tert-Butyl 3-(methylamino)propylcarbamate

Preparation 20 (12 g, 0.037 mol) was hydrogenated 45 min in 100 ml of MeOH in the presence of 0.5 g of 5percent Pd/C at 60 PSI of hydrogen. The catalyst was filtered off and the solvent was removed under reduced pressure to yield the depicted product as a colorless oil (6 g, 65percent).(3-Bromo-propyl)-carbamic acid tert-butyl ester (11.2 g, 47.0 mmol) was combined with 2.0 M Methylamine in THF (100 mL, 200 mmol) and was stirred at room temperature for 4 h. After this period, a precipitate formed in the solution. The solution was filtered and concentrated under reduced pressure to yield 7.58 g (86percent) of (3-methylamino-propyl)-carbamic acid tert-butyl ester as a clear oil. [M+H]Step 1 Synthesis of fert-Butyl (3-(methylamino)propyl)carbamate. A mixture of potassium hydroxide powder (20 molpercent, 168 mg, 3 mmol), di(lH-imidazol-l-yl)methanone (2.43 g, 15 mmol, ), and tert-butyl alcohol (15 mmol, 1.112 g) in dry toluene (76 mL) was heated at 60 °C (oil bath) with stirring for 3 hours under argon atmosphere. Then N- methyl-l, 3-diaminopropane (15 mmol, 1.322 g, 1.566 mL) was added dropwise. The resulting mixture was heated at 60 °C for another 3 hours. After allowing the reaction mixture to cool to room temperature, water was added to the mixture. Two layers were separated and the organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness, affording slightly yellow oil (0.966 g). The aqueous phase was extracted with dichloromethane (3 To a solution of N-methyl-1, 3-propanediamine 7 (5.00 g, 56.7 mmol, 1.0 eq.) in anhydrous THF (40 mL), triethylamine (15.8 mL, 113 mmol, 2.0 eq.) was added under Ar atmosphere at room temperature. tert-Butyl (3-(methylami no)propyl)carbamate A solution of N-methyl-i , 3-propanediamine (6 g, 67.9 mmol) in THF (50 mL) was cooled to 0 °C, and a solution of di-tert-butyl dicarbonate (4.6 mL, 20.3 mmol) in THF (50 mL) was added dropwise. The reaction mixture was allowed to come to room temperature, further stirred for 18 h, and concentrated under reduced pressure. Thecrude product was purified by flash column chromatography (silica gel 230-400 mesh, eluent 10percent MeOH in CHCI3 to get the undesired regioisomer tert-butyl (3- aminopropyl)(methyl)carbamate, followed by 15percent MeOH in CHCI3 to get the desired product) to afford tert-butyl (3-(methylamino)propyl)carbamate (1 g, yield 8percent) as a viscous light-yellow liquid. 1H NMR (400MHz, CDCI3) 65.06 (br s, 1H), 3.22—3.20 (m, 2H), 2.682.65 (t, J = 6.7 Hz, 2H), 2.44 (s, 3H), 2.23 (br s, 1 H), 1.72 — 1.66 (m, 2H), 1.45 (s, 9H). MS (ESI) m/z: Calculated for C9H20N202: 188.15; found: 189.2 (M-f-H).Synthesis of fert-Butyl (3-(methylamino)propyl)carbamate. A mixture of potassium hydroxide powder (20 mol%, 168 mg, 3 mmol), di(lH-imidazol-l-yl)methanone (2.43 g, 15 mmol, ), and tert-butyl alcohol (15 mmol, 1.112 g) in dry toluene (76 mL) was heated at 60 C (oil bath) with stirring for 3 hours under argon atmosphere. Then N- methyl-l, 3-diaminopropane (15 mmol, 1.322 g, 1.566 mL) was added dropwise. The resulting mixture was heated at 60 C for another 3 hours. After allowing the reaction mixture to cool to room temperature, water was added to the mixture. Two layers were separated and the organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness, affording slightly yellow oil (0.966 g). The aqueous phase was extracted with dichloromethane (3 chi 30 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to afford slightly yellow oil (0.941 g). The two fractions were combined to afford 1.9 g of desired product (10 mmol, 67%). The product was used in the next synthetic step without further purification.Synthesis of fert-Butyl (3-(methylamino)propyl)carbamate. A mixture of potassium hydroxide powder (20 mol%, 168 mg, 3 mmol), di(lH-imidazol-l-yl)methanone (2.43 g, 15 mmol, ), and tert-butyl alcohol (15 mmol, 1.112 g) in dry toluene (76 mL) was heated at 60 C (oil bath) with stirring for 3 hours under argon atmosphere. Then N- methyl-l, 3-diaminopropane (15 mmol, 1.322 g, 1.566 mL) was added dropwise. The resulting mixture was heated at 60 C for another 3 hours. After allowing the reaction mixture to cool to room temperature, water was added to the mixture. Two layers were separated and the organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness, affording slightly yellow oil (0.966 g). The aqueous phase was extracted with dichloromethane (3 chi 30 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to afford slightly yellow oil (0.941 g). The two fractions were combined to afford 1.9 g of desired product (10 mmol, 67%). The product was used in the next synthetic step without further purification.Compound 5a (376 mg, 2 mmol) was dissolved in THF (10 mL), and was added ethyl 2-bromoacetate (167 mg, 2 mmol) and Et3N (303 mg, 6 mmol) at 0 C. The reaction was warmed to room temperature, and stirred for 16 hours. Water (50 mL) was added to the reaction, and extracted with CH2Cl2 (50 mL x 3), the combined organic phase was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, the residue was purified via column chromatography (CH2Cl2/MeOH=10/1) to afford 5b (520 mg, yield 94%). MS 275.2 [M + H]+.A solution of acetyl chloride (3.25 mmol, 255 mg) in DCM (10 mL) was added to a solution of 4-1 (2.50 mmol, 470 mg) and triethylamine (1.74 mL) and DMAP (10 mg) in DCM (15 mL) at RT in 5 min. After 4 hours, MeOH (1 mL) was added to the mixture. The resulting mixture was stirred for another 1 h. The mixture was concentrated. The residue was in DCM (ca 10 mL) filtered through a pad of silica gel. The pad was washed with a mixture of DCM and methanol (100:0 to 95:5). The washing was concentrated to give the crude product (yellow solid) which was used in the following step without further purification.A mixture of KOH powder (168 mg), CDI (2.43 g, 15 mmol, ), and t- butyl alcohol (15 mmol, 1.112 g) in dry toluene (76 mL), was heated at 60 C with stirring for 3 h under argon atmosphere; then N-methyl-l, 3-diaminopropane (15 mmol, 1.322 g) was added dropwise and the resulting mixture was further heated at 60 C for 3 h. After cooling to room temperature (overnight), water was added to the mixture. The two layers were separated. The toluene phase was washed with brine, dried over sodium sulfate and concentrated to dryness, affording a slightly yellow oil (0.966 g, the desired product). The aqueous phase was extracted with DCM (4chi30 mL). The combined organic extracts were dried over Na2S04, filtered, and evaporated (slightly yellow oil, 0.941 g, slightly less pure than the oil obtained from toluene extraction). The total amount of the product obtained was 1.9 g, 10 mmol, 67%. The product was used in the following step without further purification.

Molecular Weight:188.27
XLogP3:0.9
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:6
Exact Mass:188.152477885
Monoisotopic Mass:188.152477885
Topological Polar Surface Area:50.4
Heavy Atom Count:13
Complexity:152
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes