CN104926763A - Synthetic preparation method for key intermediate of ramelteon - Google Patents

Abstract

The invention discloses a synthesis and preparation method of ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one. The preparation method uses 2,3-dihydrobenzofuran-4-carboxaldehyde as the starting material, and synthesizes the key intermediate 1,2,6,7-tetracycline of ramelteon through Grignard reaction, oxidation reaction and Nazarov ring closure reaction. Hydrogen-8H-indeno[5,4-b]furan-8-one. The preparation method has the advantages of high reaction selectivity, less side reactions, high total yield and product quality, environmental friendliness, simple process operation, high stability and controllability, and is suitable for large-scale industrial production.

Description

A kind of synthetic preparation method of ramelteon key intermediate

technical field

The invention relates to a method for synthesizing and preparing a key intermediate of ramelteon, belonging to the field of drug synthesis.

Background technique

At present, the drugs used clinically at home and abroad to treat insomnia mainly include: barbiturates, benzodiazepines Agonists, nonbenzodiazepines Receptor agonists and natural medicines with sedative and hypnotic effects. Long-term use of barbiturate sedative-hypnotics may lead to drug tolerance, dependence, severe withdrawal symptoms, low therapeutic index, and even severe liver and kidney toxicity. Therefore, such drugs are not suitable for long-term use. Benzodiazepines Agonists and nonbenzodiazepines Hypnotics can shorten the sleep latency and improve the sleep efficiency of patients with insomnia. Long-term or high-dose use does not help patients with insomnia to improve their sleep, but will cause side effects such as withdrawal, rebound insomnia, tolerance, and dependence. Natural medicines with sedative and hypnotic effects have high anti-insomnia effects whether they are unilateral or compound. However, due to the limitation of medicinal materials and the complicated processing procedures of traditional Chinese medicine, it is difficult to promote them among the crowd. Therefore, it has become an urgent clinical need to develop an oral, effective treatment of insomnia, non-addictive, and widely applicable sleeping pills.

Ramelteon (Ramelteon) is clinically used to treat insomnia with difficulty falling asleep. It is developed by Takeda Corporation of Japan, and its trade name is Rozerem. Ramelteon is the first melatonin receptor agonist approved by the FDA, which can selectively induce MT1 and MT2 receptors, but has no affinity for MT3. It can regulate the sleep cycle in the body without affecting the central nervous system in the body, and has no affinity for GABA receptors, dopamine receptors, acetylcholine receptors, norepinephrine receptors, and opioid receptors. Clinical studies have shown that ramelteon can effectively shorten the time for patients to fall asleep, increase the total sleep time, and have less impact on the next day's work and study, and the recurrence rate after drug withdrawal is also very low, which has not been seen in clinical studies Drug addiction, no obvious adverse reactions. In the future, ramelteon will play an increasingly important role in the treatment of insomnia. The chemical name of ramelteon is: (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl] Propionamide, CAS number: 196597-26-9, its chemical structure is as follows:

The synthetic method of ramelteon has been seen in many reports. The earliest literature (Journal of Medicinal Chemistry, 2002, 45, 4222～4239.) reported that the synthetic method of ramelteon is more complicated, the synthetic route is very long, the chemoselectivity of the multi-step reaction is not high, and the total yield is low. Not suitable for industrial production. The synthetic route is as follows:

Jiang Long et al. (Chinese Journal of Pharmaceutical Industry, 2009, 40, 161-164.) reported that ramelteon was obtained through 11 steps of reaction using 2,3-dihydrobenzofuran as the starting material. In this method, when constructing the key intermediate of ramelteon (i.e. 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one), a First use dibromo to take up the position, and then use catalytic hydrogenation method to remove two bromines after Fuke acylation. This method has the following problems: (1) Since the bromine atom is a strong electron-withdrawing group, it is relatively difficult to carry out bromination at two positions on the benzene ring, and the bromination reaction at the second position is difficult to complete. Similarly, in the reaction of catalytic hydrogenation to remove two bromines, the reaction is difficult to complete. Therefore, adopting the method for dibromo-occupying must bring more impurities to intermediates and final products, which affects the quality of products. (2) The bromination reaction will inevitably produce a large amount of acid waste water, which will bring great environmental protection pressure to industrialized large-scale production. (3) Similar to protection and deprotection, the method of dibromo-occupying prolongs the process route, which inevitably reduces the total yield and increases the production cost. The synthetic route is as follows:

