7-allyl-6-hydroxy-indan-1-one...Mom will teach you NMR

Thermal Claisen rearrangement on 6-allyloxy-indan-1-one,  (III) to obtain 7-allyl-6-hydroxy-indan-1-one, (IV):

• Formula: C12H12O2
• Molecular Weight: 188.22200

Synonyms:	6-hydroxy-7-prop-2-enylindan-1-one

• 
  

http://www.google.com/patents/US8242291
EXAMPLE 2

This example refers to reaction b of the process of the invention.

20 kg of the intermediate of formula (III) prepared as described in example 1 are suspended in 50 l of Dowtherm A under nitrogen flow. In an inert atmosphere, it is heated to approximately 200° C. for approximately 5 hours. Upon completion of the reaction (TLC) a clear red-brown solution is obtained, without the formation of black pitch. The reaction mixture is cooled slowly to 25° C. (a partial precipitation is observed). 100 l (5 volumes) of cyclohexane are added and it is cooled to between 0 and 5° C. for one hour. It is filtered by washing with cyclohexane and dried at reduced pressure and T=45° C. for at least 12 hours. 16.8 kg of yellow solid are obtained which is refluxed in 80 l of toluene in the presence of decolouring carbon. The suspension is filtered, washing it with hot toluene. Part of the solvent is distilled at reduced pressure until the beginning of crystallisation. It is cooled at room temperature and then to between 0 and 5° C. for at least one hour.

The filtered solid is washed with cold toluene and dried at reduced pressure at T=45° C. for at least 12 hours. 15.3 kg of intermediate (IV) are obtained in the form of an almost white solid of quality suitable for continuation of the synthesis.

¹H-NMR and mass spectroscopic analyses are performed on part of the product thus obtained, purified by chromatography for analytical purposes (silica gel, 7 parts in volume of heptane—3 parts in volume of ethyl acetate), obtaining the following results:

Electron impact mass: [M⁺]=188

¹H-NMR (500 MHz, CDCl₃): δ (ppm)

2.72 ppm, t, J=6 Hz, 2H,  AR C=OCH2 CH2 AR

3.03 ppm, t, J=6 Hz, 2H, AR C=OCH2 CH2 AR

4.03 ppm, d, J=6 Hz, 2H, ARCH2CH=CH2

5.13-5.20, Σd, 2H, ARCH2CH=CH2

5.60 ppm, s, 1H, 0H

5.98-6.10 ppm, m, 1H, CH2CH=CH2

7.13 ppm, d, J=8 Hz, 1H, AR

7.25, d, J=8 Hz, 1H. AR

PREDICT
1H NMR

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13 C NMR

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6-hydroxy-7-prop-2-enyl-2,3-dihydroinden-1-one

COSY PREDICT

HMBC PREDICT

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COCK SAYS MOM CAN TEACH YOU NMR

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6-allyloxy-indan-1-one

http://www.google.com/patents/US8242291

alkylation of the hydroxyl of 6-hydroxy-indanone, (II), to obtain 6-allyloxy-indan-1-one, (III):

EXAMPLE 1

This example refers to reaction a of the process of the invention.

20 kg of 6-hydroxy-indanone are suspended in 120 l of acetone, and 29.9 kg of potassium carbonate and 19.7 kg of allyl bromide are added. The reaction mixture is heated to reflux and checked after 15 h (TLC). It is cooled to 20-25° C. and filtered, washing the filtered solid with 40 l of acetone. The filtered solution is concentrated to dryness at reduced pressure. The oil obtained is recovered with 25 l of heptane and re-concentrated to dryness obtaining a solid (25.9 kg). The thus obtained solid is dissolved at 60° C. in 125 l of heptane, and is then cooled to 0° C. for at least one hour. It is filtered and washed with 25 l of cold heptane. 22.3 kg of intermediate (III) are obtained in a pale yellow solid form of quality suitable for continuation of the synthesis.

An ¹H-NMR (500 MHz, CDCl₃) spectroscopic analysis is performed on part of the product thus obtained, purified by chromatography for analytical purposes (silica gel, heptane 8-ethyl acetate 2), obtaining the following result:

2.74 ppm, t J=6 Hz, 2H, AR C=0 CH2CH2 AR

3.10 ppm, t, J=6 HZ, 2H, AR C=0 CH2CH2 AR

4.60 ppm, broad d, J=5 Hz, 2H, 0-CH2CH=CH2

5.32 ppm, dd, J=10 Hz, 1H, 0-CH2CH=CH2

5.45 ppm, broad dd, J=16 Hz, 1H, 0-CH2CH=CH2

6.02-6.13 ppm, m, 1H; 0-CH2CH=CH2

7.20-7.27 ppm, m, 2H, 

7.40 ppm, d, J=8 Hz, 1H.

Industriale Chimica S.R.L.

INDUSTRIAL CHEMICAL SRL

Via Grieg, 13 - 21047 - SARONNO ( VA )

Tel .:		02 96426411th
Fax:		02 the 9,621,997th
VAT:		07462480158
Cod. Tax:		07462480158
Web:

Group:

Chemical, Pharmaceutical and Leather Chemical Pharmaceutical

Production sector:

PRODUCTION DEVELOPMENT RESEARCH CHEMICALS PHARMACEUTICALS

Products:

ACTIVE CHEMICAL PHARMACEUTICAL INDUSTRY

Brands:

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SWITZERLAND SPAIN

Inglese:  Product activity:  Products:

Company Profile:

Industrial Chemistry Srl company active in Saronno since 1984, has experienced a rapid and continuous expansion going from 21 employees to more than 60 current '94. It is a group company Chemo that, by holding well 45 international patents, produces synthetic active ingredients for the preparation of many types medicines including anti-inflammatory, anti-ischemic, diuretics and steroids. As evidence of the very high quality of the productions the company markets its products are almost exclusively foreign. Industrial Chemistry also invests every year a good proportion of turnover in research. Since 1988 the company has entered in the register of highly qualified laboratories, authorized to conduct applied research in favor of small and medium industries, prepared by the Ministry of Scientific Research. In company are rigorously applied standard operating procedures for all production activities that ensure the highest level of safety for the operators and the environment. Street View Via Edvard Hagerup Grieg, 13 21047 Saronno VA, Italy

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








COSY PREDICTION

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