Synthesis and resolution of a Tolperisone metabolite

Article abstract of DOI:10.1016/S0957-4166(00)00047-1

The synthesis and resolution of a Tolperisone metabolite ((3'-hydroxy- 4'-methylphenyl)-2-methyl-3-(piperidine-1-yl)-1-propane-1-one, M1) is described. Racemic M1 was subjected to resolution by the enantiomers of camphor-10-sulfonic acid. Absolute configu

Full text of DOI:10.1016/S0957-4166(00)00047-1

Tetrahedron: Asymmetry 11 (2000) 1323±1329
Synthesis and resolution of a Tolperisone metabolite
Jozsef Balint,a Zoltan Hell,a Imre Markovits,a,*
Laszlo Parkanyib and Elemer Fogassya
aDepartment of Organic Chemical Technology, Budapest University of Technology and Economics, H-1521 Budapest,
PO Box 91, Hungary
bInstitute of Chemistry, Chemical Research Center, H.A.S., H-1525 Budapest, PO Box 17, Hungary
Received 20 January 2000; accepted 27 January 2000
Abstract
The synthesis and resolution of a Tolperisone metabolite ((30-hydroxy-40-methylphenyl)-2-methyl-3-
(piperidine-1-yl)-1-propane-1-one, M1) is described. Racemic M1 was subjected to resolution by the
enantiomers of camphor-10-sulfonic acid. Absolute con®guration was determined by X-ray di€raction
1
analysis. Enantiomeric excesses were determined by H NMR spectroscopy. # 2000 Elsevier Science Ltd.
All rights reserved.
1. Introduction
Tolperisone (2-methyl-3-(piperidino-1-yl)-1-p-toluenyl-propane-1-one, Fig. 1) had been found
to be e€ective as a central muscle relaxant.1 The enantiomers of Tolperisone have di€erent bio-
logical activities: while (+)-Tolperisone is a central muscle relaxant, the (^)-enantiomer has
bronchodilatory peripheral activity.
Figure 1. 2-Methyl-3-(piperidino-1-yl)-1-p-toluenyl-propane-1-one (Tolperisone)
1.1. Metabolism of Tolperisone
Japanese researchers2 have reported on Tolperisone metabolism, but the chemical structure of the
metabolites remains unknown. Other Japanese researchers3 observed metabolism of Tolperisone
* Corresponding author. E-mail: markovits.oct@chem.bme.hu
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00047-1

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J. Balint et al. / Tetrahedron: Asymmetry 11 (2000) 1323±1329
1324
in human objects and rats after oral administration. In this case the structures were submitted. So
in the urine of rats 13 metabolites were found while in human urine 11 were present. The human
organism can oxygenate the methyl group of the aromatic ring to a hydroxymethyl group and
even to a carboxylic group; it can reduce the carbonyl group, generate an N-oxide in the piperidine
ring and can oxygenate the aromatic ring at position 3. This last compound (30-hydroxy-tolperisone)
is racemic (M1) and its optically active forms were of interest to us; thus its synthesis and reso-
lution are discussed.
2. Results and discussion
2.1. Synthesis of M1 (Scheme 1)
A suitable way to form the desired hydroxy group at position 3 was the following: after nitra-
tion of the aromatic ring the nitro group is reduced to amine, which is then diazotized and the
diazonium salt hydrolyzed. The product 4 yields M1 after Mannich reaction with piperidine. For
nitration,4,5 reduction5±7 and diazotation5,8 several methods were tested and the most e€ective
ones are described in the Experimental. The Mannich reaction could only be carried out well
when no solvent was applied.
Scheme 1. Preparation of M1
Resolution of M1 was accomplished by (S)-(+)-camphor-10-sulfonic acid in ethyl acetate
(Scheme 2). The solid diastereoisomeric salt gave enantiomerically pure (S)-M1 after cleavage
following two resolution steps from ethyl acetate. The other enantiomer was obtained from the
mother liquor by diastereoisomeric salt formation with (R)-(^)-camphor-10-sulfonic acid.
2.2. Determination of the absolute con®guration of (S)-(+)-M1
The X-ray di€raction analysis showed that the absolute con®guration of the (+)-enantiomer is
(S) (see Fig. 2). In the crystal structure of the diastereomeric salt a water molecule with a site
occupation of 0.22 is included in the asymmetric unit. A ®nal check was made by removing the

