EP1107943A4 - Process for making 2-amino-5-cyanophenol - Google Patents
Process for making 2-amino-5-cyanophenolInfo
- 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- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims description 17
- HKZPOGZBKIWMPO-UHFFFAOYSA-N 4-amino-3-hydroxybenzonitrile Chemical compound NC1=CC=C(C#N)C=C1O HKZPOGZBKIWMPO-UHFFFAOYSA-N 0.000 title abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 11
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- 239000011261 inert gas Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 5
- 230000017858 demethylation Effects 0.000 claims description 5
- 238000010520 demethylation reaction Methods 0.000 claims description 5
- -1 sodium ethyl thiolate Chemical class 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 3
- 230000002140 halogenating effect Effects 0.000 claims description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims 3
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 150000002367 halogens Chemical class 0.000 claims 3
- 238000010438 heat treatment Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- NJQJGRGGIUNVAB-UHFFFAOYSA-N 2,4,4,6-tetrabromocyclohexa-2,5-dien-1-one Chemical compound BrC1=CC(Br)(Br)C=C(Br)C1=O NJQJGRGGIUNVAB-UHFFFAOYSA-N 0.000 description 4
- SCXGWOFGMVEUGW-UHFFFAOYSA-N 4-amino-3-methoxybenzonitrile Chemical compound COC1=CC(C#N)=CC=C1N SCXGWOFGMVEUGW-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- NGXMWCHDSDVSJY-UHFFFAOYSA-N 2,4-dibromo-6-methoxyaniline Chemical compound COC1=CC(Br)=CC(Br)=C1N NGXMWCHDSDVSJY-UHFFFAOYSA-N 0.000 description 3
- UDCXBOHQMWRTDN-UHFFFAOYSA-N 2-bromo-6-methoxyaniline Chemical compound COC1=CC=CC(Br)=C1N UDCXBOHQMWRTDN-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- 102000004890 Interleukin-8 Human genes 0.000 description 3
- 108090001007 Interleukin-8 Proteins 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- LUBJCRLGQSPQNN-UHFFFAOYSA-N 1-Phenylurea Chemical class NC(=O)NC1=CC=CC=C1 LUBJCRLGQSPQNN-UHFFFAOYSA-N 0.000 description 2
- WRFYIYOXJWKONR-UHFFFAOYSA-N 4-bromo-2-methoxyaniline Chemical compound COC1=CC(Br)=CC=C1N WRFYIYOXJWKONR-UHFFFAOYSA-N 0.000 description 2
- JZPVDNVROSCQLN-UHFFFAOYSA-N CC(O)=O.OO.Br Chemical compound CC(O)=O.OO.Br JZPVDNVROSCQLN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 229960004592 isopropanol Drugs 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VIKJECVSALYBJB-UHFFFAOYSA-N 1-(2-bromophenyl)-3-(4-cyano-2-hydroxyphenyl)urea Chemical compound OC1=CC(C#N)=CC=C1NC(=O)NC1=CC=CC=C1Br VIKJECVSALYBJB-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 102100039398 C-X-C motif chemokine 2 Human genes 0.000 description 1
- 102000016950 Chemokine CXCL1 Human genes 0.000 description 1
- 108010014419 Chemokine CXCL1 Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 101000889128 Homo sapiens C-X-C motif chemokine 2 Proteins 0.000 description 1
- 101000973997 Homo sapiens Nucleosome assembly protein 1-like 4 Proteins 0.000 description 1
- 101000947178 Homo sapiens Platelet basic protein Proteins 0.000 description 1
- 101000818522 Homo sapiens fMet-Leu-Phe receptor Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 102100036154 Platelet basic protein Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- RDOZMBAUVXVXCJ-UHFFFAOYSA-N ac1l8ijh Chemical compound Br.C([N@@](C1)C2)[N@]3C[N@@]2C[N@@]1C3 RDOZMBAUVXVXCJ-UHFFFAOYSA-N 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- KTLFENNEPHBKJD-UHFFFAOYSA-K benzyl(trimethyl)azanium;tribromide Chemical compound [Br-].[Br-].[Br-].C[N+](C)(C)CC1=CC=CC=C1.C[N+](C)(C)CC1=CC=CC=C1.C[N+](C)(C)CC1=CC=CC=C1 KTLFENNEPHBKJD-UHFFFAOYSA-K 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000002975 chemoattractant Substances 0.000 description 1
- 239000005482 chemotactic factor Substances 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 102100021145 fMet-Leu-Phe receptor Human genes 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 1
- 229940096397 interleukin-8 Drugs 0.000 description 1
- 230000021995 interleukin-8 production Effects 0.000 description 1
- 102000010681 interleukin-8 receptors Human genes 0.000 description 1
- 108010038415 interleukin-8 receptors Proteins 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- VDCLSGXZVUDARN-UHFFFAOYSA-N molecular bromine;pyridine;hydrobromide Chemical compound Br.BrBr.C1=CC=NC=C1 VDCLSGXZVUDARN-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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.
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)
| Publication Number | Publication Date |
|---|---|
| EP1107943A1 EP1107943A1 (en) | 2001-06-20 |
| EP1107943A4 true EP1107943A4 (en) | 2002-07-24 |
Family
ID=22268831
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP99943937A Withdrawn EP1107943A4 (en) | 1998-08-28 | 1999-08-26 | Process for making 2-amino-5-cyanophenol |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1107943A4 (en) |
| JP (1) | JP2003525856A (en) |
| CA (1) | CA2341711A1 (en) |
| WO (1) | WO2000012461A1 (en) |
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|---|---|---|---|---|
| AR041834A1 (en) | 2002-10-29 | 2005-06-01 | Smithkline Beecham Corp | COMPOSITE DIFENILUREA REPLACED WITH SULFONAMIDE, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE TO PREPARE SUCH COMPOSITION |
| TWI414517B (en) | 2006-04-21 | 2013-11-11 | Smithkline Beecham Corp | Il-8 receptor antagonists |
| BRPI0710559A2 (en) | 2006-04-21 | 2011-08-16 | Smithkline Beecham Corp | il-8 receptor antagonists |
Citations (4)
| 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 |
-
1999
- 1999-08-26 JP JP2000567496A patent/JP2003525856A/en not_active Withdrawn
- 1999-08-26 EP EP99943937A patent/EP1107943A4/en not_active Withdrawn
- 1999-08-26 CA CA002341711A patent/CA2341711A1/en not_active Abandoned
- 1999-08-26 WO PCT/US1999/019494 patent/WO2000012461A1/en not_active Application Discontinuation
Patent Citations (4)
| 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)
| Title |
|---|
| See also references of WO0012461A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1107943A1 (en) | 2001-06-20 |
| JP2003525856A (en) | 2003-09-02 |
| WO2000012461A1 (en) | 2000-03-09 |
| CA2341711A1 (en) | 2000-03-09 |
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