CH470338A - Process for the production of adamantyl chloroformates - Google Patents

Process for the production of adamantyl chloroformates

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Publication number
CH470338A
CH470338A CH1420068A CH1420068A CH470338A CH 470338 A CH470338 A CH 470338A CH 1420068 A CH1420068 A CH 1420068A CH 1420068 A CH1420068 A CH 1420068A CH 470338 A CH470338 A CH 470338A
Authority
CH
Switzerland
Prior art keywords
adamantyl
chloroformate
phosgene
formula
reacted
Prior art date
Application number
CH1420068A
Other languages
German (de)
Inventor
Gerzon Koert
Krumkalns Eriks
Original Assignee
Lilly Co Eli
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
Priority claimed from US427124A external-priority patent/US3345399A/en
Application filed by Lilly Co Eli filed Critical Lilly Co Eli
Priority claimed from CH71066A external-priority patent/CH475209A/en
Publication of CH470338A publication Critical patent/CH470338A/en

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K1/00General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/061General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
    • C07K1/064General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for omega-amino or -guanidino functions
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06Esters of carbamic acids
    • C07C271/32Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C271/34Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K1/00General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/061General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
    • C07K1/063General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for alpha-amino functions
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00Systems containing at least three condensed rings
    • C07C2603/56Ring systems containing bridged rings
    • C07C2603/58Ring systems containing bridged rings containing three rings
    • C07C2603/70Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74Adamantanes

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

  

  Verfahren zur Herstellung von Adamantyl-chlorformiaten    Gegenstand der vorliegenden Erfindung ist ein Ver  fahren zur Herstellung von Adamantyl-chlorformiaten,  die die     folgende    Formel I  
EMI0001.0001     
    aufweisen. In dieser Formel steht der Rest AD für einen  Adamantyl-, Methyladamantyl-,     Dimethyladamantyl-          oder    Homoadamantylrest. Das erfindungsgemässe Ver  fahren zur Herstellung der Verbindungen der Formel I  zeichnet sich dadurch aus, dass man eine Verbindung  der Formel II  AD-OH II,  in der AD die oben angegebene Bedeutung besitzt, mit  Phosgen in Anwesenheit eines tertiären Amins in einem  inerten Lösungsmittel umsetzt, wobei sich das     Adaman-          tylchlorformiat    der Formel I bildet.  



  Nach dem     erfindungsgemässen    Verfahren können  beispielsweise die folgenden Adamantylchlorformiate  hergestellt werden: Adamantyl-(1)-chlorformiat,     3,5-Di-          methyl-adamantyl-(1)-chlorformiat;        Homoadamantyl-          (3)-hlorformiat    und     3-Methyl-adamantyl-(1)-chlorfor-          miat.     



  Die nach dem     erfindungsgemässen    Verfahren herge  stellten Adamantylchlorformiate können als Zwischen  produkte bei der Herstellung von     N-Adamantyloxycar-          bonyl-derivaten    von Aminosäuren verwendet werden.  Die nach diesem Verfahren erhaltenen N-Adamantyl-    oxycarbonyl-derivate der Aminosäuren weisen die fol  gende Formel  
EMI0001.0016     
    auf, wobei in dieser Formel X eine Gruppe der For  mel  
EMI0001.0017     
    ist und AD für einen Adamantyl-, Methyladamantyl-,  Dimethyladamantyl- oder Homoadamantylrest steht, R'  ein Wasserstoffatom oder eine Alkylgruppe mit 1-4.

    Kohlenstoffatomen ist, R" ein Wasserstoffatom oder eine  Hydroxylgruppe bedeutet und R für ein Wasserstoff  atom, eine gegebenenfalls mit Hydroxylgruppen,     Carbal-          koxygruppen    mit 1-4 Kohlenstoffatomen,     Mercapto-          gruppen,    Alkylmercaptogruppen mit 1-4 Kohlenstoff  atomen oder Guanidogruppen substituierten Alkylrest  mit 1 bis 4 Kohlenstoffatomen, einen gegebenenfalls  substituierten Phenylrest, einen gegebenenfalls substi  tuierten Benzyl-, Thienyl-, Furyl, Imidazolylmethyl-,  Indolylmethyl- oder Hydroxyindolymethylrest steht oder  eine Gruppe der     Formel       
EMI0002.0000     
    bedeutet, in der R' und AD die oben angegebene  Bedeutung besitzen.  



  Adamantane und Homoadamantane, von denen sich  die oben erwähnten Adamantyl-, Methyladamantyl-,  Dimethyladamantyl-und Homoadamantylreste ableiten,  sind tricyclische, mehrfache Brückenbindungen aufwei  sende Kohlenwasserstoffe. Ihre Formeln lassen sich in  wie folgt wiedergeben:  
EMI0002.0001     
    Die Herstellung des Adamantylchlorformiate nach  dem     erfindungsgemässen    Verfahren und deren Verwen  dung zur Herstellung von weiteren Derivaten sei     anhand     des folgenden Reaktionsschemas erläutert:  
EMI0002.0004     
    In diesem Formelschema haben die Reste AD, R, R'       Sand    R" die - oben angegebene Bedeutung.

   Bei der  Durchführung der obigen Reaktionsfolge wird     1-Hydro-          xyadamantan    oder 3-Methtyl-l-hydroxadamantan oder  3,5-Dimethyl-l-hydroxyadamantan oder     3-Hydroxyho-          moadamantan    mit Phosgen in Gegenwart eines tertiären  Amins, z. B. Pyridin; Trimethylpyridin, Chinolin oder  Triäthylamin, in einem inerten Lösungsmittel, wie was  serfreiem     Benzol    oder Äther oder kohlenwasserstoffarti  gen oder ätherischen Lösungsmitteln, umgesetzt unter  Bildung des entsprechenden Adamantylchlorformiats,  welches in einem geeigneten Lösungsmittel aufbewarht  oder als weisser kristalliner     Festkörper    isoliert werden  kann.  



  Die Herstellung des     N-Adamantyloxycarbonylderi-          vates    der Aminosäure, in der die Aminogruppe geschützt  oder blockiert werden soll, geht vonstatten durch einfa  ches Vermischen des Adamantylchlorformiats mit der    Aminosäureverbindung in einem inerten Lösungsmittel       unter    leicht alkalischen Bedingungen, die durch Anwen  dung eines Lösungsmittels wie Alkohol oder Dioxan,  und verdünntem wässrigem Natriumhydroxyd oder  einem anderen gleichwertigen Stoff als     Alkalisierungs-          mittel    gesichert sind.  



  Durch die folgenden speziellen Beispiele soll die  Erfindung     näher    erläutert werden.  



  <I>Beispiel 1</I>  Eine Lösung enthaltend 20 g Phosgen in 100 ml       wasserfreiem    Benzol     wurde    mit Hilfe eines     Eiswasser-          Bades    bei etwa 20  C gehalten. Ein Gemisch enthaltend  8 g 1-Hydroxyadamantan, 6 g Pyridin und 200 ml Äther           wurde    tropfenweise unter Rühren während eines Zeit  raumes von etwa 1 Stunde zu der Phosgenlösung  hinzugefügt. Dann wurden 100     ml    wasserfreies Benzol  zugesetzt, und das Umsetzungsgemisch wurde während  etwa 1 Stunde bei Umgebungstemperatur gehalten und  sodann filtriert.

   Das Filtrat wurde über ein     Eis-Wasser-          Gemisch    gegossen und die organische Schicht, die das  Adamantyl-(1)-chlorformiat enthielt, abgetrennt und ge  trocknet. Eindampfen der Lösung im Vakuum bei  Zimmertemperatur ergab Adamantyl-(1)-chlorformiat  als weissen kristallinen Festkörper, der bei 40-4.2  C       schmolz.    Das Material wurde weiterhin gereinigt durch  Umkristallisieren aus wasserfreiem niedrig siedendem  Petroläther bei -20  C, wobei sich bei etwa 46-47  C  schmelzende     Kristalle    ergaben.  



  Adamantylchlorformiat kann im wesentlichen ohne  Zersetzung bei 4  C in Benzol-Äther-Lösung gelagert  werden, die eine geringe Menge Calciumcarbonat als  Stabilisator enthält.  



  <I>Beispiel 2</I>  Gemäss der Arbeitsweise von Beispiel 1 wurde     3,5-          Dimethyl-l-hydroxyadamantan    mit Phosgen in Benzol  lösung in Gegenwart von Pyridin unter Bildung des  Chlorformiats umgesetzt. Die Verbindung schmolz bei  etwa 5-10  C.  



