CN101671323B - Method for synthesizing 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ketone - Google Patents
Method for synthesizing 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ketone Download PDFInfo
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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 of brief synthesis route, simple operation, low cost, high yield and convenience for industrial production.
Description
Technical field
The present invention relates to the compound technical field, particularly ramelteon intermediate preparation technical field, more specifically, be meant a kind of synthetic 1,2,6, the method for 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone.
Background technology
Ramelteon is by a kind of oral hypnotic drug of Japanese Wu Tian company research and development, goes on the market through drugs approved by FDA in July, 2005.Ramelteon be first be used for the treatment of insomnia take off the melanochrome receptor stimulant, be mainly used in the treatment type insomnia that has difficulty in going to sleep, chronic insomnia and short-term insomnia are also had definite curative effect.
Compound " 1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone " (1) is the key intermediate of synthetic ramelteon.Report 1,2,6 at present, the synthetic document of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone has (Journal of Medicinal Chemistry, 2002 such as EP0885210, JP1998287665, JP1999152281, WO9732871 and Uchikawa, 45, the document of 4222-4239) delivering.These synthetic methods of having reported all are to be raw material with benzo tetrahydrofuran (THF) (2), obtain intermediate 1 through the reaction of 9 steps.There are shortcomings such as synthetic route is long, productive rate is low, cost height in this method, and at first, the literature method synthetic route is longer, needs the reaction of nine steps altogether; The second, the literature method productive rate is low, especially the 5th step reaction, and the method productive rate of our reference literature only is about 10%; The 3rd, literature method cost height need be used expensive reagent such as palladium carbon.
Summary of the invention
Main purpose of the present invention is exactly the problems and shortcomings at above existence, provides a kind of synthetic 1,2,6, the method of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone, this method has the advantage that synthetic route is brief, easy and simple to handle, cost is low, productive rate is high, be easy to suitability for industrialized production.
To achieve these goals, the technical solution used in the present invention is:
A kind of synthetic 1,2,6, the method for 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone is characterized in, comprises the following steps:
A. make compound III that the Claisen rearrangement reaction takes place in appropriate solvent and generate compound IV;
B. make described compound IV feed ozone at low temperatures and react, add sodium borohydride or POTASSIUM BOROHYDRIDE afterwards again and carry out reduction reaction and obtain compound V;
C. described compound V and methane sulfonyl chloride/Tosyl chloride are reacted in pyridine, thereby obtain compound VI/compound VI I;
D. described compound VI and/or described compound VI I are dissolved in the suitable reaction solvent, add suitable organic bases, elevated temperature reacts then, and obtaining Compound I is 1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone.
Preferably, among the step a, the temperature of described rearrangement reaction is 100 ℃～200 ℃, and described solvent is N, N-Diethyl Aniline, N, accelerine, DMF or DMA.The weight ratio of compound III and solvent is 1:3～8, reacts under 100～200 ℃ temperature 10～20 hours.
Preferably, among the step a, after described rearrangement reaction is finished, also comprise step: steam described solvent, and recrystallization.After being cooled to 10～30 ℃, decompression steams solvent, and recrystallization obtains compound IV in appropriate solvent again.The solvent that recrystallization uses comprises the mixture of ethyl acetate, acetone, methyl alcohol, ethanol, sherwood oil or above-mentioned solvent.
Preferably, among the step b, described compound IV is dissolved in the alcoholic solvent, described low temperature is-80～-60 ℃, described reaction was carried out 1～3 hour, described compound IV is 1:0.5～1.5 with the ratio of the molar weight of described POTASSIUM BOROHYDRIDE or described sodium borohydride, and described reduction reaction was reacted 0.5～1 hour under-60 ℃～-30 ℃ temperature.The weight ratio of compound IV and solvent is 1:3～5, and the flow of ozone is 1～2 liter/hour, and alcoholic solvent is methyl alcohol, ethanol or Virahol.
