Synthesis of the key intermediate of ramelteon

Article abstract of DOI:10.1016/j.cclet.2010.10.021

Asymmetric conjugated addition of allylcopper reagents derived from an allyl Grignard reagent and CuBr·Me₂S to chiral α,β-unsaturated N-acyl oxazolidinones has been achieved. The synthetic procedure was applied to the preparation of the key intermediate of the novel nonbenzodiazepine hypnotic drug, ramelteon.

Full text of DOI:10.1016/j.cclet.2010.10.021

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 264–267
www.elsevier.com/locate/cclet
Synthesis of the key intermediate of ramelteon
Shan Bao Yu a, Hao Min Liu a, Yu Luo a, Wei Lu b,
*
a Department of Chemistry, East China Normal University, Shanghai 200062, China
b Institute of Drug Discovery and Development, East China Normal University, Shanghai 200062, China
Received 16 July 2010
Available online 22 December 2010
Abstract
Asymmetric conjugated addition of allylcopper reagents derived from an allyl Grignard reagent and CuBrÁMe2S to chiral a,b-
unsaturated N-acyl oxazolidinones has been achieved. The synthetic procedure was applied to the preparation of the key
intermediate of the novel nonbenzodiazepine hypnotic drug, ramelteon.
# 2010 Wei Lu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Ramelteon; Asymmetric Michael addition; Synthesis
Ramelteon, marketed as Rozerem by Takeda Pharmaceuticals North America, is the first in a new class of sleep
agents that selectively binds to the MT1 and MT2 receptors in the suprachiasmatic nucleus (SCN) instead of binding to
GABAA receptors, such as occurs with zolpidem, eszopiclone, and zaleplon [1]. Ramelteon has been approved by the
US Food and Drug Administration (FDA) for long-term use for the treatment of insomnia characterized by the
difficulty of sleep onset. It is also the first and only prescription sleep medication that is not designated as a controlled
substance by the US Drug Enforcement Administration (DEA).
Ramelteon has a unique chemical structure, comprising a three-ring system with an asymmetric center at the
benzylic position. Due to the challenging structure, ramelteon has been a popular compound for synthetic chemists.
(S)-N-(2-(6-Methoxy-2,3-dihydro-1H-inden-1-yl)ethyl)propionamide 1 (Fig. 1) is the key intermediate for the
synthesis of ramelteon. So far, the reported synthesis of compound 1 has mainly been based on catalytic asymmetric
hydrogenation [2,3] or resolution [4] of the corresponding racemic mixtures involving difficult procedures. However,
known synthetic methods about compound 1 have many defects, involving the use of expensive metal catalysts and
phosphorus ligands, or low yield, or low ee value. As a part of our research program, we have directed our efforts
towards a more practical and efficient strategy to synthesize compound 1 using simple starting materials and reactions.
After having reviewed lots of literature, we found that conjugated addition of various nucleophiles to a,b-
unsaturated acid derivatives attached to a chiral auxiliary is an important methodology in asymmetric synthesis. For
example, oxazolidinones, which are easily obtained, have been extensively used in related asymmetric fields [5]. Thus,
we expected to introduce a stereogenic center via an asymmetric Michael addition using (S)-4-benzyloxazolidin-2-one
2 as a chiral auxiliary. Herein, we report our synthetic approach to the enantiomerially pure intermediate 1 based on a
copper-assisted conjugate addition of a Grignard reagent to chiral a,b-unsaturated N-acyl oxazolidinones.
* Corresponding author.
E-mail address: wlu@chem.ecnu.edu.cn (W. Lu).
1001-8417/$ – see front matter # 2010 Wei Lu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.10.021

[()TD$FIG]
S.B. Yu et al. / Chinese Chemical Letters 22 (2011) 264–267
265
O
O
N
N
O
O
H
H
(S)-N-(2-(6-methoxy-2,3-dihydro-1H-
inden-1-yl)ethyl)propionamide (1)
Ramelteon
Fig. 1.
[()TD$FIG]
R
O
R
O
R
Aux
*
R
R
R
Fig. 2.
Since we were not able to find any chiral 1-substituted indans with a known absolute configuration prepared from 3-
substituted indanones in the literature, we focused our attention on developing a novel synthetic strategy that would
allow for the synthesis of the enantiopure intermediate 1 with a predetermined absolute configuration. The synthetic
[()TD$FIG]
procedure we designed consisted of the decarbonylation of chiral 3-substituted indanones (Fig. 2). Optically active 3-
O
O
O
O
O
c
a
b
O
N
O
O
OH
4
5
3
Ph
O
O
f
O
O
O
d
e
N
OH
OAc
O
6
8
7
Ph
O
HO
OAc
O
OH
i
O
h
g
O
OAc
O
9
10
11
O
O
Cl
N
NH
3
O
O
N
k
O
j
H
O
12
13
1
Scheme 1. (a) Malonic acid, piperidine, pyridine. (b) (COCl)2, DMF, CH2Cl2; (S)-4-benzyloxazolidin-2-one 2, LiCl, Et3N, CH2Cl2. (c)
Allylmagnesium chloride, CuBr. Me2S, THF. (d) LiAlH4, THF. (e) AcCl, Et3N, CH2Cl2. (f) NaIO4, KMnO4, Me2CO, H2O. (g) (COCl)2,
DMF, CH2Cl2; SnCl4, CH2Cl2. (h) Pd/C, H2, H2SO4, EtOH. (i) MsCl, Et3N, CH2Cl2; phthalimide potassium salt, DMF. (j) NH2NH2, EtOH. (k)
(CH3CH2CO)2O, NaOH, THF, H2O.

