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EP1107948A4 - Synthese amelioree de 3-hydroxy-4-amino-benzonitrile - Google Patents

Synthese amelioree de 3-hydroxy-4-amino-benzonitrile

Info

Publication number
EP1107948A4
EP1107948A4 EP99943936A EP99943936A EP1107948A4 EP 1107948 A4 EP1107948 A4 EP 1107948A4 EP 99943936 A EP99943936 A EP 99943936A EP 99943936 A EP99943936 A EP 99943936A EP 1107948 A4 EP1107948 A4 EP 1107948A4
Authority
EP
European Patent Office
Prior art keywords
alkyl
optionally substituted
aryl
alkenyl
heteroaryl
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Withdrawn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
EP99943936A
Other languages
German (de)
English (en)
Other versions
EP1107948A1 (fr
Inventor
Neil H Baine
William M Clark Jr
Ann Marie Eldridge
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.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham 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 SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP1107948A1 publication Critical patent/EP1107948A1/fr
Publication of EP1107948A4 publication Critical patent/EP1107948A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
    • C07C273/1818—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from -N=C=O and XNR'R"
    • C07C273/1827—X being H
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2

Definitions

  • This invention relates to a process for making intermediates useful for making certain phenyl urea compounds.
  • the end-product phenyl urea compounds are useful in treating IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 mediated diseases.
  • Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-la, IL-lb or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP.
  • This invention provides a method for making 2-amino-5-cyano-phenol which is a useful intermediate for synthesising N-[2-hydroxy-4-cyanophenyl]-N'-[2-bromophenyl]urea, a compound disclosed in PCT application serial number PCT US96/13632, published 21 August 1997 as WIPO No. WO97/29743.
  • this invention relates to a method for making compounds of Formula (A)
  • R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
  • Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl; halosubstituted Ci -io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-ioalkoxy; azide; S(O)tR4; (CR R 8 )q S(O)tR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl C ⁇ _4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl Ci_4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Ci-4 alkyloxy; heterocyclic, heterocyclic Ci -4alkyl; heterocyclicC ⁇ _4alkyloxy; heterocyclicC2-10 alkenyl; (CR 8 R 8 )q NR4R5; (CR 8 Rs)q C(O)NR 4 R 5
  • R4 and R5 are independently, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, heterocyclic
  • C ⁇ -4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O, N or S;
  • Y is Ri ;
  • q is 0 or an integer having a value of 1 to 10;
  • m is an integer having a value of 1 to 3;
  • R6 and R7 are independently hydrogen or a C1 -4 alkyl group, or R and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
  • R 8 is hydrogen or C1 -4 alkyl
  • RlO is Ci-io alkyl C(O) 2 R8;
  • Rl 1 is hydrogen, optionally substituted C1.4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC ⁇ _4alkyl;
  • Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl;
  • Rl3 is suitably Cj-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi- 4alkyl, heterocyclic, or heterocyclicCi-4alkyl;
  • Rt ⁇ is NRgR7, alkyl, aryl, aryl Cj_4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl C1.4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C ⁇ 4 alkyl, heterocyclic C2-4 alkenyl, or camphor, all of which groups may be optionally substituted; which process comprises treating a compound of Formula (I) or (la)
  • A is the anion of an acid addition salt with an isocyanate in the presence of about an equivalent of an organic base.
  • This invention also relates to a process for making a 2-aminophenol.
  • this process comprises preparing the phenol of Formula (I) or (la)
  • A" is the anion of an acid addition saltc by treating a compound of formula (II) or (Ila) with an acid to remove the t-BOC group.
  • this invention relates to a process for making the nitrile of formula (III)
  • Rl is halogen, cyano, nitro, CF3, C(O)NR4R5, alkenyl C(O)NR4Rs, C(O) R4R1O, alkenyl C(O)ORi2, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR4R5, and preferably one of R4 or R5 is phenyl.
  • Rj is in the 4-position of the phenyl ring.
  • Rj is nitro, halogen, cyano, trifluoromethyl group, or C(O)NR4R5.
  • Y is preferably a halogen, Ci-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted arylalkyloxy, optionally substituted heteroarylalkyloxy, methylenedioxy, NR4R5, thioC]-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted Ci-4 alkyl, or hydroxy alkyl.
  • Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or disubstituted in the 2'- position or 2'-, 3'-position.
  • Y may be substituted in any of the 5 ring positions, preferably when R is OH, or SH, Y is preferably mono-substituted in the 2'-position or 3'- position, with the 4'- preferably being unsubstituted. If the ring is disubstituted, when R is OH or SH other ring substituents are preferably in the 2' or 3' position of a monocyclic ring. While both Rl and Y can both be hydrogen, it is prefered that at least one of the rings be substituted. Preferably both rings are substituted.
  • Preferred compounds include: N-[2-hydroxy-4-cyanophenyl]-N -[2-bromophenyl] urea
  • the benzoxazolinone starting material (formula 1-a) is commercially available. See for example Aldrich. It is halogenated, bromine is illustrated, by mixing it with a solution of an organic acid, and a the alkali metal salt of that acid in a molar amount about equal to that of the benzoxazolinone to give the compound of formula b. Glacial acetic acid and its sodium salt are the preferred organic acid/salt combination.
  • a suspension forms. That suspension is cooled to below ambient temperature, somewhere between 0-20 °C and then bromine is added slowly; a slight molar excess of bromine with reference to the benzoxazolinone is preferred. This mixture is stirred at ambient temperature for a period sufficient to effect the reaction, usually about 12 hours to overnight. No special conditions are required to work up the halogenated product illustrated by formula b.
  • the nitrile of formula 1 -c is prepared by treating the brominated benzoxazolinone with CuCN at a moderately elevated temperature under an inert gas in a polar solvent such as dimethyl formamide, N-methyl pyrrolidinone or dimethylsulfoxide.
  • a polar solvent such as dimethyl formamide, N-methyl pyrrolidinone or dimethylsulfoxide.
  • Zn(CN)2 or an alkali metal salt of the cyanide ion can be used to effect this cyanation reaction.
  • a transition metal catalyst such as Pd(0) or Ni(0) can be used with Zn(CN)2 and an alkali metal salt of the cyanide ion respectively.
  • the benzoxazolinone is added to the solvent followed by the CuCN (in about a 75% molar excess).
  • This mixture is heated to a temperature which is in the range of 120 - 175 °C.
  • the reaction is carried out under an inert gas, preferably nitrogen.
  • the reaction mixture is heated to the noted temperature range for about 4-8 hours.
  • the reaction is cooled to about 100 °C, a 3 to 4-fold molar excess of an alkali metal cyanide, e.g. NaCN, is added and the resulting suspension is stirred for a couple of more hours at ambient temperature. No special workup is required to recover the nitrile.
  • an alkali metal cyanide e.g. NaCN
  • the carbamate (formual 1-d) is prepared by treating the benzoxolecarbonitrile with an alkyl dicarbonate in a polar non-protic solvent in the presence of a nucleophilic addition catalyst such as dimethylaminopyridine. The reaction is run at about ambient temperature for a couple of hours or so.
  • the 1,1-dimethylethylcarbamate is treated with an organic or mineral acid. While trifluoroacetic acid is illustrated, HC1 or H2SO4 or an organic acid such as methansulfonic acid can be used in this reaction as well.
  • the carbamate is dissolved in a polar aprotic solvent, cooled, acid added, and the mixture stirred for several hours at a temperature between 0 °C and room temperature. Workup can involve precipitating the product by adding an organic solvent, cooling the resulting suspension to below freezing, and holding it at that temperature for up to 12 hours or so as a means for isolating the product.
  • the compound designated formula 1-f is made by treating the acid salt form of the amine with an isocyanate in the presence of about an equivalent of a base to scavenge the acid release when the isocyanate reacts with the amine to form the urea moiety.
  • a suitable solvent such as acetonitrile to which is added a base.
  • Piperidine is an example of a base that can be used as an acid scavenger.
  • an isocyanate is added.
  • the reaction proceeds at room temperature and is complete in the course of 1 to 3 hours or thereabouts. Workup and recovery of the product is conventional.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de 3-hydroxy-4-amino-benzonitrile.
EP99943936A 1998-08-28 1999-08-26 Synthese amelioree de 3-hydroxy-4-amino-benzonitrile Withdrawn EP1107948A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US9824998P 1998-08-28 1998-08-28
US98249P 1998-08-28
PCT/US1999/019492 WO2000012468A1 (fr) 1998-08-28 1999-08-26 Synthese amelioree de 3-hydroxy-4-amino-benzonitrile

