Triethylamine → (1S,2S,4R)-2-{[(triisopropylsilyl)oxy]methyl}-4-(tritylamino)cyclopentanol

HRID 1427333Notes

Reaction equation

HRID 1427333 reaction equation
[OH:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([NH:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][C@@H:4]1[OH:28].OC[C@]1(O)CC[C@H](NC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C1.C(N(CC)CC)C.[CH:64]([Si:67](Cl)([CH:71]([CH3:73])[CH3:72])[CH:68]([CH3:70])[CH3:69])([CH3:66])[CH3:65]>C(OCC)(=O)C.CCCCCCC.C(Cl)Cl>[CH:64]([Si:67]([CH:71]([CH3:73])[CH3:72])([CH:68]([CH3:70])[CH3:69])[O:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([NH:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:5][C@@H:4]1[OH:28])([CH3:66])[CH3:65]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 139400Triisopropylsilyl chlorideHCID 68636990(1S,3S)-1-(hydroxymethyl)-3-(tritylamino)cyclopentanol2×HCID 68907359(1S,2S,4R)-2-(hydroxymethyl)-4-(tritylamino)cyclopentan-1-ol

Product 1

HCID 68909459(1S,2S,4R)-2-{[(triisopropylsilyl)oxy]methyl}-4-(tritylamino)cyclopentanol

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 21899848Ethylacetate heptaneSolvent

Conditions

Temperature
7.5 °C

Procedure

A reactor was charged with the mixture of (1S,2S,4R)-2-(hydroxymethyl)-4-(tritylamino)cyclopentanol and (1S,3S)-1-(hydroxymethyl)-3-(tritylamino)cyclopentanol (1.87 kg total, ˜280 g of (1S,2S,4R)-2-(hydroxymethyl)-4-(tritylamino)cyclopentanol, 0.75 mol). The reactor was charged with methylene chloride (7.4 L) and the agitation started. While maintaining the temperature less than 25° C., triethylamine (210 mL, 1.5 mol) was added. While maintaining the temperature less than 25° C., triisopropylsilyl chloride (402 mL, 1.9 mol) was slowly added. The reaction mixture was allowed to stir at 20° C. to 22° C., for ˜48 hours. The reaction mixture was analyzed by TLC (50% ethyl acetate/heptane, UV visualization), which indicated the formation of the product (Rf 0.70) and the presence of unreacted (1S,3S)-1-(hydroxymethyl)-3-(tritylamino)cyclopentanol (Rf 0.15). The clear pale yellow solution was cooled to 5 to 10° C., slowly quenched with DI water (7.5 L), and the resulting layers separated. The aqueous phase was extracted with methylene chloride (3 L) and the combined organic phases were dried over anhydrous magnesium sulfate, filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give a brown oil (4.06 kg), which was purified by silica gel chromatography using multiple columns. Each column was performed as follows. A 20 cm diameter glass column was loaded with a slurry of silica gel (4.5 kg) in 10% ethyl acetate/heptane. The oil (˜1.2 kg) was loaded on the column. Combined purified material from all columns afforded the title compound (2.94 kg) as a clear oil which was used without further purification. 1H NMR (300 MHz, CDCl3, δ): 7.56-7.54 (m, 5H), 7.34-7.13 (m, 10H), 4.26 (bs, 1H), 3.86-3.81 (dd, J=10.0, 4.5 Hz, 1H), 3.65-3.60 (dd, J=10.1, 7.2 Hz, 1H), 3.41-3.37 (m, 1H), 3.07 (bs, 1H), 2.16-2.07 (m, 1H), 1.69-1.63 (m, 3H), 1.47-1.20 (m, 4H) and 1.08-1.03 (2 s, 18H).

Workup

  1. additionwas added
  2. additionwas slowly added
  3. customslowly quenched with DI water (7.5 L)
  4. customthe resulting layers separated
  5. extractionThe aqueous phase was extracted with methylene chloride (3 L)
  6. dry with materialthe combined organic phases were dried over anhydrous magnesium sulfate
  7. filtrationfiltered through a pad of diatomaceous earth
  8. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-90b866fd8a6241d682b3f7fd3ba5ebbe
Source dataset
uspto-grants-2015_01
Patent number
US08933225B2

Reaction notes

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