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WO2000078723A1 - Procede de preparation de composes butoxycarbonylimino et intermediaires pour ce procede - Google Patents

Procede de preparation de composes butoxycarbonylimino et intermediaires pour ce procede Download PDF

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Publication number
WO2000078723A1
WO2000078723A1 PCT/GB2000/002355 GB0002355W WO0078723A1 WO 2000078723 A1 WO2000078723 A1 WO 2000078723A1 GB 0002355 W GB0002355 W GB 0002355W WO 0078723 A1 WO0078723 A1 WO 0078723A1
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WO
WIPO (PCT)
Prior art keywords
tert
pyrazol
butyl
formula
butoxycarbonyl
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/GB2000/002355
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English (en)
Inventor
Michael Dennis Dowle
Peter David Howes
John Edward Robinson
Naimish Trivedi
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 AU54159/00A priority Critical patent/AU5415900A/en
Publication of WO2000078723A1 publication Critical patent/WO2000078723A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to a novel process for the preparation of butoxycarbonyiimino compounds, in particular (tert-butoxycarbonylimino- pyrazol-1-yl-methyl)-carbamic acid tert-butyl ester, otherwise known as bis-boc- 1H-pyrazole-1-carboxamidine, or bis-Boc PC, and novel intermediates.
  • butoxycarbonyiimino compounds in particular (tert-butoxycarbonylimino- pyrazol-1-yl-methyl)-carbamic acid tert-butyl ester, otherwise known as bis-boc- 1H-pyrazole-1-carboxamidine, or bis-Boc PC, and novel intermediates.
  • Bis-Boc PC is a valuable reagent for the preparation of bis-Boc protected guanidines from the corresponding amines. It is used as a reagent for the conversion of amines to monosubstituted guanidines and also in the synthesis of arginine containing peptides.
  • bis-Boc PC can be used in the synthesis of complex guanidine containing compounds for example 5- acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galactonon-2- enopyranosonic acid (zanamivir) and (1S,2S,3R,4R)-3-[(1R)-1-(acetylamino)-2- ethylbutyl]-4- ⁇ [amino(imino)methyl]amino ⁇ -2-hydroxycyclopentanecarboxylic acid (BCX-1812).
  • complex guanidine containing compounds for example 5- acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galactonon-2- enopyranosonic acid (zanamivir) and (1S,2S,3R,4R)-3-[(1R)-1-(acetylamino)-2- ethylbut
  • the invention thus provides in the first aspect a process for the preparation of compounds of formula (I):
  • R represents C ⁇ alkyl, aryl, C ⁇ alkylaryl, O-C ⁇ alkyl, O-aryl, O-C ⁇ alkylaryl, an amino acid and protected derivatives thereof;
  • n can be 0 to 20 and m can be 2 to 5. It will be understood by the person skilled in the art that m is dependent on the valency of the metal.
  • alkyl includes both straight and branched chain saturated hydrocarbon groups optionally substituted with NO 2 , CN, CO 2 R 6 , F, Cl, COR 6 , OR 6 or N(R 6 ) 2 , preferably unbranched at the ⁇ - position.
  • alkyl includes both straight and branched chain saturated hydrocarbon groups optionally substituted with NO 2 , CN, CO 2 R 6 , OCOR 6 F, Cl, COR 6 OH or NH 2 , preferably unbranched at the ⁇ - position.
  • amino acid means natural and unnatural ⁇ -amino acids preferably the natural and unnatural twenty amino acids commonly found in plant and animal proteins and listed on page 961- 962 of Fessenden and Fessenden 4 th Edition.
  • R 6 can be independently selected from hydrogen C h alky! C L galkylaryl and a protecting group selected from the groups boc, Fmoc, Cbz, and trityl.
  • R 6 represents hydrogen, C h alky! and C 1-6 alkylaryl.
  • aryl means aromatic carbocyclic and heterocyclic groups.
  • Preferred examples of aryl groups include phenyl, naphthyl, pyridyl, imidazolyl and thienyl.
  • suitable substituents include N0 2 , CN, CO 2 R 6 , F, Cl, COR 6 , C ⁇ alkyl, C ⁇ alkoxy, OR 6 , trifluoromethyl, N(R 6 ) 2 , phenyl and C ⁇ alkylaryl.
  • substituted aryl groups bear 1 , 2 or 3 substituents.
  • Preferred substituents are selected from the group NO 2 , CN, CO 2 R 6 , F, Cl, hydroxy, C ⁇ alkyl, C ⁇ alkoxy, OR 6 , trifluoromethyl, amino, phenyl and C ⁇ 6 alkylaryl.
  • R represents C ⁇ alkyl, aryl, C ⁇ alkylaryl, O-C ⁇ alkyl, O-aryl, or O-C ⁇ alkylaryl, or protected derivatives thereof More preferably R is C ⁇ alkyl, phenyl, C,. 6 alkylphenyl, O-C ⁇ alkyl, O-phenyl, and O-C L galkylphenyl.
  • R is selected from ethyl, propyl, butyl, tertbutyl, phenyl, ethylphenyl, O-ethyl, O-propyl, O-butyl, O-tertbutyl, O-pentyl, O-hexyl, O- dodecanyl, and O-phenyl.
  • M is magnesium or zinc, even more preferably magnesium.
  • n is 0 to 6.
  • X will be a halide, perchlorate, or triflate anion.
  • X will be a perchlorate, or triflate anion.
  • M is magnesium and n is 0 to 6.
  • halide means fluoride, chloride, iodide or bromide.
  • reaction is conveniently carried out in non reactive solvent preferably tetrahydrofuran or acetonitrile.
