US3133929A - Ajmaline derivatives and process therefor - Google Patents

Description

United States Patent 3,133,929 AJMALINE DERIVATIVES AND PROCESS THEREFOR Merrill Frederick Bartlett, Warren Township, N.J., as-

signor to Cilia Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Feb. 2, 1962, Ser. No. 170,793 27 Claims. (Cl. 260-293) The present invention concerns process for the demthylation of ajznaline and analogous compounds thereof. More particularly, it relates to a process for the preparation of compounds having the following formula c-------- ca \c----- on N R N I I H CH3 in which R, and R have the previously-given meaning, a salt or a quaternary ammonium compound thereof, with an oxidation reagent used in at least the amount necessary to cause the removal of four electrons from the starting material, and, if desired, converting a resulting salt into the free compound or into another salt, and/ or, if desired, converting a resulting compound into a salt or a quaternary ammonium compound thereof, and/ or, if desired, converting a resulting quaternary ammonium compound into another quaternary ammonium compound.

In the starting material, the acyl radical of the group -OAc(H) or of the acyloxy group stands primarily for the acyl radical of an aliphatic carboxylic acid, particularly a lower alkanoic acid, e.g. acetic, propionic, butyric, pivalic, 2,-2-dimethyl-butyric acid and the like, as Well as a cycloalkane carboxylic acid, in which cycloalkane has from five to seven ring carbon atoms, e.g. hexahydrobenzoic acid and the like, a cyclo-alkyl-lower alkanoic acid, in which cycloalkyl has from three to seven, particularly from five to seven, ring carbon atoms, e.g. cyclohexylacetic, B-cyclopentylpropionic acid and the like, but may also be the acyl radical of a carbocyclic aryl carboxylic acid, e.g. benzoic, 3,4,5-trimethoxybenzoic acid and the like, of a carbocyclic aryl-aliphatic carboxylic acid, e.g. cinnamic, 3,4,5-trimethoxy-cinnamic acid and the like, of a heterocyclic aryl carboxylic acid, e.g. nicotinic, isonicotinic acid and the like, or any other suitable organic carboxylic acid. The acyl group may also stand for the acyl radical of an organic sulfonic acid, e.g. methane sulfonic, ethane sulfonic, benzene sulfonic, ptoluene sulfonic acid and the like.

An oxidation reagent suitable in the above reaction does not affect other portions of the molecule and is used under non-hydrolyzing conditions. The preferred 3,133,929 Patented May 19, 1964 reagent is lead tetraacetate, which is used in the presence of an inert diluent, such as benzene, toluene, methylene chloride, glacial acetic acid and the like. Other oxidizing reagents are chromium trioxide (used as the pyridine complex or in acetone), tetranitromethane (used together with equivalent amount of pyridine in ethanol), mercuric acetate, potassium ferric cyanide, an azodicarboxylic acid ester or any other oxidizing reagent capable of removing the necessary four electrons without affecting any other portions in the starting material. The amount of the oxidizing reagent depends on the type of reagent used; in view of the fact that a total of four electrons has to be transferred for the completion of the oxidation and demethylation, at least two equivalent amounts of, for example, lead tetraacetate, have to be used, whereas at least 1.5 equivalent amounts of chromium trioxide are needed. However, the oxidizing reagent is preferably used in excess of the required amount.

The removal of the methyl group may also be achieved by subjecting a compound of the formula cz- -cu c---cu in which R, and R have the previously-given meaning, or a salt thereof, with the oxidation reagent used in about the amount necessary to cause the removal of two electrons from the starting material, the desired intermediate can be isolated.

The demethylated compounds may, therefore, also be prepared by a step-wise oxidation reaction; the starting material may be reacted first with the oxidation reagent used in about the amount necessary to cause the removal of two electrons from the starting material to form the intermediate of the formula c-Won in which R and R have the previously-given meaning, and this intermediate is then reacted with the oxidation 1;: 1;) reagent used in at least the amount necessary to cause the removal of two additional electrons to form the desired demthylated compound of the formula ca es;

in which R and R have the previously-given meaning.

The starting materials used in the procedure of this invention are known or may be prepared from the known compounds by standard methods, such as esterification and the like.

The compounds prepared according to the procedure of this invention, as well as the intermediates formed in the step-wise procedure, are new and are intended to be included within the scope of this invention. They are useful as intermediates in the preparation of pharmacological- 1y active compounds, particularly of compounds which have antifibrillatory properties, which can be utilized in the treatment of cardiac irregularities, such as auricular or ventricular arrhythms.

