CN114736204A - Preparation method of pexidaltinib structural analogue and application of pexidaltinib structural analogue in tumor resistance - Google Patents

Preparation method of pexidaltinib structural analogue and application of pexidaltinib structural analogue in tumor resistance Download PDF

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CN114736204A
CN114736204A CN202210488501.3A CN202210488501A CN114736204A CN 114736204 A CN114736204 A CN 114736204A CN 202210488501 A CN202210488501 A CN 202210488501A CN 114736204 A CN114736204 A CN 114736204A
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刘明星
童航
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Hubei University of Technology
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Abstract

The invention belongs to the technical field of preparation of antitumor drugs, and particularly discloses design and synthesis of a pexidinib analogue and application of the pexidinib analogue in preparation of an antitumor drug, and particularly relates to synthesis of a compound 5-chloro-3- { [2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidin-5-yl ] methyl } -1H-pyrrolo [2,3-b ] pyridine and application of the compound in preparation of the antitumor drug. The compound of the invention modifies and optimizes the structure of the pexidinir by a biological electron isostere principle on the basis of retaining the basic drug effect mother nucleus of the pexidinir, namely 5-chloro-7-azaindole, thereby designing a pexidinir analogue with potential anticancer activity. The compound is synthesized by taking 2-aminopyrimidine-5-carboxylic acid methyl ester and 6-trifluoromethyl nicotinaldehyde as raw materials through six-step reaction. Cytotoxicity experiments show that the compound can inhibit the proliferation of cancer cells. The apoptosis experiment further verifies that the compound has the capability of inducing cancer cell apoptosis.

Description

Preparation method of pexidaltinib structural analogue and application of pexidaltinib structural analogue in tumor resistance
Technical Field
The invention belongs to the technical field of preparation of antitumor drugs, and relates to a preparation method of a pexidinib structural analogue and an application of the pexidinib structural analogue in antitumor, in particular to a preparation method of a compound 5-chloro-3- { [2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidin-5-yl ] methyl } -1H-pyrrolo [2,3-b ] pyridine and an application of the compound in preparation of an antitumor drug.
Background
Pexidantinib (Pexidartinib), a colony stimulating factor 1 receptor (CSF-1R) inhibitor, was marketed in the United states in 2019 and approved for the treatment of tenosynoviocytomegaloma (TGCT) adult patients, was the first globally approved drug for the treatment of TGCT and was assigned the orphan drug designation. Meanwhile, in vivo and in vitro activity researches show that pexidinib also has a certain treatment effect on gastrointestinal stromal tumor, glioblastoma, acute myeloid leukemia, rheumatoid arthritis and the like. The compound of the invention modifies and optimizes the structure of the pexidinib by a biological electron isostere principle on the basis of retaining the basic drug effect mother nucleus of the pexidinib, so as to develop a new pexidinib analogue with anti-tumor activity and widen the new indications and treatment windows of the drugs.
The currently reported pexidinib analogues all use 5-chloro-7-azaindole rings as parent nuclei, and the analogues all show strong anticancer activity. Such as vemurafenib (bolag G, et al nature,2010), which was approved by the U.S. FDA for the treatment of melanoma in 2011; PLX-4720, which is capable of significantly inhibiting the proliferation of human colon cancer cell COLO205, human malignant melanoma cell a375 in vitro (paramiso KH, et al cancer research, 2011); bezuclastatin, the analogue has stronger treatment effect on gastrointestinal stromal tumor and metastatic cancer (WO 2014100620).
Based on the above reports, in order to broaden the application of the pexidinib analogue in the anticancer field, the invention expects to develop a new pexidinib analogue and explore the new anticancer activity of the compound.
Disclosure of Invention
Aiming at the defects in the prior art, in order to develop a new pexidinib analogue with anti-tumor activity, the applicant widens the new indications and treatment window of the drugs, and modifies and optimizes the structure of the pexidinib by a biological electron isostere principle on the basis of retaining the basic drug effect mother nucleus 5-chloro-7-azaindole of the pexidinib.
The first purpose of the invention is to design and synthesize a structural analogue of Pesitaglinib, namely a compound (I): 5-chloro-3- { [2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidin-5-yl ] methyl } -1H-pyrrolo [2,3-b ] pyridine having the following structural formula:
Figure BDA0003630236110000021
the molecular formula is as follows: c19H14ClF3N6
Molecular weight: 418.8082
The compound is structurally modified by utilizing a biological electron isostere principle on the basis of retaining the pharmacodynamic group 5-chloro-7-azaindole of the Pesiccatinib, so that the novel Pesiccatinib analogue is obtained, and cell experiments prove that the analogue has potential antitumor activity and application and development values.
The second purpose of the invention is to provide the application of the compound 5-chloro-3- { [2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidin-5-yl ] methyl } -1H-pyrrolo [2,3-b ] pyridine in preparing anticancer drugs.
The invention carries out preliminary in vitro activity evaluation. The result of a cytotoxicity experiment by taking a pexidininib standard substance as a control proves that the compound can obviously inhibit the growth of tumor cells HOS, MCF-7 and A549; in addition, the apoptosis experiment further proves that the compound can induce the apoptosis of HOS and A549 cells.
The compound (I) can be prepared by the following process route:
the method comprises the following steps of firstly, taking 2-aminopyrimidine-5-carboxylic acid methyl ester and 6-trifluoromethyl nicotinaldehyde as raw materials, reacting with a reducing agent, and carrying out reductive amination reaction to obtain an intermediate (II), wherein the specific reaction route is as follows:
Figure BDA0003630236110000031
wherein the structural formula of the intermediate (II) is as follows:
Figure BDA0003630236110000032
the chemical name of the intermediate (II) is as follows: methyl 2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidine-5-carboxylate.
And step two, taking the intermediate (II) as a raw material, reacting with a reducing agent, and carrying out a reduction reaction to obtain an intermediate (III), wherein the specific reaction route is as follows:
Figure BDA0003630236110000033
wherein the structural formula of the intermediate (III) is as follows:
Figure BDA0003630236110000034
the chemical name of the intermediate (III) is: [2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidin-5-yl ] methanol.
Step three, taking the intermediate (III) as a raw material, reacting with an oxidant, and carrying out an oxidation reaction to obtain an Intermediate (IV), wherein the specific reaction route is as follows:
Figure BDA0003630236110000041
wherein the structural formula of the Intermediate (IV) is as follows:
Figure BDA0003630236110000042
the chemical name of the Intermediate (IV) is as follows: 2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidine-5-carbaldehyde.
Step four, taking the Intermediate (IV) as a raw material, reacting the Intermediate (IV) with a protective group of amino, and carrying out substitution reaction to obtain an intermediate (V), wherein the specific reaction route is as follows:
Figure BDA0003630236110000043
wherein the structural formula of the intermediate (V) is as follows:
Figure BDA0003630236110000044
the chemical generic name of the intermediate (V) is: [2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl }) - (G-substituted amino) ] pyrimidine-5-carbaldehyde.
And step five, taking the intermediate (V) and 5-chloro-7-azaindole as raw materials, and carrying out addition reaction under an alkaline condition to obtain an intermediate (VI), wherein the specific reaction route is as follows:
Figure BDA0003630236110000051
wherein the intermediate (VI) has the structural formula:
Figure BDA0003630236110000052
the chemical generic name of the intermediate (VI) is: {5- [ (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) hydroxymethyl ] pyrimidin-2-yl } - { [6- (trifluoromethyl) pyridin-3-yl ] methyl } -G-substituted amine.
Taking the intermediate (VI) as a raw material, performing substitution reaction under an acidic condition to remove an amino protecting group, and simultaneously performing action with triethylsilane to remove hydroxyl, thereby obtaining the compound (I), wherein the specific reaction route is as follows:
Figure BDA0003630236110000053
in the above technical scheme, in the formula, G is a protective group of amino, preferably tert-butyloxycarbonyl, fluorenylmethoxycarbonyl, p-methoxybenzyl and the like.
On the basis of the above technical scheme, preferably, in the step one, the reducing agent is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, palladium on carbon/H2Raney nickel/H22-methylpyridine-N-borane, triethylsilane and rhodium/CO. More preferably, in the step one, the reducing agent is one of sodium cyanoborohydride, sodium triacetoxyborohydride, triethylsilane and rhodium/CO.
On the basis of the above technical scheme, preferably, in the step one, the ratio of 2-aminopyrimidine-5-carboxylic acid methyl ester: 6-trifluoromethyl nicotinaldehyde: the molar ratio of the reducing agent is 1: 1-4: 2 to 10. More preferably, in step one, the ratio of methyl 2-aminopyrimidine-5-carboxylate: 6-trifluoromethyl nicotinaldehyde: the molar ratio of the reducing agent is 1: 1.2-3: 2 to 9.
On the basis of the above technical solution, preferably, in the second step, the reducing agent is one of lithium aluminum hydride, lithium tri-sec-butylborohydride, sodium borohydride, potassium borohydride, diisobutyl aluminum hydride, sodium borohydride/magnesium chloride, sodium borohydride/aluminum chloride, and sodium borohydride/zinc chloride. More preferably, in the second step, the reducing agent is one of lithium aluminum hydride, sodium borohydride/magnesium chloride, sodium borohydride/aluminum chloride, and sodium borohydride/zinc chloride.
On the basis of the above technical scheme, preferably, in the second step, the intermediate (ii): the molar ratio of the reducing agent is 1: 1 to 5. More preferably, in step two, intermediate (ii): the molar ratio of the reducing agent is 1: 1.2 to 4.
On the basis of the above technical solution, preferably, in step three, the oxidizing agent is one of manganese dioxide, PDC oxidizing agent, PCC oxidizing agent, DMSO, dess-martin oxidizing agent, Collins reagent, 2-iodoxybenzoic acid, ammonium tetrapropylperruthenate, and tetramethylpiperidine oxide. More preferably, in the third step, the oxidizing agent is any one of dess-martin oxidizing agent, Collins reagent, tetrapropyl ammonium perruthenate and tetramethyl piperidine oxide.
