2-(2-BOC-AMINOETHOXY)ETHANOL

PROTAC Linker 11 is a PROTAC linker, which refers to the alkyl/ether composition. PROTAC Linker 11 can be used in the synthesis of a series of PROTACs. PROTACs contain two different ligands connected by a linker; one is a ligand for an E3 ubiquitin ligase and the other is for the target protein. PROTACs exploit the intracellular ubiquitin-proteasome system to selectively degrade target proteins[1].

Preparation of compound 100: To a solution of 2-(2-aminoethoxy)ethanol (2.10 g, 20 mmol) in CHA solution ofBoc20 (6.35 g, 30 mmol, 1.0 equiv.) in dichloromethane(35 mL) was added dropwise to a solution of2-(2-aminoethoxy)-ethanol (3.0 mL, 30mmol, 1.0 equiv.) in dichloromethane (20 mL) at 0 °C. The reaction mixture was5 stirred at 0 oc for 30 min and at room temperature overnight. The reaction mixturewas washed with water and the aqueous layer was extracted with dichloromethane (3x 50 mL ). The combined extracts were washed with brine, dried over N a2S04, filtered, and concentrated under vacuum. The product (5.92 g, 99 percent) was isolated inhigh purity and was used without any further purification. 1H NMR (400MHz, 10 CDCh) 8 5.29 (s, 1H), 3.71 - 3.63 (m, 2H), 3.53- 3.44 (m, 4H), 3.30-3.22 (m, 2H), 3.22-3.13 (m, 1H), 1.38 (s, 1H). 13C NMR (100 MHz, CDCh) 8 156.2, 79.3, 72.3, 70.3, 61.6, 40.4, 28.4. LRMS (ESI): [M+Nat 228.3.A solution of BocStep 1: Synthesis of tert-butyl N-[2-(2-hydroxyethoxy)ethyl] carbamate (AR)[0549] To a stirred solution of 2-(2-aminoethoxy)ethan-l-ol (AQ, 5.25 g, 49.94 mmol) in tetrahydrofuran (100 mL) was added aqueous solution of sodium bicarbonate (20percent (w/w), 40 ml) and (Boc)To a stirred solution of 2-(2-aminoethoxy)ethan-1-ol (AQ, 5.25 g, 49.94 mmol) in tetrahydrofuran (100 mL) was added aqueous solution of sodium bicarbonate (20percent (w/w), 40 ml) and (Boc)Step 1: ferf-butyl 2-(2-hydroxyethoxy)ethylcarbamate (JS136)To a solution of 2-(2-aminoethoxy)ethanol (2 ml, 19.9 mmol) in CHCIA solution of 2.62 g (12 mmol) of di-tert-butyl dicarbonate in 10 ml of ethanol was gently added to a stirred solution of 1.05 g (10 mmol) of 2-(2-aminoethoxy)ethanol in 10 ml of ethanol. To 2-(2-aminoethoxy)ethanol (1.05 g, 10.0 mmol) in chloroform (10 mL) was added di-tertbutyldicarbonate (2.19 g, 10 mmol) portionwise at 0 °C. The reaction mixture was left to stirvigorously at room temperature for 1.5 h. Water (30 mL) was added and the two phaseswhere separated. The organic phase was collected and the aqueous phase was extractedfurther with chloroform (2 × 30 mL). The organic phases were combined, dried overanhydrous MgSO4, filtered under gravity and the organic solvent removed in vacuo to givecompound 2 as a pale yellow oil (1.93 g, 9.40 mmol, 94percent).2—(2—aminoethoxy)ethanol (5 g, 47.56 mmol, 1.00 equiv) was dissolved in THF(100 mL) at 0°C and sodium hydroxide (2 g, 50.00 mmol, 1.05 equiv) was then added (solution in 25 mL of water). A solution of di—tert—butyl dicarbonate (10.38 g, 47.56 mmol, 1.00 equiv) in THF (20 mL) was added drop—wise and the reaction was then left under agitation overnight at ambient temperature. The reaction was diluted by adding 50 mL of water and the product was extracted with 3 times 75 mL of AcOEt. The organicphases were combined, washed once with 100 mL of NaC1 (sat.), then dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 9 g (92 percent) of compound 35A in the form of a yellow oil.2—(2—aminoethoxy)ethanol (5 g, 47.56 mmol, 1.00 equiv) was dissolved in THF(100 mL) at 0°C and sodium hydroxide (2 g, 50.00 mmol, 1.05 equiv) was then added (solution in 25 mL of water). A solution of di—tert—butyl dicarbonate (10.38 g, 47.56 mmol, 1.00 equiv) in THF (20 mL) was added drop—wise and the reaction was then left under agitation overnight at ambient temperature. The reaction was diluted by adding 50 mL of water and the