Chinese patent (CN20081004587.5) reports an improved method using (R)-α-phenylethylamine as a resolving agent on the basis of the above route. The synthetic route is as follows:

PCT patent (WO2006030739) reported the use of asymmetric catalytic hydrogenation to construct chiral centers. The chiral ligands used in this method are relatively expensive, and catalytic hydrogenation requires high pressure conditions. The synthetic route is as follows:

There are also documents (Organic Preparations and Procedures International, 2009, 41, 309-314.) reported that the key intermediate of ramelteon (i.e. 1,2,6,7- Tetrahydro-8H-indeno[5,4-b]furan-8-one) method, through 6 steps of reaction to obtain the target product. The starting raw material 6-methoxyindanone that this operational route adopts has a more expensive market price. The σ rearrangement needs to be completed under ultra-high temperature conditions, and there is a problem of regioselectivity. In the mesylation reaction, methanesulfonyl chloride also has a selectivity problem for phenolic hydroxyl and aliphatic primary hydroxyl. If mesylation occurs on the phenolic hydroxyl, the subsequent ring closure reaction will not be easy to react completely. The synthetic route is as follows:

Contents of the invention

The object of the present invention is to provide a synthetic preparation method for the key intermediate of ramelteon 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one, aiming at Overcome some shortcomings such as side reactions and impurities in the above synthetic method of ramelteon, large environmental pollution, difficult acquisition of starting materials, and higher production costs.

The present invention provides a method for the synthesis and preparation of ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one, whose chemical structural formula is as follows: Formula I Shown:

The key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one, the key intermediate for the synthesis of ramelteon represented by formula I provided by the present invention, is synthesized and prepared Methods as below:

(1) With 2,3-dihydrobenzofuran-4-carbaldehyde shown in formula II as the starting material, react with vinylmagnesium halide under certain conditions to obtain 1-(2,3- Dihydrobenzofuran-4-yl)-2-propen-1-ol;

(2) 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol shown in formula III reacts under oxidation conditions to obtain 1-(2,3 shown in formula IV -Dihydrobenzofuran-4-yl)-2-propen-1-one;

(3) 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one shown in formula IV reacts under acidic conditions to obtain ramelteon key intermediate shown in formula I Body 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one.

The chemical structure of the compound shown in the above formula II, formula III and formula IV and the key intermediate of ramelteon shown in formula I 1,2,6,7-tetrahydro-8H-indeno[5, 4-b] The synthetic route of furan-8-one is as follows:

In the synthetic route of the above-mentioned ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one, 2, 3-Dihydrobenzofuran-4-carbaldehyde reacts with vinylmagnesium halide to prepare 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol shown in formula III The reaction is a classic format reaction (Grignard Reaction). The Grignard reaction is one of the most widely used reactions in organic synthesis, and plays an important role in the C-alkylation of carbonyl compounds. Grignard reactions generally use ethers as reaction solvents, such as tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, isopropyl ether, tert-butyl ether, 1,4-dioxane, etc., and can also be carried out in inert aromatic solvents .

1-(2,3-dihydrobenzofuran-4-yl)-2-propene-1-alcohol is oxidized to obtain 1-(2,3-dihydrobenzofuran shown in formula IV by formula III The reaction of -4-yl)-2-propen-1-one is a common oxidation reaction of secondary alcohols to ketones. Many oxidants can easily oxidize secondary alcohols to ketones (March Advanced Organic Chemistry - Reaction, Mechanism and Structure, edited by Michael B. Smith, Jerry March, translated by Li Yanmei, Chemical Industry Press, 2011, p720～722.). Including hexavalent chromium reagents, such as chromium trioxide bipyridine (Collins reagent), chromic acid and sulfuric acid solution (Jones reagent), pyridinium chlorochromate (PCC reagent), etc.; Manganese oxide, potassium permanganate, etc.

In addition, as an oxidizing agent, hypervalent iodine reagent has been widely used in the oxidation of secondary alcohols to ketones due to its mild reaction conditions, high yield, good selectivity, and environmental friendliness (Organic Chemistry, 2006, 26, 1623～1630.). Hypervalent iodine reagents commonly used are 2-iodoxybenzoic acid (IBX) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodyl-3 (1H)-Kone (Dess-Martin reagent, DMP).

