EP1107943A4 - Process for making 2-amino-5-cyanophenol - Google Patents

Process for making 2-amino-5-cyanophenol

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Publication number
EP1107943A4
EP1107943A4 EP99943937A EP99943937A EP1107943A4 EP 1107943 A4 EP1107943 A4 EP 1107943A4 EP 99943937 A EP99943937 A EP 99943937A EP 99943937 A EP99943937 A EP 99943937A EP 1107943 A4 EP1107943 A4 EP 1107943A4
Authority
EP
European Patent Office
Prior art keywords
formula
compound
iii
aprotic solvent
cyanide
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Withdrawn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
EP99943937A
Other languages
German (de)
French (fr)
Other versions
EP1107943A1 (en
Inventor
Clifford S Labaw
Susan C Shilcrat
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 Corp
Original Assignee
SmithKline Beecham Corp
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 Corp filed Critical SmithKline Beecham Corp
Publication of EP1107943A1 publication Critical patent/EP1107943A1/en
Publication of EP1107943A4 publication Critical patent/EP1107943A4/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
    • 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

Definitions

  • PROCESS FOR MAKING 2-AMINO-5-CYANOPHENOL Scope of the Invention 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. They are disclosed in PCT application serial number PCT/US96/13632, published 21 August 1997 as WIPO No. WO97/29743 and co-pending U.S. application 08/894291.
  • Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of
  • T-cells The 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 the aforementioned PCT application.
  • This invention relates to a process for making 2-amino-5-cyanophenol.
  • this process comprises preparing the phenol of Formula (I)
  • this invention comprises a process for preparing a compound of Formula (I) from o-anisidine, which process comprises treating o-anisidine with a halogenating agent to obtain Formula (III)
  • Scheme 1 outlines the chemistry for preparing to 2-amino-5-cyanophenol, a third stage intermediate in a synthesis of N-[2-hydroxy-4-cyanophenyl]-N'-[2- bromophenyljurea.
  • stage A The p ⁇ r ⁇ bromination of o-anisidine (stage A) has been described in the literature, using several different reagents (Choudary, B. M.; Sudha, Y., and Reddy, P. N. Synlett., 1994, 450; Reeves, W. P.; and King, R. M. Synth. Comm. 1993, 23, 855; Fox, G. J.; Hallas, G.; Hepworth, J. D.; and Paskins, K. N. Org. Synth., Coll. Vol. 6, 181).
  • the crude reaction product is typically a mixture of the starting material, Formula (III), the ortho isomer 2-bromo-6-methoxy-aniline (1) and the product of over bromination, 2,4-dibromo-6-methoxy-aniline (2) below.
  • a typical crude GC product ratio for 2,4,4,6-tetrabromo-2,5-cyclohexadien-l-one was 15% o- anisidine/6% formula 1/61% o-anisidine/17% formula 2; for HBr-DMSO it was 13% o-anisidine/13% formula 1/53% Formula (II)/22% formula 2.
  • stage b was effected by treating Formula (III) with copper (I) cyanide in either refluxing NN-dimethylformamide or l-methyl-2-pyrrolidinone for 3-5 hours. While the reaction proceeded faster in l-methyl-2-pyrrolidinone, workup was difficult and it was easiest to carry the crude reaction mixture through stage c, then purify by crystallization Stage c provided a crude recovery of 75%.
  • stage c Demethylation of crude Formula (II) (stage c) was effected by several reagents: boron tribromide, sodium ethyl thiolate, and sodium cyanide in refluxing dimethyl sulfoxide.
  • boron tribromide the reaction is carried out in an aprotic solvent such as methylene chloride.
  • the reaction is carried out under an inert gas such as nitrogen. This reaction goes to completion at a reduced temperature, i.e., about -10 to +10 °C in about 1-3 hours.
  • the sodium cyanide reaction proceeds best in dimethyl sulfoxide.
  • the reaction is run under an inert gas such as nitrogen. Refluxing for 3-7 hours is needed to effect the reaction.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Toxicology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

This invention relates to a process for preparing 2-amino-5-cyanophenol.

Description

PROCESS FOR MAKING 2-AMINO-5-CYANOPHENOL Scope of the Invention 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, GROα, GROβ, GROγ and NAP-2 mediated diseases. They are disclosed in PCT application serial number PCT/US96/13632, published 21 August 1997 as WIPO No. WO97/29743 and co-pending U.S. application 08/894291.
Area of the Invention 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. M. Baggiolini et al, J. Clin. Invest. 84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144, 2223 (1990) ; Strieter, et al,
Science 243, 1467 (1989) and /. Biol Chem. 264, 10621 (1989); Cassatella et al, J. Immunol. 148, 3216 (1992).
There is a need for treatment in this field, for compounds, which are capable of binding to the IL-8 α or β receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds, which are inhibitors of IL-8 receptor binding. Such compounds have been disclosed in published patent applications exemplified by the likes of PCT/US96/13632, published 21 August 1997 as WIPO No. WO97/29743. 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 the aforementioned PCT application.
SUMMARY OF THE INVENTION This invention relates to a process for making 2-amino-5-cyanophenol. In particular, this process comprises preparing the phenol of Formula (I)
by demythelating a compound of Formula (II).
In addition, this invention comprises a process for preparing a compound of Formula (I) from o-anisidine, which process comprises treating o-anisidine with a halogenating agent to obtain Formula (III)
and displacing the bromide by a cyanide anion to obtain a compound of Formula (II) then demethylating Formula (II) to obtain the compound of Formula
(I).
Description of the Invention
Scheme 1 outlines the chemistry for preparing to 2-amino-5-cyanophenol, a third stage intermediate in a synthesis of N-[2-hydroxy-4-cyanophenyl]-N'-[2- bromophenyljurea. Scheme I
OMe stage a stage c_
(HI) (ID (I)
The pαrα bromination of o-anisidine (stage A) has been described in the literature, using several different reagents (Choudary, B. M.; Sudha, Y., and Reddy, P. N. Synlett., 1994, 450; Reeves, W. P.; and King, R. M. Synth. Comm. 1993, 23, 855; Fox, G. J.; Hallas, G.; Hepworth, J. D.; and Paskins, K. N. Org. Synth., Coll. Vol. 6, 181). The crude reaction product is typically a mixture of the starting material, Formula (III), the ortho isomer 2-bromo-6-methoxy-aniline (1) and the product of over bromination, 2,4-dibromo-6-methoxy-aniline (2) below.
1 2
The following reagents gave Formula (III) as the principle product in the reaction mixture: 2,4,4,6-tetrabromo-2,5-cyclohexadien-l-one, hexamethylenetetramine hydrobromide perbromide, benzyltrimethylammonium tribromide, tetrabutylammonium tribomide, pyridinium bromide perbromide, ammonium molybdate-potassium bromide-hydrogen peroxide-acetic acid, sodium tungstate-potassium bromide-hydrogen peroxide-acetic acid, and 48% hydrobromic acid in warm (60-80 °C) dimethyl sulfoxide. The preferred results were achieved with 2,4,4,6-tetrabromo-2,5-cyclohexadien-l-one and 48% hydrobromic acid in dimethyl sulfoxide. While 2,4,4,6-tetrabromo-2,5-cyclohexadien-l-one gave somewhat better isomer ratios, hydrobromic acid in dimethyl sulfoxide had the advantage of requiring no unusual reagent, only ordinary bulk chemicals. A typical crude GC product ratio for 2,4,4,6-tetrabromo-2,5-cyclohexadien-l-one was 15% o- anisidine/6% formula 1/61% o-anisidine/17% formula 2; for HBr-DMSO it was 13% o-anisidine/13% formula 1/53% Formula (II)/22% formula 2.
It was possible to isolate and purify Formula (III) through its sulfate salt. An ethyl acetate solution of the crude reaction mixture was treated with an ethyl acetate solution of concentrated sulfuric acid. The sulfate salt of Formula (II) crystallized from solution in enhanced purity. Recrystallization of Formula (II) from an alcohol solvent gave material of high chemical and isomeric purity. The free base was regenerated by standard aqueous extractive methodology.
Using HBr-DMSO as the brominating agent, and purifying via the sulfate salt, 100 g o-anisidine was transformed to 46 g or Formula (III).
Cyanation, (stage b) was effected by treating Formula (III) with copper (I) cyanide in either refluxing NN-dimethylformamide or l-methyl-2-pyrrolidinone for 3-5 hours. While the reaction proceeded faster in l-methyl-2-pyrrolidinone, workup was difficult and it was easiest to carry the crude reaction mixture through stage c, then purify by crystallization Stage c provided a crude recovery of 75%.
Demethylation of crude Formula (II) (stage c) was effected by several reagents: boron tribromide, sodium ethyl thiolate, and sodium cyanide in refluxing dimethyl sulfoxide. Where boron tribromide is used, the reaction is carried out in an aprotic solvent such as methylene chloride. Preferably the reaction is carried out under an inert gas such as nitrogen. This reaction goes to completion at a reduced temperature, i.e., about -10 to +10 °C in about 1-3 hours. The sodium cyanide reaction proceeds best in dimethyl sulfoxide. The reaction is run under an inert gas such as nitrogen. Refluxing for 3-7 hours is needed to effect the reaction. If sodium ethyl thiolate is used, dimethyl formamide is the solvent of choice. Again the reaction is carried out under an inert gas, nitrogen for example. Mildy elevated temperatures are needed to run the reaction; 75 to 125 °C for 30 minutes to 2 hours or so should cause the reaction to go to completion. An experimental procedure for each stage of the reaction set out in Scheme I is detailed below.
Examples Example 1 2-Methoxy-4-Bromo-Aniline
A stirred solution of o-anisidine; (104.6 g; 0.85 mol; Aldrich) in dry DMSO (1000 mL) under nitrogen, was treated with 48% HBr (185 mL; 1.64 mol; 1.9 eq; Aldrich) over 10-12 min. The reaction mixture spontaneously exothermed to -50 °C. After addition was complete, the reaction was heated to 80 °C and maintained at that temperature for 20 min. The reaction mixture was cooled to 5 °C, then partitioned between EtOAc (2L) and 1.5 N NaOH (2.4 L). After separating the phases, the aqueous layer was washed with additional EtOAc (1 L). The combined EtOAc layers were washed with H2O (2 x 2 L) and saturated brine (1 L), dried over magnesium sulfate (100 g), filtered, and concentrated in vacuo to a dark oil (163.9 g).
The crude product mixture was redissolved in EtOAc (1 L) and transfered to a stirred 2 L vessel. A solution of 18 N sulfuric acid (100 mL; 1.8 mol) in EtOAc (400 mL) was added in one portion. The EtOAc solution spontaneously exothermed to -50 °C. (If necessary to dissolve all solids, the reaction mixture was heated to reflux.) The mixture was allowed to cool slowly to ambient temperature. The resultant white crystals were collected by filtration, washed with EtOAc (100 mL) and dried to give 120.8 g Formula(III)-sulfate salt. This was recrystallized from 2- propanol (900 mL). The resultant crystals were filtered, washed with cold 2- propanol (100 mL), and force-air dried (58.7 g). To liberate the free base, the crystalline sulfate salt was partitioned between 1
N NaOH (1 L) and EtOAc (1 L). The mixture was stirred until all solids disappeared, then the phases were separated. The aqueous phase was washed with additional EtOAc (500 mL). The combined EtOAc phases were washed with H2O (1 L) and saturated brine (500 mL), then dried over magnesium sulfate (50 g). The solution was filtered, and concentrated in vacuo to produce Forumla (III) as a white solid (46.25 g; 27% yield), mp 56-58 °C. lU NMR (DMSO-d6) δ 3.75 (s, 3H), 4.86 (b, 2H), 6.55 (d, J = 8.3 Hz, IH), 6.80 (dd, J = 8.3, 2.2 Hz, IH), 6.89 (d, J = 2.2 Hz, IH). 13C NMR (DMSO-d6) δ 147.1, 137.2, 123.2, 114.7, 113.4, 106.2, 55.6.
Example 2 2-Methoxy-4-Cyano- Aniline A solution of 2-methoxy-4-bromoaniline (8.66 g; 42.9 mmol) in N,N- dimethylformamide (100 mL) under nitrogen was treated with copper (I) cyanide (5.75 g; 64.3 mmol; 1.5 eq). The reaction mixture was refluxed 5-6 h. After cooling, 10% aq FeCl3 (100 mL) and EtOAc (100 mL) were added. Stirring was continued 10 min, followed by filtration through Celite. The aqueous phase was washed with additional EtOAc (50 mL). The combined organic phases were washed with H2O (100 mL) and saturated brine (50 mL), and dried over magnesium sulfate (2.5 g). Upon concentration in vacuo, the captioned compound was isolated as a crude oil and used without further purification. lU NMR (CDC13) δ 3.76 (s, 3H), 4.75 (b), 6.57 (d, J = 8.1 Hz, IH), 6.86 (d, 7 = 1.7 Hz, IH), 7.04 (dd, 7 = 8.1, 1.7 Hz, 1H);13C NMR (CDC13) δ 146.1, 141.1, 126.6, 120.3, 113.5, 112.8, 99.2, 55.6.
Example 3 2-Amino-5-Cyano-PhenoI2-Methoxy-4-cyanoaniline was demethylated to form 2-amino-5-cyano-phenol by several reagents (a-c).
3a - Boron Tribromide: A solution of crude 2-methoxy-4-cyanoaniline (1.78 g; 12 mmol) in methylene chloride (25 mL) under nitrogen was cooled to 0 °C. A 1 M solution of boron tribromide in methylene chloride (24 mL; 24 mmol; 2 eq; Aldrich) was added dropwise over 20 min; the temperature was maintained below 5 °C. Stirring continued 2 hours at 0 °C. 5% aq NaHCO3 (100 mL)was added, followed by extraction with EtOAc (2 x 50 mL). The organic phases were washed with H2O (50 mL) and sat brine (50 mL) and dried over magnesium sulfate (4 g). The solution was filtered and concentrated in vacuo. The residue was stirred with methylene chloride (10 mL) to give the captioned compound as a solid (0.57 g; 35% yield) emerged from solution, mp 128-130 °C (d); lH NMR (DMSO-d6) δ 5.74 (s, IH), 6.62 6.63 (d, J = 8.1 Hz, IH), 6.85 (d, I = 1.8 Hz, IH), 6.98 (dd, J = 8.1, 1.8 Hz, IH), 9.78 (b, 2H); 13C NMR (DMSO-d6) δ 143.4, 142.5, 125.3, 120.7, 116.2, 113.3, 95.8.
3b - Sodium Cyanide in DMSO: Under nitrogen, a solution of crude 2- methoxy-4-cyanoaniline (0.41 g; 2.77 mmol) in dry DMSO (4 mL) was treated with solid sodium cyanide (0.68 g; 13.85 mmol; 5 eq) and heated to reflux for 5 hours. The cooled mixture was partitioned between H2O (20 mL) and EtOAc (20 mL). The pH of the aqueous phase was adjusted to 7 with 1 N HC1, and the phases were separated. The organic phase was washed with H2O (10 mL) and sat. brine (10 mL), and dried over magnesium sulfate (2 g). Concentration in vacuo gave the title compound as a tan solid (240 mg; 65% yield).
3c - Sodium Ethyl Thiolate in DMF: Under nitrogen, a solution of crude 2- methoxy-4-cyanoaniline (0.33 g; 2.23 mmol) in DMF (4 mL) was treated with a solution of sodium ethyl thiolate (0.29 g; 3.45 mmol; 1.55 eq; Aldrich) in DMF (1 mL). The reaction mixture was heated to 100 °C for 1 hour. The mixture was cooled and partitioned between saturated NH4C1 soln(10 mL) and EtOAc (10 mL). The pH of the aqueous phase was adjusted to 5 with 1 N HC1, and the phases were separated. The organic phase was washed with H2O (10 mL), saturated brine (10 mL), and dried over magnesium sulfate (1 g). Concentration in vacuo gave the title compound as a tan solid (230 mg; 77% yield).

