CN106831720B - The synthetic method and its application of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates - Google Patents
The synthetic method and its application of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 25
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 25
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 18
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 13
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 22
- 150000003851 azoles Chemical class 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- -1 iodo- 1H- pyrazol-1-yl Chemical group 0.000 claims description 21
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 18
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 claims description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 17
- 239000000047 product Substances 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 150000003053 piperidines Chemical class 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 8
- 235000019441 ethanol Nutrition 0.000 claims description 7
- 238000003328 mesylation reaction Methods 0.000 claims description 7
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 239000012530 fluid Substances 0.000 claims description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- QODYNFRPWGODQQ-UHFFFAOYSA-N 1-iodopyrrole Chemical compound IN1C=CC=C1 QODYNFRPWGODQQ-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 230000008569 process Effects 0.000 abstract description 11
- 239000002146 L01XE16 - Crizotinib Substances 0.000 abstract description 5
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 abstract description 5
- 238000012544 monitoring process Methods 0.000 abstract description 5
- 229960005061 crizotinib Drugs 0.000 abstract description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 4
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 239000002131 composite material Substances 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 229940079593 drug Drugs 0.000 description 17
- 239000003814 drug Substances 0.000 description 17
- 239000002585 base Substances 0.000 description 15
- 239000012535 impurity Substances 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 4
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 4
- 230000008859 change Effects 0.000 description 3
- 230000005311 nuclear magnetism Effects 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- AZGGNLGPTXHLRL-UHFFFAOYSA-N 1-pyrazol-1-ylpiperidine Chemical class C1CCCCN1N1N=CC=C1 AZGGNLGPTXHLRL-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- BNBWOBMWJCGQCW-UHFFFAOYSA-N tert-butyl formate pyridine Chemical compound C(C)(C)(C)OC=O.N1=CC=CC=C1 BNBWOBMWJCGQCW-UHFFFAOYSA-N 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 description 1
- UCFSYHMCKWNKAH-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical class CC1(C)OBOC1(C)C UCFSYHMCKWNKAH-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- AIGRXSNSLVJMEA-FQEVSTJZSA-N ethoxy-(4-nitrophenoxy)-phenyl-sulfanylidene-$l^{5}-phosphane Chemical compound O([P@@](=S)(OCC)C=1C=CC=CC=1)C1=CC=C([N+]([O-])=O)C=C1 AIGRXSNSLVJMEA-FQEVSTJZSA-N 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- RYEXTBOQKFUPOE-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].CC[CH2-] RYEXTBOQKFUPOE-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000005059 solid analysis Methods 0.000 description 1
- 235000015096 spirit Nutrition 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 229940049068 xalkori Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Biophysics (AREA)
- Analytical Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种双‑4‑(1H‑吡唑‑1‑基)哌啶‑1‑甲酸叔丁酯的合成方法及双‑4‑(1H‑吡唑‑1‑基)哌啶‑1‑甲酸叔丁酯的应用，它以价廉易得的N‑Boc‑4‑羟基哌啶为原料，经过甲磺酰化反应、烃化反应、格氏反应和Suzuki偶联反应，制得双‑4‑(1H‑吡唑‑1‑基)哌啶‑1‑甲酸叔丁酯，合成方法简单，过程易于控制，所得双‑4‑(1H‑吡唑‑1‑基)哌啶‑1‑甲酸叔丁酯的收率为86.7%；双‑4‑(1H‑吡唑‑1‑基)哌啶‑1‑甲酸叔丁酯可作为标准品，检测和监控克唑替尼的合成。本发明适用于合成双‑4‑(1H‑吡唑‑1‑基)哌啶‑1‑甲酸叔丁酯的合成，合成物用于检测和监控克唑替尼的合成。The invention discloses a method for synthesizing bis-4-(1H-pyrazole-1-yl)piperidine-1-tert-butyl formate and bis-4-(1H-pyrazole-1-yl)piperidine- The application of 1-tert-butyl formate, which takes N-Boc-4-hydroxypiperidine which is cheap and easy to obtain as a raw material, undergoes methanesulfonylation reaction, alkylation reaction, Grignard reaction and Suzuki coupling reaction to obtain Bis-4-(1H-pyrazole-1-yl)piperidine-1-carboxylate tert-butyl ester, the synthesis method is simple, the process is easy to control, and the obtained bis-4-(1H-pyrazole-1-yl)piperidine- The yield of 1-tert-butyl formate is 86.7%; bis-4-(1H-pyrazole-1-yl)piperidine-1-tert-butyl formate can be used as a standard to detect and monitor the synthesis of crizotinib . The invention is suitable for the synthesis of bis-4-(1H-pyrazole-1-yl)piperidine-1-carboxylate tert-butyl ester, and the composite is used for detecting and monitoring the synthesis of crizotinib.
Description
Technical field
The invention belongs to pharmaceutical fields, are related to a kind of synthetic method of pharmaceutical intermediate impurity, and in particular to double -4- (1H-
Pyrazol-1-yl) synthetic method of piperidines -1- t-butyl formate and the application of corresponding synthetic product.
Background technique
In the synthesis process of drug, it will usually which along with the generation of impurity, and impurity studies direct or indirect influence
The quality of drug, the adverse reaction that drug generates in clinical use have outside the Pass in addition to the pharmacological activity with drug itself, have
When with drug present in impurity also have very big relationship.Impurity majority in drug has potential bioactivity and cell toxicant
Property, therefore, the content of impurity may will affect Drug safety and validity, or even generate toxicity.The control of impurity of the drug
For guaranteeing that the adverse reaction of the validity, reduction drug of drug plays a key role.Miscellaneous Quality Research is drug research
Importance, it through entire drug research always.Can the impurity in drug obtain reasonable, effective control, directly
It is related to the quality controllability and safety of drug.
Gram azoles replaces Buddhist nun (Crizotinib), and chemical name is 3- [ (1R) -1- (the chloro- 3- fluorophenyl of 2,6- bis-) ethyoxyl ] -
5- 1-(4- piperidines) and -1H- pyrazoles -4- base ] -2- pyridine amine;Its structural formula is as follows:
Gram azoles is a kind of kinases inhibitor of emulative multiple target point of ATP for Buddhist nun, can effectively inhibit MET/ALK/
The cell bio-activity of ROS, and higher face is shown in the tumor patient of ALK, ROS or MET abnormal kinase respectively
Bed curative effect.On August 26th, 2011, U.S. Food and Drug Administration is according to clinicalⅰstage A8081001 and clinical II phase
The mode of the remarkable result of A8081005 express passway has approved Xalkori (Sai Kerui) (Crizotinib, gram azoles replace Buddhist nun)
For treating, there are the advanced stage of anaplastic lymphoma kinase (ALK) abnormal gene expression (Locally Advanced or metastatic) non-small cells
Lung cancer (NSCLC) patient.Reported in the literature gram of azoles is with the chloro- 3- fluoro acetophenone of 2,6- bis- for raw material for the synthetic method of Buddhist nun, warp
Reduction, chiral resolution, Mitsunobu reaction, reduction, bromo obtain intermediate [the bromo- 3- of 5- [(1R)-(chloro- 3- fluorine of 2,6- bis-
Phenyl) ethyoxyl] pyridine -2- base] amine (1);Using N-Boc-4- hydroxy piperidine as raw material, through Mesylation, 4- iodine pyrazoles N-
Then hydrocarbonylation carries out I/Mg with isopropylmagnesium chloride and exchanges, then obtain through condensation reaction with methoxyl group pinacol borate
Mesosome 4- 4-(4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) and -1H- pyrazol-1-yl ] piperidines -1- formic acid
The tert-butyl ester (2).Intermediate (1) and (2) obtain azoles in target product gram and replace through Suzuki coupling reaction, removing Boc protection
Buddhist nun.The study found that always with the presence of a kind of impurity in the synthesis process that gram azoles replaces Buddhist nun, and this impurity replaces Buddhist nun's drug in gram azoles
Association in intermediate synthesis process, and the subsequent reactions that gram azoles replaces Buddhist nun can be participated in and influence to synthesize, cause more impurity to generate,
And then increase the processing difficulty of final product, influence the purity that gram azoles replaces Buddhist nun's drug.There is no miscellaneous about this in document before
The relevant report of matter synthesis and structure.This impurity is thus synthesized, double -4- (1H- pyrazol-1-yl) piperidines -1- formic acid uncles are studied
The synthetic route of butyl ester, it may be assumed that synthesize double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates for preferably optimizing a gram azoles
There is important meaning for Buddhist nun's synthesis condition.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates
Synthetic method.It is using N-Boc-4- hydroxy piperidine cheap and easy to get as raw material, by Mesylation reaction, alkylation reaction, lattice
Double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates are made in family name's reaction and Suzuki coupling reaction, and synthetic method is simple,
Process is easily controllable, and the yield of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates of gained is 80.2-86.7%；
Another object of the present invention is to provide one kind of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates
Using it can be used as standard items, and the synthesis of Buddhist nun is replaced for detecting and monitoring gram azoles.
In order to solve the above technical problems, the technical scheme adopted by the invention is that:
A kind of synthetic method of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates, it is with N-Boc-4- hydroxyl piperazine
Pyridine is raw material, successively synthesizes 4-(4- by Mesylation reaction synthesis 1-Boc-4- methanesulfonyloxy group piperidines, alkylation reaction
Iodo- 1H- pyrazol-1-yl) -1- piperidine acid tert-butyl ester, grignard reaction synthesis 4- [ 4-(4,4,5,5- tetramethyl -1,3,2- dioxy
Heterocycle pentaborane -2- base) -1H- pyrazol-1-yl ] piperidines -1- t-butyl formate, double -4- (the 1H- pyrroles of Suzuki coupling reaction synthesis
Oxazolyl) piperidines -1- t-butyl formate.
As restriction of the invention, the reaction route of the synthetic method is as follows:
It is further limited as of the invention, sequence carries out in accordance with the following steps for it:
() Mesylation reaction
In the mixed liquor that N-Boc-4- hydroxy piperidine is dissolved in solvent and acid binding agent that volume ratio is 10:1 in -10 DEG C,
Mesyl chloride is added dropwise, keeps the temperature 2h；Add water quenching reaction, separate organic phase, petroleum ether/normal heptane that volume ratio is 62:38 is added
Crystallization of solution obtains compound 1-Boc-4- methanesulfonyloxy group piperidines, is denoted as A；
The molar ratio of the N-Boc-4- hydroxy piperidine and mesyl chloride are as follows: 1:1.3；
() alkylation reaction
It is dissolved in NMP after 4- iodine pyrazoles and cesium carbonate that molar ratio is 1:0.6~1.6 are mixed, is heated to 65~95
DEG C, it takes A to add in mixed liquor, keeps the temperature 3~5h, into filtrate plus volume ratio is water/ethanol solution of 9:1, and it is iodo- that 4-(4- is precipitated
1H- pyrazol-1-yl) -1- piperidine acid tert-butyl ester, it is denoted as B；
Wherein the molar ratio of A and 4- iodine pyrazoles is 1~1.5:1；
() grignard reaction
B is dissolved in THF, nitrogen protection at room temperature, is cooled to -30 DEG C~0 DEG C, is added dropwise contain isopropyl chloride thereto
The THF solution for changing magnesium is added dropwise heat preservation 0.5-3h, trimethylborate is added dropwise, is added dropwise and is first warming up to 0-5 DEG C and keeps the temperature
0.5-1.5h, then be warming up to 10-35 DEG C and keep the temperature 1-2h, pinacol is added, 2-4h is reacted at 40-70 DEG C, after filtering, concentration,
Solvent is added in treatment fluid, there is solid precipitation, is the iodo- 1H- pyrazol-1-yl of 4-(4-) -1- piperidine acid tert-butyl ester, after concentration
Obtain 4- [ 4-(4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) -1H- pyrazol-1-yl ] piperidines -1- formic acid
The tert-butyl ester is denoted as C；
Wherein, the molar ratio of B and isopropylmagnesium chloride is 1:1~1.4；
The molar ratio of B and pinacol is 1:1~1.5；
The molar ratio of B and trimethylborate is 1:1~2;
() Suzuki coupling reaction
It is that 1:1~1.8:3~8:0.03~0.1 B, C, cesium carbonate and tetrabutylammonium bromide are molten at room temperature by molar ratio
Solution in toluene/water, replaced 3 times with nitrogen by reaction system, and bis-triphenylphosphipalladium palladium dichloride is added, react 2 at 50~100 DEG C~
6h separates organic phase and the methanol/ethyl acetate solution that volume ratio is 2:3 is added thereto, and crystallization obtains target product, i.e.,
Double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates.
