CN115636826B - Preparation method of CDK inhibitor - Google Patents
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- CN115636826B CN115636826B CN202211346206.0A CN202211346206A CN115636826B CN 115636826 B CN115636826 B CN 115636826B CN 202211346206 A CN202211346206 A CN 202211346206A CN 115636826 B CN115636826 B CN 115636826B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 title claims abstract description 9
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 239000003054 catalyst Substances 0.000 claims abstract description 24
- 239000003446 ligand Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 64
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 46
- 239000000543 intermediate Substances 0.000 claims description 22
- 229910052763 palladium Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 9
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 8
- -1 sodium triethylborohydride Chemical compound 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- VEJCUYXHMQFYGE-UHFFFAOYSA-N cyclopentylthiourea Chemical compound NC(=S)NC1CCCC1 VEJCUYXHMQFYGE-UHFFFAOYSA-N 0.000 claims description 6
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical compound FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 claims description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 3
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 claims 1
- POFVJRKJJBFPII-UHFFFAOYSA-N N-cyclopentyl-5-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound C1(CCCC1)NC=1SC(=C(N=1)C)C1=NC(=NC=C1F)NC1=NC=C(C=C1)CN1CCN(CC1)CC POFVJRKJJBFPII-UHFFFAOYSA-N 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000012216 screening Methods 0.000 abstract description 2
- 238000001035 drying Methods 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 108091007914 CDKs Proteins 0.000 description 3
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 3
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 102000016736 Cyclin Human genes 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 102000013698 Cyclin-Dependent Kinase 6 Human genes 0.000 description 1
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 1
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- 208000037765 diseases and disorders Diseases 0.000 description 1
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- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
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- 150000003230 pyrimidines Chemical class 0.000 description 1
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Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of a CDK inhibitor, which comprises the following steps: the intermediate II and the intermediate III are used as raw materials, and a target product N-cyclopentyl-5- (2- ((5- ((4-ethylpiperazine-1-yl) methyl) pyridine-2-yl) amino) -5-fluoropyrimidin-4-yl) -4-methylthiazole-2-amine is prepared in the presence of a proper alkaline reagent, a catalyst and a ligand, and meanwhile, the synthetic route of each key intermediate is developed. The method has the advantages of mild reaction conditions, convenient post-treatment, good environmental protection and low requirements on equipment; the reaction conditions (such as a catalyst, a ligand and an alkaline reagent) obtained by screening and the like improve the reaction selectivity, effectively ensure the yield and purity of a target product, improve the product quality and are more beneficial to the industrial production of the CDK inhibitor.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a CDK inhibitor.
Background
Cell proliferation is the result of direct or indirect deregulation of the cell division cycle, and cyclin-dependent kinases (CDKs) are known as a protein kinase that are associated with various cyclin subunits and play a critical role in a variety of important regulatory pathways in cells, including cell cycle control, apoptosis, neuronal physiology, differentiation and transcription.
Certain pyrimidine compounds have been investigated for the treatment of cell proliferative diseases and disorders including cancer, such as 4-thiazole-2-pyridinamino-pyrimidine and 5-substituted-4-thiazole-pyrimidine (see International publication Nos. WO 2005/012698 and WO2013/156780, respectively). These compounds inhibit a variety of protein kinases, particularly CDKs.
The inventors of the present application disclosed a novel thiazole pyrimidine compound through patent CN108349964 a: n-cyclopentyl-5- (2- ((5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) amino) -5-fluoropyrimidin-4-yl) -4-methylthiazol-2-amine compound, which is shown to be capable of inhibiting cell proliferation by inhibiting the activity of CDK4 and/or CDK6, is currently in the clinical stage of research.
Patent CN108349964a also discloses a process for the preparation of N-cyclopentyl-5- (2- ((5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) amino) -5-fluoropyrimidin-4-yl) -4-methylthiazol-2-amine compounds, in particular as follows:
In the preparation method, the selectivity of the fluorination reaction is poor, the intermediate 1 is shown to be about 55% by reaction center control, and the intermediate 1 with the purity of more than 99.0% can be obtained by repeated silica gel column chromatography and recrystallization due to similar properties of the residual raw materials, impurities and products, the total yield of the reaction is less than 20%, a large amount of waste liquid is generated, and the environmental protection pressure is high; the preparation yield of the final product is only 29%, microwave irradiation operation is needed, the requirements on equipment are high, and the industrial production of the target product is not facilitated.