  • the reaction may be carried out at a temperature of 0 to 100 °C under reflux, preferably at a temperature in the range of 0 to 60 °C, even more preferably in the range of 20 to 50 °C, conveniently at the reflux temperature of the chosen solvent.
  • the molar ratio of metal salt to compound of formula (I) employed in the reaction is preferably from about 0.001 :1 to 0.5:1 , preferably 0.05:1.
  • the desired boc-carbonyl compound may be isolated by any conventional method from the reaction mixture, for example solvent extraction followed by crystallisation or chromatography. Further aspects of the invention are novel intermediates of formula (Ma) or (Mb).
  • a further aspect of the invention is a process for the preparation of compounds of formula (lla) and (Mb) which comprises reacting compounds of formula (III):
  • R is as defined for compounds of formula (I) with Boc 2 O in solvent in the presence of a catalyst.
  • reaction is conveniently carried out in a non-reactive solvent, such as a haloalkane, in particular dichloromethane, or tetrahydrofuran or ethyl acetate.
  • a non-reactive solvent such as a haloalkane, in particular dichloromethane, or tetrahydrofuran or ethyl acetate.
  • the reaction is conveniently carried out at ambient temperature, preferably in the range 0 to 30°C preferably 15 to 20 °C.
  • the catalyst is 4 -dimethylaminopyridine.
  • the molar ratio of catalyst to compound of formula (III) or (III) is in the range 0.2:1 to 0.001 :1 , preferably 0.05:1.
  • This reaction can be carried out in the same reaction conditions as the solution phase preparation of compounds of formula (lla) and (Mb) from compounds of formula (III) above.
  • N,N-(Diisopropyl)aminomethyipolystyrene (resin 2% crosslinked polystyrene-co- divinylbenzene).
  • reaction is conveniently carried out in a non-reactive solvent, preferably dichloromethane.
  • the reaction may be carried out at a temperature of 0 to 30 °C, preferably in the range of 15 to 30 °C.
  • the molar ratio of resin bound base to pyrazol-1-yl-methyl-carbamic acid employed in the reaction is preferably from about 1 : 0.5 to 5, more preferably 1 : 1 to 3.
  • Pyrazol-1-yl-methyl-carbamic acid hydrochloride can be purchased from Aldrich.
  • R represents O-tertbutyl
  • Bis Boc PC is available from Aldrich, Advanced ChemTech or Chem Impex International.
  • the protecting group may be removed at any convenient subsequent stage in the reaction sequence, or after the compound of formula (I) has been used as the reagent for the conversion of an amine to the corresponding guanidine on a compound.
  • the protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See for example 'Protective Groups in Organic Chemistry' Ed. J. F. W. McOmie (Plenum Press 1973) or 'Protective Groups in Organic Synthesis' by Theodora W Greene and P G M Wuts (John Wiley and Sons 1991)
  • suitable amine protecting groups include acyl type protecting groups e.g. formyl, trifluoroacetyl, acetyl, urethane type protecting groups e.g.
  • benzyloxycarbonyl (Cbz), substituted benzyloxycarbonyl, 9- fluorenylmethoxycarbonyl (Fmoc), f-butoxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl and alkyl type protecting groups e.g. benzyl, trityl, chlorotrityl.
  • Boc is tert-butoxycarbonyl.
  • Boc 2 0 is di-tert-butyl dicarbonate.
  • DMAP is 4-dimethylaminopyridine.
  • THF is tetrahydrofuran.
  • DMF is N,N-dimethylformamide.
  • DIPEA is N,N-Diisopropylethylamine.
  • DCM is Dichloromethane.
  • PyBOP is Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; and Rf represents retention factor.
  • reaction mixture was washed with water (2x500 ml), aqueous acetic acid (3 g acetic acid in 500 ml water), water (500 ml), saturated aqueous sodium hydrogen carbonate (500 ml) and brine (200 ml).
  • aqueous acetic acid 3 g acetic acid in 500 ml water
  • water 500 ml
  • saturated aqueous sodium hydrogen carbonate 500 ml
  • brine 200 ml
  • Example 2- an alternative method for preparing Intermediate 1.
  • Pyrazol-1-ylcarboxamidine hydrochloride (0.44 g) was mixed with N,N- (diisopropyl)aminomethyl polystyrene (resin 2% crosslinked polystyrene-co- divinylbenzene); (1 g 3.68 mmol base/g) in dichloromethane (5 ml).
  • a solution of di-tert-butyl dicarbonate (0.65 g) in dichloromethane (5 ml) was added and the mixture stirred at room temperature for 2 days. The mixture was filtered and the filtrate evaporated in vacuo to give the title compound as a white crystalline solid (0.53 g).
  • N-(9-Fluorenylmethoxycarbonyl)-6-aminohexanoic acid (2.4 g) was added to a stirred mixture of PyBOP (4.3 g) and diisopropylethylamine (1.98 g) in dichloromethane (50 ml) at 20 °C. After 12 hours the mixture was washed with water (50ml). The organics were dried (MgSO 4 ) filtered and evaporated. The resultant oil was purified by silica column to give Intermediate 6 as a white solid (3.0g). TLC: 1 :1 ethyl acetate/cyclohexane Rf 0.26. LC/MS: MH+ 446