1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ketone shown in formula IV reacts under acidic conditions to obtain ramelteon key intermediate 1 shown in formula I , The reaction of 2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one is a classic Nazarov cyclization reaction, which is essentially a pericyclic reaction. The research on the Nazarov cyclization reaction has been very in-depth, which is also a very mature and widely used reaction (Organic Reactions, 1994, 45, 1-158.; Tetrahedron, 2005, 61, 7577-7606.). The Nazarov reaction needs to be carried out under acidic conditions, and the most classic ones are protonic acids, such as concentrated sulfuric acid, polyphosphoric acid, phosphoric acid, perchloric acid, etc. Newer studies have found that protonic acids such as trifluoroacetic acid and trifluoromethanesulfonic acid have a negative effect on Nazarov reaction. Response is also very effective. In addition to protonic acid conditions, more studies are now using Lewis acid conditions, including traditional aluminum trichloride, tin tetrachloride, ferric chloride, boron trifluoride ether complex, etc., and the latest research shows Novel copper salts of trifluoromethanesulfonic acid, iron salts, indium salts, etc. and the Lewis acid of metal palladium have higher activity to the Nazarov reaction, and the reaction can be completed in a catalytic amount, and the reaction yield is very high (Tetrahedron , 2005, 61, 7577-7606.). In addition, environmentally friendly solid acids, such as zeolite molecular sieves or modified zeolite molecular sieves, can also catalyze the Nazarov reaction well (Applied Catalysis A: General, 2008, 336, 101-108.).

Specifically, the synthesis and preparation of the key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one of ramelteon shown in formula I provided by the present invention The method can be implemented as follows:

Step 1: Add a tetrahydrofuran solution of vinylmagnesium halide in the reaction flask, add dropwise a certain amount of 2,3-dihydrobenzofuran-4-carbaldehyde represented by formula II in an organic solvent at a certain temperature A The solution of A, after reacting for a certain period of time A, rises to room temperature, and after reacting for a certain period of time B, add saturated ammonium chloride solution, stir, extract with ethyl acetate, wash, dry, filter, and after the filtrate is evaporated under reduced pressure to remove the solvent, That is, 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol represented by formula III is obtained.

The organic solvent A described in step 1 can be selected from one of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, isopropyl ether, tert-butyl ether, 1,4-dioxane, benzene, toluene, xylene or Various mixed solvents.

The vinylmagnesium halide described in step 1 can be selected from vinylmagnesium bromide or vinylmagnesium chloride.

The reaction temperature A described in step 1 ranges from -80 to 0°C.

The range of reaction time A described in step 1 is 0.1-1 hour, and the range of reaction time B is 1-10 hours.

The molar ratio of the compound represented by formula II and vinylmagnesium halide in step 1 is 1:0.5-1.5.

Step 2 can be implemented in the following three ways.

Method 1 of step 2: In organic solvent B, at room temperature, add a certain amount of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol and a certain amount of formula III A certain amount of 2-iodylbenzoic acid is reacted at room temperature or heated up to reaction temperature B, and the reaction is detected by TLC until the raw material point disappears. After the reaction solution is cooled to room temperature, ethyl acetate is added for dilution, filtered, and the mother liquor is washed with water. , dried, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one represented by formula IV.

The organic solvent B described in method 1 of step 2 can be selected from one or more mixed solvents of dimethyl sulfoxide, tetrahydrofuran, acetonitrile, acetone, ethyl acetate, and 1,2-dichloroethane.

The range of reaction temperature B described in method one of step 2 is 40-80°C.

The molar ratio of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-alcohol and 2-iodylbenzoic acid shown in the formula III described in the method one of step 2 is 1: 1.1 ~ 3.0.

Method 2 of step 2: in an organic solvent C, at room temperature, add a certain amount of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol represented by formula III, Stir to dissolve, then add a certain amount of (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodyl-3(1H)-one, continue to react at room temperature, TLC Detect until the raw material point disappears, add ethyl acetate, 10% Na ₂ S ₂ O ₃ solution and saturated NaHCO ₃ solution, stir vigorously for 1 hour, separate the organic phase, wash, dry, filter, and evaporate the filtrate under reduced pressure After solvent, 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one represented by formula IV is obtained.

The organic solvent C described in method 2 of step 2 can be selected from one or more mixed solvents of dichloromethane, chloroform, acetonitrile, and tetrahydrofuran.

