Tetrahydrofuran → alpha-Amino-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl-1, 3-dioxolane-2-pentanamide

HRID 1067896Notes

Reaction equation

[Cl-].[Li+].O1CCCC1.O.[OH:9][CH:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:11]([N:13]([CH3:18])[C:14](=[O:17])[CH2:15][NH2:16])[CH3:12].I[CH2:26][CH2:27][CH2:28][CH:29]1[O:33][CH2:32][CH2:31][O:30]1>O>[NH2:16][CH:15]([CH2:26][CH2:27][CH2:28][CH:29]1[O:33][CH2:32][CH2:31][O:30]1)[C:14]([N:13]([CH:11]([CH3:12])[CH:10]([OH:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])=[O:17]

Participants

Conditions

Temperature: -78 °C

Procedure

A 0.5 liter, 4-necked, round-bottom flask, equipped with an overhead stirrer, thermocouple, addition funnel and a nitrogen inlet/outlet was charged with 11.4 g of lithium chloride (dried in vacuo at 130° C. for 6 hours and then at 100° C. for 18 hours prior to use), 9.1 g of diisoproylamine and 80 ml of tetrahydrofuran. After cooling to −78° C., a 2.5 M solution of n-butyllithium in hexanes (35 ml) was added over about 20 minutes while maintaining the temperature at less than or equal to −60° C. This mixture was allowed to stir at −78° C. for 45 minutes. A tetrahydrofuran solution of [R-(R*,R*)]-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl-α-aminoacetamide monohydrate [10 g., 0.04 mol, prepared as described by Myers et al., Tetrahedron Letters, Vol. 36, p. 4555-4558 (1995)] was added over 50 minutes while maintaining the temperature at less than or equal to −68° C. After the addition was complete, the mixture was stirred for an additional 45 minutes. The solution was allowed to warm to about 0° C. and held at that temperature for 45 minutes. The 2-(3-iodopropyl)-1,3-dioxolane (12 g) from part (a) was added as a tetrahydrofuran (10 ml) solution in one portion. After 3 hours reaction time at 0° C., TLC analysis indicated no observable starting material present and water (100 ml) was added as a quench. The tetrahydrofuran/hexane phase was separated from the lower aqueous phase. The aqueous phase was extracted with methylene chloride (4×100 ml). The methylene chloride phases were combined with the tetrahydrofuran/hexane phase and washed with 100 ml of brine. After drying over sodium sulfate and filtration, concentration in vacuo (bath temperature less than or equal to 40° C.) afforded an oil (9.57 g). The oil was chromatographed over silica gel 60 (column size: 3.5 cm×21 cm) eluting with 5% triethylamine in methylene chloride, collecting 100 ml fractions. Fractions number 6 through 12 were combined and concentrated in vacuo (bath temperature less than or equal to 45° C.) to afford an oil. This oil was dissolved in toluene (100 ml) and concentrated to remove residual triethylamine and give 4.54 g of the desired product as an oil.

Workup

customA 0.5 liter, 4-necked, round-bottom flask, equipped with an overhead stirrer
additionthermocouple, addition funnel and a nitrogen inlet/outlet
customdried in vacuo at 130° C. for 6 hours
additiona 2.5 M solution of n-butyllithium in hexanes (35 ml) was added over about 20 minutes
temperaturewhile maintaining the temperature at less than or equal to −60° C
temperaturewhile maintaining the temperature at less than or equal to −68° C
additionAfter the addition
stirringthe mixture was stirred for an additional 45 minutes
temperatureto warm to about 0° C.
waitheld at that temperature for 45 minutes
customAfter 3 hours reaction time at 0° C.
customThe tetrahydrofuran/hexane phase was separated from the lower aqueous phase
extractionThe aqueous phase was extracted with methylene chloride (4×100 ml)
washwashed with 100 ml of brine
dry with materialAfter drying over sodium sulfate and filtration, concentration in vacuo (bath temperature less than or equal to 40° C.)

Sources & evidence

ORD record: ord-b3c440627bed42b58afa7e172ec62591
Source dataset: uspto-grants-2001_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06248882B1

Reaction notes

Loading…