CH277202A - Process for the preparation of a methionine derivative. - Google Patents

Process for the preparation of a methionine derivative.

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Publication number
CH277202A
CH277202A CH277202DA CH277202A CH 277202 A CH277202 A CH 277202A CH 277202D A CH277202D A CH 277202DA CH 277202 A CH277202 A CH 277202A
Authority
CH
Switzerland
Prior art keywords
methionine
ester
formic acid
ammonia
ethyl acetate
Prior art date
Application number
Other languages
German (de)
Inventor
E Merck
Original Assignee
E Merck
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by E Merck filed Critical E Merck
Publication of CH277202A publication Critical patent/CH277202A/en

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/26Separation; Purification; Stabilisation; Use of additives
    • C07C319/28Separation; Purification
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton

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

Description

  

  Verfahren zur Herstellung eines     Methioninderivates.       Das Hauptpatent betrifft ein Verfahren  zur Herstellung eines     Methioninderivates,    nach  welchem aus     hlethioninestern    durch Einwir  kung von Ammoniak das     a-Amino-y-methyl-          mereapto-buttersäureamid    hergestellt wird.  



  Man gelangt nun zu einem neuen Derivat  des     AAIethionins,    wenn man erfindungsgemäss,  ausgehend von einem     Methioninester,    einer  seits Ammoniak und anderseits Ameisensäure  zur Einwirkung bringt. Hierbei entsteht das       a-Formylamino-y-metliylmereapto-buttersäure-          amid,    eine leicht in Wasser lösliche Verbin  dung, die, aus Essigester     umkristallisiert,    farb  lose Kristalle bildet, welche bei etwa 1200 C  schmelzen.

   Durch Einwirkung     verseifender     Mittel entsteht daraus     Methionin.    Vorzugs  weise verwendet man als Ausgangsmaterial  für das neue Verfahren Ester des     Methionins     mit niederen     aliphatischen    Alkoholen, insbe  sondere den     Methyl-    oder den     Äthylester.     



  Für die Behandlung mit Ammoniak eignen  sich     wässrige    oder alkoholische Ammoniak       lösungen    besonders gut. Zur Behandlung mit  Ameisensäure wird das betreffende Produkt  vorzugsweise mit wasserfreier Ameisensäure  einige Stunden erwärmt.    Das nach der Erfindung hergestellte a  Formylamino-y-methylmercapto-buttersäure  amid soll als Arzneimittel mit den Indika  tionen des     Methionins    benutzt werden. Es hat  dem     Methionin    gegenüber den Vorteil einer  grösseren Wasserlöslichkeit.

      Das     a-Formylamino-y-methylmercapto-but-          tersäureamid    hat die Formel  
EMI0001.0023     
    Es ist eine in Wasser leicht lösliche Ver  bindung, die aus Essigester in farblosen, der  ben Kristallen auskristallisiert. Eine     wässrige     Lösung der Konzentration 10 weist ein     pn    von  5,5 auf.  



  <I>Beispiele:</I>  1.     d,1-Methionin    wird zur Überführung in  das     Methylesterchlorhydrat    mit 3     Volum-          teilen    Methylalkohol, in dem 1,5     Mol    Chlor  wasserstoff gelöst sind, 2 Stunden am Rück  fluss gekocht. Der Rückstand der im Vakuum  eingedampften Lösung wird in 5     Volumteilen     Chloroform aufgenommen, und diese Lösung  unter Kühlung so lange mit     Ammoniakgas    be  handelt, als noch     Ammoniumchlorid    aus der  Lösung ausfällt. Das     Ammonchlorid    wird ab  gesaugt und mit Chloroform ausgewaschen.  Filtrat und Waschlösungsmittel werden ver  einigt und im Vakuum eingedampft.

   Der  Rückstand wird in 5     Volumteilen    Methanol  gelöst und diese Lösung unter Kühlung mit  gasförmigem Ammoniak gesättigt. Nach ein  tägigem Stehen wird die Lösung im Vakuum  eingedampft. Es     hinterbleibt        d,1-Methionin-          amid,    das nach dem     Umkristallisieren    aus  Benzol bei<B>520</B> schmilzt. Zur Weiterverarbei  tung kann auch das Rohprodukt verwendet  werden.      15 g des so hergestellten     Methioninamids     werden mit     45g    wasserfreier Ameisensäure  3 Stunden auf dem Dampfbad erwärmt. Der  Rückstand der im Vakuum eingedampften  Lösung wird nochmals mit 30 g wasserfreier  Ameisensäure 3 Stunden erwärmt.

   Schliesslich  wird im Vakuum eingedampft und der Rück  stand aus Essigester umkristallisiert, wobei  das     a-Formylamino-y-methylmercapto-butter-          säureamid    in farblosen, derben Kristallen vom  Schmelzpunkt 1200 erhalten wird.  



