CN105669585A

CN105669585A - Preparation method of cetilistat

Info

Publication number: CN105669585A
Application number: CN201610002254.6A
Authority: CN
Inventors: 吕丹
Original assignee: Beijing Xiuzheng Innovative Drug Research Institute Co Ltd
Current assignee: Beijing Xiuzheng Innovative Drug Research Institute Co Ltd
Priority date: 2016-01-06
Filing date: 2016-01-06
Publication date: 2016-06-15

Abstract

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.

Description

A kind of preparation method of Cetilistat

Technical field

The preparation method that the present invention relates to a kind of Cetilistat, belongs to process for preparing medicine technical field.

Background technology

Cetilistat (2-hexadecane oxygen base-6-methyl-4H-3, 1-benzimidazole dihydrochloride-4-ketone, cetilistat) it is a kind of long-acting and potent specific gastrointestinal lipase inhibitor developed by Alizyme company, it makes enzyme deactivation play therapeutical effect by forming covalent bond with the active ser position of gastric lipase in harmonization of the stomach small intestinal lumen and pancreatic lipase, fat (mainly triglyceride) in food can not be hydrolyzed to absorbable free fatty and monoacylglycerol by the enzyme of inactivation, indigested triglyceride can not be absorbed by the body, thus reducing energy intake, control body weight. this medicine great advantage is not act on nervous system, does not affect other enzymatic activitys of gastrointestinal, is not absorbed and does not namely enter blood, not appetite-suppressing, it is not necessary to dietary restriction. compared with existing similar drugs orlistat, Cetilistat is safer, and lower in cost. the structural formula of Cetilistat is as follows:

Said structure compound and relevant preparation method thereof disclosed in patent CN1315813C, the concrete syntheti c route disclosed in embodiment is as follows:

Said method 1 adopts 2-amino-5-ar-Toluic acid to react with chloro-carbonic acid cetyl ester; one step reaches the purpose of aminoacylates, activated carboxylic and cyclization; though this route seems easy; but actually need large excess of chloro-carbonic acid cetyl ester just can complete these to convert; and yield is very low, only 15%. Method 2 is the improvement on the basis of 1; one kettle way is still taked to prepare; it is firstly added chloro-carbonic acid cetyl ester, carries out aminoacylates, add methylchloroformate and carry out the activation of carboxyl, cyclization; compared with 1; this route decreases the consumption of chloro-carbonic acid cetyl ester to a certain extent, and yield brings up to 31%, but this method employs the methylchloroformate of severe toxicity; and still adopt column chromatography purification, be unfavorable for industrialized production.

The preparation method of another Cetilistat disclosed in patent CN1785967A:

The method is to be obtained by reacting cetyl p-methylphenyl carbamate with p-methylphenyl isocyanates for initiation material and hexadecanol, again with bromine generation phenyl ring bromo, under bis-triphenylphosphipalladium palladium dichloride catalysis, CO and water and halo aromatic ring condensation introduce carboxyl, under ethyl chloroformate effect, cyclization obtains target compound, total recovery 27% again. Palladium catalyst used by the method is expensive, and have that three waste discharge is more, severe reaction conditions, to defects such as equipment requirements are high, be unfavorable for industrialized production.

Cetilistat syntheti c route disclosed in patent CN103936687A is as follows:

This route is with 2-amino-5-ar-Toluic acid for initiation material; first carboxyl is carried out esterification protection, followed by chloro-carbonic acid cetyl ester, amino carried out acidylate, again hydrolysis of ester group sloughed, eventually pass cyclization and obtain target compound; this process route is long; and use noble metal lithium reagent, add cost.

