CN114349747A - Preparation process of LS007 impurity compound A - Google Patents
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Abstract
The invention belongs to the technical field of chemistry, and particularly relates to a preparation process of an LS007 impurity compound A. The preparation process of the LS007 impurity compound A comprises the following steps: carrying out a third reaction by taking the substance A2-2 and 3-aminobenzenesulfonic acid as main raw materials; wherein the structural formula of the substance A2-2 is shown in the specification
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation process of an LS007 impurity compound A.
Background
Proliferative diseases such as cancer are characterized by uncontrolled and unregulated cell proliferation. Protein kinases are an important class of enzymes for cancer research. The protein kinase family is one of the largest families in the human genome, and most kinases have a conserved functional domain consisting of 300 amino acid residues (250-300) constituting a catalytic domain, which contains a binding site for ATP, the phosphate group of which is covalently transferred to a substrate molecule to phosphorylate the substrate. Protein kinases can be classified according to the type of substrate they act on, for example, serine kinases, threonine kinases, tyrosine kinases, and the like.
Kinases are enzymes that catalyze the transfer of phosphate groups from high energy molecules containing phosphate to specific substrates, mediate intracellular signaling pathway activation, a variety of extracellular and other stimuli, act as molecular switches that can modulate or regulate the biological functions of target proteins, and trigger kinases to phosphorylate substrates. Extracellular stimuli can affect one or more cellular responses related to cell growth, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, protein synthesis control, and cell cycle regulation, among others. If the kinase mediates an abnormal cellular response, it will lead to a variety of diseases including, but not limited to, allergy and asthma, alzheimer's disease, autoimmune diseases, bone diseases, cancer, cardiovascular diseases, inflammatory diseases, hormone-related diseases, metabolic diseases, neurological diseases, neurodegenerative diseases, and the like.
Numerous molecules capable of inhibiting the function of protein kinases by blocking ATP binding are known in the prior art. Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases associated with various cyclin subunits, playing a key role in regulating cell cycle processes and transcription cycles. 10 different CDKs (CDK1-9 and 11) are involved in a variety of important regulatory pathways in eukaryotic cells, including cell cycle control, apoptosis, neuronal physiology, differentiation and transcription. ). In addition, CDKs, particularly CDK2, CDK7, and CDK9, are also required for viral replication processes. Inhibitors of CDKs that limit viral replication have been reported to act on a number of viruses, including human immunodeficiency virus, human cytomegalovirus, herpes virus and varicella-zoster virus.
Among them, inhibitors of CDK9 are a new strategy for the current potential treatment of cardiovascular diseases, including cardiac hypertrophy. Cardiac hypertrophy is characterized by an increase in the total amount of mRNA and protein synthesis, and CDK7 and CDK9 are the major drivers of transcription and are closely associated with cardiac hypertrophy. Thus, inhibition of CDK9 and its associated cyclins is an effective therapeutic strategy for cardiovascular diseases.
Inhibitors of CDKs may also be useful in the treatment of neurodegenerative disorders such as alzheimer's disease. The appearance of double-stranded Helical Filaments (Pair Helical fibers) associated with Alzheimer's disease was caused by the hyperphosphorylation of Tau protein by CDK5/p 25.
Chinese patent publication No. CN103373994A (incorporated herein by reference in its entirety) discloses a compound with CDK-9 inhibitory function and a preparation method thereof; the Chinese patent with publication number CN108658966A discloses tartrate and a crystal form of a compound 3- (5-fluoro-4- (4-methyl-2- (methylamino) thiazol-5-yl) pyrimidin-2-ylamino) -benzenesulfonamide (hereinafter, referred to as a compound LS007), which has good performance and potential of being developed into a selective CDK9 kinase inhibitor.
However, currently, research on impurities and quality control thereof in the synthesis process of the compound 3- (5-fluoro-4- (4-methyl-2- (methylamino) thiazol-5-yl) pyrimidin-2-ylamino) -benzenesulfonamide is still blank.
Disclosure of Invention
The invention provides a compound and a preparation process and application thereof.
In order to solve the above technical problems, the present invention provides a process for preparing a compound, comprising: carrying out a third reaction by taking the substance A2-2 and 3-aminobenzenesulfonic acid as main raw materials; wherein the structural formula of the substance A2-2 is shown in the specification
In a second aspect, the invention provides a compound A, wherein the structural formula of the compound A is shown in the specification
In a third aspect, the present invention provides the use of a compound as hereinbefore described as a standard for the analysis of a pharmaceutical compound.