  2. Durch Übergiessen von     Methioninäthyl-          ester-chlorhydrat    mit 25     o/oigem        wässrigem     Ammoniak scheidet man den freien     Äthylester     des     d,1-ll-Tethionins    als farbloses Öl vom Siede  punkt<B>860</B> C bei 0,6 mm     Quecksilberdruck    ab.  Er wird durch 3 Tage lang fortgesetztes Be  handeln mit 25     o/oigem        wässrigem    Ammoniak  in     Methioninamid    übergeführt.

   Das freie       Methioninamid    bildet farblose Kristalle, die  bei<B>520</B> C schmelzen und die sich sehr leicht  mit     alkalischer    Reaktion in Wasser auflösen.  Durch Versetzen mit 1     Mol    Eisessig in     metha-          nolischer    Lösung stellt. man daraus     das,    Acetat  her, das aus Essigester     umkristallisiert    werden  kann. Es bildet farblose Blättchen, die bei  <B>1570</B> C schmelzen.  



  10 g des so hergestellten     Methioninamid-          acetats    oder des analog mit Ameisensäure her  gestellten     Methioninamid-formiats    werden mit  100 g wasserfreier Ameisensäure 2 Stunden  am     Rüekfluss    gekocht. Die Lösung wird im  Vakuum eingedampft. Der zum überwiegen  den Teil kristallisierte Rückstand wird abge  saugt und aus Essigester umkristallisiert. Das  resultierende     a-Formylamino-y-methylmer-          capto-buttersäureamid    hat. die in Beispiel 1  angegebenen. Eigenschaften.  



  3. 142g     Methioninäthylester    werden mit  220     cms    wasserfreier Ameisensäure 3 Stun  den auf dem Dampfbad erwärmt. Die     Lösung     wird im Vakuum eingedampft und der     Rüek-          stand    mit 142     cm3    wasserfreier Ameisensäure    weitere 3 Stunden auf dem Dampfbad er  wärmt.     Sehliesslich    wird im Vakuum einge  dampft, der Rückstand in 1 Liter Methanol  aufgenommen und unter Kühlung mit Eis  wasser mit gasförmigem Ammoniak gesättigt.  Nach 24 Stunden wird im Vakuum einge  dampft und der     Rückstand,    ein braunes Öl,  in 250     em3    heissem Essigester gelöst.

   Nach dem  Erkalten wird das     Kristallisat    isoliert und  durch     Umkristallisieren    aus Essigester gerei  nigt. Man erhält     a-Formy        iamino-r-methylmer-          capto-buttersäureamid    mit den in Beispiel 1  angegebenen Eigenschaften.



  Process for the preparation of a methionine derivative. The main patent relates to a process for the production of a methionine derivative, according to which the α-amino-γ-methyl-mereapto-butyric acid amide is produced from halethionine esters by the action of ammonia.



  A new derivative of ethionine is now obtained if, according to the invention, starting from a methionine ester, ammonia on the one hand and formic acid on the other hand are brought into action. This produces the α-formylamino-y-methylmereapto-butyric acid amide, a compound which is easily soluble in water and which, when recrystallized from ethyl acetate, forms colorless crystals which melt at around 1200 ° C.

   Methionine is formed from it through the action of saponifying agents. Preference is used as the starting material for the new process esters of methionine with lower aliphatic alcohols, in particular the special methyl or ethyl ester.



  Aqueous or alcoholic ammonia solutions are particularly suitable for treatment with ammonia. For treatment with formic acid, the product in question is preferably heated for a few hours with anhydrous formic acid. The a formylamino-y-methylmercapto-butyric acid amide produced according to the invention is to be used as a medicament with the indica functions of methionine. Compared to methionine, it has the advantage of greater water solubility.

      The α-formylamino-γ-methylmercapto-but- tersäureamid has the formula
EMI0001.0023
    It is a compound that is easily soluble in water and crystallizes from ethyl acetate to form colorless crystals. An aqueous solution of concentration 10 has a pn of 5.5.



  <I> Examples: </I> 1. d, 1-methionine is refluxed for 2 hours with 3 parts by volume of methyl alcohol in which 1.5 mol of hydrogen chloride are dissolved to convert it into the methyl ester chlorohydrate. The residue of the solution evaporated in vacuo is taken up in 5 parts by volume of chloroform, and this solution is treated with ammonia gas with cooling as long as ammonium chloride still precipitates from the solution. The ammonium chloride is sucked off and washed out with chloroform. The filtrate and washing solvent are combined and evaporated in vacuo.

   The residue is dissolved in 5 parts by volume of methanol and this solution is saturated with gaseous ammonia while cooling. After standing for a day, the solution is evaporated in vacuo. What remains is d, 1-methionine amide which, after recrystallization from benzene, melts at <B> 520 </B>. The raw product can also be used for further processing. 15 g of the methionine amide thus produced are heated with 45 g of anhydrous formic acid on the steam bath for 3 hours. The residue of the solution evaporated in vacuo is heated again for 3 hours with 30 g of anhydrous formic acid.

