Resolution of 1-arylethylamines with 5-(1,2-O-isopropylidene-3,6-anhydro- α-D-glucofuranosyl) hydrogen phthalate

Article abstract of DOI:10.1016/j.tetasy.2003.07.002

The potential of the hydrogen phthalate of 1,2-O-isopropylidene-3,6- anhydro-α-D-glucofuranose 1 obtainable by the reaction of phthalic anhydride with 1,2-O-isopropylidene-3,6-anhydro-α-D-glucofuranose 8 as a new resolving agent is shown. The salts between 1 and (RS)-1-arylethylamines 2-6 and (RS)-1-arylpropylamine 7 selectively crystallize 1·(R)-salts allowing the recovery of the corresponding (R)-amines 2-7. The more soluble 1·(S)-salts were analogously processed to obtain (S)-amines, respectively. In all of the cases (R)- and (S)-amines 2-7 were obtained in high chemical yield and enantiomeric excess >98%. Resolving agent 1 has been recovered in a quantitative yield and high purity.

Full text of DOI:10.1016/j.tetasy.2003.07.002

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2683–2685
Resolution of 1-arylethylamines with
5
-(1,2-O-isopropylidene-3,6-anhydro-a- -glucofuranosyl)
D
hydrogen phthalate
Hari Babu Mereyala* and Pallavi Pola
Speciality, Gas Based Chemicals and Processes Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 23 June 2003; accepted 12 July 2003
Abstract—The potential of the hydrogen phthalate of 1,2-O-isopropylidene-3,6-anhydro-a-
D-glucofuranose 1 obtainable by the
reaction of phthalic anhydride with 1,2-O-isopropylidene-3,6-anhydro-a- -glucofuranose 8 as a new resolving agent is shown. The
D
salts between 1 and (RS)-1-arylethylamines 2-6 and (RS)-1-arylpropylamine 7 selectively crystallize 1·(R)-salts allowing the
recovery of the corresponding (R)-amines 2–7. The more soluble 1·(S)-salts were analogously processed to obtain (S)-amines,
respectively. In all of the cases (R)- and (S)-amines 2–7 were obtained in high chemical yield and enantiomeric excess >98%.
Resolving agent 1 has been recovered in a quantitative yield and high purity.
©
2003 Published by Elsevier Ltd.
Approximately 80% of drugs currently in development
are chiral. Although some may be prepared by chiral
synthesis, many will be produced through the resolution
propylidene-3,6-anhydro-a-
D
-glucofuranose
1
which
has proved to be efficient in resolving a range of
(RS)-1-arylethylamines 2–6 and (RS)-1-phenylpropyl-
amine 7.
1
of racemate. In spite of revolutionary advances in
catalytic asymmetric synthesis and enzymatic kinetic
resolution methods, the diastereomeric salt crystalliza-
The salts between 1 and the isomers of 1-phenyl-2,
2
tion method still constitutes the most practical way to
1
-(4-bromophenyl)-3,
methylphenyl)-5, 1-(2-naphthyl)-ethylamine 6 and 1-
phenylpropylamine selectively crystallized the
·(R)-diastereomeric salt from methanol allowing the
1-(4-chlorophenyl)-4,
1-(4-
separate a racemic mixture. The resolution of 1-
arylethylamines by a diastereomeric salt formation
method has been studied via the use of acidic resolving
agents such as mandelic acid and its related deriva-
7
1
recovery of (R)-1-arylethylamines from the correspond-
ing racemate in high chemical yields and enantiomeric
excesses (Scheme 1, Table 1). The corresponding (S)-1-
arylethylamines were also isolated from the more solu-
ble 1·(S)-salts present in the mother liquors in high
yield and enantiomeric excess.
3
4
tives, naphthylglycolic acid and the hydrogen phtha-
5
late of isopropylidene glycerol. Notwithstanding these
advances, there is still a need for designing an acidic
resolving agent that is (i) efficient against a wide range
of primary and secondary racemic amines, (ii) abun-
dantly available, (iii) water insoluble for recovery in
common organic solvents and (iv) has good chemical
and configurational stability. We focused our attention
on overcoming these short falls while targeting the
development of a new chiral acidic resolving agent
making use of abundantly available carbohydrate
templates.
Reaction of 1,2-O-isopropylidene-3,6-anhydro-a-
D
-glu-
cofuranose 8 (40 g, 0.16 mol) and phthalic anhydride
23.35 g, 0.16 mol) in dry pyridine (24 ml) according to
the usual procedure and work up gave 1 in a quantita-
6
(
2
D
5
tive yield as a syrup; [h]
=+15.0 (c 2.0, CHCl )
3
[
(99.4%, by HPLC). Compound 1 was characterized by
1
Herein we report the development of a new acidic
resolving agent, the hydrogen phthalate of 1,2-O-iso-
a H NMR spectrum with the appearance of H-1% at l
5.88 (d, 1H, J =4.3 Hz), H-5 at l 5.20–5.40 (m, 1H)
1,2
and aromatic protons at l 7.45–7.95 (m, 4H); FAB-MS,
+
m/z 351 (M +H). The crude oily hydrogen phthalate 1
*
Corresponding author. Tel.: +91-40-27193137; fax: +91-40-
7160387, 27160757; e-mail: mereyalahb@rediffmail.com
2
(21 g, 60 mmol) was diluted in methanol (80 ml),
0
957-4166/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2003.07.002

