CN104876853B - The synthetic method of fexofenadine hydrochloride - Google Patents

The synthetic method of fexofenadine hydrochloride Download PDF

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CN104876853B
CN104876853B CN201510336029.1A CN201510336029A CN104876853B CN 104876853 B CN104876853 B CN 104876853B CN 201510336029 A CN201510336029 A CN 201510336029A CN 104876853 B CN104876853 B CN 104876853B
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ethyl acetate
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CN104876853A (en
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张立光
尤彩芬
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Suzhou Xineng Environmental Protection Technology Co., Ltd
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Suzhou Vocational Health College
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms

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Abstract

The invention discloses the synthetic method of fexofenadine hydrochloride; the synthetic method of fexofenadine hydrochloride of the invention is raw material with 2 (4 bromophenyl) 2 methylpropanoic acids (2); by itself and nafoxidine reaction protection carboxyl, then reacted with gamma butyrolactone, generate compound 6; compound 6 reacts with paratoluensulfonyl chloride; product again with α, the piperidine carbinols of α diphenyl 4 condensation, by reduction; deprotection, is finally obtained target compound 1.This route is raw materials used cheap and easy to get, and reaction condition is gentle, and simple to operation, environmental pollution is smaller, is an industrialized route with preferable application prospect.

Description

The synthetic method of fexofenadine hydrochloride
Technical field
The invention belongs to organic synthesis field, it is related to the chemical synthesis process of fexofenadine hydrochloride.
Background technology
Fexofenadine hydrochloride (Fexofenadine hydrochloride, 1), chemistry is entitled：(±) -4- [1- hydroxyls Base -4- [4- (hydroxy benzophenone base) -1- piperidyls]-butyl]-alpha-alpha-dimethyl phenyl acetic acid hydrochloride is a kind of H1Acceptor is short of money Anti-agent.Fexofenadine hydrochloride curative effect is high, Small side effects, and effect is fast, clinically for mitigating seasonal allergic rhinitis and slow The symptom that property idiopathic urticaria causes.
The document report of relevant fexofenadine synthesis is more, is broadly divided into two major classes：(1) with ethyl phenylacetate as rise Beginning raw material, is first methylated, then through paying-gram acylation, with α, α-diphenyl -4- piperidine carbinols condensation, hydrolysis is obtained after reduction Target product.Although the Fu Zhongsun in this route is still difficult to avoid that the product of isomers by many optimizations It is raw, reduce total recovery and increased the purifying difficulty of product.And need to use a large amount of AlCl in the reaction3, environment is made Into harm.(2) to be raw material to bromo-acid methyl esters, first methylate, be condensed through sonogashira, with α, α-diphenyl -4- Piperidine carbinols are condensed, and reoxidize, and reduce, and hydrolysis obtains target product.This route is when alkynes intermediate is aoxidized, it is necessary to use HgO or Pt, toxicity is larger, easily pollutes environment, and high cost, severe reaction conditions are unfavorable for industrialized production.
The content of the invention
The technical problem to be solved：It is an object of the invention to provide a kind of synthetic method of fexofenadine hydrochloride, salt is overcome Cost of material is higher in the conventional synthetic method of sour fexofenadine, and severe reaction conditions, trivial operations, environmental pollution is larger Problem.