1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-alcohol and (1,1,1-triacetoxy )-1,1-dihydro-1,2-phenyliodyl-3(1H)-one molar ratio is 1:1.1～3.0.

Method 3 of step 2: at room temperature, a dichloromethane solution in which a certain amount of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol represented by formula III is dissolved, Add to the dichloromethane solution of freshly prepared chromium trioxide dipyridine, continue to stir the reaction at room temperature, TLC detection, until the raw material point disappears, filter, the filtrate is washed, dried, and then filtered, the filtrate is decompressed to remove the solvent After that, 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one represented by formula IV is obtained.

The molar ratio of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-alcohol and chromium trioxide dipyridine shown in the formula III described in step 2 is 1 : 5.0~7.0.

Step 3 can be realized by the following two methods.

Method 1 of step 3: at room temperature, add a certain amount of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one shown in formula IV to a certain amount of protonic acid , continue to react at room temperature or heated to temperature C, TLC detection reaction, until the raw material point disappears, the reaction solution is slowly added to the ice-water mixture to quench the reaction, and then extracted with dichloromethane for several times, after the organic phase is washed, After drying and filtering, the filtrate was evaporated to remove the solvent under reduced pressure, and recrystallized with ethanol to obtain the key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4 -b] furan-8-one.

The protonic acid described in method one of step 3 can be selected from one or more mixed acids of concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, perchloric acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.

The range of reaction temperature C described in method one of step 3 is 40-120°C.

The weight ratio of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one and protonic acid represented by formula IV described in method 1 of step 3 is 1:2.0 ~7.0.

Method 2 of step 3: In the organic solvent D, add a certain amount of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one represented by formula IV, stir and dissolve, Control the temperature of the reaction solution at temperature D, add Lewis acid. Control the temperature of the reaction solution to continue the reaction at temperature E. TLC detects the reaction until the raw material point disappears. After cooling, the reaction solution is slowly added to the ice-water mixture to quench the reaction, the organic phase is separated, and the aqueous phase is extracted with dichloromethane. Multiple times, the organic phases were combined, washed, dried, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, and then recrystallized with ethanol to obtain the key intermediate 1,2,6,7-tetra Hydrogen-8H-indeno[5,4-b]furan-8-one.

The organic solvent D described in method 2 of step 3 can be selected from one or more mixed solvents of dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, chlorobenzene, and dichlorobenzene.

The Lewis acid described in the method two of step 3 can select tin dichloride, tin tetrachloride, titanium tetrachloride, aluminum trichloride, iron trichloride, ferric perchlorate, ferrous perchlorate, three Ferric fluoromethanesulfonate, ferrous trifluoromethanesulfonate, cobalt perchlorate, copper trifluoromethanesulfonate, copper perchlorate, scandium trifluoromethanesulfonate, indium trifluoromethanesulfonate, palladium(II) acetate , bisacetonitrile palladium(II) chloride, boron trifluoride etherate complex, trimethylsilyl trifluoromethanesulfonate, zeolite molecular sieve, and modified zeolite molecular sieve.

The range of temperature D in method 2 of step 3 is -10-10°C, and the range of temperature E is 20-120°C.

The molar ratio of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one and Lewis acid represented by formula IV described in method 2 of step 3 is 1:0.01 ~1.5.

The ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one represented by formula I provided by the present invention can be used for ramelteon Synthetic preparation of amines. The specific synthetic route and method can be found in the following documents: Chinese Journal of Pharmaceutical Industry, 2009, 40, 161-164; Chinese patent CN20081004587.5; PCT patent WO2006030739.

The synthesis and preparation method of ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one shown in formula I provided by the present invention, which The innovation is reflected in the following points:

(1) Using 2,3-dihydrobenzofuran-4-carbaldehyde as the starting material to prepare the key intermediate of ramelteon shown in formula I through three-step reaction, the synthetic route is simple and the total yield is high;

(2) The selectivity of the reaction is high, without occupying a place, which greatly reduces the occurrence of side reactions, reduces the number of impurities and the content of total impurities in the final product, and is conducive to improving product quality;

(3) Bromine and other reagent raw materials that generate a large amount of acidic wastewater are not used in the route, which is more green and environmentally friendly;

(4) The process is easy to operate, has high stability and controllability, and is suitable for large-scale industrial production.

