Chemo-enzymatic synthesis of levodropropizine

Article abstract of DOI:10.1016/S0014-827X(03)00189-7

Levodropropizine, an antitussive drug, was prepared in high enantiomeric excess in three steps, starting from dichloroacetone (2). Monosubstitution of 2 with sodium benzoate and subsequent baker's yeast reduction stereoselectively afforded the corresponding chlorohydrin in 73% ee, which was converted to levodropropizine and enantiomerically enriched up to 95% ee by fractional crystallisation.

Full text of DOI:10.1016/S0014-827X(03)00189-7

Il Farmaco 58 (2003) 1029Á1032
/
www.elsevier.com/locate/farmac
Chemo-enzymatic synthesis of levodropropizine
Emilia Caselli, Giovanni Tosi, Arrigo Forni, Maria Bucciarelli, Fabio Prati *
Dipartimento di Chimica, Universita` di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy
Received 26 February 2003; accepted 10 June 2003
Abstract
Levodropropizine, an antitussive drug, was prepared in high enantiomeric excess in three steps, starting from dichloroacetone (2).
Monosubstitution of 2 with sodium benzoate and subsequent baker’s yeast reduction stereoselectively afforded the corresponding
chlorohydrin in 73% ee, which was converted to levodropropizine and enantiomerically enriched up to 95% ee by fractional
crystallisation.
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: Levodropropizine; Baker’s yeast; 3-Chloro-1,2-propanediol; 1-Benzoyloxy-3-chloropropan-2-ol
1. Introduction
Racemic dropropizine, i.e. (9
zinyl)-1,2-propanediol (1), has long been used as an
2. Experimental
/
)-3-(4-phenyl-1-pipera-
2.1. General
antitussive drug; more recently, it has been demon-
strated that the (S)-(ꢀ) enantiomer of 1 displays the
same antitussive activity with lower side effects on the
central nervous system [1,2], and nowadays this drug is
/
1H and 13C NMR spectra were recorded in CDCl3
solution on a Bruker DPX-200 MHz spectrometer;
chemical shifts are reported in d values from TMS as
internal standard; coupling constants (J) are given in
Hz. For mass spectral determinations a Finnigan MAT
SSQ A mass spectrometer was used (EI, 70 eV).
Elemental analyses were performed with a Carlo Erba
elemental analyzer 1110. Chromatographic purification
of compounds was performed on silica gel (particle size
sold as Levodropropizine, the (S)-(ꢀ
/
) enantiomer of
dropropizine.
Several synthetic routes to enantiomerically pure 1
have, therefore, been developed, including resolution
methods, both enzymatic [3,4] and non-enzymatic [5],
and the chiron synthon approach using (R)-glycidol
[6,7], (R)-glyceroltosylate [2] and (R)-3-chloropropane-
1,2-diol [8]. In view of the increasing interest in the
biocatalytic asymmetric synthesis of chiral intermediates
for pharmaceuticals [9], we report here on a new
0.05Á
PerkinÁ
were performed on a HewlettÁ
chromatograph; the conversions were evaluated on a
DB1 column (30 mꢂ0.53 mm i.d. and 5 mm film phase)
from J&W Scientific. The enantiomeric excess of (ꢁ)-4
was evaluated on a chiral ALPHA DEX 120 column (30
mꢂ0.25 mm i.d. and 0.25 mm film phase) purchased
from Supelchem, while the ee of (ꢀ)-1 was determined
/
0.20 mm). Optical rotations were measured on a
Elmer 241 polarimeter at 20 8C. GLC analyses
Packard 5890A gas
/
/
straightforward synthesis of (S)-(ꢀ)-1 in three steps
/
/
starting from dichloroacetone 2. The key step in the
asymmetric synthesis is the reduction of 1-benzoyloylxy-
3-chloropropane-2-one (3) by baker’s yeast (Saccaro-
/
/
mices cerevisiae) to furnish the chlorohydrin (R)-(ꢁ
/
)-4,
/
which can be readily converted to (S)-(ꢀ)-1.
/
by HPLC as described in the literature [7]. Fresh baker’s
yeast (Fala, Strasbourg) was purchased from a local
shop.
* Corresponding author.
E-mail address: prati.fabio@unimore.it (F. Prati).
