Article pubs.acs.org/OPRD
A New Scalable Route to 4‑(2-Hydroxyethyl)-1,3-dihydro‑2H‑indol-2one: A Key Intermediate for Ropinirole Hydrochloride Huansheng Chen, Yu Chen,* Li Yuan, and Qing Zou Shanghai AoBo Bio-pharmaceutical Technology Co., Ltd., No. 1011, Halei Road, Zhangjiang High-Tech Park, Shanghai 201203, P.R. China S Supporting Information *
ABSTRACT: A new and efficient manufacturing technology is disclosed in the present work for the preparation of 4-(2hydroxyethyl)-1,3-dihydro-2H-indol-2-one, which is a key intermediate for ropinirole hydrochloride. The whole process gives the target molecule in 71% overall yield with 99% purity. In the final step, a novel nitro reduction/ring-closing/debenzylation takes place in one pot. All the intermediates can be used directly for the next step without purification in this process.
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INTRODUCTION Ropinirole hydrochloride1 (1, Figure 1) is a known, nonergoline dopamine agonist, a selective D2-agonist, employed for
11, the key intermediate, 4-(2-hydroxyethyl)-1,3-dihydro-2Hindol-2-one (13), was formed and was finally transformed to ropinirole hydrochloride (1). In comparison with the former process, this one is more superior and is now used as the commercial route.5c Unfortunately, the total yield of this process is low for the main reason of the inefficient synthesis of 13 (less than 30% yield from 8 to 13). In adition, highly toxic reagents such as hydrazine hydrate and nitromethane are still necessary in this process. Herein we describe a new scalable route to 4-(2-hydroxyethyl)-1,3-dihydro-2H-indol-2-one (13) in an efficient way for ropinirole hydrochloride (1).
Figure 1. Ropinirole hydrochloride (1).
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RESULTS AND DISCUSSION A novel process is shown in Scheme 3 that makes it possible to avoid the drawbacks of the published methods. This process started from 2 which could be purchased commercially. Compound 2 was reduced by NaBH4 in the presence of MeSO3H to produce 2-methyl-3-nitro-phenyl ethyl alcohol (15) in 97% yield after simple washing and extraction. We conducted this reaction at lower temperature, and in the meantime, we improved the workup procedure to make crude 15 in good, pale-yellow, solid form with high purity instead of the dark-brown oil reported in the patent.8 Crude 15 was used directly to react with BnBr. At the beginning, the formation of 1-[2-(benzyloxy)ethyl]-2-methyl-3-nitrobenzene (16) was unsuccessful. Therefore, we tried to optimize this reaction. First, different bases were screened, and the results are listed in Table 1. As shown in the table, no product was observed by organic base such as Et3N or pyridine (Table 1, entries 1−3), neither by weak inorganic base such as Na2CO3, K2CO3 (Table 1, entries 4 and 5). A stronger base proved to be necessary. The desired product 16 was formed when NaH was selected as the base, but the yield was still low even if 2 equiv of NaH was used (Table 1, entries 6 and 7). In this reaction, metal hydroxides showed good activity. LiOH gave poor yield, but 2 equiv of NaOH produced 16 in 54% yield. Pleasingly, KOH was found to be the best base (Table 1, entries 8−10). Then we explored
