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

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

Uses

Used in Pharmaceutical Industry:
Cetilistat is used as a pancreatic lipase inhibitor for the treatment of obesity in both diabetic and non-diabetic patients. It specifically targets patients with type 2 diabetes mellitus (T2DM) and dyslipidemia, who have a BMI of 25 kg/m2 or higher and have not responded well to dietary treatment and/or exercise therapy. By inhibiting pancreatic lipases, cetilistat reduces fat absorption and caloric uptake from the diet, thus aiding in weight management and potentially improving overall health outcomes for these patients.

Originator

Alizyme PLC (United Kingdom)

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

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

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%.

NOVEL PROCESSES FOR THE PREPARATION OF 2-OXY-BENZOXAZINONE DERIVATIVES

Provided herein are novel, commercially viable and industrially advantageous processes for the preparation of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one, and its intermediates, in high yield and purity.

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.

Method of preparing Cetilistat through one-pot method

The invention discloses a method of preparing Cetilistat through a one-pot method. The method comprises the following steps that 2-amino-5-toluic acid is sequentially reacted with cetyl chloroformate and methane sulfonyl chloride in a mixed solution, and the Cetilistat is obtained through the one-pot method. According to the method, with selection of a mixed solution system as a reaction medium and the methane sulfonyl chloride as a lactonization reagent and adoption of the one-pot method to prepare the Cetilistat, an obtained product is high in yield and purity; the process is simple and not tedious, separation and purification of an intermediate are not needed, postprocessing is liable to operate, requirement on equipment is not high, the industrial production is facilitated.

Preparation method of cetilistat

The invention discloses a preparation method of cetilistat; the method has the advantages of concise process, easily obtained raw materials, and mild reaction conditions, and is suitable for industrialized production. According to a reaction route, 2-amino-5-methyl benzoic acid and hexadecyl chloroformate serve as starting raw materials, firstly, amino acylation is carried out, an intermediate is purified, then cyclization is carried out, and the target compound is obtained through a two-step reaction.

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.

Method for preparing cetilistat

The invention provides a method for preparing cetilistat. According to the method, 2-amidogen-5-methyl benzoic acid is adopted as an initial raw material, under existence of pyridine, the 2-amidogen-5-methyl benzoic acid reacts with chlorine acid cetyl alcohol ester in the first place, a midbody 2-(((hexadecane oxygroup) carbonyl) amidogen)-5-methyl benzoic acid is obtained, then dehydrogenation cyclization reagent is utilized to obtain the cetilistat, and the feeding sequence in step 1 is the 2-amidogen-5-methyl benzoic acid, alkali and the chlorine acid cetyl alcohol ester in sequence. The method has the remarkable advantages that the route is simple, operation is less, atom economy is better than that of other routes, and the cetilistat is suitable for large-scale production; the purity of the cetilistat at the reaction endpoint is larger than 98%, and through simple postprocessing, a final product which meets medical standards can be obtained, wherein the purity is larger than 99.5%, and the single impurity is smaller than 0.1%; the utilized solvent including dichloromethane and pyridine can be recycled for mechanical application, and the method is environmentally friendly.

A preparing method of a lipase inhibitor

The invention belongs to the technical field of medicines, and particularly relates to a preparing method of 2-(hexadecyloxy)-6-methyl-4H-3,1-benzoxazin-4-one that is a lipase inhibitor. An intermediate that is hexadecyl-2-halogen-5-methyl-benzoyl carbamate shown as a formula (II) is subjected to amide cyclization and rearrangement with N-acyl-2-halogenobenzene under catalysis of a catalyst to prepare 1-(2-halogenbenzyl)-1,3-dione. -NH in imide and halogen are subjected to dehydrohalogenation to form a lactam four-membered ring firstly, and then the benzoxazin-4-one structure is formed by a C-N rearrangement reaction. The method is characterized by high product purity, simple, feasible and safe processes and capability of meeting requirements of industrial production.

Process for preparing carbamic ester derivatives

An improved process for preparing carbamic ester derivatives of the general formula (1) by reaction with carbon monoxide and water in the presence of a palladium catalyst is provided.