(3R)-1-ethylpyrrolidin-3-amine → (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid

HRID 927886Notes

Reaction equation

HRID 927886 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4]([CH:26]=[CH2:27])[CH:3]=1.[CH2:28]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)[CH3:29]>C(O)CO.O>[CH2:28]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH:35][CH2:27][CH2:26][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:9])=[O:10])[CH2:31]1)[CH3:29]

Participants

5

Reactant 2

HCID 51663642(3R)-1-ethylpyrrolidin-3-amine2×HCID 86713253(1aRS,7bSR)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid2×

Product 1

HCID 86713267(1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acidYield 2.6%

Reagents, catalysts & solvents 2

HCID 174Ethylene GlycolSolventHCID 962WaterSolvent

Procedure

A solution of (1aRS,7bSR)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid (Intermediate 74, 0.150 g) and (R)-1-ethylpyrrolidin-3-ylamine (Intermediate 193, 0.25 g) in ethylene glycol (1 ml) was irradiated in the microwave at 200° C. for 30 minutes. After cooling, the mixture was diluted with water and loaded onto a SCX-2 SPE cartridge then washed with water, methanol and 2M ammonia in methanol. The basic fractions were combined and evaporated to dryness. The residue was purified by preparative HPLC (C18) eluting with a mixture of methanol and water, containing 0.1% ammonia, with a gradient of 10-98%. Then further purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 10-60% to give (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid (0.005 g) as a white solid.

Workup

  1. temperatureAfter cooling
  2. washthen washed with water, methanol and 2M ammonia in methanol
  3. customevaporated to dryness
  4. customThe residue was purified by preparative HPLC (C18)
  5. washeluting with a mixture of methanol and water
  6. additioncontaining 0.1% ammonia
  7. customThen further purified by preparative HPLC (C18)
  8. washeluting with a mixture of acetonitrile and water
  9. additioncontaining 0.1% formic acid

Sources & evidence

ORD record
ord-0914c29cb9e046b7aa48be0276175582
Source dataset
uspto-grants-2016_03
Patent number
US09290472B2

Reaction notes

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