WO1982003074A1 - New process for the esterification of amino acids - Google Patents

New process for the esterification of amino acids Download PDF

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Publication number
WO1982003074A1
WO1982003074A1 PCT/FR1982/000043 FR8200043W WO8203074A1 WO 1982003074 A1 WO1982003074 A1 WO 1982003074A1 FR 8200043 W FR8200043 W FR 8200043W WO 8203074 A1 WO8203074 A1 WO 8203074A1
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WIPO (PCT)
Prior art keywords
esterification
amino acid
sulfate
amino acids
ester
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PCT/FR1982/000043
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French (fr)
Inventor
Michel Flork
Jean Robert Grinda
Original Assignee
Michel Flork
Jean Robert Grinda
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Application filed by Michel Flork, Jean Robert Grinda filed Critical Michel Flork
Priority to JP57500844A priority Critical patent/JPS58500442A/en
Publication of WO1982003074A1 publication Critical patent/WO1982003074A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters

Definitions

  • the present invention relates to a new process for obtaining amino acids and the esters thus obtained.
  • the esterification of the carboxylic function in ⁇ of the amino function is an effective blocking mode to allow condensation reactions, either on the adjacent amino function, or on a function present on the carbon chain of the amino acid.
  • This is how the chain can carry a hydroxyl as in the case of serine or ⁇ acid - amino hydroxy butyric - an amino function like lysine, another carboxylic function like glutamic acid or aspartic acid or a guanidine function such as arginine. It is therefore necessary in many cases, to start a peptide synthesis to block one of the reactive functions to allow condensations on another reactive function of the molecule.
  • esterification of amino acids which constitutes one of the blocking modes, often poses difficult problems due to the proximity of an amino function. Avoid using an alkylating or aralkylating agent which could also react with the amino function. Very acidic agents or very acidic conditions must also be avoided because the protonation of the amino function deactivates the carboxylic function. In addition, esterification in an acid medium gives rise to the formation of water and the reaction tends towards an equilibrium.
  • the method according to the invention aims to solve a large number of these problems. It makes it possible to obtain an amino acid ester with an almost quantitative yield and to isolate it in pure form in a very easy manner. It makes it possible to be able to optionally recover the unreacted amino acid, in the form insoluble in the reaction medium.
  • the method consists in subjecting an amino acid to the action of an alkanol in the presence of an equimolecular amount of an alkyl sulfate and in isolating the ester thus formed in the form of acid alkyl sulfate which is converted into an oase and then reconverted into salt, if desired.
  • the process according to the invention can also be defined by the following methods which are currently preferred: 1 /
  • the alkanol is preferably an aliphatic alcohol of low molecular weight.
  • the alkyl sulfate is preferably a lower alkyl sulfate whose alkyl radical is the same as that of the alkanol.
  • reaction is carried out using equimolecular proportions of amino acid and alkyl sulfate.
  • the amino ester alkyl sulfate is converted into the base by addition of an alkaline agent.
  • the amino ester can be converted into a salt by adding a mineral or organic acid in solution in an anhydrous organic solvent.
  • esters according to the invention are known intermediates, used for peptide synthesis such as for example the synthesis of oxytocin, TRH or aspartame.
  • the following examples illustrate the invention without, however, limiting it.
  • the crystals are separated by filtration, washed with acetone and dried under vacuum or in a ventilated oven at 45 ° - 191.92 g of methyl phenylalaninate sulfate (white crystalline product) are thus obtained.
  • the mixture is concentrated to half volume and the crystallization is initiated by scraping at ordinary temperature.
  • the crystalline mixture is left to stand overnight in a cooler.
  • the crystals are separated and washed with cold ethanol and then dried.
  • the suspension is brought to reflux for 4 hours and then allowed to cool to ambient temperature.
  • the mixture After homogenization of the mixture, the mixture is heated to 80 ° C. for 6 hours then allowed to cool and the excess reagent is removed by vacuum distillation. The residual mixture is taken up by the minimum quantity of hot dioxane from which it recrystallizes by cooling. After a few hours' rest, the terbutyl sulphate of terbutyl tryptophanate is separated by filtration. The crystals are separated, wrung thoroughly, then dried at constant weight under vacuum. They are redissolved in 300 ml of methylene chloride and agitated against the current with aqueous sodium hydroxide. The organic phase is separated, washed with water until the washings are neutral, dried over sodium sulfate, filtered and then evaporated to dryness.
  • the crystalline residue is taken up in isopropyl ether.
  • the solution is diluted with an equal volume of cyclohexane.
  • Terbutyl tryptophanate gradually precipitates. It is separated by filtration, wrung, rinsed with cyclohexane and dried.
  • the residue weighing 291 g consists of pure terbutyl tryptophanate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

The invention relates to the field of the peptide chemistry. The object is an esterification process which comprises subjecting an amino acid to the action of an alkylsulfate in the presence of an equimolecular amount of an alkylsulfate and isolating the ester in the form of alkylsulfate. The esters obtained are very useful synthesis intermediate products.

