| 89% |
In dichloromethane at 20℃; |
|
| 89% |
In dichloromethane at 4 - 20℃; Inert atmosphere; |
|
| 88% |
In dichloromethane at 0 - 20℃; |
|
| 82% |
In dichloromethane at 0 - 20℃; for 0.5h; |
|
| 81% |
In tetrahydrofuran Ambient temperature; |
|
| 81% |
In dichloromethane at 0 - 20℃; |
N-tert-butyloxycarbonyl-N-methyl-N'-methyl-ethylenediamine (2)
N, N'-Dimethylethylenediamine (5.00g, 57mmol) was dissolved in CH2Cl2 (25mL) and cooled to 0°C. Di-tert-butyl dicarbonate (5.00g, 22mmol) was dissolved in CH2Cl2 (25mL) and added dropwise to the reaction flask at 0°C, and then warmed to room temperature and stirred overnight. The reaction solution was quenched with H2O (20mL), and extracted with CH2Cl2 (40mL x 2), and the combined organic layers dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using CH3OH/CH2Cl2 (1/20, V/V) as eluent to give 2 as colorless oil (4.37g, 81%), 1H NMR (400MHz, CDCl3) δ 3.39-3.36 (m, 2H, CH2), 2.95-2.90 (s, 3H, CH3), 2.76 (m, 2H, CH2), 2.48 (s, 3H, CH3), 1.48 (s, 9H, (CH3)3); HRMS (ESI) m/z [M+H]+ Calcd for C9H21N2O2+: 189.1603. Found: 189.1601. |
| 80% |
In dichloromethane |
|
| 80% |
In dichloromethane at 0 - 20℃; Inert atmosphere; |
II.1 tert-butyl methyl(2-(methylamino)ethyl)carbamate (3)
To a solution of N,N’-dimethylethylenediamine (2) (445 µL, 4.14 mmol) in DCM (7 mL) under argon, Boc2O (295 mg, 1.35 mmol) in CH2Cl2 (10 mL) was added dropwise over 30 min at 0°C. After addition, the reaction mixture was stirred at room temperature overnight. Then, solvent was evaporated under reduced pressure. The crude product was purified by purified by flash column chromatography on silica gel (CH2Cl2/MeOH,7N NH3, 97:3). The yield is given after chromatographic purification. Orange oil with 204 mg , 80% yield. RMN 1H : (400 MHz, DMSO-d6) : δ 3.18 (t, 2H, J = 6.7Hz, H5) ; 2.77 (s, 3H, H8) ; 2.55 (t, 2H, J = 6.6Hz, H6) ; 2.26 (s, 2H, H9) ; 1.38 (s, 9H, H3). LRMS (ESI, CV =20): 189.20 for [C9H21N2O2]+(100). Spectral data are in accordance with previous literature (Dal Corso et al., 2020) |
| 74% |
In dichloromethane at 0 - 20℃; Inert atmosphere; |
|
| 74% |
In dichloromethane at 20℃; for 16h; |
53
To a stirred solution of Λ/,Λ/'-dimethylethylene diamine (3.66 mL, 34 mmol) in dichloromethane (40 mL) at 0°C was added dropwise a solution of di-tert-butyl dicarbonate (2.4 g, 11 mmol) in dichloromethane (20 mL) and allowed to warm to room temperature overnight, concentrated under reduced pressure, diluted with EtOAc (100 mL), washed with water (2 * 100 mL), brine (100 mL), dried and concentrated under reduced pressure to give the title product 91 as a colourless oil (1.54 g, 74% yield). 1H NMR (400 MHz, CDCI3) δ 3.26 (t, J = 6.15 Hz, 2H), 2.81 (s, 3H), 2.66 (t, J = 6.57 Hz, 2H), 2.38 (s, 3H), 9.28 (s, 9H) ppm. |
| 72% |
In tetrahydrofuran at 0℃; for 6h; |
|
| 70% |
In dichloromethane |
|
| 62% |
In dichloromethane at 5 - 20℃; for 24h; |
|
| 61% |
In dichloromethane at 20℃; for 24h; |
71
Example 71Synthesis of tert-butyl methyl [2-(methylamino)ethyl]carbamate (VI-I) A solution of di-tert-butyl dicarbonate (2.18 g, 0.01 mol) in CH2Cl2 (120 mL) was added dropwise to a solution of N,N'-Dimethyl-ethane-1,2-diamine (1.76 g, 0.02 mol) in CH2Cl2 (40 mL) over 6 h with vigorous stirring. The reaction mixture was continued to stir for a further 18 h at room temperature. Then the solvent was concentrated in vacuo to give an oily residue, which was dissolved in 60 mL of 2M Na2CO3 aqueous solution, and extracted with CH2Cl2 (30 mL x 2). The combined organic layers were washed with 2M Na2CO3 (30 mL x 2), and dried over anhydrous MgSO4. The solvent was evaporated in vacuo to yield the product, which was purified by column chromatography (silica gel, CH2Cl2 : MeOH, 9: 1) to afford colorless oil (VI-I, 1.15 g, 61%) |
| 58% |
In tetrahydrofuran |
12 N-Boc-N,N'-dimethylethylene diamine
EXAMPLE 12 N-Boc-N,N'-dimethylethylene diamine N,N'-dimethyl ethylenediamine (8.8 g) was dissolved in 200 ml tetrahydrofuran and to this was added over a 10 min period di-t-butyldicarbonate (4.36 g) in 30 mL tetrahydrofuran. 72 hours later, the solvent was evaporated and the residue partitioned between ether and KHCO3 and the organic layer was dried (MgSO4) and evaporated to give 11.6 g title compound (58% yield). 300 MHz 1 H NMR was consistent with proposed structure. |
| 51% |
In dichloromethane at 20℃; for 23h; |
173 Intermediate 173: tert-Butyl N-methyl-N-(2-methylaminoethyl)carbamate
A solution of di-tert-butyl dicarbonate (4.95 g, 22.69 mmol) in CH2Cl2 (240 mL) was added dropwise to a stirred solution of N,N’-dimethylethane-1,2-diamine (4 g, 45.38 mmol) in CH2Cl2 (80 mL) over a period of 20h. The resulting mixture was stirred at r.t. for 3h. The mixture was then washed sequentially with sat. Na2CO3 (2 x 100 mL), water (50 mL), and sat. brine (50 mL). The organic solution was dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10% CH3OH in CH2Cl2 gave the title compound (2.177 g, 51%) as a pale yellow oil; 1H NMR: 1.40 (9H, s), 2.28 (3H, s), 2.57 (2H, t), 2.79 (3H, s), 3.20 (2H, t). |
| 51% |
In dichloromethane at 20℃; for 3h; Inert atmosphere; |
|
| 46% |
In dichloromethane at 20℃; for 4.5h; Inert atmosphere; |
|
| 45% |
With triethylamine In dichloromethane at 20℃; for 24h; |
|
| 39% |
With triethylamine In methanol at 0 - 20℃; |
|
| 24% |
With triethylamine In dichloromethane at 0 - 20℃; for 2.5h; |
1
Preparation of N-tert-Butoxycarbonyl-N, N'-dimethylethylenediamine; Λ/,Λ/-dimethylethylenediamine (1.O g, 11.3 mmol) was dissolved in anhydrous dichloromethane (10 ml.) and was treated with triethylamine (1.6 ml_, 1 1.3 mmol). The mixture EPO was cooled to 0 °C for the addition of di-terf-butyl dicarbonate (2.5 g, 1 1.3 mmol). The reaction stirred for 30 min at 0 °C then 2 hours at room temperature. The reaction mixture was then washed with water (10 ml.) and the aqueous layer extracted with further portions of dichloromethane (2 x 10 ml_). The combined organic phases were dried over NaaSCu and the solvent removed in vacuo. Purification by column chromatography (40:8:1 , dichloromethane:methanol:aqueous ammonia) yielded (508 mg, 24 %) of the desired N-tert- butoxycarbonyl-N,N'-dimethylethylenediamine as a colourless oil. |
| 24% |
With 4-dimethylaminopyridine In dichloromethane at 0 - 20℃; for 19h; |
|
| 17% |
Stage #1: di-<i>tert</i>-butyl dicarbonate; N,N′-dimethylethylenediamine In tetrahydrofuran at 0 - 20℃;
Stage #2: With ammonia hydrochloride In ethyl acetate |
D
Preparation of Methyl-(2-methylamino-ethyl)-carbamic acid tert-butyl esterTo an ice-cooled solution of N,N'-dimethyethylenediamine (10 ml_, 91.0 mmol) in dry THF (150 ml.) was added a solution of BoC2O (4.97 g, 22.8 mmol) in dry THF (50 ml.) over 30 minutes. The reaction mixture was stirred for 1 h at 00C then at rt overnight, and concentrated in vacuo. The resulting residue was taken up in a mixture of EA and a sat.NH4CI solution. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. FC (10 % MeOH in DCM) afforded the title compound as a yellow oil (2.90 g, 17%). LC-MS (analytic A, Zorbax SB-AQ column, acidic conditions): tR = 0.50 min; [M+H]+ 189.40. |
