CN109705000A - Ailamode intermediate and its synthetic method - Google Patents
Ailamode intermediate and its synthetic method Download PDFInfo
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Abstract
The invention belongs to chemicals synthesis technical fields, and in particular to a kind of Ailamode key intermediate and its synthetic method.Wherein this synthetic method includes: that -2 nitrophenol of 4- methoxyl group is finally obtained -2 tolyloxy-benzenesulfonamide of 5- methoxyl group by reduction, Ullmann reaction, Mesylation.The technological operation of the synthetic method is simple, environmental-friendly, reaction condition is mild, and final products purity is up to 99.6%, and yield is up to 93.93%, is very suitable to industrialized production.
Description
Technical field
The present invention relates to chemicals synthesis technical fields, and in particular to a kind of Ailamode key intermediate and its synthesis
Method.
Background technique
Ailamode (Iguratimod, T 614) be it is non-stay body anti-inflammatory agent (NSAIDs), the entitled 3- formamido-of chemistry
7- methylsulfonyl amido 6- phenoxy group -4H-1- benzopyrans -4- ketone is to be opened by Japan folic hill with Wei Cai drugmaker joint research and development
The novel alleviation state of an illness medicine (DMARDs) of one kind of hair, for treating rheumatic arthritis (RA) and osteoarthritis (0A) treatment.
Compared with previous DMARDs, effective rapid, curative effect is equal with efficient antirheumatic drug (SAP, MTX), but toxicity is low.
- 2 tolyloxy-benzenesulfonamide of 5- methoxyl group is a key intermediate of Ailamode synthesis technology.The prior art
Using 4- chlorine-3-nitroanisole as raw material, by etherificate, nitro reduction, Mesylation obtains required intermediate (5- methoxyl group -2
Tolyloxy-benzenesulfonamide), this method is raw material using 4- chlorine-3-nitroanisole, and reaction step is too long, final products purity
Not high with yield (79%), overall cost is excessively high, is unfavorable for industrialized production.
Expensive starting materials, purity in order to overcome the shortcomings of the prior art is not high, yield is relatively low, and present applicant proposes with 4- first
- 2 nitrophenol of oxygroup is the new road of Material synthesis Ailamode key intermediate (- 2 tolyloxy-benzenesulfonamide of 5- methoxyl group)
Line, cost of material is suitable and in liberal supply, and final products purity and yield are high, there is preferable industrial prospect.
Summary of the invention
The object of the present invention is to provide a kind of Ailamode key intermediate and its synthetic methods.
In order to solve the above-mentioned technical problems, the present invention provides a kind of synthetic method of Ailamode key intermediate, packets
Include: reduction prepares 2- amino-4-methoxyl phenol using -2 nitrophenol of 4- methoxyl group；Ullmann reaction, that is, pass through 2-
Amino-4-methoxyl phenol prepares 3- amino -4- phenoxy group-methyl phenyl ethers anisole；And Mesylation, that is, pass through 3- amino -4- benzene oxygen
Base-methyl phenyl ethers anisole prepares -2 tolyloxy-benzenesulfonamide of 5- methoxyl group.
Further, the reduction includes: to react -2 nitrophenol of 4- methoxyl group with solvent, mixed in hydrochloric acid；To reaction solution
Middle addition iron powder；And PH is adjusted to which saturated solution of sodium carbonate after reaction, is added, obtain the 2- amino-4-methoxyl
Phenol.
Further, the molar ratio of -2 nitrophenol of 4- methoxyl group and iron powder is 1:2.5-3.5.
Further, the solvent is one or more of methanol, ethyl alcohol.
Further, the Ullmann reaction includes: that potassium hydroxide is added in the 2- amino-4-methoxyl phenol, into
Row reaction；Copper powder, bromobenzene are sequentially added into reaction product, and are heated；It is cooled and poured into water and ether；And distillation, it obtains
3- amino -4- phenoxy group-the methyl phenyl ethers anisole.
Further, the 2- amino-4-methoxyl phenol, potassium hydroxide, bromobenzene, copper powder molar ratio be followed successively by 1:
1.2-1.5:1-1.2:0.01-0.03.
Further, the Mesylation includes: that the 3- amino -4- phenoxy group-methyl phenyl ethers anisole is dissolved in anhydrous pyridine,
And it is cooled to 0-5 DEG C；Methylsufonyl chloride is added dropwise to be reacted；Extract reaction solution；Washing, drying, and it is concentrated into oily；And it will
The grease pours into ethyl alcohol, and crystallization obtains -2 tolyloxy-benzenesulfonamide of 5- methoxyl group.
Further, the molar ratio of the 3- amino -4- phenoxy group-methyl phenyl ethers anisole and methylsufonyl chloride is 1:1-1.2.
Further, the reaction solution is suitable for that solvent is added before extraction；The solvent includes: EA and PE；And
The volume ratio of the two is 1:3.
Another aspect, the present invention also provides a kind of Ailamode key intermediate, the Ailamode key intermediate
Suitable for being prepared by foregoing synthetic method.
It is drawn the invention has the advantages that synthetic method of the invention prepares Chinese mugwort as raw material using -2 nitrophenol of 4- methoxyl group
Not moral key intermediate (- 2 tolyloxy-benzenesulfonamide of 5- methoxyl group), simplifies reaction step, solves in the prior art with 4-
The problems such as chlorine-3-nitroanisole is that expensive cost, the purity of raw material is not high and yield is relatively low, at low cost, yield is high, pure
The advantages that high is spent, large-scale industrial production is suitble to.
Detailed description of the invention
Present invention will be further explained below with reference to the attached drawings and examples.
Fig. 1 is the process flow chart of synthetic method of the invention；
Fig. 2 is -2 tolyloxy-benzenesulfonamide chromatograms of 5- methoxyl group of embodiment 3；
Fig. 3 is -2 tolyloxy-benzenesulfonamide chromatograms of 5- methoxyl group of embodiment 4；
Fig. 4 is -2 tolyloxy-benzenesulfonamide chromatograms of 5- methoxyl group of embodiment 5.
Specific embodiment
In conjunction with the accompanying drawings, the present invention is further explained in detail.These attached drawings are simplified schematic diagram, only with
Illustration illustrates basic structure of the invention, therefore it only shows the composition relevant to the invention.
Embodiment 1
As shown in Figure 1, the present embodiment 1 provides a kind of synthetic method of Ailamode key intermediate, comprising:
Step S1, reduction prepare 2- amino-4-methoxyl phenol using -2 nitrophenol of 4- methoxyl group；
Step S2, Ullmann reaction, i.e., prepare 3- amino -4- phenoxy group-methyl phenyl ethers anisole by 2- amino-4-methoxyl phenol；With
And
Step S3, Mesylation prepare -2 phenoxy groups of 5- methoxyl group-benzene sulfonyl by 3- amino -4- phenoxy group-methyl phenyl ethers anisole
Amine.
A kind of optional embodiment as reduction.
The mode of the reduction includes: that mixing that -2 nitrophenol of 4- methoxyl group is dissolved in 70% ethyl alcohol and 4N HCl is molten
In liquid, reaction solution is warming up to 65-75 DEG C；Then iron powder is uniformly added in 20min in three batches into reaction solution；Quickly stirring is anti-
It answers, middle control to no raw material；After the completion of reaction, saturated solution of sodium carbonate tune PH=8-9 is added, obtains 2- amino-4-methoxyl benzene
Phenol.
Optionally, the molar ratio of -2 nitrophenol of 4- methoxyl group and iron powder is 1:2.5-3.5.
Optionally, the solvent is one or more of methanol, ethyl alcohol.
A kind of optional embodiment as Ullmann reaction.
The Ullmann reaction includes: that powdered potassium hydroxide is added in 2- amino-4-methoxyl phenol to stir,
It is heated 2.5-3.5 hours at 150-160 DEG C, reacts 1 hour, then the solvent in reaction product is evaporated, obtains solvent-free production
Object (i.e. dry salt)；Copper powder, bromobenzene are sequentially added into dry salt, stirring is warming up to 190-200 DEG C, adds to changing colour at 160-180 DEG C
It is 1.5-2 hours hot.After cooling, water and ether are poured into, distillation obtains 3- amino -4- phenoxy group-methyl phenyl ethers anisole.
Optionally, the 2- amino-4-methoxyl phenol, potassium hydroxide, bromobenzene, copper powder molar ratio be followed successively by 1:
1.2-1.5:1-1.2:0.01-0.03.
A kind of optional embodiment as Mesylation.
The mode of the Mesylation includes: that 3- amino -4- phenoxy group-methyl phenyl ethers anisole is dissolved in anhydrous pyridine, solution
0-5 DEG C is cooled to, methylsufonyl chloride is added dropwise.It is added dropwise, is stirred to react at 25-30 DEG C of room temperature, solvent (volume ratio is added
EA:PE=1:3), middle to control to no raw material, reaction time about 1-1.5h.Reaction terminates, and reaction solution is poured into water, with acetic acid second
Ester is extracted twice, and merges organic phase；Then it is washed till water layer PH < 7 with 2N HCl, is washed with water and washs twice, then uses anhydrous slufuric acid
Magnesium is dry；It is finally concentrated into oily, is poured into ethyl alcohol, crystallization obtains -2 tolyloxy-benzenesulfonamide of 5- methoxyl group.Wherein, EA is
Ethyl acetate, PE are petroleum ether.
Optionally, the molar ratio of the 3- amino -4- phenoxy group-methyl phenyl ethers anisole and methylsufonyl chloride is 1:1-1.2.
The synthetic method of the present embodiment 1 prepares Ailamode key intermediate 5- by raw material of -2 nitrophenol of 4- methoxyl group
- 2 tolyloxy-benzenesulfonamide of methoxyl group, simplifies reaction step, solves and is with 4- chlorine-3-nitroanisole in the prior art
The problems such as expensive cost, the purity of raw material is not high and yield is relatively low has many advantages, such as that at low cost, yield is high, with high purity, is suitble to big
Technical scale metaplasia produces.
Embodiment 2
On the basis of embodiment 1, the present embodiment 2 provides a kind of Ailamode key intermediate, and the Ailamode is crucial
Intermediate is suitable for preparing by foregoing synthetic method.
Composition content and specific implementation process about Ailamode key intermediate are discussed referring to the correlation of embodiment 1,
Details are not described herein again.
Embodiment 3
(1) by -2 nitrophenol of 169g 4- methoxyl group be dissolved in the mixed solution of 70% ethyl alcohol of 1500ml and 40ml 4N HCl
In, reaction solution is warming up to 65 DEG C；Uniformly addition 140g iron powder is quickly stirred to react into reaction solution in three batches in 20min, in
It controls to no raw material；After the completion of reaction, saturated solution of sodium carbonate tune PH=8 are added, obtain 2- amino-4-methoxyl phenol.
(2) 67.2g powdered potassium hydroxide is added in the 2- amino-4-methoxyl phenol prepared in (1), and stirred,
It is heated 2.5 hours at 150 DEG C, obtains dry salt to fully reacting；0.63g copper powder, 157g bromobenzene are sequentially added thereto,
Stirring is warming up to 190 DEG C to after changing colour at 160 DEG C, heats 1.5 hours.1200ml water and 300ml ether are poured into after cooling, are steamed
It evaporates to obtain 3- amino -4- phenoxy group-methyl phenyl ethers anisole.
(3) the 3- amino -4- phenoxy group-methyl phenyl ethers anisole prepared in (2) is dissolved in 800ml anhydrous pyridine, solution cooling
To 0 DEG C；114.5g methylsufonyl chloride is added dropwise, is added dropwise, is stirred to react at 25 DEG C of room temperature, the solvent (volume of EA:PE is added
Than for 1:3), middle control to no raw material, reaction time 1h；After reaction, reaction solution is poured into water, is extracted with ethyl acetate two
It is secondary, merge organic phase；It is washed till water layer PH < 7 with 2N HCl, is washed with water and washs twice, after anhydrous magnesium sulfate drying, be concentrated into
It is poured into ethyl alcohol after oily, crystallization obtains -2 tolyloxy-benzenesulfonamide of 5- methoxyl group (- 2 tolyloxy-benzenesulfonamide of 5- methoxyl group
Quality is 266.93g, purity 99.328%, yield 90.39%).
Embodiment 4
(1) -2 nitrophenol of 169g 4- methoxyl group is dissolved in the mixed solution of 70% ethyl alcohol of 1500ml and 40ml 4N HCl
In, reaction solution is warming up to 70 DEG C；Then 168g iron powder is uniformly added in 20min in three batches into reaction solution.Quickly it is stirred to react,
It is middle to control to no raw material.Saturated solution of sodium carbonate tune PH=8 are added after reaction, obtain 2- amino-4-methoxyl phenol.
(2) 78.4g powdered potassium hydroxide is added in the 2- amino-4-methoxyl phenol prepared in (1) and is stirred, 155
It is heated 3 hours at DEG C, fully reacting obtains dry salt；1.26g copper powder, 172.7g bromobenzene are sequentially added thereto, are stirred at 170 DEG C
It mixes to discoloration, is warming up to 195 DEG C, heat 1.5 hours.After cooling, 1200ml water and 300ml ether are poured into, distillation obtains 3- ammonia
Base -4- phenoxy group-methyl phenyl ethers anisole.
(3) the 3- amino -4- phenoxy group-methyl phenyl ethers anisole prepared in (2) is dissolved in 800ml anhydrous pyridine, solution cooling
To 3 DEG C, 126g methylsufonyl chloride is added dropwise.It is added dropwise, is stirred to react at 28 DEG C of room temperature, the solvent (volume ratio of EA:PE is added
For 1:3), middle control to no raw material, reaction time 1.2h.After reaction, reaction solution is poured into water, is extracted with ethyl acetate two
It is secondary, merge organic phase；It is washed till water layer PH < 7 with 2N HCl, is washed with water and washs twice, it is dry with anhydrous magnesium sulfate, it is concentrated into oil
After shape, pours into ethyl alcohol and crystallize to obtain -2 tolyloxy-benzenesulfonamide of 5- methoxyl group (- 2 tolyloxy-benzenesulfonamide quality of 5- methoxyl group
For 272.61g, purity 99.606%, yield 92.57%).
Embodiment 5
(1) -2 nitrophenol of 169g 4- methoxyl group is dissolved in 1500ml70% ethyl alcohol and the mixed solution of 40ml 4N HCl,
Reaction solution is warming up to 75 DEG C；Then 196g iron powder is uniformly added in 20min in three batches into reaction solution.Quickly it is stirred to react, in
It controls to no raw material.After reaction, saturated solution of sodium carbonate tune PH=9 are added, obtain 2- amino-4-methoxyl phenol.
(2) the powdered potassium hydroxide 84g prepared in (1) is added in 2- amino-4-methoxyl phenol and is stirred, 160 DEG C
Lower heating 3.5 hours, fully reacting obtains dry salt；1.89g copper powder, 188.4g bromobenzene are sequentially added thereto, are stirred at 180 DEG C
It mixes to discoloration, is warming up to 200 DEG C, heat 2 hours.After cooling, 1200ml water and 300ml ether are poured into, distillation obtains 3- amino-
4- phenoxy group-methyl phenyl ethers anisole.
(3) the 3- amino -4- phenoxy group-methyl phenyl ethers anisole prepared in (2) is dissolved in 800ml anhydrous pyridine, solution cooling
To 5 DEG C, 137.5g methylsufonyl chloride is added dropwise.It is added dropwise, is stirred to react at 30 DEG C of room temperature, the solvent (volume of EA:PE is added
Than for 1:3), middle control to no raw material, reaction time 1.5h.After reaction, reaction solution is poured into water, is extracted with ethyl acetate
Twice, merge organic phase；It is washed till water layer PH < 7 with 2N HCl, is washed with water and washs twice, it is dry with anhydrous magnesium sulfate, it is concentrated into
After oily, pours into ethyl alcohol and crystallize to obtain -2 tolyloxy-benzenesulfonamide of 5- methoxyl group (- 2 tolyloxy-benzenesulfonamide matter of 5- methoxyl group
Amount is 276.47g, purity 99.658%, yield 93.93%).
Fig. 2 is -2 tolyloxy-benzenesulfonamide chromatograms of 5- methoxyl group of embodiment 3.
Fig. 3 is -2 tolyloxy-benzenesulfonamide chromatograms of 5- methoxyl group of embodiment 4.
Fig. 4 is -2 tolyloxy-benzenesulfonamide chromatograms of 5- methoxyl group of embodiment 5.
Embodiment 6
- 2 benzene of 5- methoxyl group that the present embodiment 6 is prepared from the synthetic method of purity, yield etc. Comprehensive Correlation embodiment 3-5
Oxygroup-benzsulfamide, specific as follows:
As shown in Fig. 2, according to -2 tolyloxy-benzenesulfonamide of 5- methoxyl group prepared by embodiment 3, peak height in chromatograms
It is 3505571, corresponding retention time is 4.819min, and can calculate it to go out purity is 99.328%；According to raw material usage amount,
The yield that -2 tolyloxy-benzenesulfonamide of 5- methoxyl group may further be obtained is 90.39%.
As shown in figure 3, according to -2 tolyloxy-benzenesulfonamide of 5- methoxyl group prepared by embodiment 4, peak value in chromatograms
Height is 3436564, and corresponding retention time is 4.829min, and can calculate its purity is 99.606%；It is used according to raw material
Amount, the yield that may further obtain -2 tolyloxy-benzenesulfonamide of 5- methoxyl group is 92.57%.
As shown in figure 4, according to -2 tolyloxy-benzenesulfonamide of 5- methoxyl group prepared by embodiment 5, peak value in chromatograms
Height is 3193674, and corresponding retention time is 5.287min, and can calculate its purity is 99.658%；It is used according to raw material
Amount, the yield that may further obtain -2 tolyloxy-benzenesulfonamide of 5- methoxyl group is 93.93%.
Therefore, in the synthetic method of the application, purity, yield and the synthesis of -2 tolyloxy-benzenesulfonamide of 5- methoxyl group
Factors in method are in relation to the relevant parameter (such as additive amount of reacting liquid temperature, iron powder, pH value) of reduction；Ullmann
Relevant parameter (dosage, acid extraction, the dosage of copper powder, the dosage of bromobenzene, the stirring temperature of such as potassium hydroxide of reaction
Degree, heating value and heating time etc.)；Relevant parameter (the dropwise addition of the dosage, methylsufonyl chloride of such as anhydrous pyridine of Mesylation
Amount, whipping temp and reaction time etc.).
The main component dosage of the synthetic method of 1 the application of table
Table 1 is the main component dosage of the synthetic method of the application.Fig. 2, Fig. 3, Fig. 4 are combined by table 1, it can be deduced that following knot
By:
(1) addition of the purity, yield and iron powder of -2 tolyloxy-benzenesulfonamide of 5- methoxyl group of the synthetic method preparation of the application
Amount is positively correlated.
(2) purity, yield and the hydroxide of -2 tolyloxy-benzenesulfonamide of 5- methoxyl group of the synthetic method preparation of the application
The dosage positive correlation of potassium, bromobenzene, copper powder.
(3) purity, yield and the methyl sulphur of -2 tolyloxy-benzenesulfonamide of 5- methoxyl group of the synthetic method preparation of the application
The dosage of acyl chlorides is positively correlated.
In conclusion synthetic method of the invention is that Material synthesis Ailamode is crucial using -2 nitrophenol of 4- methoxyl group
Intermediate, instead of 4- chlorine-3-nitroanisole in the prior art, raw material is easier to obtain, convenient for industrialization；It is leading using iron powder
Nitro is restored, then replaces etherification reaction in the prior art with ullmann reaction, passes through control reduction, Ullmann
The relevant parameter of reaction and Mesylation, is concentrated to get product, purity can be improved to 99.6%, and yield can be improved
93.93%；Have many advantages, such as that at low cost, yield is high, with high purity, is suitble to large-scale industrial production.
Taking the above-mentioned ideal embodiment according to the present invention as inspiration, through the above description, relevant staff is complete
Various changes and amendments can be carried out without departing from the scope of the technological thought of the present invention' entirely.The technology of this invention
Property range is not limited to the contents of the specification, it is necessary to which the technical scope thereof is determined according to the scope of the claim.
Claims (10)
1. a kind of synthetic method of Ailamode key intermediate characterized by comprising
Reduction prepares 2- amino-4-methoxyl phenol using -2 nitrophenol of 4- methoxyl group；
Ullmann reaction, i.e., prepare 3- amino -4- phenoxy group-methyl phenyl ethers anisole by 2- amino-4-methoxyl phenol；And
Mesylation prepares -2 tolyloxy-benzenesulfonamide of 5- methoxyl group by 3- amino -4- phenoxy group-methyl phenyl ethers anisole.
2. synthetic method according to claim 1, which is characterized in that
The reduction includes:
- 2 nitrophenol of 4- methoxyl group is reacted with solvent, mixed in hydrochloric acid；
Iron powder is added into reaction solution；And
PH is adjusted to which saturated solution of sodium carbonate after reaction, is added, obtains the 2- amino-4-methoxyl phenol.
3. synthetic method according to claim 2, which is characterized in that
The molar ratio of -2 nitrophenol of 4- methoxyl group and iron powder is 1:2.5-3.5.
4. synthetic method according to claim 2, which is characterized in that
The solvent is one or more of methanol, ethyl alcohol.
5. synthetic method according to claim 1, which is characterized in that
The Ullmann reacts
Potassium hydroxide is added in the 2- amino-4-methoxyl phenol, is reacted；
Copper powder, bromobenzene are sequentially added into reaction product, and are heated；
It is cooled and poured into water and ether；And
Distillation, obtains the 3- amino -4- phenoxy group-methyl phenyl ethers anisole.
6. synthetic method according to claim 5, which is characterized in that
The 2- amino-4-methoxyl phenol, potassium hydroxide, bromobenzene, copper powder molar ratio be followed successively by 1:1.2-1.5:1-
1.2:0.01-0.03.
7. synthetic method according to claim 1, which is characterized in that
The Mesylation includes:
3- amino -4- phenoxy group-the methyl phenyl ethers anisole is dissolved in anhydrous pyridine, and is cooled to 0-5 DEG C；
Methylsufonyl chloride is added dropwise to be reacted；
Extract reaction solution；
Washing, drying, and it is concentrated into oily；And
The grease is poured into ethyl alcohol, crystallization obtains -2 tolyloxy-benzenesulfonamide of 5- methoxyl group.
8. synthetic method according to claim 7, which is characterized in that
The molar ratio of the 3- amino -4- phenoxy group-methyl phenyl ethers anisole and methylsufonyl chloride is 1:1-1.2.
9. synthetic method according to claim 7, which is characterized in that
The reaction solution is suitable for that solvent is added before extraction；
The solvent includes: EA and PE；And
The volume ratio of the two is 1:3.
10. a kind of Ailamode key intermediate, which is characterized in that
The Ailamode key intermediate is suitable for preparing by synthetic method as described in claim 1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4954518A (en) * | 1987-10-08 | 1990-09-04 | Toyama Chemical Company, Ltd. | 4H-1-benzopyran-4-one derivative or its salt, process for producing the same and pharmaceutical composition comprising the same as active ingredient |
| CN102807515A (en) * | 2012-09-04 | 2012-12-05 | 江苏昊华精细化工有限公司 | Method for synthesizing 3-methylsulfonylamido-4-phenoxy-6-(N-formyl)amidoacetylphenol |
-
2019
- 2019-02-26 CN CN201910141524.5A patent/CN109705000A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4954518A (en) * | 1987-10-08 | 1990-09-04 | Toyama Chemical Company, Ltd. | 4H-1-benzopyran-4-one derivative or its salt, process for producing the same and pharmaceutical composition comprising the same as active ingredient |
| CN102807515A (en) * | 2012-09-04 | 2012-12-05 | 江苏昊华精细化工有限公司 | Method for synthesizing 3-methylsulfonylamido-4-phenoxy-6-(N-formyl)amidoacetylphenol |
Non-Patent Citations (3)
| Title |
|---|
| CHENGLING ZHANG ET AL.: "A Cu Nanoparticle Embedded in Electrospundoped Carbon Nanofibers as Efficient Catalysts for Ullmann O-Arylation of Aryl Halides with Various Phenols", 《CATALYSIS LETTERS》 * |
| YANFENG SUN ET AL.: "Synthesis of Br7-Br9 hydroxylated/methoxylated polybrominated diphenyl ethers (OH/MeO-PBDEs) and analyses on mass spectra and GC data of the MeO-PBDEs", 《CHEMOSPHERE》 * |
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