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CAS No. : | 24544-04-5 | MDL No. : | MFCD00008887 |
Formula : | C12H19N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WKBALTUBRZPIPZ-UHFFFAOYSA-N |
M.W : | 177.29 | Pubchem ID : | 32484 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 60.01 |
TPSA : | 26.02 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.12 cm/s |
Log Po/w (iLOGP) : | 2.63 |
Log Po/w (XLOGP3) : | 3.18 |
Log Po/w (WLOGP) : | 3.52 |
Log Po/w (MLOGP) : | 3.33 |
Log Po/w (SILICOS-IT) : | 3.11 |
Consensus Log Po/w : | 3.16 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.15 |
Solubility : | 0.125 mg/ml ; 0.000705 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.4 |
Solubility : | 0.071 mg/ml ; 0.0004 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.68 |
Solubility : | 0.0369 mg/ml ; 0.000208 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.05 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P273-P280-P305+P351+P338-P312-P337+P313-P501 | UN#: | N/A |
Hazard Statements: | H302-H319-H412 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: With hydrogen bromide In water at 20℃; for 0.25 h; Stage #2: With sodium nitrite In diethyl ether; water at -56℃; for 1.66 h; |
181 ml of 47percent HBr solution (1.57 mol) are slowly added to 35.5 g (0.20 mol) of2,6-diiodopropylaniline at room temperature during 15 minutes. The white suspension is cooled down to -56°C and 23.6 g (0.34 mol) of sodium nitrite are added in portions during 10 minutes and stirring continued at the same temperature during one hour. 250 ml of ice-cold diethyl ether are slowly added during 10 minutes and the temperature let slowly rising to -15°C during two hours until no more gas evolved. The temperature is decreased again to -56°C and 24 ml of water are added first followed by the addition of 118.5 g (0.41mol) of sodium carbonate decahydrate giving a brown suspension. The temperature is let raising to room temperature during three hours with evolution of gas starting at -32°C. The resulting orange suspension is further stirred at room temperature during 16 hours. The water phase is separated and the organic phase three times washed with water, dried and concentrated under vacuum. Further purification is done by chromatography (silica gel,heptane) giving the title product as colorless oil (yield: 38.7 g (80percent)).1HNMR (400 MHz, CDCI3): = 1.33 (d, 12 H), 3.54-3.66 (m, 2 H), 7.19-7.23 (m, 2 H),7.30-7.35 (m, I H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 5℃; for 0.333333 h; Inert atmosphere | A solution of NBS (24.59 g, 137 mmol) in DMF (160 mL) was added slowly to a solution of 2,6-diisopropylaniline (25 g, 137 mmol) in DMF (300 mL) at 0-5°C under a nitrogen atmosphere over a period of 20 minutes. The reaction mixture was stirred at 0-5°C. After the reaction was complete, water was added and the oil suspension was stirred at rt. The aqueous layer was decanted out and the remaining oil was dissolved in ethyl acetate. The organic layer was separated, washed water and brine.Evaporation gave light brown oil (35.1 g, 100percent yield). |
99% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; for 2 h; | To a stirred solution of 2,6-diisopropylaniline (14 g, 78.97 mmol, 1.00 equiv) in N,N-dimethylformamide (200 mL) at 0° C. was added a solution of NBS (14 g, 78.65 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) dropwise in 60 min. The reaction was stirred for another hour at 0° C. then water (900 mL) was added. The resulting mixture was extracted with 300 mL of ethyl acetate. The combined organic layers was washed with 3*100 mL of saturated NH4Cl solution and 1*100 mL of water then dried over anhydrous sodium sulfate and concentrated under vacuum to give 20.05 g (99percent) of 4-bromo-2,6-diisopropylaniline as a red oil. 1H NMR (400 MHz, DMSO-d6): δ 6.95 (s, 2H), 4.77 (s, 2H), 5.47-5.39 (m, 1H), 3.04-2.98 (m, 1H), 1.13 (d, J=6.8 Hz, 12H) ppm. |
97% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 48 h; | Synthesis of 4-bromo-2,6-diisopropylaniline (0199) A three neck round bottom flask was charged with 2,6-diisopropylaniline (22.96 g, 130 mmol) and DMF (Volume: 250 ml). A solution of 1-bromopyrrolidine-2,5-dione (23.05 g, 130 mmol) in 100 ml DMF was added into reaction mixture drop wise at 0° C. After addition was over; reaction mixture was stirred for 2 days at room temperature. The reaction mixture was poured into 500 ml deionized water and extracted with 3×150 ml ether. The combined extracts were washed with 150 ml deionized water, 150 ml 10percent lithium chloride, dried over MgSO4 and evaporated to dryness. The residue was purified by vacuum distillation to yield 4-bromo-2,6-diisopropylaniline (32.3 g; 97percent). |
