CN106380441A - Synthetic method of fexofenadine intermediate - Google Patents
Synthetic method of fexofenadine intermediate Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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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 invention provides a synthetic method of a fexofenadine intermediate 2-[4-[4-[4-(hydroxybenzhydryl)-1-piperidyl]-butyryl]phenyl]-2- methylmethacrylate. The method comprises the following steps: methylation of phenylacetonitrile which is used as a raw material, basic hydrolysis, weinreb amidation reaction, Friedel-crafts reaction, acid hydrolysis, esterification and condensation. The method has the following advantages: raw materials and auxiliary materials are cheap and easily available; yield is high; cost is low; there is no meta-isomer; and the method is suitable for industrial production.
Description
Technical field
The invention belongs to organic synthetic route design and its technical field of medical intermediate preparation are and in particular to a kind of non-rope
Fei Nading intermediate 2- [4- [4- [4- (hydroxy benzophenone base)-piperidino]-bytyry] phenyl] -2 Methylpropionic acid methyl ester
Synthetic method.
Background technology
Entitled 2- [4- [1- hydroxyl -4- [4- (the hydroxy benzophenone base)-piperidino] butyl] benzene of fexofenadine chemistry
Base] -2 Methylpropionic acid, molecular formula is C32H39NO4.Clinically use its racemate hydrochloride.Fexofenadine is one
Plant the receptor type antagonist of no calm, the no drowsiness effect of a new generation, it is to be developed by German He Meiluo (HMR) company,
And listed in the U.S. first after FDA approval in 1996, trade name is called Allegra, and big in Britain, Sweden, Australia
The states such as Leah list, and the sales volume in Chinese market is also on the increase at present.Fexofenadine as a kind of safe succedaneum,
Necessarily there are good economic benefit and social benefit.
Fexofenadine is by 2- [4- [4- [4- (hydroxy benzophenone base)-piperidino]-bytyry] phenyl] -2- methyl
Methyl propionate (VII) passes through hydrolysis, reduction, becomes salt to obtain.With regard to fexofenadine intermediate 2- [4- [4- [4- (hydroxyl hexichol
Methyl)-piperidino]-bytyry] phenyl] document of -2 Methylpropionic acid methyl ester (VII) and patent report have a lot, mainly
Have：
1st, with а, а-dimethyl phenyl acetic acid is raw material, passes through for United States Patent (USP) US 4254129 and German patent DE 3007498
Esterification, Friedel-Crafts reaction, it is condensed to yield.The method drawback is that para-position and two kinds of isomers of meta in Friedel-Crafts reaction, due to this
Two kinds of product separation are more difficult, so that post processing bothers, product purity is not also high.
2nd, United States Patent (USP) US 6348597B2 and document (Chinese pharmaceutical chemistry magazine, 2004,14 (2), 96) are with а, а-two
Methylphenyl acetic acid be raw material, carry out chlorination with thionyl chloride, then use N, O- dimethyl hydroxylamine hydrochloride carry out amination it is therefore an objective to
Utilization space steric effect, only produces para-position product when carrying out Friedel-Crafts reaction with 4- chlorobutyl acyl chlorides, so that product purity is improved.
But Friedel-Crafts reaction products therefrom cannot purify in the method, the impurity in product can be reacted with diphenyl -4- piperidine carbinols, fall
The purity of a low rear step and product and yield.In addition, the hydrolysis yield of amide is not high in hydrolysing step, unhydrolysed acyl
Amine is difficult to separate from product.
3rd, United States Patent (USP) US 0198233 with 4- bromine (а, а-dimethyl) phenylacetate be initiation material, in (Ph3P)4Pd/
CuBr2Catalytic action under, there is coupling reaction with 3- butyne-1-ol, then with diphenyl -4- piperidine carbinols carry out replacing anti-
Should, after with Pt do catalyst choice aoxidize three keys and obtain.But the method is from Pt costly and (Ph3P)4Pd catalyst,
Increased production cost.
4th, the Chinese patent of Application No. CN 200910153475.3, is also with 2- methyl -2- phenylpropionic acid as raw material,
The method that it improves United States Patent (USP) US 6348597B2 and document (Chinese pharmaceutical chemistry magazine, 2004,14 (2), 96), first Wei
The reaction of Yin Leibu (weinreb) amide, Friedel-Crafts reaction, it is hydrolyzed into ester and is condensed and obtains.But it is hydrolyzed into ester and uses one
Pot method, so results in the difficult separation of impurity of generation, condensation below is had a significant impact, causes purity to carry not high.
Content of the invention
In order to overcome the shortcomings of the problem of mentioned hereinbefore or presence, the present invention provides a kind of freeness of meta-isomers, work
Skill step is simple, low production cost, finished product purity are high and synthetic method that is being suitable to industrialized production.
According to the present invention, provide a kind of fexofenadine intermediate 2- [4- [4- [4- (hydroxy benzophenone base) -1- piperidines
Base]-bytyry] phenyl] and -2 Methylpropionic acid methyl ester synthetic method, by following synthetic routes：
Described synthetic method comprises the steps of：
Step 1：With benzene acetonitrile as raw material, react generation 2- methyl -2- phenyl third in the basic conditions with dimethyl sulfate
Nitrile (I)；
Step 2：2- methyl -2- phenylpropanenitrile (I) is hydrolyzed into 2- methyl -2- phenylpropionic acid (II) in the basic conditions；
Step 3：2- methyl -2- phenylpropionic acid (II) passes through Wei and generates N- methoxyl group-N, 2- diformazan because thunder butoctamide reacts
Base -2- Phenylpropionamide (III)；
Step 4：N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III) generate 2- (4- (4- chlorine by Friedel-Crafts reaction
Bytyry) phenyl)-N- methoxyl group-N, 2- dimethylpropionamide (IV)；
Step 5：2- (4- (4- chlorobutyryl) phenyl)-N- methoxyl group-N, is 2- after 2- dimethylpropionamide (IV) hydrolysis
(4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid (V)；
Step 6：2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid (V) and methanol react generation 2- (4- (4- neoprene
Acyl group) phenyl) -2 Methylpropionic acid methyl ester (VI)；
Step 7：2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid methyl ester (VI) is contracted with diphenyl -4- piperidine carbinols
Symphysis becomes 2- [4- [4- [4- (hydroxy benzophenone base)-piperidino]-bytyry] phenyl] -2 Methylpropionic acid methyl ester (VII).
Wherein, in step 1, alkali used is sodium hydroxide, potassium hydroxide, benzene acetonitrile, dimethyl sulfate, the mole ratio of alkali
For 1:2.1～3:4～6.
Wherein, alkali used by hydrolysis in step 2 is sodium hydroxide, potassium hydroxide.
Wherein, step 3 comprises:2- methyl -2- phenylpropionic acid (II) first generates acyl chlorides with thionyl chloride, then with N, O- diformazan
Base hydroxylamine hydrochloride synthesizes N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III) in the basic conditions, specifically synthesizes road
Line is as follows：
Wherein, in step 3, alkali used is potassium carbonate, cesium carbonate, sodium carbonate, 2- methyl -2- phenylpropionic acid (II), N, O- bis-
Methyl hydroxylamine hydrochloride, the mole of alkali are than for 1:1.1～1.5:2～3.
Wherein, N- methoxyl group-N in step 4,2- dimethyl -2- Phenylpropionamide (III) act in catalyst aluminum chloride
Lower reaction with 4- chlorobutanoylchloride generates 2- (4- (4- chlorobutyryl) phenyl)-N- methoxyl group-N, 2- dimethylpropionamide (IV).
Wherein, N- methoxyl group-N in step 4,2- dimethyl -2- Phenylpropionamide (III), 4- chlorobutanoylchloride, aluminum chloride
Mole than for 1:1.1～1.5:2～2.5, reaction temperature is 20～25 DEG C.
Wherein, step 5 is with the hydrolysis of 6N hydrochloric acid, and 6N hydrochloric acid used adds water configuration for technical grade 31% hydrochloric acid, heats
Temperature is 90～100 DEG C.
Wherein, step 6 comprises 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid (V) first and thionyl chloride is in methanol
It is evaporated methanol after solution heating 2h, then is passed through hydrogen chloride gas and make 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid methyl ester
(VI), heating-up temperature is 55～65 DEG C, and concrete synthetic route is as follows：
Wherein, step 7 used catalyst is potassium iodide, and alkali used is potassium bicarbonate, sodium bicarbonate, 2- (4- (4- neoprene acyl
Base) phenyl) -2 Methylpropionic acid methyl ester (VI), potassium iodide, the mole of alkali is than for 1:0.05～0.15:2～2.5, reaction temperature
For 80～95 DEG C.
The synthetic method of the present invention has that supplementary material is cheap and easy to get, high income, low cost, freeness of meta-isomers, be suitable to work
The advantages of industry metaplasia is produced.
It is that above and other objects of the present invention, feature and advantage can be become apparent, preferred embodiment cited below particularly,
It is described in detail below.
