Methyl chloroformate → Nelociguat

HRID 1888891Notes

Reaction equation

HRID 1888891 reaction equation
[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[C:16]([NH2:22])[N:15]=2)=[N:6]1.Cl[C:28]([O:30][CH3:31])=[O:29]>C(O)(C)C>[NH2:22][C:16]1[C:17]([NH:21][C:28](=[O:29])[O:30][CH3:31])=[C:18]([NH2:20])[N:19]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])[N:6]=2)[N:15]=1

Participants

4

Reactant 2

HCID 6586Methyl chloroformateHCID 113939732-(1-((2-Fluorophenyl)methyl)-1H-pyrazolo(3,4-b)pyridin-3-yl)-4,5,6-pyrimidinetriamine2×

Product 1

HCID 11690019NelociguatYield 90.8%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent2×

Conditions

Temperature
35 °C

Procedure

In a reaction vessel, 1.50 kg of the compound of the formula (VI) were initially charged in 14.25 l of isopropanol, and the mixture was heated with stirring to 35° C. 531 g of methyl chloroformate were, at a steady rate, metered in over a period of 30 min, rinsing with 750 ml of isopropanol, and the mixture was stirred at 35° C. for 16 h. The mixture was then heated to 50° C. and 3.85 l of methanol and 606 g of triethylamine were metered in with stirring at 50° C., rinsing with 450 ml of methanol. The mixture was then stirred at 50° C. for 1 h, cooled to RT and stirred at RT for 1 h. The suspended solid was filtered off with suction, washed twice with in each case 3.0 l of isopropanol/methanol (4:1) and once with 3.0 l of isopropanol and sucked dry. The moist product was dried at 50° C. for 1 h and then at 100° C. for 22 h in a vacuum drying cabinet. The weight of the product obtained was 1.793 kg or 103.3% of theory. The product of the formula (VI) contained 6.45% of isopropanol virtually unremovable by drying (partially, an isopropanol solvate was present), and the analytical content was 87.9% by weight (HPLC). Based on this content, the yield was 90.8% of theory.

Workup

  1. temperaturethe mixture was heated
  2. custommetered in over a period of 30 min
  3. washrinsing with 750 ml of isopropanol
  4. stirringthe mixture was stirred at 35° C. for 16 h
  5. temperatureThe mixture was then heated to 50° C.
  6. stirringwith stirring at 50° C.
  7. washrinsing with 450 ml of methanol
  8. stirringThe mixture was then stirred at 50° C. for 1 h
  9. temperaturecooled to RT
  10. stirringstirred at RT for 1 h
  11. filtrationThe suspended solid was filtered off with suction
  12. washwashed twice with in each case 3.0 l of isopropanol/methanol (4:1) and once with 3.0 l of isopropanol
  13. customsucked dry
  14. customThe moist product was dried at 50° C. for 1 h
  15. customat 100° C. for 22 h in a vacuum drying cabinet
  16. customThe weight of the product obtained
  17. dry with materialby drying (partially, an isopropanol solvate

Sources & evidence

ORD record
ord-54326b7a95a24061ba866976543cb9be
Source dataset
uspto-grants-2013_08
Patent number
US08501945B2

Reaction notes

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