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WO1997030972A1 - Process for the preparation of ng-monomethyl-l-arginine hydrochloride - Google Patents

Process for the preparation of ng-monomethyl-l-arginine hydrochloride 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
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WO
WIPO (PCT)
Prior art keywords
hydrochloride
monomethyl
formula
compound
arginine hydrochloride
Prior art date
Application number
PCT/EP1997/000760
Other languages
French (fr)
Inventor
Iain Gillies
Original Assignee
Glaxo Group Limited
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 Limited filed Critical Glaxo Group Limited
Priority to EP97903315A priority Critical patent/EP0882014A1/en
Priority to AU17916/97A priority patent/AU1791697A/en
Priority to JP9529780A priority patent/JP2000504738A/en
Publication of WO1997030972A1 publication Critical patent/WO1997030972A1/en

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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

The present invention relates to a process for the preparation of NG-monomethyl-L-arginine hydrochloride comprising reaction of a compound of formula (I) or an acid addition salt thereof, wherein L is a leaving group; with L-ornithine or an acid addition salt thereof.

Description

PROCESS FOR THE PREPARATION OF Nc-MONOMETHYL-L-ARGININE HYDROCHLORIDE
The present invention relates to a process for the preparation of NG- monomethyl-L-arginine hydrochloride (L-NMMA hydrochloride).
A process for preparing NG-monomethyl-L-arginine and related compounds has been described in WO94/26701. On a large scale, this process suffers from the drawback that L-NMMA has to be isolated by column chromatography.
Preparation of L-NMMA hydrochloride is also described in WO94/02453. The methods described in this publication would, however, be unsuitable for a commercial process.
An improved synthesis of NG-allyl-(L)-arginine is described by Benatowicz et al in Synthetic Communications, 22 (5), 657-661 (1993). This process used fiavianic acid and ion exchange chromatography to isolate the product.
We have now discovered a new process for the preparation of L-NMMA hydrochloride where the product can be isolated directly from the reaction mixture without the need for chromatography. The new process also results in higher yields and an improved impurity profile of the product.
Accordingly, the present invention provides a process for the preparation of NG- monomethyl-L-arginine hydrochloride comprising:
(i) reaction of a compound of formula (I)
Figure imgf000003_0001
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:
(ii) acidification to pH 4 to 5 with hydrochloric acid; then
(iii) addition of an alcoholic solvent, such as ethanol or industrial methylated spirit; then
(iv) isolation of NG-monomethyl-L-arginine hydrochloride.
In the compound of formula (I), L is a leaving group as would be understood by a person skilled in the art. Most suitably, L is the group:
Figure imgf000004_0001
wherein R1, R2, and R3 are independently selected from hydrogen, halo, C^alkyl, C^alkoxy, and aryl, including fused aryl (ie where either R1 and R2 or R2 and R3 together with the carbon atoms to which they are attached form an aryl group fused to the pyrazole). However, L may also be C^alkoxy or C^cycloalkoxy. In the most preferred aspect of the invention, L is unsubstituted pyrazole.
In the definition of L the term "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.
In the definition of L, 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. For economy and convenience, the most preferred base is lithium hydroxide. However, alkyl or aromatic amines such as imidazole may also be suitable. As would be understood by the skilled person, where the free forms of both the compound of formula (I) and of the L-ornithine are used, it may be possible to effect the reaction without adding a further base, otherwise the base is required.
According to a preferred aspect, the present invention provides a process for the preparation of NG-monomethyl-L-arginine hydrochloride comprising:
(i) reaction of pyrazole carboxamidine hydrochloride,
N
CHJNH NH
.HCl
with L-ornithine hydrochloride,
Figure imgf000005_0001
in a suitable polar solvent, for example, water, in the presence of lithium hydroxide followed by:
(ii) acidification to pH 4 to 5 with hydrochloric acid; then
(iii) addition of an alcoholic solvent, such as ethanol or industrial methylated spirit; then
(iv) isolation of NG-monomethyl-L-arginine hydrochloride. During Step (i), the reaction 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 0βC to 70°C, for example 0°C to 50°C, most preferably 10 to 30°C, most conveniently at ambient temperature.
During 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.
In 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 NG-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.
In 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.
As would be clear to a person skilled in the art, the compound of formula (I) used in the process of present invention may be replaced by methylcyanamide and this variation forms a further embodiment of the present invention.
In a further embodiment, 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. Synthetic Example
(a) Preparation of methylcyanamide
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.
(b) Preparation of 1 H-pyrazole-1-N-methylcarboxamidine hydrochloride
Pyrazole (13.62g) was added to methylcyanamide solution (250ml) prepared as described in part (a) and then a hydrogen chloride solution (4M in dioxane 53ml) added. Upon addition of the hydrogen chloride a faint white precipitate appeared momentarily then dissolved. No significant exotherm was noted. The whole was heated with stirring at reflux for 2 hours forming a yellow liquid layer.
The 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 NMR (DMSO-d6), δppm : 3.55 (s, 3); 6.78 (s, 1); 8.09 (s, 1); 8.9 (s, 1).
(c) Preparation of NG--monomethvl-L-arαinine hydrochloride
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. A cream suspension formed which changed to a yellow solution after 1 to 2 hours and a pH of ca 11. 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 (0.88NH3/MeOH 15:35).
The reaction mixture was brought to pH 4.5 with concentrated hydrochloric acid (-5ml), then ethanol (200ml) added. A few seed crystals of NG-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.
1HNMR (D20), δ ppm : 1.6 (m, 2); 1.82 (q, 2); 2.74 (s, 3); 3.15 (t, 2); 3.7 (t, 1).

