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Preparation of Crystalline Pilocarpine Methiodide
Preparation of Crystalline Pilocarpine Methiodide By NORBERT J. WOJCIECHOWSKI and BERNARD ECANOW A method for preparing crystalline pilocarpine methiodide is reported. Pilocarpine hydrochloride is converted t o isopilocarpine hydrochloride i n good yields by a convenient method. A comparison of the melting points, mixed melting points, and optical rotation data of pilocarpine methiodide and isopilocarpine methiodide show them to be different substances and not interconverted in the synthetic procedure developed.
T
of pilocarpine me thiodide has been reported by a number of workers. The salt has always been reported in the literature as an oil which could not be crystallized (1-3). The stereoisomer of pilocarpine, isopilocarpine, is reported in the literature as the crystalline methiodide salt with a meIting point of 114". A method for preparing the crystalline pilocarpine methiodide is reported in this paper. The preparation of pilocarpine methiodide required five weeks in the first synthesis, during which period it might have converted to the stereoisomer. The stereoisomer, isopilocarpine methiodide, was prepared and the two methiodide derivatives compared. A convenient method for converting pilocarpine hydrochloride t o isopilocarpine hydrochloride in good yield is also reported. HE PREPARATION
EXPERIMENTAL
Preparation of b-(Hydroxymethy1)-a-ethyl- 1,3-dimethyl Imidazolebutyric Acid Lactone Iodide (Methyl Pilocarpinium Iodide or Pilocarpine Methiodide).-In order to obtain pilocarpine base for the alkylation, a sample of pilocarpine hydrochloride U. S. P., Mallinckrodt, weighing 6.99 Gm. was dissolved in distilled water, the solution made alkaline, and extracted with portions of chloroform until the aqueous solution gave a negative Helch test. The combined chloroform solutions were washed with distilled water, filtered, and concentrated by evaporation until a limp oil remained. Methyl iodide ( 5 ml.) was added to the flask and the stoppered flask allowed to stand twelve hours. Twenty five milliliters of absolute alcohol was added to the flask and enough ether was then added, with swirling, until the solution became permanently turbid. The stoppered flask was then placed in a refrigerator for five hours. The supernatant liquid was then decanted from a precipitated yellow oil. The yellow oil was dissolved in alcohol and reprecipitated with the addition of ether and cooling in a refrigerator. This procedure was repeated for a total of five times. The yellowish oil was then collected in a glass vial and the vial placed in warm water t o drive off the residual ether. The capped vial was stored in a vacuum desiccator over Drierite and protected from light. A re-examination of the product after five weeks showed that the oil had changed to a solid yellowish mass resembling yellow wax. The thin material on the sides of the vial appeared crystalline. Scraping the solid with a spatula yielded a yellowishwhite granular material with a melting point of 121-123". Some of the solid was saved to be used as seed crystals. Received November 25, 1960, from the College of Pharmacy, University of Illinois, Chicago. Accepted for publication February 9. 1961.
