1,2-Dichloroethane → HCID 59547344, compound

HRID 2038556Notes

Reaction equation

HRID 2038556 reaction equation
[CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:25][C@@H:26]([C:52]([CH3:55])([CH3:54])[CH3:53])[C:27]([N:29]1[C@H:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][C@:31]2([O:35][C:34](=[O:36])[N:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:32]2)[CH2:30]1)=[O:28].CCN(C(C)C)C(C)C.NCCC1N=CNC=1>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([CH2:7][C:8]([NH:25][C@@H:26]([C:52]([CH3:55])([CH3:54])[CH3:53])[C:27]([N:29]2[C@H:44]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[CH2:43][C@:31]3([O:35][C:34](=[O:36])[N:33]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:32]3)[CH2:30]2)=[O:28])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1

Participants

9

Reactant 6

HCID 111,2-DichloroethaneHCID 21363Cyclohexaneacetic acidHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 59547341HCID 59547341, compoundHCID 178419017HCID 178419017, compound

Product 1

HCID 59547344HCID 59547344, compoundYield 37%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

Cyclohexylacetic acid (48 mg, 337 μmol, 1.4 eq.), EDC (65 mg, 337 μmol, 1.4 eq.) and HOBt (52 mg, 337 μmol, 1.4 eq.) were combined in DMF (0.3 mL) and stirred for 0.5 hrs. at room temp. (5S,8S)-tert-butyl 7-((S)-2-amino-3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (F1) (105 mg, 243 μmol, 1 eq.) and DIEA (118 μL 675 μmol, 2.8 eq.) were added to this mixture and the resulting mixture was stirred for 24 hrs at room temp. 1.0 M histamine (aq., 120 μL, 0.5 eq.) was added and the mixture was stirred for 0.5 h. Ethyl acetate was added and the mixture was washed with 1N HCl then 1M K2CO3 and extracted with ethyl acetate (2×). The combined organic layers were concentrated and chromatography using hexanes and ethyl acetate gave 50 mg of (5S,8S)-tert-butyl 7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (G1). 1H NMR (300 MHz, DMSO) 7.90 (d, 1 H), 7.53 (d, 2 H), 7.44-7.37 (m, 2H), 7.14 (m, 1H), 4.47 (d, 1H), 4.30-3.99 (m, 3H), 3.89-3.83 (m, 1H), 3.18 (d, 1H), 2.79-2.67 (m, 1H), 2.27-2.00 (m, 3H), 1.7-1.55 (m, 5H), 1.45-1.39 (m, 11H), 1.2-1.1 (m, 4H), 0.98-0.91 (m, 9H). Later optimization showed that steps E to G could be replaced by doing a single coupling on E1 with (S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoic acid. NMR confirmed that epimerization was not occurring.

Workup

  1. stirringthe resulting mixture was stirred for 24 hrs at room temp
  2. stirringthe mixture was stirred for 0.5 h
  3. washthe mixture was washed with 1N HCl
  4. extraction1M K2CO3 and extracted with ethyl acetate (2×)
  5. concentrationThe combined organic layers were concentrated

Sources & evidence

ORD record
ord-354d9c6aa064462ea7f6068b503bd88d
Source dataset
uspto-grants-2013_11
Patent number
US08575208B2

Reaction notes

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