Description

NOUVEAU PROCEDE D' ESTERIFICATION D ' AMINO-ACIDES NEW PROCESS FOR THE ESTERIFICATION OF AMINO ACIDS
La présente invention concerne un nouveau procédé d'obtention d'amino acides et les esters ainsi obtenus. L'esterification de la fonction carboxylique en α de la fonction aminé est un mode de blocage efficace pour permettre des réactions de condensation, soit sur la fonction aminé adjacente, soit sur une fonction présente sur la chaîne carbonée de l'amino-acide. C'est ainsi que la chaîne peut porter un hydroxyle comme dans le cas de la serine ou de l'acide ɣ - amino hydroxy butyrique - une fonction aminé comme la lysine, une autre fonction carboxylique comme l'acide glutamique ou l'acide aspartique ou une fonction guanidine comme l'arginine. Il est donc nécessaire dans beaucoup de cas, pour entamer une synthèse de peptide de bloquer une des fonctions réactives pour permettre des condensations sur une autre fonction réactive de la molécule. l'esterification des amino-acides qui constitue un des modes de blocage, pose souvent des problèmes difficiles en raison de la proximité d'une fonction aminé. Il faut éviter d'utiliser un agent alcoylant ou aralcoylant qui pourrait réagir également avec la fonction aminé. Il faut également éviter des agents très acides ou des conditions très acides car la protonation de la fonction aminé désactive la fonction carboxylique. En outre, l'esterification en milieu acide donne naissance à la formation d'eau et la réaction tend vers un équilibre. Le procédé selon l'invention vise à résoudre un grand nombre de ces problèmes. Il permet d'obtenir un ester d'amino-acide avec un rendement presque quantitatif et de l'isoler sous forme pure d'une manière très aisée. Il permet de pouvoir éventuellement récupérer l'amino-acide qui n'a pas réagi, sous forme insoluble dans le milieu réactionnel. Il comporte également l'avantage de ne pas donner naissance à la formation d'eau ce qui permet une réaction complète. Selon l'invention le procédé consiste à soumettre un amino-acide à l'action d'un alcanol en présence d'une quantité équimoléculaire d'un sulfate d'alcoyle et à isoler l'ester ainsi formé sous forme d'alcoyl sulfate acide que l'on convertit en oase puis reconvertit en sel, si désiré. Le procédé selon l'invention peut encore être défini par les modalités suivantes actuellement préférées : 1/ L' alcanol est de préférence un alcool aliphatique de bas poids moléculaires.The present invention relates to a new process for obtaining amino acids and the esters thus obtained. The esterification of the carboxylic function in α of the amino function is an effective blocking mode to allow condensation reactions, either on the adjacent amino function, or on a function present on the carbon chain of the amino acid. This is how the chain can carry a hydroxyl as in the case of serine or ɣ acid - amino hydroxy butyric - an amino function like lysine, another carboxylic function like glutamic acid or aspartic acid or a guanidine function such as arginine. It is therefore necessary in many cases, to start a peptide synthesis to block one of the reactive functions to allow condensations on another reactive function of the molecule. the esterification of amino acids which constitutes one of the blocking modes, often poses difficult problems due to the proximity of an amino function. Avoid using an alkylating or aralkylating agent which could also react with the amino function. Very acidic agents or very acidic conditions must also be avoided because the protonation of the amino function deactivates the carboxylic function. In addition, esterification in an acid medium gives rise to the formation of water and the reaction tends towards an equilibrium. The method according to the invention aims to solve a large number of these problems. It makes it possible to obtain an amino acid ester with an almost quantitative yield and to isolate it in pure form in a very easy manner. It makes it possible to be able to optionally recover the unreacted amino acid, in the form insoluble in the reaction medium. It also has the advantage of not giving rise to the formation of water which allows a complete reaction. According to the invention the method consists in subjecting an amino acid to the action of an alkanol in the presence of an equimolecular amount of an alkyl sulfate and in isolating the ester thus formed in the form of acid alkyl sulfate which is converted into an oase and then reconverted into salt, if desired. The process according to the invention can also be defined by the following methods which are currently preferred: 1 / The alkanol is preferably an aliphatic alcohol of low molecular weight.
2/ Le sulfate d'alcoyle est de préférence un sulfate d'alcoyle inférieur dont le radical alcoyle est le même que celui de l'alcanol.2 / The alkyl sulfate is preferably a lower alkyl sulfate whose alkyl radical is the same as that of the alkanol.
3/ La réaction est effectuée en utilisant des proportions équimoléculaires d'acide aminé et de sulfate d'alcoyle.3 / The reaction is carried out using equimolecular proportions of amino acid and alkyl sulfate.
4/ La réaction est effectuée au reflux de l'alcanol.4 / The reaction is carried out at reflux of the alkanol.
5/ L' alcoylsulfate d'amino ester est transformé en base par addition d'un agent alcalin.5 / The amino ester alkyl sulfate is converted into the base by addition of an alkaline agent.
6/ L'amino ester peut être converti en sel par addition d'un acide minéral ou organique en solution dans un solvant organique anhydre.6 / The amino ester can be converted into a salt by adding a mineral or organic acid in solution in an anhydrous organic solvent.
Les esters selon l'invention sont des intermédiaires connus, utilisés en vue de la synthèse peptidique comme par exemple la synthèse de l'ocytocine, du TRH ou de l'aspartame. Les exemples suivants illustrent l'invention, sans toutefois la limiter. EXEMPLE IThe esters according to the invention are known intermediates, used for peptide synthesis such as for example the synthesis of oxytocin, TRH or aspartame. The following examples illustrate the invention without, however, limiting it. EXAMPLE I
Dans un ballon équipé pour un chauffage au reflux, on charge 165 g de 1 - phényl alanine (1 mole) et 191 ml de sulfate de raéthyle et on le dilue dans 600 ml de méthanol. On chauffe le mélange au reflux sous agitation pendant 6 heures. La transformation de la phenylalanine est complète, ainsi qu'il ressort de la chromatographie en couche mince. (CCM sur plaque de silice G 60 Merck - solvant CHCI364, méthanol 30, eau 4 et acide formique 2).165 g of 1-phenyl alanine (1 mole) and 191 ml of raethyl sulphate are loaded into a flask equipped for heating under reflux and diluted in 600 ml of methanol. The mixture is heated to reflux with stirring for 6 hours. The transformation of phenylalanine is complete, as shown by thin layer chromatography. (TLC on G 60 Merck silica plate - solvent CHCI 3 64, methanol 30, water 4 and formic acid 2).
Révélation par la nynhydrine.Revelation with nynhydrin.
On concentre sous vide et on obtient 499 g de méthylsulfate de phénylalaninate de méthyle, on neutralise à 0ºC ce sel par de la soude 5N (213 ml) et on extrait la base au trichloréthane, en trois fois. Les extraits dans le trichloréthane sont séchés sur sulfate de sodium anhydre, puis concentrés sous vide. On obtient une huile (192 g) de 1 - phénylalaninate de méthyle qui peut être conservée une semaine à 0ºC. Cette huile peut être cristallisée sous forme de sulfate en la dissolvant dans l'acétone, puis en ajoutant lentement, en refroidissant, une solution à 15% d'acide sulfurique dans l'acétone, préparée extemporanément. On obtient une solution limpide légèrement rose, qui se trouble rapidement et cristallise abondamment.It is concentrated under vacuum and 499 g of methyl phenylalaninate methyl sulfate are obtained, this salt is neutralized at 0 ° C with 5N sodium hydroxide (213 ml) and the base is extracted with trichloroethane, three times. The extracts in trichloroethane are dried over anhydrous sodium sulfate, then concentrated in vacuo. An oil (192 g) of methyl 1-phenylalaninate is obtained which can be stored for one week at 0ºC. This oil can be crystallized in the form of sulfate by dissolving it in acetone, then slowly adding, while cooling, a 15% solution of sulfuric acid in acetone, prepared immediately. A clear, slightly pink solution is obtained, which quickly becomes cloudy and abundantly crystallizes.
On sépare par filtration les cristaux, on lave à l'acétone et on sèche sous vide ou en étuve ventilée à 45º - 191,92 g de sulfate de phénylalaninate de méthyle (produit cristallin blanc) sont ainsi obtenus.The crystals are separated by filtration, washed with acetone and dried under vacuum or in a ventilated oven at 45 ° - 191.92 g of methyl phenylalaninate sulfate (white crystalline product) are thus obtained.
EXEMPLE IIEXAMPLE II
Préparation du Valinate d'ethyle.Preparation of ethyl valinate.
Dans un ballon a trois tubulures, on introduit successivementIn a balloon with three tubes, we successively introduce
112 g de L - Valine et 154 g de sulfate d'ethyle. On dilue le mélange avec 450 ml d'éthanol. On porte le mélange au reflux sous agitation pendant 6 heures. On laisse ensuite refroidir.112 g of L - Valine and 154 g of ethyl sulfate. The mixture is diluted with 450 ml of ethanol. The mixture is brought to reflux with stirring for 6 hours. Then allowed to cool.
On concentre à demi volume et on amorce la cristallisation par grattage à température ordinaire. On laisse reposer le mélange cristallin une nuit en glacière. On sépare les cristaux qu'on lave avec de l'éthanol froid puis sèche.The mixture is concentrated to half volume and the crystallization is initiated by scraping at ordinary temperature. The crystalline mixture is left to stand overnight in a cooler. The crystals are separated and washed with cold ethanol and then dried.
On obtient ainsi 276 g de L-Valinaté d'ethyle sous forme d'éthylsulfate.276 g of ethyl L-valinate are thus obtained in the form of ethyl sulphate.
EXEMPLE IIIEXAMPLE III
Préparation du L-Lysinate de méthyle.Preparation of methyl L-Lysinate.
On met en suspension 147 g de L - Lysine dans 750 ml de méthanol et on y ajoute progressivement 191 ml de sulfate de méthyle .147 g of L-Lysine are suspended in 750 ml of methanol and gradually 191 ml of methyl sulfate are added thereto.
On porte la suspension au reflux pendant 4 Heures puis on la laisse refroidir à température ambiante.The suspension is brought to reflux for 4 hours and then allowed to cool to ambient temperature.
On évapore à sec le solvant sous pression réduite. Il reste un résidu pesant 404 g qui cristallise lentement. Après une nuit en glacière, on sépare les cristaux par filtration, les rince au méthanol et les sèche en étuve ventilée. On recueille ainsiThe solvent is evaporated to dryness under reduced pressure. A residue weighing 404 g remains which crystallizes slowly. After a night in a cooler, the crystals are separated by filtration, rinsed with methanol and dried in a ventilated oven. So we collect
389g5 de méthylsulfate de L - Lysinate de méthyle.389g5 L methyl methyl sulfate - Methyl lysinate.
EXEMPLE IVEXAMPLE IV
Tryptophanate de terbutyle.Terbutyl tryptophanate.
On mélange 204 g de Tryptophane et 210 g de sulfate de terbutyle et on dilue ce mélange avec 450 ml de terbutanol préalablement chauffé à 50º.204 g of Tryptophan and 210 g of terbutyl sulfate are mixed and dilute this mixture with 450 ml of terbutanol previously heated to 50º.
Après homogénéisation du mélange, on chauffe à 80e pendant 6 heures puis on laisse refroidir et on chasse l'excès de réactif par distillation sous vide. Le mélange résiduel est repris par la quantité minimale de dioxane à chaud d'où il recristallise par refroidissement. Après quelques heures de repos, on sépare le terbutyl sulfate de tryptophanate de terbutyle par filtration. Les cristaux sont séparés, essorés à fond, puis séchés à poids constant sous vide. Ils sont redissouts dans 300 ml de chlorure de méthylène et agités à contre courant avec de la soude aqueuse. La phase organique est séparée, lavée à l'eau jusqu'à neutralité des eaux de lavage, séchée sur sulfate de sodium, filtrée puis évaporée à sec. Le résidu cristallin est repris par l'ether isopropylique. On dilue la solution avec un volume égal de cyclohexane. Le tryptophanate de terbutyle précipite progressivement. On le sépare par filtration, l'essore, le rince au cyclohexane et le sèche.After homogenization of the mixture, the mixture is heated to 80 ° C. for 6 hours then allowed to cool and the excess reagent is removed by vacuum distillation. The residual mixture is taken up by the minimum quantity of hot dioxane from which it recrystallizes by cooling. After a few hours' rest, the terbutyl sulphate of terbutyl tryptophanate is separated by filtration. The crystals are separated, wrung thoroughly, then dried at constant weight under vacuum. They are redissolved in 300 ml of methylene chloride and agitated against the current with aqueous sodium hydroxide. The organic phase is separated, washed with water until the washings are neutral, dried over sodium sulfate, filtered and then evaporated to dryness. The crystalline residue is taken up in isopropyl ether. The solution is diluted with an equal volume of cyclohexane. Terbutyl tryptophanate gradually precipitates. It is separated by filtration, wrung, rinsed with cyclohexane and dried.
Le résidu pesant 291 g est constitué par le tryptophanate de terbutyle pur. The residue weighing 291 g consists of pure terbutyl tryptophanate.

Claims

1/ Un procédé d'esterification des emino-acides carictérisé en ce qu'on soumet un amino acide à l'action d'un alcanol en présence d'une quantité équimolèculaire de sulfate d'alcoyle et isole l'ester d'êmino acide sous forme d'alcoylsulfste.1 / A process for esterification of emino acids characterized in that an amino acid is subjected to the action of an alkanol in the presence of an equimolar amount of alkyl sulfate and isolates the ester of emino acid in the form of alkylsulfste.
2/ Un procédé selon la revendication 1° qui comporte l'étape supplémentaire de conversion de l'alccylsulfate d'ester d'amino-acide en base par traitement alcalin.2 / A method according to claim 1 which comprises the additional step of converting the amino acid ester alccyl sulfate to base by alkaline treatment.
3/ Un procédé selon l'une des revendications 1° et 2° dans lequel l'ester d'amino-acids sous forme de bzse est transformé en un sel d'addition avec un acide minéral ou organique en milieu anhydre. 3 / A method according to one of claims 1 ° and 2 ° wherein the amino acid ester in the form of bzse is transformed into an addition salt with a mineral or organic acid in an anhydrous medium.
PCT/FR1982/000043 1981-03-11 1982-03-11 New process for the esterification of amino acids WO1982003074A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP57500844A JPS58500442A (en) 1981-03-11 1982-03-11 Novel amino acid esterification method

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8104816A FR2501677A1 (en) 1981-03-11 1981-03-11 NEW PROCESS FOR THE ESTERIFICATION OF AMINO ACIDS
FR8104816810311 1981-03-11

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WO1982003074A1 true WO1982003074A1 (en) 1982-09-16

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JP (1) JPS58500442A (en)
FR (1) FR2501677A1 (en)
WO (1) WO1982003074A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1566375A1 (en) * 2004-02-19 2005-08-24 Goldschmidt GmbH Process for the preparation of amino acid esters and their acid addition salts

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL1005901C2 (en) * 1997-04-25 1998-10-27 Dsm Nv Method for the esterification of amino acids and peptides.

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2615042A (en) * 1951-01-27 1952-10-21 Eastman Kodak Co Process for preparing gallic esters
FR2395251A1 (en) * 1977-06-23 1979-01-19 Asahi Chemical Ind SUBSTITUTE PHENYLGLYCOLIC ACID, PHARMACEUTICALLY ACCEPTABLE SALTS AND ESTERS THEREOF AND METHODS OF PREPARATION

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2615042A (en) * 1951-01-27 1952-10-21 Eastman Kodak Co Process for preparing gallic esters
FR2395251A1 (en) * 1977-06-23 1979-01-19 Asahi Chemical Ind SUBSTITUTE PHENYLGLYCOLIC ACID, PHARMACEUTICALLY ACCEPTABLE SALTS AND ESTERS THEREOF AND METHODS OF PREPARATION

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chemistry and Industry, No. 15, 04 August 1979 (Londres, GB), N.G. JAMIESON et al. 'Synthesis of Methyl 1, 5-Dimethylpyr-Role-2-Carboxylate', see page 522 *
Journal of Heterocyclic Chemistry, Vol. 16, July 1979 (Provo, US) M.P. PERIASAMY 'Esterification of Sterically Hindered Pyrrole Carboxylic Acids using Dimethyl and Diethyl Sulfate under Mild Basic Conditions', see page 1065, right hand column experimental *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1566375A1 (en) * 2004-02-19 2005-08-24 Goldschmidt GmbH Process for the preparation of amino acid esters and their acid addition salts

Also Published As

Publication number Publication date
FR2501677B1 (en) 1983-06-17
JPS58500442A (en) 1983-03-24
JPH0372057B2 (en) 1991-11-15
EP0074968A1 (en) 1983-03-30
FR2501677A1 (en) 1982-09-17

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