WO2000012472A2 - Process for preparing certain phenyl urea compounds - Google Patents
Process for preparing certain phenyl urea compounds Download PDFInfo
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- WO2000012472A2 WO2000012472A2 PCT/US1999/019493 US9919493W WO0012472A2 WO 2000012472 A2 WO2000012472 A2 WO 2000012472A2 US 9919493 W US9919493 W US 9919493W WO 0012472 A2 WO0012472 A2 WO 0012472A2
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- optionally substituted
- alkyl
- aryl
- alkenyl
- heteroaryl
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- ASSKVPFEZFQQNQ-UHFFFAOYSA-N O=C1Oc2ccccc2N1 Chemical compound O=C1Oc2ccccc2N1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
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- 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
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- 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 certain phenyl urea compounds
- the end-product phenyl urea compounds are useful in treating IL-8, GRO ⁇ GRO ⁇ , GRO ⁇ and NAP-2 mediated diseases Background of the Invention
- Interleuk ⁇ n-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, endothehal and epithelial cells exposed to TNF, IL- l a, IL- lb or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP M Baggiohni et al, J Clin Invest 84, 1045 ( 1989), J Schroder et al, J Immunol 139.
- this invention provides a method 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 and related compounds Summary of the Invention
- this invention covers a process for making a compound of Formula
- R is any functional moiety having an lomzable hvdrogen and a pKa of 10 or less R] is independently selected from hydrogen; halogen; nitro; cyano; Cj-io alkyl: halosubstituted Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-ioalkoxy; azide; S(O)tR4; (CR Rs)q S(O)tR-4: hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl Ci-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1.4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl: heteroaryl C 1-.4 alkyloxy; heterocyclic.
- R4 and R5 are independently, optionally substituted C 1-.4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, heterocyclic Ci-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;
- R6 and R7 are independently hydrogen or a Cj -4 alkyl group, or R6 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 is hydrogen or C 1 -4 alkyl ;
- Rl ⁇ is C ⁇ _ ⁇ o alkyl C(O)2R8;
- Rl 1 is hydrogen, optionally substituted C]_4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC] -4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC]-4alkyl;
- Rl2 is hydrogen, C j-jo alkyl, optionally substituted aryl or optionally substituted arylalkyl;
- Rl3 is suitably Ci-4 alkyl, aryl, aryl C]_4alkyl, heteroaryl, heteroarylCi- 4alkyl, heterocyclic, or heterocyclicCi-4alkyl;
- R5 is NR6R7, alkyl, aryl, aryl C1-.4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl C1.4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic Cj_4 alkyl, heterocyclic C2-4 alkenyl, or camphor, all of which groups may be optionally substituted; wherein said process comprises reacting a compound of Formula (A)
- R ⁇ is the same as defined in Formula I with a nucleophile illustrated by the amine of Formula (B)
- this invention relates to a process for making a compound of Formula (I) as described above wherein the process comprises treating a benzoxazolinone of Formula (D)
- R ⁇ is halogen, cyano, nitro, CF3, C(O)NR4R5, alkenyl C(O)NR4R5, C(O) R4R1O, alkenyl C(O)ORi2, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR4R5, and preferably one of R4 or R5 is phenyl.
- a preferred ring substitution for R ⁇ is in the 4-position of the phenyl ring.
- R ⁇ is nitro, halogen, cyano, trifluoromethyl group, or C(O)NR4R5.
- Y is preferably a halogen, Cj -.4 alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted arylalkyloxy, optionally substituted heteroarylalkyloxy. methylenedioxy.
- 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 di-substituted in the 2'- position or 2'-, 3 '-position. While Y may be substituted in any of the 5 ring positions, preferably when R is
- 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 substituents are preferably in the 2' or 3' position of a monocyclic ring. While both R ⁇ 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 N-[2-hydroxy-4-cyanophenyl]-N'-[2,3-dichlorophenyl] urea N-(2-hydroxy-4-cyanophenyl)-N'-(2-(4-pyridylmethyloxy)phenyl)urea , and N-(2-hydroxy-4-cyanophenyl)-N'-(2-chlorophenyl)urea.
- Reaction Scheme 1 details in graphical form the process and representative intermediates which are the subject of this invention.
- the benzoxazolinone starting material is commercially available (formula 1- 1). See for example Aldrich. It is halogenated (formula 1-2) 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 and treating that mixture or solution with the halogen. 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.
- the nitrile of formula 1-3 is prepared by treating the halogenated benzoxazolinone with CuCN at a moderately elevated temperature under an inert gas in a polar solvent such as dimethyl formamide, N-methyl pyrrolidinone or dimethyl sulfoxide. As illustrated herein, 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.