Technical scheme：Regarding to the issue above, the invention discloses the synthetic method of fexofenadine hydrochloride, described synthesis Method comprises the steps：
S1：2- (4- bromophenyls) -2- methyl propionyl ring butylamine（4）Synthesis
In the three-necked bottle equipped with drying tube, dichloromethane is added, stirring adds 2- (4- bromophenyls) -2 Methylpropionic acid And carbonyl dimidazoles, stirring, start that nafoxidine is added dropwise, continue to stir at room temperature；Reaction is finished, and adds hydrochloric acid solution, is stirred, Stratification；Organic phase vacuum distillation, obtains yellow solid；
S2：4- hydroxyls -1- (4- (2- methyl isophthalic acids-oxygen -1- pyrrolidin-1-yls) propane -2- bases) phenyl) -1- ketone (6) conjunction Into
To sequentially adding dry THF, magnesium powder, compound (4), heating stirring in three-necked bottle under nitrogen protection；At another Dry THF, γ-butyl lactone (5), N, O- dimethyl hydroxylamine hydrochloride, sodium methoxide, under magnetic agitation are sequentially added in three-necked bottle Ice bath is cooled to 5 DEG C, in the Grignard reagent dropwise that will be made to reaction bulb；Stirred under ice bath, then be warming up to and be stirred at room temperature；Reaction Reacted with hydrochloric acid after completely, decompression steams THF, add water, ethyl acetate extraction；Ethyl acetate layer is concentrated, obtains light Yellow oil, it is not purified to direct plunge into next step；
S3：4- (4- (2- methyl isophthalic acids-oxygen -1- (pyrrolidin-1-yl) propane -2- bases) phenyl) -4- oxygen-butyl -4- methyl The synthesis of benzene sulfonyl (7)
To sequentially adding dry methylene chloride in three-necked bottle under nitrogen protection, compound (6), triethylamine, then in room temperature It is lower to be stirred to dropwise addition paratoluensulfonyl chloride in reaction bulb；Water extraction is added, dichloromethane layer is collected, ethyl alcohol recrystallization is used after being spin-dried for Obtain white solid;
S4：4- (4- (hydroxyl diphenyl methyl) piperidin-1-yl) -1- (4- (2- methyl isophthalic acids-oxygen -1- (p pyrrolidines -1- Base) propane -2- bases) phenyl) butyl -1- ketone（9）Synthesis
To sequentially adding methyltetrahydrofuran, compound (7), diphenyl piperazine methyl alcohol in three-necked bottle under nitrogen protection（8）, Triethylamine, stirs at room temperature；Add hydrochloric acid, layering, be concentrated under reduced pressure organic phase, obtains crude product, then with ethyl acetate/normal heptane weight Crystallization obtains white solid；
S5：2- (4- (1- hydroxyls -4- (4- (hydroxyl diphenyl methyl) piperidin-1-yl) butyl) phenyl) -2- methyl isophthalic acids - The synthesis of (piperidin-1-yl) propyl group -1- ketone (10)
Under nitrogen protection to ethanol is sequentially added in three-necked bottle, compound (9), sodium borohydride is stirred at room temperature；Will be full It is added dropwise in reaction bulb with ammonium chloride solution, adds ethyl acetate, water, layering, organic phase concentrated under reduced pressure obtains faint yellow oil Shape thing, is directly used in next step reaction；
S6：The synthesis of fexofenadine hydrochloride (1)
To ethanol is sequentially added in three-necked bottle under nitrogen protection, compound (10), concentrated hydrochloric acid is heated to reflux, and is cooled to room Wen Hou, adds ethyl acetate, water to collect organic phase, and water is mutually extracted with ethyl acetate again；Merge organic phase, use saturated aqueous common salt Washing, concentrates organic phase, and compound is recrystallized to obtain with ethanol/water mixed solvent（1）；
The reaction equation of described synthetic method is as follows：
Further, the synthetic method of described fexofenadine hydrochloride, described synthetic method step is specific as follows：
S1：2- (4- bromophenyls) -2- methyl propionyl ring butylamine（4）Synthesis
In the 500 mL three-necked bottles equipped with drying tube, dichloromethane 200mL is added, stirred, addition 2- (4- bromophenyls)- 2 Methylpropionic acid 24.2g (100mmol) and carbonyl dimidazoles 24.3g (150mmol), stirs 30min at room temperature, starts dropwise addition four Hydrogen pyrroles 7.8g (110mmol), continues to stir 2h at room temperature；Reaction is finished, and adds the hydrochloric acid solution 150mL of 10wt%, is stirred, Stratification；Organic phase vacuum distillation, obtains yellow solid 27.1g；
S2：4- hydroxyls -1- (4- (2- methyl isophthalic acids-oxygen -1- pyrrolidin-1-yls) propane -2- bases) phenyl) -1- ketone (6) conjunction Into