product was extracted with 3 times 75 mL of AcOEt. The organicphases were combined, washed once with 100 mL of NaC1 (sat.), then dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 9 g (92 percent) of compound 35A in the form of a yellow oil.Compound 35A: tert-butyl (2-(2-hydroxyethoxy)ethyl)carbamate O 2-(N-tert-Butoxycarbonyl-2-aminoethoxy)-ethanol 2-(2-Aminoethoxy)-ethanol (1.0 g, 9.511 mmol) was dissolved in methanol (10 ml). To this solution, di-tert-butyl carbonate (2.07 g, 9.485 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was confirmed by TLC to be complete, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:acetone=3:2) to obtain 2-(N-tert-butoxycarbonyl-2-aminoethoxy)-ethanol (1.78 g, yield: 91)General procedure: To a solution of 2a (or 2b–e, 20 mmol) in a mixture of dioxane (15 mL) and H2O (7 mL), wasadded 5N NaOH (4.8 mL) and a solution of Boc2O (5.0 g, 23 mmol) in dioxane at 0 °C. After stirred atrt overnight, the reaction mixture was concentrated in vacuo. The residue was extracted from 10percentcitric acid with AcOEt, and dried over anhydrous Na2SO4. Evaporation of the solvents gave the pureproduct 3a–e. 3a was obtained as a colorless oil (2.67 g, 83percent).Will be 2.1g molecules 1 (20 mmol), 2- (2-aminoethoxy) ethanol) was dissolved in 50 ml of ethanol, Cooling to 0 degrees, 4.36 g of di-tert-butyl dicarbonate was added and reacted at room temperature for 5 hours, Ethanol was removed, 20 ml of dichloromethane and 20 ml of water were added Dichloromethane extraction twice, The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, dried and passed through a silica gel columnThe molecule 2 was obtained in a yield of 90percent2-(2-Aminoethoxy)-1-ethanol (5, 2.0 g, 19 mmol), BocThe first step weighed diethylene glycol amine (105.1g, 1.0mol) in 1L water, Add 100 ml of tetrahydrofuran, under stirring conditions, Slowly dropwise di-tert-butyl dicarbonate(196.2 g, 0.9 mol), After 8 hours of reaction, TLC determines the reaction is complete (unfoldedPetroleum ether: ethyl acetate = 1: 1)Extracted with ethyl acetate extraction twice, Drying the ethyl acetate layer, After recovering under reduced pressure, Boc-DEG170.8g (yield: 85percent) was obtained.Amine 63 (1.0 mL, 10 mmol) was dissolved in DCM (50 mL). The solution was cooled to 0°C and di-tert-butyl dicarbonate (BocAdd a magnet to a 1L round bottom flask.Add (9.542 ml, 95.1113 mmol), Dichloromethane 150ml dissolved, Triethylamine (26.5133 ml, 190.2226 mmol) was added, Boc anhydride was added under stirring (24.9096 g, 114.1335mmol). After the reaction was completed, the reaction solution was transferred to a rotary evaporator and concentrated. Methanol was added to dissolve the mixture. Under stirring, sodium bicarbonate powder (13 g) was added to neutralize triethylamine, suction filtered, and silica gel powder was added as a solid solution. Dry method, Column chromatography eluting with a gradient of 10percent ethyl acetate/petroleum ether to 50percent ethyl acetate/petroleum ether, gradient elution with 3percent methanol/ethyl acetate to 6percent methanol/ethyl acetate.The product was collected and evaporated to give 16.3341 g of compound in a yield of 83.77percent.Add a magnet to a 1L round bottom flask.H2NCH2CH2OCH2CH2OH (9.542 ml, 95.1113 mmol) was added, Dichloromethane (150 ml) was added to dissolve and triethylamine (26.5133 ml, 190.2226 mmol) was added.Boc anhydride (24.9096 g, 114.1335 mmol) was added with stirring. The reaction is over, The reaction solution was transferred to a rotary evaporator and concentrated, dissolved in methanol, Under stirring, sodium bicarbonate powder (13g) was added to neutralize triethylamine, and suction filtration was performed.Add silica gel powder as a solid solution. Dry method, Column chromatography eluting with a gradient of 10percent ethyl acetate/petroleum ether