The preparation method of tolterodine and tartrate thereof
Technical field
The present invention relates to the preparation method of compound tolterodine [(R)-N, N-di-isopropyl-3-(2-hydroxy-5-methyl base phenyl)-3-phenylpropylamine] and tartrate thereof.
Background technology
Tolterodine (Tolterodine, 1) is (R)-N, the common name of N-di-isopropyl-3-(2-hydroxy-5-methyl base phenyl)-3-phenylpropylamine, and its structural formula is:
Tolterodine (Tolterodine) 1
Tolterodine is a kind of medicine with novel treatment urinary incontinence of unique chemical structure, it is a choline m receptor antagonist, m receptor subtype-selective to bladder is higher than the sialisterium m receptor in vivo, active metabolite is higher than parent drug, it can the competitive bladder contracts that stops carbachol to cause, the bladder m receptor is restrained the activity produced to be much higher than Histamine Receptors to pylic alpha-2-adrenoceptor of Supravesical calcium channel and ileum and to suppress the activity that produced, through a large amount of pharmacological evaluation and clinical applications, tolterodine has rapid-action, evident in efficacy, advantages such as untoward reaction is few are a kind of rising treatment urinary incontinence medicines.
US5,386, disclosing the preparation method of tolterodine and tartrate thereof in 200, is starting raw material with the trans-cinnamic acid, is condensed into 3 with p-methyl phenol, behind 4-dihydro-6-methyl-4-phenyl-2H chromen-2-one with methyl iodide methylate, esterification, with Lithium Aluminium Hydride ester group is reduced to alcoholic extract hydroxyl group then, behind the tolysulfonyl chlorine activation hydroxyl, reacts with Diisopropylamine, behind the boron tribromide demethylating, split with L-(+) tartrate.
Disclose the method for using same materials among the ZL97180147.9, but required preparation process is less, reaction can obtain target compound through 5 steps, but this route can not effectively utilize the fractionation by product, caused overall yield of reaction lower, cost is higher, is unfavorable for industrial production.
Aforesaid method all needs absolute anhydrous and have under the environment of protection of inert gas and use LiAlH
4Or DIBAL-H reducing amide or ester group, severe reaction conditions has increased the danger and the operation easier of reacting, and makes tolterodine be difficult to realize large-scale industrial production.
J.Org.Chem.1993,63, reported the route of asymmetric synthesis tolterodine among the 8067-8070, product can no longer split, but this route principal reaction reached for 16 steps together with intermediate synthetic, complex process, and yield is very low, can't realize suitability for industrialized production.
The method of another kind of asymmetric synthesis tolterodine is disclosed among the CN1414944A, than J.Org.Chem.1993,63, route among the 8067-8070 is more easy and improved yield, but this method is raw materials used and reaction process in used chiral reagent cost higher, and resulting intermediate also needs DIBAL-H or Pa/C-H
2Deng reduction, reaction conditions is harsh, and the synthesis technique step is still oversize not to be suitable for industrial production.
Summary of the invention
In view of the defective of present tolterodine synthetic method, the invention provides the preparation method that a kind of cost is low, yield is high, reaction conditions is easy to realize and be suitable for the large-scale industrial production tolterodine.
The preparation method of tolterodine of the present invention and tartrate thereof comprises the steps:
The reaction of a, p-methyl phenol 2 and trans Cinoxolone 3
The used trans Cinoxolone of this reaction is trans styryl carbinol trifluoromethayl sulfonic acid ester, trans styryl carbinol trifluoro-acetate, trans styryl carbinol p-nitrobenzoic acid ester, trans styryl carbinol 3,5-dinitrobenzoic acid ester, trans styryl carbinol 2,4, the ester that 6-trinitrobenzoic acid ester etc. has acid that strong electron-withdrawing group links to each other with the carboxylic acid group and trans styryl carbinol to form; The acid of adopting is organic acids such as mineral acid such as sulfuric acid, hydrochloric acid, phosphoric acid, Hydrogen bromide or formic acid, acetate, oxalic acid, phenylformic acid, Phenylsulfonic acid, and the condensation under the acid effect of trans Cinoxolone and p-methyl phenol obtains condenses 4 crude products;
B, condenses 4 are through obtaining racemization tolterodine 1 with the Diisopropylamine coupling;
C, usefulness L-(+)-tartrate split, and obtain L-(+)-tartrate-R-tolterodine 5 and by product L-(+)-tartrate-S-tolterodine 6;
By product L-(+)-tartrate that d, fractionation obtain-S-tolterodine 6 removes tartrate with the mineral alkali reaction, obtains S-tolterodine 1;
E, S-tolterodine 1 in solvent with the reaction of Grignard reagents such as n-Butyl Lithium, isobutyl-lithium, tert-butyl lithium and sec.-propyl bromination magnesium after, after cancellation such as saturated ammonia chloride or hydrochloric acid, three-dimensional arrangement changes, and is converted into the higher R-tolterodine 1 of curative effect;
F, R-tolterodine 1 get L-(+)-tartrate-R-tolterodine 5 with L-(+)-tartrate salify.
Above-mentioned reaction scheme is:
Step a of the present invention is under the effect of acid, make p-methyl phenol 2 and trans Cinoxolone 3 that condensation reaction take place, temperature of reaction is 75 ℃~146 ℃, reaction times is 4~25 hours, after reacting completely, quaternization mixture and organic solvent extraction, concentrating under reduced pressure gets oily matter adding recrystallization solvent then, obtains solid.Condenses 4 used extraction organic solvents are ethyl acetate, methyl acetate, toluene, dimethylbenzene, and recrystallisation solvent is one or more in methyl alcohol, ethanol, Virahol, the glycerol.
Step b is in solvent, and condenses 4 and Diisopropylamine reaction are obtained racemization tolterodine 1.
Step c is the reaction of preparation tolterodine salt, with the tolterodine and L-(+)-tartrate reaction salify and the fractionation of step b gained.
Steps d is to split by product L-(+)-tartrate-S-tolterodine 6 that obtains to remove tartrate with the mineral alkali reaction, obtains S-tolterodine 1;
Step e be S-tolterodine 1 in solvent, with the reaction of Grignard reagents such as n-Butyl Lithium, isobutyl-lithium, tert-butyl lithium and sec.-propyl bromination magnesium, change steric configuration and become R-tolterodine 1.The solvent that this reaction is adopted is alkanes, aromatics or ethers, is specially in normal hexane, Skellysolve A, sherwood oil, benzene, toluene, tetrahydrofuran (THF) or the ether one or more.What usefulness was reacted in cancellation is 10~20% ammonia chloride, 2~10% hydrochloric acid, 2~10% Hydrogen bromide, 1~5% sulfuric acid, 2~10% nitric acid, 2~10% formic acid, 2~10% acetate etc.The temperature of this reaction is-40 ℃~25 ℃, and the reaction times is 2~26 hours.
Step f is the R-tolterodine and L-(+)-tartrate reaction salify of gained.
Advantage of the present invention is: (1) initiative use p-methyl phenol 2 and trans Cinoxolone 3 carries out condensation reaction, got rid of expensive methyl iodide, and need not to use the reagent of reduction ester bonds such as DIBAL-H or Lithium Aluminium Hydride, reaction conditions gentleness; (2) chosen effective sterie configuration transforming agent, as: Grignard reagents such as n-Butyl Lithium, isobutyl-lithium, tert-butyl lithium and sec.-propyl bromination magnesium, make fractionation obtain by product and be converted into the higher principal product of curative effect, improved yield greatly, reduce production cost, be suitable for suitability for industrialized production.
Embodiment
Further elaborate preparation method of the present invention below by embodiment.
Raw materials used trans Cinoxolone can be buied or prepare easily through esterification well-known to those skilled in the art (for example, trans styryl carbinol and trifluoromethanesulfonyl chloride carry out esterification) from commercial sources.
Embodiment 1:3-(2-hydroxy-5-methyl base phenyl)-3-phenyl propylidene 3, the preparation method of 5-dinitrobenzoic acid ester (4)
In four-hole bottle, adding p-methyl phenol 2 (119g, 1.1mol) with trans styryl carbinol 3,5-dinitrobenzoic acid ester (344g, 1.0mol), vitriol oil 150mL, be warming up to 135 ℃-138 ℃, stirring reaction cooled off after 8 hours, it is neutral that sodium hydroxide with 10% is transferred PH, extract with ethyl acetate 80mL * 2, organic phase after washing, 5% wet chemical washing, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, resistates obtains 3-(2-hydroxy-5-methyl base phenyl)-3-phenyl propylidene 3,5-dinitrobenzoic acid ester (366g, 82.8%) with 800mL Virahol recrystallization.
The preparation method of embodiment 2:3-(2-hydroxy-5-methyl base phenyl)-3-phenyl propylidene methane sulfonate (4)
In four-hole bottle, add p-methyl phenol 2 (119g, 1.1mol) and trans styryl carbinol trifluoromethane sulfonyl ester (165g 1.0mol), vitriol oil 150mL, is warming up to 123 ℃-126 ℃, behind the stirring reaction 16 hours, be cooled to room temperature, it is neutral that the aqueous sodium hydroxide solution with 10% is transferred pH, extracts with ethyl acetate 800mL * 2, organic phase after washing, the washing of 5% salt of wormwood, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, resistates obtains-(2-hydroxy-5-methyl base phenyl)-3-phenyl propylidene methane sulfonate (156.8g, 84.5%) with 800mL Virahol recrystallization.
Embodiment 3:N, the preparation of N-di-isopropyl-3-(2-hydroxy-5-methyl base phenyl)-3-phenyl propyl amine 1
(371g 0.84mol) is dissolved in the 1500mL toluene, adds the 1500g diisopropylamine and mixes with products obtained therefrom among the embodiment 1, backflow stirring reaction 38 hours, steaming desolventizes, and it is 14 that the aqueous sodium hydroxide solution of resistates adding 10% is transferred pH, ethyl acetate extraction, washing, decolouring is filtered, steam and remove ethyl acetate, obtaining oily matter is N, N-di-isopropyl-3-(2-hydroxy-5-methyl base phenyl)-3-phenyl propyl amine 1 (146g, 68.4%).
The preparation of embodiment 4:L-(+)-tartrate-R-tolterodine 5
With raceme N, N-di-isopropyl-3-(2-hydroxy-5-methyl base phenyl)-3-phenyl propyl amine 1 (350g, 1.07mol), add anhydrous methanol 980mL, with the mixed back of the 1600mL anhydrous methanol of L (+)-tartrate 240g in 0 ℃ of placement crystallization that spends the night, filter, the anhydrous methanol washing gets Tolterodine tartrate (183g, 38.1%), Mp.207-208 ℃, [α]
D 25(1%, methyl alcohol)=27.4 °.
Embodiment 5:L-(+)-tartrate-S-tolterodine 6 is converted into L-(+)-tartrate-R-tolterodine 5
With by product L-(+)-tartrate-S-tolterodine 6 (240g; 0.5mol); it is neutral that the sodium hydroxide of adding 20% is transferred PH; use ethyl acetate extraction, the organic layer anhydrous magnesium sulfate drying removes solvent under reduced pressure; resistates is dissolved in the 1000mL anhydrous tetrahydro furan; ice-water bath, under nitrogen protection in-30 ℃ of hexane solution (1.1mol, 688mL that add down n-Butyl Lithiums; 1.6M); normal-temperature reaction added saturated ammonium chloride solution cancellation reaction, with 800mL * 2 dichloromethane extraction after 8 hours then; the organic layer water; the saturated common salt water washing; anhydrous sodium sulfate drying removes solvent under reduced pressure, gets oily matter; then with operating of embodiment 4 L-(+)-tartrate-R-tolterodine 5 (185g; 77%), Mp.209-210 ℃, [α]
D 25(1%, methyl alcohol)=27.4 °.
Embodiment 6:L-(+)-tartrate-S-tolterodine 6 is converted into L-(+)-tartrate-R-tolterodine 5
With by product L-(+)-tartrate-S-tolterodine 6 240g (0.5mol); after 20% sodium hydroxide solution dissolving; use ethyl acetate extraction; the organic layer washing; the saturated common salt washing; anhydrous sodium sulfate drying; remove solvent under reduced pressure, resistates dissolves with anhydrous tetrahydro furan, under the nitrogen protection; at 5-10 ℃ of tetrahydrofuran solution (1.1mol) that adds sec.-propyl bromination magnesium in batches; room temperature reaction is after 38 hours then, and 2% gets hydrochloric acid cancellation reaction, uses dichloromethane extraction; the organic layer water; the saturated common salt water washing; anhydrous sodium sulfate drying removes solvent under reduced pressure, gets oily matter; then with operating of embodiment 4 L-(+)-tartrate-R-tolterodine 5 (172g; 71.6%), Mp.207-208 ℃, [α]
D 25(1%, methyl alcohol)=27.4 °.