The remainder of the solidified mass was dissolved in alcohol, the solution decolorized with Norit A, and filtered. Ether was added until the point of first turbidity and the solution placed in the freezing compartment of a refrigerator. Within a n hour there was precipitation of a light yellow oil which settled t o the bottom of the flask. A few seed crystals were added to the solution and crystal growth was initiated. When the crystals fell into the Collected oil i t also became crystalline. After crystallization was complete (no further turbidity upon the addition of more ether) the crystals were collected on a Biichner funnel. These crystals had a melting point of 122-124O. When the synthesis was repeated, it was found that the addition of a few seed crystals to the yellow oil rapidly induced crystallization without numerous purifications or prolonged storage of these batches. Yields of 87.4 to 90.0% were obtained. The material collected from the first synthesis was combined with the crystalline solid obtained from a second synthesis. The pooled sample was dissolved in absolute methanol and the solution treated with Norit A. The solution was filtered into an Erlenmeyer flask and anhydrous ether was added to the alcohol solution in small portions almost to the point of permanent turbidity and with no precipitation of oil droplets. A few seed crystals were added t o the flask and the clear solution was placed in a refrigerator. In twelve hours the precipitated white cubical crystals were collected on a Biichner funnel by means of vacuum filtration (water aspirator). The crystals were dried in a desiccator. The crystals had a melting point (Hoover-Thomas capillary melting point apparatus) of 122.5-125'. These crystals on microanalysis showed values of N, 8.08; I, 36.08%. The calculated values for methyl pilocarpinium iodide ( C I I H I ~ N ~ O ~ C are HSI) N, 8.88; I , 36.2470. Conversion of Pilocarpine Hydrochloride to Isopilocarpine Hydrochloride.-Ten grams of pilocarpine hydrochloride was weighed into a 100-ml. beaker and placed uncovered in a 200' oven. After two hours, the melted material was removed from the oven and allowed to cool. When cool, it formed a transparent, blackish-brown glass. The mass was dissolved in 25 ml. of warm absolute alcohol. The resulting yellow solution was decolorized with the use of Norit A and filtered. Ether was added to the cooled alcohol solution until a slight turliidity persisted. The beaker was covered and placed in the freezing compartment of a refrigerator. In twelve hours the white crystals that had formed were collected, redissolved in alcohol, and filtered. Ether was added to the filtrate until a permanent turbidity persisted. The flask was placed back in the refrigerator. In twelve hours the salt was collected on a Biichner funnel and the filtrate discarded.
887
Journal of Pharmaceutical Sciences
888 TABLE I.-SPECIFICROTATIONS
[m]'?&O
Concn., Gm.
Reported Literature V:lue, C.
4-62.08
4.027
New
4-25.26
3.998 26 (18)
Compound
Pilocarpinium methyl iodide Isopilocarpinium methyl iodide
The crystals were washed with several small portions of ether and then placed in a desiccator overnight. The melting point of the crystals was 120123". The melting point of pure, air-dried isopilocarpine hydrochloride as reported by Jowett ( 3 ) is 127'. He also reports that isopilocarpine hydrochloride contains a one-half mole of water of crystallization, and when dried to constant weight at 110" the melting point of the anhydrous salt is 159".
The isopilocarpine hydrochloride obtained was placed in a 110' oven and dried for three and onehalf hours. The melting range of the dried salt was 155-158". The material was used for the preparation of the methiodide. Preparation of Methyl Isopilocarpinium 1odide.The procedure followed was essentially that used to prepare the methyl pilocarpinium iodide. Recrystallization from alcohol gave white needle crystals with a melting point of 112-114" (reported melting point 114"). Optical Rotations.-The specific rotations of the two compounds were determined by measurement in a polarimeter with water as the solvent at 20". The results are shown in Table I. REFERENCES (1) Jowett, H. A. D., J. Chem. Soc., 77,473(1900) (2) [ b i d . , 77,851(1900). (3) I b i d . . 87,794(1905).
Exhaustive Methylation of Glucosamine By NORBERT J. WOJCIECHOWSKI, RALPH DANIELS, and BERNARD BCANOW
A reported synthesis of a glucosamine quaternary derivative was investigated by chemical and infrared spectra methods. Under the conditions reported the glucosamine was found to become degraded and tetramethylammonium iodide was formed. of the chemistry of the a publication by Ellis and Honeyman (1). Additional articles may be found in Pigman's text (2) and in the publication by Kent and Whitehouse (3). An interest in the preparations of unsubstituted -0-quaternary derivatives of glucosamine prompted an investigation into the procedure reported by Coles and Bergeim (4). N EXCELLENT REVIEW
A glycosylamines appears in
EXPERIMENTAL
The procedure followed for the synthesis of a glucosamine quaternary derivative was that reported by Coles and Bergeim (5). The synthesis was repeated five times to enable the close observation of experimental conditions and reactions. Analysis and Summary of Experimental Procedure.-The action of methyl iodide and potassium hydroxide upon glucosamine under the conditions reported results in the formation of a compound with a high decomposition point. Under the conditions of the reaction, potassium iodide is one of the products formed. It is coprecipitated with the product and is therefore a contaminant which is removed only after much processing. The explanation proReceived November 18, ISGO, from the College of Pharmacy, Chicago Professional Colleges of the University of Illinois. Chicaeo. Accepted forlpublication December 28, 1960. Abstracted from a thesis submitted by Norbert J. Wojciechowski to the Graduate College of the University of Illinois in Chicago in partial fulfillment of the requirements for the degree of Master of Science, 19Gl. ~
posed by Coles and Bergeim for the increased percentage of iodine over the calculated theoretical value is unsatisfactory on the basis of additional microanalytical work. And-Calcd. for C9HzoINO6: C, 30.96; H , 5.77; I, 36.35; N, 4.01; 0, 22.91. Found (4, 5): C, 23.89, 24.03; H, 5.62, 6.09; I, 62.90, 62.90; N, 7.16, 6.65. The iodine values compare with those reported by these authors, 61.71% (Paar bomb), 61.39% (gravimetric), but are well in excess of the theoretical values for a glucosamine derivative. Inspection of the microanalytical results show the absence of any oxygen and therefore does not support the existence of a glucosamine derivative which would contain 22.91% oxygen. An average of the analytical results obtained indicates an atomic ratio of 1 nitrogen, 4 carbon, and 12 hydrogen atoms for each iodine atom, or 1 iodine, 4 carbon and 12 hydrogen atoms for each nitrogen atom, giving an empirical formula of CaHlzIN. The iodine appears t o be ionic; the compound is soluble in water and insoluble in ether. This would satisfy the general characteristics for a quaternary salt. A quaternary salt having the empirical formula CaH12IN could be represented by tetramethylammonium iodide, ( CH3)4NI. Tetramethylammonium iodide has a reported density of 1.84. A few crystals placed in carbon tetrachloride, density 1.59, sink to the bottom of the test tube but float on the surface of ethyl iodide, density 1.95.
T
of pilocarpine me thiodide has been reported by a number of workers. The salt has always been reported in the literature as an oil which could not be crystallized (1-3). The stereoisomer of pilocarpine, isopilocarpine, is reported in the literature as the crystalline methiodide salt with a meIting point of 114". A method for preparing the crystalline pilocarpine methiodide is reported in this paper. The preparation of pilocarpine methiodide required five weeks in the first synthesis, during which period it might have converted to the stereoisomer. The stereoisomer, isopilocarpine methiodide, was prepared and the two methiodide derivatives compared. A convenient method for converting pilocarpine hydrochloride t o isopilocarpine hydrochloride in good yield is also reported. HE PREPARATION
EXPERIMENTAL
Preparation of b-(Hydroxymethy1)-a-ethyl- 1,3-dimethyl Imidazolebutyric Acid Lactone Iodide (Methyl Pilocarpinium Iodide or Pilocarpine Methiodide).-In order to obtain pilocarpine base for the alkylation, a sample of pilocarpine hydrochloride U. S. P., Mallinckrodt, weighing 6.99 Gm. was dissolved in distilled water, the solution made alkaline, and extracted with portions of chloroform until the aqueous solution gave a negative Helch test. The combined chloroform solutions were washed with distilled water, filtered, and concentrated by evaporation until a limp oil remained. Methyl iodide ( 5 ml.) was added to the flask and the stoppered flask allowed to stand twelve hours. Twenty five milliliters of absolute alcohol was added to the flask and enough ether was then added, with swirling, until the solution became permanently turbid. The stoppered flask was then placed in a refrigerator for five hours. The supernatant liquid was then decanted from a precipitated yellow oil. The yellow oil was dissolved in alcohol and reprecipitated with the addition of ether and cooling in a refrigerator. This procedure was repeated for a total of five times. The yellowish oil was then collected in a glass vial and the vial placed in warm water t o drive off the residual ether. The capped vial was stored in a vacuum desiccator over Drierite and protected from light. A re-examination of the product after five weeks showed that the oil had changed to a solid yellowish mass resembling yellow wax. The thin material on the sides of the vial appeared crystalline. Scraping the solid with a spatula yielded a yellowishwhite granular material with a melting point of 121-123". Some of the solid was saved to be used as seed crystals. Received November 25, 1960, from the College of Pharmacy, University of Illinois, Chicago. Accepted for publication February 9. 1961.