The invention has the beneficial effects that the compound preparation process substance A2-2 and 3-aminobenzenesulfonic acid are used as main raw materials to carry out the third reaction to prepare the compound, and the compound is used as the standard substance of the medicinal compound. The compound and the synthesis method thereof are provided for the first time, and the compound can be used as one of main impurities in the synthesis process of the substance LS007, and has important significance on the quality control of the substance LS 007; the compound has the advantages of simple preparation process route, mild reaction conditions and good economic and social effects.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.
In order to make the aforementioned and other objects, features and advantages of the present invention comprehensible, preferred embodiments accompanied with figures are described in detail below.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a flow chart of a process for the preparation of the compound of the present invention (impurity A);
FIG. 2 is a flow chart of a process for the preparation of substance A2-2 according to the invention;
FIG. 3 is a flow chart of a process for the preparation of substance A2-1 according to the invention;
FIG. 4 is an infrared spectrum of a compound of the present invention (impurity A);
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of a compound of the present invention (impurity A);
FIG. 6 is a nuclear magnetic resonance carbon spectrum of a compound of the present invention (impurity A);
FIG. 7 is a mass spectrum of a compound of the present invention (impurity A);
FIG. 8 is a system suitability HPLC chromatogram obtained by adding LS007 to the synthesized impurity A of the present invention and the starting material compound A1-3 as a standard control;
FIG. 9 is an HPLC chromatogram of LS007 synthesized according to the prior art.
Detailed Description
To make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings, and it is apparent that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The first part
Referring to fig. 1, the present invention provides a process for the preparation of a compound (i.e., LS007 impurity a) comprising: carrying out a third reaction by taking the substance A2-2 and 3-aminobenzenesulfonic acid as main raw materials; wherein the structural formula of the substance A2-2 is shown in the specification
Alternatively, as shown in fig. 1, the third reaction comprises: mixing the substance A2-2 with 3-aminobenzenesulfonic acid, binaphthyl diphenyl phosphine, tris (dibenzylideneacetone) dipalladium, potassium carbonate and dioxane; refluxing and reacting while keeping the temperature; carrying out suction filtration while the solution is hot, and decompressing the filtrate to remove the solvent; adding ethyl acetate, and crystallizing; carrying out suction filtration; drying; obtaining the compound. Specifically, adding a substance A2-2, 3-aminobenzenesulfonic acid, binaphthyl diphenyl phosphine, tris (dibenzylideneacetone) dipalladium, potassium carbonate and dioxane into a 1L reaction kettle, refluxing, carrying out heat preservation reaction for 12h, carrying out suction filtration while the mixture is hot, removing inorganic impurities such as alkali and a catalyst, decompressing the filtrate to remove a solvent, adding ethyl acetate, crystallizing, carrying out suction filtration, and drying to obtain the compound. Optionally, in the third reaction, the molar ratio of the substance A2-2, the 3-aminobenzenesulfonic acid, the binaphthyl diphenyl phosphine, and the tris (dibenzylidene acetone) dipalladium is 1: 1-1.2: 0.2-0.6: 0.1-0.3: 2-5, and preferably 1: 1.1-1.2: 0.2-0.6: 0.1-0.3: 3-5.
The reaction formula of the third reaction is
As an alternative to the preparation of substance A2-2.