On the basis of the above technical scheme, preferably, in step three, the intermediate (iii): the molar ratio of the oxidant is 1: 0.5 to 5. More preferably, in step three, intermediate (iii): the molar ratio of the oxidant is 1: 1 to 4.
On the basis of the above technical scheme, preferably, in the step four, the amino protecting reagent is one of benzyl chloroformate, di-tert-butyl dicarbonate, fluorenylmethoxycarbonylcarbonyl chloride, p-methoxybenzyl bromide, benzyl bromide, p-toluenesulfonyl chloride, triphenylchloromethane and N-ethoxycarbonylphthalimide. More preferably, in the fourth step, the amino protecting reagent is any one of benzyl chloroformate, di-tert-butyl dicarbonate, fluorenylmethoxycarbonyl chloride and p-methoxybenzyl bromide.
On the basis of the above technical scheme, preferably, in step four, the intermediate (iv): the mol ratio of the amino protective agent is 1: 1 to 6. More preferably, in step four, intermediate (iv): the mol ratio of the amino protective agent is 1: 1.2 to 4.5.
On the basis of the above technical scheme, preferably, in the fifth step, the substance providing the alkaline environment is one or more of sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amylate and potassium tert-amylate. More preferably, in the fifth step, the substance providing the alkaline environment is one or more of sodium hydroxide, potassium carbonate, potassium tert-butoxide and potassium tert-pentoxide.
On the basis of the above technical scheme, preferably, in the fifth step, the intermediate (v): 5-chloro-7-azaindole: the molar ratio of the alkaline environment providing substances is 1: 1-3: 0.01 to 5. More preferably, in step five, intermediate (v): 5-chloro-7-azaindole: the molar ratio of the alkaline reagent is 1: 1.2-2.5: 0.01 to 4.
On the basis of the above technical scheme, preferably, in the sixth step, the substance providing an acidic environment is one of formic acid, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, phosphoric acid, trifluoroacetic acid and zinc bromide. More preferably, in the sixth step, the substance providing an acidic environment is one of hydrochloric acid, hydrobromic acid, phosphoric acid and trifluoroacetic acid.
On the basis of the above technical scheme, preferably, in the sixth step, the intermediate (vi): providing a molar ratio of acidic environment substances of 1: 0.5 to 85. More preferably, in step six, intermediate (vi): the molar ratio of the acidic reagent is 1: 1 to 80.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention synthesizes a new bioactive molecule with potential application value for the first time by using cheap and easily obtained raw materials, mild reaction conditions and a simple process route. Secondly, in the process route, the intermediate synthesized in each step is also synthesized for the first time.
(2) The compound is verified to have potential anticancer activity, can obviously inhibit the growth of HOS, MCF-7 and A549 cells in vitro, and particularly has wide application prospect for HOS and A549 cells.
Drawings
FIG. 1 is a mass spectrum of intermediate (II) methyl 2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidine-5-carboxylate according to the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of intermediate (III) of the present invention, [2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidin-5-yl ] methanol;
FIG. 3 is an infrared spectrum of an Intermediate (IV) of the present invention, namely 2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidine-5-carbaldehyde;
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of tert-butyl (5-formylpyrimidin-2-yl) { [6- (trifluoromethyl) pyridin-3-yl ] methyl } carbamate, intermediate (V) according to the present invention;
FIG. 5 is a mass spectrum of tert-butyl intermediate (VI) {5- [ (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) hydroxymethyl ] pyrimidin-2-yl } - { [6- (trifluoromethyl) pyridin-3-yl ] methyl } carbamate according to the present invention;
FIG. 6 is a NMR spectrum of 5-chloro-3- { [2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidin-5-yl ] methyl } -1H-pyrrolo [2,3-b ] pyridine, compound (I);
figure 7 is a statistical plot of the results of the HOS cytotoxicity experiments (") indicates significant differences between data with P less than 0.05,") indicates significant differences between data with P less than 0.01;
figure 8 is a statistical plot of the results of the MCF-7 cytotoxicity experiments ("×" indicates that there is a significant difference between the data and P is less than 0.001);
figure 9 is a statistical plot of the results of a549 cytotoxicity experiments ("+" indicates significant differences between data and P is less than 0.05);
fig. 10 is a graph of the results of HOS apoptosis experiments (A, B is a flow cytogram, C is a histogram statistical analysis) (") indicates significant differences between data and P is less than 0.05,") indicates significant differences between data and P is less than 0.01;
fig. 11 is a graph of the results of the a549 apoptosis test (A, B is flow cytogram, C is histogram statistical analysis) ("indicates significant difference between data and P is less than 0.05).
