CA2341718A1 - An improved synthesis of 3-hydroxy-4-amino-benzonitrile - Google Patents
An improved synthesis of 3-hydroxy-4-amino-benzonitrile Download PDFInfo
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- CA2341718A1 CA2341718A1 CA002341718A CA2341718A CA2341718A1 CA 2341718 A1 CA2341718 A1 CA 2341718A1 CA 002341718 A CA002341718 A CA 002341718A CA 2341718 A CA2341718 A CA 2341718A CA 2341718 A1 CA2341718 A1 CA 2341718A1
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- alkyl
- optionally substituted
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- alkenyl
- heteroaryl
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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
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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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
- 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
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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
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- 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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyridine Compounds (AREA)
Abstract
This invention relates to a process for making 3-hydroxy-4-amino-benzonitril e.
Description
An Improved Synthesis of 3-Hydroxy-4-Amino-Benzonitrile 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, GROoc, GROG, GROy and NAP-2 mediated diseases.
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 J. 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 a or p 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. W097/29743. 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 PCT application serial number PCT/US96/13632, published 21 August 1997 as WIPO No. W097/29743.
SUMMARY OF THE INVENTION
In a first aspect this invention relates to a method for making compounds of Formula (A) R
~ Ri)m H H ~ ~ A
( ) wherein X is oxygen;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
R1 is independently selected from hydrogen; halogen; nitro; cyano; C1_10 alkyl; halosubstituted CI-10 ~kyl; C2_10 alkenyl; CI-10 alkoxy;
halosubstituted CI-l0alkoxy; azide; S(O)tRq.; (CRgRg)q S(O)tR4; hydroxy; hydroxy substituted C 1 _4alkyl; aryl; aryl C 1 _4 alkyl; aryl C2_ 10 alkenyl; aryloxy; aryl C I
_4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2_ 10 alkenyl; heteroaryl C 1 _4 alkyloxy;
heterocyclic, heterocyclic C 1 _4alkyl; heterocyclicC I _4alkyloxy;
heterocyclicC2_ 10 alkenyl; (CRgRg)q NR4R5; (CRgRg)q C(O)NR4R5; C2_ 10 alkenyl C(O)NR4R5;
(CRgRg)q C(O)NR4R10; S(O)3H; S(O)3Rg; (CRgRg)q C(O)R11; C2-10 alkenyl C(O)RI I; C2-10 ~kenyl C(O)ORI 1; (CRgRg)q C(O)ORI I; (CRgRg)q OC(O)R1 l;
(CRgRg)qNR4C(O)R11; (CRgRg)q C(NR4)NR4R5; (CRgRg)q NR4C(NRS)R11 , (CRgRg)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;
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 i to 3;
R4 and RS are independently, optionally substituted C 1 _4 alkyl, optionally substituted aryl, optionally substituted aryl CI_4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1_4alkyl, heterocyclic, heterocyclic C I _4 alkyl, or R4 and RS 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 R1;
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 R~ are independently hydrogen or a C 1 _4 alkyl group, or R6 and R~
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;
Rg is hydrogen or C1_4 alkyl;
R I p is C I _ 10 alkyl C(O)2Rg;
R 11 is hydrogen, optionally substituted C 1 _4 alkyl, optionally substituted aryl, optionally substituted aryl C I _4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC I _4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC I _4alkyl;
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 J. 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 a or p 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. W097/29743. 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 PCT application serial number PCT/US96/13632, published 21 August 1997 as WIPO No. W097/29743.
SUMMARY OF THE INVENTION
In a first aspect this invention relates to a method for making compounds of Formula (A) R
~ Ri)m H H ~ ~ A
( ) wherein X is oxygen;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
R1 is independently selected from hydrogen; halogen; nitro; cyano; C1_10 alkyl; halosubstituted CI-10 ~kyl; C2_10 alkenyl; CI-10 alkoxy;
halosubstituted CI-l0alkoxy; azide; S(O)tRq.; (CRgRg)q S(O)tR4; hydroxy; hydroxy substituted C 1 _4alkyl; aryl; aryl C 1 _4 alkyl; aryl C2_ 10 alkenyl; aryloxy; aryl C I
_4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2_ 10 alkenyl; heteroaryl C 1 _4 alkyloxy;
heterocyclic, heterocyclic C 1 _4alkyl; heterocyclicC I _4alkyloxy;
heterocyclicC2_ 10 alkenyl; (CRgRg)q NR4R5; (CRgRg)q C(O)NR4R5; C2_ 10 alkenyl C(O)NR4R5;
(CRgRg)q C(O)NR4R10; S(O)3H; S(O)3Rg; (CRgRg)q C(O)R11; C2-10 alkenyl C(O)RI I; C2-10 ~kenyl C(O)ORI 1; (CRgRg)q C(O)ORI I; (CRgRg)q OC(O)R1 l;
(CRgRg)qNR4C(O)R11; (CRgRg)q C(NR4)NR4R5; (CRgRg)q NR4C(NRS)R11 , (CRgRg)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;
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 i to 3;
R4 and RS are independently, optionally substituted C 1 _4 alkyl, optionally substituted aryl, optionally substituted aryl CI_4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1_4alkyl, heterocyclic, heterocyclic C I _4 alkyl, or R4 and RS 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 R1;
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 R~ are independently hydrogen or a C 1 _4 alkyl group, or R6 and R~
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;
Rg is hydrogen or C1_4 alkyl;
R I p is C I _ 10 alkyl C(O)2Rg;
R 11 is hydrogen, optionally substituted C 1 _4 alkyl, optionally substituted aryl, optionally substituted aryl C I _4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC I _4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC I _4alkyl;
R12 is hydrogen, C1-10 ~kYl, optionally substituted aryl or optionally substituted arylalkyl;
R 13 is suitably C I _4 alkyl, aryl, aryl C 1 _4alkyl, heteroaryl, heteroarylC
1 _ 4alkyl, heterocyclic, or heterocyclicC 1 _4alkyl;
Rb is NR6R~, alkyl, aryl, aryl C 1 _4 alkyl, aryl C2~ alkenyl, heteroaryl, heteroaryl C 1 _q. alkyl, heteroarylC2_4 alkenyl, heterocyclic, heterocyclic C
I ~ 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 (Ia) NH3+A.
HO
NH3*A- /
I
HO
li R1 (I) or N (Ia) where 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. In particular, this process comprises preparing the phenol of Formula (I) or (Ia) NH3+A_ HO
NH3~A_ /
HO /
R~ (I) or N (Ia) where A- is the anion of an acid addition saltc by treating a compound of formula (II) or (IIa) with an acid to remove the t-BOC group.
R 13 is suitably C I _4 alkyl, aryl, aryl C 1 _4alkyl, heteroaryl, heteroarylC
1 _ 4alkyl, heterocyclic, or heterocyclicC 1 _4alkyl;
Rb is NR6R~, alkyl, aryl, aryl C 1 _4 alkyl, aryl C2~ alkenyl, heteroaryl, heteroaryl C 1 _q. alkyl, heteroarylC2_4 alkenyl, heterocyclic, heterocyclic C
I ~ 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 (Ia) NH3+A.
HO
NH3*A- /
I
HO
li R1 (I) or N (Ia) where 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. In particular, this process comprises preparing the phenol of Formula (I) or (Ia) NH3+A_ HO
NH3~A_ /
HO /
R~ (I) or N (Ia) where A- is the anion of an acid addition saltc by treating a compound of formula (II) or (IIa) with an acid to remove the t-BOC group.
HN
O ~ HO /~ O 1 HN-o ~ 1' HO~
/
~i) (IIa) (II) or N
In a third aspect this invention relates to a process for making the nitrite of formula (III) O
HN
O
/ v (III) which process comprises treating the halo-substituted compound of formula (IV) O
v O
(IV ) where X is CI, Br, or I with a cyanide salt and optionally a transition metal catalyst.
Detailed Description of the Invention The preferred compounds which can be synthesised by these methods and using these intermediates are those where RI is halogen, cyano, nitro, CF3, C(O)NR4R5, alkenyl C(O)NRq.RS, C(O) R~R10, alkenyl C(O)OR12, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR4RS, and preferably one of R4 or RS
is phenyl. A preferred ring substitution for R 1 is in the 4-position of the phenyl ring.
