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Method for synthesizing 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ketone

A technology of furan and 4-b, which is applied in the field of compound preparation and ramelteon intermediate preparation, can solve the problems of low yield, high cost and long synthetic route of literature methods, and achieve easy industrial production and simple operation , the effect of easily controllable conditions

Active Publication Date: 2010-03-17
SHANGHAI PUYI CHEM CO LTD
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Problems solved by technology

This method has disadvantages such as long synthetic route, low yield and high cost. First, the synthetic route of the literature method is relatively long, requiring nine steps of reaction in total; second, the yield of the literature method is low, especially the fifth step reaction. We refer to the literature. The yield of the method is only about 10%; third, the cost of the literature method is high, and expensive reagents such as palladium carbon are needed

Method used

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  • Method for synthesizing 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ketone
  • Method for synthesizing 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ketone
  • Method for synthesizing 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 1.1 Preparation of compound IV i.e. 7-allyl-6-hydroxyl-1-indanone

[0029] Add 0.2 g of compound III (6-allyloxy-1-indanone, self-made, see Magnetic Resonance in Chemistry; English; 38; 11; 2000; 970-974) at room temperature, N 2 Add 4ml of N,N-diethylaniline (Shanghai Chemical Reagent Company, Sinopharm Group, chemically pure) under protection, slowly heat to 180°C, and react for 10-20h. After the reaction, recover N,N-diethylaniline under reduced pressure , adding ethyl acetate for recrystallization to obtain 0.116 g of compound IV with a yield of 58%.

[0030] 1 H NMR (CDCl 3 , 500MHz): δ=2.7(t, J=6Hz, 2H), 3.0(t, J=6Hz, 2H), 4.0(d, J=6Hz, 2H), 5.1(m, 2H), 5.2(s, 1H), 6.0 (m, 1H), 7.1 (d, J=8Hz, 1H), 7.2 (d, J=8Hz, 1H).

[0031] MS (EI): m / e=188.

[0032] 1.2 Preparation of compound IV i.e. 7-allyl-6-hydroxyl-1-indanone

[0033] Add 0.2 g of compound III (6-allyloxy-1-indanone, self-made, see Magnetic Resonance in Chemistry; English; 38; 11; 2000; 970-974) at r...

Embodiment 2

[0045] 2.1 Preparation of compound V, namely 6-hydroxyl-7-(2-hydroxyl-ethyl)-1-indanone

[0046] At room temperature, 4 g of compound IV obtained in Example 1 and 100 ml of methanol were added, and ozone reaction was started at about -60° C. for 2 to 3 hours. After the reaction, blow nitrogen to drive away excess ozone, add 0.8g of sodium borohydride (Sinopharm Shanghai Chemical Reagent Company, chemically pure), and react for about 0.5 to 1 hour. After the reaction, add 5% dilute hydrochloric acid to adjust the pH to 4-5, and extract with ethyl acetate. Wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 2.4 g of compound V with a yield of 60%.

[0047] 1 H NMR (DMSO-d6, 500MHz): δ=2.6(t, J=6Hz, 2H), 2.9(t, J=6Hz, 2H), 3.2(t, J=8Hz, 2H), 3.4(m, 2H ), 4.6 (t, J=5Hz, 1H), 7.1 (d, J=8Hz, 1H), 7.2 (d, J=8Hz, 1H).

[0048] MS (EI): m / e=192.

[0049] 2.2 Preparation of compound V, namely 6-hydroxyl-7-(2-hydroxyl-ethyl)-1-indanone

...

Embodiment 3

[0066] 3.1 Preparation of compound VI i.e. 6-hydroxyl-7-(2-methanesulfonyloxy-ethyl)-1-indanone

[0067] Dissolve 0.1 g of compound V prepared in Example 2 in 0.5 ml of pyridine, cool down to -20°C, slowly add 0.04 ml of methanesulfonyl chloride (Sinopharm Shanghai Chemical Reagent Company, chemically pure), and react for 1-2 hours. After the reaction, 5% dilute hydrochloric acid was added to adjust the pH to 1-2, ethyl acetate was added to extract, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.1 g of compound VI with a yield of 75%.

[0068] 1 H NMR (CDCl 3 ): δ=2.7(t, J=5.9Hz, 2H), 3.0(t, J=5.9Hz, 2H), 3.6(t, J=6.5Hz, 2H), 4.5(t, J=6.5Hz, 2H ), 7.1 (d, J=8.0Hz, 1H), 7.2 (d, J=8.0Hz, 1H).

[0069] MS (EI): m / e=270.

[0070] 3.2 Preparation of compound VI namely 6-hydroxyl-7-(2-methanesulfonyloxy-ethyl)-1-indanone

[0071] Dissolve 0.1 g of compound V prepared in Example 2 in 5 ml of dichloromethane, add 1.0 ml of...

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Abstract

The invention provides a method for synthesizing 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ketone. The method comprises the following steps: a, performing the Claisen rearrangement reaction of a compound III in an appropriate solvent to generate a compound IV; b. supplying ozone to the compound IV at a low temperature to perform reaction, adding sodium borohydride or potassium borohydride to perform reduction reaction and obtaining a compound V; c, allowing the compound V to react with methanesulfonyl chloride or p-toluenesulfonyl chloride in pyridine so as to obtain a compound VI and a compound VII; and d, dissolving the compound VI and / or the compound VII in an appropriate reaction solvent, adding appropriate organic base, raising temperature to perform reaction, cooling the obtained product, adding diluted hydrochloric acid for washing, evaporating the solvent and obtaining a compound I, namely the 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ketone. The method has the advantages ofbrief synthesis route, simple operation, low cost, high yield and convenience for industrial production.

Description

technical field [0001] The present invention relates to the technical field of compound preparation, in particular to the technical field of ramelteon intermediate preparation, more specifically, a method for synthesizing 1,2,6,7-tetrahydro-8H-indeno[5,4-b ] furan-8-one method. Background technique [0002] Ramelteon is an oral hypnotic drug developed by Takeda Corporation of Japan, which was approved by the US FDA in July 2005. Ramelteon is the first melatonin receptor agonist used to treat insomnia. It is mainly used to treat insomnia with difficulty falling asleep, and it also has a definite effect on chronic insomnia and short-term insomnia. [0003] The compound "1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one" (1) is a key intermediate in the synthesis of ramelteon. It is currently reported that 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ones are synthesized in EP0885210, JP1998287665, JP1999152281, WO9732871 and Uchikawa et al. (Journal of Medicinal Chemistry, 2002 ...

Claims

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Application Information

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IPC IPC(8): C07D307/93
Inventor 王博罗宇
Owner SHANGHAI PUYI CHEM CO LTD
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