<synthesis of Cetilistat>(<Chinese Journal of Pharmaceuticals>2015,46 (9)) discloses following content:

This route adopts one kettle way, with pyridine solvent and acid binding agent, 2-amino-5-ar-Toluic acid and the chloro-carbonic acid cetyl ester reaction little over amount, it is subsequently adding phosphorus oxychloride to carry out molecule inner ring condensation and obtain Cetilistat, the yield of document report is 90%, but there is a large amount of shortcoming using strong and stimulating reagent pyridine, bring inconvenience to industrialized production.

In sum, develop a kind of easy and simple to handle, with low cost, facilitate the preparation method of the Cetilistat of industrialized production to have important practical significance.

Summary of the invention

For above-mentioned prior art, the preparation method that the invention provides a kind of Cetilistat, the method step is succinct, and raw material is easy to get, and reaction condition is gentle, is suitable for industrialized production.

Reaction scheme in the present invention, with 2-amino-5-ar-Toluic acid and chloro-carbonic acid cetyl ester for initiation material, first carries out aminoacylates, carries out cyclization again, obtain target compound by two-step reaction after purification of intermediate, and concrete reaction equation is as follows:

2-hexadecane oxygen base-6-methyl-4H-3,1-benzimidazole dihydrochloride-4-ketone (Cetilistat)

For the route of the present invention, respectively to reaction temperature, the kind of acid binding agent, the kind of condensing agent, solvent type etc. investigate.

Specifically, step 1 is that acylation reaction occurs under the existence of acid binding agent for compound A, compound B, obtains compound C, and acid binding agent used is the material with alkalescence, plays and neutralizes the acid that reaction generates, and promotes the effect of reaction.

Acid-base neutralization exothermic heat of reaction is obvious, it is therefore desirable to control reaction in relatively low temperature to avoid reaction excessively violent, but too low temperature can cause that reaction substrate declines with product dissolubility, affects reaction and carries out.

Acid binding agent used both can be organic base such as pyridine, triethylamine etc., it is also possible to is inorganic base such as hydroxide, carbonate etc. Selecting pyridine, triethylamine, potassium hydroxide, potassium carbonate that acylation reaction is compared respectively, the impact on reaction of the kind of investigation alkali, result is as shown in table 1.

The comparison of the different acid binding agent of table 1

Acid binding agent	Reaction condition	Conversion ratio	Reaction dissolvent
				Pyridine	15 DEG C～25 DEG C, 2 hours	90%	Dichloromethane
Triethylamine	15 DEG C～25 DEG C, 2 hours	68%	Dichloromethane
				Potassium hydroxide	15 DEG C～25 DEG C, 2 hours	72%	Dichloromethane
Potassium carbonate	15 DEG C～25 DEG C, 2 hours	70%	Dichloromethane

As can be seen from Table 1, several acid binding agents are compared, and during use triethylamine, potassium hydroxide, potassium carbonate, the extent of reaction is suitable, and during use pyridine, reaction conversion ratio is best.

Acylation reaction solvent for use has been investigated. In substrate, chloro-carbonic acid cetyl ester contains acyl chlorides structure, protonic solvent can be destroyed, therefore select non-protonic solvent as the solvent of reaction, select dichloromethane, ethyl acetate, acetone, oxolane that reaction is compared respectively, investigating the solvent impact on reaction, result is as shown in table 2.

The comparison of table 2 different solvents

Solvent	Reaction condition	Conversion ratio	Acid binding agent
				Dichloromethane	15 DEG C～25 DEG C, 2 hours	91%	Pyridine
Ethyl acetate	15 DEG C～25 DEG C, 2 hours	58%	Pyridine 3-->
				Acetone	15 DEG C～25 DEG C, 2 hours	72%	Pyridine
Oxolane	15 DEG C～25 DEG C, 2 hours	80%	Pyridine

As can be seen from Table 2, using dichloromethane and oxolane as solvent, the extent of reaction is better than ethyl acetate and acetone;From last handling process, the state of system is compared, and dichloromethane is better than oxolane.

Step 2 is that cyclization occurs compound C under the effect of condensing agent, obtains object Cetilistat. Selecting CDI, DCC, DIC, EDCI to react respectively, investigate the impact on reaction of the condensing agent kind, result is as shown in table 3.

The comparison of the different condensing agent of table 3

Condensing agent	Reaction condition	Response situation	Solvent
				CDI	20 DEG C～25 DEG C, 7 hours	Substrate most of surplus, the extent of reaction is low	Dichloromethane
DCC	20 DEG C～25 DEG C, 7 hours	Reaction generates insoluble by-product, and post processing is difficult	Dichloromethane
				DIC	20 DEG C～25 DEG C, 7 hours	It is more that reaction generates impurity	Dichloromethane
EDCI	20 DEG C～25 DEG C, 7 hours	Substrate trace remains, and generates impurity few	Dichloromethane

As can be seen from Table 3, the situation that carries out according to reaction, several condensing agents are compared, and EDCI is best to the facilitation effect of reaction.

The inventory of condensing agent has been investigated by the present invention further, select respectively 1 equivalent, 1.3 equivalents, 1.5 equivalents, 2 equivalents condensing agent react, to determine the optimum quantum of utilization of condensing agent, result is as shown in table 4.

The comparison of the different condensing agent consumption of table 4

Condensing agent consumption	Reaction condition	Conversion ratio	Condensing agent
				1 equivalent	20 DEG C～25 DEG C, 7 hours	60.7%	EDCI
1.3 equivalents	20 DEG C～25 DEG C, 7 hours	80.3%	EDCI
				1.5 equivalents	20 DEG C～25 DEG C, 7 hours	96.4%	EDCI
2 equivalents	20 DEG C～25 DEG C, 7 hours	96.3%	EDCI

As can be seen from Table 4, with the increase of condensing agent consumption, reaction conversion ratio increases, and after increasing to 1.5 equivalents, reaction conversion ratio no longer has to be increased significantly.

There is lactone structure in target product Cetilistat, this structure is unstable under protonic solvent exists, therefore select non-protonic solvent as reaction medium, select dichloromethane, ethyl acetate, acetone, oxolane that reaction is compared respectively, investigating the solvent impact on reaction, result is as shown in table 5.

The comparison of table 5 different solvents

Solvent	Reaction condition	Conversion ratio	Condensing agent
				Dichloromethane	20 DEG C～25 DEG C, 7 hours	96%	EDCI
Ethyl acetate	20 DEG C～25 DEG C, 7 hours	System is muddy, and the extent of reaction is low	EDCI
				Acetone	20 DEG C～25 DEG C, 7 hours	System is muddy, and the extent of reaction is low	EDCI
Oxolane	20 DEG C～25 DEG C, 7 hours	System is muddy, and the extent of reaction is low	EDCI

As can be seen from Table 5, adopting different solvents, the impact of reaction is relatively big, and mainly substrate and product dissolubility difference in different solvents cause, several solvents are compared, and dichloromethane is optimum solvent.

In sum, acid binding agent used by step 1 of the present invention can be organic base such as pyridine, triethylamine etc., it is also possible to be inorganic base such as hydroxide, carbonate etc., wherein preferred pyridine; Solvent is non-protonic solvent, such as dichloromethane, ethyl acetate, acetone, oxolane etc., wherein preferred dichloromethane.

Condensing agent used by step 2 cyclization of the present invention can be CDI, DCC, DIC, EDCI, wherein preferred EDCI; The consumption of condensing agent can be 1～10 equivalent, wherein preferred 1.5～2 equivalent; Solvent is non-protonic solvent, such as dichloromethane, ethyl acetate, acetone, oxolane etc., wherein preferred dichloromethane.

Technical solution of the present invention have the advantage that raw materials used, solvent, reagent are cheap and easy to get; Reaction condition is gentle, simple to operate; Overall yield of reaction is higher.

Total recovery of the present invention reaches 88%, and relatively the method yield disclosed in CN1315813C significantly improves, with<synthesis of Cetilistat>(<Chinese Journal of Pharmaceuticals>2015,46 (9)) disclosed in method yield suitable.Compared with the method disclosed in CN1315813C, present invention, avoiding the use of extremely toxic substance methylchloroformate, last handling process does not need through column chromatography purification; With<synthesis of Cetilistat>(<Chinese Journal of Pharmaceuticals>2015,46 (9)) method disclosed in is compared, the present invention uses dichloromethane to make solvent, add quantitative pyridine and make acid binding agent, the problem made troubles to industrialized production when solving with strong and stimulating pyridine solvent.

In sum, present invention achieves exploitation easy and simple to handle, with low cost, to facilitate the preparation method of the Cetilistat of industrialized production.

Accompanying drawing explanation

Fig. 1:¹H-NMR (400MHz, CDCl₃) collection of illustrative plates

Detailed description of the invention

In order to make those skilled in the art can be more fully understood that the present invention, referring to embodiment, the present invention is described. These embodiments are merely to illustrate the present invention, are not limited to the scope of the present invention.

The preparation of embodiment 1 compound C

With the decentralized compound A (15.1g) of 250mL dichloromethane in the there-necked flask of 500mL, stirring is lower adds compound B (30.5g), adds pyridine (16.1mL), drip and finish, naturally rise to room temperature reaction under ice-water bath in system.

TLC (normal hexane: ethyl acetate: glacial acetic acid=5: 1: 0.1) monitors extent of reaction, after reacting completely, adds 80mL water washing, with q. s. methylene chloride aqueous layer extracted, merging organic layer, add dilute hydrochloric acid and adjust pH to 1～2 in system, under ice-water bath, (0-10 DEG C) stirring precipitates out solid, sucking filtration, washing filter cake, eluent methylene chloride filter cake, 40 DEG C of forced air dryings, obtain 38.7g off-white color solid, yield 92.3%.

The preparation of embodiment 2 compound C

With the decentralized compound A (15.1g) of 250mL dichloromethane in the there-necked flask of 500mL, stirring is lower adds compound B (30.5g), in system, add triethylamine (27.7mL) under ice-water bath, drip and finish, naturally rise to room temperature reaction.

TLC (normal hexane: ethyl acetate: glacial acetic acid=5: 1: 0.1) monitors extent of reaction, after the extent of reaction no longer increases, adds 80mL water washing, with q. s. methylene chloride aqueous layer extracted, merging organic layer, add dilute hydrochloric acid and adjust pH to 1～2 in system, under ice-water bath, (0-10 DEG C) stirring precipitates out solid, sucking filtration, washing filter cake, eluent methylene chloride filter cake, 40 DEG C of forced air dryings, obtain 28.7g off-white color solid, yield 68.4%.

The preparation of embodiment 3 compound C

With the decentralized compound A (15.1g) of 250mL ethyl acetate in the there-necked flask of 500mL, stirring is lower adds compound B (30.5g), adds pyridine (16.1mL), drip and finish, naturally rise to room temperature reaction under ice-water bath in system.

TLC (normal hexane: ethyl acetate: glacial acetic acid=5: 1: 0.1) monitors extent of reaction, after reacting completely, adds 80mL water washing, with appropriate extraction into ethyl acetate water layer, merging organic layer, add dilute hydrochloric acid and adjust pH to 1～2 in system, under ice-water bath, (0-10 DEG C) stirring precipitates out solid, sucking filtration, washing filter cake, ethyl acetate drip washing filter cake, 40 DEG C of forced air dryings, obtain 24.6g off-white color solid, yield 58.7%.

The synthesis of embodiment 4 Cetilistat

With the decentralized compound C (120g) of 2L dichloromethane in 3L there-necked flask, under stirring, add EDCI (71.27g), stirring reaction under room temperature.

TLC (normal hexane: ethyl acetate: glacial acetic acid=50: 1: 0.1) monitors extent of reaction, after the extent of reaction is not further added by, washes 3 times × 700mL, separating organic layer, add 12g activated carbon, reflux 20min, activated carbon is filtered after being cooled to room temperature, concentrating under reduced pressure removes dichloromethane, obtains crude product and is scattered in 575mL acetonitrile, is stirred at room temperature 1 hour and makes substrate fully dispersed, ice-water bath (0-10 DEG C) stirs 3 hours, sucking filtration, 40 DEG C of forced air dryings, obtain white solid 92.2g.Yield 80.3%.¹H-NMR (400MHz, CDCl₃) δ 0.88 (3H, t, J=6.8, CH₂CH₃), 1.15～1.46 (26H, m, 13*CH₂), 1.75～1.86 (2H, m, OCH₂CH₂), 2.42 (3H, s, ArCH₃), 4.42 (2H, t, J=6.8, OCH₂), 7.32 (1H, d, J=8.3, ArH), 7.52 (1H, dd, J=8.5,2.0, ArH), 7.91 (1H, d, J=1.1, ArH)

The synthesis of embodiment 5 Cetilistat

With the decentralized compound C (120g) of 2L dichloromethane in 3L there-necked flask, under stirring, add EDCI (82.24g), stirring reaction under room temperature.

TLC (normal hexane: ethyl acetate: glacial acetic acid=50: 1: 0.1) monitors extent of reaction, washes 3 times × 700mL, separate organic layer after reacting completely, add 12g activated carbon, backflow 20min, filters activated carbon after being cooled to room temperature, concentrating under reduced pressure removes dichloromethane, obtain crude product and be scattered in 575mL acetonitrile, being stirred at room temperature 1 hour makes substrate fully dispersed, and ice-water bath (0-10 DEG C) stirs 3 hours, sucking filtration, 40 DEG C of forced air dryings, obtain white solid 110.8g. Yield 96.5%.

The synthesis of embodiment 6 Cetilistat

With the decentralized compound C (120g) of 2L dichloromethane in 3L there-necked flask, under stirring, add EDCI (109.6g), stirring reaction under room temperature.

TLC (normal hexane: ethyl acetate: glacial acetic acid=50: 1: 0.1) monitors extent of reaction, washes 3 times × 700mL, separate organic layer after reacting completely, add 12g activated carbon, backflow 20min, filters activated carbon after being cooled to room temperature, concentrating under reduced pressure removes dichloromethane, obtain crude product and be scattered in 575mL acetonitrile, being stirred at room temperature 1 hour makes substrate fully dispersed, and ice-water bath (0-10 DEG C) stirs 3 hours, sucking filtration, 40 DEG C of forced air dryings, obtain white solid 110.6g. Yield 96.3%.

Claims

1. the preparation method of a Cetilistat, it is characterised in that:

2-amino-5-ar-Toluic acid and chloro-carbonic acid cetyl ester are initiation material, first carry out aminoacylates, carry out cyclization after purification of intermediate again:

2. the preparation method of a kind of Cetilistat according to claim 1, it is characterised in that:

Step 1 is that acylation reaction occurs under the existence of acid binding agent for compound A, compound B, obtains compound C, and acid binding agent used is the material with alkalescence, plays and neutralizes the acid that reaction generates, and promotes the effect of reaction; Acid binding agent selects pyridine, triethylamine, potassium hydroxide, potassium carbonate respectively; Select non-protonic solvent as the solvent of reaction, select dichloromethane, ethyl acetate, acetone, oxolane respectively.

3. the preparation method of a kind of Cetilistat according to claim 1, it is characterised in that:

Step 2 is that cyclization occurs compound C under the effect of condensing agent, obtains object Cetilistat. Condensing agent selects CDI, DCC, DIC, EDCI respectively; Select non-protonic solvent as reaction medium, select dichloromethane, ethyl acetate, acetone, oxolane respectively.