CN104557671B - A kind of synthetic method of fexofenadine and intermediate - Google Patents
A kind of synthetic method of fexofenadine and intermediate Download PDFInfo
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- CN104557671B CN104557671B CN201310393012.0A CN201310393012A CN104557671B CN 104557671 B CN104557671 B CN 104557671B CN 201310393012 A CN201310393012 A CN 201310393012A CN 104557671 B CN104557671 B CN 104557671B
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- 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 present invention relates to fexofenadine { fexofenadine, chemical name：4 { 1 hydroxyl 4 [4 (hydroxy benzophenone base) 1 piperidyl] butyl } α, α dimethyl phenyl acetic acids（I）And its simplicity, the high-efficiency synthesis method of intermediate, this method obtain key intermediate 4 (4 chlorine, 1 bytyry) α, α dimethyl phenyl acetic acids using isopropylbenzene as raw material after paying gram acylation reaction, halogenating reaction, carbonyl intercalation reaction（IV）, then with another raw material diphenyl (4 pyridine radicals) methanol（E）React to obtain crucial pyridiniujm intermediate 4 { 4 chlorinations [4 (hydroxy benzophenone base) 1 pyridine] 1 bytyry } α, α dimethyl phenyl acetic acids（V）, then through catalytic hydrogenation, metal hydrogen reduction obtain high-purity fexofenadine.Present invention process is smooth, reaction is simple, route is short, convenient post-treatment, high income, cost are low, is a kind of ideal fexofenadine preparation method and the feasible route of industrialization.
Description
Technical field
The present invention relates to fexofenadine, chemical name：4- [1- hydroxyls -4- [4- (hydroxy benzophenone base) -1- piperidyls] -
Butyl]-α, the synthetic method of alpha-alpha-dimethyl-phenylacetic acid and its intermediate, belongs to technical field of pharmaceutical chemistry.
Background technology
Fexofenadine (fexofenadine), chemistry are entitled（±）4- [1- hydroxyls -4- [4- (hydroxy benzophenones
Base) -1- piperidyls]-butyl]-alpha, alpha-dimethyl-phenylacetic acid（I）, it is by German Hoechest Marion Roussel companies
1 receptor antagonist of histamine H of research and development, its hydrochloride listed in the U.S. first in 1996, trade name Allegra, and clinic is main
It is used to treat seasonal allergic rhinitis and chronic idiopathic urticaria etc..This product does not have nervous centralis sedation, heart
Adverse reaction is light, with first generation antihistamine drug such as diphenhydramine (diphenhydramine) and chlorphenamine
(chlorphenamine) compare, have the characteristics that antiallergic effect is stronger, security higher.
The preparation method of fexofenadine is disclosed by United States Patent (USP) US4254129 first, this route is by α, alpha-alpha-dimethyl benzene
With 4- chlorobutanoylchlorides F-K reaction occurs for ethyl acetate, then obtains fexofenadine after being condensed, hydrolyze, reduce.
The problem of this route, is difficult to separate in the 3,4 two kinds of isomers produced in friedel-crafts reaction.In world patent WO02102776
In report and replace 4- chlorobutanoylchlorides to occur friedel-crafts reaction with succinic anhydride, the 3 of generation, 4 position isomers can be with aniline into salt
Separation is recrystallized in isopropanol afterwards, but the accessory substance of the method 3 is too many, causes cost too high.In United States Patent (USP)
Reported in US6348597 and occur to pay gram acylation instead with 4- chlorobutanoylchlorides with α, alpha-alpha-dimethyl phenylacetyl N, O- dimethyl hydroxylamine
Should, although 4 products can be improved largely, 3 a small amount of accessory substances, which are appointed, can not so avoid, therefore be difficult to obtain
The fexofenadine of high-purity.
Document J.Org.Chem. 1994,2620. is reported makees raw material with to bromo-acid, through being esterified, methylating, even
The problem of connection, oxidation, reduction and hydrolysis 6 steps synthesis fexofenadine, avoid 3,4 position isomer, but this route has used oxygen
Change mercury, not only toxicity is big but also has unknown impuritie, is unfavorable for obtaining high-purity fexofenadine.JP2012087100 is equally reported
Polymorphous fexofenadine hydrochloride is obtained using this route.Patent CN102070512 is raw material with paracyanobenzoic acid ester,
Through methylating, being condensed, bromination or esterification, coupling and reductive hydrolysis prepare fexofenadine, this method has also avoided 3,4 isomeries
Body problem, but route is grown, cost of material is high, and it is more to produce waste material.