As further restriction of the invention:
Step () in, the molar ratio of the B and bis-triphenylphosphipalladium palladium dichloride catalyst is 1:0.005~0.01；
Step () in, the temperature of the Suzuki coupling reaction is 60~80 DEG C, and the time is 5~6h；
Step () in, the reaction time is 3~4h after pinacol is added.
It is limited as further:
Step () in, the solvent is one of MTBE, ether, THF or methylene chloride；
The acid binding agent is one of pyridine, triethylamine or DIEA；
The solvent being added in the treatment fluid is one or more of isopropanol, methanol, ethyl alcohol, ethyl acetate.
The present invention also provides a kind of applications of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formate, it can be used as
Standard items, detection and monitoring gram azoles replace the synthesis of Buddhist nun.
In 4- [ 4-(4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- it can be seen from synthetic route chart
Base) -1H- pyrazol-1-yl piperidines -1- t-butyl formate synthesis process in, aftertreatment fluid by again add isopropanol, first
One or more of alcohol, ethyl alcohol, ethyl acetate are used as solvent, can be by the iodo- 1H- pyrazol-1-yl of reaction raw materials 4-(4-) -1-
Piperidine acid tert-butyl ester is precipitated, by the iodo- 1H- pyrazol-1-yl of 4-(4-) -1- piperidine acid tert-butyl ester is in added solvent
Solubility is lower and 4- [ 4-(4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) -1H- pyrazol-1-yl ] piperazine
Solubility of the pyridine -1- t-butyl formate in added solvent is higher, realizes the separation of the two, and the 4-(4- post-processed is iodo-
1H- pyrazol-1-yl) -1- piperidine acid tert-butyl ester can recycle, continue to participate in grignard reaction as reaction raw materials, and 4- [ 4-
(4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) -1H- pyrazol-1-yl ] piperidines -1- t-butyl formate be close
The important intermediate of Buddhist nun is replaced at gram azoles, double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates can be used as standard items, pass through
Detection reaction is so that the yield of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates of intermediate impurities gradually decreases, finally
Improve the yield that gram azoles replaces Buddhist nun.
Due to the adoption of the above technical solution, compared with prior art, the present invention acquired technological progress is:
Synthetic method provided by the invention, it is using N-Boc-4- hydroxy piperidine cheap and easy to get as raw material, by methylsulfonyl
Change reaction, alkylation reaction, grignard reaction, Suzuki coupling reaction, double -4- (1H- pyrazol-1-yl) piperidines -1- formic acid uncles are made
Butyl ester uses the cheap trimethylborate being easy to get and pinacol for raw material during grignard reaction, and uses " one
Pot method " synthesizes, and separation is not had in reaction process, and method is simple, and process is easily controllable, double -4- (1H- pyrazol-1-yl) piperazines of gained
The yield of pyridine -1- t-butyl formate is 80.2-86.7%；Double -4- (1H- pyrazol-1-yl) piperidines -1- first synthesized by the present invention
Tert-butyl acrylate can be used as standard items, and the synthesis of Buddhist nun is replaced for detecting and monitoring gram azoles.
The present invention is suitable for synthesizing double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates, and synthetic can be used to detect
The synthesis of Buddhist nun is replaced with monitoring gram azoles.
The present invention is described in further detail below in conjunction with specific embodiment.
Detailed description of the invention
Fig. 1 is 1-Boc-4- methanesulfonyloxy group piperidines1HNMR figure；
Fig. 2 is the iodo- 1H- pyrazol-1-yl of 4-(4-) -1- piperidine acid tert-butyl ester1HNMR figure；
Fig. 3 is double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates1HNMR figure；
Fig. 4 is the mass spectrogram of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates.
Specific embodiment
Reagent as used in the following examples is available reagent unless otherwise specified, and test method is equal unless otherwise specified
Using existing test method.
The synthetic method of embodiment 1 couple of -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formate
The present embodiment is a kind of synthetic method of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates, it is according to such as
Under step sequence carry out:
(11) Mesylation reacts
1mol N-Boc-4- hydroxy piperidine is taken to be dissolved in the MTBE/ triethylamine mixed liquor that volume ratio is 10:1 in -10 DEG C
In, 1.3mol mesyl chloride (the Sheng Chang producer of mesyl chloride is Zhengzhou Hao Rong chemical products Co., Ltd), drop are added dropwise thereto
2h is kept the temperature after adding；Add water quenching reaction, separate organic phase, it is molten that petroleum ether/normal heptane mixing that volume ratio is 62:38 is added
Liquid, crystallization obtain compound 1-Boc-4- methanesulfonyloxy group piperidines, are denoted as A1；
The nuclear-magnetism figure of A1 is as shown in Figure 1, specific nuclear magnetic data is as follows:
1H NMR (CDCl3, 500 Hz, δ: ppm), 4.884 (m, 1H), 3.716 (m, 2H), 3.303
(q, 2H), 3.038 (s, 3H), 1.966 (q, 2H), 1.817 (q, 2H), 1.461 (s, 9H);
(12) alkylation reaction
4- iodine pyrazoles 1mol and cesium carbonate 0.6mol are taken, is dissolved in nmp solvent after mixing, is heated to 70 DEG C, takes
The A1 of 1.2mol is added in mixed liquor, keeps the temperature 5h, be added into filtrate volume ratio be 9:1 water/ethanol solution, product is precipitated,
Obtain the iodo- 1H- pyrazol-1-yl of 4-(4-) -1- piperidine acid tert-butyl ester, it is denoted as B1；
The nuclear-magnetism figure of B1 is as shown in Fig. 2, specific nuclear magnetic data is as follows:
1H NMR (CDCl3, 500 Hz, δ: ppm), 7.510 (s, 1H), 7.454 (s, 1H), 4.258
(q, 3H), 2.873 (s, 2H), 2.096 (d, 2H,J=12.5Hz), 1.875 (q, 2H), 1.461 (s, 9H)；
(13) grignard reaction
It takes 1mol B1 to be dissolved in THF at room temperature, -25 DEG C is cooled under nitrogen protection, be added dropwise thereto different containing 1mol
Heat preservation 2h is added dropwise in the THF solution (Shaoxing Shangyu Hua Lun Chemical Co., Ltd., specification 1.31mol/L) of propyl magnesium chloride,
Be added dropwise 2mol trimethylborate, be added dropwise and be first warming up to 5 DEG C and keep the temperature 1h, then be warming up to 10 DEG C and keep the temperature 1.5h, finally plus
Enter 1.2mol pinacol, 2.5h is reacted at 60 DEG C, aqueous isopropanol is added in treatment fluid, there is solid analysis for filtering, concentration
Out, be the iodo- 1H- pyrazol-1-yl of 4-(4-) -1- piperidine acid tert-butyl ester B1, be concentrated to get 4- 4-(4,4,5,5- tetramethyl -1,
3,2- dioxaborolanes -2- bases) -1H- pyrazol-1-yl ] piperidines -1- t-butyl formate, it is denoted as C1；Post-reaction treatment process
It is middle that the iodo- 1H- pyrazol-1-yl of 4-(4- collected is precipitated) -1- piperidine acid tert-butyl ester B1, it can recycle as raw material,
It continues to apply in this reaction, forms recycling circulation, finally improve 4- [ 4-(4,4,5,5- tetramethyls -1,3,2- dioxane penta
Borine -2- base) -1H- pyrazol-1-yl piperidines -1- t-butyl formate C1 yield, and 4- 4-(4,4,5,5- tetramethyls -1,3,
2- dioxaborolanes -2- base) -1H- pyrazol-1-yl piperidines -1- t-butyl formate C1 be synthesize gram azoles for Buddhist nun it is important in
Mesosome can improve the yield in entire synthesis process if its yield increases；
(14) Suzuki coupling reaction
1molB1,1.6mol C1,4mol cesium carbonate and 0.1mol tetrabutylammonium bromide is taken to be dissolved in toluene/water at room temperature,
Reaction system is replaced 3 times with nitrogen, and 0.005mol bis-triphenylphosphipalladium palladium dichloride catalyst is added, reacts 5.5h at 70 DEG C,
Reaction terminates to separate organic phase, and the methanol/ethyl acetate solution that volume ratio is 2:3 is added thereto, and crystallization obtains target production
Product, i.e., double -4- (1H- pyrazolyl) piperidines -1- t-butyl formates；
Double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates of the present embodiment synthesis, through analytical calculation, the target
The yield of product is 83.2%.
The iodo- 1H- pyrazol-1-yl of 4-(4- generated in step (13)) -1- piperidine acid tert-butyl ester B1 recycling two takes second place
Afterwards, the yield of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates is 81.7%；The iodo- 1H- pyrazoles-of 4-(4- generated
1- yl) -1- piperidine acid tert-butyl ester B1 recycling three times after, the receipts of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates
Rate is 79.3%；The iodo- 1H- pyrazol-1-yl of 4-(4- generated) -1- piperidine acid tert-butyl ester B1 recycle four times after, double -4-
The yield of (1H- pyrazol-1-yl) piperidines -1- t-butyl formate is 71.6%；
The nuclear-magnetism figure of target product is as shown in figure 3, specific nuclear magnetic data is as follows:
1H NMR (CDCl3, 500 Hz, δ: ppm), 7.577 (s, 1H), 7.486 (s, 1H), 4.259
(q, 3H), 2.895 (s, 2H), 2.140 (d, 2H,J=10.5Hz), 1.923 (q, 2H), 1.478 (s, 9H);
The mass spectrogram of target product is as shown in figure 4, specific mass spectrometric data is as follows:
HRMS calcd for C26H40N6O4Na [M+Na]+,523.5 found 523.5.
It can be seen from the above, synthetic route provided in the present embodiment is reliable, final synthetic product is double -4- (1H- pyrroles
Azoles -1- base) piperidines -1- t-butyl formate.
The synthetic method of the bis- -4- of embodiment 2-5 (1H- pyrazol-1-yl) piperidines -1- t-butyl formate
Embodiment 2-5 is respectively a kind of synthetic method of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates, it
Synthetic method it is similar to Example 1, the difference is that only: corresponding technical parameter is different in synthesis process, is specifically shown in
Following table.
1 technical data sheet of table
The test of 6 Suzuki coupling reaction conditional filtering of embodiment
During preparing target product, in Suzuki coupling reaction process, selection, reaction temperature, the reaction of solvent
Time, alkali number, phase transfer catalyst dosage are important, and the present embodiment has carried out following experiment to explore this condition:
Table 2-1 Suzuki coupling reaction conditional parameter table
Table 2-2 Suzuki coupling reaction conditional parameter table
Table 2-3 Suzuki coupling reaction conditional parameter table
Table 2-4 Suzuki coupling reaction conditional parameter table
Table 2-5 Suzuki coupling reaction conditional parameter table
7 Grignard reaction conditions screening experiment of embodiment
During preparing target product, during grignard reaction, reaction temperature, grignard when Grignard Reagent is added dropwise are tried
It is that the control of agent dosage and the dosage of trimethylborate, pinacol will affect reaction as a result, the present embodiment is in order to explore these
Condition, having carried out conditional filtering test concrete outcome see the table below:
Table 3-1 grignard exchange-grignard reaction -ester exchange reaction technical data sheet
Table 3-2 grignard exchange-grignard reaction -ester exchange reaction technical data sheet
Table 3-3 grignard exchange-grignard reaction -ester exchange reaction technical data sheet
Table 3-4 grignard exchange-grignard reaction -ester exchange reaction technical data sheet
In addition, the present embodiment to the solvent being added in treatment fluid in grignard reaction, carried out by isopropanol, methanol,
One or more of ethyl alcohol, ethyl acetate carry out the test of permutation and combination selection, facts proved that: by isopropanol, methanol, second
One or more of alcohol, ethyl acetate are used as solvent, can be by the iodo- 1H- pyrazol-1-yl of reaction raw materials 4-(4-) -1- piperidines
T-butyl formate is precipitated, by the iodo- 1H- pyrazol-1-yl of 4-(4-) the dissolution of -1- piperidine acid tert-butyl ester in added solvent
Spend lower and 4- [ 4-(4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) -1H- pyrazol-1-yl ] piperidines -1-
Solubility of the t-butyl formate in added solvent is higher, realizes the separation of the two, the iodo- 1H- pyrrole of the 4-(4- post-processed
Azoles -1- base) -1- piperidine acid tert-butyl ester can recycle, continues to participate in grignard reaction as reaction raw materials, and 4- 4-(4,4,5,
5- tetramethyl -1,3,2- dioxaborolanes -2- base) -1H- pyrazol-1-yl piperidines -1- t-butyl formate be synthesis gram azoles
For the important intermediate of Buddhist nun, double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates can be used as standard items, anti-by detecting
The yield of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates of intermediate impurities should be made to gradually decrease, final raising gram
Azoles replaces the yield of Buddhist nun.
Embodiment 1-5, is only presently preferred embodiments of the present invention, is not the limit of other forms made for the present invention
Fixed, any person skilled in the art is changed or is modified as equivalent change as enlightenment possibly also with above-mentioned technology contents
The equivalent embodiment of change.But all technical spirits without departing from the claims in the present invention are simple to made by above embodiments
Modification, equivalent variations and remodeling still fall within the range of the claims in the present invention protection.
Claims (9)
1. a kind of synthetic method of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates, it is characterised in that: it is with N-
Boc-4- hydroxy piperidine is raw material, successively anti-by Mesylation reaction synthesis 1-Boc-4- methanesulfonyloxy group piperidines, hydrocarbonylation
The iodo- 1H- pyrazol-1-yl of 4-(4- should be synthesized) -1- piperidine acid tert-butyl ester, grignard reaction synthesis 4- [ 4-(4,4,5,5- tetramethyl
Base -1,3,2- dioxaborolanes -2- base) -1H- pyrazol-1-yl ] piperidines -1- t-butyl formate, the conjunction of Suzuki coupling reaction
The tertiary fourth of -4- (1H- pyrazolyl) piperidines -1- formic acid in pairs；Its synthetic route is as follows:
。
2. the synthetic method of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates according to claim 1, special
Sign is it, and sequence carries out in accordance with the following steps:
() Mesylation reaction
In the mixed liquor that N-Boc-4- hydroxy piperidine is dissolved in solvent and acid binding agent that volume ratio is 10:1 in -10 DEG C, it is added dropwise
Mesyl chloride keeps the temperature 2h；Add water quenching reaction, separate organic phase, petroleum ether/n-heptane solution that volume ratio is 62:38 is added
Crystallization obtains compound 1-Boc-4- methanesulfonyloxy group piperidines, is denoted as A；
The molar ratio of the N-Boc-4- hydroxy piperidine and mesyl chloride is 1:1.3；
() alkylation reaction
It is dissolved in NMP after 4- iodine pyrazoles and cesium carbonate that molar ratio is 1:0.6~1.6 are mixed, is heated to 65~95 DEG C, takes A
It is added in mixed liquor, keeps the temperature 3~5h, into filtrate plus volume ratio is water/ethanol solution of 9:1, and the iodo- 1H- pyrrole of 4-(4- is precipitated
Azoles -1- base) -1- piperidine acid tert-butyl ester, it is denoted as B；
Wherein the molar ratio of A and 4- iodine pyrazoles is 1~1.5:1；
() grignard reaction
B is dissolved in THF, nitrogen protection at room temperature, is cooled to -30 DEG C~0 DEG C, is added dropwise contain isopropylmagnesium chloride thereto
THF solution, be added dropwise heat preservation 0.5-3h, be added dropwise trimethylborate, be added dropwise and be first warming up to 0-5 DEG C and keep the temperature 0.5-
1.5h, then be warming up to 10-35 DEG C and keep the temperature 1-2h, pinacol is added, 2-4h is reacted at 40-70 DEG C, filtering, concentration are being handled
Solvent is added in liquid, there is solid precipitation, be the iodo- 1H- pyrazol-1-yl of 4-(4-) -1- piperidine acid tert-butyl ester, be concentrated to get 4-
4-(4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) -1H- pyrazol-1-yl ] piperidines -1- t-butyl formate,
It is denoted as C；
Wherein, the molar ratio of B and isopropylmagnesium chloride is 1:1~1.4；
The molar ratio of B and pinacol is 1:1~1.5；
The molar ratio of B and trimethylborate is 1:1~2;
() Suzuki coupling reaction
It is that 1:1~1.8:3~8:0.03~0.1 B, C, cesium carbonate and tetrabutylammonium bromide are dissolved at room temperature by molar ratio
Toluene/water, reaction system are replaced 3 times with nitrogen, and bis-triphenylphosphipalladium palladium dichloride is added, and 2~6h is reacted at 50~100 DEG C,
It separates organic phase and the methanol/ethyl acetate solution that volume ratio is 2:3 is added thereto, crystallization obtains target product, i.e., double -4-
(1H- pyrazolyl) piperidines -1- t-butyl formate.
3. the synthetic method of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates according to claim 2, special
Sign is: step () in, the molar ratio of the B and bis-triphenylphosphipalladium palladium dichloride catalyst is 1:0.005~0.01.
4. the synthetic method of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates according to claim 2,
It is characterized in that: step () in, the reaction time is 3~4h after pinacol is added.
5. the synthetic method of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates according to claim 2, special
Sign is: step () in, the temperature of the Suzuki coupling reaction is 60~80 DEG C, and the time is 5~6h.
6. the synthetic method of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates according to claim 2, special
Sign is: step () in, the solvent is one of MTBE, ether, THF or methylene chloride.
7. the synthetic method of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates according to claim 2, special
Sign is: step () in, the acid binding agent is one of pyridine, triethylamine or DIEA.
8. the synthesis of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates according to any one of claim 2-7
Method, it is characterised in that: the solvent added in treatment fluid is one or more of isopropanol, methanol, ethyl alcohol, ethyl acetate.
9. the synthesis side of double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates described in any one of claim 1-8
A kind of application of made double -4- (1H- pyrazol-1-yl) piperidines -1- t-butyl formates of method, it is characterised in that: it is used for as mark
The synthesis that gram azoles replaces Buddhist nun is surveyed and is monitored in quasi- product examine.
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