CN109761803A - A kind of synthetic method of naproxen key intermediate - Google Patents
A kind of synthetic method of naproxen key intermediate Download PDFInfo
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- CN109761803A CN109761803A CN201910083148.9A CN201910083148A CN109761803A CN 109761803 A CN109761803 A CN 109761803A CN 201910083148 A CN201910083148 A CN 201910083148A CN 109761803 A CN109761803 A CN 109761803A
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Abstract
This application discloses a kind of synthetic methods of naproxen key intermediate.The application belongs to the rearrangement step prepared in naproxen, it is including the use of 2- (1 '-haloethyl) -2- (6 '-methoxyl groups -2 '-naphthalene) -5,5- dimethyl -1, catalyst is added in 3- dioxane, reaction is carried out under specific reaction condition generates 2 '-(6 '-methoxynaphthalene) -2- propionic acid -3- halogen -2,2- dimethyl propyl ester.The present processes, it overcomes to react 10 hours or more under 130 DEG C or more high temperature in traditional synthesis step and could reset complete defect, reduce energy consumption, and the reaction carries out under solvent-free conditions, while increasing reaction yield, to more environment-friendly.
Description
Technical field
The invention belongs to chemical pharmacy fields, and in particular to a kind of synthesis technology of intermediates of naproxen and its application.
Background technique
Naproxen (Naproxen) has anti-inflammatory, antipyretic, analgesic activity, is PG synthetase inhibitors.Rheumatic is closed
The curative effect of section inflammation and osteoarthritis, similar aspirin.Ah Si is not resistant to because of anaemia, gastrointestinal system disorder or other reasons
Anti-inflammatory analgesics patient, this product such as woods, Indomethacin can get promising result, while inhibit the effect of blood platelet smaller.Mesh
It is preceding to be widely applied in the world, become global one of main analgesic-antipyretic and best-selling non-prescribed medicine.
The 2 '-chloro- 2,2- dimethyl propyl ester of (6 '-methoxynaphthalene) -2- propionic acid -3- are the important centres for producing naproxen bulk pharmaceutical chemicals
Body, structure is as shown in above formula.There is an asymmetric carbon atom in the structure of naproxen, has a pair of corresponding isomers, be respectively provided with not
Same bioactivity.Some researches show that the analgesic activity of (S)-Naproxen is 28 times of (R)-isomers, therefore, (S)-Nabumetone
Raw is main active constituent, and structure is shown below.The method of current main synthesis (S)-Naproxen includes racemic
Body Split Method, chiral induction method, enzyme catalysis method and asymmetry catalysis method.
Chinese patent application CN201810431686 discloses a kind of D, the preparation method of L- naproxen, with 6- methoxy
Base -2- propionyl naphthalene is raw material, anti-to hydrolyzing using lye after carrying out bromo-reaction, ketal reaction, rearrangement reaction, hydrolysis
It answers product to carry out alkali out reaction, separates alkali division object, the solid product in alkali division object is taken to carry out water-soluble decoloration, acidification reaction,
Obtain D, L- naproxen.Its invention is further improved and optimizes on the basis of existing propionating technique, provides a kind of raising D,
L- naproxen yield and quality reduce the new process of wastewater flow rate.But it in rearrangement reaction needs that Zinc oxide catalytic is added
And need to be added toluene as reaction dissolvent, and it needs to be warming up to 113 ± 5 DEG C and insulation reaction 10 hours, it is raw in industry
Under the conditions of production, being warming up to 113 ± 5 DEG C and insulation reaction 10 hours is to need to expend great energy and increase the not true of reaction
It is qualitative, while also considerably increasing production cost.
Therefore, existing Synthesis of Dl-naproxen could be improved.
Summary of the invention
The main purpose of the application is to provide a kind of synthetic method and its application for preparing naproxen key intermediate.
The alpha-halogenate object rearrangement of aryl alkyl ketone is generally needed to be added solvent and catalyst, anti-under 130 DEG C or more high temperature
Answering could reset completely for 10 hours or more, reaction raw materials 2- (1 '-haloethyl) -2- (6 '-methoxyl groups -2 '-naphthalene)-of the invention
5,5- dimethyl -1,3- dioxanes are naphthalene ketal, to carry out rearrangement tool and acquire a certain degree of difficulty.
The problems in achieve the goals above and solution rearrangement is worked as, and the application adopts in the rearrangement step of (S)-Naproxen
With following technical scheme:
A kind of synthetic method of naproxen key intermediate comprising following steps: by chemical compounds I (2- (1 '-in reaction flask
Haloethyl) -2- (6 '-methoxyl groups -2 '-naphthalene) -5,5- dimethyl -1,3- dioxane) it is uniformly mixed with catalyst, then will be anti-
System heating fusing is answered, extractant is added after reaction and extracts, filtering removal insoluble matter is concentrated dry filtrate, obtains compound ii
(2 '-(6 '-methoxynaphthalene) -2- propionic acid -3- halogen -2,2- dimethyl propyl ester), entire reaction is to carry out in the absence of a solvent
's.
The reaction equation of the application synthesis is as follows:
Wherein, X1For chlorine, bromine, iodine or hydrogen；X2For chlorine, bromine or iodine.But work as X1When for hydrogen, X2It is not bromine.
Further, the molar ratio of chemical compounds I and the catalyst is 1:0.01~5；It is furthermore preferred that for 1:0.1~
2；It most preferably, is 1:0.1.
Further, one of catalyst zinc oxide, zinc chloride, zinc acetate.
Further, extractant is fat-soluble solvent, such as toluene, methylene chloride, ethyl acetate, ether, carbon tetrachloride.
Further, the reaction time is 0.5~8 hour；It is furthermore preferred that being 0.5~4 hour；Most preferably, it is 2 hours.
Further, reaction temperature is 85~130 DEG C；It is furthermore preferred that being 85~120 DEG C；It most preferably, is 85~90
℃。
Further, it has used 1 mole compound I and 0.1 moles zinc to be uniformly mixed in reaction, has been heated to 85~90
DEG C, it reacts 1~3 hour, is extracted to which toluene after the reaction was completed, is added, be filtered to remove insoluble matter, dry filtrate is concentrated, obtains chemical combination
Object II.
Further, the synthetic method of the application further comprises the quality using LC-MS/MS to the chemical compounds I after reaction
Score is detected, if the mass fraction for detecting chemical compounds I less than 0.5%, shows that rearrangement reaction carries out completely.
Further, the synthetic method of the application further comprises application of the method in Nabumetone GCMS computer.
It is reverse phase liquid in addition, further including using high efficiency liquid chromatography for separating and determining naproxen and its related substance
Chromatography, chromatographic column filler are octadecylsilane chemically bonded silica column, and with containing, acetonitrile, phosphate buffer flowing relative sample are molten
Liquid is eluted, and is detected using UV detector.
Mobile phase acetonitrile: phosphate buffer volume ratio is 42:58.The phosphate buffer is formulated as weighing phosphoric acid
Potassium dihydrogen 1.36g adds water 1000ml to make to dissolve, and is 2.0 with phosphorus acid for adjusting pH value；The octadecylsilane chemically bonded silica particle
Partial size is preferably 3 μm, and column length is preferably 100mm, and diameter is preferably 4.0mm.
Other analysis conditions: the column temperature that chromatographic column uses is 30~60 DEG C, preferably 50 DEG C.The flow velocity of mobile phase be 1.0~
2.0ml/min, preferably 1.5ml/min.Chromatographic column sample volume is 20ul.Used liquid chromatograph is Shimadzu LC-20AT, inspection
Survey device is UV detector, chromatographic work station Labsolutions.
We the principle of technical solution is that catalyst is inorganic salts, is difficult to dissolve in organic solvent, in tradition reaction
It in the presence of having solvent, reacts for solid-liquid two phase reaction, without using in the case where solvent in our scheme, raw material makees solvent to urging
The dissolubility of agent is preferable, reacts for uniform liquid phase reactor, therefore speeded reaction rate, reduces reaction temperature.
Due to using the technology described above, the beneficial effects of the present application are as follows:
The synthetic method of the naproxen key intermediate of the application, improving needs when preparing (S)-Naproxen at present in rearrangement step
Consume big energy and problem with high costs.Because reaction raw materials are 2- (1 '-chloroethyl) -2- (6 '-methoxyl groups -2 ' -
Naphthalene) -5,5- dimethyl -1,3- dioxane, chemical structure is naphthalene ketal, under the conventional understanding of this field, need by
It is to need to carry out continuously up to 10 that the rearrangement of naphthalene ketal, which becomes the 2 '-chloro- 2,2- dimethyl propyl ester of (6 '-methoxynaphthalene) -2- propionic acid -3-,
Multiple hours high temperature, and can just complete under the effect of the catalyst, and the yield reset is often also not high enough.We is logical
It crosses experiment and has found the technical program, temperature needed for not only reduced by only reaction reduces energy consumption, raw in large-scale industry
In production, great amount of cost is also saved, significantly increases economic benefit.Also, while reducing reaction temperature, do not make
It obtains and shortens the time of reaction so that reacting required time increase such as conventional understanding, significantly mention
High efficiency.
Detailed description of the invention
Fig. 1 is the chromatogram that embodiment 1 detected；
Fig. 2 is the chromatogram that embodiment 2 detected；
Fig. 3 is the chromatogram that embodiment 3 detected；
Fig. 4 is the chromatogram that embodiment 4 detected；
Fig. 5 is the chromatogram that embodiment 5 detected and peak table.
Specific embodiment
The application is described in further detail below by specific embodiments and the drawings.Following embodiment is only to the application
It is further described, should not be construed as the limitation to the application.
Embodiment 1
The synthesis of compound ii (the 2 '-chloro- 2,2- dimethyl propyl ester of (6 '-methoxynaphthalene) -2- propionic acid -3-).
In three mouthfuls of reaction flasks, 2- (1 '-chloroethyl) -2- (6 '-methoxyl groups -2 '-naphthalene) -5,5- diformazan is added
Base -1,3- dioxane 33.5g, zinc acetate 9.2g are uniformly mixed, and reaction system is heated to 125~130 DEG C, is melted, herein
At a temperature of react 8 hours.After the reaction was completed, methylene chloride is added to extract, filtering removal insoluble matter, filtrate concentration is dry, is produced
The chloro- 2,2- dimethyl propyl ester 32g of compounds II 2 '-(6 '-methoxynaphthalene) -2- propionic acid -3-.The chromatogram of detection is shown in Fig. 1, from
As can be seen that the mass fraction of chemical compounds I is 0.177% in figure, rearrangement reaction is carried out fully and completely.Intermediate production on No. 4 peaks
Product have finally been also converted to final product.Yield is 95.5%.
Embodiment 2
The synthesis of compounds Ⅳ (2 '-(5 '-bromo- 6 '-methoxynaphthalene) bromo- 2,2- dimethyl propyl ester of -2- propionic acid -3-).
In three mouthfuls of reaction flasks, 2- (1 '-bromoethyl) -2- (5 '-bromo- 6 '-methoxyl group -2 '-naphthalene) -5,5- is added
Dimethyl -1,3- dioxane 45.8g, zinc chloride 6.8g are uniformly mixed, and reaction system is heated to 125~130 DEG C, is melted,
It reacts 4 hours at this temperature.After the reaction was completed, ethyl acetate is added to extract, filtering removal insoluble matter, filtrate concentration is dry, obtains
To 2 '-(5 '-bromo- 6 '-methoxynaphthalene) bromo- 2,2- dimethyl propyl ester 42.2g of -2- propionic acid -3-.The chromatogram of detection is shown in Fig. 2, from
As can be seen that rearrangement reaction carries out fully and completely in figure.Intermediate products on No. 1 peak have finally been also converted to final product.It receives
Rate is 92.2%.
Embodiment 3
The synthesis of compound VI (2 '-(5 '-iodo- 6 '-methoxynaphthalene) iodo- 2,2- dimethyl propyl ester of -2- propionic acid -3-).
In three mouthfuls of reaction flasks, 2- (1 '-iodine ethyl) -2- (5 '-iodo- 6 '-methoxyl group -2 '-naphthalene) -5,5- is added
Dimethyl -1,3- dioxane 55.2g, zinc oxide 4.1g are uniformly mixed, and reaction system is heated to 125~130 DEG C, is melted,
It reacts 3 hours at this temperature.After the reaction was completed, extracted by ether is added, filtering removal insoluble matter, filtrate concentration is dry, obtains 2 '-
(5 '-iodo- 6 '-methoxynaphthalene) iodo- 2,2- dimethyl propyl ester 50g of -2- propionic acid -3-.The chromatogram of detection is shown in Fig. 3, can from figure
To find out, the mass fraction of chemical compounds I is 0.061%, and rearrangement reaction carries out fully and completely.Intermediate products on No. 6 peaks are final
It has been also converted to final product.Yield is 90.4%.
Embodiment 4
The synthesis of compound VIII (2 '-(5 '-chloro- 6 '-methoxynaphthalene) chloro- 2,2- dimethyl propyl ester of -2- propionic acid -3-).
In three mouthfuls of reaction flasks, 2- (1 '-chloroethyl) -2- (6 '-methoxyl groups -2 '-naphthalene) -5,5- diformazan is added
Base -1,3- dioxane 36.9g, zinc oxide 2.0g are uniformly mixed, and reaction system is heated to 110~115 DEG C, is melted, herein
At a temperature of react 2 hours.After the reaction was completed, toluene is added to extract, filtering removal insoluble matter, filtrate concentration is dry, obtains 2 '-(5 '-
Chloro- 6 '-methoxynaphthalene) the chloro- 2,2- dimethyl propyl ester 35.6g of -2- propionic acid -3-.The chromatogram of detection is shown in Fig. 4, can be with from figure
Find out, the mass fraction of chemical compounds I is 0.176%, and rearrangement reaction carries out fully and completely.Intermediate products on No. 3 peaks are finally
Conversion is for final product.Yield is 96.4%.
Embodiment 5
The synthesis of compound ii (the 2 '-chloro- 2,2- dimethyl propyl ester of (6 '-methoxynaphthalene) -2- propionic acid -3-).
In three mouthfuls of reaction flasks, 2- (1 '-chloroethyl) -2- (6 '-methoxyl groups -2 '-naphthalene) -5,5- diformazan is added
Base -1,3- dioxane 33.5g, zinc oxide 0.8g are uniformly mixed, and reaction system are heated to 85~90 DEG C, fusing is warm herein
Degree lower reaction 2 hours.After the reaction was completed, toluene is added to extract, filtering removal insoluble matter, filtrate concentration is dry, obtains 2 '-(6 '-first
Oxygroup naphthalene) the chloro- 2,2- dimethyl propyl ester 33.4g of -2- propionic acid -3-.The chromatogram of detection is shown in Fig. 5, it can be seen from the figure that chemical combination
The mass fraction of object I is 0.111%, and rearrangement reaction carries out fully and completely.Intermediate products on No. 6 peaks are finally also converted to
Final product.Yield is further improved, yield is finally 99.7%.
It is summarized as follows table:
Wherein, embodiment 5 is optimum embodiment.
High efficiency liquid chromatography for separating and determining naproxen and its related substance are used in above embodiments, are reverse phase liquid
Chromatography, chromatographic column filler are octadecylsilane chemically bonded silica column, and with containing, acetonitrile, phosphate buffer flowing relative sample are molten
Liquid is eluted, and is detected using UV detector.
Mobile phase acetonitrile: phosphate buffer volume ratio is 42:58.The phosphate buffer is formulated as weighing phosphoric acid
Potassium dihydrogen 1.36g adds water 1000ml to make to dissolve, and is 2.0 with phosphorus acid for adjusting pH value；The octadecylsilane chemically bonded silica particle
Partial size is preferably 3 μm, and column length is preferably 100mm, and diameter is preferably 4.0mm.
Other analysis conditions: the column temperature that chromatographic column uses is 30~60 DEG C, preferably 50 DEG C.The flow velocity of mobile phase be 1.0~
2.0ml/min, preferably 1.5ml/min.Chromatographic column sample volume is 20ul.Used liquid chromatograph is Shimadzu LC-20AT, inspection
Survey device is UV detector, chromatographic work station Labsolutions.
The foregoing is a further detailed description of the present application in conjunction with specific implementation manners, and it cannot be said that this Shen
Specific implementation please is only limited to these instructions.For those of ordinary skill in the art to which this application belongs, it is not taking off
Under the premise of from the application design, a number of simple deductions or replacements can also be made, all shall be regarded as belonging to the protection of the application
Range.
Claims (10)
1. a kind of synthetic method of naproxen key intermediate, which is characterized in that it in reaction flask the following steps are included: will change
It closes object I to be uniformly mixed with catalyst, after heating fusing, obtains compound ii, entire reaction is to carry out in the absence of a solvent
's;
Wherein, X1For chlorine, bromine, iodine or hydrogen；X2For chlorine, bromine or iodine；But work as X1When for hydrogen, X2It is not bromine.
2. synthetic method as described in claim 1, which is characterized in that mole of the chemical compounds I and the catalyst
Than for 1:0.01~5.
3. synthetic method as described in claim 1, which is characterized in that the catalyst is zinc oxide, zinc chloride, zinc acetate
One of.
4. synthetic method as described in claim 1, which is characterized in that the reaction time is 0.5~8 hour.
5. synthetic method as described in claim 1, which is characterized in that reaction temperature is 85~130 DEG C.
6. synthetic method as described in claim 1, which is characterized in that operating procedure is, in reaction flask by chemical compounds I with urge
Agent is uniformly mixed, then reaction system is heated and is melted, and extractant is added after reaction and extracts, filtering removal insoluble matter, and concentration is dry
Filtrate obtains compound ii.
7. synthetic method as claimed in claim 6, which is characterized in that the extractant is fat-soluble solvent.
8. synthetic method as claimed in claim 6, which is characterized in that used 1 mole compound I and 0.1 mole in reaction
Zinc oxide is uniformly mixed, and is heated to 85~90 DEG C, is reacted 1~3 hour, is extracted, is filtered to remove to which toluene after the reaction was completed, is added
Insoluble matter is concentrated dry filtrate, obtains compound ii.
9. synthetic method as described in claim 1, which is characterized in that further comprise using LC-MS/MS to the chemical combination after reaction
The mass fraction of object I is detected.
10. application of the synthetic method as described in any one of claims 1 to 9 in Nabumetone GCMS computer.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110146633A (en) * | 2019-05-23 | 2019-08-20 | 湖南普道医药技术有限公司 | The separation method of special impurities in a kind of nonsteroidal anti-inflammatory drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110146633A (en) * | 2019-05-23 | 2019-08-20 | 湖南普道医药技术有限公司 | The separation method of special impurities in a kind of nonsteroidal anti-inflammatory drug |
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Application publication date: 20190517 |