CN103130628A - Preparation method of nabumetone - Google Patents

Abstract

A preparation method of nabumetone comprises the following steps: using 6-methoxy-2- naphthaldehyde, acetone solvent and 10% of sodium hydroxide as catalytic agent, and obtaining intermediate after reacting the 6-methoxy-2- naphthaldehyde, the acetone solvent and the 10% of sodium hydroxide as catalytic agent for 4 to 6 hours under temperature of 40 to 60 DEG C; dissolving the intermediate in ethyl acetate, using raney nickelas the catalyst, accessing hydrogen, besides, conducting reaction for 5 hours under temperature of 20 to 30 DEG C and pressure of 0.1 to 4 MPa, and obtaining products after treatment of steps such as filtering and recrystallizing. The preparation method of the nabumetone solves the problems that working procedure is complex in the prior art, and high temperature and pressure are needed in the hydrogenation process, and the technical problem of demanding experimental requirement in catalyzing palladium and the like, therefore, operation is simple in the whole technology, raw materials are easy to obtain, reaction steps are few, yield is high, cost is low, and mass industrial production is available.

Description

A kind of preparation method of nabumetone

[technical field]

The present invention is specifically related to a kind of preparation method of NSAID (non-steroidal anti-inflammatory drug) nabumetone.

[background technology]

Nabumetone is a kind of novel nonacid NSAID (non-steroidal anti-inflammatory drug), belong to prodrug, be mainly used in rheumatismal treatment, in its body, main active metabolite can suppress the biosynthesizing of prostaglandin(PG), have stronger antipyretic-antalgic and anti-inflammatory action, this medicine much smaller than indomethacin and acetylsalicylic acid, is used for rheumatoid arthritis, osteoarthritis to the stimulation of stomach, the recent domestic market demand increases substantially year after year, and development prospect is very optimistic.Many about the industrial production process of nabumetone in recent years, mainly contain following several method:

Method one (US5750793A; EP0792860A1):

The shortcoming of this method is: due to the existence of bromine, the shortening temperature is high, and the time is long, and pressure is large, and the catalyst recovery difficulty is large simultaneously; The three wastes are difficult; Total recovery is low.

Method two (CN1982274A):

The shortcoming of this method is: with raw material 6-methoxyl group-2-formaldehyde and methyl aceto acetate is synthetic makes how, preparation section is complicated, total recovery is low, cost is high.

Method three (US4221741A; US4247709A):

The shortcoming of this method is: total recovery is 80% left and right, but raw material is expensive, and is not easy to obtain, thereby cost is high.

Method four (Journal of Catalysis, 2007,223-230):

The shortcoming of this method is: adopt heterogeneous solvent, waste water is many; The nitrogen protection that the first step Heck reaction needed is strict, complex procedures; Also will use expensive palladium catalyst in reaction, cost is high.

[summary of the invention]

Technical problem to be solved by this invention is to provide a kind of preparation method of nabumetone, and technique is simple, raw material is easy to get, reactions steps is few, yield is high, cost is low, can carry out large-scale industrial production.

The present invention solves the problems of the technologies described above by the following technical programs: a kind of preparation method of nabumetone comprises the following steps:

(1) the 6-methoxy-2-naphthaldehyde being dissolved in acetone, making catalyzer with 10% aqueous sodium hydroxide solution, is to react 4～6h under 10～40 ℃ in temperature of reaction; Then air distillation is concentrated, then adding distil water dilution in the enriched material, and regulates pH value to neutrality with concentrated hydrochloric acid, and filtration, obtain intermediate at last; Wherein, the volume ratio of described 6-methoxy-2-naphthaldehyde, acetone and sodium hydroxide is the 6-methoxy-2-naphthaldehyde: acetone: sodium hydroxide=6: 50: 1;

(2) intermediate that obtains in (1) is dissolved in ethyl acetate, 5% Raney Ni with described intermediate quality is made catalyzer, logical hydrogen, and stir 5h under 20～30 ℃, 0.1MPa-4MPa, then filter, filtrate is concentrated into half volume, at last remaining filtrate is namely got nabumetone at 0 ℃ of lower recrystallization.

