63659-18-7

Usage

Uses

Used in Cardiovascular Medicine:
Betaxolol is used as an antihypertensive agent for the treatment of high blood pressure. It works by blocking the β1 receptors in the heart, which reduces heart rate and cardiac output, leading to a decrease in blood pressure.
Used in Ophthalmology:
Betaxolol is used as an antiglaucoma medication for the treatment of open-angle glaucoma and ocular hypertension. It helps to lower intraocular pressure by reducing the production of aqueous humor in the eye, which is essential for maintaining a healthy eye pressure.
Used in Cardiology:
Betaxolol is used as a cardioselective β1-adrenergic blocker for the treatment of various cardiovascular conditions, such as angina pectoris, arrhythmias, and heart failure. By selectively blocking β1 receptors, it reduces the workload on the heart and improves its function, leading to better cardiovascular health.

Originator

Kerlone,Carriere,France,1983

Manufacturing Process

(1) 1 g of sodium hydroxide pellets (0.025 mol) is added to a suspension of 3.8 g of 4-[2-(cyclopropylmethoxy)-ethyl]-phenol in 30 ml of water. When the solution becomes homogenous, 2.3 ml of epichlorohydrin are added and the mixture is stirred for 8 hours. It is then extracted with ether and the extract is washed with water, dried over sodium sulfate and evaporated to dryness. The compound is purified by passing it over a silica column. 2.4 g of 1-[4-[2- (cyclopropylmethoxy)ethyl]-phenoxy]-2,3-epoxy-propane are thus obtained. (2) 4.9 g of the preceding compound (0.02 mol) are condensed with 25 ml of isopropylamine by contact for 8 hours at ambient temperature and then by heating for 48 hours at the reflux temperature. After evaporation to dryness, the compound obtained is crystallized from petroleum ether. 5 g (yield 80%) of 2-[[4-(2-cyclopropylmethoxy)-ethyl]-phenoxy]-3-isopropylaminopropan-2-ol are thus obtained, melting point 70° to 72°C. The hydrochloride is prepared by dissolving the base in the minimum amount of acetone and adding a solution of hydrochloric acid in ether until the pH is acid. The hydrochloride which has precipitated is filtered off and is recrystallized twice from acetone, melting point 116°C.

Therapeutic Function

Beta-adrenergic blocker

Biological Activity

betaxolol is a cardioselective beta-adrenergic receptor blocking agent. betaxolol (5 mg/kg via i.p. injection) was administered at 24 and then 44 h following the final chronic cocaine administration. animals treated with betaxolol during cocaine withdrawal

Veterinary Drugs and Treatments

Betaxolol HCl is a specific Beta1 adrenergic blocking agent which reduces aqueous humor production by decreasing cyclic-AMP synthesis in the ciliary body. This drug is a suitable substitute for timolol and because of its specific Beta1 activity, might be a first choice Beta blocking agent for patients with concurrent respiratory disease. Either levobunolol HCl or betaxolol HCl would be the first choice Beta blocking agent in a feline patient with glaucoma and asthma, although a topical carbonic anhydrates inhibitor should be considered before a Beta blocking agent in this situation. Betaxolol and the other Beta blockers should be used with caution in patients with cardiac disease.

Metabolism

Absorption of an oral dose of betaxolol (Kerlone, Betoptic) is almost complete. The drug is subject to a slight first-pass effect such that the absolute bioavailability of the drug is about 90%.Approximately 50% of administered betaxolol binds to plasma proteins, and its plasma half-life is about 20 hours; it is suitable for dosing once per day.The primary route of elimination is by liver metabolism, with only 15% of unchanged drug being excreted.