Detailed Description
To facilitate an understanding of the invention by those of ordinary skill in the art, applicants describe the invention better with reference to specific embodiments below. It should be noted that the following embodiments are only a part of the embodiments within the scope of the present patent application, and not all embodiments. Without making any inventive changes, should also be considered as within the scope of protection of the present invention.
The reagents used in the following examples, all of which were conventional, were of analytical purity, the solvents used were not further processed, the concentration of concentrated hydrochloric acid was 37 wt%, and the concentration of hydrobromic acid was 48 wt%.
Example 1 Synthesis of intermediate (II)
1.1 to a one-neck flask, 200mg of methyl 2-aminopyrimidine-5-carboxylate, 274.4mg of 6-trifluoromethylnicotinaldehyde were added, dissolved in 20ml of toluene, and 382.3mg of sodium cyanoborohydride, 1ml of concentrated hydrochloric acid were added. The reaction temperature is 100 ℃, and the reaction time is 32 h. After the reaction, the reaction mixture was poured into a flask, and 100mL of 10% m/v (m/v: g/mL, which will be omitted) aqueous potassium carbonate solution was added thereto, and the mixture was extracted with 100mL of dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and dried at 60 ℃ for 24 hours to obtain 385mg of intermediate (ii) with a yield of 94.41%.
1.1 Mass Spectrometry characterization of the intermediate (II) obtained as follows: ESI-MS (m/z): 313.09[ M + H]+See figure 1.
1.2 into a single-necked flask, 300mg of methyl 2-aminopyrimidine-5-carboxylate and 480.3mg of 6-trifluoromethylnicotinaldehyde were added, dissolved in 30ml of acetonitrile, and 1.24g of sodium triacetoxyborohydride and 1.5ml of concentrated hydrochloric acid were added. The reaction temperature is 85 ℃ and the reaction time is 36 h. After the reaction was completed, it was poured into a flask, and 150ml of 10% m/v potassium carbonate aqueous solution was added, and extracted with 200ml of methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and dried at 60 ℃ for 24 hours to obtain 526mg of intermediate (II) with a yield of 85.99%.
1.3 into a single-neck flask, 200mg of methyl 2-aminopyrimidine-5-carboxylate, 343mg of 6-trifluoromethyl nicotinaldehyde were added, dissolved in 20ml of toluene, and 5.2ml of triethylsilane and 313.7mg of glacial acetic acid were added. The reaction temperature is 100 ℃, and the reaction time is 30 h. After the reaction was completed, it was poured into a flask, and 100ml of 10% m/v potassium carbonate aqueous solution was added, and extraction was performed with 100ml of ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, rotary evaporation concentration, and drying at 60 ℃ for 24 hours to obtain 373mg of intermediate (II) with a yield of 91.47%.
Example 2 Synthesis of intermediate (III)
2.1 into a three-necked flask, 150mg of the intermediate (II) prepared in 1.1 of example 1 was added, and dissolved in 20ml of tetrahydrofuran, and the whole reaction was purged with nitrogen. 27.3mg of sodium borohydride and 131mg of zinc chloride are added. The reaction temperature is 60 ℃, and the reaction time is 42 h. After the reaction was complete, 50ml of 10% m/vNH was added4And (3) continuously stirring the Cl aqueous solution for 1h, directly filtering the reaction solution, concentrating by rotary evaporation, and drying at 70 ℃ for 24h to obtain 89mg of an intermediate (III), wherein the yield is 65.18%.
2.1 Nuclear magnetic resonance hydrogen spectroscopy characterization of the intermediate (III) obtained as follows:1h NMR (400MHz, dmso) δ 8.79-8.70(m,2H),8.23(s,1H),8.16(s,1H),7.95(dd, J ═ 8.1,1.4Hz,1H),7.86-7.83(m,1H),6.49(s,1H),4.60(d, J ═ 6.3Hz,2H),4.28(d, J ═ 4.9Hz,2H), see fig. 2.
2.2 into a three-necked flask, 200mg of the intermediate (II) prepared in 1.1 of example 1 was added, dissolved in 20ml of tetrahydrofuran, and the whole reaction was purged with nitrogen. 29.1mg of sodium borohydride and 91.5mg of magnesium chloride are added. The reaction temperature is 50 ℃ and the reaction time is 48 h. After the reaction was complete, 50ml of 10% m/vNH was added4Aqueous solution of Cl, thenStirring was continued for 1h, the reaction was directly filtered, concentrated by rotary evaporation, and dried at 70 ℃ for 24h to give 116mg of intermediate (III) in 63.72% yield.
2.3 into a three-necked flask, 300mg of the intermediate (II) prepared in 1.1 of example 1 was added, dissolved in 30ml of tetrahydrofuran, and the whole reaction was purged with nitrogen. 1.54ml of 2.5mol/L tetrahydrofuran solution of lithium aluminum hydride is added dropwise, the reaction temperature is 40 ℃, and the reaction lasts 38 hours. After the reaction was complete, 100ml of saturated NH were added4And (3) continuously stirring the Cl aqueous solution for 1h, directly filtering the reaction solution, concentrating by rotary evaporation, and drying at 70 ℃ for 24h to obtain 160mg of an intermediate (III), wherein the yield is 58.59%.