Document Synthetic Communications, 2011,2296, it was recently reported that a variation route, using isopropylbenzene as
Raw material, through pay a gram acylation, condensation, reduction, etherificate, bromination, grignard reaction and go etherificate obtain fexofenadine, this route compared with
It is short, but the protection reagent of costliness has been used, cost is very high.All routes all use the intermediate and halogenated intermediates of amine heterocyclic alcohol
Condensation reaction, this step has some unknown impurity, can influence the quality of finished product, it is difficult to obtain the fexofenadine of high-purity.
The content of the invention
The shortcomings that it is an object of the invention to overcome the prior art and deficiency, there is provided a kind of mild condition, technique are simple, behaviour
Make the fexofenadine that convenient, of low cost method obtains high-purity.Brief description of the drawings is as follows：
With isopropyl benzene raw materials friedel-crafts reaction, the synthesis of high selectivity intermediate 4- (the 4- neoprenes of 4 occur for the present invention
Acyl)-isopropylbenzene（II）；With less expensive diphenyl-(4- pyridine radicals)-methanol（E）Instead of amine heterocyclic alcohol, reduce further into
This, is initially formed key intermediate pyridinium chloride salt 4- { 4- chlorinations-[4- (hydroxy benzophenone base) -1- pyridines] -1- butyryl
Base }-alpha, alpha-dimethyl phenylacetic acid（V）, this salt-forming steps high income, easy to operate, product purity is high, avoids regular course
The condensation step of the more amine heterocyclic alcohol of middle product impurity and chloro thing；Catalytic hydrogenation obtains intermediate 4- { 4- [4- (hydroxyls again
Benzhydryl) -1- piperidyls] -1- bytyries }-alpha, alpha-dimethyl-phenylacetic acid（VI）, finally reduce to obtain object Fexofenadine
It is fixed.
Technical solution of the present invention includes the following steps：
The first step：With isopropylbenzene（A）With 4- chlorobutanoylchlorides（B）For raw material, occur to pay a gram acylation reaction preparation 4- (4- neoprenes
Acyl)-isopropylbenzene（II）.
Gram acylating reagent used of paying of the invention is excellent for the concentrated sulfuric acid, anhydrous ferric chloride, anhydrous zinc chloride, anhydrous Aluminum chloride etc.
Elect anhydrous Aluminum chloride as.
Reaction dissolvent of the present invention is isopropylbenzene, carbon disulfide, dichloromethane, 1,2- dichloroethanes etc., is preferably two
Chloromethanes.
Reaction temperature of the present invention is -10-20 DEG C, is preferably 0-5 DEG C.
When reaction time of the present invention is 1-15 small, when being preferably 1 small.
Second step：With first step product 4- (4- neoprenes acyl)-isopropylbenzene（II）With halogenating agent（C）Reaction prepares 4- (4-
Neoprene acyl)-bis (alpha, alpha-dimethylbenzyl) halogen（III）.
Reaction halogenating agent of the present invention is the bromo- 5,5- Dimethyl Hydan of TCCA, NCS, NBS, 1,3- bis-, bromine, NIS
Deng, be preferably brominated reagent.
Reaction dissolvent of the present invention is carbon tetrachloride, chloroform, benzene, 1,2- dichloroethanes etc., is preferably carbon tetrachloride.
Reaction temperature of the present invention is 50-100 DEG C, is preferably 80 DEG C.
When reaction time of the present invention is 2-24 small, when being preferably 8 small.
3rd step：With second step product 4- (4- neoprenes acyl)-bis (alpha, alpha-dimethylbenzyl) bromine（III）With carbonylation agent in strong acid
Under the conditions of prepare 4- (the chloro- 1- bytyries of 4-)-alpha, alpha-dimethyl phenylacetic acid（IV）.
Strong reagents of the present invention are the concentrated sulfuric acid, oleum, fluosulfonic acid, chlorosulfonic acid, perchloric acid, hydrogen bromide, trifluoro
Methanesulfonic acid etc., is preferably the concentrated sulfuric acid.
Reaction carbonylation agent of the present invention is formic acid or carbon monoxide, is preferably formic acid.
Reaction dissolvent formic acid of the present invention, dichloromethane, carbon tetrachloride, acetic acid, n-hexane etc., are preferably four chlorinations
Carbon.
Reaction temperature of the present invention is 0-20 DEG C, is preferably 0 DEG C.
When reaction time of the present invention is 1-10 small, when being preferably 3 small.
