WO2004031133A1 - Procede de synthese de derives de guanidine - Google Patents

Procede de synthese de derives de guanidine Download PDF

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Publication number
WO2004031133A1
WO2004031133A1 PCT/EP2003/010912 EP0310912W WO2004031133A1 WO 2004031133 A1 WO2004031133 A1 WO 2004031133A1 EP 0310912 W EP0310912 W EP 0310912W WO 2004031133 A1 WO2004031133 A1 WO 2004031133A1
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WO
WIPO (PCT)
Prior art keywords
formula
process according
synthesis
guanidine derivatives
reacting
Prior art date
Application number
PCT/EP2003/010912
Other languages
English (en)
Inventor
Ludwig Eisenhuth
Original Assignee
Flexsys B.V.
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 Flexsys B.V. filed Critical Flexsys B.V.
Priority to AU2003273939A priority Critical patent/AU2003273939A1/en
Publication of WO2004031133A1 publication Critical patent/WO2004031133A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines

Definitions

  • the invention pertains to a process for the synthesis of guanidine derivatives.
  • cyanogen chloride N ⁇ CCI
  • the invention relates to a process for the synthesis of guanidine derivatives of the formula I:
  • X is selected from OH, OM wherein M is an alkali or earth alkali metal ion, and R ⁇ R 2 wherein Ri and R 2 are independently H, C-i-C ⁇ alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, or C 5 -C ⁇ o aryl; which comprises a first step of reacting cyanogen chloride with NH 3 in an organic solvent followed by a second step of reacting the product of the first step with an amine of the formula II:
  • the process of the invention is devoid of these disadvantages and provides guanidine derivatives, particularly creatine, in high yield and purity.
  • the reaction is performed by maintaining the pH of the second step between 9 and 11, most preferably about 10.
  • the first step of the reaction is performed- in .an organic solvent.
  • any usual organic solvent may be used, as long as the solvent is inert to cyanogens chloride and cyanamide, but preferred the solvents are ethers, preferably methyl tert- butylether and dimethylethylene glycol.
  • the second step is performed in an aqueous medium, for instance by adding water to the reaction mixture. Since ethers, if used as the organic solvent, do not mix with water a two-phase reaction system is formed.
  • a quantity of ammonium chloride is formed. It is preferred to remove this salt, for instance by filtration, after having performed the first step and before starting the second step.
  • This ammonium chloride may be used as an acid to keep the pH of the second step between 9 and 11.
  • a reactor was charged with 75 g of methyl tert-butylether, after which gaseous cyanogen chloride and gaseous ammonia were fed to the solution, keeping the temperature below 40°C by cooling.
  • the precipitate (ammonium chloride) was removed by filtration and a clear solution was obtained which was stripped with nitrogen and which contained 12% of pure cyanamide (determined by Raman spectroscopy).
  • 55 g of the thus obtained organic solution (containing 6.6 g of cyanamide) were directly dosed within 3 h to 71 g of an aqueous solution containing 20.4 g of sodium sarcosinate, keeping the temperature at 50°C and the pH at 9.8 by addition of formic acid.
  • the white precipitate formed was filtered, washed with water, and dried. 16.5 g (70% yield) of creatine monohydrate were obtained with a purity > 99% according to HPLC analysis.
  • Example 1 was repeated, but the addition of formic acid was replaced by the addition of ammonium chloride, which was recovered from the first step, to control the pH in the second step. Creatine monohydrate was obtained in a yield of 68% with a purity > 99%.
  • Example 3
  • Example 1 was repeated, but using dimethylethylene glycol instead of methyl tert-butylether as the organic solvent.

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

Abstract

L'invention concerne un procédé de synthèse de dérivés de guanidine représentés par la formule (I), dans laquelle X est sélectionné dans le groupe comprenant OH, OM, M représentant un ion alcalin ou un ion métallique alcalino-terreux, et NR1R2, où R1 et R2 représentent indépendamment H, alkyle en C1-C6, alcényle en C2-C6, cycloalkyle en C3-C6 ou aryle en C6-C10. Le procédé comporte une première étape consistant à faire réagir du chlorure de cyanogène (N=CCI) avec NH3 dans un solvant organique, suivie d'une deuxième étape consistant à faire réagir une amine représentée par la formule (II), dans laquelle X a la notation mentionnée précédemment. Une troisième étape facultative consiste à transformer ensuite un composé représenté par la formule (I) en un autre composé représenté par la formule (I).
PCT/EP2003/010912 2002-10-04 2003-09-30 Procede de synthese de derives de guanidine WO2004031133A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003273939A AU2003273939A1 (en) 2002-10-04 2003-09-30 Process for the synthesis of guanidine derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP02079165.3 2002-10-04
EP02079165 2002-10-04
EP02079515 2002-10-29
EP02079515.9 2002-10-29

Publications (1)

Publication Number Publication Date
WO2004031133A1 true WO2004031133A1 (fr) 2004-04-15

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/010912 WO2004031133A1 (fr) 2002-10-04 2003-09-30 Procede de synthese de derives de guanidine

Country Status (2)

Country Link
AU (1) AU2003273939A1 (fr)
WO (1) WO2004031133A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2425341A (en) * 1944-08-11 1947-08-12 American Cyanamid Co Production of mono- and unsymmetrically disubstituted guanidines
EP0754679A1 (fr) * 1995-07-18 1997-01-22 SKW Trostberg Aktiengesellschaft Procédé de préparation de créatine ou monohydrate de créatine
US6147258A (en) * 1997-11-04 2000-11-14 Basf Aktiengesellschaft Preparation of substituted guanidine derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2425341A (en) * 1944-08-11 1947-08-12 American Cyanamid Co Production of mono- and unsymmetrically disubstituted guanidines
EP0754679A1 (fr) * 1995-07-18 1997-01-22 SKW Trostberg Aktiengesellschaft Procédé de préparation de créatine ou monohydrate de créatine
US6147258A (en) * 1997-11-04 2000-11-14 Basf Aktiengesellschaft Preparation of substituted guanidine derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CLOEZ, CANNIZZARRO: "Untersuchungen über die amidartigen Verbindungen des Cyans", JUSTUS LIEBIGS ANN. CHEM., vol. 78, 1851, pages 228 - 231, XP009006122 *

Also Published As

Publication number Publication date
AU2003273939A1 (en) 2004-04-23

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