CN103044274B - Method for synthesizing tolterodine tartrate without solvent - Google Patents
Method for synthesizing tolterodine tartrate without solvent Download PDFInfo
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- CN103044274B CN103044274B CN201210527645.1A CN201210527645A CN103044274B CN 103044274 B CN103044274 B CN 103044274B CN 201210527645 A CN201210527645 A CN 201210527645A CN 103044274 B CN103044274 B CN 103044274B
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- YYSCJLLOWOUSHH-UHFFFAOYSA-N 4,4'-disulfanyldibutanoic acid Chemical compound OC(=O)CCCSSCCCC(O)=O YYSCJLLOWOUSHH-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960003553 tolterodine tartrate Drugs 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 21
- 239000002904 solvent Substances 0.000 title claims abstract description 7
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 45
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 39
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 24
- IWTYTFSSTWXZFU-QPJJXVBHSA-N [(e)-3-chloroprop-1-enyl]benzene Chemical compound ClC\C=C\C1=CC=CC=C1 IWTYTFSSTWXZFU-QPJJXVBHSA-N 0.000 claims description 21
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 229940043279 diisopropylamine Drugs 0.000 claims description 13
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 229960004045 tolterodine Drugs 0.000 claims description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 12
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 8
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 235000007715 potassium iodide Nutrition 0.000 claims description 8
- 229960004839 potassium iodide Drugs 0.000 claims description 8
- OOCCDEMITAIZTP-QPJJXVBHSA-N (E)-cinnamyl alcohol Chemical compound OC\C=C\C1=CC=CC=C1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 claims description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- TWHNMSJGYKMTRB-KXYUELECSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;2-[(1r)-3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-methylphenol Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 TWHNMSJGYKMTRB-KXYUELECSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000005516 engineering process Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- 239000012074 organic phase Substances 0.000 description 41
- 239000008213 purified water Substances 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000000047 product Substances 0.000 description 30
- 239000000243 solution Substances 0.000 description 29
- 239000010410 layer Substances 0.000 description 28
- 238000001035 drying Methods 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 238000012544 monitoring process Methods 0.000 description 13
- 239000012141 concentrate Substances 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000000605 extraction Methods 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- -1 layering Substances 0.000 description 6
- 238000005086 pumping Methods 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 239000012320 chlorinating reagent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 230000027939 micturition Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000010583 slow cooling Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000000921 Urge Urinary Incontinence Diseases 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 206010046494 urge incontinence Diseases 0.000 description 2
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 1
- GGRLKHMFMUXIOG-UHFFFAOYSA-M 2-acetyloxyethyl(trimethyl)azanium;hydroxide Chemical compound [OH-].CC(=O)OCC[N+](C)(C)C GGRLKHMFMUXIOG-UHFFFAOYSA-M 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
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- 230000007774 longterm Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a novel preparation method for synthesizing tolterodine tartrate. The method does not need to use the solvent and overcomes the defects of complicated aftertreatment, expensive cost and low product purity of a conventional technology, the reaction time is shortened, and industrial mass production requirements are met.
Description
Technical field
The present invention relates to pharmacy field, be specifically related to a kind of method of solvent-free synthetic Tolterodine tartrate.
Background technology
Tolterodine tartrate (Tolterodine Tartrate, structural formula 1), chemistry (R)-N by name, N-di-isopropyl-3-(2-hydroxy-5-methyl base phenyl)-3 phenylpropylamine L-(+) tartrates
Structural formula 1 (Tolterodine tartrate)
Tolterodine tartrate is the novel muscarinic receptor antagonist of Pharmacia & Upjohn company of U.S. research and development, can emulatively be combined with m receptor, thereby the combination of block nerves mediator vagusstoff and m receptor, can effectively suppress the contraction of detrusor, thereby alleviate the symptoms such as frequent micturition, urgent urination and urge incontinence, its meta-bolites is stronger to the selectivity of m receptor.1998 first in Switzerland listing, and the symptoms such as the clinical frequent micturition that is mainly used in being caused by overactive bladder, urgent urination and urge incontinence, due to its good curative effect be subject to widespread use compared with little toxic side effect.