   Finally, it is evaporated in vacuo and the residue is recrystallized from ethyl acetate, the α-formylamino-γ-methylmercapto-butyric acid amide in colorless, coarse crystals with a melting point of 1200 being obtained.



  2. By pouring methionine ethyl ester chlorohydrate with 25% aqueous ammonia, the free ethyl ester of d, 1-ll-tethionine is separated as a colorless oil with a boiling point <B> 860 </B> C at 0.6 mm Mercury pressure. It is converted into methionine amide by treatment with 25% aqueous ammonia for 3 days.

   The free methionine amide forms colorless crystals which melt at <B> 520 </B> C and which dissolve very easily in water with an alkaline reaction. By adding 1 mol of glacial acetic acid in methanol solution. from it the acetate, which can be recrystallized from ethyl acetate. It forms colorless leaflets that melt at <B> 1570 </B> C.



  10 g of the methionine amide acetate prepared in this way or of the methionine amide formate prepared analogously with formic acid are refluxed with 100 g of anhydrous formic acid for 2 hours. The solution is evaporated in vacuo. The predominantly crystallized residue is filtered off with suction and recrystallized from ethyl acetate. The resulting a-formylamino-y-methylmer-capto-butyric acid amide has. those given in Example 1. Characteristics.



  3. 142 g of methionine ethyl ester are heated on the steam bath for 3 hours with 220 cms of anhydrous formic acid. The solution is evaporated in vacuo and the residue is warmed for a further 3 hours on the steam bath with 142 cm3 of anhydrous formic acid. Sehliesslich is evaporated in a vacuum, the residue is taken up in 1 liter of methanol and saturated with ice water with gaseous ammonia while cooling with ice. After 24 hours, it is evaporated in vacuo and the residue, a brown oil, is dissolved in 250 cubic meters of hot ethyl acetate.

   After cooling, the crystals are isolated and cleaned by recrystallization from ethyl acetate. A-Formy iamino-r-methylmer-capto-butyric acid amide with the properties given in Example 1 is obtained.

 

Claims (1)

PATENTANSPRUCH: Verfahren zur Herstellung eines Methionin- derivates, dadurch gekennzeichnet, dass man, ausgehend von einem Methioninester, einer seits Ammoniak und anderseits Ameisensäure zur Einwirkung bringt. Das gebildete a-For- mylamino - y - methy lmereapto-buttersäureamid ist eine in Wasser leicht lösliche Verbindung, die, aus Essigester umkristallisiert, farblose Kristalle bildet, die bei etwa 120o C schmelzen. Bei Einwirkung verseifender Mittel wird daraus Methionin gebildet. UNTERANSPRÜCHE 1. PATENT CLAIM: Process for the production of a methionine derivative, characterized in that, starting from a methionine ester, ammonia on the one hand and formic acid on the other hand are brought into action. The a-formylamino-y-methy lmereapto-butyric acid amide that is formed is a compound that is easily soluble in water, which, when recrystallized from ethyl acetate, forms colorless crystals that melt at around 120oC. When exposed to saponifying agents, methionine is formed from it. SUBCLAIMS 1. Verfahren nach Patentanspruch, da durch gel@ennzeichnet, dass ein Ester des Me- thionins mit. einem niederen aliphatischen Alkohol verwendet wird. 2. Verfahren nach Patentanspruch und Unteranspruch 1, dadurch gekennzeichnet, dass der Methy lester verwendet wird. 3. Verfahren naeh Patentanspruch und Unteransprueh 1, dadurch gekennzeichnet, dass der tbylester verwendet wird. 4. Method according to patent claim, since gel @ indicates that an ester of methionine with. a lower aliphatic alcohol is used. 2. The method according to claim and dependent claim 1, characterized in that the methyl ester is used. 3. The method according to claim and sub-claim 1, characterized in that the tbyl ester is used. 4th Verfahren nach Patentanspruch, da durch gekennzeichnet, dass man zur Formylie- rung der a-Aminogruppe einige Stunden lang wasserfreie Ameisensäure in der Wärme ein wirken lässt. Process according to patent claim, characterized in that anhydrous formic acid is allowed to act in the heat for a few hours to formylate the α-amino group.
CH277202D 1949-02-14 1949-02-14 Process for the preparation of a methionine derivative. CH277202A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH273549 1949-02-14
CH277202T 1949-02-14

Publications (1)

Publication Number Publication Date
CH277202A true CH277202A (en) 1951-08-15

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Application Number Title Priority Date Filing Date
CH277202D CH277202A (en) 1949-02-14 1949-02-14 Process for the preparation of a methionine derivative.

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CH (1) CH277202A (en)

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