Cystine dimethyl ester dihydrochloride

White Solid

To generate the diNACA, Step 1 (01NPI01-01) was performed in a 2000L glass-lined reactor using 67 kg of L-cystine. The material was treated with methanol (1323 kg, 25 vol) and thionyl chloride (80 kg, 2.41 eq) and agitated for 1 hour before heating to reflux. Once the In-Process Control (IPC) sample met the criteria of less than 1% of L-cystine remaining, the reaction was deemed complete. After cooling to 20±5 C. the methanol was exchanged with methyl t-butylether and the product isolated by filtration. Due to the scale, the isolation occurred in three portions with the first and some of the second portion being carried forward without drying. The remainder of the material was dried under vacuum to yield L-cystine dimethylester dihydrochloride.Set-up: A 2000 L glass-lined reactor; 50 kg L-Cystine; and 625 L Methanol was charged to the reactor and agitated while cooling to -10 C. 60 kg Thionyl Chloride was slowly added at ?-5 C. After addition completion, the reaction material was heated to reflux and held for 16 hours. After the reaction was verified as complete by HPLC (?0.5% starting material), the reaction was cooled to room temperature. The reaction mixture was concentrated to 6 volumes before solvent-exchanging into 3×8 volumes MTBE. The resulting slurry was agitated at room temperature for 1 hour before being filtered and washed with MTBE. The solids were dried at 45 C. under vacuum. Yield: 68.15 kg (95.9%), Purity: 95.8%Compound 2 Synthesis of cystine dimethyl ester dihydrochioride (CDME)[00261] A stream of dry hydrogen chloride gas was sparged rapidly into a suspension of cystine(10 g) in anhydrous methanol (50 mL) and agitated with a magnetic stirrer. After all the cystine had dissolved the warm solution was cooled in an ice bath, and sparging of HC1 continued to saturation at 0- 5C. The reaction mixture was protected from atmospheric moisture with a calcium chloride drying tube and allowed to stand at room temperature for 3 hours. Solvent was removed from the reaction mixture under reduced pressure on a o rotary evaporator with the water bath set at 50C. An aliquot of methanol (50 mL) was added to the resulting syrup and then concentration by rotary evaporation repeated. To the dry syrupy residue was added anhydrous ether (20 mL) resulting in spontaneous crystallization. The mixture was allowed to stand overnight at 4C and the resulting crystalline suspension was collected by filtration in a buchner funnel and washed with cold anhydrous ether (30 mL). The filter cake was dried under reduced pressure over potassium hydroxide pellets in a desiccator.A stream of dry hydrogen chloride gas was sparged rapidly into a suspension of cystine (10 g) in anhydrous methanol (50 mL) and agitated with a magnetic stirrer. After all the cystine had dissolved the warm solution was cooled in an ice bath, and sparging of HCl continued to saturation at 0-5 C. The reaction mixture was protected from atmospheric moisture with a calcium chloride drying tube and allowed to stand at room temperature for 3 hours. Solvent was removed from the reaction mixture under reduced pressure on a o rotary evaporator with the water bath set at 50 C. An aliquot of methanol (50 mL) was added to the resulting syrup and then concentration by rotary evaporation repeated. To the dry syrupy residue was added anhydrous ether (20 mL) resulting in spontaneous crystallization. The mixture was allowed to stand overnight at 4 C. and the resulting crystalline suspension was collected by filtration in a buchner funnel and washed with cold anhydrous ether (30 mL). The filter cake was dried under reduced pressure over potassium hydroxide pellets in a desiccator.

Molecular Weight:341.3
Hydrogen Bond Donor Count:4
Hydrogen Bond Acceptor Count:8
Rotatable Bond Count:9
Exact Mass:340.0085048
Monoisotopic Mass:340.0085048
Topological Polar Surface Area:155
Heavy Atom Count:18
Complexity:216
Undefined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:3
Compound Is Canonicalized:Yes