CN113636973B - Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester - Google Patents
Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester Download PDFInfo
- Publication number
- CN113636973B CN113636973B CN202111047083.6A CN202111047083A CN113636973B CN 113636973 B CN113636973 B CN 113636973B CN 202111047083 A CN202111047083 A CN 202111047083A CN 113636973 B CN113636973 B CN 113636973B
- Authority
- CN
- China
- Prior art keywords
- acid
- piperazine
- formula
- water
- organic solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- RMULRXHUNOVPEI-UHFFFAOYSA-N tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(N)N=C1 RMULRXHUNOVPEI-UHFFFAOYSA-N 0.000 title claims description 21
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000002253 acid Substances 0.000 claims abstract description 36
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000003960 organic solvent Substances 0.000 claims abstract description 21
- 239000011230 binding agent Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- ATXXLNCPVSUCNK-UHFFFAOYSA-N 5-bromo-2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Br)C=N1 ATXXLNCPVSUCNK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000009776 industrial production Methods 0.000 claims abstract description 8
- 239000012046 mixed solvent Substances 0.000 claims abstract description 7
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 239000012535 impurity Substances 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 27
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical group CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000000047 product Substances 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 8
- 239000001632 sodium acetate Substances 0.000 claims description 8
- 235000017281 sodium acetate Nutrition 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 238000010533 azeotropic distillation Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical group [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 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
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 235000011054 acetic acid Nutrition 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 238000005119 centrifugation Methods 0.000 claims description 3
- 239000010410 layer Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 230000001502 supplementing effect Effects 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 238000011084 recovery Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- -1 6-aminopyridine-3-yl Chemical group 0.000 abstract description 22
- UBCDLQPOKISIDX-UHFFFAOYSA-N 1-(6-nitropyridin-3-yl)piperazine Chemical compound C1=NC([N+](=O)[O-])=CC=C1N1CCNCC1 UBCDLQPOKISIDX-UHFFFAOYSA-N 0.000 abstract description 10
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract description 3
- 238000007670 refining Methods 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 230000007613 environmental effect Effects 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 230000009286 beneficial effect Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 5
- 229960004390 palbociclib Drugs 0.000 description 5
- SUWKOEMQNOBJEQ-UHFFFAOYSA-N tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C([N+]([O-])=O)N=C1 SUWKOEMQNOBJEQ-UHFFFAOYSA-N 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 108091007914 CDKs Proteins 0.000 description 3
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 3
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- YXVDXGVAUQKDPH-UHFFFAOYSA-N 1-(6-nitropyridin-3-yl)piperazine;hydrochloride Chemical compound Cl.C1=NC([N+](=O)[O-])=CC=C1N1CCNCC1 YXVDXGVAUQKDPH-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 238000007256 debromination reaction Methods 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YUBHMOQVHOODEI-UHFFFAOYSA-N 5-chloro-2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=N1 YUBHMOQVHOODEI-UHFFFAOYSA-N 0.000 description 1
- YYNLTCJAHPHRPI-UHFFFAOYSA-N 6-acetyl-8-cyclopentyl-5-methyl-2-[phenyl(piperidin-4-yl)methyl]pyrido[2,3-d]pyrimidin-7-one Chemical compound CC1=C(C(=O)N(C2=NC(=NC=C12)C(C3CCNCC3)C4=CC=CC=C4)C5CCCC5)C(=O)C YYNLTCJAHPHRPI-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- YROXEBCFDJQGOH-UHFFFAOYSA-N ditert-butyl piperazine-1,4-dicarboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)CC1 YROXEBCFDJQGOH-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000007674 genetic toxicity Effects 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 231100000734 genotoxic potential Toxicity 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000005748 halopyridines Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000002351 wastewater Substances 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
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses an industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-tert-butyl carboxylate, which adopts 5-bromo-2-nitropyridine and piperazine as starting materials, prepares high-purity 1- (6-nitropyridine-3-yl) piperazine through nucleophilic substitution reaction by using acid as a catalyst in a mixed solvent of an alcohol organic solvent and water, prepares high-purity 4- (6-nitropyridine-3-yl) piperazine-1-tert-butyl carboxylate by using weak base as an acid-binding agent in the presence of an organic solvent and water together with Boc anhydride, and obtains the high-purity and light-color 4- (6-aminopyridine-3-yl) piperazine-1-tert-butyl carboxylate through catalytic hydrogenation and refining decoloration. The method has the advantages of simple operation, little environmental pollution, high yield, low cost and good product quality, and is more suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to an industrial preparation method of 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester.
Background
The Palbociclib (Palbociclib), the chemical name of which is 2- [ (4-piperidyl) benzyl ] -6-acetyl-8-cyclopentyl-5-methylpyridino [2,3-d ] pyrimidin-7 (8H) -one, is developed by the company Perey, is approved to be on the market in the United states before 2 months in 2015, is an inhibitor of cyclin-dependent kinases (CDKs) 4 and 6, prevents cells from a G1 phase to an S phase by mainly regulating the cell cycle and inhibiting the activities of the (CDKs) 4 and 6 to further inhibit the DNA synthesis, and is mainly clinically used for treating patients with advanced breast cancer.
Tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate (formula (1)) is a key intermediate for the synthesis of palbociclib, has a CAS number of 571188-59-5 and a structural formula:
the literature reports that the synthesis method of the 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester mainly comprises the following two methods:
the method comprises the following steps: imaeda, yasuhiro et al (Bioorganic & Medicinal Chemistry,16 (6), 3125-3140, 2008) used 5-bromo-2-nitropyridine to react with 1-Boc-piperazine in N-methylpyrrolidinone to give tert-butyl 4- (6-nitropyridin-3-yl) piperazine-1-carboxylate, followed by catalytic hydrogenation of the nitro group with palladium on carbon in ethanol to give the target product, the reaction scheme is as follows:
the synthetic method has the advantages of short route and high yield, but the reaction cost is high because the prepared 1-Boc-piperazine (piperazine reacts with Boc anhydride) has low yield, high Boc anhydride has low utilization rate and more three wastes, and is not beneficial to environmental protection requirements, so that the 1-Boc-piperazine is high in price, contains a large amount of di-Boc-piperazine and has low purity.
The second method comprises the following steps: JV Carlinib et al reported in Chinese patent CN105384741B that 5-chloro-2-nitropyridine first reacts with piperazine in n-butanol through nucleophilic substitution reaction to obtain 1- (6-nitropyridine-3-yl) piperazine hydrochloride, then reacts with Boc anhydride in tetrahydrofuran with potassium carbonate as an acid-binding agent, and then undergoes catalytic reduction to obtain 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester, wherein the reaction route is as follows:
this route is a procedure for the preparation of 1- (6-nitropyridin-3-yl) piperazine hydrochloride, which, although giving a yield of 82.3% and a melting point range (mp > 230 ℃), is prone to potential side reactions with bimolecular halopyridines at the piperazine ends under alkaline conditions, generating bimolecular condensation by-products (Tetrahedron Letters 39 (1998) 617-620).
In the actual preparation process, we observed 2 piperazine disubstituted impurities, impurity formula (4) and impurity formula (5), the reaction route is as follows:
although the impurity formula (4) and the impurity formula (5) do not react with Boc piperazine, the solubility of the impurity formula (4) and the impurity formula (5) in n-butanol and water is low, and the impurity formula (4) and the impurity formula (5) are mostly removed by the filtration of step 2 in patent CN105384741B, but are carried into 4- (6-nitropyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester due to certain solubility in tetrahydrofuran, and derivatives of the impurity formula (6) and the impurity formula (7) are obtained by hydrogenation reduction:
both the impurity formula (6) and the impurity formula (7) are difficult to remove from tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate, and thus a high-purity product cannot be obtained.
In the process of researching palladium-carbon catalytic reduction of nitro, a trace amount of impurity shown in formula (5) is found, and in the process of palladium-carbon reduction, a debromination reaction occurs to generate a trace amount of hydrobromic acid, so that Boc group of tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate is promoted to be hydrolyzed to generate a series of impurities, wherein the impurities comprise impurities with potential genotoxicity, and the quality of a product is further influenced.
In addition, the color of the 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester reported in the literature is a brown yellow solid, and no white to off-white solid is reported. However, as an enterprise mainly comprising pharmaceutical raw material drugs and intermediates, customers put forward the requirements of light yellow solid to us.
The dosage of the palbociclib serving as a heavy bomb grade new drug is large, and the dosage of the key intermediate, namely the 4- (6-amino-3-pyridyl) piperazine-1-carboxylic acid tert-butyl ester is increased year by year. With the increasing awareness of pharmaceutical and chemical enterprises on environmental protection year by year, and in order to meet the requirements of customers pursuing high-quality products, the problem to be solved currently is to develop a synthetic method of 4- (6-aminopyridine-3-yl) piperazine-1-tert-butyl carboxylate, which has low cost, high yield, high purity, low toxicity and environmental friendliness.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an industrial preparation method of 4- (6-aminopyridin-3-yl) piperazine-1-tert-butyl carboxylate, which adopts 5-bromo-2-nitropyridine and piperazine as starting materials, takes acid as a catalyst in a mixed solvent of n-butyl alcohol and water to prepare high-purity 1- (6-nitropyridine-3-yl) piperazine through nucleophilic substitution reaction, then reacts with Boc anhydride in the presence of an organic solvent and water and takes weak base as an acid-binding agent to prepare high-purity 4- (6-nitropyridine-3-yl) piperazine-1-tert-butyl carboxylate, and then the high-purity and light-color 4- (6-aminopyridin-3-yl) piperazine-1-tert-butyl carboxylate is obtained through catalytic hydrogenation and refining decoloration. The method has the advantages of simple operation, little environmental pollution, high yield, low cost and good product quality, and is more suitable for industrial production.
The technical scheme of the invention is as follows: an industrial preparation method of 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester is characterized by comprising the following steps:
s1: in a mixed solvent of an alcohol organic solvent and water, using acid as a catalyst, reacting 5-bromo-2-nitropyridine with piperazine to generate an acid salt of a compound shown in a formula (2), adding water after the reaction is finished, recovering the solvent through azeotropic distillation to obtain an aqueous solution containing the acid salt of the compound shown in the formula (2), removing insoluble impurities through filtration, adjusting the pH value to be more than 10 with alkali, and centrifuging to obtain a high-purity wet product of the compound shown in the formula (2);
s2: reacting a wet product of the compound shown in the formula (2) with Boc anhydride in a mixed solvent of an organic solvent and water in the presence of an acid-binding agent, and carrying out aftertreatment on a reaction liquid to obtain a compound shown in the formula (3);
s3: the compound of the formula (3) is subjected to catalytic hydrogenation in a polar solvent in the presence of a catalyst and an acid-binding agent, and a crude product of the compound of the formula (1) is generated after the post-treatment;
s4: adding the crude product of the compound shown in the formula (1) into water, adding acid to dissolve the solid, decoloring with activated carbon, adjusting pH to be alkaline with sodium hydroxide solution, and performing crystallization, centrifugation, washing and drying to obtain the 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester with high purity (more than or equal to 99.8%) and white to light yellow color.
The synthetic route is as follows:
wherein,
the acid in step S1 is one or a mixture of two of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, and the like, preferably hydrobromic acid, and the molar ratio of the acid to piperazine used is 0.5 to 1.5, more preferably 1:1. One end of the amino group of piperazine is protected by the way that piperazine is a mono-acid salt, so that the generation of a bipiperazine substitution product is prevented.
