CN114989076A - Preparation method of octenidine base - Google Patents
Preparation method of octenidine base Download PDFInfo
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- CN114989076A CN114989076A CN202210636197.2A CN202210636197A CN114989076A CN 114989076 A CN114989076 A CN 114989076A CN 202210636197 A CN202210636197 A CN 202210636197A CN 114989076 A CN114989076 A CN 114989076A
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- octenidine
- reaction
- base
- amine
- organic solvent
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- SMGTYJPMKXNQFY-UHFFFAOYSA-N octenidine dihydrochloride Chemical compound Cl.Cl.C1=CC(=NCCCCCCCC)C=CN1CCCCCCCCCCN1C=CC(=NCCCCCCCC)C=C1 SMGTYJPMKXNQFY-UHFFFAOYSA-N 0.000 title claims abstract description 91
- 229960001774 octenidine Drugs 0.000 title claims abstract description 86
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000002156 mixing Methods 0.000 claims abstract description 43
- RHDWCSIBVZKRRU-UHFFFAOYSA-N n-octylpyridin-4-amine Chemical compound CCCCCCCCNC1=CC=NC=C1 RHDWCSIBVZKRRU-UHFFFAOYSA-N 0.000 claims abstract description 41
- 239000003960 organic solvent Substances 0.000 claims abstract description 35
- NUJGJRNETVAIRJ-UHFFFAOYSA-N octanal Chemical compound CCCCCCCC=O NUJGJRNETVAIRJ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 24
- 238000006268 reductive amination reaction Methods 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 238000010537 deprotonation reaction Methods 0.000 claims abstract description 18
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229960004979 fampridine Drugs 0.000 claims abstract description 16
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 14
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 35
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- GTQHJCOHNAFHRE-UHFFFAOYSA-N 1,10-dibromodecane Chemical compound BrCCCCCCCCCCBr GTQHJCOHNAFHRE-UHFFFAOYSA-N 0.000 claims description 6
- RBBNTRDPSVZESY-UHFFFAOYSA-N 1,10-dichlorodecane Chemical compound ClCCCCCCCCCCCl RBBNTRDPSVZESY-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 5
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- CKJCTZAIDVFHCX-UHFFFAOYSA-N 1,10-diiododecane Chemical compound ICCCCCCCCCCI CKJCTZAIDVFHCX-UHFFFAOYSA-N 0.000 claims description 3
- QHXLIQMGIGEHJP-UHFFFAOYSA-N boron;2-methylpyridine Chemical compound [B].CC1=CC=CC=N1 QHXLIQMGIGEHJP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 4
- 239000002585 base Substances 0.000 abstract description 39
- 238000006243 chemical reaction Methods 0.000 abstract description 35
- 239000003513 alkali Substances 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 238000001914 filtration Methods 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 238000010992 reflux Methods 0.000 description 26
- 238000001816 cooling Methods 0.000 description 25
- 239000012074 organic phase Substances 0.000 description 22
- 229910052739 hydrogen Inorganic materials 0.000 description 18
- 239000001257 hydrogen Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 16
- 238000005086 pumping Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000002390 rotary evaporation Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 9
- 239000011259 mixed solution Substances 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 5
- 238000010025 steaming Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- IXADHCVQNVXURI-UHFFFAOYSA-N 1,1-dichlorodecane Chemical compound CCCCCCCCCC(Cl)Cl IXADHCVQNVXURI-UHFFFAOYSA-N 0.000 description 1
- 241000186045 Actinomyces naeslundii Species 0.000 description 1
- 208000002064 Dental Plaque Diseases 0.000 description 1
- 241000194023 Streptococcus sanguinis Species 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 206010014801 endophthalmitis Diseases 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- PHFDTSRDEZEOHG-UHFFFAOYSA-N hydron;octan-1-amine;chloride Chemical compound Cl.CCCCCCCCN PHFDTSRDEZEOHG-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
Abstract
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of octenidine base. The invention provides a preparation method of octenidine alkali, which comprises the following steps: mixing 4-aminopyridine, octanal, a reducing agent and a first organic solvent, and carrying out reductive amination reaction to obtain N-octyl pyridine-4-amine; mixing the N-octyl pyridine-4-amine, 1, 10-dihalogenodecane, an alkaline solvent and a second organic solvent, and carrying out alkylation reaction to obtain octenidine dihydrohalide; and dissolving the octenidine dihydrohalide salt and the inorganic base in a third organic solvent, and performing deprotonation reaction to obtain the octenidine base. The preparation method provided by the invention can prepare the octenidine base only by carrying out simple chemical reaction, is simple to operate and is easy for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of octenidine base.
Background
Octenidine (Octenidine, C) 36 H 62 N 4 ) Chemical name N, N' - [1, 10-decylidene di-1 (4H) -pyridin-4-ylidene]Bis (1-octylamine), an important antimicrobial agent, can effectively inhibit the growth of streptococcus sanguis and actinomyces naeslundii, has good effects of inhibiting the generation of dental plaque and treating dental ophthalmia, and can also play a role in purifying skin, mucosa and wounds.
The existing method for preparing octenidine is complex and inconvenient to operate, for example, the preparation method disclosed in Chinese patent CN 104744354A comprises the following steps: a. pyridine reacts with thionyl chloride to obtain a compound (I), phenol and the compound (I) are mixed and react at 160 ℃, octylamine hydrochloride is added, the reaction is carried out at 220 ℃, cooling is carried out, 2mol/L hydrochloric acid is added, phenol is removed by steam distillation, 10% sodium hydroxide solution is added for alkalization, cooling and solid collection by filtration, diluted hydrochloric acid is used for dissolution and decoloration, 10% sodium hydroxide solution is added for alkalization, solid collection by filtration, washing and drying are carried out, and a white crystalline compound (III) is obtained; b. reacting the compound (III) with dichlorodecane at 120 ℃, cooling to about 100 ℃, adding dimethylformamide, stirring to dissolve, naturally cooling, and filtering to collect solids to obtain white crystalline octenidine. The preparation steps disclosed in the patent are complicated, the reaction temperature is high, the requirements on equipment are strict, and the energy consumption is high.
Disclosure of Invention
In view of the above, the invention provides a preparation method of octenidine base, which has simple steps and is easy for industrial production.
In order to solve the technical problem, the invention provides a preparation method of octenidine base, which comprises the following steps:
mixing 4-aminopyridine, octanal, a reducing agent and a first organic solvent, and carrying out reductive amination reaction to obtain N-octyl pyridine-4-amine;
mixing the N-octyl pyridine-4-amine, 1, 10-dihalogenodecane, an alkaline solvent and a second organic solvent, and carrying out alkylation reaction to obtain octenidine dihydrohalide;
and dissolving the octenidine dihydrohalide salt and the inorganic base in a third organic solvent, and performing deprotonation reaction to obtain the octenidine base.
Preferably, the temperature of the reductive amination reaction is 70-90 ℃, and the time of the reductive amination reaction is 20-30 h.
Preferably, the molar ratio of the 4-aminopyridine to the octanal is 1 (1-3).
Preferably, the reducing agent comprises sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, 2-methylpyridine borane or hydrogen.
Preferably, the alkylation reaction is carried out at the temperature of 90-100 ℃ for 12-15 h.
Preferably, the 1, 10-dihalodecane comprises 1, 10-dichlorodecane, 1, 10-dibromodecane or 1, 10-diiododecane;
the molar ratio of the N-octyl pyridine-4-amine to the 1, 10-dihalogenodecane is (1-4): 1.
Preferably, the basic solvent comprises one or more of dimethyl sulfoxide, dimethylformamide, acetone and pyridine;
the volume ratio of the mass of the N-octyl pyridine-4-amine to the volume of the alkaline solvent is 1g (5-10) mL.
Preferably, the deprotonation reaction temperature is 90-100 ℃, and the time is 8-15 h.
Preferably, the inorganic base comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate;
the molar ratio of the octenidine dihydrohalide salt to the inorganic base is 1 (1-2).
Preferably, the third organic solvent comprises dichloromethane, chloroform, benzene, toluene, tetrahydrofuran or acetonitrile;
the mass ratio of the octenidine dihydrohalide to the third organic solvent is 1g (10-15) mL.
The invention provides a preparation method of octenidine alkali, which comprises the following steps: mixing 4-aminopyridine, octanal, a reducing agent and a first organic solvent, and carrying out reductive amination reaction to obtain N-octyl pyridine-4-amine; mixing the N-octyl pyridine-4-amine, 1, 10-dihalogenodecane, an alkaline solvent and a second organic solvent, and carrying out alkylation reaction to obtain octenidine dihydrohalide; and dissolving the octenidine dihydrohalide salt and the inorganic base in a third organic solvent, and performing deprotonation reaction to obtain the octenidine base. The preparation method provided by the invention is simple to operate and easy for industrial production.
Drawings
FIG. 1 shows the preparation of N-octyl pyridin-4-amine from example 1 1 H-NMR chart;
FIG. 2 shows the preparation of octenidine dihydrochlorate obtained in example 1 1 H-NMR chart;
FIG. 3 shows octenidine base prepared in example 1 1 H-NMR chart.
Detailed Description
The invention provides a preparation method of octenidine alkali, which comprises the following steps:
mixing 4-aminopyridine, octanal, a reducing agent and a first organic solvent, and carrying out reductive amination reaction to obtain N-octyl pyridine-4-amine;
mixing the N-octyl pyridine-4-amine, 1, 10-dihalogenodecane, an alkaline solvent and a second organic solvent, and carrying out alkylation reaction to obtain octenidine dihydrohalide;
and dissolving the octenidine dihydrohalide salt and the inorganic base in a third organic solvent, and performing deprotonation reaction to obtain the octenidine base.
In the present invention, the starting materials are all commercially available products well known to those skilled in the art, unless otherwise specified.
The method mixes 4-aminopyridine, octanal, a reducing agent and a first organic solvent to carry out reductive amination reaction to obtain N-octyl pyridine-4-amine. In the present invention, the reducing agent preferably includes sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, 2-methylpyridine borane or hydrogen, more preferably sodium cyanoborohydride, sodium triacetoxyborohydride or hydrogen, and still more preferably hydrogen. In the invention, when the reducing agent is hydrogen, hydrogen is introduced into the solution to be reacted, and the pressure of the hydrogen when the hydrogen is introduced is preferably 1-2 MPa, and more preferably 1.1-1.5 MPa. The invention controls the dosage of the hydrogen by controlling the pressure of the hydrogen. In the present invention, when the reducing agent is hydrogen, a catalyst is preferably further added, and the catalyst preferably includes raney nickel, platinum carbon or palladium carbon, and more preferably raney nickel or palladium carbon; the mass ratio of the catalyst to the 4-aminopyridine is preferably 20-40: 100, and more preferably 25-35: 100. In the present invention, when the reducing agent is other than hydrogen, the molar ratio of the octanal to the reducing agent is preferably 1 (0.54 to 4), more preferably 1: (1.3-4).
In the present invention, the first organic solvent preferably includes methanol, ethanol, acetone or tetrahydrofuran, more preferably methanol, ethanol or acetone, still more preferably ethanol; the volume ratio of the mass of the 4-aminopyridine to the first organic solvent is preferably 1g (9-15) mL, and more preferably 1g (9.5-10) mL.
In the invention, the molar ratio of the 4-aminopyridine to the octanal is preferably 1 (1-3), and more preferably 1 (1-1.9).
In the present invention, the mixing is preferably performed under stirring conditions, and the stirring conditions are not particularly limited as long as the uniform mixing can be achieved.
In the invention, the temperature of the reductive amination reaction is preferably 70-90 ℃, and more preferably 75-85 ℃; the reductive amination reaction time is preferably 20-30 h, and more preferably 22-28 h.
In the present invention, it is also preferred to include after the reductive amination reaction: and cooling the product after the reductive amination reaction to room temperature, filtering to remove impurities, and performing rotary evaporation on the filtrate to obtain the N-octyl pyridine-4-amine. In the invention, the temperature of the room temperature is preferably 20-35 ℃, and more preferably 25-30 ℃. In the invention, the rotary evaporation temperature is preferably 35-45 ℃, and more preferably 38-42 ℃. The invention has no special requirement on the rotating speed and time of the rotary evaporation as long as the solvent in the reaction product can be removed. In the present invention, before the rotary evaporation when the reducing agent is hydrogen, it is preferable to further filter the system cooled to room temperature. The invention has no special requirements on the filtration, and can adopt the conventional filtration mode in the field. The catalyst in the product after the reaction is removed by filtration.
After obtaining the N-octyl pyridine-4-amine, mixing the N-octyl pyridine-4-amine, 1, 10-dihalogenodecane, an alkaline solvent and a second organic solvent, and carrying out alkylation reaction to obtain the octenidine dihydrohalide. In the present invention, the mixing preferably comprises the steps of:
dissolving the N-octyl pyridine-4-amine in a second organic solvent, and carrying out a first reflux reaction to obtain an N-octyl pyridine-4-amine solution;
mixing an N-octyl pyridine-4-amine solution and 1, 10-dihalogenodecane for the first time, and carrying out alkylation reaction to obtain primary octenidine dihydrohalide salt;
and secondly, mixing the primary octenidine dihydrohalide salt and an alkaline solvent for a second reflux reaction to obtain the octenidine dihydrohalide salt.
The method comprises the steps of dissolving the N-octyl pyridine-4-amine in a second organic solvent, and carrying out a first reflux reaction to obtain an N-octyl pyridine-4-amine solution. In the present invention, the second organic solvent preferably includes ethyl acetate or butyl acetate, more preferably butyl acetate. In the invention, the volume ratio of the mass of the N-octyl pyridine-4-amine to the volume of the second organic solvent is preferably 1g (10-15) mL, and more preferably 1g (10.6-13) mL.
In the invention, the temperature of the first reflux reaction is preferably 90-100 ℃, and more preferably 95-98 ℃; the time of the first reflux reaction is preferably 18-24 hours, and more preferably 18-20 hours.
After obtaining the N-octyl pyridine-4-amine solution, the invention mixes the N-octyl pyridine-4-amine solution and 1, 10-dihalogenodecane for the first time, and carries out alkylation reaction to obtain the primary octenidine dihydrohalide. In the present invention, the 1, 10-dihalodecane preferably includes 1, 10-dichlorodecane, 1, 10-dibromodecane or 1, 10-diiododecane, and more preferably 1, 10-dichlorodecane or 1, 10-dibromodecane. In the present invention, the molar ratio of the N-octylpyridin-4-amine to the 1, 10-dihalodecane is preferably (1 to 4):1, more preferably (1.9 to 3.7): 1.
In the invention, the temperature of the alkylation reaction is preferably 90-100 ℃, and more preferably 95-98 ℃; the time of the alkylation reaction is preferably 12-15 hours, and more preferably 13-14 hours.
After the primary octenidine dihydrohalide is obtained, the primary octenidine dihydrohalide and an alkaline solvent are mixed for a second reflux reaction to obtain the octenidine dihydrohalide. In the present invention, the basic solvent preferably includes one or more of dimethyl sulfoxide, dimethylformamide, acetone and pyridine, more preferably one or more of dimethyl sulfoxide, dimethylformamide and acetone, and still more preferably dimethyl sulfoxide and acetone. In the present invention, when the alkaline solvent includes two or more of the above-mentioned specific substances, the present invention has no special requirement for the ratio of the specific substances, and any ratio may be adopted. In embodiments of the invention the basic solvent comprises acetone, dimethylformamide or a mixture of acetone and dimethylsulfoxide; the volume ratio of the acetone to the dimethyl sulfoxide is 4: 1. In the invention, the ratio of the mass of the N-octyl pyridine-4-amine to the volume of the alkaline solvent is preferably 1g (5-10) mL, more preferably 1g (7-9) mL, and still more preferably 1g:7.58 mL.
In the present invention, the alkylation reaction product is preferably cooled prior to said second mixing. In the invention, the temperature after cooling is preferably 40-50 ℃, and more preferably 45-48 ℃. The invention has no special requirements on the cooling mode as long as the required temperature can be achieved.
In the invention, the temperature of the second reflux reaction is preferably 90-100 ℃, and more preferably 93-95 ℃; the time of the second reflux reaction is preferably 0.5-3 h, and more preferably 1-2 h.
In the present invention, the second reflux reaction is a reaction of alkylating into a quaternary ammonium salt.
In the present invention, it is preferable that the second reflux reaction further comprises: and cooling and filtering the second reflux reaction product, and drying the solid obtained by filtering. In the invention, the temperature after cooling is preferably 0-5 ℃, and more preferably 1-4 ℃. The cooling method is not particularly limited as long as the desired temperature can be achieved. The filtration is not particularly limited in the present invention, and a filtration method which is conventional in the art may be employed. In the invention, the method preferably further comprises the step of stirring the cooled solution before filtering, wherein the stirring speed is preferably 800-1000 r/min, and more preferably 900-1000 r/min; the stirring time is preferably 0.5-1.5 h, and more preferably 1-1.2 h. In the present invention, the drying is preferably a pump-out, and the pump-out is preferably an oil pump-out or a water pump-out, and more preferably an oil pump-out. The invention has no special requirement on the draining time, and the octenidine dihydrohalide solid is drained. In the present invention, the standard for draining is preferably that the solid surface is free of liquid.
After the octenidine dihydrohalide is obtained, the octenidine dihydrohalide and the inorganic base are dissolved in a third organic solvent for deprotonation reaction to obtain the octenidine base. The invention preferably dissolves inorganic alkali in water to obtain inorganic alkali solution; dissolving inorganic alkali solution and the tinidine dihydrohalide in a third organic solvent. In the present invention, the inorganic base preferably includes sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, or potassium carbonate, more preferably strong sodium oxide, strong potassium oxide, or sodium carbonate; the molar concentration of the inorganic alkali solution is preferably 0.5-2.5 mol/L, and more preferably 1-2 mol/L. In the present invention, the third organic solvent preferably includes dichloromethane, chloroform, benzene, toluene, tetrahydrofuran or acetonitrile, more preferably toluene, benzene or dichloromethane.
In the present invention, the molar ratio of the octenidine dihydrohalide salt to the inorganic base is preferably 1: (1-2); the solid-to-liquid ratio of the octenidine dihydrohalide to the third organic solvent is preferably 1g (10-15) mL, and more preferably 1g (10-12) mL.
In the invention, the temperature of the deprotonation reaction is preferably 90-100 ℃, and more preferably 93-98 ℃; the time of the deprotonation reaction is preferably 8-15 h, and more preferably 10-12 h.
In the present invention, the deprotonation reaction preferably further comprises:
collecting an organic phase in a deprotonation reaction system;
dehydrating the organic phase, and removing the organic solvent to obtain an octenidine base crude product;
and recrystallizing and drying the crude product of the octenidine base in sequence to obtain the octenidine base.
The invention collects the organic phase in the system of deprotonation reaction. The organic phase is preferably collected by a separating funnel, and the collecting mode is not particularly required by the invention and can be realized by adopting a mode well known by the technical personnel in the field.
After the organic phase is obtained, the organic phase is dehydrated and the organic solvent is removed, so that the crude product of octenidine alkali is obtained. In the present invention, the dehydrating solvent for dehydration preferably includes anhydrous sodium sulfate, and the mass ratio of the anhydrous sodium sulfate to the volume of the organic phase is preferably (0.1 to 0.3) g:1mL, and more preferably (0.2 to 0.25) g:1 mL. In the present invention, the sodium sulfate is preferably removed by filtration after dehydration with anhydrous sodium sulfate. The filtration is not particularly limited in the present invention, and a filtration method which is conventional in the art may be employed.
In the invention, the organic solvent is removed preferably by rotary evaporation, and the temperature of the rotary evaporation is preferably 35-45 ℃, and more preferably 40-43 ℃. The invention has no special requirements on the rotating speed and time of the rotary evaporation, and only needs to be capable of removing the organic solvent cleanly.
After the crude product of the octenidine base is obtained, the crude product of the octenidine base is sequentially recrystallized and dried to obtain the octenidine base. In the present invention, the solvent for recrystallization preferably includes a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether in the mixed solution of ethyl acetate and petroleum ether is preferably 20: 1. In the present invention, the drying preferably comprises pumping, and the pumping is preferably oil pumping or water pumping, and more preferably oil pumping. The invention has no special requirement on the draining time, and the octenidine alkali is only required to be drained. In the present invention, the standard for draining is preferably that the solid surface is free of liquid.
In the present invention, the reaction equation for preparing the octenidine base is shown in formula 1:
the preparation method disclosed by the invention has the advantages that the octenidine base is obtained by sequentially carrying out reductive amination reaction, alkylation reaction and deprotonation reaction, the operation is simple, high-temperature reaction is not required, the energy consumption is low, the product yield and purity are high, and the economic benefit is good.
In order to further illustrate the present invention, the following embodiments are described in detail, but they should not be construed as limiting the scope of the present invention.
Example 1
Stirring and mixing 2.1g of 4-aminopyridine, 20mL of methanol, 0.56g of palladium carbon and 2.86g of octanal, introducing hydrogen with the pressure of 1.0MPa into the mixed reaction solution, carrying out reductive amination reaction at 80 ℃ for 24 hours, cooling to 25 ℃, filtering to remove the catalyst, and carrying out rotary evaporation at 40 ℃ to obtain N-octyl pyridine-4-amine;
3.3g N-octylpyridine-4-amine is dissolved in 35mL butyl acetate at 90 ℃ to carry out a first reflux reaction for 18h, then mixed with 1.71g 1, 10-dichlorodecane and then subjected to alkylation reaction at 90 ℃ for 12 h; cooling the system after the alkylation reaction to 40 ℃, mixing the system with a mixed solution consisting of 20mL of acetone and 5mL of dimethyl sulfoxide, and carrying out a second reflux reaction at 90 ℃ for 2 h; cooling the second reflux reaction system to 0 ℃ and stirring for 1h at the rotating speed of 800 r/min; filtering, and pumping the solid obtained by filtering by using an oil pump to obtain octenidine dihydrochloride;
dissolving sodium hydroxide in water to obtain a NaOH aqueous solution with the molar concentration of 1 mol/L; mixing 1g of octenidine dihydrochloride, 10mL of toluene and 100mL of aqueous solution of NaOH, deprotonating at 90 ℃ for 10h, separating an aqueous phase and an organic phase of a system after the deprotonation reaction by using a separating funnel, collecting an organic phase, mixing 2g of anhydrous sodium sulfate and the organic phase, dehydrating, and filtering to remove the sodium sulfate; rotatably steaming the filtrate obtained by filtering at 40 ℃ to obtain an octenidine base crude product; and mixing the crude octenidine base product with 3mL of a mixed solution of ethyl acetate and petroleum ether prepared from ethyl acetate and petroleum ether according to the volume ratio of 20:1 for recrystallization, and pumping the solid obtained by recrystallization by using an oil pump to obtain the octenidine base.
Example 2
Stirring and mixing 21g of 4-aminopyridine, 200mL of ethanol, 5.6g of Raney nickel and 28.6g of octanal, introducing hydrogen with the pressure of 1.1MPa into the mixed reaction solution, carrying out reductive amination reaction at 75 ℃ for 28h, cooling to 25 ℃, filtering to remove the catalyst, and carrying out rotary evaporation at 35 ℃ to obtain N-octyl pyridine-4-amine;
dissolving 33g N-octyl pyridine-4-amine in 350mL ethyl acetate at 90 ℃ to perform a first reflux reaction for 19h, mixing the obtained product with 17.1g of 1, 10-dibromodecane, and performing an alkylation reaction for 13h at 90 ℃; cooling the system after the alkylation reaction to 45 ℃, mixing with 250mL of acetone, and carrying out a second reflux reaction at 95 ℃ for 2 h; cooling the second reflux reaction system to 4 ℃, and stirring for 1h at the rotating speed of 900 r/min; filtering, and pumping the solid obtained by filtering by using an oil pump to obtain octenidine dibromide;
dissolving potassium hydroxide in water to obtain a KOH aqueous solution with the molar concentration of 1 mol/L; mixing 10g of octenidine dibromide, 100mL of benzene and 1000mL of KOH aqueous solution, deprotonating at 95 ℃ for 12h, separating an aqueous phase and an organic phase of a system subjected to deprotonation reaction by using a separating funnel, collecting an organic phase, mixing 20g of anhydrous sodium sulfate and the organic phase, dehydrating, and filtering to remove sodium sulfate; rotatably steaming the filtrate obtained by filtering at 35 ℃ to obtain an octenidine base crude product; and mixing the crude octenidine base with 30mL of a mixed solution of ethyl acetate and petroleum ether prepared from ethyl acetate and petroleum ether according to the volume ratio of 20:1 for recrystallization, and pumping the solid obtained by recrystallization by using an oil pump to obtain the octenidine base.
Example 3
Stirring and mixing 10.5g of 4-aminopyridine, 100mL of acetone, 3g of platinum carbon and 15g of octanal, introducing hydrogen with the pressure of 2.0MPa into the mixed reaction solution, carrying out reductive amination reaction at 90 ℃ for 22h, cooling to 25 ℃, filtering to remove the catalyst, and carrying out rotary evaporation at 45 ℃ to obtain N-octyl pyridine-4-amine;
16.5g N-octyl pyridine-4-amine is dissolved in 175mL butyl acetate at 90 ℃ to carry out a first reflux reaction for 20h, then the mixture is mixed with 8.6g 1, 10-diiodochlorodecane, and then alkylation reaction is carried out for 12h at 90 ℃; cooling the system after the alkylation reaction to 40 ℃, mixing the system with 120mL of dimethylformamide, and carrying out a second reflux reaction at 95 ℃ for 2 h; cooling the second reflux reaction system to 5 ℃, and stirring for 1h at the rotating speed of 850 r/min; filtering, and pumping the solid obtained by filtering by using an oil pump to obtain octenidine diiodide;
dissolving sodium carbonate in water to obtain Na with the molar concentration of 21mol/L 2 CO 3 An aqueous solution; 5g octenidine diiodide, 50mL methylene chloride and 500mL Na 2 CO 3 Mixing the aqueous solution, deprotonating at 100 ℃ for 10h, separating the aqueous phase and the organic phase of the system after the deprotonation reaction by using a separating funnel, collecting the organic phase, mixing 10g of anhydrous sodium sulfate and the organic phase, dehydrating, and filtering to remove the sodium sulfate; rotatably steaming the filtrate obtained by filtering at 40 ℃ to obtain an octenidine base crude product; and mixing the crude octenidine base with 15mL of a mixed solution of ethyl acetate and petroleum ether prepared from ethyl acetate and petroleum ether according to the volume ratio of 20:1, recrystallizing, and pumping out the solid obtained by recrystallization by using an oil pump to obtain the octenidine base.
Example 4
Stirring and mixing 4.2g of 4-aminopyridine, 40mL of methanol, 6.72g of sodium cyanoborohydride and 10.72g of octanal, carrying out reductive amination reaction at 80 ℃ for 24 hours, cooling to 25 ℃, filtering to remove the catalyst, and carrying out rotary evaporation at 45 ℃ to obtain N-octyl pyridine-4-amine;
6.6g N-octylpyridine-4-amine is dissolved in 70mL butyl acetate, the mixture is subjected to a first reflux reaction at 95 ℃ for 20h, then is mixed with 3.42g of 1, 10-dichlorodecane, and then is subjected to an alkylation reaction at 95 ℃ for 13 h; cooling the system after the alkylation reaction to 40 ℃, mixing the system with 50mL of acetone, and carrying out a second reflux reaction at 90 ℃ for 1 h; cooling the second reflux reaction system to 3 ℃, and stirring for 1h at the rotating speed of 1000 r/min; filtering, and pumping the solid obtained by filtering by using an oil pump to obtain octenidine dihydrochloride;
potassium carbonate is dissolved in water to obtain K with the molar concentration of 2mol/L 2 CO 3 An aqueous solution; 2g octenidine dihydrochloride, 20mL toluene and 200mL K 2 CO 3 Mixing the aqueous solution, deprotonating at 97 deg.C for 10 hr, separating the aqueous phase and organic phase of the deprotonated system with a separating funnel, and collectingThe organic phase was collected, 4g of anhydrous sodium sulfate was mixed with the organic phase and dehydrated, and then sodium sulfate was removed by filtration; rotatably steaming the filtrate obtained by filtering at 40 ℃ to obtain an octenidine base crude product; and mixing the crude octenidine base product with 6mL of mixed solution of ethyl acetate and petroleum ether prepared from ethyl acetate and petroleum ether according to the volume ratio of 20:1, recrystallizing, and pumping the solid obtained by recrystallization by using an oil pump to obtain the octenidine base.
Example 5
Stirring and mixing 21g of 4-aminopyridine, 200mL of ethanol, 25.63g of sodium triacetoxyborohydride and 28.6g of octanal, carrying out reductive amination reaction at 85 ℃ for 30h, cooling to 25 ℃, filtering to remove a catalyst, and carrying out rotary evaporation at 40 ℃ to obtain N-octyl pyridine-4-amine;
dissolving 33g N-octyl pyridine-4-amine in 350mL ethyl acetate at 100 ℃ to perform a first reflux reaction for 21h, mixing the obtained product with 17.1g 1, 10-dibromodecane, and performing an alkylation reaction for 14h at 100 ℃; cooling the system after the alkylation reaction to 45 ℃, mixing the system with a mixed solution consisting of 200mL of acetone and 50mL of dimethyl sulfoxide, and carrying out a second reflux reaction at 100 ℃ for 2 h; cooling the second reflux reaction system to 4 ℃, and stirring for 1h at the rotating speed of 950 r/min; filtering, and pumping the solid obtained by filtering with an oil pump to obtain octenidine dibromide;
dissolving potassium hydroxide in water to obtain a KOH aqueous solution with the molar concentration of 1 mol/L; mixing 10g of octenidine dibromide, 100mL of benzene and 1000mL of KOH aqueous solution, deprotonating at 98 ℃ for 12h, separating an aqueous phase and an organic phase of a system subjected to the deprotonation reaction by using a separating funnel, collecting an organic phase, mixing 20g of anhydrous sodium sulfate and the organic phase, dehydrating, and filtering to remove the sodium sulfate; rotatably steaming the filtrate obtained by filtering at 40 ℃ to obtain an octenidine base crude product; and mixing the crude octenidine base product with 30mL of a mixed solution of ethyl acetate and petroleum ether prepared from ethyl acetate and petroleum ether according to the volume ratio of 20:1, recrystallizing, and pumping the solid obtained by recrystallization by using an oil pump to obtain the octenidine base.
The purities of the N-octyl pyridine-4-amine, the octenidine dihydrohalide salt and the octenidine base prepared in examples 1 to 5 were measured by gas chromatography, and the results are shown in table 1.
TABLE 1 yield and purity of the products prepared in examples 1-5
As can be seen from table 1, the octenidine base prepared according to the preparation method of the present invention has high yield and purity.
Respectively carrying out nuclear magnetic detection on the N-octyl pyridine-4-amine, the octenidine dihydrochloride and the octenidine base prepared in the example 1 to obtain a hydrogen spectrogram, wherein the hydrogen spectrogram is shown in figures 1-3. As shown in FIGS. 1 to 3, the octenidine base can be prepared by the preparation method of the invention.
Although the present invention has been described in detail with reference to the above embodiments, it is only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and the embodiments are within the scope of the present invention.
Claims (10)
1. A preparation method of octenidine base comprises the following steps:
mixing 4-aminopyridine, octanal, a reducing agent and a first organic solvent, and carrying out reductive amination reaction to obtain N-octyl pyridine-4-amine;
mixing the N-octyl pyridine-4-amine, 1, 10-dihalogenodecane, an alkaline solvent and a second organic solvent, and carrying out alkylation reaction to obtain octenidine dihydrohalide;
and dissolving the octenidine dihydrohalide salt and the inorganic base in a third organic solvent, and performing deprotonation reaction to obtain the octenidine base.
2. The method according to claim 1, wherein the temperature of the reductive amination reaction is 70 to 90 ℃ and the time of the reductive amination reaction is 20 to 30 hours.
3. The process according to claim 1 or 2, wherein the molar ratio of the 4-aminopyridine to the octanal is 1 (1-3).
4. The method of claim 3, wherein the reducing agent comprises sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, 2-picoline borane, or hydrogen gas.
5. The preparation method according to claim 1, wherein the alkylation reaction is carried out at a temperature of 90-100 ℃ for 12-15 h.
6. The production method according to claim 1 or 5, wherein the 1, 10-dihalodecane comprises 1, 10-dichlorodecane, 1, 10-dibromodecane, or 1, 10-diiododecane;
the molar ratio of the N-octyl pyridine-4-amine to the 1, 10-dihalogenodecane is (1-4): 1.
7. The production method according to claim 1 or 5, wherein the basic solvent comprises one or more of dimethyl sulfoxide, dimethylformamide, acetone and pyridine;
the volume ratio of the mass of the N-octyl pyridine-4-amine to the volume of the alkaline solvent is 1g (5-10) mL.
8. The preparation method according to claim 1, wherein the deprotonation reaction is carried out at a temperature of 90-100 ℃ for 8-15 hours.
9. The production method according to claim 1 or 8, wherein the inorganic base comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, or potassium carbonate;
the molar ratio of the octenidine dihydrohalide salt to the inorganic base is 1 (1-2).
10. The production method according to claim 1 or 8, wherein the third organic solvent comprises dichloromethane, chloroform, benzene, toluene, tetrahydrofuran or acetonitrile;
the mass ratio of the octenidine dihydrohalide to the third organic solvent is 1g (10-15) mL.
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