266
S.B. Yu et al. / Chinese Chemical Letters 22 (2011) 264–267
substituted indanones with a known stereochemistry have been reported in the literature, and have been prepared using
a classical cyclohydration from the corresponding chiral 3-substituted cinnamic acid, which can be obtained using
asymmetric synthesis procedures with a high enantiomeric purity [6–8]. The synthesis of (S)-N-(2-(6-methoxy-2,3-
dihydro-1H-inden-1-yl)ethyl)propionamide using this methodology is outlined in Scheme 1.
As shown in Scheme 1, the cinnamic acid 4 was easily obtained from 3-methoxybenzaldehyde 3 in a 95% yield, and
was condensed with (S)-4-benzyloxazolidin-2-one 2 through cinnamoyl chloride to form the chiral unit 5. Then, the
asymmetric conjugate addition of an allylcopper reagent derived from commercially available allylmagnesium
chloride and CuBrÁMe2S (allylMgCl/Cu 1:1) to the chiral cinnamic unit 5 furnished the intermediate 6 with a high
enantiomeric purity. High-pressure liquid chromatography (HPLC) analysis of the reaction mixture suggested a high
diastereomeric excess (>99%). This was confirmed in the final step. Removal of the chiral auxiliary (LiAlH4 in THF)
yielded the alcohol 7, which was protected by the acetyl group to result in compound 8 in a 90% yield. Subsequent
oxidation of the allyl compound with NaIO4/KMnO4 (6:1) gave the acid 9 in high yields without further purification.
Treating 9 with oxalyl chloride, followed by a Lewis acid-promoted Friedel–Crafts acylation afforded the indanone
10. Then, pure indanol 11 was obtained through deprotection and reduction in a one-pot procedure with Pd/C catalytic
hydrogenation in concentrated sulfuric acid in ethanol. Subsequent amination of the indanol 11 via a Gabriel synthesis
gave the indanamine 12, which, after salification (4 M HCl/EtOH), yielded the indanamine hydrochloride 13. Finally,
the reaction of this compound with propionic anhydride under alkaline conditions afforded the key target 1. HPLC
analysis [2,9] revealed an ee > 99%. At last, all the prepared compounds gave satisfactory analytical data [10].
In conclusion, an efficient enantioselective synthesis of (S)-N-(2-(6-methoxy-2,3-dihydro-1H-inden-1-yl)ethyl)-
propionamide with an absolute configuration has been achieved. Our methodology appears to be suitable for preparing
various chiral 3-substituted indanones and 1-substituted indan derivatives.
Acknowledgments
We gratefully acknowledge the Shanghai Municipal Natural Science Foundation (No. 10ZR1409600). We also
thank Lab of Organic Functional Molecules, the Sino-French Institute of ECNU for supports.
References
[1] S. Hegde, M. Schmidt, Ann. Report Med. Chem. 41 (2006) 439.
[2] T. Yamano, M. Yamashita, M. Adachi, et al. Tetrahedron: Asymmetry 17 (2006) 184.
[3] M. Yamashita, T. Yamano, Chem. Lett. 38 (2009) 100.
[4] N. Tarui, H. Watanabe, K. Fukatsu, et al. Biosci. Biotechnol. Biochem. 66 (2002) 464.