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J. Balint et al. / Tetrahedron: Asymmetry 11 (2000) 1323±1329
1325
Scheme 2. Optical resolution of M1
Figure 2. Structure of diastereomeric salt
water molecule and repeating the re®nement, which resulted in a higher R factor. We could
therefore establish that the water molecules do not form cavities through the crystal. A dis-
ordered carbon atom was found in the cyclohexane ring at position 6.
3. Experimental
3.1. Materials and methods
The 1H NMR spectra were recorded at 250 MHz on a Bruker WM250 spectrometer. Chemical
shift values are expressed in ppm values on the ꢀ scale. IR spectra of thin ®lm samples were taken
on a Perkin±Elmer 1600 series FTIR spectrophotometer. Optical rotations were determined on a
Perkin±Elmer 241 polarimeter. Thin layer chromatography was carried out using Polygram1 SIL
G/UV254 sheets. Spots were visualized by UV light or by treatment with 5% ethanolic phospho-
molybdic acid solution and heating of the dried plates. (S)- and (R)-Camphor-10-sulfonic acids
were products of Aldrich. All solvents used were freshly distilled.

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J. Balint et al. / Tetrahedron: Asymmetry 11 (2000) 1323±1329
1326
3.2. Preparation of 1-(40-methyl-30-nitrophenyl)-propane-1-one 2
Compound 1 (25 g, 0.16 mol) was added into cold nitric acid (125 ml) during stirring, the
temperature being kept below +10ꢀC. After the addition the mixture was stirred for 1 h then
poured into excess ice water. The phases were separated, the organic phase was washed with
sodium bicarbonate solution and water, dried over Na2SO4 and solvent was evaporated in vacuo:
26 g of yellow crystals. The crystals were recrystallized from hexane. Yield: 20.0 g of white crys-
tals (0.10 mol, 60%), mp 46.5±47.0ꢀC [lit.4 51ꢀC]. H NMR (CDCl3) 1.25 (t, 3H, H3, 7.22 Hz),
1
0
2.67 (s, 3H, H4 Me), 3.03 (q, 2H, H2, 7.2 Hz), 7.47 (d, 1H, H5 , 7.94 Hz), 8.09 (m, 1H, H6 , 1.55 Hz,
0
0
^1
0
7.91 Hz), 8.52 (m, 1H, H2 , 1.55 Hz). FT-IR (KBr, cm ): 3450, 2984, 2941, 2906, 1954, 1687,
1313, 1536, 1400, 1356, 1220, 914, 800; calcd for C10H11NO3: C 62.17, H 5.74, N 7.25; found: C
62.36, H 5.73, N 7.23.
3.3. Preparation of 1-(30-amino-40-methylphenyl)-propane-1-one 3
Into a mixture of water (320 ml) and iron powder (94 g, 1.68 mol) cc. HCl (5.7 ml) was added
