APPLICATION DATA This application claims benefit to US Provisional application serial no. 60/680,404 filed May 12, 2005.

BACKGROUND OF THE INVENTION

1. TECHNICAL FIELD

This invention relates to a process of making 1,3- and 1,4-diamino-phenyl intermediates using a bis-amination reaction..

2. BACKGROUND INFORMATION Aryl- and heteroaryl-substituted ureas have been described as inhibitors of cytokine production and effective therapeutics in cytokine-mediated diseases including inflammatory and autoimmune diseases. Examples of such compounds are reported in U.S. patent nos. 6,080,763 and 6,319,921, and WO 00/55139 including aryl- or heteroaryl-substituted ureas

US publication number US 2004-102492 discloses heteroaryl amide compounds which are disclosed therein as being useful as cytokine inhibitors. Particular compounds disclosed in the publication are synthesized from arylamine intermediate compounds, such as N-[3-Amino-2-methoxy-5-(l-methyl-cyclopropyl)-phenyl]- methanesulfonamide. These arylamine intermediates are produced in a multistep process which require the synthesis of 1,3-diamino-phenyl intermediates, as shown in the scheme I below:

1) (NO) ⁺ 18-crown-6-H(NO ₃ ) ₂ -

2) TMSCH ₂ N ₂ , DIPEA

As seen in scheme I, the existing process uses functionalized di-nitrobenzene intermediates that decompose at relatively low temperatures and requires the use of expensive crown ether reagents. Similar reactions for these intermediates are disclosed in US 2004-0186114.

The amination of aryl halides has been disclosed in Lee S, et al., Org. Lett. 2001 3, 2729; Huang et al. Org. Lett. 2001, 3, 3417; and in Hartwig et al. WO 03/006420. However, lacking in the field are methods for bis-amination of ortho-substituted aryl halides.

It is therefore desirable to provide a more efficient and economical synthesis for 1,3- diamino-phenyl intermediates by utilizing bis-amination of ortho-substituted aryl halides.

BRIEF SUMMARY OF THE INVENTION

It is therefore an object of the invention to provide a process of making 1,3-diamino- phenyl intermediates of the formula (I) via bis-amination of ortho-substituted aryl halides,

(I), where Ri, R ₂ and the suitable conditions of such process are described herein below.

DETAILED DESCRIPTION OF THE INVENTION

In the broadest generic embodiment, there is provided a process of making 1,3- and 1,4- diamino-phenyl intermediates of the formulas (I) or (III) via bis-amination :

preferably, formula (I); wherein

Ri is chosen from hydrogen, Cl-6 alkyl, aryl or C3-7 cycloalkyl each optionally substituted by Cl-6 alkyl, C 1-4 acyl, aroyl, C 1-4 alkoxy, Cl-6 alkoxycarbonyl each of the above may be partially or fully halogenated, carbocyclesulfonyl and -SO ₂ -CF ₃ ;

R ₂ is chosen from hydrogen, Cl-6 alkyl, C3-7 cycloalkyl optionally substituted by Cl-6 alkyl, C 1-4 acyl, aroyl, C 1-4 alkoxy, Cl-6 alkoxycarbonyl each of the above may be partially or fully halogenated, carbocyclesulfonyl, halogen and -SO ₂ -CF ₃ ;

wherein for formula II, R ₃ and R ₂ optionally fuse to form a benzo ring;

the process comprising in a one pot reaction :

providing an aryl halide of the formula (II) or (IV):

wherein Ri, R ₂ , R3 are as defined above, each X is independently halogen chosen from I and Br;

adding, in a suitable aprotic solvent including but not limited to toluene, THF, dioxane, preferably toluene; an ammonia containing compound including but not limited to triphenylsilylamine tri-n- hexylsilylamine,, trimethylsilylamine, t-butyl carbamate, benzyl carbamate, preferably triphenylsilylamine; a palladium containing compound including but not limited to Pd ₂ (dba) ₃ , Pd(dba) ₂ ,

Pd(OAc) ₂ PdCl ₂ , KaIIyI)PdCl] ₂ , preferably Pd ₂ (dba) ₃ ; a phosphine containing compound including but not limited to 2-

(dicyclohexylphosphino)biphenyl, triphenylphosphine, tri-t-butylphosphine, BINAP,

DPPF, preferably 2-(dicyclohexylphosphino)biphenyl; and LiHMDS (lithium bis-trimethylsiloamide); at a temperature of about 80-120 ⁰ C, preferably about 100 ⁰ C ; and isolating the product compound of the formula (I).

In another embodiment of the invention there is a process as described in the embodiment immediately above, and wherein:

providing an aryl halide of the formula (II);

Ri is chosen from C 1-6 alkyl, phenyl or C3-6 cycloalkyl optionally substituted by C 1-4 alkyl and C 1-4 alkoxy each of the above may be partially or fully halogenated;

R ₂ is chosen from C 1-6 alkyl, C3-6 cycloalkyl optionally substituted by C 1-4 alkyl, each of the above may be partially or fully halogenated and chloro.

