Solution-phase parallel synthesis of substituted 1,2-ethyl and 1,3-propyl diamines

Article abstract of DOI:10.1016/j.tetlet.2003.08.067

A solution-phase synthesis for the preparation of substituted 1,2-ethyl and 1,3-propyl diamines has been developed for the purpose of producing diverse lead generation libraries with a minimal scaffold. Crude products were obtained in high purity and further purified through mass guided preparative HPLC.

Full text of DOI:10.1016/j.tetlet.2003.08.067

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7575–7577
Solution-phase parallel synthesis of substituted 1,2-ethyl and
1,3-propyl diamines
Ido D. Dagan and Christopher T. Lowden*
PPD Discovery, 3500 Paramount Parkway, Morrisville, NC 27560, USA
Received 23 July 2003; revised 15 August 2003; accepted 18 August 2003
Abstract—A solution-phase synthesis for the preparation of substituted 1,2-ethyl and 1,3-propyl diamines has been developed for
the purpose of producing diverse lead generation libraries with a minimal scaffold. Crude products were obtained in high purity
and further purified through mass guided preparative HPLC.
© 2003 Elsevier Ltd. All rights reserved.
In recent years, the pharmaceutical industry has come
to rely greatly on solution-phase parallel synthesis1 as a
means of production for lead generation libraries of
small molecules. Chemists working in this area are
constantly looking for synthetic sequences that facili-
tate the expedient production of large numbers of pure
compounds with a high degree of structural diversity
and drug-like features. The following parallel synthesis
allows for variable substitution at both ends of the
diamine scaffold, and sources of diversity include alde-
hydes, alkyl halides and secondary amines. The 1,2-
ethyl- and 1,3-propyl-diamine substructure provides an
excellent core for a drug-like lead generation library,
without introducing a bulky scaffold that limits the
diversity of the library. Minimization of the scaffold
allows the library’s diversity to be defined by its source
reagents rather than the scaffold. Additionally, the
reagents and equipment necessary for library synthesis
are relatively inexpensive, making the cost per com-
pound minimal. Finally, substituted diamines such as
these have proven to possess biological activities, mak-
ing them interesting targets for a general diversity
library.2
In this procedure (Scheme 1), aldehydes were subjected
to reductive amination with ethanolamine, or 1-
amino-3-propyl alcohol. Resulting secondary amines
were alkylated with alkyl halides. Primary alcohols
were converted to chlorides, and used to alkylate
various secondary amines, giving the final products up
to 4 sites of diversity. The first two steps were per-
formed on relatively large scale with minimal work-up
and purification. The final alkylation was carried out
on a 160 mmol scale in a commercially available 96-well
array of glass vials.3 Over 600 final products were
prepared.
Chloride intermediates were analyzed through proton
NMR,4 and low resolution mass spectroscopy. Final
products were purified through mass guided preparative
HPLC and analyzed through HPLC (UV detection, 210
nm, 254 nm, ELSD), and low resolution mass spec-
troscopy. Figure 1 shows row and column reagents
from a selected library plate. Table 1 shows the results
of this analysis based on a theoretical yield of 160
mmol. Figure 2 shows example products from the
library.
Scheme 1. Synthesis of diamines.
Keywords: solution-phase parallel synthesis; 1,2-ethyldiamines; 1,3-propyldiamines.
* Corresponding author. E-mail: christopher.lowden@rtp.ppdi.com
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.067

7576
I. D. Dagan, C. T. Lowden / Tetrahedron Letters 44 (2003) 7575–7577
Figure 1. Example column and row reagents.
Table 1. Yield and purity of selected final products from example plate
Well locationa
Weight (mg)
Mol. wt.
Amount (mmol)
% Purityb
% Yieldc
A1
A11
B9
C5
C8
D10
E4
E5
32.0
49.7
19.0
21.3
21.2
38.6
35.3
35.6
17.5
29.6
45.5
23.1
351.54
448.66
379.38
408.61
393.60
441.44
429.61
388.56
365.35
435.63
440.65
371.38
91.03
110.77
50.08
52.13
53.86
87.44
82.17
91.62
47.90
67.95
103.26
62.20
81.1
90.0
97.4
94.6
94.0
92.8
82.8
89.2
94.2
81.3
87.8
96.9
46.1
62.3
30.5
30.8
31.6
50.7
42.5
51.1
28.2
34.5
56.6
37.7
F2
G4
G11
H2
Averages:
30.7
404.53
75.03
90.2
41.9
a Well locations in 96 well plate. A–H refer to rows, 1–12 refer to columns.
b % Purity based on HPLC analysis (lower value of either ELSD or UV detection is reported).
c % Yield calculated based on the following formula: (amount/160 mmol)×% purity.
1. General procedure for the synthesis of intermediates
period of 15 min, and stirred at 0°C for an additional
15 min. Water (100 mL) was added to the reaction.
Most of the methanol was removed in vacuo. The
resulting aqueous solution was extracted with chloro-
form and or ethyl acetate, dried over sodium sulfate,
filtered, and concentrated in vacuo to yield the sec-
ondary amine product. Secondary amine products were
To a stirring solution of 1-amino-2-ethyl alcohol or
1-amino-3-propyl alcohol (100 mmol) in methyl alcohol
(50 mL) was added aldehyde (100 mmol). The reaction
was cooled to 0°C in an ice bath, and sodium borohy-
dride (100 mmol) was then added portion-wise over a

