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)-2,2-dimethylnonylamino)ethyl)benzo[d]thiazol-2(3H)-one formate

HRID 1689473Notes

Reaction equation

HRID 1689473 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][CH2:32][C:33]([CH3:37])([CH3:36])[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(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[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][CH2:37][C:33]([CH3:34])([CH3:36])[CH2:32][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 5049666Sodium triacetoxyborohydrideHCID 579890309-(4-(2-Isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2,2-dimethylnonanalHCID 671669747-[(1R)-2-Amino-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one, acetate salt

Product 1

HCID 67292881(R)-4-Hydroxy-7-(1-hydroxy-2-(9-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2,2-dimethylnonylamino)ethyl)benzo[d]thiazol-2(3H)-one formate

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
0 °C

Procedure

Acetic acid (0.066 mL) was added to a mixture of 9-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2,2-dimethylnonanal (example 103, step d) (0.4 g) and (R)-7-(2-amino-1-hydroxyethyl)-4-hydroxybenzo[d]thiazol-2(3H)-one hydrochloride (WO2007027134, example 1, step d) (0.3 g) with 3 Å molecular sieves in anhydrous methanol (10 mL). The mixture was stirred for 5 min then cooled to 0° C. Sodium triacetoxyborohydride (0.16 g) was added and the resulting mixture stirred at RT for 16.5 h. The solution was filtered then concentrated in vacuo. The residue was dissolved in a mixture of acetonitrile and water and purified by preparative HPLC (Phenomenex Gemini®, Gradient: 10-40% acetonitrile in 0.1% aqueous formic acid). The fractions containing product were combined and freeze-dried to give the titled compound as a white solid. Yield 0.10 g.

Workup

  1. stirringthe resulting mixture stirred at RT for 16.5 h
  2. filtrationThe solution was filtered
  3. concentrationthen concentrated in vacuo
  4. dissolutionThe residue was dissolved in a mixture of acetonitrile and water
  5. custompurified by preparative HPLC (Phenomenex Gemini®, Gradient: 10-40% acetonitrile in 0.1% aqueous formic acid)
  6. additionThe fractions containing product
  7. customfreeze-dried

Sources & evidence

ORD record
ord-70e43c956ce3459da3a0e76e20063fba
Source dataset
uspto-grants-2012_04
Patent number
US08148373B2

Reaction notes

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