to 50percent ethyl acetate/petroleum ether3percent methanol/ethyl acetate to 6percent methanol/ethyl acetate gradient. Collect products, Evaporation to give compound 16.3431 g, yield 83.77percent.2- (2-aminoethoxy) ethanol 1 (16.0 g, 152 mmol) was dissolved in dry dichloromethane (120 mL) and Boc 2 O (33.2 g, 150 mmol) was added thereto.After stirring the reaction mixture at room temperature for 3 hours, the solvent was distilled off under reduced pressure.The crude product was purified by silica gel column chromatography to obtain Compound 2 (25.6 g) as a colorless oil. Yield 82percent.compound C (10.0 g, 0.095 mol) was dissolved in 50 mL of methylene chloride and triethylamine (11.55 g, 0.114 mol) was added to it. The solution was cooled in an ice-bath and di-tert-butylcarbonate (22.83 g, 0.105 mol) in 30 mL of methylene chloride was added through an additional funnel. The reaction was slowly warmed up to room temperature and stirred at room temperature overnight. The reaction was extracted with water and the organic phase was washed with diluted HCl solution and dried over magnesium sulfate. Solvent was evaporated and the crude product was purified by column to give 12.43 g of pure product as an oil, 64percent yield. Step 1 To an ice-cold solution of 2-(2-aminoethoxyethanol) (10 g, 95.23 mmol) indichloromethane (500 mL) was added triethylamine (19.23 g, 190.47 mmol), followed by Boc-anhydride (22.62 g, 104.76 mmol) dropwise over fifteen minutes at 0 °C. The reaction mixture was allowed to warm to rt and stirred for 18 h while monitoring by TLC.The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (400 mL) and washed with saturated ammonium chloride solution (2 x 250 mL).The organic layer was dried over anhydrous sodium sulphate and concentrated to give tert-butyl (2-(2-hydroxy)ethoxy)ethylcarbamate (10.9 g, 55.8percent) as a colorless liquid. 1HNMR (400 MHz, DMSO-i/6) δ ppm 6.76 (1H, s), 4.56 (1H, t, J=5.2 Hz), 3.50-3.46 (2H, m), 3.41-3.36 (4H, m), 3.10-3.05 (2H, m), 1.38 (9H, s).Synthesis of Boc-2-(2-aminoethoxy)ethanol 2-(2-aminoethoxy)ethanol (5.0 g, 48 mmol) was dissolved in tetrahydrofuran (THF, 50 mL). To the mixture, 2N sodium hydroxide (24 mL) was added and the entire solution was cooled in an ice bath. Di-tert-butyl dicarbonate (10 g, 48 mmol) was dissolved in THF (50 mL) and it was added to the mixture dropwise over lh in an ice bath. The reaction was brought to room temperature and stirred for 2.5 days. THF was removed under vacuum. The aqueous solution was adjusted to pH 3 with concentrated sulfuric acid. It was then extracted with ethyl acetate (EtOAc, 75 mL) twice. The organic layer was washed with water (25 mL) twice and brine (25 mL) once. It was then dried over magnesium sulfate (MgS0Step 1: (0540) To a mixture of 2-(2-aminoethoxy)ethanol (99.52 g) and ethyl acetate (200 mL) was dropwise added a mixture of di-tert-butyl dicarbonate (208.57 g) and ethyl acetate (50 mL) under ice-cooling. After stirring at room temperature for 60 hrs., the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL), washed with water (200 mL), 1N hydrochloric acid (200 mL), water (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave tert-butyl [2-(2-hydroxyethoxy)ethyl]carbamate (169.2 g) as a colorless oil. (0541) a) Preparation of Compound 45A (0376) To a stirred solution of 2-(2-aminoethoxy)ethanol (1 g, 943 μL, 9.5 mmol), TEA (1.44 g, 1.99 mL, 14.3 mmol) in acetone (10 mL) was added (Boc)To a 500mL three-necked flask were added compound BG04 3.7g (1. 0eq), (Boc)2-(2-Aminoethoxy)ethanol (10.5 g, 0.1 mol) and NaHCO

Molecular Weight:205.25
XLogP3:0.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:7
Exact Mass:205.13140809
Monoisotopic Mass:205.13140809
Topological Polar Surface Area:67.8
Heavy Atom Count:14
Complexity:165
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes