CN101450943B - Method for synthesizing drug pranlukast from tetrahydrofuran path - Google Patents
Method for synthesizing drug pranlukast from tetrahydrofuran path Download PDFInfo
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- CN101450943B CN101450943B CN2008100797140A CN200810079714A CN101450943B CN 101450943 B CN101450943 B CN 101450943B CN 2008100797140 A CN2008100797140 A CN 2008100797140A CN 200810079714 A CN200810079714 A CN 200810079714A CN 101450943 B CN101450943 B CN 101450943B
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Abstract
The invention discloses a new method for synthesizing pranlukast, in particular to a method for synthesizing medicinal pranlukast from tetrahydrofuran. The method takes the tetrahydrofuran as raw materials to prepare the pranlukast through ring opening, Friedel-Crafts alkylation, bromination, condensation and ring closing reactions. The method has the characteristics of readily available raw materials, simple reaction for preparation of an intermediate, high yield, safe reactions and suitability for industrial production, and can be used to prepare the medicinal pranlukast for treating asthma and allergic rhinitis.
Description
Technical field
The present invention relates to a kind of preparation method of LTRA pranlukast, belong to the compound field, specifically a kind of method from THF approach synthetic drugs pranlukast.
Background technology
Pranlukast is a kind of LTRA of the little wild company of Japan exploitation, and chemical name is 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-tetrazole-5-base-4H-1-chromene.Go on the market in Japan June nineteen ninety-five, the clinical treatment asthma that is mainly used in, and rise and be used for treatment of allergic rhinitis simultaneously in November, 1999.
Pranlukast is attacked the tracheal smooth muscle spasm and the contraction of lung bar that cause to leukotriene has tangible antagonistic action; Alleviate airway constriction and expiratory dyspnea effectively; Can obviously weaken sucking the early stage and later stage bronchoconstriction reaction that allergen excites, and suppress the enhancement of the non-specific BHR that the allergen inductive causes the suction histamine.Current research shows that pranlukast can alleviate rat and mouse brain ischemic injuries effectively, and the BSA that especially cerebral ischemia is caused oozes out with cerebral edema has effect preferably, explains that this medicine has the possibility that further is developed into the clinical treatment brain ischemia medicament.
The compound method of the pranlukast of existing report comprises following several kinds:
1. the pranlukast synthetic reports it is that Toda accomplishes the earliest, is raw material with 3-nitro-2-hydroxy acetophenone, with oxalic acid diethyl ester the Claisen condensation takes place, and reheat refluxes and closes ring, makes up the chromene ring; Through the synthetic ring of the method for dehydration of amide is gone up cyanic acid, this cyano compound synthesizes tetrazole with reaction of sodium azide again.Nitro on compound hydrogenating reduction under 5%Pd/C catalysis is amino, gets the target compound pranlukast with benzoic acid.This method is directly used 4-(4-benzene butoxy) benzoic acid.Synthetic route is following:
2. Robert route and Graham route all are to be raw material with 1-bromobenzene butane, the ligand compound that adopts palladium respectively be under condensation under carbonyl formylation reaction and the potassium tert.-butoxide effect of catalyzer, the acidic conditions closed loop dewater the method preparation of chromene ring.Synthetic route is following:
The Robert route:
The Graham route:
All do not disclose the route of synthesis of raw material 1-bromobenzene butane in these two kinds of synthetic routes.
3. the Masayohi synthetic route generates 2-thiocarbamoyl 1-benzopyran derivatives with 2-cyanic acid 1-benzopyran derivatives and hydrogen sulfide addition reaction under base catalysis; Generate amidrazone with the anhydrous hydrazine reaction respectively then, acidic conditions descends and Sodium Nitrite generation nitrosation reaction obtains tetrazole ring.Synthetic route is following:
The not mentioned raw materials used compound method of this route, its improvement only were embodied on synthesizing of tetrazole ring.
4. Giles, Hideki and Hayler increase substituting group on tetrazole, and condensation reaction is more prone to, but are with substituent tetrazole difficulty bigger on the synthetic nitrogen, and hazardous agents such as tetrahydrochysene lithium aluminium are used in the final reaction that removes, and are not easy to industriallization.Reaction scheme is following:
5. Lee N K is with 4-(4-benzene butoxy) phenyl cyanide and 2-hydroxyl-3-iodobenzene ethyl ketone and 1H-4-azoles base-5-ethyl formate reaction, and sulphuric acid catalysis closes ring, removes hydrogen iodide under cuprous iodide and the potassiumphosphate effect and obtains pranlukast.Reaction scheme is following:
This route is not mentioned the compound method of raw material 4-(4-benzene butoxy) phenyl cyanide, and the synthetic difficulty of 2-hydroxyl-3-iodobenzene ethyl ketone is bigger simultaneously.
Summary of the invention
The technical issues that need to address of the present invention provide a kind of new way of synthetic pranlukast, promptly from the method for THF approach synthetic drugs pranlukast.It is to be raw material with the THF, prepares the method for pranlukast through open loop, Friedel-Crafts alkylation, bromo, condensation, ring-closure reaction.This method has raw material and is easy to get, prepares that midbody reaction is simple, yield is high, reaction is safe, the characteristics of suitable suitability for industrialized production, can be used for preparing the medicine pranlukast of treating asthma, allergic rhinitis.
For solving above-mentioned technical problem, the technical scheme that the present invention adopted is:
A kind of method from THF approach synthetic drugs pranlukast, the synthetic route of this method is following:
Above-mentioned compound method may further comprise the steps:
A.4-butylene-chlorohydrin is synthetic
Add concentrated hydrochloric acid among the THF, the mass ratio that feeds intake is 1: 1.389～5.556, and 45--80 ℃ is stirred 5--18h, cooling, and dichloromethane extraction, desolventizing, underpressure distillation gets the 4-butylene-chlorohydrin;
B.4-the benzene butanols is synthetic
Get benzene, aluminum chloride mixing, 0--25 ℃ adds the 4-butylene-chlorohydrin, pours in the frozen water behind the reaction 5--10h, and separatory desolventizes, underpressure distillation, and the gained colourless transparent liquid is a 4-benzene butanols;
C.1-bromo-4-benzene butane is synthetic
4-benzene butanols, 40% Hydrogen bromide mix, and the mass ratio that feeds intake is 1: 2.857～11.428, and reflux is divided water, cooling, and separatory, organic phase desolventizes, and underpressure distillation gets 1-bromo-4-benzene butane;
D. methyl paraben is synthetic
Get PHB and methyl alcohol, the vitriol oil mixes, and screws out methyl alcohol behind the backflow 5-20h, pours in the cold water, separates out white solid, and filtration, drying get methyl paraben;
E.4-(4-benzene butoxy)-oil of Niobe is synthetic
Get 1-bromo-4-benzene butane, DMF, toluene, methyl paraben and salt of wormwood, the 5～20h that refluxes, cooling adds water, extracted in toluene, revolve steam weak yellow liquid, recrystallization, gained white solid are 4-(4-benzene butoxy)-oil of Niobe;
F.4-(4-benzene butoxy)-benzoic synthetic
Get 4-(4-benzene butoxy)-oil of Niobe, 15%NaOH solution, the 1～5h that refluxes, cooling, acidifying, filtration, drying get 4-(4-benzene butoxy)-phenylformic acid;
G. the preparation of acetate p bromophenol ester
Get bromophenol, aceticanhydride, pyridine, the mol ratio that feeds intake is 1: 1～1.5: 0.1～1, and the 3～10h that refluxes steams pyridine, acetate and excessive aceticanhydride, and underpressure distillation obtains acetate p bromophenol ester;
H.5-the preparation of bromo-2-hydroxy acetophenone
Get acetate p bromophenol ester, aluminum chloride, zellon, the mol ratio that feeds intake is 1: 1～5: 1, and 0.5～5.5h refluxes; Cooling, reaction solution is poured in 5% hydrochloric acid, dichloromethane extraction; Remove solvent under reduced pressure, obtain grey crystal form 5-bromo-2-hydroxy acetophenone;
I.5-the preparation of bromo-3-nitro-2-hydroxy acetophenone
Get 5-bromo-2-hydroxy acetophenone, tetracol phenixin, drip nitric acid in the time of 50～90 ℃, the 1～4h that refluxes, cooling is filtered, and the gained yellow solid is 5-bromo-3-nitro-2-hydroxy acetophenone;
J.3-the preparation of amino-2-hydroxy acetophenone
Get 5-bromo-3-nitro-2-hydroxy acetophenone, 5%Pd/C, methylene dichloride, methyl alcohol, concentrated hydrochloric acid, water, hydrogenation; Finish afterreaction liquid and filter, filtrate decompression is removed and is desolvated, and transfers to neutrality with sodium hydrogencarbonate, and the ginger-colored solid of gained is 3-amino-2-hydroxy acetophenone;
K.3-the preparation of [4-(4-benzene butoxy) benzene carbon amide]-2-hydroxy acetophenone
Get 4-(4-benzene butoxy) phenylformic acid, toluene, DMF, 45～105 ℃ drip SOCl
2, behind the 30min reaction solution is splashed in the toluene solution of 3-amino-2-hydroxy acetophenone, reaction 3～10h, cooling, Hydrogen chloride transfers to neutrality, and extracted in toluene is revolved steaming, and the gained light yellow crystal is 3-[4-(4-benzene butoxy) benzene carbon amide]-2-hydroxy acetophenone;
L.2-[4-(4-benzene butoxy) benzene carbon amide]-6-[1,3-dioxo-3-ethoxycarbonyl propyl group] phenol is synthetic
Pour in the Hydrogen chloride behind sodium methylate, THF, 3-[4-(4-benzene butoxy) benzene carbon amide]-2-hydroxy acetophenone, the oxalic acid diethyl ester stirring reaction 4～10h; Separate out yellow solid; Filter; Products therefrom is 2-[4-(4-benzene butoxy) benzene carbon amide]-6-[1,3-dioxo-3-ethoxycarbonyl propyl group] phenol;
M.4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-ethoxycarbonyl-4H-chromene is synthetic
Get 2-[4-(4-benzene butoxy) benzene carbon amide]-6-[1,3-dioxo-3-ethoxycarbonyl propyl group] phenol, THF, heating; Drip concentrated hydrochloric acid, the 8～15h that refluxes, cooling; Filter, the gained white solid is 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-ethoxycarbonyl-4H-chromene;
N.4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-aminocarboxyl-4H-chromene is synthetic
Getting 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-ethoxycarbonyl-4H-chromene is dissolved among the DMF; Feed dry ammonia; Reaction solution becomes redness by yellow, pours reaction solution in the cold water into, transfers to acidity; Filter, get product 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-aminocarboxyl-4H-chromene;
P.4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-cyanic acid-4H-chromene is synthetic
Get DMF, SOCl
2, 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-aminocarboxyl-4H-chromene; Pour in the cold water behind stirring 2～10h down for 0～15 ℃; Filter, the gained white solid is 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-cyanic acid-4H-chromene;
Q. pranlukast is synthetic
Get 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-cyanic acid-4H-chromene, ammonium chloride, sodiumazide, DMF, pour in the frozen water behind heating 1～8h, Hydrogen chloride transfers to acidity, filters, and the gained white solid is the finished product pranlukasts.
In the technique scheme, THF---THF, DMF---N, dinethylformamide,
Pd/C---palladium/carbon, SOCl
2---thionyl chloride.
Compound method of the present invention; Overcome the synthetic difficulty of the raw material that exists among the existing pranlukast preparation method; Be difficult for industrialized deficiency; Its technical progress that obtains is: have raw material and be easy to get, prepare that midbody reaction is simple, yield is high, reaction is safe, the characteristics of suitable suitability for industrialized production, can be used for preparing the medicine pranlukast of treating asthma, allergic rhinitis.
The present invention below will combine Figure of description and specific embodiment to do further explain.
Description of drawings
Fig. 1 is a process flow sheet of the present invention.
Embodiment
The following example only is used for explaining the present invention, does not limit the present invention.
Among each embodiment:
A, 4-butylene-chlorohydrin; B, 4-benzene butanols; C, 1-bromo-4-benzene butane;
D, methyl paraben; E, 4-(4-benzene butoxy)-oil of Niobe;
F, 4-(4-benzene butoxy)-phenylformic acid; G, acetate p bromophenol ester;
H, 5-bromo-2-hydroxy acetophenone; I, 5-bromo-3-nitro-2-hydroxy acetophenone;
J, 3-amino-2-hydroxy acetophenone;
K, 3-[4-(4-benzene butoxy) benzene carbon amide]-2-hydroxy acetophenone;
L, 2-[4-(4-benzene butoxy) benzene carbon amide]-6-[1,3-dioxy-3-methoxycarbonyl] phenol;
M, 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-methoxycarbonyl-4H-chromene;
N, 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-aminocarboxyl-4H-chromene;
P, 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-cyanic acid-4H-chromene;
Embodiment 1
A kind of method from THF approach synthetic drugs pranlukast, the synthetic route of this method is following:
With reference to process flow sheet shown in Figure 1, above-mentioned compound method may further comprise the steps:
A.4-butylene-chlorohydrin A's is synthetic
Add THF 144g, concentrated hydrochloric acid 200g in the there-necked flask, 60 ℃ of reaction 12h, cooling, dichloromethane extraction, desolventizing, underpressure distillation gets product A, i.e. the 4-butylene-chlorohydrin.
B.4-benzene butanols B's is synthetic
Add benzene 100ml, aluminum chloride 44.3g in the four-hole bottle, drip A 30g, reaction 7.5h in 12 ℃.Pour in the frozen water, separatory desolventizes, and underpressure distillation gets colourless transparent liquid B.
C.1-bromo-4-benzene butane C's is synthetic
Add B 0.38g, 40% Hydrogen bromide 1.08g in the there-necked flask, heating azeotropic band water is reduced to room temperature then, separatory, and organic phase desolventizes, and underpressure distillation gets product C 0.45g, yield 85%.
D. methyl paraben D's is synthetic
Add PHB 0.33g, methyl alcohol 1.3mL, vitriol oil 0.26mL in the four-hole boiling flask, screw out methyl alcohol behind the backflow 12.5h, pour in the cold water, separate out white solid, filtration, dry D 0.34g, the yield 94% of getting.
E.4-(4-benzene butoxy)-oil of Niobe E's is synthetic
Add C 0.45g, DMF 0.36g, toluene 1.05g, salt of wormwood 0.46g in the there-necked flask and go up step gained D, backflow 12.5h, cooling adds water, extracted in toluene, revolve steam weak yellow liquid, add ethyl alcohol recrystallization, white solid E0.57g, yield 93%.
F.4-(4-benzene butoxy)-phenylformic acid F's is synthetic
Add in the there-necked flask and go up step gained E, 2.85mL15%NaOH solution, backflow 3h is cooled to room temperature, 15% hcl acidifying, filtration, dry F 0.54g, the yield 99% of getting.
G. the preparation of acetate p bromophenol ester G
Add p bromophenol 1mol, aceticanhydride 1mol, pyridine 0.1mol, backflow 6.5h in the four-hole bottle.Steam pyridine, acetate and excessive acetic acid acid anhydride, underpressure distillation obtains G 1mol.
H.5-the preparation of bromo-2-hydroxy acetophenone H
Add aluminum chloride and each 0.5mol of zellon in the four-hole bottle, heating drips G 0.5mol, and backflow 3h is cooled to room temperature, and reaction solution is poured in the 350mL5% hydrochloric acid, dichloromethane extraction.Remove solvent under reduced pressure, obtain grey crystal form H.
I.5-the preparation of bromo-3-nitro-2-hydroxy acetophenone I
Add H0.64g, tetracol phenixin 2mL in the four-hole boiling flask, drip 0.41g nitric acid, backflow 3h when being heated to 70 ℃.Reduce to room temperature, filter, get the yellow solid 0.7g of I, yield 90%.
J.3-the preparation of amino-2-hydroxy acetophenone J
Add in the single port flask and go up step gained I, 5%Pd/C 0.4g, methylene dichloride 5mL, methyl alcohol 5.5mL, concentrated hydrochloric acid 0.3mL, water 1.2mL, hydrogenation.Finish afterreaction liquid and filter, filtrate decompression is removed and is desolvated, and transfers to neutrality with sodium hydrogencarbonate, gets the about 0.3g of ginger-colored solid J, yield 70%.
K.3-the preparation of [4-(4-benzene butoxy) benzene carbon amide]-2-hydroxy acetophenone K
Add gained 0.54g F, toluene 2mL, DMF0.004g among the step f in the there-necked flask, 75 ℃ of dripping thionyl chloride 0.26g splash into reaction solution in the toluene solution that is made by gained J of last step behind the 30min; Reaction 6.5h is cooled to room temperature, and Hydrogen chloride transfers to neutrality; Extracted in toluene; Revolve steaming, get the light yellow crystal 0.68g of K, yield 85%.
L.2-[4-(4-benzene butoxy) benzene carbon amide]-6-[1,3-dioxo-3-ethoxycarbonyl propyl group] phenol L's is synthetic
Add in the there-necked flask sodium methylate 0.55g, THF 11mL, on go on foot gained K, oxalic acid diethyl ester 0.29g, pour in the Hydrogen chloride after stirring 7h, separate out solid, filter, L 0.81g, yield 98%.
M.4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-ethoxycarbonyl-4H-chromene M's is synthetic
Step gained L, THF 24mL and an amount of concentrated hydrochloric acid are gone up in adding in the there-necked flask, backflow 12.5h, and cooling, freezing, filter, get the white solid 0.75g of M, yield 96%.
N.4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-aminocarboxyl-4H-chromene N is synthetic
Last step gained M is dissolved among the 15mL DMF, stirs down and feeds the exsiccant ammonia, and the reaction solution color becomes redness by yellow gradually, pours reaction solution in the cold water into, transfers to acidity with Hydrogen chloride, crosses to filter N0.65g, yield 89%.
P.4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-cyanic acid-4H-chromene P's is synthetic
Add DMF13mL, SOCl in the single port bottle
2Go up step gained N 0.5mL reach, after 7.5 ℃ are stirred 6h, pour in the cold water, filter, get 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-cyanic acid-4H-chromene white solid 0.5g, yield 80%.
Q. pranlukast is synthetic
Add in the single port bottle and go up step gained P, 0.07g ammonium chloride, 0.08g sodiumazide and 10mLDMF, heating 4.5h, cooling is poured in the frozen water, and Hydrogen chloride transfers to acidity, crosses to filter pranlukast white solid 0.43g, yield 78%.
Embodiment 2-embodiment 5
Embodiment 2-5 only is that with the difference of embodiment 1 the consumption conditions different, reaction of material are different, shown in table; In addition, per step output amount of substance yet different (not shown in the table) and per step output object all are not used for follow-up step.
Other content of the preparation method of above-mentioned each embodiment is consistent.
Claims (1)
1. method from THF approach synthetic drugs pranlukast, it is characterized in that: the synthetic route of this method is following:
Said compound method may further comprise the steps:
A.4-butylene-chlorohydrin is synthetic
Add concentrated hydrochloric acid among the THF, the mass ratio that feeds intake is 1: 1.389～5.556, and 45--80 ℃ is stirred 5--18h, cooling, and dichloromethane extraction, desolventizing, underpressure distillation gets the 4-butylene-chlorohydrin;
B.4-the benzene butanols is synthetic
Get benzene, aluminum chloride mixing, 0--25 ℃ adds the 4-butylene-chlorohydrin, pours in the frozen water behind the reaction 5--10h, and separatory desolventizes, underpressure distillation, and the gained colourless transparent liquid is a 4-benzene butanols;
C.1-bromo-4-benzene butane is synthetic
4-benzene butanols, 40% Hydrogen bromide mix, and the mass ratio that feeds intake is 1: 2.857～11.428, and reflux is divided water, cooling, and separatory, organic phase desolventizes, and underpressure distillation gets 1-bromo-4-benzene butane;
D. methyl paraben is synthetic
Get PHB and methyl alcohol, the vitriol oil mixes, and screws out methyl alcohol behind the backflow 5-20h, pours in the cold water, separates out white solid, and filtration, drying get methyl paraben;
E.4-(4-benzene butoxy)-oil of Niobe is synthetic
Get 1-bromo-4-benzene butane, DMF, toluene, methyl paraben and salt of wormwood, the 5～20h that refluxes, cooling adds water, extracted in toluene, revolve steam weak yellow liquid, recrystallization, gained white solid are 4-(4-benzene butoxy)-oil of Niobe;
F.4-(4-benzene butoxy)-benzoic synthetic
Get 4-(4-benzene butoxy)-oil of Niobe, 15%NaOH solution, the 1～5h that refluxes, cooling, acidifying, filtration, drying get 4-(4-benzene butoxy)-phenylformic acid;
G. the preparation of acetate p bromophenol ester
Get mol ratio and be 1: 1～1.5: 0.1～1 bromophenol, aceticanhydride, pyridine and feed intake, the 3～10h that refluxes steams pyridine, acetate and excessive aceticanhydride, and underpressure distillation obtains acetate p bromophenol ester;
H.5-the preparation of bromo-2-hydroxy acetophenone
Acetate p bromophenol ester, aluminum chloride, the zellon getting mol ratio and be 1: 1～5: 1 feed intake, the 0.5～5.5h that refluxes, cooling; Reaction solution is poured in 5% hydrochloric acid; Dichloromethane extraction removes solvent under reduced pressure, obtains grey crystal form 5-bromo-2-hydroxy acetophenone;
I.5-the preparation of bromo-3-nitro-2-hydroxy acetophenone
Get 5-bromo-2-hydroxy acetophenone, tetracol phenixin, drip nitric acid in the time of 50～90 ℃, the 1～4h that refluxes, cooling is filtered, and the gained yellow solid is 5-bromo-3-nitro-2-hydroxy acetophenone;
J.3-the preparation of amino-2-hydroxy acetophenone
Get 5-bromo-3-nitro-2-hydroxy acetophenone, 5%Pd/C, methylene dichloride, methyl alcohol, concentrated hydrochloric acid, water, hydrogenation; Finish afterreaction liquid and filter, filtrate decompression is removed and is desolvated, and transfers to neutrality with sodium hydrogencarbonate, and the ginger-colored solid of gained is 3-amino-2-hydroxy acetophenone;
K.3-the preparation of [4-(4-benzene butoxy) benzene carbon amide]-2-hydroxy acetophenone
Get 4-(4-benzene butoxy) phenylformic acid, toluene, DMF, 45～105 ℃ drip SOCl
2, behind the 30min reaction solution is splashed in the toluene solution of 3-amino-2-hydroxy acetophenone, reaction 3～10h, cooling, Hydrogen chloride transfers to neutrality, and extracted in toluene is revolved steaming, and the gained light yellow crystal is 3-[4-(4-benzene butoxy) benzene carbon amide]-2-hydroxy acetophenone;
L.2-[4-(4-benzene butoxy) benzene carbon amide]-6-[1,3-dioxo-3-ethoxycarbonyl propyl group] phenol is synthetic
Pour in the Hydrogen chloride behind sodium methylate, THF, 3-[4-(4-benzene butoxy) benzene carbon amide]-2-hydroxy acetophenone, the oxalic acid diethyl ester stirring reaction 4～10h; Separate out yellow solid; Filter; Products therefrom is 2-[4-(4-benzene butoxy) benzene carbon amide]-6-[1,3-dioxo-3-ethoxycarbonyl propyl group] phenol;
M.4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-ethoxycarbonyl-4H-chromene is synthetic
Get 2-[4-(4-benzene butoxy) benzene carbon amide]-6-[1,3-dioxo-3-ethoxycarbonyl propyl group] phenol, THF, heating; Drip concentrated hydrochloric acid, the 8～15h that refluxes, cooling; Filter, the gained white solid is 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-ethoxycarbonyl-4H-chromene;
N.4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-aminocarboxyl-4H-chromene is synthetic
Getting 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-ethoxycarbonyl-4H-chromene is dissolved among the DMF; Feed dry ammonia; Reaction solution becomes redness by yellow, pours reaction solution in the cold water into, transfers to acidity; Filter, get product 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-aminocarboxyl-4H-chromene;
P.4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-cyanic acid-4H-chromene is synthetic
Get DMF, SOCl
2, 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-aminocarboxyl-4H-chromene; Pour in the cold water behind stirring 2～10h down for 0～15 ℃; Filter, the gained white solid is 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-cyanic acid-4H-chromene;
Q. pranlukast is synthetic
Get 4-oxo-8-[4-(4-benzene butoxy) benzene carbon amide]-2-cyanic acid-4H-chromene, ammonium chloride, sodiumazide, DMF, pour in the frozen water behind heating 1～8h, Hydrogen chloride transfers to acidity, filters, and the gained white solid is the finished product pranlukasts.
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| CN104387268A (en) * | 2014-11-07 | 2015-03-04 | 济南大学 | Novel process for synthesizing Pranlukast intermediate p-phenylbutoxybenzoic acid |
| CN104402711A (en) * | 2014-11-12 | 2015-03-11 | 平湖优康药物研发有限公司 | Synthesis technology of intermediate of anti-asthma drug namely pranlukast |
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| CN108911948A (en) * | 2018-07-06 | 2018-11-30 | 杨程飞扬 | A kind of synthetic method of the bromo- 4- phenyl butane of intermediate 1- |
| CN108689843A (en) * | 2018-07-07 | 2018-10-23 | 杨程飞扬 | A kind of 4-(4- phenylbutoxies) benzoic acid synthetic method |
| 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 |
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| CN111410600A (en) * | 2020-01-21 | 2020-07-14 | 安徽省诚联医药科技有限公司 | Preparation method of p-phenylbutoxy benzoic acid |
| CN111302930B (en) * | 2020-03-12 | 2023-11-07 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of p-phenylbutoxy benzoic acid |
| 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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