Production Standard Operating Protocol
(SOP)
Progenta Zwitterionic Acid Labile Surfactant
[ALS-200-1mg / ALS-200-5mg]
[ALS-210-1mg / ALS-210-5mg]
[ALS-220-1mg / ALS-220-5mg]
I:
Production SOP:
General Methods and Materials:
1
H NMR and 13C NMR spectra were recorded on Varian 600 MHz spectrometer.
Chemical shifts were reported relative to CDCl3 ( 7.24 ppm) for 1H NMR and CDCl3 (
77.0 ppm) for 13C NMR. Infrared (IR) spectra were obtained on a FT-IR spectrometer.
Sorbtech 60A (230-400 mesh) silica gel was used for flash chromatography. Analytical
thin-layer chromatography was performed with precoated glass-backed plates (K6F 60Å,
F254) and visualized by quenching of fluorescence and by charring after treatment with panisaldehyde or phosphomolybdic acid or potassium permanganate stain. Rf values were
obtained by elution in the stated solvent ratios (v/v). Ether (Et2O), methylene chloride
(CH2Cl2) and toluene were dried by passing through activated alumina (8 x 14 mesh)
column with argon gas pressure. Commercial reagents were purchased from Fisher
Scientific or Sigma-Aldrich and used without purification unless otherwise noted. Air
and/or moisture-sensitive reactions were carried out under an atmosphere of
argon/nitrogen using oven/flamed-dried glassware and standard syringe/septa techniques.
Hexyl 2,2-bis(hexyloxy)propanoate (3)1.
O
O
O
1
Me +
OH
2
p-TsOH
Toluene
84%
O
O
O
3
O
To a solution of methyl pyruvate 1 (10.0 g, 98.0 mmol) in toluene (100 mL) was added 1hexanol 2 (40.1 g, 392 mmol) and p-TsOH (186 mg, 0.98 mmol). The mixture was heated
to reflux for 10 hours with azeotropic removal of water from the reaction mixture. The
reaction was quenched with saturated NaHCO3 (100 mL), and the reaction mixture was
extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed
with brine (100 mL) and dried over anhydrous sodium sulfate. The solvent was removed
and the residue was purified by silica gel chromatography (1→10% ethyl acetate/hexane)
1
Ono, D.; Yamamura, S.; Nakamura, M.; Takeda, T. J. Ole. Sci., 2004, 53 (2), 89-95.
to give hexyl 2,2-bis(hexyloxy)propanoate 3 (29.5 g, 84%) as a colorless oil: Rf (15%
EtOAc/hexane) = 0.53; IR (thin film, cm-1) 2956, 2930, 2860, 1746 (C=O), 1467, 1280,
1137, 1062. 1H NMR (600 MHz, CDCl3)  4.14 (t, J = 7.2 Hz, 2H), 3.48 (ddd, J = 9.0,
7.2, 6.6 Hz, 2H), 3.35 (ddd, J = 9.0, 7.2, 6.6 Hz, 2H), 1.65-1.63 (m, 2H), 1.59-1.54 (m,
4H), 1.49 (s, 3H), 1.35-1.24 (m, 18H), 0.86 (t, J = 7.2 Hz, 9H); 13C NMR (150 MHz,
CDCl3) 170.2, 99.5, 65.4, 62.6, 31.7, 31.3, 29.7, 28.5, 25.8, 25.5, 22.6, 22.5, 21.9, 14.0,
13.9.
2,2-Bis(hexyloxy)-N,N-dimethylpropanamide (4).
O
NH
O
O
3
O
O
O
o
THF, 70 C
92%
O
N
4
To a solution of ester 3 (35.8 g, 100.0 mmol) in THF (100 mL) was added a solution of
dimethyl amine in THF (100 mL, 2M, 200 mmol). The solution was refluxed for 24 h in a
pressure tube. The solvent was removed and the residue purified by silica gel
chromatography (20→40% ethyl acetate/hexane) to give 2,2-bis(hexyloxy)-N,Ndimethylpropanamide 4 (27.7 g, 92%) as a colorless oil: Rf (50% EtOAc/hexane) = 0.56;
IR (thin film, cm-1) 2929, 2863, 1652, 1461, 1389, 1368, 1104, 1061, 954, 909; 1H NMR
(600 MHz, CDCl3) 3.43(dt, J = 9.0, 6.6 Hz, 2H), 3.36 (dt, J = 9.0, 6.6 Hz, 2H), 3.18 (s,
3H), 2.91 (s, 3H), 1.56-1.51 (m, 4H), 1.48 (s, 3H), 1.33-1.22 (m, 12H), 0.84 (t, J = 7.2 Hz,
6H); 13C NMR (150 MHz, CDCl3) 169.5, 101.4, 62.4, 38.0, 37.1, 31.6, 29.8, 25.9, 22.5,
20.4, 13.9.