Referring to fig. 2, the preparation method of the substance a2-2 comprises: taking the substance A2-1 and 2, 4-dichloro-5-fluoropyrimidine as main raw materials to carry out a second reaction; wherein the structural formula of the substance A2-1 is shown in the specification
The second reaction comprises: rough preparation and refining; wherein the crude comprises: mixing the substance A2-1 with 2, 4-dichloro-5-fluoropyrimidine, potassium carbonate, tetrakis (triphenylphosphine) palladium and N, N-dimethylformamide; heating to reflux, and keeping the temperature for reaction; after the reaction is finished, filtering while the reaction is hot to remove insoluble substances; cooling the filtrate to room temperature; adding water until a product is separated out; preserving heat and performing suction filtration; leaching the filter cake with a small amount of water; drying at 60 +/-2 ℃ to obtain a crude product; the refining comprises: adding ethanol into the crude product, slowly heating to reflux, and keeping the temperature; cooling to 25 ℃ and preserving heat for 1; filtering; and drying the filter cake to obtain the substance A2-2. The reaction formula of the second reaction is:
specifically, crude: adding the substance A2-1, 2, 4-dichloro-5-fluoropyrimidine, potassium carbonate, tetrakis (triphenylphosphine) palladium and N, N-dimethylformamide into a 2L reaction bottle, heating to reflux, and carrying out heat preservation reaction for 5 hours. After the reaction, insoluble matter was removed by filtration while the reaction was still hot. Cooling the filtrate to room temperature, adding water until the product is separated out, keeping the temperature for half an hour, performing suction filtration, leaching the filter cake with a small amount of water, and drying in hot air at 60 +/-2 ℃ to obtain a crude product. Refining: transferring the crude product into a reaction bottle, adding ethanol with the volume 20 times of that of the crude product, slowly heating to reflux, preserving heat for 1h, cooling to 25 ℃, preserving heat for 1h, filtering, and drying a filter cake to obtain a substance A2-2. Alternatively, in the second reaction,
the molar ratio of the substance A2-1 to 2, 4-dichloro-5-fluoropyrimidine to potassium carbonate to tetrakis (triphenylphosphine) palladium is 1: 2.5-5: 2-5: 0.02-0.1, and preferably 1: 3-4: 2-5: 0.03-0.05.
As an alternative to the preparation of substance A2-1.
Referring to fig. 3, the preparation method of the substance a2-1 comprises the following steps: carrying out a first reaction by taking N-methylthiourea, chloropropanone and ethanol as main raw materials; the first reaction comprises: adding N-methyl thiourea, chloropropone and ethanol; stirring under heat preservation after refluxing; cooling to below 60 deg.C and adding water; keeping the temperature at 25 +/-5 ℃; carrying out suction filtration; drying to obtain the substance A2-1; the reaction formula of the first reaction is
Concretely, adding N-methylthiourea and chloropropanone into a 2L reaction bottle, adding ethanol, refluxing, keeping the temperature and stirring for 5h, cooling to below 60 ℃, adding water, keeping the temperature for half an hour at 25 +/-5 ℃, carrying out suction filtration and drying to obtain a substance A2-1. Optionally, in the first reaction, the molar ratio of N-methylthiourea to chloroacetone is 1: 1-2, preferably 1:1 to 1.2.
In the present application, the first reaction, the second reaction, and the third reaction do not necessarily indicate a certain order, but are merely intended to distinguish the reactions occurring when preparing each substance (e.g., substance A2-1 and substance A2-2). Meanwhile, the first reaction, the second reaction, and the third reaction may be only reaction processes, and may also include processes in which reactions are performed, processes in which reactants are added or pretreated before the reactions, and processes in which reaction products are purified or washed after the reactions, and thus, variations in the above description do not affect variations in the reactions in the present application. In addition, the substances A2-1 and A2-2 are used for distinguishing each intermediate product for preparing the compound, wherein A2-1 and A2-2 are only the number of the substances and have no limit on the components and the structures of each substance.
Further, the invention provides a raw material formula of the compound, which comprises the following components: 3-aminobenzenesulfonic acid and substance A2-2; wherein the structural formula of the substance A2-2 is shown in the specification
Further, the invention provides a compound A, wherein the structural formula of the compound A is shown in the specification
Further, the present invention provides the use of a compound as described hereinbefore as a standard for the analysis of pharmaceutical compounds.
Alternatively, the pharmaceutical compound is for example but not limited to LS-007(CDK kinase inhibitor targeted anticancer drugs, pyrimidine derivative drugs targeting protein kinases for anticancer). The compounds may be used as impurities in the pharmaceutical compounds for use as standards in the analysis of pharmaceutical compounds.
Specifically, the specific method of using the compound as an impurity control (hereinafter, impurity a) is as follows:
taking a proper amount of the compound, precisely weighing, adding a proper amount of dimethyl sulfoxide to dissolve, and diluting with acetonitrile-water (1: 1) as a solvent to prepare a solution containing 0.4mg in 1mL as a test solution; taking a proper amount of compound A1-3, impurity A and LS007, adding a proper amount of solvent, dissolving by ultrasound, and diluting to prepare mixed solutions containing about 4 mu g of each solution in 1mL as system applicability solutions. Measuring by high performance liquid chromatography (0512 in the four-department general regulation of 2020 edition in China pharmacopoeia).
As shown in fig. 8, 10 μ L of the system suitability solution was precisely measured and injected into a liquid chromatograph, and the chromatogram was recorded. From the figure, the relative retention times of LS007, impurity a and compound a1-3 can be seen, thus enabling the use of the compound as a standard for the analysis of pharmaceutical compounds.