95% | With tetra-N-butylammonium tribromide In tetrahydrofuran at 0℃; | 40.8 g (85 mmol) of tetra-n-butylammonium tribromide are added, at 0° C. and portionwise, to a solution of 15 g (85 mmol) of 2,6-diisopropylphenyl-amine in 200 ml of tetrahydrofuran. The medium is stirred for 2 h. It is then poured into a saturated aqueous solution of sodium thiosulphate and extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over sodium sulphate. The residue is purified by silica gel chromatography (80/20 heptane/ethyl acetate). 20.6 g of 4-bromo-2,6-diisopropylphenylamine are obtained in the form of a yellow oil (yield=95percent). |
82% | With tetra-N-butylammonium tribromide In tetrahydrofuran at 20℃; | Preparative Example P16Step 1 : 4-Bromo-2,6-diisopropylaniline (PI 6a)To a solution of 2,6-diisopropylaniline (12.5 g, 70.6 mmol) in THF was added (C4H9)4NBr3 (47 g, 85 mmol) at rt and stirred overnight. Then sat. NaHS03 solution (30 mL) was added and the mixture was extracted with Et20 (3 x 250 mL). The organic layer was washed with brine, dried over Na2S04 and concentrated to give compound P16a (19 g, 82percent). |
79% | With bromine In methanol at 20℃; | A solution of 2, [6-DIISOPROPYLANILINE] (2.0 mL, 11 mmol) in methanol (80 mL) was treated dropwise with bromine (543 μL, 10.6 mmol). The solution was stirred at room temperature for 15 min. Chloroform and 0.1 N [NAOH] were added and the organic layer was dried (Na2SO4), filtered and concentrated to an orange liquid. Kugelrohr distillation [(110 °C COMMAT; ] 0.06 Torr) afforded a colorless liquid (2.22 g 79percent): 1H NMR (400 MHz) 8 1.25 (d, J= 6.4 Hz, 12H), 2. 88 (m, 2H), 3.70 (brs, 2H), 7.11 (s, 2H) [; 13C NMR 8] 22.1, 27.9, 111.0, 125.6, 134.5, 139.3 ; Anal calcd for [C12HIGBRN] : C, 56.26 ; H, 7. 08 ; Br, 31.19 ; Found, C, 56.24 ; H, 7.07 ; Br, 30.98 |
72% | With bromine In methanol; dichloromethane at 20℃; for 24 h; | A solution of Br2(2.1 ml, 41.0 mmol, 1.05 eq.) in CH2Cl2/MeOH (100 ml, 1:1 v/v)was added to a stirring solution of 2,6-diisopropylaniline (7.4 ml,39.0 mmol, 1.0 eq.) in CH2Cl2/MeOH (200 ml, 1:1 v/v) at r.t. over2 h. The orange-red solution was stirred for 1 day. The solvents were evaporated and the resultant pink solid was washed with PE and further recristallized from CH2Cl2/PE to give the title compound as light orange-red solid (7.8 g, 28.1 mmol, 72percent).1H-NMR (300 MHz,CDCl3) [ppm]: 10.08 (s, 2H), 7.36 (s, 2H), 3.80–3.62 (m, 2H), 1.29(d, J = 6.7 Hz, 12H). The analytical data are in accordance with theliterature. |
42% | With potassium hydroxide; bromine In water; acetic acid | 4-Bromo-2,6-diisopropylaniline To a solution of 80.0 g (0.452 mol) of 2,6-diisopropylaniline in 2000 cm3 of glacial acetic acid, 23.3 ml (72.3 g, 0.452 mol) of bromine were added dropwise, while vigorously stirring, over 20 minutes. This mixture was stirred additionally for 2 hours at 40° C. The white precipitate that formed was filtered off, washed with 100 ml of acetic acid, and dried in air. The resulting white solid was added to a solution of 150 g of potassium hydroxide in 600 ml of water. This mixture was stirred for 30 minutes. The product was extracted with 3*100 ml of methyl-tert-butyl ether. The combined organic fractions were washed with Na2SO4 and evaporated to dryness. Fractional distillation gave a yellowish oil, b.p. 112-115° C./1 mm Hg. Yield 48.8 g (42percent). Anal. calc. for Cl2H18BrN: C, 56.26; H, 7.08. Found: C, 56.11; H, 7.13. 1H NMR (CDCl3): δ 7.10 (s, 2H, 3,5-H), 3.69 (br.s, 2H, NH2), 2.86 (sept, J=6.8 Hz, 2H, CHMe2), 1.23 (d, J=6.8 Hz, 12H, CHMe2). 13C{1H}NMR (CDCl3): δ 139.3, 134.5, 125.6, 111.0, 27.9, 22.1. |
540 g | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 18 h; | Apparatus set-up:A 10 L 3-necked round-bottomed flask, equipped with a mechanical overhead stirrer, nitrogen inlet and exhaust.Experimental Procedure:1. 2, 6-Diisopropyl aniline (500 g, 2.8202 mol) was dissolved in dry N, N-dimethyl formamide.It was cooled to 0 °C using an ice bath.2. N-Bromosuccinimide (501.9 g, 2.8202 mol) was added slowly portion wise.3. The reaction mixture was stirred at the room temperature for 18 h.4. After 18 h, TLC showed complete conversion of starting material.5. To the mixture, 10percent NaHCO3 solution (4 L) was added and extracted with ethyl acetate (3 x2L).6. The combined organic phase was washed with water (1 L), brine (1 L), dried over sodium sulphate and concentrated.7. The crude product was purified by silica column chromatography using 8 percent ethyl acetate in hexane as an eluent to get 540 g with 95.75 percent HPLC purity. 1H-NMR (300 MHz, CDCl3): δ[ppm] 1.26 (d, J = 6.78 Hz, 12H), 2.84 - 2.93 (m, 2H), 3.72 (br, s, 2H), 7.12 (s, 2H). |