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26921-17-5

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Identification

Name
(S)-Timolol maleate
CAS
26921-17-5
Synonyms
(S)-1-[(1,1-DIMETHYLETHYL)AMINO]-3-[[4-(4-MORPHOLINYL)-1,2,5-THIADIAZOL-3-YL]OXY]-2-PROPANOL MALEATE
(s)-1-((1,1-dimethylethyl)amino)-3-((4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl)oxy)-2-propanol (z)-2-butenedioate (1:1)
S-(-)-1-[T-BUTYLAMINO]-3-[(4-MORPHOLINO-1,2,5-THIADIAZOL-3-YL)OXY]-2-PROPANOL MALEATE SALT
S[-]-1-[T-BUTYLAMINO]-3-(4-MORPHOLINO-1,2,5-THIADIAZOL-3-YL)OXY]-2-PROPANOL MALEATE SALT
(s)-3-[3-(tert-butylamino)-2-hydroxypropoxy]-4-morpholino-1,2,5-thiadiazole monomaleate
(S)-TIMOLOL MALEATE
TIMOLOL HYDROGENMALEATE
TIMOLOL MALEATE
TIMOLOL MALEATE SALT
(-)-1-(tert-butylamino)-3-((4-morpholino-1,2,5-thiadiazol-3-yl)oxy)-2-propan
(s)-timololhydrogenmaleate
1-(tert-butylamino)-3-((4-morpholino-1,2,5-thiadiazol-3-yl)oxy)-2-propano(
betime
l-timololmaleate
mk950
olmaleate
timacor
timoptic
TIMOLOL MALEATE USP
2-Propanol, 1-(1,1-dimethylethyl)amino-3-4-(4-morpholinyl)-1,2,5-thiadiazol-3-yloxy-, (2S)-, (2Z)-2-butenedioate (1:1) (salt)
EINECS(EC#)
248-111-5
Molecular Formula
C17H28N4O7S
MDL Number
MFCD00058356
Molecular Weight
432.49
MOL File
26921-17-5.mol

Chemical Properties

Melting point 
202-203 °C(lit.)

mp 
202-203 °C(lit.)

alpha 
24405 -12.0° (c = 5 in 1N HCl); D25 -4.2°
storage temp. 
2-8°C
solubility 
H2O: soluble

form 
powder

color 
white to off-white

optical activity
[α]25/D -5.4°, c = 4.9 in 1 M HCl(lit.)
Merck 
14,9444
InChIKey
WLRMANUAADYWEA-NWASOUNVSA-N
CAS DataBase Reference
26921-17-5(CAS DataBase Reference)

Safety Data

Hazard Codes 
Xn,Xi
Risk Statements 
R22:Harmful if swallowed.
R63:Possible risk of harm to the unborn child.
R36/37/38:Irritating to eyes, respiratory system and skin .
Safety Statements 
S36:Wear suitable protective clothing .
S37/39:Wear suitable gloves and eye/face protection .
S26:In case of contact with eyes, rinse immediately with plenty of water and seek medical advice .
WGK Germany 
3

RTECS 
UA8475000

HS Code 
29349990

Hazard Information

Description
Timolol is a non-selective β-adrenergic receptor antagonist with log Kd values of -8.27, -9.86, and -6.8 for binding to human β1-, β2-, and β3-adrenoceptors, respectively. It has been reported that only the (S) enantiomer contributes to the β-blocking effects of racemic timolol, but the weakly active (R) isomer maintains a beneficial effect on intraocular pressure without the undesirable side-effect of bronchial constriction caused by non-selective action of (S)-timolol on β1 and β2 receptors. Timolol has been use alone and in fixed combinations with either prostaglandin analogs or carbonic anhydrase inhibitors to reduce intraocular pressure in research models of ocular hypertension and glaucoma.
Chemical Properties
White Solid
Originator
Blocadren,MSD,UK,1974
Uses
Anti hypertensive, Anti-glaucoma
Uses
Antihypertensive; antiarrhythmic (class II); antianginal; antiglaucoma agent.
Uses
betaadrenergic blocker
Definition
ChEBI: The maleic acid salt of the active (S)-enantiomer of timolol, comprising equimolar amounts of (S)-timolol and maleic acid.
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
Biological Activity
β 1 -adrenergic blocker.
Veterinary Drugs and Treatments
Timolol maleate is used primarily to prevent the development of primary glaucoma in the contralateral eye of a dog which has developed primary glaucoma in one eye. It only reduces intraocular pressure 3 – 10 mmHg and, therefore is of minimal usefulness in patients requiring treatment of primary acute congestive glaucoma. Timolol’s mechanism of action: decreases cyclic-AMP synthesis in non-pigmented ciliary epithelium resulting in decreased aqueous humor production. It may also cause slight miosis in dogs and cats. Timolol maleate is rarely used alone but is combined with dorzolamide solution (Cosopt?). Caution is advised with use of Beta blocking agents in cats with concurrent asthma. As timolol maleate is now available in generic form, it is the primary Beta blocker agent now used.

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