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US3117955A - 10-haloyohimbane alkaloids and process therefor - Google Patents

10-haloyohimbane alkaloids and process therefor Download PDF

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US3117955A
US3117955A US136183A US13618361A US3117955A US 3117955 A US3117955 A US 3117955A US 136183 A US136183 A US 136183A US 13618361 A US13618361 A US 13618361A US 3117955 A US3117955 A US 3117955A
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methanol
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alkaloids
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Jr John Shavel
Strandtmann Maximilian Von
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Warner Lambert Co LLC
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Warner Lambert Pharmaceutical Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D459/00—Heterocyclic compounds containing benz [g] indolo [2, 3-a] quinolizine ring systems, e.g. yohimbine; 16, 18-lactones thereof, e.g. reserpic acid lactone

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  • the present invention relates to new and novel haloyohimbane alkaloids of the formula wherein R is hydrogen or methyl, R is hydrogen, keto or hydroxyl and X is halogen, for example chlorine, fluorine or bromine.
  • This invention also relates to a method of preparing the above compounds, to the pharmaceutically acceptable nontoxic acid addition and quaternary ammonium salts thereof, and to new and novel intermediates obtained during the synthesis.
  • the compounds of our invention have significant pharmacological activity and are usefiul as anti-inflammatory agents, analgesics and tranquilizers. In addition, they are valuable intermediates in the production of other compounds of the yohimbane series.
  • the compounds of this invention bear the A, B, C, D and E rings as depicted in the above structural formula and are, generally, alkaloids of the yohirnbane series.
  • alkaloids of the yohirnbane series Depending upon the configuration of the hydrogen atom at the 3-position and the existence of cis or transfusion of the D and E rings, four different configurations are possible, that is yohirnbane, B-epiyohirnbane, alloyohimbane mid 3-epialloyohimbane.
  • the present invention includes within its scope derivatives of t ese four families of alkaloids bearing halo, R and R substituents at the 1G, 16 and 17 positions, respectively.
  • the compounds of our invention are prepared by the reaction of starting materials of the formula H k W wherein R and R are as described above, with nitrons acid at a temperature of less than 10 C. in the presence or" a halogen acid of the formula l-lX to form the corresponding IO'diaZonium halide, followed by decomposition or" this diazonium salt by the application of heat.
  • the lG-Cll9l3illllll1 halides intermediates are themselves new and novel compounds and are included within the scope of our invention.
  • the nitrous acid is generated in situ by the action of the halogen acid present either on an alkali metal nitrite such as sodium nitrite or a lower alkyl nitrite such as ethyl nitrite.
  • the diazotization may be carried out in an aqueous medium, which is generally preferred for the production of IO-chloro or IO-bromo derivatives, in which case an alkali metal nitrite furnishes the source of nitrite.
  • the 10-diazonium chloride or bromide is then converted to the desired 10-chloro and lO-bromo derivatives by heating the aqueous solution of the diazonium salt with cuprous chloride or cuprous bromide.
  • an hydrous medlurn such as ethanol is preferred, in which case a lower alkyl nitrite furnishes the source of nitrite. Heating the resulting IO-diazoniun fluoride derivative results in its conversion to the desired lO-fluoro compound.
  • the compounds of our invention having a bromo substituent at the 18- position may also be prepared by the reaction of the corresponding yohirnbane alkaloid having no substituent at the 10-posiL'on with bromine in the presence of glacial acetic acid and methanol, as described and claimed in the application of John Shavel, Jr. and iarold Ziunes, Serial No. 136,182, filed concurrently herewith.
  • the compounds of this invention may be converted into their pharmaceutically acceptable non-toxic acid addition or quaternary ammonium salts.
  • Useful acid-addition salts are those formed with such acids as maleic, furnaric, benzoic, succinic, m thylsulfonic, sulfonic, citric, tartaric, salicylic, malic, cinnamic, hydrochloric, hydrobromic, phosphoric and the like.
  • the acid addition salts may be prepared in the conventional manner, for example, by treating a solution of 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 solution of the base irr a suitable solvent with a reactive allzyl halide such as methyl iodide, ethyl bromide, n-hexyl bromide, benzyl chloride or another reactive ester such as methyl sulfate, ethyl sulfate or methyl p-toluene sulfonate.
