of 286 g. yohimbone in 900 ml. glacial acetic acid over a one hour period during which the temperature is maintained at 10. Stirring is continued at this temperature for two hours longer and the reaction mixture is then poured onto 16 liters chopped ice and and basified with ammonium hydroxide. The precipitate which forms is collected by filtration and dissolved in 6 liters methanol. To the latter solution is added a solution of g. of 50% sodium hydroxide in 2.4 liters methanol.
  • Example 111 A solution of 25 ml. glacial acetic acid in 100 ml. acetic anhydride is saturated with boron trifluoride as described in Example I. The mixture is cooled to --50 C. and a solution of 10 g. yohimbone in 50 ml. glacial acetic acid and 25 ml. acetic anhydride is added all at once. Stirring is continued at -40 to -50 C. for five minutes and then the mixture is immediately poured onto 300 ml. ice, made alkaline with ammonium hydroxide and extracted with three 100 ml. portions of ethylene dichloride.
  • Example V A mixture of 20 ml. glacial acetic acid and 75 ml. acetic anhydride is saturated with boron trifluoride and after cooling to 20 C. is reacted with 1.7 g. al'loyohimbone (added as a solution in 8 ml. glacial acetic acid) for four hours. The mixture is then poured onto crushed ice, made basic with ammonium hydroxide and extracted with chloroform. The extract is dried over sodium sulfate, filtered and evaporated to yield a non-crystallizable oil. This oil is dissolved in dilute acetic acid and the pH is adjusted to 3 with ammonium hydroxide. A small amount of gum is filtered off and the filtrate basified to pH 8. Infrared analysis of the precipitate which forms shows it to be a mixture of IO-acetylalloyohimbone and 10-acetyl-l7,l7-diacetoxyalloyohimbane.
  • the precipitate was dissolved in 75 ml. methanol and refluxed with a solution of 1.1 g. sodium hydroxide in 25 ml. water for 3 hours.
  • the methanol was removed by distillation in vacuo, about 50 ml. more water is added, and the mixture is extracted with chloroform; the chloroform solution is treated with charcoal, dried over sodium sulfate, and distilled in vacuo to near dryness.
  • the ring system is selected from the group consisting of yohimbane, 3-epiyohimbane, alloyohimbane and 3-epialloyohimbane
  • R is the acyl radical of an unsubstituted saturated aliphatic carboxylic acid of 1 to 6 carbon atoms and R is a member selected from the group consisting of hydrogen and R and the pharmaceutically acceptable non-toxic acid addition and quaternary ammonium salts thereof with a compound selected from the group consisting of methyl iodide, ethyl bromide, nhexyl bromide, benzyl chloride, methyl sulfate, ethyl sulfate and methyl p toluene sulfonate.
  • R O carboxylic acid anhydride
  • R --X carboXylic acid halide
  • a method of preparing a compound of the formula wherein the ring system is selected from the group consisting of yohimbane, 3-epiyohimbane, alloyohimbane and 3-epialloyohimbane and R is the acyl radical of an unsubstituted saturated aliphatic carboxylic acid of 1 to 6 carbon atoms which comprises treating a compound of the formula at a temperature between 40 C. and C. for about 5 to about 30 minutes with a member selected from the group consisting of a carboxylic acid anhydride (R O and a carboxylic acid halide R X wherein X is halogen and R has the meaning above in an anhydrous reaction medium in the presence of a Friedel-Crafts catalyst.
  • R O carboxylic acid anhydride
  • R X carboxylic acid halide
  • a method according to claim 10 wherein said Friedel-Crafts catalyst is boron trifluoride.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