Claims

C AIMS
A process for the preparation of NG-monomethyl-L-arginine hydrochloride comprising:
(i) reaction of a compound of formula (I):
Figure imgf000009_0001
or an acid addition salt thereof, wherein L is a leaving group;
with L-ornithine or an acid addition salt thereof, in a suitable polar solvent, optionally in the presence of a base followed by:
(ii) acidification to pH 4 to 5 with hydrochloric acid; then
(iii) addition of an alcoholic solvent; then
(iv) isolation of NG-monomethyl-L-arginine hydrochloride.
2. A process according to claim 1 wherein the compound of formula (I) is
Figure imgf000009_0002
or an acid addition salt thereof, wherein R , R2, and R3 are independently selected from hydrogen, halo, C^alkyl, C^alkoxy, and aryl, including fused aryl.
A process accordingly to claim 1 or 2 wherein the compound of formula (I) is
Figure imgf000010_0001
or an acid addition salt thereof.
4. A process according to any of claims 1 to 3 wherein the compound of formula (I) is in the form of a hydrochloride salt and a base is used in step
(i).
5. A process according to any of claims 1 to 4 wherein the compound of formula (I) is reacted with L-ornithine hydrochloride and a base is used in step (i).
6. A process according to any of claims 1 to 5 wherein lithium hydroxide is used as a base in step (i).
7. A process for the preparation of NG-monomethyl-L-arginine hydrochloride comprising:
(i) reaction of pyrazole carboxamidine hydrochloride,
CH3NH NH
.HCl
with L-ornithine hydrochloride,
Figure imgf000011_0001
in a suitable polar solvent, in the presence of lithium hydroxide followed by:
(ii) acidification to pH 4 to 5 with hydrochloric acid; then
(iii) addition of an alcoholic solvent; then
(iv) isolation of NG-monomethyl-L-arginine hydrochloride.
8. A process according to any of claims 1 to 7 whereing the resultant NG- monomethyl-L-arginine hydrochloride is further purified.
PCT/EP1997/000760 1996-02-20 1997-02-18 Process for the preparation of ng-monomethyl-l-arginine hydrochloride WO1997030972A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97903315A EP0882014A1 (en) 1996-02-20 1997-02-18 Process for the preparation of n?g -monomethyl-l-arginine hydrochloride
AU17916/97A AU1791697A (en) 1996-02-20 1997-02-18 Process for the preparation of ng-monomethyl-l-arginine hydrochloride
JP9529780A JP2000504738A (en) 1996-02-20 1997-02-18 Method for producing N-upper G-monomethyl-L-arginine hydrochloride

Applications Claiming Priority (2)

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GB9603522.5 1996-02-20
GBGB9603522.5A GB9603522D0 (en) 1996-02-20 1996-02-20 Chemical process

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WO1997030972A1 true WO1997030972A1 (en) 1997-08-28

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

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1197486A1 (en) * 2000-10-13 2002-04-17 Degussa AG Process for the preparation of 1H-pyrazole-1-carboxamidines

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994002453A1 (en) * 1992-07-24 1994-02-03 The Wellcome Foundation Limited Ng-monomethyl-l-arginine hydrochloride derivatives and their use in the treatment of septic shock

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994002453A1 (en) * 1992-07-24 1994-02-03 The Wellcome Foundation Limited Ng-monomethyl-l-arginine hydrochloride derivatives and their use in the treatment of septic shock

Cited By (2)

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

Also Published As

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

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