N,N-bis(2-chloroethyl)-(R)-alanine ethyl ester → (R)-4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-alpha-methyl-1-piperazineacetic acid ethyl ester

HRID 854064Notes

Reaction equation

HRID 854064 reaction equation
[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:12]([O:14][C:15](=[O:25])[C@@H:16]([CH3:24])[N:17]([CH2:21][CH2:22]Cl)[CH2:18][CH2:19]Cl)[CH3:13]>ClC1C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:25])[C@@H:16]([CH3:24])[N:17]1[CH2:18][CH2:19][N:11]([C:10]2[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)[CH2:22][CH2:21]1)[CH3:13]

Participants

4

Reactant 2

HCID 10172862N,N-bis(2-chloroethyl)-(R)-alanine ethyl esterHCID 117883872,3-Dihydro-1,4-benzodioxin-5-amine

Product 1

HCID 11267179(R)-4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-alpha-methyl-1-piperazineacetic acid ethyl ester

Reagents, catalysts & solvents 1

HCID 7964ChlorobenzeneSolvent

Conditions

Temperature
130 °C

Procedure

A solution of 2,3-dihydro-1,4-benzodioxin-5-amine (0.327 g; 2.16 mmol) in chlorobenzene (2 mL) is added to a solution of N,N-bis(2-chloroethyl)-(R)-alanine ethyl ester (trifluoromethanesulfonic acid salt; 0.850 g; 2.16 mmol) in the same solvent (2 mL). The stirred reaction mixture is heated at 130° C. for 15 hours, the volatiles are removed on a rotavap, and the semi-solid residue is partitioned between 10% sodium bicarbonate (15 mL) and ether. Organic extracts are washed with brine, dried over magnesium sulfate, and filtered. TLC (chloroform) shows formation of a new product with RF 0.15, (R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-α-methyl-1-piperazineacetic acid ethyl ester. Upon addition of 1N ethereal HCl, (R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-α-methyl-1-piperazineacetic acid ethyl ester is converted into its hydrochloride salt that is collected by filtration; 0.615 g (80%), mp 168–171° C. The salt can be recrystallized from ethanol-ether, or acetone-ether. 1H NMR (300 MHz, DMSO-d6) δ 1.25 (t, J=7.1 Hz, 3H), 1.58 (d, J=7.2 Hz, 3H), 3.16 (m, 2H), 3.36 (m, 2H), 4.23 (m, 4H), 4.26–4.38 (m, 3H), 4.48 (b, 4H), 6.52 (d, J=7.9 Hz, 1H), 6.57 (d, J=8 Hz, 1H), 6.76 (t, J=8 Hz, 1H), 11.3 (b, <1H).

Workup

  1. customThe stirred reaction mixture
  2. customthe volatiles are removed on a rotavap
  3. customthe semi-solid residue is partitioned between 10% sodium bicarbonate (15 mL) and ether
  4. washOrganic extracts are washed with brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. additionUpon addition of 1N ethereal HCl, (R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-α-methyl-1-piperazineacetic acid ethyl ester
  8. filtrationis collected by filtration
  9. customThe salt can be recrystallized from ethanol-ether, or acetone-ether

Sources & evidence

ORD record
ord-686ea92fbe944d68a5077e4b9e1b26d3
Source dataset
uspto-grants-2007_08
Patent number
US07256289B2

Reaction notes

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