CN102584795B - Preparing method of crizotinib - Google Patents
Preparing method of crizotinib Download PDFInfo
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- CN102584795B CN102584795B CN201210009870.6A CN201210009870A CN102584795B CN 102584795 B CN102584795 B CN 102584795B CN 201210009870 A CN201210009870 A CN 201210009870A CN 102584795 B CN102584795 B CN 102584795B
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- 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 title claims abstract description 42
- 238000000034 method Methods 0.000 title abstract description 17
- 239000002146 L01XE16 - Crizotinib Substances 0.000 title abstract 6
- 229960005061 crizotinib Drugs 0.000 title abstract 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 58
- 238000002360 preparation method Methods 0.000 claims abstract description 37
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims abstract description 26
- -1 aromatic amine compound Chemical class 0.000 claims abstract description 19
- 150000002828 nitro derivatives Chemical class 0.000 claims abstract description 14
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- 239000002904 solvent Substances 0.000 claims description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 claims description 13
- 229940067107 phenylethyl alcohol Drugs 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 230000002829 reductive effect Effects 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 8
- 239000000376 reactant Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- JQIVECLQPHOSDY-QGZVFWFLSA-N [(2s)-1,2-diphenylpyrrolidin-2-yl]methanol Chemical compound C([C@@]1(CO)C=2C=CC=CC=2)CCN1C1=CC=CC=C1 JQIVECLQPHOSDY-QGZVFWFLSA-N 0.000 claims description 5
- 239000004327 boric acid Substances 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 239000003586 protic polar solvent Substances 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 4
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 3
- 239000000843 powder Substances 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
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 claims description 2
- RZBBHJROACIOOM-UHFFFAOYSA-N 2-nitro-2H-pyridin-3-one Chemical compound [N+](=O)([O-])C1N=CC=CC1=O RZBBHJROACIOOM-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- 150000001298 alcohols Chemical group 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 239000003880 polar aprotic solvent Substances 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 2
- 238000006911 enzymatic reaction Methods 0.000 abstract description 2
- 238000010276 construction Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000001514 detection method Methods 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000005251 gamma ray Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000010025 steaming Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 150000008062 acetophenones Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000006362 organocatalysis Methods 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a preparing method of crizotinib. The preparing comprises the following steps of: 1) preparing (S)-construction phenethyl alcohol by taking acetophenone the structural formula of which is shown in a formula (1) as a raw material; 2) preparing a nitrocompound; 3) preparing an aromatic amine compound; 4) preparing a bromo-compound; 5) preparing an N-Boc compound; and 6) preparing the crizotinib. Compared with the prior art, the preparing method of the crizotinib has the advantages that 1, the conventional biological enzymatic method and chemical resolution method are replaced by an organic micromolecule catalysis method, thus the whole line is short in reaction cycle, high in yield, simple in operation, wide in raw material source and low in price; and 2) the preparing method of the crizotinib is high in total yield, the obtained product has high optical purity, the required reaction condition and reaction process are easy to control, and a new choice is provided for preparation and production of the medicament crizotinib.
Description
Technical field
The present invention relates to a kind of preparation method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine, belong to medical synthesis technical field.
Background technology
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine is the competitive micromolecular inhibitor of the ATP with the kinase catalytic activity of c-Met that a kind of oral administration biaavailability is higher, it can effectively suppress the phosphorylation of c-Met, and can effectively suppress in vitro cell proliferation, the migration and invasion (IC50 value is 5～20nmolPL) that c-Met relies on, in addition, it can also effectively suppress the vascularization that HGF stimulates the endothelial cell proliferation cause and invasion and attack and serum stimulation to cause.(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine tolerance is good, and its anti-tumor activity presents obvious dose-dependently [CancerRes., 2007,67 (9): 44082-44171].
The English name of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine:
(R)-3-(1-(2,6-dichloro-3-fluorophenyl) ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl) pyridin-2-amine; Molecular formula: C
21h
22cl
2fN
5o; Molecular weight: 449.12; Outward appearance: white powder.