To sequentially adding dry THF 100mL, magnesium powder 19.1g (190mmol), chemical combination in 500mL three-necked bottles under nitrogen protection Thing (4) 27.1g (91.8mmol), is heated to 40 DEG C of stirring 1h；Drying is sequentially added in another 500mL three-necked bottle THF100mL, γ-butyl lactone (5) 11.9g (137.7mmol）, N, O- dimethyl hydroxylamine hydrochloride 16.0g (165.2mmol), Sodium methoxide 1.86g（34.4mmol）, ice bath is cooled to 5 DEG C under magnetic agitation, in the Grignard reagent dropwise that will be made to reaction bulb； 2 h are stirred under ice bath, then is warming up to 8 h is stirred at room temperature；Reaction is quenched with 1N hydrochloric acid 50mL after reaction completely, decompression steams THF, Add water 100mL, ethyl acetate 300mL extractions.Ethyl acetate layer is concentrated, pale yellow oil 23.8g is obtained, it is not purified Direct plunge into next step；
S3：4- (4- (2- methyl isophthalic acids-oxygen -1- (pyrrolidin-1-yl) propane -2- bases) phenyl) -4- oxygen-butyl -4- methyl The synthesis of benzene sulfonyl (7)
To sequentially adding dry methylene chloride 250mL, compound (6) 23.8g in 500mL three-necked bottles under nitrogen protection (78.5mmol), triethylamine 15.9g (157mmol), then at room temperature to dropwise addition paratoluensulfonyl chloride 17.9g in reaction bulb (94.2mmol), stirs 8 h；Water 200mL extractions are added, dichloromethane layer is collected, obtains white solid with ethyl alcohol recrystallization after being spin-dried for Body 27.9g（73.2mmol）;
S4：4- (4- (hydroxyl diphenyl methyl) piperidin-1-yl) -1- (4- (2- methyl isophthalic acids-oxygen -1- (p pyrrolidines -1- Base) propane -2- bases) phenyl) butyl -1- ketone（9）Synthesis
To sequentially adding methyltetrahydrofuran 100mL, compound (7) 27.9g in 500mL three-necked bottles under nitrogen protection （73.2mmol）, diphenyl piperazine methyl alcohol（8）23.5g（87.8mmol）, triethylamine 8.9g（87.8mmol）, 8 are stirred at room temperature h；Add 1N hydrochloric acid 50mL, layering, be concentrated under reduced pressure organic phase, obtains crude product, then with ethyl acetate/normal heptane（v/v ½）Tie again Crystalline substance obtains white solid 29.9g；
S5：2- (4- (1- hydroxyls -4- (4- (hydroxyl diphenyl methyl) piperidin-1-yl) butyl) phenyl) -2- methyl isophthalic acids - The synthesis of (piperidin-1-yl) propyl group -1- ketone (10)
Under nitrogen protection to sequentially adding ethanol 300mL, compound (9) 29.9g in 500mL three-necked bottles （54.2mmol）, sodium borohydride 4.3g（114.6mmol）, 3 h are stirred at room temperature；100mL saturated ammonium chloride solutions are added dropwise to In reaction bulb, ethyl acetate 300mL, water 200mL are added, be layered, be concentrated under reduced pressure organic phase, obtains pale yellow oil 27.4g, is directly used in next step reaction；
S6：The synthesis of fexofenadine hydrochloride (1)
To sequentially adding ethanol 200mL, compound (10) 27.4g in 500mL three-necked bottles under nitrogen protection (49.4mmol), concentrated hydrochloric acid 24.7mL (296.6mmol), is heated to reflux 6 h, after being cooled to room temperature, adds ethyl acetate 200mL, water 200mL, collect organic phase, and water is mutually extracted with ethyl acetate 100mL again；Merge organic phase, use 100mL saturated common salts Water washing, concentrates organic phase, uses ethanol/water（V/V 2:1）Mixed solvent recrystallizes to obtain compound（1）22.78g.
The synthetic method of described fexofenadine hydrochloride, the yield 85.5% of described fexofenadine hydrochloride (1), Purity is 98.5%.
The synthetic method of described fexofenadine hydrochloride, described 4- (4- (hydroxyl diphenyl methyl) piperidin-1-yl)- 1- (4- (2- methyl isophthalic acids-oxygen -1- (p pyrrolidin-1-yls) propane -2- bases) phenyl) butyl -1- ketone（9）Yield be 74.0%, it is pure Degree 98.5%.
The synthetic method of described fexofenadine hydrochloride, described 4- (4- (2- methyl isophthalic acids-oxygen -1- (pyrrolidines -1- Base) propane -2- bases) phenyl) and -4- oxygen-butyl -4- Methyl benzenesulfonyls (7) yield be 93.3%, purity is 98.8%.
Beneficial effect：The synthetic method of fexofenadine hydrochloride of the invention is with 2- (4- bromophenyls) -2 Methylpropionic acid (2) Be raw material, by itself and nafoxidine reaction protection carboxyl, then with gamma-butyrolacton reaction, generate compound 6, compound 6 with to first Benzene sulfonyl chloride reacts, product again with α, α-diphenyl -4- piperidine carbinols condensation, by reduction, deprotection is finally obtained targeted Compound 1.This route is raw materials used cheap and easy to get, and reaction condition is gentle, and simple to operation, environmental pollution is smaller, and being one has The industrialized route of preferable application prospect.