Particularly useful as intermediates are the compounds of the formula CH2CH3 in which R, stands for OAc(H), in which Ac is lower alkanoyl having from two to seven carbon atoms, e.g. acetyl, propionyl, pivaloyl, 2,2-dimethyl-butyryl and the like. The compounds of the formula in which R has the previously-given meaning, R stands for H(H), OH(I-I) or OAc(H), in which Ac has the previously-given meaning, and R is hydrogen or lower alkyl, salts or quaternary ammonium compounds thereof, may be prepared by reducing in compounds of the formula in which R and R have the previously-given meaning, a salt or a quaternary ammonium compound thereof, the double bond extending from the nitrogen atom, and, if desired, converting in a resulting compound an acylated hydroxyl group into a hydroxyl group, and/ or, if desired, replacing the hydrogen attached to the indolc-nitrogen by lower alkyl, and/ or, if desired, converting a resulting salt into a free compound or into another salt, and/ or, if desired, converting a resulting compound into a salt or a quaternary ammonium compound thereof, and/ or, if desired, converting a resulting quaternary ammonium compound into another quaternary ammonium compound.

The reduction of the double bond extending from the nitrogen atom is carried out under neutral or acidic conditions. The preferred reducing reagent is catalytically activated hydrogen; suitable catalysts contain a metal of the eighth group of the Periodic System and are represented, for example, by platinum oxide (which is used in the presence of an inert solvent, e.g. anhydrous ethanol and the like) and the like. If necessary, the hydrogen may be used under increased pressure, and/ or the reaction is carried out at an elevated temperature. The removal of the double bond may also be achieved by treatment with a suitable metal-acid combination or with a complex hydride.

An acyloxy group in a resulting compound may be converted into a hydroxyl group by known hydrolysis procedures, for example, by treatment with an alkali metal hydroxide, e.g. sodium hydroxide and the like.

As previously mentioned, the resulting compounds have antifibrillatory properties and are intended to be included Within the scope of this invention. Particularly useful antifibrillatory properties are exhibited by the compounds of the formula in which R stands for OH(H) or -OAc'(H), in which Ac has the previously-given meaning, salts or lower alkyl quaternary ammonium halides thereof. Apart from having antifibrillatory properties, compounds of the above formula may also be used as intermediates for other compounds having useful antifibrillatory effects. As previously mentioned, upon alkylation of the indole nitrogen atom according to known methods, for example, by treatment of a salt of such compounds with a lower alkyl halide, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide, or by reaction of such compound with a (ll-lower alkyl sulfate, e.g. dimethyl sulfate, diethyl sulfate and the like, in the presence of a base, or by using any other suitable method, compounds of the formula u g N t a All:

CH2CH3 3 cu ctr 5 in which R, has the previously-given meaning, salts or lower alkyl quaternary ammonium halides thereof.

On the other hand, by treatment of a compound of the formula in which R has the previously-given meaning, R stands for -OH(H), and R is primarily hydrogen, as well as lower alkyl group Alk, a salt or a quaternary ammonium compound thereof, with a suitable oxidizing reagent, e.g. lead tetraacetate, chromium trioxide or any of the previously-mentioned reagents, compounds of the formula CH-CHO CH CK-[ in which R and R have the previously-given meaning, can be formed, and, if desired, converted into their salts or quaternary ammonium compounds; these compounds have antifibrillatory properties or may be used as intermediates, for example, in the conversion of the formyl group into an oximinomethyl and aminomethyl group or into a carbinol or esterified carbinol group according to known methods.

Compounds of the above type and having the formula (Iii-CHO in which R has the previously-given meaning, are intended to be included within the scope of this invention; particularly useful are those having the formula CH-CHO an er The above aldehyde compounds may also be prepared from the demethylated products of this invention; for example, upon treatment of a compound of the formula I o--en i: i N N in which R, has the previously-given meaning, and R is hydrogen or acyloxy, a salt or a quaternary ammonium compound thereof, with a base, such as an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, ammonium hydroxide, silver oxide and the like, the compounds of the formula CH2CH CHE-GHQ I a N Ci H CH CH3 in which R has the previously-given meaning, or derivatives thereof (which may also be prepared subsequently) are formed and may be used as shown above.

The intermediates formed in the demethylation procedure, which are new and are intended to be included within the scope of this invention, may also serve as starting materials for the preparation of useful compounds. Thus, upon treatment of a compound of the formula men cn cn in which R,, and R have the previously-given meaning, with a base, for example, an alkali metal hydroxide, e.g. sodium hydroxide and the like, the compounds of the formula (EH-CHO in which R has the previously-given meaning, can be prepared.

In compounds derived from ajmaline or ajmaline-type alkaloids and having either the complete or a partially degraded ajmaline carbon skeleton, the hydrogen at the 3-position has the tat-configuration.

A resulting salt may be converted into the free com- 3 pound, for example, by treating it with a base, such as an alkali metal hydroxide, e.g. sodium hydroxide and the like, an alkali metal carbonate, e.g. sodium or potassium carbonate or hydrogen carbonate and the like, ammonia and the like, or with an hydroxyl ion exchange preparation or any other suitable reagent.

A resulting salt may also be converted into another salt, for example, by treatment with a suitable metal salt, e.g. silver, sodium and the like, of an acid, or with an anion exchange resin.

A free compound may be converted into an acid addition salt thereof, for example, by reacting it with an acid, preferably in the presence of a suitable solvent or solvent mixture, and isolating the desired salt; the latter may also be in the form of a hydrate. I

A quaternary ammonium compound, particularly a lower alkyl or phenyl-lower alkyl quaternary ammonium salt, such as a halide, sulfate or sulfonate, may be prepared, according to known methods, for example, by reacting the free compound with an ester formed by a hydroxylated compound and a strong inorganic or organic acid, such as, for example, a lower alkyl halide, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, a di-lower alkyl sulfate, e.g. dimethyl sulfate, diethyl sulfate and the like, lower alkyl lower alkane sulfonate, e.g methyl or ethyl methane or ethane sulfonate and the like, a lower alkyl monocyclic carbocyclic aryl sulfonate, e.g. methyl p-toluene sulfonate and the like, or a phenyl-lower alkyl halide, e.g. benzyl, l-phenylethyl or 2- phenylethyl chloride, bromide or iodide and the like, or any other suitable reactive ester. The quaternizing reaction may be performed in the absence or presence of a suitable solvent, while cooling, or at an elevated temperature, in a closed vessel under pressure, and/or in the atmosphere of an inert gas, e.g. nitrogen.

A quaternary ammonium compound may be converted into the corresponding quaternary ammonium hydroxide, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with an anion exchange preparation, by electrodialysis and the like. From a resulting quaternary ammonium hydroxide there may be prepared quaternary ammonium salts by reacting it with an acid, with a mono-lower alkyl sulfate, e.g. methyl sulfate, ethyl sulfate and the like. A quaternary ammonium compound may also be converted directly into another quaternary ammonium salt without the formation of the quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride or with hydrochloric acid in methanol to yield the quaternary ammonium chloride, or a quaternary ammonium salt may be reacted with a suitable anion exchange preparation and converted into another quaternary ammonium salt.

The invention also comprises any modification of the process, wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to the products mentioned in the specification as preferred embodiments of the invention.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 To 1.47 g. of chromium trioxide in 30 ml. of pyridine is added 1.24 g. of 17-O-acetyl-2l-deoxy-ajmaline in 20 ml. of pyridine; the reaction mixture is stirred for 16 hours at room temperature and is then diluted with 100 ml. of mehiyiene chloride. The solution is passed through a column of basic aluminum oxide; a total of 0.98 g. of a residue is eluted with 800 ml. of methylene chloride.

This residue is rechromatographed over neutral aluminum oxide and the desired A -17-O-acetyl-1-demethyl-2l-deoxyajmaline of the formula CH2CH3 is eluted with the first portion of ml. of a 200:1- mixture of methylene chloride and methanol, M.P. 184-185"; [u] =l2 (methanol); ultraviolet absorption spectrum (in ethanol): A 219 m (e=20,800), 258 y a shoulder 224 l mln 235 m (e:3,500); infrared absorption spectrum (in Nujol): v 1743 cmf yield: 0.181 g.

In the above chromatogram, the second portion of 100 ml. of the 200:1-mixture of methylene chloride and methanol yields an amorphous fraction (0.136 g.) while the third portion of 100 ml. of the 200:1-mixture of methylene chloride and methanol gives the 17-O-acetyl-2ldeoxy-Z-hydroxy-ajmaline of the formula inc-00 0 ctt on which is recrystallized from a mixture of diethyl ether and hexane, M.P. 95-98 (or 182-184"); [a] =lO8; ultraviolet absorption spectrum (in ethanol) )t 244 mn (5:8,800), 292 m (e:2,800); k 223 m (e=2,800), 266 m (6 700); infrared absorption spectrum (in Nujol): 11 1742 cmf The starting material used in the above example may be prepared as follows: A mixture of 5.1 g. of 21-deoxyajmaline in ml. of pyridine and 40 ml. of acetic acid anhydride is allowed to stand for three days. The solution is evaporated to dryness under reduced pressure, and the residue is chromatographed on aluminum oxide. The material eluted with 100 ml. of a lzl-mixture of hexane and benzene and with ml. of benzene is combined, crystallized from methanol and water and recrystallized from a mixture of benzene and hexane to yield 17-O- acetyl-2l-deoxy-ajmaline, M.P. 146-147; [a] =|13.9 (in a 5:2-mixture of methanol and chloroform); infrared absorption spectrum (in Nujol): 11 1749 cm.

