RAMELTEON

RAMELTEON

An efficient and practical process for the synthesis of ramelteon 1, a sedative-hypnotic, is described. Highlights in this synthesis are the usage of acetonitrile as nucleophilic reagent to add to 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one 2 and the subsequent hydrogenation which successfully implement four processes (debromination, dehydration, olefin reduction, and cyano reduction) into one step to produce the ethylamine compound 13where dibenzoyl-l-tartaric acid is selected both as an acid to form the salt in the end of hydrogenation and as the resolution agent. Then, target compound 1 is easily obtained from13 via propionylation. The overall yield in this novel and concise process is almost twice as much as those in the known routes, calculated on compound 2.

A Novel and Practical Synthesis of Ramelteon

Sa Xiao , Chao Chen , Hongyan Li , Kuaile Lin , andWeicheng Zhou *

State Key Lab of New Drug & Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, State Institute of Pharmaceutical Industry, Shanghai 200437,China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/op500386g

http://pubs.acs.org/doi/abs/10.1021/op500386g

Publication Date (Web): January 6, 2015

Copyright © 2015 American Chemical Society

*Telephone: +86 21 55514600. E-mail: zhouweicheng58@163.com.

NMR, IR MASS………http://pubs.acs.org/doi/suppl/10.1021/op500386g/suppl_file/op500386g_si_001.pdf

Preparation of (S)-N-[2-(1,6,7,8-Tetrahydro-2H-indeno[5,4-b] furan-8-yl)ethyl]propionamide(1).

GAVE

white solid of 1(1.570 g, 85% yield, 99.8% ee). Purity by HPLC 99.6%.

Mp: 115−116 °C(113−115°C in literature 1 ).

1 H−NMR(400 MHz, CDCl3):

δ 1.39 (t, 3H); 1.63 (m, 1H); 1.83 (m, 1H); 2.02 (m, 1H); 2.16 (dd, J=8, 2H); 2.28 (m, 1H); 2.78 (m, 1H); 2.83 (m, 1H); 3.14 (m, 1H); 3.22 (m, 2H); 3.33 (m, 2H); 4.54 (m, 2H); 5.38 (br s, 1H); 6.61 (d, J=8, 1H); 6.97 (d, J=8, 1H).

13C−NMR(100 MHz, CDCl3):

δ 173.85, 159.56, 143.26, 135.92, 123.52, 122.28, 107.56, 71.26, 42.37, 38.17, 33.66, 31.88, 30.82, 29.86, 28.73, 10.01.

MS (ES+): m/z 282(M+Na) + .

[α]D −57.3(c=1.0, CHCl3, −57.8 in literature 1 ).

Anal. (C16H21NO2) Calc: C, 74.10; H, 8.16; N, 5.40; found: 74.09; H, 8.17; N, 5.47.

References

(1) Uchikawa, O.; Fukatsu, K.; Tokunoh, R.; Kawada, M.; Matsumoto, K.; Imai, Y.; Hinuma, S.; Kato, K.; Nishikawa, H.; Hirai, K.; Miyamoto M.; Ohkawa, S. J. Med. Chem. 2002, 45, 4222-4239.

(2) Yamano, T.; Yamashita, M.; Adachi, M.; Tanaka, M.; Matsumoto, K.; Kawada, M.; Uchikawa, O.; Fukatsu, K.; Ohkawa, S. Tetrahedron: Asymmetry. 2006, 17, 184-190.

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SYNTHESIS

http://sat.ecnu.edu.cn/Uploadnews/20120213113859628.pdf

CHINESE CHEMICAL LETTERS 22, 2011, 264 SEE SYN OF KEY INTERMEDIATE

1:(S)-N-(2-(6-Methoxy-2,3-dihydro-1H-inden-1-yl)ethyl)propionamide 1   IS THE KEY INTERMEDIATE

[a]D20 10.0 (c, 0.20, EtOH); mp 76–77 8C;

1H NMR (500 MHz, CDCl3): d1.15 (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): d173.7, 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; tRof (S)-1, 30.7 min; tR of (R)-1 (enantiomer of (S)-1), 37.1 min].

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STEREOSELECTIVE SYNTHESIS OF MELATONIN ...

https://www.heterocycles.jp/newlibrary/downloads/PDF/22186/85/1

by X Zhang - ‎2012 - ‎Cited by 3 - ‎Related articles

Ramelteon (1, Rozerem), developed by Takeda Pharmaceuticals North America, .... 1HNMR spectra and 13C NMR were recorded in CDCl3 and C2D6SO on  ...

HETEROCYCLES, Vol. 85, No. 1, 2012 73-84

https://www.heterocycles.jp/newlibrary/downloads/PDF/22186/85/1 (S)-N-[2-(1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide (1).RAMELTEON
Propionic anhydride (8 mg, 0.06mmol) was added to a stirred solution of 25 (10 mg, 0.05 mmol) and
Et3N (15 mg, 0.15 mmol) in CH2Cl2 (5 mL) at room temperature. After the mixture was stirred for 1 h at
room temperature, EtOAc and water were added. The organic layer was washed with brine and dried over
anhydrous Na2SO4. The filtrate was concentrated to give a solid, which was further purified by column
chromatography (EtOAc : petroleum ether = 2:1) to give pure 1 as a white solid (8 mg, 62%). mp
113–115 °C, 1H NMR (CDCl3) δ 1.14 (t, J = 7.6 Hz, 3H), 1.55-2.05 (m, 3H), 2.18 (q, J = 7.6 Hz, 2H),
2.20-2.35 (m, 1H), 2.70-2.99 (m, 2H), 3.05-3.50 (m, 5H), 4.48-4.60 (m, 2H), 5.46 (br, 1H ), 6.61 (d, J =
8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H). 

The enantiomeric excess of (S)-1 was determined by HPLC as >
92% [column, CHIRALPAK OD-H (4.6mm × 250mm), room temperature; eluent, hexane-EtOH-MsOH
(900:100:0.1); flow rate, 1.0 mL/min; detect, 220 nm, tR of (S)-1, 6.99 min; tR of (R)-1 (enantiomer of
(S)-1), 7.87 min].

...........................

Title: Ramelteon

CAS Registry Number: 196597-26-9

CAS Name: N-[2-[(8S)-1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl]propanamide

Manufacturers' Codes: TAK-375

Trademarks: Rozerem (Takeda)

Molecular Formula: C16H21NO2

Molecular Weight: 259.34

Percent Composition: C 74.10%, H 8.16%, N 5.40%, O 12.34%

Literature References: Melatonin MT1/MT2 receptor agonist. Prepn: S. Ohkawa et al., WO 9732871; eidem US 6034239 (1997, 2000 both to Takeda); O. Uchikawa et al., J. Med. Chem. 45, 4222 (2002). Pharmacology: N. Yukuhiro et al., Brain Res. 1027, 59 (2004). Receptor binding study: K. Kato et al., Neuropharmacology 48, 301 (2005). Reviews of development and therapeutic potential: C. Cajochen, Curr. Opin. Invest. Drugs 6, 114-121 (2005); N. N. Nguyen et al., Formulary 40, 146-155 (2005).

Properties: Crystals from ethyl acetate, mp 113-115°. [a]D20 -57.8° (c = 1.004 in chloroform).

Melting point: mp 113-115°

Optical Rotation: [a]D20 -57.8° (c = 1.004 in chloroform)

Therap-Cat: Sedative, hypnotic.

Keywords: Sedative/Hypnotic; Melatonin Receptor Agonist.

PREDICTIONS
1H NMR

13C NMR








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