The second part
Example 1
(1) Preparation of substance A2-1
Adding 25g N-methylthiourea (molecular weight 90.1, 0.28mol) and 25.6g chloropropanone (molecular weight 92.5, 0.28mol) into a 2L reaction bottle, adding 500g ethanol, refluxing, keeping the temperature, stirring for 5h, cooling to below 60 ℃, adding 1L water, keeping the temperature at 25 +/-5 ℃ for half an hour, carrying out suction filtration and drying to obtain 28.0g of a substance A2-1 (molecular weight 128.2, 0.21mol), wherein the purity is 98% and the yield is 76.4%.
(2) Preparation of substance A2-2
Crude preparation: 28g of A2-1 (molecular weight: 128.2, 0.21mol), 108.5g of 2, 4-dichloro-5-fluoropyrimidine (molecular weight: 167.0, 0.65mol), 59.9g of potassium carbonate (molecular weight: 138.2, 0.43mol), 7.70g of tetrakis (triphenylphosphine) palladium (molecular weight: 1155.6, 6.7mmol) and 541mL of N, N-dimethylformamide were put into a 2L reaction flask, and the mixture was heated to reflux and reacted for 5 hours while maintaining the temperature. After the reaction, insoluble matter was removed by filtration while the reaction was still hot. And cooling the filtrate to room temperature, adding 1084mL of water until a product is separated out, keeping the temperature for half an hour, carrying out suction filtration, leaching a filter cake with a small amount of water, and drying in hot air at 60 +/-2 ℃ to obtain a crude product.
Refining: and transferring the crude product into a reaction bottle, adding ethanol with the mass 20 times that of the crude product, slowly heating to reflux, preserving heat for 1h, cooling to 25 ℃, preserving heat for 1h, filtering, and drying a filter cake to obtain 24.3g of a substance A2-2 (with the molecular weight of 258.7, 0.094mol), wherein the purity is 98 percent, and the yield is 44.8 percent.
(3) Preparation of Compound A
12g of a substance A2-2 (molecular weight of 258.7, 0.046mol), 8.80g of 3-aminobenzenesulfonic acid (molecular weight of 173.2, 0.051mol), 5.75g of binaphthylphenylphosphine (molecular weight of 622.7, 0.01mol), 4.23g of tris (dibenzylideneacetone) dipalladium (molecular weight of 915.7, 0.005mol), 19.16g of potassium carbonate (molecular weight of 138.2, 0.14mol) and 240g of dioxane are put into a 1L reaction kettle, refluxed, reacted for 12 hours under heat preservation, filtered while hot, inorganic impurities such as alkali and a catalyst are removed, the filtrate is decompressed to remove a solvent, 48g of ethyl acetate is added for crystallization, and filtered and dried to obtain 12.5g of a compound A (molecular weight of 395.4, 0.032mol), the purity is 98 percent, and the yield is 68.2 percent.
Example 2
(1) Preparation of substance A2-1
Adding 25g N-methylthiourea (molecular weight 90.1, 0.28mol) and 31.4g chloropropanone (molecular weight 92.5, 0.34mol) into a 2L reaction bottle, adding 550g ethanol, refluxing, keeping the temperature, stirring for 5h, cooling to below 60 ℃, adding 1L water, keeping the temperature at 25 +/-5 ℃ for half an hour, carrying out suction filtration and drying to obtain 28.5g of a substance A2-1 (molecular weight 128.2, 0.22mol), wherein the purity is 98% and the yield is 77.0%.
(2) Preparation of substance A2-2
Crude preparation: 28g of A2-1 (molecular weight: 128.2, 0.21mol), 178.7g of 2, 4-dichloro-5-fluoropyrimidine (molecular weight: 167.0, 1.07mol), 88.4g of potassium carbonate (molecular weight: 138.2, 0.64mol), 12.4g of tetrakis (triphenylphosphine) palladium (molecular weight: 1155.6, 10.7mmol) and 620mL of N, N-dimethylformamide were put into a 3L reaction flask, and the mixture was heated to reflux and reacted for 5 hours while maintaining the temperature. After the reaction, insoluble matter was removed by filtration while the reaction was still hot. Cooling the filtrate to room temperature, adding 1100mL of water until the product is separated out, keeping the temperature for half an hour, carrying out suction filtration, leaching the filter cake with a small amount of water, and drying in hot air at 60 +/-2 ℃ to obtain a crude product.
