CN109134472B - Synthesis process of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine - Google Patents
Synthesis process of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine Download PDFInfo
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- CN109134472B CN109134472B CN201811098135.0A CN201811098135A CN109134472B CN 109134472 B CN109134472 B CN 109134472B CN 201811098135 A CN201811098135 A CN 201811098135A CN 109134472 B CN109134472 B CN 109134472B
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Abstract
The invention discloses a synthesis process of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine, belonging to the technical field of pharmaceutical chemistry synthesis, and being characterized in that: the method comprises the following steps: gradually adding iodine, hydrogen peroxide, 4-aminopyrazolo [3,4-d ] pyrimidine and solid superacid into an acetic anhydride solution, and obtaining 3-iodine-4-aminopyrazolo [3,4-d ] pyrimidine after the reaction is finished; dissolving 3-iodine-4-aminopyrazolo [3,4-d ] pyrimidine, 4-phenoxyphenylboronic acid and potassium phosphate in a mixed solution of 1, 4-dioxane and water, adding tetrakis (triphenylphosphine) palladium under the protection of argon, and reacting to obtain 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine.
Description
The technical field is as follows:
the invention relates to a synthesis process of an ibrutinib intermediate 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine, belonging to the technical field of chemical synthesis of medicines.
Background art:
ibrutinib (ibrutinib) chemical name is 1- [ (R) -3-4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidin-1-yl ] prop-2-en-1-one, and is the first selective Bruton tyrosine kinase BTK (bruton tyrosine kinase) inhibitor developed by Pharmacyclics and Janssen. Ibrutinib is a new drug that is marketed with rapid approval by the U.S. Food and Drug Administration (FDA), has a major role in the treatment of Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL), and is therefore very specific.
Bruton's Tyrosine Kinase (BTK) is a cytoplasmic protein material that regulates and controls the growth, proliferation, differentiation, and apoptosis of B cells. Among the multiple pathways, it is a member of the Tec tyrosine kinase family, which plays an irreplaceable role, with the exception of T and B lymphocytes, BTK being said to be expressed on all other cells associated with hematopoietic function.
Evidence suggests that ibrutinib blocks signaling of growth, proliferation and spread of non-benign B lymphocytes, and the effects on BTK activity are also non-reversible, thus significantly inhibiting tumor cell growth and proliferation. Ibrutinib has the advantage that other drugs are difficult to replace compared to other established therapeutic drugs, which provides an alternative to MCL and CLL. And 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine is an important intermediate for synthesizing ibrutinib.
The synthesis of the compound is reported in patent US7514444, wherein the process is that p-phenoxybenzoic acid is used as raw material, condensed with malononitrile, methylated by (trimethylsilyl) diazomethane, condensed with hydrazine hydrate to form pyrazole ring, and condensed with formamide to obtain the compound. In addition to the use of expensive starting materials, the process also requires the use of inexpensive (trimethylsilyl) diazomethane which is not readily available and is not stable to air and water. Therefore, the methylation reaction needs to be carried out under anhydrous and anaerobic conditions, the reaction conditions are harsh, and the process is complex.
In patent application CN103965201, after bromine halogenation of 4-amino-1H-pyrazolo [3,4-d ] pyrimidine, an ibrutinib intermediate is prepared by reaction with trimethyl p-phenoxyphenyl tin under the catalysis of tetrakis (triphenylphosphine) palladium. In the first bromination step of the reaction, the post-treatment is complex, the bromination effect is general, the second bromination step needs to be carried out in an anhydrous oxygen-free solvent and an inert environment, the existence of oxygen can even cause self-coupling of organic tin compounds, the reaction is difficult to control, and the preparation of stannides is expensive and has complex steps.
The invention content is as follows:
the invention aims to provide a green synthesis process of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine with mild reaction conditions, convenient operation, controllable cost and higher yield, solve some problems in the existing synthesis process, and find a production way suitable for industrial large-scale production.
The technical scheme adopted by the invention is as follows:
the process comprises the following steps:
gradually adding iodine, hydrogen peroxide, 4-aminopyrazolo [3,4-d ] pyrimidine and solid superacid into an acetic anhydride solution, and reacting at 50 ℃ to obtain 3-iodine-4-aminopyrazolo [3,4-d ] pyrimidine; dissolving 3-iodine-4-aminopyrazolo [3,4-d ] pyrimidine, 4-phenoxyphenylboronic acid and potassium phosphate in a mixed solution of 1, 4-dioxane and water, adding tetrakis (triphenylphosphine) palladium under the protection of argon, and reacting at 120 ℃ to obtain 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine.
Further settings are as follows:
the solid super acid involved in the reaction is: SO (SO)
4 2-/ZrO
2，SO
4 2-/TiO
2，SO
4 2-/ZrO
2-TiO
2
The solid super acid involved in the reaction is generally as follows: the oxide is dipped into 0.5-1.0mol/L sulfuric acid solution at normal temperature for overnight, washed, filtered and dried, and then is roasted for 3-8 hours at the temperature of 500-700 ℃ in a muffle furnace to obtain the required solid super acidic catalyst.
The solid super acid involved in the reaction can be washed by ethanol and reused after being calcined in a muffle furnace.
The reaction equation set by the experiment is as follows:
the principle of the invention is as follows:
the invention uses green iodo reagents hydrogen peroxide and I
2Formation of I under acidic conditions
+Compared with the traditional inorganic acid, the solid acid has the advantages that ① reaction products and the catalyst are easy to separate, the ② catalyst can be repeatedly used, the ③ catalyst has no corrosion to the reactor, the three wastes caused by the ④ waste catalyst are less, and the recyclable solid super acid is used as an acid source, so that a large amount of waste acid and waste liquid caused by the traditional inorganic acid can be avoided, and the more obtained waste acid and waste liquid are moreIs an economic and environment-friendly synthetic route. Reaction product 3-iodo-4-aminopyrazolo [3,4-d]Under the catalytic action of palladium tetrakis (triphenylphosphine), pyrimidine can realize Suzuki cross-coupling reaction with better effect with 4-phenoxyphenylboronic acid to form an ibrutinib intermediate 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d]The pyrimidine-4-amine has mild condition and considerable yield.
Better reaction yield can be obtained by adopting the following process conditions:
first ZrO is added
2Dipping the mixture into 0.6mol/L sulfuric acid solution at normal temperature overnight, washing, filtering, drying, and then roasting in an oven at 500 ℃ for 6 hours to obtain the required solid super acidic catalyst.
Preparation of 3-iodo-4-aminopyrazolo [3,4-d]Pyrimidine: adding iodine (0.51g,0.0021mol) into 6mL of DMF solution under the protection of argon gas, slowly dropwise adding a mixed solution of hydrogen peroxide (0.0013mol, 0.13mL) and DMF, and then adding 4-aminopyrazolo [3,4-d ] into the mixed solution]Pyrimidine (0.57g,0.0042mol), then cooled to 10 ℃ and slow SO addition started
4 2-/ZrO
24g of solid acid, keeping the temperature of the reaction system at 10 ℃, stirring and heating to 45 ℃ after the addition, and carrying out sample application to detect the reaction end point. After the reaction is finished, removing solid acid by suction filtration, then dropwise adding saturated sodium thiosulfate solution into the obtained mixture until starch-KI test paper does not turn blue, recovering DMF solvent under reduced pressure, then adding 25mL of ice water into the reaction solution, extracting with ethyl acetate (25mL multiplied by 3) to obtain 3-iodine-4-aminopyrazolo [3,4-d ]]Pyrimidine 0.99g, yield 90%.
The invention has the following beneficial effects:
the invention uses green iodo reagent H
2O
2And I
2Formation of I under acidic conditions
+Ions, and then electrophilic substitution reaction is carried out, waste residues generated by using a strong oxidant in the traditional reaction are avoided, and a more economical iodo product is obtained. Meanwhile, strong acid resin is used for replacing concentrated sulfuric acid in the reaction, so that the reaction is facilitated while resource utilization and environmental protection are optimized, and the yield is greatly improved. The reaction product can realize better Suzuki effect with 4-phenoxyphenyl boric acid under the catalytic action of palladium tetrakis (triphenylphosphine)Cross-coupling reaction to form ibrutinib intermediate 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d]The pyrimidine-4-amine has mild condition and considerable yield.
The invention is further described below with reference to the accompanying drawings and the detailed description.
Description of the drawings:
FIG. 1 shows 3-iodo-4-aminopyrazolo [3,4-d ] prepared in example 1 of the present invention]Of pyrimidines
1H NMR, 400M, solvent DMSO) nuclear magnetic resonance spectrum;
FIG. 2 is 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d prepared by example 4 of the present invention]Of pyrimidin-4-amines
1H NMR, 400M, solvent DMSO) nuclear magnetic resonance spectrum.
The specific implementation mode is as follows:
example 1:
preparation of 3-iodo-4-aminopyrazolo [3,4-d]Pyrimidine: adding iodine (0.51g,0.0021mol) into 6mL of DMF solution under the protection of argon gas, slowly dropwise adding a mixed solution of hydrogen peroxide (0.0013mol, 0.13mL) and DMF, and adding 4-aminopyrazolo [3,4-d ] into the mixed solution]Pyrimidine (0.57g,0.0042mol), then cooled to 10 ℃ and the addition of SO started
4 2-/ZrO
23g of solid acid, keeping the temperature of the reaction system at 10 ℃, stirring and heating to 45 ℃ after the addition, and carrying out sample application to detect the reaction end point. After the reaction is finished, removing solid acid by suction filtration, then dropwise adding saturated sodium thiosulfate solution into the obtained mixture until starch-potassium iodide test paper does not turn blue, recovering DMF solvent under reduced pressure, then adding 25mL of ice water into the reaction solution, extracting with ethyl acetate (25mL multiplied by 3) to obtain 3-iodine-4-aminopyrazolo [3,4-d ]]Pyrimidine 0.91g, yield 83%.
And (3) product structure confirmation: the NMR spectrum of the product is shown in FIG. 1.
Alternative examples 1-1 to 1-9:
based on the above process, the reaction temperature, SO, is adjusted
4 2-/ZrO
2The solid acid dosage, the ratio of iodine to sodium percarbonate dosage, yields obtained are given in the following table.
| Serial number | Temperature/. degree.C | SO 4 2-/ZrO 2/g | I 2：H 2O 2In a molar ratio of | Yield/%) |
| Alternative example 1-1 | 45 | 3 | 1:0.32 | 76 |
| Alternative examples 1 to 2 | 45 | 4 | 1:0.50 | 90 |
| Alternative examples 1 to 3 | 45 | 5 | 1:0.80 | 83 |
| Alternative examples 1 to 4 | 50 | 3 | 1:0.50 | 82 |
| Alternative examples 1 to 5 | 50 | 4 | 1:0.80 | 85 |
| Alternative examples 1 to 6 | 50 | 5 | 1:0.32 | 76 |
| Alternative examples 1 to 7 | 55 | 3 | 1:0.80 | 73 |
| Alternative examples 1 to 8 | 55 | 4 | 1:0.32 | 70 |
| Alternative examples 1 to 9 | 55 | 5 | 1:0.50 | 72 |
From the above table, the reaction temperature is 50 ℃ and SO
4 2-/ZrO
2The dosage is 4g and I
2:H
2O
2Synthesis of 3-iodo-4-aminopyrazolo [3,4-d ] under reaction conditions of ═ 1:0.50]The pyrimidine is optimal, and the yield can reach 89% after repeated experiments.
Example 2:
preparation of 3-iodo-4-aminopyrazolo [3,4-d]Pyrimidine: adding iodine (5.1g,0.021mol) into 60mL of DMF solution under the protection of argon gas, slowly dropwise adding a mixed solution of hydrogen peroxide (0.011mol, 1.1mL) and DMF, uniformly stirring, and then adding 4-aminopyrazolo [3,4-d ] into the mixture]Pyrimidine (5.7g,0.042mol), cooled to 10 ℃ and slowly added 30g of solid acid (SO)
4 2-/ZrO
2-TiO
2) And keeping the temperature of the reaction system at 10 ℃, heating to 45 ℃ after finishing dropping, and carrying out sample application monitoring. After the reaction is finished, removing solid acid by suction filtration, then dropwise adding saturated sodium thiosulfate solution into the obtained mixture until starch-potassium iodide test paper does not turn blue, recovering DMF solvent under reduced pressure, then adding 125mL of ice water into the reaction solution, adjusting the pH value to be neutral by using saturated sodium hydroxide, extracting by using ethyl acetate (125mL multiplied by 3) to obtain 3-iodine-4-aminopyrazolo [3,4-d ]]Pyrimidine 9.5g, yield 86%.
Example 3:
preparation of 3-iodo-4-aminopyrazolo [3,4-d]Pyrimidine: adding iodine (5.1g,0.021mol) into 60mL of DMF solution under the protection of argon gas, slowly dropwise adding a mixed solution of hydrogen peroxide (0.011mol, 1.1mL) and DMF, uniformly stirring, and then adding 4-aminopyrazolo [3,4-d ] into the mixture]Pyrimidine (5.7g,0.042mol), cooled to 10 ℃ and slowly added 40g of solid acid (SO)
4 2-/ZrO
2) And keeping the temperature of the reaction system at 10 ℃, heating to 40 ℃ after finishing dropping, and carrying out sample application monitoring. After the reaction is finished, removing solid acid by suction filtration, then dropwise adding saturated sodium thiosulfate solution into the obtained mixture until starch-potassium iodide test paper does not turn blue, recovering DMF solvent under reduced pressure, then adding 125mL of ice water into the reaction solution, adjusting the pH value to be neutral by using saturated sodium hydroxide, extracting by using ethyl acetate (125mL multiplied by 3) to obtain 3-iodine-4-aminopyrazolo [3,4-d ]]Pyrimidine 9.0g, yield 82%.
