26839-75-8

Basic information

• Product Name: Timolol
• Synonyms: (s)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]propan-2-ol;TIMOLOL;(-)-3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole;(s)-1-[1,1-dimethylethyl)amino]-3-[[4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy;(s)--3-yl]oxy];2-propanol,1-[(1,1-dimethylethyl)amino]-3-[[4-(4-morpholinyl)-1,2,5-thiadiazol;blocadren;s-(-)-3-(3-tert-butylamino-2-hydroxypropoxy)-4-morpholino-1,2,5-thiadiazole
• CAS NO: 26839-75-8
• Molecular Formula: C₁₃H₂₄N₄O₃S
• Molecular Weight: 316.42
• EINECS: 248-032-6
• Product Categories: Timolol
• Mol File: 26839-75-8.mol
• Article Data: 19

Chemical Properties

• Melting Point: 71.5-72.5 °C
• Boiling Point: 487.2 °C at 760 mmHg
• Flash Point: 248.5 °C
• Appearance: white crystalline powder
• Density: 1.224 g/cm³
• Vapor Pressure: 2.62E-10mmHg at 25°C
• Refractive Index: 1.548
• PKA: pKa ～9.2(H2O t = 25.0) (Uncertain)
• CAS DataBase Reference: Timolol(CAS DataBase Reference)
• NIST Chemistry Reference: Timolol(26839-75-8)
• EPA Substance Registry System: Timolol(26839-75-8)

Safety Data

• Hazardous Substances Data: 26839-75-8(Hazardous Substances Data)

Usage

Originator

Blocadren,MSD,UK,1974

Uses

Different sources of media describe the Uses of 26839-75-8 differently. You can refer to the following data:
1. Timolol is a nonselective β-adrenoblocker that prevents action of catecholamines. When used locally in the form of eye drops, intraocular pressure decreases. It is used for chronic open-angle glaucoma as well as closed-angle glaucoma.
2. Betimol(Sanofi Winthrop).
3. Timolol is a β-adrenergic blocker most commonly used to treat raised blood pressure; used to treat angina (pain from inadequate oxygen supply to the heart muscle); treatment of so me disturbances of heart rhythm; used to prevent migraine headaches; drops treat some types of glaucoma (raised pressure within the eye).

Manufacturing Process

Step A: Preparation of 3-tert-Butylamino-2-Oxopropanol - To an aqueous solution of tert-butylamine (1 mol) at ambient temperature, there is added slowly and with vigorous stirring 2 mols bromoacetol. The reaction mixture is allowed to stand at ambient temperature for about 5 hours whereupon it is made basic by the addition of sodium hydroxide. The reaction mixture then is extracted with ether, the excess amine is removed from the ethereal solution under reduced pressure and the ether then removed by evaporation to give 3-tert-butylamino-2-oxopropanol. Step B: A solution of the 3-tert-butylamino-2-oxopropanol in a mixture of pyridine hydrochloride and pyridine is treated with p-toluenesulfonylchloride. The mixture is stirred for 1/2 hour at 25° to 30°C and then poured into cold water. The solution is treated with potassium carbonate and the pyridine evaporated in vacuo at a temperature between 55° and 60°C. The aqueous residue is treated with potassium carbonate and the mixture extracted with methylene chloride. Evaporation of the dried extract provides 1- toluenesulfonyloxy-2-oxo-3-tert-butylaminopropane. Step C: Preparation of 3-Morpholino-4-(3-tert-Butylamino-2-Oxopropoxy)- 1,2,5-Thiadiazole - The 1-toluenesulfonyloxy-2-oxo-3-tert-butylaminopropane, prepared as described in Step B, (11 mols) is added to 0.80 N methanolic sodium methoxide (15 ml) at 0°C. The mixture is stirred for 15 minutes at 0° to 5°C, treated with 3-morpholino-4-hydroxy-1,2,5-thiadiazole (4.29 grams) and then refluxed for 16 hours. The solvent is evaporated in vacuo and the residue is treated with excess potassium carbonate to provide 3-morpholino- 4-(3-butylamino-2-oxopropoxy)-1,2,5-thiadiazole. Step D: Chemical Reduction Preparation of 3-Morpholino-4-(3-tert_x0002_Butylamino-2-Hydroxypropoxy)-1,2,5-Thiadiazole - The 3-morpholino-4-(3- tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole (0.01 mol) is dissolved in isopropanol (10 ml). To the solution is added sodium borohydride in portions until the initial evolution of heat and gas subsides. The excess sodium borohydride is destroyed by addition of concentrated hydrochloric acid until the mixture remains acidic. The precipitate of sodium chloride is removed, ether is added, and the solution is concentrated to crystallization. The solid material is removed by filtration and dried thus providing 3-morpholino-4-(3- tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole, MP 161° to 163°C (as hydrochloride). Alternative Step D: Reduction with a Reductate - Sucrose (1 kg) is dissolved in water (9 liters) in a 20-liter bottle equipped with a gas trap. Baker's yeast (Saccharomyces cerevisiae, 1 kg) is made into a paste with water (1 liter) and added to the sucrose solution with stirring. After lively evolution of gas begins (within 1 to 3 hours), 3-morpholino-4-(3-tert-butylamino-2-oxopropoxy)- 1,2,5-thiadiazole hydrogen maleate [1.35 mols, prepared by reaction of the 3- morpholino-4-(3-tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole with an equimolar quantity of maleic acid in tetrahydrofuran]. The mixture is allowed to stand until fermentation subsides, after which the bottle is kept in a 32°C incubator until all fermentation has ended (in approximately 1 to 3 days). The yeast is filtered off with addition of diatomaceous earth and the filtrate is evaporated to dryness to give S-3-morpholino-4β-tert-butylamino-2- hydroxypropoxy)-1,2,5-thiadiazole, MP 195° to 198°C (as hydrogen maleate), according to US Patent 3,619,370. Step E: The base may be converted to the maleate by maleic acid