Specific embodiment
1st, the synthesis of 2- methyl -2- phenylpropionic acid (II)
Embodiment 1：In 1000mL reaction bulb, add benzene acetonitrile 50g, potassium hydroxide 140g and 250mL dimethyl sulfoxide, room temperature
Stirring 1h, Deca 132g dimethyl sulfate, 35～40 DEG C of temperature control, finish, react 1h at this temperature, HPLC monitors；React
Quan Hou, reactant liquor is poured in the mixture of ice and water of 1000g stirring, dichloromethane extracts 200mL*2, merges organic faciess, successively
With water, saturated common salt washing, anhydrous sodium sulfate drying, it is concentrated to give red liquid；The red liquid obtaining is added to reaction
In bottle, sequentially add 250ml water and 85g sodium hydroxide, temperature rising reflux 48h, HPLC monitor, after reaction completely, it is cooled to 20～
25 DEG C, with dichloromethane 100mL*2 extracting impurities, give up, it is 1～2 that water layer concentrated hydrochloric acid is acidified to pH, separate out solid in a large number
Body, filters, and washing is dried, obtains lurid solid 2- methyl -2- phenylpropionic acid (II) 63g, purity 96%, two step yields
90%.Wherein, the mole of benzene acetonitrile, dimethyl sulfate, alkali is than for 1:2.4:5.6.
Embodiment 2：In 1000mL reaction bulb, add benzene acetonitrile 50g, sodium hydroxide 102.4g and 250mL dimethyl sulfoxide, room
Temperature stirring 1h, Deca 118.3g dimethyl sulfate, 35～40 DEG C of temperature control, finish, react 1h at this temperature, HPLC monitors；Instead
After answering completely, reactant liquor is poured in the mixture of ice and water of 1000g stirring, dichloromethane extracts 200mL*2, merges organic faciess,
Use water, saturated common salt washing, anhydrous sodium sulfate drying successively, be concentrated to give red liquid；The red liquid obtaining is added to
In reaction bulb, sequentially add 250ml water and 85g sodium hydroxide, temperature rising reflux 48h, HPLC monitor, after reaction completely, be cooled to
20～25 DEG C, with dichloromethane 100mL*2 extracting impurities, give up, it is 1～2 that water layer concentrated hydrochloric acid is acidified to pH, separates out a large amount of
Solid, filters, and washing is dried, and obtains lurid solid 2- methyl -2- phenylpropionic acid (II) 55g, purity 95%, two steps are received
Rate 78.6%.Wherein, the mole of benzene acetonitrile, dimethyl sulfate, alkali is than for 1:2.1:6.
Embodiment 3：In 1000mL reaction bulb, add benzene acetonitrile 50g, potassium hydroxide 95.8g and 250mL dimethyl sulfoxide, room
Temperature stirring 1h, Deca 161.5g dimethyl sulfate, 35～40 DEG C of temperature control, finish, react 1h at this temperature, HPLC monitors；Instead
After answering completely, reactant liquor is poured in the mixture of ice and water of 1000g stirring, dichloromethane extracts 200mL*2, merges organic faciess,
Use water, saturated common salt washing, anhydrous sodium sulfate drying successively, be concentrated to give red liquid；The red liquid obtaining is added to
In reaction bulb, sequentially add 250ml water and 85g sodium hydroxide, temperature rising reflux 48h, HPLC monitor, after reaction completely, be cooled to
20～25 DEG C, with dichloromethane 100mL*2 extracting impurities, give up, it is 1～2 that water layer concentrated hydrochloric acid is acidified to pH, separates out a large amount of
Solid, filters, and washing is dried, and obtains lurid solid 2- methyl -2- phenylpropionic acid (II) 63g, purity 95%, two steps are received
Rate 90%.Wherein, the mole of benzene acetonitrile, dimethyl sulfate, alkali is than for 1:3:4.
Embodiment 4：In 1000mL reaction bulb, add benzene acetonitrile 50g, sodium hydroxide 85.4g and 250mL dimethyl sulfoxide, room
Temperature stirring 1h, Deca 132g dimethyl sulfate, 35～40 DEG C of temperature control, finish, react 1h at this temperature, HPLC monitors；Reaction
After completely, reactant liquor is poured in the mixture of ice and water of 1000g stirring, dichloromethane extracts 200mL*2, merge organic faciess, according to
Secondary use water, saturated common salt washing, anhydrous sodium sulfate drying, it is concentrated to give red liquid；The red liquid obtaining is added to instead
Answer in bottle, sequentially add 250ml water and 85g sodium hydroxide, temperature rising reflux 48h, HPLC monitor, after reaction completely, be cooled to 20
～25 DEG C, with dichloromethane 100mL*2 extracting impurities, give up, it is 1～2 that water layer concentrated hydrochloric acid is acidified to pH, separate out solid in a large number
Body, filters, and washing is dried, obtains lurid solid 2- methyl -2- phenylpropionic acid (II) 58g, purity 95%, two step yields
82.9%.Wherein, the mole of benzene acetonitrile, dimethyl sulfate, alkali is than for 1:2.5:5.
The synthesis of the 2nd, N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III)
Embodiment 5：In 500mL reaction bulb, add 63g 2- methyl -2- phenylpropionic acid (II), 250mL toluene and 150g chlorine
Change sulfoxide, heating reflux reaction 2h, HPLC monitoring reaction is complete, the thionyl chloride of evaporated under reduced pressure solvent and excess, then plus 100mL
Toluene dissolves, and is cooled to 0～5 DEG C, is slowly added dropwise the solution of potassium carbonate (117g)/water (180g), adds insulated and stirred 10min,
Deca N, the solution of O- dimethyl hydroxylamine hydrochloride (40g)/water (80g), finish, warm naturally to room temperature reaction 2h, HPLC supervises
Measured reaction completely, separates organic layer, and water layer dichloromethane extracts 200mL*2, merges organic layer, uses 1N hydrochloric acid, saturation respectively
Sodium bicarbonate solution and saturated common salt washing, anhydrous sodium sulfate drying, filtering and concentrating obtains grease, vacuum distillation, collects bp:
The fraction of 112～115 DEG C/3mmHg, obtains N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III) 73g, purity 98%,
Yield 91.8%.Wherein, 2- methyl -2- phenylpropionic acid (II), N, O- dimethyl hydroxylamine hydrochloride, the mole of alkali are than for 1:
1.1:2.2.
Embodiment 6：In 500mL reaction bulb, add 63g 2- methyl -2- phenylpropionic acid (II), 250mL toluene and 150g chlorine
Change sulfoxide, heating reflux reaction 2h, HPLC monitoring reaction is complete, the thionyl chloride of evaporated under reduced pressure solvent and excess, then plus 100mL
Toluene dissolves, and is cooled to 0～5 DEG C, is slowly added dropwise the solution of cesium carbonate (375g)/water (180g), adds insulated and stirred 10min,
Deca N, the solution of O- dimethyl hydroxylamine hydrochloride (40g)/water (80g), finish, warm naturally to room temperature reaction 2h, HPLC supervises
Measured reaction completely, separates organic layer, and water layer dichloromethane extracts 200mL*2, merges organic layer, uses 1N hydrochloric acid, saturation respectively
Sodium bicarbonate solution and saturated common salt washing, anhydrous sodium sulfate drying, filtering and concentrating obtains grease, vacuum distillation, collects bp:
The fraction of 112～115 DEG C/3mmHg, obtains N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III) 75g, purity 98%,
Yield 94.3%.Wherein, 2- methyl -2- phenylpropionic acid (II), N, O- dimethyl hydroxylamine hydrochloride, the mole of alkali are than for 1:
1.1:3.
Embodiment 7：In 500mL reaction bulb, add 63g 2- methyl -2- phenylpropionic acid (II), 250mL toluene and 150g chlorine
Change sulfoxide, heating reflux reaction 2h, HPLC monitoring reaction is complete, the thionyl chloride of evaporated under reduced pressure solvent and excess, then plus 100mL
Toluene dissolves, and is cooled to 0～5 DEG C, is slowly added dropwise the solution of sodium carbonate (81.3g)/water (180g), adds insulated and stirred 10min,
Deca N, the solution of O- dimethyl hydroxylamine hydrochloride (56.1g)/water (80g), finish, warm naturally to room temperature reaction 2h, HPLC
Monitor reaction completely, separate organic layer, water layer dichloromethane extracts 200mL*2, merge organic layer, use 1N hydrochloric acid respectively, satisfy
With sodium bicarbonate solution and saturated common salt washing, anhydrous sodium sulfate drying, filtering and concentrating obtains grease, vacuum distillation, collects
bp:The fraction of 112～115 DEG C/3mmHg, obtains N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III) 60g, purity
94%, yield 75.5%.Wherein, 2- methyl -2- phenylpropionic acid (II), N, O- dimethyl hydroxylamine hydrochloride, the mole ratio of alkali
For 1:1.5:2.
Embodiment 8：In 500mL reaction bulb, add 63g 2- methyl -2- phenylpropionic acid (II), 250mL toluene and 150g chlorine
Change sulfoxide, heating reflux reaction 2h, HPLC monitoring reaction is complete, the thionyl chloride of evaporated under reduced pressure solvent and excess, then plus 100mL
Toluene dissolves, and is cooled to 0～5 DEG C, is slowly added dropwise the solution of potassium carbonate (132.4g)/water (180g), adds insulated and stirred
10min, Deca N, the solution of O- dimethyl hydroxylamine hydrochloride (48.6g)/water (80g), finish, warm naturally to room temperature reaction
2h, HPLC monitoring reaction completely, separates organic layer, water layer dichloromethane extracts 200mL*2, merges organic layer, use 1N respectively
Hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt washing, anhydrous sodium sulfate drying, filtering and concentrating obtains grease, and decompression is steamed
Evaporate, collect bp:The fraction of 112～115 DEG C/3mmHg, obtains N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III)
74g, purity 98%, yield 93.1%.Wherein, 2- methyl -2- phenylpropionic acid (II), N, O- dimethyl hydroxylamine hydrochloride, alkali
Mole is than for 1:1.3:2.5.
3rd, 2- (4- (4- chlorobutyryl) phenyl)-N- methoxyl group-N, the synthesis of 2- dimethylpropionamide (IV)
Embodiment 9：In 500mL reaction bulb, add 60g aluminum trichloride (anhydrous), 125mL dichloromethane, be cooled to -5～0
DEG C, temperature control Deca N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III) (100g)/dichloromethane (90mL) solution, plus
Finish, insulation reaction 1h, obtain solution for later use；Addition 90g aluminum trichloride (anhydrous) in 1000ml reaction bulb, 125mL dichloromethane, cold
But to -5～0 DEG C, temperature control Deca 4- chlorobutanoylchloride (95g)/dichloromethane (90mL) solution, finish, after insulation reaction 1h, cooling
0～5 DEG C, above-mentioned solution Deca is come in, keep 0～5 DEG C, finish, insulation reaction 1h, be more naturally warmed to room temperature (20～25
DEG C) reacting 48h, HPLC monitors to reaction completely, reactant liquor is poured slowly in the mixture of ice and water of 1500g stirring and is quenched, point
Go out organic layer, water layer dichloromethane extracts 200mL*2, merge organic layer, with saturated sodium bicarbonate solution, wash, saturation is eaten
Salt is washed, and anhydrous sodium sulfate drying is concentrated to give dark oil thing.After adding hexamethylene dissolution product, concentrate hexamethylene and obtain
2- (4- (4- chlorobutyryl) phenyl)-N- methoxyl group-N, 2- dimethylpropionamide (IV) 128g, purity 92%, yield 85%.Its
In, N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III), 4- chlorobutanoylchloride, the mole of aluminum chloride are than for 1:
1.4:2.5.
Embodiment 10：In 500mL reaction bulb, add 70.8g aluminum trichloride (anhydrous), 125mL dichloromethane, it is cooled to -5～
0 DEG C, temperature control Deca N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III) (100g)/dichloromethane (90mL) solution, plus
Finish, insulation reaction 1h, obtain solution for later use；Addition 90g aluminum trichloride (anhydrous) in 1000ml reaction bulb, 125mL dichloromethane, cold
But to -5～0 DEG C, temperature control Deca 4- chlorobutanoylchloride (74.8g)/dichloromethane (90mL) solution, finish, after insulation reaction 1h, fall
0～5 DEG C of temperature, above-mentioned solution Deca is come in, and keeps 0～5 DEG C, finishes, insulation reaction 1h, be more naturally warmed to room temperature (20～
25 DEG C) react 48h, HPLC monitors to reaction completely, reactant liquor is poured slowly in the mixture of ice and water of 1500g stirring and is quenched,
Separate organic layer, water layer dichloromethane extracts 200mL*2, merge organic layer, with saturated sodium bicarbonate solution, wash, saturation
Sal is washed, and anhydrous sodium sulfate drying is concentrated to give dark oil thing.After adding hexamethylene dissolution product, concentrate hexamethylene and obtain
To 2- (4- (4- chlorobutyryl) phenyl)-N- methoxyl group-N, 2- dimethylpropionamide (IV) 107g, purity 89%, yield
71.1%.Wherein, N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III), 4- chlorobutanoylchloride, the mole of aluminum chloride
Than for 1:1.1:2.5.
Embodiment 11：In 500mL reaction bulb, add 38.7g aluminum trichloride (anhydrous), 125mL dichloromethane, it is cooled to -5～
0 DEG C, temperature control Deca N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III) (100g)/dichloromethane (90mL) solution, plus
Finish, insulation reaction 1h, obtain solution for later use；Addition 90g aluminum trichloride (anhydrous) in 1000ml reaction bulb, 125mL dichloromethane, cold
But to -5～0 DEG C, temperature control Deca 4- chlorobutanoylchloride (102g)/dichloromethane (90mL) solution, finish, after insulation reaction 1h, fall
0～5 DEG C of temperature, above-mentioned solution Deca is come in, and keeps 0～5 DEG C, finishes, insulation reaction 1h, be more naturally warmed to room temperature (20～
25 DEG C) react 48h, HPLC monitors to reaction completely, reactant liquor is poured slowly in the mixture of ice and water of 1500g stirring and is quenched,
Separate organic layer, water layer dichloromethane extracts 200mL*2, merge organic layer, with saturated sodium bicarbonate solution, wash, saturation
Sal is washed, and anhydrous sodium sulfate drying is concentrated to give dark oil thing.After adding hexamethylene dissolution product, concentrate hexamethylene and obtain
To 2- (4- (4- chlorobutyryl) phenyl)-N- methoxyl group-N, 2- dimethylpropionamide (IV) 126g, purity 92%, yield
83.8%.Wherein, N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III), 4- chlorobutanoylchloride, the mole of aluminum chloride
Than for 1:1.5:2.
Embodiment 12：In 500mL reaction bulb, add 60g aluminum trichloride (anhydrous), 125mL dichloromethane, be cooled to -5～0
DEG C, temperature control Deca N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III) (100g)/dichloromethane (90mL) solution, plus
Finish, insulation reaction 1h, obtain solution for later use；Addition 90g aluminum trichloride (anhydrous) in 1000ml reaction bulb, 125mL dichloromethane, cold
But to -5～0 DEG C, temperature control Deca 4- chlorobutanoylchloride (88.4g)/dichloromethane (90mL) solution, finish, after insulation reaction 1h, fall
0～5 DEG C of temperature, above-mentioned solution Deca is come in, and keeps 0～5 DEG C, finishes, insulation reaction 1h, be more naturally warmed to room temperature (20～
25 DEG C) react 48h, HPLC monitors to reaction completely, reactant liquor is poured slowly in the mixture of ice and water of 1500g stirring and is quenched,
Separate organic layer, water layer dichloromethane extracts 200mL*2, merge organic layer, with saturated sodium bicarbonate solution, wash, saturation
Sal is washed, and anhydrous sodium sulfate drying is concentrated to give dark oil thing.After adding hexamethylene dissolution product, concentrate hexamethylene and obtain
To 2- (4- (4- chlorobutyryl) phenyl)-N- methoxyl group-N, 2- dimethylpropionamide (IV) 125g, purity 92%, yield
83.1%.Wherein, N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III), 4- chlorobutanoylchloride, the mole of aluminum chloride
Than for 1:1.3:2.3.
4th, the synthesis of 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid (V)
Embodiment 13：In 1000mL reaction bulb, sequentially add 121g 2- (4- (4- chlorobutyryl) phenyl)-N- methoxyl group-
N, 2- dimethylpropionamide (IV), 484mL dioxane, 242g 6N HCl, it is heated to 90～100 DEG C of back flow reaction 20h,
HPLC monitoring reaction completely, is cooled to room temperature, reactant liquor is poured in 400mL water, extract 200mL*3 with toluene, merge organic
Layer, washing, saturated common salt is washed, and anhydrous sodium sulfate drying is concentrated to give brownish red grease, uses hexamethylene recrystallization, obtain
Solid 2- (4- (4- chlorobutyryl) the phenyl) -2 Methylpropionic acid (V) of 95g yellow powder, purity 94%, yield 91%.
5th, the synthesis of 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid methyl ester (VI)
Embodiment 14：In 500mL reaction bulb, add 49.2g 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid
(V), 150mL toluene, 65g thionyl chloride, it is heated to 55～65 DEG C of backflow 2h, completely, decompression steams toluene for HPLC monitoring reaction
And the thionyl chloride of excess, residue 150mL toluene dissolves, and is cooled to 0～5 DEG C, and temperature control Deca 100mL absolute methanol rises
To 2h is stirred at room temperature, HPLC monitoring reaction completely, then is passed through HCl gas to saturation, stirs 1h, and HPLC monitoring reaction completely, subtracts
Pressure concentrates toluene and methanol, and residue 150mL toluene dissolves, washing, and saturated common salt is washed, anhydrous sodium sulfate drying, concentrates,
Obtain 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid methyl ester (VI) 53g, purity 90%, yield 92%.
6th, 2- [4- [4- [4- (hydroxy benzophenone base)-piperidino]-bytyry] phenyl] -2 Methylpropionic acid methyl ester
(VII) synthesis
Embodiment 15：In 1000mL reaction bulb, sequentially add 55.4g diphenyl-piperidine methanol, 42.1g potassium bicarbonate,
3.1g potassium iodide, 310mL toluene, it is heated to 80 DEG C, start to be slowly added dropwise 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid
Methyl ester (VI) (53.3g)/toluene solution (150ml), finishes, and back flow reaction about 30h, HPLC monitoring reaction is complete, by reactant liquor
It is cooled to 10～15 DEG C, filters, filtrate is concentrated to give crude product 107g；It is heated to reflux molten clear, Deca 80mL with 250mL dehydrated alcohol
Water, after backflow 30min, naturally cools to 10～15 DEG C, and insulated and stirred 4h is filtrated to get off-white powder, dries 90g；Use again
EA recrystallization, obtains white solid 2- [4- [4- [4- (hydroxy benzophenone base)-piperidino]-bytyry] phenyl] -2- methyl
Methyl propionate (VII) 77.4g, purity 99.5%, yield 80%.Wherein, 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid
Methyl ester (VI), potassium iodide, the mole of alkali are than for 1:0.1:2.23.
Embodiment 16：In 1000mL reaction bulb, sequentially add 55.4g diphenyl-piperidine methanol, 47.1g potassium bicarbonate,
1.6g potassium iodide, 310mL toluene, it is heated to 85 DEG C, start to be slowly added dropwise 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid
Methyl ester (VI) (53.3g)/toluene solution (150ml), finishes, and back flow reaction about 30h, HPLC monitoring reaction is complete, by reactant liquor
It is cooled to 10～15 DEG C, filters, filtrate is concentrated to give crude product 107g；It is heated to reflux molten clear, Deca 80mL with 250mL dehydrated alcohol
Water, after backflow 30min, naturally cools to 10～15 DEG C, and insulated and stirred 4h is filtrated to get off-white powder, dries 89g；Use again
EA recrystallization, obtains white solid 2- [4- [4- [4- (hydroxy benzophenone base)-piperidino]-bytyry] phenyl] -2- methyl
Methyl propionate (VII) 75g, purity 99.3%, yield 77.5%.Wherein, 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid
Methyl ester (VI), potassium iodide, the mole of alkali are than for 1:0.05:2.5.
Embodiment 17：In 1000mL reaction bulb, sequentially add 55.4g diphenyl-piperidine methanol, 31.7g sodium bicarbonate,
4.7g potassium iodide, 310mL toluene, it is heated to 90 DEG C, start to be slowly added dropwise 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid
Methyl ester (VI) (53.3g)/toluene solution (150ml), finishes, and back flow reaction about 30h, HPLC monitoring reaction is complete, by reactant liquor
It is cooled to 10～15 DEG C, filters, filtrate is concentrated to give crude product 107g；It is heated to reflux molten clear, Deca 80mL with 250mL dehydrated alcohol
Water, after backflow 30min, naturally cools to 10～15 DEG C, and insulated and stirred 4h is filtrated to get off-white powder, dries 85g；Use again
EA recrystallization, obtains white solid 2- [4- [4- [4- (hydroxy benzophenone base)-piperidino]-bytyry] phenyl] -2- methyl
Methyl propionate (VII) 70g, purity 99%, yield 72.3%.Wherein, 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid first
Ester (VI), potassium iodide, the mole of alkali are than for 1:0.15:2.
Embodiment 18：In 1000mL reaction bulb, sequentially add 55.4g diphenyl-piperidine methanol, 34.8g sodium bicarbonate,
3.1g potassium iodide, 310mL toluene, it is heated to 95 DEG C, start to be slowly added dropwise 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid
Methyl ester (VI) (53.3g)/toluene solution (150ml), finishes, and back flow reaction about 30h, HPLC monitoring reaction is complete, by reactant liquor
It is cooled to 10～15 DEG C, filters, filtrate is concentrated to give crude product 107g；It is heated to reflux molten clear, Deca 80mL with 250mL dehydrated alcohol
Water, after backflow 30min, naturally cools to 10～15 DEG C, and insulated and stirred 4h is filtrated to get off-white powder, dries 86g；Use again
EA recrystallization, obtains white solid 2- [4- [4- [4- (hydroxy benzophenone base)-piperidino]-bytyry] phenyl] -2- methyl
Methyl propionate (VII) 71g, purity 99%, yield 73.3%.Wherein, 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid first
Ester (VI), potassium iodide, the mole of alkali are than for 1:0.1:2.2.
Although the present invention is disclosed as above with preferred embodiment, so it is not limited to the present invention, any affiliated technology
The technical staff in field, without departing from the spirit and scope of the present invention, when can make a little change and improvement, the therefore present invention
Protection domain when being defined depending on as defined in claim.
Claims (10)
1. a kind of fexofenadine intermediate 2- [4- [4- [4- (hydroxy benzophenone base)-piperidino]-bytyry] phenyl] -2-
The synthetic method of methylpropionic acid methyl esters is it is characterised in that press following synthetic routes：
Described synthetic method comprises the steps of：
Step 1：With benzene acetonitrile as raw material, react generation 2- methyl -2- phenylpropanenitrile in the basic conditions with dimethyl sulfate
(I)；
Step 2：2- methyl -2- phenylpropanenitrile (I) is hydrolyzed into 2- methyl -2- phenylpropionic acid (II) in the basic conditions；
Step 3：2- methyl -2- phenylpropionic acid (II) passes through Wei because of thunder butoctamide reaction generation N- methoxyl group-N, 2- dimethyl -2-
Phenylpropionamide (III)；
Step 4：N- methoxyl group-N, 2- dimethyl -2- Phenylpropionamide (III) generate 2- (4- (4- neoprene acyl by Friedel-Crafts reaction
Base) phenyl)-N- methoxyl group-N, 2- dimethylpropionamide (IV)；
Step 5：2- (4- (4- chlorobutyryl) phenyl)-N- methoxyl group-N, is 2- (4- after 2- dimethylpropionamide (IV) hydrolysis
(4- chlorobutyryl) phenyl) -2 Methylpropionic acid (V)；
Step 6：2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid (V) and methanol react generation 2- (4- (4- chlorobutyryl)
Phenyl) -2 Methylpropionic acid methyl ester (VI)；
Step 7：2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid methyl ester (VI) and the condensation life of diphenyl -4- piperidine carbinols
Become 2- [4- [4- [4- (hydroxy benzophenone base)-piperidino]-bytyry] phenyl] -2 Methylpropionic acid methyl ester (VII).
2. synthetic method according to claim 1 it is characterised in that in step 1 alkali used be sodium hydroxide, hydroxide
Potassium, benzene acetonitrile, dimethyl sulfate, the mole of alkali are than for 1:2.1～3:4～6.
3. preparation method according to claim 1 is it is characterised in that alkali used by hydrolysis in step 2 is sodium hydroxide, hydrogen-oxygen
Change potassium.
4. preparation method according to claim 1 is it is characterised in that step 3 comprises:2- methyl -2- phenylpropionic acid (II)
First generate acyl chlorides with thionyl chloride, then with N, O- dimethyl hydroxylamine hydrochloride synthesizes N- methoxyl group-N, 2- bis- in the basic conditions
Methyl -2- Phenylpropionamide (III), concrete synthetic route is as follows：
5. preparation method according to claim 4 it is characterised in that in step 3 alkali used be potassium carbonate, cesium carbonate, carbon
Sour sodium, 2- methyl -2- phenylpropionic acid (II), N, O- dimethyl hydroxylamine hydrochloride, the mole of alkali are than for 1:1.1～1.5:2～
3.
6. preparation method according to claim 1 is it is characterised in that N- methoxyl group-N, 2- dimethyl -2- benzene in step 4
Base propionic acid amide. (III) reacts generation 2- (4- (4- chlorobutyryl) benzene under the effect of catalyst aluminum chloride with 4- chlorobutanoylchloride
Base)-N- methoxyl group-N, 2- dimethylpropionamide (IV).
7. preparation method according to claim 6 is it is characterised in that N- methoxyl group-N, 2- dimethyl -2- benzene in step 4
Base propionic acid amide. (III), 4- chlorobutanoylchloride, the mole of aluminum chloride are than for 1:1.1～1.5:2～2.5, reaction temperature be 20～
25℃.
8. it is characterised in that step 5 is to be hydrolyzed with 6N hydrochloric acid, 6N hydrochloric acid used is preparation method according to claim 1
Technical grade 31% hydrochloric acid adds water configuration, and heating-up temperature is 90～100 DEG C.
9. preparation method according to claim 1 it is characterised in that step 6 comprise 2- (4- (4- chlorobutyryl) phenyl)-
2 Methylpropionic acid (V) is first evaporated methanol with thionyl chloride after methanol solution heating 2h, then is passed through hydrogen chloride gas and makes 2- (4- (4-
Chlorobutyryl) phenyl) -2 Methylpropionic acid methyl ester (VI), heating-up temperature be 55～65 DEG C, concrete synthetic route is as follows：
10. preparation method according to claim 1 it is characterised in that step 7 used catalyst be potassium iodide, alkali used
For potassium bicarbonate, sodium bicarbonate, 2- (4- (4- chlorobutyryl) phenyl) -2 Methylpropionic acid methyl ester (VI), potassium iodide, alkali mole
Amount ratio is 1:0.05～0.15:2～2.5, reaction temperature is 80～95 DEG C.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010031895A1 (en) * | 1993-06-25 | 2001-10-18 | Merrell Dow Pharmaceuticals Inc. | Novel intermediates useful for the preparation of antihistaminic piperidine derivatives |
| WO2005019175A1 (en) * | 2003-08-26 | 2005-03-03 | Cipla Limited | Fexofenadine polymorphs and processes of preparing the same |
| CN101585768A (en) * | 2009-06-06 | 2009-11-25 | 浙江大学宁波理工学院 | Method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methacrylate |
| CN101585805A (en) * | 2009-06-06 | 2009-11-25 | 浙江大学宁波理工学院 | Preparation method of an antiallergic agent fexofenadine hydrochloride |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010031895A1 (en) * | 1993-06-25 | 2001-10-18 | Merrell Dow Pharmaceuticals Inc. | Novel intermediates useful for the preparation of antihistaminic piperidine derivatives |
| CN1168717C (en) * | 1993-06-25 | 2004-09-29 | 默里尔药物公司 | Novel intermediates for prepn. of antihisatminic 4-diphenylmethyl/diphenymethoxy piperidine derivatives |
| WO2005019175A1 (en) * | 2003-08-26 | 2005-03-03 | Cipla Limited | Fexofenadine polymorphs and processes of preparing the same |
| CN101585768A (en) * | 2009-06-06 | 2009-11-25 | 浙江大学宁波理工学院 | Method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methacrylate |
| CN101585805A (en) * | 2009-06-06 | 2009-11-25 | 浙江大学宁波理工学院 | Preparation method of an antiallergic agent fexofenadine hydrochloride |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113387797A (en) * | 2021-05-31 | 2021-09-14 | 常州工程职业技术学院 | Preparation method of key intermediate of erlotinib |
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