Resolution of (±)-threo-methylphenidate with (R)-(-)-binaphthyl-2,2′-diyl hydrogen phosphate: 0.5 M equiv of resolving agent is better than 1 M equiv

Article abstract of DOI:10.1021/op990195z

Resolution of (±)-threo-methylphenidate (1) with 0.5 M equiv of (R)-(-)-binaphthyl-2,2′-diyl hydrogen phosphate (4) is described. Use of 0.5 M equiv of 4 was found to be better than 1 M equiv for the resolution of (±)-threo-methylphenidate (1) under diffe

Full text of DOI:10.1021/op990195z

Organic Process Research & Development 2000, 4, 55−59
Resolution of (()-threo-Methylphenidate with (R)-(-)-Binaphthyl-2,2′-diyl
Hydrogen Phosphate: 0.5 M Equiv of Resolving Agent Is Better than 1 M Equiv
Mahavir Prashad,* Bin Hu, Oljan Repicˇ, Thomas J. Blacklock, and Peter Giannousis
Process Research & DeVelopment, Chemical & Analytical DeVelopment, NoVartis Institute for Biomedical Research,
59 Route 10, East HanoVer, New Jersey 07936, U.S.A.
Abstract:
hydrochloride (1) was first reported with (R)-(-)-binaphthyl-
2,2′-diyl hydrogen phosphate (4) in 1987 by Patrick et al.,
to afford 2.5 Several classical resolution as well as enzymatic
hydrolysis methods for the resolution of (()-threo-meth-
ylphenidate hydrochloride (1) and its precursors have been
reported recently by us6,7 and by others.8-13 A synthesis of
2 has also been reported recently14 that utilized an enan-
tiopure amino acid (D-pipecolic acid) as the starting material,
which in turn was prepared by the resolution of (()-pipecolic
acid using tartaric acid. We recently reported15 the first
enantioselective synthesis of 2 in >99% enantiomeric purity,
which has been followed by several reports.16-18 Enantiose-
lective synthesis of (2S,2′R)-erythro-methylphenidate has also
been reported recently by us19 and in a patent20 because it
could potentially be epimerized to 2.
At the onset of this project in our laboratories, we were
interested in the preparation of 2 by the resolution of (()-1
free base with (R)-(-)-binaphthyl-2,2′-diyl hydrogen phos-
phate (4; BNDHP) in an acetone-methanol (95:5) mixture,
reported by Patrick et al,5 although 4 was an expensive
reagent. Recently, these conditions were found to be non-
reproducible and yielded 2 with only 92.6% enantiopurity
(2R,2′R:2S,2′S ) 96.3:3.7), even after an additional recrys-
tallization,10 compared to 99% enantiopurity reported by
Resolution of (()-threo-methylphenidate (1) with 0.5 M equiv
of (R)-(-)-binaphthyl-2,2′-diyl hydrogen phosphate (4) is de-
scribed. Use of 0.5 M equiv of 4 was found to be better than 1
M equiv for the resolution of (()-threo-methylphenidate (1)
under different conditions to yield diastereomeric (2R,2′R)-
threo-methylphenidate‚(R)-(-)-binaphthyl-2,2′-diyl hydrogen
phosphate salt (3) with excellent enantiopurity. The diastere-
omeric salt 3 afforded pure (2R,2′R)-(+)-threo-methylphenidate
hydrochloride (2) in high enantiopurity and yield.
Introduction
Resolutions provide a speedy access to enantiopure
compounds and could result in a practical method in those
cases where the racemic material is readily available. Usually
1 M equiv of the resolving agent is used to resolve a racemic
compound. However, theoretically and of course ideally, only
0.5 M equiv of the resolving agent is required to form the
diastereomeric salt with one enantiomer from the racemic
mixture. Use of 0.5 or 1 equiv of the same resolving agent
is known to give the similar resolution.1 But to the best of
our knowledge, it has not been reported that use of 1 equiv
of the resolving agent gives poorer resolution compared to
0.5 equiv of the same resolving agent. In this paper, we
would like to report such a rare example of the resolution
of (()-threo-methylphenidate hydrochloride (1, Ritalin hy-
drochloride) with (R)-(-)-binaphthyl-2,2′-diyl hydrogen
phosphate (4).
(5) Patrick, K. S.; Caldwell, R. W.; Ferris, R. M.; Breese, G. R. J. Pharmacol.
Exp. Ther. 1987, 241, 152-158.
(6) Prashad, M.; Har, D.; Repicˇ, O.; Blacklock, T. J.; Giannousis, P.
Tetrahedron: Asymmetry 1998, 9, 2133-2136.
(7) Prashad, M.; Har, D.; Repicˇ, O.; Blacklock, T. J.; Giannousis, P.
Tetrahedron: Asymmetry 1999, 10, 3111-3116.
(()-threo-Methylphenidate hydrochloride (1, Ritalin hy-
drochloride) is a mild nervous system stimulant marketed
for the treatment of children with attention deficit hyperac-
tivity disorder (ADHD). (2R,2′R)-(+)-threo-Methylphenidate
hydrochloride (2) has been reported to be 52 to 38 times3
more active than the corresponding (2S,2′S)-(-)-threo-
methylphenidate hydrochloride. Whereas the original syn-
thesis2,4 of (2R,2′R)-(+)-threo-methylphenidate hydrochloride
(2), reported in 1958 by Rometsch, utilized the resolution
of (()-erythro-R-phenyl-R-(2-piperidyl)acetamide to obtain
enantiopure l-erythro-R-phenyl-R-(2-piperidyl)acetamide,
which was subjected to epimerization, hydrolysis, and
esterification, the resolution of (()-threo-methylphenidate
(8) Zeitlin, A. L.; Stirling, D. I. U.S. Patent No. 5,733,756, March 31, 1998.
(9) Faulconbridge, S.; Zavareh, H. S.; Evans, G. R.; Langston, M. World Patent
Application No. WO 98/25902, June 18, 1998.
(10) Harris, M. C. J.; Zavareh, H. S. World Patent Application No. WO 97/
27176, July 31, 1997.
(11) Zavareh, H. S. World Patent Application No. WO 97/32851, September
12, 1997.
(12) Zavareh, H. S.; Potter, G. A. World Patent Application No. WO 98/31668,
July 23, 1998.
(13) Khetani, V.; Luo, Y.; Ramaswamy, S. World Patent Application No. WO
98/52921, November 26, 1998.
(14) Thai, D. L.; Sapko, M. T.; Reiter, C. T.; Bierer, D. E.; Perel, J. M. J. Med.
Chem. 1998, 41, 591-601.
(15) Prashad, M.; Kim, H. Y.; Lu, Y.; Har, D.; Repicˇ, O.; Blacklock, T. J.;
Giannousis, P. J. Org. Chem. 1999, 64, 1750-1753.
(16) Axten, J. M.; Ivy, R.; Krim, L.; Winkler, J. D. J. Am. Chem. Soc. 1999,
121, 6511-6512.
(17) Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. Org. Lett.
1999, 1, 175-178.
(1) Reider, P. J.; Davis, P.; Hughes, D. L.; Grabowski, E. J. J. J. Org. Chem.
1987, 52, 955-957.
(18) Davies, H. M. L.; Hansen, T.; Hopper, D. W.; Panaro, S. A. J. Am. Chem.
Soc. 1999, 121, 6509-6510.
(19) Prashad, M.; Liu, Y.; Kim, H. Y.; Repicˇ, O.; Blacklock, T. J. Tetrahe-
dron: Asymmetry 1999, 10, 3479-3482.
(20) Seido, N.; Nishikawa, T.; Sotoguchi, T.; Yuasa, Y.; Miura, T.; Kumoba-
yashi, H. U.S. Patent 5,859,249, January 12, 1999.
(2) Rometsch, R. U.S. Patent 2,957,880, October 25, 1960.
(3) Maxwell, R. A.; Chaplin, E.; Eckhardt, S. B.; Soares, J. R.; Hite, G. J.
Pharmacol. Exp. Ther. 1970, 173, 158-165.
(4) Rometsch, R. U.S. Patent 2,838,519, June 10, 1958.
10.1021/op990195z CCC: $19.00 © 2000 American Chemical Society and The Royal Society of Chemistry
Published on Web 12/11/1999
Vol. 4, No. 1, 2000 / Organic Process Research & Development
•
55

Table 1. Resolution of (()-threo-methylphenidate free base (0.7 g) in acetone-methanol
enantiopurity
of 3
(2R,2′R):(2S,2′S)
yield
(%)
of 3
molar
equiv of 4
solvent
(ratio)
total
(mL)
temp
(°C)
time
(h)
entry
1
2
3
4
5
6
7
8
9
1.0
0.8
0.8
0.7
0.7
0.6
0.52
0.5
0.52
acetone-MeOH
(95.0:5.0)
acetone-MeOH
(95.0:5.0)
acetone-MeOH
(95.0:5.0)
acetone-MeOH
(95.0:5.0)
acetone-MeOH
(95.0:5.0)
acetone-MeOH
(95.0:5.0)
acetone-MeOH
(95.0:5.0)
acetone-MeOH
(98.0:2.0)
15
15
10
15
10
15
15
15
15
r.t.
16
12
12
12
12
16
16
16
16
55.5:44.5
62.8:37.2
56.4:43.6
92.0:8.0
61.0:39.0
98.9:1.1
97.9:2.1
100: 0
66.7
40.1
58.5
38.4
52.7
33.8
28.6
30.9
37.8
65 f r.t. f 0
65 f r.t. f 0
65 f r.t. f 0
65 f r.t. f 0
r.t.
r.t.
r.t.
r.t.
acetone
97.4:2.6
Scheme 1
of acetone and methanol at different concentrations. The
diastereomeric salt was isolated by filtration in each case
and the enantiopurity was determined by a chiral HPLC
method using a Daicel Chiralpak AD column. The results
are summarized in Table 1. With 1 M equiv of 4, the (2R,2′R:
2S,2′S) ratio in the diastereomeric salt 3 was only 55.5:44.5
(entry 1). Interestingly, a decrease in the amount of 4 led to
an improved resolution. Excellent results were obtained when
the resolution was carried out using close to 0.5 equiv of 4.
With 0.6 or 0.52 equiv of 4 (entries 6 and 7), the (2R,2′R:
2S,2′S) ratios in 3 were 99:1 and 98:2, respectively.
Furthermore, the yield of 3 under these conditions was also
good. Good resolution with higher yield was also achieved
with less methanol (acetone-methanol ) 98:2) or in pure
acetone with 0.5 equiv of 4 (entries 8 and 9). However, a
clear solution was never observed in case of pure acetone
as solvent. These results clearly demonstrated that 0.5 M
equiv of 4 gave better resolution than 1 equiv. In fact, since
the theoretical yield is 50%, the high yields (over 25%;
entries 6-9) were especially interesting. This suggested that
a quick exchange between the (2S,2′S)-threo-methylphenidate‚
(R)-BNDHP salt and (2R,2′R)-threo-methylphenidate free
base in the solution was taking place.
Because preparation of the (()-1 free base from the
hydrochloride salt required an extra step and a solvent
exchange, we decided to investigate the resolution of (()-
1‚HCl salt directly in a mixture of methanol and water as
solvent in the presence of 4-methylmorpholine as a base.
Such a direct resolution of (()-1‚HCl salt has been developed
in our laboratories using di-benzoyl-D-tartaric acid as the
resolving agent.7 The direct resolution of (()-1‚HCl salt with
0.5 equiv of 4 in methanol-water mixture in the presence
of 4-methylmorpholine was studied under various conditions.
The results are summarized in Table 2. Poor results were
obtained with a methanol-water ratio of 1.2:1 (Table 2, entry
1). Excellent resolution was achieved with a methanol-water
ratio from 1.6:1 to 2:1 (entries 5, 14, and 15), affording 3
with undetectable amounts of the undesired (2S,2′S)-enan-
tiomer. A comparison of entries 5 with 6, and 15 with 16,
Patrick et al.5 However, both of these reports lacked critical
experimental details, in particular the volume of the solvent
used in the resolution step and the recrystallization step. In
our hands, the resolution of (()-1 free base with 4 under
literature conditions (except unknown solvent volume) gave
diastereomeric salt (3) with poor enantiopurity (2R,2′R:2S,2′S
) 62.8:37.2). This prompted us to investigate the resolution
of (()-1 free base with 4 in detail. Herein, we describe our
results on the resolution of (()-1 with 0.5 M equiv of 4,
which clearly demonstrated that 0.5 M equiv of 4 is better
than 1 M equiv. Our newly developed conditions (Scheme
1) are highly reproducible and are suitable for scale-up, if
necessary, because 4 is now cheaper and available in bulk
amounts.
Results and Discussion
We reasoned that the molar ratio of (()-1 and 4 and/or
solvent volume may be critical parameters in this resolution.
We investigated the resolution of (()-1 free base, which was
generated by treatment of (()-1‚HCl salt with aqueous
sodium hydroxide in isopropyl acetate followed by complete
removal of solvent, with variable amounts of 4 in a mixture
56
•
Vol. 4, No. 1, 2000 / Organic Process Research & Development

Table 2. Direct resolution of (()-threo-methylphenidate‚HCl (3.0 mmol) with 4 (1.5 mmol) in the presence of
4-methylmorpholine (3.0 mmol)
enantiopurity
yield
(%)
of 3
MeOH
(mL)
H2O
(mL)
ratio
(MeOH-H2O)
total
(mL)
temp
(°C)
time
(h)
of 3
entry
(2R,2′R):(2S,2′S)
1
2
3
4
5
6
7
8a
9a
10b
11
12
13
14
15
16
17
18
19
8.4
6
9
7
5
6
3
6
6
4
6
6
6
6
4
4
5.5
5
5
2.5
5
1.2:1
1.2:1
1.5:1
1.5:1
1.6:1
1.6:1
1.6:1
1.6:1
1.6:1
1.6:1
1.6:1
1.8:1
1.8:1
1.8:1
2.0:1
2.0:1
2.0:1
2.0:1
2.0:1
15.4
11
15
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
3
16
16
16
3
16
3
3
16
3
3
3
16
3
3
74.9:25.1
69.6:30.4
69.6:30.4
61.8:38.2
99.1:0.9
68.6:31.4
73.7:26.3
75.8:24.2
65.3:34.7
78.2:21.8
94.2:5.8
68.4:31.6
64.1:35.9
100: 0
38.4
42.4
35.5
39.5
26.0
32.1
32.1
28.7
32.1
24.1
27.5
33.2
33.2
24.6
4.4
9.6
9.6
6.4
9.6
9.6
9.6
9.6
7.2
7.2
9.9
10
10
5
7.5
15.6
15.6
10.4
15.6
15.6
15.6
15.6
11.2
11.2
15.4
15
100: 0
29.8 (2 crops)
21.8
35.0
20.1
37.3
15
7.5
15
7.5
16
3
3
73.6:26.4
62.6:37.4
97.8:2.2
59.4:40.6
10
5
2.5
r.t.
16
a With 1.65 mmol of 4-methylmorpholine. b With 6.0 mmol of 4-methylmorpholine.
Table 3. Resolution of (()-threo-methylphenidate free base (3.0 mmol) in isopropyl acetate-methanol
enantiopurity
yield
(%)
of 3
total
(mL)
temp
(°C)
time
(h)
of 3
entry
molar equiv of 4
solvent (ratio)
(2R,2′R):(2S,2′S)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
0.5
0.5
0.5
0.5
0.5
1.0
i-PrOAc-MeOH (95.0:5.0)
i-PrOAc-MeOH (92.5:7.5)
i-PrOAc-MeOH (90.0:10.0)
i-PrOAc-MeOH (90.0:10.0)
i-PrOAc-MeOH (90.0:10.0)
i-PrOAc-MeOH (90.0:10.0)
i-PrOAc-MeOH (90.0:10.0)
i-PrOAc-MeOH (90.0:10.0)
i-PrOAc-MeOH (87.5:12.5)
i-PrOAc-MeOH (87.5:12.5)
i-PrOAc-MeOH (85.0:15.0)
i-PrOAc-MeOH (85.0:15.0)
i-PrOAc-MeOH (80.0:20.0)
i-PrOAc-MeOH (80.0:20.0)
15
15
15
15
15
11
7.5
25
15
11
7.5
15
15
15
r.t.
r.t.
r.t.
r.t.
0
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
72
16
3
86.2:13.8
89.8:10.2
100: 0
99.1:0.9
100: 0
98.2:1.8
80.7:19.3
55.9:44.1
100: 0
98.4:1.6
89.3:10.7
100: 0
43.6
40.1
35.5
39.5
39.0
40.1
43.6
75.1
35.5
36.0
39.5
32.1
26.4
62.5
16
16
16
16
72
16
16
72
72
16
16
100: 0
65.4:34.6
suggested that under these conditions longer resolution time
led to a poor resolution. When the reaction was continued
for a longer time, the (2S,2′S)-threo-methylphenidate‚(R)-
BNDHP salt also crystallized in the end. Again use of 1 equiv
of 4 under these conditions gave poor results (2R,2′R:2S,2′S
) 60.0:40.0). A comparison of entries 5 with 7, and 15 with
17, indicated that lower solvent amounts also afforded 3 with
significantly lower enantiopurity. In addition, further cooling
of the mixture to 0 °C also led to slightly lower enantiopurity
of 3 (compare entries 5 with 11, and 15 with 18). These
results suggested that long reaction time, low solvent
amounts, and lower temperature have adverse effects on the
direct resolution of (()-1‚HCl salt with 0.5 M equiv of 4 in
methanol-water solvent system. In addition, using more or
less of 4-methylmorpholine also led to unsatisfactory resolu-
tion (entries 8-10). This led us to believe that although using
(()-1‚HCl salt directly is convenient, the narrow window
for all these parameters to achieve a good resolution may
prove difficult to control at a large scale in the pilot plant.
Therefore, we decided to go back to the (()-1 free base
approach.
Because (()-1 free base from the hydrochloride salt was
generated with aqueous NaOH in isopropyl acetate as the
solvent, we decided to investigate the resolution in isopropyl
acetate and methanol mixture. This would avoid the solvent
exchange step after the free base generation, which was
necessary for the acetone-methanol conditions. In fact, it
was found that the combination of isopropyl acetate and
methanol was the best solvent mixture we discovered so far
for the resolution of (()-1 free base with 0.5 M equiv of 4.
These results are summarized in Table 3. The resolution of
(()-1 free base with different ratios of isopropyl acetate and
methanol and different total volumes of this solvent system
was first studied in detail. A comparison of entries 1-3
Vol. 4, No. 1, 2000 / Organic Process Research & Development
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57

suggested that an increase in the amount of methanol (from
95:5 to 90:10) in the isopropyl acetate-methanol mixture
led to an increase in the enantiopurity of 3. With isopropyl
acetate-methanol ratio from 90:10 to 80:20, 3 was obtained
with excellent enantiopurity and no undesired (2S,2′S)-
enantiomer could be detected (entries 3, 9, 12, and 13). A
decrease in the total volume of the solvent mixture led to a
slight decrease in the enantiopurity of 3 (entries 6 and 10),
although if only half the volume of the solvent was used,
the enantiopurity was significantly lower (compare entries
11 and 12, 3 and 7). As expected, an increase in the amount
of methanol in this solvent mixture led to a lower yield of
3. In contrast to the methanol-water solvent system as
observed previously, the longer resolution time or cooling
to 0 °C did not affect the enantiopurity of 3 under these new
conditions involving an isopropyl acetate-methanol mixture
(entries 3-5). Even after 72 h (entry 12) or cooling to 0 °C
(entry 5), no undesired (2S,2′S)-enantiomer could be detected
in 3. Once again use of 1 equiv of 4, even with large amount
of solvent (entry 8) or with an isopropyl acetate-methanol
ratio of 80:20 (entry 14), led to poor resolution. The
solubilities of (2R,2′R)- and (2S,2′S)-threo-methylphenidate‚
(R)-BNDHP diastereomeric salts at 25 °C were 2.4 and 10.3
mg/mL, respectively, in a 90:10 mixture of isopropyl
acetate-methanol, and 3.4 and 24.4 mg/mL, respectively,
in a 80:20 mixture of isopropyl acetate-methanol. The
conditions utilizing a 85:15 ratio of isopropyl acetate-
methanol over 90:10 were selected for further scale-up to
allow a wider margin, which should further increase the
robustness of the process in the pilot plant. These conditions
(Table 3; entry 12) were selected for a scale-up. Actually, a
scale-up to 0.27 mol of (()-1 gave a better yield of the
diastereomeric salt 3 (36%) compared to 32% on a smaller
scale (3.0 mmol; entry 12).
approach” to the resolution of racemates,21 one must also
consider to use 0.5 M equiv of the resolving agent in cases
where the resolution is cumbersome. The diastereomeric salt
3 yielded 2 in excellent enantiopurity and yield.
Experimental Section
Melting points were measured on a Buchi 535 melting
point apparatus. 1H NMR spectra were recorded on a Bruker
300 instrument. Enantiopurities were determined after gen-
erating the free base from the salts either by capillary
electrophoresis on a Beckman P/ACE 5000 series instrument
(capillary: fused silica, 75 µm (i.d.) × 361 µm (o.d.) × 77
cm (70 cm effective separation length), 800 µm aperture;
detection: 214 nm; injection: 4.5 s, pressure; run voltage:
28 kV (363 V/cm); run time: 32 min; polarity: positive;
temperature: 23 °C; current: 115-130 (µA); separation
electrolyte: 100 mM phosphate, pH 2.0, 10% methanol, 5
mM heptakis (2,6-di-O-methyl)-â-cyclodextrin, or by chiral
HPLC on a Rainin Dynamax system using a Daicel Chiralpak
AD column (4.6 × 250 mm) and a mixture of hexane-
ethanol-methanol-TFA (96:2:2:0.1) as the mobile phase
(isocratic at a flow rate of 0.8 mL/min and UV detector at
230 nm).
Preparation of (2R,2′R)-(+)-threo-Methylphenidate
Hydrochloride (2) by Resolution of (()-1 Free Base in
Isopropyl Acetate-Methanol Mixture. A 1-L, four-necked,
round-bottomed flask, equipped with a mechanical stirrer,
digital thermometer, and heating cooling bath was charged
with (()-threo-methylphenidate hydrochloride (1, 72.85 g;
0.27 mol) and isopropyl acetate (450 mL). The mixture was
stirred at room temperature (23-25 °C), and to the suspen-
sion was added a solution of NaOH (18.0 g) and NaCl (72.0
g) in water (315 mL) over a period of 5 min while
maintaining an internal temperature 20-25 °C. The suspen-
sion was allowed to stir for 30 min until all the solids
dissolved, to obtain a two-phase mixture. The organic layer
(∼500 mL), containing (()-threo-methylphenidate free base,
was separated, filtered to remove any suspended particles,
and saved for the resolution step.
A 3-L, four-necked, round-bottomed flask, equipped with
a mechanical stirrer, digital thermometer, heating mantle, and
addition funnel was charged with (R)-(-)-binaphthyl-2,2′-
diyl hydrogen phosphate (4; 47.02 g, 0.135 mol), methanol
(202.5 mL), and isopropyl acetate (652.5 mL). The suspen-
sion was stirred and heated to an internal temperature at 65
°C, and the above-prepared organic layer (∼500 mL,
containing (()-1 free base) was added over a period of 15
min while maintaining an internal temperature of 60-65 °C
to obtain a clear solution. To this solution were added seeds
of (2R,2′R)-threo-methylphenidate‚(R)-(-)-binaphthyl-2,2′-
diyl hydrogen phosphate salt (3, 50 mg). The reaction mixture
was allowed to cool to room temperature (23-25 °C) over
a period of 2 h, and the stirring was continued at the same
temperature for an additional 2 h. The heterogeneous mixture
was cooled to an internal temperature of 0-5 °C over a
The (2R,2′R)-threo-methylphenidate‚(R)-BNDHP diaster-
eomeric salt (3) was treated with NaOH in isopropyl acetate
to yield a solution of (2R,2′R)-threo-methylphenidate free
base. Treatment of this solution with aqueous HCl gave crude
2, which was recrystallized from water-HCl mixture to
afford crystalline 2. No (2S,2′S)-enantiomer (by HPLC) or
1
resolving agent (by H NMR) could be detected in 2. The
overall yield of recrystallized 2 was 31.4%. The resolving
agent 4 was also recovered in 83% yield and was recyclable.
Conclusions
A detailed investigation on the preparation of (2R,2′R)-
(+)-threo-methylphenidate hydrochloride (2) by the resolu-
tion of (()-threo-methylphenidate (1) with (R)-(-)-binaphthyl-
2,2′-diyl hydrogen phosphate (4) is described. Resolution
with 1 M equiv of this resolving agent did not give
satisfactory results. However, 0.5 M equiv led to an excellent
resolution under various conditions in high yields. Such a
resolution is unique in that there are no reports where 1 equiv
of the resolving agent leads to poor resolution, while .05
equiv gives such excellent results. These results suggested
that in addition to using the recently reported “family
(21) Vries, T.; Wynberg, H.; Echten, E. V.; Koek, J.; Hoeve, W. T.; Kellogg,
R. M.; Broxterman, Q. B.; Minnaard, A.; Kaptein, B.; Sluis, S. V. D.;
Hulshof, L.; Kooistra, J. Angew. Chem., Int. Ed. 1998, 37, 2349-2354.
58
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period of 15 min and stirred at the same temperature for an
additional 2 h. The solids were collected by filtration, washed
with a precooled mixture (0-5 °C) of isopropyl acetate-
methanol (85:15 v/v) in two equal portions of 75 mL each,
and dried at 50-55 °C (100 mmHg) to afford (2R,2′R)-threo-
methylphenidate‚(R)-(-)-binaphthyl-2,2′-diyl hydrogen phos-
phate salt (3, 56.85 g; 36.2%); mp ) 246-247 °C decomp;
(2R,2′R):(2S,2′S) ) 99.9:<0.1. Lit.2 mp ) 210-211 °C;
[R]25D +88 (1% in MeOH); IR (KBr, cm-1) 1739; 1H NMR
(CD3OD, δ) 1.35-1.58 (m, 3H), 1.65-1.93 (m, 3H), 3.11
(dt, 1H, J ) 3.5 and 12.6 Hz), 3.4-3.5 (m, 1H), 3.7 (s, 3H),
3.84 (dt, 1H, J ) 3.5 and 10.0 Hz), 3.99 (d, 1H, J ) 10.0
Hz), 7.25-7.44 (m, 5H); 13C NMR (CD3OD, δ) 22.78, 23.23,
27.54, 46.63, 53.4, 55.2, 59.18, 129.59, 129.62, 130.36,
135.25, 173.22; MS (m/e) 234 (MH+). Anal. Calcd for
C14H20ClNO2: C, 62.33; H, 7.47; N, 5.19; Cl, 13.14.
Found: C, 62.31; H, 7.36; N, 5.15; Cl, 13.11.
[R]25 -316.7 (c ) 1.0, MeOH); (2R,2′R):(2S,2′S) ) 99.2:
D
0.8.
To a suspension of (2R,2′R)-threo-methylphenidate‚(R)-
(-)-binaphthyl-2,2′-diyl hydrogen phosphate salt (3, 56.85
g) in isopropyl acetate (853 mL) and water (942 mL) was
added a solution of sodium hydroxide (23.46 g) in water
(195 mL) over a period of 5-10 min while maintaining an
internal temperature at 20-25 °C. All of the solids dissolved,
and another solid precipitated immediately. The three-phase
mixture was stirred for 30 min and filtered. The biphasic
filtrate was saved. The solids were washed with isopropyl
acetate (3 × 285 mL) in another filtration flask. The solids
were saved to recover the resolving agent. The organic layer
was separated from the biphasic filtrate. The aqueous layer
was extracted with the second filtrate (855 mL). The aqueous
layer was saved to recover the resolving agent. The combined
organic layers were washed with water (50 mL) and filtered.
The filtrate was cooled to 0-2 °C (internal temperature),
and to it was added concentrated hydrochloric acid (14.45
g; 37%) over a period of 10 min while maintaining an
internal temperature <10 °C. The heterogeneous mixture was
warmed to room temperature over a period of 45 min. The
solids were collected by filtration, washed with isopropyl
acetate (2 × 50 mL), and dried at 50-55 °C (100 mmHg)
to afford crude (2R,2′R)-(+)-threo-methylphenidate hydro-
chloride (2, 24.62 g).
Resolution of (()-threo-Methylphenidate Free Base
with 4 in Acetone-Methanol. A suspension of (()-threo-
methylphenidate free base (0.7 g; 3.0 mmol) and (R)-(-)-
binaphthyl-2,2′-diyl hydrogen phosphate (4; 0.52 g; 1.5
mmol) in a mixture of acetone-methanol (98:2 v/v; 15 mL)
was heated to an internal temperature at 65 °C over 15 min,
to achieve a gentle reflux. All of the solids dissolved, and
another solid separated out. The heterogeneous mixture was
refluxed for an additional 10 min. The reaction mixture was
cooled to 22 °C over 1 h and was stirred at this temperature
overnight (16 h). The solids were collected by filtration,
washed with acetone-methanol mixture (98:2 v/v; 2 mL),
and dried to afford (2R,2′R)-threo-methylphenidate‚(R)-
(-)-binaphthyl-2,2′-diyl hydrogen phosphate salt (3, 0.54 g;
31%). (2R,2′R:2S,2′S) ) 100:0.
Direct Resolution of (()-threo-Methylphenidate Hy-
drochloride with 4 in the Presence of 4-Methylmorpho-
line. A clear solution of (()-threo-methylphenidate hydro-
chloride (1, 0.81 g; 3.0 mmol), (R)-(-)-binaphthyl-2,2′-diyl
hydrogen phosphate (4; 0.52 g; 1.5 mmol), and 4-methyl-
morpholine (0.3 g; 3.0 mmol) in methanol (9.6 mL) was
heated to an internal temperature at 40-50 °C. To this
solution was added water (6.0 mL), followed by (2R,2′R)-
threo-methylphenidate‚(R)-(-)-binaphthyl-2,2′-diyl hydrogen
phosphate salt (3, 2 mg) seeds. The reaction mixture was
cooled to 20-25 °C over a period of 1 h and allowed to stir
at this temperature for an additional 3 h. The solids were
collected by filtration, washed with a precooled (0 °C)
mixture of methanol-water (1.6:1, v/v, 2 mL), and dried to
afford (2R,2′R)-threo-methylphenidate‚(R)-(-)-binaphthyl-
2,2′-diyl hydrogen phosphate salt (3, 0.47 g; 27%). (2R,2′R:
2S,2′S) ) 99.1:0.9.
Crude (2R,2′R)-(+)-threo-methylphenidate hydrochloride
(2, 24.62 g) was added to hot water (29.0 g; preheated to an
internal temperature of 74-75 °C). The mixture was heated
to an internal temperature of 80-82 °C to obtain a clear
solution. The solution was cooled to room temperature (20-
22 °C) over a period of 45 min to obtain a suspension. To
the resulting suspension was added concentrated hydrochloric
acid (9.0 g; 37%) over a period of 10 min while maintaining
an internal temperature <25 °C. The mixture was cooled to
0-5 °C over a period of 15 min and was allowed to stir at
this temperature for an additional 30 min. The solids were
collected by filtration, washed with cold water (2 × 4.0 mL;
precooled to 0-5 °C) and dried at 50-55 °C (100 mmHg)
for 16 h to obtain pure (2R,2′R)-(+)-threo-methylphenidate
hydrochloride (2, 22.89 g) as a white crystalline solid; yield
Acknowledgment
We thank Ms. J. Xu for the solubility data.
Received for review September 7, 1999.
OP990195Z
31.4%; mp ) 222-224 °C; [R]25 +84 (c ) 1.0, MeOH);
D
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