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Sulfonamide compound intermediate, salt thereof and preparation method thereof
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A technology of sulfonamides and compounds, which is applied in the field of intermediates of sulfonamides, and can solve problems such as unfavorable industrial production, harsh reaction conditions, and low product yields
Inactive Publication Date: 2013-08-14
上海温康化学研发有限公司 +1
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[0007] The technical problem to be solved by the present invention is: in order to overcome the defects of harsh reaction conditions, low product yield, difficult purification and unfavorable industrial production in the existing method for preparing TG101209 (formula I), a method as described in formula I is provided. The intermediate of TG101209 sulfonamide compounds shown, its salt and its preparation method
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Embodiment 1
[0054]
[0055] Dissolve compound 1 (2.3g, 6.5mmol) in 40mL of methanol, add 2.0mL of 36.5% concentrated hydrochloric acid, stir or vibrate with ultrasonic waves, so that all solids are dissolved. Concentrate under reduced pressure to remove the solvent and excess aqueous hydrochloric acid to obtain a yellow solid residue. Slurry was performed with ethyl acetate and filtered to obtain 2.77 g of yellow powdery solid, namely hydrochloride IV-a, with a yield of 99.6%. This intermediate was used directly in the next step without isolation.
[0056] Proton spectrum data of compound IV-a: 1 H-NMR (400MHz, DMSO-d6): δ9.135(s, 1H), 8.126(s, 1H), 8.114(s, 1H), 7.92~7.90(m, 1H), 7.575.54(m, 3H ), 3.74 (brs, 2HCl), 2.205 (s, 3H), 1.14 (s, 9H). The purity was 100% by HPLC (254nm).
Embodiment 2
[0058]
[0059] Compound 1 (2.3 g, 6.5 mmol) was dissolved in 20 mL of acetic acid and stirred for 30 minutes to completely dissolve the solid. Concentration under reduced pressure to remove excess acetic acid (also solvent) gave a yellow solid residue. Slurry with ethyl acetate and filter to obtain a yellow powdery solid, which is acetate IV-c. 2.70 g, 100% yield. This intermediate was used directly in the next step without isolation.
[0060] Proton spectrum data of compound IV-c: 1 H-NMR (400MHz, DMSO-d6): δ9.174(s, 1H), 8.186(s, 1H), 8.162(s, 1H), 7.98~7.90(m, 1H), 7.62~7.60(m, 2H ), 7.568(s, 1H), 3.72(brs, 1H, CH 3 CO 2 H), 2.253(s, 3H), 1.95(s, 3H), 1.056(s, 9H); the purity was 98.5% by HPLC (254nm).
Embodiment 3
[0062]
[0063] Compound 1 (2.3g, 6.5mmol) was dissolved in 40mL of dichloromethane, 10mL of trifluoroacetic acid was added, and stirred or oscillated by ultrasonic waves to dissolve all the solids. Concentrate under reduced pressure to remove the solvent and excess trifluoroacetic acid to obtain a yellow solid residue. Slurry was made with ethyl acetate and filtered to obtain a yellow powdery solid, namely 3.03 g of trifluoroacetate IV-b, with a yield of 100%. This intermediate was used directly in the next step without isolation.
[0064] Proton spectrum data of compound IV-b: 1 H-NMR (400MHz, DMSO-d6): δ9.041(s, 1H), 8.048(s, 1H), 8.025(s, 1H), 7.82~7.78(m, 1H), 7.50~7.46(m, 2H ), 7.43(s, 1H), 4, 187(brs, 2H, 2CF 3 CO 2 H), 2.115(s, 3H), 1.056(s, 9H). The purity was 100% by HPLC (254nm).
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Abstract
The invention discloses compounds as shown in a formula III. The invention also discloses a preparation method of salts of sulfonamide compounds as shown in the formula III, comprising carrying out a coupling reaction for a compound of a formula IV and a compound 2 in a solvent, wherein the temperature is 35-200 DEG C, n2=1-4, and X is a protonic acid which can be removed by distillation under reduced pressure. The invention also discloses a preparation method of sulfonamide compounds as shown in the formula I, inlcuding: (1) preparing a compound of the formula III as the above method; and (2) reacting the compound of the formula III obtained in the step (1) with a base in a solvent with a reflux temperature of 0 DEG C; wherein X is a protonic acid; and n2=1-4. The invention also discloses compounds as shown in the formula IV. The preparation method of the present invention is mild in reaction conditions, high in yield, simple in purification and suitable for industrial production.
Description
technical field [0001] The invention relates to an intermediate of a sulfonamide compound, a salt thereof and a preparation method thereof. Background technique [0002] TG101209, the chemical name is (N-tert-butyl-3-(5-methyl-2-[4-(4-methyl-1-piperazine)anilino]-4-aminopyrimidine)-benzenesulfonamide, Has the structural formula: [0003] [0004] TG101209 is a selective inhibitor of JAK2 proteinkinase jointly developed by TargeGen of the United States, Harvard Medical School, and the Mayo Clinic of Minnesota; preclinical intracellular and extracellular experiments show that it can select Sexual suppression leads to the V617F mutation and MPLW515L mutation of the JAK2 gene, which is an important cause of myeloproliferative diseases; it can treat Polycythemia Vera (PV), Essential Thrombocythemia (Essential Thrombocythemia, ET), primary Activity in diseases such as primary myelofibrosis (PMF). Its biological activity was reported by A. Pardanani et al., published in the ...
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