Preferably, among the step b, after described ozone feeds end, also comprise step: feed nitrogen and drive described ozone away; Described reduction reaction also comprises step after finishing: adding dilute hydrochloric acid adjusting pH value is 4～5, then with the appropriate solvent extraction, and washing, dry, evaporate to dryness, recrystallization again.Feed nitrogen and be used to drive away redundant ozone, add an amount of POTASSIUM BOROHYDRIDE or sodium borohydride again; The solvent that extraction is used comprises methylene dichloride, chloroform, ethyl acetate, and the solvent that recrystallization uses comprises the mixture of ethyl acetate, sherwood oil, acetone, isopropyl ether or above-mentioned solvent.
Preferably, among the step c, described compound V is 1:0.9～1.2 with the ratio of the molar weight of described methane sulfonyl chloride or described Tosyl chloride, and the temperature of described reaction is-30 ℃～-10 ℃, and the time of described reaction is 1～2 hour.
Preferably, among the step c, described reaction also comprises step after finishing: adding dilute hydrochloric acid or dilute sulphuric acid is 1～2 to the pH value, adds the appropriate solvent extraction again, through washing, drying.
Preferably, in the steps d, described reaction solvent is ethyl acetate or chloroform, and described organic bases is pyridine, triethylamine or N, the N-diisopropylethylamine; The mol ratio of described compound VI and/or described compound VI I and described organic bases is 1:1～3, and described being reflected under 50 ℃～100 ℃ carried out 3～10 hours, and described refrigerative temperature is a room temperature, and the time of described continuation reaction is 5～10 hours.
Preferably, in the steps d, after described continuation reaction finishes, also comprise step: cooling, adding dilute hydrochloric acid or dilute sulphuric acid is 1～2 to the pH value, through washing, dry, evaporate to dryness.
Raw material 6-allyloxy-1-indone (compound III) that the present invention adopts can be according to existing document (as MagneticResonance in Chemistry; English; 38; 11; 2000; 970～974) synthetic easily.
Beneficial effect of the present invention is as follows:
1. to adopt 6-allyloxy-1-indone (compound III) be raw material in the present invention, obtain compound 1 through reactions such as Claisen rearrangement, ozonize/reduction, esterification, replacements, 2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone, synthetic route is brief, the yield height, total recovery can reach 35%～40%;
2. the present invention does not relate to the use of expensive reagent, has reduced cost;
3. easy and simple to handle, condition that synthetic method of the present invention relates to are easily controlled, and are easy to suitability for industrialized production.
Embodiment
In order more to be expressly understood technology contents of the present invention, now further specify as follows in conjunction with the embodiments:
Embodiment 1
1.1 compound IV is the preparation of 7-allyl group-6-hydroxyl-1-indone
(method is referring to Magnetic Resonance inChemistry for 6-allyloxy-1-indone, self-control to add compound III under the room temperature; English; 38; 11; 2000; 970～974) 0.2g, N
2Protection adds N down, and N-Diethyl Aniline (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 4ml slowly is heated to 180 ℃; reaction 10～20h, after reaction finishes, reclaim under reduced pressure N, N-Diethyl Aniline; add re-crystallizing in ethyl acetate, get compound IV 0.116g, yield 58%.
1H?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)。
MS(EI)：m/e＝188。
1.2 compound IV is the preparation of 7-allyl group-6-hydroxyl-1-indone
(method is referring to Magnetic Resonance inChemistry for 6-allyloxy-1-indone, self-control to add compound III under the room temperature; English; 38; 11; 2000; 970～974) 0.2g, N
2Protection adds N down, and accelerine (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 4ml slowly is heated to 180 ℃; reaction 10～20h, after reaction finishes, reclaim under reduced pressure N, accelerine; add re-crystallizing in ethyl acetate, get compound IV 0.10g, yield 50%.
1H?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)。
MS(EI)：m/e＝188。
1.3 compound IV is the preparation of 7-allyl group-6-hydroxyl-1-indone
(method is referring to Magnetic Resonance inChemistry for 6-allyloxy-1-indone, self-control to add compound III under the room temperature; English; 38; 11; 2000; 970～974) 0.2g, N
2Protection adds N down, and N-Diethyl Aniline (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 4ml slowly is heated to 100 ℃; reaction 20h, after reaction finishes, reclaim under reduced pressure N, N-Diethyl Aniline; add re-crystallizing in ethyl acetate, get compound IV 0.116g, yield 58%.
