Acetic Acid → (R)-4-Hydroxy-7-(1-hydroxy-2-(9-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-3,3-dimethylnonylamino)ethyl)benzo[d]thiazol-2(3H)-one formate

HRID 1689541Notes

Reaction equation

HRID 1689541 reaction equation
[C:1]([OH:4])(=[O:3])C.[CH:5]([C:8]1[S:9][CH:10]=[C:11]([C:13]([N:15]2[CH2:20][C:19]3([CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:37])([CH3:36])[CH2:33][CH:34]=O)[CH2:22][CH2:21]3)[O:18][CH2:17][CH2:16]2)=[O:14])[N:12]=1)([CH3:7])[CH3:6].C(O)(=O)C.[NH2:42][CH2:43][C@@H:44]([C:46]1[C:54]2[S:53][C:52](=[O:55])[NH:51][C:50]=2[C:49]([OH:56])=[CH:48][CH:47]=1)[OH:45].C([BH3-])#N.[Na+]>CO>[CH:1]([OH:4])=[O:3].[OH:56][C:49]1[C:50]2[NH:51][C:52](=[O:55])[S:53][C:54]=2[C:46]([C@@H:44]([OH:45])[CH2:43][NH:42][CH2:34][CH2:33][C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][C:19]3([O:18][CH2:17][CH2:16][N:15]([C:13]([C:11]4[N:12]=[C:8]([CH:5]([CH3:7])[CH3:6])[S:9][CH:10]=4)=[O:14])[CH2:20]3)[CH2:25][CH2:24]2)=[CH:47][CH:48]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 5003444Sodium cyanoborohydrideHCID 579893649-(4-(2-Isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-3,3-dimethylnonanalHCID 671669747-[(1R)-2-Amino-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one, acetate salt

Product 1

HCID 67292868(R)-4-Hydroxy-7-(1-hydroxy-2-(9-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-3,3-dimethylnonylamino)ethyl)benzo[d]thiazol-2(3H)-one formate

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Acetic acid (0.035 mL) was added to a stirred solution of 9-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-3,3-dimethylnonanal (example 279, step f) (195 mg) and (R)-7-(2-amino-1-hydroxyethyl)-4-hydroxybenzo[d]thiazol-2(3H)-one hydrochloride (WO2007027134, example 1, step d) (161 mg) in methanol (10 mL) and after a minute sodium cyanoborohydride (51 mg) was added and the reaction mixture stirred at room temperature for 1.5 h. The mixture was concentrated and then partitioned between THF (12 mL) and a mixture of brine and saturated sodium bicarbonate solution (10:1, 12 mL). The layers were separated and the organic phase dried over sodium sulfate, filtered and evaporated. The resulting material was purified by preparative HPLC (Phenomenex Gemini®, Gradient: 5-40% acetonitrile in 0.1% aqueous formic acid). The fractions containing product were combined and freeze-dried to afford the titled compound as a white solid. Yield 0.038 g.

Workup

  1. concentrationThe mixture was concentrated
  2. custompartitioned between THF (12 mL)
  3. additiona mixture of brine and saturated sodium bicarbonate solution (10:1, 12 mL)
  4. customThe layers were separated
  5. dry with materialthe organic phase dried over sodium sulfate
  6. filtrationfiltered
  7. customevaporated
  8. customThe resulting material was purified by preparative HPLC (Phenomenex Gemini®, Gradient: 5-40% acetonitrile in 0.1% aqueous formic acid)
  9. additionThe fractions containing product
  10. customfreeze-dried

Sources & evidence

ORD record
ord-c0bc327d96bc4fa2a27607876c06c9fe
Source dataset
uspto-grants-2012_04
Patent number
US08148373B2

Reaction notes

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