United States Patent 3 120 528 DERIVATHVES 0F lf-KETOYOHIMBANE ALKA- LUED AND PROCESS THEREFUR John Shavel, .llr., Mendharn, N.J., assignor to Warnen Lambert Pharmaceutical Company, Morris Plains, Ni,
a corporation of Delaware No Drawing. Filed Feb. 1t), 1%1, Ser. No. 88,306 11 Claims. (Cl. 260-287) The present invention relates to new and novel derivatives of 17-ketoyohimbane alkaloids of the formulae:
and
A I B C N wherein R is the acyl radical of an aliphatic carboxylic acid containing 1 to 6 carbon atoms and R is hydrogen or R and to the pharmaceutically acceptable non-toxic acid addition and quaternary ammonium salts thereof. This invention also relates to a new and novel method of preparing these compounds from 17-ketoyohimbane alkaloids.
The compounds of this invention are I0-acyl-17-keto or l0-acyl-l7,17-diacyloxy or 17,17-diacyloxy derivatives of the ring system comprised of the rings denoted by A, B, C, D and E of the above formulae. Depending upon the configuration of the hydrogen atom at the 3- position and the presence of cisor transfusion of the D and E rings four different compounds are possible in this ring system. In yohimbane and 3-epiyohimbane, the D and E rings are transfused, thetwo compounds difiering by reason of different configurations of the hydrogen atom at the 3-position. In alloyohimbane and 3-epialloyohimbane, the D and E rings are cisfused, the two compounds again differing from each other by reason of different configurations of the hydrogen atom at the 3- position. The present invention includes within its scope 10-acyl-17-keto, 10-acyl-17,17-diacyloxy, and 17,17-diacyloxy derivatives of yohimbane, 3-epiyohimbane, alloyhimbane and 3-epialloyohimbane. These new compounds are all prepared from 17-ketoyohimbane alkaloids, specifically from yohimbone, 3-epiyohimbone, alloyohimbone and 3-epialloyhimbone by the procedure to be de scribed hereinafter.
Included within the scope of the new compounds of this invention are lO-acetylyohimbone, 10-acetyl-l7,17-di acetoxyyohimbane, IO-propionylyohimbone, 10-propionyl- 17,17-dipropionoxyyohimbane, 10-acetyl-3epiyohimbone, 10 acetylalloyohimbone, 10 acetyl-3epialloyohimbone, 10 acetyl-17,l7-diacetoxy-3epiyohimbane, 10-acetyl-17,
2 17-diacetoxyalloyohimbane, 10-acetyl-17,17-diacetoxy-3- epialloyohimbane, IO-butrylyohimbone, 10-valerylyohimbone, lO-hexanoylyohimbone, 17,17-diacetoxyyohimbane, 17,17 diacetoxy-3epiyohimbane, 17,17-diacetoxyalloyohimbane, 17,17-diacetoxy-3epialloyohimbane, 17,17-dipropionoxyyohimbane, 17,l7-dibutyroxyyohimbane, l7, l'l-divaleroxyyohimbane and the like.
The new and novel compounds of this invention have interesting pharmacological activity with minimal toxicity and are useful as analgesics, tranquilizers and hypotensive agents. They are also valuable intermediates in the production of other alkaloids of the yohimbane series. For example, the 10-acyl-17,17-diacyloxy derivatives are valuable intermediates in the production of the corresponding IO-acyl-17-keto derivatives by the method to be described hereinafter.
It has now been found that the new and novel compounds of this invention may be prepared by the reaction of a 17-ketoyohimbane alkaloid, that is yohimbone, 3- epiyohimbone, alloyohimbone or 3-epialloyohimbone with an acid anhydride or an acyl halide having R acyl groups at a temperature between +25 C. and 50 C. for between 5 minutes and 4 hours in the presence of a Friedel- Crafts catalyst. When this reaction is carried out within a temperature range +25 C. and '40 C. for '30 minutes to 4 hours, the reaction mixture contains largely the 10-acyl-17,17-diacyloxy and 10-acyl-17-keto derivatives, of the formulae:
N H i O 0 R1 R1 and respectively, where R is an acyl radical of an aliphatic carboxylic acid containing 1 to 6 carbon atoms. Reaction conditions of 40 to 50 C. for 5 to 30 minutes favor the production of the 17,17-diacyloxy derivative of the formula:
A Friedel-Crafts catalyst is employed in the reaction, for example boron trifiuoride, aluminum chloride, aluminum bromide, stannic chloride, ferric chloride, ferric bromide, hydrofluoric acid, polyphosphoric acid, titanium tetrachloride, sulfuric acid and the like. It has been found that boron trifluoride is a particularly effective catalyst in the production of the compounds of this invention.
