JP2002523487A - Improved synthesis of 3-hydroxy-4-amino-benzonitrile - Google Patents

Abstract

  (57) [Summary] The present invention relates to a method for producing 3-hydroxy-4-amino-benzonitrile.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for producing an intermediate useful for producing a specific phenylurea compound. The final product phenylurea compound is IL-8, GROα, GROβ, GRO
Useful for treating gamma and NAP-2-mediated diseases.

BACKGROUND OF THE INVENTION [0002] Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. This can be TNF, IL-1a, IL-1b or L
Produced by most nucleated cells, including macrophages, fibroblasts, endothelial cells and epithelial cells exposed to PS, and neutrophils themselves when exposed to chemotactic factors such as LPS or FMLP. M. Baggiolini et al., J. Clin. Invest. 8
4, 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).

[0003] There is a need in the art for treatment of compounds that have the ability to bind to IL-8α or β receptors. Thus, symptoms associated with increased IL-8 production, which involves chemotaxis of neutrophils and T-cell subsets to sites of inflammation, are associated with IL-8
Compounds that are inhibitors of receptor binding would benefit. Such compounds are disclosed in published patent applications exemplified by PCT / US96 / 13632 published August 21, 1997 as WO 97/29743. The present invention, WO97 / 21 August 1997
N- [2-, a compound disclosed in PCT / US96 / 13632 published as 29743
Provided is a method for producing 2-amino-5-cyano-phenol, which is a useful intermediate for the synthesis of hydroxy-4-cyanophenyl] -N '-[2-bromophenyl] urea.

[0004] In a first aspect, the present invention provides a compound of formula (A):

Embedded imageWherein X is oxygen; R is a functional group having an ionizable hydrogen and having a pKa of 10 or less;₁Is independently hydrogen; halogen; nitro; cyano; C_1-10Alkyl;
Halo-substituted C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy;
Halo-substituted C_1-10Alkoxy; azide; S (O)_tR₄; (CR₈R₈)_qS (O) _t R₄Hydroxy; hydroxy-substituted C_1-4Alkyl; aryl; aryl C _1-4 Alkyl; aryl C_2-10Alkenyl; aryloxy; aryl C _1-4 Alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl
C_2-10Alkenyl; heteroaryl C_1-4Alkyloxy; heterosa
Iclic, heterocyclic C_1-4Alkyl; heterocyclic C_{1- 4} Alkyloxy; heterocyclic C_2-10Alkenyl; (CR₈R₈)_q NR₄R₅; (CR₈R₈)_qC (O) NR₄R₅C_2-10Alkenyl C (O) N
R₄R₅; (CR₈R₈)_qC (O) NR₄R₁₀S (O)₃H; S (O)₃R₈; (
CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁C_2-10
Alkenyl C (O) OR₁₁; (CR₈R₈)_qC (O) OR₁₁; (CR₈R₈)_qO
C (O) R₁₁; (CR₈R₈)_qNR₄C (O) R₁₁; (CR₈R₈)_qC (NR₄)
NR₄R₅; (CR₈R₈)_qNR₄C (NR₅) R₁₁, (CR₈R₈)_qS (O)₂ NR₄R₅Or two R₁The group together has 5-6 members
It may form a saturated ring (where alkyl, aryl, arylalkyl,
T is an integer of 0 or 1 to 10; t is an integer of 0 or 1 or 2; s is an integer of 1 to 3 R₄And R₅Is independently an optionally substituted C_1-4Alkyl, substituted
Optionally substituted aryl, optionally substituted aryl C_1-4Alkyl,
Optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 Alkyl, heterocyclic, heterocyclic C_1-4With alkyl
Is or R₄And R₅Together with the nitrogen to which they are attached
5- to 7-membered ring optionally containing an additional heteroatom selected from, N or S
Y is R₁Q is 0 or an integer of 1 to 10; m is an integer of 1 to 3;₆And R₇Is independently hydrogen or C_1-4Is an alkyl group, or
Is R₆And R₇Together with the nitrogen to which they are attached
Forms a 5- to 7-membered ring which may contain additional heteroatoms selected from sulfur
R;₈Is hydrogen or C_1-4R is alkyl;₁₀Is C_1-10Alkyl C (O)₂R₈R₁₁Is hydrogen, optionally substituted C_1-4Alkyl, even if substituted
Good aryl, optionally substituted aryl C_1-4Alkyl, substituted
Optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4Archi
, An optionally substituted heterocyclic, or an optionally substituted
Terror cyclic C_1-4R is alkyl;₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl or
R is an optionally substituted arylalkyl;₁₃Is, appropriately, C_1-4Alkyl, aryl, aryl C_1-4Archi
, Heteroaryl, heteroaryl C_1-4Alkyl, heterocyclic,
Or heterocyclic C_1-4R is alkyl;_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, ant
C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl,
Heteroaryl C_2-4Alkenyl, heterocyclic, heterocyclic
C_1-4Alkyl, heterocyclic C_2-4Alkenyl or camphor
And all of these groups may be substituted.] A compound represented by the formula (I) or (Ia) in the presence of about 1 equivalent of an organic base:

