CN106588897A - New preparation method of Pranlukast - Google Patents
New preparation method of Pranlukast Download PDFInfo
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- CN106588897A CN106588897A CN201710110643.5A CN201710110643A CN106588897A CN 106588897 A CN106588897 A CN 106588897A CN 201710110643 A CN201710110643 A CN 201710110643A CN 106588897 A CN106588897 A CN 106588897A
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- C07—ORGANIC CHEMISTRY
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention provides a new preparation method of drug Pranlukast for treating asthma. The new preparation method includes the specific steps that with 2-aminophenol-4-sulfonic acid as a starting material, a key intermediate 3-amino-2-hydroxyacetophenone is prepared by means of acylation, Fries rearrangement and deprotection, then reacts with 4-(phenylbutoxy)benzoic acid, and then is subjected to condensation with ethyl 1H-tetrazole-5-acetate, and finally preparation is achieved through ring closing under the acidic condition. Compared with the prior art, the raw material used for the new preparation method is low in price and easy to obtain, industrialization of a process can be achieved easily, and the obtained final product is high in purity; and no dangerous process exists, equipment is simple, and the route is novel.
Description
Technical field
The present invention relates to field of medicaments, specifically a kind of new preparation process of pranlukast.
Background technology
Pranlukast (pranlukast, 1), chemical entitled N- [4- oxo -2- (1H-TETRAZOLE -5- bases) -4H-1- benzo pyrroles
Mutter -8- bases] -4- (4- phenylbutoxies) Benzoylamide, it is the LTRA of Japanese Ono companies research and development, nineteen ninety-five
First in Japan's listing, clinic is mainly used as asthma and antiallergic agent.To preventing and treating Zhong Er Yan ﹑ dysmenorrheas and psoriasises etc.
There is good efficacy；Simultaneously animal cerebral ischemia is significantly improved, and Central nervous system untoward reaction is light.
The synthesis of existing pranlukast has following several：
1st, patent：WO2005077942 reports the synthesis of pranlukast with the iodo- 2- hydroxy acetophenones of 3- as initiation material, with four nitrogen
Azoles ethyl ester is condensed, and then dehydration condensation is condensed to yield pranlukast with to benzene butyl phenyl ether Methanamide.Initiation material in the technique
Synthesis difficulty is larger, relatively costly.Concrete route is as follows：
2nd, patent：The synthesis of EP0173516 report pranlukasts is with 8- amino -4- oxo -2-（5-1H-4 oxazolyls）- 4H-1- benzene
And pyrans and compound to the chloride compounds of benzene butoxybenzoic acid through acylation reaction, one-step synthesis pranlukast.The work
Skill route is only completed through a step, but the Material synthesis step needed for the technique is more, and route is long, and yield is low, high cost.Specifically
Route is as follows：
And 8- amino -4- oxo -2-（5-1H-4 oxazolyls）The synthetic route of -4H-1- .alpha.-5:6-benzopyrans is as follows, and which is with 3- nitro -2-
Hydroxy acetophenone is raw material, and Jing condensations, dehydration condensation, ammonolysis are dehydrated into nitrile, and cyano compound is being synthesized with reaction of sodium azide
Tetrazole ring, is preparing 8- amino -4- oxo -2- through hydro-reduction（5-1H-4 oxazolyls）- 4H-1- .alpha.-5:6-benzopyrans.Such as
Document：Journal of Medicinal Chemistry. 1988,31(1).84-91.
In addition, the synthesis of 3- nitro -2- hydroxy acetophenones has two lines.Scheme one, such as patent WO 2009085256 is with 2- hydroxyls
Benzoylformaldoxime is that raw material Jing nitrifications are obtained, but yield is relatively low；Scheme two, such as document Synthesis, 2004,11：1789-
1792 with adjacent nitro acetophenol as raw material, the radiation synthesis under microwave, although yield is higher, but is not suitable for big production.