Preferably R 1 is nitro, halogen, cyano, trifluoromethyl group, or C(O)NR4R5.
S Y is preferably a halogen, C 1-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted arylalkyloxy, optionally substituted heteroarylalkyloxy, methylenedioxy, NR4RS, thioC 1 _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 S ring positions, preferably when R
is OH, or SH, Y is preferably mono-substituted in the 2'-position or 3'-position, with 1S 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 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.
The roadmap for synthesizing compounds of Formula (A) is set out in 2S Scheme I. The compounds given in this scheme are illustrative of the process and any of the analogs of these compounds as defined for Formula (A) can be made by this processs.
Scheme 1 O O
HN~ HN-~/
O Br2, AcOH O CuCN (l.7eq) AcONa, 90% ~ DMF, 150 °C
/ : ~ / 88%
Br O
O Hv HN-~ N O
p 1 a. t-Boc20 THF HO 20%TFA/CH2CI2 DMAP, Et N
71%
b. MeOH, iCzC03 66%
CN RCN
Br OH / ~ TiCl4, PhCH~ NC ~ /
O
v j / C~NH N N
CH3CN, 25% °C H H
CN OH Br 63%
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. 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 illustrated by formula b.
The nitrite 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. Alternatively Zn(CN)2 or an alkali metal salt of the cyanide ion can be used to effect this cyanation reaction. In addition 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. 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 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 nitrite.
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.
To remove the t-BOC group and form the NH2-acid form of the compound (formula 1-e) the I,l-dimethylethylcarbamate is treated with an organic or mineral acid. While trifluoroacetic acid is illustrated, HCl or H2S04 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. As a preferred practice the salt is dissolved in 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. Then 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.
An experimental procedure for each stage of the reaction set out in Scheme I
is detailed below. These experimentals are set out solely for the purpose of illustrating the invention. What is reserved to the inventors is to be determined by reference to the claims, not to the following examples.
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 ( 118 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 captioned compound as a white solid (374 g, 89.7%): mp 186.0-187.0 °C; 'H NMR
(DMSO-dfi) 811.8 (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 ( 110 ml) was added 6-bromo-2(3H)-benzoxazolone 1 S (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, Hz0 (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 captioned compound as a tan solid (33.2 g, 88.5%): mp >220 °C; 'H NMR (DMSO-d~) 8 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 1,1-Dimethylethyl (4-cyano-2-hydroxyphenyl) carbamate To a solution of THF (500 ml) was added 2,3-dihydro-4-hydroxy-2-oxo-6-benzoxazolecarbonitrile (25 g, 0.156 mole), Et,N (26 ml, 0.187 mole) and DMAP
(3.81 g, 0.031 mole). To the solution was added di-tert-butyl dicarbonate (44.3 g, 0.202 mole) in three portions over 10 minutes and the mixture stirred at room temperature for 2 h. The reaction mixture was then concentrated in vacuo to give a brown oil (40 g) which was diluted with MeOH (500 ml) and stirred for 1 h at room temperature. K.,CO, (21.5 g, O.I56 mole) was added and stirring continued for 1.5 h.
The inorganic solids were then filtered, the filtrate partitioned with EtOAc and H,O, and the organic phase filtered through SiOz ( I 50 g). The filtrate was concentrated in vacuo to give the captioned compound as a light yellow solid (24 g, 66%
yield): mp 170.0-171.0 °C; 'H NMR (DMSO-d~) s 8.1 (s, 1H), 7.9 (d, J=8.0 Hz, 1 H), 7.2 (d, J=8.0 Hz, 1 H), 7.1 (s, 1 H).
Example 4 4-Amino-3-hydroxybenzonitrile, Trifluoroacetic Acid Salt To a solution of CH=Cl, ( 1000 ml) was added 1,1-dimethylethyl (4-cyano-2-hydroxyphenyl) carbamate (24 g, 0.102 mole) and the suspension cooled to 0 °C.
