FR2510565A1 - PROCESS FOR THE PREPARATION OF A- (3,4,5-TRIMETHOXYBENZOYLTHIO) -PROPIONYL GLYCINE - Google Patents

PROCESS FOR THE PREPARATION OF A- (3,4,5-TRIMETHOXYBENZOYLTHIO) -PROPIONYL GLYCINE Download PDF

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Publication number
FR2510565A1
FR2510565A1 FR8214305A FR8214305A FR2510565A1 FR 2510565 A1 FR2510565 A1 FR 2510565A1 FR 8214305 A FR8214305 A FR 8214305A FR 8214305 A FR8214305 A FR 8214305A FR 2510565 A1 FR2510565 A1 FR 2510565A1
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Prior art keywords
trimethoxybenzoylthio
glycine
preparation
och
propionyl
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FR8214305A
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FR2510565B1 (en
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Cyril Beck
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Norton Healthcare Ltd
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Norton Healthcare Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C325/00—Thioaldehydes; Thioketones; Thioquinones; Oxides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/28—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

PROCEDE DE PREPARATION DE L'A-(3,4,5-TRIMETHOXYBENZOYLTHIO)-PROPIONYL GLYCINE, COMPOSE UTILE POUR SES PROPRIETES THERAPEUTIQUES. CE PROCEDE CONSISTE A ACYLER LA GLYCINE AVEC L'ACIDE A-(3,4,5-TRIMETHOXYBENZOYLTHIO)-PROPIONIQUE.PROCESS FOR THE PREPARATION OF A- (3,4,5-TRIMETHOXYBENZOYLTHIO) -PROPIONYL GLYCINE, A COMPOUND USEFUL FOR ITS THERAPEUTIC PROPERTIES. THIS PROCESS CONSISTS OF ACYLTING GLYCINE WITH A- (3,4,5-TRIMETHOXYBENZOYLTHIO) -PROPIONIC ACID.

Description

La présente invention concerne un nouveau procédé de préparation de l'o -The present invention relates to a novel process for the preparation of o -

( 3,4,5-triméthoxybenzoylthio)-propionyl glycine:  (3,4,5-trimethoxybenzoylthio) propionyl glycine:

CH 3 CH CO NH H 2 COOHCH 3 CH CO NH H 2 COOH

S OCHS OCH

I AI A

CO> (OCH 3CO> (OCH 3

OCH 3 a) Le composé (I) décrit dans la demande de brevet italien n 25883 A/80 du,1/11/1980 possède d'utiles propriétés thérapeutiques pour le traitement  OCH 3 a) Compound (I) described in Italian Patent Application No. 25883 A / 80 of 1/11/1980 has useful therapeutic properties for treatment

des brcnchopathies, des hépatopathies et des suites d'empoisonnement.  brachyopathies, hepatopathies and poisonings.

Selon la demande de brevet mentionnée ci-dessus, celui-ci est obtenu  According to the patent application mentioned above, this one is obtained

par acylation de l' c-mercaptopropionyl glycine avec le chlorure de 3,4,5-  by acylation of c-mercaptopropionyl glycine with 3,4,5-chloro

triméthoxybenzoyle Cela implique évidemment l'utilisation d'o -mercapto-  trimethoxybenzoyl This obviously involves the use of o -mercapto

propionyl glycine, produit cher et qui possède une odeur persistante et désa-  propionyl glycine, an expensive product with a persistent odor and

gréable; de plus, les rendements de réaction ne sont pas très satisfaisants.  gréable; in addition, the reaction yields are not very satisfactory.

A présent, on a trouvé qu'il est possible d'obtenir (I) de façon satisfaisante par acylation de la glycine (III) avec un dérivé activé de l'acide,-( 3,4,5 triméthoxybenzoylthio) propionique (II), selon le schéma ci-dessous:  It has now been found that it is possible to obtain (I) satisfactorily by acylation of glycine (III) with an activated derivative of (3,4,5-trimethoxybenzoylthio) propionic acid (II) , according to the diagram below:

CH 3 -CH COY NH 2 CH 2 -COOHCH 3 -CH COY NH 2 CH 2 -COOH

S +S +

CO ArCO Ar

(II) (III)(II) (III)

dans lequel Ar représente le résidu 3,4,5-triméthoxyphényle, tandis que Y représente un groupe activant, tel que Cl, -O-CO-O al Ikyle, alcoxyle Le produit intermédiaire (II) est quant à lui facilement accessible, par exemple  wherein Ar represents the 3,4,5-trimethoxyphenyl residue, while Y represents an activating group, such as Cl, -O-CO-O-alkyl, alkoxyl. The intermediate product (II) is in turn easily accessible by example

par acylation de l'acide thiopropionique avec le chlorure de 3,4,5triméthoxy-  by acylation of thiopropionic acid with 3,4,5-trimethoxychloride

benzoyle La réaction se déroule de préférence à des températures inférieures a 20 C, pour des durées comprises entre 4 et 20 heures On sépare le produit par filtration puis par recristallisation ultérieure Les exemples suivants illustrent le procédé selon l'invention:  benzoyl The reaction is preferably carried out at temperatures below 20 ° C. for periods of between 4 and 20 hours. The product is separated by filtration and then by subsequent recrystallization. The following examples illustrate the process according to the invention:

Exemple 1Example 1

a) acide v-( 3,4,5-triméthoxybenzoylthio) propionique A une solution de 3, 3 kg de K 2 CO dans 9 litres d'eau, on ajoute, entre 15 et 20 C, 767 ml d'acide 3-thiopropionique (aide tholatique ommercia, et 2001 C, 767 ml d'acidecç-thiopropionique (acide thiolactique commercial, densité 1,2); ensuite, à la même température et en deux fractions, on ajoute 2 kg de chlorure de 3,4,5-triméthoxybenzoyle Aprèsune nuit d'agitation à température ambiante, on acidifie avec H Cl 1:1 et on extrait  (a) v- (3,4,5-trimethoxybenzoylthio) propionic acid To a solution of 3.3 kg of K 2 CO in 9 liters of water is added, between 15 and 20 C, 767 ml of thiopropionic acid (thecotic aid ommercia, and 2001 C, 767 ml of α-thiopropionic acid (commercial thiolactic acid, density 1,2), then, at the same temperature and in two fractions, 2 kg of chloride of 3.4, 5-trimethoxybenzoyl After stirring overnight at room temperature, acidified with HCl 1: 1 and extracted

avec trois portions de 15 litres de toluène Après lavage à l'eau et évapo-  with three 15-liter portions of toluene After washing with water and evapo-

ration de la solution de toluène, on recueille 2,6 kg d'un produit huileux  of the toluene solution, 2.6 kg of an oily

dont les données analytiques concordent avec l'analyse calculée.  whose analytical data is consistent with the calculated analysis.

b) Oî-( 3,4,5-triméthoxybenzoylthio) propionyl glycine (I) On ajoute graduellement le composé obtenu au stade précédent a) ( 2,6 kg) à 7 litres de chlorure de thionyle On laisse sous agitation toute la nuit, on évapore l'excès de SO C 12, on traite avec 3 litres de benzène et on évaporee a nouveau sous vide On ajoute graduellement le résidu obtenu ( 2, 7 kg) à une solution de 730 g de glycine et 290 g de K 2 C O 03 dans 10 litres d'eau, en évitant que la température n'excède 20 C Une fois l'addition terminée, on laisse sous agitation toute la nuit à température ambiante, puis on ajoute  b) O- (3,4,5-trimethoxybenzoylthio) propionyl glycine (I) The compound obtained in the preceding stage a) (2.6 kg) is gradually added to 7 liters of thionyl chloride. The mixture is stirred overnight, the excess SO 2 C 12 was evaporated, treated with 3 liters of benzene and evaporated again in vacuo. The residue obtained (2.7 kg) was gradually added to a solution of 730 g of glycine and 290 g of K 2 CO 03 in 10 liters of water, avoiding that the temperature does not exceed 20 C Once the addition is complete, it is left stirring overnight at room temperature, then added

une solution glacée de H Cl 1:1 pour un obtenir un p H 2 On sépare le préci-  an ice-cold solution of HCl 1: 1 to obtain a p H 2.

pité par filtration, on lave vigoureusement à l'eau et on recristallise dans le méthanol On obtient 2,03 kg de produit avec un p f de 172-174 C  filtered, washed vigorously with water and recrystallized from methanol. 2.03 kg of product with a mp of 172 ° -174 ° C. were obtained.

(rendement environ 68 %).(yield about 68%).

Exemple 2Example 2

On dissout 288 g ( 1 mole) d'acide "-( 3,4,5-triméthoxybenzoylthio) propioni-  288 g (1 mole) of "- (3,4,5-trimethoxybenzoylthio) propionic acid are dissolved

que obtenu selon l'exemple la)dans 5 litres de chloroforme, auquel on ajoute en refroidissant à 10-15 C, 108 g ( 1 mole) de chlorocarbonate d'éthyle puis  obtained according to Example 1a) in 5 liters of chloroform, to which is added while cooling to 10-15 C, 108 g (1 mole) of ethyl chlorocarbonate then

101 g ( 1 mole) de triéthylamine A la solution d'anhydride mixte ainsi obte-  101 g (1 mole) of triethylamine to the mixed anhydride solution thus obtained.

nue on ajoute 75 g ( 1 mole) de glycine, en brassant Après 36 heures d'agi-  75 g (1 mole) of glycine are added, stirring after 36 hours of stirring.

tation à température ambiante; on traite avec 2 kg de glace pilée et on ajoute H Cl 1:1 jusqu'à ce que la solution soit acide (p H 1-2) On sépare  at room temperature; treated with 2 kg of crushed ice and added HCl 1: 1 until the solution is acidic (p H 1-2).

la solution de chloroforme, on lave a l'eau et on évapore jusqu'à siccité.  the chloroform solution, washed with water and evaporated to dryness.

On recristallise le résidu dans l'éthanol; on obtient (I) avec un rendement  The residue is recrystallized from ethanol; we obtain (I) with a yield

de 63 %, p f 173-175 C.63%, mp 173-175C.

Claims (2)

REVENDICATIONS 1 Procédé de préparation de 1 ' "-( 3,4,5-triméthoxybenzoylthio) propionyl glycine de formule: CH 3 CH CO NH CH 2 COOH  Process for the preparation of 1 '- (3,4,5-trimethoxybenzoylthio) propionyl glycine of the formula: CH 3 CH 2 CO 2 CH 2 COOH 3 OCH 23 OCH 2 S 3S 3 CO ' OCH 3CO 'OCH 3 OCH 3 caractérisé en ce qu'on acyle la glycine (III) avec un dérivé activé de l'acide o-( 3,4,5-triméthoxybenzoylthio) propionique (II) selon le schéma ci-dessous:  OCH 3 characterized in that glycine (III) is acylated with an activated derivative of o- (3,4,5-trimethoxybenzoylthio) propionic acid (II) according to the scheme below: CH 3 CH COY NH 2 -CH 2 COOH(I)CH 3 CH COY NH 2 -CH 2 COOH (I) 1 +1 + CO ArCO Ar (II) (III)(II) (III) dans lequel Ar représente le résidu 3,4,5-triméthoxyphényle, Y représentant  wherein Ar represents the 3,4,5-trimethoxyphenyl residue, Y being un groupe activant.an activating group. 2 Procédé selon la revendication 1, caractérisé en ce que Y repré-  Process according to Claim 1, characterized in that Y represents sente le chlore.smell the chlorine. 3 Procédé selon la revendication 1, caractérisé en ce que Y repré-  3. Process according to claim 1, characterized in that Y represents sente le résidu C 2 H 50-C-O-.C 2 H 50-C-O- residue. 2 5 Oi O2 5 Oi O
FR8214305A 1981-04-07 1982-08-18 PROCESS FOR THE PREPARATION OF A- (3,4,5-TRIMETHOXYBENZOYLTHIO) -PROPIONYL GLYCINE Expired FR2510565B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IT20976/81A IT1144700B (en) 1981-04-07 1981-04-07 PROCEDURE FOR THE PREPARATION OF A GLYCINE DERIVATIVE

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FR2510565A1 true FR2510565A1 (en) 1983-02-04
FR2510565B1 FR2510565B1 (en) 1985-08-30

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FR8206097A Expired FR2503152B1 (en) 1981-04-07 1982-04-07 PROCESS FOR THE PREPARATION OF A- (3,4,5-TRIMETHOXYBENZOYLTHIO) -PROPIONYL GLYCINE
FR8214305A Expired FR2510565B1 (en) 1981-04-07 1982-08-18 PROCESS FOR THE PREPARATION OF A- (3,4,5-TRIMETHOXYBENZOYLTHIO) -PROPIONYL GLYCINE

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Country Status (7)

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JP (1) JPS5941985B2 (en)
CA (1) CA1171877A (en)
DE (1) DE3212766A1 (en)
FI (1) FI821046L (en)
FR (2) FR2503152B1 (en)
GB (1) GB2096144B (en)
IT (1) IT1144700B (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3243369A1 (en) * 1982-11-24 1984-05-24 Basf Ag, 6700 Ludwigshafen BIS- (BENZOYLTHIO) CARBONIC ACIDS, THEIR PRODUCTION AND USE FOR THE PRODUCTION OF ACTIVE SUBSTANCES
DE3533124A1 (en) * 1985-09-17 1987-03-26 Bosch Gmbh Robert SPARK PLUG WITH GLIDING RANGE
JPH0745461B2 (en) * 1985-12-19 1995-05-17 旭化学工業株式会社 Thiobenzoic acid derivative, sensitizer for heat-sensitive recording comprising the derivative, and heat-sensitive recording material containing the same
CN103562713B (en) * 2011-08-17 2015-07-08 日本特殊陶业株式会社 Gas sensor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3246025A (en) * 1961-11-02 1966-04-12 Santen Pharmaceutical Co Ltd Mercaptopropionic acid derivatives
FR2495145A1 (en) * 1980-11-11 1982-06-04 Ausonia Farma Srl A- (3,4,5-TRIMETHOXYBENZOYLTHIO) PROPIONYLGLYCIN, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3246025A (en) * 1961-11-02 1966-04-12 Santen Pharmaceutical Co Ltd Mercaptopropionic acid derivatives
FR2495145A1 (en) * 1980-11-11 1982-06-04 Ausonia Farma Srl A- (3,4,5-TRIMETHOXYBENZOYLTHIO) PROPIONYLGLYCIN, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME

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CA1171877A (en) 1984-07-31
DE3212766A1 (en) 1982-11-04
FI821046L (en) 1982-10-08
JPS57179155A (en) 1982-11-04
FR2503152B1 (en) 1985-10-25
GB2096144B (en) 1984-12-19
FI821046A0 (en) 1982-03-24
FR2503152A1 (en) 1982-10-08
GB2096144A (en) 1982-10-13
JPS5941985B2 (en) 1984-10-11
IT1144700B (en) 1986-10-29
IT8120976A0 (en) 1981-04-07
FR2510565B1 (en) 1985-08-30

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