CN106977475A - A kind of NSAIDs moors the synthetic method of horse former times cloth key intermediate - Google Patents
A kind of NSAIDs moors the synthetic method of horse former times cloth key intermediate Download PDFInfo
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- CN106977475A CN106977475A CN201710433498.4A CN201710433498A CN106977475A CN 106977475 A CN106977475 A CN 106977475A CN 201710433498 A CN201710433498 A CN 201710433498A CN 106977475 A CN106977475 A CN 106977475A
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- 0 CC(C)(C(OC(C=C1)=CC=C*1N)=O)Br Chemical compound CC(C)(C(OC(C=C1)=CC=C*1N)=O)Br 0.000 description 3
- YOCIJWAHRAJQFT-UHFFFAOYSA-N CC(C)(C(Br)=O)Br Chemical compound CC(C)(C(Br)=O)Br YOCIJWAHRAJQFT-UHFFFAOYSA-N 0.000 description 1
- JQHALAGGGRONSF-UHFFFAOYSA-N CC1(C=CC(O)=CC=C1)[N+]([O-])=O Chemical compound CC1(C=CC(O)=CC=C1)[N+]([O-])=O JQHALAGGGRONSF-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
- C07D307/58—One oxygen atom, e.g. butenolide
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides the synthetic method that a kind of NSAIDs moors horse former times cloth key intermediate, comprises the following steps：Step S1, nitrophenol is dissolved in organic solvent A, at 0 10 DEG C, and organic base A is added dropwise, then it is added dropwise after bromine isobutyl acylbromide, completion of dropping, reacts at room temperature 0.2 2 hours, then add water and reaction is quenched, organic phase is separated, post-treated step obtains compound 1 after mashing；Step S2, compound 1 and compound 2 are dissolved in tetrahydrofuran, cool to 20 DEG C, are added dropwise after organic base B and are reacted, add water and reaction is quenched, plus organic solvent B extraction, merge organic phase, washed with 0.5M sodium hydroxide solutions, then dry, concentrate, be beaten to obtain the pool horse former times cloth key intermediate.Isobutyl bromide nitrobenzene phenolic ester used in the present invention has synthesis simple, and high income, cost is low, and equipment requirement is low, and violent in toxicity cyanide is not produced, and pollution is few, the advantages of storage facilitates.
Description
Technical field
The present invention relates to the synthesis side that a kind of NSAIDs moors horse former times cloth (polmacoxib) key intermediate
Method, belongs to chemical industry and medicine intermediate production field.
Background technology
It is a kind of cox-2 inhibitors to moor horse former times cloth (Polmacoxib), belongs to NSAIDs, was obtained in 2015
Korean foods drug safety portion (MFDS) listing approval, ratifies to be used to treat osteoarthritis.Document report, Polmacoxib be by
Compound A converts what is obtained by a series of, and compound A synthesis is the key of Polmacoxib synthesis.According to document report
(WO2015080435A1) with the following method is mainly adopted in road, compound A synthesis, and concrete technology route is as follows：
The major defect of this method is：(1) raw materials used third level natural division and bromine isobutyryl cyanogen, facile hydrolysis produces hypertoxic cyanogen
Salt dissolving or hydrogen cyanide, very high requirement is proposed to production equipment and operating process；(2) extremely toxic substance cyanogen is contained in accessory substance
Change sodium, waste water and dregs are difficult to handle.
The content of the invention
It is simple to operate it is an object of the invention to provide a kind of initiation material small toxicity, the pool horse former times cloth of accessory substance small toxicity
The synthetic method of key intermediate, to overcome the drawbacks described above that prior art is present.
The present invention is achieved through the following technical solutions：
A kind of NSAIDs moors the synthetic method of horse former times cloth key intermediate, comprises the following steps：
Step S1, nitrophenol is dissolved in organic solvent A, under the conditions of 0-10 DEG C, and organic base A is added dropwise, then drips
Plus bromine isobutyl acylbromide, after completion of dropping, react at room temperature 0.2-2 hours, then add water and reaction is quenched, separate organic phase, it is described to have
The mutually post-treated step of machine, the bromo- 2- rnethyl-propanoic acids-nitrobenzene phenolic esters of 2-, i.e. compound 1 are obtained after mashing solvent orange 2 A mashing；
Step S2, compound 1 and 2- (3- fluorophenyls) -1- (4- methyl mercaptos phenyl) ethyl ketone, i.e. compound 2 are dissolved in
In tetrahydrofuran, -20 DEG C are cooled to, organic base B is slowly added dropwise, after dripping, stirs 0.5 hour, adds water and reaction is quenched, added with
Machine solvent B is extracted, and merges organic phase, and organic phase is washed with 0.5M sodium hydroxide solutions, then dried, and is concentrated, the B mashing of mashing solvent
Obtain the pool horse former times cloth key intermediate, 2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl mercapto) phenyl] -3 (2H) furans
Ketone, i.e. compound A.
As optimal technical scheme, in step S1, the nitrophenol is selected from 2- nitrophenols, 3- nitrophenols or 4- nitre
One kind in base phenol, preferably 4- nitrophenols.
In step S1, the one kind of the organic solvent A in tetrahydrofuran and dichloromethane, preferably dichloromethane.
In step S1, the organic base A is selected from triethylamine, and diisopropyl ethyl is pressed and one kind in pyridine, preferably three second
Amine.
In step S1, the mashing solvent orange 2 A is one kind in normal heptane and petroleum ether, preferably petroleum ether.
In step S1, the nitrophenol, organic base A, the mol ratio of bromine isobutyl acylbromide are 1/1.0-1.5/1.0-1.5,
It is preferred that 1/1.1/1.1.
In step S1, the post-processing step includes organic phase using watery hydrochloric acid successively, and sodium carbonate liquor is washed, anhydrous slufuric acid
Sodium is dried, and is filtered, concentration.Watery hydrochloric acid used is preferably 0.5M watery hydrochloric acid, and sodium carbonate liquor preferred mass concentration used is 5%
Sodium carbonate liquor.
In step S2, the organic base B is selected from lithium hexamethyldisilazide, sodium hexamethyldisilazide and hexamethyl
One kind in two silicon substrate potassamides, preferably sodium hexamethyldisilazide.
In step S2, the organic solvent B is petroleum ether.
In step S2, the one kind of the mashing solvent B in methanol and ethanol, preferably methanol.
In step S2, the compound 1, compound 2, organic base B mol ratio are 1/2.0-3.0/3.0-4.0, preferably
1/2.3/3.2。
Concrete technology route of the present invention is as follows：
Technical scheme compared with the existing technology, has the advantages that：
1st, the initiation material nitrophenol small toxicity used, cheap and easy to get, ample supply of commodities on the market.
2nd, it is solid under the normal temperature state of compound 1, chemical property is relatively stablized, meets water and do not decompose, normal temperature is saved and not degenerate.
3rd, without using or producing violent in toxicity (cyanide) in course of reaction, equipment requirement is low, and environmental pollution is small, waste water
Waste liquid is disposable.
Embodiment
Present pre-ferred embodiments are given below, to describe technical scheme in detail.
Embodiment 1
Step 1：The synthesis of the bromo- 2- rnethyl-propanoic acids of 2--(4- nitros) phenol ester (compound 1)
4- nitrophenols 30.1g is dissolved in 300mL dichloromethane, at 0-10 DEG C, triethylamine 24.1g is added dropwise, so
Bromine isobutyl acylbromide 50.2g is added dropwise afterwards, after dripping, is stirred at room temperature 0.5 hour, then adds water and reaction is quenched, separate organic phase, have
Machine mutually uses 0.5M diluted acids successively, and 5% sodium carbonate liquor is washed, anhydrous sodium sulfate drying, filters, concentration, after petroleum ether mashing
To compound 1, yield 95.6%.
Step 2：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl mercapto) phenyl] -3 (2H) furanones (compound A)
Synthesis；
26.5g compounds 1 and 10.4g compounds 2 are dissolved in tetrahydrofuran, -20 DEG C is cooled to, pregnancy is slowly added dropwise
The silicon substrate Sodamide (2M, 57.2mL) of base two, after dripping, stirs half an hour, adds water and reaction is quenched, plus petroleum ether extraction, merges
Organic phase, organic phase is washed with 0.5M sodium hydroxide solutions, is then dried, concentration, and compound A, yield 78% are beaten to obtain with methanol.
Embodiment 2
Step 1：The synthesis of the bromo- 2- rnethyl-propanoic acids of 2--(2- nitros) phenol ester (compound 1)
2- nitrophenols 30.1g is dissolved in 300mL dichloromethane, at 0-10 DEG C, diisopropyl ethyl amine is added dropwise
30.8g, is then added dropwise bromine isobutyl acylbromide 50.2g, after dripping, is stirred at room temperature 0.5 hour, then adds water and reaction is quenched, separate
Organic phase, organic phase uses 0.5M watery hydrochloric acid successively, and 5% sodium carbonate liquor is washed, anhydrous sodium sulfate drying, filters, concentration, normal heptane
Compound 1, yield 91.8% are obtained after mashing.
Step 2：2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl mercapto) phenyl] -3 (2H) furanones (compound A)
Synthesis；
26.5g compounds 1 and 10.4g compounds 2 are dissolved in tetrahydrofuran, -20 DEG C is cooled to, pregnancy is slowly added dropwise
The silicon substrate Sodamide (2M, 57.2mL) of base two, after dripping, stirs half an hour, adds water and reaction is quenched, plus petroleum ether extraction, merges
Organic phase, organic phase is washed with 0.5M sodium hydroxide solutions, is then dried, concentration, and compound A, yield 71% are beaten to obtain with ethanol.
Claims (10)
1. a kind of NSAIDs moors the synthetic method of horse former times cloth key intermediate, it is characterised in that comprise the following steps：
Step S1, nitrophenol is dissolved in organic solvent A, under the conditions of 0-10 DEG C, and organic base A is added dropwise, bromine is then added dropwise
After isobutyl acylbromide, completion of dropping, react at room temperature 0.2-2 hours, then add water and reaction is quenched, separate organic phase, the organic phase
Post-treated step, the bromo- 2- rnethyl-propanoic acids-nitrobenzene phenolic esters of 2-, i.e. compound 1 are obtained after mashing solvent orange 2 A mashing；
Step S2, by compound 1 and 2- (3- fluorophenyls) -1- (4- methyl mercaptos phenyl) ethyl ketone, i.e. compound 2, is dissolved in tetrahydrochysene
In furans, -20 DEG C are cooled to, organic base B is slowly added dropwise, after dripping, stirs 0.5 hour, adds water and reaction is quenched, it is molten added with machine
Agent B is extracted, and merges organic phase, and organic phase is washed with 0.5M sodium hydroxide solutions, then dried, and is concentrated, and mashing solvent B is beaten to obtain institute
State and moor horse former times cloth key intermediate, 2,2- dimethyl -4- (3- fluorophenyls) -5- [4- (methyl mercapto) phenyl] -3 (2H) furanones,
That is compound A.
2. the method as described in claim 1, it is characterised in that the nitrophenol is selected from 2- nitrophenols, 3- nitrophenols
Or one kind in 4- nitrophenols.
3. the method as described in claim 1, it is characterised in that the nitrophenol is 4- nitrophenols.
4. the method as described in claim 1, it is characterised in that in step S1, the organic solvent A is selected from tetrahydrofuran and two
One kind in chloromethanes, the organic base A is selected from triethylamine, diisopropyl ethyl press and pyridine in one kind, the mashing is molten
Agent A is one kind in normal heptane and petroleum ether, and the nitrophenol, organic base A, the mol ratio of bromine isobutyl acylbromide are 1/1.0-
1.5/1.0-1.5。
5. the method as described in claim 1, it is characterised in that the organic solvent A is dichloromethane, the organic base A is
Triethylamine, the mashing solvent orange 2 A is petroleum ether.
6. the method as described in claim 1, it is characterised in that the nitrophenol, organic base A, mole of bromine isobutyl acylbromide
Than for 1/1.1/1.1.
7. the method as described in claim any one of 1-6, it is characterised in that in step S1, the post-processing step includes will
Organic phase uses watery hydrochloric acid successively, and sodium carbonate liquor is washed, anhydrous sodium sulfate drying, filters, concentration.
8. the method as described in claim 1, it is characterised in that in step S2, the organic base B is selected from the silicon substrate ammonia of hexamethyl two
One kind in base lithium, sodium hexamethyldisilazide and potassium hexamethyldisilazide, the organic solvent B is selected from petroleum ether,
The one kind of the mashing solvent B in methanol and ethanol, the compound 1, compound 2, organic base B mol ratio are 1/
2.0-3.0/3.0-4.0。
9. the method as described in claim 1, it is characterised in that the organic base B is sodium hexamethyldisilazide, described to beat
Slurry solvent B is methanol.
10. the method as described in claim 1, it is characterised in that the compound 1, compound 2, organic base B mol ratio are
1/2.3/3.2。
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710433498.4A CN106977475B (en) | 2017-06-09 | 2017-06-09 | A kind of synthetic method of non-steroidal anti-inflammatory drugs pool horse former times cloth key intermediate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710433498.4A CN106977475B (en) | 2017-06-09 | 2017-06-09 | A kind of synthetic method of non-steroidal anti-inflammatory drugs pool horse former times cloth key intermediate |
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| CN106977475A true CN106977475A (en) | 2017-07-25 |
| CN106977475B CN106977475B (en) | 2019-04-19 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020238529A1 (en) * | 2019-05-31 | 2020-12-03 | 江苏天士力帝益药业有限公司 | Parecoxib impurity reference substance and preparation method therefor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098535A (en) * | 2014-07-25 | 2014-10-15 | 南通市华峰化工有限责任公司 | Preparation method for 4-(3-fluorine phenyl)-2,2-phenyl-5-(4-(methylmercapto-)phenyl) furan-3(2H)-ketone |
| CN105061341A (en) * | 2015-08-21 | 2015-11-18 | 宁波百思佳医药科技有限公司 | Acyl triazole compound and acetophenone-substituted phenyl methyl sulfoxide compound and preparing methods and application thoseof |
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2017
- 2017-06-09 CN CN201710433498.4A patent/CN106977475B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098535A (en) * | 2014-07-25 | 2014-10-15 | 南通市华峰化工有限责任公司 | Preparation method for 4-(3-fluorine phenyl)-2,2-phenyl-5-(4-(methylmercapto-)phenyl) furan-3(2H)-ketone |
| CN105061341A (en) * | 2015-08-21 | 2015-11-18 | 宁波百思佳医药科技有限公司 | Acyl triazole compound and acetophenone-substituted phenyl methyl sulfoxide compound and preparing methods and application thoseof |
Non-Patent Citations (2)
| Title |
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| A.JACQUES等: "Nitinol Modified by In Situ Generated Diazonium from Its Nitro Precursor for the SI-ATRP of 2-Hydroxyethyl Methacrylate", 《JOURNAL OF THE ELECTROCHEMICAL SOCIETY》 * |
| KI-WHA LEE等: "A Facile One-Pot Synthesis of 4,5-Diaryl-2,2-dimethyl-3(2H)-furanones", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020238529A1 (en) * | 2019-05-31 | 2020-12-03 | 江苏天士力帝益药业有限公司 | Parecoxib impurity reference substance and preparation method therefor |
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