Beneficial effect of the present invention is: the problem that has solved the complex procedures that exists in existing technique, when particularly containing bromo element in raw material, hydrogenation process needs the High Temperature High Pressure problem, and the technical problems such as experimental implementation requirement of the harshness in palladium catalysis, make that whole technological operation is simple, raw material is easy to get, reactions steps is few, yield is high, cost is low, can carry out large-scale industrial production.

[description of drawings]

The invention will be further described in conjunction with the embodiments with reference to the accompanying drawings.

Fig. 1 is the NMR (Nuclear Magnetic Resonance) spectrum figure of nabumetone in the present invention.

[embodiment]

A kind of preparation method of nabumetone comprises the following steps:

(1) the 6-methoxy-2-naphthaldehyde being dissolved in acetone, making catalyzer with 10% aqueous sodium hydroxide solution, is to react 4～6h under 10～40 ℃ in temperature of reaction; Then air distillation is concentrated, then adding distil water dilution in the enriched material, and regulates pH value to neutrality with concentrated hydrochloric acid, and filtration, obtain intermediate at last; Wherein, the volume ratio of described 6-methoxy-2-naphthaldehyde, acetone and sodium hydroxide is the 6-methoxy-2-naphthaldehyde: acetone: sodium hydroxide=6: 50: 1;

(2) intermediate that obtains in (1) is dissolved in ethyl acetate, 5% Raney Ni with described intermediate quality is made catalyzer, logical hydrogen, and stir 5h under 20～30 ℃, 0.1MPa-4MPa, then filter, filtrate is concentrated into half volume, at last remaining filtrate is namely got nabumetone at 0 ℃ of lower recrystallization.

The synthesis technique of described nabumetone as shown in the formula:

Following content provides exemplary embodiment of the present invention, and these embodiment are only exemplary, and is not used in restriction scope of the present invention as herein described, and these embodiment only are used for illustrating implementation method of the present invention:

Embodiment 1

15 kilograms of 6-methoxy-2-naphthaldehydes are dissolved in the acetone of 250 liters, are to stir under 20 ℃ in temperature of reaction, slowly splash into 5 liters of 10% sodium hydroxide solutions, continue to stir 4 hours; The acetone of 2/3rds volumes in reaction solution is collected in air distillation, approximately 100 liters of dilutions of adding distil water in the enriched material again, and regulate the pH value to neutral with concentrated hydrochloric acid, namely there is a large amount of yellow solids to separate out, filter to such an extent that the intermediate of 17.1 kilograms is 4-(2-methoxynaphthalen-6-yl) but-3-en-2-one (4-(2-methoxynaphthalene-6-yl)-3-butene-2-ketone), yield is 94%;

17.1 kilograms, intermediate is dissolved in the ethyl acetate of 120 liters, Raney Ni with 0.9 kilogram is made catalyzer, pass into the hydrogen that pressure is 2MPa under 30 ℃ of stirrings, reacted 5 hours, filtering recovering catalyst, and after filtrate is concentrated into half volume, be cooled to zero degree, slowly separate out faint yellow solid, filtering and collect faint yellow solid is 16 kilograms of nabumetones, and its yield is 94%.

Embodiment 2

60 kilograms of 6-methoxy-2-naphthaldehydes are dissolved in the acetone of 1000 liters, are to stir under 10 ℃ in temperature of reaction, slowly splash into 20 liters of 10% sodium hydroxide solutions, continue to stir 5 hours; The acetone of 2/3rds volumes in reaction solution is collected in air distillation, approximately 400 liters of dilutions of adding distil water in the enriched material again, and regulate the pH value to neutral with concentrated hydrochloric acid, namely there is a large amount of yellow solids to separate out, filter to such an extent that the intermediate of 67.7 kilograms is 4-(2-methoxynaphthalen-6-yl) but-3-en-2-one (4-(2-methoxynaphthalene-6-yl)-3-butene-2-ketone), yield is 93%;

67.7 kilograms, intermediate is dissolved in the ethyl acetate of 480 liters, Raney Ni with 3.49 kilograms is made catalyzer, pass into the hydrogen that pressure is 4MPa under 20 ℃ of stirrings, reacted 5 hours, filtering recovering catalyst, and after filtrate is concentrated into half volume, be cooled to zero degree, slowly separate out faint yellow solid, filtering and collect faint yellow solid is 64.2 kilograms of nabumetones, and its yield is 94%.

Embodiment 3

60 kilograms of 6-methoxy-2-naphthaldehydes are dissolved in the acetone of 1000 liters, are to stir under 40 ℃ in temperature of reaction, slowly splash into 20 liters of 10% sodium hydroxide solutions, continue to stir 6 hours; The acetone of 2/3rds volumes in reaction solution is collected in air distillation, approximately 400 liters of dilutions of adding distil water in the enriched material again, and regulate the pH value to neutral with concentrated hydrochloric acid, namely there is a large amount of yellow solids to separate out, filter to such an extent that the intermediate of 65.7 kilograms is 4-(2-methoxynaphthalen-6-yl) but-3-en-2-one (4-(2-methoxynaphthalene-6-yl)-3-butene-2-ketone), yield is 90%;

65.7 kilograms, intermediate is dissolved in the ethyl acetate of 480 liters, Raney Ni with 3.3 kilograms is made catalyzer, pass into the hydrogen that pressure is 0.1MPa under 25 ℃ of stirrings, reacted 5 hours, filtering recovering catalyst, and after filtrate is concentrated into half volume, be cooled to zero degree, slowly separate out faint yellow solid, filtering and collect faint yellow solid is 63 kilograms of nabumetones, and its yield is 95%.

The product that above-described embodiment is made adopts NMR (Nuclear Magnetic Resonance) spectrum to characterize, and concrete outcome is seen Fig. 1, is shown by nmr spectrum data, and the product that makes really is nabumetone, and yield of the present invention reaches more than 94%.

The present invention operates simple and easy, and production cost is low:

(1) all operations is substantially all to operate under the room temperature normal pressure, need not to keep away oxygen and keeps away water;

(2) all raw materials such as 6-methoxy-2-naphthaldehyde, acetone and Raney Ni all cheaply are easy to get;

(3) reaction acetone recoverable used, reaction agents useful for same ethyl acetate can be used for the solvent of recrystallization again as reaction solution in aftertreatment, not only saved cost, and reduced a lot of operation sequences.

The invention solves the problem of the complex procedures that exists in existing technique, when particularly containing bromo element in raw material, hydrogenation process needs the High Temperature High Pressure problem, and the technical problems such as experimental implementation requirement of the harshness in palladium catalysis, make that whole technological operation is simple, raw material is easy to get, reactions steps is few, yield is high, cost is low, can carry out large-scale industrial production.

Claims (1)

1. the preparation method of a nabumetone is characterized in that: comprise the following steps:

(1) the 6-methoxy-2-naphthaldehyde being dissolved in acetone, making catalyzer with 10% aqueous sodium hydroxide solution, is to react 4～6h under 10～40 ℃ in temperature of reaction; Then air distillation is concentrated, then adding distil water dilution in the enriched material, and regulates pH value to neutrality with concentrated hydrochloric acid, and filtration, obtain intermediate at last; Wherein, the volume ratio of described 6-methoxy-2-naphthaldehyde, acetone and sodium hydroxide is the 6-methoxy-2-naphthaldehyde: acetone: sodium hydroxide=6: 50: 1;

(2) intermediate that obtains in (1) is dissolved in ethyl acetate, 5% Raney Ni with described intermediate quality is made catalyzer, logical hydrogen, and stir 5h under 20～30 ℃, 0.1MPa-4MPa, then filter, filtrate is concentrated into half volume, at last remaining filtrate is namely got nabumetone at 0 ℃ of lower recrystallization.

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