66722-57-4

Basic information

• Product Name: [[4-[[2-(1-Methylethoxy)ethoxy]methyl]phenoxy]methyl]oxirane
• Synonyms: [[4-[[2-(1-Methylethoxy)ethoxy]methyl]phenoxy]methyl]oxirane;[[4-[[2-Isopropoxyethoxy]methyl]phenoxy]methyl]oxirane;2-[[4-[[2-(1-Methylethoxy)ethoxy]methyl]phenoxy]methyl]oxirane;Oxirane, [[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]methyl]- (9CI);2-[[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]methyl]-oxira
• CAS NO: 66722-57-4
• Molecular Formula: C₁₅H₂₂O₄
• Molecular Weight: 266.33
• EINECS: 1308068-626-2
• Product Categories: Aromatics Compounds;Aromatics;Intermediates;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 66722-57-4.mol
• Article Data: 3

Chemical Properties

• Boiling Point: 362.6 °C at 760 mmHg
• Flash Point: 118.2 °C
• Appearance: pale yellow oil
• Density: 1.084 g/cm³
• Vapor Pressure: 3.99E-05mmHg at 25°C
• Refractive Index: 1.508
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), Methanol (Sparingly)
• CAS DataBase Reference: [[4-[[2-(1-Methylethoxy)ethoxy]methyl]phenoxy]methyl]oxirane(CAS DataBase Reference)
• NIST Chemistry Reference: [[4-[[2-(1-Methylethoxy)ethoxy]methyl]phenoxy]methyl]oxirane(66722-57-4)
• EPA Substance Registry System: [[4-[[2-(1-Methylethoxy)ethoxy]methyl]phenoxy]methyl]oxirane(66722-57-4)

Safety Data

• Hazardous Substances Data: 66722-57-4(Hazardous Substances Data)

Usage

Chemical Properties

Pale Yellow Oil

Uses

An intermediate for the synthesis of Bisoprolol.

InChI:InChI=1/C15H22O4/c1-12(2)17-8-7-16-9-13-3-5-14(6-4-13)18-10-15-11-19-15/h3-6,12,15H,7-11H2,1-2H3

Synthetic route

4-(2-isopropoxy-ethoxymethyl)-phenol (177034-57-0) + epichlorohydrin (106-89-8) → 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4)

Conditions	Yield
With potassium hydroxide In dimethyl sulfoxide Heating;

2-(1-methylethoxy)-ethanol (109-59-1) → 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: cation exchange resin AG 50W-X8 / Heating 2: KOH / dimethylsulfoxide / Heating View Scheme

(4-hydroxyphenyl)methanol (623-05-2) → 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: cation exchange resin AG 50W-X8 / Heating 2: KOH / dimethylsulfoxide / Heating View Scheme

4-[(2-isopropoxyethoxy)methyl]-phenol sodium salt + epichlorohydrin (106-89-8) → 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4)

Conditions	Yield
In water at 60 - 65℃; for 1h;

6-[4-(2-aminoethoxy)-3-methyl-phenyl]-3(2H)-pyridazinone (133155-44-9) + 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4) → 6-[4-[2-[3-(4-(2-isopropoxyethoxy-methyl)phenoxy)-2-hydroxy-propylamino]ethoxy]-3-methyl-phenyl]-3(2H)-pyridazinone (133155-22-3)

Conditions	Yield
	35%

6-[4(2-Amino-ethoxy)-phenyl]-4,5-dihydro-2H-pyridazin-3-one (117826-24-1) + 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4) → 6-[4-[2-[3-(4-((2-isopropoxyethoxy)methyl)phenoxy)-2-hydroxy-propylamino]ethoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone (133154-64-0)

Conditions	Yield
	25%

6-[4-(3-aminopropylsulphonyl]phenyl]-3(2H)-pyridazinone + 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4) → 6-[4-[3-[3-(4-(2-Isopropoxyethoxymethyl)phenoxy)-2-hydroxypropylamino]propylsulphonyl]phenyl]-4,5-dihydro-3(2H)-pyridazinone (133155-15-4)

Conditions	Yield
	23%

6-4-(3-aminopropoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone + 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4) → 6-[4-[3-[3-(4-(2-Isopropoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]propoxy]-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone (133154-51-5)

Conditions	Yield
	21%

6-[4-(2-amino-ethoxy)-3-chloro-phenyl]-4,5-dihydro-2H-pyridazin-3-one (133155-51-8) + 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4) → 6-[4-[2-[3-(4-(2-isopropoxyethoxy-methyl)phenoxy)-2-hydroxy-propylamino]ethoxy]-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone (133154-57-1)

Conditions	Yield
	19%

6-[4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone + 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4) → 6-[4-[2-[3-(4-(2-isopropoxyethoxy-methyl)phenoxy)-2-hydroxy-propylamino]ethoxy]-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone (133154-47-9)

Conditions	Yield
	16%

6-[4-(3-amino-propoxy)-3-chloro-phenyl]-4,5-dihydro-2H-pyridazin-3-one (133177-69-2) + 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4) → 6-[4-[3-[3-(4-(2-isopropoxyethoxy-methyl)phenoxy)-2-hydroxy-propylamino]propoxy]-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone (133154-54-8)

Conditions	Yield
	15%

6-[1-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)pyridazinone (133155-42-7) + 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4) → 6-[1-[2-[3-(4-(2-Isopropoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone-dihydrochloride

Conditions	Yield
	13%

6-[1-(2-amino-2,2-dimethylethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone (133155-59-6) + 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4) → 6-[1-[2-[3-(4-(2-Isopropoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]-2,2-dimethyl-ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone (133155-00-7)

Conditions	Yield
	9%

1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4) → 1-(p-2-isopropoxyethoxymethylphenoxy)-3-amino-propan-2-ol (333316-11-3)

Conditions	Yield
With ammonium hydroxide In methanol at 75℃;

6-[4-(2-aminoethoxy)-phenyl]-3(2H)-pyridazinone + 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4) → 6-[4-[2-[3-(4-(2-isopropoxyethoxymethyl)phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-3(2H)-pyridazinone (133154-45-7)

1-(p-2-isopropoxyethoxymethylphenoxy)-3-isopropylideneamino-propan-2-ol (66722-64-3) + 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4) → bisoprolol Fumarate (105878-43-1) + 1-(p-2-isopropoxyethoxymethylphenoxy)-3-amino-propan-2-ol (333316-11-3)

Conditions	Yield
With ammonia

isopropylamine (75-31-0) + 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene (66722-57-4) → bisoprolol

Conditions	Yield
Stage #1: 1-(2,3-epoxypropoxy)-4-[2-(isopropoxy)-ethoxymethyl]-benzene With sodium tetrahydroborate In methanol at 15 - 20℃; for 1h; Stage #2: isopropylamine In methanol at 15℃; for 7h; Heating / reflux;

Upstream product

• 177034-57-0 4-(2-isopropoxy-ethoxymethyl)-phenol 
• 106-89-8 epichlorohydrin 
• 623-05-2 (4-hydroxyphenyl)methanol 
• 109-59-1 2-(1-methylethoxy)-ethanol 

Downstream Products

• 105878-43-1 bisoprolol Fumarate 
• 333316-11-3 1-(p-2-isopropoxyethoxymethylphenoxy)-3-amino-propan-2-ol 
• 111051-40-2 bisoprolol 
• 133154-45-7 6-[4-[2-[3-(4-(2-isopropoxyethoxymethyl)phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-3(2H)-pyridazinone 
• 133155-00-7 6-[1-[2-[3-(4-(2-Isopropoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]-2,2-dimethyl-ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone 
• 133154-51-5 6-[4-[3-[3-(4-(2-Isopropoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]propoxy]-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone 
• 133154-64-0 6-[4-[2-[3-(4-((2-isopropoxyethoxy)methyl)phenoxy)-2-hydroxy-propylamino]ethoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone 
• 133155-22-3 6-[4-[2-[3-(4-(2-isopropoxyethoxy-methyl)phenoxy)-2-hydroxy-propylamino]ethoxy]-3-methyl-phenyl]-3(2H)-pyridazinone 

Relevant articles and documents

Bisoprolol-based 18F-PET tracer: Synthesis and preliminary in vivo validation of β1-blocker selectivity for β1-adrenergic receptors in the heart

The selectivity of a drug toward various isoforms of the target protein family is important in terms of toxicology. Typically, drug or candidate selectivity is assessed by in vitro assays, but in vivo investigations are currently lacking. Positron emission tomography (PET) allows the non-invasive determination of the in vivo distribution of a radiolabeled drug, which can provide in vivo data regarding drug selectivity. Since the discovery of propranolol, a non-selective β-blocker inhibiting both β1- and β2-adrenoreceptors (β-ARs), various selective β1-blockers, including bisoprolol, have been developed to overcome disadvantages associated with β2-AR inhibition. As a proof of concept, we performed an in vivo PET study to understand the selectivity and efficacy of bisoprolol as a selective β-blocker toward β1-AR, as the heart and peripheral smooth muscles demonstrate distinct populations of β1- and β2-ARs. Biodistribution of 18F-labeled bisoprolol (1, [18F]bisoprolol) showed the retention of its uptake in the heart compared with other β-AR-rich organs at late time points post-injection. The competitive blocking assay using unlabeled bisoprolol exhibited no inhibition of [18F]bisoprolol uptake in any organ but exhibited significantly rapid loss of radioactivity between two different time points in β1-AR-rich organs such as the heart and brain. Furthermore, the organ-to-blood ratio revealed the slow excretion and better accumulation of [18F]bisoprolol inside the heart. Collectively, the ex vivo biodistribution and blocking study presented insightful evidence to better comprehend the in vivo distribution pattern of bisoprolol as a selective inhibitor targeting β1-ARs in the heart and provided the possibility of PET as an in vivo technique for evaluating drug selectivity.

Synthesis of ICI-118551 and bisoprolol, putative selective tracer for bets-adrenergic receptor subtypes

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