1H?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)。
MS(EI)：m/e＝188。
1.4 compound IV is the preparation of 7-allyl group-6-hydroxyl-1-indone
(method is referring to Magnetic Resonance inChemistry for 6-allyloxy-1-indone, self-control to add compound III under the room temperature; English; 38; 11; 2000; 970～974) 0.2g, N
2Protection adds N down, and N-Diethyl Aniline (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 4ml slowly is heated to 200 ℃; reaction 10h, after reaction finishes, reclaim under reduced pressure N, N-Diethyl Aniline; add re-crystallizing in ethyl acetate, get compound IV 0.116g, yield 58%.
1H?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)。
MS(EI)：m/e＝188。
Embodiment 2
2.1 compound V is the preparation of 6-hydroxyl-7-(2-hydroxyl-ethyl)-1-indone
Add compound IV 4g, methyl alcohol 100ml that embodiment 1 obtains under the room temperature, begin logical ozone reaction 2～3h about-60 ℃.Reaction finishes the logical nitrogen in back and drives redundant ozone away, adds 0.8g sodium borohydride (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure), about reaction 0.5～1h.Reaction finishes the back and adds 5% dilute hydrochloric acid adjusting pH to 4～5, uses ethyl acetate extraction.Saturated salt washing, anhydrous sodium sulfate drying, filtration, concentrate compound V2.4g, yield 60%.
1H?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)。
MS(EI)：m/e＝192。
2.2 compound V is the preparation of 6-hydroxyl-7-(2-hydroxyl-ethyl)-1-indone
Add compound IV 4g, methyl alcohol 100ml that embodiment 1 obtains under the room temperature, begin logical ozone reaction 2～3h about-60 ℃.Reaction finishes the logical nitrogen in back and drives redundant ozone away, adds 1.0g POTASSIUM BOROHYDRIDE (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure), about reaction 0.5～1h.Reaction finishes the back and adds 5% dilute hydrochloric acid adjusting pH to 4～5, uses ethyl acetate extraction.Saturated salt washing, anhydrous sodium sulfate drying, filtration, concentrate compound V2.4g, yield 60%.
1H?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)。
MS(EI)：m/e＝192。
2.3 compound V is the preparation of 6-hydroxyl-7-(2-hydroxyl-ethyl)-1-indone
Add compound IV 4g, methyl alcohol 100ml that embodiment 1 obtains under the room temperature, begin logical ozone reaction 2～3h about-80 ℃.Reaction finishes the logical nitrogen in back and drives redundant ozone away, adds 0.8g sodium borohydride (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure), about reaction 0.5～1h.Reaction finishes the back and adds 5% dilute hydrochloric acid adjusting pH to 4～5, uses ethyl acetate extraction.Saturated salt washing, anhydrous sodium sulfate drying, filtration, concentrate compound V2.4g, yield 60%.
1H?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)。
MS(EI)：m/e＝192。
2.3 compound V is the preparation of 6-hydroxyl-7-(2-hydroxyl-ethyl)-1-indone
Add compound IV 4g, methyl alcohol 100ml that embodiment 1 obtains under the room temperature, begin logical ozone reaction 2～3h about-60 ℃.Reaction finishes the logical nitrogen in back and drives redundant ozone away, is warmed up to-50 ℃, adds 0.8g sodium borohydride (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure), about reaction 0.5～1h.Reaction finishes the back and adds 5% dilute hydrochloric acid adjusting pH to 4～5, uses ethyl acetate extraction.Saturated salt washing, anhydrous sodium sulfate drying, filtration, concentrate compound V2.2g, yield 55%.