Example 3 Synthesis of Intermediate (IV)
3.1 into a three-necked flask, 200mg of the intermediate (III) prepared in 2.1 of example 2 was added, dissolved in 20ml of dichloromethane, and the whole reaction was purged with nitrogen. 332.9mg of ammonium tetrapropylperruthenate was added to the reaction mixture, and after the reaction was completed, the mixture was poured into a flask, 100ml of a 10% m/v potassium carbonate aqueous solution was added, and the mixture was extracted with 100ml of ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and dried at 60 ℃ for 24 hours to obtain 184mg of Intermediate (IV) with a yield of 92.66%.
3.1 Infrared Spectrum characterization of the obtained Intermediate (IV) is as follows: IR (KBr) v 2965,2212,1942,1661,1578,1408,1027cm-1See fig. 3.
3.2 into a three-necked flask, 150mg of the intermediate (III) prepared in 2.1 of example 2 was added, dissolved in 20ml of dichloromethane, and the whole reaction was purged with nitrogen. 218mg Collins reagent is added, the reaction temperature is 30 ℃, and the reaction is carried out for 6 h. After the reaction was completed, it was poured into a flask, 100ml of 10% m/v potassium carbonate aqueous solution was added, extracted with 100ml of ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and dried at 60 ℃ for 24 hours to obtain 134mg of Intermediate (IV) with a yield of 89.97%.
3.3 into a three-necked flask, 250mg of the intermediate (III) prepared in 2.1 of example 2 was added, dissolved in 30ml of dichloromethane, and the whole reaction was purged with nitrogen. Adding 218mg of tetramethylpiperidine oxide, and reacting at 40 ℃ for 5 hours. After the reaction was completed, the reaction mixture was poured into a flask, and 200ml of a 10% m/v potassium carbonate aqueous solution was added, followed by extraction with 200ml of ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, rotary evaporation and concentration, and drying at 60 ℃ for 24 hours to obtain 209mg of Intermediate (IV) with a yield of 84.2%.
Example 4 Synthesis of intermediate (V)
4.1 into a one-neck flask, 300mg of the Intermediate (IV) prepared in 3.1 of example 3 was added and dissolved in 30ml of methylene chloride. 464mg of di-tert-butyl dicarbonate, 295. mu.L of triethylamine and 19.5mg of 4-dimethylaminopyridine are added. And reacting for 45 hours at room temperature. After the reaction, the reaction mixture was poured into a flask, 200ml of water was added, and the mixture was extracted with 300ml of ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and dried at 60 ℃ for 24 hours to obtain 225mg of intermediate (v) with a yield of 55.36%.
4.1 NMR hydrogen spectroscopy characterization of the intermediate (V) obtained as follows:1h NMR (400MHz, dmso) δ 9.56(s,1H),8.69(s,2H),7.94(d, J ═ 8.4Hz,1H),7.56(s,1H),6.68(s,1H),5.13(s,2H),1.43(dd, J ═ 10.0,3.1Hz,9H), see fig. 4.
4.2 into a single-neck flask, 150mg of the Intermediate (IV) prepared in 3.1 of example 3 was added and dissolved in 20ml of methylene chloride. 181.3mg of benzyl chloroformate, 111. mu.L of triethylamine, and 6.5mg of 4-dimethylaminopyridine were added. The reaction temperature is 40 ℃ and the reaction time is 48 h. After the reaction, the reaction mixture was poured into a flask, 100ml of water was added, extraction was performed with 200ml of ethyl acetate, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and dried at 60 ℃ for 24 hours to obtain 150mg of intermediate (v) with a yield of 73.81%.
4.3 into a single-neck flask, 250mg of the Intermediate (IV) prepared in 3.1 of example 3 was added, and dissolved in 30ml of dichloromethane. 343.7mg of fluorenylmethoxycarbonylcarbonyl chloride, 184.7. mu.L of triethylamine and 6.5mg of 4-dimethylaminopyridine were added. The reaction temperature is 50 ℃ and the reaction time is 36 h. After the reaction, the reaction mixture was poured into a flask, and 200ml of water was added, followed by extraction with 300ml of ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, rotary evaporation and concentration, and drying at 60 ℃ for 24 hours to obtain 261mg of intermediate (V) with a yield of 77.06%.
Example 5 Synthesis of intermediate (VI)
5.1 into a one-neck flask, 300mg of intermediate (V) prepared in 4.1 of example 4 was added and dissolved in 30ml of methanol. 143.7mg of 5-chloro-7-azaindole and 7.2mg of potassium carbonate were added. The reaction temperature is 30 ℃ and the reaction time is 40 h. After the reaction was completed, the reaction mixture was poured into a flask, 200ml of water was added, and the mixture was extracted with 250ml of ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and dried at 70 ℃ for 24 hours to obtain 298mg of intermediate (VI) with a yield of 70.99%.