at 80ꢀC and then 2 (45.7 g, 0.24 mol) was also added at 95±100ꢀC. The reaction mixture was
re¯uxed for 2.5 h and the hot mixture was ®ltered; the precipitate was washed with acetone (300
ml). From the ®ltrate the acetone was removed, the aqueous phase was washed with dichloro-
methane (4Â50 ml). The organic phase was clari®ed by charcoal, dried over Na2SO4 and evapo-
rated. Yield: 34.26 g (0.21 mol, 89%) of brown crystals. It was recrystallized from a mixture of
ꢀ
ꢀ
1
toluene and hexane. Yield: 23.23 g (0.14 mol, 59%), mp 76.5±77.0 C [lit.6 85.5±86 C]. H NMR
0
(CDCl3) 1.19 (t, 3H, H3, 7.27 Hz), 2.20 (s, 3H, H4), 2.93 (q, 2H, H2, 7.27 Hz), 3.85 (s, 2H, H3 ),
^1
0
0
0
7.10 (d, 1H, H5 , 8.11 Hz), 7.27 (s, 1H, H6 ), 7.28 (d, 1H, H2 , 8.11 Hz). FT-IR (KBr, cm ): 3486,
3375, 3247, 3028, 2978, 2936, 2898, 1901, 1663, 1625, 1570, 1510, 1452, 1416, 1359, 1290, 1221,
1188, 1149, 971, 796; calcd for C10H13NO: C 73.59, H 8.03, N 8.58; found: C 73.88, H 8.06, N
8.56.
3.4. Preparation of 1-(3-hydroxy-4-methylphenyl)-propane-1-one 4
To the cooled mixture of water (170 ml) and 96% sulfuric acid (38 ml) 3 (22.06 g, 0.135 mol)
was added, the temperature being kept below 10ꢀC and then NaNO2 (9.79 g, 0.142 mol) was also
added below 10ꢀC. The reaction mixture was stirred at 70ꢀC for 1 h. The reaction mixture was
cooled, the precipitate was ®ltered and washed until the pH of the dripped solution was less than
6. Yield: 21.17 g (0.13 ml, 96%), which was recrystallized from toluene. Yield: 17.42 g (0.11 mol,
79%), mp 119±121ꢀC [lit.8 120±122ꢀC]. H NMR (CDCl3) 2.22 (t, 3H, H3, 7.27 Hz), 2.31 (s, 3H,
1
0
H4 Me), 2.98 (q, 2H, H2, 7.25 Hz), 4.50 (s, 1H, OH), 7.18 (d, 1H, H5 , 8.11 Hz), 7.42 (d, 1H, H6 ,
0
0
^1
0
7.73 Hz), 7.60 (s, 1H, H2 ). FT-IR (KBr, cm ): 3412, 3076, 2988, 2933, 1671, 1608, 1582, 1450,
1421, 1408, 1379, 1274, 1243, 1197, 1176, 1129, 879, 785, 713, 612; calcd for C10H12O2: C 73.15,
H 7.37; found: C 73.12, H 7.34.
3.5. Preparation of 2-methyl-3-(piperidine-1-yl)-1-(30-hydroxy-40-methylphenyl)-propane 1-one M1
A mixture of 4 (3.7 g, 0.023 mol), piperidine hydrochloride (2.96 g) and ethanolic HCl (1.2 ml)
was stirred at 100±110ꢀC for 3 hours. To the cooled reaction mixture water was added and the
mixture was extracted with dichloromethane (3Â20 ml). The pH of the aqueous solution was set

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J. Balint et al. / Tetrahedron: Asymmetry 11 (2000) 1323±1329
1327
to 8 by 1 M solution of Na2CO3, then it was extracted with dichloromethane (3Â50 ml), the
organic phase dried over Na2SO4 and evaporated. Yield: 4.3 g of brown oil, to which maleic
acid (2.0 g) was added in isopropanol (7.7 ml) and it was recrystallized twice. Yield: 2.0 g (5.2
ꢀ
mmol, 22.6%), mp 147.5±148.5 C. 1H NMR (CDCl3) 1.22 (m, 3H, H2Me), 1.28 (m, 1H, H4 ), 1.80
00
0
0
00
0
00
00
(m, 5H, H4 , 2ÂH2 , 2ÂH3 b), 2.30 (s, 3H, H4 Me), 2.55 (m, 1H, H2 b), 2.77 (m, 1H, H2 ), 3.01
00
(m, 1H, H3), 3.31 (m, 1H, H2 b), 3.61 (m, 1H, H2 ), 3.80 (m, 1H, H3), 4.29 (m, 1H, H2), 6.26
00
0
0
0
(s, 2H, maleic acid), 7.21 (d, 1H, H5 , 7.77 Hz), 7.45 (d, 1H, H6 , 7.69 Hz), 7.57 (s, 1H, H2 ).
FT-IR (KBr, cm^1): 3405, 3050, 2940, 1863, 2780, 1673, 1582, 1458, 1353, 1280, 1245, 1202, 1174,
1112, 1013, 864, 728; calcd for C20H27NO6: C 63.65, H 7.21, N 3.71; found: C 63.60, H 7.24, N
3.72.
3.5.1. Preparation of the free bases
M1-Maleate (5.0 g, 13.25 mmol) was dissolved in a solution of NaOH (1.3 g, 32.5 mmol) in
water (15 ml). The mixture was extracted with ethyl acetate (3Â5 ml), the organic phase was dried
over Na2SO4 and the solvent was evaporated. Yield: 3.36 g (12.85 mmol, 97%) of oil, which
solidi®ed slowly [mp 62±65ꢀC (recryst. from hexane: 65±67ꢀC)]. H NMR (CDCl3) 1.14 (d, 3H,
1
0
H2Me, 7.13 Hz), 1.38 (m, 2H), 1.52 (m, 4H), 2.27 (s, 3H, H4 Me), 2.43 (m, 5H), 3.02 (m, 1H), 3.74
0
0
(m, 1H), 7.14 (d, 1H, H5, 7.74 Hz), 7.41 (d, 1H, H6 , 7.79 Hz), 7.45 (s, 1H, H2 ). FT-IR (KBr,
cm^1): 3424, 2935, 2852, 2814, 1670, 1608, 1584, 1449, 1423, 1282, 1258, 1174, 1104, 993, 762;
calcd for C16H23NO2: C 73.53, H 8.87, N 5.36; found: C 73.32, H 8.90, N 5.38.
3.6. Resolution of M1
3.6.1. Preparation of S-(+)-M1
To the solution of M1 (3.3 g, 12.63 mmol) in ethyl acetate (10 ml) (S)-camphor-10-sulfonic acid
monohydrate (3.16 g, 12.6 mmol) in 15 ml ethyl acetate was added. The solution was cooled to 0±
5ꢀC, then it was inoculated and the mixture was left to crystallize for 40 min. It was ®ltered,
washed with ethyl acetate (3Â1 ml) and dried: 1.55 g, 3.14 mmol. The precipitate was dissolved in
ethyl acetate (10 ml) and washed with 1 M bicarbonate solution. The organic phase was dried and
evaporated. Yield: 0.81 g (3.1 mmol, [ꢁ]D=+29.0 (c=1, methanol)) of oil.
This procedure was repeated twice. Yield: 1.03 g of white crystals, [ꢁ]D=+50.3 (c=1, meth-
anol), mp 173±174ꢀC, after cleavage 0.52 g (2.0 mmol, 31.5%) of white crystalline base,
[ꢁ]D=+34.1 (c=1, methanol), mp 102±104ꢀC. Its enantiomeric excess was determined with the
1
aid of R-(^)-1-(9-anthryl)-2,2,2-tri¯uoroethanol. In the H NMR spectrum of M1 and the chiral
solvating agent (excess: 2.73) it is recognizable that the signal of H2Me was split into two doublets
(0.92 ppm, 1.07 ppm, Á=76.7 Hz). In the case of the spectrum of (S)-(+)-enantiomer and chiral
solvating agent (excess: 3.13) the peaks at 0.92 ppm were missing, so we could establish that the
optical purity of the sample is higher than 95%.
3.6.2. Preparation of (R)-(^)-M1
The mother liquor of the resolution was washed with 3Â15 ml 1 M solution of Na2CO3. The
organic phase was dried and evaporated: 2.26 g of oil (8.65 mmol, [ꢁ]D=^9.9 (c=1, methanol)).
The (R)-(^)-enantiomer was retrieved like the other, but using (R)-camphor-10-sulfonic acid
monohydrate. Yield: 1.68 g (3.4 mmol) of white crystals, [ꢁ]D=^49.8 (c=1, methanol), mp 170±
172ꢀC, after cleavage 0.81 g (3.10 mmol, 49.1%) of white crystalline base, [ꢁ]D=^33.8 (c=1,
methanol), mp 101±103ꢀC.