  • a reactive allzyl halide such as methyl iodide, ethyl bromide, n-hexyl bromide, benzyl chloride or another 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 a conventional pharmaceutical carrier to form tablets, capsules, elixirs, solutions, suspensions, suppositories and the like.
  • the precipitated yellowish material is filtered off, washed with water and suspended in 50 ml. water.
  • the suspension is heated on a steam bath at 6080 until a sample gives no pink or red color upon coupling with B-naphtol in alkaline medium.
  • Aqueous ammonia is added until the mixture turns dark blue.
  • the mixture is extracted with two 50 ml. portions of chloroform.
  • the combined extracts are treated with charcoal and anhydrous Na SO filtered and evaporated in vacuo to dryness.
  • the residue is refluxed for one hour with 400 ml. acetonitrile.
  • the solution is decanted from a small amount of insoluble gum of red color and concentrated in vacuo to a volume of 75 ml.
  • the dry diazonium salt is then heated slowly to 90 to 100 and maintained at this temperature for 3 hours at which time the ,B-naphthol test for diazonium salts is negative.
  • the mixture is cooled, basified with aqueous ammonia containing pieces of ice and is extracted with three 15 ml. portions of chloroform.
  • the extracts are combined, treated with charcoal and anhydrous sodium sulfate, filtered and evaporated to dryness.
  • the residue is taken up in ml. acetonitrile, filtered and the filtrate evaporated to dryness.
  • the residue is dissolved in a minimum amount of ethyl acetate and chromatographed over 3 g. acid washed alumina using ethyl acetate as eluant.
  • keto and hydroxyl and the pharmaceutically acceptable non-toxic acid addition and quaternary ammonium salts thereof with a compound selected from the group con- 5 sisting of methyl iodide, ethyl bromide, n-hexyl bromide,

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

United States Patent 3,117,955 IliB-HALOYOHIMBANE ALKALOEDS AND PROCESS THEREFGR John Shavel, J12, Mendham, and Maximilian von Strandemann, Roclraway Township, N..l., assignors to Warner- Lamhert Pharmaceutical Company, Morris Plains,
Ni, a corporation of Delaware No Drawing. Filed Sept. 6, 1951, Ser. No. 136,183 11 Claims. (Cl. 2613-141) The present invention relates to new and novel haloyohimbane alkaloids of the formula wherein R is hydrogen or methyl, R is hydrogen, keto or hydroxyl and X is halogen, for example chlorine, fluorine or bromine. This invention also relates to a method of preparing the above compounds, to the pharmaceutically acceptable nontoxic acid addition and quaternary ammonium salts thereof, and to new and novel intermediates obtained during the synthesis.
The compounds of our invention have significant pharmacological activity and are usefiul as anti-inflammatory agents, analgesics and tranquilizers. In addition, they are valuable intermediates in the production of other compounds of the yohimbane series.
The compounds of this invention bear the A, B, C, D and E rings as depicted in the above structural formula and are, generally, alkaloids of the yohirnbane series. Depending upon the configuration of the hydrogen atom at the 3-position and the existence of cis or transfusion of the D and E rings, four different configurations are possible, that is yohirnbane, B-epiyohirnbane, alloyohimbane mid 3-epialloyohimbane. The present invention includes within its scope derivatives of t ese four families of alkaloids bearing halo, R and R substituents at the 1G, 16 and 17 positions, respectively.
We have now found that the compounds of our invention are prepared by the reaction of starting materials of the formula H k W wherein R and R are as described above, with nitrons acid at a temperature of less than 10 C. in the presence or" a halogen acid of the formula l-lX to form the corresponding IO'diaZonium halide, followed by decomposition or" this diazonium salt by the application of heat. The lG-Cll9l3illllll1 halides intermediates are themselves new and novel compounds and are included Within the scope of our invention.
Starting materials of the above formula are described Patented jam. l4, 1964 ice in the application of John Shavel, Jr., Serial No. 136,189, filed concurrently herewith.