Structural formula is as follows:
In the synthesis step of c-Met inhibitor (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine, the asymmetric synthesis of intermediate (2) is the key of synthesising target compound.Mainly contain at present two kinds of synthesis techniques:
1) original patent (WO2006021881A2, WO2007066187A2, WO2009036404A2) discloses the synthetic of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and key intermediate (2).Above-mentioned publication is mainly to see following formula by the synthetic key intermediate (2) of method of esterase catalyzed hydrolysis; take substituted acetophenone as raw material through reduction, acetylize two steps obtain compd A 2; A2 obtains the mixture of S2 and R1 again by enzymatic method; continue the mixture that methylsulfonyl obtains R3 and S2; acetylize, hydrolysis obtains key intermediate (2).The shortcoming of the method is: 1. the enzymic catalytic reaction required time of compd A 2 is long, severe reaction conditions; 2. reaction yield is low, complicated operation, experiment poor reproducibility; 3. enzyme catalyst is expensive; 4. be difficult to large-scale industrial production.
2) chemical resolution method (CN101735198A)
With raceme phenylethyl alcohol with the separated chirality that obtains after resolving agent (0.5-0.9 equivalent) condensation for phenylethyl alcohol (2), further through polystep reactions such as condensations, reduction, bromo, coupling, deprotection, prepare (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.The inventive method is prepared (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine, and raw material is easy to get, reaction conditions gentle, optical purity is good, but split, a step is the highest can only 50% yield, so whole route yield (seeing following formula) on the low side.
Summary of the invention
The object of the invention is in order to overcome available technology adopting biological enzyme, step number is many, cycle is long and chemical resolution method yield is low, the shortcoming that is unfavorable for scale operation, provide a kind of employing asymmetry catalysis method one-step synthesis key intermediate (2) with low cost, easy and simple to handle, yield is high, optical purity good and be applicable to the preparation method of the (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine of scale operation.
The preparation method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine of the present invention, comprises the following steps:
1) take structural formula methyl phenyl ketone is as the formula (1) raw material, in solvent by the catalysis of organic micromolecule catalyst Cat*, at reductive agent metal borohydride A
1with trialkylchlorosilane A
2effect under, asymmetric reduction is the phenylethyl alcohol of structural formula (S)-configuration as the formula (2), temperature of reaction is 20～80 ℃;
2) by the phenylethyl alcohol of (the S)-configuration making in previous step in solvent with reactant A
3, reactant A
4and structural formula 2-nitro-3-pyridone is as the formula (3) at catalyzer C
1the lower reaction of effect obtains structural formula nitro-compound as the formula (4), described reactant A
3for triphenyl phosphorus, described reactant A
4for DEAD or DIAD, temperature of reaction is-20～30 ℃;
3) by the structural formula making in previous step nitro-compound as the formula (4) in solvent with reductive agent A
5reaction generating structure formula aromatic amine compound as the formula (5), temperature of reaction is-20～30 ℃;
4) by the structural formula making in previous step aromatic amine compound as the formula (5) in solvent with compd A
6reaction generating structure formula bromo-derivative as the formula (6), described A
6for brominated reagent NBS or bromine, temperature of reaction is-20～30 ℃;
5) by bromo-derivative as the formula (6) of the structural formula making in previous step and structural formula boric acid ester as the formula (7) in solvent with alkali A
7with catalyzer C
2acting in conjunction generating structure formula N-Boc compound as the formula (8), temperature of reaction is 0～130 ℃;
6) by the structural formula making in previous step N-Boc compound as the formula (8) in solvent with sour A
8reaction obtains structural formula (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine as the formula (9), and temperature of reaction is-10～50 ℃.
Hydroborate A in described step (1)
1be selected from sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, zinc borohydride; Described trialkylchlorosilane A
2be selected from trimethylchlorosilane, chlorotriethyl silane, tri-tert chlorobutane or TERT-BUTYL DIMETHYL CHLORO SILANE; Described organic micromolecule catalyst Cat* is selected from (S)-diphenylprolinol; Described solvent is alcohols, ethers or its mixed solvent; Described temperature of reaction is 70 ℃.
Catalyzer C1 in described step (2) is DMAP (DMAP); Described solvent is ether solvent; Described temperature of reaction is room temperature.
Described ether solvent is tetrahydrofuran (THF) or ether.
Reductive agent A in described step (3)
5for reduced iron powder or zinc powder; Described solvent is protic solvent; Described temperature of reaction is room temperature.
Described protic solvent is selected from ethanol, acetic acid or its mixed solvent.
Solvent in described step (4) is tetracol phenixin; Described temperature of reaction is room temperature.
A in described step (5)
7for alkali-metal carbonate or supercarbonate; Described C
3for palladium, four triphenyl phosphorus palladiums or dichloro two triphenyl phosphorus palladiums; Described solvent is polar aprotic solvent; Temperature of reaction is 87 ℃.
Described A
7for salt of wormwood, described solvent is dimethyl formamide.
Sour A in described step (6)
8for HCl or trifluoroacetic acid; Described solvent is in ethyl acetate, tetrahydrofuran (THF), dioxane or the mixed solvent of its two or more solvents; Temperature of reaction is 25 ℃.
The preparation method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine of the present invention, compared with prior art has the following advantages:
1, the present invention uses organocatalysis method to replace existing biological enzyme and chemical resolution method, and the whole piece route reaction cycle is short, and yield is high, simple to operate, and raw material sources are wide, cheap;
2, the method total recovery of preparing (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine provided by the invention high, product optical purity high, react required condition and reaction process is easy to control, for the preparation of medicine (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and produce new selection is provided.
Accompanying drawing explanation
Fig. 1 is the preparation flow figure of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine of the present invention.
Fig. 2 is the mass spectrum of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine of the present invention.
Fig. 3 is (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine of the present invention
1hNMR report.
Embodiment
By the following examples the present invention is further described, but not in order to limit the present invention.
The method of preparing (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine of the present embodiment, comprises the following steps:
1) preparation of the phenylethyl alcohol of (S)-configuration
The trimethylchlorosilane (130g, 1.2mol) newly steaming is joined to the dry THF (5L) of sodium borohydride (45g, 1.2mol).Reaction mixture, 70 ℃ of heating 1 hour, is chilled to room temperature, adds the THF solution (0.1mol, 2L) of (S)-diphenylprolinol.When without γ-ray emission, slowly add the THF solution (1mol, 2L) of methyl phenyl ketone.After reacting completely, add the aqueous hydrochloric acid (5L) of 2N.With ether (10L) extraction three times.The organic phase merging is with saturated common salt water washing three times.Dry, concentrated.Obtain white solid, yield 98%, ee value: 96%.
2) preparation of nitro-compound
By 94g triphenylphosphine, 52g phenylethyl alcohol and 38g3-hydroxyl-nitropyridine are dissolved in 200mL tetrahydrofuran (THF), are cooled to 0 ℃, add the DIAD of 72.4g.Mixture is stirring at room 3h under nitrogen protection, after TLC detection reaction is complete, and concentration of reaction solution, thick product column chromatography (EA:HEX=1:4) obtains white solid nitro-compound, yield: 85%.
3) preparation of aromatic amine compound
By after 41g nitro-compound and 200mL acetic acid and the mixing of 220mL ethanol, slowly add 6.95g iron filings, then, slowly be warming up to reflux state and stir 1 hour, after TLC detection reaction is complete, adding 500mL ether and 500mL water, reaction solution neutralizes with sodium carbonate, layering, and organic phase is with NaHCO
3the aqueous solution, dry after water and salt solution washing, filter, concentrated, obtain pink solid, yield: 96%.
4) preparation of bromo-derivative
35g aromatic amine compound is dissolved in acetonitrile, is down to 0 ℃, add 20.7gNBS, stir 15 minutes, concentrated, add ether and water, after organic phase is dry, obtain yellow solid bromo-derivative, yield 97%.
5) preparation of N-Boc compound
7.08g bromo-derivative and 6.4g boric acid ester are dissolved in 70mLDMF, add containing 5.4gNa
2cO
3the 17mL aqueous solution, with nitrogen replacement air three times, add 596mgPd (PPh
3)
2cl
2use again nitrogen replacement air three times, reaction mixture is warmed up to 87 ℃ and stirs 16 hours, after TLC detection reaction is complete, is down to room temperature, add the dilution of 600mL ethyl acetate, diatomite filtration, with ethyl acetate washing, the ethyl acetate of merging is concentrated after with dried over sodium sulfate, thick product is through column chromatography purification, yield: 65%.