  <I>Beispiel 3</I>  Homoadamantyl-(3)-chlorformiat wurde gemäss der  Arbeitsweise von Beispiel 1 aus Phosgen und     3-Hydro-          xyhomoadamantan    hergestellt. Die Verbindung, die in  kristalliner Form aus Petroläther bei -50  C isoliert  wurde, schmolz unter etwa 0  C.



  Process for the preparation of adamantyl chloroformates The present invention provides a process for the preparation of adamantyl chloroformates which have the following formula I
EMI0001.0001
    exhibit. In this formula, the radical AD stands for an adamantyl, methyladamantyl, dimethyladamantyl or homoadamantyl radical. The inventive method for the preparation of the compounds of the formula I is characterized in that a compound of the formula II AD-OH II, in which AD has the meaning given above, is reacted with phosgene in the presence of a tertiary amine in an inert solvent, whereby the adamantyl chloroformate of the formula I is formed.



  The following adamantyl chloroformates, for example, can be prepared by the process according to the invention: adamantyl (1) chloroformate, 3,5-dimethyl adamantyl (1) chloroformate; Homoadamantyl (3) chloroformate and 3-methyl adamantyl (1) chloroformate.



  The adamantyl chloroformates produced by the process according to the invention can be used as intermediate products in the production of N-adamantyloxycarbonyl derivatives of amino acids. The N-adamantyl oxycarbonyl derivatives of the amino acids obtained by this process have the following formula
EMI0001.0016
    on, where in this formula X is a group of the formula
EMI0001.0017
    and AD stands for an adamantyl, methyladamantyl, dimethyladamantyl or homoadamantyl radical, R 'is a hydrogen atom or an alkyl group with 1-4.

    Is carbon atoms, R "denotes a hydrogen atom or a hydroxyl group and R denotes a hydrogen atom, an alkyl radical with 1 to 4 which is optionally substituted with hydroxyl groups, carbalkoxy groups with 1-4 carbon atoms, mercapto groups, alkyl mercapto groups with 1-4 carbon atoms or guanido groups 4 carbon atoms, an optionally substituted phenyl radical, an optionally substituted benzyl, thienyl, furyl, imidazolylmethyl, indolylmethyl or hydroxyindolymethyl radical or a group of the formula
EMI0002.0000
    means in which R 'and AD have the meaning given above.



  Adamantanes and homoadamantanes, from which the above-mentioned adamantyl, methyladamantyl, dimethyladamantyl and homoadamantyl radicals are derived, are tricyclic hydrocarbons with multiple bridge bonds. Their formulas can be expressed as follows:
EMI0002.0001
    The preparation of the adamantyl chloroformate by the process according to the invention and its use for the preparation of further derivatives will be explained using the following reaction scheme:
EMI0002.0004
    In this equation, the radicals AD, R, R 'Sand R "have the meaning given above.

   When carrying out the above reaction sequence, 1-hydroxyadamantane or 3-methyl-1-hydroxadamantane or 3,5-dimethyl-1-hydroxyadamantane or 3-hydroxyho- moadamantane with phosgene in the presence of a tertiary amine, eg. B. pyridine; Trimethylpyridine, quinoline or triethylamine, in an inert solvent, such as serfreiem benzene or ether or kohlenwasserstoffarti conditions or ethereal solvents, converted to form the corresponding Adamantylchlorformat, which can be stored in a suitable solvent or isolated as a white crystalline solid.



  The preparation of the N-adamantyloxycarbonyl derivative of the amino acid in which the amino group is to be protected or blocked is done by simply mixing the adamantyl chloroformate with the amino acid compound in an inert solvent under slightly alkaline conditions, which can be achieved by using a solvent such as alcohol or Dioxane, and dilute aqueous sodium hydroxide or another equivalent substance are secured as alkalizing agents.



  The invention is illustrated by the following specific examples.



  <I> Example 1 </I> A solution containing 20 g of phosgene in 100 ml of anhydrous benzene was kept at about 20 ° C. using an ice-water bath. A mixture containing 8 g of 1-hydroxyadamantane, 6 g of pyridine and 200 ml of ether was added dropwise to the phosgene solution with stirring over a period of about 1 hour. 100 ml of anhydrous benzene was then added and the reaction mixture was held at ambient temperature for about 1 hour and then filtered.

   The filtrate was poured over an ice-water mixture and the organic layer, which contained the adamantyl (1) chloroformate, was separated off and dried. Evaporation of the solution in vacuo at room temperature gave adamantyl (1) chloroformate as a white crystalline solid which melted at 40-4.2 ° C. The material was further purified by recrystallization from anhydrous low-boiling petroleum ether at -20.degree. C., which resulted in crystals melting at about 46-47.degree.



  Adamantyl chloroformate can be stored essentially without decomposition at 4 C in a benzene-ether solution that contains a small amount of calcium carbonate as a stabilizer.



  <I> Example 2 </I> According to the procedure of Example 1, 3,5-dimethyl-l-hydroxyadamantane was reacted with phosgene in benzene solution in the presence of pyridine to form the chloroformate. The compound melted at around 5-10 C.



  <I> Example 3 </I> Homoadamantyl (3) chloroformate was prepared according to the procedure of Example 1 from phosgene and 3-hydroxyhomoadamantane. The compound, which was isolated in crystalline form from petroleum ether at -50 C, melted below about 0 C.

 

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung eines Adamantylchlorfor- miates der Formel I EMI0003.0012 in der AD einen Adamantyl-, Methyladamantyl-, Dime- thyladamantyl- oder Homoadamantylrest bedeutet, da durch gekennzeichnet, dass man eine Verbindung der Formel II AD-OH II, in der AD die oben angegebene Bedeutung besitzt, mit Phosgen in Anwesenheit eines tertiären Amins in einem inerten Lösungsmittel umsetzt, wobei sich das Adaman- tylchlorformiat der Formel I bildet, UNTERANSPRÜCHE 1. PATENT CLAIM Process for the production of an adamantyl chloroformate of the formula I. EMI0003.0012 in AD denotes an adamantyl, methyladamantyl, dimethyladamantyl or homoadamantyl radical, characterized in that a compound of the formula II AD-OH II, in which AD has the meaning given above, is combined with phosgene in the presence of a tertiary amine Reacts in an inert solvent, forming the adamantyl chloroformate of the formula I, SUBClaims 1. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man 1-Hydroxyadamantan mit Phosgen umsetzt, wobei sich das Adamantyl-(1)-chlorformiat bildet. 2. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man 3,5-Dimethyl-l-hydroxyadamantan mit Phosgen umsetzt, wobei sich das 3,5-Dimethyl- adamantyl -(1)-chlorformiat bildet. 3. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man 3-Hydroxyhomoadamantan mit Phosgen umsetzt, wobei sich das Homoadamantyl -(3)- chlorformiat bildet. Process according to patent claim, characterized in that 1-hydroxyadamantane is reacted with phosgene, the adamantyl (1) chloroformate being formed. 2. The method according to claim, characterized in that 3,5-dimethyl-l-hydroxyadamantane is reacted with phosgene, the 3,5-dimethyl-adamantyl - (1) chloroformate being formed. 3. The method according to claim, characterized in that 3-hydroxyhomoadamantane is reacted with phosgene, the homoadamantyl - (3) - chloroformate is formed. 4.Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass man 3-Methyl-l-hydroxyadamantan mit Phosgen umsetzt, wobei sich das 3-Methyl-adamantyl- (1)-chlorformiat bildet. 4. The method according to claim, characterized in that 3-methyl-l-hydroxyadamantane is reacted with phosgene, the 3-methyl-adamantyl- (1) chloroformate being formed.
CH1420068A 1965-01-21 1966-01-19 Process for the production of adamantyl chloroformates CH470338A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US427124A US3345399A (en) 1965-01-21 1965-01-21 Carbamate esters of adamantane, mono-and di-methyladamantane and homoadamantane
CH71066A CH475209A (en) 1965-01-21 1966-01-19 Process for the preparation of N-adamantyloxycarbonyl derivatives of x-amino acids and L-amino acid esters
US615356A US3369041A (en) 1965-01-21 1967-02-13 Adamantyl carbazates

Publications (1)

Publication Number Publication Date
CH470338A true CH470338A (en) 1969-03-31

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Application Number Title Priority Date Filing Date
CH1420068A CH470338A (en) 1965-01-21 1966-01-19 Process for the production of adamantyl chloroformates

Country Status (1)

Country Link
CH (1) CH470338A (en)

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