CN1939891A - Pharmaceutical synthesis of 4-methoxy-alpha-methyl-phenethylamine - Google Patents
Pharmaceutical synthesis of 4-methoxy-alpha-methyl-phenethylamine Download PDFInfo
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- CN1939891A CN1939891A CN 200510030292 CN200510030292A CN1939891A CN 1939891 A CN1939891 A CN 1939891A CN 200510030292 CN200510030292 CN 200510030292 CN 200510030292 A CN200510030292 A CN 200510030292A CN 1939891 A CN1939891 A CN 1939891A
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- Prior art keywords
- methyl
- alpha
- phenylethylamine
- methoxyl group
- pharmaceutically
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- NEGYEDYHPHMHGK-UHFFFAOYSA-N para-methoxyamphetamine Chemical compound COC1=CC=C(CC(C)N)C=C1 NEGYEDYHPHMHGK-UHFFFAOYSA-N 0.000 title abstract 3
- 230000015572 biosynthetic process Effects 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 230000035484 reaction time Effects 0.000 claims abstract description 5
- 239000000852 hydrogen donor Substances 0.000 claims abstract description 4
- 238000006264 debenzylation reaction Methods 0.000 claims abstract 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000010189 synthetic method Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 3
- 229940043232 butyl acetate Drugs 0.000 claims description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 6
- ZZIZZTHXZRDOFM-UHFFFAOYSA-N 2-(2-ethoxyphenoxy)ethyl-[1-(4-methoxy-3-sulfamoylphenyl)propan-2-yl]azanium;chloride Chemical compound Cl.CCOC1=CC=CC=C1OCCNC(C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-UHFFFAOYSA-N 0.000 abstract description 4
- 229960003198 tamsulosin hydrochloride Drugs 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract 1
- 229940117803 phenethylamine Drugs 0.000 abstract 1
- 238000001914 filtration Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- ZZIZZTHXZRDOFM-XFULWGLBSA-N tamsulosin hydrochloride Chemical compound [H+].[Cl-].CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-XFULWGLBSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940093334 flomax Drugs 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 239000002389 essential drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N ornithyl group Chemical class N[C@@H](CCCN)C(=O)O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229960002613 tamsulosin Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
一种新的盐酸坦索罗辛关键中间体4－甲氧基－α－甲基－苯乙胺药学上可接受盐的合成方法，以4－甲氧基－α－甲基－N－(1－苯基)－苯乙胺药学上可接受盐和甲酸铵在钯炭加氢催化剂存在下进行脱苄反应制备4－甲氧基－α－甲基－苯乙胺药学上可接受盐。本发明的制备方法，使用价廉易得的甲酸铵作为供氢体代替氢气作为反应氢源，反应在普通容器中即可进行，避免了高压釜的使用，反应时间大大缩短，收率达90％以上，制备方法易实现规模生产。A new method for synthesizing the pharmaceutically acceptable salt of tamsulosin hydrochloride key intermediate 4-methoxy-α-methyl-phenethylamine, using 4-methoxy-α-methyl-N-( 1-phenyl)-phenethylamine pharmaceutically acceptable salt and ammonium formate undergo debenzylation reaction in the presence of palladium-carbon hydrogenation catalyst to prepare 4-methoxy-α-methyl-phenethylamine pharmaceutically acceptable salt. The preparation method of the present invention uses cheap and easy-to-obtain ammonium formate as a hydrogen donor instead of hydrogen as a reaction hydrogen source, and the reaction can be carried out in an ordinary container, avoiding the use of an autoclave, the reaction time is greatly shortened, and the yield reaches 90% % or more, the preparation method is easy to realize large-scale production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to treat the synthetic method of the medicine tamsulosin hydrochloride key intermediate 4-methoxyl group-Alpha-Methyl-phenylethylamine pharmaceutically-acceptable salts of benign prostatic hyperplasia.
Background technology
Tamsulosin hydrochloride is the long-acting α 1A of a prostatoplasia diseases adrenergic receptor retarding agent, by the exploitation of Japanese Yamanouchi drugmaker, 1993 in Japanese Initial Public Offering, successively transfer (the Abbott of Abbott Laboratories, trade(brand)name Flomax) and 65 national list marketings of the Boehringer Ingelheim (Boehringer Ingelheim, trade(brand)name Flomax) and the whole world.Threw in China market in 1996, commodity Kazakhstan by name happy (Harnal).These product promptly show powerful growth momentum after China's listing, share of market climbs up and up, and has entered the national essential drugs catalogue.The benign prostatic hyperplasia clinical symptom is alleviated in the contraction of the inhibition prostate gland unstriated muscle that this medicine is special rapidly, good effect, and untoward reaction is few.Tamsulosin global marketing volume reached more than 1,900,000,000 dollars in 2003, ranked the 15th of global best-selling drugs in 2003.Its leading position in treatment hyperplasia of prostate medicine series has been established in its high efficiency and security.
Synthesizing of tamsulosin hydrochloride key intermediate 4-methoxyl group-Alpha-Methyl-phenylethylamine hydrochloride, U.S. Pat 4000197 and document J.Med.Chem., 1973,5 (16), 480-483 report method mainly is that 4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine hydrochloride takes off the benzyl preparation by palladium charcoal catalytic hydrogenation, and synthetic route is as follows:
There is following shortcoming in this method:
1. use the high-pressure hydrogenation still, equipment requirements is higher.
2. long reaction time reacted completely in 48 hours.
Yield is low, only is 62-68%.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of new 4-methoxyl group-Alpha-Methyl-phenylethylamine pharmaceutically-acceptable salts, have above-mentioned defective, make preparation technology more help the industrialization operation to overcome prior art.
Unless dated especially, the term of Cai Yonging " pharmacy acceptable salt " has as giving a definition herein:
Can enumerate salt particularly with mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, acid salt with organic acids such as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, ethyl sulfonic acid and acidic amino acids such as aspartic acid, L-glutamic acid, or the salt that forms with alkali, as sodium, potassium, etc. the salt of mineral alkali, or the salt that forms with basic aminoacidss such as Methionin, arginine, ornithines.
The technical scheme of the inventive method is as described below:
Replace hydrogen as the reaction hydrogen source with ammonium formiate as hydrogen donor, be reflected in the common vessel and can carry out, avoid the use of autoclave, the reaction times shortens greatly, and yield increases.Synthetic route is as follows:
According to the present invention, its concrete preparation method comprises the steps:
With 4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine pharmaceutically-acceptable salts and ammonium formiate mol ratio 1: 0.5～20 and palladium charcoal weight ratio 1: 0.01～0.5 0～150 ℃ of following reaction 0.25～10 hour in organic solvent, reaction finishes the back filtration catalizer, collect target product 4-methoxyl group-Alpha-Methyl-phenylethylamine pharmaceutically-acceptable salts after reclaiming solvent, yield reaches more than 90%.
Described 4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine pharmaceutically-acceptable salts comprise (R, R)-, (S, S)-, (S, R)-, (R, S)-four kind of optical isomer.
Described palladium charcoal comprises 0.1%～40% palladium charcoal hydrogenation catalyst.
The mol ratio of 4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine pharmaceutically-acceptable salts and ammonium formiate is preferably 1: 2～and 10,4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine pharmaceutically-acceptable salts and palladium charcoal weight ratio be preferably 1: 0.05～and 0.2.Temperature of reaction is preferably 30～120 ℃.
Said organic solvent comprises alcohols (such as methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol), water, ester class (such as ethyl acetate, butylacetate), ethers (such as ether, isopropyl ether, tetrahydrofuran (THF)), hydro carbons (such as benzene,toluene,xylene, hexanaphthene, hexane, sherwood oil) also comprises the mixture of above-mentioned solvent.
The present invention has adopted new preparation method, uses raw material cheap and easy to get, mild condition, and aftertreatment is simple, reaction yield height, good product purity.The preparation method easily realizes scale production.
Adopting method of the present invention to prepare 4-methoxyl group-Alpha-Methyl-phenylethylamine pharmaceutically-acceptable salts has the following advantages:
1. use ammonium formiate cheap and easy to get to replace hydrogen as the reaction hydrogen source, be reflected in the common vessel and can carry out, avoided the use of autoclave as hydrogen donor.
2. the reaction times shortens greatly, shortens to 0.25～10 hour by 48 hours of bibliographical information.
3. yield reaches more than 90%.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment do not constitute any restriction to the present invention.Fusing point among the embodiment is measured with capillary tube technique, and thermometer is not calibrated;
1H-NMR AM 400 type nuclear magnetic resonance analyser records, chemical shift is represented with δ (ppm).
Embodiment 1
With (R, R)-the palladium charcoal hydrogenation catalyst 3g of 4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine hydrochloride 30g and ammonium formiate 12.4g and 10%, add 500ml methyl alcohol, reflux 3 hours, cooling back filtration catalizer, collect target product R-4-methoxyl group-Alpha-Methyl-phenylethylamine hydrochloride 18.4g, yield 93% after reclaiming solvent.
1HNMR (CDCl
3) δ: 1.29 (d, 3H ,-CH
3), 2.58～2.75 (m, 2H ,-CH
2-), 3.16 (m, 1H ,-CH-), 3.79 (S, 3H ,-OCH
3), 6.84 (d, 2H), 7.14 (d, 2H); EI-MS (m/z): 166[(M+H), 100], 149 (48); Ultimate analysis (C
10H
16ClNO) measured value (calculated value, %): C59.46 (59.55), H7.72 (7.80), N6.84 (6.95); [α]
D 25=-22.5 ℃ of (C=2, H
2O); Mp:250～251 ℃.
Embodiment 2
With (S, S)-the palladium charcoal hydrogenation catalyst 1.5g of 4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine hydrobromate 30g and ammonium formiate 27.1g and 10%, add 500ml ethanol, reflux 4 hours, cooling back filtration catalizer, collect target product S-4-methoxyl group-Alpha-Methyl-phenylethylamine hydrobromate 19.2g, yield 91% after reclaiming solvent.Ultimate analysis (C
10H
16BrNO) measured value (calculated value, %): C48.65 (48.79), H6.52 (6.55), N5.64 (5.69).
Embodiment 3
With (R, S)-the palladium charcoal hydrogenation catalyst 0.6g of 4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine hydrochloride 3g and ammonium formiate 6.2g and 5%, add the 50ml tetrahydrofuran (THF), reflux 3 hours, cooling back filtration catalizer, collect target product R-4-methoxyl group-Alpha-Methyl-phenylethylamine hydrochloride 1.78g, yield 90% after reclaiming solvent.
Embodiment 4
With (S, R)-the palladium charcoal hydrogenation catalyst 0.6g of 4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine hydrochloride 3g and ammonium formiate 2.48g and 10%, add the 50ml butylacetate, reflux 5 hours, cooling back filtration catalizer, collect target product S-4-methoxyl group-Alpha-Methyl-phenylethylamine hydrochloride 1.82g, yield 92% after reclaiming solvent.Ultimate analysis (C
10H
16ClNO) measured value (calculated value, %): C59.56 (59.55), H7.82 (7.80), N6.89 (6.95); [α]
D 25=+22.4 ℃ of (C=2, H
2O); Mp:251～253 ℃.
More than show and described ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in the foregoing description and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (7)
1. the synthetic method of midbody compound 4-methoxyl group-Alpha-Methyl-phenylethylamine pharmaceutically-acceptable salts, it is characterized in that, replace hydrogen as the reaction hydrogen source with ammonium formiate as hydrogen donor, 4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine pharmaceutically-acceptable salts and ammonium formiate and palladium charcoal are carried out the hydrogenation debenzylation reaction make target product.
2. synthetic method according to claim 1 is characterized in that described hydrogenation debenzylation reaction carries out under 0～150 ℃, the reaction times is 0.25～10 hour.
3. synthetic method according to claim 1 is characterized in that described hydrogenation debenzylation reaction can be to carry out in following solvent environment: methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol, water, ethyl acetate, butylacetate, ether, isopropyl ether, tetrahydrofuran (THF), benzene,toluene,xylene, hexanaphthene, hexane, sherwood oil or the mixture of these solvents arbitrarily.
4. synthetic method according to claim 1, it is characterized in that 4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine pharmaceutically-acceptable salts comprise (R, R)-, (S, S)-, (S, R)-, (R, S)-four kind of optical isomer.
5. according to claim 1 or 4 described synthetic methods, it is characterized in that described palladium charcoal comprises 0.1%～40% palladium charcoal hydrogenation catalyst.
6. according to claim 1 or 4 described synthetic methods, it is characterized in that, the mol ratio of 4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine pharmaceutically-acceptable salts and ammonium formiate is 1: 0.5～20,4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine pharmaceutically-acceptable salts and palladium charcoal weight ratio 1: 0.01～0.5.
7. synthetic method according to claim 6, it is characterized in that, the mol ratio of 4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine pharmaceutically-acceptable salts and ammonium formiate is 1: 2～10,4-methoxyl group-Alpha-Methyl-N-(1-phenyl)-phenylethylamine pharmaceutically-acceptable salts and palladium charcoal weight ratio 1: 0.05～0.2, temperature of reaction is 30～120 ℃.
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| JPS6054342A (en) | 1983-09-05 | 1985-03-28 | Agency Of Ind Science & Technol | Preparation of vanillylamine hydrochloride |
| CN1300115C (en) * | 2004-03-26 | 2007-02-14 | 厦门大学 | Method for synthesizing 1,2,3,4 ramification of tetrahydro-isoquinoline |
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| CN111170900B (en) * | 2020-03-18 | 2022-12-13 | 珠海润都制药股份有限公司 | Preparation method of tamsulosin impurity with high optical purity |
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