Ih ^' another "eπϊB'ό'dϊnteϊϊt df the invention there is a process as described in the embodiment immediately above, and wherein:

Ri is C 1-3 alkoxy optionally partially or fully halogenated;

R ₂ is chosen from C 1-6 alkyl, C3-6 cycloalkyl optionally substituted by C 1-3 alkyl, each of the above may be partially or fully halogenated and chloro.

The following are representative compounds which can be made by the process described herein:

Synthetic Examples

Example 1: General Procedure A. LiHMDS (803 mg, 4.8 mmol, 2.4 equiv.) and 4 mL toluene were added to the aryl halide (2.0 mmol), triphenylsilylamine (1.32 g, 4.8 mmol, 2.4 equiv.), Pd ₂ (dba) ₃ (74 mg, 0.08 mmol, 4 mol%) and 2-(dicyclohexylphosphino)biphenyl (68 mg, 0.19 mmol, 9.6 mol%). The reaction mixture was heated to 100 ⁰ C for 17 h. The mixture was cooled to 25 ⁰ C and quenched with IN HCl (5 mL). The mixture was stirred for 5 min and basified to pH 12 with IN NaOH. The mixture was stirred for 5 min, the layers separated and the organic layer concentrated. The residue was dissolved in 10 mL EtOAc and jo-toluenesulfonic acid (760 mg, 4.0 mmol, 2.0 equiv.) was added. The

p"reclpϊtkϊe' WaVflReMd lhd partitioned between 10 niL water and 10 mL EtOAc. The aqueous layer was basified to pH 12 with IN NaOH. The layers were separated. The organic layer was dried over Na ₂ SO ₄ and concentrated.

2,6-Diamino-4-methylanisole

2.4 equiv. LiHMDS

73%

General Procedure A was followed using 2,6-dibromo-4-methylanisole (5.6 g, 20 mmol), triphenylsilylamine (13.2 g, 48 mmol, 2.4 equiv.), Pd ₂ (dba) ₃ (740 mg, 0.8 mmol, 4 mol%), 2-(dicyclohexylphosphino)biphenyl (680 mg, 1.9 mmol, 9.6 mol%), LiHMDS (8 g, 48 mmol, 2.4 equiv.) and 40 mL toluene. The reaction mixture was heated to 100 ⁰ C for 17 h. The mixture was cooled to room temperature and quenched with IN HCl (50 mL). The mixture was stirred at room temperature for 5 min and basified to pH 12 with IN NaOH. The mixture was stirred for 5 min, the layers separated and the organic layer was concentrated. The residue was dissolved in 100 mL EtOAc and />-toluenesulfonic acid (7.6 g, 40 mmol, 2.0 equiv.) was added. The precipitate was filtered and partitioned between 100 mL water and 100 mL EtOAc. The aqueous layer was basified to pH 12 with IN NaOH and the layers were separated. The organic layer was dried over Na ₂ SO ₄ and concentrated. The product was isolated as an orange oil in 70% yield (2.15g). ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.02 (s, 2 H), 3.76 (br s overlapping s, 4 H + 3 H), 2.17 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 139.4, 134.4, 132.5, 106.9, 59.0, 20.9; HRMS calcd for C ₈ H ₁₃ N ₂ O (M + H) 153.1022, found 153.1021. [7142-138]

2,6-Diaminotoluene

General Procedure A was followed using 1,3-dibromotoluene (500 mg, 2.0 mmol). The product was isolated as a brown solid in 86% yield (220 mg). ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.84 (t, J = 7.8, 1 H), 6.20 (d, J = 7.8, 2 H) ₅ 3.60-3.45 (br s, 4 H), 2.05 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 145.1, 126.7, 107.2, 106.6, 10.2; HRMS calcd for C ₇ H _n N ₂ O (M + H) 123.0916, found 123.0921.

2-ChIoro-5-fluorobenzene-l,3-diamine

General Procedure A was followed using l-chloro-2,6-dibromo-4-fluorobenzene (577 mg, 2.0 mmol). The product was isolated as a brown-red solid in 87% yield (280 mg). ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.93 (d, J = 10.1, 2 H), 4.09 (br s, 4 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 163.6, 161.2, 144.4, 144.3, 92.6, 92.3; HRMS calcd for C ₆ H ₇ N ₂ FCl (M + H) 161.0276, found 161.0282. [7142-134]

2,5-Diamino-l,4-xyIene

General Procedure A was followed using 2,5-dibromo-l,4-xylene (528 mg, 2.0 mmol). The product was isolated as a red oil in 66% yield (180 mg). ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.40 (s, 2 H), 3.30-3.05 (br s, 4 H), 2.10 (s, 6 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 136.6, 121.5, 117.9, 17.0; HRMS calcd for C ₈ H ₁₃ N ₂ (M + H) 137.1073, found 137.1069.

1,4-Diaminonaphthalene

General Procedure A was followed using 1,4-dibromonaphthalene (572 mg, 2.0 mmol). The product was isolated as a yellow solid in 76% yield (240 mg). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.87 (m, 2 H), 7.49 (m, 2 H), 6.68 (s, 2 H), 3.80 (br s, 4 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 134.8, 125.0, 121.7, 110.9; H RMS calcd for C ₁₀ H ₁₀ N ₂ (M + H) 158.0843, found 158.0837.

2,6-Diamino-4-isopropylanisole

General Procedure A was followed using 2,6-dibromo-4-isopropylanisole (616 mg, 2.0 mmol). The product was isolated as an orange oil in 74% yield (266 mg). ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.10 (s, 2 H), 3.84 (br s, 4 H), 3.76 (s, 3 H), 2.68 (septuplet, J = 6.9, 1 H), 1.17 (d, J = 6.9, 6 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 145.9, 139.2, 133.1, 104.9, 58.6, 33.8, 23.9; HRMS calcd for C ₁₀ H ₁₇ N ₂ O (M + H) 181.1335, found 181.1337.

2,6-Diamino-4-te/Ϋ-butylanisole

'General Procedure h was followed using 2,6-dibromo-4-te/t-butylanisole (644 mg, 2.0 mmol). The product was isolated as an orange oil in 69% yield (268 mg). ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.23 (s, 2 H), 3.75 (s, 3 H overlapping br s, 4 H), 1.24 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 148.1, 139.1, 132.7, 103.9, 58.4, 34.2, 31.3; HRMS calcd for C ₁₁ Hi ₉ N ₂ O (M + H) 195.1491, found 195.1500.

Example 2: General Procedure B.

LiHMDS (12.2 g, 73.1 mmol, 2.6 equiv.) and 90 mL toluene were added to the aryl halide (28 mmol), triphenylsilylamine (20.1 g, 73.1 mmol, 2.6 equiv.), Pd ₂ (dba) ₃ (515 mg, 0.6 mmol, 2 mol%) and 2-(dicyclohexylphosphino)biphenyl (475 mg, 1.3 mmol, 4.8 mol%) . The reaction mixture was heated to 100 ⁰ C for 17 h. The mixture was cooled to 25 ⁰ C, quenched with IN HCl (30 mL) and neutralized to pH 8-9 with 3N NaOH. The mixture was stirred for 5 min, the layers separated and the organic layer was concentrated under reduced pressure. The residue was dissolved in 100 mL MTBE and j9-toluenesulfonic acid (10.6 g, 60.0 mmol, 2.1 equiv.) was added. The precipitate was filtered and taken in 50 mL water and 100 mL MTBE. The aqueous layer was basified to pH 10 with 3N NaOH. The layers were separated and the organic layer was dried over Na ₂ SO ₄ and concentrated.

2-Methoxy-5-(l-methyl-cyclopropyl)-benzene-l,3-diamine

65%

General Procedure B was followed using l,3-dibromo-2-methoxy-5-(l- methylcyclopropyl)-benzene (9.0 g, 28.0 mmol). The product was isolated as a deep red oil in 65% yield (3.6 g) and 96% purity (by ¹ H NMR assay). ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.10 (s, 2 H), 4.08 (br s, 4 H), 3.68 (s, 3 H), 1.24 (s, 3 H), 0.69 (m, 2 H), 0.54

MHz, CDCl ₃ ): δ 144.1, 138.7, 133.4, 106.0, 58.8, 25.9, 19.5, 15.4; HRMS calcd for CnH ₁₇ N ₂ O (M + H) 193.1335, found 193.1336.

Example 3: General Procedure C

To the aryl halide (2.0 mmol), Pd ₂ (dba) ₃ (37 mg, 0.04 mmol, 2 mol%) and 2- (dicyclohexylphosphino)biphenyl (34 mg, 0.1 mmol, 4.8 mol%) were added LiHMDS (803 mg, 4.8 mmol, 2.4 equiv.) and 4 mL toluene. The reaction mixture was stirred at room temperature for 17 h. At reaction completion, the mixture was quenched with IN HCl (5 mL) and stirred at room temperature for 5 min. Then, it was basified to pH = 12 with IN NaOH and the layers were separated. The organic layer was concentrated.

5-Chlorobenzene-l,3-diamine

87%

General Procedure C was followed using 5-chloro-l,3-dibromobenzene (540 mg, 2.0 mmol). The product was isolated as a brown oil in 97% yield (299 mg, 105% mass recovery and 83% purity). ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.10 (s, 2 H), 5.87 (s, 1 H), 3.60 (br s, 4 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 148.3, 135.5, 105.9, 99.7; HRMS calcd for C ₆ H ₈ N ₂ Cl (M + H) 143.0370, found 143.0369.