Example 2 A mixture of 1.03 g. of chromium trioxide in 50 ml. of pyridine and 0.7 g. of 17,21-dideoxy-ajmaline in pyridine is treated as shown in Example 1. The desired A -l-demethyl-17,21-dideoxy-ajmaline of the formula M.P. 188; ultraviolet absorption spectrum (in ethanol): k 219 m (e:22,100), 256 m (e=5,200); A 235 m (e=3,900), is eluted from the column with methylene chloride and is crystallized from a mixture of diethyl ether and hexane.

The amorphous 17,2l-dideoxy-2-hydroxy-ajmaline of the formula CHQCH eluted with methylene chloride containing 1 percent of methanol, is characterized as the diperchlorate (recrystallized from ethanol), M.P. 340; ultraviolet absorption spectrum (in ethanol): lt 244 m (e=l0,900), 292 mu (e=3,800); A 220 m (e=2,900), 264 m (:900).

CH CH melts at 208209 after crystallization from a mixture of ethyl acetate and diethyl ether; ultraviolet absorption spectrum (in ethanol): )t 219 m (e=21,800), 258 m (s=4,800); l 236 m (e=3,600); infrared absorption spectrum (in Nujol): 11 1739 cm.

From the more polar eluates of the chromatogram and the crystallization mother liquors of the A -17-epi-O-acetyl- 1-demethyl-2l-deoxy-ajmaline, a mixture consisting mainly of 17-epi-O-acetyl-2l-deoxy-2 hydroxy-ajmaline contaminated with some A -17-epi-O-acetyl-l-demethyl-Zldeoxy-ajamalinecan be obtained.

The starting material used in the above example is prepared as follows:: A mixture of 3.0 g. of 2l-deoxy-ajmamine and 4.1 g. of fluorenone is dried under reduced pressure in a round-bottomed flask while stirring with a magnetic stirrer. About 4 g. of freshly sublimed potassium teritary butoxide is added, followed by 500 ml. of dry benzene and the reaction vessel is flushed with dry nitrogen. The solution is refluxed for 45 minutes, then cooled and treated with dilute sulfuric acid. The yellow solution is extracted with an excess of dilute sulfuric acid, the acid solution is made basic with a concentrated aqueous solution of sodium hydroxide and extracted with methylene chloride. After drying, the solvent is removed and the residue is crystallized from acetone to yield the 17,21- dideoxy-17-oxo-ajmaline, M.P. l54-l56; [a] =-I350 (in chloroform); infrared absorption spectrum (in Nujol): u 1735 cm.- yield: 2.54 g.

A mixture of 2.0 g. of 17,21-dideoxy-17-oxo-ajmaline and 2.0 g. of sodium borohydride in 80 ml. of ethanol is stirred at room temperature for about 16 hours. Water is added, the organic material is extracted with methylene chloride and the residue from the organic solution is crystallized from methanol to yield 1.21 g. of 21-deoxy-l7-epiajmaline, M.P. 262264; [a] =+347 (in chloroform).

A solution of 0.2 g. of 21-deoxy-17-epi-ajmaline in an excess of acetic acid anhydride and pyridine is allowed to stand at room temperature overnight. The solvent is evaporated, the residue is chromatographed on neutral aluminum oxide, and the desired 17-epi-O-acetyl-21-deoxy-ajmaline, M.P. l68-169 [a] =-|178 (chloroform), is eluated with benzene.

1 0 Example 4 To a solution of 0.5 g. of 17-0-acetyl-2l-deoxy-ajmaline and 0.76 g. of lead tetraacetate (1.1 g. equivalent) in 20 m1. of benzene is stirred at room temperature for seventy minutes. The solution is washed with 50 ml. of water, and the aqueous washing is brought to pH 7 by adding a 10 percent aqueous solution of sodium hydroxide. The resulting precipitate is filtered oil, the filtrate is extracted with methylene chloride to yield 0.094 g. of an amorphous residue, the infrared spectrum of which is identical with that of 17-O-acetyl-2-hydroxy-2l-deoxyajmaline (Example 1) containing some A -l7-O-acetyl-1- demethyl-Zl-deoxy-ajmaline (Example '1).

Example 5 A solution of 1.0 g. of 2l-deoxy-ajmaline in 25 ml. of acetic acid anhydride is refluxed for a short period and is then cooled and treated with 1.57 g. of lead tetraacetate (1 equivalent); the reaction mixture is stirred for one hour at room temperature and then filtered. The filtrate is evaporated to dryness, and the residue is chromatographed on neutral aluminum oxide (Activity III). A total of 0.952 g. of residue is collected from the benzene (150 ml.) and methylene chloride (200 ml.) eluates, which is again chromatographed on basic aluminum oxide (Activity 111). A total of 0.23 g. is eluted with a 1:1- mixture of hexane and benzene, 0.383 g. with benzene and 0.244 g. with a 1:1-mixture of benzene and methylene chloride. The amorphous benzene eluate has an infrared spectrum which is identical with that of 17-0- acetyl-21-deoxy-2-hydroxy-ajmaline (Example 1) and crystallizes from a mixture of diethyl ether and hexane to yield 0.064 g. of the crystalline product, M.P. 8595; [u] =98.4 (in methanol).

Example 6 Over a period of two minutes, 99.5 g. of lead tetraacetate is added to 18.8 g. of 17-O-acetyl-2l-deoxy-ajmaline in 1500 ml. of benzene, and stirring is continued for an additional hour. The reaction mixture is filtered through neutral aluminum oxide (Activity III); a total of 18.14 g. is eluted with 2500 ml. of benzene, which is crystallized from diethyl ether to yield the desired A -17-O- acetyl-1-demethyl-2l-deoxy ajmaline, which is identical with the product obtained according to the procedure of Example 1. From the crystallization mother liquors an additional 0.234 g. of the desired product can be isolated, and upon rechromatographing the crystallization mother liquor a further amount of 2.4 g. of the A -17-O-acetyl-ldemethyl-Zl-deoxy-ajmaline can be obtained.

Example 7 To a solution of 8.07 g. of crude 17-O-acetyl-2l-deoxy- Z-hydroxy-ajmaline in benzene is added 32.4 g. of lead tetraacetate (3 equivalents), the solution is stirred for twenty minutes, and then filtered through a column containing neutral aluminum oxide (Activity III). The material eluted with 450 m1. of a 1:4-mixture of methylene chloride and benzene yields the A -17-O-acetyl-l-demethyl-2l-deoxy-ajmaline, M.P. 182-183; yield: 41 percent, Which is identical with the product obtained according to the procedure of Example 1.

Example 8 To a solution of 2.22 g. of 17-epi-O-acetyl-21-deoxyajmaline in ml. of benzene is treated with 11.73 g. of lead tetraacetate; the reaction is maintained at room temperature for one hour. The solution is then filtered through a column of neutral aluminum oxide (Activity III), and the combined eluates with benzene and methylene chloride yield 3.32 g. of a residue which is chromatographed on neutral aluminum oxide (Activity III). The material eluated with mixtures of benzene and methylene chloride and with methylene chloride is crystallized from diethyl ether to yield 0.63 g. of A -17-epi-O-acetyl-1-deareas-12a 11 methyl-2l-deoxy-ajrnaline, M.P. 206-207", which is identi cal with the product obtained according to the procedure described in Example 3.

Example 9 A mixture of 0.99 g. of crude 17-cpi-O-acetyl-21-deoxy- 2-hydroxy-ajmaline (Example 3) in benzene and 3.74 g. of lead tetraacetate is stirred at room temperature for thirty minutes. The reaction mixture is filtered through a column of neutral aluminum oxide (Activity III); 0.195 g. of a residue is eluted with 50 ml. of a lzl-mixture of benzene and methylene chloride and crystallized from diethyl ether to yield 0.118 g. of A -17-epi-O-acetyl-1- demethyl-2l-deoxy-ajmaline, which is identical with the product obtained according to the procedures described in Examples 3 and 8.

Example A solution of 2.12 g. of 17,21-dide0xy-ajrna1ine in 100 ml. of benzene is treated at room temperature with 12.8 g. of lead tetraacetate; the reaction is maintained for ninety minutes and the solution is then filtered through a column of neutral aluminum oxide (Activity III). The first eulate with 100 ml. of benzene yields 0.463 g. of the A -1-dernethyl-17,2l-dideoxy-ajmaline, M.P. 188189, when crystallized from diethyl ether, while the subse quent benzene and methylene chloride eluates are rechromatographed to yield an additional amount of the desired product, which is identical with the compound re sulting from the procedure described in Example 2.

Example 11 A mixture of 1.05 g. of 17,21-dideoxy-ajmaline in 60 ml. of benzene and 1.73 g. of lead tetraacetate (1 equivalent) is stirred at room temperature for thirty minutes, and is then filtered first through a paper filter and then through a column of neutral aluminum oxide (Activity 111). The material eluted with 600 ml. of benzene is crystallized from a mixture of methanol and water yielding 0.259 g. of 17,21-dideoxy-2-hydroxy-ajmaline, M.P. 87-89", which is identical with the product obtained according to the procedure described in Example 2.