Trifluoroacetic acid ( 100 ml, 1.29 mole) was added in one portion, the solution stirred for 0.5 h at 0 °C and for 4 h at room temperature. The reaction mixture was then partially concentrated to 750 ml total volume and EtOAc (250 ml) added to cause immediate precipitation. The suspension was cooled for 12 h at -10 °C, filtered and dried to give the captioned compound as a white solid ( 18 g, 71 °lo): mp 164.0-166.0 °C; 'H NMR (DMSO-d~) s 7.0 (d, J=8.0 Hz, 1 H), 6.9 (s, 1 H), 6.65 (d, J=8.0 Hz, 1 H).
Example 5 N-(2-Bromophenyl)-N'-(2-hydroxy-4-cyanophenyl) urea To a solution of CH,CN (360 ml) was added 4-amino-3-hydroxybenzonitrile trifluoroacetic acid salt ( 18 g, 0.072 mole) and piperidine (7.2 ml, 0.072 mole). The solution was stirred at room temperature for 15 minutes followed by the addition of 2-bromophenyl isocyanate (9.85 ml, 0.079 mole). After 2 h of stirring at room temperature, a precipitate formed which was cooled to -10 °C for 12 h.
The precipitate was filtered and dried to give the title compound as a white solid (15.2 g, 63%): mp 203.5-205.0 °C; 'H NMR (DMSO-d~) 810.8 (bs, 1 H), 9.35 (s, 1 H), 9.1 (s, 1 H), 8.3 (d, J=8.5 Hz, 1 H), 7.9 (dd, J=8.3, 1.5 Hz, 1 H), 7.6 (dd, J=8.3, 1.5 Hz, 1 H), 7.3 (t, J=8.3 Hz, 1 H), 7.2 (dd, J=8.3, 1.5 Hz, 1 H), 7.15 (s, 1 H), 7.0 (t, J=8.3 Hz, 1 H).
O ~ HO /~ O 1 HN-o ~ 1' HO~
/
~i) (IIa) (II) or N
In a third aspect this invention relates to a process for making the nitrite of formula (III) O
HN
O
/ v (III) which process comprises treating the halo-substituted compound of formula (IV) O
v O
(IV ) where X is CI, Br, or I with a cyanide salt and optionally a transition metal catalyst.
Detailed Description of the Invention The preferred compounds which can be synthesised by these methods and using these intermediates are those where RI is halogen, cyano, nitro, CF3, C(O)NR4R5, alkenyl C(O)NRq.RS, C(O) R~R10, alkenyl C(O)OR12, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR4RS, and preferably one of R4 or RS
is phenyl. A preferred ring substitution for R 1 is in the 4-position of the phenyl ring.
Preferably R 1 is nitro, halogen, cyano, trifluoromethyl group, or C(O)NR4R5.
S Y is preferably a halogen, C 1-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted arylalkyloxy, optionally substituted heteroarylalkyloxy, methylenedioxy, NR4RS, thioC 1 _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 S ring positions, preferably when R
is OH, or SH, Y is preferably mono-substituted in the 2'-position or 3'-position, with 1S 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 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.
The roadmap for synthesizing compounds of Formula (A) is set out in 2S Scheme I. The compounds given in this scheme are illustrative of the process and any of the analogs of these compounds as defined for Formula (A) can be made by this processs.
Scheme 1 O O
HN~ HN-~/
O Br2, AcOH O CuCN (l.7eq) AcONa, 90% ~ DMF, 150 °C
/ : ~ / 88%
Br O
O Hv HN-~ N O
p 1 a. t-Boc20 THF HO 20%TFA/CH2CI2 DMAP, Et N
71%
b. MeOH, iCzC03 66%
CN RCN
Br OH / ~ TiCl4, PhCH~ NC ~ /
O
v j / C~NH N N
CH3CN, 25% °C H H
CN OH Br 63%
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. 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 illustrated by formula b.
The nitrite 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. Alternatively Zn(CN)2 or an alkali metal salt of the cyanide ion can be used to effect this cyanation reaction. In addition 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. 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 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 nitrite.
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.
To remove the t-BOC group and form the NH2-acid form of the compound (formula 1-e) the I,l-dimethylethylcarbamate is treated with an organic or mineral acid. While trifluoroacetic acid is illustrated, HCl or H2S04 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. As a preferred practice the salt is dissolved in 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. Then 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.
