Novel synthesis of fosphenytoin: Anti-convulsant prodrug

Article abstract of DOI:10.1080/00397910802005281

A simple, new synthesis of fosphenytoin sodium 1, a prodrug, via imidate ester and employing mild reaction conditions is described. Copyright Taylor & Francis Group, LLC.

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Novel Synthesis of
Fosphenytoin: Anti-Convulsant
Prodrug
Chandrashekar R. Elati a , Srinivas Gangula a , Anitha
Naredla a , S. Ashok b , Apurba Bhattacharya a
Rakeshwarar Bandichhor a
&
a Innovation Plaza, Dr. Reddy's Laboratories Ltd.,
Bachupally, Qutubullapur, India
b Department of Chemistry, Osmania University,
Hyderabad, India
Published online: 28 Aug 2008.
To cite this article: Chandrashekar R. Elati , Srinivas Gangula , Anitha Naredla , S.
Ashok , Apurba Bhattacharya & Rakeshwarar Bandichhor (2008): Novel Synthesis of
Fosphenytoin: Anti-Convulsant Prodrug, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 38:17, 2950-2957
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Synthetic Communications1, 38: 2950–2957, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802005281
Novel Synthesis of Fosphenytoin:
Anti-Convulsant Prodrug
Chandrashekar R. Elati,1 Srinivas Gangula,1 Anitha Naredla,1
S. Ashok,2 Apurba Bhattacharya,1 and Rakeshwarar Bandichhor
1Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Bachupally,
Qutubullapur, India
2Department of Chemistry, Osmania University, Hyderabad, India
Abstract: A simple, new synthesis of fosphenytoin sodium 1, a prodrug,
via imidate ester and employing mild reaction conditions is described.
Keywords: Anti-convulsant, hemiaminol, imidate ester
INTRODUCTION
Fosphenytoin sodium 1 as shown in Fig. 1 is a well-known anti-
convulsant agent for the treatment of epileptic disorder, which is avail-
able in the market as Cerebyx1.[1] The mode of action of fosphenytoin
involves the modulation of sodium channels of neurons that effectively
prevents the convulsion.
In particular, the action potential across the neurons is accomplished
through the sodium channels, and each sodium channel exists in three
states: (a) resting state where the sodium ions are not allowed to enter
into the cell, (b) active state where the enhanced influx of sodium ions
are prevalent, and (c) inactive state where the sodium ions are not
allowed at all. Fosphenytoin, a prodrug that provides phenytoin in vivo
com blocks movements of ions through the sodium channels during
propagation of the action potential and therefore blocks or limits the
development of maximal convulsions.
Recevied December 25, 2007.
Address correspondence to Rakeshwarar Bandichhor, Innovation Plaza, IPD,
R&D, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45, 46, and 54, Bachupally,
Qutubullapur, R. R. Dist. 500073, AP, India. DBL-IPD Communication Number
IPDO-IPM-00081. E-mail: rakeshwarb@drreddys.com
2950

Novel Synthesis of Fosphenytoin
2951
Figure 1. API’s structural framework.
The reported synthetic method[2] for fosphenytoin sodium 1 prodrug
involves four steps as shown in Scheme 1. Synthesis of 1 commences with
the nucleophilic addition of phenytoin 2 to formaldehyde to give 3,
which upon chlorination using thionylchloride provided intermediate 4.
Phosphorylation of intermediate 4 using silver dibenzyl phosphate
yielded the corresponding ester product 5, which on hydrogenolysis
and subsequent treatment with sodium hydroxide provided fosphenytoin
sodium 1. This process has certain disadvantages: (a) aforementioned
process requires silver dibenzyl phosphate, and this reagent is expensive
and light sensitive, (b) it is not efficient, as unwanted by-product silver
chloride gets generated, which requires strict process control for silver
metal estimation in the final API, and (c) usage of hazardous chemicals
such as thionyl chloride and a range of solvents makes this method not
environmentally friendly and less attractive for industrial scale-up.
Scheme 1. Precedented approach.

2952
C. R. Elati et al.
Scheme 2. Alternative synthesis: using -OMs as a leaving group.
A recent patent described a short and good-yielding method utilizing
mesylester of hydroxymethyl phenytoin as key synthetic transformation[3]
as shown in Scheme 2. The sulfonate derivative 7 was more reactive than
the halide (e.g., 4) that made the process efficient.
RESULTS AND DISCUSSION
In recent years trichloroacetamidate is widely used in organic transforma-
tions that avoid the heavy-metal salts as promoters[4], We took advantage
of this fact and designed our synthetic route, which proved to be non-
infringing and cost-effective; this article explores quantification of a base
followed by imidate ester formation and the effect of solvents that
afforded 1 in high yield. Herein, we report an economic and efficient
novel synthesis of 1 in good yield with optimal purity employing mild
reaction conditions, with relatively less consumption of reagents and
energy.
Scheme 3. Novel synthetic approach.

Novel Synthesis of Fosphenytoin
2953
Figure 2. De-formylation: formation of major by-product 2.
As presented the novel synthesis of 1 in Scheme 3, we were able to
synthesize advanced intermediate 5 only in two steps. Preparation of
the formylated intermediate 3 was accomplished by following the known
protocol as presented in Scheme 1 (first step). Base-mediated formation
of imidate ester 6 that involves in situ nucleophilic substitution with
dibenzylphosphate afforded 5 in moderate yield. Finally, the synthesis
of 1 was accomplished by hydrogenolysis and subsequent sodium salt
formation.
Imidation of 3 with trichloroacetonitrile in the presence of different
inorganic bases (e.g., potassium carbonate, sodium carbonate, and
sodium bicarbonate) with solvents such as tetrahydrofuran, dichloro-
methane, acetone, ethylacetate, toluene, and heptane at different reac-
tion conditions gave be, poor yield because of the formation of 2 and
3 as shown in Fig. 2. The emergence of 2 can be envisioned as an onset
of base-catalyzed hemiaminol to amine and aldehyde equilibrium shift.
However, we found in our optimization efforts that the DBU-catalyzed
transformation afforded imidate ester 6 in good yield and purity
(entry 3, Table 1). The employed sterically hindered base (DBU) was
Table 1. Screening of bases: formation of 6 in the presence of 1.2 equiv. of
trichloroacetonitrile
HPLC yield (%)
Entry
Base (equiv.)
2
3
6
1
2
3
4
5
6
Potassium carbonate (0.32)
Potassium carbonate (0.5)a
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.025)
DABCO (0.75)
Sodium hydride (2.8)
DMAP (0.5)
5.8
65.5
1.04
15.7
0.19
6.72
8.4
25.0
0.4
27.5
5.9
47.2
—
79.9
30.2
—
8.2
34.3
aTreatment of 3 with K2CO3 in the absence of CCl3CN.

2954
C. R. Elati et al.
Figure 3. Rearrangement leading to amide 8.
found to be easier to handle and commercially available. For large-
scale preparation, the use of 0.3 equiv. of DBU appeared to be
sufficient for the optimum imidation of 3 that afforded 6 in ꢀ80% yield
(HPLC).
In control experiments under these conditions, the reaction without
usage of trichloroacetonitrile predominantly produced 2 (entry 2, Table 1).
We also observed the formation of intermediate 8 as result of intermo-
lecular rearrangement of 6,[5] as shown in Fig. 3, in the presence of more
than 0.05 eq. of DBU. Its quantification is summarized in Table 2.
The solvents were screened to find a common solvent to efficiently
effect the transformations of 3 to 6 and then to 5. The results are
summarized in Table 3. Although the transformations were smooth in
most of the solvents employed, the best results were obtained with the
acetonitrile (entry 2, Table 3).
We realized later that the acetonitrile and carried-over impurities, if
any, were not compatible with the further debenzylation step. Therefore,
we preferred to isolate 5 by employing various solvent combinations.
Among the tested solvent combinations, isopropanal=n-heptane in a 2:3
ratio was found to be the best choice for isolation of 5 in good yield
and purity.
Table 2. Impact of quantity of DBU on the formation of 8
HPLC yield (%)
DBU: number
of equivalence
Entry
2
3
6
8
1
2
3
4
5
0.025
0.05
0.075
0.1
1.04
4.6
1.45
1.35
0.4
2.7
2.26
0.44
1.39
79.9
60.3
66.3
65.4
2.7
4.65
6.4
9.1
1.0
14.9
4.23
33.6

Novel Synthesis of Fosphenytoin
2955
Table 3. Solvent screening for the synthesis of 5
Entry
Solvent
3 to 5 overall yield (%)
1
2
3
4
5
6
7
Acetone
Acetonitrile
Dichloromethane
Ethyl acetate
Tetrahydrofuran
N,N-Dimethylformamide
Toluene
31.0
39.4
35.4
23.0
27.7
5.2
6.2
CONCLUSION
In conclusion, we accomplished a novel synthesis of 1 with consistency
and significant reduction in energy consumption (most of the transforma-
tions were carried out at ambient conditions; no cryogenics or higher
temperatures were involved) at an industrial scale.
EXPERIMENTAL
All commercially available reagents and solvents were used as received.
1
The H NMR spectra were measured on a Varian Gemini 200- or 400-
MHz FT NMR spectrometer; the chemical shifts are reported in d parts
per million (ppm) relative to TMS. The Fourier transform-infrared
(FT-IR) spectra were recorded in the solid state as KBr dispersion using
a Perkin-Elimer 1650 FT-IR spectrometer. The mass spectrum (70 eV)
was recorded on a HP-5989a liquid chromatography-mass spectroscopy
(LC-MS) spectrometer.
3-Hydroxymethyl-5,5-diphenyl-imidazolidine-2,4-dione (3)
Potassium carbonate (0.64 kg, 4.64 mmol) and 37% aqueous formalde-
hyde (14.7 kg, 180.55 mmol) were added to a suspension of phenytoin
(13.0 kg, 51.58 mmol) in water (390 L, 1547.6 mmol). After stirring for
3 h at 25ꢁC, the resulting suspension was filtered, washed with water
(78 L), and dried at 50ꢁC for 5 h to afford 13.82 kg of hydroxymehtyl-
phenytoin as a white crystalline solid in 95% yield and 96% purity
(HPLC).

2956
C. R. Elati et al.
Phosphoric Acid Dibenzyl Ester 2,5-Dioxo-4,4-diphenyl-imidazolidin-1-
ylmethyl Ester (5)
Trichloroacetonitrile (9.1 kg, 63.82 mmol) was added to a suspension
of hydroxymethylphenytoin (12.0 kg, 42.55 mmol) in acetonitrile (108 L,
2117.47 mmol). After stirring for 20 min at 25ꢁC, a solution of 1,8-diazo-
bicyclo[5,4,0]undec-7-ene (DBU) (0.16 kg, 10.63 mmol) in acetonitrile
(12.0 L, 234 mmol) was added to the resulting suspension slowly over
10 min to afford a clear solution that was additionally stirred for 3 h at
25ꢁC. After completion of the reaction to form 6 (measured by thin-layer
chromatography, TLC) a solution of dibenzylphosphate (9.47 kg,
34.0 mmol) in acetonitrile (120 L, 2352.9 mmol) was added slowly over
25 min at 25ꢁC and stirred for 3 h. After completion of the reaction to
form 5 (TLC), the solvent was distilled off completely, and ethylacetate
(36 L, 562.5 mol) and water (120 L) were added to the resulting residue
and stirred for 15 min. The organic layer was treated with water
(2 ꢂ 120 L), evaporated under vacuum, and treated with a 3:2 ratio of
ispropanol–heptane (48 L) to afford 9.1 kg of 5 as a white crystalline solid
in 39.4% yield and 96% purity (HPLC).
1
Imidate 6: H NMR (400 MHz, DMSO-d6): d 9.8(s, 1H), d 7.1–7.4
(m, 10H), d 5.2 (s, 2H); MS (ES) calcd. for C18H14Cl3N3O3 (Mþ )
426.68; found 424.90, 448.00 (Mþ þ Na).
2,4-Imidazolidinedione-5,5-diphenyl-3-[(phosphonooxy)
methyl], Disodium (1)
To a solution of 5 (9.4 kg, 17.31 mmol) in methanol (156 L), 5% palladium
was added on activated carbon (0.94 kg). After stirring for 2 h at 25ꢁC
under hydrogen pressure of 3.0–3.5 kg=cm2, the reaction progress was
monitored by TLC. Upon completion the catalyst was filtered off, the sol-
vent was removed under vaccum and residue was dissolved in acetone
(128 L, 2206 mmol). Sodium hydroxide solution (1.37 kg, 0.03 mmol)
was added to afford 1 as a crystalline solid (5.46 kg) in 78% yield and
99.5% purity (high-pressure liquid chromatography [HPLC]).
Rearranged Amide Derivative (8)
To a suspension of hydroxymethylphenytoin (20 g, 42.55 mmol) in
dichloromethane (202 mL), trichloroacetonitrile (15.3 g, 0.10 mmol) was
added. After stirring for 20 min at 25ꢁC, a suspension of DBU (10.7 g,
0.07 mmol) in dichloromethane (10 mL, 0.12 mmol) was added slowly
over 10 min. After stirring for 30 min at 25ꢁC (completion of reaction;

Novel Synthesis of Fosphenytoin
2957
TLC), the solvent was removed under vacuum, and the residue was dis-
solved in toluene. Compound 8 was isolated as a solid (21.0 g) in 70%
yield and 95.4% purity (HPLC). 1H NMR (400 MHz, DMSO-d6) d
11.2 (s, 1H), d 7.2–7.4 (m, 10H), d 5.0 (s, 2H); MS (ES) calcd. for
C18H14Cl3N3O3 (Mþ ) 426.68; found 424.90.
Spectroscopic data of the known compounds (3, 5, and 1) are in
agreement with the reported values.
ACKNOWLEDGMENT
The authors thank the management of Dr. Reddy’s Laboratories Ltd. for
supporting this work. We thank Dr. Y. Ravindra Kumar for discussion
related to NMR spectroscopy.
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1. Luer, M. S. Fosphenytoin. Neurol. Res. 1998, 20, 178–182.
2. Stella, V. J.; Sloan, K. B. 5,5-Diphenylhydantoin. US Patent 4260769, 1981.
3. Volker, K. Process for the preparation of sodium fosphenytoin. US Patent
2005272706, 2005.
4. Ali, I. A. I.; Abdel-Rahman, A. A.-H.; Ashry, E. S. H. E.; Schmidt R.
Phthalimidomethylation of O-nucleophiles with O-phthalimidomethyl
trichloroacetimidate: A powerful imidomethylating agent for O-protection.
Synthesis 2003, 1065–1070, and references cited there in.
5. Shi, W.; Jiang, N.; Zhang S.; Wu, W.; Du, D.; Wang, J. Unusual reaction of
b-hydroxy a-diazo carbonyl compounds with ClCCN=NaH and Rh(II)-
catalyzed reaction of b-trichloroacetylamino a-diazo carbonyl compounds.
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