CN111961006A - Method for synthesizing intermediate of trilithiotinib triazole - Google Patents
Method for synthesizing intermediate of trilithiotinib triazole Download PDFInfo
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- CN111961006A CN111961006A CN202010760917.7A CN202010760917A CN111961006A CN 111961006 A CN111961006 A CN 111961006A CN 202010760917 A CN202010760917 A CN 202010760917A CN 111961006 A CN111961006 A CN 111961006A
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- C07—ORGANIC CHEMISTRY
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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Abstract
A method for synthesizing a lignitinib triazole intermediate by taking propiolic acid as a raw material through a Click reaction comprises the following steps: the method comprises the following steps: taking anisole as a raw material, and carrying out Friedel-crafts acylation reaction on the anisole and 4-chlorobutyryl chloride to obtain gamma-chloro-4-methoxy butanone; step two: reacting gamma-chloro-4-methoxybenzene butanone with sodium azide, propiolic acid, a copper catalyst, sodium ascorbate, alkali and a solvent to obtain 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone; step three: 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone in a trifluoroacetic acid/triethylsilane system to reduce the carbonyl group to methylene; step four: demethylation of 1- [4- (4-methoxyphenyl) butyl ] -1H-1,2,3-triazole with 40% hydrobromic acid gave the intermediate, 4- [4- (1H-1,2, 3-triazol-1-yl) butyl ] phenol, xylitinib. The method greatly shortens the reaction path, and has the advantages of easily available raw materials, mild reaction conditions, simple and convenient operation, high yield and the like.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to a method for synthesizing a lignatinib triazole intermediate by using propiolic acid as a raw material.
Background
Ligninib (Mubritinib, TAK-165), chemically known as 1- (4- (4- ((2- ((1E) -2- (4- (Trifluoromethyl) phenyl) vinyl) -4-oxazolyl) methoxy) phenyl) butyl) -1H-1,2,3-triazole (1- (4- (4- ((2- ((1E) -2- (4- (trifluoromethylphenyl) ethenyl) -4-oxozolyl) methoxy) phenyl) butyl) -1H-1,2, 3-triazoie, is a potent inhibitor of the human epidermal growth factor receptor 2(HER2) tyrosine kinase, and is a drug developed by wutian corporation for the treatment of cancer. The structure is as follows:
the lignitinib has an inhibiting effect on diseases such as breast cancer, non-small cell lung cancer, bladder cancer, renal cell carcinoma, prostate cancer and the like, has a good effect, and is expected to become a new medicine for treating breast cancer, bladder cancer, renal cancer and androgen-independent prostate cancer. The lignitinib is also an Electron Transport Chain (ETC) compound I inhibitor, induces apoptosis of acute myeloid leukemia cells by inhibiting mitochondrial activity, and has high anti-leukemia activity in vitro and in vivo.
WO/2001/77107 discloses a method for synthesizing lignitinib. Mainly relates to the synthesis of two key intermediates, and the synthetic route is as follows: 4- (4-benzyloxy phenyl) -3-butylene-1-alcohol 6 is obtained by Wittig reaction by taking 4-benzyloxy benzaldehyde 5 as a raw material, 4- (4-hydroxy butyl) phenol 7 is obtained by 10 percent of palladium/hydrocarbon, 4- [4- (benzyloxy) phenyl ] -1-butanol 8 is obtained by protecting hydroxyl with benzyl bromide, 4- [4- (benzyloxy) phenyl ] butyl methanesulfonate 9 is generated with methanesulfonyl chloride under the condition of triethylamine, and then the 4- [4- (benzyloxy) phenyl ] butyl methanesulfonate is converted into benzyl 4- (4-iodobutyl) phenyl ether 10. Then condensed with 1H-1,2,3-triazole to obtain 1- [4- (4-benzyloxy phenyl) butyl ] -1H-1,2,3-triazole 11. Deprotection to obtain 4- [4- (1H-1,2, 3-triazole-1-yl) butyl ] phenol A. Then taking 4-trifluoromethyl cinnamic acid 12 as a raw material, amidating to obtain (E) -3- (4-trifluoromethyl phenyl) -2-acrylamide 13, refluxing the compound 13 and 1, 3-dichloroacetone in toluene to obtain 4-chloromethyl-2- [ E-2- (4-trifluoromethyl phenyl) vinyl ] -1, 3-oxazole B, and finally condensing the intermediate A and the intermediate B to obtain a final product of the lignitinib.
