CN111808017B - Nitrogen-containing heterocyclic compound, and preparation method and application thereof - Google Patents
Nitrogen-containing heterocyclic compound, and preparation method and application thereof Download PDFInfo
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- CN111808017B CN111808017B CN202010778855.2A CN202010778855A CN111808017B CN 111808017 B CN111808017 B CN 111808017B CN 202010778855 A CN202010778855 A CN 202010778855A CN 111808017 B CN111808017 B CN 111808017B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- -1 Nitrogen-containing heterocyclic compound Chemical class 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 21
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000000605 extraction Methods 0.000 claims description 10
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 10
- LTEKQAPRXFBRNN-UHFFFAOYSA-N piperidin-4-ylmethanamine Chemical compound NCC1CCNCC1 LTEKQAPRXFBRNN-UHFFFAOYSA-N 0.000 claims description 10
- JFDMLXYWGLECEY-UHFFFAOYSA-N 2-benzyloxirane Chemical compound C=1C=CC=CC=1CC1CO1 JFDMLXYWGLECEY-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000002390 rotary evaporation Methods 0.000 claims description 8
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical group [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 7
- 208000019695 Migraine disease Diseases 0.000 claims description 6
- 206010027599 migraine Diseases 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 239000003495 polar organic solvent Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000002274 desiccant Substances 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- 230000002194 synthesizing effect Effects 0.000 abstract description 6
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- UCRHFBCYFMIWHC-UHFFFAOYSA-N piperaquine Chemical compound ClC1=CC=C2C(N3CCN(CC3)CCCN3CCN(CC3)C=3C4=CC=C(C=C4N=CC=3)Cl)=CC=NC2=C1 UCRHFBCYFMIWHC-UHFFFAOYSA-N 0.000 description 7
- 229950006717 piperaquine Drugs 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229960002164 pimobendan Drugs 0.000 description 5
- GLBJJMFZWDBELO-UHFFFAOYSA-N pimobendane Chemical compound C1=CC(OC)=CC=C1C1=NC2=CC=C(C=3C(CC(=O)NN=3)C)C=C2N1 GLBJJMFZWDBELO-UHFFFAOYSA-N 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 150000002391 heterocyclic compounds Chemical class 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 3
- 102000034527 Retinoid X Receptors Human genes 0.000 description 3
- 108010038912 Retinoid X Receptors Proteins 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
Abstract
The invention provides a nitrogenous heterocyclic compound, a preparation method and application thereof, and the synthesis method adopted by the invention is unique, simple in process, easy in raw material acquisition, low in post-treatment pollution, and very high in purity and yield, and the terminal primary amino enables the compound to be used as an intermediate for synthesizing other compounds.
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and relates to a nitrogenous heterocyclic compound, a preparation method and application thereof.
Background
Heterocyclic compounds are ubiquitous in the structure of drug molecules, are important intermediate products for synthesizing drugs, are important compounds related to biology, and play an important role in organic synthesis.
In international patent applications PCT 2002100352 and PCT 2002080928 are disclosed nitrogen-containing heterocyclic derivatives having the following structures:it can be used as an NMDA/NR2B receptor analog to relieve headache and migraine, but the preparation method of the derivative disclosed by the derivative is complex and takes a long time.
Therefore, in order to prepare the medicine for treating migraine with a simpler preparation method and higher yield, the preparation method has important significance for developing the nitrogen-containing heterocyclic ring intermediates.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a nitrogenous heterocyclic compound, and a preparation method and application thereof.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
in one aspect, the present invention provides a nitrogen-containing heterocyclic compound having a structure represented by formula I:
in the invention, the chemical name of the compound with the structure shown in the formula I is 1-phenyl-3- [ (4-aminomethyl) azacyclohexane ] -2-propanol (1-phenyl-3- [ (4-aminomethyl) azacyclohexane ] -2-propanol), and the formula is as follows: C15H24N2O, molecular weight: 248.37, abbreviated as pimozene (pimobenzene) in the present invention, is a heterocyclic compound containing nitrogen heteroatoms, is commonly found in the structure of drug molecules, and is an important intermediate product for synthesizing drugs and is an important compound related to biology. The heterocyclic compound also contains hydroxyl and amino groups, is easy to synthesize compounds capable of reacting with the functional groups, and plays an important role in organic synthesis.