2,2-Bis(hexyloxy)-N,N-dimethylpropan-1-amine (5).
O
LiAlH4
O
O
O
O
94%
4
N
5
N
To a mixture of LiAlH4 (3.46 g, 91.2 mmol) in Et2O (200 mL) was added a solution of
ester 3 (25.0 g, 82.9 mmol) in Et2O (100 mL). After addition, the mixture was refluxed
for 6 hours. The reaction mixture was cooled to 0 oC and quenched with ethyl acetate (20
mL) and H2O (20 mL). The mixture was added saturated potassium sodium tartrate (300
mL) and stirred at 23 oC for 12 hours. The mixture was extracted with Et2O (2 x 200 mL)
and the combined organic layers were dried over anhydrous sodium sulfate. The solvent
was removed and the residue was purified by silica gel chromatography (10→20% ethyl
acetate/hexane + 1% Et3N) to give 2,2-bis(hexyloxy)-N,N-dimethylpropan-1-amine 5
(22.41 g, 94%) as a colorless oil: Rf (30% EtOAc/hexane + 2% Et3N) = 0.62; IR (thin
film, cm-1) 2930, 2863, 2817, 2766, 1460, 1378, 1130, 1063, 1045, 955, 876; 1H NMR
(600 MHz, CDCl3) 3.38 (t, J = 7.2 Hz, 4H), 2.40 (s, 2H), 2.27 (s, 6H), 1.52-1.47 (m,
4H), 1.36 (s, 3H), 1.34-1.24 (m, 12H), 0.86 (t, J = 7.2 Hz, 6H); 13C NMR (150 MHz,
CDCl3) 101.4, 64.4, 60.4, 47.2, 31.8, 30.1, 26.0, 22.6, 21.6, 14.0.
2,2-Bis(hexyloxy)-N,N-Dimethyl-N-(3-sulfopropyl)-1-propanaminium inner salt2
O
S
O
5
O
N
O
O
O
87%
6
O
N
SO3
To a solution of amine 5 (5.80 g, 20.2 mmol) in acetone (40 mL) was added 1,3-propane
sultone (4.93 g, 40.4 mmol). The reaction mixture was stirred at 60 oC for 10 h and then
the reaction was quenched with DMAP (2.50 g, 20.5mmol). The reaction mixture was
stirred for another 10 h before being poured into aqueous NaHCO3 (sat., 100 mL). The
solution was extracted with chloroform (3 x 100 mL). The combined organic layers was
washed with brine and dried over anhydrous sodium sulfate. The solvent was removed to
give the zwitterionic surfactant 6 (7.18 g, 87%) as a white solid: Rf (80% MeOH/EtOAc)
= 0.58; IR (thin film, cm-1) 2935, 2861, 2236, 1471, 1197, 1039, 912, 731; 1H NMR (600
MHz, CDCl3) 3.86-3.83 (m, 2H), 3.51-3.47 (m, 4H), 3.49 (s, 2H), 3.30 (s, 6H), 2.87 (t,
J = 6.6 Hz, 2H), 2.30-2.23 (m, 2H), 1.55-1.50 (m, 4H), 1.48 (s, 3H), 1.32-1.24 (m, 12H),
0.86 (t, J = 7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) 100.6, 67.9, 65.8, 62.9, 52.5,
47.7, 31.5, 29.8, 25.9, 22.5, 21.6, 19.7, 14.0.
II.
2
Quality Assurance Testing
Quality assurance testing and Critical Micellular Concentration (CMC)
determination are performed by NMR analysis.
Rouhana, L. L.; Jaber, J. A.; Schlenoff, J. B. Langmuir, 2007, 23(26), 12799-12801.