1H?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)。
MS(EI)：m/e＝192。
2.4 compound V is the preparation of 6-hydroxyl-7-(2-hydroxyl-ethyl)-1-indone
Add compound IV 4g, methyl alcohol 100ml that embodiment 1 obtains under the room temperature, begin logical ozone reaction 2～3h about-60 ℃.Reaction finishes the logical nitrogen in back and drives redundant ozone away, is warmed up to-30 ℃, adds 0.8g sodium borohydride (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure), about reaction 0.5～1h.Reaction finishes the back and adds 5% dilute hydrochloric acid adjusting pH to 4～5, uses ethyl acetate extraction.Saturated salt washing, anhydrous sodium sulfate drying, filtration, concentrate compound V2.0g, yield 50%.
1H?NMR(DMSO-d6，500MHz)：δ＝2.6(t，J＝6Hz，2H)，2.9(t，J＝6Hz，2H)，3.2(t，J＝8Hz，2H)，34(m，2H)，4.6(t，J＝5Hz，1H)，7.1(d，J＝8Hz，1H)，7.2(d，J＝8Hz，1H)。
MS(EI)：m/e＝192。
Embodiment 3
3.1 compound VI is the preparation of 6-hydroxyl-7-(2-methanesulfonyloxy group-ethyl)-1-indone
The compound V0.1g of embodiment 2 preparations is dissolved in the 0.5ml pyridine, cools to-20 ℃, slowly add methylsulfonyl chloride (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.04ml, reaction 1～2h.Reaction finishes the back and adds 5% dilute hydrochloric acid and regulate pH to 1～2, adds ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration, concentrate compound VI 0.1g, yield 75%.
1H?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)。
MS(EI)：m/e＝270。
3.2 compound VI is the preparation of 6-hydroxyl-7-(2-methanesulfonyloxy group-ethyl)-1-indone
The compound V0.1g of embodiment 2 preparations is dissolved in the 5ml methylene dichloride, adds triethylamine 1.0ml, cool to-20 ℃, slowly add methylsulfonyl chloride (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.04ml, reaction 1～2h.Reaction finishes the back and adds 5% dilute hydrochloric acid and regulate pH to 1～2, adds ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration, concentrate compound VI 0.1g, yield 75%.
1H?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)。
MS(EI)：m/e＝270。
3.3 compound VI is the preparation of 6-hydroxyl-7-(2-methanesulfonyloxy group-ethyl)-1-indone
The compound V0.1g of embodiment 2 preparations is dissolved in the 0.5ml pyridine, cools to-30 ℃, slowly add methylsulfonyl chloride (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.04ml, reaction 1～2h.Reaction finishes the back and adds 5% dilute hydrochloric acid and regulate pH to 1～2, adds ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration, concentrate compound VI 0.1g, yield 75%.
1H?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)。
MS(EI)：m/e＝270。
3.4 compound VI is the preparation of 6-hydroxyl-7-(2-methanesulfonyloxy group-ethyl)-1-indone
The compound V0.1g of embodiment 2 preparations is dissolved in the 0.5ml pyridine, cools to-10 ℃, slowly add methylsulfonyl chloride (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.04ml, reaction 1～2h.Reaction finishes the back and adds 5% dilute hydrochloric acid and regulate pH to 1～2, adds ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration, concentrate compound VI 0.1g, yield 75%.
1H?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)。
MS(EI)：m/e＝270。
Embodiment 4
4.1 compound VI I is the preparation of 6-hydroxyl-7-(2-tolysulfonyl oxygen base-ethyl)-1-indone
The compound V0.1g of embodiment 2 preparations is dissolved in the 0.5ml pyridine, cools to-20 ℃, slowly add Tosyl chloride (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.10g, reaction 1-2h.Reaction finishes the back and adds 5% dilute hydrochloric acid and regulate pH to 1～2, adds ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration, concentrate compound VI I 0.14g, yield 80%.
1H?NMR(CDCl
3)：δ＝2.35(s，3H)，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)，7.40(d，J＝7.0Hz，2H)，7.82(d，J＝7.0Hz，2H)。
MS(EI)：m/e＝346。
4.2 compound VI I is the preparation of 6-hydroxyl-7-(2-tolysulfonyl oxygen base-ethyl)-1-indone
The compound V0.1g of embodiment 2 preparations is dissolved in the 5ml methylene dichloride, adds triethylamine 1.0ml,, cool to-20 ℃, slowly add Tosyl chloride (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.10g, reaction 1～2h.Reaction finishes the back and adds 5% dilute hydrochloric acid and regulate pH to 1～2, adds ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration, concentrate compound VI I 0.14g, yield 80%.
