CN101624356A - Method for producing alexidine - Google Patents
Method for producing alexidine Download PDFInfo
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- CN101624356A CN101624356A CN200910090479A CN200910090479A CN101624356A CN 101624356 A CN101624356 A CN 101624356A CN 200910090479 A CN200910090479 A CN 200910090479A CN 200910090479 A CN200910090479 A CN 200910090479A CN 101624356 A CN101624356 A CN 101624356A
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- LFVVNPBBFUSSHL-UHFFFAOYSA-N alexidine Chemical compound CCCCC(CC)CNC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NCC(CC)CCCC LFVVNPBBFUSSHL-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 229950010221 alexidine Drugs 0.000 title claims abstract description 28
- 238000004519 manufacturing process Methods 0.000 title abstract description 8
- 238000009835 boiling Methods 0.000 claims abstract description 86
- 239000002904 solvent Substances 0.000 claims abstract description 56
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 54
- 238000001953 recrystallisation Methods 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 30
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 22
- -1 2-ethyl Chemical group 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000000376 reactant Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims description 16
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 13
- 238000000746 purification Methods 0.000 claims description 11
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 229940094933 n-dodecane Drugs 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- YXZZOMVBHPCKMM-UHFFFAOYSA-N 2-[6-[[amino-(cyanoamino)methylidene]amino]hexyl]-1-cyanoguanidine Chemical compound N#CNC(N)=NCCCCCCN=C(N)NC#N YXZZOMVBHPCKMM-UHFFFAOYSA-N 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 32
- 239000000047 product Substances 0.000 description 32
- 239000007787 solid Substances 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000012065 filter cake Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000002798 polar solvent Substances 0.000 description 5
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000003746 solid phase reaction Methods 0.000 description 4
- 238000010671 solid-state reaction Methods 0.000 description 4
- 150000003457 sulfones Chemical class 0.000 description 4
- 150000003462 sulfoxides Chemical class 0.000 description 4
- IIYFAKIEWZDVMP-UHFFFAOYSA-N tridecane Chemical compound CCCCCCCCCCCCC IIYFAKIEWZDVMP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ZCTQGTTXIYCGGC-UHFFFAOYSA-N Benzyl salicylate Chemical compound OC1=CC=CC=C1C(=O)OCC1=CC=CC=C1 ZCTQGTTXIYCGGC-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- DIOQZVSQGTUSAI-NJFSPNSNSA-N decane Chemical group CCCCCCCCC[14CH3] DIOQZVSQGTUSAI-NJFSPNSNSA-N 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000003746 feather Anatomy 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- DCAYPVUWAIABOU-UHFFFAOYSA-N hexadecane Chemical compound CCCCCCCCCCCCCCCC DCAYPVUWAIABOU-UHFFFAOYSA-N 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- YCOZIPAWZNQLMR-UHFFFAOYSA-N pentadecane Chemical compound CCCCCCCCCCCCCCC YCOZIPAWZNQLMR-UHFFFAOYSA-N 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- BGHCVCJVXZWKCC-UHFFFAOYSA-N tetradecane Chemical compound CCCCCCCCCCCCCC BGHCVCJVXZWKCC-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- OAYXUHPQHDHDDZ-UHFFFAOYSA-N 2-(2-butoxyethoxy)ethanol Chemical compound CCCCOCCOCCO OAYXUHPQHDHDDZ-UHFFFAOYSA-N 0.000 description 1
- RWLALWYNXFYRGW-UHFFFAOYSA-N 2-Ethyl-1,3-hexanediol Chemical compound CCCC(O)C(CC)CO RWLALWYNXFYRGW-UHFFFAOYSA-N 0.000 description 1
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 description 1
- QGLVWTFUWVTDEQ-UHFFFAOYSA-N 2-chloro-3-methoxyphenol Chemical compound COC1=CC=CC(O)=C1Cl QGLVWTFUWVTDEQ-UHFFFAOYSA-N 0.000 description 1
- JNWRGTDFPPYRAD-UHFFFAOYSA-N 2-ethylhexan-1-amine;hydron;chloride Chemical compound Cl.CCCCC(CC)CN JNWRGTDFPPYRAD-UHFFFAOYSA-N 0.000 description 1
- XXFSYINDUHLBIL-UHFFFAOYSA-N 2-o-butyl 1-o-methyl benzene-1,2-dicarboxylate Chemical class CCCCOC(=O)C1=CC=CC=C1C(=O)OC XXFSYINDUHLBIL-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- GQRDWFDDWOBCLS-UHFFFAOYSA-N C1(=CC=CC=C1)OCC(=S)OCCO Chemical compound C1(=CC=CC=C1)OCC(=S)OCCO GQRDWFDDWOBCLS-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 1
- 208000025157 Oral disease Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- 229960005082 etohexadiol Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000002070 germicidal effect Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- CALVPZNSFFEPJG-UHFFFAOYSA-N guanidine;dihydrochloride Chemical compound Cl.Cl.NC(N)=N CALVPZNSFFEPJG-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000030194 mouth disease Diseases 0.000 description 1
- QNIVIMYXGGFTAK-UHFFFAOYSA-N octodrine Chemical compound CC(C)CCCC(C)N QNIVIMYXGGFTAK-UHFFFAOYSA-N 0.000 description 1
- 229960001465 octodrine Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- RBNWAMSGVWEHFP-UHFFFAOYSA-N trans-p-Menthane-1,8-diol Chemical compound CC(C)(O)C1CCC(C)(O)CC1 RBNWAMSGVWEHFP-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
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Abstract
The invention relates to a method for producing alexidine, which comprises the following step: enabling 2-ethylhexyl-1-amine hydrochloride to react with 1,6-bis (N3-cyano-N1-guanidino) hexane in a molten state in a high boiling solvent to generate the alexidine. The method for producing the alexidine has the advantages of simple operation, convenient control, small hazard and high yield, thereby being suitable for industrial production.
Description
Technical field
The present invention relates to produce the method for alexidine (alexidine), relate in particular to the method for suitability for industrialized production alexidine.
Background technology
Alexidine, systematic naming method is 1-[N-[6-[[amino-[(N '-(2-ethylhexyl) amidino) amino] methylene radical] amino] hexyl] amidino]-2-(2-ethylhexyl) guanidine dihydrochloride (be 1-[N '-[6-[[amino-[(N '-(2-ethylhexyl) carbamimidoyl) amino] methylidene] amino] hexyl] carbamimidoyl]-2-(2-ethylhexyl) guanidinedihydrochloride), has great broad-spectrum antibacterial, germicidal action, it is a kind of medicine of sterilization and disinfection preferably, to the anti-microbial effect of Gram-positive and negative bacterium, even serum is being arranged, it is still effective when blood etc. exist.Early stage in the latter stage seventies and the eighties, alexidine is widely used in collutory, treats and take precautions against various oral diseases.Recent years, because the hypotoxicity and the germ-resistant broad spectrum of alexidine, it has been used in other some treatments, as collyrium or treatment cancer.
Yet up to the present, two pieces of pertinent literatures (Cobum, R.A.B., P.J. are only arranged; Evans, R.T.; Genco, R.J.; Fischman, S.L.Journal of MedicinalChemistry 1978,21,828-829; And Denis M.Bailey, C.G.D., Stephanie J.Hoff, Patsy L.Schulenberg, John R.O ' Connor; DonaldA.Paris, a.A.M.S.Journal of Medicinal Chemistry 1984,27 1457-1464) has the preparation method who reports alexidine, and they have all adopted the synthetic method of solid phase:
The benefit of this method is environmentally friendly, does not need the participation of solvent.But shortcoming also is significantly, and reaction is difficult to control: 1) reaction system can not become good dispersed system, thereby causes granularity, the degree of uniformity of composition, the purity of finished product all to be difficult to repetition; 2) in reaction process, the unexpected heat release of reaction system meeting if the conductivity of selected oil bath or other systems of heating is bad, then can cause temperature of reaction too high, and cause the generation of by product; 3) the same second reason, the unexpected heat release of reaction also can cause safe hidden danger.These three shortcomings have brought very big problem for the suitability for industrialized production of alexidine.
Therefore, the method that need a kind ofly to be convenient to control, danger is little, yield rate is high is synthesized alexidine, so that carry out suitability for industrialized production.
Summary of the invention
The problem of the method poor repeatability that the technical problem that the present invention will solve is a prior art.
Another technical problem that the present invention will solve is the problem that the method for prior art produces by product.
Another technical problem that the present invention will solve is the unsafe problem of method of prior art.
Another technical problem that the present invention will solve is the inefficient problem of method of prior art.
In order to solve the problems of the technologies described above, the invention provides the method for producing alexidine (Alexidine), comprise: make the 2-ethyl oneself-hydrochloride and 1 of 1-amine, 6-two (N3-cyano group-N1-guanidine radicals) hexane reacts with molten state in high boiling solvent, with the generation alexidine.
The boiling point of high boiling solvent is equal to or higher than the reactant melt temperature, and for example, the boiling point of described high boiling solvent is equal to or higher than 140 ℃, preferably be equal to or higher than 145 ℃, further preferably be equal to or higher than 150 ℃, also further preferably be equal to or higher than 156 ℃, more preferably be equal to or higher than 160 ℃, further more preferably be equal to or higher than 170 ℃, also more preferably be equal to or higher than 180 ℃, for example, be higher than 190 ℃, be higher than 200 ℃, be higher than 220 ℃.
High boiling solvent is selected from least a in low-pole high boiling solvent and the nonpolar high boiling solvent, preferred nonpolar high boiling solvent.
The moment of dipole of preferred described high boiling solvent is equal to or less than 2.1D, further preferably be equal to or less than 1.8D, more preferably preferably be equal to or less than 1.5D, also be more preferably less than and equal 1.3D, also further preferably smaller or equal to 1.0D, most preferably smaller or equal to 0.8D, also most preferably smaller or equal to 0.5D, also further most preferably smaller or equal to 0.3D, for example smaller or equal to the moment of dipole of glycol ether, also for example smaller or equal to the moment of dipole of gamma-butyrolactone.
Described high boiling solvent is selected from least a in high boiling alkane, high-boiling point alcohol, high boiling ester, the high boiling point ether, more preferably at least a in high boiling alkane, high boiling ester, the high boiling point ether, high boiling alkane most preferably for example preferably is selected from least a in n-decane, n-dodecane, diethylene glycol dimethyl ether, glycol ether, the gamma-butyrolactone.
Temperature of reaction is equal to or higher than 140 ℃, and preferable range is at 140～180 ℃, and more preferably 150～180 ℃, 152～180 ℃, also more preferably 156～180 ℃, most preferably 152～172 ℃, also most preferably 160～172 ℃.
Reactant 1, the concentration of 6-two (N3-cyano group-N1-guanidine radicals) hexane is 0.01～10mol/L, preferred 0.01～5mol/L, preferred 0.05～5mol/L, more preferably 0.4～1.3mol/L.
The 2-ethyl oneself-add-on of the hydrochloride of 1-amine is than reactant 1,6-two (N3-cyano group-N1-guanidine radicals) hexane is excessive.
Reaction times is 1min～10h, preferred 5min～5h, further preferred 5min～3h, also further preferred 15min～3h, more preferably 15min～2.5h, also more preferably 15min～2h, most preferably 30min～2h.
Further comprise and separating and/or purification step.
Separate and/or purification step comprises extraction, redeposition, recrystallization, distillation, decant, filtration, centrifugal, washing, evaporation, stripping and absorption or its combination of at least two kinds, preferred extraction, redeposition, recrystallization or its combination of at least two kinds.Preferred recrystallization adopts water as solvent.
The present invention introduces high boiling organic solvent and reacts, and has improved reaction efficiency greatly.And when having solved the shortcoming that solid state reaction generates alexidine cleverly, and reduced the difficulty of aftertreatment and purification.
Method of the present invention has simple to operate, is convenient to control, and dangerous little, the advantage that yield rate is high is very suitable for industrial production.
Description of drawings
Fig. 1 is the embodiment of the invention 6 products obtained therefroms
1H NMR spectrogram.
Fig. 2 is the embodiment of the invention 6 products obtained therefroms
13C NMR spectrogram.
Fig. 3 A is the HPLC spectrogram of 1 products obtained therefrom of the embodiment of the invention 1 recrystallization.
Fig. 3 B is the HPLC spectrogram of 2 products obtained therefroms of the embodiment of the invention 1 recrystallization.
Fig. 3 C is the HPLC spectrogram of 3 products obtained therefroms of the embodiment of the invention 1 recrystallization.
Fig. 4 A, 4B are respectively the HPLC spectrogram and the data of 3 products obtained therefroms of comparative example 2 recrystallizations.
Fig. 5 A is the HPLC spectrogram of 1 products obtained therefrom of the embodiment of the invention 3 recrystallizations.
Fig. 5 B is the HPLC spectrogram of 3 products obtained therefroms of the embodiment of the invention 3 recrystallizations.
Fig. 6 A is the HPLC spectrogram of 1 products obtained therefrom of the embodiment of the invention 4 recrystallizations.
Fig. 6 B is the HPLC spectrogram of 3 products obtained therefroms of the embodiment of the invention 4 recrystallizations.
Fig. 7 A is the HPLC spectrogram of 1 products obtained therefrom of comparative example 1 recrystallization of the present invention.
Fig. 7 B is the HPLC spectrogram of 3 products obtained therefroms of comparative example 1 recrystallization of the present invention.
Fig. 8 A is the HPLC spectrogram of 2 products obtained therefroms of the embodiment of the invention 5 recrystallizations.
Fig. 8 B is the HPLC spectrogram of 3 products obtained therefroms of the embodiment of the invention 5 recrystallizations.
Fig. 9 A is the HPLC spectrogram of 1 products obtained therefrom of the embodiment of the invention 6 recrystallizations.
Fig. 9 B is the HPLC spectrogram of 3 products obtained therefroms of the embodiment of the invention 6 recrystallizations.
Figure 10 A is the HPLC spectrogram of 1 products obtained therefrom of the embodiment of the invention 7 recrystallizations.
Figure 10 B is the HPLC spectrogram of 3 products obtained therefroms of the embodiment of the invention 7 recrystallizations.
Figure 11 A is the HPLC spectrogram of 1 products obtained therefrom of the embodiment of the invention 8 recrystallizations.
Figure 11 B is the HPLC spectrogram of 3 products obtained therefroms of the embodiment of the invention 8 recrystallizations.
Figure 12 A is the HPLC spectrogram of 1 products obtained therefrom of the embodiment of the invention 9 recrystallizations.
Embodiment
According to an aspect of the present invention, the method of producing alexidine is provided, comprise: a) make octodrine (be the 2-ethyl oneself-1-amine, English name: hydrochloride 2-ethylhexan-1-amine) and 1,6-two (N3-cyano group-N1-guanidine radicals) hexane (English name: 1,6-di (N3-Cyano-N 1-guanidino) hexane) in high boiling solvent, reacts, to generate alexidine.
Reaction of the present invention is to carry out under the reactant molten state.
A kind of preferred embodiment in, method of the present invention may further comprise the steps:
A1) the 2-ethyl oneself-hydrochloride of 1-amine mixes with high boiling solvent, is increased to the temperature that is lower than temperature of reaction;
A2) add 1,6-two (N3-cyano group-N1-guanidine radicals) hexane is increased to temperature of reaction and reacts.
A kind of preferred embodiment in, method of the present invention may further comprise the steps:
A1) with the 2-ethyl oneself-hydrochloride of 1-amine is increased to the temperature that is lower than temperature of reaction;
A2) add high boiling solvent and 1,6-two (N3-cyano group-N1-guanidine radicals) hexane is increased to temperature of reaction and reacts.
A kind of preferred embodiment in, method of the present invention further may further comprise the steps:
B) separation and/or purification step.
(1) high boiling solvent
Reaction of the present invention is to carry out under the reactant molten state, therefore says that the boiling point of employed high boiling solvent among the present invention will be equal to or higher than the reactant melt temperature at least.
Employed high boiling solvent is meant that boiling point is equal to or higher than the solvent of temperature of reaction among the present invention.The boiling point of employed high boiling solvent is equal to or higher than 140 ℃ among the present invention, preferably be equal to or higher than 145 ℃, further preferably be equal to or higher than 150 ℃, also further preferably be equal to or higher than 156 ℃, more preferably be equal to or higher than 160 ℃, further more preferably be equal to or higher than 170 ℃, also more preferably be equal to or higher than 180 ℃, for example, be higher than 190 ℃, be higher than 200 ℃, be higher than 220 ℃.
Preferred high boiling solvent and reaction raw materials and reaction product does not react and stable solvent under reaction conditions.High boiling solvent is preferably weak polar solvent or nonpolar high boiling solvent, more preferably nonpolar high boiling solvent.The moment of dipole of preferred described high boiling solvent is equal to or less than 2.1D (7fCfm), further preferably be equal to or less than 1.8D, more preferably preferably be equal to or less than 1.5D, also be more preferably less than and equal 1.3D, also further preferably smaller or equal to 1.0D, most preferably smaller or equal to 0.8D, also most preferably smaller or equal to 0.5D, also further most preferably smaller or equal to 0.3D, for example smaller or equal to the moment of dipole of glycol ether, also for example smaller or equal to the moment of dipole of gamma-butyrolactone.
High boiling solvent can be high boiling alkane, high-boiling point alcohol, high boiling ester, high boiling point ether, preferred high boiling alkane, high-boiling point alcohol, high boiling ester, high boiling point ether, more preferably high boiling alkane, high boiling ester, high boiling point ether, most preferably high boiling alkane.
High boiling alkane can be C
10-C
16The alkane of straight or branched, preferred C
10-C
15The alkane of straight or branched, more preferably C
10-C
14The alkane of straight or branched, also more preferably C
10-C
13The alkane of straight or branched, most preferably C
10-C
12The alkane of straight or branched.
High boiling alkane also can be C
12-C
20Replace or unsubstituted naphthenic hydrocarbon.
The example of high boiling alkane is decane, undecane, dodecane, tridecane, the tetradecane, pentadecane, n-Hexadecane, preferred decane, undecane, dodecane, tridecane, more preferably n-decane, n-undecane, n-dodecane, most preferably n-decane, n-dodecane.
The example of high-boiling point alcohol is Trivalin SF, terpinol, ethylene glycol (glycol), glycol ether (DEG), triglycol, 1, ammediol, 1,2,3-glycerol (glycerine), ethohexadiol, 1,4-butyleneglycol, dipropylene glycol, 3-methyl isophthalic acid, 5-pentanediol, preferred glycol ether.
The example of high boiling ester is gamma-butyrolactone, acetate of butyl carbitol, methoxymethyl ether propionic ester, Whitfield's ointment primary isoamyl alcohol, wintergreen oil, benzyl salicylate, benzyl propionate, butyl phthalate methyl esters, preferred gamma-butyrolactone.
The example of high boiling point ether is diethylene glycol dimethyl ether (DME), diphenyl ether, ethylene glycol bisthioglycolate phenyl ether, benzylic ether, preferred diethylene glycol dimethyl ether.
Various high boiling solvents can be used alone, but also also mix together.
In experiment, find, when adopting methyl-sulphoxide (DMSO) as high boiling solvent, the reaction product complexity, side reaction is more, only has a small amount of target product to generate.
The inventor unexpectedly finds, adopts weak polar solvent or nonpolar high boiling solvent, and especially nonpolar high boiling solvent is during as high boiling solvent, productive rate height, by product seldom, the product purity height of gained.
Preferred high boiling solvent does not comprise high polar solvent, does not particularly comprise sulfone and sulfoxide, promptly except sulfone and the sulfoxide.
Preferred high boiling solvent does not comprise sulfone, sulfoxide and nitrile, promptly except sulfone, sulfoxide and the nitrile.
(2) temperature of reaction
Reaction of the present invention is to carry out under the reactant molten state, and temperature of reaction should be equal to or higher than the reactant melt temperature.For example, temperature of reaction of the present invention is equal to or higher than 140, preferably is equal to or higher than 145 ℃, further preferably be equal to or higher than 150 ℃, also further preferably be equal to or higher than 156 ℃, more preferably be equal to or higher than 160 ℃, further more preferably be equal to or higher than 170 ℃.Temperature of reaction of the present invention is less than or equal to 180 ℃, preferably is lower than 180 ℃, more preferably less than 175 ℃.
The scope of temperature of reaction of the present invention can be 140～180 ℃, further preferred 145～180 ℃, and more preferably 150～180 ℃, 152～180 ℃, also more preferably 156～180 ℃, most preferably 152～172 ℃, also most preferably 160～172 ℃.
(3) concentration of reactants
Preferred 2-ethyl oneself-add-on of the hydrochloride of 1-amine is than reactant 1,6-two (N3-cyano group-N1-guanidine radicals) hexane is excessive, preferably excessive slightly.
The 2-ethyl oneself-hydrochloride and 1 of 1-amine, the mol ratio of 6-two (N3-cyano group-N1-guanidine radicals) hexane is 2: 1～3: 1, preferred 2: 1～2.5: 1, further preferred 2: 1～2.3: 1, more preferably 2.05: 1～2.3: 1, most preferably 2.1～2.3: 1.Reactant 2-ethyl oneself-hydrochloride and 1 of 1-amine, 6-two (N3-cyano group-N1-guanidine radicals) hexane mol ratio can be 2: 1, preferred 2.01: 1, further preferred 2.05: 1, also further preferred 2.1: 1, more preferably 2.2: 1, also more preferably 2.3: 1.
(4) reaction times
Reaction times is had no particular limits, and those of ordinary skills can determine the reaction times by experiment according to reactant concn, temperature of reaction, solvent etc.Reaction times can be 1min～10h, preferred 5min～5h, further preferred 5min～3h, also further preferred 15min～3h, more preferably 15min～2.5h, also more preferably 15min～2h, most preferably 30min～2h.Consider production cost and productive rate, the special preferred reaction time is 30min.
(5) separation and/or purification
Method of the present invention can comprise the post-processing operation step product being separated and/or purify, and reclaims high boiling solvent.
B) separate and/or purification step can extraction, redeposition, recrystallization, distillation, decant, filtration, centrifugal, washing, evaporation, stripping and absorption or its combination of at least two kinds, preferred extraction, redeposition, recrystallization or its combination of at least two kinds.
A kind of preferred embodiment in, b) separate and/or purification step comprises: b1) alexidine is separated from reaction mixture.A kind of preferred embodiment in, step b1) undertaken by extraction.
Step b) is separated and/or purification may further include step: b2) redeposition.Step b2) redeposition for example can be undertaken by following: with step b1) in the alexidine solid that obtains be dissolved in second solvent, add the 3rd solvent (precipitation agent), wherein the 3rd solvent can reduce the solubleness of alexidine in second solvent, thereby the alexidine solid is separated out.
Method of the present invention may further include following steps: b3) recrystallization.With step b1) or step b2) the alexidine solid that obtains carries out recrystallization.Step b3) can carry out one or many.
A kind of preferred embodiment in, b) separate and/or purify and comprise:
B1) extraction; B2) redeposition; B3) recrystallization.
Extraction agent can use alcohols, for example methyl alcohol, ethanol.At step b2) in the redeposition, can be with ethanol as solvent, with acetone as precipitation agent.At step b3) in the recrystallization, preferably make water carry out recrystallization.B3) recrystallization can carry out one or many.
At b3) after the recrystallization, can further include step: b4) redeposition.B2) redeposition and b3) recrystallization can hocket repeatedly.
The inventor unexpectedly finds, adopts water to carry out recrystallization as solvent, the product purity height.
A kind of preferred embodiment in, post-processing operation step (separate and/or purify) comprising:
A) be cooled to 50 ℃ of interior temperature, slowly add methyl alcohol, reflux and stirred 10 minutes, form two-phase muddiness liquid.Filter, the filtrate separatory, lower floor is evaporated to dried.
B) add ethanol, the dissolving that refluxes is reduced to 50 ℃ and is dripped acetone, separates out solid.Filter, the filter cake washing with acetone dries.
C) be scattered in the water, be warming up to 90 ℃, room temperature is slowly reduced in dissolving fully, reduces to 10 ℃ again, separates out solid, filters, and filter cake washes with water, dries.
D) be evaporated to driedly, add ethanol, the dissolving that refluxes is reduced to 50 ℃ and is dripped acetone, separates out solid.Filter, the filter cake washing with acetone dries.
E) cooling adds acetone and disperses, and filters, and the filter cake washing with acetone dries.
A kind of preferred embodiment in, with the 2-ethyl oneself-hydrochloride of 1-amine is with after high boiling solvent mixes, add 1 down at 120 ℃, 6-two (N3-cyano group-N1-guanidine radicals) hexane, then after reacting half an hour under 180 ℃, through filtering and three recrystallizations, can obtain white solid, productive rate 52%.
A kind of preferred embodiment in, selected high boiling solvent is decane and dodecane, range of reaction temperature is 156 ℃-180 ℃, the concentration of reactants scope is 0.4-1.3mol/L, the reaction times was from 0.5 hour to 2 hours.
Method of the present invention can be carried out in traditional equipment that is purchased or device, and those of ordinary skills can be according to the reaction conditions of the inventive method equipment or the device used of designing institute voluntarily.Agents useful for same is all commercially available, also can make by oneself.
The present invention introduces high boiling organic solvent and reacts, and has improved reaction efficiency greatly.And when having solved the shortcoming that solid state reaction generates alexidine cleverly, and reduced the difficulty of aftertreatment and purification.
Method of the present invention has simple to operate, is convenient to control, and dangerous little, the advantage that yield rate is high is very suitable for industrial production.
Embodiment
(I) instrument
HPLC chromatogram: Agilent 1100 chromatographic instruments that adopt Agilent company.
Chromatographic condition: carry out the purity that HPLC analyzes analytic sample having on Agilent 1100 chromatographic instruments of UV detector (190-400nm), use C18 reversed-phase column (SHISEIDO MGII C 18,4.6mm * 150mm, particle diameter 5 μ m).Adopt water and acetonitrile (0.05%TFA) as elutriant, carry out gradient elution with the flow velocity of 1.0mL/min.LC-MS carries out on the HP1100-micromassZMD4000 instrument with UV detector (190-400nm), adopts C18 reversed-phase column (ZORBAX, XDB-C18,4.6mm * 50mm, particle diameter 5 μ m).
Nuclear magnetic resonance analyser: the AV-400 nuclear magnetic resonance analyser that adopts Bruker company.
(II) experiment
Example I
In the 1L three-necked bottle, drop into 5N HCl (124mL, 0.620mol), add in the ice-water bath temperature below 30 ℃ in liquid level drip down the 2-ethyl oneself-1-amine (60g, 0.464mol).Drip complete oil bath and steam moisture for 130 ℃, add decane (500mL) and 1 after temperature is higher than 120 ℃ in treating, and 6-two (N3-cyano group-N1-guanidine radicals) hexane (50g, 0.200mol).180 ℃ of reactions of white suspension oil bath outside.When interior temperature reaches 140 ℃, form the two-phase fused solution, when interior temperature is higher than 156 ℃, become light yellow suspension, form mashed prod after about again 30 minutes.Temperature is 100 ℃ in being cooled to, and slowly adds methyl alcohol (500mL), refluxes and stirs 10 minutes, forms the muddy liquid of two-phase.Filter, the filtrate separatory, n-decane (400mL) is reclaimed on the upper strata, and lower floor is evaporated to dried, gets light yellow semisolid.Add ethanol (500mL), the dissolving that refluxes is reduced to 60 ℃ and is dripped acetone (2.5L), separates out solid.Filter, filter cake is placed and is spent the night with acetone (100mL) washing, room temperature, gets white solid 70g (yield 60.1%).This solid dispersed is warming up to 90 ℃ in 700mL water, room temperature is slowly reduced in dissolving fully, reduces to 10 ℃ again, separates out solid, filters, and filter cake washes (50mL) with water, dries, and gets white solid 68g (not complete drying).HPLC purity 99.01%.This white solid redispersion is warming up to 90 ℃ in 700mL water, room temperature is slowly reduced in dissolving fully, reduces to 10 ℃ again, separates out solid, filters, and filter cake washes (50mL) with water, dries, and gets white solid 60.2g (yield: 52%).HPLC purity 99.2%.
1H-NMR(DMSO-d
6，400MHz，25℃)δ：7.67(s，4H)，6.90(s，8H)，3.05(m，8H)，1.42(s，6H)，1.28(m，20H)，0.83(m，12H)。
In the 1L three-necked bottle, drop into 5N HCl (124mL, 62.0mol), add in the ice-water bath temperature below 30 ℃ in liquid level drip down the 2-ethyl oneself-1-amine (60.0g, 0.464mol).Drip complete oil bath 130 ℃ (temperature that refer to oil bath) and steam moisture, treat to add DME (500mL) and 1 after interior temperature (temperature that refers to reaction system) is higher than 120 ℃, and 6-two (N3-cyano group-N1-guanidine radicals) hexane (50.0g, 0.2mol).White suspension heats with oil bath, under 152 ℃ temperature of reaction, reacts and forms mashed prod after 30 minutes.Temperature is 50 ℃ in being cooled to, and slowly adds acetone (500mL), forms muddy liquid.Filter, collect filter cake, get light yellow semisolid.Add ethanol (500mL), the dissolving that refluxes is reduced to 60 ℃ and is dripped acetone (2.5L), separates out solid.Filter, filter cake is placed and is spent the night with acetone (100mL) washing, room temperature, gets white solid 53.5g (yield 46%).HPLC purity 96.4%.
1 recrystallization: this solid dispersed is warming up to 90 ℃ in 700mL water, and room temperature is slowly reduced in dissolving fully, reduces to 10 ℃ again, separates out solid, filters, and filter cake washes (50mL) with water, dries, and gets white solid.
2 recrystallizations: this white solid redispersion is warming up to 90 ℃ in 700mL water, and room temperature is slowly reduced in dissolving fully, reduces to 10 ℃ again, separates out solid, filters, and filter cake washes (50mL) with water, dries, and gets white solid.HPLC purity 98.8%.
3 recrystallizations: this white solid redispersion is warming up to 90 ℃ in 700mL water, and room temperature is slowly reduced in dissolving fully, reduces to 10 ℃ again, separates out solid, filters, and filter cake washes (50mL) with water, dries, and gets white solid 45.1g (yield: 39%).HPLC purity 99.5%.
Except carrying out according to condition listed in table 1 and the table 2, the remaining reaction condition is identical with embodiment 1.
Comparative example 1
Comparative example 1 is with document Coburn, R.A.B., P.J.; Evans, R.T.; Genco, R.J.; Fischman, S.L.Journal of Medicinal Chemistry 1978,21, the condition among the 828-829 is carried out.Find in experiment: 1) during solid state reaction, be not easy to obtain homodisperse system, thereby cause when carrying out the reaction of feather weight and above amount, the product purity that obtains is not enough; 2) be a thermopositive reaction when carrying out that chemical bond generates, when carrying out the reaction of feather weight and above amount, temperature extremely is difficult to control, and when temperature was higher than 180 ℃, product began to decompose; 3) the solid state reaction heat transfer is inhomogeneous, and causing not only influences the outward appearance of final product, and stick on the reactor wall in the coloured variation of portion of product near heating liquid (or heating appliances), is difficult to remove.
Comparative example 2
Except carrying out according to condition listed in table 1 and the table 2, the remaining reaction condition is identical with embodiment 1.
The reaction conditions and the data of the comparative example and the embodiment of the invention are listed in table 1 and the table 2.
Table 1 different solvents and temperature of reaction and time are for the influence of reaction
| Embodiment | Solvent | Concentration (mol/L) | Temperature of reaction | Reaction times | HPLC purity | Productive rate |
| ??1 | ??DME | ??0.4 | ??152℃ | ??0.5h | ??99.5％ | ??39％ |
| ??3 | Gamma-butyrolactone | ??0.4 | ??160℃ | ??2h | ??98.1％ | ??39.3％ |
| ??4 | ??DEG | ??0.8 | ??160℃ | ??2h | ??97.6％ | ??24.9％ |
| ??5 | N-dodecane | ??0.4 | ??160℃ | ??0.5h | ??99.5％ | ??45％ |
| ??6 | N-decane | ??0.4 | ??160℃ | ??0.5h | ??99.5％ | ??60.6％ |
| ??7 | N-decane | ??0.4 | ??140℃ | ??2h | ??99.8％ | ??27.5％ |
| ??8 | N-decane | ??0.4 | ??172℃ | ??0.5 | ??100％ | ??41.2％ |
| ??9 | N-decane | ??1.3 | ??160℃ | ??0.5 | ??92％ | ??47％ |
| Comparative example 1 | Solvent-free | ??- | ??170℃ | ??0.5h | ??99.8％ | ??36.5％ |
| Comparative example 2 | ??DMSO | ??0.8 | ??160℃ | ??2h | ??- | ??- |
Annotate: 1) " concentration " is meant 1, the concentration of 6-two (N3-cyano group-N1-guanidine radicals) hexane in the table;
2) " HPLC purity " is meant the product purity of measuring with HPLC (in peak area) in the table.
Table 2 recrystallization number of times is to the influence of product purity
| |
1 HPLC purity of recrystallization (productive rate) | 2 HPLC purity of recrystallization (productive rate) | 3 HPLC purity of recrystallization (productive rate) |
| ?1 | ??96.4％(46％) | ??98.8％ | ??99.5％(39％) |
| ?3 | ??80.2(85％) | ??98.1％(39.3) | |
| ?4 | ??86.5％(44.7％) | ??- | ??97.6％(24.9％) |
| ?5 | ??(60.9％) | ??99.3％ | ??99.5％(45％) |
| ?6 | ??98.3％ | ??- | ??99.5％(60.6％) |
| ?7 | ??95.9％(40.4％) | ??- | ??99.8％(27.5％) |
| ?8 | ??96.5％(53％) | ??- | ??100％(41.2％) |
| ?9 | ??92％(47％) | ??- | ??92％(47％) |
| Comparative example 1 | ??95.8％(53％) | ??- | ??99.8％(36.5％) |
| Comparative example 2 | ??- | ??- | ??- |
See that from experimental data the effect of weak polar solvent and non-polar solvent is better than polar solvent, adopt the DMSO of polarity maximum to be difficult to obtain product, what effect was best is nonpolar several solvent such as n-decane and dodecane.Other high boiling non-polar solvent also will have good result.
Certainly, the present invention also can have other embodiments, and the above is the preferred embodiments of the present invention only, is not to be used for limiting protection scope of the present invention; Without departing from the spirit of the invention, those of ordinary skills are every to make various corresponding variations and modification according to content of the present invention, all belongs to the protection domain of claim of the present invention.
Claims (10)
1. produce the method for alexidine, comprising:
Make the 2-ethyl oneself-hydrochloride and 1 of 1-amine, 6-two (N3-cyano group-N1-guanidine radicals) hexane reacts with molten state in high boiling solvent, with the generation alexidine.
2. method according to claim 1, it is characterized in that, the boiling point of described high boiling solvent is equal to or higher than the reactant melt temperature, for example, the boiling point of described high boiling solvent is equal to or higher than 140 ℃, preferably be equal to or higher than 145 ℃, further preferably be equal to or higher than 150 ℃, also further preferably be equal to or higher than 156 ℃, more preferably be equal to or higher than 160 ℃, further more preferably be equal to or higher than 170 ℃, also more preferably be equal to or higher than 180 ℃, for example, be higher than 190 ℃, be higher than 200 ℃, be higher than 220 ℃.
3. method according to claim 1, it is characterized in that, described high boiling solvent is selected from least a in low-pole high boiling solvent and the nonpolar high boiling solvent, preferred nonpolar high boiling solvent, the moment of dipole of preferred described high boiling solvent is equal to or less than 2.1D, further preferably be equal to or less than 1.8D, more preferably preferably be equal to or less than 1.5D, also be more preferably less than and equal 1.3D, also further preferably smaller or equal to 1.0D, most preferably smaller or equal to 0.8D, also most preferably smaller or equal to 0.5D, also further most preferably smaller or equal to 0.3D, for example smaller or equal to the moment of dipole of glycol ether, also for example smaller or equal to the moment of dipole of gamma-butyrolactone.
4. method according to claim 1 and 2, it is characterized in that, described high boiling solvent is selected from least a in high boiling alkane, high-boiling point alcohol, high boiling ester, the high boiling point ether, at least a in preferred high boiling alkane, high boiling ester, the high boiling point ether, high boiling alkane most preferably for example is selected from least a in n-decane, n-dodecane, diethylene glycol dimethyl ether, glycol ether, the gamma-butyrolactone.
5. according to each described method of claim 1 to 4, it is characterized in that temperature of reaction is equal to or higher than 140 ℃, preferable range is at 140～180 ℃, and more preferably 150～180 ℃, 152～180 ℃, also more preferably 156～180 ℃, most preferably 152～172 ℃, also most preferably 160～172 ℃.
6. according to each described method of claim 1 to 5, it is characterized in that, reactant 1, the concentration of 6-two (N3-cyano group-N1-guanidine radicals) hexane is 0.01～10mol/L, preferred 0.01～5mol/L, more preferably 0.05～5mol/L, most preferably 0.4～1.3mol/L.
7. according to each described method of claim 1 to 6, it is characterized in that, the 2-ethyl oneself-add-on of the hydrochloride of 1-amine is than reactant 1,6-two (N3-cyano group-N1-guanidine radicals) hexane is excessive.
8. according to each described method of claim 1 to 7, it is characterized in that the reaction times is 1min～10h, preferred 5min～5h, further preferred 5min～3h, also further preferred 15min～3h, more preferably 15min～2.5h, also more preferably 15min～2h, most preferably 30min～2h.
9. according to each described method of claim 1 to 8, it is characterized in that, further comprise and separating and/or purification step.
10. method according to claim 9, it is characterized in that, described separation and/or purification step comprise extraction, redeposition, recrystallization, distillation, decant, filtration, centrifugal, washing, evaporation, stripping and absorption or its combination of at least two kinds, preferred extraction, redeposition, recrystallization or its combination of at least two kinds, further preferred recrystallization adopts water to carry out.
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