6) preparation of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine
Solid 100mgN-Boc compound is dissolved in a small amount of methylene dichloride, 0 ℃ of stirring, adds the ethyl acetate solution 2mL of 4NHCl, stir after 20 minutes, after TLC detection reaction is complete, removal of solvent under reduced pressure, add 10mL water, with sodium bicarbonate solid, regulate pH=10, dry after use dichloromethane extraction, concentrated, recrystallization, obtain off-white color solid, yield 90%, ee%:99%.
The preparation method of the present embodiment, comprises the following steps:
1) preparation of the phenylethyl alcohol of (S)-configuration
The trimethylchlorosilane (130g, 1.2mol) newly steaming is joined to the dry THF (5L) of POTASSIUM BOROHYDRIDE (65g, 1.2mol).Reaction mixture, 70 ℃ of heating 1 hour, is chilled to room temperature, adds the THF solution (0.1mol, 2L) of (S)-diphenylprolinol.When without γ-ray emission, slowly add the THF solution (1mol, 2L) of methyl phenyl ketone.After reacting completely, add the aqueous hydrochloric acid (5L) of 2N.With ether (10L) extraction three times.The organic phase merging is with saturated common salt water washing three times.Dry, concentrated.Obtain white solid, yield 96%, ee value: 96%.
2) preparation of nitro-compound
By 94g triphenylphosphine, 52g phenylethyl alcohol and 38g3-hydroxyl-nitropyridine are dissolved in 200mL tetrahydrofuran (THF), are cooled to 0 ℃, add the DEAD of 62.4g.Mixture is stirring at room 3h under nitrogen protection, after TLC detection reaction is complete, and concentration of reaction solution, thick product column chromatography (EA:HEX=1:4) obtains white solid nitro-compound, yield 83%.
3) preparation of aromatic amine compound
By after 41g nitro-compound and 200mL acetic acid and the mixing of 220mL ethanol, slowly add 6.95g iron filings, then, slowly be warming up to reflux state and stir 1 hour, after TLC detection reaction is complete, adding 500mL ether and 500mL water, reaction solution neutralizes with sodium carbonate, layering, and organic phase is with NaHCO
3the aqueous solution, dry after water and salt solution washing, filter, concentrated, obtain a pink solid, yield: 93%.
4) preparation of bromo-derivative
35g aromatic amine compound is dissolved in acetonitrile, is down to 0 ℃, add 20.7gNBS, stir 15 minutes, concentrated, add ether and water, after organic phase is dry, obtain yellow solid bromo-derivative, yield: 95%.
5) preparation of N-Boc compound
7.08g bromo-derivative and 6.4g boric acid ester are dissolved in 70mLDMF, add containing 5.4gNa
2cO
3the 17mL aqueous solution, with nitrogen replacement air three times, add 596mgPd (PPh
3)
2cl
2use nitrogen replacement air three times, reaction mixture is warmed up to 87 ℃ and stirs 16 hours again, after TLC detection reaction is complete, be down to room temperature, add the dilution of 600mL ethyl acetate, diatomite filtration, washs by ethyl acetate, the ethyl acetate merging is concentrated after with dried over sodium sulfate, thick product, through column chromatography purification, obtains light yellow solid, yield 62%.
6) preparation of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine
Solid 100mgN-Boc compound is dissolved in a small amount of methylene dichloride, 0 ℃ of stirring, adds the ethyl acetate solution 2mL of 4NHCl, stir after 20 minutes, after TLC detection reaction is complete, removal of solvent under reduced pressure, add 10mL water, with sodium bicarbonate solid, regulate pH=10, dry after use dichloromethane extraction, concentrated, recrystallization, obtain off-white color solid, yield 89%, ee%:99%.
The preparation method of the present embodiment, comprises the following steps:
1) preparation of the phenylethyl alcohol of (S)-configuration
The TERT-BUTYL DIMETHYL CHLORO SILANE (180g, 1.2mol) of newly steaming is joined to the dry THF (5L) of POTASSIUM BOROHYDRIDE (65g, 1.2mol).Reaction mixture, 70oC heating 1 hour, is chilled to room temperature, adds the THF solution (0.1mol, 2L) of (S)-diphenylprolinol.When without γ-ray emission, slowly add the THF solution (1mol, 2L) of methyl phenyl ketone.After reacting completely, add the aqueous hydrochloric acid (5L) of 2N.With ether (10L) extraction three times.The organic phase merging is with saturated common salt water washing three times.Dry, concentrated.Obtain white solid, yield 97%, ee value: 96%.
2) preparation of nitro-compound
By 94g triphenylphosphine, 52g phenylethyl alcohol and 38g3-hydroxyl-nitropyridine are dissolved in 200mL tetrahydrofuran (THF), are cooled to 0 ℃, add the DEAD of 62.4g.Mixture is stirring at room 3h under nitrogen protection, after TLC detection reaction is complete, and concentration of reaction solution, thick product column chromatography (EA:HEX=1:4) obtains white solid nitro-compound, yield: 83%.
3) preparation of aromatic amine compound
By after 41g nitro-compound and 200mL acetic acid and the mixing of 220mL ethanol, slowly add 8.07g zinc powder, then, slowly be warming up to reflux state and stir 1 hour, after TLC detection reaction is complete, adding 500mL ether and 500mL water, reaction solution neutralizes with sodium carbonate, layering, and organic phase is with NaHCO
3the aqueous solution, dry after water and salt solution washing, filter, concentrated, obtain a pink solid, yield: 86%.
4) preparation of bromo-derivative
35g aromatic amine compound is dissolved in acetonitrile, is down to 0 ℃, add 18.6gNBS, stir 15 minutes, concentrated, add ether and water, after organic phase is dry, obtain yellow solid bromo-derivative, yield 88%.
5) preparation of N-Boc compound
7.08g bromo-derivative and 6.4g boric acid ester are dissolved in 70mLDMF, add containing 5.4gNa
2cO
3the 17mL aqueous solution, with nitrogen replacement air three times, add 596mgPd (PPh
3)
2cl
2use nitrogen replacement air three times, reaction mixture is warmed up to 87 ℃ and stirs 16 hours again, after TLC detection reaction is complete, be down to room temperature, add the dilution of 600mL ethyl acetate, diatomite filtration, washs by ethyl acetate, the ethyl acetate merging is concentrated after with dried over sodium sulfate, thick product, through column chromatography purification, obtains faint yellow solid, yield 59%.
6) preparation of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine
Solid 100mgN-Boc compound is dissolved in a small amount of methylene dichloride, 0 ℃ of stirring, adds trifluoroacetic ethyl acetate solution (M=1) 2mL, stir after 20 minutes, after TLC detection reaction is complete, removal of solvent under reduced pressure, add 10mL water, with sodium bicarbonate solid, regulate pH=10, dry after use dichloromethane extraction, concentrated, recrystallization, obtain off-white color solid, yield 78%, ee:99.9%.
MSm/e450 (M+1) (see figure 1).
1hNMR (DMSO, 300MHz) (see figure 2) δ 7.92 (s, 1H), 7.76 (s, 1H), 7.58 (m, 1H), 7.53 (s, 1H), 7.45 (m, 1H), 6.90 (s, 1H), 6.10 (m, 1H), 5.55 (bs, 1H), 4.14 (m, 1H), 3.05 (m, 2H), 2.58 (m, 2H), 1.94 (m, 1H), 1.80 (d, 3H), 1.76 (m, 1H).
Claims (9)
1. a preparation method for (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine, is characterized in that, comprises the following steps:
1) take structural formula methyl phenyl ketone is as the formula (1) raw material, in solvent by the catalysis of organic micromolecule catalyst Cat*, at reductive agent metal borohydride A
1with trialkylchlorosilane A
2effect under, asymmetric reduction is the phenylethyl alcohol of structural formula (S)-configuration as the formula (2), temperature of reaction is 20～80 ℃;
2) by the phenylethyl alcohol of (the S)-configuration making in previous step in solvent with reactant A
3, reactant A
4and structural formula 2-nitro-3-pyridone is as the formula (3) at catalyzer C
1the lower reaction of effect obtains structural formula nitro-compound as the formula (4), described reactant A
3for triphenyl phosphorus, described reactant A
4for DEAD or DIAD, temperature of reaction is-20～30 ℃;
3) by the structural formula making in previous step nitro-compound as the formula (4) in solvent with reductive agent A
5reaction generating structure formula aromatic amine compound as the formula (5), temperature of reaction is-20～30 ℃;
4) by the structural formula making in previous step aromatic amine compound as the formula (5) in solvent with compd A
6reaction generating structure formula bromo-derivative as the formula (6), described A
6for brominated reagent NBS or bromine, temperature of reaction is-20～30 ℃;
5) by bromo-derivative as the formula (6) of the structural formula making in previous step and structural formula boric acid ester as the formula (7) in solvent with alkali A
7with catalyzer C
2acting in conjunction generating structure formula N-Boc compound as the formula (8), temperature of reaction is 0～130 ℃;
6) by the structural formula making in previous step N-Boc compound as the formula (8) in solvent with sour A
8reaction obtains structural formula (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine as the formula (9), and temperature of reaction is-10～50 ℃;
Hydroborate A in described step (1)
1be selected from sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, zinc borohydride; Described trialkylchlorosilane A
2be selected from trimethylchlorosilane, chlorotriethyl silane, tri-tert chlorobutane or TERT-BUTYL DIMETHYL CHLORO SILANE; Described organic micromolecule catalyst Cat* is selected from (S)-diphenylprolinol; Described solvent is alcohols, ethers or its mixed solvent.
2. the preparation method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine according to claim 1, is characterized in that, the catalyzer C in described step (2)
1for DMAP; Described solvent is ether solvent; Described temperature of reaction is room temperature.
3. the preparation method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine according to claim 2, is characterized in that, described ether solvent is tetrahydrofuran (THF) or ether.
4. the preparation method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine according to claim 1, is characterized in that, the reductive agent A in described step (3)
5for reduced iron powder or zinc powder; Described solvent is protic solvent; Described temperature of reaction is room temperature.
5. the preparation method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine according to claim 4, is characterized in that, described protic solvent is selected from ethanol, acetic acid or its mixed solvent.
6. the preparation method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine according to claim 1, is characterized in that, the solvent in described step (4) is tetracol phenixin; Described temperature of reaction is room temperature.
7. the preparation method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine according to claim 1, is characterized in that, the A in described step (5)
7for alkali-metal carbonate or supercarbonate; Described C
2for palladium, four (triphenyl phosphorus) palladium or dichloro two (triphenyl phosphorus) palladium; Described solvent is polar aprotic solvent; Temperature of reaction is 87 ℃.
8. the preparation method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine according to claim 7, is characterized in that, described A
7for salt of wormwood, described solvent is dimethyl formamide.
9. the preparation method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine according to claim 1, is characterized in that, the sour A in described step (6)
8for HCl or trifluoroacetic acid; Described solvent is the mixed solvent of ethyl acetate, tetrahydrofuran (THF), dioxane or its two or more solvents; Temperature of reaction is 25 ℃.
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| CN103319311B (en) * | 2012-03-23 | 2015-09-30 | 浙江九洲药物科技有限公司 | The preparation method of Crizotinib intermediate (1S)-1-(the chloro-3-fluorophenyl of 2,6-bis-) ethanol |
| CN102898449B (en) * | 2012-09-21 | 2015-06-03 | 同济大学 | Method for synthesizing Crizotinib intermediate |
| CN104829468B (en) * | 2014-02-10 | 2017-03-08 | 成都先基生化科技有限公司 | （R）The asymmetric preparation method of albuterol hydrochloride |
| CN105016977A (en) * | 2014-04-30 | 2015-11-04 | 重庆华邦制药有限公司 | Method for industrially preparing chiral halogenated phenethyl alcohol derivatives |
| CN105348265A (en) * | 2014-08-19 | 2016-02-24 | 蔡苹 | Preparation and applications of 2,4-disubstituted heterocyclic triazole compound having ALK and c-met inhibition activity |
| CN105820113B (en) * | 2015-01-07 | 2018-04-20 | 爱技特科技（北京）有限公司 | A kind of gram of azoles replaces the preparation method of Buddhist nun's chiral intermediate |
| CN105924431B (en) * | 2016-05-31 | 2018-08-07 | 甘肃皓骏医药科技有限责任公司 | Compound gram azoles replaces the synthesis technology of Buddhist nun |
| CN113816943B (en) * | 2017-12-25 | 2024-02-13 | 重庆圣华曦药业股份有限公司 | Resolution method of droxidopa key intermediate |
| CN108383703B (en) * | 2018-03-30 | 2021-08-03 | 兰州紫东药业有限公司 | 3' -chlorophenylpropanol synthesis process |
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