According to the synthetic route, the intermediate A and the intermediate B are mainly condensed to form the lignitinib, and in the prior art, the synthetic method of the lignitinib intermediate A has the defects that:
(1) the method has the advantages of longer steps, seven-step reaction, low yield and total yield of only 11%;
(2) side reactions are easy to occur, and the mixture of 1-substituted-1, 2,3-triazole and 2-substituted-1, 2,3-triazole is often obtained by introducing triazole through N-alkylation reaction, so that the yield of the intermediate A is low and the reaction selectivity is poor;
(3) the post-treatment is complex and the product separation is difficult. The mixture of the 1-substituted-1, 2,3-triazole and the 2-substituted-1, 2,3-triazole is difficult to separate and is not beneficial to industrial production.
Therefore, how to improve the synthesis yield of the intermediate A and explore a new reaction route are problems which need to be solved for further promoting the synthesis and application of the lignatinib product.
Disclosure of Invention
The invention aims to provide a method for synthesizing a xylitinib intermediate 4- [4- (1H-1,2, 3-triazol-1-yl) butyl ] phenol A, which has the advantages of mild reaction conditions, less side reactions and high yield of the prepared intermediate A.
The invention provides a method for synthesizing a lignitinib triazole intermediate, which comprises the following reaction route:
further, the method comprises the following steps:
(1) taking anisole (1) as a raw material, and carrying out Friedel-crafts acylation reaction on the anisole (1) and 4-chlorobutyryl chloride to obtain gamma-chloro-4-methoxybenzene butanone (2);
(2) reacting gamma-chloro-4-methoxybenzene butanone (2) with sodium azide, adding propiolic acid, a copper catalyst, sodium ascorbate and alkali after the reaction is completed to obtain 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone (3);
(3) reducing ketocarbonyl to methylene by 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone (3) in a trifluoroacetic acid/triethylsilane system to obtain 1- [4- (4-methoxyphenyl) butyl ] -1H-1,2,3-triazole (4);
(4) demethylation of 1- [4- (4-methoxyphenyl) butyl ] -1H-1,2,3-triazole (4) with hydrobromic acid gave the intermediate, 4- [4- (1H-1,2, 3-triazol-1-yl) butyl ] phenol (a), of xylitinib.
Wherein, in the step (2): dissolving gamma-chloro-4-methoxybenzyl butanone in a solvent, adding sodium azide, reacting for 2-5 h at 60-70 ℃, detecting complete reaction by Thin Layer Chromatography (TLC), adding propiolic acid, a copper catalyst, alkali and sodium ascorbate into the reaction liquid, continuing to react for 1-8 h at 60-100 ℃, detecting complete reaction by Thin Layer Chromatography (TLC), diluting the reaction liquid by ethyl acetate, sequentially washing an organic layer by saturated saline water and water, drying by anhydrous sodium sulfate, filtering, concentrating, carrying out column chromatography separation, and distilling under reduced pressure to remove the solvent to obtain the product.
The mol ratio of the gamma-chloro-4-methoxybenzene butanone, the sodium azide, the propiolic acid, the copper catalyst, the alkali and the sodium ascorbate is as follows: 1 (1-3), (0.1-0.5), (0.2-1).
The copper catalyst comprises cuprous iodide, cuprous bromide or cupric sulfate pentahydrate.
The base comprises cesium carbonate, potassium carbonate or 1, 8-diazabicycloundec-7-ene (DBU).
The solvent used includes N, N-Dimethylformamide (DMF) or dimethyl sulfoxide (DMSO).
In the step (4), the concentration of hydrobromic acid used is 40% by mass.
The method synthesizes the intermediate of the xylitinib triazole through Friedel-crafts acylation, Click reaction, reduction reaction and the like, has simple operation, high yield and good selectivity, and is convenient for industrialization.
Detailed Description
The invention is further illustrated by the following examples. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
Step (1) Synthesis of Gamma-chloro-4-methoxybenzyl butanone 2
Anisole 1(1.93g,17.87mmol), anhydrous aluminum chloride (1.55g,11.62mmol) and 3mL of dried dichloromethane were added into a three-necked flask, 4-chlorobutyryl chloride (1.26g,8.94mmol) was slowly added dropwise at 0 ℃, after completion of the dropwise addition, the ice water bath was removed, the reaction was stirred at 15 ℃ for 1 hour, after completion of the detection by Thin Layer Chromatography (TLC), ice water was added to quench, dichloromethane was extracted, the organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, separated by column chromatography (petroleum ether/ethyl acetate 125/1), and dried by spin-drying. The product gamma-chloro-4-methoxy phenyl butanone 2 (white crystal) is obtained, and the yield is 99 percent.
And (3) data characterization:
1H NMR(600MHz,DMSO-d6)7.94(d,J＝8.9Hz,2H),7.04(d,J＝8.9Hz,2H),3.84(s,3H),3.70(t,J＝6.7Hz,2H),3.11(t,J＝7.1Hz,2H),2.05(p,J＝6.9Hz,2H).13C NMR(151MHz,DMSO-d6)197.72,163.59,130.68,129.87,114.28,56.18,45.39,35.19,27.47.
HR-MS(ESI):calcd.for C11H14ClO2[M+H]+:213.0677,found:213.0679.
step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (18.34mg,0.2821mmol) and DMF into a sealed tube, dissolving, reacting for 3h at 70 ℃, detecting by TLC after the reaction is completed, adding propiolic acid (32.94mg,0.4702mmol), cuprous iodide (8.96mg,0.0470mmol), cesium carbonate (38.3mg,0.1176mmol) and sodium ascorbate (18.63mg,0.0940mmol) into the sealed tube, continuing the reaction at 100 ℃ for 5h, detecting the reaction by TLC, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal) with a yield of 91%.
And (3) data characterization:
1H NMR(600MHz,DMSO-d6)8.17(s,1H),7.91(d,J＝8.7Hz,2H),7.73(s,1H),7.03(d,J＝8.7Hz,2H),4.45(t,J＝7.1Hz,2H),3.83(s,3H),2.99(t,J＝7.1Hz,2H),2.15(p,J＝7.1Hz,2H).13C NMR(151MHz,DMSO-d6)197.64,163.59,133.70,130.66,129.85,125.21,114.28,56.20,49.06,34.68,25.08.
HR-MS(ESI):calcd.for C13H16N3O2[M+H]+:246.1237,found:246.1233.
step (3) Synthesis of 1- [4- (4-methoxyphenyl) butyl ] -1H-1,2,3-triazole 4
Adding compound 3(150mg,0.6115mmol) and 4.0mL trifluoroacetic acid (TFA) into a sealed tube, dropwise adding triethylsilane (0.195mL,1.220mmol), stirring at 15 ℃ for 24H, detecting by TLC (thin-layer chromatography), adding ethyl acetate for dilution, sequentially washing an organic layer with saturated aqueous sodium bicarbonate solution, saturated brine and water, drying over anhydrous sodium sulfate, filtering, concentrating, performing column chromatography (dichloromethane/methanol is 200/1), and performing rotary evaporation to obtain a pure product 1- [4- (4-methoxyphenyl) butyl ] -1H-1,2,3-triazole 4 (white crystals) with the yield of 92%. And (3) data characterization:
1H NMR(600MHz,Chloroform-d)7.69(s,1H),7.50(s,1H),7.06(d,J＝8.5Hz,2H),6.82(d,J＝8.5Hz,2H),4.38(t,J＝7.2Hz,2H),3.78(s,3H),2.59(t,J＝7.6Hz,2H),1.93(p,J＝7.3Hz,2H),1.61(tt,J＝9.6,6.6Hz,2H).13C NMR(151MHz,Chloroform-d)157.90,133.79,133.45,129.26,123.14,113.84,55.28,50.04,34.23,29.74,28.38.
HR-MS(ESI):calcd.for C13H18N3O[M+H]+:232.1444,found:232.1447.
step (4) Synthesis of 4- [4- (1H-1,2, 3-triazol-1-yl) butyl ] phenol A
Compound 4(200mg,0.8647mmol) and 3ml of 40% aqueous HBr were added to the sealed tube, heated to 80 ℃ and reacted for 24 h. After the reaction was completed by TLC, the temperature was lowered to room temperature. Diluting with water, adjusting pH to about 6 with saturated sodium bicarbonate solution, extracting with dichloromethane for three times, combining organic phases, adding anhydrous sodium sulfate, drying, filtering, concentrating, separating by column chromatography (dichloromethane/methanol is 100/1), and rotary steaming to obtain pure 4- [4- (1H-1,2, 3-triazol-1-yl) butyl ] phenol A (white crystal) with yield of 84%.
And (3) data characterization:
1H NMR(600MHz,DMSO-d6)9.15(s,1H),8.10(s,1H),7.71(s,1H),6.94(d,J＝8.4Hz,2H),6.65(d,J＝8.4Hz,2H),4.37(t,J＝7.1Hz,2H),2.46(t,J＝7.6Hz,2H),1.79(p,J＝7.2Hz,2H),1.44(tt,J＝9.4,6.7Hz,2H).13C NMR(151MHz,DMSO-d6)155.78,133.70,132.21,129.60,125.13,115.48,49.40,34.00,29.84,28.59.
HR-MS(ESI):calcd.for C12H16N3O[M+H]+:218.1288,found:218.1295.
example 2
Step (1) is as follows, and steps (2), (3) and (4) are the same as in example 1.
Step (1) Synthesis of Gamma-chloro-4-methoxybenzyl butanone 2
Anisole 1(1.93g,17.85mmol), anhydrous aluminum chloride (1.55g,11.62mmol) and 3mL of dry chlorobenzene were added into a three-necked flask, 4-chlorobutyryl chloride (1.26g,8.92mmol) was slowly added dropwise at 0 ℃, after completion of the dropwise addition, the ice water bath was removed, the reaction was stirred at 15 ℃ for 1 hour, after completion of the detection by Thin Layer Chromatography (TLC), ice water was added to quench, dichloromethane was extracted, the organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, separated by column chromatography (petroleum ether/ethyl acetate 125/1), and dried by spin-drying. The product gamma-chloro-4-methoxy phenyl butanone 2 (white crystal) is obtained, and the yield is 96 percent.
Example 3
Step (1) is as follows, and steps (2), (3) and (4) are the same as in example 1.
Step (1) Synthesis of Gamma-chloro-4-methoxybenzyl butanone 2
Anisole 1(1.00g,7.09mmol), anhydrous aluminum chloride (1.23g,9.22mmol) and 3mL of dry dichloromethane are added into a three-necked flask, 4-chlorobutyryl chloride (0.77g,7.09mmol) is slowly added dropwise at 0 ℃, after the dropwise addition is finished, the ice water bath is removed, the reaction is stirred at 15 ℃ for 1h, after the completion of the reaction is detected by Thin Layer Chromatography (TLC), ice water is added for quenching, dichloromethane is used for extraction, an organic layer is washed with water, dried by anhydrous sodium sulfate, filtered, concentrated, separated by column chromatography (petroleum ether/ethyl acetate is 125/1) and dried by spinning. The product gamma-chloro-4-methoxy phenyl butanone 2 (white crystal) is obtained with the yield of 92 percent.
Example 4
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (18.34mg,0.2821mmol) and DMF into a sealed tube, dissolving, reacting for 4h at 60 ℃, detecting by TLC after the reaction is completed, adding propiolic acid (32.94mg,0.4702mmol), cuprous iodide (8.96mg,0.0470mmol), cesium carbonate (38.3mg,0.1176mmol), sodium ascorbate (18.63mg,0.0940mmol) into the sealed tube, reacting at 60 ℃ for 5h, detecting by TLC after the reaction is completed, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal) with a yield of 83%.
Example 5
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (45.85mg,0.7053mmol) and DMF into a sealed tube for dissolving, reacting for 2h at 70 ℃, detecting by TLC after the reaction is complete, adding propiolic acid (32.94mg,0.4702mmol), cuprous iodide (8.96mg,0.0470mmol), cesium carbonate (38.3mg,0.1176mmol) and sodium ascorbate (18.63mg,0.0940mmol) into the sealed tube, continuing the reaction at 100 ℃ for 1h, detecting the reaction by TLC, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal) with a yield of 81%.
Example 6
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (15.28mg,0.2351mmol) and DMF into a sealed tube, dissolving, reacting for 2h at 70 ℃, detecting by TLC after the reaction is completed, adding propiolic acid (32.94mg,0.4702mmol), cuprous iodide (8.96mg,0.0470mmol), cesium carbonate (38.3mg,0.1176mmol) and sodium ascorbate (18.63mg,0.0940mmol) into the sealed tube, continuing the reaction at 100 ℃ for 1h, detecting the reaction by TLC, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal) in 77% yield.
Example 7
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (18.34mg,0.2821mmol) and DMF into a sealed tube, dissolving, reacting for 2h at 70 ℃, detecting by TLC after the reaction is completed, adding propiolic acid (16.47mg,0.2351mmol), cuprous iodide (8.96mg,0.0470mmol), cesium carbonate (38.3mg,0.1176mmol) and sodium ascorbate (18.63mg,0.0940mmol) into the sealed tube, continuing the reaction at 100 ℃ for 4h, detecting the reaction by TLC, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal) with a yield of 76%.
Example 8
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (18.34mg,0.2821mmol) and DMF into a sealed tube, dissolving, reacting for 2h at 70 ℃, detecting by TLC after the reaction is completed, adding propiolic acid (49.40mg,0.7053mmol), cuprous iodide (8.96mg,0.0470mmol), cesium carbonate (38.3mg,0.1176mmol) and sodium ascorbate (18.63mg,0.0940mmol) into the sealed tube, continuing the reaction at 100 ℃ for 4h, detecting the reaction by TLC, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal) with a yield of 91%.
Example 9
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (18.34mg,0.2821mmol) and DMF into a sealed tube, dissolving, reacting for 2h at 70 ℃, detecting by TLC after the reaction is completed, adding propiolic acid (32.94mg,0.4702mmol), cuprous iodide (8.96mg,0.0470mmol), potassium carbonate (16.25mg,0.1176mmol), sodium ascorbate (18.63mg,0.0940mmol) into the sealed tube, continuing to react at 100 ℃ for 3h, detecting by TLC after the reaction is complete, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal) with a yield of 75%.
Example 10
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (18.34mg,0.2821mmol) into a sealed tube, dissolving in DMSO, reacting at 70 ℃ for 2h, detecting by TLC after the reaction is completed, adding propiolic acid (32.94mg,0.4702mmol), cuprous iodide (8.96mg,0.0470mmol), potassium carbonate (16.25mg,0.1176mmol), sodium ascorbate (18.63mg,0.0940mmol) into the sealed tube, continuing to react at 100 ℃ for 3h, detecting by TLC after the reaction is complete, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal) with a yield of 74%.
Example 11
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (18.34mg,0.2821mmol) and DMF into a sealed tube, dissolving, reacting for 2h at 70 ℃, detecting by TLC after the reaction is completed, adding propiolic acid (32.94mg,0.4702mmol), cuprous iodide (8.96mg,0.0470mmol), DBU (17.90mg,0.1176mmol) and sodium ascorbate (18.63mg,0.0940mmol) into the sealed tube, continuing to react at 100 ℃ for 3h, detecting the reaction by TLC, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal) with a yield of 76%.
Example 12
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (18.34mg,0.2821mmol) and DMF into a sealed tube, dissolving, reacting for 2h at 70 ℃, detecting by TLC after the reaction is completed, adding propiolic acid (32.94mg,0.4702mmol), cuprous iodide (4.48mg,0.0240mmol), cesium carbonate (38.3mg,0.1176mmol) and sodium ascorbate (18.63mg,0.0940mmol) into the sealed tube, continuing to react at 100 ℃ for 8h, detecting by TLC after the reaction is complete, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal) with a yield of 68%.
Example 13
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (18.34mg,0.2821mmol) and DMF into a sealed tube, dissolving, reacting for 2h at 70 ℃, detecting by TLC after the reaction is completed, adding propiolic acid (32.94mg,0.4702mmol), cuprous iodide (22.39mg,0.1176mmol), cesium carbonate (38.3mg,0.1176mmol), sodium ascorbate (18.63mg,0.0940mmol) into the sealed tube, continuing the reaction at 100 ℃ for 2h, detecting the reaction by TLC, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal), with a yield of 87%.
Example 14
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (18.34mg,0.2821mmol), DMF for dissolving, reacting at 70 ℃ for 2H, detecting by TLC after the reaction is complete, adding propiolic acid (32.94mg,0.4702mmol), blue vitriol (11.76mg,0.0470mmol), cesium carbonate (38.3mg,0.1176mmol), sodium ascorbate (18.63mg,0.0940mmol), continuing to react at 100 ℃ for 8H, detecting by TLC after the reaction is complete, diluting the reaction solution with ethyl acetate, washing the organic layer with saturated saline water and water in turn, drying with anhydrous sodium sulfate, filtering, concentrating, separating by column chromatography (dichloromethane/methanol is 100/1), rotary steaming to obtain pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal), the yield thereof was found to be 84%.
Example 15
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (18.34mg,0.2821mmol) and DMF into a sealed tube, dissolving, reacting for 2h at 70 ℃, detecting by TLC after the reaction is completed, adding propiolic acid (32.94mg,0.4702mmol), cuprous iodide (8.96mg,0.0470mmol), cesium carbonate (38.3mg,0.1176mmol) and sodium ascorbate (46.58mg,0.2351mmol) into the sealed tube, continuing the reaction at 100 ℃ for 8h, detecting the reaction by TLC, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal) with a yield of 91%.
Example 16
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (18.34mg,0.2821mmol) and DMF into a sealed tube, dissolving, reacting for 2h at 70 ℃, detecting by TLC after the reaction is completed, adding propiolic acid (32.94mg,0.4702mmol), cuprous iodide (8.96mg,0.0470mmol), cesium carbonate (38.3mg,0.1176mmol), sodium ascorbate (9.32mg,0.0470mmol) into the sealed tube, continuing the reaction at 100 ℃ for 8h, detecting the reaction by TLC, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal) with a yield of 70%.
Example 17
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (18.34mg,0.2821mmol) and DMF into a sealed tube, dissolving, reacting for 2h at 70 ℃, detecting by TLC after the reaction is completed, adding propiolic acid (32.94mg,0.4702mmol), cuprous iodide (4.48mg,0.0024mmol), cesium carbonate (15.32mg,0.0470mmol), sodium ascorbate (9.32mg,0.0470mmol) into the sealed tube, continuing the reaction at 100 ℃ for 4h, detecting the reaction by TLC, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal) with a yield of 34%.
Example 18
Step (2) is as follows, and steps (1), (3) and (4) are the same as in example 1.
Step (2) Synthesis of 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3
Adding compound 2(50mg,0.2351mmol), sodium azide (18.34mg,0.2821mmol) and DMF into a sealed tube, dissolving, reacting for 2h at 70 ℃, detecting by TLC after the reaction is completed, adding propiolic acid (32.94mg,0.4702mmol), cuprous iodide (8.96mg,0.0470mmol), cesium carbonate (76.6mg,0.2351mmol) and sodium ascorbate (46.58mg,0.2351mmol) into the sealed tube, continuing the reaction at 100 ℃ for 2h, detecting the reaction by TLC, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and water in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane/methanol 100/1), and rotary evaporated to give the pure product 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone 3 (white crystal) with a yield of 86%.
Example 19
Step (4) is as follows, and steps (1), (2) and (3) are the same as in example 1.