The alcohol organic solvent in the step S1 is one of n-butyl alcohol, n-amyl alcohol, isoamyl alcohol, tertiary butyl alcohol, sec-butyl alcohol and 1-propanol, and preferably n-butyl alcohol; the ratio thereof to water is 10 (V/V) from 0.3 to 5, preferably 10.
The molar ratio of 5-bromo-2-nitropyridine to piperazine in step S1 is 1.2 to 2, preferably 1.2. The amount of piperazine is increased, which is beneficial to the generation of mono-substituted products of piperazine and the reduction of di-substituted products of piperazine, but from the viewpoint of environmental protection, the amount of piperazine is reduced as much as possible on the premise of not influencing the reaction result, which is beneficial to the treatment of three wastes and the requirement of environmental protection.
The reaction temperature in step S1 is 50 to 100 ℃ and preferably 60 to 65 ℃.
And (2) recovering the solvent azeotropically in the step (S1), obtaining a mixture of the solvent and water through azeotropic distillation in a mode of supplementing water in batches, separating out the organic solvent and the water through liquid separation, wherein the organic solvent is directly used for the next batch of reaction, and the water is used for the azeotropic distillation of the materials in the next batch, so that zero emission of the solvent is realized.
In the step S1, dimeric impurities of the formula (4) and the formula (5) are removed by filtration, and then the mixture is adjusted to be alkaline by alkali to obtain a high-purity compound of the formula (2).
The piperazine disubstituted impurities generated in the reaction process, namely the two impurities shown in the formula (4) and the formula (5), are slightly dissolved in an organic solvent under an acidic condition and are insoluble in water. The method comprises the steps of replacing reaction liquid with water by adopting an azeotropic organic solvent removal mode, dissolving intermediate formula (2) acid salt in water, directly removing a small amount of piperazine disubstituted impurities through filtration, adjusting the pH value of the reaction liquid to be more than 10 by adopting the characteristic that a compound of formula (2) has low solubility in strong alkali, separating out intermediate formula (2), obtaining an intermediate formula (2) wet product through centrifugation, and directly carrying out next reaction without drying.
The acid-binding agent in the step S2 is one of sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, sodium acetate, sodium hydroxide and potassium hydroxide, preferably sodium carbonate, and the molar ratio of the compound in the formula (2) to the acid-binding agent and Boc anhydride is 1.2-1.8.
The organic solvent in step S2 is one of dichloromethane, chloroform, toluene, tetrahydrofuran and dioxane, preferably toluene and dichloromethane.
The post-processing in step S2 is: heating until the solid is dissolved, standing for liquid separation, separating out an aqueous layer, washing an organic layer, concentrating under reduced pressure, and recrystallizing.
The catalyst in the step S3 is one of palladium carbon, platinum carbon and raney nickel, preferably platinum carbon, and the mass ratio of the compound of formula (3) to the catalyst is 1.
The acid-binding agent in step S3 is one of sodium acetate, potassium acetate, triethylamine, ammonia water, sodium carbonate and sodium bicarbonate, preferably sodium acetate. The molar ratio of the compound of the formula (3) to the acid-binding agent is 1:0.01 to 0.1, preferably 1. Catalytic hydrogenation reduction of nitro, debromination reaction of trace impurity of formula (5), dissolving generated hydrogen bromide in water generated by hydrogenation reduction, leading reaction liquid to have certain acidity, leading Boc group to have trace degradation, leading to generation of a plurality of trace impurities in compound of formula (1), wherein the trace impurities comprise impurities with genetic toxicity warning structures. And a small amount of acid binding agent is added to neutralize generated hydrobromic acid so as to prevent degradation of Boc groups, and the purity and quality of the product are improved.
The polar solvent in step S3 is one of methanol, ethanol, isopropanol, and n-butanol, preferably methanol. The methanol is more beneficial to recovery and treatment, the economic cost is lower, and meanwhile, the methanol also has certain solubility on the acid-binding agent sodium acetate.
The reaction temperature in step S3 is 10 to 60 ℃ and preferably 10 to 30 ℃.
The post-processing of step S3 is: filtering, concentrating the filtrate under reduced pressure to dryness, and recrystallizing with n-heptane.
The acid in step S4 is one of acetic acid, formic acid, citric acid, oxalic acid and propionic acid, preferably acetic acid.
The invention has the technical characteristics and beneficial effects that:
1. the invention uses 5-bromo-2-nitropyridine and piperazine, uses organic solvent such as n-butyl alcohol and water as mixed solvent, uses hydrobromic acid and the like as catalyst to prepare acid salt of 1- (6-nitropyridin-3-yl) piperazine, realizes the recycling of the solvent through azeotropic distillation, removes the generated micro-piperazine double substitution through filtration, and obtains high-purity 1- (6-nitropyridin-3-yl) piperazine (formula (2)) through alkali adjustment. The reaction condition of the step is mild, the post-treatment is simple, the product does not need to be dried, the quality is good, the yield is high, and the material feeding is directly carried out according to 100 percent. The organic solvent can be repeatedly used, and the wastewater is inorganic salt, is easy to treat and is more suitable for industrial production.
2. According to the invention, a 1- (6-nitropyridin-3-yl) piperazine wet product is directly adopted to react with Boc anhydride in a two-phase system, inorganic substances are removed through liquid separation and washing, reduced pressure distillation and recrystallization are carried out to obtain high-purity 4- (6-nitropyridin-3-yl) piperazine-1-tert-butyl carboxylate (formula (3)), and the evaporated organic solvent can be directly recycled and reused.
3. The invention prepares the 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (formula (1)) by adding an acid-binding agent such as sodium acetate and adopting cheaper platinum carbon and the like as a catalyst to carry out hydrogenation reduction on nitro. The addition of the acid-binding agent prevents the degradation of Boc group, prevents the generation of potential genotoxic impurities, improves the safety of the product and further improves the safety of the palbociclib.
4. The invention creatively removes macromolecular groups influencing the color by the characteristic that the 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester is dissolved in weak acid and adopting an activated carbon decoloring mode, and obtains the high-purity and light-color 4- (6-amino-3-pyridyl) piperazine-1-carboxylic acid tert-butyl ester by adjusting alkali.
In sum, the invention provides a preparation method which is suitable for industrial production and has high quality, low cost, environmental friendliness, high yield (more than or equal to 85 percent) and high purity (the purity can reach 99.9 percent) for synthesizing the 4- (6-aminopyridin-3-yl) piperazine-1-tert-butyl carboxylate.
Detailed Description
The present invention will be further described with reference to specific examples so that those skilled in the art may better understand the present invention, but the present invention is not limited thereto.
Example 1: laboratory preparation of 1- (6-nitropyridin-3-yl) piperazine (compound of formula (2))
In a 2000ml reaction flask, 101.5g (0.5 mol) of 5-bromo-2-nitropyridine, 51.6g (0.6 mol) of anhydrous piperazine, 1000ml of n-butanol, 100ml of water and 100g of hydrobromic acid (48%) are added, and the reaction is stirred for 24 hours at a controlled temperature of 60 to 65 ℃. After the reaction, 300ml of water is added, reduced pressure distillation is carried out, 1200ml of water is supplemented in a stage supplementing mode, and distillation is carried out until distillate becomes clear. Insoluble solids were removed by filtration and the mother liquor was adjusted to pH12 with 30% sodium hydroxide to precipitate a bright yellow solid. Filtering, collecting solid to obtain 1- (6-nitro-3-pyridyl) piperazine wet product, calculating the yield by 100%, directly putting into the next step for reaction, and the HPLC purity is more than or equal to 99.5%.
