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WO1999044996A1 - Procede relatif a l'elaboration d'acide 3-hydroxy-5-[1,4,5,6-tetrahydro-5-hydroxy-2-pyrimidinyle)amino]benzoique - Google Patents

Procede relatif a l'elaboration d'acide 3-hydroxy-5-[1,4,5,6-tetrahydro-5-hydroxy-2-pyrimidinyle)amino]benzoique Download PDF

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Publication number
WO1999044996A1
WO1999044996A1 PCT/US1999/003279 US9903279W WO9944996A1 WO 1999044996 A1 WO1999044996 A1 WO 1999044996A1 US 9903279 W US9903279 W US 9903279W WO 9944996 A1 WO9944996 A1 WO 9944996A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
reacting
produce
hydroxy
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/US1999/003279
Other languages
English (en)
Inventor
Peter G. Ruminski
Hwang-Fun Lu
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.)
GD Searle LLC
Original Assignee
GD Searle LLC
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 GD Searle LLC filed Critical GD Searle LLC
Priority to AU27668/99A priority Critical patent/AU2766899A/en
Publication of WO1999044996A1 publication Critical patent/WO1999044996A1/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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C07D239/14—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms

Definitions

  • the present invention is directed to a process for preparing a compound of the formula
  • the process comprises reacting 3-amino-5- hydroxybenzoic acid with ammonium thiocyanate to produce a thiourea of the formula
  • the compound produced by the present process is useful in preparing pharmaceutical agents, such as the ⁇ v ⁇ 3 integrin antagonists generally described in W097/08174.
  • the process of the present invention comprises reacting 3-amino-5- hydroxybenzoic acid with ammonium thiocyanate to produce a thiourea of the formula
  • the invention is directed to a process for preparing a compound of the formula CO 2 H
  • the process can be varied by substituting various reactants and reagents which are known by those with skill in the art which are commercially available reactants or reagents, or reactants which can be prepared by conventional methodology.
  • ammonium thiocyanate can be replaced with sodium or potassium thiocyanate
  • aqueous HCI can be replaced with another aqueous acid.
  • methylating step Mel can be replaced with dimethyl sulfate or other methylating agents known to those skilled in the art and ethanol can, for example, be replaced with tetrahydrofuran.
  • DMA can, for example, be replaced with dimethylformamide and salts other than HCI can be produced as would be readily apparent to those with skill in the art.
  • MgSO 4 magnesium sulfate
  • 3-amino-5-hydroxybenzoic acid (A) (Tetrahedron, Vol. 39, No. 24, pp 4189-4192, 1983) is reacted with ammonium thiocyanate in aqueous HCI at elevated temperatures to yield thiourea (B).
  • thiocyanate salts or other solvents may be substituted for those exemplified as would be apparent to those skilled in the art.
  • Thiourea (B) is then reacted with methyl iodide in absolute ethanol at elevated temperatures to produce (C).
  • Methylating agents other than methyl iodide and solvents other than ethanol can be used to produce (C) in an analogous manner.
  • (C) is then reacted with 1 ,3-diamino-2-hydroxy propane in dimethylacetamide (DMA) at elevated temperatures to give the desired product (D).
  • DMA dimethylacetamide
  • the HCI salt of (D) is formed after exposure to HCI.
  • Solvents other than DMA can be freely substituted and salts other than HCI can be formed as would be apparent to those skilled in the art
  • Example 2 The product from Example 1 (4.25 g, 0.014 mole) and methyl iodide (2.85 g, 0.02 mole) in absolute ethanol (30 mL) were stirred at reflux for 2 hours. The solvent was removed under vacuum. The residue was slurried with ethyl ether (2X, 1 hour each; then 1X overnight) and the ether was decanted off each time. The solid was then dried under vacuum to yield the desired product as a light yellow solid (5.09 g).

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)

Abstract

L'invention concerne un procédé relatif à l'élaboration d'un composé représenté par la formule (I), y compris les sels d'addition de ce composé.
PCT/US1999/003279 1998-03-04 1999-02-22 Procede relatif a l'elaboration d'acide 3-hydroxy-5-[1,4,5,6-tetrahydro-5-hydroxy-2-pyrimidinyle)amino]benzoique Ceased WO1999044996A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU27668/99A AU2766899A (en) 1998-03-04 1999-02-22 Process for preparing 3- hydroxy- 5-((1, 4,5,6- tetrahydro-5-hydroxy- 2- pyrimidinyl)amino)benzoic acid

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7671198P 1998-03-04 1998-03-04
US60/076,711 1998-03-04

Publications (1)

Publication Number Publication Date
WO1999044996A1 true WO1999044996A1 (fr) 1999-09-10

Family

ID=22133741

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/003279 Ceased WO1999044996A1 (fr) 1998-03-04 1999-02-22 Procede relatif a l'elaboration d'acide 3-hydroxy-5-[1,4,5,6-tetrahydro-5-hydroxy-2-pyrimidinyle)amino]benzoique

Country Status (3)

Country Link
AU (1) AU2766899A (fr)
WO (1) WO1999044996A1 (fr)
ZA (1) ZA991107B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8716226B2 (en) 2012-07-18 2014-05-06 Saint Louis University 3,5 phenyl-substituted beta amino acid derivatives as integrin antagonists
US9085606B2 (en) 2012-07-18 2015-07-21 Saint Louis University Beta amino acid derivatives as integrin antagonists
US10035778B2 (en) 2015-12-30 2018-07-31 Saint Louis University Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
A. P. T. EASSON, F. L. PYMAN: "CCCCXVI. - Amidines of Pharmacological Interest", J. CHEM. SOC., 1931, pages 2991 - 3001, XP002106224 *
H. FOKS ET AL.: "Studies on pyrazine derivatives. XXX. Synthesis of pyrazinylamino-1,3-diazacyclalkanes of potential circulatory activity", ACTA POL. PHARM., vol. 54, no. 1, 1997, pages 55 - 62, XP002106225 *
K. WEINHARDT ET AL.: "Synthesis and Antidepressant Profiles of Phenyl-Substituted 2-Amino- and 2-[(Alkoxycarbonyl)amino]-1,4,5,6-tetrahydropyrimidines", J. MED. CHEM., vol. 28, no. 6, 1985, pages 694 - 698, XP002058417 *
L. S. HAFNER, R. EVANS: "Preparation of 2-Imino- and 2-Nitrimino-1,3-diazacycloalkanes", J. ORG. CHEM., vol. 24, 1959, pages 1157 - 1159, XP002106227 *
M. PROTIVA ET AL.: "1-Aryl- and 1-(arylmethyl)-4-guanylpiperazines and other heterocyclic and alicyclic guanidine derivatives", COLLECT. CZECH. CHEM. COMMUN., vol. 40, 1975, pages 3904 - 3923, XP000574972 *
S. S. G. SIRCAR, K. K. PATNAIK: "Preparation of antibacterials from organo-mercurials. Part II", J. INDIAN CHEM. SOC., vol. 27, 1950, pages 535 - 538, XP002106223 *
T. NAKAYAMA ET AL.: "Synthesis and Structure-Activity Study of Protease Inhibitors. V. Chemical Modification of 6-Amidino-2-naphthyl 4-Guanidinobenzoate", CHEM. PHARM. BULL., vol. 41, no. 1, 1993, pages 117 - 125, XP002106226 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8716226B2 (en) 2012-07-18 2014-05-06 Saint Louis University 3,5 phenyl-substituted beta amino acid derivatives as integrin antagonists
US9085606B2 (en) 2012-07-18 2015-07-21 Saint Louis University Beta amino acid derivatives as integrin antagonists
US10035778B2 (en) 2015-12-30 2018-07-31 Saint Louis University Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
US10577330B2 (en) 2015-12-30 2020-03-03 Saint Louis University Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists

Also Published As

Publication number Publication date
ZA991107B (en) 2000-02-14
AU2766899A (en) 1999-09-20

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