The nitrous acid is generated in situ by the action of the halogen acid present either on an alkali metal nitrite such as sodium nitrite or a lower alkyl nitrite such as ethyl nitrite. The diazotization may be carried out in an aqueous medium, which is generally preferred for the production of IO-chloro or IO-bromo derivatives, in which case an alkali metal nitrite furnishes the source of nitrite. The 10-diazonium chloride or bromide is then converted to the desired 10-chloro and lO-bromo derivatives by heating the aqueous solution of the diazonium salt with cuprous chloride or cuprous bromide. In the preparation of the ltl-fiuoro derivatives, an hydrous medlurn such as ethanol is preferred, in which case a lower alkyl nitrite furnishes the source of nitrite. Heating the resulting IO-diazoniun fluoride derivative results in its conversion to the desired lO-fluoro compound.
The compounds of our invention having a bromo substituent at the 18- position may also be prepared by the reaction of the corresponding yohirnbane alkaloid having no substituent at the 10-posiL'on with bromine in the presence of glacial acetic acid and methanol, as described and claimed in the application of John Shavel, Jr. and iarold Ziunes, Serial No. 136,182, filed concurrently herewith.
The compounds of this invention may be converted into their pharmaceutically acceptable non-toxic acid addition or quaternary ammonium salts. Useful acid-addition salts are those formed with such acids as maleic, furnaric, benzoic, succinic, m thylsulfonic, sulfonic, citric, tartaric, salicylic, malic, cinnamic, hydrochloric, hydrobromic, phosphoric and the like. The acid addition salts may be prepared in the conventional manner, for example, by treating a solution of 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 solution of the base irr a suitable solvent with a reactive allzyl halide such as methyl iodide, ethyl bromide, n-hexyl bromide, benzyl chloride or another reactive ester such as methyl sulfate, ethyl sulfate or methyl p-toluene sulfonate.
For therapeutic use, the new and novel compounds of this invention, either as the free base or in the form of a pharmaceutically acceptable, nontoxic acid addition or quaternary ammonium salt, may be formulated with a conventional pharmaceutical carrier to form tablets, capsules, elixirs, solutions, suspensions, suppositories and the like.
The following examples are included in order further to illustrate the present invention:
EXAMPLE 1 l O-Ch loroyoh imbane To a solution of 7.72 IO-aminoyohirnbane dihydrochloride nronohydrate in 350 ml. Water and 10 ml. concentrated hydrochloric acid is added a solution of 1.6 g. sodium nitrite in 50 ml. Water dropWise with stirring over a period of about one hour. The temperature is maintained at 2 to 5 C. The mixture is stirred at the reaction temperature and the excess reagent is decomposed by the addition of urea.
To 200 ml. of this solution of lfl-diazoniurnyohimbane chloride is added 20 ml. of a solution of cuprous chloride, freshly prepared from cuprous sulfate in accordance with the procedure described in Organic Syntheses, vol. 1, p. 170. The resulting suspension is stirred for one hour a room temperature, heated on a steam bath for one hour and, finally, refluxed for 20 minutes. Aqueous ammonia is added until the solution turns dark blue in color. The
mixture is then extracted with three 250 ml. portions of chloroform, the extracts are dried over sodium sulfate EXAMPLE 2 1 O-Bromoyohfmbane To a solution of 0.3 g. lil-aminoyohimbane in 25 ml. aqueous HBr a solution of 0.075 g. NaNO in 12.5 ml. water is added dropwise under stirring at 2 to 5 over a period of 100 min. The resulting solution is added to a freshly prepared solution of CuBr, which is obtained from 0.63 g. CuSG and 0.2 g. of copper turnings accord ing to the procedure described in Organic Syntheses, vol. I, p. 136.
The precipitated yellowish material is filtered off, washed with water and suspended in 50 ml. water. The suspension is heated on a steam bath at 6080 until a sample gives no pink or red color upon coupling with B-naphtol in alkaline medium. Aqueous ammonia is added until the mixture turns dark blue. The mixture is extracted with two 50 ml. portions of chloroform. The combined extracts are treated with charcoal and anhydrous Na SO filtered and evaporated in vacuo to dryness. The residue is refluxed for one hour with 400 ml. acetonitrile. The solution is decanted from a small amount of insoluble gum of red color and concentrated in vacuo to a volume of 75 ml. The precipitated red material is filtered off and discarded. The solution is evaporated to dryness. Recrystallization of the residue twice from methanol yields -bromoyohimbane, M.P. 211214, (00, 69 (pyridine, c.=0.5).