the treatment of Parkinson’s disease with a lot fewer undesirable side effects than other dopaminergic agents. It is also a drug approved by the FDA to treat restless leg syndrome, which is a neurologic disorder that affects sensation and movement in the legs and causes the legs to feel uncomfortable. Ropinirole hydrochloride (1) is developed by GlaxoSmithKline (GSK),2 the brand name Requip and the chemical name 4-[2(di-n-propylamino)ethyl]-1,3-dihydro-2H-indol-2-one monohydrochloride. Several synthetic methods of ropinirole hydrochloride (1) have been reported recently,3 two of which are the main processes developed by GSK. The first process (Scheme 1)4 comprised conversion of 2-methyl-3-nitrophenyl acetic acid (2) to 2-methyl-3-nitro-N,N-di-n-propylphenethylamine (5) after three steps. Compound 5 then reacted with diethyl oxalate to afford pyruvic acid (6), which was subsequently cleaved by hydroperoxide anion to produce [2-nitro-6-[2-(N,N-di-npropylamino)ethyl]phenyl]acetic acid hydrochloride (7). Ropinirole hydrochloride (1) was finally obtained from 7 by catalytic hydrogenation. However, this process suffers from the drawbacks such as the use of toxic, expensive, and flammable borane as well as the low total yield of 1 (24% from 2). In the second process (Scheme 2),5 isochroman (8) was used as the starting material to produce nitrostyrene (10) by ringopening reaction, followed by Sommelet oxidation6 and subsequent reaction with nitromethane. Conversion of 10 to 3-chlorooxindole (11) proceeded well via a FeCl3-mediated cyclization.7 After reductive dechlorination and hydrolysis of © XXXX American Chemical Society
Received: January 31, 2013
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Scheme 1. First process
Scheme 2. Second process
amounts of this base as well as solvents as shown in Table 2. From Table 2, we could see that the yield was increased to the
Scheme 3. Synthesis of 4-(2-hydroxyethyl)-1,3-dihydro2H-indol-2-one, 13
Table 2. Screen of the amount of KOH and solvent for the benzylation of compound 15a entry
KOH (equiv)
solvent
yield (%)b
1 2 3 4 5 6
3 4 1.5 3 3 3
acetone acetone acetone THF DMF DCM
93 92 49 79 70 65
a
All reactions were carried out with 15, BnBr (1.1 equiv), and KOH in solvent at 25 °C for 24 h. bIsolated yield.
Table 1. Screen of the base for the benzylation of compound 15a b
entry
base
1 2 3 4 5 6 7 8 9 10
Et3N Et3N pyridine Na2CO3 K2CO3 NaH (1.2 equiv) NaH LiOH NaOH KOH
solvent
yield (%)
acetone DCM DCM acetone acetone THF THF acetone acetone acetone
−d −d −d −d −d 31 44 11 54 66
maximum of 93% when 3 equiv of KOH was used. However, the yield was not helped when the amount of KOH was increased further. Meanwhile, decreased amounts of KOH led to lower yields (Table 2, entries 1−3). In addition, a rapid solvent screen showed that acetone was superior to others (Table 2, entries 4−6). Crude 16 could be used directly for the next step. [2-Nitro-6-[2-(benzyloxy)ethyl]phenyl]acetic acid (17) was formed as a yellow solid after crude 16 reacted successively with diethyl oxalate in the presence of sodium ethoxide and hydroperoxide anion. It turned out that the protection of the hydroxyl group on 15 was necessary. We also tried to use unmasked 15 to react directly with diethyl oxalate (Scheme 4). If this worked, the procedure for the protection of hydroxyl group could be omitted. Instead, a large amount of olefin (19)9 was found as an impurity. The experiment showed that 19 was easily formed in 80% yield, presumptively through the intermediate ethyl 2methyl-3-nitrophenethyl oxalate (18), if unprotected 15 reacted with diethyl oxalate in the base (Scheme 5).
c
a
All reactions were carried out with 15, BnBr (1.1 equiv), and base in solvent at 25 °C for 24 h. b2 equiv of base was used except in entry 6. c Isolated yield. dNo product formation was observed by TLC, and 15 was recovered.
B
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Scheme 4. Attempted reaction with unprotected compound 15
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EXPERIMENTAL SECTION General. Melting points were recorded on an RY-1 melting point apparatus and are uncorrected. 1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on a Bruker Avance 400 spectrometer in CDCl3 or DMSO-d6 using tetramethylsilane (TMS) as internal standards. J values are given in hertz. Mass spectra were recorded on a Finnigan MAT-95/711 spectrometer. Elemental analysis was performed on an MOD1106 instrument. HPLC analysis was performed by a standard method on a Wondasil C18 column, 250 mm × 4.6 mm (5 μm); λ = 210 nm; mobile phase: A (CH3CN)/B (0.5% TEA), 10:90 v/v. The HPLC analysis data are reported in area % and are not adjusted to weight %. 2-Methyl-3-nitro-phenyl Ethyl Alcohol (15). To a stirred solution of 2 (2.85 kg, 14.6 mol) in THF (14 L) was added NaBH4 (1.39 kg, 36.6 mol) at 10 °C. Then MeSO3H (1.40 kg, 14.6 mol) was added dropwise to the mixture at 10 °C. The mixture was stirred for 16 h, poured into ice water (20 L), and extracted with EtOAc (2 × 10 L). The combined organic layer was washed with brine (20 L), dried with anhydrous Na2SO4, filtered, and concentrated to afford 15 (2.59 kg, 98%) as a paleyellow oil with 98% purity by HPLC (retention time: 27.4 min), which solidified when standing at 10 °C. Crude 15 was used directly for the next step without further purification. Mp: 29−31 °C. 1H NMR (CDCl3, 400 MHz): δ = 2.40 (s, 3H), 2.89 (br s, 1H), 2.95 (t, J = 6.8 Hz, 2H), 3.80 (q, J = 6.4 Hz, 2H), 7.24 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ = 14.8, 36.5, 62.0, 122.2, 126.3, 130.5, 133.9, 139.9, 151.3; ESI-MS (m/z) 182 [M + H]+. 1-[2-(Benzyloxy)ethyl]-2-methyl-3-nitrobenzene (16). To a solution of 15 (2.59 kg, 14.3 mol) in acetone (15 L) was added KOH (2.40 kg, 42.9 mol). Then BnBr (2.69 kg, 15.7 mol) was added dropwise to the mixture at 0−10 °C. The mixture was slowly warmed to 25 °C and stirred for 24 h. EtOAc (12 L) was added after the solvent was evaporated. The mixture was washed with water (12 L). Then the separated organic layer was washed with brine (12 L), dried with anhydrous Na2SO4, filtered, and concentrated to afford crude 16 (4.20 kg) as a brown oil with 90% purity by HPLC (retention time: 33.7 min) and used directly for next step without further purification. A sample of purified 16 as a yellow oil was analyzed as follows: 1H NMR (CDCl3, 400 MHz): δ = 2.37 (s, 3H), 2.99 (t, J = 7.2 Hz, 2H), 3.65 (t, J = 7.2 Hz, 2H), 4.49 (s, 2H), 7.20−7.32 (m, 6H), 7.38 (d, J = 7.2 Hz, 1H), 7.57 (dd, J = 8.4, J = 0.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ = 14.9, 33.9, 69.5, 73.1, 122.1, 126.2, 127.6, 127.7, 128.5, 130.5, 133.7, 138.1, 140.3, 151.5; ESI-MS (m/z) 272 [M + H]+. [2-Nitro-6-[2-(benzyloxy)ethyl]phenyl]acetic Acid (17). To a solution of EtONa (2.28 kg, 33.5 mol) in THF (8 L) was added diethyl oxalate (2.93 kg, 20.1 mol). Then a solution of crude 16 (4.20 kg) in THF (6 L) was added dropwise to the mixture at 0−10 °C. The mixture was slowly warmed to 25 °C and stirred for 24 h. After THF was evaporated, a solution of
Scheme 5. Formation of 19 by the presumptive intermediate 18
The next step was very critical. We had planned to obtain 13 in a one-pot course by nitro-reduction/ring-closing/debenzylation, but at the beginning, the reaction proceeded very slowly in a hydrogen atmosphere under normal pressure. Luckily, acetic acid was found to accelerate the reaction. When 1 equiv of acetic acid was added, 17 was transformed smoothly in ethyl acetate to 13 in one pot. During the course, the intermediate 4(2-benzyloxyethyl)-1,3-dihydro-2H-indol-2-one (20, Figure 2)10 was detected which could be transformed completely to
Figure 2. Intermediate (20).
13 in the end. It seemed that the reduction of the nitro group proceeded a little faster than debenzylation under the abovementioned conditions. Once the nitro group was reduced, the ring-closing reaction happened quickly. After simple operation, 13 was crystallized as a white solid with 99% purity in 71% total yield from 2, when solvent was concentrated to 10% of the total volume. With 13 in hand, the remaining two steps could be conducted according to the literature5 to complete the synthesis of ropinirole hydrochloride (1).
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CONCLUSION A new and efficient manufacturing technology was developed for the preparation of 4-(2-hydroxyethyl)-1,3-dihydro-2Hindol-2-one (13), a key intermediate for ropinirole hydrochloride (1). 2-Methyl-3-nitrophenyl acetic acid (2) was used as the stating material which was transformed to 16 through reduction and benzylation. 17 could be obtained after 16 reacted successively with diethyl oxalate in the presence of sodium ethoxide and hydroperoxide anion. A novel nitro reduction/ring-closing/debenzylation took place in one pot to produce this key intermediate 13 in the total yield of 71% with 99% purity. Notably, all the intermediates could be used directly for the next step without purification. C
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Alonso Marin, Y.; Bessa Sanchez, M. U.S. Patent 7,230,118 B2, 2007; Chem. Abstr. 2007, 142, 447116;(d) Bertolino, A.; Bor, A.; Garaczi, S.; Lukacs, F.; Orosz, G.; Schneider, G. U.S. Pat. Appl.2005/0192338 A1, 2005; Chem. Abstr. 2005, 143, 248282. (4) (a) Gallagher, G., Jr.; Lavanchy, P. G.; Wilson, J. M.; Hieble, J. P.; DeMarinis, R. M. J. Med. Chem. 1985, 28, 1533. (b) DeMarinis, R. M.; Gallagher, G., Jr.; Hall, R. F.; Franz, R. G.; Webster, C.; Huffman, W. F.; Schwartz, M. S.; Kaiser, C.; Ross, S. T.; Wilson, J. W.; Hieble, P. J. Med. Chem. 1986, 29, 939. (5) (a) Giles, R.; Walsgrove, T. C. U.S. Patent 5,336,781 A, 1994; Chem. Abstr. 1994, 116, 106086. (b) Dagger, R. E.; Fortunak, J. M.; Mastrocola, A. J. Heterocycl. Chem. 1995, 32, 875. (c) Hayler, J. D.; Howie, S. L. B.; Giles, R. G.; Negus, A.; Oxley, P. W.; Walsgrove, T. C.; Whiter, M. Org. Process Res. Dev. 1998, 2, 3. (6) Campaigne, E.; Bourgeois, R. C.; McCarthy, W. C. Org. Synth. 1963, 4, 918. (7) Guillaumel, J.; Demerseman, P.; Platzer, N.; Brévard, C.; Clavel, J.-M.; Royer, R. Tetrahedron 1980, 36, 2459. (8) Soni, R, R.; Acharya, H, H.; Shah, H. R.; Shah, T. R.; Reddy, B. R. U.S. Pat. Appl. 2008/0262244 A1, 2008; Chem. Abstr. 2008, 146, 7822. (9) The testified experiment was conducted as follows: To a solution of EtONa (13.62 g, 0.20 mol) in THF (60 mL) was added diethyl oxalate (17.52 g, 0.12 mol). Then a solution of 15 (18.11 g, 0.10 mol) in THF (50 mL) was added dropwise to the mixture at 0−10 °C. The mixture was slowly warmed to 25 °C and stirred for 6 h. Water (150 mL) was added slowly at 0 °C, then 37% aq HCl was added until pH = 7. The organic layer was separated after EtOAc (150 mL) was added. Then the separated organic layer was washed with brine (150 mL), dried with anhydrous Na2SO4, filtered, and concentrated to afford an oil. The product was purified via silica gel column chromatography using EtOAc/hexane (1:10) as eluent to yield 13.0 g (80%) of 19 as yellow oil: 1H NMR (CDCl3, 400 MHz): δ = 2.28 (s, 3H), 5.32 (dd, J = 11.2, 0.8 Hz, 1H), 5.52 (dd, J = 17.6, 0.8 Hz, 1H), 6.81 (dd, J = 17.6, 11.2 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ = 15.1, 118.5, 123.0, 126.4, 129.2, 130.0, 133.9, 140.1, 151.3; ESI-MS (m/z) 164 [M + H]+. (10) A sample of 20 as an off-white solid purified by column chromatography was analyzed as follows: Mp: 94.5−95.5 °C. 1H NMR (CDCl3, 400 MHz): δ = 2.84 (t, J = 6.8 Hz, 2H), 3.45 (s, 2H), 3.67 (t, J = 6.8 Hz, 2H), 4.50 (s, 2H), 6.73 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.25−7.34 (m, 5H), 8.51 (br s, 1H); 13 C NMR (CDCl3, 100 MHz): δ = 33.6, 35.4, 69.8, 73.0, 108.1, 122.8, 124.8, 127.6, 127.7, 128.0, 128.5, 135.4, 138.3, 142.8, 178.6; ESI-MS (m/z) 268 [M + H]+.
NaOH (1.03 kg, 25.8 mol) in H2O (15 L) was added. Then 30% H2O2 (4.56 kg, 40.2 mol) was added dropwise to the mixture at 0−10 °C. The solution was stirred for 3 h at the same temperature before quenching with Na2SO3 (3.0 kg). A yellow solid precipitated when 12 N HCl (5 L) was added. This solid was filtrated and washed with H2O (2 × 10 L) to give crude wet 17 (5.0−6.0 kg) as a yellow solid with 95% purity by HPLC (retention time: 26.2 min) by filtration and used directly for the next step. Another batch of crude, wet solid (synthesis from the same quantity of 15) was dried at 60 °C under vacuum after filtration to afford 17 (3.98 kg, 88% from 15) as a yellow solid. Mp: 111−112 °C. 1H NMR (CDCl3, 400 MHz): δ = 3.00 (t, J = 6.8 Hz, 2H), 3.66 (t, J = 6.8 Hz, 2H), 4.03 (s, 2H), 4.46 (s, 2H), 7.21−7.37 (m, 6H), 7.49 (d, J = 7.2 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 10.10 (br s, 1H); 13C NMR (CDCl3, 100 MHz): δ = 33.7, 34.2, 69.9, 73.2, 123.3, 127.4, 127.7, 127.8, 128.1, 128.5, 135.1, 137.8, 141.4, 150.3, 176.1; ESI-MS (m/z) 316 [M + H]+. 4-(2-Hydroxyethyl)-1,3-dihydro-2H-indol-2-one (13). To a solution of crude wet 17 (5.0−6.0 kg) in EtOAc (80 L) was added 10% Pd/C (400 g). HOAc (730 mL) was then added. The reaction was stirred under H2 atmosphere at 40 °C for 36 h. The reaction mixture was filtered, and the filtrate was washed with saturated aq sodium bicarbonate (12 L). Solid was crystallized on standing 24 h after solvent was concentrated to 10% of the total volume. This solid was filtered, washed with EtOAc (400 mL), and dried at 40 °C under vacuum to afford 13 (1.84 kg, 71% from 2) as a white solid with 99% purity by HPLC (retention time: 19.0 min). Mp: 145−147 °C (lit. mp 147−149).5b 1H NMR (DMSO-d6, 400 MHz): δ = 2.64 (t, J = 6.8 Hz, 2H), 3.44 (s, 2H), 3.59 (q, J = 6.8 Hz, 2H), 4.62 (t, J = 5.2 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 10.30 (s, 1H); 13C NMR (DMSO-d6, 100 MHz): δ = 35.2, 36.8, 61.5, 107.4, 122.5, 125.4, 127.8, 136.1, 143.8, 176.9; ESI-MS (m/z) 178 [M + H]+. Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.73; H, 6.20; N, 7.82.
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ASSOCIATED CONTENT
S Supporting Information *
1
H and 13C NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel: +86(21)51320130. Fax: +86(21)51320368. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Prof. Dr. Dawei Ma for his generous support and constant encouragement. We are also grateful for the cooperation of the colleagues of the analytic department.
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REFERENCES
(1) DeMarinis, R. M.; Hieble, J. P. Drugs Future 1989, 14, 781. (2) Gallagher, G., Jr. U.S. Patent 4,452,808, 1984; Chem. Abstr. 1984, 101, 72605. (3) (a) Fortunak, J. M. U.S. Patent 4,997,954, 1991; Chem. Abstr. 1991, 110, 212605;(b) Wells, A. S.; Lewis, N. J.; Walsgrove, T. C.; Oxley, P.; Fortunak, J. M. WO/1994/15918, 1994; Chem. Abstr. 1994, 121, 179494;(c) Bosch Cartes, J.; Pujol Olle, X.; Del Rio Pericacho, J.; D
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