CN108912030A - A kind of synthetic method of imrecoxib - Google Patents
A kind of synthetic method of imrecoxib Download PDFInfo
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- CN108912030A CN108912030A CN201810862551.7A CN201810862551A CN108912030A CN 108912030 A CN108912030 A CN 108912030A CN 201810862551 A CN201810862551 A CN 201810862551A CN 108912030 A CN108912030 A CN 108912030A
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- methanesulfonylphenyl
- methylphenyl
- imrecoxib
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- AUODSZBPSARHFZ-LFIBNONCSA-O CC1C=CC(/C=C(\c(cc2)ccc2S(C)(=O)=[OH+])/[N+]([O-])=O)=CC1 Chemical compound CC1C=CC(/C=C(\c(cc2)ccc2S(C)(=O)=[OH+])/[N+]([O-])=O)=CC1 AUODSZBPSARHFZ-LFIBNONCSA-O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
Abstract
A kind of synthetic method of imrecoxib, step：(E) -1- carries out methanesulfonylphenYl -1- nitro -2- p-methylphenyl ethylene with isocyanide yl acetate to condensation and cyclization to react in the system of base reagent and solvent；Obtained 3- p-methylphenyl -4- is subjected to reduction reaction in go back original reagent and the system of solvent to methanesulfonylphenYl pyrroles -2- carboxylate at -78 DEG C；Obtained 3- p-methylphenyl -4- is subjected to oxidation reaction to methanesulfonylphenYl pyrrole-2-aldehyde in the system of hydrogen peroxide and solvent；Obtained 3- p-methylphenyl -4- is subjected to substitution reaction to methanesulfonylphenYl -3- pyrrolidin-2-one and 1- halopropane or hydro carbons sulfonic acid propyl ester derivative in the system of base reagent and solvent, obtains imrecoxib.Simplify and optimize reaction step and technological operation is simple, helps to reduce cost；The impurity of reaction is few, controllable, embodies environmentally protective；Starting material and reagent used are easy to get.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical fields, and in particular to a kind of synthetic method of imrecoxib.
Background technique
Novel C OX-2 selective depressant imrecoxib (Imrecoxib) be Jiangsu Heng Rui company take the lead in independent research at
1.1 kind new medicines of function have obtained national FDA for treating the pain symptom of relief from osteoarthritis and post-surgical inflammation at present
Approval listing.The entitled N- n-propyl -3- p-methylphenyl -4- of its chemistry is to methanesulfonylphenYl -3- pyrrolidin-2-one, chemistry
Structural formula is：
In future certain variation will occur for the fiest-tire medication of osteoarthritis, and specific C OX-2 is (a kind of to cause arthritis
Pain and inflammation Cycloxygenase) inhibitor may replace current paracetamol become osteoarthritis fiest-tire medication.
Future is in the Change Pattern of osteoarthritis fiest-tire medication, so that Ai Rui former times has good market prospects.
Preparation method in relation to imrecoxib has multiple patent reports, and patent CN1134413C, US20040029951 is public
A kind of synthetic route for preparing imrecoxib opened, using 4- mesyl styrene oxide as starting material, through nucleophilic ring opening, acyl
Amination, oxidation and cyclization and etc. obtain imrecoxib, as follows：
The oxidation reaction being directed to uses the oxidants such as Jone ' s reagent or pyridine chromium trioxide, oxidation reaction yield compared with
Low, product is not readily separated purifying, and the residual of crome metal will affect the product quality of bulk pharmaceutical chemicals.Patent CN107586268A is above-mentioned
Some compounds are changed on the basis of route, second step selects 4- methylphenyl acetic acid rather than its acyl chlorides reagent, thus uses
Expensive condensing agent such as CDI etc. promotes the reaction to complete, and is unfavorable for the further genralrlization of industrialized production.
Imrecoxib method is prepared disclosed in patent CN102206178B using different synthetic routes, but still with valuableness
Condensing agent carries out condensation reaction, and synthetic route is as follows：
The synthetic route of imrecoxib is prepared disclosed in patent CN104193664B, as follows：
R in formula1、R2For chlorine or bromine, which needs to use highly basic as condensing agent to carry out cyclization, by
Impurity is continuously generated in each step and by-product is more, be unfavorable for post-processing and is purified, it is difficult to reach the quality requirement of bulk pharmaceutical chemicals.
In view of this, it is necessary to explore process flow is short, easy to operate, low in cost, safety and environmental protection and use the Chinese mugwort of suitable industrialized production
The synthetic method of auspicious former times cloth.
Summary of the invention
For the deficiencies in the prior art and defect, the object of the present invention is to provide a kind of synthesis sides of imrecoxib
Method, the technical solution used for：
The synthetic route of imrecoxib：
In formula, R is Me or Et；X be Cl, Br, I,
Specific step is as follows for the synthetic method of imrecoxib：
A) synthesis 3- p-methylphenyl -4- is to methanesulfonylphenYl pyrroles's -2- carboxylate：By (E) -1- to mesyl benzene
Base -1- nitro -2- p-methylphenyl ethylene carries out condensation and cyclization with isocyanide yl acetate in the system of base reagent and solvent and reacts,
3- p-methylphenyl -4- is obtained to methanesulfonylphenYl pyrroles's -2- carboxylate；
B) synthesis 3- p-methylphenyl -4- is to methanesulfonylphenYl pyrrole-2-aldehyde：It will be by 3- that step A) is obtained to first
Base phenyl -4- in go back original reagent and the system of solvent, goes back methanesulfonylphenYl pyrroles -2- carboxylate at -78 DEG C
Original reaction, obtains 3- p-methylphenyl -4- to methanesulfonylphenYl pyrrole-2-aldehyde；
C) synthesis 3- p-methylphenyl -4- is to methanesulfonylphenYl -3- pyrrolidin-2-one：The 3- that will be obtained by step B)
P-methylphenyl -4- carries out oxidation reaction to methanesulfonylphenYl pyrrole-2-aldehyde in the system of hydrogen peroxide and solvent, obtains
3- p-methylphenyl -4- is to methanesulfonylphenYl -3- pyrrolidin-2-one；
D imrecoxib) is synthesized：It will be by 3- p-methylphenyl -4- that step C) is obtained to methanesulfonylphenYl -3- pyrroles
Alkane -2- ketone and 1- halopropane or hydro carbons sulfonic acid propyl ester derivative carry out substitution reaction in the system of base reagent and solvent, obtain
Imrecoxib.
In a specific embodiment of the invention, step A) described in isocyanide yl acetate be isocyanide guanidine-acetic acid first
Ester or isocyano acid B ester；3- p-methylphenyl-the 4- is 3- to methyl to methanesulfonylphenYl pyrroles's -2- carboxylate
Phenyl -4- is to methanesulfonylphenYl pyrroles -2- carboxylate methyl ester or 3- p-methylphenyl -4- to methanesulfonylphenYl pyrroles's -2- carboxylic
Acetoacetic ester；The base reagent is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, uncle
Sodium butoxide, potassium tert-butoxide, 11 carbon -7- alkene of sodium isopropylate, tert-pentyl alcohol potassium or 1,8- diazabicyclo [5.4.0]；Described is molten
Agent is methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, tert-pentyl alcohol, tetrahydrofuran, N,N-dimethylformamide, 2-
Methyltetrahydrofuran, methyl tertiary butyl ether(MTBE) or toluene.
In another specific embodiment of the invention, step A) described in (E) -1- to methanesulfonylphenYl -1-
The molar ratio of nitro -2- p-methylphenyl ethylene, isocyanide yl acetate and base reagent is 1.0: 1.1~1.5: 1.5~2.0.
In another specific embodiment of the invention, step B) described in 3- p-methylphenyl -4- to methylsulfonyl
Base phenylpyrrole -2- carboxylate is for 3- p-methylphenyl -4- to methanesulfonylphenYl pyrroles -2- carboxylate methyl ester or 3- to methylbenzene
Base -4- is to methanesulfonylphenYl pyrroles's -2- carboxylic acid, ethyl ester；The go back original reagent is diisobutyl aluminium hydride or bis- (2- methoxies
Base oxethyl) sodium aluminum hydride；The solvent is methylene chloride, 1,2- dichloroethanes, chloroform, toluene or dimethylbenzene.
In another specific embodiment of the invention, step B) described in 3- p-methylphenyl -4- to methylsulfonyl
The molar ratio of base phenylpyrrole -2- carboxylate and go back original reagent is 1.0: 1.1~1.5.
Of the invention there are one in specific embodiment, step C) described in solvent be methanol, ethyl alcohol, positive third
Alcohol, isopropanol, n-butanol, the tert-butyl alcohol or tert-pentyl alcohol.
In a still more specific embodiment of the invention, step C) described in 3- p-methylphenyl -4- to methylsulphur
Aminosulfonylphenyl pyrrole-2-aldehyde, hydrogen peroxide molar ratio be 1.0: 10.0~100.0.
In an of the invention and then specific embodiment, step D) described in 1- halopropane be n-propyl chloride, 1-
N-Propyl Bromide or 1- iodopropane；The hydro carbons sulfonic acid propyl ester derivative is for methylsulphur propyl propionate, trifluoromethanesulfonic acid propyl ester or to toluene
Sulfonic acid propyl ester；The base reagent is sodium hydride, hydrofining, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, isopropanol
Sodium, tert-pentyl alcohol potassium, sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate or sodium carbonate；The solvent is N, N- dimethyl methyl
Amide, tetrahydrofuran, 2- methyltetrahydrofuran, toluene, methyl tertiary butyl ether(MTBE), acetonitrile or N-Methyl pyrrolidone.
Step D in yet a further embodiment of the present invention) described in 3- p-methylphenyl -4- to first
The molar ratio of sulfonvlphenyl -3- pyrrolidin-2-one, 1- halopropane or hydro carbons sulfonic acid propyl ester derivative and base reagent is 1.0:
1.1~1.5: 1.5~2.0.
Of the invention again and then in a specific embodiment, step A) described in the temperature of condensation and cyclization reaction be
20~35 DEG C, be condensed cyclization reaction time be 12~for 24 hours；Step B) described in reduction reaction time be 2~6h；Step
C the temperature of the oxidation reaction described in) is 20~40 DEG C, and the reaction time is 24~72h；Step D) described in substitution reaction
Temperature be 50~100 DEG C, the reaction time be 12~for 24 hours.
Technical solution provided by the invention has the advantages that：First, relative to prior art, it is significant simplified and excellent
Reaction step is changed and technological operation is simple, has helped to reduce cost；Second, the impurity of reaction is few, controllable, pollution-free produce
It is raw, environmentally protective effect can be embodied；Third, starting material and reagent used are easy to get, bulk pharmaceutical chemicals can be met with mass production
Use demand, be suitable for industrialized production.
Specific embodiment
Technical solution of the present invention is further non-limitingly described in detail below in conjunction with several embodiments.Wherein originate
Raw material (E) -1- can be by by 4- nitromethyla -1- mesyl benzene to methanesulfonylphenYl -1- nitro -2- p-methylphenyl ethylene
Condensation reaction with p-tolyl aldehyde is prepared, referring to document《Tetrahedron Vol.46,No.21,pp.7587-
7598,1990》Related manufacturing processes.
The route of the synthetic method of the imrecoxib of the following examples 1 to 3 is：
In formula, R is Me or Et；X be Cl, Br, I,
Embodiment 1：
A) synthesis 3- p-methylphenyl -4- is to methanesulfonylphenYl pyrroles's -2- carboxylate methyl ester：
(E) -1- is dissolved in isopropanol (300mL) to methanesulfonylphenYl -1- nitro -2- p-methylphenyl ethylene (21.0g), adds
Enter sodium hydroxide (4.0g), stirs and ice bath is cooled to 5~10 DEG C, the isopropanol of Methyl isocyanoacetate (7.2g) is added dropwise
(12mL) solution rises to 30 DEG C of reaction 18h to fully reacting, and after post-treated, gained crude product ethyl alcohol recrystallization obtains 3- to first
Base phenyl -4- is to methanesulfonylphenYl pyrroles's -2- carboxylate methyl ester, off-white powder 23.2g, yield 95%.
B) synthesis 3- p-methylphenyl -4- is to methanesulfonylphenYl pyrrole-2-aldehyde：
3- p-methylphenyl -4- is dissolved in methylene chloride to methanesulfonylphenYl pyrroles -2- carboxylate methyl ester (23.0g)
(350mL) is cooled to -78 DEG C, and the hexane solution of bis- (2- methoxy ethoxy) sodium aluminum hydrides (13.8g) is added dropwise, and heat preservation is anti-
It answers 2h to fully reacting, dilute hydrochloric acid quenching reaction liquid is added dropwise under low temperature, is warmed to room temperature, post-treated, gained crude product ethyl alcohol weight
Crystallization, obtains 3- p-methylphenyl -4- to methanesulfonylphenYl pyrrole-2-aldehyde, off-white powder 17.5g, yield 83%.
C) synthesis 3- p-methylphenyl -4- is to methanesulfonylphenYl -3- pyrrolidin-2-one：
3- p-methylphenyl -4- is dissolved in methanol (300mL) methanesulfonylphenYl pyrrole-2-aldehyde (17.0g), is added dropwise double
Oxygen water (0.50mol), 40 DEG C of reactions are for 24 hours to fully reacting, and after post-treated, gained crude product ethyl alcohol recrystallization obtains 3- to first
Base phenyl -4- is to methanesulfonylphenYl -3- pyrrolidin-2-one, off-white powder 14.9g, yield 91%.
D imrecoxib) is synthesized：
3- p-methylphenyl -4- is dissolved in methyl tertiary butyl ether(MTBE) to methanesulfonylphenYl -3- pyrrolidin-2-one (14.5g)
(250mL) is added potassium tert-butoxide (7.5g), and mixture reflux 1h is down to room temperature, is added dropwise trifluoromethanesulfonic acid propyl ester (9.4g), rises
To 50 DEG C of reactions for 24 hours to fully reacting, after post-treated, gained crude product ethyl alcohol and isopropyl alcohol mixed solvent recrystallization must end
Auspicious former times cloth, off-white powder 14.7g, yield 90%.
Embodiment 2：
A) synthesis 3- p-methylphenyl -4- is to methanesulfonylphenYl pyrroles's -2- carboxylic acid, ethyl ester：
(E) -1- is dissolved in tetrahydrofuran (180mL) to methanesulfonylphenYl -1- nitro -2- p-methylphenyl ethylene (12.0g),
It is added potassium carbonate (9.4g), stirs and ice bath is cooled to 5~10 DEG C, the tetrahydrofuran of isocyano acid B ester (5.6g) is added dropwise
(10mL) solution rises to 35 DEG C of reaction 12h to fully reacting, and after post-treated, gained crude product ethyl alcohol recrystallization obtains 3- to first
Base phenyl -4- is to methanesulfonylphenYl pyrroles's -2- carboxylic acid, ethyl ester, off-white powder 13.5g, yield 93%.
B) synthesis 3- p-methylphenyl -4- is to methanesulfonylphenYl pyrrole-2-aldehyde：
3- p-methylphenyl -4- is dissolved in toluene (180mL) methanesulfonylphenYl pyrroles -2- carboxylic acid, ethyl ester (13.0g), cold
But to -78 DEG C, it is added dropwise the hexane solution of diisobutyl aluminium hydride (6.3g), insulation reaction 4h to fully reacting drips under low temperature
Add dilute hydrochloric acid quenching reaction liquid, be warmed to room temperature, post-treated, gained crude product ethyl alcohol recrystallization obtains -4- pairs of 3- p-methylphenyl
MethanesulfonylphenYl pyrrole-2-aldehyde, off-white powder 9.2g, yield 80%.
C) synthesis 3- p-methylphenyl -4- is to methanesulfonylphenYl -3- pyrrolidin-2-one：
3- p-methylphenyl -4- is dissolved in ethyl alcohol (150mL) methanesulfonylphenYl pyrrole-2-aldehyde (9.0g), is added dropwise double
Oxygen water (1.33mol), 30 DEG C of reaction 40h to fully reacting, after post-treated, gained crude product ethyl alcohol recrystallization obtains 3- to first
Base phenyl -4- is to methanesulfonylphenYl -3- pyrrolidin-2-one, off-white powder 8.5g, yield 98%.
D imrecoxib) is synthesized：
3- p-methylphenyl -4- is dissolved in tetrahydrofuran (150mL) to methanesulfonylphenYl -3- pyrrolidin-2-one (8.0g),
It is added cesium carbonate (14.3g), mixture reflux 1h is down to room temperature, is added dropwise 1- iodopropane (5.4g), rises to 80 DEG C of reaction 16h extremely
Fully reacting, after post-treated, gained crude product ethyl alcohol and isopropyl alcohol mixed solvent recrystallization obtain imrecoxib, off-white color is solid
Body 7.9g, yield 88%.
Embodiment 3：
A) synthesis 3- p-methylphenyl -4- is to methanesulfonylphenYl pyrroles's -2- carboxylate methyl ester：
(E) -1- is dissolved in methanol (100mL) methanesulfonylphenYl -1- nitro -2- p-methylphenyl ethylene (5.6g), is added
1,8- diazabicyclo [5.4.0], 11 carbon -7- alkene (5.4g), is stirred and ice bath is cooled to 5~10 DEG C, and isocyanide guanidine-acetic acid is added dropwise
Methanol (6mL) solution of methyl esters (2.6g) rises to 20 DEG C of reactions for 24 hours to fully reacting, after post-treated, gained crude product ethyl alcohol
Recrystallization, obtains 3- p-methylphenyl -4- to methanesulfonylphenYl pyrroles's -2- carboxylate methyl ester, off-white powder 6.3g, yield
96%.
B) synthesis 3- p-methylphenyl -4- is to methanesulfonylphenYl pyrrole-2-aldehyde：
3- p-methylphenyl -4- is dissolved in chloroform (100mL) methanesulfonylphenYl pyrroles -2- carboxylate methyl ester (6.2g), cold
But to -78 DEG C, it is added dropwise the hexane solution of diisobutyl aluminium hydride (3.6g), insulation reaction 6h to fully reacting drips under low temperature
Add dilute hydrochloric acid quenching reaction liquid, be warmed to room temperature, post-treated, gained crude product ethyl alcohol recrystallization obtains -4- pairs of 3- p-methylphenyl
MethanesulfonylphenYl pyrrole-2-aldehyde, off-white powder 4.4g, yield 78%.
C) synthesis 3- p-methylphenyl -4- is to methanesulfonylphenYl -3- pyrrolidin-2-one：
3- p-methylphenyl -4- is dissolved in isopropanol (80mL) methanesulfonylphenYl pyrrole-2-aldehyde (4.0g), is added dropwise double
Oxygen water (1.17mol), 20 DEG C of reaction 72h to fully reacting, after post-treated, gained crude product ethyl alcohol recrystallization obtains 3- to first
Base phenyl -4- is to methanesulfonylphenYl -3- pyrrolidin-2-one, off-white powder 3.7g, yield 97%.
D imrecoxib) is synthesized：
3- p-methylphenyl -4- is dissolved in N,N-dimethylformamide to methanesulfonylphenYl -3- pyrrolidin-2-one (3.2g)
(60mL) is added sodium hydroxide (0.8g), and mixture reflux 1h is down to room temperature, is added dropwise methylsulphur propyl propionate (2.0g), rises to 100
DEG C reaction 12h is to fully reacting, after post-treated, gained crude product ethyl alcohol and isopropyl alcohol mixed solvent recrystallization, and get Ai Rui former times
Cloth, off-white powder 3.1g, yield 87%.
Claims (10)
1. a kind of synthetic method of imrecoxib, it is characterised in that include the following steps：
A）3- p-methylphenyl -4- is synthesized to methanesulfonylphenYl pyrroles's -2- carboxylate：By (E) -1- to methanesulfonylphenYl -
1- nitro -2- p-methylphenyl ethylene carries out condensation and cyclization with isocyanide yl acetate in the system of base reagent and solvent and reacts, and obtains
To 3- p-methylphenyl -4- to methanesulfonylphenYl pyrroles's -2- carboxylate；
B）3- p-methylphenyl -4- is synthesized to methanesulfonylphenYl pyrrole-2-aldehyde：It will be by step A）Obtained 3- is to methylbenzene
Base -4- in go back original reagent and the system of solvent, carries out restoring at -78 DEG C anti-to methanesulfonylphenYl pyrroles -2- carboxylate
It answers, obtains 3- p-methylphenyl -4- to methanesulfonylphenYl pyrrole-2-aldehyde；
C）3- p-methylphenyl -4- is synthesized to methanesulfonylphenYl -3- pyrrolidin-2-one：It will be by step B）Obtained 3- is to first
Base phenyl -4- carries out oxidation reaction to methanesulfonylphenYl pyrrole-2-aldehyde in the system of hydrogen peroxide and solvent, obtains 3- pairs
Aminomethyl phenyl -4- is to methanesulfonylphenYl -3- pyrrolidin-2-one；
D）Synthesize imrecoxib：It will be by step C）Obtained 3- p-methylphenyl -4- is to methanesulfonylphenYl -3- pyrrolidines -2-
Ketone and 1- halopropane or hydro carbons sulfonic acid propyl ester derivative carry out substitution reaction in the system of base reagent and solvent, obtain Ai Ruixi
Cloth.
2. a kind of synthetic method of imrecoxib according to claim 1, it is characterised in that step A）Described in isocyanide
Yl acetate is Methyl isocyanoacetate or isocyano acid B ester；3- p-methylphenyl-the 4- is to methanesulfonylphenYl
Pyrroles's -2- carboxylate is 3- p-methylphenyl -4- to methanesulfonylphenYl pyrroles -2- carboxylate methyl ester or 3- p-methylphenyl -4-
To methanesulfonylphenYl pyrroles's -2- carboxylic acid, ethyl ester；The base reagent is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, hydrogen
Potassium oxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropylate, tert-pentyl alcohol potassium or 1,8- diazabicyclo
[5.4.0] 11 carbon -7- alkene；The solvent be methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, tert-pentyl alcohol,
Tetrahydrofuran, N,N-dimethylformamide, 2- methyltetrahydrofuran, methyl tertiary butyl ether(MTBE) or toluene.
3. a kind of synthetic method of imrecoxib according to claim 1, it is characterised in that step A）Described in (E)-
1- is 1.0 to the molar ratio of methanesulfonylphenYl -1- nitro -2- p-methylphenyl ethylene, isocyanide yl acetate and base reagent:
1.1~1.5∶1.5~2.0。
4. a kind of synthetic method of imrecoxib according to claim 1, it is characterised in that step B）Described in 3- pairs
Aminomethyl phenyl -4- is 3- p-methylphenyl -4- to methanesulfonylphenYl pyrroles -2- to methanesulfonylphenYl pyrroles's -2- carboxylate
Carboxylate methyl ester or 3- p-methylphenyl -4- are to methanesulfonylphenYl pyrroles's -2- carboxylic acid, ethyl ester；The go back original reagent is two isobutyls
Base aluminum hydride or bis- (2- methoxy ethoxy) sodium aluminum hydrides；The solvent be methylene chloride, 1,2- dichloroethanes, chloroform,
Toluene or dimethylbenzene.
5. a kind of synthetic method of imrecoxib according to claim 1, it is characterised in that step B）Described in 3- pairs
Aminomethyl phenyl -4- is 1.0: 1.1 ~ 1.5 to the molar ratio of methanesulfonylphenYl pyrroles -2- carboxylate and go back original reagent.
6. a kind of synthetic method of imrecoxib according to claim 1, it is characterised in that step C）Described in solvent
For methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol or tert-pentyl alcohol.
7. a kind of synthetic method of imrecoxib according to claim 1, it is characterised in that step C）Described in 3- pairs
Aminomethyl phenyl -4- is 1.0: 10.0 ~ 100.0 to the molar ratio of methanesulfonylphenYl pyrrole-2-aldehyde, hydrogen peroxide.
8. a kind of synthetic method of imrecoxib according to claim 1, it is characterised in that step D）Described in 1- halogen
Propane is n-propyl chloride, 1- N-Propyl Bromide or 1- iodopropane；The hydro carbons sulfonic acid propyl ester derivative is methylsulphur propyl propionate, fluoroform
Sulfonic acid propyl ester or propyl p-toluenesulfonate；The base reagent be sodium hydride, hydrofining, sodium methoxide, sodium ethoxide, sodium tert-butoxide,
Potassium tert-butoxide, sodium isopropylate, tert-pentyl alcohol potassium, sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate or sodium carbonate；The solvent
For N,N-dimethylformamide, tetrahydrofuran, 2- methyltetrahydrofuran, toluene, methyl tertiary butyl ether(MTBE), acetonitrile or N- methylpyrrole
Alkanone.
9. a kind of synthetic method of imrecoxib according to claim 1, it is characterised in that step D）Described in 3- pairs
Aminomethyl phenyl -4- tries methanesulfonylphenYl -3- pyrrolidin-2-one, 1- halopropane or hydro carbons sulfonic acid propyl ester derivative and alkali
The molar ratio of agent is 1.0: 1.1 ~ 1.5: 1.5 ~ 2.0.
10. a kind of synthetic method of imrecoxib according to claim 1, it is characterised in that step A）Described in condensation
The temperature of cyclization be 20 ~ 35 DEG C, be condensed cyclization reaction time be 12 ~ for 24 hours；Step B）Described in reduction reaction when
Between be 2 ~ 6h；Step C）Described in oxidation reaction temperature be 20 ~ 40 DEG C, the reaction time be 24 ~ 72h；Step D）Described in
Substitution reaction temperature be 50 ~ 100 DEG C, the reaction time be 12 ~ for 24 hours.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111747874A (en) * | 2019-03-29 | 2020-10-09 | 成都同心纵横生物医药有限公司 | Ericoxib intermediate and preparation method and application thereof |
| CN115073350A (en) * | 2022-07-04 | 2022-09-20 | 苏州富士莱医药股份有限公司 | Preparation method of erexib |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20040029951A1 (en) * | 2002-08-08 | 2004-02-12 | Research Institute Of Material Medica, Chinese Academy Of Medical Sciences; | Sulfonyl-containing 3,4-diaryl-3-pyrrolin-2-ones, preparation method, and medical use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111747874A (en) * | 2019-03-29 | 2020-10-09 | 成都同心纵横生物医药有限公司 | Ericoxib intermediate and preparation method and application thereof |
| CN111747874B (en) * | 2019-03-29 | 2022-05-03 | 成都同心纵横生物医药有限公司 | Ericoxib intermediate and preparation method and application thereof |
| CN115073350A (en) * | 2022-07-04 | 2022-09-20 | 苏州富士莱医药股份有限公司 | Preparation method of erexib |
| CN115073350B (en) * | 2022-07-04 | 2023-09-12 | 苏州富士莱医药股份有限公司 | Preparation method of eremophilone |
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