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J. Balint et al. / Tetrahedron: Asymmetry 11 (2000) 1323±1329
1328
In the case of the spectrum of (R)-(^)-enantiomer and chiral solvating agent (excess: 2.77) the
peaks at 1.1 ppm were missing, so we could establish that the enantiomeric excess of the sample is
higher than 95%.
3.7. X-Ray crystallography
Crystals were obtained as follows: the diastereoisomeric salt ([ꢁ]D=+50.3 (c=1, methanol)) of
(S)-(+)-M1 ([ꢁ]D=+34.1 (c=1, methanol)) and (S)-camphor-10-sulfonic acid monohydrate (1.71
g, 3.46 mmol) was dissolved in hot ethyl acetate (7.5 ml). The solution was cooled to room tem-
perature, inoculated and left to crystallize overnight. The crystals were ®ltered and air-dried:
20
D
white needles (0.54 g, 1.1 mmol, 32%), ‰ꢁŠ +50.3 (c=1, methanol), mp 174±175ꢀC. Intensity
data were collected on an Enraf±Nonius CAD4 di€ractometer (graphite monochromator; Cu±Ka
radiation, l=1.54180 A) at 293(2) K in the range 3.60ꢁꢂꢁ75.00ꢀ using !±2ꢂ scans. The inten-
sities of three standard re¯ections were monitored regularly every 60 min. The intensities of the
standard re¯ections remained constant within experimental error throughout the data collection.
Hydrogen atomic positions were calculated from assumed geometry except H18, which was
located in di€erence maps. The obvious hydrogen bonding contacts generated hydrogen atomic
positions of the disordered water molecule. Hydrogen atoms were included in structure factor
calculations but they were not re®ned. The isotropic displacement parameters of the hydrogen
atoms were approximated from the U (equiv.) value of the atom they bonded. The riding model
was applied to the hydrogen atoms.
Full matrix re®nement on F2 was performed using all re¯ections. A ®nal check was made with
removing the water molecule and repeating the re®nement that resulted in R1=0.0386 versus
0.0329, wR2=0.1119 versus 0.0903 for the observed re¯ections. The water molecule with partial
occupancy was therefore retained.
.
Crystal data, experimental and re®nement details: empirical formula, C26H39NO6S 0.22H2O;
formula weight, 511.68; temperature, 293(2) K; wavelength, 1.54184 A; crystal system, ortho-
rhombic; space group, P212121; unit cell dimensions, a=8.537(1) A, b=13.180(1) A, c=24.556(1)
A, volume, 2763.0(4) A3; Z, 4; density (calculated), 1.196 Mg/m3; absorption coecient, m,
1.361 mm^1; F(000), 1073; crystal size, 0.30Â0.20Â0.15 mm; ꢂ range for data collection,
3.60ꢁꢂꢁ75.00ꢀ; index ranges, ^9ꢁhꢁ10, ^16ꢁkꢁ16, ^30ꢁlꢁ30; re¯ections collected, 6428;
independent re¯ections, 5537 [R(int.)=0.0140]; absorption correction, semi-empirical absorption
correction; re®nement method, full-matrix least-squares anisotropic on F2; data/restraints/para-
meters 5537/58/337; goodness-of-®t on F2, 1.051; ®nal R indices [I>2s(I)], R1=0.0329,
wR2=0.0903; R indices (all data), R1=0.0411, wR2=0.0939; absolute structure parameter,
0.012(3); extinction coecient, 0.0051(3); largest di€. peak, 0.152 eA^3; largest di€. hole, ^0.233
eA^3.
Neutral atomic scattering factors and anomalous scattering factors were taken from the Inter-
national Tables for X-ray Crystallography, Vol. C (Vol. IV).9±13
Acknowledgements
The Hungarian OTKA Foundation (Project Nos: T29251) is gratefully acknowledged for
®nancial support. J.B. thanks the Zoltan Magyary Foundation and OTKA (D 32705) for a
postdoctoral fellowship.

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1329
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