Reaction pressure of the present invention is 1-40 bars, is preferably 1.5 bars.
4th step：With the 3rd step product 4- (the chloro- 1- bytyries of 4-)-alpha, alpha-dimethyl phenylacetic acid（IV）With diphenyl-
(4- pyridine radicals)-methanol（E）Directly reaction prepares 4- { 4- chlorinations-[4- (hydroxy benzophenone base) -1- pyridines] -1- butyryl
Base }-alpha, alpha-dimethyl phenylacetic acid（V）.
3rd step product of the present invention（IV）Dosage be raw material（E）0.8-1.2 times of mole dosage, is preferably 1.05
Times.
Reaction dissolvent of the present invention is excellent for acetone, butanone, dichloromethane, chloroform, toluic acid, tetrahydrofuran, acetonitrile etc.
Elect butanone as.
Reaction temperature of the present invention is 50-120 DEG C, is preferably 80 DEG C.
When reaction time of the present invention is 1-24 small, when being preferably 10 small.
5th step：With the 4th step product 4- { 4- chlorinations-[4- (hydroxy benzophenone base) -1- pyridines] -1- bytyries } -
Alpha, alpha-dimethyl phenylacetic acid（V）Under a certain pressure catalytic hydrogenation prepare 4- 4- [4- (hydroxy benzophenone base) -1- piperidyls] -
1- bytyries }-alpha, alpha-dimethyl-phenylacetic acid（VI）.
Catalysts of the present invention are 10% palladium carbon, 5% palladium carbon, palladium dydroxide, platinum dioxide etc., are preferably 10% palladium
Carbon.
Reaction hydrogen source of the present invention is hydrogen, formic acid, ammonium formate, triethylsilane, cyclohexadiene etc., is preferably formic acid
Ammonium.
Reaction dissolvent of the present invention is methanol, ethanol, ethyl acetate etc., is preferably methanol.
Reaction temperature of the present invention is 20-80 DEG C, is preferably 60 DEG C.
When reaction time of the present invention is 5-30 small, when being preferably 20 small.
Reaction pressure of the present invention is 1-20 bars, is preferably 5 bars.
6th step：With the 5th step product 4- { 4- [4- (hydroxy benzophenone base) -1- piperidyls] -1- bytyries }-α, α-two
Methyl-benzeneacetic acid（VI）Reduction prepares finished product fexofenadine to I in alkaline conditions（I）.
Reaction base of the present invention is lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, phosphorus
Sour potassium etc., is preferably potassium hydroxide.
Reaction base amount of the present invention is the 5th step product（VI）1-2.5 times of mole dosage, is preferably 1.5 times.
Reaction reducing agent of the present invention for lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, borine etc.,
Preferably potassium borohydride.
Reaction dissolvent of the present invention is any combination of water and following organic solvent：Methanol, ethanol, isopropanol, tetrahydrochysene
Furans etc., is preferably water and methanol 1:5.
Reaction temperature of the present invention is 0-80 DEG C, is preferably 50 DEG C.
When reaction time of the present invention is 1-20 small, when being preferably 4 small.
The beneficial effects of the invention are as follows provide a kind of short synthetic route, mild condition, technique be simple and convenient to operate, into
This cheap method obtains the fexofenadine of high-purity.
Embodiment
In order to which clearly the present invention will be described, the specific embodiment party below by way of specific embodiment to the present invention
Formula is illustrated in more detail.However, it should be understood that specific embodiment as described below be only used for the present invention carry out it is exemplary
Illustrate, not for the restriction that any property is carried out to the present invention, wherein material used, reagent, catalyst etc. are only representativeness
, it is not limited to cited situation.Person of ordinary skill in the field can be to the present invention by reading following explanation
The change and improvement for not departing from the protection domain that the claims in the present invention are limited are made, these changes and improvement are also at this hair
In bright claimed scope.
Embodiment 1
（1）166.7 grams are added in 2 liters of there-necked flask under equipped with mechanical agitator and nitrogen protection（1.25mol）Three
Aluminium chloride and 450 milliliters of dichloromethane, after being cooled to 0-5 DEG C, are added dropwise 140 milliliters（1.25mol）4- chlorobutanoylchlorides（B）, 30 points
Dripped in clock.Then 143g was added dropwise in 40 minutes（1.19mol）Isopropylbenzene（A）, temperature is at 5-10 DEG C in holding.The reaction was continued
After 30 minutes, reaction solution is carefully slowly poured into 1 kilogram of frozen water, room temperature is slowly returned under stirring, split-phase, water is mutually with 400 milliliters
Dichloromethane extracts.Merge organic phase, washed once with 500 milliliters of saturated sodium bicarbonates.Less than 30 DEG C of revolving steams dichloromethane,
280 grams of yellow oils are obtained, with the mixed solvent of isopropyl alcohol and water in -10 DEG C of crystallizations, filtering, filter cake isopropanol and washing
Wash, be dried in vacuo to obtain 252 grams of 4- (4- neoprenes acyl)-isopropylbenzene（II）, yield 94%；MP: 38-39°C,1H NMR (DMSO-
d6) δ = 1.25 (d, 6H, (CH3)2), 2.23 (qui, 2H, CH2), 2.98 (sept, 1H, CH), 3.15
(t, 2H, CH2), 3.69 (t, 2H, CH2), 7.33 (d, 2H, Ar-H), 7.90 (d, 2H, Ar-H)。
（2）224 grams are added in the there-necked flask of the 3L under equipped with mechanical agitator and nitrogen protection（1mol）4- (4- neoprenes
Acyl)-isopropylbenzene（II）, 180 grams（1.01mol）NBS, 0.8 gram of AIBN and 1 liter of carbon tetrachloride, then 2 be heated to reflux 20 it is small when,
Cooling, filters off not tolerant, carbon tetrachloride washing, and filtrate is washed twice with 500 milliliters of frozen water, and 300 milliliters of saturated common salts are washed once,
Anhydrous sodium sulfate is dried, and carbon tetrachloride is evaporated off in filtering, filtrate, and Liquid Residue is with the mixed solvent of isopropyl alcohol and water at -10 DEG C
Crystallization, filtering, filter cake isopropanol and water washing, are dried in vacuo to obtain 288 grams of 4- (4- neoprenes acyl)-α, alpha-alpha-dimethyl benzyl bromine
（III）, yield 94%；MP: 35.5-36.5°C,1H-NMR (CDCl3): δ = 2.20 (s, 6H, (CH3)2), 2.23
(qui, 2H, CH2), 3.17 (t, 2H, CH2), 3.68 (t, 2H, CH2), 7.71 (dt, 2H, Ar-H),
7.94 (dt, 2H, Ar-H)。
（3）250 milliliters of concentrated sulfuric acids of addition in the there-necked flask of the 1L under equipped with mechanical agitator and nitrogen protection, 60 grams
（0.2 mol）4- (4- neoprenes acyl)-bis (alpha, alpha-dimethylbenzyl) bromine（III）With 40 milliliter of 65% oleum, then slowly drip at 20 DEG C
Add 55 grams of anhydrous formic acids, when time for adding about 3 is small, continue room temperature reaction 2 it is small when.Reaction solution is poured slowly into 3L frozen water, with 20% hydrogen
Sodium oxide molybdena adjusts pH to 2.5, and 500 milliliters of toluene are extracted twice, and merges organic phase and is washed once with 300 milliliters of saturated common salts again,
Anhydrous sodium sulfate is dried, and filtering, filtrate steams more than half toluene, is about left 300 milliliters of toluene solutions, and cooling crystallization, is filtered,
Filter cake is washed with a small amount of cold toluene, and vacuum drying, obtains 48 grams of 4- (the chloro- 1- bytyries of 4-)-alpha-alpha-dimethyl phenyl acetic acid（IV）,
Yield 89%；MP: 78.5-80.5°C,1H-NMR (CDCl3): δ = 1.63 (s, 6H, (CH3)2), 2.23 (qui,
2H, CH2), 3.17 (t, 2H, CH2), 3.67 (t, 2H, CH2), 7.51 (d, 2H, Ar-H), 7.93 (d,
2H, Ar-H), 12.60 (brs, 1H, COOH)。
（4）40 grams are added in 500 milliliters of there-necked flask under equipped with magnetic stirring apparatus and nitrogen protection（0.149 mol）
4- (the chloro- 1- bytyries of 4-)-alpha, alpha-dimethyl phenylacetic acid（IV）With 200 milliliters of butanone, after being heated to 80 DEG C of dissolved clarifications, at 5 minutes
It is interior to be added dropwise 38 grams（0.145 mol）Diphenyl-(4- pyridine radicals)-methanol（E）100 milliliters of butanone solutions, it is small to be then refluxed for 10
When, 0 DEG C of crystallization is progressively cooled to, is filtered, filter cake is washed with butanone, is dried in vacuo, is obtained 75 grams of 4- { 4- chlorinations-[4- (hydroxyls two
Benzyl) -1- pyridines] -1- bytyries }-alpha, alpha-dimethyl phenylacetic acid（V）, yield 96%；MP: 203°C (dec.),1NMR (CDCl3) δ = 9.10 (d, 2H, Py-H), 8.52 (d, 2H, Py-H), 7.68 (d, 2H, Ar-H),
7.50-7.43 (m, 6H, Ar-H), 7.30-7.24 (m, 4H, Ar-H), 7.22-7.15 (m, 2H, Ar-H),
4.67 (t, 2H, NCH2), 3.2 (t, 2H, CH2), 2.35 (t, 2H, CH2), , 1.62 (s, 6H, (CH3)
2)。
（5）In 2 boosting force containers, 50 grams are added（0.101mol）4- { 4- chlorinations-[4- (hydroxy benzophenone base) -1-
Pyridine] -1- bytyries }-alpha, alpha-dimethyl phenylacetic acid（V）With 500 ml methanols, 13 grams of ammonium formates and 5 gram of 10% palladium carbon, lead to
Enter hydrogen, 5 bar pressures are kept, when 60 DEG C of reactions 20 are small.After cooling pressure release, 300 ml methanols are steamed, with 1N hydrochloric acid
Solution adjusts pH to 5.5-6, heats dissolved clarification, is cooled to 0 DEG C of crystallization, filters, and filter cake is washed with water, and is dried in vacuo, obtains 45 grams of 4-
{ 4- [4- (hydroxy benzophenone base) -1- piperidyls] -1- bytyries }-alpha, alpha-dimethyl-phenylacetic acid（VI）, yield 90%；MP:
165-167°C, 1NMR (MeOD-d3) δ = 7.98 (d, 2H, Ar-H), 7.59-7.11 (m, 12H, Ar-H),
3.64-3.59 (m, 2H), 3.22-3.03 (m, 6H), 2.92-2.85 (m, 1H), 2.11-2.08 (m, 2H),
1.90-1.80 (m, 4H) 1.60 (s, 6H)。
（6）40 grams are added in there-necked flask of 500 milliliters equipped with magnetic stirring apparatus（0.08mol）4- { 4- [4- (hydroxyls
Benzhydryl) -1- piperidyls] -1- bytyries }-alpha, alpha-dimethyl-phenylacetic acid（VI）With 150 ml methanols, 0 DEG C of drop is cooled to
Add the potassium hydroxide solution of 80 milliliters of 1N, after dripping dissolved clarification, add 4.32 grams（0.08 mol）Potassium borohydride, it is anti-to return to room temperature
Answer 1 it is small when after, add 2.16 grams of potassium borohydrides, be warming up to 50 DEG C reaction 3 it is small when.Then with 50% phosphorus acid for adjusting pH to 5, analysis
Go out solid, filter, filter cake washing.Wet finished product methanol and water mixed solvent recrystallizing and refining, obtain 35 grams of high-purity Fexofenadines
It is fixed（I）, yield 87%, HPLC contents>99.7%；MP: 188–191°C.1H NMR (MeOD-d3) δ: 1.63 (s, 6H,
(CH3)2), 1.72-1.78 (m, 2H, CH2), 2.16 (t, 2H, CH2), 2.74 (m, 1H, CH), 2.85
(m, 4H, (CH2)2), 2.98 (m, 4H, (CH2)2), 3.48 (d, 2H, CH2), 4.68 (s, 1H, CH),
7.18 (t, 2H, Ar-H), 7.28–7.38 (m, 8H, Ar-H), 7.51 (d, 4H, Ar-H), 13C NMR
(CDCl3): δ = 20.36, 23.73, 26.44, 35.85, 41.16, 45.48, 45.48, 51.59, 55.77,
71.35, 78.22, 125.20, 125.64, 125.68, 126.05, 127.89, 143.50, 144.04, 146.66,
177.56; MS (ESI+ion) m/z: [M+H] = 503.2。
Embodiment 2
4- (4- neoprenes the acyl)-bis (alpha, alpha-dimethylbenzyl) bromine prepared with examples detailed above 1（III）For raw material.Stirred equipped with machinery
Mix and 300 milliliters of concentrated sulfuric acids are added in the there-necked flask of device and the 1L under nitrogen protection, 60 grams（0.2 mol）Raw material（III）, then 20
55 grams of anhydrous formic acids are slowly added dropwise at DEG C（D）, when time for adding about 3 is small, continue room temperature reaction 2 it is small when.Reaction solution is poured slowly into
3L frozen water, pH to 2.5 is adjusted with 20% sodium hydroxide, and 500 milliliters of toluene are extracted twice, and merges organic phase again with 300 milliliters of saturations
Salt is washed once, anhydrous sodium sulfate drying, filtering, and filtrate steams more than half toluene, is about left 300 milliliters of toluene solutions,
Cooling crystallization, filtering, filter cake are washed with a small amount of cold toluene, are dried in vacuo, are obtained 45 g of compound（IV）, yield 83%.Other steps
With example 1, target product fexofenadine is prepared（I）.