5.1 Mass Spectrometry characterization of intermediate (VI) obtained as follows: ESI-MS (m/z): 533.13[ M-H]-See fig. 5.
5.2 to a one-necked flask, 200mg of intermediate (V) prepared in 4.1 of example 4 was added and dissolved in 20ml of methanol. 119.7mg of 5-chloro-7-azaindole and 4.7mg of potassium tert-butoxide are added. The reaction temperature is 40 ℃ and the reaction time is 35 h. After the reaction, the reaction mixture was poured into a flask, 100ml of water was added, extraction was performed with 200ml of ethyl acetate, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and dried at 70 ℃ for 24 hours to obtain 178mg of intermediate (VI) with a yield of 63.61%.
5.3 to a single-neck flask, 150mg of intermediate (V) prepared in 4.1 of example 4 was added and dissolved in 20ml of methanol. 83.8mg of 5-chloro-7-azaindole and 2.4mg of sodium hydroxide were added. The reaction temperature is 45 ℃ and the reaction time is 48 h. After the reaction, the reaction mixture was poured into a flask, 100ml of water was added, extraction was performed with 200ml of ethyl acetate, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and dried at 70 ℃ for 24 hours to obtain 111mg of intermediate (VI) with a yield of 52.89%.
Example 6 Synthesis of Compound (I)
6.1 into a single-neck flask, 250mg of intermediate (VI) prepared in 5.1 of example 5 was added, and dissolved in 30ml of acetonitrile. 5.58ml triethylsilane, 3.17ml hydrobromic acid were added. The reaction temperature is 85 ℃ and the reaction time is 28 h. After completion of the reaction, the reaction mixture was poured into a flask, and 150ml of a 5% m/v potassium carbonate aqueous solution was added, followed by extraction with 200ml of ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, and rotary evaporation and concentration. Firstly, using ethanol to concentrate: water 1: 4(v: v) and then recrystallizing with ethanol: water 1: 6(v: v), adding 1g of activated carbon for decoloring, naturally cooling and crystallizing, and drying at 70 ℃ for 24 hours to obtain 126mg of the compound (I) with the yield of 64.37%.
6.1 Nuclear magnetic resonance Hydrogen Spectroscopy characterization of the Compound (I) obtained as follows:1h NMR (400MHz, dmso) δ 11.88(s,1H),10.15(s,1H),8.71(s,2H),8.19(d, J ═ 2.3Hz,1H),7.97(d, J ═ 1.3Hz,1H),7.92(s,1H),7.70(d, J ═ 8.0Hz,1H), 7.57-7.55 (m,1H), 6.45-6.44 (m,1H),4.54(s,2H), 3.94-3.70 (m,2H), see fig. 6.
6.2 into a single-neck flask, 200mg of intermediate (VI) prepared in 5.1 of example 5 was added, and it was dissolved in 20ml of acetonitrile. 4.17ml of triethylsilane and 1.93ml of concentrated hydrochloric acid were added. The reaction temperature is 85 ℃ and the reaction time is 25 h. After completion of the reaction, the reaction mixture was poured into a flask, 100ml of a 5% m/v potassium carbonate aqueous solution was added, and the mixture was extracted with 150ml of ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. Firstly, using ethanol to concentrate: 1 in water: 4(v: v) and then recrystallizing with ethanol: water 1: 6(v: v), adding 0.8g of activated carbon for decoloring, naturally cooling and crystallizing, and drying at 70 ℃ for 24 hours to obtain 85mg of the compound (I) with the yield of 54.28%.
6.3 into a single-neck flask, 300mg of intermediate (VI) prepared in 5.1 of example 5 was added, and dissolved in 30ml of acetonitrile. 6.7ml of triethylsilane, 3ml of trifluoroacetic acid were added. The reaction temperature is 85 ℃ and the reaction time is 30 h. After the reaction, the mixture was poured into a flask, and 200ml of a 5% m/v aqueous potassium carbonate solution was added, followed by extraction with 300ml of ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, and rotary evaporation and concentration. Firstly, using ethanol to concentrate: water 1: 4(v: v), and then recrystallizing with ethanol: water 1: 6(v: v), adding 1.5g of activated carbon for decoloring, naturally cooling for crystallization, and drying to obtain 139mg of the compound (I) with the yield of 59.18%.
The following compounds (I) used in examples 7 and 8 were all the compounds (I) obtained in 6.1 of example 6.