Therefore, how to develop a preparation method of the N-cyclopentyl-5- (2- ((5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) amino) -5-fluoropyrimidin-4-yl) -4-methylthiazol-2-amine compound with high yield, high purity and environment friendliness is a key point for realizing industrial production of the compound.
Disclosure of Invention
In order to overcome the deficiencies in the prior art described above, the present invention provides a method for preparing a CDK inhibitor N-cyclopentyl-5- (2- ((5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) amino) -5-fluoropyrimidin-4-yl) -4-methylthiazol-2-amine.
The technical scheme for solving the technical problems is as follows:
The invention provides a preparation method of a CDK inhibitor, which comprises the following steps:
(1) Reacting cyclopentylthiourea with 1-chloroacetone in the presence of an acid binding agent to generate a compound shown in a formula IIa;
(2) Substitution of the compound of formula IIa with a brominating agent to produce a compound of formula IIb;
(3) Reacting a compound of formula IIb with a bis-pinacolato borate in the presence of a palladium-based catalyst and a ligand to form a compound of formula IIc;
(4) Reacting a compound of formula IIc with 2, 4-dichloro-5-fluoropyrimidine in the presence of a palladium-based catalyst to form intermediate II;
(5) Reacting 1-ethylpiperazine with 2-nitro-5-aldehyde pyridine in the presence of a reducing agent to produce a compound of formula IIIa;
(6) Reducing the compound of formula IIIa by Pd/C under the protection of hydrogen to obtain an intermediate III;
(7) In the presence of an alkaline reagent, a palladium catalyst and a ligand, reacting the intermediate II with the intermediate III to obtain a target product, namely a compound of a formula I;
Further, the acid-binding agent in the step (1) is selected from one or more of pyridine, triethylamine or DIEA, preferably pyridine; the molar ratio of the cyclopentylthiourea to the acid binding agent is 1:1-1.5, preferably 1:1.1;
further, the reaction temperature in the step (1) is 20-30 ℃ and the reaction time is 3-6 h;
further, the brominating agent in the step (2) is selected from one or more of Br 2, NBS or carbon tetrabromide, preferably NBS; the molar ratio of the compound of formula IIa to brominating agent is from 1:1 to 1.2, preferably 1:1;
further, the reaction temperature in the step (2) is 10-20 ℃ and the reaction time is 1-2 h;
Further, the palladium catalyst in the step (3) is selected from one or more of palladium acetate, bis (triphenylphosphine) palladium chloride and tris (dibenzylideneacetone) dipalladium, preferably palladium acetate; the ligand is selected from tricyclohexylphosphine; the molar ratio of the palladium catalyst, the ligand, the compound of formula IIb and the bis-pinacolato borate is 0.05-0.15:0.1-0.2:1:1-2, preferably 0.1:0.18:1:1.5;
Furthermore, potassium acetate is also required to be added in the step (3); the molar ratio of potassium acetate to the compound of formula IIb is 2-4:1, preferably 3:1;
further, the reaction temperature in the step (3) is 90-100 ℃ and the reaction time is 5-8 h;
Further, the palladium catalyst in the step (4) is selected from one or more of palladium acetate, bis (triphenylphosphine) palladium chloride and tris (dibenzylideneacetone) dipalladium, preferably bis (triphenylphosphine) palladium chloride; the molar ratio of the palladium catalyst to the compound of formula IIc is 0.05-0.15:1, preferably 0.1:1;
Furthermore, sodium carbonate is also added in the step (4), and the molar ratio of the sodium carbonate to the compound of the formula IIc is 2-4:1, preferably 3:1;
Further, the reaction temperature in the step (4) is the solvent reflux temperature, and the reaction time is 2-6 h;
Further, the reducing agent in the step (5) is selected from one or more of sodium borohydride, potassium borohydride, sodium triethylborohydride or lithium aluminum hydride, preferably sodium triethylborohydride; the molar ratio of the reducing agent to the 1-ethylpiperazine is 1-1.1:1, preferably 1.05:1;
