EP1107948A1

EP1107948A1 - An improved synthesis of 3-hydroxy-4-amino-benzonitrile

Info

Publication number: EP1107948A1
Application number: EP99943936A
Authority: EP
Inventors: Neil H. Baine; William M. Clark, Jr.; Ann Marie Eldridge
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd
Priority date: 1998-08-28
Filing date: 1999-08-26
Publication date: 2001-06-20
Also published as: CA2341718A1; JP2002523487A; WO2000012468A1; EP1107948A4

Abstract

This invention relates to a process for making 3-hydroxy-4-amino-benzonitrile.

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, GROα, GROβ, GROγ 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 /. 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 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 PCT application serial number PCT US96/13632, published 21 August 1997 as WIPO No. WO97/29743.

SUMMARY OF THE INVENTION

In a first aspect this invention relates to a method 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;

Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl; halosubstituted Ci -io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-ioalkoxy; azide; S(O)tR4; (CR R₈)q S(O)tR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl Cι_4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl Ci_4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Ci-4 alkyloxy; heterocyclic, heterocyclic Ci -4alkyl; heterocyclicCι_4alkyloxy; heterocyclicC2-10 alkenyl; (CR₈R₈)q NR4R5; (CR₈Rs)q C(O)NR₄R₅; C₂-10 alkenyl C(O)NR4 5; (CR₈R₈)q C(O)NR₄Rl0; S(O)₃H; S(O)₃Rs; (CR₈Rs)q C(O)Rι 1; C₂-10 alkenyl C(O)Ri 1; C2-10 alkenyl C(O)ORi l; (CR₈R₈)q C(O)ORi 1; (CR₈R₈)q OC(O)Rι ι_; (CR₈R₈)qNR4C(O)Rn ; (CR₈R₈)q C(NR4)NR₄R₅; (CR₈R₈)q NR₄C(NR₅)Rn , (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 Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Cι_4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, heterocyclic

Cι -4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O, N or S; Y is Ri ; q is 0 or an integer having a value of 1 to 10; m is an integer having a value of 1 to 3;

R6 and R7 are independently hydrogen or a C1 -4 alkyl group, or R and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;

R₈ is hydrogen or C1 -4 alkyl;

RlO is Ci-io alkyl C(O)₂R8;

Rl 1 is hydrogen, optionally substituted C1.4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicCι_4alkyl; Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl;

Rl3 is suitably Cj-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi- 4alkyl, heterocyclic, or heterocyclicCi-4alkyl;

Rtø is NRgR7, alkyl, aryl, aryl Cj_4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl C1.4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic Cμ4 alkyl, heterocyclic C2-4 alkenyl, or camphor, all of which groups may be optionally substituted; which process comprises treating a compound of Formula (I) or (la)

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 (la)

where A" is the anion of an acid addition saltc by treating a compound of formula (II) or (Ila) with an acid to remove the t-BOC group.

In a third aspect this invention relates to a process for making the nitrile of formula (III)

N

(HI)

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. Detailed Description of the Invention

The preferred compounds which can be synthesised by these methods and using these intermediates are those where Rl is halogen, cyano, nitro, CF3, C(O)NR4R5, alkenyl C(O)NR4Rs, C(O) R4R1O, alkenyl C(O)ORi2, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR4R5, and preferably one of R4 or R5 is phenyl. A preferred ring substitution for Rj is in the 4-position of the phenyl ring.

Preferably Rj is nitro, halogen, cyano, trifluoromethyl group, or C(O)NR4R5. Y is preferably a halogen, Ci-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted arylalkyloxy, optionally substituted heteroarylalkyloxy, methylenedioxy, NR4R5, thioC]-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted Ci-4 alkyl, or hydroxy alkyl. Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or disubstituted in the 2'- position or 2'-, 3'-position.

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 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 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

CN CN

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 nitrile of formula 1 -c is prepared by treating the brominated benzoxazolinone with CuCN at a moderately elevated temperature under an inert gas in a polar solvent such as dimethyl formamide, N-methyl pyrrolidinone or dimethylsulfoxide. 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 nitrile.

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 1,1-dimethylethylcarbamate is treated with an organic or mineral acid. While trifluoroacetic acid is illustrated, HC1 or H2SO4 or an organic acid such as methansulfonic acid can be used in this reaction as well. The carbamate is dissolved in a polar aprotic solvent, cooled, acid added, and the mixture stirred for several hours at a temperature between 0 °C and room temperature. Workup can involve precipitating the product by adding an organic solvent, cooling the resulting suspension to below freezing, and holding it at that temperature for up to 12 hours or so as a means for isolating the product.

The compound designated formula 1-f is made by treating the acid salt form of the amine with an isocyanate in the presence of about an equivalent of a base to scavenge the acid release when the isocyanate reacts with the amine to form the urea moiety. 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; 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 (110 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, H₂O (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; Η NMR (DMSO-d₆) 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 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), Et₃N (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,CO₃ (21.5 g, 0.156 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 SiO₂ (150 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; Η NMR (DMSO-d₆) δ 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,C1₂ (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%): mp 164.0-166.0 °C; Η NMR (DMSO-d₆) δ 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 CH₃CN (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; Η NMR (DMSO-d₆) δ 10.8 (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

What is claimed is:

1. A process for making compounds of Formula (A)

wherein

X is oxygen;

Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl; halosubstituted Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-ioalkoxy; azide; S(O)tR4; (CR₈R )q S(O)tR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl C╬╣_4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1.4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Ci-4 alkyloxy; heterocyclic, heterocyclic C╬╣_4alkyl; heterocyclicCi-4alkyloxy; heterocyclicC2-10 alkenyl; (CR₈R₈)q NR4R5; (CR₈R₈)q C(O)NR₄R₅; C₂-10 alkenyl C(O)NR4R5; (CR₈R₈)q C(O)NR4Rl╬╕; S(O)₃H; S(O)₃R8; (CR₈R₈)q C(O)R╬╣ l; C₂-10 alkenyl C(O)Rn; C2-10 alkenyl C(O)OR╧Ç; (CR₈R₈)q C(O)ORn; (CR₈R₈)q OC(O)Rn_; (CR₈R₈)qNR₄C(O)Rn; (CR₈R₈)q C(NR4)NR₄R₅; (CR₈R₈)q NR₄C(NR₅)Rn , (CR₈R₈)q S(O)2NR4R5, or two Rl 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 Ci-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 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 C _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 C 1.4 alkyl;

RlO is C 1-10 alkyl C(O)2R8;

Rl 1 is hydrogen, optionally substituted Cj-4 alkyl, optionally substituted aryl, optionally substituted aryl Cj-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCj-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicCi-4alkyl;

Rl2 is hydrogen, Ci-io 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 NR5R7, alkyl, aryl, aryl C1.4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl C _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; Rl is halogen, cyano, nitro, CF3, C(O)NR4R5, alkenyl C(O)NR4R5, C(O) R4R10, alkenyl C(O)ORi2, 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-hy droxy-4-cy anopheny 1] -N '- [2 , 3 -dichloropheny 1] urea N-(2-hydroxy-4-cy anophenyl)-N '-(2-(4-pyridylmethyloxy)phenyl)urea , or N-(2-hydroxy-4-cyanophenyl)-N'-(2-chlorophenyl)urea.

5. A process for making the compound Formula (I)

N

(I)

which process comprises treating a compound of Formula (II) with an acid to remove the BOC group.

N (II)

A process for making the compound of formula (III)

N (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.