Embodiment 3
4- (4- neoprenes the acyl)-bis (alpha, alpha-dimethylbenzyl) bromine prepared with examples detailed above 1（III）For raw material.Stirred equipped with machinery
Mix in the there-necked flask of device and the lower 1L of nitrogen protection and add 300 milliliters of concentrated sulfuric acids, then slow 55 grams of nothings of dropwise addition at the same time at 20 DEG C
Water beetle acid（D）With 60 grams（0.2 mol）Raw material（III）200 milliliters of carbon tetrachloride solutions, when time for adding about 3 is small, continue room
When temperature reaction 2 is small.Reaction solution is poured slowly into 3L frozen water, and pH to 2.5,500 milliliters of toluene extractions two are adjusted with 20% sodium hydroxide
It is secondary, merge organic phase and washed once with 300 milliliters of saturated common salts again, anhydrous sodium sulfate drying, is filtered, filtrate steams most
Toluene and carbon tetrachloride, are about left 300 milliliters of mixed solutions, and cooling crystallization, is filtered, and filter cake is washed with a small amount of cold toluene, vacuum
It is dry, obtain 42 grams of 4- (the chloro- 1- bytyries of 4-)-alpha-alpha-dimethyl phenyl acetic acid（IV）, yield 78%.Other steps are the same as example 1, system
It is standby go out target product fexofenadine（I）.
Embodiment 4
4- (the chloro- 1- bytyries of the 4-)-alpha, alpha-dimethyl phenylacetic acid prepared with examples detailed above 1（IV）For raw material.Equipped with
40 grams are added in 500 milliliters of there-necked flask under magnetic stirring apparatus and nitrogen protection（0.149 mol）Raw material（IV）With 300 milliliters
Acetonitrile, after being heated to 80 DEG C of dissolved clarifications, is added dropwise 38 grams in 5 minutes（0.145 mol）150 milliliters of acetonitrile solutions of compound E, so
When reflux 10 is small afterwards, 200 milliliters of acetonitriles are steamed, progressively cool to 0 DEG C of crystallization, filtered, filter cake is washed with acetonitrile, and vacuum is done
It is dry, obtain 70 g of compound V, yield 89%.Other steps prepare target product fexofenadine with example 1（I）.
Embodiment 5
4- (the chloro- 1- bytyries of the 4-)-alpha, alpha-dimethyl phenylacetic acid prepared with examples detailed above 1（IV）For raw material.Equipped with
40 grams are added in 500 milliliters of there-necked flask under magnetic stirring apparatus and nitrogen protection（0.149 mol）Raw material（IV）With 300 milliliters
Toluene, after being heated to 100 DEG C of dissolved clarifications, is added dropwise 38 grams in 5 minutes（0.145 mol）150 milliliters of toluene solutions of compound E,
Be then refluxed for 10 it is small when, steam 200 milliliters of toluene, progressively cool to 0 DEG C of crystallization, filter, filter cake washs with toluene, vacuum
It is dry, obtain 72 grams of 4- { 4- chlorinations-[4- (hydroxy benzophenone base) -1- pyridines] -1- bytyries }-alpha-alpha-dimethyl phenyl acetic acid
（V）, yield 92%.Other steps prepare target product fexofenadine with example 1（I）.
Embodiment 6
4- { 4- chlorinations-[4- (hydroxy benzophenone base) -1- pyridines] -1- bytyries }-α prepared with examples detailed above 1,
Alpha-alpha-dimethyl phenyl acetic acid（V）For raw material.In 1 liter of there-necked flask under equipped with magnetic stirring apparatus and nitrogen protection, 50 grams are added
（0.101 mol）Raw material（V）With 500 ml methanols, 13 grams of ammonium formates and 5 gram of 10% palladium carbon, be heated to reflux 3 it is small when after adding
13 grams of ammonium formates, are so repeated 2 times, and steam 300 ml methanols, and pH to 4 is adjusted with 1N hydrochloric acid solutions, heat dissolved clarification, cold
But it is washed with water to 0 DEG C of crystallization, filtering, filter cake, is dried in vacuo, obtains 42 grams of 4- { 4- [4- (hydroxy benzophenone base) -1- piperidines
Base] -1- bytyries }-alpha, alpha-dimethyl-phenylacetic acid（VI）, yield 82%.It is non-to prepare target product with example 1 for other steps
Fexofenadine（I）.
Embodiment 7
4- { 4- [4- (hydroxy benzophenone base) -1- piperidyls] -1- the bytyries }-α prepared with examples detailed above 1, alpha, alpha-dimethyl
Base-phenylacetic acid（VI）For raw material.40 grams are added in there-necked flask of 500 milliliters equipped with magnetic stirring apparatus（0.08 mol）Raw material
（VI）With 150 ml methanols, the potassium hydroxide solution of 0 DEG C of dropwise addition, 80 milliliters of 1N is cooled to, after dripping dissolved clarification, adds 3 grams
（0.08 mol）Sodium borohydride, return to room temperature reaction 1 it is small when after, add 1.5 grams of sodium borohydrides, it is 3 small to be warming up to 50 DEG C of reactions
When.Then with 50% phosphorus acid for adjusting pH to 5, solid, filtering, filter cake washing are separated out.Wet finished product is tied again with methanol and water mixed solvent
Crystalline substance is refined, obtains 35 grams of high-purity fexofenadines（I）, yield 87%, HPLC contents>99.6%.
Claims (7)
1. a kind of method for preparing fexofenadine fexofenadine, comprises the following steps that：
The first step：4- (4- neoprenes acyl)-isopropylbenzene（II）By isopropylbenzene（A）With 4- chlorobutanoylchlorides（B）In having under strong acid effect
Occur to pay gram acylation reaction and obtain in solvent；
Second step：4- (4- neoprenes acyl)-bis (alpha, alpha-dimethylbenzyl) bromine（III）By 4- (4- neoprenes acyl)-isopropylbenzene（II）Tried with halo
Agent（C）, halogenating agent used is TCCA, NCS, one kind in NBS, bromo- 5, the 5- Dimethyl Hydan of 1,3- bis-, bromine, NIS,
React and obtain under initiator catalysis, X is chlorine, bromine, iodine in general formula III；
3rd step：4- (the chloro- 1- bytyries of 4-)-alpha, alpha-dimethyl phenylacetic acid（IV）By 4- (4- neoprenes acyl)-bis (alpha, alpha-dimethylbenzyl)
Bromine（III）With anhydrous formic acid（D）React and obtain under strongly acidic conditions；
4th step：4- { 4- chlorinations-[4- (hydroxy benzophenone base) -1- pyridines] -1- bytyries }-alpha, alpha-dimethyl phenylacetic acid
（V）By diphenyl-(4- pyridine radicals)-methanol（E）With 4- (the chloro- 1- bytyries of 4-)-alpha, alpha-dimethyl phenylacetic acid（IV）Organic
Directly react and obtain in solvent；
5th step：4- { 4- [4- (hydroxy benzophenone base) -1- piperidyls] -1- bytyries }-alpha, alpha-dimethyl-phenylacetic acid（VI）
By 4- { 4- chlorinations-[4- (hydroxy benzophenone base) -1- pyridines] -1- bytyries }-alpha, alpha-dimethyl phenylacetic acid（V）Certain
Depress catalytic hydrogenation and obtain；
6th step：Fexofenadine I can be by 4- { 4- [4- (hydroxy benzophenone base) -1- piperidyls] -1- bytyries }-α, alpha, alpha-dimethyl
Base-phenylacetic acid（VI）In the mixed solvent is reduced and obtained in alkaline conditions
。
2. preparation method according to claim 1, strong acid used in the first step is the concentrated sulfuric acid, anhydrous ferric chloride, anhydrous chlorination
One or both of zinc, anhydrous Aluminum chloride；Dosage is isopropylbenzene（A）1.0-1.5 times of mole dosage；4- chlorobutanoylchlorides used
（B）Dosage be isopropylbenzene（A）0.8-1.2 times of mole dosage；Solvent for use for isopropylbenzene, carbon disulfide, dichloromethane, 1,
One kind in 2- dichloroethanes, dosage need solvent 1-5mL for every gram of isopropylbenzene；Its reaction temperature is -10-20 DEG C；The reaction
When time is 1-15 small.
