282526-98-1

Basic information

• Product Name: Cetilistat
• Synonyms: cetilistat;Cetilistat(Alt-962);Cetilstat;2-(Hexadecyloxy)-6-methyl-4H-3,1-benzoxazin-4-one;2-(Hexadecycloxy)-6-methyl-4H-3,1-benzoxazin-4-one;4H-3,1-Benzoxazin-4-one,2-(hexadecyloxy)-6-Methyl-;Xinli orlistat;Cetilistat (282526-98-1)
• CAS NO: 282526-98-1
• Molecular Formula: C₂₅H₃₉NO₃
• Molecular Weight: 401.58
• EINECS: 1308068-626-2
• Product Categories: Aromatics;Heterocycles;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;API;Cetilistat;Other series
• Mol File: 282526-98-1.mol
• Article Data: 11

Chemical Properties

• Melting Point: 72.0 to 76.0 °C
• Boiling Point: 509.671 °C at 760 mmHg
• Flash Point: 158.925 °C
• Appearance: Off-white cryst.
• Density: 1.02
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.521
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), Ethyl Acetate (Slightly)
• PKA: 2.96±0.20(Predicted)
• CAS DataBase Reference: Cetilistat(CAS DataBase Reference)
• NIST Chemistry Reference: Cetilistat(282526-98-1)
• EPA Substance Registry System: Cetilistat(282526-98-1)

Safety Data

• Hazardous Substances Data: 282526-98-1(Hazardous Substances Data)

Usage

Description

Cetilistat (also known as ATL-962) was approved in September 2013 by the Japanese Ministry of Health, Labor and Welfare for the treatment of obesity, limited to patients with both type 2 diabetes mellitus (T2DM) and dyslipidemia, and with a body mass index (BMI)25 kg/m2 in spite of dietary treatment and/or exercise therapy. As with orlistat, cetilistat works via inhibition of pancreatic lipases in the gut to inhibit fat absorption and thereby reduce caloric uptake from diet. The medicinal chemistry program has not been described in the scientific literature, but the patent describing cetilistat also describes the synthesis of analogs with varied aryl substituents and lipophilic tails. The synthesis of cetilistat involves condensation of a hexadecylcarbonochloridate with 2-amino-5-methylbenzoic acid; other analogs were synthesized by varying the carbonochloridate and 2-aminobenzoic acid components. Cetilistat is a potent inhibitor of human and rat pancreatic lipase with IC50s of 15 and 136 nM, respectively, with little inhibition of trypsin or chymotrypsin.

Chemical Properties

Off-white Cryst

Originator

Alizyme PLC (United Kingdom)

Uses

A novel pancreatic lipase inhibitor for the treatment of obesity in both diabetic and non-diabetic patients.

Brand name

Oblean

Synthesis

Commercially available hexadecanol (21) was treated with phosgene in THF/toluene to give the corresponding chloroformate (22), which was immediately subjected to commercial 2-amino-5- methylbenzoic acid (23) in pyridine. Subsequent slow addition of methyl chloroformate at room temperature resulted in the formation of cetilistat (IV), which was produced in 31% overall yield from hexadecanol.

InChI:InChI=1/C25H39NO3/c1-3-4-5-6-7-8-9-10-11-12-13-14-15-16-19-28-25-26-23-18-17-21(2)20-22(23)24(27)29-25/h17-18,20H,3-16,19H2,1-2H3

Synthetic route

2-(((hexadecyloxy)carbonyl)amino)5-methylbenzoic acid (890655-08-0) → 2-hexadecyloxy-6-methyl-4-chloro-1-benzoxazin-4-one (282526-98-1)

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Solvent; Reagent/catalyst;	96.5%
With 1,1'-carbonyldiimidazole In dichloromethane Reagent/catalyst;	92%
With pyridine; chloroformic acid ethyl ester at 0 - 10℃; for 1h; Reagent/catalyst; Concentration;	85.5%

hexadecanyl p-trifluoromethylsulfonate → 2-hexadecyloxy-6-methyl-4-chloro-1-benzoxazin-4-one (282526-98-1)

Conditions	Yield
With triethylamine In dichloromethane Cooling with ice; Reflux;	90%

hexadecyl-2-iodo-5-methylbenzoyl-carbamate → 2-hexadecyloxy-6-methyl-4-chloro-1-benzoxazin-4-one (282526-98-1)

Conditions	Yield
With copper(l) iodide; calcium chloride In 1,4-dioxane for 3h; Inert atmosphere; Reflux;	81%

hexadecyl-2-bromo-5-methylbenzoyl-carbamate → 2-hexadecyloxy-6-methyl-4-chloro-1-benzoxazin-4-one (282526-98-1)

Conditions	Yield
With magnesium sulfate; copper(I) bromide In toluene for 3h; Inert atmosphere; Reflux;	71%

2-(((hexadecyloxy)carbonyl)amino)5-methylbenzoic acid (890655-08-0) + chloroformic acid ethyl ester (541-41-3) → 2-hexadecyloxy-6-methyl-4-chloro-1-benzoxazin-4-one (282526-98-1)

Conditions	Yield
With pyridine In ice-water

1-Hexadecanol (36653-82-4) → 2-hexadecyloxy-6-methyl-4-chloro-1-benzoxazin-4-one (282526-98-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 3 h / 20 °C 2: copper(I) bromide; magnesium sulfate / toluene / 3 h / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 3 steps 1.1: acetonitrile / 2.5 h / 25 - 65 °C 2.1: triethylamine / 7 h / 25 - 90 °C 3.1: pyridine / dichloromethane / 0.17 h / 25 - 30 °C 3.2: 4 h / 0 - 35 °C View Scheme

cetyl chloroformate (26272-90-2) → 2-hexadecyloxy-6-methyl-4-chloro-1-benzoxazin-4-one (282526-98-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 4 h / 20 °C / Reflux 2: copper(l) iodide; calcium chloride / 1,4-dioxane / 3 h / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 3 h / 0 - 20 °C 2: periodic acid; chromium(VI) oxide; acetic anhydride / acetonitrile / 1.5 h / 0 - 20 °C 3: copper(l) iodide; calcium chloride / 1,4-dioxane / 3 h / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 3 h / 0 - 20 °C 2: periodic acid; chromium(VI) oxide; acetic anhydride / acetonitrile / 1.5 h / 0 - 20 °C 3: copper(I) bromide; magnesium sulfate / toluene / 3 h / Inert atmosphere; Reflux View Scheme

Kohlensaeure-di-n-hexadecylester (13784-52-6) → 2-hexadecyloxy-6-methyl-4-chloro-1-benzoxazin-4-one (282526-98-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: dmap / dichloromethane / 18 h / 20 °C 2: copper(I) bromide; magnesium sulfate / toluene / 3 h / Inert atmosphere; Reflux View Scheme

hexadecyl-2-bromo-5-methylbenzyl-carbamate → 2-hexadecyloxy-6-methyl-4-chloro-1-benzoxazin-4-one (282526-98-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: periodic acid; chromium(VI) oxide; acetic anhydride / acetonitrile / 1.5 h / 0 - 20 °C 2: copper(I) bromide; magnesium sulfate / toluene / 3 h / Inert atmosphere; Reflux View Scheme

2-(hexadecyloxycarbonyl)amino-5-methylbenzoic acid methyl ester → 2-hexadecyloxy-6-methyl-4-chloro-1-benzoxazin-4-one (282526-98-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium carbonate / tetrahydrofuran; water 2: 1,1'-carbonyldiimidazole / dichloromethane View Scheme

2-Amino-5-methylbenzoic acid (2941-78-8) → 2-hexadecyloxy-6-methyl-4-chloro-1-benzoxazin-4-one (282526-98-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: sulfuric acid / 20 °C 2: pyridine / dichloromethane / 2 h / 20 °C / Inert atmosphere; Cooling with ice 3: lithium carbonate / tetrahydrofuran; water 4: 1,1'-carbonyldiimidazole / dichloromethane View Scheme

2-amino-5-methylbenzoic acid methyl ester hydrogen sulfate → 2-hexadecyloxy-6-methyl-4-chloro-1-benzoxazin-4-one (282526-98-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 2 h / 20 °C / Inert atmosphere; Cooling with ice 2: lithium carbonate / tetrahydrofuran; water 3: 1,1'-carbonyldiimidazole / dichloromethane View Scheme

2-hexadecyloxy-6-methyl-4-chloro-1-benzoxazin-4-one (282526-98-1) → 2-(hexadecyloxycarbonyl)amino-5-methylbenzoic acid methyl ester

Conditions	Yield
In methanol; dichloromethane at 40℃; for 5h; Solvent; Temperature; Reflux;	98.1%

Upstream product

• 282526-14-1 .beta.-D-Glucopyranoside, methyl 2-deoxy-2-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethylamino-1-thio- 
• 282526-04-9 .beta.-D-Glucopyranoside, methyl 2-azido-2-deoxy-1-thio- 
• 28252-55-3 H-GLN(DOD)-OME HCL 
• 28252-53-1 N-ALPHA CARBOBENZOXY-N-GAMMA-(4,4'-DIMETHOXY)BENZHYDRYL-L-GLUTAMINE ALPHA-METHYL ESTER 
• 282525-14-8 FMOC-DL-3-(FURAN-2-YL)-3-AMINO-PROPIONIC ACID 
• 282525-12-6 FMOC-3-AMINO-3-(2-THIENYL)PROPIONIC ACID 
• 282525-00-2 Cyclopentaneacetic acid, 1-[[(1,1-dimethylethoxy)carbonyl]amino]- (9CI) 
• 282524-99-6 Cyclopentaneacetic acid, 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]- (9CI) 
• 282524-98-5 FMOC-1-AMINO-CYCLOHEXANE ACETIC ACID 
• 282524-97-4 Cyclopentanecarboxylic acid, 2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]- (9CI) 
• 282524-96-3 Cyclohexanecarboxylic acid, 2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]- (9CI) 
• 282524-95-2 3-TERT-BUTOXYCARBONYLAMINO-HEXANOIC ACID 
• 28252-49-5 Z-GLN(DOD)-OH 
• 282524-94-1 3-(9 H-FLUOREN-9-YLMETHOXYCARBONYLAMINO)-HEXANOIC ACID 

Downstream Products

• 282527-18-8 2-Pyridinecarboxylicacid,1,2,3,6-tetrahydro-6-(2-propenyl)-,(2S,6S)-(9CI) 
• 282527-19-9 2-Pyridinecarboxylicacid,1,2,3,6-tetrahydro-6-(2-propynyl)-,(2S,6S)-(9CI) 
• 28252-76-8 2,8-Dichloro-1,5-naphthyridine 
• 28252-80-4 4,8-Dichloro-1,5-naphthyridine 
• 28252-81-5 3,8-Dichloro-1,5-naphthyridine 
• 282528-23-8 Cyclobuta[g]quinoxaline, 6,7-dihydro- 
• 28252-82-6 2,4-Dichloro-1,5-naphthyridine 
• 282528-30-7 2,3-Bis(broMoMethyl)pyrazine 
• 28252-85-9 2,7-Dichloro-1,5-naphthyridine 
• 282528-59-0 (1-[(TERT-BUTOXY)CARBONYL]-5-METHYL-1H-PYRROL-2-YL)BORONIC ACID 
• 282528-61-4 5-METHOXY-1H-INDOLE-2-BORONIC ACID 
• 282528-62-5 5-CHLORO-1H-INDOLE-2-BORONIC ACID 
• 282528-65-8 2H-Pyrrol-2-one,4-butoxy-1,5-dihydro-(9CI) 
• 2825-28-7 3-thioxobutyramide hydrochloride 

Recommend Products

• 282526-98-1  2-hexadecyloxy-6-methyl-4-chloro-1-benzoxazin-4-one 
• 2941-78-8  2-Amino-5-methylbenzoic acid 
• 13784-52-6  Kohlensaeure-di-n-hexadecylester 
• 26272-90-2  cetyl chloroformate 
• 36653-82-4  1-Hexadecanol 
• 890655-08-0  2-(((hexadecyloxy)carbonyl)amino)5-methylbenzoic acid 
• 541-41-3  chloroformic acid ethyl ester