Triethylamine → N-{(6S,9R)-6-(2,3-Difluorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl}-1-oxo-2,8-diazaspiro[4,5]decane-8-carboxamide

HRID 1664947Notes

Reaction equation

HRID 1664947 reaction equation
C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]3([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27]3)=[N:24][N:25]=[C:20]2[C@H:19]([NH2:33])[CH2:18][CH2:17]1.[C:34]([N:41]1[CH:45]=[CH:44]N=[CH:42]1)(N1C=CN=C1)=[O:35].[C:46]1(=[O:56])[C:50]2(CCNC[CH2:51]2)[CH2:49][CH2:48][NH:47]1>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]3([C:29]([F:32])([F:30])[F:31])[CH2:27][CH2:28]3)=[N:24][N:25]=[C:20]2[C@H:19]([NH:33][C:34]([N:41]2[CH2:42][CH2:51][C:50]3([C:46](=[O:56])[NH:47][CH2:48][CH2:49]3)[CH2:44][CH2:45]2)=[O:35])[CH2:18][CH2:17]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 682631,1'-Carbonyldiimidazole2×HCID 222250112,8-Diazaspiro[4.5]decan-1-oneHCID 67438617HCID 67438617, compound

Product 1

HCID 59722586N-{(6S,9R)-6-(2,3-Difluorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl}-1-oxo-2,8-diazaspiro[4,5]decane-8-carboxamideYield 56.3%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

Triethylamine (16 μL, 0.112 mmol) was added to a solution of the bis hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-amine (20 mg, 0.045 mmol) and 1,1′-carbonyldiimidazole (13 mg, 0.079 mmol) in tetrahydrofuran (1.0 mL) at 0° C. After 20 min, additional 1,1′-carbonyldiimidazole (7.3 mg, 0.045 mmol) was added. After 30 min, the hydrochloride salt of 2,8-diazaspiro[4.5]decan-1-one (11 mg, 0.056 mmol) and dichloromethane (1.0 mL) were added and the mixture was heated to 60° C. After 16 h, the reaction was concentrated. Purification by reverse phase HPLC (C-18, 10% acetonitrile/water→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (14 mg). MS 553.2315 (M+1).

Workup

  1. waitAfter 30 min
  2. waitAfter 16 h
  3. concentrationthe reaction was concentrated
  4. customPurification by reverse phase HPLC (C-18, 10% acetonitrile/water→100% acetonitrile with 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-06c0be3ee22b4551bb379a152864c80b
Source dataset
uspto-grants-2011_10
Patent number
US08039460B2

Reaction notes

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