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

• 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 

Relevant articles and documents

Process for efficiently synthesizing Cetilistat by taking 2-amino-5-methyl benzoic acid as raw material

The invention discloses a process for efficiently synthesizing Cetilistat by taking 2-amino-5-methyl benzoic acid as a raw material. The process comprises the steps: taking 2-amino-5-methyl benzoic acid as a raw material, and carrying out transesterification on 2-amino-5-methyl benzoic acid and triphosgene under the action of organic base catalysis to generate an intermediate c, namely 6-methyl-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione; carrying out a reaction on sulfonyl chloride (d) with a specific structure with n-hexadecanol under the condition of base catalysis to generate an intermediatef; and finally, carrying out an alkylation reaction on oxygen atoms of the intermediate c and the intermediate f in the presence of organic base to generate the target product Cetilistat. According tothe method, the reaction steps for synthesizing the Cetilistat are few, the process route is short, side reactions are few, the yield of the final product is high, and the purity is more than 99%.

A west for favorable department his preparation method

The invention discloses a preparation method of cetilistat, which has the advantages of high yield, mild reaction conditions and the like and can easily implement industrial production. The method comprises the following steps: (1) reacting methyl 2-amino-5-halobenzoate with triphosgene to obtain 2-methoxycarbonyl-4-halophenylisocyanate; adding hexadecanol to generate methyl 2-(hexadecaalkoxycarbonylamino)-5-halobenzoate; (2) adding the methyl 2-(hexadecaalkoxycarbonylamino)-5-halobenzoate, methyl boron dihydroxide and alkali into water and an organic solvent, adding a palladium catalyst, and reacting to obtain methyl 2-(hexadecaalkoxycarbonylamino)-5-methylbenzoate; (3) carrying out esterolysis reaction on the methyl 2-(hexadecaalkoxycarbonylamino)-5-methylbenzoate to obtain 2-(hexadecaalkoxycarbonyl)-5-methylbenzoic acid; (4) suspending the 2-(hexadecaalkoxycarbonyl)-5-methylbenzoic acid in pyridine, and cyclizing under the action of a dehydrating agent; and purifying and carrying out crystal transformation to obtain the cetilistat.

A he west for favorable department method of preparation

The invention discloses a method for preparing cetilistat, which belongs to the technical field of the medicine preparation method, and is used for solving the problems of high three wastes, low yield and high cost in the current preparation method. The method comprises the following steps: 1)esterifying a compound A(2-amino-5-methyl benzoic acid) or its salt; 2) acylating an esterification object in the step 1) and chloroformic acid n-cetanol ester; 3)removing ester group of the compound obtained in the step 2) to obtain 2-(cetane carbonyl oxygen)amino-5-methyl benzoic acid; and 4)cyclizing the compound in the step 3) to obtain the target products. By improving the production steps, the invention provides the synthetic method with simple operation, high efficiency, and convenient industrial production for the cetilistat product.