´
0014-827X/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0014-827X(03)00189-7

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E. Caselli et al. / Il Farmaco 58 (2003) 1029Á1032
/
2.2. 1-Benzoyloxy-3-chloropropan-2-one (3) [10]
reduced pressure and the residue purified by column
chromatography (ethyl acetateÁlight petroleum 1:1 to
ethyl acetate 100%) to give (Á)-5 as a pale yellow oil
(83% yield), showing [a]Dꢃ 6.0 (c 3.0, H2O); (lit. [12]
(R)-(Á) [a]Dꢃ 8.2, c 1, H2O, 99.5% ee).
/
Dichloroacetone 2 (10 g, 79 mmol) was added in one
portion to a solution of NaHCO3 (4 g, 48 mmol) and
benzoic acid (4.8 g, 39 mmol) in dry DMF (150 ml) at
0 8C. The reaction was stirred at this temperature for 3
h, then at room temperature (r.t.) for a further 12 h. The
reaction mixture was diluted with H2O and extracted
/
/
ꢀ
/
/
/
Á
/
2.5. Levodropropizine (1)
with light petroleumÁethyl acetate (95:5); the collected
/
Phenyl-piperazine (0.71 ml, 4.65 mmol) was added to
organic phases were washed with water and brine and
dried over MgSO4. The solvent was removed under
reduced pressure and the residue purified by crystal-
a solution of (ꢁ)-4 (500 mg, 2.33 mmol), 73% ee in
/
isopropyl alcohol (10 ml). The resulting solution was
refluxed for 24 h, when TLC analysis showed disap-
pearance of 4 and formation of a new product, which
was occasionally isolated and identified as 1-benzoy-
loxy-3-(4-phenyl-piperazin-1-yl)-2-propanol (6). NaOH
(93 mg, 2.33 mmol) was added and the solution was
refluxed for a further 1.5 h. The resulting mixture was
cooled at room temperature, the white precipitate
(sodium benzoate) filtered off and the solvent removed
under reduced pressure. The crude residue was purified
by column chromatography (EtOAc:EtOH:NH4OH,
lization with boiling n-exane (250 ml) to give 5.78 g of 3
1
as pale yellow solid (70%), m.p. 89Á
/
92 8C. H NMR
(CDCl3): d 4.28 (2H, s, CH2Cl), 5.17 (2H, s, CH2O),
7.46Á7.57 (2H, m, meta Ph), 7.59Á7.70 (1H, m, para
Ph), 8.08Á
8.18 (2H, m, ortho Ph). 13C NMR (CDCl3): d
46.3, 67.3, 129.0, 130.3, 134.1, 166.2, 196.9. MS (EI, 70
eV) m/z: 213Á215 ([Mꢁ 214 (1), 211Á
1]ꢁ, 0.5%), 212Á
/
/
/
/
/
/
/
213 (2), 177 (4), 163 (25), 105 (100), 77 (44), 51 (16).
Anal. Found: C, 57.12; H, 4.85. Calc. for C10H9ClO3: C,
56.49; H, 4.27%.
8:2:0.3) to give 331 mg (60% yield) of (ꢀ
yellow solid, [a]Dꢃ 17.7 (c 3.0, CH2Cl2), ee 73%.
Crystallization from dichloromethane/hexane afforded
(ꢀ)-(1) (235 mg), ee 95%.
(ꢀ
)-1: 1H NMR (CDCl3): d 2.47 (1H, dd, J 12.5, 4.1,
NCH2CHOH), 2.55Á2.95 (5H, m, CH2CH2NPhꢁ
/)-1 as pale
/
ꢀ
/
2.3. 1-Benzoyloxy-3-chloropropan-2-ol (4) [11]
/
A suspension of baker’s yeast (43 g) in water (850 ml)
was preincubated at 30 8C for 30 min; thereafter, a
solution of the chloroketone 3 (2 g, 94 mmol) in DMSO
(5 ml) was added and the resulting mixture was
magnetically stirred at 30 8C for 3 h, until a GLC
analysis showed up to 95% conversion. The mixture was
centrifuged, the yeast re-suspended in water (50 ml) and
re-centrifuged. The collected aqueous phases were
/
/
/
NCH2CHOH), 3.24 (4H, t, J 5.0, CH2NPh), 3.40 (2H,
b, 2 OH), 3.57 (1H, dd, J 11.4, 4.8, CH2OH), 3.77 (1H,
dd, J 11.4, 3.7, CH2OH), 3.90 (1H, sextuplet, J 4.4,
CHOH), 6.90 (1H, t, 7.2, arom. para), 6.95 (2H, d, J
8.8, arom. ortho), 7.30 (2H, dd, J 7.2, 8.8, arom. meta).
13C NMR (CDCl3): d 49.6, 53.8, 60.9, 65.4, 67.6, 116.5,
120.3, 129.5, 151.5. MS (EI, 70 eV) m/z: 236 (Mꢁ), 205,
176, 175 (base peak), 160, 132, 120, 104, 88, 77, 70. Anal.
Found: C, 66.39; H, 8.77; N, 12.05. Calc.: C, 66.07; H,
8.53; N, 11.85%.
extracted with ethyl acetate (5ꢂ200 ml) and the organic
/
phases washed with water (100 ml), brine (50 ml) and
dried (MgSO4). The solvent was removed under reduced
pressure and the residue purified by column chromato-
graphy (light petroleumÁ
compound 4, which was recovered (60% yield) as a pale
yellow oil, [a]Dꢃ 2.0 (c 1, CHCl3), 73% ee.
)-4: H NMR (200 MHz, CDCl3): d 3.13 (1H, b,
/ethyl acetate 7:3) to afford
/
ꢁ
/
2.6. 1-Benzoyloxy-3-(4-phenyl-piperazin-1-yl)-2-
propanol
1
(ꢁ
/
OH), 3.70 (1H, dd, J 11.3, 5.0, CH2Cl), 3.75 (1H, dd, J
11.3, 5.7, CH2Cl), 4.24 (1H, quintet, J 5.3, CHOH),
(ꢀ
(CDCl3):
CH2CH2NPh), 2.80Á
3.15Á3.40 (4H, m, CH2NPh), 4.10Á
CHOH), 4.38 (1H, dd, J 11.5, 5.6, CH2O), 4.47 (1H,
dd, J 11.5, 4.1, CH2O), 6.91 (1H, tt, J 7.2, 1.0, meta
PhN), 6.96 (2H, dd, J 8.8, 1.0, ortho Ph), 7.31 (2H, dd, J
/
)-6: [a]Dꢃ
/
ꢀ
/
6.8 (c 1.03, CHCl3). 1H NMR
2.75 (4H, m, NCH2CHOHꢁ
3.00 (2H, m, CH2CH2NPh),
4.28 (1H, m,
4.39Á
/
4.58 (2H, m, CH2O), 7.38Á/7.51 (2H, m, meta Ph),
d
2.55Á
/
/
7.52Á
/
7.65 (1H, m, para Ph), 8.01Á
/
8.11 (2H, m, ortho
Ph). 13C NMR (50 MHz, CDCl3): d 46.4, 66.1, 70.1,
125.2, 128.9, 130.1, 133.8, 167.1. MS (EI, 70 eV) m/z:
/
/
/
215Á
/
217 ([Mꢁ
/
1]ꢁ), 197Á
199, 165, 123, 105 (base peak),
92, 77, 51. Anal. Found: C, 56.08; H, 5.29. Calc.: C,
/
55.96; H, 5.17%.
8.8, 7.3, meta PhN), 7.44Á
/
7.66 (3H, m, metaꢁ
/
para
PhCO), 8.05Á
/
8.15 (2H, m, ortho PhCO). 13C NMR
(CDCl3): d 49.6, 53.2, 60.8, 65.7, 67.4, 116.5, 120.3,
128.8, 129.5, 130.1, 133.5, 151.5, 166.9. MS (EI, 70 eV)
2.4. (R)-3-Chloro-1,2-propanediol (5) [12]
A solution of (ꢁ
NaOH (28 mg, 0.70 mmol) in absolute ethanol (5 ml)
was refluxed for 2 h. The solvent was removed under
/
)-4 (0.150 g, 0.70 mmol), 73% ee, and
m/z: 341 ([Mꢁ
1]ꢁ), 340, 176, 175 (base peak), 160, 132,
105, 77, 70. Anal. Found: C, 69.71; H, 7.93; N, 8.19.