The reaction is carried out in the liquid phase under anhydrous conditions. The reaction mixture may also contain a carboxylic acid or ester thereof corresponding to the acid anhydride or acid halide, that is a carboxylic acid of the formula R OH or an ester of the formula R OR wherein R is a lower alkyl'group of 1 to 6 carbon atoms.
In carrying out the reaction, the acylating agent (acid anhydride or acyl halide), either with or Without the corresponding acid or ester, is initially saturated with catalyst, preferably at a temperature within the range of 20 C. to +10 C. The temperature of the resulting mixture is then adjusted to the desired reaction temperature and the 17-ketoyohimbane alkaloid starting material is added, either as a solid or as a solution in the acylating agent or in an inert organic solvent, such as methylene chloride, dioxan, tetra hydrofuran and the like. The reaction mixture is then stirred at the reaction temperature to completion.
Where the above-described reaction has been carried out under conditions which favor the production of the 17,17-diacyloxy derivatives (40 to 50 C., to 30 minutes), the reaction mixture is poured onto ice at the conclusion of the reaction, the resulting mixture is made alkaline and is then extracted with such organic solvents as ethylene dichloride and chloroform. The product is recovered from the extract by crystallization.
Where the reaction has been carried out under conditions favoring the production of the lO-acyl-l7-keto or l0-acyl-l7,l7-diacyloxy derivatives (+25 to 40 C., 30 minutes to 4 hours), the reaction mixture is poured onto ice at the conclusion of the reaction, the resulting mixture made alkaline and then extracted with organic solvents. The products may be separated and recovered by fractional crystallization and may be further purified by crystallization and chromatography.
I have also found that the 10-acyl-17,17-diacyloxy derivatives may be converted to the 10-acyl-17-keto derivatives by treatment with an aqueous mineral acid or alkali metal hydroxide solution, or by treatment with an alcohol solution of an alkali metal alkoxide. Thus, where the only desired product is the 10-acyl-17-keto derivative, the oil remaining after the above described extraction may be treated with acid, base or alkali metal alkoxide to convert any of the 10-acyl-17,17-diacyloxy derivative therein to the corresponding 10-acyl-17-keto derivative which is then recovered and purified by crystallization.
It is to be understood that the new and novel compounds of this invention may be used as the free base or may be converted into the corresponding pharmaceutically acceptable non-toxic acid addition and quaternary ammonium salts. Exemplary of non-toxic acid addition salts are those formed with maleic, fumaric, benzoic, ascorbic, succinic, bismethylenesalicylic, methylsulfonic, ethane-disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, stearic palmitic, itaconic, glycolic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, sulfamic phosphoric and nitric acids. The acid addition salts may be prepared in the conventional manner, for example, by treating a solution or suspension of the free base in an organic solvent with the desired acid, and then recovering the salt which forms by crystallization techniques. The quaternary salts are prepared by heating a suspension of the base in a suitable solvent with a reactive alkyl halide such as methyl iodide, ethyl bromide, n-hexyl bromide, benzyl chloride or a reactive ester such as methyl sulfate, ethyl sulfate or methyl p-toluene sulfonate.
For therapeutic use, the new and novel compounds of this invention, as the free base, or as their acid addition or quaternary ammonium salts, may be formulated with conventional pharmaceutical carriers into dosage unit forms, such as tablets, capsules, elixirs, suppositories, solutions, suspensions and the like.
The following examples are included in order further to illustrate the present invention:
Example I A mixture of 25 ml. glacial acetic acid in 400 ml. acetic anhydride is saturated with boron trifiuoride at 0 C. by passing boron trifluoride into the solution for 15 minutes. The resulting solution is cooled to -20 C. and 50 g. yohimbone are added. The reaction mix ture is agitated for 2 hours and is then poured onto crushed ice. The suspension is made basic with ammonium hydroxide and extracted with chloroform. The extract is dried over sodium sulfate, filtered and evaporated to yield an oil which on crystallization from acetonitrile yields 25.8 g. crystals (fraction A) and a mother liquor (fraction ML).