3. preparation method according to claim 1, halogenating agent used in second step is TCCA, NCS, NBS, 1,3- bis- are bromo-
One kind in 5,5- Dimethyl Hydan, bromine, NIS, dosage are 0.35-1.2 times of Formula II compound mole dosage；Solvent for use
For one kind in carbon tetrachloride, chloroform, benzene, 1,2- dichloroethanes；Its reaction temperature is 50-100 DEG C；Reaction time used is 2-
24 it is small when.
4. preparation method according to claim 1, strong reagents used in the 3rd step are the concentrated sulfuric acid, oleum, fluosulfonic acid,
One or both of chlorosulfonic acid, perchloric acid, hydrogen bromide, trifluoromethanesulfonic acid, dosage are the 5-50 of formula III compound mole dosage
Times；Carbonylation agent used is formic acid, and dosage is 3-20 times of formula III compound mole dosage；Reaction dissolvent used for formic acid,
One kind in dichloromethane, carbon tetrachloride, acetic acid, n-hexane；Its reaction temperature is 0-20 DEG C；Reaction time used is small for 1-10
When.
5. preparation method according to claim 1, two kinds of reactants of four-step reaction are（E）With（IV）Mole dosage
Than for 0.8-1.2；Solvent for use is acetone, one kind in butanone, dichloromethane, chloroform, benzoic acid, tetrahydrofuran, acetonitrile；Its
Reaction temperature is 50-120 DEG C；When reaction time used is 1-24 small.
6. preparation method according to claim 1, the catalyst of hydrogenation used in the 5th step is 10% palladium carbon, 5% palladium carbon,
One kind in palladium dydroxide, platinum dioxide；The hydrogen source of hydrogenation used is hydrogen, formic acid, ammonium formate, triethylsilane, ring
One kind in hexadiene；Reaction dissolvent used is methanol, one kind in ethanol, ethyl acetate；Its reaction temperature is 20-80 DEG C；
Its reaction pressure is 1-20 bars；When reaction time used is 5-30 small.
7. preparation method according to claim 1, alkali used in the 6th step is lithium hydroxide, sodium hydroxide, potassium hydroxide, carbon
One or both of sour sodium, potassium carbonate, sodium phosphate, potassium phosphate；Base amount is 4- { 4- [4- (hydroxy benzophenone base) -1- piperidines
Base] -1- bytyries }-alpha, alpha-dimethyl-phenylacetic acid（VI）1-2.5 times of mole dosage；Reducing agent used is lithium borohydride, boron
One kind in sodium hydride, potassium borohydride, sodium cyanoborohydride, borine；Dosage is（VI）0.5-5 times of mole dosage；It is used anti-
Answer any combination of the solvent for one of water and following organic solvent：Methanol, ethanol, isopropanol, tetrahydrofuran, dioxane；Its
Reaction temperature is 0-80 DEG C；When reaction time used is 1-20 small.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4254129A (en) * | 1979-04-10 | 1981-03-03 | Richardson-Merrell Inc. | Piperidine derivatives |
| US5606064A (en) * | 1994-11-08 | 1997-02-25 | Bayer Aktiengesellschaft | Process for the preparation of benzyl-piperidylmethyl-indanones |
| CN101570476A (en) * | 2004-06-30 | 2009-11-04 | 塞诺菲-安万特德国有限公司 | Method for carbonylating phenylalkyl derivatives by means of carbon monoxide |
| CN101671292A (en) * | 2009-10-10 | 2010-03-17 | 浙江大学宁波理工学院 | Synthetic method of fexofenadine hydrochloride |
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| CN1159277C (en) * | 1993-06-25 | 2004-07-28 | 默里尔药物公司 | New intermediate for preparation of anti-histamine piperidine derivatives |
| US7498345B2 (en) * | 2004-09-17 | 2009-03-03 | Albany Molecular Research, Inc. | Process for production of piperidine derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4254129A (en) * | 1979-04-10 | 1981-03-03 | Richardson-Merrell Inc. | Piperidine derivatives |
| US5606064A (en) * | 1994-11-08 | 1997-02-25 | Bayer Aktiengesellschaft | Process for the preparation of benzyl-piperidylmethyl-indanones |
| CN101570476A (en) * | 2004-06-30 | 2009-11-04 | 塞诺菲-安万特德国有限公司 | Method for carbonylating phenylalkyl derivatives by means of carbon monoxide |
| CN101671292A (en) * | 2009-10-10 | 2010-03-17 | 浙江大学宁波理工学院 | Synthetic method of fexofenadine hydrochloride |
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