CN105859728B - A kind of preparation method that Buddhist nun is replaced according to Shandong - Google Patents
A kind of preparation method that Buddhist nun is replaced according to Shandong Download PDFInfo
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- CN105859728B CN105859728B CN201610365263.1A CN201610365263A CN105859728B CN 105859728 B CN105859728 B CN 105859728B CN 201610365263 A CN201610365263 A CN 201610365263A CN 105859728 B CN105859728 B CN 105859728B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 81
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000006751 Mitsunobu reaction Methods 0.000 claims abstract description 7
- 230000002140 halogenating effect Effects 0.000 claims abstract description 7
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 5
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 4
- 238000011938 amidation process Methods 0.000 claims abstract description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 34
- -1 propylene carboxylic acid Chemical class 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 12
- 230000009435 amidation Effects 0.000 claims description 12
- 238000007112 amidation reaction Methods 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- PRAYXGYYVXRDDW-LURJTMIESA-N [(2s)-piperidin-2-yl]methanol Chemical class OC[C@@H]1CCCCN1 PRAYXGYYVXRDDW-LURJTMIESA-N 0.000 claims description 8
- 239000007821 HATU Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 238000010511 deprotection reaction Methods 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- 239000007818 Grignard reagent Substances 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- 150000004795 grignard reagents Chemical class 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 229940126214 compound 3 Drugs 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 239000005055 methyl trichlorosilane Substances 0.000 claims description 3
- JLUFWMXJHAVVNN-UHFFFAOYSA-N methyltrichlorosilane Chemical compound C[Si](Cl)(Cl)Cl JLUFWMXJHAVVNN-UHFFFAOYSA-N 0.000 claims description 3
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 238000006073 displacement reaction Methods 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- YMJLEPMVGQBLHL-UHFFFAOYSA-N 1h-pyrazole-5-carbonitrile Chemical compound N#CC1=CC=NN1 YMJLEPMVGQBLHL-UHFFFAOYSA-N 0.000 claims 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical class BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims 1
- 239000012964 benzotriazole Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 21
- FFNKBQRKZRMYCL-UHFFFAOYSA-N 5-amino-1h-pyrazole-4-carbonitrile Chemical compound NC1=NNC=C1C#N FFNKBQRKZRMYCL-UHFFFAOYSA-N 0.000 abstract description 7
- 239000006227 byproduct Substances 0.000 abstract description 6
- 239000000047 product Substances 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 5
- 239000007858 starting material Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 description 80
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000012043 crude product Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 241000238370 Sepia Species 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 238000009413 insulation Methods 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 3
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 3
- 229960001507 ibrutinib Drugs 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 description 2
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical group OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- AQSCHALQLXXKKC-UHFFFAOYSA-N 4-phenylmethoxybenzoic acid Chemical class C1=CC(C(=O)O)=CC=C1OCC1=CC=CC=C1 AQSCHALQLXXKKC-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 150000001470 diamides Chemical class 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- KADXVMRYQRCLAH-UHFFFAOYSA-N n'-iodobutanediamide Chemical class NC(=O)CCC(=O)NI KADXVMRYQRCLAH-UHFFFAOYSA-N 0.000 description 1
- QCCWVNLOJADEAV-UHFFFAOYSA-N n,n-dimethyl-1h-pyrrol-3-amine Chemical class CN(C)C=1C=CNC=1 QCCWVNLOJADEAV-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229960003347 obinutuzumab Drugs 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/12—Organo silicon halides
- C07F7/121—Preparation or treatment not provided for in C07F7/14, C07F7/16 or C07F7/20
- C07F7/122—Preparation or treatment not provided for in C07F7/14, C07F7/16 or C07F7/20 by reactions involving the formation of Si-C linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of preparation methods that Buddhist nun is replaced according to Shandong, belong to technical field of medicine synthesis.Preparation method is specially：3 amino, 4 cyano pyrazole and Formamidine acetate are starting material, obtain replacing Buddhist nun according to Shandong through ring-closure reaction, halogenating reaction, nucleophilic substitution, Mitsunobu reactions, amidation process.This method raw material is easy to get, mild condition, technological operation and controllability is strong, at low cost, high income, by-product are easy to purifying and obtain high-quality product less.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of synthetic method of Buddhist nun is replaced according to Shandong.