Step (4) Synthesis of 4- [4- (1H-1,2, 3-triazol-1-yl) butyl ] phenol A
To the sealed tube, compound 4(40mg,0.1730mmol) and 2ml of 40% aqueous HBr were added, heated to 80 ℃ and reacted for 18 h. After the reaction was completed by TLC, the temperature was lowered to room temperature. Diluting with 10mL of water, adding 4N NaOH dropwise to alkalify the reaction solution to about pH 12, and extracting with dichloromethane three times. The pH of the aqueous phase was adjusted to about 6 with 6N HCl, extracted three times with dichloromethane, dried over anhydrous sodium sulfate and rotary evaporated to give the product 4- [4- (1H-1,2, 3-triazol-1-yl) butyl ] phenol A (white crystals) in 64% yield.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. It will be readily apparent to those skilled in the art that various modifications to these embodiments and the generic principles defined herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments. Those skilled in the art should appreciate that many modifications and variations are possible in light of the above teaching without departing from the scope of the invention.
Claims (8)
1. A method for synthesizing a lignitinib triazole intermediate is characterized by comprising the following steps:
2. the method for synthesizing the intermediate of the xylitinib triazole according to claim 1, which is characterized by comprising the following steps of:
(1) taking anisole (1) as a raw material, and carrying out Friedel-crafts acylation reaction on the anisole (1) and 4-chlorobutyryl chloride to obtain gamma-chloro-4-methoxybenzene butanone (2);
(2) reacting gamma-chloro-4-methoxybenzene butanone (2) with sodium azide completely, and then adding propiolic acid, a copper catalyst, sodium ascorbate and alkali to react to obtain 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone (3);
(3) reducing ketocarbonyl to methylene by 1- (4-methoxyphenyl) -4- (1H-1,2, 3-triazol-1-yl) -1-butanone (3) in a trifluoroacetic acid/triethylsilane system to obtain 1- [4- (4-methoxyphenyl) butyl ] -1H-1,2,3-triazole (4);
(4) demethylation of 1- [4- (4-methoxyphenyl) butyl ] -1H-1,2,3-triazole (4) with hydrobromic acid gave the intermediate, 4- [4- (1H-1,2, 3-triazol-1-yl) butyl ] phenol (a), of xylitinib.
3. The method for synthesizing the intermediate of lignitinib triazole according to claim 2, characterized in that in step (2): dissolving gamma-chloro-4-methoxybenzyl butanone in a solvent, adding sodium azide, reacting for 2-5 hours at 60-70 ℃, detecting complete reaction by thin layer chromatography, adding propiolic acid, a copper catalyst, alkali and sodium ascorbate into the reaction liquid, continuing to react for 1-8 hours at 60-100 ℃, detecting complete reaction by thin layer chromatography, diluting the reaction liquid by ethyl acetate, sequentially washing an organic layer by saturated saline water and water, drying by anhydrous sodium sulfate, filtering, concentrating, separating by column chromatography, and removing the solvent by reduced pressure distillation to obtain a product.
4. The method for synthesizing the intermediate of the xylitinib triazole according to claim 2, wherein the molar ratio of the gamma-chloro-4-methoxybenzyl butanone, the sodium azide, the propiolic acid, the copper catalyst, the alkali and the sodium ascorbate in the step (2) is as follows: 1 (1-3), (0.1-0.5), (0.2-1).
5. The method for synthesizing the intermediate of trilithiotinib triazole according to claim 2, wherein the copper catalyst in step (2) comprises cuprous iodide, cuprous bromide, or cupric sulfate pentahydrate.
6. The method for synthesizing the intermediate of lignitinib triazole according to claim 2, wherein the base in step (2) comprises cesium carbonate, potassium carbonate or 1, 8-diazabicycloundec-7-ene.
7. The method for synthesizing the intermediate of lignitinib triazole according to claim 2, wherein the solvent in step (2) comprises N, N-dimethylformamide or dimethyl sulfoxide.
8. The method for synthesizing the intermediate of lignitinib triazole according to claim 2, wherein the concentration of hydrobromic acid in the step (4) is 40% by mass.
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