An experimental procedure for each stage of the reaction set out in Scheme I
is detailed below. These experimentals are set out solely for the purpose of illustrating the invention. What is reserved to the inventors is to be determined by reference to the claims, not to the following examples.
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 ( 118 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 captioned compound as a white solid (374 g, 89.7%): mp 186.0-187.0 °C; 'H NMR
(DMSO-dfi) 811.8 (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 ( 110 ml) was added 6-bromo-2(3H)-benzoxazolone 1 S (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, Hz0 (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 captioned compound as a tan solid (33.2 g, 88.5%): mp >220 °C; 'H NMR (DMSO-d~) 8 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 1,1-Dimethylethyl (4-cyano-2-hydroxyphenyl) carbamate To a solution of THF (500 ml) was added 2,3-dihydro-4-hydroxy-2-oxo-6-benzoxazolecarbonitrile (25 g, 0.156 mole), Et,N (26 ml, 0.187 mole) and DMAP
(3.81 g, 0.031 mole). To the solution was added di-tert-butyl dicarbonate (44.3 g, 0.202 mole) in three portions over 10 minutes and the mixture stirred at room temperature for 2 h. The reaction mixture was then concentrated in vacuo to give a brown oil (40 g) which was diluted with MeOH (500 ml) and stirred for 1 h at room temperature. K.,CO, (21.5 g, O.I56 mole) was added and stirring continued for 1.5 h.
The inorganic solids were then filtered, the filtrate partitioned with EtOAc and H,O, and the organic phase filtered through SiOz ( I 50 g). The filtrate was concentrated in vacuo to give the captioned compound as a light yellow solid (24 g, 66%
yield): mp 170.0-171.0 °C; 'H NMR (DMSO-d~) s 8.1 (s, 1H), 7.9 (d, J=8.0 Hz, 1 H), 7.2 (d, J=8.0 Hz, 1 H), 7.1 (s, 1 H).
Example 4 4-Amino-3-hydroxybenzonitrile, Trifluoroacetic Acid Salt To a solution of CH=Cl, ( 1000 ml) was added 1,1-dimethylethyl (4-cyano-2-hydroxyphenyl) carbamate (24 g, 0.102 mole) and the suspension cooled to 0 °C.
Trifluoroacetic acid ( 100 ml, 1.29 mole) was added in one portion, the solution stirred for 0.5 h at 0 °C and for 4 h at room temperature. The reaction mixture was then partially concentrated to 750 ml total volume and EtOAc (250 ml) added to cause immediate precipitation. The suspension was cooled for 12 h at -10 °C, filtered and dried to give the captioned compound as a white solid ( 18 g, 71 °lo): mp 164.0-166.0 °C; 'H NMR (DMSO-d~) s 7.0 (d, J=8.0 Hz, 1 H), 6.9 (s, 1 H), 6.65 (d, J=8.0 Hz, 1 H).
Example 5 N-(2-Bromophenyl)-N'-(2-hydroxy-4-cyanophenyl) urea To a solution of CH,CN (360 ml) was added 4-amino-3-hydroxybenzonitrile trifluoroacetic acid salt ( 18 g, 0.072 mole) and piperidine (7.2 ml, 0.072 mole). The solution was stirred at room temperature for 15 minutes followed by the addition of 2-bromophenyl isocyanate (9.85 ml, 0.079 mole). After 2 h of stirring at room temperature, a precipitate formed which was cooled to -10 °C for 12 h.
The precipitate was filtered and dried to give the title compound as a white solid (15.2 g, 63%): mp 203.5-205.0 °C; 'H NMR (DMSO-d~) 810.8 (bs, 1 H), 9.35 (s, 1 H), 9.1 (s, 1 H), 8.3 (d, J=8.5 Hz, 1 H), 7.9 (dd, J=8.3, 1.5 Hz, 1 H), 7.6 (dd, J=8.3, 1.5 Hz, 1 H), 7.3 (t, J=8.3 Hz, 1 H), 7.2 (dd, J=8.3, 1.5 Hz, 1 H), 7.15 (s, 1 H), 7.0 (t, J=8.3 Hz, 1 H).
Claims (6)
- What is claimed is:
A process for making compounds of Formula (A) wherein X is oxygen;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
R1 is independently selected from hydrogen; halogen; nitro; cyano; C1-10 alkyl; halosubstituted C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy;
halosubstituted C1-10alkoxy; azide; S(O)t R4; (CR8R8)q S(O)t R4; hydroxy; hydroxy substituted C1-4alkyl; aryl; aryl C1-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1-4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl C1-4 alkyloxy;
heterocyclic, heterocyclic C1-4alkyl; heterocyclicC1-4 alkyloxy;
heterocyclicC2-10 alkenyl; (CR8R8)q NR4R5; (CR8R8)q C(O)NR4R5; C2-10 alkenyl C(O)NR4R5;
(CR8R8)q C(O)NR4R10; S(O)3H; S(O)3R8; (CR8R8)q C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; (CR8R8)q C(O)OR11; (CR8R8)q OC(O)R11;
(CR8R8)q NR4C(O)R11; (CR8R8)q C(NR4)NR4R5; (CR8R8)q NR4C(NR5)R11 , (CR8R8)q S(O)2NR4R5, or two R1 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 C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, 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 R1;
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 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;
R8 is hydrogen or C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC1-4alkyl;
R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
R13 is suitably C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl;
R b is NR6R7, alkyl, aryl, aryl C1-4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl C1-4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4 alkyl, heterocyclic C2-4 alkenyl, or camphor, all of which groups may be optionally substituted;
which process comprises treating a compound of Formula I
with an isocyanate in the presence of about an equivalent of an organic base. - 2. The process of claim 1 wherein the product is a compound of Formula (A) wherein R is OH; R1 is halogen, cyano, nitro, CF3, C(O)NR4R5, alkenyl C(O)NR4,R5, C(O) R4R10, alkenyl C(O)OR12, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR4R5; one of R4 or R5 is phenyl, and Y is halogen.
- 3. The process of claim 1 wherein the organic base is piperidine.
- 4. The process of claim 3 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.
- 5. A process for making the compound of Formula (I) which process comprises treating a compound of Formula (II) with an acid to remove the BOC group.
- 6. A process for making the compound of formula (III) which process comprises treating the halo-substituted compound of formula (IV) where X is Cl, Br, or I with a cyanide salt and optionally a transition metal catalyst.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9824998P | 1998-08-28 | 1998-08-28 | |
| US60/098,249 | 1998-08-28 | ||
| PCT/US1999/019492 WO2000012468A1 (en) | 1998-08-28 | 1999-08-26 | An improved synthesis of 3-hydroxy-4-amino-benzonitrile |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2341718A1 true CA2341718A1 (en) | 2000-03-09 |
Family
ID=22268356
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002341718A Abandoned CA2341718A1 (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) |
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| MY143477A (en) | 2002-10-29 | 2011-05-31 | Smithkline Beecham Corp | 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 |
| PT2009992E (en) | 2006-04-21 | 2012-09-06 | Glaxosmithkline Llc | Il-8 receptor antagonists |
| RU2008145871A (en) | 2006-04-21 | 2010-05-27 | Смитклайн Бичам Корпорейшн (US) | IL-8 RECEPTOR ANTAGONISTS |
| 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 |
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| 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 | |
| CA1181070A (en) * | 1979-11-28 | 1985-01-15 | Kiyoshi Murase | Process of producing 2-hydroxyoxanilic acid derivatives |
| EP0809492A4 (en) * | 1995-02-17 | 2007-01-24 | Smithkline Beecham Corp | Il-8 receptor antagonists |
-
1999
- 1999-08-26 EP EP99943936A patent/EP1107948A4/en not_active Withdrawn
- 1999-08-26 CA CA002341718A patent/CA2341718A1/en not_active Abandoned
- 1999-08-26 JP JP2000567502A patent/JP2002523487A/en not_active Withdrawn
- 1999-08-26 WO PCT/US1999/019492 patent/WO2000012468A1/en not_active Application Discontinuation
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| Publication number | Publication date |
|---|---|
| EP1107948A4 (en) | 2002-01-02 |
| WO2000012468A1 (en) | 2000-03-09 |
| EP1107948A1 (en) | 2001-06-20 |
| JP2002523487A (en) | 2002-07-30 |
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