In another aspect, the present invention provides a method for preparing the nitrogen-containing heterocyclic compound as described above, the method comprising the steps of:
(1) The 4-aminomethylpiperidine is contacted with benzaldehyde to react to obtain a compound shown in a formula II;
(2) The compound shown in the formula II is contacted with (2, 3-epoxypropyl) benzene to react to obtain a compound shown in the formula III;
(3) The compound shown in the formula III is contacted with an acid solution to be heated for removing benzyl, so that a compound shown in the formula IV is obtained;
(4) And (3) contacting the compound shown in the formula IV with an alkali solution to remove HCl, so as to obtain the nitrogen-containing heterocyclic compound shown in the formula I.
The synthesis method provided by the invention has the advantages of short synthesis route, simple process, easily available raw materials, simple post-treatment, good quality and high yield, and is suitable for synthesizing the drug intermediate.
Preferably, the molar ratio of 4-aminomethylpiperidine to benzaldehyde in step (1) is preferably 1:1.
Preferably, the temperature of the contacting of step (1) is 90-130 ℃, e.g. 90 ℃, 95 ℃, 98 ℃, 100 ℃, 105 ℃, 110 ℃, 115 ℃, 120 ℃, 125 ℃ or 130 ℃.
Preferably, the contact time of step (1) is from 10 minutes to 1 hour, for example 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 50 minutes or 1 hour.
Preferably, the reaction of step (1) is carried out by means of microwave heating. If the reaction is carried out under the condition of high-temperature reflux, the reaction efficiency is low and the product yield is low.
After the reaction of step (1), the first organic solvent is removed, preferably by rotary evaporation.
Preferably, the reactions of step (1) and step (2) are carried out in a polar organic solvent, preferably absolute ethanol.
Preferably, the molar ratio of the compound of formula II to (2, 3-epoxypropyl) benzene in step (2) is (1-1.5): 1, for example, 1:1, 1.05:1, 1.1:1, 1.15:1, 1.18:1, 1.2:1, 1.23:1, 1.25:1, 1.28:1, 1.3:1, 1.35:1, 1.38:1, 1.4:1, 1.45:1, 1.48:1, or 1.5:1, etc.
Preferably, the contact temperature of step (2) is 90-130 ℃, e.g. 90 ℃, 95 ℃, 98 ℃, 100 ℃, 105 ℃, 110 ℃, 115 ℃, 120 ℃, 125 ℃ or 130 ℃.
Preferably, the time of the reaction of step (2) is 15 minutes to 2 hours, for example 15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.3 hours, 1.5 hours, 1.8 hours or 2 hours.
Preferably, the reaction of step (2) is carried out by means of microwave heating.
Preferably, the solvent is concentrated after the reaction of step (2), preferably by rotary evaporation.
Preferably, the acid solution of step (3) is hydrochloric acid, and the concentration of the hydrochloric acid is preferably 1.5N-2N, such as 1.5N, 1.7N, 1.9N, 2N, etc.
Preferably, the time of the reaction of step (3) is 4-6 hours, for example 4 hours, 4.5 hours, 4.8 hours, 5 hours, 5.3 hours, 5.5 hours, 5.8 hours or 6 hours.
Preferably, the temperature of the heating in step (3) is 35-50 ℃, e.g. 35 ℃, 38 ℃, 40 ℃, 42 ℃, 45 ℃, 48 ℃ or 50 ℃.
Preferably, after the reaction of removing benzyl groups in the step (3) is finished, the extraction is performed by using an organic solvent which is not mutually soluble in water, and the extraction times are preferably 3-5 times.
Preferably, the water-immiscible organic solvent is dichloromethane and/or chloroform, etc.
