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WO1997030972A1 - Procede de preparation de ng-monomethyl-l-hydrochlorure d'arginine - Google Patents

Procede de preparation de ng-monomethyl-l-hydrochlorure d'arginine Download PDF

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Publication number
WO1997030972A1
WO1997030972A1 PCT/EP1997/000760 EP9700760W WO9730972A1 WO 1997030972 A1 WO1997030972 A1 WO 1997030972A1 EP 9700760 W EP9700760 W EP 9700760W WO 9730972 A1 WO9730972 A1 WO 9730972A1
Authority
WO
WIPO (PCT)
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.)
Ceased
Application number
PCT/EP1997/000760
Other languages
English (en)
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
Priority to EP97903315A priority Critical patent/EP0882014A1/fr
Priority to JP9529780A priority patent/JP2000504738A/ja
Priority to AU17916/97A priority patent/AU1791697A/en
Publication of WO1997030972A1 publication Critical patent/WO1997030972A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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.

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

Abstract

L'invention concerne un procédé de préparation de NG-monométhyl-L-hydrochlorure d'arginine consistant à faire réagir un composé présentant la formule (I) ou un sel d'addition d'acide de ce dernier, où L est un groupe labile, avec une L-ornithine ou un sel d'addition d'acide de cette dernière.
PCT/EP1997/000760 1996-02-20 1997-02-18 Procede de preparation de ng-monomethyl-l-hydrochlorure d'arginine Ceased WO1997030972A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97903315A EP0882014A1 (fr) 1996-02-20 1997-02-18 Procede de preparation de n?g -monomethyl-l-hydrochlorure d'arginine
JP9529780A JP2000504738A (ja) 1996-02-20 1997-02-18 Ｎ▲上ｇ▼―モノメチル―ｌ―アルギニン塩酸塩の製造法
AU17916/97A AU1791697A (en) 1996-02-20 1997-02-18 Process for the preparation of ng-monomethyl-l-arginine hydrochloride

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9603522.5A GB9603522D0 (en) 1996-02-20 1996-02-20 Chemical process
GB9603522.5 1996-02-20

Publications (1)

Publication Number Publication Date
WO1997030972A1 true WO1997030972A1 (fr) 1997-08-28

Family

ID=10789060

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/000760 Ceased WO1997030972A1 (fr) 1996-02-20 1997-02-18 Procede de preparation de ng-monomethyl-l-hydrochlorure d'arginine

Country Status (11)

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

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1197486A1 (fr) * 2000-10-13 2002-04-17 Degussa AG Procédé pour la préparation des 1H-pyrazole-1-carboxamidines

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994002453A1 (fr) * 1992-07-24 1994-02-03 The Wellcome Foundation Limited Derives d'hydrochlorure de ng-monomethyl-l-arginine et leur utilsation dans le traitement du choc septique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994002453A1 (fr) * 1992-07-24 1994-02-03 The Wellcome Foundation Limited Derives d'hydrochlorure de ng-monomethyl-l-arginine et leur utilsation dans le traitement du choc septique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1197486A1 (fr) * 2000-10-13 2002-04-17 Degussa AG Procédé pour la préparation des 1H-pyrazole-1-carboxamidines
US6410745B1 (en) 2000-10-13 2002-06-25 Degussa Ag Process for preparing 1-guanylpyrazole acid adducts

Also Published As

Publication number Publication date
ZA971398B (en) 1997-08-20
EP0882014A1 (fr) 1998-12-09
AR005903A1 (es) 1999-07-21
TW370520B (en) 1999-09-21
ID15968A (id) 1997-08-21
CO4761060A1 (es) 1999-04-27
GB9603522D0 (en) 1996-04-17
PE43198A1 (es) 1998-08-26
AU1791697A (en) 1997-09-10
JP2000504738A (ja) 2000-04-18

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