(S)-Timolol maleate CAS 26921-17-5

Introduction：Basic information about (S)-Timolol maleate CAS 26921-17-5, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

(S)-Timolol maleate Basic information

• Product Name: (S)-Timolol maleate
• Synonyms: 2-Propanol, 1-(1,1-dimethylethyl)amino-3-4-(4-morpholinyl)-1,2,5-thiadiazol-3-yloxy-, (2S)-, (2Z)-2-butenedioate (1:1) (salt);TIMOLOL HYDROGENMALEATE;TIMOLOL MALEATE;TIMOLOL MALEATE SALT;(S)-TIMOLOL MALEATE;(s)-3-[3-(tert-butylamino)-2-hydroxypropoxy]-4-morpholino-1,2,5-thiadiazole monomaleate;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
• CAS: 26921-17-5
• MF: C17H28N4O7S
• MW: 432.49
• EINECS: 248-111-5
• Product Categories: BLOCADREN;Active Pharmaceutical Ingredients;Adrenoceptor;26921-17-5
• Mol File: 26921-17-5.mol

(S)-Timolol maleate Chemical Properties

• Melting point: 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 Rotation: [α]25/D -5.4°, c = 4.9 in 1 M HCl(lit.)
• Water Solubility: H2O: soluble ethanol: soluble
• ε(extinction coefficient): 8,700 at 294nm at 1M
• Merck: 14,9444
• InChIKey: WLRMANUAADYWEA-NWASOUNVSA-N
• SMILES: C1(=NSN=C1OC[C@@H](O)CNC(C)(C)C)N1CCOCC1.C(/C(=O)O)=C/C(=O)O |&1:7,r|
• CAS DataBase Reference: 26921-17-5(CAS DataBase Reference)

Safety Information

• Hazard Codes: Xn,Xi
• Risk Statements: 22-63-36/37/38
• Safety Statements: 36-37/39-26
• WGK Germany: 3
• RTECS: UA8475000
• HS Code: 29349990
• Storage Class: 11 - Combustible Solids
• Hazard Classifications: Acute Tox. 4 Oral Repr. 2

(S)-Timolol maleate Usage And Synthesis

Description

Timolol is a non-selective β-adrenergic receptor antagonist with log K_d 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

betaadrenergic blocker

Uses

Antihypertensive; antiarrhythmic (class II); antianginal; antiglaucoma agent.

Uses

Anti hypertensive, Anti-glaucoma

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 aqueoussolution of tert-butylamine (1 mol) at ambient temperature, there is addedslowly and with vigorous stirring 2 mols bromoacetol. The reaction mixture isallowed to stand at ambient temperature for about 5 hours whereupon it ismade basic by the addition of sodium hydroxide.
The reaction mixture then is extracted with ether, the excess amine isremoved from the ethereal solution under reduced pressure and the etherthen removed by evaporation to give 3-tert-butylamino-2-oxopropanol.Step B: A solution of the 3-tert-butylamino-2-oxopropanol in a mixture ofpyridine 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 pyridineevaporated in vacuo at a temperature between 55° and 60°C. The aqueousresidue is treated with potassium carbonate and the mixture extracted withmethylene 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 methanolicsodium 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 theresidue 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 inisopropanol (10 ml). To the solution is added sodium borohydride in portionsuntil the initial evolution of heat and gas subsides. The excess sodiumborohydride is destroyed by addition of concentrated hydrochloric acid untilthe mixture remains acidic. The precipitate of sodium chloride is removed,ether is added, and the solution is concentrated to crystallization. The solidmaterial 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 (ashydrochloride).
Alternative Step D: Reduction with a Reductate - Sucrose (1 kg) is dissolvedin 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) andadded 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 anequimolar quantity of maleic acid in tetrahydrofuran]. The mixture is allowedto stand until fermentation subsides, after which the bottle is kept in a 32°Cincubator until all fermentation has ended (in approximately 1 to 3 days). Theyeast is filtered off with addition of diatomaceous earth and the filtrate isevaporated 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.

Clinical Use

Beta-adrenoceptor blocker:
Hypertension
Angina
Glaucoma
Migraine prophylaxis

Veterinary Drugs and Treatments

Timolol maleate is used primarily to prevent the development ofprimary glaucoma in the contralateral eye of a dog which has developedprimary glaucoma in one eye. It only reduces intraocularpressure 3 – 10 mmHg and, therefore is of minimal usefulness inpatients requiring treatment of primary acute congestive glaucoma.Timolol’s mechanism of action: decreases cyclic-AMP synthesis innon-pigmented ciliary epithelium resulting in decreased aqueoushumor production. It may also cause slight miosis in dogs and cats.Timolol maleate is rarely used alone but is combined with dorzolamidesolution (Cosopt?). Caution is advised with use of Betablocking agents in cats with concurrent asthma. As timolol maleateis now available in generic form, it is the primary Beta blocker agentnow used.

Drug interactions

Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: NSAIDs antagonise hypotensive effect.
Anti-arrhythmics: increased risk of myocardialdepression and bradycardia; increased risk ofbradycardia, myocardial depression and AV blockwith amiodarone; increased risk of myocardialdepression and bradycardia with flecainide.
Antidepressants: enhanced hypotensive effect withMAOIs.
Antihypertensives: enhanced hypotensive effect;increased risk of withdrawal hypertension withclonidine; increased risk of first dose hypotensiveeffect with post-synaptic alpha-blockers such asprazosin.
Antimalarials: increased risk of bradycardia withmefloquine.
Antipsychotics: enhanced hypotensive effect withphenothiazines.
Calcium-channel blockers: increased risk ofbradycardia and AV block with diltiazem;hypotension and heart failure possible withnifedipine and nisoldipine; asystole, severehypotension and heart failure with verapamil.
Cytotoxics: possible increased risk of bradycardiawith crizotinib.
Diuretics: enhanced hypotensive effect.
Fingolimod: possibly increased risk of bradycardia.
Moxisylyte: possible severe postural hypotension.
Sympathomimetics: severe hypertension withadrenaline and noradrenaline and possibly withdobutamine; also response to adrenaline may bereduced.

Metabolism

Timolol undergoes significant hepatic metabolism, but first pass metabolism is low. The metabolites are excreted in the urine with some unchanged timolol.

References

[1] G. TOSI. Biocatalytic Asymmetric Synthesis of (S)‐ and (R)‐Timolol.[J]. ChemInform, 2004, 116 49. DOI: 10.1002/chin.200445149
[2] De Souza, F.I., Zumiotti, A.V., and Da Silva, C.F. Neuregulins 1-α and 1-β on the regeneration the peripheral nerves[J]. Acta Ortop Bras.
[3] JIN-WEI CHENG. Intraocular pressure-lowering effects of commonly used fixed-combination drugs with timolol: a systematic review and meta-analysis.[J]. PLoS ONE, 2012: e45079. DOI: 10.1371/journal.pone.0045079
[4] NI LI MD. Travoprost compared with other prostaglandin analogues or timolol in patients with open-angle glaucoma or ocular hypertension: meta-analysis of randomized controlled trials[J]. Clinical and Experimental Ophthalmology, 2006, 34 8: 755-764. DOI: 10.1111/j.1442-9071.2006.01237.x

(S)-Timolol maleate Preparation Products And Raw materials

• Raw materials: tert-Butylamine-->Tosyl chloride-->Sodium borohydride-->Maleic acid