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau procédé de préparation de composés butoxycarbonylimino, en particulier l'ester de tert-butyle de l'acide (tert- butoxycarbonylimino-pyrazol-1-yl-méthyl)-carbamique, également connu sous le nom de bis-boc-1H-pyrazole-1-carboxamidine ou bis-Boc PC. L'invention concerne également de nouveaux intermédiaires.
PCT/GB2000/002355 1999-06-19 2000-06-16 Procede de preparation de composes butoxycarbonylimino et intermediaires pour ce procede Ceased WO2000078723A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU54159/00A AU5415900A (en) 1999-06-19 2000-06-16 Process for the preparation of butoxycarbonylimino compounds and intermediates therefor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9914306.7 1999-06-19
GBGB9914306.7A GB9914306D0 (en) 1999-06-19 1999-06-19 Chemical process

Publications (1)

Publication Number Publication Date
WO2000078723A1 true WO2000078723A1 (fr) 2000-12-28

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AU (1) AU5415900A (fr)
GB (1) GB9914306D0 (fr)
WO (1) WO2000078723A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7186855B2 (en) 2001-06-11 2007-03-06 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7232924B2 (en) 2001-06-11 2007-06-19 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1513280A (en) * 1974-12-19 1978-06-07 Bottu Therapeutic pyrazole derivatives
EP0743320A2 (fr) * 1995-05-18 1996-11-20 Bristol-Myers Squibb Company Promédicaments ayant un groupe guanidine ou amidine acylé

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1513280A (en) * 1974-12-19 1978-06-07 Bottu Therapeutic pyrazole derivatives
EP0743320A2 (fr) * 1995-05-18 1996-11-20 Bristol-Myers Squibb Company Promédicaments ayant un groupe guanidine ou amidine acylé

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
M. S. BERNATOWICZ ET AL., TETRAHEDRON LETTERS, vol. 34, no. 21, 1993, pages 3389 - 92, XP000939028 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US6972341B2 (en) 2001-06-11 2005-12-06 Xeno Port, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7186855B2 (en) 2001-06-11 2007-03-06 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7232924B2 (en) 2001-06-11 2007-06-19 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
US7423169B2 (en) 2001-06-11 2008-09-09 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
US7790708B2 (en) 2001-06-11 2010-09-07 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8168623B2 (en) 2001-06-11 2012-05-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US9238616B2 (en) 2001-06-11 2016-01-19 Xenoport, Inc. Prodrugs of gaba analogs, compositions and uses thereof
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof

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AU5415900A (en) 2001-01-09
GB9914306D0 (en) 1999-08-18

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