CN100500642C - Method of preparing tuoteludin - Google Patents
Method of preparing tuoteludin Download PDFInfo
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- CN100500642C CN100500642C CNB2006100294922A CN200610029492A CN100500642C CN 100500642 C CN100500642 C CN 100500642C CN B2006100294922 A CNB2006100294922 A CN B2006100294922A CN 200610029492 A CN200610029492 A CN 200610029492A CN 100500642 C CN100500642 C CN 100500642C
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Abstract
The present invention discloses a preparation method of thoterodine and its L-tartrate. Said preparation method includes the following steps: using paracresol and cinnamic acid to prepare 6-methyl-4-phenyl-3,4-coumaran, using it to further prepare 3-(2-hydroxy-5-methylphenyl)-3-phenylpropanol, further preparing 3-(2-hydroxy-5-methylphenyl)-3-phenyl halogenated propane, then further preparing 3-(2-hydroxy protecting group-5-methylphenyl)-3-phenyl halogenated propane, and further preparing N,N-diisopropylamine-3-(2-hydroxy protecting group-5-methylphenyl)-3-phenylprophlamine, finally obtaining racemic thoterodine, then using L-(t)-tartaric acid to resolve racemic thoterodine so as to obtain L-(+)-tarlaric acid-R-thoterodine.
Description
Technical field
The present invention relates to tolterodine shown in a kind of preparation general formula (I), and the method for L-tartrate.
Background technology
Bladder excessive activities (Overactive Bladder) is the major cause that causes the urinary incontinence, is usually expressed as the frequent micturition and the urgent urination of accompanying or not accompanying the urgent urinary incontinence.Bladder excessive activities is the bad a kind of common cause of grownup's bladder control, is a kind of general and poignant problem, and has influence on people's quality of life.This disease sickness rate in women and the elderly is higher.The deep alkali acceptor of poison is considered to regulate the initial carrier of detrusor contractions, so the medicine mechanism of action of normal use is the malicious deep alkali acceptor of retardance, reaches the purpose (as muscarine antagonist class medicine) of the non-random detrusor contractions of reduction.The L-Tolterodine tartrate is the deep alkali acceptor of a kind of novel potent poison, the bladder contracts that can stop carbachol to cause competitively.Show that through a large amount of pharmacological evaluation and clinical applications the L-Tolterodine tartrate has the curative effect height to the urinary incontinence, therefore the characteristics that untoward reaction is few have been widely used in the treatment urinary incontinence in recent years.
In U.S. Patent No. 5,382, in 600, the chemical structure information of tolterodine is at first disclosed, its chemistry (+)-R-3-(2-hydroxy-5-methyl base phenyl) by name-N, N-di-isopropyl-3-phenylpropylamine, its structural formula are (I):
The preparation method of L-Tolterodine tartrate has been described in this patent simultaneously, it is that raw material is through condensation and cyclization that described method relates to trans-cinnamic acid and p-cresol, obtain 3, methylate and esterification with methyl iodide behind 4-dihydro-6-methyl-4-phenyl-2H-benzofuran-2-ones, then in ether solvent, methyl esters is reduced to corresponding substituted propanol with Lithium Aluminium Hydride, utilize tolysulfonyl chlorine activation hydroxyl, the reaction of Acibenzolar and Diisopropylamine obtains corresponding aminate then, and utilize boron tribromide to remove methyl, split salify with L-tartrate at last.The reagent of using in this synthetic route, as price costlinesses such as Lithium Aluminium Hydride, boron tribromide and pyridines, and severe reaction conditions, the high operation easier of reactivity hazard is big, causes the difficulty of suitability for industrialized production.U.S. Patent No. 5922514 has been reported a route that synthesis step is short, it is that raw material is through condensation and cyclization that this route relates to trans-cinnamic acid and p-cresol, obtain 3, behind 4-dihydro-6-methyl-4-phenyl-2H-benzofuran-2-ones, directly become acetal with DIBAL-H reduction ester group, then obtaining racemic tolterodine under the catalysis of palladium carbon He behind the Diisopropylamine generation reductive amination process, splitting and salify with L-tartrate at last.But it is expensive that DIBAL-H that uses in this route and palladium carbon price all compare, and when using DIBAL-H, operation easier is also bigger, and is relatively more dangerous, is difficult to realize industrialization.Andersson, people such as Pher G. be at the magazine J.Org.Chem.1998 of American Chemical Society, and 63, P8067～8070 page disclose a kind of method of asymmetric synthesis tolterodine, have avoided fractionation.This method relates to utilizes the Evans prothetic group as chiral source, and when the Michael addition reaction took place, the ee value of induced reaction 98% obtained almost single enantiomer.But the employed chirality prothetic group of this method costs an arm and a leg, and simultaneously, also relate to expensive reagent such as Lithium Aluminium Hydride, palladium carbon and cuprous bromide dimethyl sulphide, and synthetic route does not solve the synthetic technological condition harshness, unworkable problem equally.
