827-61-2

Basic information

• Product Name: Aceclidine
• Synonyms: 1-AZABICYCLO[2.2.2]OCTAN-3-OL, ACETATE (ESTER);3-Acetoxyquinuclidine;3-Quinuclidinol acetate ester;3-Quinuclidinyl acetate;(3R)-1-Azabicyclo[2.2.2]oct-3-yl acetate;Aceclidine;Acetic acid 1-azabicyclo[2.2.2]octane-3-yl ester;Acetic acid quinuclidin-3-yl ester
• CAS NO: 827-61-2
• Molecular Formula: C₉H₁₅NO₂
• Molecular Weight: 169.2209
• EINECS: 212-574-1
• Mol File: 827-61-2.mol
• Article Data: 12

Chemical Properties

• Boiling Point: 298.52°C (rough estimate)
• Flash Point: 85 °C
• Appearance: /
• Density: 1.0873 (rough estimate)
• Vapor Pressure: 0.107mmHg at 25°C
• Refractive Index: 1.4780 (estimate)
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• PKA: 9.22±0.33(Predicted)
• CAS DataBase Reference: Aceclidine(CAS DataBase Reference)
• NIST Chemistry Reference: Aceclidine(827-61-2)
• EPA Substance Registry System: Aceclidine(827-61-2)

Safety Data

• Hazardous Substances Data: 827-61-2(Hazardous Substances Data)

Usage

Originator

Glacostat ,MSD-Chibret ,France ,1966

Manufacturing Process

A mixture of 274 g of methyl isonicotinate, 367 g of ethyl bromoacetate and 125 cc of ethyl alcohol was stirred without heating for 4 hours in a flask equipped with a reflux condenser. (The reaction was exothermic and precautions were taken to keep the temperature below 70°C.) The reaction mixture was then left for 15 hours at room temperature. The reaction product (1-carbethoxymethyl-4-carbornethoxy-pyridinium bromide) was obtained in crystalline form. (It formed prisms melting at 166- 169°C after recrystallization from a mixture of isopropanol and acetone.) It was not necessary to isolate it. For the following reduction step, the reaction mixture was brought into solution by the addition of about 1 liter of warm ethyl alcohol. It was then hydrogenated at about 30 atm pressure in the presence of 2 g of platinum oxide. The temperature rose during this reaction to about 40°C. After the calculated amount of hydrogen had been absorbed, the catalyst was filtered off, the solution was concentrated in vacuum, and the residual syrup was dissolved in ice water. Benzene was added and the mixture was made alkaline with an excess of concentrated ice cold potassium carbonate solution. The temperature was kept low by continuous addition of ice, and the benzene layer was separated and dried with sodium sulfate. The dried benzene solution was concentrated in vacuum and the residual oil was distilled in vacuum. BP 30 mm = 175-182°C, nD 25= 1.4613-1.4628. During the reduction, partial alcoholysis occurred, and the product isolated was 1- carbethoxymethyl-4-"carbalkoxy"-piperidine, wherein "carbalkoxy" represents a mixture of carbomethoxy and carbethoxy. 100 g of potassium were pulverized in 200 cc of hot toluene in a heated three-neck flask equipped with an efficient condenser, stirrer and dropping funnel. To the refluxing potassium suspension were added in small portions 229 g of the product of the previous step and about 700 cc of toluene. This addition had to be carried out very cautiously; the onset of the exothermic reaction is sometimes delayed. The addition was finished in about 1 hour. To complete the reaction, the refluxing and stirring were continued for about 4 hours. The reaction mixture was then cooled to about +5°C and about 50 cc isopropanol were added to decompose unreacted potassium. Then 2.5 liters of concentrated hydrochloric acid were added and the mixture was refluxed for 15 hours, and then concentrated in vacuum to dryness. To the residue was added with cooling an excess of 50% potassium hydroxide. Ether was then added and the resulting mixture was filtered through a fritted glass funnel, thus removing the precipitated potassium chloride. The ethereal and aqueous layers were separated, and the aqueous layer was extracted repeatedly with 500 cc portions of ether. The organic solutions were combined, dried over sodium sulfate and concentrated in vacuum. Aqueous hydrochloric acid was added to the residue until the solution became acid. The mixture was then diluted with distilled water to about 300 cc, heated with decolorizing charcoal, filtered and concentrated in vacuum to dryness. The residue was treated with isopropanol, and the precipitated crystalline product was filtered off. The product was recrystallized from a mixture of water and isopropanol and was identified as 1-azabicyclo[2.2.2]-3-octanone hydrochloride; prisms, MP 311- 313°C, with decomposition. A solution of 50 g of the above ketone-hydrochloride in 30 cc of water was made alkaline by the addition of 30 g of potassium hydroxide. After the alkali was dissolved, 35 g of granular potassium carbonate were added. The free basic ketone was then extracted from the viscous mixture by shaking with 4 portions of hot benzene (300 cc in each portion). The benzene extracts were decanted, filtered over sodium sulfate in order to remove any suspended alkali, and concentrated in vacuum. The residual lszabicyclo[2.2.2]-3-octanone was purified by sublimation (50-70°C/0.5 mm Hg); it can also be purified by recrystallization from petroleum ether. It formed feathery crystals melting at 147-148°C. The product was reduced as follows: A solution of 50 g of 1-azabicyclo[2.2.2]-3-octanone hydrochloride in 200 cc of water was hydrogenated at room temperature and 50 atm pressure with 1 g of platinum oxide as catalyst. After the calculated amount of hydrogen had been absorbed, the mixture was filtered and concentrated in vacuum to dryness. The residual product was recrystallized from a mixture of methanol and acetone and formed prisms melting above 300°C. It was identified as 1- azabicyclo[2.2.2]-3-octanol hydrochloride. A solution of 50 g of 1-azabicyclo[2.2.2]-3-octanol hydrochloride in 30 cc water was made alkaline with 30 g of potassium hydroxide. After the alkali was dissolved 35 g of granular potassium carbonate were added. The free basic alcohol was then extracted from the viscous mixture by shaking with four portions of boiling benzene (300 cc in each portion). The benzene extracts were decanted and filtered over anhydrous sodium sulfate, to remove any suspended alkali. The combined benzene solutions were concentrated in vacuum. The residue was recrystallized from benzene and identified as lszabicyclo[2.2.2]-3-octanol, MP 221-223°C. The product can also be purified by recrystallization from acetone, or by sublimation in vacuum (120°C/20 mm Hg). The alcohol was reacted with acetic anhydride to give the product aceclidine.

