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Preparation method of ibrutinib intermediate
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A technology for ibrutinib and intermediates, applied in the field of drug synthesis, can solve the problems of low yield, low purity, and high reaction requirements of intermediate I, and achieve the effect of simple operation and high purity
Pending Publication Date: 2022-01-14
LUNAN PHARMA GROUP CORPORATION
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Problems solved by technology
[0016] In order to solve the problems of low yield, low purity and high reaction requirements of ibrutinib important intermediate I in the prior art, the present invention provides a new preparation method; the reaction yield of the method is high, the cycle is short, The applicable conditions are wider, and the operation and production are safer
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Embodiment 1
[0036] In a 200ml single-necked bottle, add intermediate II (3.03g, 10mmol), (S)-1-tert-butyloxy-3-hydroxypiperidine (2.82g, 14mmol), 1,2-diiodoethane ( 3.38g, 12mmol), triphenyl phosphate (3.92g, 12mmol) and tetrahydrofuran (30ml), 30 ℃ of stirring reaction to intermediate II consumption, 0~5 ℃ after adding 5M dilute hydrochloric acid (24mL, 120mmol), the reaction finishes to 30ml of purified water and dichloromethane (20ml) were added to the reaction, and the aqueous phase was neutralized to pH=9 with 30% sodiumhydroxide solution, and a solid was precipitated, filtered, and the solid was dried in vacuo to obtain Intermediate I with a yield of 98.5%, HPLC 99.92% pure.
Embodiment 2
[0038]In a 200ml single-necked bottle, add intermediate II (3.03g, 10mmol), (S)-1-tert-butyloxy-3-hydroxypiperidine (2.42g, 12mmol), 1,2-diiodoethane ( 3.38g, 12mmol), triphenylphosphine (3.15g, 12mmol) and tetrahydrofuran (30ml), stirred reaction at 0 ℃ until intermediate II was consumed, and added 2M dilute hydrochloric acid (60mL, 120mmol) at 0~5 ℃, the reaction ended 30ml of purified water and dichloromethane (20ml) were added to the reaction, the aqueous phase was neutralized to PH=8 with 30% sodiumhydroxide solution, a solid was precipitated, filtered, and the solid was dried in vacuo to obtain Intermediate I with a yield of 94.5%, HPLC 99.82% purity.
[0039] Example 2
[0040] In a 200ml single-necked bottle, add intermediate II (3.03g, 10mmol), (S)-1-tert-butyloxy-3-hydroxypiperidine (4.03g, 20mmol), 1,2-diiodoethane ( 3.38g, 12mmol), triphenylphosphine (3.15g, 12mmol) and tetrahydrofuran (30ml), stirred reaction at 50 ℃ until the intermediate II was consumed, and ...
Embodiment 3
[0042] In a 200mL single-necked bottle, add intermediate II (3.03g, 10mmol), (S)-1-tert-butyloxy-3-hydroxypiperidine (2.01g, 10mmol), 1,2-diiodoethane ( 3.38g, 12mmol), triphenylphosphine (3.15g, 12mmol) and 1,4-dioxane (30ml), stirred at 55°C until intermediate II was consumed, and then added 8M dilute hydrochloric acid (15mL , 120mmol), after the reaction, add 30ml of purified water and dichloromethane (20ml) to the reaction, the aqueous phase is neutralized to PH=9 with 30% sodiumhydroxide solution, the solid is precipitated, filtered, and the solid is vacuum-dried to obtain intermediate I , yield 87.7%, HPLC purity 99.68%.
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Abstract
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of an ibrutinib intermediate. According to the invention, 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine is taken as a raw material and reacts with (S)-1-tert-butyloxy-3-hydroxypiperidine under the mixed catalysis of organic phosphorus / phosphine and diiodoalkane, and then deprotection is conducted to obtain the important ibrutinib intermediate, namely (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. According to the method, organic phosphorus / phosphine and diiodoalkane are used as catalysts, the problems that the product yield of a traditional Mitsunobu reaction is not high, and the requirement for the acidity of a nucleophilic reagent is high are solved, a reaction is milder, economical and environmentally friendly, yield is high, and the method is suitable for industrial production.
Description
technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of an ibrutinib intermediate. Background technique [0002] Ibrutinib (ibrutinib), also known as Ibrutinib, is an oral heavyweight Bruton's tyrosinekinase (BTK) inhibitor new anti-cancerdrug jointly developed by American Pharmacyclics and Johnson & Johnson. Since it was approved for marketing by the US FDA in 2013, tinib has been granted 4 breakthrough drug designations by the FDA, respectively for mantle celllymphoma (MCL), chronic lymphocytic leukemia (CLL / SLL), Waldenstrom macroglobulin Treatment of anemia (WM) and chronic graft-versus-host disease (cGVHD). Ibrutinib chemical name: 1-[3(R)-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl ]-1-piperidinyl]-2-propene-1-one, the chemical structural formula is as follows: [0003] [0004] Because of its good clinical performance, ibrutinib has attracted great attention ...
Claims
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