Preferably, the alkaline solution in step (4) is an aqueous solution of sodium hydroxide, preferably at a concentration of 20-40% by mass, for example 20%, 22%, 25%, 28%, 30%, 33%, 35%, 38% or 40%.
Preferably, the reaction time for the removal of HCl in step (4) is 2-30 minutes, e.g., 2, 5, 8, 10, 15, 18, 20, 25, 28 or 30 minutes.
Preferably, the HCl-removing reaction in step (4) is completed and then extracted with a water-immiscible organic solvent, and the number of extraction times is preferably 3-5.
Preferably, the water-immiscible organic solvent is dichloromethane and/or chloroform, etc.
Preferably, the extraction is followed by drying with a drying agent, preferably anhydrous magnesium sulfate and/or anhydrous calcium chloride, and the dried product is placed in a vacuum drying oven for use.
Preferably, the drying time is preferably 16-24 hours, such as 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, etc.
In the invention, ultra-dry absolute ethyl alcohol is taken as a reaction solvent of the step (1) and the step (2), microwave reaction is carried out, dichloromethane is taken as a solvent for extraction after the reaction of the step (3) and the step (4), and the reaction route is shown in the following formula.
The nitrogenous heterocyclic compound has the advantages of short synthetic route, simple process, easily available raw materials, simple post-treatment, good quality and high yield, and is suitable for synthesizing a drug intermediate.
In another aspect, the invention provides the use of a nitrogen-containing heterocyclic compound as described above in the preparation of a medicament for treating migraine.
The nitrogenous heterocyclic compound can be used as a drug intermediate, and provides raw material support for preparing a drug for treating migraine. The migraine agent may be an NMDA/NR2B receptor analog, for example
If the preparation steps of the present invention are used to synthesize piperaquine Mo Ben, and thus prepare the NMDA/NR2B receptor analog, the yield will be improved and the procedure will be greatly simplified.
The term "contacting" as used in the present invention is to be understood in a broad sense as it may be any way that enables a chemical reaction of at least two reactants, for example by mixing the two reactants under suitable conditions. The reactants to be contacted may be mixed under stirring as needed, and thus the type of stirring is not particularly limited, and for example, mechanical stirring, that is, stirring under the action of mechanical force, may be used.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a novel nitrogen-containing heterocyclic compound piperaquine Mo Ben and a synthesis method thereof, wherein the synthesis method is unique, the process is simple, raw materials are easy to obtain, the post-treatment pollution is small, the purity and the yield are very high, and the terminal primary amino enables the compound to be used as an intermediate for synthesizing other compounds, so that the novel nitrogen-containing heterocyclic compound has wide application in the field of medicine preparation.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of pimobendan, a compound prepared in example 1.
FIG. 2 is a mass spectrum of pimobendan, a compound prepared in example 1.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
The compound pimobendan prepared in the following examples was subjected to nuclear magnetic resonance hydrogen spectroscopy (switzerland, bruk, AV 400) under the following conditions: water is an internal standard, and the solvent is methanol; high resolution electrospray mass spectrometry (HR-ESI/MS, broker, solarix 9.4T) with methanol as solvent.
Example 1
4-aminomethylpiperidine (1.48 mL,12.3 mmol) and benzaldehyde (1.28 mL,12.3 mmol) were dissolved in 9.5mL of ultra-dry absolute ethanol, then heated by microwave at 120deg.C for 15min, the solvent was concentrated, and 2.71g of the compound of formula II was obtained after drying.
The compound (310 mg,1.54 mmol) with the structural formula II and (2, 3-epoxypropyl) benzene (21 mg,1.28 mmol) are taken and dissolved in 10mL of ultra-dry ethanol, after microwave heating to 120 ℃ and maintaining for 20min, the reaction is stopped, when cooling to room temperature, the reactant is taken out, the solvent is concentrated to about 1mL, dilute hydrochloric acid (3 mL, 1.2N) is added to the residue and the mixture is heated to 40 ℃ for reaction for 4h. After the obtained product was extracted three times with 8mL of methylene chloride, the aqueous phase was adjusted to pH 11 with aqueous sodium hydroxide solution, extracted three times with 8mL of methylene chloride, and the organic phase was demulsified with saturated brine and washed to neutrality. The resulting organic phase was dried over anhydrous magnesium sulfate, concentrated by rotary evaporation to remove the solvent, and dried under vacuum to give 325mg of 1-phenyl-3- [ (4-aminomethyl) azacyclohexane ] -2-propanol (piperaquine Mo Ben) as a yellow viscous form, which was a compound of formula I in 89% yield.
The nuclear magnetic hydrogen spectrum of pimobendan is shown in figure 1, 1 h NMR (400 mhz, cd3od_spe) delta 7.29-7.14 (m, 1H), 4.02-3.94 (m, 1H), 2.94 (td, j=8.0, 3.6hz, 1H), 2.74-2.69 (m, 2H), 2.49 (d, j=6.4 hz, 2H), 2.36 (d, j=6.0 hz, 2H), 2.08 (td, j=11.5, 1.9hz, 1H), 1.95 (td, j=11.7, 2.0hz, 1H), 1.71 (d, j=11.0 hz, 2H), 1.39-1.27 (m, 1H), 1.26-1.14 (m, 2H). Mass spectrum results of pimobendan are shown in fig. 2, m/z= 249.19, less hetero-peaks and are consistent with theoretical calculations. These results demonstrate the successful preparation of the compound of formula I, 1-phenyl-3- [ (4-aminomethyl) azacyclohexane in high purity]-2-propanol.
Example 2
4-aminomethylpiperidine (1.48 mL,12.3 mmol) and benzaldehyde (1.28 mL,12.3 mmol) were dissolved in 9.5mL of ultra-dry absolute ethanol, then heated by microwave at 100deg.C for 30min, the solvent was concentrated, and 2.71g of the compound of formula II was obtained after drying.
The compound (310 mg,1.54 mmol) with the structural formula II and (2, 3-epoxypropyl) benzene (21 mg,1.28 mmol) are taken and dissolved in 10mL of ultra-dry ethanol, after microwave heating to 100 ℃ and maintaining for 40min, the reaction is stopped, when cooling to room temperature, the reactant is taken out, the solvent is concentrated to about 1mL, dilute hydrochloric acid (3 mL, 1.2N) is added to the residue and the mixture is heated to 40 ℃ for 4h. After the obtained product was extracted three times with 8mL of methylene chloride, the aqueous phase was adjusted to pH 11 with aqueous sodium hydroxide solution, extracted three times with 8mL of methylene chloride, and the organic phase was demulsified with saturated brine and washed to neutrality. The resulting organic phase was dried over anhydrous magnesium sulfate, concentrated by rotary evaporation to remove the solvent, and dried under vacuum to give 325mg of 1-phenyl-3- [ (4-aminomethyl) azacyclohexane ] -2-propanol (piperaquine Mo Ben) as a yellow viscous compound of formula I in a yield of 85%.
Example 3
4-aminomethylpiperidine (1.48 mL,12.3 mmol) and benzaldehyde (1.28 mL,12.3 mmol) were dissolved in 9.5mL of ultra-dry absolute ethanol, then heated by microwave at 120deg.C for 15min, the solvent was concentrated, and 2.71g of the compound of formula II was obtained after drying.
The compound (383 mg,1.92 mmol) with the structural formula II and (2, 3-epoxypropyl) benzene (217 mg,1.28 mmol) are taken and dissolved in 10mL of ultra-dry ethanol, after microwave heating to 120 ℃ and maintaining for 20min, the reaction is stopped, when cooling to room temperature, the reactant is taken out, the solvent is concentrated to about 1mL, dilute hydrochloric acid (3 mL, 1.2N) is added to the residue and the mixture is heated to 40 ℃ for reaction for 4h. After the obtained product was extracted three times with 8mL of methylene chloride, the aqueous phase was adjusted to pH 11 with aqueous sodium hydroxide solution, extracted three times with 8mL of methylene chloride, and the organic phase was demulsified with saturated brine and washed to neutrality. The obtained organic phase was dried over anhydrous magnesium sulfate, the solvent was removed by rotary evaporation, and 325mg of 1-phenyl-3- [ (4-aminomethyl) azacyclohexane ] -2-propanol (piperaquine Mo Ben) was obtained as a yellow viscous state after vacuum drying, which was a compound of the structural formula I, and the yield was 83%.
Example 4
4-aminomethylpiperidine (1.48 mL,12.3 mmol) and benzaldehyde (1.28 mL,12.3 mmol) were dissolved in 9.5mL of ultra-dry absolute ethanol, then heated by microwave at 120deg.C for 15min, the solvent was concentrated, and 2.71g of the compound of formula II was obtained after drying.
The compound (310 mg,1.54 mmol) of the structural formula II and (2, 3-epoxypropyl) benzene (21 mg,1.28 mmol) are taken and dissolved in 10mL of ultra-dry ethanol, after microwave heating to 120 ℃ and keeping for 2 hours, the reaction is stopped, when cooling to room temperature, the reactant is taken out, the solvent is concentrated to about 1mL, dilute hydrochloric acid (3 mL, 1.2N) is added into the residue, and the mixture is heated to 40 ℃ for reaction for 4 hours. After the obtained product was extracted three times with 8mL of methylene chloride, the aqueous phase was adjusted to pH 11 with aqueous sodium hydroxide solution, extracted three times with 8mL of methylene chloride, and the organic phase was demulsified with saturated brine and washed to neutrality. The resulting organic phase was dried over anhydrous magnesium sulfate, concentrated by rotary evaporation to remove the solvent, and dried under vacuum to give 325mg of 1-phenyl-3- [ (4-aminomethyl) azacyclohexane ] -2-propanol (piperaquine Mo Ben) as a yellow viscous form, which was a compound of formula I in a yield of 87%.
Example 5
4-aminomethylpiperidine (1.48 mL,12.3 mmol) and benzaldehyde (1.28 mL,12.3 mmol) were dissolved in 9.5mL of ultra-dry absolute ethanol, then heated by microwave at 120deg.C for 15min, the solvent was concentrated, and 2.71g of the compound of formula II was obtained after drying.
The compound (310 mg,1.54 mmol) with the structural formula II and (2, 3-epoxypropyl) benzene (21 mg,1.28 mmol) are taken and dissolved in 10mL of ultra-dry ethanol, after microwave heating to 120 ℃ and maintaining for 20min, the reaction is stopped, when cooling to room temperature, the reactant is taken out, the solvent is concentrated to about 1mL, dilute hydrochloric acid (3 mL, 1.2N) is added to the residue and the mixture is heated to 40 ℃ for reaction for 6h. After the obtained product was extracted three times with 8mL of methylene chloride, the aqueous phase was adjusted to pH 11 with aqueous sodium hydroxide solution, extracted three times with 8mL of methylene chloride, and the organic phase was demulsified with saturated brine and washed to neutrality. The resulting organic phase was dried over anhydrous magnesium sulfate, concentrated by rotary evaporation to remove the solvent, and dried under vacuum to give 325mg of 1-phenyl-3- [ (4-aminomethyl) azacyclohexane ] -2-propanol (piperaquine Mo Ben) as a yellow viscous form, which was a compound of formula I in a yield of 76%.
The products prepared in examples 2-5 were also subjected to nuclear magnetic resonance hydrogen spectroscopy and high resolution electrospray mass spectrometry, which demonstrated that examples 2-5 successfully prepared the compounds of formula I in high purity.
Comparative example 1
The comparative example differs from example 1 only in that a compound of formula II was prepared by high temperature refluxing, as follows: 4-aminomethylpiperidine (1.48 mL,12.3 mmol) was dissolved in 9.5mL of ultra-dry absolute ethanol, benzaldehyde (1.28 mL,12.3 mmol) was added, heated under reflux under nitrogen for 24 hours, and the progress of the reaction was determined by TLC plate and ninhydrin staining.
The TLC plate results indicated: when the reaction end point was reached, much amino remained in the obtained reaction liquid as compared with example 1, and the yield was only 60%, indicating that the reaction efficiency of the method was low.
The applicant states that the process of the invention is illustrated by the above examples, but the invention is not limited to, i.e. does not mean that the invention must be carried out in dependence on the above process steps. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of selected raw materials, addition of auxiliary components, selection of specific modes, etc. fall within the scope of the present invention and the scope of disclosure.
Claims (20)
1. A method for preparing a nitrogen-containing heterocyclic compound, which is characterized in that the nitrogen-containing heterocyclic compound has a structure shown in a formula I:
the preparation method comprises the following steps:
(1) The 4-aminomethylpiperidine is contacted with benzaldehyde to react to obtain a compound shown in a formula II;
(2) The compound shown in the formula II is contacted with (2, 3-epoxypropyl) benzene to react to obtain a compound shown in the formula III;
(3) The compound shown in the formula III is contacted with hydrochloric acid to be heated for removing benzyl, so as to obtain the compound shown in the formula IV;
(4) Contacting a compound shown in a formula IV with an alkali solution to remove HCl and obtain a nitrogen-containing heterocyclic compound shown in a formula I;
the reaction in the step (1) is carried out by utilizing a microwave heating mode, the contact temperature in the step (1) is 90-130 ℃, the contact time in the step (1) is 10 minutes-1 hour, the contact temperature in the step (2) is 90-130 ℃, the reaction time in the step (2) is 15 minutes-2 hours, the reaction time in the step (3) is 4-6 hours, the heating temperature in the step (3) is 35-50 ℃, and the reaction time for removing HCl in the step (4) is 2-30 minutes.
2. The method of claim 1, wherein the molar ratio of 4-aminomethylpiperidine to benzaldehyde in step (1) is 1:1.
3. The process of claim 1, wherein the reactions of step (1) and step (2) are carried out in a polar organic solvent.
4. A method of preparation according to claim 3, wherein the polar organic solvent is absolute ethanol.
5. A process according to claim 3, wherein after the reaction in step (1), the polar organic solvent is removed by spin evaporation.
6. The process according to claim 1, wherein the molar ratio of the compound of formula II to (2, 3-epoxypropyl) benzene in step (2) is 1 to 1.5.
7. The method according to claim 1, wherein the reaction in step (2) is performed by means of microwave heating.
8. A process according to claim 3, wherein the solvent is concentrated after the reaction in step (2), and the solvent concentration is rotary evaporation.
9. The method of claim 1, wherein the hydrochloric acid has a concentration of 1.5N-2N.
10. The process according to claim 1, wherein the benzyl group-removing reaction in step (3) is completed, and the benzyl group-removing reaction is followed by extraction with a water-immiscible organic solvent.
11. The method according to claim 10, wherein the number of extractions is 3 to 5.
12. The method according to claim 10, wherein the water-immiscible organic solvent is dichloromethane and/or chloroform.
13. The preparation method according to claim 1, wherein the alkaline solution in the step (4) is an aqueous solution of sodium hydroxide, and the mass percentage concentration is 20-40%.
14. The process according to claim 1, wherein the HCl-free reaction of step (4) is followed by extraction with a water-immiscible organic solvent.
15. The method of claim 14, wherein the number of extractions is 3-5.
16. The method of claim 14, wherein the water-immiscible organic solvent is dichloromethane and/or chloroform.
17. The method of claim 14, wherein the extraction is followed by drying with a desiccant.
18. The method of claim 17, wherein the desiccant is anhydrous magnesium sulfate and/or anhydrous calcium chloride.
19. The method of claim 17, wherein the drying time is 16-24 hours.
20. The use of the nitrogen-containing heterocyclic compound prepared by the preparation method according to claim 1 in the preparation of a medicament for treating migraine.
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