Refining: and transferring the crude product into a reaction bottle, adding ethanol with the mass 20 times that of the crude product, slowly heating to reflux, preserving heat for 1h, cooling to 25 ℃, preserving heat for 1h, filtering, and drying a filter cake to obtain 24.8g of a substance A2-2 (with the molecular weight of 258.7, 0.096mol), wherein the purity is 98 percent, and the yield is 45.7 percent.
(3) Preparation of Compound A
12g of the substance A2-2 (molecular weight: 258.7, 0.046mol), 9.56g of 3-aminobenzenesulfonic acid (molecular weight: 173.2, 0.055mol), 17.4g of binaphthylphenylphosphine (molecular weight: 622.7, 0.028mol), 12.8g of tris (dibenzylideneacetone) dipalladium (molecular weight: 915.7, 0.014mol), 31.8g of potassium carbonate (molecular weight: 138.2, 0.23mol) and 280g of dioxane were put into a 1L reactor, refluxed, reacted for 12 hours while maintaining the temperature, filtered while hot, and inorganic impurities such as an alkali and a catalyst were removed, the filtrate was subjected to vacuum filtration to remove the solvent, 48g of ethyl acetate was added to precipitate crystals, and subjected to suction filtration and drying, thereby obtaining 12.9g of the compound A (molecular weight: 395.4, 0.033mol), with a purity of 98% and a yield of 70.3%.
Third part
See FIGS. 4-7, this section by IR spectroscopy, NMR, Hydrogen (C)1H-NMR) and nuclear magnetic resonance carbon Spectroscopy (C13C-NMR), mass spectrum of the compound prepared in example 1 was examined to verify its structure. Wherein the structural characterization includes, but is not limited to, IR, UV, HRMS, H-NMR, C-NMR.
(1) Infrared spectrum (IR)
The model of the testing instrument: PE spectrum two; test unit: shanghai Zhangjiang grain public service platform, Inc.; the sample preparation method comprises the following steps: the ATR method.
With reference to fig. 4 and table 1, the infrared spectroscopy result shows that the sample has obvious NH, S ═ O and heteroaromatic rings, so that the infrared spectroscopy data of the object to be labeled are consistent with the molecular structure of the compound.
Infrared spectral data for the compounds of Table 1
(2) Nuclear magnetic resonance hydrogen spectrum (1H-NMR) and nuclear magnetic resonance carbon Spectroscopy (C13C-NMR)
A deuterated reagent: about 9mg of CLS1601C-20161222-01 was dissolved in 0.50mL of DMSO-d 6; each group of the compound may be numbered
a) Magnetic resonance hydrogen spectrum (1H-NMR)
Hydrogen spectroscopic data for compounds of table 2
| Serial number | Chemical shift δH(ppm) | Multiplicity J[Hz] | Number of protons | 1H-1H COSY |
| 1 | 2.93 | s | 3 | 2 |
| 2 | 8.56 | S, |
1 | 1 |
| 3 | / | / | / | / |
| 4 | / | / | / | / |
| 5 | / | / | / | / |
| 6 | 2.51 | s | 3 | / |
| 7 | / | / | / | / |
| 8 | / | / | / | / |
| 9 | 8.47 | d,3.2 | 1 | / |
| 10 | / | / | / | / |
| 11 | 9.61 | S, |
1 | / |
| 12 | / | / | / | / |
| 13 | 7.99 | |
1 | 17,15 |
| 14 | / | / | / | / |
| 15 | 7.22-7.23 | |
1 | 16,13,17 |
| 16 | 7.22-7.23 | |
1 | 15,17 |
| 17 | 7.66-7.69 | |
1 | 16,15,13 |
| 18 | / | / | / | / |
b) Magnetic resonance hydrogen spectrum nuclear magnetic resonance carbon spectrum (13C-NMR)
TABLE 3 carbon Spectroscopy data for Compounds
(3) Mass spectrometry
Mass spectral data for the compounds of Table 4
| Mass to charge ratio (m/z) | Remarks for note |
| 396.1 | [M+H]+ |
The mass spectrum results of the compounds showed that the measured molecular weight of 396.0591(M +1) in the HRMS analysis was consistent with the theoretical molecular weight of 396.0595(M +1), and the molecular formula C was deduced from the measured molecular weight15H15FN5O3S2With compounds of formula C15H15FN5O3S2+ H are identical. The mass spectrum of the compound shows that the molecular weight is 395, and the results of comprehensive infrared spectroscopy (IR), nuclear magnetic resonance hydrogen spectrum (1H-NMR) and carbon spectrum (13C-NMR) can confirm that the molecular structure of the sample is consistent with the molecular structure of the compound.