- a polar solvent such as dimethyl formamide, N-methyl pyrrolidinone or dimethyl sulfoxide.
- 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
- the urea (formula 1-4) is made by treating the benzoxazolinone with an amine in the presence of a Lewis acid.
- exemplary Lewis acids include Ti, Al or Sn (TiCl4, tributyltin chloride, and diethylaluminum).
- the nitrile of Formula A or Al is added to a mixture of the salt of the amine and a Lewis acid in a non-polar solvent; 2-bromoaniline is illustrated in Scheme 1.
- Example 1 6-Bromo-2(3H)-benzoxazolone To a solution of glacial acetic acid (1500 ml) was added sodium acetate (222 g, 2.70 mole) and 2-benzoxazolinone (300 g, 2.22 mole). The suspension was cooled to 15 °C, bromine (1 18 ml, 2.29 mole) added dropwise over 1 h and the mixture stirred for 12 h at ambient temperature.
- Example 2 2,3-Dihydro-4-hydroxy-2-oxo-6-benzoxazolecarbonitrile To a solution of DMF (1 10 ml) was added 6-bromo-2(3H)-benzoxazolone (50 g, 0.234 mole) and CuCN (89.6 g, 0.398 mole) and the mixture heated to 150 °C for 6 h under nitrogen. The reaction was then cooled to 100 °C, H,O (200 ml) and NaCN (36 g, 0.734 mole) added, the suspension stirred for 2h at ambient temperature and partitioned with EtOAc at 70 °C.
- 6-bromo-2(3H)-benzoxazolone 50 g, 0.234 mole
- CuCN 89.6 g, 0.398 mole
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
This invention relates to a process for making certain phenyl urea compounds by using a Lewis acid to effect the ring opening of a benzoxazolinone by an amine.
Description
Process for Preparing Certain Phenyl rea Compounds Scope of the Invention
This invention relates to a process 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 Background of the Invention
Interleukιn-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, endothehal and epithelial cells exposed to TNF, IL- l a, IL- lb or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP M Baggiohni et al, J Clin Invest 84, 1045 ( 1989), J Schroder et al, J Immunol 139. 3474 ( 1987) and J Immunol 144, 2223 ( 1990) , Stπeter, et al, Science 243, 1467 (1989) and J Bwl 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
Specifically this invention provides a method 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 and related compounds Summary of the Invention
In a first aspect this invention covers a process for making a compound of Formula
X is oxygen,
R is any functional moiety having an lomzable hvdrogen and a pKa of 10 or less
R] is independently selected from hydrogen; halogen; nitro; cyano; Cj-io alkyl: halosubstituted Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-ioalkoxy; azide; S(O)tR4; (CR Rs)q S(O)tR-4: hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl Ci-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1.4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl: heteroaryl C 1-.4 alkyloxy; heterocyclic. heterocyclic Cj-4alkyl; heterocyclicCι_4alkyloxy; heterocyclicC2-10 alkenyl; (CR8R8)q NR4R5; (CR8Rs)q C(O)NR4Rs; C2-10 alkenyl C(O)NR4Rs; (CR8R8)q C(O)NR4Rlθ; S(O)3H; S(O)3R8: (CR8 s)q C(O)Rn ; C2-10 alkenyl C(O)Rι l ; C2-IO alkenyl C(O)ORι ] ; (CR8R8)q C(O)ORj 1 ; (CR8R8)q OC(O)Rι 1 ; (CR8R8)qNR4C(O)Rι 1 ; (CR8R8)q C(NR4)NR4R5; (CR8Rs)q NR4C(NR5)R11 , (CRsR8)q S(O)2NR4R5, or two R\ moieties together may form a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl. heterocyclic moities may be optionally substituted; q is 0 or an integer having a value of 1 to 10; t is 0 or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3;
R4 and R5 are independently, optionally substituted C 1-.4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, heterocyclic Ci-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 Rj ; 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 Cj -4 alkyl group, or R6 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 is hydrogen or C 1 -4 alkyl ;
Rlθ is Cι_ιo alkyl C(O)2R8;
Rl 1 is hydrogen, optionally substituted C]_4 alkyl, optionally substituted aryl, optionally substituted aryl Cι_4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC] -4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC]-4alkyl;
Rl2 is hydrogen, C j-jo alkyl, optionally substituted aryl or optionally substituted arylalkyl;
Rl3 is suitably Ci-4 alkyl, aryl, aryl C]_4alkyl, heteroaryl, heteroarylCi- 4alkyl, heterocyclic, or heterocyclicCi-4alkyl;
R5 is NR6R7, alkyl, aryl, aryl C1-.4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl C1.4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic Cj_4 alkyl, heterocyclic C2-4 alkenyl, or camphor, all of which groups may be optionally substituted; wherein said process comprises reacting a compound of Formula (A)
where R\ is the same as defined in Formula I with a nucleophile illustrated by the amine of Formula (B)
where Y is the same as defined above in the presence of a Lewis acid to open the oxazolinone ring of Formula (A) to form the urea of Formula (I).
In a second aspect, this invention relates to a process for making a compound of Formula (I) as described above wherein the process comprises treating a benzoxazolinone of Formula (D)
with a halogen in the presence of an acid to form a compound of Formula (C);
Halo
H (Al)
reacting Formula A 1 with a nucleophile illustrated by Formula (B)
where Y is the same as defined in Formula I in the presence of a Lewis acid to open the oxazolinone ring of Formula (A) and form the compound of Formula (I) where R is OH and Rj is CN.
The preferred compounds which can be synthesised by these methods and using these intermediates are those where R\ is halogen, cyano, nitro, CF3, C(O)NR4R5, alkenyl C(O)NR4R5, C(O) R4R1O, alkenyl C(O)ORi2, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR4R5, and preferably one of R4 or R5 is phenyl. A preferred ring substitution for R\ is in the 4-position of the phenyl ring.
Preferably R\ is nitro, halogen, cyano, trifluoromethyl group, or C(O)NR4R5. Y is preferably a halogen, Cj -.4 alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted arylalkyloxy, optionally substituted heteroarylalkyloxy. methylenedioxy. NR4R5, thioC j -4alkyl. thioaryl, halosubstituted alkoxy, optionally substituted C 1 -.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 di-substituted in the 2'- position or 2'-, 3 '-position. While 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 substituents are preferably in the 2' or 3' position of a monocyclic ring. While both R\ 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 N-[2-hydroxy-4-cyanophenyl]-N'-[2,3-dichlorophenyl] urea N-(2-hydroxy-4-cyanophenyl)-N'-(2-(4-pyridylmethyloxy)phenyl)urea , and N-(2-hydroxy-4-cyanophenyl)-N'-(2-chlorophenyl)urea. Specific Embodiments of the Invention
Reaction Scheme 1 details in graphical form the process and representative intermediates which are the subject of this invention.
Scheme 1
The benzoxazolinone starting material is commercially available (formula 1- 1). See for example Aldrich. It is halogenated (formula 1-2) 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 and treating that mixture or solution with the halogen. Glacial acetic acid and its sodium salt are the preferred organic acid/salt combination. In the case of the illustrated benzoxazolinone, 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.
The nitrile of formula 1-3 is prepared by treating the halogenated benzoxazolinone with CuCN at a moderately elevated temperature under an inert gas
in a polar solvent such as dimethyl formamide, N-methyl pyrrolidinone or dimethyl sulfoxide. As illustrated herein, 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. Then the reaction is cooled to about 100 °C, a 3 to 4-fold molar excess of 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. The urea (formula 1-4) is made by treating the benzoxazolinone with an amine in the presence of a Lewis acid. Exemplary Lewis acids include Ti, Al or Sn (TiCl4, tributyltin chloride, and diethylaluminum). The nitrile of Formula A or Al is added to a mixture of the salt of the amine and a Lewis acid in a non-polar solvent; 2-bromoaniline is illustrated in Scheme 1. About a 5-7 molar excess of the amine is used and about 2-3 molar excess of the Lewis acid is used. This mixture is refluxed for several hours, for example 5-6 hours. Isolating the product involves cooling the reaction mixture to about 0 °C, partitioning with aqueous mineral acid organic solvent and filtering the organic layer through SiO
The following examples are given to illustrate the invention but are not to be taken as limiting what is covered by the claims.
Examples Example 1 6-Bromo-2(3H)-benzoxazolone To a solution of glacial acetic acid (1500 ml) was added sodium acetate (222 g, 2.70 mole) and 2-benzoxazolinone (300 g, 2.22 mole). The suspension was cooled to 15 °C, bromine (1 18 ml, 2.29 mole) added dropwise over 1 h and the mixture stirred for 12 h at ambient temperature. The solids were then filtered, washed with H,O (3 x 500 ml) and dried under vacuum to give the title compound as a white solid (374 g, 89.7%): mp 186.0- 187.0 °C; Η NMR (DMSO-d6) δ 11.8 (s, 1 H), 7.6 (s, 1 H), 7.3 (d, J=8.0 Hz, 1 H), 7.0 (d, J=8.0 Hz, 1 H).
