CN104387268A - Novel process for synthesizing Pranlukast intermediate p-phenylbutoxybenzoic acid - Google Patents
Novel process for synthesizing Pranlukast intermediate p-phenylbutoxybenzoic acid Download PDFInfo
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/32—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by introduction of halogenated alkyl groups into ring compounds
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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Abstract
The invention discloses a novel process for synthesizing Pranlukast intermediate p-phenylbutoxybenzoic acid, belonging to the field of medicinal chemistry. The process is characterized by comprising the following steps: by using low-price 1,4-dichlorobutane as an initial raw material, carrying out reactions such as Friedel-Crafts alkylation, substitution and hydrolysis, thereby obtaining the p-phenylbutoxybenzoic acid. The method has the characteristics of cheap and easily available raw materials, short process route, low cost, reaction safety, environment friendliness and the like and is suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical synthesis, specifically a kind ofly synthesize the novel process of pranlukast intermediate to benzene butoxybenzoic acid.
Background technology
June nineteen ninety-five, antasthmatic pranlukast went on the market in Japan, and in November, 1999 rises and is used for the treatment of allergic rhinitis simultaneously.Pranlukast is leukotriene C/D4 Receptor antagonist (LTRAs), toxicity is extremely low, it optionally can suppress the activity of the many skins of airway smooth muscle leukotriene, on arachidonic acid metabolism enzyme almost without impact, simultaneously to vagusstoff, serotonins etc. are without antagonistic action, to LTC4, LTD4, LTE4 etc. all have remarkable suppression, particularly the main component of person's windpipe smooth muscle contraction is caused to LTD4() there is restraining effect, it is to the generation of asthma, development and control play an important role, do not affect P450 drug metabolizing enzyme, interaction can not be produced between medicine, the metabolism in body is not affected yet.Research shows, pranlukast not only answers the asthma of type in clinical application to spy, and all have good therapeutic action to the bronchial asthma of the other types such as mixed type, dye type, outbreak type, chronic type and non-season, be asthmatic medicament exploitation in recent years and one of focus studied.
The research of current China to this medicine is also in the starting stage, and to the intermediate of benzene butoxybenzoic acid as pranlukast, market demand rises gradually.
The pranlukast intermediate reported contains 4-phenyl butane and the methyl p-hydroxybenzoate condensation of leavings group mainly through 1 to the synthetic method of benzene butoxybenzoic acid, then hydrolysis is obtained to benzene butoxybenzoic acid.Synthetic route is as follows:
In formula, X is chlorine, bromine atoms and CH
3sO
3-etc., this is a comparatively ripe route.Therefore how efficiently to synthesize 1 4-phenyl butane intermediate containing leavings group, just become the core content of the present invention's research.Next, we mainly inquire into the synthetic route of this intermediate.
The synthetic method of 1 that has the reported 4-phenyl butane containing leavings group mainly contains following several:
1., in Japanese Patent JP-3-95144 in 1991, take tetrahydrofuran (THF) as raw material, obtain 4-phenyl-halide butane through open loop, Friedel-Crafts alkylation and halo.Its synthetic route is as follows:
In formula, X is halogen atom.The synthetic method cheaper starting materials of the 4-phenyl butyl halide reported in this patent is easy to get, but in report, do not describe the concrete yield of each step reaction.
2. nineteen ninety-five, European patent EP 637580 reports the synthetic route of 4-phenyl-bromide butane, and it take allyl bromide 98 as raw material, obtains product through grignard reaction, replacement and addition.Its synthetic route is as follows:
Although this route is brief, use hydrogen bromide to carry out anti-Markovnikov addition to double bond, operability is not strong, and yield is low, and cost is improved greatly.
3. 1999, Japanese Patent JP11292808 reported the synthetic route of 4-phenyl-bromide butane, took gamma-butyrolactone as starting raw material, obtained product through Hydrogen bromide open loop addition, chloro, Friedel-Crafts acidylate, reduction.Its synthetic route is as follows:
This synthetic route cheaper starting materials is easy to get, but carbonyl reduction condition is harsh, and yield is low, and the corresponding increase of cost, is not suitable for suitability for industrialized production.
4. calendar year 2001, in the synthetic route of the 4-phenyl-bromide butane that Japanese Patent JP2001131099 reports, take phenyl-magnesium-bromide as starting raw material, and direct and Isosorbide-5-Nitrae-dibromobutane is obtained by reacting product.Its synthetic route is as follows:
This synthetic route is brief, but starting raw material is expensive, is not suitable for suitability for industrialized production.
5. 2009, in the graphical Synthetic Routes of the pranlukast of a report, describing the synthesis of 4-phenyl-bromide butane, took Succinic anhydried as starting raw material, obtains 4-phenyl-bromide butane through Friedel-Crafts acidylate, reduction, esterification, reduction and bromo.Its synthetic route is as follows:
Although this route starting raw material price is cheap, reaction scheme is tediously long, and carbonyl and ester group reduction difficulty, make cost greatly increase, be not suitable for suitability for industrialized production.
6. 2010, Zhao meticulous with specialty chemicals on report the synthetic method of 4-phenylbutoxy sulphonate, it with the chloro-n-butyl alcohol of 4-for starting raw material, through Reactive Synthesis 4-phenylbutoxy sulphonates such as Friedel-Crafts alkylation, replacements.Synthetic route is as follows:
The synthetic route of document report, does not illustrate the preparation method of the chloro-n-butyl alcohol of starting raw material 4-, and requires that the chloro-n-butyl alcohol of 4-is fresh preparation.
Summary of the invention
The object of the invention is for overcoming above-mentioned technical deficiency, providing a kind of and synthesizing the novel process of pranlukast intermediate to benzene butoxybenzoic acid.It is with Isosorbide-5-Nitrae-dichlorobutane for raw material, prepares pranlukast intermediate to benzene butoxybenzoic acid through Friedel-Crafts alkylation, replacement, hydrolysis reaction.The method has cheaper starting materials and is easy to get, and operational path is short, and cost is lower, reaction safety, and the features such as environmental protection, are applicable to suitability for industrialized production.
Technical scheme of the present invention is as follows:
Synthesize the novel process of pranlukast intermediate to benzene butoxybenzoic acid, this operational path is as follows:
Above-mentioned operational path comprises the following steps:
A. the synthesis of 4-phenyl-chloride butane
With Isosorbide-5-Nitrae-dichlorobutane for solvent, add dry benzene, its mol ratio is 1:0.2 ~ 0.5, adds catalyzer in batches, and it is 0.3 ~ 0.5:1 with the mol ratio of benzene, control temperature of reaction 0 ~ 15 oC.React complete, add the mixed solution (volume ratio 5:1) of frozen water and concentrated hydrochloric acid, benzene extracts, and dry, underpressure distillation obtains 4-phenyl-chloride butane;
B. to the synthesis of benzene butoxybenzoic acid methyl esters
Get the said products 4-phenyl-chloride butane, add DMF, methyl p-hydroxybenzoate, salt of wormwood, Sodium Bromide and TEBA, under 50 oC, react 11 h.React complete cool to room temperature, add a certain amount of water, dichloromethane extraction, removed under reduced pressure methylene dichloride, obtain benzene butoxybenzoic acid methyl esters;
C. to the synthesis of benzene butoxybenzoic acid
Get the said products to benzene butoxybenzoic acid methyl esters, add NaOH solution and the ethanol of a certain amount of 15%.After back flow reaction 3 ~ 4 h, steam ethanol, be acidified to pH=2, separate out white solid, filter, dry, obtain product to benzene butoxybenzoic acid.
The mol ratio of Isosorbide-5-Nitrae-dichlorobutane and benzene described in above-mentioned steps a is 1:0.2 ~ 0.5, preferred 1:0.4; Described catalyzer comprises aluminum chloride, zinc chloride and tin tetrachloride etc., preferred aluminum chloride; The mol ratio of described catalyzer and benzene is 0.3 ~ 0.5:1, preferred 0.4:1; Described temperature of reaction is 0 ~ 15 oC, preferably 5 oC.
