CN109400507A - The synthesis of Ailamode intermediate impurities - Google Patents
The synthesis of Ailamode intermediate impurities Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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Abstract
The invention discloses a kind of synthetic methods of Ailamode intermediate impurities, belong to chemicals synthesis field.The present invention is to obtain the iodo- 4- phenoxy group-methyl phenyl ethers anisole of 3- by sandmeyer reaction iodo, then obtain 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole through catalysed reaction of copper using intermediate 5- methoxyl group -2- phenoxybenzamine as starting material.It is of the invention mainly to have many advantages, such as that step is simple, high income, good product purity, it controls for the quality of the research of the impurity of Ailamode and its intermediate and final finished and provides help.
Description
Technical field
The invention belongs to chemicals synthesis technical fields, more specifically to a kind of antirheumatic new drug Ailamode
Key intermediate impurity 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole synthesis.
Background technique
Ailamode is a kind of non-steroid anti-inflammatory drug, by Japan folic hill and Wei Cai drugmaker cooperative research and development, chemical name
It is a kind of novel resist for N- [3- (formamido) -4- oxygen -6- phenoxy group -4H-1- chromene -7- base] Methanesulfomide (1)
Rheumatism small-molecule drug.The synthesis of existing document report Ailamode is with 4- chlorine-3-nitroanisole (2) for raw material, through 7
Step reaction obtains, as shown in reaction equation process type 1.Wherein, 3- methylsulfonyl amido -4- phenoxy group methyl phenyl ethers anisole (4) is among key
Body.But a kind of process impurity 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole is also easy to produce in its preparation process
(5), which can participate in subsequent reactions, ultimately generate the impurity of finished product (1), i.e. N- [3- (formamido) -4- oxygen -6- benzene oxygen
Base -4H-1- benzene well pyrans -7- base] two Methanesulfomides (6), and influence the purity of finished product.In order to carry out Ailamode intermediate and
The research of finished product impurity, and establish quality standard and carry out final product quality control, it needs to intermediate impurities 3- (bis- methylsulfonyl of N, N-
Base) it is prepared by amido -4- phenoxy group methyl phenyl ethers anisole (5), and mesyl chloride is directlyed adopt to 3- methylsulfonyl amido -4- phenoxy group benzene
The preparation method that methyl ether (4) is replaced can not obtain the enough products of purity because separating difficulty.Therefore, develop a kind of efficient
The new method of intermediate impurities 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole (5) is prepared to this process impurity
The control of the quality of research and target product (1) is particularly important.
Summary of the invention
In view of the above technical problems existing in the prior art, the present invention provides one kind by intermediate 5- methoxyl group -2- benzene oxygen
Base aniline (3) is the method that starting material prepares 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole (5).The preparation
Method and step is simple, high income, purity are good, provides for the research of the impurity of Ailamode and its intermediate and final product quality control
It helps.
It is described that technical scheme is as follows:
The present invention provides a kind of Ailamode intermediate impurities 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole
Synthetic method, this method with intermediate 5- methoxyl group -2- phenoxybenzamine (3) be starting material, pass through sandmeyer reaction
Iodo obtains the iodo- 4- methoxyl group of 3--methyl phenyl ethers anisole (7), then obtains 3- (N, N- dimesyl) amido -4- benzene through catalysed reaction of copper
Oxygroup methyl phenyl ethers anisole (5).
A synthetic route of the invention is as shown in reaction process formula 2.
Technical solution of the present invention is reacted in two steps, and specific preparation process is as follows:
Step 1: the synthesis of compound (7), i.e. sandmeyer reaction:
5- methoxyl group -2- phenoxybenzamine and p-methyl benzenesulfonic acid are dissolved in acetonitrile, sodium nitrite and iodine are added dropwise at room temperature
The aqueous solution for changing potassium is simultaneously stirred to fully reacting, using obtaining the iodo- 4- methoxyl group-benzene of 3- after extraction, cleaning, drying and suction filtration
Methyl ether.Wherein the molar ratio of 5- methoxyl group -2- phenoxybenzamine, p-methyl benzenesulfonic acid, sodium nitrite and potassium iodide is 1:3:2:2.
Above-mentioned last handling process specifically includes: into reaction solution plus after water, being extracted with methyl tertiary butyl ether(MTBE), then with quality hundred
Score is the washing of 10% hypo solution, and dry with anhydrous sodium sulfate, and finally by filtering, filtrate is concentrated to get 3-
Iodo- 4- methoxyl group-methyl phenyl ethers anisole crude product.
Step 2: the synthesis of compound (5), i.e. catalysed reaction of copper:
Dimethanesulfonyl amine is dissolved in solvent, the iodo- 4- methoxyl group of 3--methyl phenyl ethers anisole (7) is added, catalyst, catalyst is matched
Body, acid binding agent, under nitrogen protection, heating reaction.It is cooled to room temperature after reaction, obtains 3- through filtering, cleaning, drying, suction filtration
(N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole.
Above-mentioned last handling process specifically includes: filtering after ethyl acetate is added into reaction solution, filter cake is washed through ethyl acetate
It washs, saturated common salt water washing, anhydrous sodium sulfate is dry, filters, and last filtrate is concentrated to get 3- (N, N- dimesyl) amido-
4- phenoxy group methyl phenyl ethers anisole crude product.
In above-mentioned second step solvent be DMSO, DMF, dimethylbenzene, one of NMP, preferably DMF, one of DMSO,
Most preferably DMSO.
Catalyst is copper catalyst in above-mentioned second step, and copper catalyst is Cu (OAc)2, Cu (OAc)2·H2O, CuSO4,
CuBr2One of, preferably Cu (OAc)2, Cu (OAc)2·H2One of O, most preferably Cu (OAc)2·H2O。
Preferable yield in order to obtain needs that catalyst ligand, catalyst ligand DMEDA, 8- hydroxyl is added in preparation
Quinoline, one of 1,10- phenanthroline, most preferably 1,10- phenanthroline.
For the acid generated in neutralization reaction, acid binding agent, acid binding agent K are added in preparation2CO3, K3PO4, Cs2CO3In
One kind, most preferably K2CO3。
Reaction temperature is 100~120 DEG C in above-mentioned second step, and most preferably 100 DEG C, the reaction time is 5~12h, most preferably
8h。
The iodo- 4- methoxyl group-methyl phenyl ethers anisole of reaction raw materials 3-, dimethanesulfonyl amine, copper catalyst, catalyst ligand, acid binding agent
Molar ratio be 1:1.0~1.3:0.04~0.16:0.1~0.3:1.6~2.2, most preferably 1:1.2:0.1:0.2:2.
It is had the following beneficial effects: compared with existing well-known technique using technical solution provided by the invention
(1) present invention, which provides, a kind of prepares Ailamode intermediate impurities 3- (N, N- dimesyl) amido -4- benzene oxygen
The variation route of base methyl phenyl ethers anisole, this route are obtained by two-step reaction, i.e., pass through by raw material of intermediate 5- methoxyl group -2- phenoxybenzamine
It is available through catalysed reaction of copper again after iodide reaction.
(2) route that the present invention designs can directly obtain higher degree using 5- methoxyl group -2- phenoxybenzamine as raw material
Intermediate impurities (5), content >=98.0%, be conducive to Ailamode intermediate quality controling research and final product quality control
Research.And the method for using mesyl chloride to replace 3- methylsulfonyl amido -4- phenoxy group methyl phenyl ethers anisole (4) it is difficult because separating due to
The impurity (5) that high-purity can not be prepared also is unable to satisfy the requirement of finished product impurity research.
(3) high income of Ailamode intermediate impurities (5) made from the route that the present invention uses, purity is good, draws Chinese mugwort
Subsequent miscellaneous Quality Research is not of great significance in moral synthesis technology.
Detailed description of the invention
Fig. 1 schemes for the H-NMR of intermediate impurities (5) obtained in the embodiment of the present invention；
Fig. 2 is intermediate impurities (5) obtained in the embodiment of the present invention13C-NMR figure.
Specific embodiment
The present invention will be further described with reference to the examples below.
Embodiment 1
Step 1: the preparation of the iodo- 4- methoxyl group of 3--methyl phenyl ethers anisole (7):
4.6mmol 5- methoxyl group -2- phenoxybenzamine and 13.9mmol p-methyl benzenesulfonic acid are taken, adds 40mL acetonitrile to dissolve, room
The lower aqueous solution 10mL that sodium nitrite containing 9.2mmol and 9.2mmol potassium iodide is added dropwise of temperature.It is stirred at room temperature 5 hours, TLC monitoring is anti-
It should be complete.Add water 50mL, is extracted, washed with 10% hypo solution, anhydrous slufuric acid with methyl tertiary butyl ether(MTBE) (30mL × 2)
Sodium is dry.It filters, filtrate is concentrated to give crude product.Column chromatographic purifying (petroleum ether: ethyl acetate=10:1 elution) obtains light yellow oil
Shape object 0.97g, yield 65.2%.1H-NMR(600MHz,CDCl3) δ: 7.38 (dd, 1H, J=2.4Hz, Ar-H), 7.15-7.18
(m, 1H, Ar-H), 6.87 (d, 4H, J=2.7Hz, Ar-H), 6.85 (d, 1H, J=2.0Hz, Ar-H), 6.83 (d, 1H, J=
1.5Hz,Ar-H),3.81(s,3H,-OCH3)。
Step 2: the preparation of intermediate impurities 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole (5):
2.9mmol dimethanesulfonyl amine is dissolved in 5mL solvent DMSO, the iodo- 4- methoxyl group-benzene first of 2.5mmol 3- is added
Ether, 0.25mmol Cu (OAc)2·H2O, 0.5mmol 1,10- phenanthroline, 5.0mmol potassium carbonate, nitrogen protection are heated to 100
DEG C heat preservation 8 hours, TLC monitor fully reacting.It is cooled to room temperature, ethyl acetate 20mL, filtering is added, filter cake is washed with ethyl acetate
It washs, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.It filters, filtrate is concentrated to give crude product.Column chromatographs (petroleum
Ether: ethyl acetate=3:1 elution) white solid, yield 85.2% are obtained, purity is 98.2% (HPLC area normalization
Method).M.p.136~137 DEG C,1H-NMR(600MHz,DMSO-d6),δ:7.39-7.42(m,2H,Ar-H),7.21(s,1H,Ar-
), H 7.15-7.18 (m, 1H, Ar-H), 7.05-7.08 (m, 3H, Ar-H), 6.89 (d, 1H, J=12.0Hz, Ar-H), 3.80
(s,3H,-OCH3),3.52(s,6H,-N(SO2CH3)2).13C-NMR(600MHz,DMSO-d6),δ:156.85(C),155.50
(C),149.23(C),130.55(CH),125.80(C),124.40(CH),119.99(CH),119.19(CH),118.38
(CH),117.76(CH),56.37(CH3),44.07(CH3), it is consistent with the structure of intermediate impurities.ESI-MS,m/z:372.7
[M+H]+。
Embodiment 2
Step 1: the preparation of the iodo- 4- methoxyl group of 3--methyl phenyl ethers anisole (7) is identical as the first step in embodiment 1.
Step 2: the preparation of intermediate impurities 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole (5):
2.2mmol dimethanesulfonyl amine is dissolved in 4mL solvent xylene, the iodo- 4- methoxyl group-benzene first of 2mmol3- is added
Ether, 0.2mmol Cu (OAc)2, 0.4mmol 1,10- phenanthroline, 4mmol potassium carbonate, nitrogen protection, be heated to 120 DEG C heat preservation 5
Hour, TLC monitors fully reacting.It is cooled to room temperature, ethyl acetate 20mL, filtering is added, filter cake is washed with ethyl acetate, is merged
Organic phase, saturated common salt water washing, anhydrous sodium sulfate are dry.It filters, filtrate is concentrated to give crude product.Column chromatographs (petroleum ether: acetic acid second
Ester=3:1 elution) obtain white solid, yield 68%.
Embodiment 3
Step 1: the preparation of the iodo- 4- methoxyl group of 3--methyl phenyl ethers anisole (7) is identical as the first step in embodiment 1.
Step 2: the preparation of intermediate impurities 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole (5):
2.4mmol dimethanesulfonyl amine is dissolved in 3mL solvent DMSO, the iodo- 4- methoxyl group-benzene first of 2mmol 3- is added
Ether, 0.2mmol Cu (OAc)2·H2O, 0.4mmol 1,10- phenanthroline, 4mmol potassium carbonate, nitrogen protection are heated to 120 DEG C
Heat preservation 5 hours, TLC monitor fully reacting.It is cooled to room temperature, ethyl acetate 20mL, filtering is added, filter cake is washed with ethyl acetate
It washs, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.It filters, filtrate is concentrated to give crude product.Column chromatographs (petroleum
Ether: ethyl acetate=3:1 elution) obtain white solid, yield 72%.
Embodiment 4
Step 1: the preparation of the iodo- 4- methoxyl group of 3--methyl phenyl ethers anisole (7) is identical as the first step in embodiment 1.
Step 2: the preparation of intermediate impurities 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole (5):
2.4mmol dimethanesulfonyl amine is dissolved in 3mL solvent DMSO, the iodo- 4- methoxyl group-benzene first of 2mmol 3- is added
Ether, 0.2mmol Cu (OAc)2·H2O, 0.4mmol 1,10- phenanthroline, 4mmol potassium carbonate, nitrogen protection are heated to 100 DEG C
Heat preservation 8 hours, TLC monitor fully reacting.It is cooled to room temperature, ethyl acetate 20mL, filtering is added, filter cake is washed with ethyl acetate
It washs, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.It filters, filtrate is concentrated to give crude product.Column chromatographs (petroleum
Ether: ethyl acetate=3:1 elution) obtain white solid, yield 86%.
Embodiment 5
Step 1: the preparation of the iodo- 4- methoxyl group of 3--methyl phenyl ethers anisole (7) is identical as the first step in embodiment 1.
Step 2: the preparation of intermediate impurities 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole (5):
2.4mmol dimethanesulfonyl amine is dissolved in 4mL solvent NMP, the iodo- 4- methoxyl group-methyl phenyl ethers anisole of 2mmol 3- is added,
0.2mmol Cu(OAc)2·H2O, 0.4mmol 1,10- phenanthroline, 4mmol potassium carbonate, nitrogen protection are heated to 100 DEG C of heat preservations
8 hours, TLC monitored fully reacting.It is cooled to room temperature, ethyl acetate 20mL, filtering is added, filter cake is washed with ethyl acetate, is closed
And organic phase, saturated common salt water washing, anhydrous sodium sulfate are dry.It filters, filtrate is concentrated to give crude product.Column chromatographs (petroleum ether: acetic acid
Ethyl ester=3:1 elution) obtain white solid, yield 72%.
Embodiment 6
Step 1: the preparation of the iodo- 4- methoxyl group of 3--methyl phenyl ethers anisole (7) is identical as the first step in embodiment 1.
Step 2: the preparation of intermediate impurities 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole (5):
2.4mmol dimethanesulfonyl amine is dissolved in 5mL solvent xylene, the iodo- 4- methoxyl group-benzene of 2.1mmol 3- is added
Methyl ether, 0.2mmol CuBr2, 4mmol potassium carbonate, nitrogen protection, be heated to 120 DEG C keep the temperature 5 hours, TLC monitor fully reacting.
It is cooled to room temperature, ethyl acetate 20mL, filtering is added, filter cake is washed with ethyl acetate, merges organic phase, saturated common salt washing
It washs, anhydrous sodium sulfate is dry.It filters, filtrate is concentrated to give crude product.Column chromatography (petroleum ether: ethyl acetate=3:1 elution) obtains white
Color solid, yield 16%.
Embodiment 7
Step 1: the preparation of the iodo- 4- methoxyl group of 3--methyl phenyl ethers anisole (7) is identical as the first step in embodiment 1.
Step 2: the preparation of intermediate impurities 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole (5):
2.4mmol dimethanesulfonyl amine is dissolved in 4mL solvent xylene, the iodo- 4- methoxyl group-benzene first of 2mmol 3- is added
Ether, 0.2mmol Cu (OAc)2, 0.4mmol DMEDA, 4mmol potassium carbonate, nitrogen protection, be heated to 120 DEG C keep the temperature 5 hours,
TLC monitors fully reacting.It is cooled to room temperature, ethyl acetate 20mL, filtering is added, filter cake is washed with ethyl acetate, is merged organic
Phase, saturated common salt water washing, anhydrous sodium sulfate are dry.It filters, filtrate is concentrated to give crude product.Column chromatography (petroleum ether: ethyl acetate=
3:1 elution) obtain white solid, yield 56%.
Embodiment 8
Step 1: the preparation of the iodo- 4- methoxyl group of 3--methyl phenyl ethers anisole (7) is identical as the first step in embodiment 1.
Step 2: the preparation of intermediate impurities 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole (5):
2.6mmol dimethanesulfonyl amine is dissolved in 5mL solvent DMF, the iodo- 4- methoxyl group-methyl phenyl ethers anisole of 2mmol3- is added,
0.2mmol Cu(OAc)2·H2O, 0.4mmol 1,10- phenanthroline, 4mmol potassium carbonate, nitrogen protection are heated to 100 DEG C of heat preservations
8 hours, TLC monitored fully reacting.It is cooled to room temperature, ethyl acetate 20mL, filtering is added, filter cake is washed with ethyl acetate, is closed
And organic phase, saturated common salt water washing, anhydrous sodium sulfate are dry.It filters, filtrate is concentrated to give crude product.Column chromatographs (petroleum ether: acetic acid
Ethyl ester=3:1 elution) obtain white solid, yield 78%.
Embodiment 9
Step 1: the preparation of the iodo- 4- methoxyl group of 3--methyl phenyl ethers anisole (7) is identical as the first step in embodiment 1.
Step 2: the preparation of intermediate impurities 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole (5):
2.4mmol dimethanesulfonyl amine is dissolved in 4mL solvent xylene, the iodo- 4- methoxyl group-benzene first of 2mmol 3- is added
Ether, 0.2mmol Cu (OAc)2·H2O, 0.4mmol 1,10- phenanthroline, 4mmol cesium carbonate, nitrogen protection are heated to 120 DEG C
Heat preservation 5 hours, TLC monitor fully reacting.It is cooled to room temperature, ethyl acetate 20mL, filtering is added, filter cake is washed with ethyl acetate
It washs, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.It filters, filtrate is concentrated to give crude product.Column chromatographs (petroleum
Ether: ethyl acetate=3:1 elution) obtain white solid, yield 65%.
Embodiment 10
Step 1: the preparation of the iodo- 4- methoxyl group of 3--methyl phenyl ethers anisole (7) is identical as the first step in embodiment 1.
Step 2: the preparation of intermediate impurities 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole (5):
2mmol dimethanesulfonyl amine is dissolved in 4mL solvent DMSO, the iodo- 4- methoxyl group-methyl phenyl ethers anisole of 2mmol 3- is added,
0.08mmol CuSO4, 0.2mmol 8-hydroxyquinoline, 3.2mmol potassium carbonate, it is 5 small to be heated to 120 DEG C of heat preservations nitrogen protection
When, TLC monitors fully reacting.It is cooled to room temperature, ethyl acetate 20mL, filtering is added, filter cake is washed with ethyl acetate, is associated with
Machine phase, saturated common salt water washing, anhydrous sodium sulfate are dry.It filters, filtrate is concentrated to give crude product.Column chromatographs (petroleum ether: ethyl acetate
=3:1 elution) obtain white solid, yield 35%.
Embodiment 11
Step 1: the preparation of the iodo- 4- methoxyl group of 3--methyl phenyl ethers anisole (7) is identical as the first step in embodiment 1.
Step 2: the preparation of intermediate impurities 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole (5):
2.6mmol dimethanesulfonyl amine is dissolved in 4mL solvent xylene, the iodo- 4- methoxyl group-benzene first of 2mmol 3- is added
Ether, 0.32mmol Cu (OAc)2·H2O, 0.6mmol 1,10- phenanthroline, 4.4mmol tripotassium phosphate, nitrogen protection are heated to
120 DEG C keep the temperature 12 hours, and TLC monitors fully reacting.It is cooled to room temperature, ethyl acetate 20mL is added, filtering, filter cake is with acetic acid second
Ester washing merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.It filters, filtrate is concentrated to give crude product.Column chromatographs (stone
Oily ether: ethyl acetate=3:1 elution) obtain white solid, yield 62%.
Schematically the present invention and embodiments thereof are described above, description is not limiting, institute in attached drawing
What is shown is also one of embodiments of the present invention, and actual structure is not limited to this.So if the common skill of this field
Art personnel are enlightened by it, without departing from the spirit of the invention, without creatively designing and the technical solution
Similar embodiment, is within the scope of protection of the invention.
Claims (10)
1. a kind of synthetic method of Ailamode intermediate impurities 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole,
Characterized by comprising the following steps:
Using intermediate 5- methoxyl group -2- phenoxybenzamine as starting material, the iodo- 4- benzene of 3- is obtained by sandmeyer reaction iodo
Oxygroup-methyl phenyl ethers anisole, then 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole is obtained through catalysed reaction of copper.
2. the synthetic method of intermediate impurities according to claim 1, it is characterised in that: the sandmeyer reaction step
It is rapid as follows:
5- methoxyl group -2- phenoxybenzamine and p-methyl benzenesulfonic acid are dissolved in acetonitrile, sodium nitrite and potassium iodide are added dropwise at room temperature
Aqueous solution and stir to fully reacting, using obtaining the iodo- 4- methoxyl group-benzene first of 3- after extraction, cleaning, drying and suction filtration
Ether；
Wherein the molar ratio of 5- methoxyl group -2- phenoxybenzamine, p-methyl benzenesulfonic acid, sodium nitrite and potassium iodide is 1:3:2:2.
3. the synthetic method of intermediate impurities according to claim 2, it is characterised in that: above-mentioned last handling process specifically wraps
It includes:
It into reaction solution plus after water, is extracted with methyl tertiary butyl ether(MTBE), then is washed with mass percent for 10% hypo solution
It washs, and dry with anhydrous sodium sulfate, finally by filtering, filtrate is concentrated to get the iodo- 4- methoxyl group-methyl phenyl ethers anisole crude product of 3-.
4. the synthetic method of intermediate impurities according to claim 1, it is characterised in that: the catalysed reaction of copper step
It is as follows:
Dimethanesulfonyl amine is dissolved in solvent, the iodo- 4- methoxyl group-methyl phenyl ethers anisole of 3- is added, catalyst, catalyst ligand, ties up acid
Agent, under nitrogen protection, heating reaction；It is cooled to room temperature after reaction, obtains 3- (N, N- bis- through filtering, cleaning, drying, suction filtration
Mesyl) amido -4- phenoxy group methyl phenyl ethers anisole.
5. the synthetic method of intermediate impurities according to claim 4, it is characterised in that: above-mentioned last handling process specifically wraps
It includes:
It is filtered after ethyl acetate is added into reaction solution, filter cake is washed through ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate
It is dry, it filters, last filtrate is concentrated to get 3- (N, N- dimesyl) amido -4- phenoxy group methyl phenyl ethers anisole crude product.
6. the synthetic method of intermediate impurities according to claim 4, it is characterised in that: the solvent is DMSO,
DMF, dimethylbenzene, one of NMP；The catalyst is Cu (OAc)2, Cu (OAc)2·H2O, CuSO4, CuBr2In one
Kind；The acid binding agent is K2CO3, K3PO4, Cs2CO3One of；The catalyst ligand be DMEDA, 8-hydroxyquinoline,
One of 1,10- phenanthroline.
7. the synthetic method of intermediate impurities according to claim 7, it is characterised in that: the solvent is DMF, DMSO
One of；The catalyst is Cu (OAc)2, Cu (OAc)2·H2One of O；The acid binding agent is K2CO3；It is described
Catalyst ligand is 1,10- phenanthroline.
8. the synthetic method of intermediate impurities according to claim 7, it is characterised in that: the solvent is DMSO；Institute
The catalyst stated is Cu (OAc)2·H2O。
9. the synthetic method of intermediate impurities according to claim 4, it is characterised in that: the reaction temperature is 100
~120 DEG C, the reaction time is 5~12h；The iodo- 4- methoxyl group-methyl phenyl ethers anisole of the 3-, dimethanesulfonyl amine, copper catalyst, catalysis
Agent ligand, acid binding agent molar ratio be 1:1.0~1.3:0.04~0.16:0.1~0.3:1.6~2.2.
10. the synthetic method of intermediate impurities according to claim 9, it is characterised in that: reaction temperature is 100 DEG C, instead
It is 8h between seasonable；The 3- iodo- 4- methoxyl group-methyl phenyl ethers anisole, dimethanesulfonyl amine, copper catalyst, catalyst ligand, acid binding agent
Molar ratio is 1:1.2:0.1:0.2:2.
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| JPWO2021241725A1 (en) * | 2020-05-29 | 2021-12-02 | ||
| WO2021241725A1 (en) * | 2020-05-29 | 2021-12-02 | 富士フイルム富山化学株式会社 | High-purity n-(5-methoxy-2-phenoxyphenyl)methanesulfonamide and method for producing same |
| JP7453365B2 (en) | 2020-05-29 | 2024-03-19 | 富士フイルム富山化学株式会社 | High purity N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide and its production method |
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