Example 2 2,3-Dihydro-4-hydroxy-2-oxo-6-benzoxazolecarbonitrile To a solution of DMF (1 10 ml) was added 6-bromo-2(3H)-benzoxazolone (50 g, 0.234 mole) and CuCN (89.6 g, 0.398 mole) and the mixture heated to 150 °C for 6 h under nitrogen. The reaction was then cooled to 100 °C, H,O (200 ml) and NaCN (36 g, 0.734 mole) added, the suspension stirred for 2h at ambient temperature and partitioned with EtOAc at 70 °C. The organic phase was washed
with H,O (2 x 150 ml) and concentrated in vacuo to give the title compoud as a tan solid (33.2 g, 88.5%): mp >220 °C; Η NMR (DMSO-d ) δ 7.8 (s, 1 H), 7.6 (d, J=8.0 Hz, 1 H), 7.2 (d, J=8.0 Hz, 1 H).
Example 3 N-(2-BromophenyI)-N '-(2-hydroxy-4-cyanophenyl) Urea
A solution of 2-bromoanaline (6.8 g, 39.5 mmol) in toluene (10mL)/dichloromethane (lOmL) was added to sodium hydride (60%, 1.65g, 41.0mmol) and the mixture was warmed to 60 °C for 45 minutes. The mixture was cooled to 5 °C and ΗCI4 (1.37 mL, 12.6 mmol) was added over 15 minutes. 2,3- Dihydro-4-hydrozy-2-oxo-6-benzoxazole carbonitrile (l.Og, 6.0 mmol) was added and the mixture heated at reflux for 5.5 hours. The reaction was cooled to 0 °C, partitioned with 15% HC1 (25 ml) and EtOAc (150 ml), and the organic phase filtered through SiO, (50 g). The filtrate was concentrated in vacuo to give a brown solid comprising the title product (0.7 g, 58.6%).
Claims
1. A process for making a compound of Formula
X is oxygen;
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; Cj-io alkoxy; halosubstituted Ci-ioalkoxy; azide; S(O)tR4; (CRsRs)q S(O)tR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl C1 -.4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1-.4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Cj -4 alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; heterocyclicCi-4alkyloxy; heterocyclicC2-10 alkenyl; (CR8R8)q NR4R5; (CRsR8)q C(O)NR4R5; C2-10 alkenyl C(O)NR4R5; (CR8R8)q C(O)NR4Rlθ; S(O)3H; S(O)3R8; (CR8R8)q C(O)Rι 1 ; C2-10 alkenyl C(O)Rn ; C2-10 alkenyl C(O)ORn ; (CR8R8)q C(O)ORn ; (CR8R8)q OC(O)Rn ; (CR8R8)qNR4C(O)Rι ι ; (CR8R8)q C(NR4)NR4R5; (CR8R8)q NR4C(NR5)RU , (CR8Rδ)q S(O)2NR4R5, or two R\ moieties together may form a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted; q is 0 or an integer having a value of 1 to 10; q is 0 or an integer having a value of 1 to 10; t is 0 or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3; R4 and R5 are independently optionally substituted C1 -.4 alkyl, optionally substituted aryl, optionally substituted aryl Cι_4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-.4a.kyl, heterocyclic, heterocyclic C1-.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 Cι_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;
R8 is hydrogen or Cj-4 alkyl;
RlO is Ci-10 alkyl C(O)2R8;
Rl 1 is hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Cι-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicCi-4alkyl;
Rl2 is hydrogen, Cj-io alkyl, optionally substituted aryl or optionally substituted arylalkyl;
Rl3 is suitably Ci-4 alkyl, aryl, aryl Cι_4alkyl, heteroaryl, heteroarylCi- 4alkyl, heterocyclic, or heterocyclicCi-4alkyl;
R ) is NRgR7, alkyl, aryl, aryl Cι_4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl C -.4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic Cj_4 alkyl, heterocyclic C2.4 alkenyl, or camphor, all of which groups may be optionally substituted; wherein said process comprises reacting a compound of Formula (A)
with a nucleophile illustrated by the amine of Formula (B)
in the presence of a Lewis acid to open the oxazolinone ring of Formula (A) to form the urea of Formula (I).
2. The process of claim 1 wherein the Lewis acid is ΗC14, tributyltin chloride, or diethylaluminum.
3. The process of claim 1 wherein the product is a compound of Formula I where
Rl is halogen, cyano, nitro, CF3, C(O)NR4R5, alkenyl C(O)NR4R5, C(O) R4R1O, alkenyl C(O)ORi2, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR4R5, and preferably one of R4 or R5 is phenyl;
Y is halogen, Cj-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted arylalkyloxy, optionally substituted heteroarylalkyloxy, methylenedioxy, NR4R5, thioCi-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted Ci-4 alkyl, or hydroxy alkyl; and R is OH.
