CN1396162A - Xanthiphenyl ketamine or its salt and its preparing process - Google Patents
Xanthiphenyl ketamine or its salt and its preparing process Download PDFInfo
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- CN1396162A CN1396162A CN 02125318 CN02125318A CN1396162A CN 1396162 A CN1396162 A CN 1396162A CN 02125318 CN02125318 CN 02125318 CN 02125318 A CN02125318 A CN 02125318A CN 1396162 A CN1396162 A CN 1396162A
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- China
- Prior art keywords
- xanthiphenyl
- ketamine
- salt
- methyl
- acid
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- Granted
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 36
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 title claims description 41
- 229960003299 ketamine Drugs 0.000 title claims description 36
- 238000000034 method Methods 0.000 title abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 110
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 56
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- 239000002253 acid Substances 0.000 claims abstract description 21
- 238000001035 drying Methods 0.000 claims abstract description 9
- 238000005406 washing Methods 0.000 claims abstract description 7
- 238000010992 reflux Methods 0.000 claims abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 39
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 33
- 229960004756 ethanol Drugs 0.000 claims description 28
- -1 ketamine salt amine Chemical class 0.000 claims description 26
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 15
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 14
- FXMXAFDOFYLVFW-UHFFFAOYSA-N 3-hydroxy-4-phenylbut-3-en-2-one Chemical compound CC(=O)C(O)=CC1=CC=CC=C1 FXMXAFDOFYLVFW-UHFFFAOYSA-N 0.000 claims description 13
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 13
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 12
- 229920002866 paraformaldehyde Polymers 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 235000006408 oxalic acid Nutrition 0.000 claims description 9
- 239000000376 reactant Substances 0.000 claims description 8
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 3
- UPXRTVAIJMUAQR-UHFFFAOYSA-N 4-(9h-fluoren-9-ylmethoxycarbonylamino)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1C(C(O)=O)N(C(=O)OC(C)(C)C)CC1NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 UPXRTVAIJMUAQR-UHFFFAOYSA-N 0.000 claims description 2
- 229960004184 ketamine hydrochloride Drugs 0.000 claims description 2
- 150000003840 hydrochlorides Chemical class 0.000 claims 2
- 238000001914 filtration Methods 0.000 abstract description 2
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 abstract 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 230000003472 neutralizing effect Effects 0.000 abstract 1
- OSDZHDOKXGSWOD-UHFFFAOYSA-N nitroxyl;hydrochloride Chemical compound Cl.O=N OSDZHDOKXGSWOD-UHFFFAOYSA-N 0.000 abstract 1
- OCNIKEFATSKIBE-UHFFFAOYSA-N p-hydroxyphenylbut-3-ene-2-one Chemical compound CC(=O)C=CC1=CC=C(O)C=C1 OCNIKEFATSKIBE-UHFFFAOYSA-N 0.000 abstract 1
- 229920006324 polyoxymethylene Polymers 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 68
- 235000019441 ethanol Nutrition 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 14
- 235000019253 formic acid Nutrition 0.000 description 14
- 238000003756 stirring Methods 0.000 description 12
- RRIRDPSOCUCGBV-UHFFFAOYSA-N methylenedioxyphenethylamine Chemical compound NCCC1=CC=C2OCOC2=C1 RRIRDPSOCUCGBV-UHFFFAOYSA-N 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 206010019280 Heart failures Diseases 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 208000024172 Cardiovascular disease Diseases 0.000 description 4
- 229910021536 Zeolite Inorganic materials 0.000 description 4
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 4
- 230000005611 electricity Effects 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- 239000010457 zeolite Substances 0.000 description 4
- 235000002566 Capsicum Nutrition 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 239000006002 Pepper Substances 0.000 description 3
- 241000722363 Piper Species 0.000 description 3
- 235000016761 Piper aduncum Nutrition 0.000 description 3
- 235000017804 Piper guineense Nutrition 0.000 description 3
- 235000008184 Piper nigrum Nutrition 0.000 description 3
- 206010063837 Reperfusion injury Diseases 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 230000004217 heart function Effects 0.000 description 3
- 230000002107 myocardial effect Effects 0.000 description 3
- 239000012454 non-polar solvent Substances 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 2
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 2
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- 229940123457 Free radical scavenger Drugs 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 239000000496 cardiotonic agent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 208000031225 myocardial ischemia Diseases 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 235000015961 tonic Nutrition 0.000 description 2
- 230000001256 tonic effect Effects 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229910014033 C-OH Inorganic materials 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 229910014570 C—OH Inorganic materials 0.000 description 1
- 229910014569 C—OOH Inorganic materials 0.000 description 1
- 206010014418 Electrolyte imbalance Diseases 0.000 description 1
- 208000007201 Myocardial reperfusion injury Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
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- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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Landscapes
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for preparing xanthiphenyl ketoamine or its salt includes such steps as reflux reaction of p-hydroxy benzylidenacetone, N-methyl piperethanamine hydrochloride and polyformaldehyde in absolute alcohol for 6-9.5 hr until fully solidifying, filtering, washing, recrystallizing 1-2 times, then drying to obtain xanthiphenyl ketoamine hydrochloride, neutralizing to obtain xanthiphenyl ketoamine, and reaction on acid to obtain the corresponding salt. Its advantages are simple process, high output rate and high purity.
Description
Invention field
The present invention relates to novel compounds of a class and preparation method thereof, specifically, the present invention relates to Xanthiphenyl ketamine, Xanthiphenyl ketamine salt and preparation method thereof with cardiac stimulant vasodilative effect.
Background technology
Heart failure is the end stage eventually of cardiovascular diseases, the mortality ratio height.Myocardial infarction and reperfusion injury of cardiac muscle are to cause major reason in heart failure.Experimental study both domestic and external shows that calcium antagonist and free-radical scavengers have the treatment myocardial infarction and to the effect of anti reperfusion injury.Yet most of calcium antagonists suppress myocardial contraction, reduce heart function, and clinical application is restricted.Free-radical scavengers is to not directly influence of heart function, and its clinical effectiveness is not identified as yet.
Principle of reatment in heart failure is a cardiac stimulant, expands blood vessel and diuresis.Cardiac tonic improves heart output by strengthening myocardial contraction, keeps the blood supply of vitals such as heart and brain kidney; Expand blood vessel medicine and diuretic(s) by lowering cardiac load, the protection heart function.Yet, cardiotonic glycoside, catecholamine, the toxic reaction of phosphodiesterase inhibitor all types of cardiac tonics such as (PDEI) is bigger, because they reach the effect that strengthens myocardial contraction mainly by increasing intracellular calcium concentration, there is arrhythogenic danger, easily causes intracellular calcium overload.Diuretic(s) Chang Zuowei drug of first choice is used for heart failure, still easily causes side effects such as electrolyte disturbance.The research in modern age represents that angiotensin converting enzyme inhibitor (ACEI) has the treatment congestive heart failure, and to resisting myocardial ischemia and the effect of reperfusion injury, its long-term effect waits to observe.
In a word, development has the effect characteristics, and toxic side effects is little, and the new drug of the treatment cardiovascular diseases that chemical structure is novel is clinical pressing for, and helps to deepen the understanding to the pathophysiological mechanism of cardiovascular diseases.
Summary of the invention
The object of the present invention is to provide pharmaceutically acceptable salt of Xanthiphenyl ketamine or its, described Xanthiphenyl ketamine or its pharmaceutically acceptable salt can be treated cardiovascular diseases, and toxic side effects is little.
Another object of the present invention is to provide pharmaceutically synthetic method of acceptable salt of Xanthiphenyl ketamine or its, described synthetic method is simple, yield is high, product purity is high, can directly obtain medicinal Peperphentonamine hydrochloride.
To achieve these goals, the technical solution used in the present invention is: a kind of Xanthiphenyl ketamine and salt compounds thereof, and its chemical structure is:
Wherein X is acid or 0 such as hydrochloric acid, Hydrogen bromide, oxalic acid, succsinic acid and toxilic acid, and when X was 0, described compound was an Xanthiphenyl ketamine.
Preferred described compound is the Xanthiphenyl ketamine hydrochloride, molecular weight C
21H
24O
4NCl=389.5.
The preparation method of compound of the present invention is: will be to hydroxyl benzylideneacetone and N-methyl piperethanamine salt hydrochlorate, Paraformaldehyde 96 in dehydrated alcohol, react through Mannich under the acidic conditions, reflux is all solidified to reactant, obtains Peperphentonamine hydrochloride through aftertreatment.
In the reaction, with respect to 0.1-0.15mol to the hydroxyl benzylideneacetone, the consumption of N-methyl piperethanamine salt hydrochlorate is that the consumption of 0.07-0.20mol, Paraformaldehyde 96 is 0.5-1.5mol, the consumption of dehydrated alcohol is 150-400ml, described acidic conditions is PH3-5, heating is reflected under the backflow and carries out, and the reaction times is 6-9.5 hour.
Preferred reaction conditions is: 0.1mol to hydroxyl benzylideneacetone and 0.1-0.12mol N-methyl piperethanamine salt hydrochlorate, 0.9-1.2mol Paraformaldehyde 96 in the 200-300ml dehydrated alcohol, the acidic conditions of PH3-4 refluxes down and all solidified to reactant in anti-7-8.5 hour, obtains Peperphentonamine hydrochloride through aftertreatment.
Described aftertreatment be with reactant filter, washing, with wherein a kind of of dehydrated alcohol, 95% ethanol, ether, 1-2 after drying of recrystallization.
Described aftertreatment also comprises uses activated carbon decolorizing.
The productive rate of reaction is 50-70%, and the purity of described Peperphentonamine hydrochloride is greater than 98.5%, 168～170 ℃ of fusing points.
With preferred compound Peperphentonamine hydrochloride is example, and reaction process is expressed as follows:
The Peperphentonamine hydrochloride that obtains neutralizes through alkaline solution, obtains Xanthiphenyl ketamine.Xanthiphenyl ketamine respectively with acid-responss such as Hydrogen bromide, oxalic acid, succsinic acid or toxilic acid, obtain Xanthiphenyl ketamine hydrobromate, Xanthiphenyl ketamine oxalate, Xanthiphenyl ketamine succinate, Xanthiphenyl ketamine maleate salt respectively.
Xanthiphenyl ketamine salt also can adopt the similar method with the Peperphentonamine hydrochloride preparation method, and difference is to hydroxyl benzylideneacetone and the corresponding reactant salt of N-methyl piperethanamine.
The chemical structure of the N-methyl piperethanamine salt in of the present invention is:
Wherein X is acid such as hydrochloric acid, Hydrogen bromide, oxalic acid, succsinic acid or toxilic acid.Title is respectively N-methyl piperethanamine salt hydrochlorate, N-methyl piperethanamine hydrobromate, N-methyl piperethanamine oxalate, N-methyl piperethanamine succinate, N-methyl piperethanamine maleate.
Preferred X is a hydrochloric acid, just N-methyl piperethanamine salt hydrochlorate.
The preparation method of N-methyl piperethanamine salt of the present invention is: the condensation in polar solvent of homopiperony lamine and phenyl aldehyde, N-benzal base pepper salt that obtains and methyl-sulfate reaction N methylate, product is handled with acid/ethanol solution, obtains the N-methyl piperethanamine salt.
Specifically, the preparation method of N-methyl piperethanamine salt of the present invention comprises the steps:
1) homopiperony lamine and phenyl aldehyde back flow reaction acetalation in polar solvent, the mol ratio of homopiperony lamine and phenyl aldehyde is 0.4-1.2, reaction times 15-21 hour, removes the phenyl aldehyde that desolvates and do not have reaction, the N-benzal base pepper salt that obtains;
2) the 50-130 ℃ of reaction in non-polar solvent of N-benzal base pepper salt and methyl-sulfate made it N in 20-60 minute and methylates, the consumption of methyl-sulfate be the homopiperony lamine mole number 0.8-1.5 doubly;
3) except that after desolvating, added the alcoholic solvent back flow reaction 20-60 minute, with the methyl-sulfate of decomposing excessive;
4) add less water, the back that stirs is removed and is desolvated and residual phenyl aldehyde, obtains thickness oily matter N-methyl piperethanamine vitriol;
5) in thickness oily matter, add saturated substantially acid/anhydrous alcohol solution to PH be 1-4, separate out N-methyl piperethanamine salt solid gradually.
Wherein, the polar solvent in the step 1) is methyl alcohol, ethanol, propyl alcohol one of them or THF, the consumption of solvent be homopiperony lamine and phenyl aldehyde gross weight 0.6-2 doubly.
Step 2) non-polar solvent in is one of them or a hexanaphthene of benzene,toluene,xylene, the consumption of non-polar solvent be homopiperony lamine and phenyl aldehyde gross weight 0.2-2 doubly.
Removing in the step 3) desolvated and can adopt the distillatory method, and described alcoholic solvent is methyl alcohol, ethanol or the third, and consumption is homopiperony lamine and phenyl aldehyde gross weight 0.3-2 a times.
The amount that adds entry in the step 4) is 5-30ml, and the back that stirs is removed and desolvated and residual phenyl aldehyde.
Alcohol in the step 5) is methyl alcohol, ethanol or propyl alcohol, and acid is a kind of of hydrochloric acid, Hydrogen bromide, oxalic acid, succsinic acid or toxilic acid etc.
Removing described in the above-mentioned steps desolvated, and can adopt the method for underpressure distillation.
The N-methyl piperethanamine salt solid that obtains can also be further with acetone or anhydrous diethyl ether washing, so that improve the purity of product N-methyl piperethanamine salt.
Above-mentioned preparation method's productive rate is 35-60wt%.
With the preferred N-methyl piperethanamine salt of the present invention hydrochlorate is example, and reaction process is expressed as follows:
The synthetic route of N-methyl piperethanamine salt hydrochlorate of the present invention is reasonable in design, and synthesis technique is easy and simple to handle, and raw material is easy to get, stable reaction conditions, and the reaction yield height, good product purity can be used as the intermediate of synthetic hydrochloric acid Xanthiphenyl ketamine or other compounds.
Among the present invention, owing to adopt Paraformaldehyde 96, reduced the consumption of solvent dehydrated alcohol, the amount of water reduces in the reaction, has improved reflux temperature and concentration of reactants, has shortened the reaction times; Directly obtain the product solid, need not enriched product solution, by filtering and recrystallization directly obtains product, the yield and the purity of product improve greatly, can obtain direct medicinal Peperphentonamine hydrochloride, and the cost of Peperphentonamine hydrochloride is reduced greatly.
The synthetic route of Peperphentonamine hydrochloride of the present invention is reasonable in design, and synthesis technique is easy and simple to handle, and raw material is easy to get, stable reaction conditions, and the yield height, and do not have serious " three wastes " and pollute.Waste reaction solution mostly is acid, alkaline solution, can discharge through simple process, is fit to industrial production requirement fully.Method synthetic Peperphentonamine hydrochloride purity height of the present invention, toxic side effect are low, might develop into treatment in heart failure, to resisting myocardial ischemia and the new drug of reperfusion injury.
Describe the present invention in detail below in conjunction with the drawings and specific embodiments.
Description of drawings
Accompanying drawing 1 is the high pressure liquid chromatography figure of method synthetic Peperphentonamine hydrochloride of the present invention;
Accompanying drawing 2 is high pressure liquid chromatography figure of comparative example method synthetic Peperphentonamine hydrochloride of the present invention.
Embodiment
Be embodiments of the invention below, described embodiment is used to describe the present invention rather than restriction the present invention.
Embodiment 1
Adopt following method to synthesize N-methyl piperethanamine salt hydrochlorate:
1.09mol homopiperony lamine (intermediate of Northeast Pharmaceutical Factory) and 1.96mol phenyl aldehyde are placed flask at the bottom of the 1000ml garden, mix, emit a large amount of heat, add 300ml dehydrated alcohol mixing, add zeolite, the heating of electricity consumption hot tap, back flow reaction 18 hours, concentrating under reduced pressure is removed ethanol, removes unreacted phenyl aldehyde with the oil pump concentrating under reduced pressure again, gets reddish-brown oily matter, behind the cool to room temperature, add 200ml toluene and 1.09mol methyl-sulfate again, outer temperature is maintained at about 120 ℃ of reactions 30 minutes, and room temperature leaves standstill cooling, treat the top toluene layer that inclines again after the layering, and then 75% ethanol of adding 300ml, back flow reaction is 30 minutes again, gets dark red-brown opaque liq.Adding distil water 10ml, shake up the back under whipped state, use water pump to remove ethanol, toluene and water equal solvent under reduced pressure, remove phenyl aldehyde with the oil pump concentrating under reduced pressure again, get the opaque thickness oily matter of dark red-brown, in the extremely thick thing of gained, add saturated substantially HCl/ ethanol solution to PH=3, separate out a large amount of N-methyl piperethanamine salt hydrochlorate solids gradually, filter, solid is washed repeatedly, is washed with anhydrous diethyl ether with acetone, gets subalbous solid 89g, yield: 38%, mp:186～188 ℃ (dec.).R
f=0.23 (developping agent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08).
Obtain the hydroxyl benzylideneacetone through the Claisen-Schmidt condensation reaction with acetone under alkaline condition by p-Hydroxybenzaldehyde.
21.5g (0.1mol) N-methyl piperethanamine salt hydrochlorate and 30g (1mol) Paraformaldehyde 96 are placed the 500ml round-bottomed bottle, add 240ml dehydrated alcohol and 2ml concentrated hydrochloric acid, make solution be acid, outer temperature remains in the 90-100 ℃ of oil bath and heats, after being stirred to solid and all dissolving, reheat stirred about 30 minutes, cold slightly, add hydroxyl benzylideneacetone 16.2g ((0.1mol), about 8.0 hours of backflow stirring reaction, slowly separate out solid in the reaction process, in reaction flask, all solidify.Detect R with TLC
f=0.38 (developping agent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), reaction is complete substantially.Filter, solid is washed repeatedly with the refrigerative dehydrated alcohol, drying.Get faint yellow solid 27.3g.This solid is with 95% ethanol heated and stirred, the very fast whole dissolvings of solid are lurid settled solution, use the 3g activated carbon decolorizing again, get lurid settled solution, put and slowly separate out the white powder solid after cold, and then put the refrigerator cooling, and filter, get subalbous Peperphentonamine hydrochloride pulverulent solids, wash with dehydrated alcohol, vacuum-drying, heavy 22g, yield: 69%.mp：168～170℃。R
f=0.38 (launches neat: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), ultimate analysis is near theoretical value, and high pressure liquid chromatography detects, and purity is about 99.3%, referring to Fig. 1.Results of elemental analyses:
Mass spectrum: m/s 218,135.Infrared absorption spectrum (IR) detected result sees Table 1: table 1IR spectral results
Proton nmr spectra (DMSO-d
6, TMS) the results are shown in Table 2
| Element | ??C??(％) | ??H??(％) | ??N??(％) | ??Cl??(％) |
| Calculated value | ??64.69 | ??6.16 | ??3.59 | ??9.114 |
| Measured value | ??64.57 | ??6.19 | ??3.69 | ??9.01 |
| ??64.78 | ??6.04 | ??3.44 | ??9.14 |
| Absorption peak (cm -1) | Oscillatory type | Group | Absorption peak strength |
| ????3080 ????2960 | ??vas??C-H | Phenyl ring CH 2 | ????S ????M |
| ????1684 | ??vas??C＝O | The unsaturated C=O of α β | ????M |
| ????1655 ????1593 ????1514 | ??vas??C＝C | Phenyl ring connects the phenyl ring of carbonyl | Weak S M |
| ????1284 ????1242 ????1192 ????1111 ????1032 ????970 ????924 | ? ??vas??C-OH | The phenolic hydroxyl group phenyl ring | ? ????M ? ? ????M |
| ????1192，1169 | ??vas ??c-o-c-o-c | On the phenyl ring | ????M |
| ????823 | ??vas??C-H | Phenyl ring (1,4-two replaces) | ????M |
Structural formula:
Table 2 Peperphentonamine hydrochloride
1H-NMR composes resolution table
6.3.4 carbon-13 nmr spectra and carbon, the relevant spectrum of hydrogenation displacement study see Table 3:
| Sequence number | Chemical shift (δ) | The peak type | Proton number | Corresponding proton |
| ????21 | ????2.796 | ????s | ????3H | ????N-CH 3 |
| ????13 | ????2.910 | ????br.t | ????2H | ????-CH 2 |
| ????11 | ????3.281 | ????br.m | ????2H | ????-CH 2 |
| ????10 | ????3.320 | ????br.t | ????2H | ????-CH 2 |
| ????12 | ????3.421 | ????br.m | ????2H | ????-CH 2 |
| ????20 | ????5.896 | ????s | ????2H | ????-OCH 2O- |
| ????8 | ????6.659 | ???d，J＝16.5Hz | ????1H | ????-C-H |
| ????19 | ????6.746 | ???dd，J＝8.0Hz ???J＝1.50Hz | ????1H | ????-C-H |
| ????18 | ????6.80 | ???d，J＝8.0Hz | ????1H | ????-C-H |
| ????2，6 | ????6.823 | ???A 2B 2，d，J＝9.0Hz | ????2H | ????-C-H |
| ????15 | ????6.861 | ???d，J＝1.50Hz | ????1H | ????-C-H |
| ????3，5 | ????7.533 | ???A 2B 2，d，J＝9.0Hz | ????2H | ????-C-H |
| ????7 | ????7.582 | ???d，J＝16.5Hz | ????1H | ????-C-H |
| ????1 | ????10.195 | ???Br.s?D 2The O exchange | ????1H | ????-C-OOH |
Table 3. Peperphentonamine hydrochloride
13C-NMR composes resolution table
| The carbon sequence number | Chemical shift (δ) | The carbon sequence number | Chemical shift (δ) |
| ?? C-1 | ??160.260 | ??C-13 | ??29.109 |
| ??C-2，6 | ??115.939 | ??C-14 | ??130.630 |
| ??C-4 | ??125.020 | ??C-15 | ??109.129 |
| ??C-3，5 | ??130.555 | ??C-16 | ??146.009 |
| ??C-7 | ??143.714 | ??C-17 | ??147.361 |
| ??C-8 | ??122.551 | ??C-18 | ??108.318 |
| ??C-9 | ??196.187 | ??C-19 | ??121.805 |
| ??C-10 | ??33.886 | ??C-20 | ??100.839 |
| ??C-11 | ??55.959 | ??C-21 | ??39.384 |
| ??C-12 | ??50.236 |
Embodiment 2
17.2g (0.08mol) N-methyl piperethanamine salt hydrochlorate and 24g (0.8mol) Paraformaldehyde 96 are placed the 500ml round-bottomed bottle, add 200ml dehydrated alcohol and 1.5ml concentrated hydrochloric acid, make PH be about 3-4,100 ℃ of oil bath temperatures are after heated and stirred to solid all dissolves, reheat, stirring about 20 minutes, cold slightly, add hydroxyl benzylideneacetone 16.2g ((0.1mol), about 6.0 hours of backflow stirring reaction, slowly separate out solid in the reaction process, in reaction flask, all solidify.Detect R with TLC
f=0.38 (developping agent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), reaction is complete substantially.Filter, solid is washed repeatedly with dehydrated alcohol, drying.Get faint yellow solid.This solid 95% ethyl alcohol recrystallization obtains pale yellow powder shape solid, cools off then, filters, and uses absolute ethanol washing, gets subalbous Peperphentonamine hydrochloride pulverulent solids, vacuum-drying, heavy 15.58g, yield: 60.1%.mp：167～169℃。R
f=0.38 (developping agent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), ultimate analysis is near theoretical value, and high pressure liquid chromatography detects, and purity is about 98.6%.
Embodiment 3
25.8g (0.12mol) N-methyl piperethanamine salt hydrochlorate and 36g (1.2mol) Paraformaldehyde 96 are placed the 500ml round-bottomed bottle, add 320ml dehydrated alcohol and 2.0mol concentrated hydrochloric acid, make PH be about 4,90 ℃ of oil bath temperatures are after heated and stirred to solid all dissolves, reheat, stirring 10 minutes, cold slightly, add to hydroxyl benzylideneacetone 16.2g (0.1mol) about 9.5 hours of backflow stirring reaction, slowly separate out solid in the reaction process, in reaction flask, all solidify.Detect R with TLC
f=0.38 (developping agent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), reaction is complete substantially.Filter, solid is washed repeatedly, is dried with dehydrated alcohol, gets faint yellow solid.This solid ethyl alcohol recrystallization obtains faint yellow Peperphentonamine hydrochloride pulverulent solids, cools off then, filters, and uses absolute ethanol washing, gets subalbous pulverulent solids, vacuum-drying, yield: 62%.mp：167～169℃。R
f=0.38 (developping agent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), ultimate analysis is near theoretical value, and high pressure liquid chromatography detects, and purity is about 98.8%.
Embodiment 4
43.0g (0.2m0l) N-methyl piperethanamine salt hydrochlorate and 45g (1.5mol) Paraformaldehyde 96 are placed the 1000ml round-bottomed bottle, add 400ml dehydrated alcohol and concentrated hydrochloric acid, make PH be about 3-4,95 ℃ of oil bath temperatures are after heated and stirred to solid all dissolves, reheat, stirring 25 minutes, cold slightly, add hydroxyl benzylideneacetone 24.3g ((0.15mol), about 7 hours of backflow stirring reaction, slowly separate out solid in the reaction process, in reaction flask, all solidify.Detect R with TLC
f=0.38 (developping agent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), reaction is complete substantially.Filter, solid with dehydrated alcohol wash repeatedly, drying, faint yellow solid.This solid ethyl alcohol recrystallization obtains pale yellow powder shape solid, cools off then, filters, and uses absolute ethanol washing, gets subalbous Peperphentonamine hydrochloride pulverulent solids, vacuum-drying, yield: 56.4%.mp：167～169℃。R
f=0.38 (developping agent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), ultimate analysis is near theoretical value, and high pressure liquid chromatography detects, and purity is about 98.5%.
Embodiment 5
32.25g (0.15mol) N-methyl piperethanamine salt hydrochlorate and 45g (1.5mol) Paraformaldehyde 96 are placed the 1000ml round-bottomed bottle, add 350ml dehydrated alcohol and concentrated hydrochloric acid, adjust PH and be about 3-5,100 ℃ of oil bath temperatures, after heated and stirred to solid all dissolves, add hydroxyl benzylideneacetone 16.2g ((0.1mol), about 7.5 hours of backflow stirring reaction, slowly separate out solid in the reaction process, in reaction flask, all solidify.Detect R with TLC
f=0.38 (developping agent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), reaction is complete substantially.Filter out solvent, solid is washed repeatedly with dehydrated alcohol, drying.Get faint yellow solid.This solid is with 95% ethanol heated and stirred, the very fast whole dissolvings of solid are lurid settled solution, use the 3g activated carbon decolorizing again, lurid settled solution, put and slowly separate out the white powder solid after cold, cool off then, filter, get subalbous pulverulent solids, wash vacuum-drying with dehydrated alcohol, obtain Peperphentonamine hydrochloride, yield: 58.9%.mp：168～170℃。R
f=0.38 (developping agent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), ultimate analysis is near theoretical value, and high pressure liquid chromatography detects purity 99.5%
Embodiment 6
1.5g Peperphentonamine hydrochloride, sodium hydrogen carbonate solution (pH=9) that 200ml is saturated and 80 ethyl acetate are mixed, stirring at room three hours, solid dissolve gradually settled solution, the intact R of TLC reaction
f=0.49 (developping agent: CH
2Cl
2: CH
3OH=10: 0.8), tell the upper strata ethyl acetate solution, wash neutrality with water, use anhydrous sodium sulfate drying, filter, get subalbous pulverulent solids, wash with anhydrous diethyl ether, vacuum-drying gets Xanthiphenyl ketamine pulverulent solids 1.3g, yield: 95.6%.mp：142～143℃。Results of elemental analyses and theoretical value are approaching.
Embodiment 7
It according to mol ratio 1: 1.2 ratio, Xanthiphenyl ketamine is reacted salify with acid such as Hydrogen bromide, oxalic acid, succsinic acid or toxilic acids respectively under the room temperature in ethyl acetate, the TLC monitoring reaction, to the Xanthiphenyl ketamine disappearance, wash neutrality with water, use anhydrous sodium sulfate drying, filter, get subalbous pulverulent solids, wash vacuum-drying with anhydrous diethyl ether.Obtain Xanthiphenyl ketamine hydrobromate, Xanthiphenyl ketamine oxalate, Xanthiphenyl ketamine succinate, Xanthiphenyl ketamine maleate respectively, results of elemental analyses and theoretical value are approaching.
Experimental example 8
Adopt following method to synthesize N-methyl piperethanamine salt hydrochlorate:
0.8mol homopiperony lamine (intermediate of Northeast Pharmaceutical Factory) and 1.0mol phenyl aldehyde are placed flask at the bottom of the 1000ml garden, mix, emit a large amount of heat, add 200ml anhydrous methanol mixing, add zeolite, the heating of electricity consumption hot tap, back flow reaction 21 hours, concentrating under reduced pressure is removed methyl alcohol, removes unreacted phenyl aldehyde with the oil pump concentrating under reduced pressure again, gets reddish-brown oily matter, behind the cool to room temperature, add 100ml benzene and 1.0mol methyl-sulfate again, outer temperature is maintained at about 80 ℃ of reactions 60 minutes, and room temperature leaves standstill cooling, treat the benzene layer that inclines top again after the layering, and then 75% ethanol of adding 200ml, back flow reaction is 40 minutes again, gets dark red-brown opaque liq.Adding distil water 15ml shakes up the back under whipped state, uses water pump to remove ethanol, toluene and water equal solvent under reduced pressure, remove phenyl aldehyde with the oil pump concentrating under reduced pressure again, get the opaque thickness oily matter of dark red-brown, in the extremely thick thing of gained, add saturated substantially HCl/ ethanol solution to PH=4, separate out a large amount of solids gradually, filter, solid is washed repeatedly, is washed with anhydrous diethyl ether with acetone, gets subalbous solid, yield: 35%, mp:186～188 ℃ (dec.).R
f=0.23 (developping agent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08).
Experimental example 9
1.2mol homopiperony lamine (intermediate of Northeast Pharmaceutical Factory) and 1.5mol phenyl aldehyde are placed flask at the bottom of the 1000ml garden, mix, emit a large amount of heat, add the anhydrous THF mixing of 400ml, add zeolite, the heating of electricity consumption hot tap, back flow reaction 15 hours, the water pump concentrating under reduced pressure is removed THF, removes unreacted phenyl aldehyde with the oil pump concentrating under reduced pressure again, gets reddish-brown oily matter, behind the cool to room temperature, add 200ml toluene and 1.4mol methyl-sulfate again, outer temperature is maintained at about 130 ℃ of reactions 40 minutes, and room temperature leaves standstill cooling, treat the top toluene layer that inclines again after the layering, and then 75% ethanol of adding 400ml, back flow reaction is 50 minutes again, gets dark red-brown opaque liq.Adding distil water 20ml shakes up the back under whipped state, uses water pump to remove ethanol, toluene and water equal solvent under reduced pressure, remove phenyl aldehyde with the oil pump concentrating under reduced pressure again, get the opaque thickness oily matter of dark red-brown, in the extremely thick thing of gained, add saturated substantially HCl/ absolute methanol solution to PH=1-3, separate out a large amount of solids gradually, filter, solid is washed repeatedly, is washed with anhydrous diethyl ether with acetone, gets subalbous solid, yield: 40%, mp:186～188 ℃ (dec.).R
f=0.23 (developping agent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08).
Experimental example 10
0.4mol homopiperony lamine (intermediate of Northeast Pharmaceutical Factory) and 0.8mol phenyl aldehyde are placed flask at the bottom of the 1000ml garden, mix, emit a large amount of heat, add 150ml dehydrated alcohol mixing, add zeolite, the heating of electricity consumption hot tap, back flow reaction 20 hours, the water pump concentrating under reduced pressure is removed ethanol, removes unreacted phenyl aldehyde with the oil pump concentrating under reduced pressure again, gets reddish-brown oily matter, behind the cool to room temperature, add 45ml hexanaphthene and 0.6mol methyl-sulfate again, outer temperature is maintained at about 100 ℃ of reactions 20 minutes, and room temperature leaves standstill cooling, treat the top toluene layer that inclines again after the layering, and then 75% ethanol of adding 200ml, back flow reaction is 50 minutes again, gets dark red-brown opaque liq.Adding distil water 12ml shakes up the back under whipped state, uses water pump to remove ethanol, hexanaphthene and water equal solvent under reduced pressure, remove phenyl aldehyde with the oil pump concentrating under reduced pressure again, get the opaque thickness oily matter of dark red-brown, in the extremely thick thing of gained, add saturated substantially HCl/ absolute methanol solution to PH=3.5, separate out a large amount of solids gradually, filter, solid is washed repeatedly, is washed with anhydrous diethyl ether with acetone, gets subalbous solid, yield: 380%, mp:186～188 ℃ (dec.).R
f=0.23 (developping agent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08).
Embodiment 11
Method with reference to embodiment 9, difference is to add saturated substantially oxalic acid/ethanol solution to Ph=2 in the thickness oily matter that finally obtains, separate out a large amount of solids gradually, filter, solid is washed repeatedly, is washed with anhydrous diethyl ether with acetone, get subalbous N-methyl piperethanamine oxalate solid, refer again to the synthetic Xanthiphenyl ketamine oxalate of method of embodiment 2.
Embodiment 12
Method with reference to embodiment 10, difference is to add saturated substantially succsinic acid/ethanol solution to Ph=3 in the thickness oily matter that finally obtains, separate out a large amount of solids gradually, filter, solid is washed repeatedly, is washed with anhydrous diethyl ether with acetone, get subalbous N-methyl piperethanamine succinate solid, refer again to the synthetic Xanthiphenyl ketamine succinate of method of embodiment 2.
Embodiment 13
Method with reference to embodiment 10, difference is to add saturated substantially toxilic acid/ethanol solution to Ph=4 in the thickness oily matter that finally obtains, separate out a large amount of solids gradually, filter, solid is washed repeatedly, is washed with anhydrous diethyl ether with acetone, gets subalbous N-methyl piperethanamine maleate solid.Refer again to the synthetic Xanthiphenyl ketamine maleate of method of embodiment 2.
Embodiment 14
With reference to the method for embodiment 8, acid/ethanol solution such as that difference is to add is saturated substantially, oxalic acid, succsinic acid or toxilic acid is to Ph=l-3.
Comparative example
In 100ml ethanol, 0.018mol,, add 5ml 36% formaldehyde and 5ml hydrochloric acid again with 5ml 36% formaldehyde and 0.018mol N-methyl piperethanamine salt hydrochlorate stirring and refluxing 3 hours under PH3-4 to hydroxyl-phenyl-1-butylene-3-ketone, continue reaction 7 hours, be concentrated into solid and occurred, put and be chilled to room temperature, put refrigerator again 2 hours, the solid that suction filtration is separated out, use the ether washed twice, get the 3.4g white solid, yield 44%.Use the anhydrous diethyl ether recrystallization, obtain Peperphentonamine hydrochloride, fusing point 157-9 ℃.The HPLC spectrogram of product is seen Fig. 2.
Claims (9)
1. Xanthiphenyl ketamine, Xanthiphenyl ketamine salt, its chemical structure is:
Wherein X is acid or 0 such as hydrochloric acid, Hydrogen bromide, oxalic acid, succsinic acid and toxilic acid.
2. Xanthiphenyl ketamine according to claim 2, Xanthiphenyl ketamine salt, described Xanthiphenyl ketamine salt are the Xanthiphenyl ketamine hydrochloride.
3. the preparation method of an Xanthiphenyl ketamine, Xanthiphenyl ketamine salt amine, it is characterized in that comprising the steps: with to hydroxyl benzylideneacetone and N-methyl piperethanamine salt hydrochlorate, Paraformaldehyde 96 in dehydrated alcohol, react reflux through Mannich under the acidic conditions, all solidify to reactant, get Peperphentonamine hydrochloride through aftertreatment.
4. the preparation method of Xanthiphenyl ketamine according to claim 3, Xanthiphenyl ketamine salt amine is characterized in that also comprising Peperphentonamine hydrochloride is neutralized through alkaline solution, obtains Xanthiphenyl ketamine.
5. the preparation method of Xanthiphenyl ketamine according to claim 4, Xanthiphenyl ketamine salt amine, it is characterized in that Xanthiphenyl ketamine is reacted with Hydrogen bromide, oxalic acid, succsinic acid or toxilic acid respectively, obtain Xanthiphenyl ketamine hydrobromate, Xanthiphenyl ketamine oxalate, Xanthiphenyl ketamine succinate, Xanthiphenyl ketamine maleate respectively.
6. the preparation method of Peperphentonamine hydrochloride according to claim 3, it is characterized in that with respect to 0.1-0.15mol the hydroxyl benzylideneacetone, the consumption of N-methyl piperethanamine salt hydrochlorate is that the consumption of 0.07-0.20mol, Paraformaldehyde 96 is 0.5-1.5mol, the consumption of dehydrated alcohol is 150-400ml, described acidic conditions is pH=3-5, heating is reflected under the backflow and carries out, and the reaction times is 6-9.5 hour.
7. according to the preparation method of claim 2 or 3 described Peperphentonamine hydrochlorides, it is characterized in that, wherein 0.1mol to hydroxyl benzylideneacetone and 0.1-0.12mol N-methyl piperethanamine salt hydrochlorate, 0.9-1.2mol Paraformaldehyde 96 in the 200-300ml dehydrated alcohol, all solidified to reactant in back flow reaction 7-8.5 hour under the acidic conditions of PH3-4, obtain Peperphentonamine hydrochloride through aftertreatment.
8. according to the preparation method of claim 2 or 3 described Peperphentonamine hydrochlorides, it is characterized in that, described aftertreatment be with reactant filter, washing, with wherein a kind of of dehydrated alcohol, 95% ethanol, ether, 1-2 after drying of recrystallization.
9. the new preparation method of Peperphentonamine hydrochloride according to claim 5 is characterized in that, described aftertreatment also comprises uses activated carbon decolorizing.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008095328A1 (en) | 2007-01-31 | 2008-08-14 | Guangzhou Zhongwei Biotechnology Ltd | A kind of hydrochloric piperphentonamine freeze-dried powder injection, preparation methods and uses thereof |
| CN101235027B (en) * | 2007-01-31 | 2010-11-10 | 广州市众为生物技术有限公司 | Xanthiphenylketamine crystal and its preparation method and medical use |
| CN102028681B (en) * | 2009-09-24 | 2012-05-30 | 广州市众为生物技术有限公司 | Application of pentaerythritoneamine or salt thereof in preparation of drugs for preventing/treating encephalopathy |
| CN101928274B (en) * | 2009-06-26 | 2013-03-13 | 广州市众为生物技术有限公司 | Peperphentonamine derivative |
| CN102977081A (en) * | 2012-10-22 | 2013-03-20 | 广西师范大学 | Homopiperony lamine pyridine -2- formaldehyde and synthetic method and application thereof |
| CN106892892A (en) * | 2017-01-17 | 2017-06-27 | 内蒙古医科大学 | Fragrant oxygen acid derivative containing piperonyl cyclonene and preparation method thereof |
-
2002
- 2002-07-24 CN CNB021253188A patent/CN1164585C/en not_active Expired - Lifetime
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008095328A1 (en) | 2007-01-31 | 2008-08-14 | Guangzhou Zhongwei Biotechnology Ltd | A kind of hydrochloric piperphentonamine freeze-dried powder injection, preparation methods and uses thereof |
| CN101235027B (en) * | 2007-01-31 | 2010-11-10 | 广州市众为生物技术有限公司 | Xanthiphenylketamine crystal and its preparation method and medical use |
| US8513301B2 (en) | 2007-01-31 | 2013-08-20 | Guangzhou Zhongwei Biotechnology Ltd. | Kind of piperphentonamine hydrochloride lyophilized powder for injection and preparation and use thereof |
| CN101928274B (en) * | 2009-06-26 | 2013-03-13 | 广州市众为生物技术有限公司 | Peperphentonamine derivative |
| CN102028681B (en) * | 2009-09-24 | 2012-05-30 | 广州市众为生物技术有限公司 | Application of pentaerythritoneamine or salt thereof in preparation of drugs for preventing/treating encephalopathy |
| CN102977081A (en) * | 2012-10-22 | 2013-03-20 | 广西师范大学 | Homopiperony lamine pyridine -2- formaldehyde and synthetic method and application thereof |
| CN102977081B (en) * | 2012-10-22 | 2015-03-18 | 广西师范大学 | Homopiperony lamine pyridine -2- formaldehyde and synthetic method and application thereof |
| CN106892892A (en) * | 2017-01-17 | 2017-06-27 | 内蒙古医科大学 | Fragrant oxygen acid derivative containing piperonyl cyclonene and preparation method thereof |
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|---|---|
| CN1164585C (en) | 2004-09-01 |
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Free format text: FORMER OWNER: BEIJING SIHUAN PHARMACEUTICAL CO., LTD. HAINAN SIHUAN PHARMACEUTICAL CO.,LTD HAINAN SIHUAN RESEARCH INSTITUTE OF CARDIO-CEREBRAL VASCULAR MEDICINE CO., LTD. SHENZHEN SIHUAN PHARMACEUTICAL CO., LTD. |
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Free format text: CORRECT: ADDRESS; FROM: 510620 GUANGZHOU, GUANGDONG PROVINCE TO: 510663 GUANGZHOU, GUANGDONG PROVINCE |
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Effective date of registration: 20110907 Address after: 510663 Guangzhou City Luogang District of Guangzhou high tech Industrial Development Zone, Science City E413 skim Springs Road No. 3 Guangzhou international business incubator District E room Patentee after: GUANGZHOU MUNICIPAL ZHONGWEI BIOTECHNOLOGY Co.,Ltd. Address before: 510620 No. 133 Sports West Road, Tianhe, Guangdong, Guangzhou Co-patentee before: BEIJING SIHUAN PHARMACEUTICAL Co.,Ltd. Patentee before: GUANGZHOU MUNICIPAL ZHONGWEI BIOTECHNOLOGY Co.,Ltd. Co-patentee before: HAINAN SIHUAN PHARMACEUTICAL Co.,Ltd. Co-patentee before: Hainan Sihuan Cardiovascular Drug Research Institute Co.,Ltd. Co-patentee before: Shenzhen Sihuan Pharmaceutical Co.,Ltd. |
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Owner name: WUXI JIMIN KEXIN SHANHE PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: ZHONGWEI BIOTECHNOLOGY CO LTD, GUANGZHOU CITY Effective date: 20140121 |
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Effective date of registration: 20140121 Address after: 214000 No. 12 Changjiang Road, New District, Jiangsu, Wuxi Patentee after: WUXI JIMIN KEXIN SHANHE PHARMACEUTICAL Co.,Ltd. Address before: 510633 Guangdong city of Guangzhou province Luogang District of Guangzhou high tech Industrial Development Zone, Science City E413 skim Springs Road No. 3 Guangzhou international business incubator District E room Patentee before: GUANGZHOU MUNICIPAL ZHONGWEI BIOTECHNOLOGY Co.,Ltd. |
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Address after: 214028 Changjiang South Road, new Wu District, Wuxi, Jiangsu Province, No. 12 Patentee after: Wuxi Jiyu Shanhe Pharmaceutical Co.,Ltd. Address before: No.12, Changjiang Road, New District, Wuxi, Jiangsu Province Patentee before: WUXI JIMIN KEXIN SHANHE PHARMACEUTICAL Co.,Ltd. |
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Granted publication date: 20040901 |
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