Technical progress acquired by the present invention is: have cheaper starting materials and be easy to get, operational path is short, and cost is lower, reaction safety, and the feature of environmental protection, is applicable to suitability for industrialized production.
Embodiment
Below in conjunction with specific examples, the invention will be further described.
Embodiment 1
A. the synthesis of 4-phenyl-chloride butane
In 100 mL there-necked flasks, add dry Isosorbide-5-Nitrae-dichlorobutane (15 mL) and dry benzene (5 mL), in ice bath, stir under 4 ~ 5 oC, add aluminum chloride (2.26 g) in batches.After reaction terminates, slowly add 10 mL frozen water and concentrated hydrochloric acid mixed solution (volume ratio is 5:1), stir 10 min, separate organic phase, benzene aqueous phase extracted, organic phase is merged, with 20 mL water washings twice, gained organic phase MgSO
4drying, filter, filtrate decompression removes unreacted benzene and Isosorbide-5-Nitrae-dichlorobutane, and gained light yellow transparent liquid is 4-phenyl-chloride butane.
B. to the synthesis of benzene butoxybenzoic acid methyl esters
In 100 mL there-necked flasks, add the said products 4-phenyl-chloride butane, DMF(15 mL).Under mechanical stirring, add methyl p-hydroxybenzoate (0.6 g, 3.95 mmol) successively, salt of wormwood (1.1 g, 7.9 mmol), NaBr(0.1 g), TEBA(0.2 g), be heated to 50 oC, insulation reaction 11 h.React complete, be down to room temperature, add 20 mL water washings, dichloromethane extraction, gained organic phase removed under reduced pressure methylene dichloride, obtains orange liquid 1.06 g, and be benzene butoxybenzoic acid methyl esters, yield is 95%.
C. to the synthesis of benzene butoxybenzoic acid
In 100 mL there-necked flasks, add above-mentioned products obtained therefrom, 15% NaOH solution with (3 mL) and ethanol (10 mL), back flow reaction 3 h in oil bath.React complete, steam ethanol, be acidified to pH=2, produce white solid, filter, gained solid recrystallisation from isopropanol, obtains benzene butoxybenzoic acid 0.9 g, yield 90%.
Embodiment 2
A. the synthesis of 4-phenyl-chloride butane
In 100 mL there-necked flasks, add dry Isosorbide-5-Nitrae-dichlorobutane (20 mL) and dry benzene (5 mL), stir under 4 ~ 5 oC in ice bath, add aluminum chloride (2.9 g) in batches.After reaction terminates, slowly add 10 mL frozen water and concentrated hydrochloric acid mixed solution (volume ratio is 5:1), stir 10 min, separate organic phase, benzene aqueous phase extracted, merge organic phase, with 20 mL water washings twice, gained organic phase MgSO
4drying, filter, filtrate decompression removes unreacted benzene and Isosorbide-5-Nitrae-dichlorobutane, and gained light yellow transparent liquid is 4-phenyl-chloride butane.
B. to the synthesis of benzene butoxybenzoic acid methyl esters
In 100 mL there-necked flasks, add the said products 4-phenyl-chloride butane, DMF(15 mL).Under mechanical stirring, add methyl p-hydroxybenzoate (0.6 g, 3.95 mmol) successively, salt of wormwood (1.1 g, 7.9 mmol), NaBr(0.1 g), TEBA(0.2 g), be heated to 50 oC, insulation reaction 11 h.React complete, be down to room temperature, add 20 mL water washings, dichloromethane extraction, gained organic phase removed under reduced pressure methylene dichloride, obtains orange liquid 1.07 g, and be benzene butoxybenzoic acid methyl esters, yield is 96%.
C. to the synthesis of benzene butoxybenzoic acid
In 100 mL there-necked flasks, add above-mentioned products obtained therefrom, 15% NaOH solution (3 mL) and ethanol (10 mL), back flow reaction 3 h in oil bath.React complete, steam ethanol, be acidified to pH=2, produce white solid, filter, gained solid recrystallisation from isopropanol, obtains benzene butoxybenzoic acid 0.92 g, yield 92%.
Embodiment 3
A. the synthesis of 4-phenyl-chloride butane
In 100 mL there-necked flasks, add dry Isosorbide-5-Nitrae-dichlorobutane 25 mL and dry benzene 5 mL, in ice bath, 10 oC stir, and add aluminum chloride (3.76 g) in batches.After reaction terminates, slowly add 10 mL frozen water and concentrated hydrochloric acid mixed solution (volume ratio is 5:1), stir 10 min, separate organic phase, benzene aqueous phase extracted, merge organic phase, with 20 mL water washings twice, gained organic phase MgSO
4drying, filter, filtrate decompression removes unreacted benzene and Isosorbide-5-Nitrae-dichlorobutane, and gained light yellow transparent liquid is 4-phenyl-chloride butane.
B. to the synthesis of benzene butoxybenzoic acid methyl esters
In 100 mL there-necked flasks, add the said products 4-phenyl-chloride butane, DMF(15 mL).Under mechanical stirring, add methyl p-hydroxybenzoate (0.6 g, 3.95 mmol) successively, salt of wormwood (1.1 g, 7.9 mmol), NaBr(0.1 g), TEBA(0.2 g), be heated to 50 oC, insulation reaction 11 h.React complete, be down to room temperature, add 20 mL water washings, dichloromethane extraction, gained organic phase removed under reduced pressure methylene dichloride, obtains orange liquid 1.05 g, and be benzene butoxybenzoic acid methyl esters, yield is 94%.
C. to the synthesis of benzene butoxybenzoic acid
In 100 mL there-necked flasks, add above-mentioned products obtained therefrom, 15% NaOH solution (3 mL) and ethanol (10 mL), back flow reaction 3 h in oil bath.React complete, steam ethanol, be acidified to pH=2, produce white solid, filter, gained solid recrystallisation from isopropanol, obtains benzene butoxybenzoic acid 0.89 g, yield 89%.
Embodiment 4
A. the synthesis of 4-phenyl-chloride butane
In 100 mL there-necked flasks, add dry Isosorbide-5-Nitrae-dichlorobutane (30 mL) and dry benzene (5 mL), stir under 10 oC in ice bath, add aluminum chloride (2.9 g) in batches.After reaction terminates, slowly add 10 mL frozen water and concentrated hydrochloric acid mixed solution (volume ratio is 5:1), stir 10 min, separate organic phase, benzene aqueous phase extracted, merge organic phase, with 20 mL water washings twice, gained organic phase MgSO
4drying, filter, filtrate decompression removes unreacted benzene and Isosorbide-5-Nitrae-dichlorobutane, and gained light yellow transparent liquid is 4-phenyl-chloride butane.
B. to the synthesis of benzene butoxybenzoic acid methyl esters
In 100 mL there-necked flasks, add the said products 4-phenyl-chloride butane, DMF(15 mL), under mechanical stirring, add methyl p-hydroxybenzoate (0.6 g successively, 3.95 mmol), salt of wormwood (1.1 g, 7.9 mmol), NaBr(0.1 g), TEBA(0.2 g), be heated to 50 oC, insulation reaction 11 h.React complete, under being down to room temperature, add 20 mL water washings, dichloromethane extraction, the decompression of gained organic phase steams methylene dichloride, and obtain orange liquid 1.06 g, be benzene butoxybenzoic acid methyl esters, yield is 95%.
C. to the synthesis of benzene butoxybenzoic acid
In 100 mL there-necked flasks, add above-mentioned products obtained therefrom, 15% NaOH solution (3 mL) and ethanol (10 mL), back flow reaction 3 h in oil bath.React complete, steam ethanol, be acidified to pH=2, produce white solid, filter, gained solid recrystallisation from isopropanol, obtains benzene butoxybenzoic acid 0.9 g, yield 90%.
Embodiment 5
A. the synthesis of 4-phenyl-chloride butane
In 100 mL there-necked flasks, add dry Isosorbide-5-Nitrae-dichlorobutane (15 mL) and dry benzene (5 mL), stir under 13 oC in ice bath, add zinc chloride 2.26 g in batches, tlc and gas-chromatography following response process, after reaction terminates, slowly add 10 mL frozen water and concentrated hydrochloric acid mixed solution (volume ratio is 5:1), stir 10 min, separate organic phase, benzene aqueous phase extracted, merge organic phase, with 20 mL water washings twice, gained organic phase MgSO
4drying, filter, filtrate decompression removes unreacted benzene and Isosorbide-5-Nitrae-dichlorobutane, and gained light yellow transparent liquid is 4-phenyl-chloride butane.
B. to the synthesis of benzene butoxybenzoic acid methyl esters
In 100 mL there-necked flasks, add the said products 4-phenyl-chloride butane, DMF(15 mL), under mechanical stirring, add methyl p-hydroxybenzoate (0.6 g successively, 3.95 mol), salt of wormwood (1.1 g, 7.9 mmol), NaBr(0.1 g), TEBA(0.2 g), be heated to 50 oC, insulation reaction 11 h.React complete, be down to room temperature, add 20 mL water washings, dichloromethane extraction, the decompression of gained organic phase steams methylene dichloride, and obtain orange liquid 1.07 g, be benzene butoxybenzoic acid methyl esters, yield is 96%.
C. to the synthesis of benzene butoxybenzoic acid
In 100 mL there-necked flasks, add above-mentioned products obtained therefrom, 15% NaOH solution (3 mL) and ethanol (10 mL), back flow reaction 3 h in oil bath.React complete, steam ethanol, be acidified to pH=2, produce white solid, filter, gained solid recrystallisation from isopropanol, obtains benzene butoxybenzoic acid 0.92 g, yield 92%.
Embodiment 6
A. the synthesis of 4-phenyl-chloride butane
In 100 mL there-necked flasks, add dry Isosorbide-5-Nitrae-dichlorobutane (20 mL) and dry benzene (5 mL), stir under 3 oC in ice bath, add zinc chloride 2.9 g in batches.After reaction terminates, slowly add 10 mL frozen water and concentrated hydrochloric acid mixed solution (volume ratio is 5:1), stir 10 min, separate organic phase, a certain amount of benzene of aqueous phase extracts, and merges organic phase, with 20 mL water washings twice, and gained organic phase MgSO
4drying, filter, filtrate decompression distills out unreacted benzene and Isosorbide-5-Nitrae-dichlorobutane, and gained light yellow transparent liquid is 4-phenyl-chloride butane.
B. to the synthesis of benzene butoxybenzoic acid methyl esters
In 100 mL there-necked flasks, add the said products 4-phenyl-chloride butane, DMF(15 mL).Under mechanical stirring, add methyl p-hydroxybenzoate (0.6 g, 3.95 mmol) successively, salt of wormwood (1.1 g, 7.9 mmol), NaBr(0.1 g), TEBA(0.2 g), be heated to 50 oC, insulation reaction 11 h.React complete, be down to room temperature, add 20 mL water washings, dichloromethane extraction, the decompression of gained organic phase steams methylene dichloride, and obtain orange liquid 1.07 g, be benzene butoxybenzoic acid methyl esters, yield is 96%.
C. to the synthesis of benzene butoxybenzoic acid
In 100 mL there-necked flasks, add above-mentioned products obtained therefrom, 15% NaOH solution (3 mL) and ethanol (10 mL), back flow reaction 3 h in oil bath.React complete, steam ethanol, be acidified to pH=2, produce white solid, filter, gained solid recrystallisation from isopropanol, obtains benzene butoxybenzoic acid 0.91 g, yield 91%.
Embodiment 7
A. the synthesis of 4-phenyl-chloride butane
In 100 mL there-necked flasks, add dry Isosorbide-5-Nitrae-dichlorobutane (20 mL) and dry benzene (5 mL), stir under 3 oC in ice bath, add tin tetrachloride 2.2 g in batches.After reaction terminates, slowly add 10 mL frozen water and concentrated hydrochloric acid mixed solution (volume ratio is 5:1), stir 10 min, separate organic phase, benzene aqueous phase extracted, merge organic phase, with 20 mL water washings twice, gained organic phase MgSO
4drying, filter, filtrate decompression removes unreacted benzene and Isosorbide-5-Nitrae-dichlorobutane, and gained light yellow transparent liquid is 4-phenyl-chloride butane.
B. to the synthesis of benzene butoxybenzoic acid methyl esters
In 100 mL there-necked flasks, add the said products 4-phenyl-chloride butane, DMF(15 mL).Under mechanical stirring, add methyl p-hydroxybenzoate (0.6 g, 3.95 mol) successively, salt of wormwood (1.1 g, 7.9 mol), NaBr(0.1 g), TEBA(0.2 g), be heated to 50 oC, insulation reaction 11 h.React complete, be down to room temperature, add 20 mL water washings, dichloromethane extraction, gained organic phase removed under reduced pressure methylene dichloride, obtains orange liquid 1.06 g, and be benzene butoxybenzoic acid methyl esters, yield is 95%.
C. to the synthesis of benzene butoxybenzoic acid
In 100 mL there-necked flasks, add above-mentioned products obtained therefrom, 15% NaOH solution (3 mL) and ethanol (10 mL), back flow reaction 3 h in oil bath.React complete, steam ethanol, be acidified to pH=2, produce white solid, filter, gained solid recrystallisation from isopropanol, obtains benzene butoxybenzoic acid 0.91 g, yield 91%.
Embodiment 8
A. the synthesis of 4-phenyl-chloride butane
In 100 mL there-necked flasks, add dry Isosorbide-5-Nitrae-dichlorobutane (25 mL) and dry benzene (5 mL), stir under 5 oC in ice bath, add aluminum chloride (2.9 g) in batches.After reaction terminates, slowly add 10 mL frozen water and concentrated hydrochloric acid mixed solution (volume ratio is 5:1), stir 10 min, separate organic phase, benzene aqueous phase extracted, merge organic phase, with 20 mL water washings twice, gained organic phase MgSO
4drying, filter, filtrate decompression removes unreacted benzene and Isosorbide-5-Nitrae-dichlorobutane, and gained light yellow transparent liquid is 4-phenyl-chloride butane.
B. to the synthesis of benzene butoxybenzoic acid methyl esters
In 100 mL there-necked flasks, add the said products 4-phenyl-chloride butane, DMF(15 mL).Under mechanical stirring, add methyl p-hydroxybenzoate (0.6 g, 3.95 mol) successively, salt of wormwood (1.1 g, 7.9 mol), NaBr(0.1 g), TEBA(0.2 g), be heated to 50 oC, insulation reaction 11 h.React complete, be down to room temperature, add 20 mL water washings, dichloromethane extraction, gained organic phase removed under reduced pressure methylene dichloride, obtains orange liquid 1.07 g, and be benzene butoxybenzoic acid methyl esters, yield is 96%.
C. to the synthesis of benzene butoxybenzoic acid
In 100 mL there-necked flasks, add above-mentioned products obtained therefrom, 15% NaOH solution (3 mL) and ethanol (10 mL), back flow reaction 3 h in oil bath.React complete, steam ethanol, be acidified to pH=2, produce white solid, filter, gained solid recrystallisation from isopropanol, obtains benzene butoxybenzoic acid 0.91 g, yield 91%.
The specific embodiment of the present invention is described although above-mentioned in conjunction with the embodiments; but not limiting the scope of the invention; one of ordinary skill in the art should be understood that; on the basis of technical scheme of the present invention, those skilled in the art do not need to pay various amendment or distortion that creative work can make still within protection scope of the present invention.
Claims (6)
1. synthesize the novel process of pranlukast intermediate to benzene butoxybenzoic acid, it is characterized in that: the method has following synthetic route.
2. a kind ofly synthesize the novel process of pranlukast intermediate to benzene butoxybenzoic acid as claimed in claim 1, it is characterized in that described operational path comprises the following steps:
A. the synthesis of 4-phenyl-chloride butane
With Isosorbide-5-Nitrae-dichlorobutane for solvent, add dry benzene, its mol ratio is 1:0.2 ~ 0.5, adds catalyzer in batches, and it is 0.3 ~ 0.5:1 with the mol ratio of benzene, control temperature of reaction 0 ~ 15 oC;
React complete, add the mixed solution (volume ratio 5:1) of frozen water and concentrated hydrochloric acid, benzene extracts, and dry, underpressure distillation obtains 4-phenyl-chloride butane;
B. to the synthesis of benzene butoxybenzoic acid methyl esters
To in the said products 4-phenyl-chloride butane, add DMF, methyl p-hydroxybenzoate, salt of wormwood, Sodium Bromide and TEBA, under 50 oC, react 11 h; React complete cool to room temperature, add a certain amount of water, dichloromethane extraction, removed under reduced pressure methylene dichloride, obtain benzene butoxybenzoic acid methyl esters;
C. to the synthesis of benzene butoxybenzoic acid
Get the said products to benzene butoxybenzoic acid methyl esters, add NaOH solution and the ethanol of a certain amount of 15%; After back flow reaction 3 ~ 4 h, steam ethanol, be acidified to pH=2, separate out white solid, filter, dry, obtain product to benzene butoxybenzoic acid.
3. as described in claim 2 step a, the mol ratio of Isosorbide-5-Nitrae-dichlorobutane and benzene is 1:0.2 ~ 0.5, preferred 1:0.4.
4. the catalyzer as described in claim 2 step a, comprises aluminum chloride, zinc chloride and tin tetrachloride etc., preferred aluminum chloride.
5. as described in claim 2 step a, the mol ratio of catalyzer and benzene is 0.3 ~ 0.5:1, preferred 0.4:1.
6. as described in claim 2 step a, temperature of reaction is 0 ~ 15 oC, preferably 5 oC.
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Cited By (6)
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| CN105732367A (en) * | 2016-03-23 | 2016-07-06 | 叶芳 | P-phenylbutoxy benzoic acid and preparation method thereof |
| CN108558916A (en) * | 2018-05-22 | 2018-09-21 | 昆山力田医化科技有限公司 | A kind of synthesis technology to benzene butoxybenzoic acid |
| 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 |
| CN110258107A (en) * | 2019-06-12 | 2019-09-20 | 山东丰源轮胎制造股份有限公司 | A kind of ammoniation modified processing method of aramid fiber surface |
| CN110357772A (en) * | 2019-07-22 | 2019-10-22 | 杭州煌森生物科技有限公司 | A kind of preparation method of pair of benzene butoxybenzoic acid |
| 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 |
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| CN101450943A (en) * | 2008-11-10 | 2009-06-10 | 河北科技大学 | Method for synthesizing drug pranlukast from tetrahydrofuran path |
| CN103539630A (en) * | 2013-10-24 | 2014-01-29 | 昆山力田医化科技有限公司 | Preparation method of 1-chloro-4-phenyl butane |
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| CN105732367A (en) * | 2016-03-23 | 2016-07-06 | 叶芳 | P-phenylbutoxy benzoic acid and preparation method thereof |
| CN108558916A (en) * | 2018-05-22 | 2018-09-21 | 昆山力田医化科技有限公司 | A kind of synthesis technology to benzene butoxybenzoic acid |
| 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 |
| CN110258107A (en) * | 2019-06-12 | 2019-09-20 | 山东丰源轮胎制造股份有限公司 | A kind of ammoniation modified processing method of aramid fiber surface |
| CN110357772A (en) * | 2019-07-22 | 2019-10-22 | 杭州煌森生物科技有限公司 | A kind of preparation method of pair of benzene butoxybenzoic acid |
| 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 |
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