azalanstat
- CAS No.
- 143393-27-5
- Chemical Name:
- azalanstat
- Synonyms
- Rs-21607;Rs 21607;azalanstat;Unii-2nl79ni1ws;Azalanstat [inn];Azalanstat mesylate;Benzenamine, 4-[[[(2S,4S)-2-[2-(4-chlorophenyl)ethyl]-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl]thio]-;Benzenamine, 4-(((2-(2-(4-chlorophenyl)ethyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methyl)thio)-, (2S-cis)-
- CBNumber:
- CB61377064
- Molecular Formula:
- C22H24ClN3O2S
- Molecular Weight:
- 429.96
- MDL Number:
- MFCD00867553
- MOL File:
- 143393-27-5.mol
| Melting point | 151 °C |
|---|---|
| Boiling point | 647.7±40.0 °C(Predicted) |
| Density | 1.31±0.1 g/cm3(Predicted) |
| pka | 6.88±0.12(Predicted) |
| FDA UNII | 2NL79NI1WS |
azalanstat Chemical Properties,Uses,Production
Originator
Azalanstat,Syntex
Uses
Hypolipidemic.
Manufacturing Process
A stirred solution of 4-chlorophenethyl alcohol (131.0 g) and
triphenylphosphine (241.3 g) in dry THF (500 ml) at 0°C was treated portionwise
over 30 min with N-bromosuccinimide (163.75 g). The resulting black
solution was stirred overnight at room temperature, whereupon the THF was
evaporated and the residue stirred with ether. The solution was filtered and
the filtrate evaporated and treated with hexane. The stirred mixture was
filtered, evaporated, and the residue distilled under reduced pressure to give
100.0 g of 4-chlorophenethyl bromide as a colorless liquid, boiling point 85°C (3 mm Hg).
To a flame-dried flask containing magnesium turnings under ether was added
4-chlorophenethyl bromide in anhydrous ether at such a rate as to maintain a
gentle reflux. When the addition was complete, the mixture was heated under
reflux for an additional hour and then treated dropwise over 1 h with vinyl
bromide in ether maintaining a gentle reflux. The resulting mixture was stirred
overnight at room temperature and then poured onto ice-cold dilute sulfuric
acid. The product was extracted with ethyl acetate and the combined extracts
were washed with dilute aqueous potassium carbonate, dried MgSO4 and
evaporated. The resulting brown oil was distilled under reduced pressure to
give 4-(4-chlorophenyl)but-1-ene.
To a solution of 4-(4-chlorophenyl)but-1-ene in dichloromethane was added
dropwise with stirring a mixture of 40% peracetic acid and sodium acetate.
The resulting mixture was heated under reflux, cooled, and stirred with water.
The dichloromethane layer was separated, washed with dilute aqueous
potassium carbonate until neutral, water, and dried (MgSO4) and evaporated
to give 4-(4-chlorophenyl)-1,2-epoxybutane as a colorless oil.
To a suspension of sodium hydride (50% dispersion in mineral oil) in dry DMF
under nitrogen was added imidazole in dry DMF with stirring at such a rate as
to keep the temperature below 65°C (ice bath). When the evolution of gas
had ceased, 4-(4-chlorophenyl)-1,2-epoxybutane was added dropwise and the
mixture stirred overnight at room temperature. The resulting brown solution
was added water, extracted with ethyl acetate and the combined extracts were
washed with water 3 times, dried (MgSO4) and evaporated to give an oil
which crystallized. Washing the solid with ether and filtration give 1-(4-(4-
chlorophenyl)-2-hydroxybutyl)imidazole.
A solution of oxalyl chloride (74.8 g) in dry dichloromethane (1350 ml) at
below -70°C under a nitrogen atmosphere was treated with dry
dimethylsulfoxide (91.5 ml) in methylene chloride (270 ml) dropwise over 15-
20 min while maintaining the temperature of the reaction mixture below -
50°C. After an additional 5 min a solution of (+/)-1-(4-(4-chlorophenyl)-2-
hydroxybutyl)imidazole (128.3 g) in a mixture of dimethylsulfoxide (50 ml)
and methylene chloride (200 ml) was added over a period of 20 min keeping
the reaction mixture at temperatures below -65°C. After a further 15 min dry
triethylamine (300 ml) was added rapidly and after 15 min the reaction
mixture was allowed to warm to 0°C. Water (20 ml) was then added to the
reaction mixture, the methylene chloride then removed by evaporation and
the resulting slurry was then treated with water and filtered. The filter cake
was washed well with ice water, cold ethyl acetate and then dried in air to
yield 118.0 g of 4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one.
A mixture of 4-(4-chlorophenyl)-1-(imidazol-1-yl)butan-2-one (50.0 g), ptoluenesulfonic
acid monohydrate (42.07 g) and glycerol (37.0 g) in toluene
(200 ml) was heated under reflux, with stirring, through a Dean-Stark trap for
6 h. The two layers were allowed to separate and the hot toluene (upper
layer) decanted and discarded. The lower layer was poured into 2 N sodium
hydroxide (500 ml), the transfer completed by washing the flask with 1 N
sodium hydroxide and methylene chloride, and the product extracted with
methylene chloride (4x200 ml). The extracts were dried (MgSO4) evaporated and the residue recrystallized from toluene to give 61.4 g of (cis/trans)-2-(2-
(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-hydroxymethyl-1,3-
dioxolane, melting point 96°-110°C.
(cis/trans)-2-[2-(4-Chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4-
hydroxymethyl-1,3-dioxolane (39.7 g) in pyridine (150 ml) at 0°C was treated
drop-wise with stirring with methanesulfonyl chloride (10.6 ml) and the
mixture stirred overnight. The resulting solid mass was stirred with ether (500
ml) to break up the solid, filtered and washed well with ether to give
(cis/trans)-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4-
(methylsulfonyloxy)methyl-1,3-dioxolane hydrochloride, melting point 107°-
110°C (recrystallized from dichloromethane/isopropanol).
The (cis/trans)-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4-
(methylsulfonyloxy)methyl-1,3-dioxolane hydrochloride was basified with
aqueous potassium carbonate solution, extracted with ethyl acetate (2x400
ml) and the extracts washed, dried (MgSO4) and evaporated. The resulting
semicrystalline mass was chromatographed on silica gel (900.0 g) eluting with
dichloromethane, aqueous ethyl acetate (2.2% water) to give 25.4 g of (+/-)-
cis-2-(2-(4-chlorophenyl)ethyl)-2-(imidazol-1-yl)methyl-4-
(methylsulfonyloxy)methyl-1,3-dioxolane, as a snow white solid, melting point
93.5°-96°C. Further elution gave, after a small mixed fraction, pure (+/-)-
trans-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4-
(methylsulfonyloxy)methyl-1,3-dioxolane, as a white solid, melting point 93°-
95°C.
A mixture of (+/-)-cis-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-yl)methyl-4-
(methylsulfonyloxy)methyl-1,3-dioxolane (31.0 g), 4-aminothiophenol (12.6 g)
and anhydrous potassium carbonate (23.1 g) in acetone (250 ml) was stirred
overnight under reflux under nitrogen. The reaction mixture was then
evaporated to dryness, and the resulting residue was extracted with
methylene chloride (300 ml) and filtered. The solid filter cake was then
washed with methylene chloride (200 ml). The methylene chloride extracts
were then combined and concentrated and flash chromatographed on a silica
gel eluting with methylene chloride followed by 30% acetone in methylene
chloride. The pure product was dissolved in a minimum amount of hot ethyl
acetate (125 ml), the solution diluted with an equal volume of hot hexane and
seeded to give 30.0 g of (+/-)-cis-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-
yl)methyl-4-(4-amino-phenylthio)methyl-1,3-dioxolane, melting point 121°-
122.5°C.
In practice it is usually used as hydrochloride.
Therapeutic Function
Antihyperlipidemic
Enzyme inhibitor
This imidazole-containing agent (FW = 429.96 g/mol), also known as RS- 21607, inhibits both inducible heme oxygenase-1 and constitutive heme oxygenase-2 (rat IC50 = 5.3 and 24.5 μM, respectively). The m aminophenyl analogue is a slightly stronger inhibitor of heme oxygenase-1 (IC50 = 1 μM). Azalanstat is a stronger inhibitor of lanosterol 14a demethylase (rat and human Ki = 2.5 and 0.79 nM, respectively). The other three stereoisomers are weaker inhibitors of the demethylase. Target(s): aromatase, or CYP19; cholestanetriol 26-monooxygenase, or cholesterol 27-monooxygenase; cholesterol 7a-monooxygenase (CYP7)3,4; cholesterol monooxygenase, side-chain cleaving; CYP1A1; CYP1A2; CYP2C9; CYP2D6; heme oxygenase; progesterone 6b-monooxygenase, or CYP3A; progesterone 16a monooxygenase; steroid 11b monooxygenase; steroid 17a monooxygenase, or steroid 17a/20-lyase; steroid 21 monooxygenase; sterol 14-demethylase, or CYP5; lanosterol 14a-demethylase.
azalanstat Preparation Products And Raw materials
Raw materials
1of4
Preparation Products
azalanstat Suppliers
| Supplier | Tel | Country | ProdList | Advantage | |
|---|---|---|---|---|---|
| TargetMol Chemicals Inc. | +1-781-999-5354 +1-00000000000 | marketing@targetmol.com | United States | 19892 | 58 |
| TargetMol Chemicals Inc. | 4008200310 | marketing@tsbiochem.com | China | 24131 | 58 |
| Suzhou Meishi Biotechnology Co., Ltd. | 1173954148q | meishipharma@126.com | China | 20035 | 58 |
| Nantong QuanYi Biotechnology Co., Ltd | 0513-66337626 18051384581 | sales@chemhifuture.com | China | 4030 | 58 |
| Supplier | Advantage |
|---|---|
| TargetMol Chemicals Inc. | 58 |
| TargetMol Chemicals Inc. | 58 |
| Suzhou Meishi Biotechnology Co., Ltd. | 58 |
| Nantong QuanYi Biotechnology Co., Ltd | 58 |