Embedded image [Wherein, A ⁻ is an anion of an acid addition salt].

[0005] The present invention also relates to a method for producing 2-aminophenol. Specifically, the method comprises reacting a compound of formula (II) or (IIa):

Embedded image By removing the t-BOC group by treating the compound represented by the formula (I) or (Ia):

Embedded image Wherein A ⁻ is an anion of an acid addition salt.

[0006] In a third aspect, the present invention provides a compound of formula (III):

Embedded image A method for producing a nitrile represented by the formula (IV):

Embedded image Wherein X is Cl, Br or I. A method comprising treating a halo-substituted compound of formula I with a cyanide salt and optionally a transition metal catalyst.

(Detailed Description of the Invention) These methods can be used to synthesize these intermediates.
A preferred compound is R₁Is halogen, cyano, nitro, CF₃, C (O) NR₄R ₅ , Alkenyl C (O) NR₄R₅, C (O) R₄R₁₀, Alkenyl C (O) OR_{1 2} , Heteroaryl, heteroarylalkyl, heteroarylalkenyl, or
Or S (O) NR₄R₅And preferably R₄Or R₅One of them is Pheni
Is a compound that is R₁A preferred ring substitution for is at position 4 of the phenyl ring.
is there.

Preferably, R ₁ is a nitro, halogen, cyano, trifluoromethyl group, or C (O) NR ₄ R ₅ .

Y is preferably halogen, C _1-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted aryl alkyloxy, optionally substituted heteroaryl alkyloxy, methylenedioxy, _NR 4 _{R 5,} thio _{C 1 -4} alkyl, thioaryl, halosubstituted alkoxy, optionally substituted _{C 1 -4} alkyl or hydroxy, Alkyl. Y is more preferably halogen monosubstituted, halogen disubstituted, alkoxy monosubstituted, alkoxy disubstituted, methylenedioxy, aryl or alkyl, more preferably these groups are
It is mono- or di-substituted at the 2′-position or 2 ′, 3′-position.

[0010] Y may be substituted at any of the five ring positions, but preferably R
Is preferably OH or SH, Y is preferably mono-substituted at the 2′-position or 3′-position, preferably not substituted at the 4′-position. When the ring is disubstituted and R is OH or SH, the other ring substituents are preferably at the 2 'or 3' position of the monocyclic ring. R ₁ and Y can both be hydrogen, but it is preferred that at least one ring is substituted. Preferably, both rings are substituted.

Preferred compounds include the following compounds: 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.

A synthetic scheme of the compound represented by the formula (A) is described in Scheme I. The compounds obtained in this scheme are exemplary of the process and analogs of these compounds defined for formula (A) can be prepared by this process.

[0013]

Embedded image

The benzoxazolinone starting material (Formula 1-a) is commercially available. See, for example, Aldrich. Halogenation (exemplifying bromine) by mixing benzoxazolinone with a solution of an organic acid and an alkali metal salt of the acid in approximately equimolar amounts gives a compound of formula b. Glacial acetic acid and its sodium salt are a preferred organic acid / salt combination. In the case of the exemplified benzoxazolinones, a suspension is formed. The suspension is cooled below room temperature to approximately 0-20 ° C. and then the bromine is added slowly; a slight molar excess of bromine over benzoxazolinone is preferred. The mixture is stirred at room temperature for a time sufficient for the reaction to take place, usually about 12 hours to overnight. No special conditions are required for working up the halogenated product of formula b.