1H?NMR(CDCl
3)：δ＝2.35(s，3H)，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)，7.40(d，J＝7.0Hz，2H)，7.82(d，J＝7.0Hz，2H)。
MS(EI)：m/e＝346。
4.3 compound VI I is the preparation of 6-hydroxyl-7-(2-tolysulfonyl oxygen base-ethyl)-1-indone
The compound V0.1g of embodiment 2 preparations is dissolved in the 0.5ml pyridine, cools to-30 ℃, slowly add Tosyl chloride (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.10g, reaction 1-2h.Reaction finishes the back and adds 5% dilute hydrochloric acid and regulate pH to 1～2, adds ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration, concentrate compound VI I 0.14g, yield 80%.
1H?NMR(CDCl
3)：δ＝2.35(s，3H)，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)，7.40(d，J＝7.0Hz，2H)，7.82(d，J＝7.0Hz，2H)。
MS(EI)：m/e＝346。
4.4 compound VI I is the preparation of 6-hydroxyl-7-(2-tolysulfonyl oxygen base-ethyl)-1-indone
The compound V0.1g of embodiment 2 preparations is dissolved in the 0.5ml pyridine, cools to-10 ℃, slowly add Tosyl chloride (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.10g, reaction 1-2h.Reaction finishes the back and adds 5% dilute hydrochloric acid and regulate pH to 1～2, adds ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration, concentrate compound VI I 0.14g, yield 80%.
1H?NMR(CDCl
3)：δ＝2.35(s，3H)，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)，7.40(d，J＝7.0Hz，2H)，7.82(d，J＝7.0Hz，2H)。
MS(EI)：m/e＝346。
Embodiment 5
5.1 Compound I is 1,2,6, the preparation of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone
The compound VI 0.2g of embodiment 3 preparations is dissolved among the ethyl acetate 2ml, adds triethylamine (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.21ml, reflux (77 ℃) reaction 5～6h.After reaction finishes, add 1N hydrochloric acid and regulate pH to 1～2, ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate, cross post and obtain Compound I 81mg, yield 60%.
M.p.133-134℃。
1H?NMR(CDCl
3)：δ＝2.6(t，J＝5.9Hz，2H)，3.1(t，J＝5.9Hz，2H)，3.4(t，J＝8.8Hz，2H)，4.6(t，J＝8.8Hz，2H)，7.0(d，J＝8.1Hz，1H)，7.2(d，J＝8.1Hz，1H)。
MS(EI)：m/e＝174。
5.2 Compound I is 1,2,6, the preparation of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone
The compound VI 0.2g of embodiment 3 preparations is dissolved among the ethyl acetate 2ml, adds pyridine (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.22ml, reflux (77 ℃) reaction 5～6h.After reaction finishes, add 1N hydrochloric acid and regulate pH to 1-2, ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate, cross post and obtain Compound I 87mg, yield 65%.
M.p.133-134℃。
1H?NMR(CDCl
3)：δ＝2.6(t，J＝5.9Hz，2H)，3.1(t，J＝5.9Hz，2H)，3.4(t，J＝8.8Hz，2H)，4.6(t，J＝8.8Hz，2H)，7.0(d，J＝8.1Hz，1H)，7.2(d，J＝8.1Hz，1H)。
MS(EI)：m/e＝174。
5.3 Compound I is 1,2,6, the preparation of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone
The compound VI 0.2g of embodiment 3 preparations is dissolved among the ethyl acetate 2ml, adds N, N-diethyl Isopropylamine (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.30ml, reflux (77 ℃) reaction 5～6h.After reaction finishes, add 1N hydrochloric acid and regulate pH to 1～2, ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate, cross post and obtain Compound I 94mg, yield 70%.
M.p.133-134℃。
1H?NMR(CDCl
3)：δ＝2.6(t，J＝5.9Hz，2H)，3.1(t，J＝5.9Hz，2H)，3.4(t，J＝8.8Hz，2H)，4.6(t，J＝8.8Hz，2H)，7.0(d，J＝8.1Hz，1H)，7.2(d，J＝8.1Hz，1H)。
MS(EI)：m/e＝174。
5.4 Compound I is 1,2,6, the preparation of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone
The compound VI 0.2g of embodiment 3 preparations is dissolved among the ethyl acetate 2ml, adds triethylamine (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.21ml, be heated to 50 ℃, reaction 10h.After reaction finishes, add 1N hydrochloric acid and regulate pH to 1～2, ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate, cross post and obtain Compound I 81mg, yield 60%.
M.p.133-134℃。
1H?NMR(CDCl
3)：δ＝2.6(t，J＝5.9Hz，2H)，3.1(t，J＝5.9Hz，2H)，3.4(t，J＝8.8Hz，2H)，4.6(t，J＝8.8Hz，2H)，7.0(d，J＝8.1Hz，1H)，7.2(d，J＝8.1Hz，1H)。
MS(EI)：m/e＝174。
5.5 Compound I is 1,2,6, the preparation of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone
The compound VI 0.2g of embodiment 3 preparations is dissolved among the ethyl acetate 2ml, adds pyridine (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.22ml, be heated to 50 ℃, reaction 10h.After reaction finishes, add 1N hydrochloric acid and regulate pH to 1-2, ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate, cross post and obtain Compound I 87mg, yield 65%.
M.p.133-134℃。
1H?NMR(CDCl
3)：δ＝2.6(t，J＝5.9Hz，2H)，3.1(t，J＝5.9Hz，2H)，3.4(t，J＝8.8Hz，2H)，4.6(t，J＝8.8Hz，2H)，7.0(d，J＝8.1Hz，1H)，7.2(d，J＝8.1Hz，1H)。
MS(EI)：m/e＝174。
5.6 Compound I is 1,2,6, the preparation of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone
The compound VI 0.2g of embodiment 3 preparations is dissolved among the ethyl acetate 2ml, adds N, N-diethyl Isopropylamine (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.30ml is heated to 50 ℃ of reaction 10h, reaction 5～6h.After reaction finishes, add 1N hydrochloric acid and regulate pH to 1～2, ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate, cross post and obtain Compound I 94mg, yield 70%.
M.p.133-134℃。
1H?NMR(CDCl
3)：δ＝2.6(t，J＝5.9Hz，2H)，3.1(t，J＝5.9Hz，2H)，3.4(t，J＝8.8Hz，2H)，4.6(t，J＝8.8Hz，2H)，7.0(d，J＝8.1Hz，1H)，7.2(d，J＝8.1Hz，1H)。
MS(EI)：m/e＝174。
Embodiment 6
6.1 Compound I is 1,2,6, the preparation of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone
The compound VI I0.2g of embodiment 4 preparations is dissolved among the ethyl acetate 2ml, adds triethylamine (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.4ml, reflux (77 ℃) reaction 5～6h, (the ethyl acetate backflow temperature is 77 ℃).After reaction finishes, add 1N hydrochloric acid and regulate pH to 1-2, ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate, cross post and obtain Compound I 65mg, yield 65%.
M.p.133-134℃。
1H?NMR(CDCl
3)：δ＝2.6(t，J＝5.9Hz，2H)，3.1(t，J＝5.9Hz，2H)，3.4(t，J＝8.8Hz，2H)，4.6(t，J＝8.8Hz，2H)，7.0(d，J＝8.1Hz，1H)，7.2(d，J＝8.1Hz，1H)。
MS(EI)：m/e＝174。
6.2 Compound I is 1,2,6, the preparation of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone
The compound VI I0.2g of embodiment 4 preparations is dissolved among the ethyl acetate 2ml, adds pyridine (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.4ml, reflux (77 ℃) reaction 5～6h, (the ethyl acetate backflow temperature is 77 ℃).After reaction finishes, add 1N hydrochloric acid and regulate pH to 1～2, ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate, cross post and obtain Compound I 70mg, yield 70%.
M.p.133-134℃。
1H?NMR(CDCl
3)：δ＝2.6(t，J＝5.9Hz，2H)，3.1(t，J＝5.9Hz，2H)，3.4(t，J＝8.8Hz，2H)，4.6(t，J＝8.8Hz，2H)，7.0(d，J＝8.1Hz，1H)，7.2(d，J＝8.1Hz，1H)。
MS(EI)：m/e＝174。
6.3 Compound I is 1,2,6, the preparation of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone
The compound VI I0.2g of embodiment 4 preparations is dissolved among the ethyl acetate 2ml; add N, N-diethyl Isopropylamine (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.6ml; reflux (77 ℃) reaction 5～6h, (the ethyl acetate backflow temperature is 77 ℃).After reaction finishes, add 1N hydrochloric acid and regulate pH to 1～2, ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate, cross post and obtain Compound I 75mg, yield 75%.
M.p.133-134℃。
1H?NMR(CDCl
3)：δ＝2.6(t，J＝5.9Hz，2H)，3.1(t，J＝5.9Hz，2H)，3.4(t，J＝8.8Hz，2H)，4.6(t，J＝8.8Hz，2H)，7.0(d，J＝8.1Hz，1H)，7.2(d，J＝8.1Hz，1H)。
MS(EI)：m/e＝174。
6.4 Compound I is 1,2,6, the preparation of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone
The compound VI I0.2g of embodiment 4 preparations is dissolved among the ethyl acetate 2ml, adds triethylamine (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.4ml, be heated to 50 ℃, reaction 10h, (the ethyl acetate backflow temperature is 77 ℃).After reaction finishes, add 1N hydrochloric acid and regulate pH to 1-2, ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate, cross post and obtain Compound I 65mg, yield 65%.
M.p.133-134℃。
1H?NMR(CDCl
3)：δ＝2.6(t，J＝5.9Hz，2H)，3.1(t，J＝5.9Hz，2H)，3.4(t，J＝8.8Hz，2H)，4.6(t，J＝8.8Hz，2H)，7.0(d，J＝8.1Hz，1H)，7.2(d，J＝8.1Hz，1H)。
MS(EI)：m/e＝174。
6.5 Compound I is 1,2,6, the preparation of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone
The compound VI I0.2g of embodiment 4 preparations is dissolved among the ethyl acetate 2ml, adds pyridine (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.4ml, be heated to 50 ℃, reaction 10h, (the ethyl acetate backflow temperature is 77 ℃).After reaction finishes, add 1N hydrochloric acid and regulate pH to 1～2, ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate, cross post and obtain Compound I 70mg, yield 70%.
M.p.133-134℃。
1H?NMR(CDCl
3)：δ＝2.6(t，J＝5.9Hz，2H)，3.1(t，J＝5.9Hz，2H)，3.4(t，J＝8.8Hz，2H)，4.6(t，J＝8.8Hz，2H)，7.0(d，J＝8.1Hz，1H)，7.2(d，J＝8.1Hz，1H)。
MS(EI)：m/e＝174。
6.6 Compound I is 1,2,6, the preparation of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone
The compound VI I0.2g of embodiment 4 preparations is dissolved among the ethyl acetate 2ml, adds N, N-diethyl Isopropylamine (Shanghai chemical reagents corporation of traditional Chinese medicines group, chemical pure) 0.6ml is heated to 50 ℃, reaction 10h, (the ethyl acetate backflow temperature is 77 ℃).After reaction finishes, add 1N hydrochloric acid and regulate pH to 1～2, ethyl acetate extraction, saturated salt washing, anhydrous sodium sulfate drying, filtration concentrate, cross post and obtain Compound I 75mg, yield 75%.