4. The process of claim 1 wherein Y is halogen.
5. The process of claim 1 wherein R\ is CN.
6. The process of claim 3 where the Lewis acid is TiCl4.
7. The process of claim 6 wherein the product is N-[2-hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea
N-[2-hydroxy-4-cyanophenyl]-N'-[2,3-dichlorophenyl] urea
N-(2-hydroxy-4-cyanophenyl)-N'-(2-(4-pyridylmethyloxy)phenyl)urea , or
N-(2-hydroxy-4-cyanophenyl)-N'-(2-chlorophenyl)urea.
7. A process for making a compound of Formula (I) according to claim 1 wherein the process comprises treating a benzoxazolinone of Formula (D)
with a halogen in the presence of an acid to form a compound of Formula (C);
Halo
reacting Formula (Al) with a nucleophile illustrated by Formula (B)
in the presence of a Lewis acid to open the oxazolinone ring of the compound of Formula (A) and form the compound of Formula (I) where R is OH, R is CN and Y is hydrogen; halogen; nitro; cyano; Ci-io alkyl; halosubstituted Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Cj-ioalkoxy; azide; S(O)tR4; (CR R8)q S(O)tR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl C1-.4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl Ci-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Cj-4 alkyloxy; heterocyclic, heterocyclic Cj-4alkyl; heterocyclicCi-4alkyloxy; heterocyclicC2-10 alkenyl; (CR8R8)q NR4R5; (CR8R8)q C(O)NR4R5; C2-IO alkenyl C(O)NR4R5; (CR8R8)q C(O)NR4Rι0; S(O)3H; S(O)3R8; (CR8R8)q C(O)Rι 1; C2-10 alkenyl C(O)Rj 1 ; C2-10 alkenyl C(O)ORn ; (CR8R8)q C(O)ORn ; (CR8R8)q OC(O)Rn; (CR8R8)qNR4C(O)Rn ; (CR8R8)q C(NR4)NR4R5; (CR8R8)q NR4C(NR5)RU , (CR8R8)q S(O)2NR4R5, or two Ri moieties together may form a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002341697A CA2341697A1 (en) | 1998-08-28 | 1999-08-26 | Process for preparing certain phenyl urea compounds |
| JP2000571046A JP2002525278A (en) | 1998-08-28 | 1999-08-26 | Method for producing specific phenylurea compound |
| EP99945212A EP1107949A4 (en) | 1998-08-28 | 1999-08-26 | Process for preparing certain phenyl urea compounds |
| US09/763,743 US6372933B1 (en) | 1999-08-26 | 1999-09-26 | Process for preparing certain phenyl urea compounds |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9829098P | 1998-08-28 | 1998-08-28 | |
| US60/098,290 | 1998-08-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2000012472A2 true WO2000012472A2 (en) | 2000-03-09 |
| WO2000012472A3 WO2000012472A3 (en) | 2000-06-29 |
Family
ID=22268648
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1999/019493 WO2000012472A2 (en) | 1998-08-28 | 1999-08-26 | Process for preparing certain phenyl urea compounds |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1107949A4 (en) |
| JP (1) | JP2002525278A (en) |
| CA (1) | CA2341697A1 (en) |
| WO (1) | WO2000012472A2 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE487014C (en) * | 1927-10-23 | 1929-12-09 | I G Farbenindustrie Akt Ges | Process for the preparation of urea derivatives |
| DE3029922A1 (en) * | 1980-08-07 | 1982-03-04 | Bayer Ag, 5090 Leverkusen | METHOD FOR THE PRODUCTION OF PLASTIC PRECASTORS HAVING OXAZOLIN-2-ON-RINGS AND THE USE THEREOF FOR THE PRODUCTION OF HIGH-MOLECULAR PLASTICS |
-
1999
- 1999-08-26 JP JP2000571046A patent/JP2002525278A/en not_active Withdrawn
- 1999-08-26 WO PCT/US1999/019493 patent/WO2000012472A2/en not_active Application Discontinuation
- 1999-08-26 EP EP99945212A patent/EP1107949A4/en not_active Withdrawn
- 1999-08-26 CA CA002341697A patent/CA2341697A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP1107949A2 (en) | 2001-06-20 |
| EP1107949A4 (en) | 2002-08-07 |
| JP2002525278A (en) | 2002-08-13 |
| WO2000012472A3 (en) | 2000-06-29 |
| CA2341697A1 (en) | 2000-03-09 |
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