2
684
H. B. Mereyala, P. Pola / Tetrahedron: Asymmetry 14 (2003) 2683–2685
Scheme 1.
treated with (RS)-2 (7.2 g, 60 mmol) briefly boiled for
min and allowed to slowly cool (3 h) to 15°C. The
precipitate formed was filtered and washed with cold
efficiently by this procedure to obtain (R)- and (S)-
amines 3–7 respectively in good yield and e.e (Table 1,
entries ii–vii). 13.0 g of the diastereomeric 1·(R)-4 salt
obtained by the first crystallization (entry iii) was
recrystallized in dichloromethane/hexane to obtain 11.7
g (90%) of salt, that on decomposition gave (R)-4 (97%
yield) in enhanced purity (99.3% e.e). In all cases, the
resolving agent 1 was recovered quantitatively and in
good purity. Further investigations about 1’s reuse and
additional application may reveal its full potential.
3
methanol (20 ml) to obtain 13.1 g the corresponding
1
·(R)-2 diastereomeric salt (Table 1). The salt was
treated with 10% aq. HCl (100 ml) after which
dichloromethane (100 ml) was added to recover the
hydrogen phthalate
aqueous phase was neutralized with 10% aq. NaHCO3
80 ml) and extracted into dichloromethane (50 ml) to
isolate 3.30 g of (R)-2 (Table 1, entry i in high e.e
1
quantitatively. The acidic
(
(
(
98.8%) on the basis of HPLC on a chiral Crownpak
CR ) column. The mother liquors were concentrated
In summary the development and application of a new
acidic resolving agent hydrogen phthalate of 1,2-O-iso-
+
to a residue and recrystallized in chloroform/hexane to
afford 12.95 g (27 mmol) of the diastereomeric salt
propylidene-3,6-anhydro-a- -glucofuranose 1 that can
D
be used to obtain enantiomerically pure (>98%) (R)-
and (S)-1-arylethylamines from the corresponding race-
mates has been achieved. Among several other carbo-
hydrate templates studied for the purpose, 1 was found
to be superior. Its stability, quantitative recovery and
1
·(S)-2, (entry i). After analogous treatment it gave 3.28
g of (S)-2 in good yield and e.e (99.0%) (entry i). All
the other (RS)-1-aryl ethylamines 3–6 (60 mmol) and
(
RS)-1-phenylpropylamine 7 (60 mmol) were resolved
Table 1. Preparation of (R) and (S)-1-arylethylamines from the corresponding racemates by selective crystallization of the
a
respective salts with 1
f
f
Entry
(RS)-Amine
1·(R)-Salt
1·(S)-salt
(%yield ), mp , [h]
(R)-Amine
(S)-Amine
b
c
e
D
b
c
e
D
b
d
b
d
(
%yield ), mp , [h]
(%yield ), [h] , ee
(%yield ), [h] , ee
D
D
i
ii
iii
iv
v
2
3
4
5
6
7
(92.8), 142, +22
(91.0), 150, +19
(91.8), 148, +28
(92.2), 134, +12
(91.6), 135, −23
(89.5), 140, +22
(90.3), 134, +25
(89.3), 125, +12
(89.5), 127, +26
(87.0), 126, +11
(86.1), 130, −19
(90.5), 130, +26
(97.4), +29.4, 98.8
(97.6), +24.3, 98.7
(96.7), +23.2, 98.5
(98.5), +32.1, 99.0
(96.8), +20.4, 98.9
(97.8), +19.8, 98.9
(97.7), −29.5, 99.0
(98.8), −24.2, 98.5
(97.1), −23.1, 98.6
(97.0), −31.9, 98.7
(96.5), −20.6, 99.0
(98.1), −19.7, 98.6
vi
a
All crystallizations were carried out using equivalent amounts of racemic amines and 1.
Relative to the theoretical amount.
b
c
In °C.
d
7
+
%
Enantiomeric excess of the amines determined by reverse-phase chiral HPLC analysis on a Crownpak(CR) column from Daicel (elutant aq.
HClO4 at pH 1.5).
At 25°C.
e
f
Specific rotation was determined and the value compared at the concentration and temperature referred to in their corresponding references.5

H. B. Mereyala, P. Pola / Tetrahedron: Asymmetry 14 (2003) 2683–2685
2685
ability to resolve both the enantiomers indicate the
potential of the resolving agent. Application of the
resolving agent for other amines will be reported in due
course.
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