Brand name

Cholinergic Glaucostat (Kingshill Pharmaceuticals, Inc, Switzerland).

Therapeutic Function

Miotic, Cholinomimetic

Safety Profile

Poison by ingestion, subcutaneous,and intravenous routes. When heated to decomposition itemits toxic fumes of NOx.

InChI:InChI=1/C9H15NO2/c1-7(11)12-9-6-10-4-2-8(9)3-5-10/h8-9H,2-6H2,1H3/p+1/t9-/m0/s1

Upstream product

• 108-24-7 acetic anhydride 
• 1619-34-7 3-quinuclidinol 
• 34286-16-3 2-ethoxycarbonyl-3-quinuclidinone 
• 1838-39-7 ethyl N-ethoxycarbonylmethyl-4-piperidinecarboxylate 
• 1193-65-3 3-quinuclidinone hydrochloride 
• 76656-18-3 3-Acetoxy-1-(2-methyl-acryloyloxymethyl)-1-azonia-bicyclo[2.2.2]octane; chloride 

Downstream Products

• 41967-35-5 Br^(1-)*C₁₆H₂₂NO₂⁽¹⁺⁾ 
• 25333-42-0 (R)-quinuclidin-3-ol 
• 3684-26-2 (S)-quinuclidin-3-ol 
• 142999-61-9 (S)-N-(S)-1-Aza-bicyclo[2.2.2]oct-3-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-propionamide 
• 6530-09-2 (S)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride 
• 75447-69-7 1-p-methoxybenzoyloxymethyl-3-acetoxyquinuclidinium chloride 
• 75447-71-1 m-bromobenzoyloxymethyl-3-acetoxyquinuclidinium chloride 
• 75447-74-4 p-bromobenzoyloxymethyl-3-acetoxyquinuclidinium chloride 
• 73360-21-1 1-benzyl-3-acetoxyquinuclidinium chloride 
• 73360-13-1 1-<(benzyloxy)methyl>-3-acetoxyquinuclidinium bromide 
• 75447-75-5 p-nitrobenzoyloxymethyl-3-acetoxyquinuclidinium chloride 
• 73360-17-5 1-(phenylacetoxy)-3-acetoxyquinuclidinium chloride 
• 75447-72-2 m-nitrobenzoyloxymethyl-3-acetoxyquinuclidinium chloride 
• 75447-73-3 p-chlorobenzoyloxymethyl-3-acetoxyquinuclidinium chloride 

Relevant articles and documents

Preparation method of optical activity 3-quinuclidinol

The invention relates to an intermediate synthesis method, belongs to the field of organic synthesis, and particularly relates to a preparation method of optical activity 3-quinuclidinol with the advantages that the operation is simple and convenient, the cost is low, and the method is suitable for industrial production. An intermediate of 3-quinuclidinol is obtained by using 4-nipecotic acid as astarting material through esterification, nucleophilic substitution, Dieckmann condensation, decarboxylation, salification, reduction, acetylization, chemical resolution and the like. The reaction formula is shown in the description.

Stereoselective synthesis of the optical isomers of a new muscarinic receptor antagonist, quinuclidin-3-yl 2-(cyclopent-1-enyl)-2-hydroxy-2- phenylacetate

The enantiopure isomers of a new muscarinic receptor antagonist, quinuclidin-3-yl 2-(cyclopent-1-enyl)-2-hydroxy-2-phenylacetate were synthesised by a practical stereoselective synthetic method, using pivaldehyde as steric hindrance agent from the chiral starting material, (S) or (R)-mandelic acid. The isomers were obtained with 72-78% yields in 98-99% e.e.

A practical chemoenzymatic process to access (R)-quinuclidin-3-ol on scale

(±)-3-Butyryloxyquinuclidinium butyrate 6 (2 M, 571 g/L), prepared from (±)-quinuclidin-3-ol 1 and butyric anhydride, undergoes enantioselective hydrolysis by an Aspergillus melleus protease {1.0% (w/v)} in water in the presence of Ca(OH)2 to keep the reaction at pH 7 and trap butyric acid that is introduced as part of (±)-6 and generated by the enzymatic hydrolysis. After a 24 h period, extraction with n-heptane provides (R)-quinuclidin-3-yl butyrate 5a, which, on methanolysis with Na2CO3, is converted into (R)-1, a common pharmacophore of neuromodulators acting on muscarinic receptors, in 96% ee and 42% overall yield from (±)-1. The unwanted antipode (S)-1, which is extracted into n-butanol and purified via its hydrochloride salt in 89% ee and 40% overall yield from (±)-1, can be racemized by the catalysis of Raney Co at 140°C under an atmosphere of H2 (5 kg/cm2) to regenerate (±)-1 in 97% yield.