The nitrile of formula 1-c can be obtained by treating the brominated benzoxazolinone with CuCN in a polar solvent such as dimethylformamide, N-methylpyrrolidinone or dimethylsulfoxide under an inert gas at a moderately high temperature. It is manufactured by doing. Alternatively, the cyanation reaction can be carried out using Zn (CN) ₂ or an alkali metal salt of cyanide ion. Further, a transition metal catalyst such as Pd (0) or Ni (0) can be used together with Zn (CN) ₂ and an alkali metal salt of cyanide ion, respectively. As exemplified herein, benzoxazolinone is added to the solvent, followed by CuCN (about 75% molar excess). The mixture is heated to a temperature in the range of 120-175C. The reaction is carried out under an inert gas, preferably under nitrogen. The reaction mixture is heated at this temperature for about 4-8 hours. The reaction is then cooled to about 100 ° C., a 3-4 fold molar excess of an alkali metal cyanide, eg, NaCN, is added and the resulting suspension is stirred at room temperature for at least 2 hours.
No specific work-up is required to recover the nitrile.

The carbamates (Formula 1-d) are prepared by treating the benzoxazolecarbonitrile with an alkyl dicarbonate in a polar aprotic solvent in the presence of a nucleophilic addition catalyst such as dimethylaminopyridine. . The reaction is performed at about room temperature for about 2 hours.

The t-BOC group is removed and the compound NH₂-To form the acid form (Formula 1-e)
Then, the 1,1-dimethylethyl carbamate is treated with an organic or mineral acid. bird
Fluoroacetic acid is exemplified, but similarly, HCl or H
₂SO₄Alternatively, an organic acid such as methanesulfonic acid can be used. Cal
The bamate is dissolved in a polar aprotic solvent, cooled, the acid is added and the mixture is brought to 0
Stir for a few hours at between ℃ and room temperature. In the post-treatment, an organic solvent is added as a means for isolating the product.
And the resulting suspension is cooled below the coagulation temperature and held at that temperature for up to about 12 hours.
Including doing.

The compound of formula 1-f is prepared by treating the acid salt form of an amine with an isocyanate in the presence of about 1 equivalent of a base and reacting the isocyanate with the amine to form a urea moiety. Cut off the parts. As a preferred method, the salt is dissolved in a suitable solvent such as acetonitrile, and a base is added thereto. Piperidine is an example of a base that can be used as an acid scavenger. Then the isocyanate is added. The reaction is performed at room temperature and is completed in about 1-3 hours. Work-up and recovery of the product is conventional.

Experimental methods for each step of the reaction described in Scheme I are described in detail below. These experimental examples are described merely for the purpose of illustrating the present invention. What is retained by the inventors should be determined with respect to the claims, rather than the examples below.

Examples Example 1 6-Bromo-2 (3H) -benzoxazolone Sodium acetate (222 g, 2.70 mol) in a solution of glacial acetic acid (1500 ml)
And 2-benzoxazolinone (300 g, 2.22 mol) were added. The suspension was cooled to 15 ° C., bromine (118 ml, 2.29 mol) was added dropwise over 1 hour and the mixture was stirred at room temperature for 12 hours. The solid is then filtered and H ₂ O (
(3 x 500 ml) and dried in vacuo to give the title compound as a white solid (
374 g, 89.7%): mp 186.0-187.0 ° C; ¹ H NMR (DMSO
−d ₆ ) δ 11.8 (s, 1H), 7.6 (s, 1H), 7.3 (d, J = 8.0)
Hz, 1H), 7.0 (d, J = 8.0 Hz, 1H).

Example 2 2,3-Dihydro-4-hydroxy-2-oxo-6-benzoxazolecarbonitrile A solution of DMF (110 ml) in 6-bromo-2 (3H) -benzoxazolone (
50 g, 0.234 mol) and CuCN (89.6 g, 0.398 mol) were added and the mixture was heated to 150 ° C. under nitrogen for 6 hours. The reaction was then brought to 100 ° C.
H ₂ O (200 ml) and NaCN (36 g, 0.734 mol) were added and the suspension was stirred at room temperature for 2 hours and partitioned at 70 ° C. with EtOAc.
The organic phase was washed with H ₂ O (2 × 150 ml) and concentrated in vacuo to give the title compound as a tan solid (33.2 g, 88.5%): mp> 220 ° C .; ¹ H NMR.
(DMSO-d ₆ ) δ 7.8 (s, 1H), 7.6 (d, J = 8.0 Hz, 1H)
, 7.2 (d, J = 8.0 Hz, 1H).