Example 7 cytotoxicity assay
Human breast cancer MCF-7 cells and human lung cancer A549 cells, which were donated by professor Hooka of Hukanghong university of Industrial university, Hubei, human osteosarcoma HOS cells were purchased from Wuhan Protechs Ltd, MTT reagent was purchased from Wuhan Pogyote Ltd, DMEM high-sugar medium (500ml), MEM medium (500ml), and pancreatin digest (0.25% m/v, 100ml) were purchased from Wuhan Pogyote Ltd. MCF-7 and A549 cells were cultured in a DMEM high-glucose medium, and HOS cells were cultured in MEM medium. In addition, anticancer activity of compound (I) was confirmed by using a commercially available Pexidantinib standard (purchased from Targetmol Co., Ltd., U.S.A., purity: 99.66%) as a control. Selecting cells with good growth state for experiment, treating cells in T25 bottle with 1ml pancreatin digestive juice for 2min, transferring cells into 96-well plate to ensure cell number to be 104Putting into a constant temperature incubator (37 deg.C, 5% CO)2Hereinafter, the same shall not be repeated), and culturing for 24 h. And (3) after the cells recover, removing old culture medium in the holes, adding 100 mu l of prepared administration culture medium (the pexidinib standard substance and the compound (I) are dissolved by DMSO in advance and then diluted by a certain multiple by the culture medium) into each hole, and after the addition, putting the holes into a constant-temperature incubator to culture for 24 hours. Mu.l of MTT solution was added to each well and incubated for 4h in the dark. Firstly, absorbing the solution in each hole as much as possible, then adding 150 mu l of DMSO into each hole, placing the hole in a shaking table (the shaking frequency is 150 times/min), shaking for 10-15 min, and detecting the absorbance value (OD value) of each hole at 490nm on a microplate reader. Cell viability was 100% (OD-blank OD of experimental group)/(OD-blank OD of control group). The experimental group is that the hole contains cells, and 100 mul of administration culture medium is added; the control group contained cells in the wells and 100. mu.l of culture medium was added; blank is no cells in the well and only 100. mu.l of medium is added.
The cytotoxicity experiments were repeated three times, each concentration experiment containing 5 experimental wells. According to the calculation result, statistical analysis is carried out in Origin 8.0 software. The corresponding data are shown in tables 1-3, and the results are shown in FIGS. 7-9.
Toxicity of the compounds of table 1 to HOS cells as% cell viability.
Figure BDA0003630236110000131
TABLE 2 toxicity of compounds on MCF-7 cells in% cell viability.
Figure BDA0003630236110000141
Table 3 toxicity of compounds to a549 cells as% cell viability.
Figure BDA0003630236110000142
It can be seen from tables 1-3 and FIGS. 7-9 that compound (I) significantly inhibited HOS cell growth at nanomolar concentrations compared to Pexidinib standards as the concentrations administered increased. In addition, compound (I) also inhibits the growth of MCF-7 and A549 cells at micromolar concentrations.
Example 8 apoptosis assay
The Annexin V-FITC/PI apoptosis detection kit is purchased from Jiangsu Keyki Biotechnology GmbH. Similarly, pexidinib standards were used as controls to verify the ability of compound (i) to induce apoptosis in cancer cells. Selecting cells with good growth state for experiment, treating the cells in a T25 bottle with pancreatin digestive juice (same as example 7), diluting the digested cells with culture medium, transferring the cell suspension to a 6-well plate (adding 2ml per well to ensure that the number of cells per well is 1-5 × 105And (4) putting the mixture into a constant-temperature incubator and culturing for 24 hours. After the cells were rejuvenated, the old medium in the wells was discarded, 2ml of pre-prepared dosing medium was added to each well (preparation method same as example 7), and the wells were placed in a constant temperature incubator and incubated for 48 h. The solution in the 6-hole plate is respectively sucked into the corresponding 6 centrifugal tubes, and then the residual patches in the holes are treated by pancreatin digestive juiceAnd (3) wall cells, and collecting digested cells in corresponding 6 centrifugal tubes. The tubes were centrifuged to collect sedimented cells, and then 2ml of a PBS solution (0.01 mol/L, pH 7.4) was added to each tube, washed, and washed 2 times. And centrifuging again, collecting settled cells, adding 100 mu L of 1 XBinding Buffer solution into each centrifugal tube, slightly blowing and mixing uniformly, adding 5 mu L of Annexin V-FITC and 10 mu L of PI solution again, slightly blowing and mixing uniformly. And standing and incubating for about 15min under the condition of keeping out of the sun. Add 400. mu.L of 1 XBinding Buffer solution into 6 centrifuge tubes again, blow gently and mix well. Collecting the cell suspension in a 6-branch flow tube through a 300-mesh screen, wrapping the outer wall of the flow tube with tinfoil paper, placing the flow tube in a foam box filled with crushed ice in advance, and freezing and storing in a dark place. And finally, detecting by using a flow cytometer to ensure that the samples are completely detected within 1 hour. Each 6-well plate belongs to a group of concentration gradient experiments, and the apoptosis experiment is repeated three times. Flow cytometric plots were processed using FlowJo V10 software and flow data was statistically analyzed using Origin 8.0 software. The corresponding data are shown in tables 4-5, and the results are shown in FIGS. 10-11.
Compounds of table 4 induce apoptosis of HOS cells, in% of total apoptotic cells.
Figure BDA0003630236110000151
The compounds of table 5 induced apoptosis of a549 cells, in% of total apoptotic cells.