In existing technology mainly with the initial reaction such as styracin, phenylacrolein raw material, for example: patent EP0960109A1, US5922914 etc. has reported, utilize identical starting raw material (p-cresol and styracin) first to prepare 3 under sulfuric acid catalysis condition, 4-dihydro-6-4-phenyl-2H-chromen-2-one, rear with reductive agent (LiAlH
4, DIBAL etc.) and 6-methyl 4-phenyl chroman-2-alcohol of reduction, then obtain the tolterodine free alkali of racemization with Diisopropylamine reduction amination under Pd/C exists, split and obtain target product finally by L-(+) tartrate.But the synthesising method reacting condition in above-mentioned report is all very harsh, and reactivity hazard is high, operation easier is large, makes tolterodine be difficult to realize large-scale industrial production.
Patent documentation EP2364966, EP2281801 disclose respectively the synthetic method taking cinnamyl chloride as raw material, but owing to all having used organic solvent toluene, methyl alcohol, ethanol etc. as reaction solvent in two technical schemes, easily there is etherificate and produce byproduct in reaction solvent, makes subsequent disposal very difficult.
Patent documentation WO2007147547 has reported the synthetic method taking cinnamyl chloride as raw material, it first replaces and obtains N with Diisopropylamine, N-diisopropyl benzene allylamine, obtaining the tolterodine of racemization with p-cresol effect, finally split and obtain target compound, the raw materials used cinnamyl chloride price of this technique is higher, and methylsulfonic acid is easy to enter in product in last handling process, cause product purity lower, therefore application is restricted.
Summary of the invention
The technical problem to be solved in the present invention is: overcome the synthetic technique shortcoming of prior art unresolvable tartaric acid tolterodine, provide a kind of route simple, operate simple and easy, product yield is high, meet the new Tolterodine tartrate synthetic route of the large production requirement of industry.
We have proposed a kind of method of novel synthetic Tolterodine tartrate, and concrete scheme route is as follows:
The present invention is synthetic to be comprised:
Step 1: styryl carbinol, thionyl chloride reaction, obtain product cinnamyl chloride;
Step 2: cinnamyl chloride, Diisopropylamine, alkali, iodide reaction, obtain product N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine;
Step 3:N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine, p-cresol, tosic acid reaction, obtain racemize tolterodine;
Step 4: racemize tolterodine, tartrate, dehydrated alcohol reaction, obtain tolterodine L-(+) tartrate.
In above-mentioned steps 1, described styryl carbinol and the feed ratio of chlorinating agent are 1: 1.
In above-mentioned steps 1, styryl carbinol solution is cooled to after 5-25 DEG C, drips chlorinating agent and react, temperature of reaction is 10-75 DEG C; React complete after, add dichloromethane extraction product.
In above-mentioned steps 2, described iodide are the one in potassiumiodide, sodium iodide.
In above-mentioned steps 2, described alkali is organic bases or mineral alkali, is specially the one in Anhydrous potassium carbonate, anhydrous sodium carbonate, sodium bicarbonate, saleratus, triethylamine, Diisopropylamine; Selecting excellent is Carbon Dioxide hydrogen potassium.
In above-mentioned steps 2, described cinnamyl chloride and the molar ratio of iodide are 1: 0.1; Temperature of reaction is 80-130 DEG C.After completion of the reaction, in reaction solution, add equivalent methylene dichloride and water to extract 2-6 time, separate, get organic layer, further use toluene and pure water washed product.
In above-mentioned steps 3, described N, the molar ratio of N-di-isopropyl-3-phenyl-2-propenyl-1-amine and tosic acid is 1: 1～1: 2, preferably 1: 1.1; Reaction times is 4-8 hour, and temperature of reaction is 80-130 DEG C.After completion of the reaction, in reaction solution, add ethyl acetate and pure water, after stirring, leave standstill separatory, organic phase solution regulates pH to 9-10, and organic layer is got in layering, and washing concentrating obtains product.
In above-mentioned steps 4, racemize tolterodine and tartaric molar ratio are 1: 1.1.Reaction is carried out in dehydrated alcohol, first racemize tolterodine is dissolved in dehydrated alcohol, and heating, as reaction solution; Again tartaric ethanol solution is dripped in reaction solution, slow cooling to 0 DEG C, growing the grain 18-36 hour, suction filtration is dry, obtains crude product product, continues to obtain Tolterodine tartrate fine work with dehydrated alcohol recrystallization.
That contriver gropes, independently creates and obtain through long-term, a large amount of experiments in technical scheme of the present invention.Compared with the technology of this technical scheme and existing synthetic Tolterodine tartrate, there is following advantage:
The first, in step 1, adopt and utilize styryl carbinol and chlorinating agent to synthesize cinnamyl chloride under condition of no solvent, obtained the high-quality product of high yield, first chlorinating agent thionyl chloride is used for to this experiment.
The second, in step 2, adopt cinnamyl chloride and Diisopropylamine, utilize alkali, iodide are made catalyzer and under solvent-free condition, are reacted and synthesized the high-quality product of high yield.In reaction process, adopt solvent-free synthetic technology, solved and on conventional art, formed a difficult problem for etherificate by product because of the use of alcoholic solvent, and shortened the reaction times.
Three, in step 3, adopted tosic acid to replace the methylsulphonic acid that in conventional art, corrodibility is strong, price is relatively expensive, the relative methylsulphonic acid of aftertreatment is easy: methylsulphonic acid is easy to enter in product in last handling process, causes product purity lower; And, because methylsulphonic acid is corrosive thick liquid, be difficult to transport, the inconvenience that feeds intake, tosic acid is solid, has overcome disadvantageous factor in above industrial production.This reaction is simultaneously also to carry out under condition of no solvent.
Specific embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiment are only for the present invention is described, the scope that it does not limit the present invention in any way.
Experimental technique in following embodiment, if no special instructions, is ordinary method.Chemical feedstocks, reagent material etc. used in following embodiment, if no special instructions, is commercially available purchase product.
Wherein, the cinnamyl chloride relating in this specification sheets embodiment, the purity detecting of two kinds of materials of Tolterodine tartrate, condition is as follows:
(1) detection of cinnamyl chloride
Gas chromatographic detection (GC) condition: chromatographic column: Agilent DB-wax 30.0m length × 0.32mm internal diameter and film thickness 0.25um; Sampler temperature: 200 DEG C; Detector temperature: 250 DEG C; Post flow: 2.0ml/min; Post case: 60 DEG C of 40 DEG C/min are warming up to 220 DEG C; Solvent: CH
2cl
2; Sample size: 1ul.
(2) detection of Tolterodine tartrate
High performance liquid phase detects (HPLC) condition: chromatographic column: Yi Lite C18 (HyPersil ODSZ) 250mm length × 4.6mm internal diameter and 5um particle diameter; Column temperature: 40 DEG C; Flow velocity: 1.0ml/min; Moving phase: NH
4cl is dissolved in 500ml water and 500ml acetonitrile, regulates pH value to 3.01; Detect wavelength: 282nm; Sample size: 10um
Embodiment 1
At 250ml there-necked flask, add styryl carbinol (20.1g, 0.15mol), reactant solution is cooled to 5-10 DEG C with ice-water bath, slowly drip thionyl chloride (18g, 0.15mol).Dropwise the water-bath of recession deicing, 60 DEG C are refluxed 3 hours.TLC monitoring has been reacted, and is cooled to and under room temperature condition, adds 50ml purified water, and then add methylene dichloride 50ml to extract once, and dichloromethane layer washs once with 6% sodium hydrogen carbonate solution 50ml, separatory.Wash at twice dichloromethane layer by 100ml purified water, collect dichloromethane layer, then use anhydrous sodium sulfate drying 1h, filter, concentrate to obtain cinnamyl chloride 22.7g, productive rate: 99%, GC purity 97%.
Embodiment 2
By cinnamyl chloride (49.6g, 0.325mol), Diisopropylamine (65.8g, 0.65mol), Anhydrous potassium carbonate (45g, 0.325mol), potassiumiodide (2.7g, 0.01625mol) join successively 500ml there-necked flask, be heated to 100 DEG C of back flow reaction 8h.TLC monitoring has been reacted, and reaction solution is transferred to 2L there-necked flask, adds successively purified water 500ml, methylene dichloride 260ml, extracting and demixing.Water layer adds respectively methylene dichloride 130ml extracting twice again.Merge organic phase, with the washing of 200ml purified water, layering, organic phase anhydrous sodium sulfate drying 1h, filters, concentrated organic phase.Concentrated product is transferred in 1L there-necked flask, adds 500ml purified water, and 260ml toluene, with 36.5%HCl adjusting pH to 2, layering.Use respectively toluene 130ml washed twice water layer, stratified pumping phase.Water regulates pH to 12 with NaOH solution, adds normal hexane 260ml extraction, and organic phase is got in layering, again add normal hexane 130ml aqueous phase extracted, merge organic layer twice, wash at twice organic phase with purified water 400ml, organic phase is got in layering, add anhydrous sodium sulfate drying 1h, filter, concentrate to obtain N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine 67.1g, productive rate: 95%, GC purity 98%.
Embodiment 3
By cinnamyl chloride (49.6g, 0.325mol), Diisopropylamine (65.8g, 0.65mol), anhydrous sodium carbonate (34.45g, 0.325mol), potassiumiodide (2.7g, 0.01625mol) join successively 500ml there-necked flask, be heated to 100 DEG C of back flow reaction 8h.TLC monitoring has been reacted, and reaction solution is transferred to 2L there-necked flask, adds successively purified water 1000ml, methylene dichloride 260ml, extracting and demixing.Water layer adds respectively methylene dichloride 130ml extracting twice again.Merge organic phase, with the washing of 200ml purified water, layering, organic phase anhydrous sodium sulfate drying 1h, filters, concentrated organic phase.Concentrated product is transferred in 1L there-necked flask, adds 500ml purified water, and 260ml toluene, with 36.5%HCl adjusting pH to 2, layering.Use respectively toluene 130ml washed twice water layer, stratified pumping phase.Water regulates pH to 12 with NaOH solution, adds normal hexane 260ml extraction, and organic phase is got in layering, again add normal hexane 130ml aqueous phase extracted, merge organic layer twice, wash at twice organic phase with purified water 400ml, organic phase is got in layering, add anhydrous sodium sulfate drying 1h, filter, concentrate to obtain N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine 65.4g, productive rate: 93%, GC purity 97%.
Embodiment 4
By cinnamyl chloride (49.6g, 0.325mol), Diisopropylamine (65.8g, 0.65mol), sodium bicarbonate (27.30g, 0.325mol), sodium iodide (2.454g, 0.01625mol) join successively 500ml there-necked flask, be heated to 100 DEG C of back flow reaction 8h.TLC monitoring has been reacted, and reaction solution is transferred to 2L there-necked flask, adds successively purified water 1000ml, methylene dichloride 260ml, extracting and demixing.Water layer adds respectively methylene dichloride 130ml extracting twice again.Merge organic phase, with the washing of 200ml purified water, layering, organic phase anhydrous sodium sulfate drying 1h, filters, concentrated organic phase.Concentrated product is transferred in 1L there-necked flask, adds 500ml purified water, and 260ml toluene, with 36.5%HCl adjusting pH to 2, layering.Use respectively toluene 130ml washed twice water layer, stratified pumping phase.Water regulates pH to 12 with NaOH solution, adds normal hexane 260ml extraction, and organic phase is got in layering, again add normal hexane 130ml aqueous phase extracted, merge organic layer twice, wash at twice organic phase with purified water 400ml, organic phase is got in layering, add anhydrous sodium sulfate drying 1h, filter, concentrate to obtain N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine 64.2g, productive rate: 91%, GC purity 98%.
Embodiment 5
By cinnamyl chloride (49.6g, 0.325mol), Diisopropylamine (65.8g, 0.65mol), triethylamine (32.83g, 0.325mol), potassiumiodide (2.7g, 0.01625mol) joins 500ml there-necked flask successively, is heated to 100 DEG C of back flow reaction 8h.TLC monitoring has been reacted, and reaction solution is transferred to 2L there-necked flask, adds successively purified water 1000ml, methylene dichloride 260ml, extracting and demixing.Water layer adds respectively methylene dichloride 130ml extracting twice again.Merge organic phase, with the washing of 200ml purified water, layering, organic phase anhydrous sodium sulfate drying 1h, filters, concentrated organic phase.Concentrated product is transferred in 1L there-necked flask, adds 500ml purified water, and 260ml toluene, with 36.5%HCl adjusting pH to 2, layering.Use respectively toluene 130ml washed twice water layer, stratified pumping phase.Water regulates pH to 12 with NaOH solution, adds normal hexane 260ml extraction, and organic phase is got in layering, again add normal hexane 130ml aqueous phase extracted, merge organic layer twice, wash at twice organic phase with purified water 400ml, organic phase is got in layering, add anhydrous sodium sulfate drying 1h, filter, concentrate to obtain N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine 58.6g, productive rate: 83%, GC purity 95%.
Embodiment 6
By cinnamyl chloride (49.6g, 0.325mol), Diisopropylamine (65.8g, 0.65mol), triethylamine (32.83g, 0.325mol), potassiumiodide (2.7g, 0.01625mol) joins 500ml there-necked flask successively, is heated to 100 DEG C of back flow reaction 8h.TLC monitoring has been reacted, and reaction solution is transferred to 2L there-necked flask, adds successively purified water 1000ml, methylene dichloride 260ml, extracting and demixing.Water layer adds respectively methylene dichloride 130ml extracting twice again.Merge organic phase, with the washing of 200ml purified water, layering, organic phase anhydrous sodium sulfate drying 1h, filters, concentrated organic phase.Concentrated product is transferred in 1L there-necked flask, adds 500ml purified water, and 260ml toluene, with 36.5%HCl adjusting pH to 2, layering.Use respectively toluene 130ml washed twice water layer, stratified pumping phase.Water regulates pH to 12 with NaOH solution, adds normal hexane 260ml extraction, and organic phase is got in layering, again add normal hexane 130ml aqueous phase extracted, merge organic layer twice, wash at twice organic phase with purified water 400ml, organic phase is got in layering, add anhydrous sodium sulfate drying 1h, filter, concentrate to obtain N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine 58g, productive rate: 82%, GC purity 97%.
Embodiment 7
By cinnamyl chloride (49.6g, 0.325mol), Diisopropylamine (65.8g, 0.65mol), Anhydrous potassium carbonate (22.42g, 0.163mol), potassiumiodide (2.7g, 0.01625mol), join successively 500ml there-necked flask, be heated to 100 DEG C of back flow reaction 8h.TLC monitoring has been reacted, and reaction solution is transferred to 2L there-necked flask, adds successively purified water 1000ml, methylene dichloride 260ml, extracting and demixing.Water layer adds respectively methylene dichloride 130ml extracting twice again.Merge organic phase, with the washing of 200ml purified water, layering, organic phase anhydrous sodium sulfate drying 1h, filters, concentrated organic phase.Concentrated product is transferred in 1L there-necked flask, adds 500ml purified water, and 260ml toluene, with 36.5%HCl adjusting pH to 2, layering.Use respectively toluene 130ml washed twice water layer, stratified pumping phase.Water regulates pH to 12 with NaOH solution, adds normal hexane 260ml extraction, and organic phase is got in layering, again add normal hexane 130ml aqueous phase extracted, merge organic layer twice, wash at twice organic phase with purified water 400ml, organic phase is got in layering, add anhydrous sodium sulfate drying 1h, filter, concentrate to obtain N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine 61.4g, productive rate 87%, product purity 97%.
Embodiment 8
In 250ml there-necked flask, add successively N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine (10g, 0.046mol), p-cresol (25.5g, 0.235mol), tosic acid (15.9g, 0.092mol), is heated to 80 DEG C of reaction 4h.TLC monitoring has been reacted, and is cooled to room temperature, in reaction flask, adds respectively ethyl acetate 100ml and purified water 100ml, stirs 10min, leaves standstill separatory, and organic phase regulates pH to 9, layering with aqueous sodium hydroxide solution.Ethyl acetate layer washs once by 100ml purified water, and separatory is collected ethyl acetate layer, uses anhydrous sodium sulfate drying 1h, filters, and concentrates to obtain oily product 12.1g, productive rate: 84.5%.HPLC purity 95%.
Embodiment 9
In 250ml there-necked flask, add successively N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine (10g, 0.046mol), p-cresol (25.5g, 0.235mol), tosic acid (15.9g, 0.092mol), is heated to 120 DEG C of reaction 4h.TLC monitoring has been reacted, and is cooled to room temperature, in reaction flask, adds respectively ethyl acetate l00ml and purified water 100ml, stirs 10min, leaves standstill separatory, and organic phase regulates pH to 9, layering with aqueous sodium hydroxide solution.Ethyl acetate layer washs once by l00ml purified water, and separatory is collected ethyl acetate layer, uses anhydrous sodium sulfate drying 1h, filters, and concentrates to obtain oily product 12.5g, productive rate: 87.3%.HPLC purity 95%.
Embodiment 10
In 250ml there-necked flask, add successively N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine (10g, 0.046mol), p-cresol (25.5g, 0.235mol), tosic acid (15.9g, 0.092mol), is heated to 130 DEG C of reaction 4h.TLC monitoring has been reacted, and is cooled to room temperature, in reaction flask, adds respectively ethyl acetate l00ml and purified water l00ml, stirs l0min, leaves standstill separatory, and organic phase regulates pH to 9.5, layering with aqueous sodium hydroxide solution.Ethyl acetate layer washs once by l00ml purified water, and separatory is collected ethyl acetate layer, uses anhydrous sodium sulfate drying lh, filters, and concentrates to obtain oily product 13.6g, productive rate: 95%.HPLC purity 96%.
Embodiment 11
In 250ml there-necked flask, add successively N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine (10g, 0.046mol), p-cresol (25.5g, 0.235mol), tosic acid (15.9g, 0.092mol), is heated to 130 DEG C of reaction 4h.TLC monitoring has been reacted, and is cooled to room temperature, in reaction flask, adds respectively ethyl acetate 100ml and purified water 100ml, stirs 10min, leaves standstill separatory, and organic phase regulates pH to 10, layering with aqueous sodium hydroxide solution.Ethyl acetate layer washs once by 100ml purified water, and separatory is collected ethyl acetate layer, uses anhydrous sodium sulfate drying 1h, filters, and concentrates to obtain oily product 12.6g, productive rate: 88%.HPLC purity 96%.
Embodiment 12
In 250ml there-necked flask, take racemize tolterodine (20g, 61.4mmol) and be dissolved in 200ml dehydrated alcohol, be heated to 60 DEG C.Tartrate (10.2g, 67.5mmol) be dissolved in hot dehydrated alcohol 200ml, slowly be added dropwise to above-mentioned solution, add rear backflow 1h, then slow cooling to 0 DEG C, growing the grain 24h, suction filtration, washs solid product, 40 DEG C of condition drying under reduced pressure at twice with 80ml ice ethanol, obtain product 12.2g, productive rate: 46%.
Among 250ml there-necked flask, add Tolterodine tartrate crude product (12.2g, 28.2mmol), then adding 600ml dehydrated alcohol backflow 0.5h, then slow cooling room temperature, leaves standstill growing the grain 24h, suction filtration, with 40ml ice washing with alcohol solid product, 40 DEG C of condition drying under reduced pressure, obtain Tolterodine tartrate fine work 9g, productive rate: 73.8%.HPLC purity: 99.9%, ee value 99.5%, [a]
25(1%, methanol)=28.2 °.
Embodiment 13
By N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine (10g, 0.046mol), p-cresol (25.5g, 0.235mol), A acid (0.165mol) adds 250ml there-necked flask, is heated to 130 DEG C of reactions 4 hours.TLC monitoring has been reacted, and is cooled to room temperature, and reaction solution is transferred to 500ml there-necked flask, adds toluene 200ml, and purified water 200ml, with the aqueous solution adjusting pH to 9.5 of alkali, stratification.Purify and wash toluene layer with 100ml, separatory, collects toluene layer, uses anhydrous sodium sulfate drying 1h, filters, the concentrated oily product that to obtain.
The impact of table a different catalysts on step 3
By table, a can find out, while selecting tosic acid, productive rate is higher, and product purity is better, reaches industrial pharmaceutical production requirement.
Embodiment 14
At 250ml there-necked flask, add styryl carbinol (20.1g, 0.15mol), reactant solution is cooled to 5 to 10 DEG C with ice-water bath, slowly drip chlorinating agent B.Dropwise the water-bath of recession deicing, 60 DEG C are refluxed 3 hours.TLC monitoring has been reacted, and is cooled to and under room temperature condition, adds 50ml purified water, and then add methylene dichloride 50ml to extract once, and dichloromethane layer washs once with 6% sodium hydrogen carbonate solution 50ml, separatory.Wash at twice dichloromethane layer by 100ml purified water, collect dichloromethane layer, then use anhydrous sodium sulfate drying 1h, filter, concentrate to obtain cinnamyl chloride.
The impact of table b differential responses raw material on step 1
From the experimental result of table b, can find out, select the raw material of thionyl chloride as reaction, experimental implementation process is simple, and productive rate is the highest, and product purity reaches 97%.
Claims (9)
1. a method for synthetic Tolterodine tartrate, comprising:
Step 1: styryl carbinol, thionyl chloride reaction, obtain product cinnamyl chloride;
Step 2: cinnamyl chloride, Diisopropylamine, iodide and alkali reaction, obtain product N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine, the reaction of described step 2 is carried out under condition of no solvent;
Step 3:N, N-di-isopropyl-3-phenyl-2-propenyl-1-amine, p-cresol, tosic acid reaction, obtain racemize tolterodine;
Step 4: racemize tolterodine, tartrate, dehydrated alcohol reaction, obtain tolterodine L-(+) tartrate.
2. the method for synthetic Tolterodine tartrate according to claim 1, is characterized in that: in described step 2, iodide are the one in potassiumiodide, sodium iodide.
3. the method for synthetic Tolterodine tartrate according to claim 2, is characterized in that: in described step 2, iodide are potassiumiodide.
4. the method for synthetic Tolterodine tartrate according to claim 1, is characterized in that: in described step 2, alkali is the one in Anhydrous potassium carbonate, anhydrous sodium carbonate, sodium bicarbonate, saleratus, triethylamine, Diisopropylamine.
5. the method for synthetic Tolterodine tartrate according to claim 4, is characterized in that: in described step 2, alkali is Anhydrous potassium carbonate.
6. the method for synthetic Tolterodine tartrate according to claim 1, is characterized in that: in described step 2, the mol ratio of cinnamyl chloride and iodide is 1:0.1.
7. the method for synthetic Tolterodine tartrate according to claim 1, is characterized in that: in described step 3, and N, the mol ratio of N-di-isopropyl-3-phenyl-2-propenyl-1-amine and tosic acid is 1.1～1:2.
8. the method for synthetic Tolterodine tartrate according to claim 7, is characterized in that: in described step 3, and N, the mol ratio of N-di-isopropyl-3-phenyl-2-propenyl-1-amine and tosic acid is 1:1.1.
9. the method for synthetic Tolterodine tartrate according to claim 1, is characterized in that: in described step 4, racemize tolterodine and tartaric mol ratio are 1:1.1.
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| CN101759571A (en) * | 2010-01-28 | 2010-06-30 | 浙江大学 | Preparation method of N,N-diisopropylethylamine |
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| WO2004089281A2 (en) * | 2003-04-08 | 2004-10-21 | Hetero Drugs Limited | Novel polymorphs of tolterodine tartrate |
| ES2268987B1 (en) * | 2005-08-05 | 2008-02-01 | Ragactives, S.L. | PROCEDURE FOR OBTAINING 3,3-DIFENYLPROPILAMINS. |
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