ChemicalBook CAS DataBase List PILOCARPINE

PILOCARPINE synthesis

4synthesis methods

Product Name:PILOCARPINE
CAS Number:92-13-7
Molecular formula:C11H16N2O2
Molecular Weight:208.26

Pilocarpine, 3-ethyl-4-(1-methyl-5-imidazolymethyl)tetrahydrofuran-2-one (13.1.22), is an alkaloid that is made from leaves of the tropic plant Pilocarpus jaborandi. It is synthesized in a few different ways [25–32], the most relevant of which seems to be from 2-ethyl-3-carboxy-2-butyrolactone [25–27], which with the help of thionyl chloride is turned into the acid chloride (13.1.15) and further reacted with diazomethane and ethanol, to give the corresponding ethyl ester (Arndt–Eistert reaction), which is hydrolyzed into the acid (13.1.16). The resulting acid (13.1.16) is again changed into the acid chloride (13.1.17) by thionyl chloride. The obtained acid chloride is treated with diazomethane. But in this case the intermediate forming ketene is treated with hydrogen chloride to give the chloroketone (13.1.18). Reacting this with potassium phthalimide and subsequent removal of the phthalimide protecting group by acid hydrolysis gives the aminoketone (13.1.19), which is reacted with an acidic solution of potassium thiocyanate, forming 3-ethyl-4-(2- mercapto-5-imidazolylmethyl)tetrahydrofuran-2-one (13.1.20). Mild oxidation of this product allows to remove the mercapto- group from the product (13.1.20), giving 3-ethyl- 4-(5-imidazolylmethyl)tetrahydrofuran-2-one (13.1.21). Alkylation of the resulting product with methyl iodide leads to the formation of pilocarpine (13.1.22).

2(3H)-Furanone, 4-[(2,3-dihydro-3-methyl-2-thioxo-1H-imidazol-4-yl)methyl]-3-ethyldihydro-

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Yield:92-13-7 69.3 mg (84%)

Reaction Conditions:

with ammonium hydroxide;nitric acid;sodium nitrite in water

Steps:

1 Example 1
Example 1 0.10 g(0.40 mmol) of 3-ethyl-dihydro-4-[(1-methyl-1H-2-mercaptoimidazol-5-yl)methyl]-2(3H)-furanone and 0.3 ml (4.7 mmol) of concentrated nitric acid were added to 2.0 ml of water, and the mixture was stirred for 5 minutes under ice-cooling. To the mixture was added 42 mg(0.60 mmol) of sodium nitrite and the stirring was continued for additional 30 minutes. Then, the temperature of the mixture was raised to room temperature followed by stirring for further 2 hours. After the reaction was complete, the reaction mixture was made alkaline by adding 0.5 ml of 35% aqueous ammonia and extracted with 5 ml of chloroform. The chloroform extract was dried over anhydrous sodium sulfate and evaporated to give 69.3 mg (84%) of pilocarpine as white crystals. The crystals were dissolved in ethanol, filtrated to remove insolubles, 0.1 ml of concentrated hydrochloric acid added, and evaporated to give 77 mg (79%) of white crystals having a m.p. of 200-203°C. ¹H-NMR and mass spectrum (molecular ion peak at 208) of the crystals thus obtained are identical with those of the authentic sample pilocarpine hydrochloride.

References:

MITSUI PETROCHEMICAL INDUSTRIES, LTD. EP404175, 1990, A1

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