Example 3 1,1-Dimethylethyl (4-cyano-2-hydroxyphenyl) carbamate 2,3-Dihydro-4-hydroxy-2-oxo-6-benzoxazolecarbonitrile in a solution of THF (500 ml). (25 g, 0.156 _{mol), Et 3 N (26ml,} 0.187 mol) and DMAP (3.81 g, 0.031 mol)
Was added. Di-tert-butyl dicarbonate (44.3 g, 0.202 mol) was added to the solution in three portions over 10 minutes and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo to give a brown oil (40 g) which was
Diluted with OH (500 ml) and stirred at room temperature for 1 hour. K ₂ CO ₃ (21.5 g
, 0.156 mol) was added and stirring was continued for 1.5 hours. Then, the inorganic solid was filtered and the filtrate was partitioned between EtOAc and _{H 2} O, the organic phase SiO ₂ (150 g
). The filtrate was concentrated in vacuo to give the title compound as a pale yellow solid (24g
, Yield 66%): mp 170.0-171.0 ° C; ¹ H NMR (DMSO-d ₆
) Δ 8.1 (s, 1H), 7.9 (d, J = 8.0 Hz, 1H), 7.2 (d, J
= 8.0 Hz, 1H), 7.1 (s, 1H).

Example 4 4-Amino-3-hydroxybenzonitrile trifluoroacetate 1,2-dimethylethyl (4-cyano-) was added to a solution (1000 ml) of CH ₂ Cl _2.
2-Hydroxyphenyl) carbamate (24 g, 0.102 mol) was added and the suspension was cooled to 0 <0> C. Trifluoroacetic acid (100 ml, 1.29 mol) was added in one portion and the solution was stirred at 0 ° C. for 0.5 h and then at room temperature for 4 h. The reaction mixture was then partially concentrated to a total volume of 750 ml, and EtOAc (250 m
Addition of 1) resulted in immediate precipitation. The suspension was cooled at −10 ° C. for 12 hours, filtered and dried to give the title compound as a white solid (18 g, 71%): mp 16
4.0-166.0 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 7.0 (d, J = 8.0)
Hz, 1H), 6.9 (s, 1H), 6.65 (d, J = 8.0 Hz, 1H).

Example 5 N- (2-Bromophenyl) -N ′-(2-hydroxy-4-cyanophenyl) urea A solution of CH ₃ CN (360 ml) in 4-amino-3-hydroxybenzonitrile trifluoro Acetate (18 g, 0.072 mol) and piperidine (7.2 m
1, 0.072 mol) was added. The solution is stirred at room temperature for 15 minutes, then
-Bromophenyl isocyanate (9.85 ml, 0.079 mol) was added.
After stirring at room temperature for 2 hours, the precipitate formed was cooled to -10 ° C for 12 hours. The precipitate was filtered and dried to give the title compound as a white solid (15.2g, 63
%): Melting point 203.5-205.0 ° C; ¹ H NMR (DMSO-d ₆ ) δ 10.
8 (bs, 1H), 9.35 (s, 1H), 9.1 (s, 1H), 8.3 (d, J
= 8.5 Hz, 1H), 7.9 (dd, J = 8.3, 1.5 Hz, 1H), 7.6 (
dd, J = 8.3, 1.5 Hz, 1H), 7.3 (t, J = 8.3 Hz, 1H), 7
.2 (dd, J = 8.3, 1.5 Hz, 1H), 7.15 (s, 1H), 7.0 (t
, J = 8.3 Hz, 1H).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 263/58 C07D 263/58 // C07B 61/00 300 C07B 61/00 300 (72) Inventor William M. Clark Jr. United States 08690 Gates Mill Coat 150, Hamilton Square, New Jersey Anne-Marie Eldridge Inventor United States 19401 Coles Blvd 2312, Norristown, PA 19401 F-term (reference) 4C055 AA01 BA01 CA01 DA06 DA16 DB04 DB10 FA15 FA32 FA37 4C056 AA01 AB01 AC02 AD03 AE03 AF04 CA15 CC01 CD10 4H006 AA02 AC52 AC57 BA51 BC34 QN30 4H039 CA73 CD10

Claims (6)

[Claims] (1) Formula (A):Wherein X is oxygen; R is a functional group having an ionizable hydrogen and having a pKa of 10 or less;₁Is independently hydrogen; halogen; nitro; cyano; C_1-10Alkyl;
Halo-substituted C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy;
Halo-substituted C_1-10Alkoxy; azide; S (O)_tR₄; (CR₈R₈)_qS (O) _t R₄Hydroxy; hydroxy-substituted C_1-4Alkyl; aryl; aryl C _1-4 Alkyl; aryl C_2-10Alkenyl; aryloxy; aryl C _1-4 Alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl
C_2-10Alkenyl; heteroaryl C_1-4Alkyloxy; heterosa
Iclic, heterocyclic C_1-4Alkyl; heterocyclic C_{1- 4} Alkyloxy; heterocyclic C_2-10Alkenyl; (CR₈R₈)_q NR₄R₅; (CR₈R₈)_qC (O) NR₄R₅C_2-10Alkenyl C (O) N
R₄R₅; (CR₈R₈)_qC (O) NR₄R₁₀S (O)₃H; S (O)₃R₈; (
CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁C_2-10
Alkenyl C (O) OR₁₁; (CR₈R₈)_qC (O) OR₁₁; (CR₈R₈)_qO
C (O) R₁₁; (CR₈R₈)_qNR₄C (O) R₁₁; (CR₈R₈)_qC (NR₄)
NR₄R₅; (CR₈R₈)_qNR₄C (NR₅) R₁₁, (CR₈R₈)_qS (O)₂ NR₄R₅Or two R₁The group together has 5-6 members
It may form a saturated ring (where alkyl, aryl, arylalkyl,
T is an integer of 0 or 1 to 10; t is an integer of 0 or 1 or 2; s is an integer of 1 to 3 R₄And R₅Is independently an optionally substituted C_1-4Alkyl, substituted
Optionally substituted aryl, optionally substituted aryl C_1-4Alkyl,
Optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 Alkyl, heterocyclic, heterocyclic C_1-4With alkyl
Is or R₄And R₅Together with the nitrogen to which they are attached
5- to 7-membered ring optionally containing an additional heteroatom selected from, N or S
Y is R₁Q is 0 or an integer of 1 to 10; m is an integer of 1 to 3;₆And R₇Is independently hydrogen or C_1-4Is an alkyl group, or
Is R₆And R₇Together with the nitrogen to which they are attached
Forms a 5- to 7-membered ring which may contain additional heteroatoms selected from sulfur
R;₈Is hydrogen or C_1-4R is alkyl;₁₀Is C_1-10Alkyl C (O)₂R₈R₁₁Is hydrogen, optionally substituted C_1-4Alkyl, even if substituted
Good aryl, optionally substituted aryl C_1-4Alkyl, substituted
Optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4Archi
, An optionally substituted heterocyclic, or an optionally substituted
Terror cyclic C_1-4R is alkyl;₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl or
R is an optionally substituted arylalkyl;₁₃Is, appropriately, C_1-4Alkyl, aryl, aryl C_1-4Archi
, Heteroaryl, heteroaryl C_1-4Alkyl, heterocyclic,
Or heterocyclic C_1-4R is alkyl;_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, ant
C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl,
Heteroaryl C_2-4Alkenyl, heterocyclic, heterocyclic
C_1-4Alkyl, heterocyclic C_2-4With alkenyl or kalflu
And all of these groups may be substituted.] A compound represented by the formula (I): ## STR2 ## in the presence of about 1 equivalent of an organic base.A method comprising treating a compound represented by the formula with an isocyanate. 2. The product wherein R is OH; R ₁ is halogen, cyano, nitro, CF ₃ , C (O) NR ₄ R ₅ , alkenyl C (O) NR ₄ R ₅ , C (O) R ₄ R _{1 0,} alkenyl C (O) _{oR 12,} heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or _{S (O) NR 4 R 5} ,; one of _{R 4} or _{R 5} is phenyl, The method according to claim 1, wherein the compound is a compound represented by the formula (A) wherein Y is halogen. 3. The method according to claim 1, wherein the organic base is piperidine. 4. The method according to claim 3, wherein the product is the following compound: 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 compound of the formula (I): A method for producing a compound represented by the formula (II): A method comprising treating the compound represented by the above with an acid to remove the BOC group. 6. A compound of the formula (III): A method for producing a compound represented by the formula (IV): Wherein X is Cl, Br, or I. A method comprising treating a halo-substituted compound of formula I with a cyanide salt and optionally a transition metal catalyst.