Summary of the invention
Technical problem to be solved by this invention provides a kind of novel method for preparing tolterodine and L-tartrate thereof, and this method cost is low, and reaction conditions is easy to realize, and reaction yield height, constant product quality, is convenient to suitability for industrialized production.
The technical solution used in the present invention: a kind of preparation chemical formula is the method for the tolterodine of (I), comprises the following steps:
A. addition condensation reaction takes place and obtains chemical formula and be the 6-methyl-4-phenyl-3 of (II), 4-melilotine in p-cresol and styracin under sulfuric acid catalysis;
B. chemical formula is the 6-methyl-4-phenyl-3 of (II), the 4-melilotine is in solvent, in the presence of reductive agent and catalyzer, make 3-(2-hydroxy-5-methyl base the phenyl)-3-phenyl propanol of chemical formula through ring-opening reaction for (III), wherein said solvent is selected from one or more the mixed solvent in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF) or the isopropyl ether, described reductive agent is selected from sodium borohydride or POTASSIUM BOROHYDRIDE, and described catalyzer is selected from iodine, zinc chloride, aluminum chloride or boron trifluoride diethyl etherate;
C. chemical formula is 3-(2-hydroxy-5-methyl base the phenyl)-3-phenyl propanol and the halogenating agent generation halogenating reaction of (III), obtain 3-(2-hydroxy-5-methyl base the phenyl)-3-phenyl halogenopropane of chemical formula for (IV), wherein said halogenating agent is selected from phosphorus tribromide, carbon tetrabromide, phosphorus trichloride, phosphorus oxychloride or sulfur oxychloride;
D. chemical formula is 3-(2-hydroxy-5-methyl base the phenyl)-3-phenyl halogenopropane and the hydroxyl protection radical reaction of (IV), make 3-(2-hydroxyl protecting group-5-the aminomethyl phenyl)-3-phenyl halogenopropane of chemical formula for (V), wherein said hydroxyl protecting group is selected from ester class, silicon ethers or benzyl oxide class, R representation hydroxy protecting group in the chemical formula (IV);
E. chemical formula be 3-(2-hydroxyl protecting group-5-the aminomethyl phenyl)-3-phenyl halogenopropane of (V) in solvent with Diisopropylamine generation linked reaction, make the N of chemical formula for (VI), N '-Diisopropylamine-3-(2-hydroxyl protecting group-5-aminomethyl phenyl)-3-phenylpropylamine, wherein said solvent is selected from acetonitrile, glycol dimethyl ether, toluene, dimethylbenzene or dimethyl formamide;
F. chemical formula is the N of (VI), and N '-Diisopropylamine-3-makes the tolterodine of described chemical formula for (I) after (2-hydroxyl protecting group-5-aminomethyl phenyl)-the 3-phenylpropylamine removes hydroxyl protecting group.
Ester class hydroxyl protecting group described in the step (d) is selected from ethanoyl, propionyl or benzoyl.
Silicon ethers hydroxyl protecting group described in the step (d) is selected from trimethyl silicon based, the silica-based or triisopropylsilyl of tertiary butyl dimethyl.
Benzyl oxide class hydroxyl protecting group described in the step (d) is selected from benzyl or 4-methoxy-benzyl.
The temperature of linked reaction is controlled to be 80～100 ℃ in the step (e).