Claims

What is claimed is:
1. A process for preparing a compound of Formula (I),
which process comprises demythelating a compound of Formula (II).
2. The process of claim 1 wherein the demethylation is carried out using boron tribromide in an aprotic solvent, sodium cyanide in dimethyl sulfoxide, or sodium ethyl thiolate in dimethyl formamide.
3. The process of claim 2 wherein the demethylation is carried out using boron tribromide in an aprotic solvent under an inert gas at temperatures between - 10 and +10 °C for about 1-3 hours.
4. The process of claim 2 wherein the demethylation is carried out using sodium cyanide in an aprotic solvent under an inert gas at reflux for about 3-7 hours.
5. The process of claim 2 wherein the demethylation is carried out using sodium ethyl thiolate in an aprotic solvent under an inert gas and heating the solution to about 75 to 125 °C for about 30 minutes to 2 hours.
6. A process for preparing a compound of Formula (I)
from o-anisidine, which process comprises treating o-anisidine with a halogenating agent to obtain Formula (III)
NH,
O
halo (III)
where halo is any halogen and displacing the halogen by a cyanide anion to obtain a compound of Formula (II)
and, demethylated Formula (II) to obtain the compound of Formula (I). 7. A process for making a compound of Formula (III)
where halo is any halogen which process comprises treating a compound of Formula A
with a halogenating agent in dimethylsulfoxide.
8. A process for preparing a compound of Formula (II)
which process comprises treating a compound of Formula (III)
with copper (I) cyanide in an aprotic solvent.
EP99943937A 1998-08-28 1999-08-26 Process for making 2-amino-5-cyanophenol Withdrawn EP1107943A4 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US9833598P 1998-08-28 1998-08-28
US98335P 1998-08-28
PCT/US1999/019494 WO2000012461A1 (en) 1998-08-28 1999-08-26 Process for making 2-amino-5-cyanophenol

Publications (2)

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EP1107943A1 EP1107943A1 (en) 2001-06-20
EP1107943A4 true EP1107943A4 (en) 2002-07-24

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EP99943937A Withdrawn EP1107943A4 (en) 1998-08-28 1999-08-26 Process for making 2-amino-5-cyanophenol

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JP (1) JP2003525856A (en)
CA (1) CA2341711A1 (en)
WO (1) WO2000012461A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200418812A (en) 2002-10-29 2004-10-01 Smithkline Beecham Corp IL-8 receptor antagonists
WO2007124423A2 (en) 2006-04-21 2007-11-01 Smithkline Beecham Corporation Il-8 receptor antagonists
EA014958B1 (en) 2006-04-21 2011-04-29 Смитклайн Бичам Корпорейшн Il-8 receptor antagonists

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1792156A (en) * 1928-01-17 1931-02-10 Gen Aniline Works Inc 5-halogen-2-amino-1-alkyloxy and 1-aralkyloxy-benzenes and intermediate products thereof and process of preparing them
EP0100172A1 (en) * 1982-07-23 1984-02-08 Imperial Chemical Industries Plc Amide derivatives
US5508464A (en) * 1986-11-07 1996-04-16 L'oreal Process for the preparation of 5,6-dihydroxyindole and intermediate compounds
WO1998033763A1 (en) * 1997-01-30 1998-08-06 American Home Products Corporation Substituted hydroxy-anilino derivatives of cyclobutene-3,4-diones

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1792156A (en) * 1928-01-17 1931-02-10 Gen Aniline Works Inc 5-halogen-2-amino-1-alkyloxy and 1-aralkyloxy-benzenes and intermediate products thereof and process of preparing them
EP0100172A1 (en) * 1982-07-23 1984-02-08 Imperial Chemical Industries Plc Amide derivatives
US5508464A (en) * 1986-11-07 1996-04-16 L'oreal Process for the preparation of 5,6-dihydroxyindole and intermediate compounds
WO1998033763A1 (en) * 1997-01-30 1998-08-06 American Home Products Corporation Substituted hydroxy-anilino derivatives of cyclobutene-3,4-diones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO0012461A1 *

Also Published As

Publication number Publication date
EP1107943A1 (en) 2001-06-20
JP2003525856A (en) 2003-09-02
CA2341711A1 (en) 2000-03-09
WO2000012461A1 (en) 2000-03-09

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