Calc.: C, 70.56; H, 7.61; N, 8.02%.
/

E. Caselli et al. / Il Farmaco 58 (2003) 1029Á
/1032
1031
i
Scheme 1. (i) NaHCO3, ArCOOH, DMF; (ii) Baker’s Yeast, water, 30 8C, 3 h; (iii) NaOH, EtOH, reflux 2.5 h; (iv) 1-phenylpiperazine, PrOH,
reflux, 24 h, then NaOH, reflux 1 h.
3. Results and discussion
enzyme inhibitors, such as allyl alcohol, allyl bromide
[11] or cysteine [15], lowered conversions and enantio-
selectivity. It is noteworthy that the literature recently
reported the synthesis of 3 (in two steps from 3-chloro-
This new three-step procedure, developed for the
asymmetric synthesis of levodropropizine, depicted in
Scheme 1, starts from dichloroacetone (2): the primary
alcoholic functionality is introduced as benzoic ester by
nucleophilic displacement of one chlorine atom, afford-
ing compound 3, and the stereoselective reduction of the
prochiral ketonic group affords the secondary alcoholic
moiety (compound 4); finally, the 4-phenyl-1-piperazi-
nyl group is introduced with a second nucleophilic
displacement with 1-phenylpiperazine.
In the first step, the monosubstitution of a chlorine
atom of dichloroacetone is achieved in DMF solution by
in situ generated sodium benzoate: the reaction proceeds
at room temperature, affording 1-benzoyloxy-3-chloro-
propane-2-one (3), recovered in 70% yield after extrac-
tion and subsequent crystallisation of the crude from
boiling hexane. Monosubstitution at dichloroacetone,
albeitalready reported [13], is not easily achievable
owing to the high reactivity of both the chlorine atoms;
the nucleophilic displacement here described occurs
under mild conditions with a weak nucleophile, selec-
tively affording the desired product in 70% chemical
1,2-propanediol 5) and its biocatalytic reduction to (ꢀ)-
/
4 [14] with different microorganisms: the present
approach does appear to be an improvement in the
synthesis of the haloketone and shows opposite stereo-
selectivity. The absolute configuration of (ꢁ)-4 ob-
/
tained by yeast reduction was established as (R), based
upon chemical correlation with the configurationally
known (R)-(ꢀ
which was in fact obtained by reaction of (ꢁ
ethanolic sodium hydroxide.
Compound (R)-(ꢁ)-4 was shown to be a useful C3
chiral synthon through its conversion to levodropropi-
zine (ꢀ)-1. Nucleophilic substitution of the halogen
/
)-3-chloro-1,2-propanediol (ꢀ
/
)-(5) [12],
/)-4 with
/
/
with 1-phenylpiperazine, as well as the removal of the
benzoyl moiety, were subsequentially conducted in ‘one
pot’ procedure in refluxing i-propanol. Levodropropi-
zine (ꢀ)-1 was isolated in the correct (S) configuration
/
in 60% yield and 73% ee; the enantiomeric excess,
determined by HPLC as described in the literature [7],
proved that no racemization occurred. Fractional crys-
tallization from dichloromethaneÁhexane afforded le-
/
yield; traces (B4%, GLC) of disubstituted product, i.e.
/
vodropropizine in 95% ee.
1,3-dibenzoyloxypropan-2-one, were detected in the
crude extract (GC/MS) but easily removed by the
crystallisation. The present synthesis of 3 is particularly
attractive when compared with that described in the
literature [10,14] for this compound, namely, a twostep
procedure starting from chloropropanediol (11% overall
yield in Ref. [10], not reported in Ref. [14]).
The asymmetric reduction of prochiral haloketone 3
was carried out with baker’s yeast (see experimental
procedures), resulting in complete conversion after 3
Acknowledgements
The authors gratefully thank Dr. Giuseppe Cannazza
for HPLC ee determination of levodropropizine and the
Centro Interdipartimentale Grandi Strumenti (Univer-
sita` di Modena e Reggio Emilia) for instrumental
measurements.
hours; the corresponding chlorohydrin (ꢁ
/
)-1-benzoy-
loxy-3-chloropropan-2-ol (ꢁ)-4, (60% yield) was ob-
/
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