| 17% |
In tetrahydrofuran at 0 - 20℃; |
D
To an ice-cooled solution of N,N'-dimethyethylenediamine (10 mL, 91.0 mmol) in dry THF (150 mL) was added a solution of Boc2O (4.97 g, 22.8 mmol) in dry THF (50 mL) over 30 minutes. The reaction mixture was stirred for 1 h at 0° C. then at rt overnight, and concentrated in vacuo. The resulting residue was taken up in a mixture of EA and a sat. NH4Cl solution. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. FC (10% MeOH in DCM) afforded the title compound as a yellow oil (2.90 g, 17%).LC-MS (analytic A, Zorbax SB-AQ column, acidic conditions): tR=0.50 min; [M+H]+=189.40. |
| 4.9 g |
In ethyl acetate for 1h; |
|
|
With triethylamine In tetrahydrofuran at 20℃; for 96h; |
|
|
In dichloromethane at 0 - 20℃; for 2.75h; |
20
Example 20Preparation of (E)-methyl 4-(methyl(2-((4Z,7Z,10Z,13Z,16Z,19Z)-N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)amino)-4-oxobut-2-enoate (Compound I-104) tert-Butyl methyl(2-(methylamino)ethyl)carbamate was prepared as follows: N1,N2-dimethylethane-1,2-diamine (40 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0° C. A solution of di-tert-butylcarbonate (4.0 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0° C. over a period of 15 min. The resulting reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl methyl(2-(methylamino)ethyl)carbamate. This amine was subjected to the same reaction conditions outlined earlier in the preparation of (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate. The desired product, namely (E)-methyl 4-(methyl(2-((4Z,7Z,10Z,13Z,16Z,19Z)-N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)amino)-4-oxobut-2-enoate, was obtained after purification by silica gel chromatography. MS (EI) calcd for C31H46N2O4: 510.35. found 511 (M+1). |
|
In tetrahydrofuran at 0 - 20℃; for 20h; |
|
|
In dichloromethane at 20℃; |
|
| 6.8 g |
In dichloromethane at 0 - 20℃; for 18h; |
1 Step 1: Preparation of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (0460) (Compound BC-1)
To a solution of N,N'-dimethylethane-l,2-diamine (40.4 g) in DCM (300 mL) was added a solution of Boc20 (10 g, 10.6 mL, 45.8 mmol) in DCM (100 mL) dropwise at 0 °C over 1 hr. The reaction mixture was stirred at room temperature for 18 hrs. The organic layer was washed with saturated aqueous NaHC03 (50 mL), brine (50 mL), dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography to afford ie/t-butyl N-methyl-N-[2- (methylamino)ethyl]carbamate (6.8 g, Compound BC-1) as a yellow oil. 1H NMR (400MHz, CDC13) δ ppm: 3.34 (br. s., 2H), 2.89 (s, 3H), 2.74 (t, / = 6.7 Hz, 2H), 2.46 (s, 3H), 1.47 (s, 9H). |
| 190 mg (22%) |
In dichloromethane |
2 Step. A: N-Methyl-N'-methyl-N'-t-butoxycarbonylethylenediamine
Step. A: N-Methyl-N'-methyl-N'-t-butoxycarbonylethylenediamine A solution of 1 gram (4.58 mmole) of di-t-butyl-dicarbonate in 8 mL of CH2 Cl2 at 0° C. was treated with 0.98 mL (9.16 mmole) of N-methyl-N'-methylethylenediamine. After 20 min the cooling bath was removed and the mixture allowed to warm to 22° C. After 4 hours the mixture was concentrated in vacuo. The residue was purified by flash chromatography on 68 g silica gel eluding with 1 liter of 100:9:0.3 CH2 Cl2:MeOH: ammonia water, then 500 mL of 100:11:0.3 CH2 Cl2:MeOH: ammonia water to give 190 mg (22%) of a volatile oil. |
| 2.1 g |
In dichloromethane at 0 - 25℃; for 4h; |
24.1 First step: tert-butyl methyl (2-(methylamino)ethyl)carbamate
Add in a 100mL single-mouth bottleN1,N2-dimethylethyl-1,2-diamine (4g, 45mmol), cooled to about 0 °C in an ice bath,Then (Boc) 2O (5 g, 23 mmol) in DCM (20 mL)The temperature was raised to 25 ° C and the reaction was stirred for 4 h.Concentrated under reduced pressure, a saturated sodium carbonate solution was added to the residue, and extracted three times with ethyl acetate (30 mL×3).The organic phase was combined, washed three times with saturated brine (20 mL×3) and dried over anhydrous sodiumThe mixture was suction filtered under reduced pressure, and the filtrate was evaporated.The crude product was purified by column chromatography eluting with EtOAc EtOAcConcentration under reduced pressure gave 2.1 g of a yellow oil. |
| 9 g |
In dichloromethane at 20℃; Cooling with ice; |
11 Example 11 Synthesis of Compound 11
The compound N,N'-dimethylethylenediamine (20 g, 0.226 mol)Soluble in 100mL of dichloromethane,50 mL of Boc anhydride (14.8 g, 0.068 mol) was added dropwise in an ice water bath.Dichloromethane mixture,Drop the room temperature reaction,The progress of the reaction was monitored by TLC (DCM: MeOH = 10:1). filter,The dry filtrate was concentrated under reduced pressure at 40 °C.After the column, the product was 9g. |
| 6.8 g |
In dichloromethane at 0 - 20℃; for 19h; |
1 Step 1: Preparation of tert-butyl N-methyl-N-[2-(methylamino)ethyl] carbamate (Compound BC-1)
To a solution of N,N’-dimethylethane-1,2-diamine (40.4 g) in DCM (300 mL) was added a solution of Boc2O (10 g, 10.6 mL, 45.8 mmol) in DCM (100 mL) dropwise at 0 °C over 1 hr. The reaction mixture was stirred at room temperature for 18 hrs. The organic layer was washed with saturated aqueous NaHCO3 (50 mL), brine (50 mL), dried overNa2SO4 and concentrated in vacuo. The residue was purified by column chromatography toafford tert-butyl N-methyl-N- [2-(methylamino)ethyl]carbamate (6.8 g, Compound BC-i)as a yellow oil. 1H NMR (400MHz, CDCl3) 5 ppm: 3.34 (br. s., 2H), 2.89 (s, 3H), 2.74 (t, J= 6.7 Hz, 2H), 2.46 (s, 3H), 1.47 (s, 9H). |
| 6.8 g |
In dichloromethane at 0 - 20℃; for 19h; |
1 Step 1: Preparation of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (Compound BC-1)
To a solution of N,N'-dimethylethane-1,2-diamine (40.4 g) in DCM (300 mL) was added a solution of Boc2O (10 g, 10.6 mL, 45.8 mmol) in DCM (100 mL) dropwise at 0° C. over 1 hr. The reaction mixture was stirred at room temperature for 18 hrs. The organic layer was washed with saturated aqueous NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to afford tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (6.8 g, Compound BC-1) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm: 3.34 (br. s., 2H), 2.89 (s, 3H), 2.74 (t, J=6.7 Hz, 2H), 2.46 (s, 3H), 1.47 (s, 9H). |
|
In dichloromethane at 0℃; |
|
|
With triethylamine In dichloromethane at 0 - 20℃; for 15h; |
|
|
In dichloromethane at 20℃; for 24h; |
|
|
In dichloromethane at 0℃; Inert atmosphere; |
|
|
In dichloromethane at -20 - 20℃; for 2h; |
|
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