Publications (2)

Publication Number Publication Date
EP1107948A1 EP1107948A1 (fr) 2001-06-20
EP1107948A4 true EP1107948A4 (fr) 2002-01-02

Family

ID=22268356

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99943936A Withdrawn EP1107948A4 (fr) 1998-08-28 1999-08-26 Synthese amelioree de 3-hydroxy-4-amino-benzonitrile

Country Status (4)

Country Link
EP (1) EP1107948A4 (fr)
JP (1) JP2002523487A (fr)
CA (1) CA2341718A1 (fr)
WO (1) WO2000012468A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY143477A (en) 2002-10-29 2011-05-31 Smithkline Beecham Corp Il-8 receptor antagonists
CN101374941A (zh) 2005-12-29 2009-02-25 人类起源公司 采集和保存胎盘干细胞的改良组合物及其使用方法
UA98456C2 (en) 2006-04-21 2012-05-25 Смитклайн Бичам Корпорейшн Il-8 receptor antagonists
WO2007124423A2 (fr) 2006-04-21 2007-11-01 Smithkline Beecham Corporation Antagonistes du récepteur de l'il-8
JP5270943B2 (ja) * 2008-03-28 2013-08-21 大阪瓦斯株式会社 フルオレン誘導体およびこのフルオレン誘導体を用いたアミノ基含有フルオレン誘導体の製造方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2195076A (en) * 1936-10-24 1940-03-26 Gen Aniline & Film Corp Process of replacing halogen in cyclic halogen compounds and product thereof
US3689550A (en) * 1968-03-21 1972-09-05 Ciba Geigy Ag N-hydroxyphenyl-n{40 -phenylureas

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1181070A (fr) * 1979-11-28 1985-01-15 Kiyoshi Murase Methode de preparation de derives de l'acide 2- hydroxyoxanilique
EP0809492A4 (fr) * 1995-02-17 2007-01-24 Smithkline Beecham Corp Antagonistes des recepteurs d'il-8

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2195076A (en) * 1936-10-24 1940-03-26 Gen Aniline & Film Corp Process of replacing halogen in cyclic halogen compounds and product thereof
US3689550A (en) * 1968-03-21 1972-09-05 Ciba Geigy Ag N-hydroxyphenyl-n{40 -phenylureas

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002181268, Database accession no. 2102159 *
P J KOCIENSKI: "Protecting Groups", 1994, GEORG THIEME VERLAG, STUTTGART, XP002181269 *
See also references of WO0012468A1 *
YOH, SOO-DONG ET AL, JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 2., 1989, CHEMICAL SOCIETY. LETCHWORTH., GB, pages 7-14, ISSN: 1472-779X *

Also Published As

Publication number Publication date
JP2002523487A (ja) 2002-07-30
CA2341718A1 (fr) 2000-03-09
EP1107948A1 (fr) 2001-06-20
WO2000012468A1 (fr) 2000-03-09

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