[5] B.E. Rossiter, N.M. Swingle, Chem. Rev. 92 (1992) 771.
¨
[6] P.G. Andersson, H.E. Schink, K. Osterlund, J. Org. Chem. 63 (1998) 8067.
[7] D.L. Romero, P.R. Manninen, F. Han, et al. J. Org. Chem. 64 (1999) 4980.
[8] D.J. Pippel, M.D. Curtis, H. Du, et al. J. Org. Chem. 63 (1998) 2.
[9] O. Uchikawa, K. Fukatsu, R. Tokunoh, et al. J. Med. Chem. 45 (2002) 4222.
[10] 5: [a]D20 +39.1 (c, 1.0, CHCl3); mp 69–71 8C; 1H NMR (500 MHz, CDCl3): d 2.86 (q, 1H, J = 9.5 Hz), 3.37 (dd, 1H, J = 3.1 Hz, J = 13.4 Hz),
3.85 (s, 3H), 4.22 (m, 2H), 4.81 (m, 1H), 6.96 (m, 1H), 7.14 (s, 1H), 7.24–7.36 (m, 7H), 7.90 (m, 2H). 13C NMR (100 MHz, CDCl3): d 165.1,
159.8, 153.4, 146.2, 135.8, 135.3, 129.8, 129.4, 128.9, 127.2, 121.3, 117.2, 116.6, 113.3, 66.1, 55.3, 55.2, 37.8. EI-MS: 337 ([M]+); HR-MS
337.1314 ([M]+, C20H19NO4; Calcd. 337.1315). 6: [a]D20 +61.6 (c, 1.0, CHCl3); mp 66–67 8C; 1H NMR (500 MHz, CDCl3): d 2.45 (m, 2H),
2.66 (m, 1H), 3.29 (dd, 2H, J = 4.0 Hz, J = 15.0 Hz), 3.20–3.41 (m, 2H), 3.79 (s, 3H), 4.00 (m, 1H), 4.07 (m, 1H), 4.51 (m, 1H), 5.02 (m, 2H),
5.70 (m, 1H), 6.74 (d, 1H, J = 8.0 Hz), 6.79 (s, 1H), 6.84 (d, 1H, J = 8.0 Hz), 7.16–7.33 (m, 6H). 13C NMR (100 MHz, CDCl3): d 172.8, 159.6,
153.4, 145.3, 136.0, 135.3, 129.3, 128.9, 127.3, 120.0, 116.9, 113.4, 113.3, 111.8, 60.1, 55.2, 55.1, 41.4, 40.9, 40.8, 37.8. EI-MS: 379 ([M]+);
HR-MS 379.1783 ([M]+, C23H25NO4; Calcd. 379.1784). 7: [a]D20 +0.3 (c, 1.0, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.79 (m, 1H), 1.97 (m,
1H), 2.37 (t, 2H, J = 7.0 Hz), 3.47 (m, 1H), 3.54 (m, 1H), 3.80 (s, 3H), 4.97 (m, 2H), 5.66 (m, 1H), 6.72–6.78 (m, 3H), 7.21 (t, 1H, J = 8.0 Hz).
13C NMR (100 MHz, CDCl3): d 159.6, 146.2, 136.6, 129.3, 120.0, 116.1, 113.6, 111.1, 60.8, 55.0, 42.2, 42.8, 38.5. HR-MS 245.1519
([M+Na]+, C14H22O2Na; Calcd. 245.1517). 8: [a]D20 +20.0 (c, 1.0, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.86 (m, 1H), 1.99 (s, 3H), 2.35 (m,
1H), 2.38 (m, 2H), 2.72 (m, 1H), 3.80 (s, 3H), 3.87 (m, 1H), 3.96 (m, 1H), 4.97 (m, 2H), 5.65 (m, 1H), 6.70 (d, 1H, J = 1.4 Hz), 6.74 (m, 2H),
7.21 (t, 1H, J = 7.9 Hz). 13C NMR (100 MHz, CDCl3): d 170.9, 159.7, 145.6, 136.4, 129.4, 119.9, 116.3, 113.6, 111.3, 62.8, 55.1, 42.5, 41.1,
34.3, 20.8. EI-MS: 248 ([M]+); HR-MS 248.1411 ([M]+, C15H20O3; Calcd. 248.1412). 9: [a]D20 +11.0 (c, 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3): d 1.87 (m, 1H), 1.96 (s, 3H), 2.01 (m, 1H), 2.65 (d, 2H, J = 7.4 Hz), 3.20 (m, 1H), 3.79 (s, 3H), 3.85 (m, 1H), 3.99 (m, 1H), 6.72 (s, 1H),
6.75 (m, 2H), 7.21 (t, 1H, J = 7.9 Hz). 13C NMR (100 MHz, CDCl3): d 177.1, 171.1, 159.7, 144.0, 129.7, 119.5, 113.3, 111.8, 62.2, 55.0, 41.0,
38.5, 34.6, 20.7. HR-MS 289.1051 ([M+Na]+, C14H18NaO5; Calcd. 289.1052). 10: [a]D À26.0 (c, 1.0, CHCl3); mp 67–68 8C; 1H NMR
20
(500 MHz, CDCl3): d 1.79 (m, 1H), 2.05 (s, 3H), 2.24 (m, 1H), 2.41 (dd, 1H, J = 3.4 Hz, J = 19.0 Hz), 2.86 (dd, 1H, J = 7.6 Hz, J = 19.0 Hz),

