1-Bromo-2-Chloroethane → Dimethyl 1-(2-chloroethyl)cyclohexane-1,3-dicarboxylate

Temperature

0 °C

A solution of N,N-diisopropylamine (4.5 mL, 32 mmol) in tetrahydrofuran (25 mL) was cooled at −78° C. and treated with 1.6 M of n-butyllithium in hexane (19 mL). The reaction was warmed to 0° C., stirred for 5 minutes, then cooled back to −78° C. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (15 mL, 120 mmol) was added dropwise over 20 minutes, then a solution of cyclohexane-1,3-dicarboxylic acid dimethyl ester (5.0 g, 25 mmol) in tetrahydrofuran (10 mL) was added dropwise and the mixture stirred for 1 hour at the same temperature. Then a solution of 1-bromo-2-chloroethane (2.9 mL, 35 mmol) in tetrahydrofuran (8 mL) was added dropwise. The reaction was allowed to return slowly to room temperature and stirred overnight. The reaction mixture was cooled to 0° C. and quenched with saturated ammonium chloride solution. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with a small amount of water and extracted with dichloromethane (4×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified with chromatography to give the intermediate 1-(2-chloro-ethyl)-cyclohexane-1,3-dicarboxylic acid dimethyl ester (1.22 g). A solution of N,N-diisopropylamine (0.91 mL, 6.50 mmol) in tetrahydrofuran (10 mL) was cooled at −78° C. and treated with 1.6 M of n-butyllithium in hexane (4.06 mL). The reaction was warmed to 0° C., stirred for 5 minutes, and then cooled back to −78° C. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.24 mL, 18.6 mmol) was added dropwise over 20 minutes, then a solution of 1-(2-chloro-ethyl)-cyclohexane-1,3-dicarboxylic acid dimethyl ester (1.22 g, 4.64 mmol) in tetrahydrofuran (10 mL) was added dropwise and the mixture was stirred for 1 hour at the same temperature. The reaction was allowed to return slowly at room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride solution and concentrated under reduced pressure. The resulting residue was diluted with a small amount of water and extracted with dichloromethane (4×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to give crude product (3.05 g) containing DMPU. The product was used in the next step without further purification.

1. temperaturecooled back to −78° C
2. stirringthe mixture stirred for 1 hour at the same temperature
3. customto return slowly to room temperature
4. stirringstirred overnight
5. temperatureThe reaction mixture was cooled to 0° C.
6. customquenched with saturated ammonium chloride solution
7. concentrationThe reaction mixture was concentrated under reduced pressure
8. additionthe resulting residue was diluted with a small amount of water
9. extractionextracted with dichloromethane (4×50 mL)
10. dry with materialdried over anhydrous sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated under reduced pressure
13. customThe resulting residue was purified with chromatography

ORD record

ord-cb6c4625c71d4a21ae4c7d026c1ccf99

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08921370B2