Additionally, 8- amino -4- oxo -2-（5-1H-4 oxazolyls）The synthesis of -4H-1- .alpha.-5:6-benzopyrans can also by 3- amino -
2- hydroxy acetophenones are raw material, with tetrazoleacetic acid ester condensation in the presence of two silicon substrate amine of hexamethyl and n-BuLi, are reset,
Cyclization is prepared.The process overall yields 41.3%, but the hazardous agents such as the n-BuLi of costliness are used, and reaction condition is severe
Carve.3- amino -2- hydroxy acetophenone market prices are more expensive simultaneously.Concrete route is as follows：
3rd, patent WO9532199 is also with 8- amino -4- oxo -2-（5-1H-4 oxazolyls）- 4H-1- .alpha.-5:6-benzopyrans are former for starting
Material.Simultaneously under the reagent such as palladium catalyst and DBU, CO (carbon monoxide converter) gas are passed through, with bromobenzene butyl phenyl ether through being condensed to yield
Pranlukast.The technique has gone out Material synthesis difficulty greatly, on the other hand uses the palladium catalyst of costliness and a poisonous oxidation
Carbon gas, therefore it is unfavorable for industrialized production.Concrete route is as follows：
4th, with p bromophenol as raw material, Jing is acylated patent WO9734885, and Fries resets, nitrification, condensation simultaneously cyclization, then palladium carbon
Catalysis reduction-debromination, obtains 2- Ethyl formate -8- nitro -4- oxo -4H-1- .alpha.-5:6-benzopyrans.But the yield of this step debrominate
Only 55%.Product after debrominate produces 8- amino -4- oxo -2- (5-1H- with reaction of sodium azide through ammonolysis, dehydration
Tetrazole radical) -4H-1- .alpha.-5:6-benzopyrans.The process route is long, uses palladium carbon catalysis reduction, complex operation, cost in route twice
Height, is unfavorable for large-scale production.Concrete route is as follows：
5th, the preparation method of the pranlukast of patent WO9412492 report is with N- (3- acetyl group -2- hydroxy phenyls) -4- (4-
Butoxy phenyl) this Methanamide and tetrazoleacetic acid ester condensation, then cyclization is into the preparation method of pranlukast.The technique is not given
Go out the synthetic route of initiation material, also do not provide the yield of each step reaction.Its synthetic route is as follows：
6th, the method for the synthesis pranlukast of patent WO9725040 report is with intermediate 8- amino -4- oxo -2- (5-1H- tetra-
Oxazolyl) protection of -4H-1- .alpha.-5:6-benzopyrans and acetal the acyl chlorides compound Jing condensation reaction to benzene butoxybenzoic acid, then slough guarantor
Shield base, synthetically prepared pranlukast.The initiation material that the technique is used needs multistep reaction synthesis to obtain, relatively costly.
7th, the synthetic method of the pranlukast of patent WO9734885 report is with N- (3- acetyl group -2- hydroxy benzeness second
Base) -4- (4- butoxy phenyls) this Methanamide and tetrazoleacetic acid sodium is condensed, and after rearrangement, cyclization obtains pranlukast again.The work
There is no the synthetic method for reporting two initiation materials in skill, according to the report of other pertinent literatures, the conjunction of the two initiation materials
Obtain into multistep reaction is needed.Concrete route is as follows：
8. the method for the synthesis pranlukast of patent WO9600225 report is the tetrazoleacetic acid ester and N- to protect（3- acetyl
Base -2- hydroxy phenyls）-4-（4- butoxy phenyls）This Methanamide is condensed, and takes off the synthesis of amino protecting group after cyclization dehydration again
Method.The technique is larger in the tetrazole difficulty of synthetic nitrogen upper band substituent group, and final deprotection reaction uses tetrahydrochysene lithium aluminium etc.
Expensive hazardous agents, complex operation, high cost are unfavorable for large-scale production.Concrete route is as follows：
9th, patent WO9531445 is with 8- [4- with regard to the synthesis of pranlukast（4- butoxy phenyls）This Methanamide] amine -4- oxygen
Generation -4H-1- .alpha.-5:6-benzopyran -2- nitriles are raw material, under the catalysis of triethylamine, produce one similar to the knot narrowed with hydrazine hydrate effect
Structure is passed through H2S gases, generate thioamides, then the amidine structural compounds with hydrazine effect production project, and the compound exists again
React with sodium nitrite in aqueous acetic acid, cyclization production tetrazole is obtained pranlukast.The synthesis technique reactions steps are more,
Also need to hydrazine reaction same at low temperature, expensive, complex operation.With hydrogen sulfide gas, also it is unfavorable for operating and keeping the safety in production.
The synthetic method of initiation material is not reported simultaneously.Concrete synthetic route is as follows：
The content of the invention
It is an object of the invention to provide a kind of new preparation process of pranlukast, to solve to propose in above-mentioned background technology
Problem.
Synthetic route of the present invention is as follows：
The present invention provides following technical scheme：
A kind of preparation method for treating asthmatic medicament pranlukast, comprises the following steps：
The first step：The preparation of 3- acetamido -4- acetyloxybenzenesulfonic acids（I）
With Ortho-Aminophenol -4- sulfonic acid and acetic anhydride as raw material, mol ratio is 1:2.1, in polar solvent, exist in alkali or acid
Under 3- acetamido -4- acetyloxybenzenesulfonic acids are synthesized（I）.
Solvent therein selects acetic acid, methanol, ethanol, pyridine, DMF, dichloromethane, chloroform etc..It is preferred that methanol, ethanol.
Alkali selects pyridine, DMAP, triethylamine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, diisopropylethylamine etc., preferred pyrrole
Pyridine, triethylamine.Acid selects concentrated sulphuric acid, p-methyl benzenesulfonic acid, PPA etc..It is preferred that concentrated sulphuric acid.
I
Second step：The preparation of 3- amino -2- hydroxy acetophenones（II）
One pot process 3- amino -2- hydroxy acetophenones.3- acetamido -4- acetoxy acetophenones in aprotic solvent,
Jing Catalyzed by Anhydrous Aluminium Chloride carries out Fries rearrangements, acid hydrolysis one pot process 3- amino -2- hydroxy acetophenones.
Solvent therein selects Nitrobenzol.Acid selects dilute sulfuric acid, dilute hydrochloric acid.It is preferred that dilute hydrochloric acid.
II
3rd step：The preparation (III) of 2- acetyl group -6- [4- (4- benzene butoxy) benzamido] phenol
The quality reaction synthesis acyl chlorides such as 4- (benzene butoxy) benzoic acid and thionyl chloride, reaction temperature room temperature-backflow, response time
2-8h, then the complete thionyl chloride of recovered under reduced pressure unreacted, is then synthesized with 3- amino -2- hydroxy acetophenones at low temperature
2- acetyl group -6- [4- (4- benzene butoxy) benzamido] phenol (III).
Chloride can select thionyl chloride, oxalyl chloride, preferred thionyl chloride.Acylated solvent selects dichloromethane, chlorine
Imitative, ethyl acetate, tetrahydrofuran etc..It is preferred that dichloromethane.Alkali inorganic base or organic base, such as sodium hydroxide, potassium hydroxide, carbon
Sour sodium, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, DMAP etc., preferred pyridine, triethylamine.Reaction temperature is controlled at 5 DEG C
Below.Response time 2-3h.
III
4th step：The preparation of 2- [4- (4- benzene butoxy) benzamido] -6- (1,3- dicarbapentaborane -3- tetrazole bases) phenol
(IV)
It is molten that 2- acetyl group -6- [4- (4- benzene butoxy) benzamido] phenol is dissolved in aprotic, polar with tetrazole Ethyl formate
In agent, mol ratio is 1:(1.05-1.1), condensation reaction is carried out under base catalysiss synthesize 2- [4- (4- benzene butoxy) benzoyls
Amino] -6- (1,3- dicarbapentaborane -3- tetrazole bases) phenol (IIII).Temperature control room temperature is to 90 DEG C.Response time 1-2h.
Solvent selects methanol, ethanol, DMF.Alkali select Feldalat NM, Sodium ethylate, potassium tert-butoxide, potassium hydroxide, sodium hydroxide,
Sodamide. etc..It is preferred that potassium tert-butoxide.
IV
5th step：The preparation (V) of pranlukast
2- [4- (4- benzene butoxy) benzamido] -6- (1,3- dicarbapentaborane -3- tetrazole bases) phenol is dissolved in dehydrated alcohol,
Under acid catalysiss, back flow reaction synthesis pranlukast (V) is to slowly warm up to.Acid concentrated sulphuric acid, it is 1 that consumption is mol ratio:1.
V
Compared with prior art, the invention has the beneficial effects as follows：Raw materials used low price is easy to get, and technique easily realizes industry
Change, gained final products purity is high.Without dangerous technique, equipment is simple, and route is novel.
Specific embodiment
Technical scheme in the embodiment of the present invention will be clearly and completely described below, it is clear that described embodiment is only
Only it is a part of embodiment of the invention, rather than the embodiment of whole.Based on the embodiment in the present invention, ordinary skill
The every other embodiment obtained under the premise of creative work is not made by personnel, belongs to the scope of protection of the invention.
Embodiment 1：The preparation (I) of 3- acetamido -4- acetyloxybenzenesulfonic acids
Take Ortho-Aminophenol -4- sulfonic acid (189g), acetic anhydride（224g）, methanol 400g, 10 milliliters of concentrated sulphuric acid, back flow reaction 4h.
After reaction terminates, recovered under reduced pressure methanol is cooled to room temperature, adds saturated sodium bicarbonate solution to adjust to pH9- in reaction system
10,400 milliliters of ethyl acetate extractions, are washed to neutrality, and anhydrous sodium sulfate drying is filtered, and decompression and solvent recovery obtains light yellow solid
Body 264g, yield 97%.
Embodiment 2：The synthesis of 3- amino -2- hydroxy acetophenones.
3- acetamido -4- acetyloxybenzenesulfonic acid 136g are taken, is dissolved in 300 milliliters of Nitrobenzol, add anhydrous tri-chlorination
Aluminum 133g, is heated to reflux 5h, and after reaction terminates, recovered under reduced pressure major part solvent is cooled to room temperature, and under ice bath, reactant liquor is slow
It is added in 30% dilute hydrochloric acid, 2h is stirred at room temperature, be to slowly warm up to backflow, react 4h, after reaction terminates, reactant liquor is cooled to
Room temperature, adds 20% sodium hydroxide solution to adjust pH9-10 in reaction system.300 milliliters of chloroform extractions are added, in being washed to
Property, anhydrous sodium sulfate drying, filtration, filtrate decompression recovery, residue petroleum ether：Ethyl acetate=1:3 recrystallization it is light yellow solid
Body 65.7g, yield 87%.
Embodiment 3：The preparation (III) of 2- acetyl group -6- [4- (4- benzene butoxy) benzamido] phenol
4- (benzene butoxy) benzoic acid 270g is taken, adds 270g thionyl chlorides, 50 DEG C of insulation reaction 3h after reaction terminates, to reduce pressure
Reclaim the complete thionyl chloride of unreacted.It is passed through nitrogen and blows off thionyl chloride.Being cooled to room temperature adds 270g dichloromethane standby.Claim
Take 151g 3- amino -2- hydroxy acetophenones to be dissolved in 200g dichloromethane, add pyridine 160g, Deca 4- (benzene fourth under ice bath
Epoxide) Benzenecarbonyl chloride. dichloromethane solution, during Deca temperature be less than 10 DEG C, completion of dropping, 10 DEG C of insulation reaction 2h,
After reaction terminates, dilute hydrochloric acid is added in reaction system, pH is adjusted to 2-3, point liquid, dichloromethane layer is washed to neutrality, anhydrous
Sodium sulfate is dried, and filters, and concentration obtains red brown solid, petroleum ether：Ethyl acetate=1:1 is recrystallized to give 334g, yield
84%.
Embodiment 4：2- [4- (4- benzene butoxy) benzamido] -6- (1,3- dicarbapentaborane -3- tetrazole bases) phenol
Prepare (IV)
2- acetyl group -6- [4- (4- benzene butoxy) benzamido] phenol 202g is taken, is dissolved in 300 milliliters of DMF, delayed under ice bath
It is slow add potassium tert-butoxide 224g, addition to finish after, react 1h under ice bath, backward system in Deca tetrazole Ethyl formate 80g
DMF solution（DMF, 100 milliliters）, completion of dropping, system are to slowly warm up to 80 DEG C of reaction 1h.After reaction terminates, recovered under reduced pressure
Most of solvent, afterwards residue be cooled to room temperature, be poured slowly in 500 milliliters of frozen water, adjusted to pH2-3 with dilute hydrochloric acid, in a large number
Yellow solid is separated out, and is filtered, and filter cake is washed to neutrality, is vacuum dried to obtain crude product 232g, yield 91%.
Embodiment 5：The preparation (V) of pranlukast
4.2- [4- (4- benzene butoxy) benzamido] -6- (1,3- dicarbapentaborane -3- tetrazole bases) phenol 232g is taken, is dissolved in
In 400 milliliters of dehydrated alcohol, 90g concentrated sulphuric acids under ice bath, are slowly added dropwise, after completion of dropping, are to slowly warm up to backflow, after reaction 2h,
Reaction terminates, and is cooled to room temperature, and a large amount of white solids are separated out, and are filtered, and filter cake ice washing with alcohol, 70% ethyl alcohol recrystallization are obtained
White solid 207g, yield 93%.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of spirit or essential attributes without departing substantially from the present invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit is required rather than described above is limited, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.Any reference in claim should not be considered as and limit involved claim.
Moreover, it will be appreciated that although this specification is been described by according to embodiment, not each embodiment is only wrapped
Containing an independent technical scheme, this narrating mode of description is only that those skilled in the art should for clarity
Using description as an entirety, the technical scheme in each embodiment can also Jing it is appropriately combined, form those skilled in the art
Understandable other embodiment.
Claims (6)
1. a kind of new preparation process of pranlukast, it is characterised in that including following synthesis steps：
（1）The preparation of 3- acetamido -4- acetyloxybenzenesulfonic acids（I）：
With Ortho-Aminophenol -4- sulfonic acid and acetic anhydride as raw material, mol ratio is 1:2.1, in polar solvent, exist in alkali or acid
Under 3- acetamido -4- acetyloxybenzenesulfonic acids are synthesized（I）, reaction equation is：
（I）
Wherein, polar solvent is acetic acid, methanol, ethanol, pyridine, DMF, dichloromethane or chloroform, and alkali is pyridine, DMAP, three second
Amine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or diisopropylethylamine, acid are concentrated sulphuric acid, p-methyl benzenesulfonic acid or PPA；
（2）The preparation of 3- amino -2- hydroxy acetophenones（II）：
In atent solvent, under Catalyzed by Anhydrous Aluminium Chloride, compound I occur Fries reset, Jing acid hydrolysis, obtain 3- amino-
2- hydroxy acetophenones, reaction equation is：
（II）
Wherein, solvent is Nitrobenzol, and acid is dilute sulfuric acid or dilute hydrochloric acid；
（3）The preparation (III) of 2- acetyl group -6- [4- (4- benzene butoxy) benzamido] phenol：
4- (benzene butoxy) benzoic acid and thionyl chloride are synthesized acyl chlorides, reaction temperature room temperature-backflow, response time 2-8h,
Then the complete thionyl chloride of recovered under reduced pressure unreacted, is then synthesized 2- second with 3- amino -2- hydroxy acetophenones at low temperature
Acyl group -6- [4- (4- benzene butoxy) benzamido] phenol (III), response time 2-3h, reaction equation is：
（III）
Wherein, acylated solvent is dichloromethane, chloroform, ethyl acetate or tetrahydrofuran, and alkali is inorganic base or organic base, is hydrogen
Sodium oxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine or DMAP；
（4）The preparation (IV) of 2- [4- (4- benzene butoxy) benzamido] -6- (1,3- dicarbapentaborane -3- tetrazole bases) phenol：
It is molten that 2- acetyl group -6- [4- (4- benzene butoxy) benzamido] phenol is dissolved in aprotic, polar with tetrazole Ethyl formate
In agent, mol ratio is 1：1.05-1.1, carries out condensation reaction synthesis 2- [4- (4- benzene butoxy) benzene carbon amides under base catalysiss
Base] -6- (1,3- dicarbapentaborane -3- tetrazole bases) phenol (IIII), to 90 DEG C, response time 1-2h reacts temperature control room temperature
Formula is：
（IV）
Wherein, solvent be methanol, ethanol or DMF, alkali be Feldalat NM, Sodium ethylate, potassium tert-butoxide, potassium hydroxide, sodium hydroxide or
Sodamide.；
（5）The preparation (V) of pranlukast：
2- [4- (4- benzene butoxy) benzamido] -6- (1,3- dicarbapentaborane -3- tetrazole bases) phenol is dissolved in dehydrated alcohol,
Under acid catalysiss, back flow reaction synthesis pranlukast (V) is to slowly warm up to, reaction equation is：
（V）
Wherein acid concentrated sulphuric acid, consumption is and 2- [4- (4- benzene butoxy) benzamido] -6- (1,3- dicarbapentaborane -3-, four nitrogen
Oxazolyl) phenol mol ratio 1:1.
2. the new preparation process of pranlukast according to claim 1, it is characterised in that step（1）In polar solvent
For methanol or ethanol, alkali is pyridine or triethylamine, and acid is concentrated sulphuric acid.
3. the new preparation process of pranlukast according to claim 1, it is characterised in that step（2）In acid be dilute salt
Acid.
4. the new preparation process of pranlukast according to claim 1, it is characterised in that step（3）In acylation it is molten
Agent is dichloromethane, and alkali is pyridine or triethylamine.
5. the new preparation process of pranlukast according to claim 1, it is characterised in that step（3）In low temperature for control
System is below 5 DEG C.
6. the new preparation process of pranlukast according to claim 1, it is characterised in that step（4）Middle alkali is the tert-butyl alcohol
Potassium.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106995366A (en) * | 2017-06-07 | 2017-08-01 | 上海微巨实业有限公司 | A kind of novel preparation method of the hydroxy acetophenone of 3 amino 2 |
| CN107098822A (en) * | 2017-06-07 | 2017-08-29 | 上海微巨实业有限公司 | A kind of preparation method for preparing the hydroxy acetophenone of 3 amino of Pranlukast key intermediate 2 |
| CN108947984A (en) * | 2018-09-17 | 2018-12-07 | 烟台万润药业有限公司 | A kind of preparation method of Pranlukast |
| CN109824537A (en) * | 2019-04-03 | 2019-05-31 | 重庆医药高等专科学校 | A kind of preparation method of N- (3- acetyl group -2- hydroxy phenyl) acetamide |
| CN110423206A (en) * | 2019-07-17 | 2019-11-08 | 天津大学 | The method of cyclohexanone oxime, cyclohexanone and toluene is separated from Ammoximation reaction product |
| CN110423204A (en) * | 2019-08-09 | 2019-11-08 | 昆山力田医化科技有限公司 | A kind of preparation method of Pranlukast intermediate |
| CN110938052A (en) * | 2018-09-21 | 2020-03-31 | 重庆圣华曦药业股份有限公司 | Industrial preparation method of intermediate of pranlukast as anti-asthma drug |
| CN111960957A (en) * | 2020-09-09 | 2020-11-20 | 太仓康源化建医药有限公司 | Preparation method of pranlukast intermediate |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106995366A (en) * | 2017-06-07 | 2017-08-01 | 上海微巨实业有限公司 | A kind of novel preparation method of the hydroxy acetophenone of 3 amino 2 |
| CN107098822A (en) * | 2017-06-07 | 2017-08-29 | 上海微巨实业有限公司 | A kind of preparation method for preparing the hydroxy acetophenone of 3 amino of Pranlukast key intermediate 2 |
| CN107098822B (en) * | 2017-06-07 | 2021-05-28 | 上海微巨实业有限公司 | Preparation method for pranlukast key intermediate 3-amino-2-hydroxyacetophenone |
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| CN110423206A (en) * | 2019-07-17 | 2019-11-08 | 天津大学 | The method of cyclohexanone oxime, cyclohexanone and toluene is separated from Ammoximation reaction product |
| CN110423206B (en) * | 2019-07-17 | 2022-07-08 | 天津大学 | Method for separating cyclohexanone oxime, cyclohexanone and toluene from ammoximation reaction product |
| CN110423204A (en) * | 2019-08-09 | 2019-11-08 | 昆山力田医化科技有限公司 | A kind of preparation method of Pranlukast intermediate |
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