Unlock instant, AI-driven research and patent intelligence for your innovation.

Preparation method of key intermediate ethyl 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)acrylate for synthesizing ramelteon

A technology of ethyl acetate and ligand, applied in the field of preparation of key intermediate 2-ethyl acrylate, can solve the problems of long synthesis route, unsatisfactory total yield and the like

Inactive Publication Date: 2015-09-16
SHANGHAI KEEPONTECH
View PDF8 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the current literature, its synthetic route is relatively long, and the total yield is not ideal.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of key intermediate ethyl 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)acrylate for synthesizing ramelteon
  • Preparation method of key intermediate ethyl 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)acrylate for synthesizing ramelteon
  • Preparation method of key intermediate ethyl 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)acrylate for synthesizing ramelteon

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The synthesis of embodiment 1.2-iodo-4-(2-bromoethoxy)-acetophenone (formula 2 compound)

[0028]

[0029] Under the protection of argon, add the compound of formula 1 (1000g, 3058.5mmol) into a dry three-necked flask, dissolve the dry DCM (5000ml), cool to 0°C in an ice bath, add acetyl chloride (290g, 3670mmol), and slowly add AlCl in batches 3 (530g, 4660mmol), add Bi to rise to room temperature and react for 1-3 hours, the reaction is complete, pour into ice water to quench the reaction, filter, extract the aqueous phase with DCM, combine the organic phases, concentrate, wash with saturated brine, anhydrous sulfuric acid Dry over sodium, filter and concentrate to give a light yellow solid (crude).

[0030] Recrystallization: heat and dissolve an appropriate amount of ethyl acetate, add 5 times the volume of petroleum ether, let stand overnight, precipitate crystals, filter, and dry to obtain white crystals (that is, the compound of formula 2, 565 g, yield 50%). ...

Embodiment 2

[0032] Example 2. Synthesis of (E)-3-(5-acetyl-2,3-dihydrobenzofuran-4-yl)-ethyl acrylate (compound of formula 3)

[0033]

[0034] Add formula 2 compound (20g, 54.20mmol), metal catalyst palladium acetate (365mg, 1.63mmol), ligand triphenylphosphine (2.84g, 10.84mmol), potassium carbonate (22.04g, 159.78mmol), Heck reaction acceptor ethyl acrylate (27013g, 271.01mmol), norbornene (15.31g, 162.60mmol), dissolved in dry DME (ethylene glycol dimethyl ether) (80mL), refluxed at 80°C for 12h, the reaction was almost complete, filtered , concentrated, after EA was dissolved, washed twice with water, saturated saline, dried over anhydrous sodium sulfate, concentrated, and recrystallized with an appropriate amount of ethanol to obtain light yellow crystals (ie compound of formula 3, 7.10 g, yield 50%).

[0035] Formula 3 compound: 1 HNMR (400MHz, CDCl 3)δ8.08(d, J=16.3Hz, 1H), 7.70(d, J=8.4Hz, 1H), 6.81(d, J=8.4Hz, 1H), 6.16-5.92(m, 1H), 4.65( t, J=8.7Hz, 2H), 4.27(q, J=7.2Hz, ...

Embodiment 3

[0036] Synthesis of Example 3.2-(6-oxo-2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)ethyl acrylate (compound of formula 4)

[0037]

[0038] The compound of formula 3 (100g, 384.19mmol) was dissolved in N,N-dimethylformamide (300mL), cesium carbonate (200g, 640mmol) was added, stirred at room temperature overnight, water was added under ice cooling, and ethyl acetate extracted 3 times, Washed 4 times with saturated brine, dried over sodium sulfate, and evaporated the solvent under reduced pressure to obtain the compound of formula 4 (94 g, 94%) as a brown liquid.

[0039] Formula 4 compound: 1 H NMR (400MHz, CDCl 3 )δ7.61(d, J=8.3Hz, 1H), 6.83(d, J=8.3Hz, 1H), 4.85-4.60(m, 2H), 4.14(q, J=7.2Hz, 2H), 3.74( td, J=7.5, 3.9Hz, 1H), 3.39-3.18(m, 2H), 3.05-2.84(m, 2H), 2.61-2.36(m, 2H), 1.23(t, 3H). 13 C NMR (101MHz, CDCl 3 )δ204.77, 171.62, 166.62, 153.44, 130.26, 124.95, 122.48, 110.38, 72.63, 60.10, 43.36, 38.36, 33.69, 27.03, 14.15.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a preparation method of a key intermediate ethyl 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)acrylate for synthesizing ramelteon. The method comprises the following steps: carrying out a Friedel-Crafts acylation reaction on a compound of formula 1 and acetyl chloride in the presence of an organic solvent and an acid catalyst to obtain a compound of formula 2; coupling the compound of formula 2 in an organic solvent in the presence of an alkali, norbornene, a ligand and a metal catalyst to obtain a compound of formula 3; adding the compound of formula 3 to an organic solvent, adding an alkali, and carrying out ring closure to obtain a compound of formula 4; and hydrogenating the compound of formula 4 to remove a benzyl carbonyl group to obtain a compound of formula (I). Compared with previous literature methods, the preparation disclosed in the invention has the advantages of short production route, high total yield, high purity, less device corrosion, low cost, and easy industrialization realization; and the preparation method is carried out in common organic solvents, and the solvents can be recycled, so the environment pollution is maximally reduced.

Description

technical field [0001] The invention belongs to the field of chemistry and chemical engineering, and relates to a key intermediate 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl) for the synthesis of ramelteon Preparation method of ethyl acrylate. Its structural formula is as (I): [0002] [0003] There is a chiral carbon in the molecule, and the compound in the formula (I) is a racemate. technical background [0004] Ramelteon (Ramelteon), the chemical name is (S)-N-[2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)] Propionamide, developed by Japan's Takeda Company, was approved by the US FDA in September 2005. Ramelteon is a melatonin receptor agonist that can mimic the physiological effects of melatonin secreted by the pineal gland, helping to regulate the sleep cycle and improve sleep quality. Its mechanism of action is: this product is a melatonin receptor agonist, and melatonin MT 1 and MT 2 Receptors have higher affinity for MT 1 and MT 2 Receptors exhi...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/77
CPCC07D307/77
Inventor 温珂熊祖育霍达
Owner SHANGHAI KEEPONTECH