A kind of method for preparing tolterodine L-tartrate comprises the following steps: chemical formula is split racemization for tolterodine and L-(+)-tartrate of (I), makes L-(+)-tartrate-R-tolterodine that chemical formula is (VII).
Beneficial effect of the present invention, raw material of the present invention is cheap and easy to get, and is easy and simple to handle, need not to use reagent such as Lithium Aluminium Hydride or DIBAL-H.Reaction yield height of the present invention, cost is low, and the three wastes of generation are few.Process stabilizing of the present invention, the final product quality height is fit to suitability for industrialized production.
Embodiment
Below by embodiment the present invention is described in further detail, the preparation method of tolterodine is as follows:
(a) be that raw material under sulfuric acid catalysis addition condensation reaction takes place with p-cresol and styracin, obtain 6-methyl-4-phenyl-3,4-melilotine (II).
(b) Compound I I makes 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl propanol (III) through ring-opening reaction in the presence of reductive agent.
(c) under the effect of halogenating agent, make compound III generation halogenating reaction, obtain 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl halogenopropane (IV).
(d) with various hydroxyl protecting groups the phenolic hydroxyl group of compound IV is realized protection, make 3-(2-hydroxyl protecting group-5-aminomethyl phenyl)-3-phenyl halogenopropane (V).
(e) compound V and Diisopropylamine coupling make N, N-Diisopropylamine-3-(2-hydroxyl protecting group-5-aminomethyl phenyl)-3-phenylpropylamine (VI).
(f) after compound VI removes hydroxyl protecting group, make the tolterodine (I) of racemization.
Split racemization tolterodine I with L-(+)-tartrate, can further make L-(+)-tartrate-R-tolterodine (VII) and by product L-(+)-tartrate-S-tolterodine (VIII).
Above-mentioned reaction scheme is:
Wherein, the solvent of reaction can be selected toluene, dimethylbenzene or solvent-free for use in the step of the present invention (a); Be preferably solvent-free reaction.Reaction can be carried out at 110～150 ℃ in the step (a); Preferable reaction temperature is 140～150 ℃.Reaction solvent is selected from the mixed solvent of methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), isopropyl ether etc. or tetrahydrofuran (THF) and alcoholic solvent in the step (b).The solvent of reaction is preferably methyl alcohol, ethanol in the step (b).The reductive agent of reaction is sodium borohydride or POTASSIUM BOROHYDRIDE in the step (b), and with Louis's acid as catalyst.Useful as catalysts iodine, zinc chloride, aluminum chloride, boron trifluoride ether solution etc. are arranged.The reductive agent of reaction is preferably sodium borohydride and iodine in the step (b).Halide reagent can be selected from phosphorus tribromide, carbon tetrabromide, phosphorus trichloride, phosphorus oxychloride or sulfur oxychloride etc. in the step (c).The halide reagent of reaction is preferably phosphorus tribromide, phosphorus trichloride in the step (d).In the step (d) ester class protecting group be selected from ethanoyl, propionyl, benzoyl etc. any one.Ester class protecting group is preferably ethanoyl in the step (d).In the step (d) silicon ethers protecting group be selected from trimethyl silicon based, tertiary butyl dimethyl is silica-based, triisopropylsilyl etc. any one.Reaction silicon ethers protecting group is preferably trimethyl silicon based in the step (d).In the step (d) the benzyl oxide protecting group be selected from benzyl, 4-methoxy-benzyl etc. any one.Benzyl oxide class protecting group is preferably benzyl in the step (d).In the step (e) reaction solvent be selected from acetonitrile, glycol dimethyl ether, toluene, dimethylbenzene or dimethyl formamide etc. any one.Reaction solvent is preferably glycol dimethyl ether, toluene in the step (e).Reaction can be carried out at 75～110 ℃ in the step (e), and preferable reaction temperature is 85～100 ℃.In the step (f), remove the alkali that uses in the reaction of ester class protecting group and be selected from sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium ethylate, sodium methylate etc.Alkali is preferably sodium hydroxide, salt of wormwood in the step (f).The solvent of saponification reaction is selected from methyl alcohol, ethanol, Virahol, water etc. any one or its mixture in the step (f).The solvent of saponification reaction is preferably ethanol, water in the step (f).In the step (f), remove the Lewis acid that uses in the reaction of silicon ethers protecting group and be selected from hydrofluoric acid, tetrabutyl fluoride amine, boron trifluoride diethyl etherate, acetum etc.The Lewis acid that removes the use of silicon ethers protecting group in the step (f) is preferably boron trifluoride diethyl etherate or acetic acid.In the step (f), the solution that removes in the reaction of benzyl oxide class protecting group is selected from methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), ethyl acetate etc.The solvent of hydrogenation is preferably methyl alcohol, ethanol in the step (f).In the step (f), remove the catalyzer that uses in the reaction of benzyl oxide class protecting group and be selected from Raney's nickel, palladium carbon, palladium hydroxide carbon etc.The catalyzer of hydrogenation is preferably Raney's nickel and palladium carbon in the step (f).
Embodiment one
6-methyl-4-phenyl-3, the preparation of 4-melilotine (II)
In the there-necked flask of 500ml, (100g is 0.675mol) with p-cresol (76g to add styracin, 0.704), stir down and be heated to 100 ℃, and maintain under this temperature behind the stirring 30min, slowly drip the vitriol oil (16ml, 0.27mol), drip and finish, slowly be heated to 140～150 ℃, and maintain under this reaction reaction 6h, after the cooling, divide and go sulfuric acid layer, add the 500mL methylene dichloride, organic layer is with the 10% aqueous sodium carbonate weakly alkaline that neutralizes, tell organic layer, air distillation, and after reclaiming methylene dichloride, the residue that obtains alcohol-water (250ml:20ml) recrystallization, get more than the about 150g of white crystals yield: 93%, fusing point: 81～83 ℃.
Embodiment two
The preparation of 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl propanol (III)
Be equipped with in the there-necked flask of reflux at 1000mL, add 6-methyl-4-phenyl-3, (119g, 0.5mol), with the dissolve with ethanol of 500mL, (12.65g 50mmol), after stirring, adds NaBH to the 4-melilotine in batches to add iodine again
4(19g 0.5mol), finishes, be heated to backflow, be retained to TLC and detect till the no raw material, need 5 hours approximately, reaction system is cooled to normal temperature, slowly drips the saturated ammonium chloride solution of 200mL water and 200mL, till not having bubble and overflow to reaction system, after removing part ethanol under reduced pressure, add the ethyl acetate of 500mL, stir half an hour after, standing demix, organic layer washes with water, dry concentrate thick product, yield 95%.
Embodiment three
The preparation of 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl propanol (III)
Be equipped with in the there-necked flask of reflux at 1000mL, add 6-methyl-4-phenyl-3, (119g, 0.5mol), with the tetrahydrofuran (THF) dissolving of 500mL, (6.67g 0.05mol), after stirring, adds KBH to the 4-melilotine in batches to add aluminum chloride again
4(27g 0.5mol), finishes, be heated to backflow, be retained to TLC and detect till the no raw material, need 5 hours approximately, reaction system is cooled to normal temperature, slowly drips the saturated ammonium chloride solution of 200mL water and 200mL, till not having bubble and overflow to reaction system, after removing part ethanol under reduced pressure, add the ethyl acetate of 500mL, stir half an hour after, standing demix, organic layer washes with water, dry concentrate thick product, yield 94%.
Embodiment four
The preparation of 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl propanol (III)
Be equipped with in the there-necked flask of reflux at 1000mL, add 6-methyl-4-phenyl-3, and the 4-melilotine (119g, 0.5mol), isopropyl ether dissolving with 500mL, add boron trifluoride ether solution 5mL again,, after stirring, add KBH4 (27g in batches, 0.5mol), finish, be heated to backflow, being retained to TLC detects till the no raw material, need 5 hours approximately, reaction system is cooled to normal temperature, slowly drip the saturated ammonium chloride solution of 200mL water and 200mL, till not having bubble and overflow to reaction system, after removing part ethanol under reduced pressure, add the isopropyl ether of 200mL, stir half an hour after, standing demix, organic layer washes with water, dry concentrate thick product, yield 92%.
Embodiment five
The preparation of 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl-chloride propane (IV)
Be equipped with in the there-necked flask of reflux at 1000mL, add 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl propanol (96.8g, 0.4mol), anhydrous diethyl ether dissolving with 500mL, and reaction system is cooled to 0 ℃, (21.9g, diethyl ether solution 150mL 0.16mol) drip the complete room temperature that is warming up to slowly to drip phosphorus trichloride, being stirred to TLC detects till the no raw material, the saturated sodium bicarbonate solution that adds 800mL, standing demix, the water layer extracted with diethyl ether of 500mL, merge organic layer, use saturated sodium bicarbonate and water washing successively, dry back concentrates, and thick product is directly used in next step reaction.
Embodiment six
The preparation of 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl-chloride propane (IV)
Be equipped with in the there-necked flask of reflux at 1000mL, add 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl propanol (96.8g, 0.4mol), isopropyl ether dissolving with 500mL, and reaction system is cooled to 0 ℃, slowly (57g, isopropyl ether solution 150mL 0.48mol) drip the complete room temperature that is warming up to dripping thionyl chloride, being stirred to TLC detects till the no raw material, the saturated sodium bicarbonate solution that adds 800mL, standing demix, water layer extracts with the isopropyl ether of 500mL, merge organic layer, use saturated sodium bicarbonate and water washing successively, dry back concentrates, and thick product is directly used in next step reaction.
Embodiment seven
The preparation of 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl-bromide propane (IV)
Be equipped with in the there-necked flask of reflux at 1000mL, add 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl propanol (96.8g, 0.4mol), isopropyl ether dissolving with 500mL, and reaction system is cooled to 0 ℃, (43g, isopropyl ether solution 150mL 0.16mol) drip the complete room temperature that is warming up to slowly to drip phosphorus tribromide, being stirred to TLC detects till the no raw material, the saturated sodium bicarbonate solution that adds 800mL, standing demix, water layer extracts with the isopropyl ether of 500mL, merge organic layer, use saturated sodium bicarbonate and water washing successively, dry back concentrates, and thick product is directly used in next step reaction.
Embodiment eight
The preparation of 3-(2-acetoxyl group-5-aminomethyl phenyl)-3-phenyl-chloride propane
In the there-necked flask of 500mL, add 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl-chloride propane (15.6g, 60mmol) be dissolved in the methylene dichloride of 200mL, and reaction system is cooled to 0 ℃, add triethylamine (16.7mL, 0.12mol), dripping acetyl chloride (4.7mL slowly, 100mL dichloromethane solution 66mmol), drip Bi Ziran and be raised to room temperature, and behind the stirring reaction 6h, reactant is added in the frozen water of 300mL, the layering extraction, the dichloromethane extraction inorganic layer that adds 100mL merges organic phase, washing, dry and concentrated, obtain thick product.
Embodiment nine
The preparation of 3-(2-benzoyloxy-5-aminomethyl phenyl)-3-phenyl-chloride propane
In the there-necked flask of 500mL, add 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl-chloride propane (15.6g, 60mmol) be dissolved in the methylene dichloride of 200mL, and reaction system is cooled to 0 ℃, (16.7mL 0.12mol), slowly drips Benzoyl chloride (7.6mL to add triethylamine, 100mL dichloromethane solution 66mmol), drip Bi Ziran and be raised to room temperature, and behind the stirring reaction 6h, reactant is added in the frozen water of 300mL, the layering extraction, the dichloromethane extraction inorganic layer that adds 100mL merges organic phase, washing, dry and concentrated, obtain thick product.
Embodiment ten
The preparation of 3-(2-acetoxyl group-5-aminomethyl phenyl)-3-phenyl-bromide propane
In the there-necked flask of 500mL, add 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl-bromide propane (18.3g, 60mmol) be dissolved in the methylene dichloride of 200mL, and reaction system is cooled to 0 ℃, add triethylamine (16.7mL, 0.12mol), dripping acetyl chloride (4.7mL slowly, 100mL dichloromethane solution 66mmol), drip Bi Ziran and be raised to room temperature, and behind the stirring reaction 6h, reactant is added in the frozen water of 300mL, the layering extraction, the dichloromethane extraction inorganic layer that adds 100mL merges organic phase, washing, dry and concentrated, obtain thick product.
Embodiment 11
The preparation of 3-(2-benzoyloxy-5-aminomethyl phenyl)-3-phenyl-bromide propane
In the there-necked flask of 500mL, add 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl-chloride propane (18.3g, 60mmol) be dissolved in the methylene dichloride of 200mL, and reaction system is cooled to 0 ℃, add triethylamine (16.7mL, 0.12mol), slowly drip Benzoyl chloride (7.6mL, 66mmol) 100
The mL dichloromethane solution drips Bi Ziran and is raised to room temperature, and behind the stirring reaction 6h, reactant is added in the frozen water of 300mL, the layering extraction, and the dichloromethane extraction inorganic layer of adding 100mL merges organic phase, and washing is dry and concentrated, obtains thick product.
Embodiment 12
The preparation of 3-(2-trimethylsiloxy group-5-aminomethyl phenyl)-3-phenyl-chloride propane
In the there-necked flask of 500mL, add 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl-chloride propane (15.6g, 60mmol) be dissolved in the methylene dichloride of 200mL, and reaction system is cooled to 0 ℃, (16.7mL 0.12mol), slowly drips trimethylchlorosilane (7.1mL to add triethylamine, 100mL dichloromethane solution 66mmol), drip Bi Ziran and be raised to room temperature, and behind the stirring reaction 6h, reactant is added in the frozen water of 300mL, the layering extraction, the dichloromethane extraction inorganic layer that adds 100mL merges organic phase, washing, dry and concentrated, obtain thick product.
Embodiment 13
The preparation of 3-(2-trimethylsiloxy group-5-aminomethyl phenyl)-3-phenyl-bromide propane
In the there-necked flask of 500mL, add 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl-chloride propane (18.3g, 60mmol) be dissolved in the methylene dichloride of 200mL, and reaction system is cooled to 0 ℃, (16.7mL 0.12mol), slowly drips trimethylchlorosilane (7.1mL to add triethylamine, 100mL dichloromethane solution 66mmol), drip Bi Ziran and be raised to room temperature, and behind the stirring reaction 6h, reactant is added in the frozen water of 300mL, the layering extraction, the dichloromethane extraction inorganic layer that adds 100mL merges organic phase, washing, dry and concentrated, obtain thick product.
Embodiment 14
The preparation of 3-(2-benzyloxy-5-aminomethyl phenyl)-3-phenyl-chloride propane
In the there-necked flask of 500mL, add 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl-chloride propane (15.6g, 60mmol) be dissolved in the N of 200mL, in N '-dimethyl formamide, and reaction system be cooled to 0 ℃, add salt of wormwood (16.6g, 0.12mol), slowly drip Benzyl Chloride (7.6mL, 20mL N 66mmol), N '-dimethyl formamide solution, drip Bi Ziran and be raised to room temperature, and behind the stirring reaction 12h, reactant is added in the frozen water of 300mL, the layering extraction, the dichloromethane extraction inorganic layer that adds 300mL merges organic phase, washing, dry and concentrated, obtain thick product.
Embodiment 15
The preparation of 3-(2-benzyloxy-5-aminomethyl phenyl)-3-phenyl-bromide propane
In the there-necked flask of 500mL, add 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl-bromide propane (18.3g, 60mmol) be dissolved in the N of 200mL, in N '-dimethyl formamide, and reaction system be cooled to 0 ℃, add salt of wormwood (16.6g, 0.12mol), slowly drip Benzyl Chloride (7.6mL, 20mL N 66mmol), N '-dimethyl formamide solution, drip Bi Ziran and be raised to room temperature, and behind the stirring reaction 12h, reactant is added in the frozen water of 300mL, the layering extraction, the dichloromethane extraction inorganic layer that adds 300mL merges organic phase, washing, dry and concentrated, obtain thick product.
Embodiment 16
N, the preparation of N '-Diisopropylamine-3-(2-acetoxyl group-5-aminomethyl phenyl)-3-phenylpropylamine
In the there-necked flask of 500mL, (15.1g 50mmol) is dissolved in the glycol dimethyl ether of 100mL, adds Diisopropylamine (15.1g to add 3-(2-acetoxyl group-5-aminomethyl phenyl)-3-phenyl-chloride propane, 0.15mol), behind reaction system reflux 6h, cooling is added to reactant in the water of 200mL, the ethyl acetate extraction that adds 100mL, organic phase water washing after drying after decompression removes solvent, obtains thick product.
Embodiment 17
N, the preparation of N '-Diisopropylamine-3-(2-trimethylsiloxy group-5-aminomethyl phenyl)-3-phenylpropylamine
In the there-necked flask of 500mL, (18.9g 50mmol) is dissolved in the N of 150mL to add 3-(2-trimethylsiloxy group-5-aminomethyl phenyl)-3-phenyl-bromide propane, in N '-dimethyl formamide, the adding Diisopropylamine (15.1g, 0.15mol), behind reaction system reflux 6h, cooling, reactant is added in the water of 200mL, adds the ethyl acetate extraction of 200mL, organic phase water washing after drying, after decompression removes solvent, obtain thick product.
Embodiment 18
N, the preparation of N '-Diisopropylamine-3-(2-benzyloxy-5-aminomethyl phenyl)-3-phenylpropylamine
In the there-necked flask of 500mL, (19.7g 50mmol) is dissolved in the acetonitrile of 150mL, adds Diisopropylamine (15.1g to add 3-(2-benzyloxy-5-aminomethyl phenyl)-3-phenyl-bromide propane, 0.15mol), behind reaction system reflux 6h, cooling is added to reactant in the water of 200mL, the ethyl acetate extraction that adds 200mL, organic phase water washing after drying after decompression removes solvent, obtains thick product.Embodiment 19
N, N '-Diisopropylamine-3-(2-hydroxy-5-methyl base phenyl)-3-phenylpropylamine
In the there-necked flask of 250mL, add N, N '-Diisopropylamine-3-(2-acetoxyl group-5-aminomethyl phenyl)-3-phenylpropylamine (7.34g, 20mmol) be dissolved in the ethanol of 50mL, and adding salt of wormwood under stirring (2.8g, 20mmol), after keeping reaction to stir 12h at normal temperatures, remove ethanol under the decompression, add the water of 100mL and the ethyl acetate of 200mL, concentrate after the organic layer drying and obtain crude product.
Embodiment 20
N, N '-Diisopropylamine-3-(2-hydroxy-5-methyl base phenyl)-3-phenylpropylamine
In the there-necked flask of 250mL, add N, (7.94g 20mmol) is dissolved in the tetrahydrofuran (THF) of 50mL N '-Diisopropylamine-3-(2-trimethylsiloxy group-5-aminomethyl phenyl)-3-phenylpropylamine, stirs following 3
The boron trifluoride ether solution of mL after the maintenance reaction is stirred 6h at normal temperatures, adds the water of 100mL and the ethyl acetate of 200mL, concentrates after the organic layer drying and obtains crude product.
Embodiment 21
N, N '-Diisopropylamine-3-(2-hydroxy-5-methyl base phenyl)-3-phenylpropylamine
In the there-necked flask of 250mL, add N, N '-Diisopropylamine-3-(2-benzyloxy-5-aminomethyl phenyl)-3-phenylpropylamine (8.3g, 20mmol) be dissolved in the ethanol of 50mL, stir the palladium carbon that adds 0.42g 10% down, behind the hydrogenation 6h, filter away palladium carbon under the normal pressure, remove ethanol under the decompression and obtain crude product.
Embodiment 22
The preparation of L-Tolterodine tartrate
With N, (3.25g 10mmol) is dissolved in the dehydrated alcohol of 100mL N '-Diisopropylamine-3-(2-hydroxy-5-methyl base phenyl)-3-phenylpropylamine, adds L-tartrate (1.35g, ethanol solution 25mL 10mmol), under 4 ℃, stir and spend the night, suction filtration, obtaining white solid is crude product, twice of ethyl alcohol recrystallization of this crude product, obtain white needle-like crystals, fusing point is 209～210 ℃, and optically-active is
(1%, MeOH) [the document fusing point is 210～211 ℃, optically-active
】
Above said content only is the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technical scheme of the present invention is done, all should belong to protection scope of the present invention.
Claims (5)
1. a method for preparing chemical formula for the tolterodine of (I) comprises the following steps:
A. addition condensation reaction takes place and obtains chemical formula and be the 6-methyl-4-phenyl-3 of (II), 4-melilotine in p-cresol and styracin under sulfuric acid catalysis;
B. chemical formula is the 6-methyl-4-phenyl-3 of (II), the 4-melilotine is in solvent, in the presence of reductive agent and catalyzer, make 3-(2-hydroxy-5-methyl base the phenyl)-3-phenyl propanol of chemical formula through ring-opening reaction for (III), wherein said solvent is selected from one or more the mixed solvent in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF) or the isopropyl ether, described reductive agent is selected from sodium borohydride or POTASSIUM BOROHYDRIDE, and described catalyzer is selected from iodine, zinc chloride, aluminum chloride or boron trifluoride diethyl etherate;
C. chemical formula is 3-(2-hydroxy-5-methyl base the phenyl)-3-phenyl propanol and the halogenating agent generation halogenating reaction of (III), obtain 3-(2-hydroxy-5-methyl base the phenyl)-3-phenyl halogenopropane of chemical formula for (IV), wherein said halogenating agent is selected from phosphorus tribromide, carbon tetrabromide, phosphorus trichloride, phosphorus oxychloride or sulfur oxychloride;
D. chemical formula is 3-(2-hydroxy-5-methyl base the phenyl)-3-phenyl halogenopropane and the hydroxyl protection radical reaction of (IV), make 3-(2-hydroxyl protecting group-5-the aminomethyl phenyl)-3-phenyl halogenopropane of chemical formula for (V), wherein said hydroxyl protecting group is selected from ester class, silicon ethers or benzyl oxide class, R representation hydroxy protecting group in the chemical formula (IV);
E. chemical formula be 3-(2-hydroxyl protecting group-5-the aminomethyl phenyl)-3-phenyl halogenopropane of (V) in solvent with Diisopropylamine generation linked reaction, make the N of chemical formula for (VI), N '-Diisopropylamine-3-(2-hydroxyl protecting group-5-aminomethyl phenyl)-3-phenylpropylamine, wherein said solvent is selected from acetonitrile, glycol dimethyl ether, toluene, dimethylbenzene or dimethyl formamide;
F. chemical formula is the N of (VI), and N '-Diisopropylamine-3-makes the tolterodine of described chemical formula for (I) after (2-hydroxyl protecting group-5-aminomethyl phenyl)-the 3-phenylpropylamine removes hydroxyl protecting group
2. the preparation method of tolterodine according to claim 1, it is characterized in that: the ester class hydroxyl protecting group described in the step (d) is selected from ethanoyl, propionyl or benzoyl.
3. the preparation method of tolterodine according to claim 1, it is characterized in that: the silicon ethers hydroxyl protecting group described in the step (d) is selected from trimethyl silicon based, the silica-based or triisopropylsilyl of tertiary butyl dimethyl.
4. the preparation method of tolterodine according to claim 1, it is characterized in that: the benzyl oxide class hydroxyl protecting group described in the step (d) is selected from benzyl or 4-methoxy-benzyl.
5. the preparation method of tolterodine according to claim 1 is characterized in that: the temperature of linked reaction is controlled to be 80～100 ℃ in the step (e).
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| CNB2006100294922A CN100500642C (en) | 2006-07-28 | 2006-07-28 | Method of preparing tuoteludin |
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| CN101445462B (en) * | 2008-12-29 | 2011-05-25 | 药源药物化学（上海）有限公司 | Method for preparing tolterodine and tartrate thereof |
| CN102329244A (en) * | 2010-07-13 | 2012-01-25 | 凯瑞斯德生化(苏州)有限公司 | Preparation method and intermediate compound of RS-tolterodine |
| US9085509B2 (en) * | 2011-04-07 | 2015-07-21 | Alembic Pharmaceuticals Limited | Process for preparing fesoterodine |
| CN107628965B (en) * | 2017-09-21 | 2020-06-02 | 浙江大学 | Synthesis method of N, N-diisopropyl amino propionamide |
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