Diethyl chlorophosphate → (2'R,9S)-7-(4-chlorophenyl)-2'-(methoxymethyl)-4,5,13-trimethylspiro[3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene-9,1'-cyclopropane]

HRID 1772334Notes

Reaction equation

HRID 1772334 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:23]([CH3:24])=[C:22]([CH3:25])[S:21][C:10]=3[NH:11][C:12](=O)[C@@:13]3([CH2:16][C@H:15]3[CH2:17][O:18][CH3:19])[N:14]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].P(Cl)(=O)(OCC)OCC.[C:41]([NH:44][NH2:45])(=O)[CH3:42]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:23]([CH3:24])=[C:22]([CH3:25])[S:21][C:10]=3[N:11]3[C:41]([CH3:42])=[N:44][N:45]=[C:12]3[C@@:13]3([CH2:16][C@H:15]3[CH2:17][O:18][CH3:19])[N:14]=2)=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 13139Diethyl chlorophosphateHCID 14039AcetohydrazideHCID 23665647Potassium tert-butoxideHCID 136338064(1S,2R)-5'-(4-chlorophenyl)-2-(methoxymethyl)-6',7'-dimethylspiro[cyclopropane-1,3'-thieno[2,3-e][1,4]diazepin]-2'(1'H)-one

Product 1

HCID 57345408(2'R,9S)-7-(4-chlorophenyl)-2'-(methoxymethyl)-4,5,13-trimethylspiro[3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene-9,1'-cyclopropane]Yield 86.9%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (1S,2R)-5′-(4-chlorophenyl)-2-(methoxymethyl)-6′,7′-dimethylspiro-[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one (3.7, 9.87 mmol) in anhydrous THF (200 mL) at −78° C. was slowly added a solution of potassium tert-butoxide (12.34 mL, 12.34 mmol). The resulting dark brown solution was warmed to rt and stirred for 30 min. The reaction was cooled to −78° C. before diethyl phosphorochloridate (2.85 mL, 19.74 mmol) was slowly added. Once the addition was completed, the reaction was warmed to rt for 60 to 90 min before acetohydrazide (2.193 mg, 29.6 mmol) was added. The reaction was then heated to 60° C. for 2 h before MeOH (5 mL) and silica gel were sequentially added. The solvent was removed under vacuum, the dry silica gel was packed, and the product was purified by flash chromatography (EtOAc/hexane 3:7 to 100:0) to give (1S,2R)-4′-(4-chlorophenyl)-2-(methoxymethyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine] as a solid (3.54 g). LRMS (M+H)+: 413 m/z. 1H NMR (two conformers detected in ˜1:1 ratio) (400 MHz, DMSO-d6) δ 7.42-7.55 (m, 4H), 3.82 (dd, J=7.32, 10.99 Hz, 0.5H), 3.71 (dd, J=6.41, 11.22 Hz, 0.5H), 3.39 (s, 1.5H), 3.21 (dd, J=6.29, 10.87 Hz, 0.5H), 3.04 (dd, J=7.67, 10.87 Hz, 0.5H), 2.97 (s, 1.5H), 2.60 (s, 3H), 2.39 (s, 1.5H), 2.38 (s, 1.5H), 2.16-2.27 (m, 0.5H), 2.05 (dd, J=5.26, 9.38 Hz, 0.5H), 1.58 (s, 1.5H), 1.54 (s, 1.5H), 1.43-1.51 (m, 0.5H), 1.33-1.40 (m, 0.5H), 1.03 (dd, J=5.38, 9.27 Hz, 0.5H), 0.61 (t, J=6.07 Hz, 0.5H).

Workup

  1. additionwas slowly added
  2. additionOnce the addition
  3. additionwas added
  4. additionwere sequentially added
  5. customThe solvent was removed under vacuum
  6. customthe product was purified by flash chromatography (EtOAc/hexane 3:7 to 100:0)

Sources & evidence

ORD record
ord-19dad78eca384c42bd049d98824faded
Source dataset
uspto-grants-2016_02
Patent number
US09249161B2

Reaction notes

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