The remainder of the solidified mass was dissolved in alcohol, the solution decolorized with Norit A, and filtered. Ether was added until the point of first turbidity and the solution placed in the freezing compartment of a refrigerator. Within a n hour there was precipitation of a light yellow oil which settled t o the bottom of the flask. A few seed crystals were added to the solution and crystal growth was initiated. When the crystals fell into the Collected oil i t also became crystalline. After crystallization was complete (no further turbidity upon the addition of more ether) the crystals were collected on a Biichner funnel. These crystals had a melting point of 122-124O. When the synthesis was repeated, it was found that the addition of a few seed crystals to the yellow oil rapidly induced crystallization without numerous purifications or prolonged storage of these batches. Yields of 87.4 to 90.0% were obtained. The material collected from the first synthesis was combined with the crystalline solid obtained from a second synthesis. The pooled sample was dissolved in absolute methanol and the solution treated with Norit A. The solution was filtered into an Erlenmeyer flask and anhydrous ether was added to the alcohol solution in small portions almost to the point of permanent turbidity and with no precipitation of oil droplets. A few seed crystals were added t o the flask and the clear solution was placed in a refrigerator. In twelve hours the precipitated white cubical crystals were collected on a Biichner funnel by means of vacuum filtration (water aspirator). The crystals were dried in a desiccator. The crystals had a melting point (Hoover-Thomas capillary melting point apparatus) of 122.5-125'. These crystals on microanalysis showed values of N, 8.08; I, 36.08%. The calculated values for methyl pilocarpinium iodide ( C I I H I ~ N ~ O ~ C are HSI) N, 8.88; I , 36.2470. Conversion of Pilocarpine Hydrochloride to Isopilocarpine Hydrochloride.-Ten grams of pilocarpine hydrochloride was weighed into a 100-ml. beaker and placed uncovered in a 200' oven. After two hours, the melted material was removed from the oven and allowed to cool. When cool, it formed a transparent, blackish-brown glass. The mass was dissolved in 25 ml. of warm absolute alcohol. The resulting yellow solution was decolorized with the use of Norit A and filtered. Ether was added to the cooled alcohol solution until a slight turliidity persisted. The beaker was covered and placed in the freezing compartment of a refrigerator. In twelve hours the white crystals that had formed were collected, redissolved in alcohol, and filtered. Ether was added to the filtrate until a permanent turbidity persisted. The flask was placed back in the refrigerator. In twelve hours the salt was collected on a Biichner funnel and the filtrate discarded.
887
Journal of Pharmaceutical Sciences
888 TABLE I.-SPECIFICROTATIONS
[m]'?&O
Concn., Gm.
Reported Literature V:lue, C.
4-62.08
4.027
New
4-25.26
3.998 26 (18)
Compound
Pilocarpinium methyl iodide Isopilocarpinium methyl iodide
The crystals were washed with several small portions of ether and then placed in a desiccator overnight. The melting point of the crystals was 120123". The melting point of pure, air-dried isopilocarpine hydrochloride as reported by Jowett ( 3 ) is 127'. He also reports that isopilocarpine hydrochloride contains a one-half mole of water of crystallization, and when dried to constant weight at 110" the melting point of the anhydrous salt is 159".
The isopilocarpine hydrochloride obtained was placed in a 110' oven and dried for three and onehalf hours. The melting range of the dried salt was 155-158". The material was used for the preparation of the methiodide. Preparation of Methyl Isopilocarpinium 1odide.The procedure followed was essentially that used to prepare the methyl pilocarpinium iodide. Recrystallization from alcohol gave white needle crystals with a melting point of 112-114" (reported melting point 114"). Optical Rotations.-The specific rotations of the two compounds were determined by measurement in a polarimeter with water as the solvent at 20". The results are shown in Table I. REFERENCES (1) Jowett, H. A. D., J. Chem. Soc., 77,473(1900) (2) [ b i d . , 77,851(1900). (3) I b i d . . 87,794(1905).
Exhaustive Methylation of Glucosamine By NORBERT J. WOJCIECHOWSKI, RALPH DANIELS, and BERNARD BCANOW
A reported synthesis of a glucosamine quaternary derivative was investigated by chemical and infrared spectra methods. Under the conditions reported the glucosamine was found to become degraded and tetramethylammonium iodide was formed. of the chemistry of the a publication by Ellis and Honeyman (1). Additional articles may be found in Pigman's text (2) and in the publication by Kent and Whitehouse (3). An interest in the preparations of unsubstituted -0-quaternary derivatives of glucosamine prompted an investigation into the procedure reported by Coles and Bergeim (4). N EXCELLENT REVIEW
A glycosylamines appears in
EXPERIMENTAL
The procedure followed for the synthesis of a glucosamine quaternary derivative was that reported by Coles and Bergeim (5). The synthesis was repeated five times to enable the close observation of experimental conditions and reactions. Analysis and Summary of Experimental Procedure.-The action of methyl iodide and potassium hydroxide upon glucosamine under the conditions reported results in the formation of a compound with a high decomposition point. Under the conditions of the reaction, potassium iodide is one of the products formed. It is coprecipitated with the product and is therefore a contaminant which is removed only after much processing. The explanation proReceived November 18, ISGO, from the College of Pharmacy, Chicago Professional Colleges of the University of Illinois. Chicaeo. Accepted forlpublication December 28, 1960. Abstracted from a thesis submitted by Norbert J. Wojciechowski to the Graduate College of the University of Illinois in Chicago in partial fulfillment of the requirements for the degree of Master of Science, 19Gl. ~
posed by Coles and Bergeim for the increased percentage of iodine over the calculated theoretical value is unsatisfactory on the basis of additional microanalytical work. And-Calcd. for C9HzoINO6: C, 30.96; H , 5.77; I, 36.35; N, 4.01; 0, 22.91. Found (4, 5): C, 23.89, 24.03; H, 5.62, 6.09; I, 62.90, 62.90; N, 7.16, 6.65. The iodine values compare with those reported by these authors, 61.71% (Paar bomb), 61.39% (gravimetric), but are well in excess of the theoretical values for a glucosamine derivative. Inspection of the microanalytical results show the absence of any oxygen and therefore does not support the existence of a glucosamine derivative which would contain 22.91% oxygen. An average of the analytical results obtained indicates an atomic ratio of 1 nitrogen, 4 carbon, and 12 hydrogen atoms for each iodine atom, or 1 iodine, 4 carbon and 12 hydrogen atoms for each nitrogen atom, giving an empirical formula of CaHlzIN. The iodine appears t o be ionic; the compound is soluble in water and insoluble in ether. This would satisfy the general characteristics for a quaternary salt. A quaternary salt having the empirical formula CaH12IN could be represented by tetramethylammonium iodide, ( CH3)4NI. Tetramethylammonium iodide has a reported density of 1.84. A few crystals placed in carbon tetrachloride, density 1.59, sink to the bottom of the test tube but float on the surface of ethyl iodide, density 1.95.