1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → methyl 2-(4-(((1R,3S)-3-((tert-butoxycarbonyl)amino)-2,2,3-trimethylcyclopentyl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carbonyl)hydrazinecarbodithioate

HRID 1408988Notes

Reaction equation

HRID 1408988 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:32])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27](O)=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH:63]([C:65]([S:67][CH3:68])=[S:66])[NH2:64]>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:32])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([NH:64][NH:63][C:65]([S:67][CH3:68])=[S:66])=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:30])[CH3:31])=[O:7])([CH3:2])([CH3:4])[CH3:3]

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 3034069MethyldithiocarbazateHCID 867077164-(((1R,3S)-3-((tert-butoxycarbonyl)amino)-2,2,3-trimethylcyclopentyl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid

Product 1

HCID 86707721methyl 2-(4-(((1R,3S)-3-((tert-butoxycarbonyl)amino)-2,2,3-trimethylcyclopentyl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carbonyl)hydrazinecarbodithioateYield 76%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 4-((1R,3S)-3-(tert-butoxycarbonylamino)-2,2,3-trimethylcyclopentylamino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (500 mg, 1.122 mmol, from Step 3 of Example 346). HOBT (206 mg, 1.347 mmol) and DIEA (0.490 mL, 2.81 mmol) in DMF (4 mL) were added EDCI (280 mg, 1.459 mmol) and methyl hydrazinecarbodithioate (144 mg, 1.178 mmol) at 23° C. The reaction mixture was stirred for 1.5 hrs followed by the addition of 25 mL of water. The solids were removed. The water phase was extracted with EtOAc (2×30 mL). The combined organic phase was washed with 10% LiCl solution (2×20 mL), 20 mL of brine and dried over Na2SO4. Filtration and concentration gave methyl 2-(4-(((1R,3S)-3-((tert-butoxycarbonyl)amino)-2,2,3-trimethylcyclopentyl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carbonyl)hydrazinecarbodithioate (466.5 mg, 76% yield). MS (ES+) m/z: 550.08 (M+H); HPLC retention time: 3.168 min (analytical HPLC Method F).

Workup

  1. customThe solids were removed
  2. extractionThe water phase was extracted with EtOAc (2×30 mL)
  3. washThe combined organic phase was washed with 10% LiCl solution (2×20 mL), 20 mL of brine
  4. dry with materialdried over Na2SO4
  5. filtrationFiltration and concentration

Sources & evidence

ORD record
ord-8621e466c6124edd82b79cd0b0ff187b
Source dataset
uspto-grants-2014_12
Patent number
US08921368B2

Reaction notes

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