CN109651397A - A kind of Laura is for Buddhist nun's intermediate and prepares the method that Laura replaces Buddhist nun - Google Patents
A kind of Laura is for Buddhist nun's intermediate and prepares the method that Laura replaces Buddhist nun Download PDFInfo
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- CN109651397A CN109651397A CN201910071289.9A CN201910071289A CN109651397A CN 109651397 A CN109651397 A CN 109651397A CN 201910071289 A CN201910071289 A CN 201910071289A CN 109651397 A CN109651397 A CN 109651397A
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- laura
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- 238000000034 method Methods 0.000 title claims description 21
- 229940125782 compound 2 Drugs 0.000 claims abstract description 21
- 239000007858 starting material Substances 0.000 claims abstract description 7
- 229940125904 compound 1 Drugs 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 47
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 229940125898 compound 5 Drugs 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- 238000009413 insulation Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- 229910052763 palladium Inorganic materials 0.000 claims description 10
- 238000010792 warming Methods 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 5
- 239000007821 HATU Substances 0.000 claims description 5
- 238000001514 detection method Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 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 4
- 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 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 3
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 229940093956 potassium carbonate Drugs 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 125000002524 organometallic group Chemical group 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- IIXWYSCJSQVBQM-LLVKDONJSA-N lorlatinib Chemical compound N=1N(C)C(C#N)=C2C=1CN(C)C(=O)C1=CC=C(F)C=C1[C@@H](C)OC1=CC2=CN=C1N IIXWYSCJSQVBQM-LLVKDONJSA-N 0.000 description 6
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- 229950001290 lorlatinib Drugs 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000007859 condensation product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000010903 husk Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 1
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 1
- 102100037840 Dehydrogenase/reductase SDR family member 2, mitochondrial Human genes 0.000 description 1
- 101000686031 Homo sapiens Proto-oncogene tyrosine-protein kinase ROS Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- 108010087367 P-glycoprotein 2 Proteins 0.000 description 1
- 101710188053 Protein D Proteins 0.000 description 1
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 description 1
- 101710132893 Resolvase Proteins 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000010276 construction Methods 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
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 102220197960 rs1057519783 Human genes 0.000 description 1
- -1 stirring Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a kind of Lauras to replace Buddhist nun's intermediate, wherein Laura is for Buddhist nun's intermediate as shown in compound 2:It is starting material with compound 1, according to synthetic route prepare compound 2 as follows:The present invention is disclosed with compound 2 as starting material simultaneously, prepares Laura according to synthetic route as follows for Buddhist nun:Technical solution disclosed by the invention, provide a kind of low cost, low-carbon environment-friendly Laura for the synthetic method of Buddhist nun and its intermediate, which has certain industrialized production and application prospect.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, and in particular to be a kind of Laura for Buddhist nun's intermediate and prepare Laura for Buddhist nun
Method.
Background technique
Laura replaces Buddhist nun (Lorlatinib), and structure is as follows:
Studies have shown that Laura shows significant cell to ALK and a large amount of ALK clinic saltant types for Buddhist nun (Lorlatinib)
Activity, such as BaF3- in the HCC78 people NSCLC cell containing SLC34A2-ROS1 fusions and expression people CD74-ROS1
In CD74-ROS1 cell, Laura significantly inhibits cell Proliferation for Buddhist nun (Lorlatinib), and induces cell apoptosis.
In the NSCLC cell containing non-mutant ALK or saltant type ALK fusions, Laura replaces Buddhist nun (Lorlatinib)
Also effective growth inhibitory activity is shown, and is induced cell apoptosis.In rat body, Laura is for Buddhist nun (Lorlatinib) display
Low plasma clearance out, appropriate distribution volume, reasonable half-life period, the outlet sensibility mediated to low P- glycoprotein 1 is low, and
Bioavilability is 100%.
In vivo, in the NIH3T3 heteroplastic transplantation model for expressing people CD74-ROS1 and Fig-ROS1, PF-06463922 table
Reveal Leukopenia antitumaous effect, by inhibition ROS1 phosphorylation and downstream signaling molecule, and to the cell cycle in tumour
The inhibition of protein D 1 plays a role.
In load tumour transplatation object, it is overexpressed EML4-ALK, EML4-ALK-L1196M, EML4-ALK-G1269A, EML4-
In the Mice Body of ALK-G1202R or NPM-ALK, Laura also shows significant anti-tumor activity for Buddhist nun.
Laura replaces Buddhist nun, as anticancer drug, extensive clinical application, and clinically shows more superior control
Therapeutic effect.Increasingly increase accordingly, with respect to Laura for the market demand of Buddhist nun.In turn, about Laura for Buddhist nun process route or its change
Into Patents documents have been reported that.
Patent No.: WO.2014207606A1 discloses a kind of synthetic method that Laura replaces Buddhist nun, the following institute of synthetic route
Show:
The thinking of above-mentioned synthesis technology is with compound 9 for starting material, first carries out condensation reaction and obtains condensation product 25, then
Condensation product 25 is subjected to coupling cyclization, then sloughs protection, obtains Laura for Buddhist nun's object construction molecule.
But above-mentioned synthesis route cost is excessively high, overall yield is not high.Concrete reason is: process route is excessively superfluous
Long, operating procedure is excessively many and diverse, causes synthetic route impurity content height, overall yield low.
Therefore it provides a kind of green, economic, environmental protection, the simple Laura of process route are for the synthesis of Buddhist nun's bulk pharmaceutical chemicals, meaning weight
Greatly.
Summary of the invention
Technical problem to be solved by the present invention lies in provide a kind of Laura for Buddhist nun's intermediate and prepare Laura for Buddhist nun's
Method.
The present invention is to solve above-mentioned technical problem by the following technical programs:
A kind of Laura replaces Buddhist nun's intermediate, and structure is as shown in compound 2:
The synthetic route of above compound 2 is as follows:
Successively organic solvent is added as molten in reactor in Weigh Compound 1, duplex pinacol borate, inorganic base
Agent is stirred, and under the conditions of nitrogen protection, organic metal palladium catalyst is added, finishes, and logical nitrogen drives air in reactor, reaction
System is warming up to 70-80 DEG C, and insulation reaction 4-5h, TLC detect fully reacting, reaction solution concentration, extraction, isolated compound
2。
Preferably, the organic metal palladium catalyst is Pd (Dppf)2Cl2Or Pd (Ph3P)4, the organic solvent is
Benzene, toluene, DMF, NMP, any solvent in Isosorbide-5-Nitrae-dioxane, the inorganic base are potassium carbonate, any in sodium carbonate
Kind alkali.
Preferably, it is that starting material prepares Laura for Buddhist nun with compound 2, synthetic route is as follows:
Present invention simultaneously discloses use above-mentioned Laura to prepare the method that Laura replaces Buddhist nun, synthesis for Buddhist nun's intermediate for starting material
Route is as follows:
It is above-mentioned prepare Laura for Buddhist nun method the following steps are included:
The preparation of S1, compound 4: successively Weigh Compound 2, compound 3, potassium carbonate, organic metal palladium catalyst are added
Into reactor, after organic solvent is added in reactor, it is passed through nitrogen into reaction system and drives air, reaction system is warming up to
70-80 DEG C, insulation reaction 4-5h fully reacting, to complete, reaction system is cooled to room temperature for TLC detection reaction, after separating water layer,
Reaction solution is concentrated under reduced pressure, and obtains compound 4；
The preparation of S2, compound 5:
Weigh Compound 4 is added in reactor, and organic solvent, water, potassium hydroxide, reaction system stirring are added in reactor
It is warming up to 25-35 DEG C, insulation reaction 4-5h, fully reacting is recovered under reduced pressure solvent to doing, hydrochloric acid solution is added into reaction solution,
Reaction solution pH to 2.0-3.0 is adjusted, solid is precipitated, and filters, and filter cake drying obtains compound 5；
S3, Laura replace the preparation of Buddhist nun:
Compound 5, DMF, DIPEA are successively added into reactor, stirs, HATU is added to reactor in whipping process
In, 60~70 DEG C of reactions are warming up to, after fully reacting, water quenching reaction is added in insulation reaction 4-5h, after being extracted, being separated
Buddhist nun is replaced to Laura.
Preferably, the molar ratio of compound 2 and compound 3, potassium carbonate is 1:1:2, organic gold in the step S1
The additive amount for belonging to palladium catalyst is the 7% of 1 mass of compound, and compound 4 and the molar ratio of potassium hydroxide are in the step S2
The molar ratio of compound 5 and DIPEA, HATU are 1:1.2:3 in 1:1.1, the step S3.
Preferably, the organic metal palladium catalyst is Pd (Dppf)2Cl2Or Pd (Ph3P)4, the organic solvent is
Benzene, toluene, DMF, NMP, any solvent in Isosorbide-5-Nitrae-dioxane.
The present invention has the advantage that compared with prior art
The present invention discloses a kind of method that Laura replaces Buddhist nun's intermediate and prepares Laura for Buddhist nun, compared with prior art, the present invention
A kind of Laura has been synthesized for Buddhist nun's intermediate, and Buddhist nun is replaced using intermediate synthesis Laura, has provided the Laura of a grain husk grain husk for Buddhist nun
Synthesis route, relatively traditional process route, synthesis route disclosed by the invention is not only at low cost and yield
Height, environment-friendly and green have industrial applications prospect.
Detailed description of the invention
Fig. 1 is the hydrogen spectrogram that Laura replaces Buddhist nun in the embodiment of the present invention 5；
Fig. 2 is that the Laura being prepared in the embodiment of the present invention 5 replaces the liquid phase figure of Buddhist nun；
Wherein, liquid phase figure is that Laura will be prepared in embodiment 5 to be detected for Nietzsche with LC-MS, and liquid phase figure is LC-
MS detects the liquid phase figure part in spectrogram；
Fig. 3 is that the Laura being prepared in the embodiment of the present invention 5 replaces the mass spectrogram of Buddhist nun；
Wherein, mass spectrogram is that Laura will be prepared in embodiment 5 to be detected for Nietzsche with LC-MS, mass spectrogram LC-
MS detects the mass spectrogram part in spectrogram.
Specific embodiment
It elaborates below to the embodiment of the present invention, the present embodiment carries out under the premise of the technical scheme of the present invention
Implement, the detailed implementation method and specific operation process are given, but protection scope of the present invention is not limited to following implementation
Example.
Embodiment 1
A kind of Laura replaces Buddhist nun's intermediate, and structure is as shown in compound 2:
The preparation of 2 compound 2 of embodiment
The synthetic route of compound 2 is as follows:
The preparation method of compound 2, comprising the following steps:
Successively Weigh Compound 1 (22.9g, 0.1mol), duplex pinacol borate (30.47g, 0.12mol), potassium carbonate
Isosorbide-5-Nitrae-dioxane of 500mL is added as solvent, stirring, nitrogen protection condition in reactor in (16.58g, 0.12mol)
Under, it is added 1.61g Pd (Dppf)2Cl2As catalyst (catalyst quality is the 7% of 1 mass of compound), finishes, lead to nitrogen
Air in reactor is driven, reaction system is warming up to 75 DEG C, and reaction solution is concentrated for insulation reaction 4h, TLC detection fully reacting
It is dry, ethyl acetate 300mL, water 200mL is added, organic phase is collected in stirring, layering, and aqueous layer with ethyl acetate 300mL extracts one again
It is secondary, merge organic phase, carries out column chromatography for separation after organic phase concentration, obtain compound 2 (24.45g), yield 88.6%.
Embodiment 3
Laura replaces the preparation of Buddhist nun:
Laura is as follows for the synthetic route of Buddhist nun:
One, the preparation of compound 4
The synthetic route of compound 4 is as follows:
The preparation method of compound 4, comprising the following steps:
Successively Weigh Compound 2 (27.6g, 0.1mol), compound 3 (40.4g, 0.11mol), potassium carbonate (27.6g,
0.2mol)、1.5g Pd(Dppf)2Cl2(the 3% of 2 gross mass of compound) it is added in reactor in reactor as catalyst
After the organic solvent of 300mL, it is passed through nitrogen into reaction system and drives air, reaction system is warming up to 80 DEG C, insulation reaction 4h
Fully reacting, to complete, reaction system is cooled to room temperature for TLC detection reaction, and after separating water layer, reaction solution is concentrated under reduced pressure, and is obtained
Compound 4 (29.3g), yield 79.6%.
Two, the preparation of compound 5
The synthetic route of compound 5 is as follows:
The preparation method of compound 5, comprising the following steps:
Weigh Compound 4 (43.8g, 0.1mol) be added reactor in, in reactor be added 200mL methanol, 100mL water,
10g potassium hydroxide, reaction system stirring are warming up to 30 DEG C, insulation reaction 4h, and solvent is recovered under reduced pressure to dry, addition in fully reacting
Hydrochloric acid solution adjusts reaction solution pH to 2.0 into reaction solution, and solid is precipitated, and filters, and filter cake drying obtains compound 5 (41.7g),
Yield 98.3%.
Three, Laura is for Buddhist nun's preparation
Laura is as follows for the synthetic route of Buddhist nun:
S3, Laura replace the preparation method of Buddhist nun, comprising the following steps:
Compound 5 (42.1g, 0.1mol), DIPEA (15.51g, 0.12mol) are successively added into reactor, stirring is stirred
HATU (114.12g, 0.3mol) is added into reactor during mixing, is warming up to 65 DEG C of reactions, insulation reaction 5h has reacted
Quan Hou, be added water 500mL quenching reaction after, in reactor, be added 500mL ethyl acetate extracted, separate water layer, water layer with
After 500mL ethyl acetate extracts again, it is associated with ethyl acetate layer, after ethyl acetate is concentrated, concentrate is obtained through column chromatography for separation
Buddhist nun (35.56g) is replaced to Laura, yield 87.6%, Laura replaces the structural characterization of Buddhist nun and assay as shown in Figs. 1-3.
Wherein, Fig. 2 is that Laura replaces the LC-MS of Buddhist nun to detect the liquid phase figure detection part in spectrogram, and each peak number rises in spectrogram
Time beginning, retention time, end time, peak height, peak area, peak area percent are as shown in table 1:
Table 1
Wherein, Fig. 3 is that Laura detects Mass Spectrometer Method part in spectrogram for the LC-MS of Buddhist nun, in spectrogram each mass-to-charge ratio from
Sub- peak value, abundance are as shown in table 2:
Table 2
| Matter/lotus ratio | Charge number | Abundance |
| 407.231 | 1 | 19472474 |
| 407.4078 | 1 | 1165409.25 |
| 408.4127 | 1 | 5367392.5 |
| 409.2366 | 1 | 378438.09 |
| 429.2147 | 1 | 786435.31 |
| 430.2179 | 1 | 1269463.25 |
| 445.1902 | 1 | 267908.06 |
| 835.4063 | 1 | 1447246.25 |
| 836.4094 | 1 | 750105.06 |
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (9)
1. a kind of Laura replaces Buddhist nun's intermediate, which is characterized in that structure is as shown in compound 2:
2. Laura according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that the synthetic route of the compound 2 is as follows:
3. the preparation method that Laura according to claim 2 replaces Buddhist nun's intermediate, which comprises the following steps:
Successively Weigh Compound 1, duplex pinacol borate, inorganic base are added organic solvent as solvent, stir in reactor
It mixes, under the conditions of nitrogen protection, organic metal palladium catalyst is added, finishes, logical nitrogen drives air in reactor, reaction system liter
For temperature to 70-80 DEG C, insulation reaction 4-5h, TLC detect fully reacting, reaction solution concentration, extraction, isolated compound 2.
4. the preparation method that Laura according to claim 3 replaces Buddhist nun's intermediate, which is characterized in that the Organometallic Palladium is urged
Agent is Pd (Dppf)2Cl2Or Pd (Ph3P)4, the organic solvent is benzene, in toluene, DMF, NMP, Isosorbide-5-Nitrae-dioxane
Any solvent, the inorganic base are potassium carbonate, any alkali in sodium carbonate.
5. Laura according to claim 4 replaces Buddhist nun's intermediate, which is characterized in that prepare labor with compound 2 for starting material
It draws and replaces Buddhist nun, synthetic route is as follows:
6. a kind of use Laura as described in any one in claim 1-5 to prepare Laura for starting material for Buddhist nun's intermediate for Buddhist nun's
Method, which is characterized in that synthetic route is as follows:
7. the method as claimed in claim 6 for preparing Laura and replacing Buddhist nun, which comprises the following steps:
The preparation of S1, compound 4:
Successively Weigh Compound 2, compound 3, potassium carbonate, organic metal palladium catalyst are added into reactor, add in reactor
After entering organic solvent, it is passed through nitrogen into reaction system and drives air, reaction system is warming up to 70-80 DEG C, insulation reaction 4-5h
Fully reacting, to complete, reaction system is cooled to room temperature for TLC detection reaction, and after separating water layer, reaction solution is concentrated under reduced pressure, and is obtained
Compound 4；
The preparation of S2, compound 5:
Weigh Compound 4 is added in reactor, and organic solvent, water, potassium hydroxide, reaction system stirring heating are added in reactor
To 25-35 DEG C, insulation reaction 4-5h, fully reacting is recovered under reduced pressure solvent to doing, hydrochloric acid solution is added into reaction solution, adjusts anti-
Liquid pH to 2.0-3.0 is answered, solid is precipitated, and filters, and filter cake drying obtains compound 5；
S3, Laura replace the preparation of Buddhist nun:
Compound 5, DMF, DIPEA are successively added into reactor, stirs, HATU is added into reactor in whipping process,
Be warming up to 60~70 DEG C of reactions, after fully reacting, water quenching reaction is added in insulation reaction 4-5h, extracted, separate after obtain labor
It draws and replaces Buddhist nun.
8. the method as claimed in claim 7 for preparing Laura and replacing Buddhist nun, which is characterized in that compound 2 and chemical combination in the step S1
Object 3, potassium carbonate molar ratio be 1:1:2, the additive amount of the organic metal palladium catalyst is the 7% of 1 mass of compound, described
The molar ratio of compound 4 and potassium hydroxide is 1:1.1 in step S2, and compound 5 and DIPEA, HATU's rubs in the step S3
You are than being 1:1.2:3.
9. the method as claimed in claim 7 for preparing Laura and replacing Buddhist nun, which is characterized in that the organic metal palladium catalyst is Pd
(Dppf)2Cl2Or Pd (Ph3P)4, the organic solvent is benzene, toluene, DMF, NMP, any molten in Isosorbide-5-Nitrae-dioxane
Agent.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110530998A (en) * | 2019-09-16 | 2019-12-03 | 山东省药学科学院 | A kind of Laura is for Buddhist nun and containing Laura for the detection method in relation to substance in the preparation of Buddhist nun |
| CN112457293A (en) * | 2020-11-30 | 2021-03-09 | 商河探荣新技术开发中心 | Application of TBTU in preparation of anti-cancer drugs |
| CN112724077A (en) * | 2020-12-29 | 2021-04-30 | 武汉利昌医药科技有限公司 | Synthetic method of Laolatinib intermediate |
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| CN104169286A (en) * | 2012-03-06 | 2014-11-26 | 辉瑞大药厂 | Macrocyclic derivatives for the treatment of proliferative diseases |
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| CN104169286A (en) * | 2012-03-06 | 2014-11-26 | 辉瑞大药厂 | Macrocyclic derivatives for the treatment of proliferative diseases |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110530998A (en) * | 2019-09-16 | 2019-12-03 | 山东省药学科学院 | A kind of Laura is for Buddhist nun and containing Laura for the detection method in relation to substance in the preparation of Buddhist nun |
| CN112457293A (en) * | 2020-11-30 | 2021-03-09 | 商河探荣新技术开发中心 | Application of TBTU in preparation of anti-cancer drugs |
| CN112724077A (en) * | 2020-12-29 | 2021-04-30 | 武汉利昌医药科技有限公司 | Synthetic method of Laolatinib intermediate |
| CN112724077B (en) * | 2020-12-29 | 2023-07-11 | 武汉利昌医药科技有限公司 | Synthesis method of loratidine intermediate |
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