Tetrahydro-2-furancarbonyl chloride → HCID 136984160, compound

HRID 1427360Notes

Reaction equation

HRID 1427360 reaction equation
[CH3:1][C:2]1[NH:3][C:4]([C:12]([O:14]CC)=O)=[C:5]([CH:7]2[CH2:11][CH2:10][CH2:9][O:8]2)[N:6]=1.O1CCCC1C(Cl)=O.N[N:26]1C(C(OCC)=O)=C(C2CCCO2)[N:28]=[C:27]1C>>[CH3:1][C:2]1[N:3]2[C:4]([C:12](=[O:14])[NH:28][CH:27]=[N:26]2)=[C:5]([CH:7]2[CH2:11][CH2:10][CH2:9][O:8]2)[N:6]=1

Participants

4

Reactant 3

HCID 551254Tetrahydro-2-furancarbonyl chlorideHCID 117678137HCID 117678137, compoundHCID 178470393HCID 178470393, compound

Product 1

HCID 136984160HCID 136984160, compound

Procedure

Ethyl 2-methyl-4-(tetrahydrofuran-2-yl)-1H-imidazole-5-carboxylate (C52) [prepared in an analogous manner to C63 in Preparation P2, by employing tetrahydrofuran-2-carbonyl chloride as starting material] (0.4 mol) was converted to ethyl 1-amino-2-methyl-4-(tetrahydrofuran-2-yl)-1H-imidazole-5-carboxylate (C53) using the general method for synthesis of C64 in Preparation P2. In this case, due to enhanced water-solubility, extraction was carried out with a mixture of ethyl acetate and tetrahydrofuran. The isolated material was judged by proton NMR analysis to be a 3:1 mixture of C53 and its regioisomer ethyl 1-amino-2-methyl-5-(tetrahydrofuran-2-yl)-1H-imidazole-4-carboxylate. The mixture was subjected to reaction with formamide and formamidine acetate, as described for the synthesis of P2 in Preparation P2. After the reaction was cooled to room temperature, it was partitioned between water and a mixture of ethyl acetate and tetrahydrofuran. The extracts were concentrated in vacuo, dissolved in a small volume of ethyl acetate, and the product was extracted into aqueous potassium carbonate solution. Adjustment of the aqueous layer to a mildly acidic pH resulted in precipitation of the product. Additional product was obtained by evaporating the aqueous layer to dryness, triturating the residue with methanol and filtering. The filtrate was treated with a small amount of water, and the methanol was removed in vacuo. Additional product precipitated from the aqueous residue. Combined yield: 13.5 g, 61 mmol, 15%. LCMS m/z 221.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 11.71 (br s, 1H), 7.81 (s, 1H), 5.33 (dd, J=6.8, 6.8 Hz, 1H), 3.87-3.93 (m, 1H), 3.70-3.76 (m, 1H), 2.46 (s, 3H), 2.04-2.18 (m, 3H), 1.85-1.96 (m, 1H).

Workup

  1. customfor synthesis of C64
  2. customin Preparation P2
  3. extractionIn this case, due to enhanced water-solubility, extraction
  4. additionwas carried out with a mixture of ethyl acetate and tetrahydrofuran
  5. additiona 3:1 mixture of C53 and its regioisomer ethyl 1-amino-2-methyl-5-(tetrahydrofuran-2-yl)-1H-imidazole-4-carboxylate
  6. customThe mixture was subjected to reaction with formamide and formamidine acetate
  7. customas described for the synthesis of P2 in Preparation P2
  8. customit was partitioned between water
  9. additiona mixture of ethyl acetate and tetrahydrofuran
  10. concentrationThe extracts were concentrated in vacuo
  11. dissolutiondissolved in a small volume of ethyl acetate
  12. extractionthe product was extracted into aqueous potassium carbonate solution
  13. customAdjustment of the aqueous layer to a mildly acidic pH resulted in precipitation of the product
  14. customAdditional product was obtained
  15. customby evaporating the aqueous layer to dryness
  16. customtriturating the residue with methanol
  17. filtrationfiltering
  18. additionThe filtrate was treated with a small amount of water
  19. customthe methanol was removed in vacuo
  20. customAdditional product precipitated from the aqueous residue

Sources & evidence

ORD record
ord-6295a9e005e84c6e877a9a4e6cc3fb46
Source dataset
uspto-grants-2015_01
Patent number
US08933224B2

Reaction notes

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