Crystal of upatinib intermediate compound and preparation method thereof

A compound and crystal technology, applied in the field of drug synthesis, can solve the problems of unfavorable scale-up production, large amount of solvents, cumbersome operation, etc., and achieve the effect of controllable process, low cost and good repeatability

Inactive Publication Date: 2021-02-26
SUZHOU PENGXU PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The intermediates are all purified by column chromatography, which is cumbersome to operate, requires the use of a large amount of solvents, and produces more solid waste, which is not conducive to environmental protection and

Method used

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  • Crystal of upatinib intermediate compound and preparation method thereof
  • Crystal of upatinib intermediate compound and preparation method thereof
  • Crystal of upatinib intermediate compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] The preparation method of the oxalate salt form C of compound I:

[0073] Dissolve 400 mg of compound I in 4 mL of isopropyl acetate, slowly add 94 mg / 4 mL of oxalic acid dihydrate in isopropyl acetate dropwise at 20-30°C, stir at room temperature for 2 h, filter and drain to obtain a solid 204 mg, the sampling test HPLC purity was 99.82%.

[0074] 2theta d interval Relative Strength% 9.26 9.55 40.54 10.04 8.81 17.63 12.62 7.01 24.42 15.87 5.58 24.87 16.18 5.48 33.76 16.66 5.32 26.40 16.91 5.24 67.12 18.10 4.90 19.03 20.14 4.41 29.72 20.75 4.28 24.13 21.57 4.12 29.38 22.56 3.94 100.00 25.21 3.53 18.46 25.39 3.51 27.92

Embodiment 2

[0076] Amorphous preparation method of Compound I (refer to patent WO2011068881, Example AA.1.160, page 363 and its related reference examples; WO2019016745, Example 27&28, pages 40-41):

[0077]

[0078] Dissolve 2.0 g of compound 3 in 10 mL of 1,4-dioxane, slowly add 6 mL of 33% HBr / CH 3 COOH, stirred at 20-30°C for 2 hours, the reaction was complete, added 10 mL of water to quench the reaction, added 10 mL of toluene, stirred and separated, continued to add 10 mL of toluene to the water phase, stirred and separated to obtain the water phase, adjusted the pH of the system to 7 with NaOH ~8, add 20 mL of dichloromethane, stir and separate to obtain an organic phase, add 10 mL of Brine to the organic phase for washing, and obtain a dichloromethane solution of compound 4, which is designated as solution A. Take another 25mL three-necked flask, add 895mg N,N-carbonyldiimidazole, add 10mL dichloromethane, add 547mg 2,2,2-trifluoroethylamine at 20-30°C, stir for 1 hour, record ...

Embodiment 3

[0080] The preparation method of the crystal form A of compound I:

[0081] Dissolve 1 g of compound I in 5 mL of isopropyl acetate, heat to 50-60 °C, add 100 mg of compound I seed crystals, the system slowly precipitates more solids, slowly cool down to 20-30 °C, and stir for 2 h , Suction filtration to obtain 650 mg of compound I with a purity of 99.74%.

[0082] HNMR data:

[0083] 1 H NMR (400 MHz, d-DMSO) δ 8.77 (m, 1H), 8.05-8.03 (m, 2H), 7.99-7.97 (m,1H), 7.59 (s, 1H), 7.46-7.43 (m, 3H ), 6.96-6.93 (m, 1H), 4.34-4.29 (m, 1H),3.88-3.65 (m, 5H), 3.27-3.23 (m, 1H), 2.35 (s, 3H), 1.04-0.99 (m , 1H), 0.82-0.77 (m, 1H), 0.63-0.60 (m, 3H).

[0084] 2theta d interval Relative Strength% 5.32 16.60 100.00 7.88 11.21 15.15 8.42 10.51 19.19 9.03 9.79 18.93 10.58 8.36 17.93 10.96 8.07 19.27 12.01 7.37 16.33 13.20 6.71 34.73 13.64 6.49 22.90 15.96 5.55 15.91 17.18 5.16 22.68 18.15 4.89 34.91 ...

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Abstract

The invention provides crystal of an upatinib intermediate compound, upatinib intermediate compound salt and a preparation method of the corresponding crystal and upatinib intermediate compound salt.The method provided by the invention relates to a high-purity target compound obtained by crystallizing or salifying an upatinib intermediate or a corresponding acid. The crystal form and salt of theupatinib intermediate are simple and convenient to prepare and operate, the raw materials are cheap and easy to obtain, the purification effect on the upatinib intermediate is good, and industrial production is facilitated. R=Cbz or CONHCH2CF3.

Description

technical field [0001] The present application relates to the field of pharmaceutical synthesis, in particular, to preparation methods of upadatinib intermediate compound crystals, salts and corresponding crystals and salts. Background technique [0002] The specific causes of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are unknown, but it is speculated from medical practice that they have an important relationship with some defects in the immune function of patients. Rheumatoid arthritis has a long course of disease, and because it often has immune dysfunction, patients often die due to complications such as cardiovascular, infection, and impaired renal function. [0003] At present, JAK inhibitors are one of the means to effectively treat such immune system diseases. Among them, Upadacitinib, as AbbVie's new drug for the treatment of rheumatoid arthritis and an experimental new drug for psoriatic arthritis, uses a new target JAK1 inhibitor, JAK1 is a kinase ...

Claims

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Application Information

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IPC IPC(8): C07D487/14C07C51/41C07C55/07
CPCC07B2200/13C07C51/412C07C55/07C07D487/14
Inventor 李丕旭王鹏程文蒋强华魏强
Owner SUZHOU PENGXU PHARM TECH CO LTD
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