Analysis.Calc.: C, 63.51; H, 6.45; N, 7.80; Br, 22.24. Found: C, 63.29; H, 6.55; N, 7.58; Br, 22.53.
EXAMPLE 3 J O-Fluoroyohim bane To a solution of 0.45 g. IO-aminoyohimbane in 7.5 ml. 10% ethanolic HP is added a solution of 0.5 ml. ethyl nitrite in 1 ml. absolute ethanol, dropwise with stirring at -5 to 0. The addition requires about 115 minutes. Cold absolute ether is added to the resulting greenish solution and the precipitate constituting 10-diazoniumyohimbane fluoride is filtered oil, washed with cold ether and dried in vacuo over H 501, for minutes. (Decomposition point 90110).
The dry diazonium salt is then heated slowly to 90 to 100 and maintained at this temperature for 3 hours at which time the ,B-naphthol test for diazonium salts is negative.
The mixture is cooled, basified with aqueous ammonia containing pieces of ice and is extracted with three 15 ml. portions of chloroform. The extracts are combined, treated with charcoal and anhydrous sodium sulfate, filtered and evaporated to dryness. The residue is taken up in ml. acetonitrile, filtered and the filtrate evaporated to dryness. The residue is dissolved in a minimum amount of ethyl acetate and chromatographed over 3 g. acid washed alumina using ethyl acetate as eluant. The first twenty-five 2.5 ml. fractions are combined and evaporated in vacuo. Recrystallization of the residue from acetonitrile yields 0.046 g. of IO-fiuoroyohimbane, MP. 188-190, (00, 110 (pyridine, .=0.5
Analysis.Calc.: C, 76.47; H, 7.77; N, 9.39; F, 6.37. Found: C, 76.31; H, 7.78; N, 9.46; F, 6.69.
EXAMPLE 4 ZO-Brom0-16u-Methyly0himb0ne To a solution of 3.1 g. 16a-methylyohimbone in a mixture of 25 ml. glacial acetic acid and 50 ml. meth anol is added dropwise with stirring at room temperature a solution of 1.6 g. bromine in 4 ml. glacial acetic acid, the addition taking about 15 minutes for completion. After stirring for an additional 15 minutes, the mixture is allowed to stand overnight at room temperature. The solid which separates is collected and washed on the filter with 25 ml. methanol. It is then refluxed with 50 ml. methanol, filtered while hot, and washed on the filter with 10 ml. hot methanol. The insoluble solid is partitioned between chloroform and aqueous ammonium hydroxide solution. The chloroform solution is dried over sodium sulfate and distilled in vacuo to dryness. The residue is recrystallized twice from methanol to give 760 mg. of 10-bromo-l6a-methylyohimbone,, MP. 276-280, (00 -61 (pyridine, c.=0.67).
Analysis.Calc.: C, 62.02; H, 5.98; N, 7.23; Br, 20.63. Found: C, 61.70; H, 6.25; N, 7.20; Br, 20.89.
EXAMPLE 5 I O-Bromo-I 6m-Methylyohimbol To a solution of 15.5 g. l6a-methylyohimbol in a mixture of 125 ml. glacial acetic acid and 125 ml. methanol is added dropwise with stirring at room temperature a solution of 8.2 g. bromine in 15 ml. glacial acetic acid, the addition taking about 15 minutes for completion. After stirring for an additional 15 minutes, the mixture is allowed to stand overnight at room temperature. The mixture is allowed to evaporate spontaneously (without heat) to a volume of ml. and then is treated with 500 ml. absolute ether. The white precipitate which separates from solution is collected and triturated with two 25 ml. portions of methanol. The insoluble solid is partitioned between chloroform and aqueous ammonium hydroxide solution. The aqueous layer is further extracted with chloroform, the combined chloroform layers are dried over sodium sulfate, and distilled in vacuo to dryness. The residue becomes crystalline on trituration with 25 ml. acetonitrile. The crystals are collected and recrystallized from 50 ml. acetonitrile to give 6.5 g. of crystals, M.P. 227-234, (04),; 0 (pyridine, c.:0.62), +21 (methanol, c.=0.5). Another recrystallization from acetonitrile gives, MP. 233237, (00 0 (pyridine, c.:0.7), +2l (methanol, c.:0.5).
