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WO1997048678A1 - Procede de preparation de sels organiques de n'n-diacetylcystine - Google Patents

Procede de preparation de sels organiques de n'n-diacetylcystine Download PDF

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Publication number
WO1997048678A1
WO1997048678A1 PCT/SE1997/001068 SE9701068W WO9748678A1 WO 1997048678 A1 WO1997048678 A1 WO 1997048678A1 SE 9701068 W SE9701068 W SE 9701068W WO 9748678 A1 WO9748678 A1 WO 9748678A1
Authority
WO
WIPO (PCT)
Prior art keywords
protonated form
organic base
diacetylcystine
preparation
alkali metal
Prior art date
Application number
PCT/SE1997/001068
Other languages
English (en)
Inventor
Michael Lofthagen
Original Assignee
Astra Aktiebolag (Publ)
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 SE9602418A external-priority patent/SE9602418D0/xx
Priority claimed from SE9602476A external-priority patent/SE9602476D0/xx
Application filed by Astra Aktiebolag (Publ) filed Critical Astra Aktiebolag (Publ)
Priority to AU32813/97A priority Critical patent/AU3281397A/en
Publication of WO1997048678A1 publication Critical patent/WO1997048678A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/22—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides
    • C07C319/24—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides by reactions involving the formation of sulfur-to-sulfur bonds

Definitions

  • the present invention relates to a new process for the preparation of organic salts of N,N' diacetylcystine [DiNAC].
  • N-acetyl-L-cysteine is a well-known compound which is used as a therapeutic agent against chronic obstructive pulmonary diseases and chronic bronchitis.
  • L-DiNAC the corresponding disulphide of N-acetyl-L-cysteine, i.e. L-DiNAC, acts as a potent immunostimulator (SE patent appliprotonated form No. 9002067-8), showing an activity comparable to contemporary immunostimulants such as sodium diethyl dithiocarbamate or 2,2'-dithiobisethanol.
  • the organic salts described in WO 93/11104 are generally prepared by mixing DiNAC and an organic amine, each dissolved or dispersed in a solvent or solvent mixture. Solvents such as water, alcohols, glycols, ketones, amides, sulphoxides or other polar solvents or solvent mixtures may be used.
  • the salt either precipitates directly from the reaction mixture, or is obtained by the addition of a less polar solvent or by evaporation or lyophilisation.
  • the salt can be prepared by oxidation of the appropriate N- acetylcysteine salt in an aqueous or alcoholic solution, followed by precipitation as above.
  • the oxidation may be effected chemically, using, e.g., hydrogen peroxide or a halogen; alternatively, the oxidation may be effected electrochemically.
  • Example 13 in WO 93/11104 describes oxidation of N-acetyl-L-cysteine with hydrogen peroxide in the presence of 1 mole equivalent of sodium hydroxide at a temperature below 10°C, followed by protonation of the product formed with the aid of an activated protonated form exchanger.
  • the filtrate is collected, L-lysine is added and di-L-lysinium- N,N'-diacetyl-L-cystinate is crystallised from refluxing ethanol.
  • the method involves many steps and is therefore time-consuming. It is important that the temperature during the exothermic oxidation is kept below 25°C, which requires intensive cooling. Otherwise too much decomposition will occur, resulting in a low yield of an impure product.
  • Example 19 in WO 93/11104 describes a simpler process for the preparation of di-L- lysinium-N,N'-diacetyl-L-cystinate by dissolving N-acetyl-L-cysteine and L-lysine in deionised water, adding hydrogen peroxide dropwise while stirring and keeping the temperature below 25°C, and stirring the reaction mixture for an additional 4 hours before the product, di-L-lysinium-N.N'-diacetyl-L-cystinate, can be precipitated. This procedure is also time consuming.
  • the present invention provides a new process for the preparation of organic salts of DiNAC, the process being faster than the previous methods, generally giving rise to low decomposition and thus purer products. Furthermore, the new process makes it possible to work at relatively high temperatures, thus requiring less cooling during the oxidation reaction.
  • the invention provides a process for the preparation of organic salts of N,N' diacetylcystine, having the formulae
  • N,N'-diacetylcystine is the D-, L- or meso form, or a mixture thereof
  • each of R + and R 2+ is the protonated form of an organic base, preferably selected from lysine, ethylenediamine, N.N'-dibenzylethylene-diamine, adamantanamine, N-benzyl-2- phenylethylamine, piperazine or ammonia.
  • the process includes providing a solutioa comprising N-acetyl-L-cysteine, an organic base, a catalytic amount of an alkali metal hydroxide, and a solvent, where the solvent is water or alcohol, and applying an oxidant to the solution.
  • a catalytic amount is 0.001 mole equivalents.
  • the temperature may be controlled during the oxidation; for example, the temperature may be kept below about 45°C.
  • the product may then be precipitated from an alcohol or aqueous alcohol, and isolated.
  • a preferred product prepared by the process of the invention is di-L-lysinium-N,N'- diacetyl-L-cystinate.
  • the organic salts prepared according to the invention include hydrated and solvated salts, e.g., solvated with lower alkanols.
  • catalytic amount is meant a trace amount of alkali metal hydroxide sufficient to catalyse the described reaction; preferably at least 0.001 mole equivalent compared to the N-acetyl-L-cysteine is used, or up to 0.01 or 0.1 mole equivalent. Preferably no more than 0.5 mole equivalent is used. In one embodiment of the invention, about 0.1 mole equivalent of the alkali metal hydroxide is used.
  • the temperature during oxidation can be up to the reflux temperature of the chosen solvent, but is preferably up to about 45°C, above which decomposition starts to be noticeable. Below about 5°C, the reaction mixture becomes difficult to stir, and the lower limit for the temperature during oxidation will depend on the stirring equipment. With appropriate stirring equipment, temperatures of below 0°C may be possible, although temperatures of at least 0°C are preferred, more preferably temperatures of 5°C or above.
  • Suitable alkali metal hydroxides are, e.g., sodium, potassium or lithium hydroxide.
  • the oxidation may be effected either chemically, using, e.g., hydrogen peroxide or halogen as oxidising agent, or electrochemically.
  • the salt precipitates directly from the solution or it may be obtained, for example, by the addition of or to a less polar solvent or by evaporation or lyophilisation.
  • the process may be aided using crystals of Di-L-lysinium-N,N'-diacetyl-L-cystinate to promote crystallisation.
  • the product may be recrystallised for higher purity.
  • L-lysine monohydrate 200 kg, 1.0 eq.
  • N-acetyl-L-cysteine 200 kg, 1.0 eq.
  • potassium hydroxide 6.8 kg, 0.08 eq.
  • reaction solution was then added to a refluxing slurry of di-L-lysiniurn-N,N'-diacetyl- L-cystinate (16 kg) in ethanol (2600 L).

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

Abstract

L'invention concerne un nouveau procédé de préparation de sels d'une base organique et de N,N'-diacétylcystine (DiNAC), selon lequel on oxyde une N-alcétylcystéine dans une solution aqueuse ou alcoolique en présence de la base organique, ou un sel contenant des formes protonnées de la base organique, et une quantité catalytique d'un hydroxyde de métal alcalin, après quoi on isole le produit.
PCT/SE1997/001068 1996-06-18 1997-06-17 Procede de preparation de sels organiques de n'n-diacetylcystine WO1997048678A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU32813/97A AU3281397A (en) 1996-06-18 1997-06-17 Process for the preparation of organic salts of n'n-diacetylcystine

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE9602418A SE9602418D0 (sv) 1996-06-18 1996-06-18 Process for the preparation of organic salts of N'N-diacetylcystine
SE9602418-7 1996-06-18
SE9602476A SE9602476D0 (sv) 1996-06-24 1996-06-24 Process for the preparation of organic salts of N'N -diacetylcystine
SE9602476-5 1996-06-24

Publications (1)

Publication Number Publication Date
WO1997048678A1 true WO1997048678A1 (fr) 1997-12-24

Family

ID=26662682

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1997/001068 WO1997048678A1 (fr) 1996-06-18 1997-06-17 Procede de preparation de sels organiques de n'n-diacetylcystine

Country Status (4)

Country Link
AR (1) AR007398A1 (fr)
AU (1) AU3281397A (fr)
ID (1) ID20507A (fr)
WO (1) WO1997048678A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011104A1 (fr) * 1991-11-29 1993-06-10 Ab Astra Sels organiques de cystine de n, n'-diacetyle

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011104A1 (fr) * 1991-11-29 1993-06-10 Ab Astra Sels organiques de cystine de n, n'-diacetyle

Also Published As

Publication number Publication date
AU3281397A (en) 1998-01-07
ID20507A (id) 1998-12-31
AR007398A1 (es) 1999-10-27

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