In conclusion, the compound and the preparation process, the raw material formula and the application thereof of the invention take the substance A2-2 and 3-aminobenzenesulfonic acid as main raw materials to carry out the third reaction to prepare the compound and are used as the standard substance of the medicinal compound, not only are the compound and the synthetic method thereof provided for the first time, but also the compound can be used as one of main impurities in the synthetic process of LS007, and has important significance for the quality control of LS 007. The compound is prepared by taking N-methylthiourea and chloropropanone as initial raw materials, and the content of the medicinal compound can be accurately calibrated.
In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (8)
1. A process for preparing LS007 impurity compound A, which is characterized by comprising the following steps:
carrying out a third reaction by taking the substance A2-2 and 3-aminobenzenesulfonic acid as main raw materials; wherein
The structural formula of the substance A2-2 is shown in the specification
2. The production process according to claim 1,
the third reaction comprises:
mixing the substance A2-2, 3-aminobenzenesulfonic acid, binaphthyl diphenyl phosphine, tris (dibenzylideneacetone) dipalladium, potassium carbonate and a solvent, refluxing and carrying out heat preservation reaction to obtain the compound; the molar ratio of the A2-2 to the 3-aminobenzenesulfonic acid to the binaphthyl diphenyl phosphine to the tris (dibenzylideneacetone) dipalladium to the potassium carbonate is 1: 1-1.2: 0.2-0.6: 0.1-0.3: 2-5.
3. The production process according to claim 1,
the reaction formula of the third reaction is
4. The production process according to claim 1,
the preparation method of the substance A2-2 comprises the following steps:
taking the substance A2-1 and 2, 4-dichloro-5-fluoropyrimidine as main raw materials to carry out a second reaction; wherein
The structural formula of the substance A2-1 is shown in the specification
5. The production process according to claim 4,
the second reaction comprises: mixing and dissolving the substance A2-1, 2, 4-dichloro-5-fluoropyrimidine, potassium carbonate and tetrakis (triphenylphosphine) palladium in a reaction solvent; heating to reflux, and carrying out heat preservation reaction to obtain a substance A2-2; the molar ratio of the substance A2-1 to the 2, 4-dichloro-5-fluoropyrimidine to the potassium carbonate to the tetrakis (triphenylphosphine) palladium is 1: 2.5-5: 2-5: 0.02-0.1.
6. The production process according to claim 4,
the second reaction has the formula
7. The production process according to claim 4,
the preparation method of the substance A2-1 comprises the following steps:
carrying out a first reaction by taking N-methylthiourea and chloropropanone as main raw materials to obtain a substance A2-1;
the reaction formula of the first reaction is
8. The production process according to claim 7,
the molar ratio of the N-methylthiourea to the chloropropanone is 1: 1.0 to 1.2.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103373994A (en) * | 2012-04-19 | 2013-10-30 | 癌症研究技术有限公司 | Therapeutic compounds |
| US20170173021A1 (en) * | 2014-04-04 | 2017-06-22 | Memorial Sloan-Kettering Cancer Center | Method and kits for identifying of cdk9 inhibitors for the treatment of cancer |
| CN107118207A (en) * | 2017-05-22 | 2017-09-01 | 苏州东南药业股份有限公司 | The preparation method of one class CDK inhibitor |
| CN108658966A (en) * | 2018-06-20 | 2018-10-16 | 常州千红生化制药股份有限公司 | The tartrate and its crystal form of selective CDK9 inhibitor |
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2021
- 2021-07-05 CN CN202110755779.8A patent/CN114349747A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103373994A (en) * | 2012-04-19 | 2013-10-30 | 癌症研究技术有限公司 | Therapeutic compounds |
| US20170173021A1 (en) * | 2014-04-04 | 2017-06-22 | Memorial Sloan-Kettering Cancer Center | Method and kits for identifying of cdk9 inhibitors for the treatment of cancer |
| CN107118207A (en) * | 2017-05-22 | 2017-09-01 | 苏州东南药业股份有限公司 | The preparation method of one class CDK inhibitor |
| CN108658966A (en) * | 2018-06-20 | 2018-10-16 | 常州千红生化制药股份有限公司 | The tartrate and its crystal form of selective CDK9 inhibitor |
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