Example 4:
2g of 3-iodo-4-aminopyrazolo [3,4-d]Pyrimidine (7.7mmol), 3.28g p-phenoxy-phenylboronic acid (15.4mmol) and 5.28g K
3PO
4(23.0mmol) is dissolved in 25mL of dioxane and 10mL of water, after stirring for 5-8min, argon is introduced for 20min, 1.4g of palladium tetrakis (triphenylphosphine) is added (1.2mmol), after argon is introduced for 10min again, heating is started, reaction is carried out for 24h at 120 ℃, and the reaction is finishedThen cooled to room temperature, stirred for 24h to precipitate the product, the reaction mixture was washed with 25mL of water and filtered, and the filtered solid was again washed with 75mL of methanol, washed with 50mL of ethanol and dried in a drying oven. To obtain 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d]Pyrimidin-4-amine 1.75g, 75% yield.
And (3) product structure confirmation: the NMR spectrum of the product is shown in FIG. 2.
Claims (4)
1. A synthesis process of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine is characterized by comprising the following steps:
gradually adding iodine, hydrogen peroxide and 4-amino pyrazolo [3,4-d ] into acetic anhydride solution]Pyrimidine and solid superacid, and 3-iodine-4-amino pyrazolo [3,4-d is obtained after the reaction]A pyrimidine; the solid super acid involved in the reaction is: SO (SO)
4 2-/ZrO
2，SO
4 2-/TiO
2，SO
4 2-/ZrO
2-TiO
2Washing solid super acid in the reaction by ethanol, and repeatedly using the solid super acid after calcining in a muffle furnace;
dissolving 3-iodine-4-aminopyrazolo [3,4-d ] pyrimidine, 4-phenoxyphenylboronic acid and potassium phosphate in a mixed solution of 1, 4-dioxane and water, adding tetrakis (triphenylphosphine) palladium under the protection of argon, and reacting to obtain 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine.
2. The process of claim 1 for the synthesis of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine, wherein: the preparation method of the solid super acid comprises the following steps: the oxide is dipped into 0.5-1.0mol/L sulfuric acid solution at normal temperature overnight, washed, filtered and dried, and then is roasted for 3-8 hours at the temperature of 500-700 ℃ in a muffle furnace to obtain the required solid super acid.
3. 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d according to claim 1]The synthesis process of the pyrimidine-4-amine is characterized by comprising the following steps: synthesis of 3-iodo-4-aminopyrazolo [3,4-d]In the reaction of pyrimidine, the reaction temperature is 50 DEG C
2:H
2O
2In a molar ratio of 1:0.50, SO
4 2-/ZrO
2The amount used was 4 g.
4. The process of claim 1 for the synthesis of 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine, wherein:
preparing solid super acid: first ZrO is added
2Soaking the mixture into 0.6mol/L sulfuric acid solution at normal temperature overnight, washing, filtering, drying, and roasting in an oven at 500 ℃ for 6 hours to obtain the required solid super acid;
preparation of 3-iodo-4-aminopyrazolo [3,4-d]Pyrimidine: adding 0.51g of iodine into 6mL of DMF solution under the protection of argon, slowly dropwise adding a mixed solution of 0.0013mol of hydrogen peroxide and DMF, and then adding 4-aminopyrazolo [3,4-d]Pyrimidine 0.57g, then cooled to 10 ℃ and slow SO addition started
4 2-/ZrO
24g of solid acid, keeping the temperature of the reaction system at 10 ℃, stirring and heating to 45 ℃ after the solid acid is added, and carrying out sample application to detect the reaction end point; after the reaction is finished, removing solid acid by suction filtration, then dropwise adding a saturated sodium thiosulfate solution into the obtained mixture until starch-KI test paper does not turn blue, recovering DMF solvent under reduced pressure, then adding 25mL of ice water into the reaction solution, and extracting with ethyl acetate to obtain 3-iodine-4-aminopyrazolo [3,4-d ]]Pyrimidine 0.99g, yield 90%.
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| DE102006003444A1 (en) * | 2006-01-25 | 2007-07-26 | Lanxess Deutschland Gmbh | Method for iodinating substituted azole compound and acid addition compound by converting substituted 1H-triazoles compound, with an oxidizing agent and elementary iodine and/or iodine compound in presence of a solvent or its mixture |
| US7718662B1 (en) * | 2009-10-12 | 2010-05-18 | Pharmacyclics, Inc. | Pyrazolo-pyrimidine inhibitors of bruton's tyrosine kinase |
| JP6495886B2 (en) * | 2013-03-15 | 2019-04-03 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Heteroaromatic compounds as BTK inhibitors |
| WO2015018333A1 (en) * | 2013-08-06 | 2015-02-12 | Fujian Haixi Pharmaceuticals Co., Ltd | Inhibitors of bruton's tyrosine kinase |
| CN107759602B (en) * | 2016-08-17 | 2020-04-21 | 中国科学院上海药物研究所 | Compound containing conjugated allene structure, pharmaceutical composition and application thereof |
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