Analysis.-Calc.: C, 61.69; H, 6.47; N, 7.20; Br, 20.53. Found: C, 61.36; H, 6.63; N, 7.07; Br, 20.90.
EXAMPLE 6 J O-Bromoyolzimbone Attempts to react yohimbone with bromine by the procedure of Example 4 result in low yields. Conversion of yohimbone to its dimethyl ketal (17,17-dimethoxyyohimbaue) prior to reaction with bromine resulted in a markedly improved yield.
A mixture of 73.5 g. yohimbone, 75 ml. 6 N methanolic hydrogen chloride, 100 ml. acetone dimethyl ketal, and 3000 ml. methanol is refluxed until the infrared spectrum of a small sample showed complete absence of carbonyl absorption; this requires 34 hours time. The resulting solution is distilled at atmospheric pressure to a volume of about 1000 ml. and then is allowed to stand overnight at room temperature. The crystals which separate are collected and the filtrate is concentrated further to obtain additional crops of yohimbone dimethyl ketal hydrochloride. The combined crops are partitioned between aqueous ammonium hydroxide and methylene chloride and the methylene chloride solution is dried over sodium sulfate and distilled in vacuo to dryness to yield an oil. This is refluxed with 250 ml. methanol and allowed to stand at room temperature whereupon 77.6 g. of crystalline yohimbone dimethyl ketal base separates out; MP. 124127, ((1) 58 (pyridine, c.=0.65). The infrared spectrum showed complete absence of carbonyl.
A solution of 34 g. yohimbone dimethyl ketal, prepared as described above, in a mixture of 350 ml. glacial acetic acid and 700 ml. methanol is cooled to 40 to -50 and a solution of 17.6 g. bromine in 50 ml. glacial acetic acid is added dropwise with stirring over a period of 20 minutes. The reaction mixture is stirred at this temperature for an additional 30 minutes. To the solution are then added 8 liters absolute ether and the resulting precipitate is collected by filtration; it is partitioned be tween chloroform and aqueous ammonium hydroxide and the chloroform solution is distilled in vacuo to dryness. The resulting oil is dissolved in 300 ml. glacial acetic acid and 900 ml. water, and ml. concentrated hydrochloric acid are added. The resulting solution is heated on a steam bath (60) for minutes, cooled, and basified by the addition of ammonium hydroxide. The resulting precipitate is Washed with water, air-dried and crystallized from methanol to give 16.5 g. of 10- bromoyohimbone, M.P. 298-300, ((1) 66 (pyridine, c.=0.53).
Analysis.Calc.: C, 61.13; H, 5.67; N, 7.51; Br, 21.41. Found: C, 61.35; H, 5.83; N, 7.44; Br, 21.50.
In the foregoing examples, all temperatures are given in degrees Centigrade.
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 our invention.
Having described our invention, what We desire to secure by Letters Patent is:
1. A member selected from the group consisting of compounds of the formula wherein X is halogen, R is a member selected from the group consisting of hydrogen and methyl and R is a member selected from the group consisting of hydrogen,
keto and hydroxyl, and the pharmaceutically acceptable non-toxic acid addition and quaternary ammonium salts thereof with a compound selected from the group con- 5 sisting of methyl iodide, ethyl bromide, n-hexyl bromide,
benzyl chloride, methyl sulfate, ethyl sulfate and methyl p-toluene sulfonate.
2. IO-bromoyohimbane.
3. IO-chloroyohimbane. 10 4.10-fluoroyohimbane.
5. 10-bromol6u-methylyohimbone. 6. 10-bromo-l6u-methylyohimbol. 7. l0-bromoyohimbone. 8. A compound of the formula 15 Tl l W H r wherein X is halogen, R is a member selected from the group consisting of hydrogen and methyl and R is a member selected from the group consisting of hydrogen, keto and hydroxyl.
9. 10-diazoniumyohimbane chloride.
10. IO-diazoniumyohimbane bromide.
11. IO-diazoniumyohimbane fluoride.
No references cited.

Claims (1)

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA
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