CN109651418A - A kind of method that Laura replaces Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate and Organometallic Palladium catalytic coupling to prepare Laura for Buddhist nun - Google Patents
A kind of method that Laura replaces Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate and Organometallic Palladium catalytic coupling to prepare Laura for Buddhist nun Download PDFInfo
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- CN109651418A CN109651418A CN201910079162.1A CN201910079162A CN109651418A CN 109651418 A CN109651418 A CN 109651418A CN 201910079162 A CN201910079162 A CN 201910079162A CN 109651418 A CN109651418 A CN 109651418A
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- compound
- buddhist nun
- laura
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 238000000034 method Methods 0.000 title claims abstract description 26
- 229910052763 palladium Inorganic materials 0.000 title claims abstract description 25
- 239000000126 substance Substances 0.000 title claims abstract description 19
- 230000008878 coupling Effects 0.000 title claims abstract description 13
- 238000010168 coupling process Methods 0.000 title claims abstract description 13
- 238000005859 coupling reaction Methods 0.000 title claims abstract description 13
- 230000003197 catalytic effect Effects 0.000 title claims description 9
- 125000002524 organometallic group Chemical group 0.000 title claims description 9
- 229940125904 compound 1 Drugs 0.000 claims abstract description 18
- 229910052751 metal Inorganic materials 0.000 claims abstract description 14
- 239000002184 metal Substances 0.000 claims abstract description 14
- 229940125782 compound 2 Drugs 0.000 claims abstract description 8
- 230000008569 process Effects 0.000 claims abstract description 8
- 239000007858 starting material Substances 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 15
- 229940126214 compound 3 Drugs 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000009413 insulation Methods 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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 238000010792 warming Methods 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- 238000001514 detection method Methods 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 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 5
- 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
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 4
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229940093956 potassium carbonate Drugs 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
- 238000001035 drying Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 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
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000007791 liquid phase Substances 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
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000010903 husk Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 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
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000010276 construction 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
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 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 1
- 229950001290 lorlatinib Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- -1 stirring Substances 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (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 bulk pharmaceutical chemicals synthetic intermediate, wherein Laura replaces the structure of Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate as shown in compound 2:It is starting material according to synthetic route prepare compound 2 as follows with compound 1:The present invention is disclosed with compound 2 as starting material simultaneously, and machine catalyzing by metal palladium coupling prepares the method that Laura replaces Buddhist nun:Not only process route is short for synthetic route disclosed by the invention, and synthesis yield is high, and high financial profit.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, and in particular to be a kind of Laura for Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate and organic
Catalyzing by metal palladium coupling prepares the method that Laura replaces Buddhist nun.
Background technique
Laura is one potent for Buddhist nun (Lorlatinib), the inhibitor of dual ALK/ROS1, is clinically used for cancer
Treatment, Laura replace the structure of Buddhist nun as shown in formula A:
The synthetic route of Buddhist nun is replaced about Laura, Patents documents and paper periodical have been reported that, such as world patent number
Are as follows: WO.2013132376A1, it was recently reported that Laura replaces Buddhist nun's synthetic route as shown in formula B:
In synthetic route shown in formula B, using Ⅹ Ⅻ compound of formula as starting material intermediate, it is coupled by Suzuki, it will
Ⅹ Ⅻ compound of formula is coupled with Ⅹ VIII compounds, then is deprotected, is hydrolyzed, and is finally condensed cyclization and is obtained object construction production
Object.
But the prior art is disclosed to synthesize the side that Laura replaces Buddhist nun about Ⅹ Ⅻ compound of formula for starting material intermediate
Method, not only process route is tediously long, and synthesis total recovery is low, and causing Laura to have not only for the synthesis of Buddhist nun, process costs are high, and grasp
Make the defects of step is more.
Therefore, a kind of completely new intermediate that can be synthesized Laura and replace Buddhist nun is developed, and synthesizes Laura using the intermediate
For the method for Buddhist nun, defective workmanship disclosed in above-mentioned prior art is overcome, the industrialization production meaning weight of Buddhist nun is replaced for improving Laura
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 bulk pharmaceutical chemicals synthetic intermediate and organic
Catalyzing by metal palladium coupling prepares the method that Laura replaces Buddhist nun.
The present invention is to solve above-mentioned technical problem by the following technical programs:
A kind of Laura replaces Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate, and structure is as shown in compound 1:
The synthetic route of above compound 1 is as follows:
Compound 1 the preparation method is as follows:
Successively organic solvent is added as molten in reactor in Weigh Compound X, 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
1。
Preferably, the additional amount of the palladium catalyst is the 3% of compound X mass, the compound X and duplex pinacol
Borate, inorganic base molar ratio be 1:1.2:1.2.
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, Laura is prepared for Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate for Buddhist nun with Laura, synthetic route is as follows:
The present invention is disclosed using Laura for Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate as starting material simultaneously, Organometallic Palladium catalytic coupling
The method that Laura replaces Buddhist nun is prepared, synthetic route is as follows:
Above-mentioned Organometallic Palladium catalytic coupling prepare Laura for Buddhist nun method the following steps are included:
The preparation of S1, compound 3: successively Weigh Compound 1, compound 2, 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 3；
The preparation of S2, compound 4:
After reactor is added in Weigh Compound 3, 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, solvent is recovered under reduced pressure to dry, addition dilute hydrochloric acid solution to reactor in fully reacting
In, it is stirred to react 35-40min, TLC detection reaction terminates, continues to add hydrochloric acid tune reaction solution pH to 2.0-3.0, filter, filter cake
Drying, obtains compound 4；
S3, Laura replace the preparation of Buddhist nun:
Compound 4, 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 1 and compound 2, potassium carbonate is 1:1.1:2 in the step S1, described organic
The additive amount of metal palladium catalyst is the 7% of 1 mass of compound, the molar ratio of compound 3 and potassium hydroxide in the step S2
For 1:1.1, the molar ratio of compound 4 and DIPEA, HATU are 1:1.2:3 in 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 Laura and prepares Laura for Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate and Organometallic Palladium catalytic coupling and replace
The method of Buddhist nun is compared with prior art, relatively traditional the present invention provides the synthesis route that the Laura of a grain husk grain husk replaces Buddhist nun
Process route, synthesis route disclosed by the invention is not only at low cost and high income, 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 2；
Fig. 2 is that the Laura being prepared in the embodiment of the present invention 2 replaces the liquid phase figure of Buddhist nun；
Wherein, liquid phase figure is that Laura will be prepared in embodiment 2 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 2 replaces the mass spectrogram of Buddhist nun；
Wherein, mass spectrogram is that Laura will be prepared in embodiment 2 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 bulk pharmaceutical chemicals synthetic intermediate, and structure is as shown in compound 1:
Embodiment 2
A kind of Laura being prepared using embodiment 1 replaces Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate as starting material, Organometallic Palladium
Catalytic coupling prepares Laura for Buddhist nun, and synthetic route is as follows:
The preparation of compound 1:
A kind of Laura is as follows for Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate, that is, compound 1 synthetic route:
The preparation method of compound 1, comprising the following steps:
Successively by compound X (32.9g, 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 0.98g Pd (Dppf)2Cl2As catalyst (catalyst quality is the 3% 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 1 (32.9g), yield 87.5%.
The preparation of compound 3:
The synthetic route of compound 3 is as follows:
The preparation method of compound 3, comprising the following steps:
Successively Weigh Compound 1 (37.6g, 0.1mol), compound 2 (40.48g, 0.11mol), potassium carbonate (27.6g,
0.2mol)、1.13g Pd(Dppf)2Cl2(the 3% of 1 gross mass of compound) as catalyst in reactor, add in reactor
After the Isosorbide-5-Nitrae-dioxane for entering 300mL, it is passed through nitrogen into reaction system and drives air, reaction system is warming up to 80 DEG C, heat preservation
4h fully reacting is reacted, to complete, reaction system is cooled to room temperature for TLC detection reaction, and after separating water layer, reaction solution decompression is dense
Contracting, obtains compound 3 (36.7g), yield 83.6%.
The preparation of compound 4:
The synthetic route of compound 4 is as follows:
The preparation method of compound 4, comprising the following steps:
Weigh Compound 3 (43.8g, 0.1mol) be added reactor in, in reactor be added 200mL methanol, 100mL water,
Potassium hydroxide (6.2g, 0.11mol), reaction system stirring are warming up to 30 DEG C, insulation reaction 4h, and fully reacting is recovered under reduced pressure molten
Dilute hydrochloric acid solution is added into reactor to doing in agent, is stirred to react 40min, and TLC detection reaction terminates, continues to add hydrochloric acid tune
Reaction solution pH to 2.0 is filtered, and filter cake drying obtains compound 4 (42.1g), yield 99.2%.
Four, final product Laura replaces the preparation of Buddhist nun:
Laura is as follows for the synthetic route of Buddhist nun:
Prepare the method that Laura replaces Buddhist nun, comprising the following steps:
Successively into reactor be added compound 4 (42.4g, 0.1mol), 500mLDMF, DIPEA (15.51g,
0.12mol), it stirs, HATU (114.12g, 0.3mol) is added into reactor in whipping process, is warming up to 65 DEG C of reactions,
Insulation reaction 5h after fully reacting, after water 500mL quenching reaction is added, in reactor, is added 500mL ethyl acetate and is extracted
It takes, separates water layer, after water layer is extracted again with 500mL ethyl acetate, be associated with ethyl acetate layer, it is dense after ethyl acetate is concentrated
Contracting object obtains Laura through column chromatography for separation for Buddhist nun (31.87g), yield 78.5%, the structural characterization and content that Laura replaces Buddhist nun are such as
Shown in Fig. 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 bulk pharmaceutical chemicals synthetic intermediate, which is characterized in that structure is as shown in compound 1:
2. a kind of Laura according to claim 1 replaces Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate, which is characterized in that the compound 1
Synthetic route it is as follows:
The compound 1 the preparation method is as follows:
Successively Weigh Compound X, 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 1.
3. a kind of Laura according to claim 2 replaces Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate, which is characterized in that the palladium catalyst
Additional amount be the 3% of compound X mass, the compound X and duplex pinacol borate, inorganic base molar ratio be 1:
1.2:1.2。
4. the preparation method that a kind of Laura according to claim 3 replaces Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate, which is characterized in that institute
Stating organic metal palladium catalyst is Pd (Dppf)2Cl2Or Pd (Ph3P)4, the organic solvent be benzene, toluene, DMF, NMP, 1,
Any solvent in 4- dioxane, the inorganic base are potassium carbonate, any alkali in sodium carbonate.
5. a kind of Laura according to claim 4 replaces Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate, which is characterized in that be with compound 1
Starting material prepares Laura for Buddhist nun, and synthetic route is as follows:
6. a kind of use Laura as described in any one in claim 1-5, for starting material, to have for Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate
Machine catalyzing by metal palladium coupling prepares the method that Laura replaces Buddhist nun, which is characterized in that synthetic route is as follows:
7. Organometallic Palladium catalytic coupling according to claim 6 prepares the method that Laura replaces Buddhist nun, which is characterized in that including
Following steps:
The preparation of S1, compound 3:
Successively Weigh Compound 1, compound 2, 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 3；
The preparation of S2, compound 4:
After reactor is added in Weigh Compound 3, 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, dilute hydrochloric acid solution is added into reactor, stirs
Mixing reaction 35-40min, TLC detection reaction terminates, and continues to add hydrochloric acid tune reaction solution pH to 2.0-3.0, filter, filter cake drying,
Obtain compound 4；
S3, Laura replace the preparation of Buddhist nun:
Compound 4, 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. Organometallic Palladium catalytic coupling according to claim 7 prepares the method that Laura replaces Buddhist nun, which is characterized in that described
The molar ratio of compound 1 and compound 2, potassium carbonate is 1:1.1:2, the additive amount of the organic metal palladium catalyst in step S1
It is the 7% of 1 mass of compound, the molar ratio of compound 3 and potassium hydroxide is 1:1.1 in the step S2, in the step S3
The molar ratio of compound 4 and DIPEA, HATU are 1:1.2:3.
9. Organometallic Palladium catalytic coupling according to claim 7 prepares the method that Laura replaces Buddhist nun, which is characterized in that described
Organic metal palladium catalyst is Pd (Dppf)2Cl2Or Pd (Ph3P)4, the organic solvent is benzene, toluene, DMF, NMP, Isosorbide-5-Nitrae-
Any solvent in dioxane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910079162.1A CN109651418A (en) | 2019-01-25 | 2019-01-25 | A kind of method that Laura replaces Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate and Organometallic Palladium catalytic coupling to prepare Laura for Buddhist nun |
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| Application Number | Priority Date | Filing Date | Title |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN112824417A (en) * | 2019-11-21 | 2021-05-21 | 上海天慈国际药业有限公司 | Preparation method of Laolatinib |
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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 |
| CN109232607A (en) * | 2018-09-20 | 2019-01-18 | 沈阳药科大学 | Laura replaces the synthetic method of Buddhist nun |
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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 |
| CN109232607A (en) * | 2018-09-20 | 2019-01-18 | 沈阳药科大学 | Laura replaces the synthetic method of Buddhist nun |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112824417A (en) * | 2019-11-21 | 2021-05-21 | 上海天慈国际药业有限公司 | Preparation method of Laolatinib |
| 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 |
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