S.B. Yu et al. / Chinese Chemical Letters 22 (2011) 264–267
267
3.39 (m, 1H), 3.88 (s, 3H), 4.18 (m, 2H), 6.91 (m, 2H), 7.67 (t, 1H, J = 4.6 Hz). 13C NMR (100 MHz, CDCl3): d 203.7, 170.9, 165.4, 160.5,
130.0, 125.4, 115.5, 108.9, 62.6, 55.7, 43.1, 35.3, 34.7, 20.9. EI-MS: 248 ([M]+); HR-MS 248.1047 ([M]+, C14H26O4; Calcd. 248.1049). 11:
[a]D À15.0 (c, 1.0, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.70 (m, 2H), 2.05 (s, 1H), 2.13 (m, 1H), 2.32 (m, 1H), 2.76 (m, 1H), 2.85 (m,
20
1H), 3.21 (m, 1H), 3.78 (s, 3H), 3.80 (m, 2H), 6.71 (d, 1H, J = 8.2 Hz), 6.77 (s, 1H), 7.26 (d, 1H, J = 8.2 Hz). 13C NMR (100 MHz, CDCl3): d
158.7, 148.6, 135.8, 124.9, 112.1, 109.3, 61.5, 55.4, 41.7, 37.8, 32.7, 30.6. EI-MS: 192 ([M]+); HR-MS 215.1040 ([M+Na]+, C12H16NaO2;
Calcd. 215.1043). 12: 1H NMR (500 MHz, CDCl3): d 1.83 (m, 2H), 2.24 (s, 1H), 2.41 (m, 1H), 2.78 (m, 1H), 2.86 (m, 1H), 3.11 (m, 1H), 3.77 (s,
3H), 3.81 (m, 2H), 6.68 (dd, 1H, J = 1.8 Hz, 8.2 Hz), 6.79 (s, 1H), 7.08 (d, 1H, J = 8.2 Hz), 7.71 (m, 2H), 7.84 (m, 2H). 13C NMR (100 MHz,
20
CDCl3): d 168.4, 158.7, 147.8, 135.8, 133.9, 132.2, 124.9, 123.2, 112.6, 108.9, 55.4, 42.6, 36.5, 33.4, 32.4, 30.6. 13: [a]D À27.0 (c, 0.20,
H2O); mp 174–175 8C; 1H NMR (500 MHz, DMSO–d6): d 1.66 (m, 2H), 2.09 (m, 1H), 2.24 (m, 1H), 2.70 (m, 1H), 2.80 (m, 3H), 3.12 (m, 1H),
3.71 (s, 3H), 6.71 (d, 1H, J = 8.2 Hz), 6.76 (s, 1H), 7.11 (d, 1H, J = 8.2 Hz), 8.18 (s, 3H). 13C NMR (100 MHz, DMSO–d6): d 158.3, 147.4,
135.0, 124.9, 112.2, 109.1, 55.1, 41.6, 37.1, 31.9, 31.7, 29.9. 1: [a]D À10.0 (c, 0.20, EtOH); mp 76–77 8C; 1H NMR (500 MHz, CDCl3): d
20
1.15 (t, 3H, J = 7.5 Hz), 1.60 (m, 1H), 1.70 (m, 1H), 2.02 (m, 1H), 2.19 (q, 2H, J = 7.5 Hz), 2.32 (m, 1H), 2.76 (m, 1H), 2.85 (m, 1H), 3.11 (m,
1H), 3.41 (m, 2H), 3.79 (s, 3H), 5.48 (s, 1H), 6.71 (dd, 1H, J = 2.0 Hz, 8.5 Hz), 6.75 (s, 1H), 7.11 (d, 1H, J = 8.0 Hz). 13C NMR (100 MHz,
DMSO–d6): d 173.7, 158.7, 148.1, 135.8, 124.9, 112.3, 109.2, 55.5, 42.7, 37.9, 34.8, 32.5, 30.6, 29.8, 9.9. EI-MS: 247 ([M]+); HR-MS 247.1572
([M]+, C15H21NO2; Calcd. 247.1571). The enantiomeric excess of (S)-1 was determined by HPLC as >99.9% [column, CHIRALPAK AS-H
(4.6 mm  250 mm), room temperature; eluent, hexane-2-propanol-trifluoroacetic acid (90:10:0.1); flow rate, 1.0 mL/min; detect, 290 nm; tR
of (S)-1, 30.7 min; tR of (R)-1 (enantiomer of (S)-1), 37.1 min].