InChI:InChI=1/C18H29NO3/c1-14(2)19-11-17(20)13-22-18-7-5-15(6-8-18)9-10-21-12-16-3-4-16/h5-8,14,16-17,19-20H,3-4,9-13H2,1-2H3

Synthetic route

isopropylamine (75-31-0) + 1-[2-(cyclopropyl-methoxy)-ethyl]-4-(2,3-epoxypropoxy)-benzene (63659-17-6) → betaxolol (63659-18-7)

Conditions	Yield
for 24h; Ambient temperature;	90%
for 48h; Heating; Yield given;
In water at 0 - 35℃;

RS 1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol (884340-61-8) + diiodomethane (75-11-6) → betaxolol (63659-18-7)

Conditions	Yield
With diethylzinc In toluene at 0℃; for 16h;	84%

2-Phenyl-3-isopropyl-5-[[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]methyl]oxazolidine → betaxolol (63659-18-7)

Conditions	Yield
With hydrogenchloride In isopropyl alcohol	74%

4-[2-(cyclopropylmethoxy)-ethyl]-phenol (63659-16-5) → betaxolol (63659-18-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaOH / H2O / 12 h / Ambient temperature 2: 48 h / Heating View Scheme

1-benzyloxy-4-(2-cyclopropylmethoxyethyl)benzene (63659-15-4) → betaxolol (63659-18-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 84 percent / H2 / 5percent Pd/C / tetrahydrofuran / 50 - 60 °C / 2585.7 Torr 2: NaOH / H2O / 12 h / Ambient temperature 3: 48 h / Heating View Scheme

2-(4-benzyloxyphenyl)ethanol (61439-59-6) → betaxolol (63659-18-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) NaH / 1.) DMF, 2.) DMF, 60 deg, 18 h 2: 84 percent / H2 / 5percent Pd/C / tetrahydrofuran / 50 - 60 °C / 2585.7 Torr 3: NaOH / H2O / 12 h / Ambient temperature 4: 48 h / Heating View Scheme

2-<4-(phenylmethoxy)phenyl>acetic acid ethyl ester (56441-69-1) → betaxolol (63659-18-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: 86 percent / LiAlH4 / tetrahydrofuran / 3 h / Ambient temperature 2: 1.) NaH / 1.) DMF, 2.) DMF, 60 deg, 18 h 3: 84 percent / H2 / 5percent Pd/C / tetrahydrofuran / 50 - 60 °C / 2585.7 Torr 4: NaOH / H2O / 12 h / Ambient temperature 5: 48 h / Heating View Scheme

betaxolol Hydrochloride (63659-19-8) → betaxolol (63659-18-7)

Conditions	Yield
With Dowex Marathon 11 chloride form In water

betaxolol (63659-18-7) + acetic anhydride (108-24-7) → 1-(N-acetyl-N-isopropyl)amino-3-<4-(2-cyclopropylmethoxy)ethyl>phenoxyprop-2-yl acetate (169613-96-1)

Conditions	Yield
With pyridine for 24h; Ambient temperature;	100%
With pyridine; triethylamine at 20℃;

betaxolol (63659-18-7) + acetic anhydride (108-24-7) → N-{(R)-3-[4-(2-Cyclopropylmethoxy-ethyl)-phenoxy]-2-hydroxy-propyl}-N-isopropyl-acetamide + Acetic acid (S)-2-(acetyl-isopropyl-amino)-1-[4-(2-cyclopropylmethoxy-ethyl)-phenoxymethyl]-ethyl ester (169613-97-2)

Conditions	Yield
With pyridine for 24h; Ambient temperature; Yield given. Yields of byproduct given;

betaxolol (63659-18-7) + cyclopropanecarboxylic acid chloride (4023-34-1) → cyclopropanecarboxylic acid 2-[4-(2-cyclopropylmethoxy-ethyl)-phenoxy]-1-(isopropylamino-methyl)-ethyl ester

Conditions	Yield
Acylation;

betaxolol (63659-18-7) → betaxolol Hydrochloride (63659-19-8)