further, the reaction temperature in the step (5) is 20-30 ℃ and the reaction time is 8-12 h;
further, the hydrogen in the step (6) is micro-positive pressure; the reaction temperature is 50-60 ℃ and the reaction time is 5-8 h;
Further, the palladium catalyst in the step (7) is selected from one or more of palladium acetate, bis (triphenylphosphine) palladium chloride or tris (dibenzylideneacetone) dipalladium, preferably tris (dibenzylideneacetone) dipalladium; the ligand is selected from 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene; the molar ratio of the palladium catalyst, the ligand, the intermediate II and the intermediate III is 0.03-0.08:0.1-0.2:1-1.2:1-1.2, preferably 0.05:0.15:1:1;
Further, the alkaline reagent in the step (7) is selected from one or more of potassium carbonate, sodium acetate, cesium carbonate or potassium phosphate, preferably cesium carbonate; the mol ratio of the alkaline reagent to the intermediate II to the intermediate III is 1-2:1-1.2:1-1.2, preferably 1.5:1:1;
Further, the reaction temperature in the step (7) is 95-100 ℃ and the reaction time is 2-4 hours;
Further, the step (7) further comprises the steps of filtering, crystallizing and drying the reaction liquid when the reaction liquid is hot.
The Chinese naming of the compound in the invention conflicts with the structural formula, and the structural formula is taken as the reference; except for obvious structural errors.
The invention has the beneficial effects that:
the invention prepares the target product N-cyclopentyl-5- (2- ((5- ((4-ethylpiperazine-1-yl) methyl) pyridine-2-yl) amino) -5-fluoropyrimidine-4-yl) -4-methylthiazol-2-amine through a brand new synthetic route, and simultaneously develops synthetic routes of all key intermediates. The method has the advantages of mild reaction conditions, convenient post-treatment, good environmental protection and low requirements on equipment; the reaction conditions (such as a catalyst, a ligand and an alkaline reagent) obtained by screening and the like improve the reaction selectivity, effectively ensure the yield and purity of a target product, improve the product quality and are more beneficial to the industrial production of the CDK inhibitor.
Drawings
Fig. 1: the hydrogen profile of the target compound prepared in example 1;
Fig. 2: a spectrum of the target compound prepared in example 1.
Detailed Description
The invention is illustrated but not limited by the following examples. Simple alternatives and modifications of the invention will be apparent to those skilled in the art and are within the scope of the invention as defined by the appended claims.
Example 1:
preparation of Compounds of formula IIa
144.2G of cyclopentylthiourea (molecular weight 144.24,1.0 mol), 92.52g of 1-chloroacetone (molecular weight 92.52,1.0 mol), 87.0g of pyridine (molecular weight 79.10,1.1 mol) and 1442mL of ethanol are weighed in a 10L reaction kettle, stirred, and reacted at room temperature for 4h; pouring the reaction solution into 4326mL of water, and stirring for 1h at room temperature; after suction filtration and drying of the filter cake 155.3g of the compound of the formula IIa (molecular weight 182.29, 0.850 mol) are obtained, with a purity of 99.7% and a molar yield of 85.2%.
Preparation of Compounds of formula IIb
In a 5L reaction flask, 182.3g of the compound of formula IIa (molecular weight 182.29,1.0 mol) and 2735mL of dichloromethane are weighed respectively, and the solid solution is stirred; cooling, adding 178.0g NBS (molecular weight 177.98,1.0 mol) in batches at 10 ℃, and preserving heat for 1.5h at 10-20 ℃; the solvent was distilled off under reduced pressure, 2188mL of 50% (v/v) ethanol/water solution was added, and stirred at room temperature for 1h; suction filtration and drying of the filter cake gave 227.5g of the compound of the formula IIb (molecular weight 261.18,0.871 mol), purity 98.5%, molar yield 87.1%.
Preparation of Compounds of formula IIc
261.2G of the compound of formula IIb (molecular weight 261.18,1.0 mol), 380.9g of bis-pinacolato borate (molecular weight 253.94,1.5 mol), 294.4g of potassium acetate (molecular weight 98.14,3.0 mol), 22.5g of palladium acetate (molecular weight 224.51,0.1 mol), 50.5g of tricyclohexylphosphine (molecular weight 280.43,0.18 mol) and 1946.4mL of dimethyl sulfoxide are weighed into a 5L reaction vessel, stirred, replaced with nitrogen and protected; heating, and reacting at 90-100 ℃ for 6h; filtering while the mixture is hot, and crystallizing the filtrate at room temperature for 1h; suction filtration and drying of the filter cake gave 216.1g of the compound of the formula IIc (molecular weight 307.25,0.701 mol), purity 98.2%, molar yield 70.1%.
Preparation of intermediate II
In a 10L reaction vessel, 308.3g of the compound of formula IIc (molecular weight 308.25,1.0 mol), 167.0g of 2, 4-dichloro-5-fluoropyrimidine (molecular weight 166.96,1.0 mol), 318.0g of sodium carbonate (molecular weight 105.99,3.0 mol), 70.2g of bis (triphenylphosphine) palladium chloride (molecular weight 701.90,0.1 mol), 1400mL of water and 4200mL of DME were weighed, stirred, warmed to reflux and incubated for 4 hours; filtering while the mixture is hot, cooling the filtrate to room temperature, and preserving heat and crystallizing for 2 hours; suction filtration and filter cake drying gave 256.7g of the intermediate II compound (molecular weight 312.79, 0.823mol), purity 98.9% and molar yield 82.1%.
Preparation of Compounds of formula IIIa
114.2G of 1-ethylpiperazine (molecular weight 114.19,1.0 mol), 152.1g of 2-nitro-5-aldehyde pyridine (molecular weight 152.11,1.0 mol) and 3042mL of dichloromethane were weighed into a 5L reaction vessel, and 186.9g of sodium triethylborohydride (molecular weight 177.98,1.05 mol) were added in portions at 20℃with stirring; then preserving the temperature for 10 hours at room temperature; dripping 80mL of water for extraction and deactivation, decompressing and evaporating the solvent, adding 1710mL of 75% (v/v) ethanol/water solution, and stirring for 1h at room temperature; after suction filtration and drying of the filter cake 240.5g of the compound of formula IIIa (molecular weight 250.30,0.961 mol) are obtained, with a purity of 99.4% and a molar yield of 96.1%.
Preparation of intermediate III
In a 10L reaction kettle, 250.3g of a compound shown in formula IIIa (with a molecular weight of 250.30 and a molecular weight of 1.0 mol), 25.0g of palladium-carbon and 2003mL of ethanol are respectively weighed, stirred, and respectively subjected to nitrogen replacement, hydrogen replacement and hydrogen micro-positive pressure maintaining; heating and preserving heat for 6 hours at 50-60 ℃; cooling, filtering palladium carbon at room temperature, adding 4006mL of water into the system, and stirring at room temperature for 1h; after suction filtration and drying of the filter cake 216.6g of the intermediate III compound (molecular weight 220.32,0.983 mol) are obtained, with a purity of 99.6% and a molar yield of 98.3%.
Preparation of Compounds of formula I (target Compounds)
312.8G of intermediate II (molecular weight 312.79,1.0 mol), 220.3g of intermediate III (molecular weight 220.32,1.0 mol), 45.8g of tris (dibenzylideneacetone) dipalladium (molecular weight 915.73,0.05 mol), 86.8g of 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (molecular weight 578.62,0.15 mol), 448.73g of cesium carbonate (molecular weight 325.82,1.5 mol) and 3128mL of 1, 4-dioxane are weighed into a 5L reaction vessel, respectively, stirred, nitrogen substituted, protected; heating, and reacting at 95-100 ℃ for 3h; filtering while the mixture is hot, and crystallizing the filtrate at room temperature for 1h; suction filtration and filter cake drying gave 454.9g of the title compound (molecular weight 496.65,0.916 mol), purity 98.6%, molar yield 91.6%.
The target compound prepared above was examined by nuclear magnetic resonance hydrogen spectroscopy (1 H-NMR) and mass spectrometry to verify its structure, see fig. 1-2. Wherein the structural characterization includes but is not limited to HRMS, H-NMR.
Nuclear magnetic resonance hydrogen spectrum (1 H-NMR)
TABLE 1 Hydrogen Spectrometry data for target Compounds
1 H-NMR (DMSO-d 6) gave 15 sets of peak integration ratios (from low to high) of 1:1:1:1:1:1:2:3:2:8:2:4:2:3, for a total of 33 hydrogen protons, consistent with the number of protons of the target compound.
33 Aromatic hydrogen signals exist, ⑴ δH28.32 (1H, s) respectively, which are consistent with 11-NH-in the structure; ⑵ δH2.30 (1H, d) corresponds to H 13 in the structure; ⑶ δH2.22 (1H, d) corresponds to 20-NH-in the structure; ⑷ δH2.13 (1H, s) corresponds to H 10 in the structure; (5) δH27.69 (1H, dd) corresponds to H 7 in the structure; ⑹ δH25.62 (1H, d) corresponds to H 8 in the structure; ⑺ δH2.89 (1H, m) corresponds to H 21 in the structure; ⑻ δH2.50 (2H, s) corresponds to H 5 in the structure; ⑼ δH2.59 (3H, d) corresponds to H 18 in the structure; (10) δH2.54 (2H, q) corresponds to H 2 in the structure; ⑾ δH2.48 (8H, br) corresponds to 2H 3、2H4 in the structure; ⑿ δH2.15 (2H, m) corresponds to H 22 in the structure; ⒀ δH2.80 (4H, m) corresponds to H 22、H23 in the structure; ⒁ δH2.68 (2H, m) corresponds to H 23 in the structure; ⒂ δH2.13 (3H, t) corresponds to H 1 in the structure.
Mass spectrometry
Table 2 mass spectrometry data for target compounds
The mass-to-charge ratio of the peak of the test sample [ M+H ] + is 497, the molecular weight of the sample is 496, and the molecular weight of the sample is consistent with that of the target compound; the molecular weight of the test sample is even, and the molecule should contain an even number of N atoms, which corresponds to 8N atoms in the target compound. The measured mass of the [ M+H ] + peak of the sample measured by HRMS is 497.2719, the error of the theoretical value 496.2533 is +18.6mDa, the ionic molecular formula is C 25H34FN8 S, the molecular formula is C 25H33FN8 S, and the result is consistent with the molecular formula of the target compound.
And (3) estimating the test sample as the target compound by combining data analysis of nuclear magnetic resonance hydrogen spectrum (1H-NMR) and HRMS.
Example 2:
preparation of intermediate II
In a 10L reaction vessel, 308.3g of the compound of formula IIc (molecular weight 308.25,1.0 mol), 167.0g of 2, 4-dichloro-5-fluoropyrimidine (molecular weight 166.96,1.0 mol), 318.0g of sodium carbonate (molecular weight 105.99,3.0 mol), 22.5g of palladium acetate (molecular weight 224.51,0.1 mol), 1400mL of water and 4200mL of DME were weighed, respectively, stirred, warmed to reflux and incubated for 4 hours; filtering while the mixture is hot, cooling the filtrate to room temperature, and preserving heat and crystallizing for 2 hours; after suction filtration and drying of the filter cake 189.4g of said intermediate II compound (molecular weight 312.79,0.606 mol), purity 98.4% and molar yield 60.6% were obtained.
Example 3:
preparation of Compounds of formula I (target Compounds)
312.8G of intermediate II (molecular weight 312.79,1.0 mol), 220.3g of intermediate III (molecular weight 220.32,1.0 mol), 45.8g of tris (dibenzylideneacetone) dipalladium (molecular weight 915.73,0.05 mol), 86.8g of 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (molecular weight 578.62,0.15 mol), 144.17g of sodium tert-butoxide (molecular weight 96.11,1.5 mol) and 3128mL of 1, 4-dioxane were weighed into a 5L reaction vessel, respectively, stirred, and replaced with nitrogen gas for protection; heating, and reacting at 95-100 ℃ for 3h; filtering while the mixture is hot, and crystallizing the filtrate at room temperature for 1h; suction filtration and filter cake drying gave 398.2g of the target compound (molecular weight 496.65, 0.803 mol), 91.6% purity, 80.2% molar yield.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and improvements could be made by those skilled in the art without departing from the inventive concept, which falls within the scope of the present invention.
Claims (10)
1. A method of preparing a CDK inhibitor comprising the steps of:
(1) Reacting cyclopentylthiourea with 1-chloroacetone in the presence of an acid binding agent to generate a compound shown in a formula IIa; the acid binding agent is selected from one or more of pyridine, triethylamine or DIEA; the molar ratio of the cyclopentyl thiourea to the acid-binding agent is 1:1-1.5;
(2) Substitution of the compound of formula IIa with a brominating agent to produce a compound of formula IIb; the brominating agent is selected from one or more of Br 2, NBS or carbon tetrabromide; the molar ratio of the compound of the formula IIa to the brominating agent is 1:1-1.2;
(3) Reacting a compound of formula IIb with a bis-pinacolato borate in the presence of a palladium-based catalyst and a ligand to form a compound of formula IIc; the palladium catalyst is selected from one or more of palladium acetate, bis (triphenylphosphine) palladium chloride and tris (dibenzylideneacetone) dipalladium; the ligand is selected from tricyclohexylphosphine; the molar ratio of the palladium catalyst, the ligand, the compound shown in the formula IIb and the duplex pinacol borate is 0.05-0.15:0.1-0.2:1:1-2;
(4) Reacting a compound of formula IIc with 2, 4-dichloro-5-fluoropyrimidine in the presence of a palladium-based catalyst to form intermediate II; the palladium catalyst is selected from one or more of palladium acetate, bis (triphenylphosphine) palladium chloride and tris (dibenzylideneacetone) dipalladium; the molar ratio of the palladium catalyst to the compound shown in the formula IIc is 0.05-0.15:1;
(5) Reacting 1-ethylpiperazine with 2-nitro-5-aldehyde pyridine in the presence of a reducing agent to produce a compound of formula IIIa; the reducing agent is one or more selected from sodium borohydride, potassium borohydride, sodium triethylborohydride or lithium aluminum hydride; the mol ratio of the reducing agent to the 1-ethylpiperazine is 1-1.1:1;
(6) Reducing the compound of formula IIIa by Pd/C under the protection of hydrogen to obtain an intermediate III;
(7) In the presence of an alkaline reagent, a palladium catalyst and a ligand, reacting the intermediate II with the intermediate III to obtain a target product, namely a compound of a formula I; the palladium catalyst is selected from one or more of palladium acetate, bis (triphenylphosphine) palladium chloride or tris (dibenzylideneacetone) dipalladium; the ligand is selected from 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene; the molar ratio of the palladium catalyst to the ligand to the intermediate II to the intermediate III is 0.03-0.08:0.1-0.2:1-1.2:1-1.2
。
2. The method according to claim 1, wherein the molar ratio of the cyclopentylthiourea to the acid-binding agent in the step (1) is 1:1.1.
3. The process of claim 1, wherein the molar ratio of the compound of formula IIa to the brominating agent in step (2) is 1:1.
4. The process of claim 1, wherein the molar ratio of palladium catalyst, ligand, compound of formula IIb to bis-pinacolato borate in step (3) is 0.1:0.18:1:1.5.
5. The process of claim 1, wherein the molar ratio of palladium catalyst to compound of formula IIc in step (4) is 0.1:1.
6. The process of claim 1, wherein the molar ratio of reducing agent to 1-ethylpiperazine in step (5) is 1.05:1.
7. The method of claim 1, wherein the hydrogen in step (6) is micro-positive pressure; the reaction temperature is 50-60 ℃ and the reaction time is 5-8 h.
8. The method according to claim 1, wherein the molar ratio of palladium catalyst, ligand, intermediate II to intermediate III in step (7) is 0.05:0.15:1:1.
9. The preparation method according to claim 1, wherein the alkaline reagent in the step (7) is one or more selected from potassium carbonate, sodium acetate, cesium carbonate and potassium phosphate; the molar ratio of the alkaline reagent to the intermediate II to the intermediate III is 1-2:1-1.2:1-1.2.
10. The method according to claim 1, wherein the reaction temperature in the step (7) is 95 to 100 ℃ and the reaction time is 2 to 4 hours.
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