Background technology
It is chemical entitled according to Shandong for Buddhist nun (English name Ibrutinib, trade (brand) name IMBRUVICA)：1- [3 (R)-[4- amino -3-
(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases] -1- piperidyls] -2- propylene -1- ketone.The medicine is by the U.S.
Johnson＆Johnson presses down with the bruton's tyrosine kinase (BTK) that Pharmacyclics Inc. companies of the U.S. research and develop jointly
Preparation.It is second new drug (first is obinutuzumab) through the breakthrough drug channel approvals of FDA, while also enjoys
The administrative protection of 7 years after other two buff of FDA and listing.On November 13rd, 2013, Food and Drug Adminstration of the US
(FDA) treatments of the Imbruvica (Ibrutinib- replaces Buddhist nun according to Shandong) available for lymphoma mantle cell (MCL) is had approved.MCL is one
The rare non-Hodgkin lymphoma of kind, 6% is about accounted in all non-Hodgkin lymphoma cases in the U.S..Usually it is diagnosed as
During MCL, cancer cell has diffused to lymph node, marrow and other organs.Its structure is shown below.
At present, have according to Shandong for the synthetic method main literature and patent of Buddhist nun：chemMedChem.2007,2(1):58-61,
Patent CN1031211999, patent CN103626774, patent CN104557945A, patent WO2014022390 and
WO2012158795.Its primary synthetic methods is as follows：
Document：chemMedChem.2007,2(1):Raw material 4- benzyloxybenzoic acids are used in 58-61 as starting material,
Acyl chlorides is obtained through acylated, intermediate 7, intermediate 7 and TMSCH is obtained by the reaction with malononitrile in acyl chlorides2N2Intermediate 8 is obtained by the reaction, in
Mesosome 8 and hydrazine hydrate ring closure reaction obtain intermediate 9, and intermediate 4,4 He of intermediate is obtained by the reaction in methylamine high temperature in intermediate 9
Deprotection obtains intermediate 5 after piperidine alcohols carry out Mitsunobu reactions, and last intermediate 5 obtains mesh with acryloyl chloride amidation
It marks product and replaces Buddhist nun according to Shandong.The route reaction temperature is high, is also easy to produce a large amount of by-products, total recovery is low, it is difficult to realize industrialized production
It is required that.
Patent WO2012158795 is similar with patent WO2014022390 synthetic methods, with raw material 1H- pyrazolos [3,4-
D] pyrimidine -4- amine be starting material, carry out iodide reaction with N- iodosuccinamides and obtain intermediate 2, intermediate 2 and piperidine alcohols
It carries out substitution reaction and obtains intermediate 11, intermediate 11 is with raw material 12 in 1,1'- bis- (diphenyl phosphine) ferrocene palladium chloride
(II) catalysis is lower carries out Suzuki coupling reactions, intermediate 5 is obtained after deprotection, intermediate 5 obtains again with acryloyl chloride amidation
To target product Buddhist nun is replaced according to Shandong.Catalyst 1,1'- bis- (diphenyl phosphine) ferrocene dichloride with high costs is used in the route
Palladium (II), in addition, final step amidation by-product is more, yield is low, it is difficult to realize industrialized production.
It is starting material that 1H- pyrazolos [3,4-d] pyrimidine -4- amine is equally used in patent US7514444, with N- iodo fourths
Diamides carries out iodide reaction and obtains intermediate 2, and intermediate 2 is first with boronic acid compounds in catalyst 1,1'- bis- (diphenyl phosphine)
Under ferrocene palladium chloride (II) effect, microwave condition carries out Suzuki coupling reactions and obtains intermediate 4, intermediate 4 again with piperazine
For pyridine alcohol into every trade Mitsunobu condensation reactions, deprotection obtains intermediate 5, and intermediate 5 is obtained with acryloyl chloride amidation according to Shandong
For Buddhist nun.This method is adjusted with method in patent WO2012158795 and patent WO2014022390, only reaction sequence.It should
Route is equally using expensive (diphenyl phosphine) the ferrocene palladium chlorides of catalyst 1,1'- bis- (II).It is difficult using microwave in reaction
With operation, in addition, final step amidation by-product is more, yield is low, and whole route is costly and difficult to realize industrialized production.
Invention content
It is an object of the invention to overcome the These characteristics of the prior art, a kind of raw material is provided and is easy to get, reaction condition is mild,
Easy to operate, at low cost, the high-quality suitable industrialized production of high income the preparation method that Buddhist nun is replaced according to Shandong.
The specific technical solution of the present invention is：
The purpose of the present invention is what is reached in this way,
A kind of preparation method that Buddhist nun is replaced according to Shandong, its step are as follows：
(1) ring closure reaction：3- amino -4- cyano pyrazoles are dissolved in organic solvent, room temperature under nitrogen protects lower and acetic acid first
Amidine occurs heating and intermediate 1 is obtained by the reaction；
(2) halogenating reaction：Intermediate 1 occurs halogenating reaction with N- N-halosuccinimides and obtains intermediate 2,
(3) nucleophilic substitution：Intermediate 2 carries out nucleophilic displacement of fluorine with intermediate 3 under catalyst action and obtains intermediate
4；
(4) Mitsunobu reacts：Intermediate 4 is with (S) -2- (methylol) piperidines -1- t-butyl formates in catalyst triphen
Under base phosphine, diisopropyl azodiformate occur Mitsunobu reaction, after in acid condition deprotection obtain intermediate 5；
(5) amidation process：Intermediate 5 occurs amidation with propylene carboxylic acid and obtains target product 6, i.e., replaces Buddhist nun according to Shandong.
It is preferred that the 3- amino -4- cyano pyrazoles and the molar ratio of Formamidine acetate are 1：1-1：1.3；
It is preferred that the 3- amino -4- cyano pyrazoles are 90-120 DEG C, more preferable 100 DEG C with Formamidine acetate reaction temperature；
It is preferred that the solvent of 1 recrystallization of intermediate is toluene and acetic acid, volume ratio 1：1；
It is preferred that the N- N-halosuccinimides that halogenating reaction uses are sub- for N- N-iodosuccinimides or N- bromos succinyl
One kind in amine；
It is preferred that the catalyst that intermediate 2 and 3 nucleophilic substitution of intermediate use is one kind in palladium carbon or Raney's nickel, more
It is preferred that palladium carbon；
It is preferred that intermediate 4 and the molar ratio of (S) -2- (methylol) piperidines -1- t-butyl formates are in Mitsunobu reactions
1：1.5：1：3；
It is preferred that 10 DEG C -40 DEG C of Mitsunobu reaction temperatures；
The preparation method of intermediate 3 under nitrogen protection, causes to obtain centre through iodine for 4- bromophenyls-phenyl ether and magnesium chips
Compound 3 is obtained by the reaction in state grignard reagent with methyl trichlorosilane afterwards；
It is preferred that the acid of deprotection is halogenated acid, one kind in trifluoroacetic acid；
It is preferred that the condensing agent that intermediate 5 is used with the generation amidation of propylene carboxylic acid is 2- (three nitrogen of 7- azos benzo
Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU)；
It is preferred that the acid binding agent that intermediate 5 is used with the generation amidation of propylene carboxylic acid is triethylamine, and pyridine, 4- dimethylamino pyrroles
Pyridine, one kind in n,N-diisopropylethylamine, more preferable n,N-diisopropylethylamine.
It is that 3- amino -4- cyano pyrazoles are dissolved in glycol monoethyl ether that specific step, which is, under room temperature under nitrogen protection
Add in Formamidine acetate, while the lower heating reaction of system nitrogen protection.It filters, is obtained in crude product after room temperature is cooled to after the reaction was complete
Mesosome 1, intermediate 1 recrystallize, and the white solid of purity >=99% is obtained by filtration.Intermediate 1 is dissolved in DMF, and it is halogenated to add in N-
Halogenating reaction occurs for succimide, and heating reaction terminates to raw material, and intermediate 2 is obtained by filtration in system after being quenched with water.It is intermediate
Body 2 is dissolved in Isosorbide-5-Nitrae-dioxane solvent with homemade intermediate 3, adds in alkali and catalyst palladium carbon, and heating reaction is complete to raw material,
It is extracted after solvent is evaporated off with THF, intermediate 4 is obtained after being spin-dried for solvent again.Intermediate 4 and (S) -2- (methylol) piperidines -1-
T-butyl formate is dissolved in THF, while adds in catalyst triphenylphosphine, diisopropyl azodiformate, 10-40 DEG C of generation
Mitsunobu reacts, and solvent is evaporated off after the reaction was complete after raw material, while add in dichloromethane (DCM), remove-insurance under acid condition
Shield adds in water into system after the reaction was complete, is layered, and organic layer dry filter obtains intermediate 5 after being spin-dried for.Finally, propylene carboxylic
Acid, HATU, DIPEA stir the DMF solution that intermediate 5 is added dropwise after a period of time again in DMF, amidation occur, the reaction was complete
After add in water, be extracted with ethyl acetate simultaneously, organic phase drying obtains target product 6, refines up to purity >=99% after concentration
Sterling.
Advantageous effect
1st, the raw material that first step ring closure reaction of the present invention uses is cheap and easily-available, high income >=80%, centre obtained by the reaction
Body 1 can be refined by recrystallization method, be conducive to improve the purity of lower step product；
2nd, the synthesis of intermediate 4 of the present invention is because being raw material with homemade intermediate 3, can use palladium carbon or Raney's nickel as being catalyzed
Agent avoids in document using costliness and is difficult to (diphenyl phosphine) the ferrocene palladium chlorides of 1,1'- bis- (II) of amplification quantity as urging
Agent can not only reduce cost, but also be suitable for industrialization production requirements；
3rd, Mitsunobu reactions of the present invention and deprotection reaction are carried out continuously, and can reduce numerous and diverse operating procedure, while can
To reduce the generation of by-product；
4th, in final step amidation of the present invention Fu's acid is added using the carboxyl in condensing agent HATU activation propylene carboxylic acids
Agent DIPEA, while the DMF solution of intermediate 5 is added dropwise, the progress of reaction can be slowed down, avoided anti-using acryloyl chloride acyl in document
The drawbacks of answering violent by-product more；
5th, whole process route uses raw material is cheap and easily-available, mild condition, easy to operate, yield is good, total recovery highest
Up to 42.1%.
Description of the drawings
Fig. 1 is the nuclear magnetic spectrogram of the compounds of this invention 6
Fig. 2 is nuclear magnetic spectrogram of the compounds of this invention 6 in 5.5-8.0ppm stage spectrum peak positions
Fig. 3 is nuclear magnetic spectrogram of the compounds of this invention 6 in 1.5-5.5ppm stage spectrum peak positions
Specific embodiment
Embodiment 1
The preparation of intermediate 1
54.05g (0.5mol) 3- amino -4- cyano pyrazoles, in 540mL glycol monoethyl ethers, room are added in 1L reaction bulbs
Warm nitrogen protection is lower to add in 52.06g (0.5mol) Formamidine acetate, the protection of system nitrogen, 90 DEG C of reaction 48h.It is dropped after the reaction was complete
It warms to room temperature, there are a large amount of solids to be precipitated in system at this time, filtering is considered cake 100mL 2 rinses of methanol point, obtained among crude product
Body 61.9g, crude product 250mL toluene and 250mL Recrystallisation from acetic acid, filtering obtain the white solid 55.40g of purity >=99%,
Yield：82.0%, HPLC：99.9%.
The preparation of intermediate 2
40.54g (0.3mol) intermediate 1, DMF360mL is added in into 1L reaction bulbs, while adds in N- iodos succinyl Asia
Amine 101.24g (0.45mol), system are warming up in 80 DEG C of reactions 22-24h, TLC and control, and the reaction was complete for raw material.It is added in into system
360mL water quenchings are gone out reaction, have a large amount of sepia solids to be precipitated in system at this time.Filtering considers cake and dries to obtain 63.67g sepias
Solid crude product, yield：81.3%, HPLC:96.7%.1HNMR(δppm,DMSO-D6,400MHz):14.06(s,1H),8.34
(s, 1H), 3.78 (t, J=5.0Hz, 4H), 3.73 (t, J=5.0Hz, 4H)
The preparation of intermediate 4
450mL anhydrous tetrahydro furans (THF) are added in 1L reaction bulbs, while add in 7.92g (0.33mol) magnesium chips and 0.1g
Iodine is heated to 40 DEG C, and lower dropwise addition 74.7g (0.3mol) 4- bromophenyls-phenyl ether of nitrogen protection and 100mL ether are matched after 30min
Into solution.45min drops finish, filtered after insulation reaction 3-4h, filtrate be spin-dried for grignard reagent is for use.
2L reaction bulbs separately are taken, 500mL anhydrous THF, 134.5g (0.9mol) methyl trichlorosilane, system are added in into system
0-5 DEG C is cooled to, above-mentioned grignard reagent is added in after temperature stabilization.20-25 DEG C of insulated and stirred 2-3h is warming up to after 1h, at this time in
It is complete to control raw material fundamental reaction.200mL toluene is added in into system, is filtered after stirring 30min, filtrate is spin-dried for obtaining intermediate 3
It is directly used in lower step.
Above-mentioned system is dissolved in 480mL Isosorbide-5-Nitraes-dioxane, at the same add in 78.3g (0.3mol) intermediate 2 and
33.67g (0.6mol) potassium hydroxide, nitrogen protection is lower to add in 3.9g palladium carbons.It is anti-that raw material is controlled in system back flow reaction 4-6h, TLC
Should be complete, stop reaction.System filters, a small amount of Isosorbide-5-Nitrae dioxane rinse of filter cake, and filtrate merges.Filtrate decompression is spin-dried for, residual
Object adds in 200mLTHF in, is filtered after stirring 15min, filtrate is spin-dried for obtaining the crude product about 80.12g of intermediate 4, yield
88.0%, HPLC:98.34%.
The preparation of intermediate 5
The about 60.67g of intermediate 4 (0.2mol) and (S) -2- (methylol) piperidines -1- t-butyl formates 60.38g
(0.3mol) is dissolved in 360mLTHF, while adds in 78.69g (0.3mol) triphenylphosphine.System starts to drip after being cooled to 0-5 DEG C
The solution that 60.66g (0.3mol) diisopropyl azodiformates and 300mL tetrahydrofurans is added to be made into, 1h drops finish.System slowly rises
To 30 DEG C of insulation reactions for 24 hours, solvent is evaporated off in temperature after the reaction was complete after raw material, while adds in dichloromethane (DCM) 450mL, room temperature
It is filtered after lower stirring 10min, hydrogen chloride gas is passed through in filtrate, while stir 4h, 300mL is added in into system after the reaction was complete
Water, layering, organic layer are washed after being washed till neutrality with 5% sodium bicarbonate solution with saturated common salt again, and organic layer dry filter is spin-dried for
After obtain the about 62.18g of intermediate 5, yield：80.45%.
The preparation of Buddhist nun's (compound 6) is replaced according to Shandong
Sequentially add 450mLDMF in 2L reaction bulbs, 14.4g (0.2mol) propylene carboxylic acid, 114.07g (0.3mol) HATU,
38.775g (0.3mol) DIPEA, be stirred at room temperature 1h be added dropwise into system 77.29g intermediates 5 and 350mLDMF configuration it is molten
Liquid, 40-60min drops finish.It is controlled in TLC, 450mL water, 10g sodium chloride is added in, while add in 500mL ethyl acetate after the reaction was complete
Stirring layering, water layer are extracted with 300mLX3 ethyl acetate, merge organic layer, organic layer is washed with 600mL saturated common salts, organic
It is mutually dry, crude product is obtained after concentration and replaces Buddhist nun according to Shandong, crude product ethyl acetate and normal heptane are refining to obtain the sterling of HPLC >=99%
75.59g yields：89.2%.
1HNMR(δppm,400MHz,DMSO-d6):8.26(s,1H),7.67(m,2H),7.41(m,2H),7.15(m,
5H), 6.87 (dd, J=16.5,10.5Hz, 1.0H), 6.72 (dd, J 16.5,10.5Hz, 1.0H), 6.10 (dd, J28.3,
17.3Hz, 1H), 5.69 (d, J12.2Hz, 0.5H), 5.59 (d, J=10.1Hz, 0.5H), 4.71 (m, 1H), 4.55 (d, J=
12.5Hz,1H),4.20(m,1H),4.06(m,0.5H),3.70(m,0.5H),3.29(m,0.5H),3.20(m,1H),3.00
(m,0.5H),2.26(m,1H),2.11(m,1H),1.92(m,1H),1.59(m,1H)；MS(ESI)m/z(percent):[M+
H]+441.20335
Embodiment 2
The preparation of intermediate 1
54.05g (0.5mol) 3- amino -4- cyano pyrazoles, in 540mL glycol monoethyl ethers, room are added in 1L reaction bulbs
Warm nitrogen protection is lower to add in 62.47g (0.6mol) Formamidine acetate, the protection of system nitrogen, 100 DEG C of reaction 46h.It is dropped after the reaction was complete
It warms to room temperature, there are a large amount of solids to be precipitated in system at this time, filtering is considered cake 100mL 2 rinses of methanol point, obtained among crude product
Body 63.8g, crude product 250mL toluene and 250mL Recrystallisation from acetic acid, filtering obtain the white solid 56.41g of purity >=99%,
Yield：83.5%, HPLC：99.93%.
The preparation of intermediate 2
40.54g (0.3mol) intermediate 1, DMF360mL is added in into 1L reaction bulbs, while adds in N- bromos succinyl Asia
Amine 80.1g (0.45mol), system are warming up in 80 DEG C of reactions 22-24h, TLC and control, and the reaction was complete for raw material.It is added in into system
360mL water quenchings are gone out reaction, have a large amount of sepia solids to be precipitated in system at this time.Filtering considers cake and dries to obtain 58.34g sepias
Solid crude product, yield：74.5%, HPLC:95.48%.
The preparation of intermediate 4
The about 56.64g of compound 3 (0.2mol) homemade in embodiment 1 is dissolved in 480mL Isosorbide-5-Nitraes-dioxane, simultaneously
78.3g (0.3mol) intermediate 2 and 33.67g (0.6mol) potassium hydroxide are added in, nitrogen protection is lower to add in 3.9g Raney's nickels.Body
It is back flow reaction 6-8h, controlling raw material in TLC, the reaction was complete, stops reaction.System filters, and filter cake is moistened with a small amount of Isosorbide-5-Nitrae dioxane
It washes, filtrate merges.Filtrate decompression is spin-dried for, and residue adds in 200mLTHF in, is filtered after stirring 15min, filtrate is spin-dried for obtaining
The crude product of intermediate 4 about 74.74g, yield 82.1%, HPLC:97.14%.
The preparation of intermediate 5
The about 60.67g of intermediate 4 (0.2mol) and (S) -2- (methylol) piperidines -1- t-butyl formates 80.51g
(0.4mol) is dissolved in 400mLTHF, while adds in 78.69g (0.3mol) triphenylphosphine.System starts to drip after being cooled to 0-5 DEG C
The solution that 60.66g (0.3mol) diisopropyl azodiformates and 300mL tetrahydrofurans is added to be made into, 1h drops finish.System slowly rises
To 30 DEG C of insulation reaction 22h solvent is evaporated off, while add in dichloromethane (DCM) 500mL, room temperature in temperature after the reaction was complete after raw material
It is filtered after lower stirring 10min, hydrogen chloride gas is passed through in filtrate, while stir 4h, 300mL is added in into system after the reaction was complete
Water, layering, organic layer are washed after being washed till neutrality with 5% sodium bicarbonate solution with saturated common salt again, and organic layer dry filter is spin-dried for
After obtain the about 65.70g of intermediate 5, yield：85.0%.
The preparation of Buddhist nun's (compound 6) is replaced according to Shandong
Sequentially add 450mLDMF in 2L reaction bulbs, 14.4g (0.2mol) propylene carboxylic acid, 114.07g (0.3mol) HATU,
38.775g (0.3mol) DIPEA is stirred at room temperature 1h and 77.29g intermediates 5 and the solution of 350mLDMF configurations is added dropwise into system,
40-60min drops finish.It is controlled in TLC, 450mL water, 10g sodium chloride is added in, while add in 500mL ethyl acetate and stir after the reaction was complete
Layering is mixed, water layer is extracted with 300mLX3 ethyl acetate, merges organic layer, and organic layer is washed with 600mL saturated common salts, organic phase
It is dry, crude product is obtained after concentration and replaces Buddhist nun according to Shandong, crude product ethyl acetate and normal heptane are refining to obtain the sterling of HPLC >=99%
75.59g yields：89.2%.
Embodiment 3
The preparation of intermediate 1
54.05g (0.5mol) 3- amino -4- cyano pyrazoles, in 540mL glycol monoethyl ethers, room are added in 1L reaction bulbs
Warm nitrogen protection is lower to add in 67.68g (0.65mol) Formamidine acetate, the protection of system nitrogen, 120 DEG C of reaction 45h.After the reaction was complete
Room temperature is cooled to, there are a large amount of solids to be precipitated in system at this time, filtering is considered cake 100mL 2 rinses of methanol point, obtained in crude product
Mesosome 62.2g, crude product 250mL toluene and 250mL Recrystallisation from acetic acid, filtering obtain the white solid of purity >=99%
56.82g yield：84.1%, HPLC：99.91%.
The preparation of intermediate 2
40.54g (0.3mol) intermediate 1, DMF360mL is added in into 1L reaction bulbs, while adds in N- iodos succinyl Asia
Amine 101.24g (0.45mol), system are warming up in 80 DEG C of reactions 22-24h, TLC and control, and the reaction was complete for raw material.It is added in into system
360mL water quenchings are gone out reaction, have a large amount of sepia solids to be precipitated in system at this time.Filtering considers cake and dries to obtain 64.37g sepias
Solid crude product, yield：82.2%, HPLC:95.9%.
The preparation of intermediate 4
Above-mentioned system is dissolved in 480mL Isosorbide-5-Nitraes-dioxane, at the same add in 78.3g (0.3mol) intermediate 2 and
33.67g (0.6mol) potassium hydroxide, nitrogen protection is lower to add in 3.9g palladium carbons.It is anti-that raw material is controlled in system back flow reaction 4-6h, TLC
Should be complete, stop reaction.System filters, a small amount of Isosorbide-5-Nitrae dioxane rinse of filter cake, and filtrate merges.Filtrate decompression is spin-dried for, residual
Object adds in 200mLTHF in, is filtered after stirring 15min, filtrate is spin-dried for obtaining the crude product about 83.03g of intermediate 4, yield
91.2%, HPLC:97.65%.
The preparation of intermediate 5
The about 60.67g of intermediate 4 (0.2mol) and (S) -2- (methylol) piperidines -1- t-butyl formates 120.76g
(0.6mol) is dissolved in 450mLTHF, while adds in 78.69g (0.3mol) triphenylphosphine.System starts after being cooled to 0-5 DEG C
The solution that 60.66g (0.3mol) diisopropyl azodiformates and 300mL tetrahydrofurans are made into is added dropwise, 1h drops finish.System is slow
40 DEG C of insulation reaction 22.5h are warming up to, solvent is evaporated off after the reaction was complete after raw material, while add in dichloromethane (DCM) 450mL,
It is filtered after stirring 10min at room temperature, 22.4mL trifluoroacetic acids is added in filtrate, while stir 2h, after the reaction was complete into system
300mL water, layering are added in, organic layer is washed after being washed till neutrality with 5% sodium bicarbonate solution with saturated common salt again, organic layer drying
Filtering obtains the about 62.71g of intermediate 5, yield after being spin-dried for：80.14%.
The preparation of Buddhist nun's (compound 6) is replaced according to Shandong
Sequentially add 450mLDMF in 2L reaction bulbs, 14.4g (0.2mol) propylene carboxylic acid, 114.07g (0.3mol) HATU,
38.775g (0.3mol) DIPEA is stirred at room temperature 1h and 77.29g intermediates 5 and the solution of 350mLDMF configurations is added dropwise into system,
40-60min drops finish.It is controlled in TLC, 450mL water, 10g sodium chloride is added in, while add in 500mL ethyl acetate and stir after the reaction was complete
Layering is mixed, water layer is extracted with 300mLX3 ethyl acetate, merges organic layer, and organic layer is washed with 600mL saturated common salts, organic phase
It is dry, crude product is obtained after concentration and replaces Buddhist nun according to Shandong, crude product ethyl acetate and normal heptane are refining to obtain the sterling of HPLC >=99%
74.15g yields：87.5%.
Claims (10)
1. a kind of preparation method that Buddhist nun is replaced according to Shandong, it is characterised in that:
(1) ring closure reaction：3- amino -4- cyano pyrazoles are dissolved in organic solvent, room temperature under nitrogen protection is lower and Formamidine acetate is sent out
Intermediate 1 is obtained by the reaction in raw heating；
(2) halogenating reaction：Intermediate 1 occurs halogenating reaction with N- N-halosuccinimides and obtains intermediate 2,
(3) nucleophilic substitution：Intermediate 2 carries out nucleophilic displacement of fluorine with intermediate 3 under catalyst action and obtains intermediate 4, institute
Catalyst is stated as one kind in palladium carbon or Raney's nickel；
(4) Mitsunobu reacts：Intermediate 4 is with (S) -2- (methylol) piperidines -1- t-butyl formates in catalyst triphenyl
Under phosphine, diisopropyl azodiformate occur Mitsunobu reaction, after in acid condition deprotection obtain intermediate 5,
(5) amidation process：Intermediate 5 occurs amidation with propylene carboxylic acid and obtains target product 6, i.e., replaces Buddhist nun according to Shandong.
2. the preparation method according to claim 1 that Buddhist nun is replaced according to Shandong, it is characterised in that：3- amino -4- in the step (1)
The molar ratio of cyano pyrazole and Formamidine acetate is that 1: 1-1: 1.3,3- amino -4- cyano pyrazoles are with Formamidine acetate reaction temperature
90-120℃。
3. the preparation method according to claim 2 that Buddhist nun is replaced according to Shandong, it is characterised in that：3- amino -4- in the step (1)
Cyano pyrazole is 100 DEG C with Formamidine acetate reaction temperature.
4. the preparation method that Buddhist nun is replaced according to Shandong according to claims 1 to 3 any one, it is characterised in that：The step (1)
Intermediate 1 obtained by the reaction is recrystallized, and recrystallizes the solvent used as toluene and acetic acid, volume ratio 1: 1.
5. the preparation method according to claim 1 or 2 that Buddhist nun is replaced according to Shandong, it is characterised in that：Described in the step (2)
N- N-halosuccinimides are one kind in N- N-iodosuccinimides or N- bromo-succinimides.
6. the preparation method according to claim 1 or 2 that Buddhist nun is replaced according to Shandong, it is characterised in that：
The preparation method of the intermediate 3 under nitrogen protection, causes to obtain centre through iodine for 4- bromophenyls-phenyl ether and magnesium chips
Compound 3 is obtained by the reaction in state grignard reagent with methyl trichlorosilane afterwards.
7. the preparation method according to claim 1 or 2 that Buddhist nun is replaced according to Shandong, it is characterised in that：Intermediate in the step (4)
4 with the molar ratio of (S) -2- (methylol) piperidines -1- t-butyl formates be 1: 1.5-1: 3.
8. the preparation method according to claim 7 that Buddhist nun is replaced according to Shandong, it is characterised in that：Reaction temperature in the step (4)
10℃-40℃。
9. according to claims 1 or 2 or the preparation method that Buddhist nun is replaced according to Shandong, it is characterised in that：Remove-insurance in the step (4)
The acid used is protected as halogenated acid, one kind in trifluoroacetic acid.
10. the preparation method according to claim 1 or 2 that Buddhist nun is replaced according to Shandong, it is characterised in that：It is intermediate in the step (5)
Amidation occurs for body 5 and propylene carboxylic acid using condensing agent and acid binding agent, the condensing agent for 2- (7- azos benzotriazole)-
N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU), the acid binding agent be triethylamine, pyridine, 4-dimethylaminopyridine,
One kind in n,N-diisopropylethylamine.
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| CN107233344B (en) * | 2017-07-20 | 2021-03-02 | 河南师范大学 | Preparation method of antitumor drug ibrutinib |
| CN107383017B (en) * | 2017-07-20 | 2020-01-14 | 河南师范大学 | Efficient preparation method of ibrutinib |
| CN108623606B (en) * | 2018-08-02 | 2019-11-12 | 杭州中美华东制药有限公司 | A kind of synthetic method for replacing Buddhist nun according to Shandong |
| CN111004239B (en) * | 2018-10-08 | 2022-09-13 | 上海柏狮生物科技有限公司 | Preparation method of ibrutinib precursor |
| CN109134474A (en) * | 2018-10-17 | 2019-01-04 | 海门慧聚药业有限公司 | The preparation of Buddhist nun's intermediate is replaced according to Shandong |
| CN110759915A (en) * | 2019-09-05 | 2020-02-07 | 雅本化学股份有限公司 | Preparation method of ibrutinib |
| CN111116593B (en) * | 2019-11-27 | 2020-11-24 | 河北合佳医药科技集团股份有限公司 | Continuous preparation method of imatinib |
| CN111423443A (en) * | 2020-04-03 | 2020-07-17 | 广州科锐特生物科技有限公司 | Preparation method of 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine |
| CN113583001A (en) * | 2021-07-13 | 2021-11-02 | 江苏君若药业有限公司 | Preparation of ibrutinib |
| CN114276355B (en) * | 2022-01-26 | 2023-04-07 | 江苏阿尔法药业股份有限公司 | Preparation method of ibrutinib |
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| CN102746305A (en) * | 2006-09-22 | 2012-10-24 | 药品循环公司 | Inhibitors of bruton's tyrosine kinase |
| CN103965201A (en) * | 2014-04-30 | 2014-08-06 | 淮海工学院 | Method for synthesizing intermediate 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine of Ibrutinib |
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