Example 2: laboratory preparation of 4- (6-nitropyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (compound of formula (3))
And (2) adding all the prepared 1- (6-nitropyridin-3-yl) piperazine wet product, 1000ml of toluene, 500ml of water and 79.5g (0.75 mol) of sodium carbonate into a 2000ml reaction bottle, controlling the reaction temperature to be 10-30 ℃, slowly adding 131g (0.6 mol) of Boc anhydride, continuing the reaction for 1h after the addition is finished, and detecting by TLC until the raw materials disappear. After the reaction is finished, heating to 95 ℃, standing and separating liquid after the solid is dissolved, separating a water layer, adding 500ml of water into an organic layer, keeping the temperature at 90-95 ℃, washing once, evaporating about 500ml of toluene under reduced pressure, cooling to 0-10 ℃, stirring, crystallizing, filtering, and drying to obtain 142g of bright yellow solid, wherein the yield of the two steps is 92.2%, and the purity is 99.8% (HPLC).
Example 3: industrial preparation of 1- (6-nitropyridin-3-yl) piperazine (compound of formula (2))
1000L of n-butanol, 100kg of water, 100kg of hydrobromic acid (48%), 101.5kg of 5-bromo-2-nitropyridine and 51.6kg of anhydrous piperazine are sequentially added into a 2000L glass lining reaction kettle, and stirred and reacted for 24 hours at the temperature of 60-65 ℃. After the reaction, 300kg of purified water was added, the distillation was carried out under reduced pressure, 1200kg of purified water was further supplemented, and the distillation was stopped after the distillate was observed to be no longer turbid. Filter-pressing by adopting a bag filter, washing by 50kg of water, adjusting the pH value of filtrate to 12 by using 30% sodium hydroxide, cooling to 0-10 ℃, centrifuging to obtain 135kg (wet weight) of bright yellow solid, wherein the HPLC purity is 99.7%, and directly putting the bright yellow solid into the next step for reaction according to 100%.
Example 4: industrial preparation of 4- (6-nitropyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (compound of formula (3))
1000L of dichloromethane, 500kg of water, 80kg of sodium carbonate and 135kg of the wet 1- (6-nitropyridine-3-yl) piperazine product prepared in the previous step are sequentially added into a 2000L stainless steel reaction kettle, the temperature is reduced to 10 ℃, 131kg of Boc anhydride is slowly added, the reaction is continued for 1h after the addition is finished, and the reaction end point is controlled by TLC. After the reaction, the mixture was allowed to stand for layering, the organic layer was washed once with 500kg of water, methylene chloride was recovered by atmospheric distillation, and the residual solvent was distilled under reduced pressure. Adding 500L of toluene, heating until the solid is dissolved, cooling to 0-10 ℃, stirring, crystallizing, centrifuging, and drying to obtain 145kg of bright yellow solid, wherein the yield of the two steps is 94.2%, and the purity is 99.9% (HPLC).
Example 5: industrial production of tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate (Compound of formula (1))
Into a 2000L autoclave, 1000L of anhydrous methanol, 145kg of tert-butyl 4- (6-nitropyridin-3-yl) piperazine-1-carboxylate and 0.77kg of sodium acetate were charged, and the mixture was replaced with nitrogen gas 3 times, and 5kg of platinum carbon was dispersed in 100L of methanol and charged into the autoclave. The nitrogen is replaced three times, and hydrogen is introduced for reaction for 3 hours. Filter pressing, washing with 100L of methanol, collecting platinum carbon, recycling, concentrating the filtrate under reduced pressure to dryness, adding 1000L of n-heptane, cooling to room temperature, stirring for crystallization, centrifuging, washing with n-heptane, and drying to obtain 126kg of brown solid with yield of 96.3% and purity of 99.7%.
2000kg of water, 126kg of crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate and 30kg of acetic acid were added to a 3000L reaction kettle, and stirred at room temperature until the solid was dissolved, 3kg of activated carbon (Japanese aigret) was added thereto, and the mixture was further stirred for 1 hour, filtered and washed with 100kg of water. Adjusting the pH value of the mother liquor to 10 by using 10 percent sodium hydroxide, cooling to 0-10 ℃ for crystallization for 2h, centrifuging, washing with water, and drying to obtain 122kg of off-white solid, wherein the refining yield is 96.8 percent, and the purity is 99.9 percent (HPLC).
Claims (7)
1. An industrial preparation method of 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester is characterized by comprising the following steps:
s1: in a mixed solvent of an alcohol organic solvent and water, using acid as a catalyst, reacting 5-bromo-2-nitropyridine with piperazine to generate an acid salt of a compound shown in a formula (2), adding water after the reaction is finished, recovering the solvent through azeotropic distillation to obtain an aqueous solution containing the acid salt of the compound shown in the formula (2), removing insoluble impurities through filtration, adjusting the pH value to be more than 10 with alkali, and centrifuging to obtain a high-purity wet product of the compound shown in the formula (2); the reaction temperature is 60-65 ℃; the acid is hydrobromic acid; the alcohol organic solvent is n-butyl alcohol, and the volume ratio of the alcohol organic solvent to water is 10.3-5; the molar ratio of the 5-bromo-2-nitropyridine to the piperazine is 1.2;
s2: reacting a wet product of the compound of the formula (2) with Boc anhydride in a mixed solvent of an organic solvent and water in the presence of an acid-binding agent, and carrying out aftertreatment on a reaction liquid to obtain a compound of the formula (3); the organic solvent is dichloromethane or toluene;
s3: carrying out catalytic hydrogenation on the compound of the formula (3) in a polar solvent in the presence of a catalyst and an acid-binding agent, and carrying out aftertreatment to generate a crude product of the 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester; the catalyst is platinum carbon; the acid-binding agent is sodium acetate; the polar solvent is methanol;
s4: adding the crude product into water, adding acid to dissolve the solid, decoloring the solid by using activated carbon, adjusting the pH value to be alkaline by using an alkali solution, and performing crystallization, centrifugation, washing and drying to obtain a pure 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester product;
the structural formulas of the compound of the formula (2) and the compound of the formula (3) are as follows:
2. the industrial process according to claim 1, wherein in step S1,
the azeotropic recovery of the solvent is carried out in a mode of supplementing water in batches, a mixture of the solvent and water is obtained by azeotropic distillation, the organic solvent and water are separated by liquid separation, the organic solvent is directly used for the next batch of reaction, and the water is used for the azeotropic distillation of the materials in the next batch.
3. The industrial process according to claim 1, wherein in step S2,
the acid-binding agent is one of sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, sodium acetate, sodium hydroxide and potassium hydroxide.
4. The industrial production method according to claim 1, wherein the post-treatment in step S2 is: heating until the solid is dissolved, standing for liquid separation, separating out an aqueous layer, washing an organic layer, concentrating under reduced pressure, and recrystallizing.
5. The industrial production method according to claim 1, wherein the reaction temperature in the step S3 is 10 to 60 ℃.
6. The industrial process according to claim 1, wherein the post-treatment of step S3 is: filtering, concentrating the filtrate under reduced pressure to dryness, and recrystallizing with n-heptane.
7. The industrial production method according to any one of claims 1 to 6, wherein the acid in the step S4 is one of acetic acid, formic acid, citric acid, oxalic acid and propionic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111047083.6A CN113636973B (en) | 2021-09-07 | 2021-09-07 | Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111047083.6A CN113636973B (en) | 2021-09-07 | 2021-09-07 | Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113636973A CN113636973A (en) | 2021-11-12 |
| CN113636973B true CN113636973B (en) | 2023-04-07 |
Family
ID=78425280
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111047083.6A Active CN113636973B (en) | 2021-09-07 | 2021-09-07 | Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113636973B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724078B (en) * | 2021-01-13 | 2022-10-18 | 山东邹平大展新材料有限公司 | Method for removing impurities of piparide intermediate |
| CN114805194B (en) * | 2022-06-29 | 2022-09-20 | 南京威凯尔生物医药科技有限公司 | Continuous hydrogenation method of 2-nitropyridine derivative and application thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101671297B (en) * | 2008-09-11 | 2012-05-09 | 上海药明康德新药开发有限公司 | Method for synthesizing 4-(3-iodo-2-pyridinyl) piperazine compound |
| NZ602362A (en) * | 2010-03-11 | 2014-11-28 | Gilead Connecticut Inc | Imidazopyridines syk inhibitors |
| US20120115878A1 (en) * | 2010-11-10 | 2012-05-10 | John Vincent Calienni | Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof |
| CN108026030B (en) * | 2015-09-18 | 2020-10-09 | 正大天晴药业集团股份有限公司 | Preparation method of deuterated compound |
| CN108290899B (en) * | 2016-06-06 | 2020-09-18 | 深圳市塔吉瑞生物医药有限公司 | Substituted pyrrolopyrimidine compound and application thereof |
| AU2017364807B2 (en) * | 2016-11-28 | 2021-05-13 | Teijin Limited | Pyrido[3, 4-d]pyrimidine derivative and pharmaceutically acceptable salt thereof |
| CN109369517A (en) * | 2018-10-24 | 2019-02-22 | 郑传花 | A kind of preparation method for treating breast cancer medicines intermediate |
-
2021
- 2021-09-07 CN CN202111047083.6A patent/CN113636973B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN113636973A (en) | 2021-11-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113636973B (en) | Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester | |
| WO2013049605A1 (en) | Processes for the preparation of an intermediate in the synthesis of eltrombopag | |
| CN107793418A (en) | Industrial production method of tofacitinib citrate | |
| CN111470983B (en) | Preparation method of bromhexine hydrochloride | |
| CN112062767B (en) | Preparation method and intermediate of rumepilone | |
| CN112062726B (en) | Preparation method of 2-amino-4, 6-dichloro-5-formamido pyrimidine | |
| CN105440034A (en) | Preparation method of linagliptin and intermediate thereof | |
| EP2131843B1 (en) | Process for the synthesis of glyt-1 inhibitors | |
| CN115960059A (en) | Method for synthesizing furosemide impurity D with high yield and high purity | |
| CN113278021B (en) | Preparation method of 1, 7-diazaspiro [3.5] nonane-7-tert-butyl formate and oxalate thereof | |
| CN111646991B (en) | Preparation method of avibactam sodium intermediate | |
| JP6947354B2 (en) | How to make linagliptin | |
| CN110483388B (en) | Preparation method of nicotinic acid derivative | |
| KR101485418B1 (en) | A synthetic method of high purity mirtazapine | |
| CN111574463A (en) | Riagliptin intermediate compound IV | |
| CN111233864B (en) | Method for industrially producing doxofylline | |
| CN112176011B (en) | Method for preparing valaciclovir hydrochloride through enzyme catalysis | |
| CN111606929B (en) | Preparation method of Degatinib | |
| CN117843620B (en) | Purification preparation method of voronoi fumarate | |
| CN115894525B (en) | Lornoxicam Synthesis method of intermediate | |
| CN113773323B (en) | Preparation method of 3R-amino substituted butyramide derivative | |
| CN109896967B (en) | Preparation method of m-diethylaminophenol | |
| CN118126029A (en) | Preparation method of piribedil | |
| CN118125995A (en) | Synthesis method of 1- (2-methoxyphenyl) piperazine hydrochloride | |
| CN115974726A (en) | Method for separating metformin hydrochloride crude product |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 251400 No. 12, Taixing East Street, Jibei Economic Development Zone, Jiyang District, Jinan City, Shandong Province Applicant after: Shandong Baoyuan Pharmaceutical Co.,Ltd. Address before: Strong in Jiyang County of Ji'nan City, 251400 North Street, Shandong Province Economic Development Zone Applicant before: SHANDONG BOYUAN PHARMACEUTICAL Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |