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Method for preparing ramelteon intermediate by racemization

A compound and catalyst technology, applied in the field of preparing ramelteon intermediates, can solve the problems of being unsuitable for industrial production, expensive reagents, and high cost, and achieve the effects of environmental protection, simple post-processing, and low cost

Active Publication Date: 2017-05-31
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] The technical problem to be solved by the present invention is to overcome the existing method for constructing the benzylic chiral carbon of ramelteon intermediate, which needs to use expensive reagents, the cost is very high, or the yield is low, which is not suitable for industrial production etc. defect, provides a kind of (R)-2-(1,6,7,8-tetrahydro-2H-indeno(5,4-b)furan-8-yl)acetic acid (abbreviated as R type- Ⅰ) The method of racemization realizes recycling to make up for the deficiency that the resolution reaction causes the yield to be on the low side

Method used

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  • Method for preparing ramelteon intermediate by racemization
  • Method for preparing ramelteon intermediate by racemization
  • Method for preparing ramelteon intermediate by racemization

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Example 1 ： 2-(1,2,6,7- Tetrahydro -8H- Indeno -[5,4,-b] Furan -8- Subunit ) Preparation of acetic acid

[0040]Type R-I (10.0g, 0.046mol) and acetic acid (100ml) were placed in a three-necked flask, stirred and dissolved, and Cu(NO3)2·3H2O (2.214g, 0.009mol) and 65% TBHP (peroxide tert-butanol), 21.2ml, 0.137mol), heated to 70°C, reacted for 8h, TLC detected that the raw material basically disappeared, cooled to room temperature, added the reaction solution into 500ml water, stirred for 2h, extracted with ethyl acetate (100ml×3 times ), combined organic phases, washed with saturated brine for 3 times, dried over anhydrous sodium sulfate, suction filtered, rotary evaporated, and passed through the column to obtain yellow oil II (7.46g, 75%), ESI-MS (m / z): 215[ M-H]+, 1HNMR (400MHz, CDCl3) δ: 3.02~3.04(t, 2H), 3.34(s, 2H), 3.40~3.44(t, 2H), 4.64~4.69(t, 2H), 6.15( s,1H),6.85~6.87(d,1H),7.11~7.13(d,1H)

Embodiment 2

[0041] Example 2 ： 2-(1,2,6,7- Tetrahydro -8H- Indeno -[5,4,-b] Furan -8- Subunit ) Preparation of acetic acid

[0042] Type R-I (10.0g, 0.046mol), acetonitrile (90ml) and acetic acid (10ml) were placed in a three-necked flask, stirred and dissolved, then Cu(NO3)2·3H2O (2.214g, 0.009mol) and 65 %TBHP (21.2ml, 0.137mol), heated up to 70°C, reacted for 8h, TLC detected that the raw materials basically disappeared, cooled to room temperature, added the reaction solution to 500ml of water, stirred for 2h, extracted with ethyl acetate (100ml×3 times), The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, rotary evaporated, and passed through the column to obtain yellow oil II (7.40 g, 75%), ESI-MS (m / z): 215 [M- H]+,1HNMR(400MHz,CDCl3)δ:3.02~3.04(t,2H),3.34(s,2H),3.40~3.44(t,2H),4.64~4.69(t,2H), 6.15(s, 1H), 6.85~6.87(d,1H), 7.11~7.13(d,1H)

Embodiment 3

[0043] Example 3 ： 2-(1,2,6,7- Tetrahydro -8H- Indeno -[5,4,-b] Furan -8- Subunit ) Preparation of acetic acid

[0044] Type R-I (10.0g, 0.046mol) and acetic acid (100ml) were dissolved in a three-necked flask, stirred and dissolved, then Cu(NO3)2·3H2O (2.214g, 0.009mol) and 65% TBHP (21.2ml , 0.137mol), heated to 30°C, reacted for 24h, TLC detected that the raw materials basically disappeared, cooled to room temperature, added the reaction solution to 500ml water, stirred for 2h, extracted with ethyl acetate (100ml×3 times), combined the organic phase, saturated Washed with saline for 3 times, dried over anhydrous sodium sulfate, suction filtered, rotary evaporated, passed through the column to obtain yellow oil II (7.34g, 74%), ESI-MS (m / z): 215[M-H]+, 1HNMR (400MHz, CDCl3) δ: 3.02~3.04(t,2H), 3.34(s,2H), 3.40~3.44(t,2H), 4.64~4.69(t,2H), 6.15(s,1H), 6.85~ 6.87(d,1H),7.11~7.13(d,1H)

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Abstract

The invention discloses a racemization method of (R)-2-(1,6,7,8-tetrahydro-2H-indeno(5,4-b)furan-8-yl)acetic acid (R-I). The method comprises the following steps: 1) in an organic solvent and under the action of a radical initiator and a catalyst, R-I undergoes oxydehydrogenation to be converted to a compound II; and 2) in an organic solvent, the compound II undergoes hydrogenation reduction in the presence of a hydrogenation catalyst so as to obtain racemate-I. By the preparation method, use of expensive catalysts is avoided. In addition, cost is low and post-treatment is simple. Waste is changed into valuable things, and discharge of ''three wastes (waste gas, waste water and industrial residue)'' is reduced. The method is beneficial to environment protection. Yield of the product is high; the insufficiency of low yield caused by the resolution reaction in the Route Three is made up. The method can be used for synthesis of ramelteon and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and specifically relates to (R)-2-(1,6,7,8-tetrahydro-2H-indeno(5,4-b)furan-8-yl)acetic acid (abbreviated as Form R-I) racemization to prepare ramelteon intermediate. Background technique [0002] Ramelteon (English name: Ramelteon) is a melatonin receptor agonist developed by Takeda Corporation of Japan. It can selectively act on MT1 and MT2 receptors and can be used to treat insomnia characterized by difficulty falling asleep. Can increase slow wave sleep (SWS) and rapid eye movement sleep (REW), thereby reducing insomnia. In addition, this product has almost no affinity for GABA receptors, dopamine receptors, acetylcholine receptors, opioid receptors, etc., and has a completely different mechanism of action from traditional sedative hypnotics, and helps regulate sleep cycles and improve sleep quality Without obvious addiction, it is the first sedative-hypnotics not included in special contro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/77
CPCC07D307/77
Inventor 林快乐周伟澄丁胜吕训磊于洁李丹徐声辉
Owner SHANGHAI INST OF PHARMA IND
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