EP0882014A1 - Verfahren zur herstellung von n -monomethyl-l-arginine hydrochlorid - Google Patents

Verfahren zur herstellung von n -monomethyl-l-arginine hydrochlorid

Info

Publication number
EP0882014A1
EP0882014A1 EP97903315A EP97903315A EP0882014A1 EP 0882014 A1 EP0882014 A1 EP 0882014A1 EP 97903315 A EP97903315 A EP 97903315A EP 97903315 A EP97903315 A EP 97903315A EP 0882014 A1 EP0882014 A1 EP 0882014A1
Authority
EP
European Patent Office
Prior art keywords
hydrochloride
monomethyl
formula
compound
arginine hydrochloride
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97903315A
Other languages
English (en)
French (fr)
Inventor
Iain Gillies
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
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 Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP0882014A1 publication Critical patent/EP0882014A1/de
Withdrawn legal-status Critical Current

Links

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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups

Definitions

  • the present invention relates to a process for the preparation of N G - monomethyl-L-arginine hydrochloride (L-NMMA hydrochloride).
  • the present invention provides a process for the preparation of N G - monomethyl-L-arginine hydrochloride comprising:
  • L-ornithine or an acid addition salt thereof preferably a hydrochloride salt thereof, wherein L is a leaving group; with L-ornithine or an acid addition salt thereof, preferably a hydrochloride salt thereof, in a suitable polar solvent, for example, water, optionally in the presence of a base followed by:
  • L is a leaving group as would be understood by a person skilled in the art. Most suitably, L is the group:
  • R 1 , R 2 , and R 3 are independently selected from hydrogen, halo, C ⁇ alkyl, C ⁇ alkoxy, and aryl, including fused aryl (ie where either R 1 and R 2 or R 2 and R 3 together with the carbon atoms to which they are attached form an aryl group fused to the pyrazole).
  • L may also be C ⁇ alkoxy or C ⁇ cycloalkoxy. In the most preferred aspect of the invention, L is unsubstituted pyrazole.
  • aryl means a 5 to 10 membered mono- or bi- cyclic aromatic system optionally including 1 to 3 heteroatoms selected from nitrogen, sulphur, and oxygen wherein the aromatic system is optionally substituted by 1 to 5 groups selected from halo, C ⁇ alkyl, and C ⁇ alkoxy. Suitable examples of such aryl substituents include phenyl and naphthyl.
  • the term "halo" means fluoro, chloro, bromo or iodo.
  • the base used in step (i) may be any inorganic or organic base which liberates the free form of the compound of formula (I) and/or of L-omithine and which, in the presence of hydrochloric acid, forms a by-product which is soluble in the solvent mixture produced in step (iii) of the reaction.
  • the most preferred base is lithium hydroxide.
  • alkyl or aromatic amines such as imidazole may also be suitable.
  • the present invention provides a process for the preparation of N G -monomethyl-L-arginine hydrochloride comprising:
  • Step (iv) isolation of N G -monomethyl-L-arginine hydrochloride may proceed at high pH, such as pH 9 to 12; however it is preferable to maintain a pH in the range 10 to 11, for example between 10 and 10.5 by addition of acid, for example concentrated hydrochloric acid.
  • the reaction is suitably carried out at a non-extreme temperature, such as 0 ⁇ C to 70°C, for example 0°C to 50°C, most preferably 10 to 30°C, most conveniently at ambient temperature.
  • step (ii) the hydrochloric acid is preferably added to give a pH of around 4.5 such that the mono-hydrochtoride salt is obtained in optimal yield.
  • step (iii) the purpose of the alcoholic solvent is to act as a solvent for the by ⁇ products of the reaction and as a non-solvent for the product N G -monomethyl-L- arginine hydrochloride. Therefore, the invention includes within its scope, any variation of step (iii), for example, substitution of the alcoholic solvent which fulfils this purpose.
  • step (iv) the product L-NMMA hydrochloride may be isolated directly from the reaction mixture by crystallisation, for example by adding seed crystals of L- NMMA hydrochloride and stirring the reaction mixture at a non-extreme temperature, such as -5°C to 30°C most conveniently at ambient temperature.
  • the resultant product may optionally be further purified, for example by recrystallisation from a suitable solvent or mixture of solvents.
  • the present invention provides the novel intermediates of formula (I), such as pyrazole carboxamidine and salts thereof, in particular pyrazole carboxamidine hydrochloride.
  • the intermediates of formula (I) are commercially avavilable or may be prepared from commercially available starting materials by standard methods of chemistry, for example, by reaction of the appropriate pyrazole with methyl cyanamide.
  • Cyanogen bromide (21.2g) was dissolved in tetrahydrofuran (THF) (150ml) with sodium carbonate (42.4g) present. The whole was stirred and cooled to between -10 to 20°C and over this range of temperature, methylamine (2M solution in THF, 100ml) was added over 10 minutes. The stirred reaction mixture was then left to react for 2 hours at -15 to 20°C, then allowed to warm to 10°C before filtering off the solid sodium salts to give a clear solution of methylcyanamide in THF.
  • THF tetrahydrofuran
  • reaction mixture was then allowed to cool with stirring and a few crystals of presolidified product added. A cake of product resulted, this was broken up and stirred to give an off white solid/liquid mixture. To this was added diethyl ether (50ml) with stirring, then the whole was filtered to give an off white waxy solid. The solid was dried in vacuo at 50°C to give 22.6g of a cream solid product, mp 153-154°C. NMR analysis showed it to contain ca 5% pyrazole.
  • 1H-Pyrazole-1-N-methylcarboxamidine hydrochloride (12.85g), prepared as described in part (b), and L-ornithine hydrochloride (8.43g) were mixed in water, pH 2 to 3.
  • Lithium hydroxide monohydrate (5.45g) was added to give a pH of 10.1.
  • the pH was brought down and maintained between 10 and 10.5 with concentrated hydrochloric acid. After 3-4 days stirring at room temperature between this pH range no ornithine was detected by t.l.c. silica (0.88NH 3 /MeOH 15:35).
  • reaction mixture was brought to pH 4.5 with concentrated hydrochloric acid (-5ml), then ethanol (200ml) added. A few seed crystals of N G -monomethyl-L- arginine hydrochloride were added and the whole stirred at room temperature for 3 days giving a white crystalline precipitate. This was filtered off to give 6g of the title product, mp 219-221°C with gas evolution.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP97903315A 1996-02-20 1997-02-18 Verfahren zur herstellung von n -monomethyl-l-arginine hydrochlorid Withdrawn EP0882014A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9603522 1996-02-20
GBGB9603522.5A GB9603522D0 (en) 1996-02-20 1996-02-20 Chemical process
PCT/EP1997/000760 WO1997030972A1 (en) 1996-02-20 1997-02-18 Process for the preparation of ng-monomethyl-l-arginine hydrochloride

Publications (1)

Publication Number Publication Date
EP0882014A1 true EP0882014A1 (de) 1998-12-09

Family

ID=10789060

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97903315A Withdrawn EP0882014A1 (de) 1996-02-20 1997-02-18 Verfahren zur herstellung von n -monomethyl-l-arginine hydrochlorid

Country Status (11)

Country Link
EP (1) EP0882014A1 (de)
JP (1) JP2000504738A (de)
AR (1) AR005903A1 (de)
AU (1) AU1791697A (de)
CO (1) CO4761060A1 (de)
GB (1) GB9603522D0 (de)
ID (1) ID15968A (de)
PE (1) PE43198A1 (de)
TW (1) TW370520B (de)
WO (1) WO1997030972A1 (de)
ZA (1) ZA971398B (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10050900A1 (de) * 2000-10-13 2002-04-25 Degussa Verfahren zur Herstellung von 1-Guanylpyrazolsäureadditionsprodukten

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9215816D0 (en) * 1992-07-24 1992-09-09 Wellcome Found Arginine derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9730972A1 *

Also Published As

Publication number Publication date
CO4761060A1 (es) 1999-04-27
WO1997030972A1 (en) 1997-08-28
JP2000504738A (ja) 2000-04-18
AU1791697A (en) 1997-09-10
TW370520B (en) 1999-09-21
PE43198A1 (es) 1998-08-26
GB9603522D0 (en) 1996-04-17
AR005903A1 (es) 1999-07-21
ID15968A (id) 1997-08-21
ZA971398B (en) 1997-08-20

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