CN102584795A - Preparing method of crizotinib - Google Patents
Preparing method of crizotinib Download PDFInfo
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- CN102584795A CN102584795A CN2012100098706A CN201210009870A CN102584795A CN 102584795 A CN102584795 A CN 102584795A CN 2012100098706 A CN2012100098706 A CN 2012100098706A CN 201210009870 A CN201210009870 A CN 201210009870A CN 102584795 A CN102584795 A CN 102584795A
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- 238000000034 method Methods 0.000 title abstract description 17
- 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 abstract description 7
- 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 59
- 238000002360 preparation method Methods 0.000 claims abstract description 41
- 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 22
- 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 6
- 150000003851 azoles Chemical class 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 230000002829 reductive effect Effects 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-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
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- 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
- 239000012046 mixed solvent Substances 0.000 claims description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-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
- 229910021529 ammonia Inorganic materials 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
- 235000015177 dried meat Nutrition 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
- 101100136092 Drosophila melanogaster peng gene Proteins 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
- 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
- 229960000549 4-dimethylaminophenol Drugs 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
- JQIVECLQPHOSDY-KRWDZBQOSA-N [(2r)-1,2-diphenylpyrrolidin-2-yl]methanol Chemical compound C([C@]1(CO)C=2C=CC=CC=2)CCN1C1=CC=CC=C1 JQIVECLQPHOSDY-KRWDZBQOSA-N 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
- 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
- 229910052763 palladium Inorganic materials 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
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 claims 1
- 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
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000010276 construction 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000012141 concentrate Substances 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
- 238000001035 drying Methods 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 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
- QBPDSKPWYWIHGA-UHFFFAOYSA-N 3-hydroxy-2-nitropyridine Chemical compound OC1=CC=CN=C1[N+]([O-])=O QBPDSKPWYWIHGA-UHFFFAOYSA-N 0.000 description 3
- 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
- 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 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007789 gas Substances 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
- 239000011734 sodium Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017550 sodium carbonate 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
- 238000010792 warming Methods 0.000 description 3
- 0 *C([N+]([O-])=O)=*(*)O Chemical compound *C([N+]([O-])=O)=*(*)O 0.000 description 2
- 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
- 230000009545 invasion Effects 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 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
- 201000011510 cancer Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000012292 cell migration 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
- 230000000694 effects Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000013508 migration 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
- 239000002512 suppressor factor Substances 0.000 description 1
- 230000002194 synthesizing effect 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 that azoles belongs to medical synthesis technical field for Buddhist nun's preparation method in a kind of gram.
Background technology
In the gram azoles for the Buddhist nun be a kind of oral administration biaavailability higher have a competitive micromolecular inhibitor of the kinase catalytic active ATP of c-Met; It can effectively suppress the phosphorylation of c-Met; And cell proliferation, migration and the invasion and attack that can rely at external effective inhibition c-Met (the IC50 value is 5～20nmolPL); 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.Azoles is good for Buddhist nun's tolerance in the gram, and its anti-tumor activity presents tangible dose-dependently [Cancer Res., 2007,67 (9): 44082-44171].
Azoles replaces Buddhist nun's English name in the gram:
(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 following:
Azoles is in Buddhist nun's the synthesis step in c-Met suppressor factor gram, and the asymmetric synthesis of midbody (2) is the key of synthesising target compound.Mainly contain two kinds of synthesis techniques at present:
1) (WO2006021881A2, WO2007066187A2 WO2009036404A2) disclose azoles synthesizing for Buddhist nun and key intermediate (2) in the gram to original patent.Above-mentioned publication mainly is to synthesize key intermediate (2) formula as follows through the method for esterase catalyzed hydrolysis; With the substituted acetophenone is that raw material obtains compd A 2 through reduction, two steps of acetylize; A2 obtains the mixture of S2 and R1 again through enzymatic method; Continue the mixture that methylsulfonylization obtains R3 and S2, acetylize, hydrolysis obtain key intermediate (2).The shortcoming of this 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 costs an arm and a leg; 4. be difficult to large-scale industrial production.
2) chemical resolution method (CN101735198A)
Obtain chirality for phenylethyl alcohol (2) to separate after raceme phenylethyl alcohol and resolving agent (0.5-0.9 equivalent) condensation, further prepare in the gram azoles for the Buddhist nun through polystep reactions such as condensation, reduction, bromo, coupling, deprotections.Azoles is for the Buddhist nun in the inventive method preparation gram, and raw material is easy to get, reaction conditions gentle, optical purity is good, but splitting a step the highlyest can only have 50% yield, so whole route yield (formula as follows) on the low side.
Summary of the invention
The objective of the invention is in order to overcome the available technology adopting biological enzyme; Step number is many; Cycle is long and the 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 that azoles is for Buddhist nun's preparation method in the gram of scale operation.
Azoles may further comprise the steps for Buddhist nun's preparation method in the gram of the present invention:
1) is raw material with structural formula suc as formula the methyl phenyl ketone shown in (1), in solvent, passes through 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 suc as formula (the S)-configuration shown in (2), temperature of reaction is 20～80 ℃;
2) phenylethyl alcohol that will go up (S)-configuration of making in the step in solvent with reactant A
3, reactant A
4And structural formula reacts under catalyzer C1 effect suc as formula the 2-nitro-3-pyridone shown in (3) and obtains structural formula suc as formula the nitro-compound shown in (4), described reactant A
3Be triphenyl phosphorus, described reactant A
4Be DEAD or DIAD, temperature of reaction is-20～30 ℃;
3) will go up in the step structural formula that makes suc as formula the nitro-compound shown in (4) in solvent with reductive agent A
5Reaction generating structure formula is suc as formula the aromatic amine compound shown in (5), and temperature of reaction is-20～30 ℃;
4) will go up in the step structural formula that makes suc as formula the aromatic amine compound shown in (5) in solvent with compd A
6Reaction generating structure formula is suc as formula the bromo-derivative shown in (6), described A
6Be brominated reagent NBS or bromine, temperature of reaction is-20～30 ℃;
5) will go up in the step structural formula that makes suc as formula the bromo-derivative shown in (6) and structural formula suc as formula the boric acid ester shown in (7) in solvent with alkali A
7With catalyzer C
2Acting in conjunction generating structure formula is suc as formula the N-Boc compound shown in (8), and temperature of reaction is 0～130 ℃;
6) will go up in the step structural formula that makes suc as formula the N-Boc compound shown in (8) in solvent with sour A
8Reaction obtains structural formula and replaces the Buddhist nun suc as formula azoles in the gram shown in (9), and temperature of reaction is-10～50 ℃.
Hydroborate A in the described step (1)
1Be selected from Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN, 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 (R)-diphenylprolinol, (R)-xylyl dried meat ammonia alcohol, (R)-dinaphthyl dried meat ammonia alcohol or derivatives thereof; Described solvent is alcohols, ethers or its mixed solvent; Described temperature of reaction is 70 ℃.
Catalyzer C in the described step (2)
1Be DMAP (4-Dimethylamino pyridine); Described solvent is an ether solvent; Described temperature of reaction is a room temperature.
Described ether solvent is THF or ether.
Reductive agent A in the described step (3)
5Be reduced iron powder or zinc powder; Described solvent is a protic solvent; Described temperature of reaction is a room temperature.
Described protic solvent is selected from ethanol, acetate or its mixed solvent.
Solvent in the described step (4) is a tetracol phenixin; Described temperature of reaction is a room temperature.
A in the described step (5)
7Be alkali-metal carbonate or supercarbonate; Described C
3Be palladium, four triphenyl phosphorus palladiums or dichloro two triphenyl phosphorus palladiums; Described solvent is a polar aprotic solvent; Temperature of reaction is 87 ℃.
Described A
7Be salt of wormwood, described solvent is a N.
Sour A in the described step (6)
8Be HCl or trifluoroacetic acid; Described solvent is in ETHYLE ACETATE, THF, the dioxane or the mixed solvent of its two or more solvents; Temperature of reaction is 25 ℃.
Azoles compared with prior art has the following advantages for Buddhist nun's preparation method in the gram of the present invention:
1, the present invention uses the organic molecule catalysis 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, and are cheap;
2, provided by the inventionly prepare in the gram that azoles product optical purity high for Buddhist nun's method total recovery, institute is high, the required condition of reaction and reaction process is easy to control, prepare for the Buddhist nun and production provides new selection for azoles in the medicine gram.
Description of drawings
Fig. 1 is the preparation flow figure that azoles replaces the Buddhist nun in the gram of the present invention.
Fig. 2 is the mass spectrum that azoles replaces the Buddhist nun in the gram of the present invention.
Fig. 3 is that azoles replaces the Buddhist nun's in the gram of the present invention
1The HNMR report.
Embodiment
Below through embodiment the present invention is further specified, but be not in order to limit the present invention.
Azoles is for the Buddhist nun in the embodiment 1 preparation gram
Present embodiment prepare that azoles may further comprise the steps for Buddhist nun's method in the gram:
1) (S)-preparation of the phenylethyl alcohol of configuration
(130g 1.2mol) joins Peng Qinghuana (45g, dry THF 1.2mol) (5L) with the trimethylchlorosilane that newly steams.Reaction mixture is chilled to room temperature 70 ℃ of heating 1 hour, and the THF solution of adding (S)-diphenylprolinol (0.1mol, 2L).When waiting not have gas and producing, slowly add methyl phenyl ketone THF solution (1mol, 2L).After reacting completely, add the aqueous hydrochloric acid (5L) of 2N.With ether (10L) extraction three times.The organic phase that merges is with saturated common salt water washing three times.Drying concentrates.Obtain white solid, yield 98%, ee value: 96%.
2) preparation of nitro-compound
With the 94g triphenylphosphine, 52g phenylethyl alcohol and 38g 3-hydroxyl-nitropyridine are dissolved in the 200mL THF, are cooled to 0 ℃, add the DIAD of 72.4g.Mixture is stirring at room 3h under nitrogen protection, after the TLC detection reaction is complete, and concentration of reaction solution, thick product column chromatography (EA: HEX=1: 4) obtain the white solid nitro-compound, yield: 85%.
3) preparation of aromatic amine compound
After 41g nitro-compound and 200mL acetic acid and the mixing of 220mL ethanol, slowly add the 6.95g iron filings, then; Slowly be warming up to reflux state and stirred 1 hour, the TLC detection reaction fully after, add 500mL ether and 500mL water; Reaction solution neutralizes with yellow soda ash, layering, and organic phase is with NaHCO
3The aqueous solution, water and salt solution washing after drying filter, and concentrate, and obtain pink solid, yield: 96%.
4) preparation of bromo-derivative
The 35g aromatic amine compound is dissolved in the acetonitrile, reduces to 0 ℃, add 20.7g NBS, stirred 15 minutes, concentrate, add ether and water, obtain the yellow solid bromo-derivative after the organic phase drying, yield 97%.
5) preparation of N-Boc compound
7.08g bromo-derivative and 6.4g boric acid ester are dissolved among the 70mL DMF, add and contain 5.4g Na
2CO
3The 17mL aqueous solution, with nitrogen replacement air three times, add 596mg Pd (PPh
3)
2Cl
2, use the nitrogen replacement air again three times, reaction mixture is warmed up to 87 ℃ and stirred 16 hours; After the TLC detection reaction is complete, reduce to room temperature, add the dilution of 600mL ETHYLE ACETATE; Diatomite filtration, with ETHYLE ACETATE washing, the ETHYLE ACETATE of merging concentrates after with dried over sodium sulfate; Thick product is through column chromatography purification, yield: 65%.
6) in the gram azoles for Buddhist nun's preparation
Solid 100mg N-Boc compound is dissolved in a small amount of methylene dichloride,, adds the ethyl acetate solution 2mL of 4N HCl, stir after 20 minutes 0 ℃ of stirring; After the TLC detection reaction was complete, removal of solvent under reduced pressure added 10mL water, regulates pH=10 with sodium bicarbonate solid; Use the dichloromethane extraction after drying, concentrate recrystallization; Obtain the off-white color solid, yield 90%, ee%:99%.
Azoles is for the Buddhist nun in the embodiment 2 preparation grams
The preparation method of present embodiment may further comprise the steps:
1) (S)-preparation of the phenylethyl alcohol of configuration
(130g 1.2mol) joins POTASSIUM BOROHYDRIDE 97MIN (65g, dry THF 1.2mol) (5L) with the trimethylchlorosilane that newly steams.Reaction mixture is chilled to room temperature 70 ℃ of heating 1 hour, and the THF solution of adding (S)-diphenylprolinol (0.1mol, 2L).When waiting not have gas and producing, slowly add methyl phenyl ketone THF solution (1mol, 2L).After reacting completely, add the aqueous hydrochloric acid (5L) of 2N.With ether (10L) extraction three times.The organic phase that merges is with saturated common salt water washing three times.Drying concentrates.Obtain white solid, yield 96%, ee value: 96%.
2) preparation of nitro-compound
With the 94g triphenylphosphine, 52g phenylethyl alcohol and 38g 3-hydroxyl-nitropyridine are dissolved in the 200mL THF, are cooled to 0 ℃, add the DEAD of 62.4g.Mixture is stirring at room 3h under nitrogen protection, after the TLC detection reaction is complete, and concentration of reaction solution, thick product column chromatography (EA: HEX=1: 4) obtain the white solid nitro-compound, yield 83%.
3) preparation of aromatic amine compound
After 41g nitro-compound and 200mL acetic acid and the mixing of 220mL ethanol, slowly add the 6.95g iron filings, then; Slowly be warming up to reflux state and stirred 1 hour, the TLC detection reaction fully after, add 500mL ether and 500mL water; Reaction solution neutralizes with yellow soda ash, layering, and organic phase is with NaHCO
3The aqueous solution, water and salt solution washing after drying filter, and concentrate, and obtain a pink solid, yield: 93%.
4) preparation of bromo-derivative
The 35g aromatic amine compound is dissolved in the acetonitrile, reduces to 0 ℃, add 20.7g NBS, stirred 15 minutes, concentrate, add ether and water, obtain the yellow solid bromo-derivative after the organic phase drying, yield: 95%.
5) preparation of N-Boc compound
7.08g bromo-derivative and 6.4g boric acid ester are dissolved among the 70mL DMF, add and contain 5.4g Na
2CO
3The 17mL aqueous solution, with nitrogen replacement air three times, add 596mg Pd (PPh
3)
2Cl
2, use the nitrogen replacement air again three times, reaction mixture is warmed up to 87 ℃ and stirred 16 hours; After the TLC detection reaction is complete, reduce to room temperature, add the dilution of 600mL ETHYLE ACETATE; Diatomite filtration, with ETHYLE ACETATE washing, the ETHYLE ACETATE of merging concentrates after with dried over sodium sulfate; Thick product obtains light yellow solid, yield 62% through column chromatography purification.
6) in the gram azoles for Buddhist nun's preparation
Solid 100mg N-Boc compound is dissolved in a small amount of methylene dichloride,, adds the ethyl acetate solution 2mL of 4N HCl, stir after 20 minutes 0 ℃ of stirring; After the TLC detection reaction was complete, removal of solvent under reduced pressure added 10mL water, regulates pH=10 with sodium bicarbonate solid; Use the dichloromethane extraction after drying, concentrate recrystallization; Obtain the off-white color solid, yield 89%, ee%:99%.
Azoles is for the Buddhist nun in the embodiment 3 preparation grams
The preparation method of present embodiment may further comprise the steps:
1) (S)-preparation of the phenylethyl alcohol of configuration
(180g 1.2mol) joins POTASSIUM BOROHYDRIDE 97MIN (65g, dry THF 1.2mol) (5L) with the TERT-BUTYL DIMETHYL CHLORO SILANE that newly steams.Reaction mixture is chilled to room temperature 70oC heating 1 hour, and the THF solution of adding (S)-diphenylprolinol (0.1mol, 2L).When waiting not have gas and producing, slowly add methyl phenyl ketone THF solution (1mol, 2L).After reacting completely, add the aqueous hydrochloric acid (5L) of 2N.With ether (10L) extraction three times.The organic phase that merges is with saturated common salt water washing three times.Drying concentrates.Obtain white solid, yield 97%, ee value: 96%.
2) preparation of nitro-compound
With the 94g triphenylphosphine, 52g phenylethyl alcohol and 38g 3-hydroxyl-nitropyridine are dissolved in the 200mL THF, are cooled to 0 ℃, add the DEAD of 62.4g.Mixture is stirring at room 3h under nitrogen protection, after the TLC detection reaction is complete, and concentration of reaction solution, thick product column chromatography (FA: HEX=1: 4) obtain the white solid nitro-compound, yield: 83%.
3) preparation of aromatic amine compound
After 41g nitro-compound and 200mL acetic acid and the mixing of 220mL ethanol, slowly add the 8.07g zinc powder, then; Slowly be warming up to reflux state and stirred 1 hour, the TLC detection reaction fully after, add 500mL ether and 500mL water; Reaction solution neutralizes with yellow soda ash, layering, and organic phase is with NaHCO
3The aqueous solution, water and salt solution washing after drying filter, and concentrate, and obtain a pink solid, yield: 86%.
4) preparation of bromo-derivative
The 35g aromatic amine compound is dissolved in the acetonitrile, reduces to 0 ℃, add 18.6g NBS, stirred 15 minutes, concentrate, add ether and water, obtain the yellow solid bromo-derivative after the organic phase drying, yield 88%.
5) preparation of N-Boc compound
7.08g bromo-derivative and 6.4g boric acid ester are dissolved among the 70mL DMF, add and contain 5.4g Na
2CO
3The 17mL aqueous solution, with nitrogen replacement air three times, add 596mg Pd (PPh
3)
2Cl
2, use the nitrogen replacement air again three times, reaction mixture is warmed up to 87 ℃ and stirred 16 hours; After the TLC detection reaction is complete, reduce to room temperature, add the dilution of 600mL ETHYLE ACETATE; Diatomite filtration, with ETHYLE ACETATE washing, the ETHYLE ACETATE of merging concentrates after with dried over sodium sulfate; Thick product obtains faint yellow solid, yield 59% through column chromatography purification.
6) in the gram azoles for Buddhist nun's preparation
Solid 100mg N-Boc compound is dissolved in a small amount of methylene dichloride,, adds trifluoroacetic ethyl acetate solution (M=1) 2mL, stir after 20 minutes 0 ℃ of stirring; After the TLC detection reaction was complete, removal of solvent under reduced pressure added 10mL water, regulates pH=10 with sodium bicarbonate solid; Use the dichloromethane extraction after drying, concentrate recrystallization; Obtain the off-white color solid, yield 78%, ee:99.9%.
MS m/e 450 (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 (10)
1. azoles is characterized in that for Buddhist nun's preparation method in the gram, may further comprise the steps:
1) is raw material with structural formula suc as formula the methyl phenyl ketone shown in (1), in solvent, passes through 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 suc as formula (the S)-configuration shown in (2), temperature of reaction is 20～80 ℃;
2) phenylethyl alcohol that will go up (S)-configuration of making in the step in solvent with reactant A
3, reactant A
4And structural formula suc as formula the 2-nitro-3-pyridone shown in (3) at catalyzer C
1Effect reaction down obtains structural formula suc as formula the nitro-compound shown in (4), described reactant A
3Be triphenyl phosphorus, described reactant A
4Be DEAD or DIAD, temperature of reaction is-20～30 ℃;
3) will go up in the step structural formula that makes suc as formula the nitro-compound shown in (4) in solvent with reductive agent A
5Reaction generating structure formula is suc as formula the aromatic amine compound shown in (5), and temperature of reaction is-20～30 ℃;
4) will go up in the step structural formula that makes suc as formula the aromatic amine compound shown in (5) in solvent with compd A
6Reaction generating structure formula is suc as formula the bromo-derivative shown in (6), described A
6Be brominated reagent NBS or bromine, temperature of reaction is-20～30 ℃;
5) will go up in the step structural formula that makes suc as formula the bromo-derivative shown in (6) and structural formula suc as formula the boric acid ester shown in (7) in solvent with alkali A
7With catalyzer C
2Acting in conjunction generating structure formula is suc as formula the N-Boc compound shown in (8), and temperature of reaction is 0～130 ℃;
6) will go up in the step structural formula that makes suc as formula the N-Boc compound shown in (8) in solvent with sour A
8Reaction obtains structural formula and replaces the Buddhist nun suc as formula azoles in the gram shown in (9), and temperature of reaction is-10～50 ℃.
2. azoles is characterized in that the hydroborate A in the described step (1) for Buddhist nun's preparation method in the gram according to claim 1
1Be selected from Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN, 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 (R)-diphenylprolinol, (R)-xylyl dried meat ammonia alcohol, (R)-dinaphthyl dried meat ammonia alcohol or derivatives thereof; Described solvent is alcohols, ethers or its mixed solvent; Described temperature of reaction is 70 ℃.
3. azoles is characterized in that the catalyzer C in the described step (2) for Buddhist nun's preparation method in the gram according to claim 1
1Be DMAP; Described solvent is an ether solvent; Described temperature of reaction is a room temperature.
4. azoles is characterized in that for Buddhist nun's preparation method described ether solvent is THF or ether in the gram according to claim 3.
5. azoles is characterized in that the reductive agent A in the described step (3) for Buddhist nun's preparation method in the gram according to claim 1
5Be reduced iron powder or zinc powder; Described solvent is a protic solvent; Described temperature of reaction is a room temperature.
6. azoles is characterized in that for Buddhist nun's preparation method described protic solvent is selected from ethanol, acetate or its mixed solvent in the gram according to claim 5.
7. azoles is characterized in that for Buddhist nun's preparation method the solvent in the described step (4) is a tetracol phenixin in the gram according to claim 1; Described temperature of reaction is a room temperature.
8. azoles is characterized in that the A in the described step (5) for Buddhist nun's preparation method in the gram according to claim 1
7Be alkali-metal carbonate or supercarbonate; Described C
3Be palladium, four triphenyl phosphorus palladiums or dichloro two triphenyl phosphorus palladiums; Described solvent is a polar aprotic solvent; Temperature of reaction is 87 ℃.
9. azoles is characterized in that described A for Buddhist nun's preparation method in the gram according to claim 8
7Be salt of wormwood, described solvent is a N.
10. azoles is characterized in that the sour A in the described step (6) for Buddhist nun's preparation method in the gram according to claim 1
8Be HCl or trifluoroacetic acid; Described solvent is in ETHYLE ACETATE, THF, the dioxane or the mixed solvent of its two or more solvents; Temperature of reaction is 25 ℃.
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| CN102898449A (en) * | 2012-09-21 | 2013-01-30 | 同济大学 | Method for synthesizing Crizotinib intermediate |
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| CN102898449A (en) * | 2012-09-21 | 2013-01-30 | 同济大学 | Method for synthesizing Crizotinib intermediate |
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