Recrystallization of fraction A from acetonitrile yields a first crop of 6.9 g. (fraction A and a total in three successive crops of 16.9 g. (fraction A Mother liquor fraction ML is evaporated to a gum which is dissolved in a minimal amount of acetonitrile and chromatographed over acid-washed alumina using acetonitrile as eluant. Concentration of the eluate by evaporation followed by chilling yields 6.5 g. (fraction B). Fractions A and B are combined and recrystallized from acetonitrile to yield 9.3 g. crystals and a mother liquor (fraction ML A further recrystallization of the solids from acetonitrile yields pure IO-acetyl- 17,17-diacetoxyyohimbane, M.P. 22823l C. (dec.), 23 (chloroform, c.=0.83), +4 (pyridine, c.=0.52).
AnaIysis.-Calc.: C, 68.47; H, 6.90; N, 6.39. Found: C, 68.43; H, 6.85; N, 6.43.
Fraction ML is evaporated and the residue is com= bined with fraction A This mixture is added to a solution of sodium methoxide prepared by adding 6 g. sodi um to 300 ml. absolute methanol and refluxed for 3 hours. The mixture is concentrated to a small volume and Water is added. The precipitate which forms is washed with water, dried and recrystallized from acetonitrile to yield 9.4 g. crystals. Recrystallization from acetonitrile yields pure IO-acetylyohimbone (as the hydrate), M.P. 258-260 C. (dec.), [M -82 (chloroform, c.=0.79), -73 (pyridine, c.=0.64).
Analysis.-Calc.: C, 71.16; H, 7.39; N, 7.91. Found: C, 71.22; H, 7.76; N, 8.13.
Example 11 A solution of ml. glacial acetic acid and 1400 ml. acetic anhydride is saturated with boron trifluoride as described in Example I and to the mixture is added a solution of 286 g. yohimbone in 900 ml. glacial acetic acid over a one hour period during which the temperature is maintained at 10. Stirring is continued at this temperature for two hours longer and the reaction mixture is then poured onto 16 liters chopped ice and and basified with ammonium hydroxide. The precipitate which forms is collected by filtration and dissolved in 6 liters methanol. To the latter solution is added a solution of g. of 50% sodium hydroxide in 2.4 liters methanol. After stirring over-night, the mixture is concentrated to a slurry, 8 liters of water are added, and the resulting mixture cooled to 7 C. to give a precipitate which is collected and dried. The dried precipitate is dissolved in a mixture of 900 ml. chloroform and 1800 ml. methanol and the solution distilled at atmospheric pressure until crystals form. Yield: 195.5 g.; M.P. 247-252 C. The recrystallization process is repeated using 450 ml. chloroform and 900 ml. methanol to give 142 g. (64%) of IO-acetylyohimbone, M.P. 257-258.5 C. (dec.).
The above product is suspended in 3.5 liters water, heated to 60, and concentrated hydrochloric acid is added until a clear strongly acidic solution is obtained. This is cooled to C. and the resulting precipitate collected and dried. This crude hydrochloride is suspended in 1000 ml. acetonitrile, heated to boiling, and 450 ml. water added to effect almost complete solution. This is filtered to remove a small amount of insoluble material and cooled to yield 119 g. pure -acetylyohimbone hydrochloride (as the hemihydrate), M.P. 298300 C. (dec.), [M 27 (95% aqueous pyridine, c.=0.75).
Analysis.Calc.: C, 66.04; H, 6.86; N, 7.33. Found: C, 66.14; H, 6.96; N, 7.38.
Example 111 A solution of 25 ml. glacial acetic acid in 100 ml. acetic anhydride is saturated with boron trifluoride as described in Example I. The mixture is cooled to --50 C. and a solution of 10 g. yohimbone in 50 ml. glacial acetic acid and 25 ml. acetic anhydride is added all at once. Stirring is continued at -40 to -50 C. for five minutes and then the mixture is immediately poured onto 300 ml. ice, made alkaline with ammonium hydroxide and extracted with three 100 ml. portions of ethylene dichloride. The dried (over sodium sulfate) ethylene dichloride solution is evaporated to dryness and the residue crystallized from ethyl acetate to give 9.7 g. of material. Recrystallization from aqueous ethanol yields 8.2 g. of material which upon crystallization from acetonitrile yields pure 17,17- diacetoxyyohirnbane, M.P. 226-228" C. (dec.); [ah- 26 (chloroform c.=0.75).
Analysis.Calc.: C, 69.50; H, 7.35; N, 7.05; O-acetyl, 21.66. Found: C, 69.43; H, 7.55; N, 6.98; O-acetyl, 21.53.
Example IV A solution of 125 ml. methylene chloride in 275 ml. acetic anhydride is saturated with boron trifluoride as described in Example I. To this solution is added 10 g. 3-epiyohimbone and the resulting mixture is stirred at -20 to 30" C. for 1.5 hours. The material is then poured onto crushed ice, basified by the addition of ammonium hydroxide and extracted with chloroform. The chloroform solution is dried over sodium sulfate and distilled to dryness to yield an oil which after two crystallizations from acetonitrile gives 6.2 g. of material, M.P. 3l03l2 C. (dec.)-. Recrystallization from methanol yields pure 10-acetyl-3-epiyohirnbone, M.P. 308- 311 C. (dec.), 80 (pyridine, c.=0.6).
Analysis.Calc.: C, 74.97; H, 7.19; N, 8.33. Found: C, 75.00; H, 7.28; N, 8.27.
Example V A mixture of 20 ml. glacial acetic acid and 75 ml. acetic anhydride is saturated with boron trifluoride and after cooling to 20 C. is reacted with 1.7 g. al'loyohimbone (added as a solution in 8 ml. glacial acetic acid) for four hours. The mixture is then poured onto crushed ice, made basic with ammonium hydroxide and extracted with chloroform. The extract is dried over sodium sulfate, filtered and evaporated to yield a non-crystallizable oil. This oil is dissolved in dilute acetic acid and the pH is adjusted to 3 with ammonium hydroxide. A small amount of gum is filtered off and the filtrate basified to pH 8. Infrared analysis of the precipitate which forms shows it to be a mixture of IO-acetylalloyohimbone and 10-acetyl-l7,l7-diacetoxyalloyohimbane.
In order to convert the latter into the former, the precipitate was dissolved in 75 ml. methanol and refluxed with a solution of 1.1 g. sodium hydroxide in 25 ml. water for 3 hours. The methanol was removed by distillation in vacuo, about 50 ml. more water is added, and the mixture is extracted with chloroform; the chloroform solution is treated with charcoal, dried over sodium sulfate, and distilled in vacuo to near dryness. The gummy residue is refluxed with 10 ml. acetonitrile and refrigerated to yield 0.68 g. of crystalls, constituting 10acetylalloyohimbone (with /2 mol acetonitrile), M.P. 158-163 C. (dec.), [uJ 76 (pyridine, c.=0.5).
Analysis.--Calc.: C, 74.02; H, 7.20; N, 7.81. Found: C, 74.20; H, 7.30; N, 7.67.
It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from the spirit of my invention.
Having described my invention, What I desire to secure by Letters Patent is:
l. A member selected from the group consisting of alkaloid derivatives selected from the group consisting of compounds of the formulae N N H and H Lt
wherein the ring system is selected from the group consisting of yohimbane, 3-epiyohimbane, alloyohimbane and 3-epialloyohimbane, R is the acyl radical of an unsubstituted saturated aliphatic carboxylic acid of 1 to 6 carbon atoms and R is a member selected from the group consisting of hydrogen and R and the pharmaceutically acceptable non-toxic acid addition and quaternary ammonium salts thereof with a compound selected from the group consisting of methyl iodide, ethyl bromide, nhexyl bromide, benzyl chloride, methyl sulfate, ethyl sulfate and methyl p toluene sulfonate.
. 10-acetyl-17,17-diacetoxyyohimbane.
. 10-acetylyohimbone.
. 10-acetylyohimbone hydrochloride.
. 17,17-diacetoxyyohimbane.
. l0-acetyl-3-epiyohimbone.
. IO-acetylalloyohimbone.
A method of preparing a member selected from the group consisting of compounds of the formulae and at a temperature between C. and 40 C. for about minutes to about 4 hours with a member selected from the group consisting of a carboxylic acid anhydride (R O and a carboXylic acid halide R --X wherein X is halogen and R has the meaning above in an anhydrous reaction medium in the presence of a Friedel-Crafts catalyst.
9. A method according to claim 8 wherein said Friedel- Crafts catalyst is boron trifiuoride.
10. A method of preparing a compound of the formula wherein the ring system is selected from the group consisting of yohimbane, 3-epiyohimbane, alloyohimbane and 3-epialloyohimbane and R is the acyl radical of an unsubstituted saturated aliphatic carboxylic acid of 1 to 6 carbon atoms which comprises treating a compound of the formula at a temperature between 40 C. and C. for about 5 to about 30 minutes with a member selected from the group consisting of a carboxylic acid anhydride (R O and a carboxylic acid halide R X wherein X is halogen and R has the meaning above in an anhydrous reaction medium in the presence of a Friedel-Crafts catalyst.
11. A method according to claim 10 wherein said Friedel-Crafts catalyst is boron trifluoride.
No references cited.

Claims (1)

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF ALKALOID DERIVATIVES SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMLUAE
US88306A 1961-02-10 1961-02-10 Derivatives of 17-ketoyohimbane alkaloids and process therefor Expired - Lifetime US3120528A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US88306A US3120528A (en) 1961-02-10 1961-02-10 Derivatives of 17-ketoyohimbane alkaloids and process therefor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US88306A US3120528A (en) 1961-02-10 1961-02-10 Derivatives of 17-ketoyohimbane alkaloids and process therefor

Publications (1)

Publication Number Publication Date
US3120528A true US3120528A (en) 1964-02-04

Family

ID=22210596

Family Applications (1)

Application Number Title Priority Date Filing Date
US88306A Expired - Lifetime US3120528A (en) 1961-02-10 1961-02-10 Derivatives of 17-ketoyohimbane alkaloids and process therefor

Country Status (1)

Country Link
US (1) US3120528A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3291800A (en) * 1963-07-23 1966-12-13 Warner Lambert Pharmaceutical 3-substituted derivatives of yohimbane alkaloids and process for their production

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3291800A (en) * 1963-07-23 1966-12-13 Warner Lambert Pharmaceutical 3-substituted derivatives of yohimbane alkaloids and process for their production

Similar Documents

Publication Publication Date Title
SU508193A3 (en) Preparation method - (methoxymethyl-furylmethyl) -6,7-benzomorphanes or morphinanes
NO154116B (en) PROCEDURE AND LAMEL PREPARATION DEVICE FOR SUPPLY AND DISTRIBUTION OF A COMPOSITION TO A LAMEL PREPARATION DEVICE.
US3830803A (en) 5-loweralkyl-1-phenyl-1,3,4,6-tetrahydro-5h-benz(f)-2,5-oxazocines and 4-ones
US2824874A (en) Reserpic acid and derivatives
US3120528A (en) Derivatives of 17-ketoyohimbane alkaloids and process therefor
SU645581A3 (en) Method of obtaining d-2-halogen-6-methyl-8-cyanomethyl- or d-2-halogen-6-methyl-8-carboxamidomethylergolines
US3228945A (en) Methyl and i,g-dimethyl-b-(a-hydroxy- alkyl)-ergoline i derivatives
US2977365A (en) 3-dehydroyohimbanes and their preparation
JPH0352465B2 (en)
NO118975B (en)
US3120539A (en) 10-acyl derivatives of ajmalicine and process therefor
US3120529A (en) 10-acyl derivatives of apoyohimbine and process therefor
US3159623A (en) 18-hydroxymethylene derivatives of yohimbone
DE1065422B (en) Process for the production of lysergic acid, its N-derivatives and esters
US3119827A (en) 10-acyl yohimbanes and process therefor
US3139434A (en) 10-substituted yohimbanes
US3120531A (en) 10-bromoyohimbine alkaloids
US2809199A (en) Process and intermediates for preparing rauwolscine and derivatives
US3120530A (en) 10-alkylamidoyohimbine esters
US3364198A (en) Process for the production of n6-methyltubercidin and intermediate
US3578670A (en) Nicotinamide intermediates and process for preparing same
US2140480A (en) 3-keto-d-pentonic acid lactone and process for the manufacture of same
US3228940A (en) Methyl- and i,g-dimethyl-ergoline nitriles
US3049551A (en) Novobiocin intermediate and process therefor
US2939870A (en) Derivatives of dibenzo-cycloheptadiene and a process of preparing same