Example 12 A soltuion of 4,27 g. of 17,2l-di-O-acetyl-ajmaline in 150 ml. of benzene is concentrated to a volume of about 100 ml. and 19.2 g. of lead tetraacetate (4 equivalents) are added; the reaction mixture is stirred at room temperature for ninety minutes and is then filtered through a column containing neutral aluminum oxide (Activity III). The benzene and methylene chloride eluates are rechromatographed on neutral aluminum oxide (Activity 11), and the fractions eluted with 800 ml. of a 1: l-mixture of benzene and hexane, 400 ml. of benzene and 200 ml. of a lzl-mixture of benzene and methylene chloride are combined and crystallized from diethyl ether yielding A 17,21 di O acetyl 1 demethyl-ajmaline of the formula which melts at 154161; [a] =+2Z.2 (in methanol). The starting material used in the above procedure is described by Anet et al., J. Chem. 800., page 1242 (1954).

Example 13 A mixture of 10.27 g. of 17,2l-di-Oacetyl-ajmaline in 800 ml. of benzene and 46.5 g. of lead tetraacetate (4 equivalents) is stirred at room temperature for thirty minutes and is then filtered through a column containing neutral aluminum oxide (Activity III) to yield with a total of 2,800 ml. of benzene three fractions of residue weighing a total of 10.4 g. The first fraction yields 0.696 g. of A 17,21 di O acetyl 1 demethyl ajmaline, M.P. l63-164 (see Example 12). The remaining fractions and the crystallization mother liquor of the first fraction are combined and chromatographed on neutral aluminum oxide (Activity II). The fractions eluted with benzene, mixtures of benzene and methylene chloride and methylene chloride yield 1.094 g. of A 17,21 di O- acetyl l demethyl ajmaline, M.P. -165. The material eluted with methylene chloride containing from 1 to 4 percent of methanol yield 3.01 g. of A 17 O- acetyl 1 demethyl ajmaline of the formula which melts at 240-242 after recrystallization from ethyl acetate; [a] =+18.7 (in methanol).

Example 14 A mixture of 14.0 g. of 17,21 di O acetyl isoajmaline in 1200 m1. of benzene and 42.2 g. of lead tetraacetate is stirred at room temperature for twenty minutes. An additional amount of 21.6 g. of lead tetra-acetate is added and stirring is continued for an additional hour. The solution is filtered through a column of neutral aluminum oxide (Activity III) and a residue of 13.69 g. is eluted with a total of 3,000 ml. of benzene. This material is rechromatographed on neutral aluminum oxide (Activity 11). The material (3.89 g.) eluted with benzene, mixtures of benzene and methylene chloride, and methylene chloride represents amorphous A 17,21 di- O-acetyl-l-demethyl-isoajmaline of the formula which melts at 242-243 after recrystallization from a mixture of ethanol and diethyl ether.

The starting material used in the above procedure is described by Anet et al., 100. cit.

Example 15 A mixture of 1.19 g. of A 17 O acetyl 1 demethyl-21-deoxy-ajmaline and 0.33 g. of platinum oxide in 70 ml. of methanol is shaken for 2% hours in a hydrogen atmosphere under a pressure of about 3.3 atmos- 13 pheres. The catalyst is filtered 01f, the solvent is evaporated, and the residue is chromatographed on neutral aluminum oxide. The fraction (1.05 g.) eluted with methylene chloride yields the 17 O acetyl l demethyl-Zl-deoxy-Z-epi-ajmaline of the formula CH2CH3 which melts at 144-145 upon crystallization from a mixture of diethyl ether and hexane and at 145146 after sublimation; [a] =+3 (in a 5:3 mixture of methanol and chloroform); ultraviolet absorption spectrum (in ethanol): A 242 m (e=6,700), 292 m (e=2,600); and A 222 m (5:2,900), 265 m (6 670).

Example 16 A mixture of 0.39 g. of A l demethyl 17,21 dideoxy-a 'maline and 0.2 g. of platinum oxide in 50 ml. of methanol is shaken for two hours in a hydrogen atmosphere under a pressure of about 3.4 atmospheres. The reaction mixture is worked up as described in Example 15; 0.26 g. of a material is eluted with benzene and is crystallized from a mixture of diethyl ether and diisopropyl ether to yield the l-demethyl-17,21-dideoxy-2-epiajmaline of the formula CH2CH3 which melts at 84-89.

Example 17 A mixture of 1.762 g. of A -17-O-acetyl-1-demethylajmaline and 0.4 g. of platinum oxide in 150 ml. of methanol is shaken for eight hours in hydrogen under a pressure of 3.5 atmospheres. The catalyst is removed, the solvent is evaporated and the residue is chromatographed on neutral aluminum oxide (Activity III). A total of 0.79 g. of the amorphous 17-O-acetyl-l-dernethyl-Z-epiajmaline of the formula is eluted with 300- ml. of a mixture of benzene and methylene chloride, 450 ml. of methylene chloride and 300 ml. of methylene chloride containing 1 percent methanol.

Example 18 A mixture of 0.54 g. of A -17,2l-di-O-acetyl-1-demeth yl-ajmaline and 0.55 g. of platinum oxide in '50 ml. of methanol is shaken in hydrogen under a pressure of 3 atmospheres. After 18 hours the reaction is interrupted, the catalyst is filtered off, the solvent is evaporated, and the residue is chromatographed on neutral aluminum oxide (Activity Ill). The material eluted with 100 ml. of methylene chloride is crystallized from diethyl ether yielding 0.113 g. of 17,2l-di-O-acetyl-1-demethyl-2-epiajmaline of the formula H C-OC-O 3 CH on N -C0-CH N g 3 H H CH CH which melts at 200-202 after recrystallization from a mixture of methylene chloride and diethyl ether; [a] =|30.82 (methanol).

Example 19 A mixture of 1.61 g. of 17-O-acetyl-l-demethyl-Zl-deoxy-2-epi-ajmaline and 20 ml. of a 4 N aqueous solution of sodium hydroxide in 50 ml. of methanol is refluxed for two hours and a part of the solvent is evaporated. The residue is extracted with methylene chloride, the solvent is evaporated, and the residue is crystallized from diethyl ether yielding the 1-demethyl-2l-deoxy-Z-epiajarnaline, which melts at 209-2l0 after recrystallization from a mixture of ethanol and diethyl ether; [a] =+94.3 (in chloroform).

Example 20 A mixture of 0.79 g. of l7-O-acetyl-l-dernethyl-Z-epiajmaline and an excess of 10 N aqueous sodium hydroxide in 25 ml. of methanol is refluxed for two hours. The solvent is partly evaporated, and the residue is extracted with methylene chloride. The organic solution is washed with water, dried over sodium sulfate and evaporated to yield 0.52 g. of a residue which crystallizes from ethanol to yield the desired 1-demethyl-Z-epi-ajmaline, M.P. 189- 191"; [a] =-+84.2l (in methanol).

Example 21 To a solution of 0.414 g. of A -17-O-acetyl-1-demethyl- 21-deoxy-2-epi-ajmaline in 4 ml. of methanol is added 5.0 ml. of methyl iodide while refluxing and maintaining an atmosphere of nitrogen. After 1 /2 hours, the solution is evaporated, and the desired A -17-O-acetyl-1-demethyl-2l-deoxy-ajmaline methiodide, M.P. 273274, is crystallized from ethanol, [a] =3.74 (methanol); yield: 0.38 g.

Example 22 To a solution of 0.051 g. of 17-O-acetyl-1-demethyl-2ldeoxy-Z-epi-ajmaline in 0.5 ml. of methanol is added 1 ml. of methyl iodide. After standing at room temperature for five minutes, the solvent is evaporated and the residue is crystallized from a mixture of ethanol and ethyl acetate to yield 0.054 g. of 17-O-acetyl-l-demethyl-2ldeoxy-2-epi-ajmaline methiodide, M.P. 28l283 (after recrystallization from a mixture of ethanol and ethyl acetate); [a] =2.72 (in methanol).

Example 23 Example 24 A mixture of 0.1 g. of 1-demethy1-2l-deoxy-Z-epiajmaline and 2 ml. of methyl iodide in 1 ml. of methanol is heated in a sealed tube at 110 for 18 hours. The solution is evaporated and the residue is crystallized from a mixture of ethanol and ethyl acetate to yield 21-deoxy-2- epi-ajmaline methiodide, M.P. 326328 after two recrystallizations from the above solvent mixture.

Two portions of 0.05 g. each of 21-deoxy-2-epi-ajmaline methiodide is pyrolized at 330 under reduced pressure. The resulting product is resublimed at 195 under reduced pressure and is then dissolved in methylene chloride. The solution is washed with dilute ammonium hydroxide, dried and concentrated to dryness. The residue is crystallized from a mixture of ethanol and ethyl acetate to yield 0.031 g. of 21-deoxy-2-epi-ajmaline of the formula it a I H CH3 Cl'igdlig which melts at 242243 after recrystallization from a mixture of theanol and ethyl acetate; [a] =9.6 (in a 5:2-mixture of methanol and chloroform).

Example 25 which melts at 208-211.

Example 26 To a solution of 0.101 g. of A -17-O-acetyl-1-demethyl- 21-deoxy-ajmaline in 5 ml. of methanol is added 2 ml. of a 2 N aqueous solution of sodium hydroxide. The result precipitate is filtered off and crystallized from methanol to yield 0.063 g. of l-demethyl-Zl-deoxy-ajmalal B of the formula CH CH which melts at 265-266; [a] =|12 (in pyridine).

Example 27 A solution of 0.42 g. of l-demethyl-2l-deoxy-ajmalal B in aqueous methanol is treated with an exces of sodium hero-hydride to yield 0.348 g. of l-demethyl-Zl-deoxyajmalol B by crystallization from methanol; the compound melts at 250-25 1 after two recrystallizations from ethanol.

1.6 What is claimed is: 1. Process for the preparation of a compound of the formula in which R, stands for a member selected from the group consisting of H(H) and OAc(H), in which Ac is lower alkanoyl, and R is a member selected from the group consisting of hydrogen, hydroxyl and lower alkanoyloxy, which comprises reacting a member selected from the group consisting of a compound of the formula --CHI I H II CH3 in which R and R have the previously-given meaning, and an acid addition salt thereof, with an oxidation reagent selected from the group consisting of lead tetraacetate, chromium trioxide, tetranitromethane, mercuric acetate, and potassium ferric cyanide, used in at least the amount necessary to cause the removal of four electrons from the starting material, and in a non-hydrolizing medium.

2. A member selected from the group consisting of a compound of the formula cn crt C CH in which R stands for a member selected from the group consisting of -H(H) and OAc(H), in which Ac is 17 lower alkanoyl, and R is a member selected from the group consisting of hydrogen, hydroxyl and lower alkanoyloxy, which comprises reacting a member selected from the group consisting of a compound of the formula in which R,, and R have the previously-given meaning thereof, with an oxidation reagent selected from the group consisting of lead tetraacetate, chromium trioxide, tetranitro-methane, mercuric acetate, and potassium ferric cyanide, used in about the amount necessary to cause the removal of two electrons from the starting material, and in a non-hydrolizing medium.

12. Process according to claim 1, which comprises using lead tetraacetate as the oxidizing reagent.

13. Process according to claim 1, which comprises using chromium trioxide as the oxidizing reagent.

14. A member selected from the group consisting of a compound of the formula N2 on N E N/ I 3 H CHQCHE,

in which R stands for a member selected from the group consisting of H(H) and OAc(H), in which Ac is lower alkanoyl, and R is a member selected from the group consisting of hydrogen, hydroxyl and lower alkanoyloxy, an acid addition salt and a lower alkyl quaternary ammonium compound thereof.

15. 17-O-acetyl-21-deoXy-2-hydroXy-ajmaline.

16. 17,21-dideoxy-2-hydroxy-ajmaline.

17. A member selected from the group consisting of a compound of the formula ca ca c on in which R,, stands for a member selected from the group consisting of H(H) and --OAc(H), in which Ac is lower alkanoyl, and R is a member selected from the group consisting of hydrogen, hydroxy and lower alkanoyloxy, which comprises reacting a member selected from the group consisting of a compound of the formula in which R, and R have the previously-given meaning, and an acid addition salt thereof, with an oxidation reagent selected from the group consisting of lead tetraacetate, chromium trioxide, tetranitromethane, mercuric acetate, and potassium ferric cyanide, used in at least the amount necessary to cause the removal of two electrons from the starting material, and in a non-hydrolyzing medium.

References Cited in the file of this patent UNITED STATES PATENTS 2,786,843 Huebner Mar. 26, 1957 2,977,365 Weisenborn et a1. Mar. 28, 1961 2,986,562 Huebner May 30, 1961 OTHER REFERENCES Richters Organic Chemistry, Elsevier Publishing Co., vol. IV, New York (1947), pages 62 and 65.

Anet et al.: Jour. Chem. Soc. (1954), page 1242.

Theilheimer: Syn. Methods of Organic Chemistry, vol. 9 (1955), page 407.

Wenkert et al.: Jour. Amer. Chem. Soc., vol. 79 (1957), pages 1519 and 1520.

Siddiqui et al.: Pakistan Jour. Sci. Ind. Res. (1959), pages 88 and 89.

Bartlett et al.: Jour. Amer. Chem. Soc., vol. 82 (1960), pages 3792-3793.

Kobayashi: Chemical Abstracts, vol. pages 18517 and 18518, QD1.A51.

Franck: Naturwissenschaften, vol. 47 (1960), page 174, Q 3.N7.

Gosset et al.: Bull. Soc. Chim. Fr. (1961), pages 1033-1035, QD LS4.

UNITED STATES PATENT ormen CERTIFICATE G CORRECTION Patent No, 3 133 929 May 19, 1964 Merrill Frederick Bartlett It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column l8 lines 9 to 17 for that portion of the formula i N read reading same column 18 lines 24 to 32 the formula should appear as shown below instead of as in the patent:

JH CH Signed and sealed this 22nd day of September 1964;

(SEAL) Attest:

ERNEST W0 SWIDER EDWARD JO BRENNER Attesting Officer Commissioner of Patents

Claims (2)

1. 2. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUND OF THE FORMULA
2. 14. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA