WO2013098826A1

WO2013098826A1 - "a process for the preparation of n-[2-[(acetylthio) methyl]-1-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof"

Info

Publication number: WO2013098826A1
Application number: PCT/IN2011/000889
Authority: WO
Inventors: Dodda Mohan Rao
Original assignee: Symed Labs Limited
Priority date: 2011-12-26
Filing date: 2011-12-26
Publication date: 2013-07-04

Abstract

The present invention provides a process for the preparation of N-[2-[(acetylthio) methyl]-1-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof.

Description

"A PROCESS FOR THE PREPARATION OF N-[2-[(ACETYLTHIO) METHYL]-!- OXO-3-PHENYLPROPYL] GLYCINE PHENYL METHYL ESTER AND

INTERMEDIATES THEREOF"

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to a process for the preparation of N-[2-[(acetylthio) methyl]- l-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof.

2. Description of the Related Art

Racecadotril is a neutral endopeptidase inhibitor used as antidiarrheal in the treatment of chronic cardiac insufficiency and is available under the brand names Hidrasec and Tiorfan. Racecadotril is chemically known as N-[2-[(acetylthio) methyl]- l-oxo-3-phenylpropyl] glycine phenyl methyl ester, (herein after referred by its generic name racecadotril) and represented by the formula (I).

U.S. Patent No. US 4,513,009 describes amino acid derivatives including racecadotril, a pharmaceutical composition and a method of treatment.

The US'009 patent also discloses a process for the preparation of racecadotril which is illustrated by below scheme:

U.S. Patent No. US 6,835,851 B2 discloses a process for the preparation of racecadotril which is illustrated by scheme below:

European Patent No. EP 0501870B 1 discloses a process for the preparation of racec

Racecadotril

The use of coupling agents like hydroxyl benzotriazole (HOBT) and dicyclohexyl amine carbodiimide (DCC) generally induces the formation of side products such as dicyclohexylurea. These side products do lead to major problems, wherein purification by chromatography may be contemplated, but the side products are extremely difficult to remove on an industrial scale.

Consequently, efforts have been made to replace the peptidic coupling step

so as to avoid the formation of side products associated with the use of the coupling agents. Thus, it appears that, even if the preparation of N-(mercaptoacyl)amino acid derivatives from .alpha.-substituted acrylic acids by Michael addition of a thio acid and conversion of acid to acid chloride by using thionyl chloride and then coupling of an amino ester may be advantageous on a laboratory scale, such reactions are difficult to adapt on an industrial use.

The aforementioned processes described above involves expensive reagents such as hydroxyl benzotriazole (HOBT) and dicyclohexyl amine carbodiimide (DCC) and hazardous reagent like thionyl chloride thus rendering the processes expensive and not feasible on industrial scale.

Hence there is a need in the art to provide improved processes for the preparation of racecadotril and its intermediates, which avoids the use of hazardous and expensive reagents, formation of side products and impurities without affecting the yield and purity of the desired product racecadotril.

The process of present invention is simple, cost effective, eco-friendly, reproducible, robust and is well suited on commercial scale.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a process for the preparation of N-[2- [(acetylthio) methyl]-! -oxo-3-phenylpropyl] glycine phenyl methyl ester compound of formula

(I)

(I)

comprising:

a) reacting the compound of formula IV

(IV)

with the compound alkyl chloroformate f formula (V)

(V)

Where R is C1-C6 alkyl straight chain or branched chain or aryl.

in the presence of suitable base to afford the compound of formula VI

(VI)

Where R is C1-C6 alkyl straight chain or branched chain or aryl.

b) reacting the compound of formula VI with the compound glycine benzyl ester

thereof of formula II

II

Wherein HX is acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, methylsulfonic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, maleic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, benezenesulfonic, hydroxyethanesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p- amino salicylic, 2-phenoxybenzoic, and 2-acetoxy benzoic acid;

in the presence of suitable base to provide the compound of formula (la).

The compound of formula la thus obtained is further subjected to purification by conventional techniques like crystallization using suitable solvent(s) or a mixture thereof or their aqueous mixtures to provide the pure compound of formula I.

In another aspect, the present invention provides an intermediate compound of formula

VI

(VI)

Where R is C1-C6 alkyl straight chain or branched chain or aryl. BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 : is a schematic representation of process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present invention, there is provided a process for the preparation of N-[2-[(acetylthio) methyl]-l-oxo-3-phenylpropyl] glycine phenyl methyl ester compound of formula (I)

(I)

comprising:

a) reacting the compound of formula (IV)

(IV)

with the compound alkyl chloroformate of formula (V)

(V)

Where R is C1-C6 alkyl straight chain or branched chain or aryl.

in the presence of suitable base to afford the compound of formula (VI)

b) reacting the compound of formula (VI) with the compound glycine benzyl ester or a salt thereof of formula (II)

(II)

Wherein HX is acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, methylsulfonic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, maleic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, benezenesulfonic, hydroxyethanesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p- aminosalicylic, 2-phenoxybenzoic, and 2-acetoxy benzoic acid;

in the presence of suitable base to provide the compound of formula (la).

The compound of formula la which is a crude form of racecadotril thus obtained is subjected to purification using suitable solvent(s) or a mixture thereof or their aqueous mixtures to provide the pure compound of formula I.

The R groups in the compounds of formula V and VI can be Ci-C₆ alkyl straight chain or branched or aryl namely methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, allyl, cyclohexyl, benzyl, phenyl, para nitro phenyl etc. preferably the R- group is ethyl.

The preferable compounds suitable for the preparation of compounds of formula V include but are limited to ethyl chloro formate, benzyl chloro formate, isobutyl chloro formate, allyl chloro formate, phenyl chloro formate, paranitro phenyl chloro formate or mixtures thereof. Preferably ethyl chloro formate.

The suitable base that can be used in step a) include inorganic or organic base. Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, ammonia and the like; and the organic bases such as triethylamine, tripropylamine, pyridine, dimethyl amino pyridine, diisopropylamine, diisopropylethylamine and the like, or mixture thereof, preferably triethylamine. The organic solvents that can be used in step a) is selected from the group consisting of halogenated solvents such as dichloromethane, ethylene dichloride , chloroform, chlorobenzene, and the like; hydrocarbon solvents such as toluene, xylene, cyclohexane, n- hexane and the like; esters such as ethyl acetate, isopropyl acetate and the like: or mixtures thereof in various proportions without limitation. Preferably, dichloromethane is being used.

The reaction temperature and time in step (a) should be suitable to bring the reaction to completion at a minimum time, without the production of unwanted side products. The reaction temperature is from about -20°C to about 40°C. Preferably at about -5°C to about 10 °C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent(s) employed. The time period is from about 1 hour to about 10 hours, preferably from about 1 hour to 5 hours.

In step b) the compound of formula II is being used in acid addition salt form that can be organic or inorganic acid salt namely hydrobromic acid salt, iodic acid salt, hydrogen sulfate salt, besylate salt, paratoluene sulfonate salt, mesylate salt, tartarate salt and the like. Preferably paratoluene sulfonate is being prepared.

The suitable base that is being used in step b) include inorganic or organic base. Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, ammonia and the like; and the organic bases such as triethylamine, tripropylamine, pyridine, dimethyl amino pyridine, diisopropylamine, diisopropylethylamine and the like, or a mixture thereof, preferably triethylamine.

The organic solvent that is being used in step b) is selected from the group consisting of halogenated solvents such as dichloromethane, ethylene dichloride and the like; hydrocarbon solvents such as toluene, xylene, and the like; esters such as ethyl acetate, isopropyl acetate and the like; or a mixture thereof. Preferably, dichloromethane is being used.

The reaction step (b) is performed at temperature from about -5°C to about 30°C. preferably from about 0°C to about 10°C. The time period required for the reaction to complete may vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent(s) employed. Typically, the time period is from about 30minutes to about 10 hours, preferably from about 30 minutes to about 5 hours.

As a general rule, the base is used in an amount of greater than two molar equivalents relative to the amount of acid chloride introduced. The amino ester (II) itself is advantageously used in slight excess relative to the compound of (VI), and preferably in an amount of between 1 and 1.2 molar equivalents relative to the acid chloride.

The reaction steps (a) and (b) described above can optionally be carried out in a single pot.

The intermediate compound of formula VI is optionally isolated.

In another embodiment of the present invention, there is provided an intermediate compound of formula VI

(VI)

Where R is C1-C6 alkyl straight chain or branched chain or aryl.

The compounds of formula VI has been identified, characterized and confirmed by spectral data like IR, MASS etc.

After completion of the reaction, isolation of the desired compound from the reaction mixture can be carried out by common operation, but in consideration of the physical properties of the desired compound, crystallization, extraction, washing, column chromatography, etc. may be combined.

The intermediate compounds can be optionally purified by recrystallization, using a solvent or mixture of solvents; or by converting into their corresponding acid addition salt and then processed back to the respective free base or free acid compounds.

As a matter of fact, the inventors' studies have shown that, contrary to the acid chloride intermediate obtained after the preliminary step of addition of the thioacid, which cannot be purified on industrial scale, the acid chloride directly obtained from the acrylic acid is distillable, which allows the improvement of the purity of the obtained corresponding advanced intermediate compound, even in an industrial process, which may be exploited on an industrial scale, and which is advantageous not only with regard to its cost but also to the_yield and purity of the obtained compounds. Racecadotril crude (la) obtained above is further purified by conventional crystallization processes in solvents selected from the group consisting of (Ci-C₄)-alcohols, ketones, a mixture of (Ci-C₄)-alcphol with water, a mixture of (C₂-C₈)-ethers. Preferably, a mixture of (Ci-C₄)-alcohol with water. More preferably, a mixture of methanol and water in any proportion optionally with carbon treatment.

Advantageously, the process of present invention avoids the use of hazardous reagents like thionly chloride and expensive reagents like hydroxyl benzotriazole (HOBT) and dicyclohexylamine carbodiimide (DCC) thus providing the intermediates with higher yields and purities thus leading to higher yields and purities of the final product.

Advantageously, the process according to the present invention preferably yields racecadotril (I) substantially pure form. Thus the racecadotril (I) obtained by the processes of present invention has purity at least about 98 area % by HPLC, preferably at least about 99 area%. More preferably at least about 99.5 area % by HPLC.

The starting intermediate of formula (IV) is commercially available and can be prepared by any of the methods known in the art for ex. U.S. Patent No. US 4,513,009.

The present invention provides simple, ecofriendly, economic, reproducible, robust process for preparation of racecadotril, which are viably adaptable on a commercial scale.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention.

It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

Example-1: Preparation of Racecadotril (I):

Step A) Preparation of 2-acetyIsulfanyI methyI-3-phenyI propionic acid (IV)

16.2 g of 2-benzylacrylic acid and 12.3 ml of thioacetic acid were were charged into a clean and dry R.B.flask and stirred at about 30°C for about 1 hour. The reaction mixture was heated to about 60°C and stirred for about 4 hours.The excess of thioacetic acid was distilled off completely to afford the title compound as residue. Yield: 23.8 g. Step B) Preparation of Racecadotril crude (la)

23.8 g. of 2-acetyl sulfanylmethyl-3-phenyl-propionic acid (IV), 200ml of methylene chloride and 16.7 ml of triethylamine were charged into a clean and dry R.B.flask. 10. 5 ml of ethylchloroformate was added at about -5°C. The resultant reaction mixture was stirred at about 0°C for about 30 min. 33.7 g of glycine benzyl ester p-tosyalte (II), 14 ml of triethylamine and 100ml of methylene chloride was added as a mixture to the reaction mass at about 0°C. Then the resultant reaction mixture was stirred at about 0°C for about 1 hr. followed by at about 30°C for about 30 min. After completion of the reaction as determined by TLC, the reaction mass was washed with 65 ml of distilled water, 65 ml 4% sodium bicarbonate solution and followed by 65 ml distilled water. The organic and aqueous phases were separated and the solvent was distilled completely, 2 x 50 ml Isopropyl alcohol was charged and again distilled off the solvent completely to give residue. The residue

obtained was triturated with a mixture of isopropyl alcohol 4 ml) and n-hexane (94 ml) at about 5°C to the title compound as crude. Yield: 34 g.

ExampIe-2: Purification of Racecadotril (Crude):

34 g. of crude Racecadotril and 35 ml of 20 % v/v aqueous .methanol were charged in a clean and dry R.B.flask and heated to about 65°C. 3g. of SP.carbon was charged and stirred at about 65°C for about 10 min. The reaction suspension was stirred at about 65°C for about 10 min. The reaction suspension was filtered on hyflow bed (diatomous earth) and washed the hyflow bed with 30 ml of aqueous methanol. The filtrate obtained was cooled to about 0°C for about 30 min. The solid separated was filtered and the solid obtained washed with 60 ml of precooled aqueous methanol to afford the pure racecadotril (I).

Yield: 29 g.; Purity by HPLC: 99.5 area %; The overall yield is 75.3%.

Claims

We Claim:

1) A process the preparation of N-[2-[(acetylthio) methyl]-! -oxo-3-phenylpropyl] glycine phenyl methyl ester com ound of formula (I)

(I)

comprising:

a) reacting the compound of formula IV

(IV)

with the compound alkyl chloroformate of formula V

(V)

Where R is C1-C6 alkyl straight chain or branched chain or aryl.

in the presence of suitable base to afford the compound of formula VI

(VI)

Where R is C1-C6 alkyl straight chain or branched chain or aryl.

b) reacting the compound of formula VI with the compound glycine benzyl ester or a salt thereof of formula II II

in the presence of a suitable base to provide the compound of formula (la).

2) The process of claim 1 , wherein the preferable compounds suitable for the preparation of compounds of formula V include but are limited to ethyl chloro formate, benzyl chloro formate, isobutyl chloro formate, allyl chloro formate, phenyl chloro formate, paranitro phenyl chloro formate; preferably ethyl chloro formate.

3) The process of claim 1, wherein the suitable base used in step a) is selected from

inorganic bases like sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, ammonia; organic bases like triethylamine, tripropylamine, pyridine, dimethyl amino pyridine, diisopropylamine,

diisopropylethylamine or a mixture thereof, preferably triethylamine.

4) The process of claim 1, wherein the organic solvents that can be used in step a) is

selected from halogenated solvents like dichloromethane, ethylene dichloride ;

hydrocarbon solvents like toluene, xylene; esters like ethyl acetate or a mixture thereof preferably, dichloromethane.

5) The process of claim 1 , wherein the reaction step (a) is carried out at temperature from about -10°C to about 30°C,preferably at about -5°C to about 5°C and the time period is from about 1 hour to about 10 hours, preferably from about 1 hour to 5 hours. 6) The process of claim 1 , wherein the compound of formula II is being used in step (a) is in acid addition salt form that can be organic or inorganic acid salt namely hydrobromic acid salt, iodic acid salt, hydrogen sulfate salt, besylate salt, paratoluene sulfonate salt, mesylate salt, tartarate salt; preferably in the form of paratoluene sulfonate.

7) The process of claim 1, wherein the suitable base that is being used in step b) is selected include inorganic or organic base. Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, ammonia and the like; and the organic bases such as triethylamine, tripropylamine, pyridine, dimethyl amino pyridine, diisopropylamine, diisopropylethylamine; or a mixture thereof, preferably triethylamine.

8) The process of claim 1, wherein the organic solvent that is being used in step b) is

selected from halogenated solvents like dichloromethane, ethylene dichloride;

hydrocarbon solvents like toluene, xylene; esters like ethyl acetate; or a mixture thereof, preferably, dichloromethane is being used.

9) The process of claim 1 , wherein the reaction step (b) is performed at temperature from

about -5°C to about 30°C, preferably from about 0°C to about 10 °C and the time period from about 30minutes to about 10 hours, preferably from about 30 minutes to about 5 hours.

10) The processes of preceding claims, wherein the crude racecadotril (la) obtained above is further purified to provide racecadotril (I) by conventional crystallization processes using solvents selected from the group consisting of (Ci-C₄)-alcohols, ketones, a mixture of (Ci- C₄)-alcohol with water, a mixture of (C₂-C₈)-ethers, preferably, a mixture of (Cj-C₄)- alcohol with water. More preferably, a mixture of methanol and water in any proportion optionally with carbon treatment.

11) Racecadotril (I) obtained by the process of claim 10, has a purity of at least about

99 area % as determined by HPLC. 12) Racecadotril (I ) obtained by the process of claim 10, has individual impurity less than about 0.1 area % and total impurities less than about 0.5 area % as determined by HPLC

13) An intermediate compound of formula VI

(VI)

Where R is C1-C6 alkyl straight chain or branched chain or aryl.