WO2000012468A1 - An improved synthesis of 3-hydroxy-4-amino-benzonitrile - Google Patents
An improved synthesis of 3-hydroxy-4-amino-benzonitrile Download PDFInfo
- Publication number
- WO2000012468A1 WO2000012468A1 PCT/US1999/019492 US9919492W WO0012468A1 WO 2000012468 A1 WO2000012468 A1 WO 2000012468A1 US 9919492 W US9919492 W US 9919492W WO 0012468 A1 WO0012468 A1 WO 0012468A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- optionally substituted
- aryl
- alkenyl
- heteroaryl
- Prior art date
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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)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99943936A EP1107948A4 (en) | 1998-08-28 | 1999-08-26 | An improved synthesis of 3-hydroxy-4-amino-benzonitrile |
CA002341718A CA2341718A1 (en) | 1998-08-28 | 1999-08-26 | An improved synthesis of 3-hydroxy-4-amino-benzonitrile |
JP2000567502A JP2002523487A (en) | 1998-08-28 | 1999-08-26 | Improved synthesis of 3-hydroxy-4-amino-benzonitrile |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US9824998P | 1998-08-28 | 1998-08-28 | |
US60/098,249 | 1998-08-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000012468A1 true WO2000012468A1 (en) | 2000-03-09 |
Family
ID=22268356
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/019492 WO2000012468A1 (en) | 1998-08-28 | 1999-08-26 | An improved synthesis of 3-hydroxy-4-amino-benzonitrile |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1107948A4 (en) |
JP (1) | JP2002523487A (en) |
CA (1) | CA2341718A1 (en) |
WO (1) | WO2000012468A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7709485B2 (en) | 2002-10-29 | 2010-05-04 | Glaxosmithkline Llc | IL-8 receptor antagonists |
US7893089B2 (en) | 2006-04-21 | 2011-02-22 | GlaxoSmithKline, LLC | IL-8 receptor antagonists |
US8097626B2 (en) | 2006-04-21 | 2012-01-17 | Glaxosmithkline Llc | IL-8 receptor antagonists |
US9598669B2 (en) | 2005-12-29 | 2017-03-21 | Anthrogenesis Corporation | Composition for collecting placental stem cells and methods of using the composition |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5270943B2 (en) * | 2008-03-28 | 2013-08-21 | 大阪瓦斯株式会社 | Fluorene derivative and method for producing amino group-containing fluorene derivative using the fluorene derivative |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4457872A (en) * | 1979-11-28 | 1984-07-03 | Yamanouchi Pharmaceutical Co. | 2-Hydroxyoxanilic acid derivatives |
US5886044A (en) * | 1995-02-17 | 1999-03-23 | Smithkline Beecham Corporation | IL-8 receptor antagonists |
Family Cites Families (2)
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 |
SE370866B (en) * | 1968-03-21 | 1974-11-04 | Ciba Geigy Ag |
-
1999
- 1999-08-26 CA CA002341718A patent/CA2341718A1/en not_active Abandoned
- 1999-08-26 WO PCT/US1999/019492 patent/WO2000012468A1/en not_active Application Discontinuation
- 1999-08-26 EP EP99943936A patent/EP1107948A4/en not_active Withdrawn
- 1999-08-26 JP JP2000567502A patent/JP2002523487A/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4457872A (en) * | 1979-11-28 | 1984-07-03 | Yamanouchi Pharmaceutical Co. | 2-Hydroxyoxanilic acid derivatives |
US5886044A (en) * | 1995-02-17 | 1999-03-23 | Smithkline Beecham Corporation | IL-8 receptor antagonists |
Non-Patent Citations (2)
Title |
---|
EASSON A.P.T.: "The Search for Chemotherapeutic Amidines. Part XVIII. Substituted 4,4'- Diamidinodiphenylamines", 1961, pages 1029 - 1037, XP002925355 * |
See also references of EP1107948A4 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7709485B2 (en) | 2002-10-29 | 2010-05-04 | Glaxosmithkline Llc | IL-8 receptor antagonists |
US9598669B2 (en) | 2005-12-29 | 2017-03-21 | Anthrogenesis Corporation | Composition for collecting placental stem cells and methods of using the composition |
US9725694B2 (en) | 2005-12-29 | 2017-08-08 | Anthrogenesis Corporation | Composition for collecting and preserving placental stem cells and methods of using the composition |
US7893089B2 (en) | 2006-04-21 | 2011-02-22 | GlaxoSmithKline, LLC | IL-8 receptor antagonists |
US8097626B2 (en) | 2006-04-21 | 2012-01-17 | Glaxosmithkline Llc | IL-8 receptor antagonists |
Also Published As
Publication number | Publication date |
---|---|
JP2002523487A (en) | 2002-07-30 |
EP1107948A1 (en) | 2001-06-20 |
EP1107948A4 (en) | 2002-01-02 |
CA2341718A1 (en) | 2000-03-09 |
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