Specific embodiment
Key instrument and material
2- (4- bromophenyls) -2 Methylpropionic acid, carbonyl dimidazoles, nafoxidine, GBL, N, O- dimethyl hydroxylamine Hydrochloride（Lark waffle Technology Co., Ltd.）, magnesium powder, sodium methoxide, triethylamine, paratoluensulfonyl chloride, sodium borohydride (traditional Chinese medicines Chemical reagent Co., Ltd), diphenyl piperazine methyl alcohol (West Asia reagent）.
Bruker ARX300 NMRs (German Bruker companies), the high performance liquid chromatographs of Agilent 1100.
2- (4- bromophenyls) -2- methyl propionyl ring butylamine（4）Synthesis
In the 500 mL three-necked bottles equipped with drying tube, dichloromethane 200mL is added, under stirring, add 2- (4- bromobenzenes Base) -2 Methylpropionic acid 24.2g (100mmol) and carbonyl dimidazoles（CDI）24.3g (150mmol), stirs 30min at room temperature, Start that nafoxidine 7.8g (110mmol) is added dropwise, continue to stir 2h at room temperature.Reaction is finished, and adds 10% hydrochloric acid 150ml, is stirred Mix, stratification.Organic phase vacuum distillation, obtains yellow solid 27.1g（Yield 92.0%）, [HPLC is normalized purity 93.0% Method：Permaphase ODS post (4.6mm × 250mm, 5 μm)；Mobile phase：Acetonitrile-phosphate buffer（pH 3.0）, Detection wavelength 254nm, 25 DEG C of column temperature], it is not purified to direct plunge into next step.
4- hydroxyls -1- (4- (2- methyl isophthalic acids-oxygen -1- pyrrolidin-1-yls) propane -2- bases) phenyl) -1- ketone (6) synthesis
To sequentially adding dry THF 100mL, magnesium powder 19.1g (190mmol), chemical combination in 500mL three-necked bottles under nitrogen protection Thing (4) 27.1g (91.8mmol), is heated to 40 DEG C of stirring 1h.Drying is sequentially added in another 500ml three-necked bottle THF100mL, γ-butyl lactone (5) 11.9g (137.7mmol）, N, O- dimethyl hydroxylamine hydrochloride 16.0g (165.2mmol), Sodium methoxide 1.86g（34.4mmol）, ice bath is cooled to 5 DEG C under magnetic agitation, in the Grignard reagent dropwise that will be made to reaction bulb. 2 h are stirred under ice bath, then is warming up to 8 h is stirred at room temperature.Reaction is quenched with 1N hydrochloric acid 50ml after reaction completely, decompression steams THF, Add water 100ml, ethyl acetate 300ml extractions.Ethyl acetate layer is concentrated, pale yellow oil 23.8g is obtained（Yield 85.5%）, it is not purified to direct plunge into next step.
4- (4- (2- methyl isophthalic acids-oxygen -1- (pyrrolidin-1-yl) propane -2- bases) phenyl) -4- oxygen-butyl -4- methylbenzenes The synthesis of sulphonyl (7)
To sequentially adding dry methylene chloride 250mL, compound (6) 23.8g in 500mL three-necked bottles under nitrogen protection (78.5mmol), triethylamine 15.9g (157mmol), then at room temperature to dropwise addition paratoluensulfonyl chloride 17.9g in reaction bulb (94.2mmol), stirs 8 h.Water 200ml extractions are added, dichloromethane layer is collected, obtains white solid with ethyl alcohol recrystallization after being spin-dried for Body 27.9g（73.2mmol）, mp.124~127 DEG C yield 93.3%, [the HPLC normalization methods of purity 98.8%：Permaphase ODS post (4.6mm × 250mm, 5 μm)；Mobile phase：Acetonitrile-phosphate buffer（pH 3.0）, Detection wavelength 254nm, 25 DEG C of column temperature],1H- NMR（CDCl3）δ：1.45 (s, 6H, 2 × CH3), 1.78(m, 4H, 2×CH2), 2.05~2.10 (m, 2H, CH2), 2.38(s, 3H, Ar-CH3), 3.02(t, 2H, J=6Hz, CO-CH2), 3.30~3.60 (m, 4H, 2 × CH2-N), 4.13 (t, 2H, J=6Hz), 7.30~8.02 (m, 8H, Ph-H）
4- (4- (hydroxyl diphenyl methyl) piperidin-1-yl) -1- (4- (2- methyl isophthalic acids-oxygen -1- (p pyrrolidin-1-yls) third Alkane -2- bases) phenyl) butyl -1- ketone（9）Synthesis
To sequentially adding methyltetrahydrofuran 100ml, compound (7) 27.9g in 500mL three-necked bottles under nitrogen protection （73.2mmol）, diphenyl piperazine methyl alcohol（8）23.5g（87.8mmol）, triethylamine 8.9g（87.8mmol）, 8 are stirred at room temperature h.Add 1N hydrochloric acid 50ml, layering, be concentrated under reduced pressure organic phase, obtains crude product, then with ethyl acetate/normal heptane（v/v ½）Tie again Crystalline substance obtains white solid 29.9g, yield 74.0%, mp.113~116 DEG C, purity 98.5%,1H-NMR（CDCl3）δ：1.41 (s, 6H, 2×CH3), 1.71~2.03 (m, 6H, COCH2 CH2 CH2, (CH2)2 CHCPh2OH), 1.8(m, 4H,2×CH2), 2.52(m, 2H, CH2-N), 2.80(m, 2H, CO-CH2), 3.30~3.60 (m, 4H, 2 × CH2-N), 4.13(t, 2H, J=6Hz), 7.02~7.48 (m, 14H, Ph-H).