Therapeutic Function

Antiarrhythmic, Antiglaucoma

Contact allergens

Timolol was implicated in allergic contact dermatitis due to beta-blocker agents in eyedrops.

Metabolism

Timolol (Timoptic) is almost completely absorbed from the gastrointestinal tract. Peak plasma levels occur 2 to 4 hours after oral administration; the plasma halflife of timolol is approximately 5.5 hours.The extensive tissue distribution of timolol into lung, liver, and kidney is similar to that of other -blockers. Approximately 70% of the drug is excreted in the urine within 24 hours, mostly as highly polar unconjugated metabolites. Only 6% of an administered dose is recovered in the feces. Although timolol is approved for the topical treatment of elevated intraocular pressure, there is limited information about its pharmacokinetics following administration by this route.The drug apparently can reach the systemic circulation after intraocular instillation, but plasma levels are only about 7% of those achieved in the aqueous humor.

InChI:InChI=1/C13H24N4O3S/c1-13(2,3)14-8-10(18)9-20-12-11(15-21-16-12)17-4-6-19-7-5-17/h10,14,18H,4-9H2,1-3H3/t10-/m0/s1

Upstream product

• 30165-97-0 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole 
• 45720-12-5 tert-butyl({[(2S)-oxiran-2-yl]methyl})amine 
• 30165-96-9 3-Morpholino-4-chloro-1,2,5-thiadiazole 
• 194861-99-9 ((2Ξ,5S)-3-tert-butyl-2-phenyl-oxazolidin-5-yl)-methanol 
• 29023-48-1 timolol 
• 58827-68-2 4-{4-[(2R/S)-oxiran-2-ylmethoxy]-1,2,5-thiadiazol-3-yl}morpholine 
• 75-64-9 tert-butylamine 
• 30315-46-9 (S)-1-tert-butylamino-2,3-dihydroxypropane 
• 26921-17-5 timolol maleate 
• 295776-81-7 (S)-3-[4-(N-morpholino)-1,2,5-thiadiazolyloxy]propane-1,2-diol 
• 935528-00-0 (2R)-1-chloro-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]propan-2-ol 
• 85665-60-7 (R,S)-5-(hydroxymethyl)-3-tert-butyloxazolidin-2-one 
• 69500-53-4 4-{4-[(2S)-oxiran-2-ylmethoxy]-1,2,5-thiadiazol-3-yl}morpholine 
• 507-19-7 t-butyl bromide 

Downstream Products

• 26921-17-5 timolol maleate 
• 1215295-18-3 1-(tert-butylamino)-3-(4-morpholino-1,2,5-thiadiazol-3-yloxy)propan-2-yl 4-(3-thioxo-3H-1,2-dithiol-4-yl)benzoate 
• 1058180-07-6 C₂₀H₃₈N₄O₆S 
• 30165-97-0 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole 
• 1167426-99-4 C₂₃H₃₃N₅O₉S 
• 1167426-97-2 C₂₃H₃₃N₅O₉S 
• 1167426-95-0 C₂₄H₃₅N₅O₉S 
• 1167426-93-8 C₂₄H₃₅N₅O₉S 
• 1167426-91-6 C₂₄H₃₄N₆O₁₂S 
• 1167426-87-0 C₂₃H₃₃N₅O₉S 
• 1167426-85-8 C₂₂H₃₁N₅O₈S 
• 1167426-83-6 C₂₂H₃₁N₅O₈S 

Relevant articles and documents

Biocatalytic asymmetric synthesis of (S)- and (R)-Timolol

A new biocatalytic route for the synthesis of both enantiomers of Timolol (1) is described. Starting from 3,4-dichloro-1,2,5-thiadiazole (2), (R)- and (S)-Timolol (87% ee) were obtained in 35% and 30% overall yield, respectively. Asymmetric reduction of the intermediate haloketone 5 with baker's yeast afforded the corresponding halohydrin 6 in the optically active form (87% ee), which gave the R enantiomer (distomer) of Timolol. The S enantiomer (eutomer) was obtained via inversion of configuration of the halohydrin following the Mitsunobu procedure.

An improved process of separation of R- and S-timolol

Diastereomeric timolol tartrates 4 are obtained in a one-pot synthesis from the racemic base 2 and optically active O,O-diacetyl- or O,O,- dibenzoyltartaric anhydrides 3, as only one of the diastereomers precipitates from acetone solution. Acidic hydrolysis as the corresponding 4 leads to timolol in high yield and optical purity.

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