I. D. Dagan, C. T. Lowden / Tetrahedron Letters 44 (2003) 7575–7577
7577
Figure 2. Example products.
Acknowledgements
dissolved in DMF (30 mL), and potassium carbonate
(1.2 equiv.) was added. Alkyl halides (1.1 equiv.) were
then added. The reaction was stirred at rt for 2–24 h.
Water (200 mL) was added, the aqueous solution was
extracted with ethyl acetate (200 mL), and the organic
phase was washed with water (3×300 mL). The organic
phase was dried with sodium sulfate, filtered, and con-
centrated in vacuo. Amino alcohol products were dis-
solved in chloroform (50 mL), and thionyl chloride (2.0
equiv.) was added. The reaction was stirred at rt for
2–24 h, diluted with chloroform (100 mL) and washed
with saturated aqueous sodium bicarbonate (2×100
mL). The organic phase was dried with sodium sulfate,
filtered, and concentrated in vacuo to yield the desired
alkyl chloride intermediate for plate synthesis. In most
cases, the products required purification by flash
chromatography.
The authors would like to thank Charles Arrington and
Ben Carroll for their work on HPLC and mass spectro-
scopic analysis.
References
1. For recent reviews on solution-phase parallel synthesis,
see: (a) Hall, D. G.; Manku, S.; Wang, F. J. Comb. Chem.
2001, 3, 125–150; (b)Thomson, L. A. Curr. Opin. Chem.
Biol. 2000, 4, 324–337; (c) Sun, C. M. Comb. Chem. High
Throughput Screen. 1999, 6, 299–318; (d) Wentworth, P.
Trends Biotechnol. 1999, 17, 448–452.
2. (a) Badolo, L.; Hanocq, M.; Dubois, J. Cell Biol. Toxicol.
1998, 14, 419–428; (b) DeCosta, B. R.; Radesca, L.;
DiPaolo, L.; Bowen, W. D. J. Med. Chem. 1992, 35,
38–47; (c) Choi, S.-W.; Elmaleh, D. R.; Hanson, R. N.;
Fischman, A. J. J. Med. Chem. 1999, 42, 3647–3656; (d)
Sawanishi, H.; Wakusawa, S.; Murakami, R.; Miyamoto,
K.; Tanaka, K.; Yoshifuji, S. Chem. Pharm. Bull. 1994, 42,
1459–1462.
2. General procedure for plate synthesis and
purification
Solutions of alkyl chlorides A–H (0.8 M in DMF),
secondary amines 1–12 (0.8 M in DMF) and diiso-
propylethylamine (2.0 M in DMF) were prepared.
Alkyl chloride solutions A–H (200 mL/well) were added
to their corresponding rows in 96-well plates. Diiso-
propylethylamine solution (100 mL/well) was then
added to each well. Next, amines 1–12 (200 mL/well)
were added to their corresponding columns. The result-
ing solutions were capped securely with strip caps and
heated to 70°C in aluminum blocks for 3 days. Strip
caps were then removed, and solvent was evaporated to
dryness with a nitrogen stream. Crude products were
evaluated through mass spectroscopy and HPLC. Over
90% of the reaction wells yielded the desired molecular
weight. Final products were purified through mass-
guided preparative HPLC. Product containing fractions
were transferred to tared vials, concentrated in vacuo,
and evaluated through HPLC with UV (254 nm), and
ELS detection.
3. A 96-position microtiter plate formatted aluminum heat-
ing block obtained from Kontes was loaded with 1 mL
glass vials from Wheaton.
1
4. Example H NMR data for plate B3 row reagents; com-
pound A: (250 MHz, CDCl3) l 7.30–7.12 (10H, m), 3.63
(2H, s), 3.50 (2H, t, J=6.5 Hz), 2.77–2.67 (4H, m), 2.64
(2H, t, J=7.0 Hz), 1.93–1.83 (2H, m); compound C: (250
MHz, CDCl3) l 7.28–7.15 (6H, m), 6.96–6.87 (2H, m),
3.86 (2H, d, J=0.8 Hz), 3.53 (2H, t, J=6.5 Hz), 2.80–2.70
(4H, m), 2.66 (2H, t, J=7.0 Hz), 1.94–1.83 (2H, m);
compound D: (250 MHz, CDCl3) l 7.55 (1H, d, J=8.3
Hz), 7.35 (1H, d, J=2.3 Hz), 7.26–7.22 (2H, m), 6.96–6.90
(2H, m), 3.81 (2H, d, J=0.8 Hz), 3.68 (2H, s), 3.57 (2H, t,
J=6.8 Hz), 2.64 (2H, t, J=6.8 Hz), 2.00–1.90 (2H, m);
compound H: (250 MHz, CDCl3) l 7.62 (1H, d, J=8.3
Hz), 7.36 (1H, d, J=2.3 Hz), 7.27–7.23 (2H, m), 6.95–6.92
(2H, m), 3.90 (2H, s), 3.79 (2H, s), 3.54 (2H, t, J=6.8 Hz),
2.90 (2H, t, J=7.3 Hz).