M.p.133-134℃。
1H?NMR(CDCl
3)：δ＝2.6(t，J＝5.9Hz，2H)，3.1(t，J＝5.9Hz，2H)，3.4(t，J＝8.8Hz，2H)，4.6(t，J＝8.8Hz，2H)，7.0(d，J＝8.1Hz，1H)，7.2(d，J＝8.1Hz，1H)。
MS(EI)：m/e＝174。
In sum, of the present invention synthetic 1,2,6, the method for 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone has the advantage that synthetic route is brief, easy and simple to handle, cost is low, productive rate is high, be easy to suitability for industrialized production.
Need to prove, all quote in this application as a reference, just quoted as a reference separately as each piece document at all documents that the present invention mentions.Should understand in addition, above-described is specific embodiments of the invention and the know-why used, after having read above-mentioned teachings of the present invention, those skilled in the art can make various changes or modifications and not deviate from spirit of the present invention and scope the present invention, and these equivalent form of values fall within the scope of the invention equally.
Claims (8)
1. one kind is synthesized 1,2,6, and the method for 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone is characterized in that, comprises the following steps:
A. make compound III that the Claisen rearrangement reaction takes place in appropriate solvent and generate compound IV, described solvent is N, N-Diethyl Aniline, N, accelerine, DMF or DMA;
B. make described compound IV feed ozone at low temperatures and react, described low temperature is-80～-60 ℃, adds sodium borohydride or POTASSIUM BOROHYDRIDE afterwards again and carries out reduction reaction and obtain compound V;
C. described compound V and methane sulfonyl chloride/Tosyl chloride are reacted in pyridine, thereby obtain compound VI/compound VI I;
D. described compound VI and/or described compound VI I are dissolved in the suitable reaction solvent, add suitable organic bases,
Elevated temperature reacts then, and obtaining Compound I is 1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone,
2. according to claim 1 synthetic 1,2,6, the method for 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone is characterized in that, among the step a, the temperature of described rearrangement reaction is 100 ℃～200 ℃.
3. according to claim 1 synthetic 1,2,6, the method for 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone is characterized in that, among the step a, after described rearrangement reaction is finished, also comprises step: steam described solvent, and recrystallization.
4. according to claim 1 synthetic 1,2,6, the method for 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone, it is characterized in that, among the step b, described compound IV is dissolved in the alcoholic solvent, and described reaction was carried out 1～3 hour, described compound IV is 1: 0.5～1.5 with the ratio of the molar weight of described POTASSIUM BOROHYDRIDE or described sodium borohydride, and described reduction reaction was reacted 0.5～1 hour under-60 ℃～-30 ℃ temperature.
5. according to claim 1 synthetic 1,2,6, the method for 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone is characterized in that, among the step b, described ozone feed finish after, also comprise step: feed nitrogen and drive described ozone away; Described reduction reaction also comprises step after finishing: adding dilute hydrochloric acid adjusting pH value is 4～5, then with the appropriate solvent extraction, and washing, dry, evaporate to dryness, recrystallization again.
6. according to claim 1 synthetic 1,2,6, the method of 7-tetrahydrochysene-8H-indeno [5,4-b] furans-8-ketone is characterized in that, among the step c, described compound V is 1: 0.9～1.2 with the ratio of the molar weight of described methane sulfonyl chloride or described Tosyl chloride, and the temperature of described reaction is-30 ℃～-10 ℃, and the time of described reaction is 1～2 hour.
7. according to claim 1 synthetic 1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] method of furans-8-ketone, it is characterized in that, among the step c, after described reaction finishes, also comprise step: adding dilute hydrochloric acid or dilute sulphuric acid is 1～2 to the pH value, adds the appropriate solvent extraction again, through washing, drying.
8. according to claim 1 synthetic 1,2,6,7-tetrahydrochysene-8H-indeno [5,4-b] method of furans-8-ketone, it is characterized in that, in the steps d, after described reaction finishes, also comprise step: cooling, adding dilute hydrochloric acid or dilute sulphuric acid is 1～2 to the pH value, through washing, dry, evaporate to dryness.
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| 叶敏等.治疗失眠症新药雷美替胺.《中国新药杂志》.2006,第15卷(第15期),1309-1312. * |
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