N-BOC-M-PHENYLENEDIAMINE

To a solution of tert-butyl (3-nitrophenyl) carbamate (10.75 g, 45.12 mmol) in MeOH(150 mL) was added catalyst 10percent Pd/C (0.48 g). The reaction mixture was stirred at rt underH2 overnight, and filtered. The filtrate was concentrated in vacuo. The residue was purifiedby a silica gel column chromatography (PE / EtOAc (V / V) = 4 : 1) to give the titlecompound as a pale yellow solid (7.59 g, 8 1percent).To a solution of tert-butyl (3-nitrophenyl)carbamate (10.75 g, 45.12 mmol) in MeOH (150 mL) was added catalyst 10percent Pd/C (0.48 g). In a 100 mL round-bottomed flask, 5-nitro-t-butoxycarbonylaniline (10.75 g, 45.12 mmol) was dissolved in methanol (150 mL), 10percent palladium on carbon (0.48 g) was added, and the reaction was stirred at room temperature under hydrogen overnight.The reaction is completed, filtered, and the filtrate is evaporated under reduced pressure to remove the solvent.The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) = 4/1) to give a pale yellow solid (7.59 g, 81percent).To a solution of 1, 3-phenylenediamine (9) (5 g, 46 mmol, 4equiv.), in DCM (30 mL) on ice, was added a solution of Boc2O (2.4 mL, 11.5 mmol, 1 equiv.) in DCM (10 mL) dropwise. The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by column chromatography using silica gel as stationary phase (elution system - EA/Hexane 4: 6) to give the desired product as a light pink solid (2.7 g, 99percent). Rf 0.26 (EA/Hexane 2: 3); 1H NMR (400 MHz, CDCl3) d 7.03(t, J 8.0 Hz, 1H), 6.97 (s, 1H), 6.54 (ddd, J 8.0, 2.0, 0.8 Hz, 1H), 6.40(s, 1H), 6.36 (ddd, J 7.9, 2.2, 0.8 Hz, 1H), 1.51 (s, 9H); MS (ESI) 209.1[MH].To a suspension of 1, 3-phenylenediamine (8.2 g; 75.4 mmol) in methylene chloride (21 mL) at room temperature was added dropwise over one hour a solution of di-tert-butyldicarbonate (2.7 g, 12.6 mmol) in methylene chloride (130 mL). The solution was then stirred overnight at room temperature. After 18 h reaction, the solution was evaporated to dryness under reduced pressure. The residual oil was dissolved in ethyl acetate (50 mL) and washed with 2N sodium carbonate (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and evaporated to dryness. The crude residue was purified on a BIOTAGE.(TM). 4OS column (silica, hexane/AcOEt 95:5 to 1:1) to yield ./V-l-tert-butyloxycarbonyl-l, 3-phenylene- diamine as a white solid (2.4 g, 93percent). This compound (40 mg, 0.2 mmol) and diisopropylethylamine (50 μL, 0.3 mmol) were added to a solution of 6-chloro-N-9- alkylated purine (35 mg, 0.1 mmol) in n-butanol (2.0 mL) at room temperature. After 48 h reaction at 90tert-butyl 3-aminophenvlcarbamate (P); To a solution of D (3.24 g, 30.0 mmol) in THF(20 mL), Boc20 (2.18 g, 10.0 mmol) was added under N2. The reaction mixture was stirred at room temperature for 24 h. MTBE (50 mL) was added to dilute, then the mixture was washed with water (20 mL x 3). Organic layer was combined and dried with Na2S04, filtered, and evaporated to dryness. The residue was purified using column chromatography (silica gel, 1:1 hexane/EtOAc). The fractions containing product were evaporated to dryness under vacuum to yield compound P as a white solid (1.92 g, 9.2 mmol, 92percent). Example 33; (3-Aminophenyl)carbamic acid tert-butyl ester (45). A solution of di-tert-butyl-dicarbonate (2 g, 9.16 mmol, 1 equiv.) in dioxane (25 mL) was added over a period of 30 min to a solution of 1, 3-phenylenediamine (2 g, 18.5 mmol, 2 equiv.) in dioxane (25 mL). The mixture was allowed to stir for 22 h, and the solvent was removed using a rotary evaporator. The residue was purified by flash column chromatography on silica gel (EtOAc:hexane=2:1) to afford 1.7 g of product (89percent based on dicarbonate) as a peach color solid: Compound 6 was obtained by the following procedure. In Methanol (240 mL), m-phenylenediamine (7.81 g, 72.2 mmol) was dissolved. To the mixture, di-t-butoxycarbonate (16.5 mL, 71.8 mmol) and triethylamine (10 mL, 71.5 mmol) were added. The mixture was stirred for 30 minutes at 0°C in a shade under argon atmosphere and then stirred overnight at room temperature to obtain an m-phenylenediamine reaction solution. The m-phenylenediamine reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by medium-pressure silica gel chromatography (500 g, chloroform:methanol=10:1 to 7:1) to obtain a yellowish white crystal serving as Compound 6. Compound 6 was obtained at the yield of 13.3 g (88percent). Also, a 1H NMR (400 MHz, CDCl3) was conducted on Compound 6 so obtained to find that δ7.03 (1H, dd , J=7.8, 8.1 Hz, aromatic H, δ6.54 (1H, d, J=8.1 Hz, aromatic H), δ6.36 (1H, t, J=7.8 Hz, aromatic H), δ3.67 (2H, s, NH2), δ1.51 (9H, m, CH3.x.3 of BOC). An ESI-MS (positive) was conducted to find that the m/z was 209.1 [(M+H)+].Preparation 9. (3- (l-Methylpiperidin-4-ylamino) phenyl) carbamic acid tert-butyl ester; Add a solution of di-tert-butyl dicarbonate (5.04 g, 23.11 mmol) in chloroform (100 mL + 100 mL rinse) to a solution of 1, 3-phenylenediamine (5.0 g, 46.23 mmol) in chloroform (100 mL). Stir at room temperature overnight. Wash with sodium hydroxide (IN aq. , 200 mL) and separate the organic layer. Purify through flash chromatography (ethylacetate/hexanes 1/4 to 1/1) to provide (3-amino-phenyl) -carbamic acid tert-butyl ester (4.17 g, 87percent). Combine (3-aminophenyl) carbamic acid tert-butyl ester (0. 156 g, 0. 756 mmol), 1- methylpiperidin-4-one (0.093 mL, 0.756 mmol), sodium triacetoxyborohydride (208 mg, 0.982 mmol), acetic acid (0.043 mL, 0.756 mmol) and dichloromethane (8 mL). Stir at room temperature overnight. Dilute with dichloromethane (5 mL) and wash twice with sodium hydroxide (10 mL 1N aq. ). Combine the organic layers and wash with saturated aqueous NaCl (10 mL). Dry over magnesium sulfate, filter under reduced pressure and concentrate to dryness. Purify by flash chromatography on a Biotage silica cartridge eluting with a 20/1 mixture of dichloromethane and 2N ammonia in methanol to give the free base of the title compound. Dissolve the residue in diethyl ether and treat with ethereal hydrogen chloride. Triturate the resulting gum with ether to give the title compound as a white solid: mp 124-5°C ; mass spectrum (ion spray): m/z = 306.2 (M+1), H NMR (CDC13) : 7.06 (t, J= 8.0 Hz, 1H), 6.86 (bs, 1H), 6.51-6. 48 (m, 1H), 6.42 (bs, 1H), 6.30-6. 27 (m, 1H), 3.60 (bs, 1H), 3.30 (bs, 1H), 2.80 (bd, J= 11. 8 Hz, 2H), 2.31 (s, 3H), 2.19-2. 02 (m, 4H), 1.89 (bs, 2H), 1.52 (s, 9 H).tert-butyl 3-aminophenylcarbamateH2NNH2 Boc2O, DCM H2NNAOThe preparation of Compound 11 was carried out as follows. Firstly, m-phenylenediamine (0.50g, 4.62mmol) was dissolved in methanol (35mL). Then, (Boc)m-phenylenediamine (0.500g, 4.62mmol), (Boc)2O (0.92mL, 4.02mmol) and triethylamine (1.4 mL, 9.98 mmol)were added to a mixed solvent system of 1, 4-dioxane and water (30 mL, 2:1 V/V) that has been cooled to 0°C. Afterstirring for 1 hour at 0°C, the reaction system was recovered to room temperature and stirred for another 10 hours. Thereaction solution was concentrated under reduced pressure to yield yellow oil, which was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and then with saturated brine. The final organic phase was driedwith magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified with silica gelcolumn chromatography (n-hexane: ethyl acetate = 10:1 ∼ 8:1 ∼ 4:1 ∼ 2:1 ∼ 1:1) to give Compound 2 (0.48 g, yield: 58percent)as a white solid.Step 1: m-phenylenediamine (0.500 g, 4.62 mmol), (Boc)(BOCfeO (KTo a mixture of compound 24-1 (10 g, 92.59 mmol) in MeOH which was cooled down to −10° C., was added slowly BocA. To a mixture of benzene-1, 3-diamine (1.0 g, 18.5 mmol) in DCM (25 mL) was added BOC anhydride (3.2 ml, 27.8 mmol) and the mixture was stirred for 15 h at an ambient temperature. The mixture was concentration in vacuo and the mono-carbamate was separated from the mixture via radial chromatography (4 mm plate, 10percent ethyl acetate/hexanes to 33percent ethyl acetate/hexanes gradient elution) to give 219 mg (11percent) of (3-amino-phenyl)-carbamic acid tert-butyl ester as a white solid:

Molecular Weight:208.26
XLogP3:1.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:208.121177757
Monoisotopic Mass:208.121177757
Topological Polar Surface Area:64.4
Heavy Atom Count:15
Complexity:223
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes