CN113248356B - Industrial production method of 4-hydroxy-1-indanone - Google Patents
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Abstract
The invention discloses an industrial production method of 4-hydroxy-1-indanone, which relates to the technical field of organic chemistry, and takes dihydrocoumarin as a raw material, the dihydrocoumarin is subjected to hydrolysis reaction under the catalysis of hydrochloric acid to obtain an intermediate 1, and the intermediate 1 is subjected to cyclization reaction with polyphosphoric acid under the catalysis of strong acid resin to obtain the 4-hydroxy-1-indanone. The preparation method has the advantages of short route, easily available raw materials, high yield, moderate reaction conditions, suitability for industrial production, less three wastes, environmental friendliness, easiness in operation and stable process.
Description
The technical field is as follows:
the invention relates to the technical field of organic chemistry, in particular to an industrial production method of 4-hydroxy-1-indanone.
Background art:
4-hydroxy-1-indanone, CAS:40731-98-4, is an important pharmaceutical and chemical intermediate, phenolic hydroxyl and ketone in the molecular structure are two relatively active reaction sites, and can perform nucleophilic addition reaction of phenolic hydroxyl and also perform a series of reactions of ketone, so that 4-hydroxy-1-indanone can be used as an important reaction block of pharmaceutical and chemical intermediates, and some bulk drugs and new drugs are used as important fragments in the research stage of the screening stage of the new drugs, the market demand is continuously rising every year, and the method has good application prospects.
The existing method for preparing 4-hydroxy-1-indanone is single, is not easy to operate, cannot be used for large-scale production, and needs to develop a method which is easy for industrial production.
Route 1: WO2014082379 uses dihydrocoumarin as a raw material, and carries out rearrangement reaction with sodium chloride and aluminum trichloride at 180-220 ℃ to obtain 4-hydroxy-1-indanone with the yield of 70-85%. Although the synthesis steps of the route are few, the yield is high, the reaction temperature is too high, and incomplete reaction can be caused if the reaction temperature is reduced; when the batch is enlarged to 1kg, the system cannot be stirred, so that local overheating and carbonization are caused; and a large amount of excessive aluminum trichloride is required to participate in the reaction, a large amount of strong-acid wastewater is generated after the system is quenched, the environmental pollution is serious, and the excessive reaction temperature also has great potential safety hazard and cannot be used for large-scale production.
Route 2: WO2010127855 uses dihydrocoumarin as a raw material, and obtains an intermediate 1 through alkaline hydrolysis and condensation reaction, an intermediate 2 is obtained through cyclization reaction of the intermediate 1, and 4-hydroxy-1-indanone is obtained through hydrolysis and deprotection of the intermediate 2, wherein the yield is 37%. The method has low yield, requires ultralow temperature of-50 ℃, and is not beneficial to industrial production.
Through the analysis of the route 1 and the route 2, the inventor designs a route 3, the four steps are total, the dihydrocoumarin is hydrolyzed by acid to obtain an intermediate 1, the intermediate 1 is reacted with acetic anhydride and thionyl chloride to obtain an intermediate 2, the intermediate 2 is reacted with Lewis acid by a one-pot method to obtain an intermediate 3, and the intermediate 3 is hydrolyzed to obtain a product. However, it is surprising that dihydrocoumarin is ultimately obtained instead of 4-hydroxy-1-indanone.
The mechanism of scheme 3 is presumably as follows:
the intermediate 2 is combined with aluminum trichloride to form a transition state, meanwhile, negative charges of phenol oxygen attack carbonyl carbon, acetyl is taken as a leaving group to leave to obtain an intermediate 3, and the intermediate 3 leaves aluminum salt under the action of acid to obtain the dihydrocoumarin.
Aiming at the problems in the route 3, the inventor deeply improves the route to successfully obtain the industrial production method of the 4-hydroxy-1-indanone, and the method has the advantages of short route, mild preparation conditions and high yield, and is suitable for industrial scale-up production.
The invention content is as follows:
the technical problem to be solved by the invention is to provide an industrial production method of 4-hydroxy-1-indanone, which is characterized in that dihydrocoumarin is used as a raw material, and the product 4-hydroxy-1-indanone is prepared through two-step reaction, so that the method has the advantages of short route, mild preparation conditions, high yield, simple operation and suitability for industrial production.
The technical problem to be solved by the invention is realized by adopting the following technical scheme:
an industrial production method of 4-hydroxy-1-indanone, which takes dihydrocoumarin as a raw material, the dihydrocoumarin is hydrolyzed under the catalysis of hydrochloric acid to obtain an intermediate 1, and the intermediate 1 and polyphosphoric acid are cyclized under the catalysis of strong acid resin to obtain 4-hydroxy-1-indanone;
the synthetic route is as follows:
the industrial production method of the 4-hydroxy-1-indanone comprises the following steps:
(1) Preparation of intermediate 1: mixing hydrochloric acid and dihydrocoumarin, heating for reaction, cooling, performing suction filtration, washing with water, and drying to obtain an intermediate 1;
(2) Preparation of 4-hydroxy-1-indanone: mixing toluene, the intermediate 1 and strong acid resin, adding polyphosphoric acid, heating for reaction, cooling, adding ice water, stirring, performing suction filtration, layering, washing with water, adding activated carbon, heating for decolorization, performing suction filtration, cooling, concentrating, crystallizing, performing suction filtration, and drying to obtain 4-hydroxy-1-indanone;
the molar ratio of the hydrochloric acid to the dihydrocoumarin is (4.0-10.0) to 1.0.
The mass ratio of the intermediate 1, the strong acid resin and the polyphosphoric acid is 1 (0.01-0.1) to 2.5-6.
The strong acid resin is macroporous strong acid styrene cation exchange resin.
The cyclization reagent in the field is Preferably Polyphosphoric Acid (PPA), and the intermediate 1 is added into PPA for reaction at first, but the problem of difficult stirring exists; the toluene is replaced by the solvent, and the reaction is difficult to be carried out. For this purpose, DMF is used as solvent and the reaction can be carried out, but DMF cannot be recovered and requires a large amount of water. The method comprehensively considers that a reaction system which takes toluene as a solvent and takes strong acid resin as a catalyst is adopted, the reaction can be well carried out, the yield is high, and the toluene can be recycled and reused, so that the method is suitable for industrial production.
The mechanism of the cyclization reaction is as follows:
the intermediate 1 forms a transition state 1 under the action of strong acid resin, and a benzene ring has a tendency of being activated and has a certain ring closing direction under the influence of the strong acid resin; smoothly closing the transition state 1 to form a transition state 2; dehydrating the transition state 2 under the action of PPA, and simultaneously removing strong acid resin to obtain 4-hydroxy-1-indanone.
The invention has the beneficial effects that:
(1) The preparation method has the advantages of short route, easily obtained raw materials, high yield and moderate reaction conditions;
(2) The preparation method is suitable for industrial production;
(3) The preparation method disclosed by the invention has the advantages of less three wastes and better environmental friendliness;
(4) The preparation method is easier to operate and has stable process.
Description of the drawings:
FIG. 1 is a nuclear magnetic hydrogen spectrum of intermediate 1 prepared by the route of the present invention;
FIG. 2 is a nuclear magnetic hydrogen spectrum of the product prepared in route 3;
FIG. 3 is a nuclear magnetic hydrogen spectrum of the product prepared by the inventive route.
The specific implementation mode is as follows:
in order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further explained below by combining the specific embodiments and the attached drawings.
The strongly acidic resin used in the following embodiment is a D001 macroporous strongly acidic styrene-based cation exchange resin.
Example 1
Preparation of intermediate 1:
6M hydrochloric acid (840 ml) and dihydrocoumarin (148g, 1.0 mol) were added to a 1L reactor, and after the addition, the reaction was heated to 100 ℃ to complete the reaction for 3 hours. The temperature is reduced by 25 ℃, the filtration is carried out, the filter cake is washed by water and dried to obtain 158 g of pink solid, and the yield is 95%. The nuclear magnetic spectrum is shown in figure 1. 1 H NMR(400MHz,DMSO)δ(ppm):12.07(s,1H),7.07-7.02(m,2H),7.00-6.68(m,2H),2.76-2.74(m,2H),2.49-2.45(m,2H)。
Preparation of 4-hydroxy-1-indanone:
toluene (600 ml), intermediate 1 (133g, 0.9 mol) and strongly acidic resin (2.6 g) were added to a 1L reaction vessel, polyphosphoric acid (399 g) was added in portions with stirring, and after the addition, the reaction was heated to 115 ℃ to react for 4 hours, and the reaction was completed. Cooling to 20 ℃, adding ice water (1200 ml) into the reaction liquid in batches, stirring for 30 minutes, carrying out suction filtration to recover strong acid resin, layering the filtrate, washing an organic layer with water, adding activated carbon (13 g), heating to 115 ℃ for decoloration for 1 hour, carrying out suction filtration, cooling, concentrating to obtain about 400ml of toluene, cooling to 5 ℃ for crystallization, carrying out suction filtration, and drying to obtain 114.6g of white-like solid which is 4-hydroxy-1-indanone with the yield of 86%. The nuclear magnetic spectrum is shown in figure 3. 1 H NMR(400MHz,DMSO)δ(ppm):9.979(s,1H),7.283-7.245(m,1H),7.124-7.061(m,2H),2.968-2.941(m,2H),2.636-2.608(m,2H)。
Example 2
Preparation of intermediate 1:
6M hydrochloric acid (84L) and dihydrocoumarin (14.8kg, 100mol) are pumped into a 100L reaction kettle, and after the addition is finished, the reaction kettle is heated to 100 ℃ for reaction for 5 hours, and the reaction is completed. The temperature is reduced by 25 ℃, the filtration is carried out, the filter cake is washed by water and dried to obtain 15.95 kg of pink solid, and the yield is 96%.