2- (4- (1- hydroxyls -4- (4- (hydroxyl diphenyl methyl) piperidin-1-yl) butyl) phenyl) -2- methyl isophthalic acids-(piperazine Pyridine -1- bases) propyl group -1- ketone (10) synthesis
Under nitrogen protection to sequentially adding ethanol 300ml, compound (9) 29.9g in 500mL three-necked bottles （54.2mmol）, sodium borohydride 4.3g（114.6mmol）, 3 h are stirred at room temperature.100ml saturated ammonium chloride solutions are added dropwise to In reaction bulb, ethyl acetate 300ml, water 200ml are added, be layered, be concentrated under reduced pressure organic phase, obtains pale yellow oil 27.4g, yield 91.3%.It is directly used in next step reaction.
The synthesis of fexofenadine hydrochloride (1)
To sequentially adding ethanol 200ml, compound (10) 27.4g in 500mL three-necked bottles under nitrogen protection (49.4mmol), concentrated hydrochloric acid 24.7ml (296.6mmol), is heated to reflux 6 h, after being cooled to room temperature, adds ethyl acetate 200ml, water 200ml, collect organic phase, and water is mutually extracted with ethyl acetate 100ml again.Merge organic phase, use 100ml saturated common salts Water washing, concentrates organic phase, uses ethanol/water（V/V 2:1）Mixed solvent recrystallizes to obtain compound（1）22.78g.Yield 85.5%, mp.194~197 DEG C of (document [4] mp.195~198 DEG C) HPLC determine purity 98.5%,1H-NMR（CDCl3）δ：1.42 (s, 6H, 2 × CH3), 1.57~2.0 (m, 8H,CHCH2CH2CH2, CH(CH2)2), 2.49(m, 2H, CH2-CH2-CH2 - N), 2.78~3.37 (m, 5H, 2 × CH2-N, CH-OH), 4.57 (m,1H,CH- OH), 7.03~7.50 (m, 14H, Ph-H)。
From compound 2 to compound 3, initially we use HATU and HOBT as condensation reagent, although conversion ratio is higher, But the impurity urea for producing, is difficult to remove in subsequent several steps reaction with the method for crystallization.CDI is being used instead for condensation reagent Afterwards, although can also produce the impurity that nafoxidine and CDI are condensed, but be easily removed, the technique that have finally chosen CDI.
It is the committed step of this synthetic route from compound 4 to compound 6.We have attempted two reaction conditions,
(1) reacted with compound 4 at -78 DEG C with highly basic butyl lithium, form attack GBL after carbanion, generation Compound 6, is shown in formulas below：
(2) compound 4 is made after grignard reagent attack GBL again, generates compound 6.
First method needs to be reacted under the conditions of extremely low temperature, and can generate the impurity 1 of overreaction.And second method Reaction condition is gentle, and high conversion rate, impurity is less, so selected by herein.
The condition examination of synthesis compound 9
The synthetic reaction formula of compound 9 is as follows：
When synthesizing compound 9 from compound 7, a cyclization impurity 2 is had in the basic conditions and is generated.And on compound 7 Different alkali has conclusive influence to generation impurity in different leaving group R and reaction.Therefore we are to the two factors Investigated, concrete outcome is shown in Table 1.
The synthetic route of 1 compound of table 9 examines or check table
Sequence number R Solvent Alkali Temperature Product Impurity level（%）
1 Br DMF 25 0 75
2 Br THF 25 32 37
3 Cl DMF 25 40 27
4 Cl THF 25 56 18
5 OTs DMF 25 74 10
6 OTs THF 25 88 4
7 OTs THF DIPEA 25 82 5
From experimental result as can be seen that being easier generation cyclization impurity in the reaction that inorganic base is participated in, and it is with-OTs The reaction conversion ratio of leaving group is best.So finally we have selected with compound 7（- OTs is leaving group）It is raw material, three Ethamine makees alkali, and THF is solvent, is reacted at room temperature, has obtained preferable synthesis technique.

Claims (1)

1. the synthetic method of fexofenadine hydrochloride, it is characterised in that described synthetic method comprises the steps：
S1：2- (4- bromophenyls) -2- methyl propionyl ring butylamine（4）Synthesis
In the three-necked bottle equipped with drying tube, dichloromethane is added, stirring adds 2- (4- bromophenyls) -2 Methylpropionic acids and carbonyl Base diimidazole, stirring starts that nafoxidine is added dropwise, and continues to stir at room temperature；Reaction is finished, and adds hydrochloric acid solution, and stirring stands Layering；Organic phase vacuum distillation, obtains yellow solid；
S2：4- hydroxyls -1- (4- (2- methyl isophthalic acids-oxygen -1- pyrrolidin-1-yls) propane -2- bases) phenyl) -1- ketone (6) synthesis
To sequentially adding dry THF, magnesium powder, compound (4), heating stirring in three-necked bottle under nitrogen protection；In another three neck Dry THF, γ-butyl lactone (5), N, O- dimethyl hydroxylamine hydrochloride, sodium methoxide, ice bath under magnetic agitation are sequentially added in bottle 5 DEG C are cooled to, in the Grignard reagent dropwise that will be made to reaction bulb；Stirred under ice bath, then be warming up to and be stirred at room temperature；Reaction is complete Reacted with hydrochloric acid afterwards, decompression steams THF, add water, ethyl acetate extraction；Ethyl acetate layer is concentrated, obtains faint yellow Grease, it is not purified to direct plunge into next step；
S3：4- (4- (2- methyl isophthalic acids-oxygen -1- (pyrrolidin-1-yl) propane -2- bases) phenyl) -4- oxygen-butyl -4- methylbenzene sulphurs The synthesis of acyl (7)
To sequentially adding dry methylene chloride in three-necked bottle under nitrogen protection, compound (6), triethylamine, then at room temperature to Paratoluensulfonyl chloride stirring is added dropwise in reaction bulb；Water extraction is added, dichloromethane layer is collected, obtains white with ethyl alcohol recrystallization after being spin-dried for Color solid;
S4：4- (4- (hydroxyl diphenyl methyl) piperidin-1-yl) -1- (4- (2- methyl isophthalic acids-oxygen -1- (p pyrrolidin-1-yls) third Alkane -2- bases) phenyl) butyl -1- ketone（9）Synthesis
To sequentially adding methyltetrahydrofuran, compound (7), diphenyl piperazine methyl alcohol in three-necked bottle under nitrogen protection（8）, three second Amine, stirs at room temperature；Hydrochloric acid is added, layering, organic phase concentrated under reduced pressure obtains crude product, then recrystallized with ethyl acetate/normal heptane Obtain white solid；
S5：2- (4- (1- hydroxyls -4- (4- (hydroxyl diphenyl methyl) piperidin-1-yl) butyl) phenyl) -2- methyl isophthalic acids-(piperidines - 1- yls) propyl group -1- ketone (10) synthesis
Under nitrogen protection to ethanol is sequentially added in three-necked bottle, compound (9), sodium borohydride is stirred at room temperature；By saturation chlorine Change ammonium salt solution to be added dropwise in reaction bulb, add ethyl acetate, water, layering, organic phase concentrated under reduced pressure obtains faint yellow oily Thing, is directly used in next step reaction；
S6：The synthesis of fexofenadine hydrochloride (1)
To sequentially adding ethanol in three-necked bottle under nitrogen protection, compound (10), concentrated hydrochloric acid is heated to reflux, after being cooled to room temperature, Ethyl acetate, water is added to collect organic phase, water is mutually extracted with ethyl acetate again；Merge organic phase, use saturated common salt water washing, Concentration organic phase, compound is recrystallized to obtain with ethanol/water mixed solvent（1）；
The reaction equation of described synthetic method is as follows：
。
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