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Preparation method of drug for treating chronic granulocytic leukemia

A methyl and ethynyl technology, applied in the field of medicinal chemistry, can solve the problem of not being able to obtain the target

Active Publication Date: 2014-03-26
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] J.Med.Chem.2010(53):4701-4719 reported the above two routes, but route one uses Pd(PPh3)4 / CuI / Et3N conditions for sonagashira reaction, the product is mainly a diyne by-product obtained by alkyne coupling, and the target Ponatinib is basically not obtained

Method used

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  • Preparation method of drug for treating chronic granulocytic leukemia
  • Preparation method of drug for treating chronic granulocytic leukemia
  • Preparation method of drug for treating chronic granulocytic leukemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: Preparation of 3-ethynyl-4-methyl-N-[4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide

[0047]

[0048] Step A: Preparation of 3-iodo-4-methyl-N-[4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide:

[0049] Add 3-iodo-4-methyl-benzoic acid (2.62g, 10mmol) and 10ml of thionyl chloride into a round bottom flask, reflux at 78°C for 4 hours, remove volatile substances by rotary evaporator to obtain 3-iodo-4 - Methyl-benzoyl chloride. In a round bottom flask was added 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylaniline (2.27 g, 8.3 mmol), 3-iodo-4-methyl-benzoyl chloride (10mmol), 15ml tetrahydrofuran, 10ml triethylamine, stirred at room temperature for 4 hours. with saturated NaHCO 3 Solution washing, adding ethyl acetate and water extraction, washing with saturated NaCl solution, anhydrous NaCl 2 SO 4 After drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column ...

Embodiment 2

[0061]Example 2: Preparation of 3-ethynyl-4-methyl-N-[4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide

[0062]

[0063] Step A: Preparation of methyl 4-methyl-3-trimethylsilylethynylbenzoate

[0064] Methyl 4-methyl-3-iodobenzoate (15 g, 54.33 mmol), bistriphenylphosphine palladium dichloride (1.91 g, 2.72 mmol), cuprous iodide (1.03 g, 5.43 mmol) were added to In a 50ml round-bottomed two-neck flask, nitrogen was replaced three times. Under nitrogen protection, trimethylsilylacetylene (21.6mL, 162.99 mmol) and triethylamine (12.5 mL, 86.93 mmol) were added, heated to 60°C and stirred overnight. , TLC monitored the reaction and found that the raw material 4-methyl-3-iodobenzoic acid methyl ester was completely consumed, the reaction solution was evaporated under reduced pressure to remove the solvent, added ethyl acetate and water for extraction, combined the organic phases, washed with saturated brine, and anhydrous sodium sulfate dry. It was dried in ...

Embodiment 3

[0072] Example 3 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazine-1- Base) methyl] -3-trifluoromethylphenyl} benzamide

[0073]

[0074] Add 3-ethynyl-4-methyl-N-[4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide (126mg ,0.3mmol), 3-bromoimidazo[1,2-b]pyridazine (59mg,0.3mmol), Pd(PPh 3 ) 2 Cl 2 (11mg, 0.02mmol), PCy 3 (8mg, 0.04mmol), Cs 2 CO 3 (99mg, 0.3mmol), DBU 0.3ml, DMF 10ml, replace the air with argon for 5 minutes, seal, and stir at 80°C for 8 hours. Extract with ethyl acetate (15ml×4), combine the organic phases, add anhydrous Na 2 SO 4 dry. The organic solution was concentrated under reduced pressure, and the residue was purified by silica gel column to obtain the target compound with a yield of 58%.

[0075] 1 HNMR (CDCl 3 ,500MHz): 8.48(d,1H,Ar-H),8.31(s,1H,Ar-H),8.06(s,1H,-NH),8.06(s,1H,Ar-H), 7.98(d ,1H,Ar-H)7.93(d,1H,Ar-H),7.90(s,1H,Ar-H),7.83(q,1H,Ar-H),7.72(d,1H,Ar-H) ,7.38(d,1H,Ar-H),7.14(q,1H,...

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Abstract

The invention relates to a preparation method of a drug for treating chronic granulocytic leukemia, belonging to the field of medical chemistry, and specifically relates to a preparation method of 3-[2-(imidazo[1,2-b] pyridazine-3-yl) acetenyl]-4-methyl-N-{4-[4-methyl piperazine-1-yl] methyl}-3- trifluoromethyl phenyl} benzoyl amide (ponatinib). The method comprises the following steps: adding a phosphine ligand and cesium carbonate at the same time by taking Pd(PPh3)2Cl2 as a catalyst; adding strong base DBU or adding CuI as a cocatalyst to carry out sonagashira reaction, wherein the phosphine ligand is selected from tricyclohexyl phosphine (PCy3), tri-tert-butyl phosphine (PtBu3) or tri(funan-2-yl) phosphine (P(2-furyl)3). The method disclosed by the invention is complete in reaction, does not have or has extremely few diyne byproduct of alkyne coupling, and is easy to separate and purity.

Description

[0001] technical field [0002] The invention belongs to the field of medicinal chemistry and relates to 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4- [(4-methylpiperazin-1-yl)methyl]-3-trifluoromethylphenyl}benzamide (ponatinib) preparation method. [0003] Background technique [0004] 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl Base]-3-trifluoromethylphenyl}benzamide (Ponatinib) is an oral multi-target enzyme inhibitor developed by Ariad, which can effectively inhibit the signal regulated by BCR-ABL, and its indication is chronic granulocyte leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), especially effective for imatinib-resistant T315I variant chronic myelogenous leukemia. [0005] Ponatinib is a broad-spectrum BCR-ABL inhibitor that inhibits BCR-ABL (IC 50 =0.37nmol / L) and all its mutants, including the T315I variant that is resistant to various therapeutic dr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D295/135
CPCC07D295/135C07D487/04
Inventor 王勇赵立文陈宏雁张迪徐信张仓张宏兴
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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