Figure BDA0003630236110000161
As can be seen from tables 4-5 and fig. 10-11, with increasing concentrations of administration, compound (i) induced apoptosis of HOS cells at nanomolar concentrations and a549 cells at micromolar concentrations compared to the pexidinib standard, and compound (i) induced apoptosis in both cells more strongly than the pexidinib standard.

Claims (10)

1. The compound 5-chloro-3- { [2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidin-5-yl ] methyl } -1H-pyrrolo [2,3-b ] pyridine having the following structural formula:
Figure FDA0003630236100000011
2. a method for preparing the compound of claim 1, wherein the compound (I) is prepared by using 2-aminopyrimidine-5-carboxylic acid methyl ester and 6-trifluoromethyl nicotinaldehyde as raw materials and carrying out 6 steps of reactions including reductive amination, reduction, oxidation, substitution, nucleophilic addition and substitution.
3. The process according to claim 2, wherein compound (i) is synthesized by the steps of:
taking 2-aminopyrimidine-5-carboxylic acid methyl ester and 6-trifluoromethyl nicotinaldehyde as raw materials, reacting with a reducing agent, and carrying out reductive amination reaction to obtain an intermediate (II);
step two, the intermediate (II) reacts with a reducing agent to perform a reduction reaction to obtain an intermediate (III);
step three, the intermediate (III) reacts with an oxidant to generate an oxidation reaction to obtain an Intermediate (IV);
step four, carrying out substitution reaction on the Intermediate (IV) and a protecting group of amino to obtain an intermediate (V);
fifthly, carrying out addition reaction on the intermediate (V) and 5-chloro-7-azaindole under an alkaline condition to obtain an intermediate (VI);
sixthly, carrying out substitution reaction on the intermediate (VI) under an acidic condition, removing an amino protecting group, and simultaneously acting with triethylsilane to remove hydroxyl to obtain a target compound (I);
Figure FDA0003630236100000012
Figure FDA0003630236100000021
wherein, -G is an amino protecting group.
4. The method of claim 3, wherein in step one, the reducing agent is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, palladium on carbon/H2Raney nickel/H22-methylpyridine-N-borane, triethylsilane and rhodium/CO; the 2-aminopyrimidine-5-carboxylic acid methyl ester: 6-trifluoromethyl nicotinaldehyde: the molar ratio of the reducing agent is 1: 1-4: 2 to 10.
5. The preparation method according to claim 3, wherein in the second step, the reducing agent is one of lithium aluminum hydride, lithium tri-sec-butylborohydride, sodium borohydride, potassium borohydride, diisobutylaluminum hydride, sodium borohydride/magnesium chloride, sodium borohydride/aluminum chloride, and sodium borohydride/zinc chloride; the intermediate (II): the molar ratio of the reducing agent is 1: 1 to 5.
6. The method of claim 3, wherein in step three, the oxidant is one of manganese dioxide, PDC oxidant, PCC oxidant, DMSO, dess-Martin oxidant, Collins reagent, 2-iodoxybenzoic acid, ammonium tetrapropylperruthenate, tetramethylpiperidine oxide; the intermediate (III): the molar ratio of the oxidant is 1: 0.5 to 5.
7. The method of claim 3, wherein in step four, the amino protecting reagent is one of benzyl chloroformate, di-tert-butyl dicarbonate, fluorenylmethoxycarbonyl chloride, p-methoxybenzyl bromide, benzyl bromide, p-toluenesulfonyl chloride, triphenylchloromethane, and N-ethoxycarbonylphthalimide; the Intermediate (IV): the mol ratio of the amino protective agent is 1: 1 to 6.
8. The preparation method according to claim 3, wherein in the fifth step, the substance providing the alkaline environment is one or more of sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amylate and potassium tert-amylate; the intermediate (V): 5-chloro-7-azaindole: providing a molar ratio of alkaline environment substances of 1: 1-3: 0.01 to 4.
9. The preparation method according to claim 3, wherein in the sixth step, the substance providing an acidic environment is one of formic acid, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, phosphoric acid, trifluoroacetic acid, and zinc bromide; the intermediate (VI): providing a molar ratio of acidic environment substances of 1: 0.5 to 85.
10. Use of the compound 5-chloro-3- { [2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidin-5-yl ] methyl } -1H-pyrrolo [2,3-b ] pyridine of claim 1 for the preparation of an anticancer drug;
use of the compound 5-chloro-3- { [2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidin-5-yl ] methyl } -1H-pyrrolo [2,3-b ] pyridine of claim 1 for the preparation of a medicament for inhibiting the growth of human osteosarcoma cells HOS, human breast cancer cells MCF-7 and/or human lung cancer cells a 549;
use of the compound 5-chloro-3- { [2- ({ [6- (trifluoromethyl) pyridin-3-yl ] methyl } amino) pyrimidin-5-yl ] methyl } -1H-pyrrolo [2,3-b ] pyridine according to claim 1 for the preparation of a medicament for inducing apoptosis of tumor cells HOS and/or a 549.
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