Preparation of 4-hydroxy-1-indanone:
toluene (60L), intermediate 1 (13.3 kg, 90mol) and strong acid resin (260 g) are pumped into a 100L reaction kettle, polyphosphoric acid (3.99 kg) is added in batches under stirring, and after the addition is finished, the reaction is heated to 115 ℃ for 6 hours, and the reaction is completed. Cooling to 20 ℃, adding ice water (120L) into the reaction liquid in batches, stirring for 40 minutes, carrying out suction filtration to recover strong acid resin, layering the filtrate, washing an organic layer with water, adding activated carbon (1.3 kg), heating to 115 ℃ for decoloration for 2 hours, carrying out suction filtration, cooling, concentrating to obtain about 40L of methylbenzene, cooling to 5 ℃ for crystallization, carrying out suction filtration, and drying to obtain 11.73 kg of off-white solid which is 4-hydroxy-1-indanone with the yield of 88%.
Comparative example 1 (No Strong acid resin)
Preparation of intermediate 1:
6M hydrochloric acid (840 ml) and dihydrocoumarin (148g, 1.0 mol) were added to a 1L reactor, and after the addition, the reactor was heated to 100 ℃ to react for 3 hours, and the reaction was complete. The temperature is reduced by 25 ℃, the filtration is carried out, the filter cake is washed by water and dried to obtain 156.3 g of pink solid, and the yield is 94%.
Preparation of 4-hydroxy-1-indanone:
toluene (600 ml) and intermediate 1 (133g, 0.9mol) are added into a 1L reaction kettle, polyphosphoric acid (399 g) is added in batches under stirring, after the addition is finished, the reaction is heated to 115 ℃ to react for 4 hours, the reaction can not be completed, and the stirring reaction is continued for 4 hours, so that the reaction can not be completed. Cooling to 20 ℃, adding ice water (1200 ml) into the reaction liquid in batches, stirring for 30 minutes, carrying out suction filtration to recover strong acid resin, layering the filtrate, washing an organic layer with water, adding activated carbon (13 g), heating to 115 ℃ for decoloration for 1 hour, carrying out suction filtration, cooling, concentrating to obtain about 400ml of toluene, cooling to 5 ℃ for crystallization, wherein crystallization cannot be carried out, concentrating to dryness, and carrying out column chromatography purification to obtain 53.3g of white-like solid which is 4-hydroxy-1-indanone with the yield of 40%.
COMPARATIVE EXAMPLE 2 (route 1)
Preparation of 4-hydroxy-1-indanone:
adding anhydrous aluminum trichloride (2500g, 18.75mol) and sodium chloride (500g, 8.5 mol) into a 5-liter reaction bottle, strongly stirring, heating to 200 ℃ for dissolving, keeping the temperature of 200 ℃ until most of liquid can be dissolved, dropwise adding dihydrocoumarin (500g, 3.375 mol), reacting for 2 hours, tracking a TLC point plate, and completely reacting. Cooling to 130 ℃, pouring into ice water (7.5L) to quench the reaction, adding concentrated hydrochloric acid (2.5L) until the system is strongly acidic, stirring for 30 minutes, filtering, washing with water, and drying to obtain 375 g of brown solid with yield: 75 percent.
Comparative example 3 (route 1 pilot test)
Preparation of 4-hydroxy-1-indanone:
anhydrous aluminum trichloride (25kg, 187.5 mol) and sodium chloride (5kg, 85mol) are added into a 50-liter reaction bottle, strong stirring is carried out, the mixture is heated to 200 ℃ for dissolution, dihydrocoumarin (5kg, 33.75mol) is dropwise added while the temperature is kept at 200 ℃, the reaction is carried out for 4 hours, TLC point plate tracking is carried out, the reaction can not be completed, and the stirring is difficult. The stirring reaction is continued for 4 hours, the reaction is complete, and the system is blackened. Cooling to 130 ℃, pouring into ice water (75L) for quenching reaction, adding concentrated hydrochloric acid (25L) until the system is strong acid, stirring for 40 minutes, carrying out suction filtration, washing with water, and drying to obtain 3kg of brownish black solid, adding ethyl acetate (12L) into the brownish black solid, heating to 60 ℃ to dissolve the brownish black solid, wherein a lot of black insoluble substances are not dissolved completely, carrying out suction filtration, and concentrating the filtrate to obtain 1.6 kg of brown solid, wherein the yield is as follows: 32 percent.
As can be seen from example 1, example 2, comparative example 1, comparative example 2 and comparative example 3, the yield is stable and the operation is convenient in the preparation route 4; the route 1 is a solid reaction, has high temperature, is difficult to stir, is easy to carbonize and cannot be industrially produced; route 4 does not reinforce acidic resin, and cannot completely react, so that the purification method is complicated and the yield is low.
COMPARATIVE EXAMPLE 4 (route 3)
Preparation of intermediate 1:
6M hydrochloric acid (840 ml) and dihydrocoumarin (148g, 1.0 mol) were added to a 1L reactor, and after the addition, the reaction was heated to 100 ℃ to complete the reaction for 3 hours. The temperature is reduced by 25 ℃, the filtration is carried out, the filter cake is washed by water and dried to obtain 156.2 g of pink solid, and the yield is 94%.
Preparation of intermediate 2:
adding the intermediate 1 (16.8g, 0.087mol) and acetic anhydride (14.3g, 0.14mol) into a reaction kettle, heating to 80 ℃ for reacting for 1 hour, completely reacting, concentrating to dryness, adding methylene dichloride (185 ml) and 2 drops of DMF into the concentrate, dropwise adding thionyl chloride (25.7g, 0.217mol) within 20 ℃, heating to 80 ℃ for reacting for 2 hours after the addition is finished, completely reacting, concentrating to dryness to obtain an intermediate 2, and directly carrying out the next reaction without purification.
Preparation of intermediate 3:
dichloromethane (100 ml) and aluminium trichloride (50.8g, 0.381mol) are added into a reaction bottle, a dichloromethane (50 ml) solution of intermediate 2 (theoretical 0.087 mol) is dropwise added under stirring, after the addition is completed, the mixture is heated to 45 ℃ to react for 1 hour, the reaction is completed, the temperature is reduced, the mixture is poured into ice water (200 ml) in batches, layers are separated, a water layer is extracted by dichloromethane, organic layers are combined, and the mixture is concentrated to obtain 7.7 g of light yellow liquid with the yield of 60%.
1 H NMR(400MHz,CDCl 3 )δ(ppm):7.30-7.21(m,2H),7.14-7.06(m,2H),3.05-3.01(m,2H),2.83-2.79(m,2H)。
As can be seen from comparative example 4, intermediate 3 in preparation scheme 3 is dihydrocoumarin.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (2)
1. An industrial production method of 4-hydroxy-1-indanone, which is characterized in that: taking dihydrocoumarin as a raw material, carrying out hydrolysis reaction on the dihydrocoumarin under the catalysis of hydrochloric acid to obtain an intermediate 1, and carrying out cyclization reaction on the intermediate 1 and polyphosphoric acid under the catalysis of strong acid resin to obtain 4-hydroxy-1-indanone;
the synthetic route is as follows:
the molar ratio of the hydrochloric acid to the dihydrocoumarin is (4.0-10.0) to 1.0;
the mass ratio of the intermediate 1 to the strong acid resin to the polyphosphoric acid is 1 (0.01-0.1) to 2.5-6;
the strong acid resin is macroporous strong acid styrene cation exchange resin.
2. The industrial production method of 4-hydroxy-1-indanone according to claim 1, characterized in that: the method comprises the following steps:
(1) Preparation of intermediate 1: mixing hydrochloric acid and dihydrocoumarin, heating for reaction, cooling, performing suction filtration, washing with water, and drying to obtain an intermediate 1;
(2) Preparation of 4-hydroxy-1-indanone: mixing toluene, the intermediate 1 and strong acid resin, adding polyphosphoric acid, heating for reaction, cooling, adding ice water, stirring, performing suction filtration, layering, washing with water, adding activated carbon, heating for decolorization, performing suction filtration, cooling, concentrating, crystallizing, performing suction filtration, and drying to obtain 4-hydroxy-1-indanone.
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