Conditions	Yield
With hydrogenchloride In acetone at 10 - 15℃; pH=2.0;

betaxolol (63659-18-7) → (S)-betaxolol hydrochloride

Conditions	Yield
Multi-step reaction with 4 steps 1: pyridine; triethylamine / 20 °C 2: Rhodotorula mucilaginosa DQ832198 / 12 h / 28 °C / pH 6 / Microbiological reaction; phosphate-citric acid buffer 3: sodium hydroxide / methanol / 20 °C 4: hydrogenchloride / water / 20 °C View Scheme

betaxolol (63659-18-7) → (-)-Betaxolol (93221-48-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine; triethylamine / 20 °C 2: Rhodotorula mucilaginosa DQ832198 / 12 h / 28 °C / pH 6 / Microbiological reaction; phosphate-citric acid buffer 3: sodium hydroxide / methanol / 20 °C View Scheme

betaxolol (63659-18-7) → Acetic acid (S)-2-(acetyl-isopropyl-amino)-1-[4-(2-cyclopropylmethoxy-ethyl)-phenoxymethyl]-ethyl ester (169613-97-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine; triethylamine / 20 °C 2: Rhodotorula mucilaginosa DQ832198 / 12 h / 28 °C / pH 6 / Microbiological reaction; phosphate-citric acid buffer View Scheme

betaxolol (63659-18-7) → (+)-Betaxolol (91878-53-4) + (-)-Betaxolol (93221-48-8)

Conditions	Yield
With diethylamine In acetonitrile Reagent/catalyst; Resolution of racemate;

Upstream product

• 63659-16-5 4-[2-(cyclopropylmethoxy)-ethyl]-phenol 
• 63659-15-4 1-benzyloxy-4-(2-cyclopropylmethoxyethyl)benzene 
• 61439-59-6 2-(4-benzyloxyphenyl)ethanol 
• 884340-61-8 RS 1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol 
• 75-11-6 diiodomethane 
• 63659-19-8 betaxolol Hydrochloride 
• 56441-69-1 2-<4-(phenylmethoxy)phenyl>acetic acid ethyl ester 
• 75-31-0 isopropylamine 
• 63659-17-6 1-[2-(cyclopropyl-methoxy)-ethyl]-4-(2,3-epoxypropoxy)-benzene 

Downstream Products

• 169613-97-2 Acetic acid (S)-2-(acetyl-isopropyl-amino)-1-[4-(2-cyclopropylmethoxy-ethyl)-phenoxymethyl]-ethyl ester 
• 169613-96-1 1-(N-acetyl-N-isopropyl)amino-3-<4-(2-cyclopropylmethoxy)ethyl>phenoxyprop-2-yl acetate 
• 91878-53-4 (+)-Betaxolol 
• 93221-48-8 (-)-Betaxolol 
• 63659-19-8 betaxolol Hydrochloride 

Relevant academic research and scientific papers

The solid-state structure of the β-blocker metoprolol: a combined experimental and in silico investigation

Metoprolol {systematic name: (RS)-1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol}, C15H25NO3, is a cardioselective β1-adrenergic blocking agent that shares part of its molecular skeleton with a large number of other β-blockers. Results from its solid-state characterization by single-crystal and variable-temperature powder X-ray diffraction and differential scanning calorimetry are presented. Its molecular and crystal arrangements have been further investigated by molecular modelling, by a Cambridge Structural Database (CSD) survey and by Hirshfeld surface analysis. In the crystal, the side arm bearing the isopropyl group, which is common to other β-blockers, adopts an all-trans conformation, which is the most stable arrangement from modelling data. The crystal packing of metoprolol is dominated by an O—H…N/N…H—O pair of hydrogen bonds (as also confirmed by a Hirshfeld surface analysis), which gives rise to chains containing alternating R and S metoprolol molecules extending along the b axis, supplemented by a weaker O…H—N/N—H…O pair of interactions. In addition, within the same stack of molecules, a C—H…O contact, partially oriented along the b and c axes, links homochiral molecules. Amongst the solid-state structures of molecules structurally related to metoprolol deposited in the CSD, the β-blocker drug betaxolol shows the closest analogy in terms of three-dimensional arrangement and interactions. Notwithstanding their close similarity, the crystal lattices of the two drugs respond differently on increasing temperature: metoprolol expands anisotropically, while for betaxolol, an isotropic thermal expansion is observed.

PROCESS FOR PREPARATION OF PHENOXYPROPANOL AMINES

The present invention describes an improved method for the preparation of l-[4-{2- (cyclopropylmethoxy)ethyl}phenoxy]-3-[(1-methylethyl)amino]-2-propanol of Formula-(I) and its pharmaceutically acceptable salt, which comprises reacting 4 - [ 2 — (Cyclopropylmethoxy) ethyl] phenol with epichlorohydrin in presence of mild base and polar protic solvent to isolate 1 - {4 - [2 - (cyclopropylmethoxy)ethyl] - phenoxy} - 2, 3 - epoxy propane, which is further reacted with isopropyl amine to get betaxolol formula (I).

THERAPY FOR COMPLICATIONS OF DIABETES

A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.

ANTIHYPERTENSIVE THERAPY

A new use of darusentan is provided in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy with one or more drugs. The composition comprises darusentan in an amount providing a therapeutically effective daily dose; wherein (a) the composition is orally deliverable and/or (b) the daily dose of darusentan is effective to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures. Further provided is a new use of darusentan in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy, wherein the composition is administered adjunctively with at least one diuretic and at least one antihypertensive drug selected from ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers.

FLUORESCENCE BASED DETECTION OF SUBSTANCES

A method for the fluorescent detection of a substance, the method comprising providing particles comprising a metal or a metal oxide core, wherein one or more optionally fluorescently tagged antibodies or human specific peptide nucleic acid (PNA) oligomers for binding to a substance is/are bound, directly or indirectly, to the surface of the metal or metal oxide; contacting a substrate, which may or may not have the substance on its surface, with the particles for a time sufficient to allow the antibody/PNA oligomer to bind with the substance; removing those particles which have not bound to the substrate; if the antibodies or PNA oligomers are not fluorescently tagged, contacting the substrate with one or more fluorophores that selectively bind with the antibody and/or substance, then optionally washing the substrate to remove unbound fluorophores; and illuminating the substrate with appropriate radiation to show the fluorophores on the substrate.

RS 1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol, process for preparation thereof and process for preparation of RS betaxolol

The present invention relates to RS 1-{4-[2-(allyloxy)-ethyl]phenoxy}-3-isopropylamino propan-2-ol of the formula (1), process for preparation thereof by selective allylation of p-hydroxy phenyl ethanol and use thereof in a preparation of RS betaxolol of formula (2)

Process for the selective alkylation of betaxolol intermediates

The present invention relates to a process for the selective alkylation of intermediates of betaxolol.

A chemoenzymatic route to both enantiomers of betaxolol

Evaluation of some of the possible lipase-catalyzed transformations has been done in order to prepare both enantiomers of betaxolol. Resolution of betaxolol by lipase-catalyzed hydrolysis of its bisacetylated derivatives 4 led to (-)- and (+)-enantiomers with an ee of 20 and 60%, respectively. When the resolution was performed on the chlorohydrin precursor 6 of betaxolol, (-)- and (+)-enantiomers were obtained with an ee of 91 and 75%, respectively.

Process for preparing substituted phenol ethers via oxazolidine-structure intermediates

Phenol ethers such as 1-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-3-[(1-methylethyl)amino]-2-propanol, otherwise known as betaxolol, of formula: STR1 are prepared from p-hydroxyphenethyl alcohol by first reacting at the phenolic group, with epichlorohydrin followed by isopropylamine, to prepare the required secondary amine-hydroxy side chain. Protection of the alcoholic group is not required during these steps. Then the secondary amine-alcohol group is protected by reaction with a suitable aldehyde such as benzaldehyde to form an oxazolidine ring protectant while the alcohol chain is elaborated. The oxazolidine ring protectant is removed by simple acid hydrolysis.