In a word, the synthesis and preparation method of the key intermediate of synthetic ramelteon shown in formula I provided by the present invention has high reaction selectivity, few side reactions, high overall yield and product quality, environmental friendliness, and process operation It has the advantages of simplicity, high stability and controllability, and is suitable for large-scale industrial production.

Detailed ways

The following typical embodiments are used to illustrate the present invention. Simple replacements or improvements made by those skilled in the art are within the technical solutions protected by the present invention.

Example 1: Synthesis and preparation of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol (Ⅲ)

The reaction formula is as follows:

Add 1050mL (1.05mol) of 1.0M tetrahydrofuran solution of vinylmagnesium bromide into the reaction flask, start stirring, cool the reaction solution to -10～-5°C, add dropwise 2,3-dihydrobenzofuran-4 -formaldehyde (148.2g, 1.00mol) in tetrahydrofuran (500mL) solution, and control the temperature of the reaction solution not to exceed -5°C. After the dropwise addition, keep the temperature at -10～-5°C and react for half an hour, then slowly raise the temperature to room temperature to continue the reaction. After 6 hours, 300 mL of saturated aqueous ammonium chloride solution was added, stirred for 30 minutes, and extracted three times with ethyl acetate (800 mL×3). The organic phase was washed once each with saturated sodium chloride solution (300 mL) and water (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 173.6 g of a yellow oil with a yield of 98.5%.

Example 2: Synthesis and preparation of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one (IV)

The reaction formula is as follows:

At room temperature, add 750 mL of dimethyl sulfoxide solvent into the reaction flask, and then add 150.0 g of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol described in formula III (0.85mol), stirring and dissolving, adding 360g (1.29mol) of 2-iodobenzoic acid (IBX) in batches at room temperature, and the addition was completed in about 10 minutes. After continuing to react at room temperature for 2 hours, TLC detected that the raw material point disappeared. Add 2.5L of ethyl acetate, stir for 15 minutes, filter, wash the filtrate twice with water (850mL×2), dry over anhydrous sodium sulfate, filter, and distill the filtrate to remove the solvent under reduced pressure to obtain 139.2g of a yellow oil. The rate is 94.1%.

Example 3: Synthesis and preparation of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one (IV)

The reaction formula is as follows:

Add 1500 mL of dichloromethane and 130.0 g (0.74 mol) of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol described in formula III to the reaction flask, stir to dissolve 410 g (0.97 mol) of (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodide-3(1H)-one (DMP) was added at room temperature. After continuing to react at room temperature for 2 hours, TLC detected that the raw material point disappeared. Add 1000 mL of ethyl acetate, 150 mL of 10% Na ₂ S ₂ O ₃ solution and 200 mL of saturated NaHCO ₃ solution, stir vigorously for 1 hour, separate the organic phase, and wash with saturated brine (800 mL) and water (800 mL) once each , dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 124.8 g of a yellow oil with a yield of 97.3%.

Example 4: Synthesis and preparation of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one (IV)

The reaction formula is as follows:

Add 1000 mL of anhydrous dichloromethane into the reaction flask, start stirring, and control the temperature of the system not to exceed 20°C, add 492.0 g (4.92 mol) of dry chromium trioxide and 778.3 g of anhydrous pyridine ( 9.84mol), after continuing to stir at room temperature for 1 hour, 1-(2,3-dihydrobenzofuran-4-yl)-2-propene-1-alcohol (144.5g, 0.82mol) in dichloromethane (400mL) solution, and continue to react at room temperature for 1 hour, TLC detection, the raw material point disappeared. After the reaction solution was filtered, the filtrate was washed once with saturated brine (300mL) and water (400mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 121.7g of a yellow oil with a yield of 85.4% .

Example 5: Synthesis and preparation of ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (I)

The reaction formula is as follows:

At room temperature, add 300ml of trifluoromethanesulfonic acid and 94.0g (0.54mol ), after continuing to react at room temperature for 17 hours, TLC detected that the raw material point disappeared. The reaction solution was poured into 300 g of ice-water mixture, stirred for 30 minutes, and extracted three times with dichloromethane (400 ml×3). The organic phase was washed once each with saturated brine (300 mL) and water (300 mL), dried over anhydrous sodium sulfate, and filtered. After the filtrate was evaporated to remove the solvent under reduced pressure, the residue was recrystallized with ethanol to obtain 67.6 g of an off-white solid. The rate is 71.9%.

Example 6: Synthesis and preparation of ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (I)

The reaction formula is as follows:

Add 450ml of dichloromethane and 98.5g (0.56mol) of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one shown in formula IV into the reaction flask, stir and dissolve 100 g (0.62 mol) of anhydrous ferric chloride was slowly added under the control system temperature not exceeding 10° C., and then the temperature was raised to room temperature and reacted for 8 hours. TLC detected that the raw material point disappeared. The reaction solution was poured into 260g of ice-water mixture, after stirring for half an hour, the organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (150ml×2). Water (200 mL) was washed once each, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to remove the solvent under reduced pressure, and the residue was recrystallized with ethanol to obtain 91.6 g of off-white solid, yield 93.0%.

Example 7: Synthesis and preparation of ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (I)

The reaction formula is as follows:

Add 450ml of 1,2-dichloroethane and 92.3g (0.53mol ), after stirring and dissolving, 19.2 g (0.053 mol) of copper trifluoromethanesulfonate was slowly added under control of the temperature of the system not exceeding 10° C., and then heated to room temperature and reacted for 16 hours. TLC detected that the raw material point disappeared. Pour the reaction solution into 200g of ice-water mixture, stir for half an hour, separate the organic phase, then extract the water phase with 1,2-dichloroethane twice (150ml×2), combine the organic phases and wash with saturated salt Water (200 mL) and water (200 mL) were washed once each, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure, and the residue was recrystallized with ethanol to obtain 88.9 g of off-white solid with a yield of 96.3%.

Claims (7)

1. a synthetic preparation method of ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one shown in formula I, characterized in The synthetic preparation method is as follows: Step 1: Using 2,3-dihydrobenzofuran-4-carbaldehyde shown in formula II as the starting material, react with vinylmagnesium halide under certain conditions to obtain 1-(2,3- Dihydrobenzofuran-4-yl)-2-propen-1-ol; Step 2: 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol shown in formula III is reacted under oxidation conditions to obtain 1-(2,3 -Dihydrobenzofuran-4-yl)-2-propen-1-one; Step 3: 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one shown in formula IV is reacted under acidic conditions to obtain the key intermediate of ramelteon shown in formula I Body 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one; The chemical structures of the compounds represented by the above-mentioned formulas I to IV and the key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b] of ramelteon shown in formula I The synthetic route of furan-8-one is as follows: 2. the ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one shown in a kind of formula I according to claim 1 The synthetic preparation method is characterized in that the method of step 1 is as follows: Add tetrahydrofuran solution of vinylmagnesium halide in the reaction flask, and drop a certain amount of 2,3-dihydrobenzofuran-4-carbaldehyde shown in formula II in organic solvent A at a certain temperature A. , after reacting for a certain time A, rise to room temperature, and after reacting for a certain time B, add saturated ammonium chloride solution, stir, extract with ethyl acetate, wash, dry, filter, and after the filtrate decompresses to remove the solvent, the formula 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol shown in III; Wherein the organic solvent A can be selected from one or more of tetrahydrofuran, ether, ethylene glycol dimethyl ether, isopropyl ether, tert-butyl ether, 1,4-dioxane, benzene, toluene, xylene Mixed solvent; The vinylmagnesium halide described therein can be selected from vinylmagnesium bromide or vinylmagnesium chloride; The range of reaction temperature A described therein is -80～0 ℃; Wherein the scope of the reaction time A is 0.1 to 1 hour, and the scope of the reaction time B is 1 to 10 hours; The molar ratio of the 2,3-dihydrobenzofuran-4-carbaldehyde represented by the formula II to the vinylmagnesium halide is 1:0.5-1.5. 3. the ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one shown in a kind of formula I according to claim 1 The synthetic preparation method is characterized in that step 2 can adopt following method: In organic solvent B, at room temperature, add a certain amount of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol and a certain amount of 2-iodyl Benzoic acid, then react at room temperature or warm up to reaction temperature B, TLC detects the reaction until the raw material point disappears, after the reaction solution is cooled to room temperature, add ethyl acetate to dilute, filter, and wash the mother liquor with water, dry, filter, and the filtrate After distilling off the solvent under reduced pressure, 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one represented by formula IV was obtained; The organic solvent B mentioned therein can be selected from one or more mixed solvents in dimethyl sulfoxide, tetrahydrofuran, acetonitrile, acetone, ethyl acetate, and 1,2-dichloroethane; Wherein said reaction temperature B ranges from 40 to 80°C; The molar ratio of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol and 2-iodylbenzoic acid represented by formula III is 1:1.1～3.0 . 4. the ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one shown in a kind of formula I according to claim 1 The synthetic preparation method is characterized in that step 2 can adopt following method: In the organic solvent C, at room temperature, add a certain amount of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol shown in formula III, stir to dissolve and then add a certain amount of Amount of (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodide-3(1H)-one, continue to react at room temperature, TLC detection, until the raw material point disappears , add ethyl acetate, 10% Na ₂ S ₂ O ₃ solution and saturated NaHCO ₃ solution, stir vigorously for 1 hour, separate the organic phase, wash, dry, filter, and evaporate the filtrate to obtain the formula 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one shown in IV; Wherein the organic solvent C can be selected from one or more mixed solvents in dichloromethane, chloroform, acetonitrile, tetrahydrofuran; 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-alcohol and (1,1,1-triacetoxy)-1,1 represented by formula III described therein - The molar ratio of dihydro-1,2-phenyliodo-3(1H)-one is 1:1.1～3.0. 5. The ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one shown in a kind of formula I according to claim 1 The synthetic preparation method is characterized in that step 2 can adopt following method: At room temperature, a dichloromethane solution in which a certain amount of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol represented by formula III was dissolved was added to freshly prepared tris In the dichloromethane solution of chromium oxide dipyridine, continue to stir the reaction at room temperature, detect by TLC, until the raw material point disappears, filter, the filtrate is washed, dried, and then filtered, after the filtrate is decompressed to remove the solvent, the formula IV is obtained The indicated 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one; The molar ratio of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol represented by formula III and chromium trioxide bipyridine is 1:5.0-7.0. 6. The ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one shown in a kind of formula I according to claim 1 The synthetic preparation method is characterized in that step 3 can adopt following method: At room temperature, add a certain amount of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one shown in formula IV to a certain amount of protonic acid, continue at room temperature or heat The reaction was carried out at temperature C, and the reaction was detected by TLC until the raw material point disappeared. The reaction solution was slowly added to the ice-water mixture to quench the reaction, and then extracted several times with dichloromethane. After the organic phase was washed, dried, filtered, the filtrate was reduced to After removing the solvent by steaming under pressure, recrystallize with ethanol to obtain the key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8 of ramelteon shown in formula I -ketone; Wherein said protic acid can be selected from one or more mixed acids in concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid; Wherein said reaction temperature C ranges from 40 to 120°C; The weight ratio of the 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one represented by the formula IV and the protonic acid is 1:2.0-7.0. 7. The ramelteon key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one shown in a kind of formula I according to claim 1 The synthetic preparation method is characterized in that step 3 can adopt following method: In the organic solvent D, add a certain amount of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one shown in formula IV, stir and dissolve, and control the temperature of the reaction solution at At temperature D, a Lewis acid is added. Control the temperature of the reaction solution to continue the reaction at temperature E. TLC detects the reaction until the raw material point disappears. After cooling, the reaction solution is slowly added to the ice-water mixture to quench the reaction, the organic phase is separated, and the aqueous phase is extracted with dichloromethane. Multiple times, the organic phases were combined, washed, dried, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, and then recrystallized with ethanol to obtain the key intermediate 1,2,6,7-tetra Hydrogen-8H-indeno[5,4-b]furan-8-one; The organic solvent D described therein can be selected from one or more mixed solvents in dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, chlorobenzene, and dichlorobenzene; The Lewis acid described therein can be selected from tin dichloride, tin tetrachloride, titanium tetrachloride, aluminum trichloride, ferric chloride, ferric perchlorate, ferrous perchlorate, ferric trifluoromethanesulfonate , ferrous trifluoromethanesulfonate, cobalt perchlorate, copper trifluoromethanesulfonate, copper perchlorate, scandium trifluoromethanesulfonate, indium trifluoromethanesulfonate, palladium(II) acetate, diacetonitrile chloride One of palladium (II), boron trifluoride etherate, trimethylsilyl trifluoromethanesulfonate, zeolite molecular sieve, and modified zeolite molecular sieve; Wherein the temperature D ranges from -10 to 10°C, and the temperature E ranges from 20 to 120°C; The molar ratio of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one represented by formula IV to Lewis acid is 1:0.01-1.5.