CN107337634B - A kind of preparation method of Abbe Seeley midbody compound - Google Patents
A kind of preparation method of Abbe Seeley midbody compound Download PDFInfo
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- CN107337634B CN107337634B CN201710751725.8A CN201710751725A CN107337634B CN 107337634 B CN107337634 B CN 107337634B CN 201710751725 A CN201710751725 A CN 201710751725A CN 107337634 B CN107337634 B CN 107337634B
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- 238000002360 preparation method Methods 0.000 title claims description 32
- 150000001875 compounds Chemical class 0.000 title claims description 29
- PHBVTMQLXNCAQO-UHFFFAOYSA-N 5-(aminomethyl)pyridin-2-amine Chemical compound NCC1=CC=C(N)N=C1 PHBVTMQLXNCAQO-UHFFFAOYSA-N 0.000 claims description 29
- 239000002585 base Substances 0.000 claims description 25
- RGDQRXPEZUNWHX-UHFFFAOYSA-N 3-methylpyridin-2-amine Chemical compound CC1=CC=CN=C1N RGDQRXPEZUNWHX-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 16
- KYPOHTVBFVELTG-UPHRSURJSA-N (z)-but-2-enedinitrile Chemical compound N#C\C=C/C#N KYPOHTVBFVELTG-UPHRSURJSA-N 0.000 claims description 15
- -1 1,5- diazabicyclo [4.3.0] -5- nonyl Chemical group 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 10
- 238000006482 condensation reaction Methods 0.000 claims description 9
- 235000019270 ammonium chloride Nutrition 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 7
- 150000002825 nitriles Chemical class 0.000 claims description 7
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 238000007033 dehydrochlorination reaction Methods 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 2
- 238000005815 base catalysis Methods 0.000 claims description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 150000001336 alkenes Chemical class 0.000 claims 2
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 claims 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical class O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims 1
- 150000001342 alkaline earth metals Chemical class 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- 239000000047 product Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 239000007791 liquid phase Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000006073 displacement reaction Methods 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- UZWDCWONPYILKI-UHFFFAOYSA-N n-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine Chemical compound C1CN(CC)CCN1CC(C=N1)=CC=C1NC1=NC=C(F)C(C=2C=C3N(C(C)C)C(C)=NC3=C(F)C=2)=N1 UZWDCWONPYILKI-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000012805 post-processing Methods 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- ZCIFWRHIEBXBOY-UHFFFAOYSA-M 6-aminopyridine-3-carboxylate Chemical compound NC1=CC=C(C([O-])=O)C=N1 ZCIFWRHIEBXBOY-UHFFFAOYSA-M 0.000 description 2
- PVUKGNBRJFTFNJ-UHFFFAOYSA-N 6-bromopyridine-3-carbaldehyde Chemical compound BrC1=CC=C(C=O)C=N1 PVUKGNBRJFTFNJ-UHFFFAOYSA-N 0.000 description 2
- JHKLCZNDTUKHHI-UHFFFAOYSA-N 6-nitronicotinic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)N=C1 JHKLCZNDTUKHHI-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229950001573 abemaciclib Drugs 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 238000004176 ammonification Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- KPADFPAILITQBG-UHFFFAOYSA-N non-4-ene Chemical compound CCCCC=CCCC KPADFPAILITQBG-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- KYPOHTVBFVELTG-OWOJBTEDSA-N (e)-but-2-enedinitrile Chemical compound N#C\C=C\C#N KYPOHTVBFVELTG-OWOJBTEDSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical group CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- HTILAHGQNCCYSQ-UHFFFAOYSA-N 1-ethylpiperazine piperazine Chemical compound N1CCNCC1.C(C)N1CCNCC1 HTILAHGQNCCYSQ-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102000005483 Cell Cycle Proteins Human genes 0.000 description 1
- 108010031896 Cell Cycle Proteins Proteins 0.000 description 1
- 229940123587 Cell cycle inhibitor Drugs 0.000 description 1
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 102000013698 Cyclin-Dependent Kinase 6 Human genes 0.000 description 1
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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
- C07D213/73—Unsubstituted amino or imino radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
The present invention relates to a kind of preparation methods of Abbe Seeley midbody compound.This method is cyclized to obtain 2- amino -5- aminomethyl-pyridine using maleonitrile and nitromethane condensation plus hydrogen, and then and (2- chloroethyl) the ethamine cyclization of N, N- bis- prepares 5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine.The compound can be used for the preparation of Abbe Seeley.The present invention is few without using expensive reagent, atom economy rate height, side reaction, safety, and product yield and purity is high, raw material is cheap and easy to get, easy to operate, at low cost.
Description
Technical field
The present invention relates to a kind of preparation methods of Abbe Seeley midbody compound, belong to technical field of medical chemistry.
Background technique
Abbe Seeley (I), the entitled Abemaciclib or bemaciclib of English, No. CAS is [1231929-97-7], trip
From alkali form structure formula as shown in formula I.Abbe Seeley is a kind of oral cell cycle inhibitor (product generation of Li Lai company exploitation
Number it is LY2835219), cancer cell can be blocked and specifically inhibiting cell cycle protein dependent kinase (CDK4 and CDK6)
Growth.The Abbe Seeley that breast cancer group expansion data based on phase test JPBA shows is late or metastatic is newborn
Safety and validity in gland cancer female patient, U.S. FDA authorized its " breakthrough therapeutic agent " title in 2015.In addition
Phase iii clinical trial of the Abbe Seeley for patients with lung cancer is also underway.
United States Patent (USP) US2010160340 and world patent WO2016110224 reports Abbe Seeley synthetic method,
Middle 5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine (formula II) is its key intermediate.Currently, 5- (4- ethyl piperazidine-
1- yl) methyl-2-amino pyridine (II compound of formula) synthetic method mainly include the following types:
1,5- (4- ethyl piperazidine -1- base) is obtained through imidization, hydrogenation using 6- bromopyridine -3- formaldehyde and n-ethylpiperazine
Methyl -2- bromopyridine, then in LiHMDS and catalyst Pd2(dba)3- Cy-Johnphos catalysis or cuprous oxide catalysis ammonification,
5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine is prepared, it is following (referring to United States Patent (USP) to be described as synthetic route 1
US2010160340):
The raw materials used 6- bromopyridine -3- formaldehyde price of 1 method of synthetic route is higher, is not easy to obtain, used in aminating reaction
LiHMDS price is high, high operation requirements, catalyst Pd2(dba)3- Cy-Johnphos price is high, and ammonification yield is low.
2, it is starting material with 6- aminonicotinate, is methylol, first by amido protecting, Lithium Aluminium Hydride reduction ester group
Sulphonyl esterification, n-ethylpiperazine replace, amino deprotection prepares 5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine, description
It is following (referring to WO2009141386) for synthetic route 2:
2 step of synthetic route is longer, and raw materials used 6- aminonicotinate price is high, Lithium Aluminium Hydride valence needed for restoring ester group
Lattice are high, high operation requirements, and production hidden danger is big, and yield is low, are unfavorable for product cost reduction and industrialized production.
3, it is starting material with 6- nitronicotinic acid, utilizes acid and the direct amidation of n-ethylpiperazine, hydrogenation hydrogenating reduction nitre
Base, Lithium Aluminium Hydride reducing carbonyl synthesize 5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine, and it is as follows to be described as synthetic route 3
(referring to Chinese patent CN106316935A):
6- nitronicotinic acid used in synthetic route 3 and the direct amidation method of n-ethylpiperazine, need using DIPEA (N, N-
Diisopropyl ethyl amine) and PyBop (hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus), price is higher, in addition
Can not still it overcome using drawback brought by Lithium Aluminium Hydride.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of inexpensive, safety and environmental protection Abbe Seeley intermediate compound
The preparation method of object, this method are high, secondary without using expensive reagent and the unsafe Lithium Aluminium Hydride of operation, atom economy rate
Reaction is few.Abbe Seeley intermediate of the present invention is 5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine (II), is had
Structure shown in formula II.
Term explanation:
Maleonitrile: also known as Isosorbide-5-Nitrae-maleonitrile, flumaronitrile, anti-maleic nitrile, molecular formula are C4H2N2, it is of the invention
Initial feed.
Compound shown in II compound of formula, formula II and 5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine (II) are at this
It is had the same meaning in invention；The target product of compound preparation method of the present invention is used as Abbe Seeley intermediate.
Technical solution of the present invention is as follows:
A kind of preparation method of compound shown in formula II,
Comprising steps of
(1) under base catalysis, 5- nitro -4- nitromethyla -2,4- penta is made in maleonitrile and nitromethane condensation reaction
Diene nitrile (III)；
The base catalyst is selected from 11 carbon -7- alkene (DBU) of 1,8- diazabicylo, 1,5- diazabicyclo [4.3.0] -
One or a combination set of 5- nonene (DBN)；
(2) in the presence of a hydrogenation catalyst, make 5- nitro -4- nitromethyla -2,4- pentadiene nitrile (III) through catalytic hydrogenation
Nitro is restored, while cyclisation obtains 2- amino -5- aminomethyl-pyridine (IV)；
(3) in a solvent, make the dechlorination under alkali effect of 2- amino -5- aminomethyl-pyridine (IV) and N, N- Dichloroethyl ethamine
Change hydrogen cyclic condensation, 5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine (II) is made.
According to the method for the present invention, preferred processing condition and amount ratio are as follows in each step:
Preferably, the dosage of alkali described in step (1) is the 1-5% of maleonitrile quality.The maleonitrile and nitro
The molar ratio of methane is 1:(1~5), further preferably, 1:2~3.
Preferably, setting-up point is 80~130 DEG C, preferably 100~120 DEG C in step (1).Condensation reaction time is
2~8 hours；It is preferred that 5 hours or so.End of reaction is directly used in step (2) without separation.In step (1), maleonitrile and
While nitromethane reaction generates intermediate 5- nitro -4- nitromethyla -2,4- pentadiene nitrile (III), ammonia is generated, every 1 rubs
You can produce 1 mole of ammonia at maleonitrile reaction.
Preferably, reaction described in step (2) carries out in alcoholic solvent；Preferably, the alcoholic solvent be methanol, ethyl alcohol or
Isopropanol；It is further preferred that being also added with ammonium chloride and water in reaction system.The ammonium chloride is raw in reacting with step (1)
At ammonia formed buffer system, be conducive to the suitable pH value of holding system；The pH is about 5-6, in favor of nitro reduction and shape
At pyridine ring.The molar ratio of the ammonium chloride and maleonitrile is 1~2:1.
According to the present invention, a preferred embodiment is, after step (1) condensation reaction is finished, is cooled to room temperature, to institute
It obtains and alcoholic solvent, ammonium chloride, water is added in reaction system；Preferably, the mass ratio of the water and maleonitrile is 0.5-2.0:1.
The ammonia that step (1) condensation reaction generates is soluble in water, forms buffer system, organic base DBU, DBN with ammonium chloride and ammonium hydroxide
Participation forms buffer system.
Preferably, hydrogenation catalyst described in step (2) is palladium charcoal or Raney Ni, and preferred palladium carbon catalyst dosage is 5-
The 0.5%~5% of nitro -4- nitromethyla -2,4- pentadiene nitrile (III) quality, further preferred catalyst amount are 1%
~3% mass ratio；Preferred raney nickel catalyst dosage is 5- nitro -4- nitromethyla -2,4- pentadiene nitrile (III) quality
1%~15%, further preferred catalyst amount is 5%~10% mass ratio.
Preferably, catalytic hydrogenation reaction temperature is 20~80 DEG C in step (2), Hydrogen Vapor Pressure 0.1-0.5MPa.Into one
Preferably, catalytic hydrogenation reaction temperature is 40~65 DEG C to step, Hydrogen Vapor Pressure 0.15-0.4MPa.Most preferably, catalytic hydrogenation reaction temperature
Degree is 50~55 DEG C, Hydrogen Vapor Pressure 0.2-0.3MPa.The catalytic hydrogenation reaction 3~8 hours, it is 4-6 hours further preferred,
Most preferably 5 hours.
Step (2) after reaction, can be post-processed by the prior art.Currently preferred post-processing approach is such as
Under: step (2) after reaction, after nitrogen displacement 2-3 times, is filtered to remove palladium-carbon catalyst, and filtrate concentration is evaporated, and methyl is added
Tertiary butyl ether is dissolved by heating, is filtered while hot, and filtrate is cooled to 0-5 DEG C of crystallization, is filtered, dry, obtains light yellow solid 2- amino -5-
Aminomethyl-pyridine.
Preferably, in step (3), mole of the 2- amino -5- aminomethyl-pyridine (IV) and N, N- Dichloroethyl ethamine
Than for 1:1~4.Further preferably, the molar ratio of 1:1.2~2, most preferably 1:1.5 molar ratio.
Preferably, solvent described in step (3) be one or a combination set of methylene chloride, chloroform, 1,2- methylene chloride,
The weight ratio of the solvent and 2- amino -5- aminomethyl-pyridine (IV) is (3~15): 1.It is further preferred that in step (3)
Feed way is, by N, the mixed solution of N- Dichloroethyl ethamine and the solvent is added drop-wise in reaction system.
Preferably, step (3) alkali is inorganic base, can be alkali metal hydroxide, alkaline earth metal hydroxide, alkali gold
Belong to carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates hydrogen；Preferably, the alkali is carbonic acid
Sodium, potassium carbonate, sodium bicarbonate, saleratus；Base amount and the molar ratio of 2- amino -5- aminomethyl-pyridine are 1-3:1.
Preferably, step (3) condensation reaction temperature is 20~80 DEG C, further preferably, 25~50 DEG C；The condensation
The annulation time 2~8 hours.Most preferably, first in 30~35 DEG C of dropwise addition N, the mixing of N- Dichloroethyl ethamine and the solvent
Solution is added dropwise after finishing, and reacts 2~4 hours then at 35~45 DEG C.
Products obtained therefrom 5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine (II), is used to prepare Abbe Seeley (I).
Method of the invention is described as following synthetic route 4:
Product postprocessing can be by the prior art.The present invention provides following post-processing approach: step (3) reaction terminates
Afterwards, reaction solution is cooled to 20~25 DEG C, layering, water layer is extracted with dichloromethane 2-3 times, merges organic phase, is distilled to recover two
Methyl tertiary butyl ether and active carbon are added into residue, stirs decoloration at 80~82 DEG C, filters while hot, filtrate is cooling for chloromethanes
It crystallizes, filters to 0-5 DEG C, it is dry, obtain white solid 5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine.
Target product 5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine of the invention obtained is post-processed above
It (II) is white solid, fusing point is 126.0-127.5 DEG C, liquid phase purity 99.3~99.7%.
Technical characterstic of the invention and the utility model has the advantages that
1, the synthetic method new the present invention provides Abbe Seeley intermediate, be condensed using maleonitrile and nitromethane,
Hydrogen is added to be cyclized to obtain 2- amino -5- aminomethyl-pyridine, then and N, N- Dichloroethyl ethamine cyclization prepare 5- (4- ethyl piperazidine -
1- yl) methyl-2-amino pyridine.Wherein, maleonitrile and nitromethane are condensed to yield 5- nitro -4- nitromethyla -2,4- penta
Diene nitrile (III), inventors have surprisingly discovered that the active methylene of the product and carbon-carbon double bond, thermal stability is poor, and high temperature steams
It is easy to polymerize when evaporating；Therefore the present invention compares the characteristic for being easy to be reduced using nitro with cyano, will directly contain 5- nitro -4- nitre
The reaction liquid hydrogenating reduction of ylmethyl -2,4- pentadiene nitrile (III) obtains amino, while amino and cyano addition cyclization, generates
2- amino -5- the aminomethyl-pyridine of stable structure.Then the amino of aminomethyl and the active difference of pyridine ring type amidogen, Gao Xuan are utilized
Selecting property and N, N- (2- Dichloroethyl) ethamine react to obtain target product.
2, process characteristic of the invention is that atom economy rate is high, environmentally protective.Related unit operating procedure avoids
Issuable side reaction, it is easy to operate,.Meanwhile in conjunction with the characteristic of intermediate, using reasonable post-processing scheme, in reduction
Between product product distillation process polymerization.In addition, in dehydrochlorination condensation reaction, N, N- Dichloroethyl ethamine it is dense
It spends particularly significant property, is added dropwise N, when the solution of N- Dichloroethyl ethamine and methylene chloride, N in system, N- Dichloroethyl ethamine
Concentration is lower always, advantageously reduces side reaction, especially reduces the side reaction of intermolecular dehydrochlorination, such as uses N, N- dichloro
Ethyl ethamine is added at one time, and will lead to N, and the concentration of N- Dichloroethyl ethamine is instantaneously higher, causes side reaction, reduces yield.
3, the raw materials used in the present invention is general chemical products, and cost is generally lower than the prior art, and raw material is easy to get；It avoids making
With reagent toxic, irritant and in the presence of operation hidden danger, so that process flow is easy to operate, safety, reaction condition is mild, instead
Should be selectively good, product purity is high, and it is at low cost, be conducive to the green work of Abbe Seeley (Abemaciclib or bemaciclib)
Industry production application.
Specific embodiment
The present invention is described in detail with reference to embodiments, but the present invention is not only limited to this.
Maleonitrile also known as flumaronitrile used in embodiment, anti-maleic nitrile, raw materials and reagents are commercial product.Embodiment
Described in " % " be weight percentage, except special instruction.
The preparation of embodiment 1:2- amino -5- aminomethyl-pyridine (IV)
Into 250 milliliters of stainless steel pressure kettles, 15.5 grams of (0.2 mole) maleonitriles of addition, 0.5 gram of DBU, 25.0 grams
(0.41 mole) nitromethane, 120 DEG C are stirred to react 4 hours, generate 5- nitro -4- nitromethyla -2,4- pentadiene nitrile (III),
It is subsequently cooled to 20-25 DEG C, 150 grams of methanol solvates of addition into autoclave pressure, 15.0 grams of ammonium chlorides, 15.0 grams of water, 0.5 gram 5%
Palladium-carbon catalyst after nitrogen displacement three times, is passed through hydrogen, and holding Hydrogen Vapor Pressure is 0.2-0.3MPa, and 50-55 DEG C is reacted 5 hours.
After nitrogen displacement three times, it is filtered to remove palladium carbon, filtrate concentration is evaporated, 100 grams of methyl tertiary butyl ethers are added and (recrystallizes and decolourizes molten
Agent), it dissolves by heating, filters while hot, filtrate is cooled to 0-5 DEG C and crystallizes 4 hours, filters, and it is dry, obtain 22.5 grams of light yellow solid 2-
Amino -5- aminomethyl-pyridine (IV), liquid phase purity 99.5%, product yield 90.7%.
The preparation of embodiment 2:2- amino -5- aminomethyl-pyridine (IV)
Into 250 milliliters of stainless steel pressure kettles, 15.5 grams of (0.2 mole) maleonitriles of addition, 0.6 gram of DBN, 25.0 grams
(0.41 mole) nitromethane, 120 DEG C are stirred to react 4 hours, are subsequently cooled to 20-25 DEG C, and 150 grams of first are added into autoclave pressure
Alcoholic solvent, 15.0 grams of ammonium chlorides, 15.0 grams of water, 3.0 gram of 50% raney nickel catalyst are passed through hydrogen after nitrogen displacement three times, protect
Holding Hydrogen Vapor Pressure is 0.2-0.3MPa, and 50-55 DEG C is reacted 5 hours.After nitrogen displacement three times, it is filtered to remove Raney Ni, filtrate is dense
Contracting is evaporated, and 100 grams of methyl tertiary butyl ether recrystallizations are added, obtain 21.7 grams of light yellow solid 2- amino -5- aminomethyl-pyridines (IV), liquid
Phase purity 99.2%, product yield 87.2%.
The preparation of embodiment 3:5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine (II)
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer and condenser pipe, 100 grams of 1,2- dichloroethanes are added,
25.0 grams are added dropwise between 30~35 DEG C for 12.5 grams of (0.1 mole) 2- amino -5- aminomethyl-pyridines (IV), 30.0 grams of potassium carbonate
(0.15 mole) N, the solution of N- Dichloroethyl ethamine and 20 grams of 1,2- dichloroethanes, drop finishes within about 2 hours, hereafter 30~35 DEG C it is anti-
It answers 6 hours.20~25 DEG C are cooled to, layering, water layer is extracted twice with 1,2- dichloroethanes, 20 grams every time, is merged organic phase, is steamed
Evaporate recycling 1,2- dichloroethanes is added 75 grams of methyl tertiary butyl ethers into residue, 0.5 gram of active carbon, stirs at 80~82 DEG C de-
It color 1 hour, filters while hot, filtrate is cooled to 0-5 DEG C of crystallization, filters, and it is dry, obtain 18.2 grams of white solid 5- (4- ethyl piperazine
Piperazine -1- base) methyl-2-amino pyridine, yield 82.7%, liquid phase purity 99.3%.
The nuclear magnetic data of products therefrom is as follows:
1HNMR (400MHz, DMSO-d6) δ: 1.02 (3H, t), 2.25-2.50 (10H, m), 3.25 (2H, m), 4.96
(2H, s), 6.40 (1H, d), 7.25 (1H, m), 7.74 (1H, d).
The preparation of embodiment 4:5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine (II)
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer and condenser pipe, it is added 100 grams of methylene chloride, 12.5 grams
(0.1 mole) 2- amino -5- aminomethyl-pyridine (IV), 25.0 grams of sodium carbonate, being added dropwise 25.0 grams between 30~35 DEG C, (0.15 rubs
You) N, the solution of N- Dichloroethyl ethamine and 30 grams of methylene chloride, drop finishes within about 2 hours, hereafter reacts 4 hours for 35~40 DEG C.It is cold
But to 20~25 DEG C, layering, water layer is extracted with dichloromethane twice, 20 grams every time, is merged organic phase, is distilled to recover dichloromethane
75 grams of methyl tertiary butyl ethers are added into residue for alkane, and 0.5 gram of active carbon, stirring decoloration 1 hour, is filtered while hot at 80~82 DEG C,
Filtrate is cooled to 0-5 DEG C of crystallization, filters, dry, obtains 18.0 grams of white solid 5- (4- ethyl piperazidine -1- base) methyl -2- ammonia
Yl pyridines, yield 81.8%, liquid phase purity 99.5%.
The preparation of comparative example 1:5- nitro -4- nitromethyla -2,4- pentadiene nitrile (III)
To be connected to stirring, thermometer, reflux condensing tube and device for absorbing tail gas (ammonia that absorbing reaction generates) 500 millis
It rises in four-hole boiling flask, 78.0 grams of (1.0 moles) maleonitriles of addition, 2.0 grams of DBU, 122.0 grams of (2.0 moles) nitromethanes,
100 DEG C of return stirrings react 6 hours, are subsequently cooled to 60 DEG C, vacuum distillation (165-175 DEG C/5mmHg) obtains 93.6 grams of 5- nitre
Base -4- nitromethyla -2,4- pentadiene nitrile (III), yield 51.1%, gas phase purity 97.6%.
The preparation of comparative example 2:5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine (II)
Into 500 milliliters of four-hole boiling flasks for being connected to stirring, thermometer and condenser pipe, it is added 120 grams of methylene chloride, 12.5 grams
(0.1 mole) 2- amino -5- aminomethyl-pyridine (IV), 25.0 grams of sodium carbonate, 25.0 grams of (0.15 mole) N, N- Dichloroethyl second
Amine, 35~40 DEG C are reacted 4 hours.20~25 DEG C are cooled to, layering, water layer is extracted with dichloromethane twice, 20 grams every time, merges
Organic phase is distilled to recover methylene chloride, 75 grams of methyl tertiary butyl ethers of addition into residue, 0.5 gram of active carbon, stirs at 80~82 DEG C
Decoloration 1 hour to be mixed, is filtered while hot, filtrate is cooled to 0-5 DEG C of crystallization, filters, and it is dry, obtain 9.7 grams of faint yellow solid 5- (4- second
Base piperazine -1- base) methyl-2-amino pyridine, yield 44.1%, liquid phase purity 99.6%.
Claims (20)
1. a kind of preparation method of compound shown in formula II,
Ⅱ
Comprising steps of
(1) under base catalysis, 5- nitro -4- nitromethyla -2,4- pentadiene is made in maleonitrile and nitromethane condensation reaction
Nitrile (III)；
The base catalyst is selected from 11 carbon -7- alkene (DBU) of 1,8- diazabicylo, 1,5- diazabicyclo [4.3.0] -5- nonyl
One or a combination set of alkene (DBN)；
(2) in the presence of a hydrogenation catalyst, make 5- nitro -4- nitromethyla -2,4- pentadiene nitrile (III) through catalytic hydrogenating reduction
Nitro, while cyclisation obtains 2- amino -5- aminomethyl-pyridine (IV)；
(3) in a solvent, make 2- amino -5- aminomethyl-pyridine (IV) and N, N- Dichloroethyl the ethamine dehydrochlorination under alkali effect
5- (4- ethyl piperazidine -1- base) methyl-2-amino pyridine (II) is made in cyclic condensation.
2. the preparation method of II compound of formula as described in claim 1, it is characterised in that the dosage of alkali described in step (1) is
The 1-5% of maleonitrile quality；The molar ratio of the maleonitrile and nitromethane is 1:1 ~ 5.
3. the preparation method of II compound of formula as described in claim 1, it is characterised in that maleonitrile described in step (1) and
The molar ratio of nitromethane is 1:2 ~ 3.
4. the preparation method of II compound of formula as described in claim 1, it is characterised in that setting-up point is 80 in step (1)
~130℃。
5. the preparation method of II compound of formula as described in claim 1, it is characterised in that setting-up point is in step (1)
100~120℃。
6. the preparation method of II compound of formula as described in claim 1, it is characterised in that reaction described in step (2) is in alcoholic solvent
Middle progress.
7. the preparation method of II compound of formula as claimed in claim 6, which is characterized in that the alcoholic solvent is methanol.
8. the preparation method of II compound of formula as claimed in claim 6, it is characterised in that be also added in the reaction system
Ammonium chloride and water.
9. the preparation method of II compound of formula as described in claim 1, which is characterized in that hydrogenation catalyst described in step (2)
For palladium charcoal or Raney Ni；The palladium carbon catalyst dosage is 5- nitro -4- nitromethyla -2,4- pentadiene nitrile (III) quality
0.5%~5%；The raney nickel catalyst dosage is the 1% ~ 15% of 5- nitro -4- nitromethyla -2,4- pentadiene nitrile (III) quality.
10. the preparation method of II compound of formula as described in claim 1, which is characterized in that catalytic hydrogenation reaction in step (2)
Temperature is 20 ~ 80 DEG C, Hydrogen Vapor Pressure 0.1-0.5MPa.
11. the preparation method of II compound of formula as described in claim 1, which is characterized in that catalytic hydrogenation reaction in step (2)
Temperature is 40 ~ 65 DEG C, Hydrogen Vapor Pressure 0.15-0.4MPa.
12. the preparation method of II compound of formula as described in claim 1, which is characterized in that in step (3), the 2- amino-
The molar ratio of 5- aminomethyl-pyridine (IV) and N, N- Dichloroethyl ethamine is 1:1 ~ 4.
13. the preparation method of II compound of formula as described in claim 1, which is characterized in that in step (3), the 2- amino-
The molar ratio of 5- aminomethyl-pyridine (IV) and N, N- Dichloroethyl ethamine is 1:1.2 ~ 2.
14. the preparation method of II compound of formula as described in claim 1, which is characterized in that solvent described in step (3) is two
One or a combination set of chloromethanes, chloroform；The weight ratio of the solvent and 2- amino -5- aminomethyl-pyridine (IV) be (3 ~
15):1。
15. the preparation method of II compound of formula as described in claim 1, which is characterized in that the feed way in step (3) is,
By N, the mixed solution of N- Dichloroethyl ethamine and the solvent is added drop-wise in reaction system.
16. the preparation method of II compound of formula as described in claim 1, which is characterized in that step (3) alkali is alkali metal hydrogen
Oxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkaline-earth metal carbon
Sour hydrogen salt hydrogen.
17. the preparation method of II compound of formula as described in claim 1, which is characterized in that step (3) alkali be sodium carbonate,
Potassium carbonate, sodium bicarbonate or saleratus.
18. the preparation method of II compound of formula as described in claim 1, which is characterized in that in step (3), the base amount and
The molar ratio of 2- amino -5- aminomethyl-pyridine is 1-3:1.
19. the preparation method of II compound of formula as described in claim 1, which is characterized in that step (3) condensation reaction temperature
It is 20 ~ 80 DEG C.
20. the preparation method of II compound of formula as described in claim 1, which is characterized in that step (3) condensation reaction, first
In 30 ~ 35 DEG C of dropwise addition N, the mixed solution of N- Dichloroethyl ethamine and the solvent is added dropwise after finishing, then at 35 ~ 45 DEG C of reactions 2 ~ 4
Hour.
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