Compound and application thereof in synthesis of ribociclib

A compound and reaction technology, applied in the field of compound and its application in the synthesis of rebocoxib, can solve the problem of eliminating heavy metal residues and achieve the effect of reducing and removing heavy metal residues and complete substitution reactions

Inactive Publication Date: 2019-04-02
SUZHOU PENGXU PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The existing process route is prepared by Pd-catalyzed coupling reaction, using more noble metal catalysts, the coupling reaction is only two steps away from the final drug active molecule, and there are high requirements for the elimination of heavy metal residues

Method used

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  • Compound and application thereof in synthesis of ribociclib
  • Compound and application thereof in synthesis of ribociclib
  • Compound and application thereof in synthesis of ribociclib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019]

[0020] Add 3.0g of compound 2, 3.0g of potassium fluoride and 1.0g of tetrabutylammonium hydrogensulfate into the reaction flask, add 30mL of dimethyl sulfoxide and then raise the temperature to 150°C for 24 hours, monitor the reaction by TLC and use 100mL of water The reaction was quenched, then extracted twice with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was collected by filtration. After spinning to dry the solvent, the product was purified by n-heptane / ethyl acetate column chromatography with a yield of 53%.

[0021] M+H molecular ion peak 277.1;

[0022] 1 H NMR (400MHz, CDCl 3 ) δ 8.77 (1H, d), 6.58 (1H, s), 4.75-4.90 (1H, m),3.18 (3H, s), 3.13 (3H, s), 2.30-2.45 (2H, m), 1.95- 2.15 (4H, m), 1.60-1.75 (2H, m).

Embodiment 2

[0024]

[0025] 600 mg of compound 5 was dissolved in 3 mL of toluene solution. At 0~10°C, add 2mL of 1mol / L LiHMDS solution in tetrahydrofuran, and stir for 1h. At 0-10°C, 292 mg of compound 2 in toluene was added, and slowly returned to room temperature for 5 h. After the reaction was monitored by HPLC, 6mL of saturated ammonium chloride was used to quench the reaction, the liquid was separated to obtain the organic phase, dried with anhydrous sodium sulfate, the filtrate was collected by filtration and spin-dried to dry the solvent, and then purified by n-heptane / ethyl acetate column chromatography to obtain Off-white solid, yield 54%.

[0026] M+H molecular ion peak 535.3;

[0027] 1 H NMR (400MHz, CDCl 3 ) δ 8.70 (1H, s), 8.37 (1H, d), 8.02 (1H, d), 7.99(1H, s), 7.33 (1H, dd), 6.44 (1H, s), 4.72-4.85 (1H, ( 2H, m), 1.49 (9H, s).

Embodiment 3

[0029]

[0030] 900 mg of compound 5 was dissolved in 10 mL of toluene solution. At 0~10°C, add 4mL of 1mol / L LiHMDS solution in tetrahydrofuran, and stir for 1h. At 0-10°C, 450 mg of compound 1 in toluene was added, and slowly returned to room temperature for 2.5 h. After the reaction was monitored by HPLC, 9 mL of saturated ammonium chloride was used to quench the reaction, the liquid was separated to obtain an organic phase, and dried using anhydrous sodium sulfate. The filtrate was collected by filtration and spin-dried to dry the solvent, and purified by n-heptane / ethyl acetate column chromatography. A off-white solid was obtained with a yield of 86%.

[0031] M+H molecular ion peak 535.3;

[0032] 1 H NMR (400MHz, CDCl 3 ) δ 8.70 (1H, s), 8.37 (1H, d), 8.02 (1H, d), 7.99(1H, s), 7.33 (1H, dd), 6.44 (1H, s), 4.72-4.85 (1H, ( 2H, m), 1.49 (9H, s).

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Abstract

The invention discloses a compound and application thereof in synthesis of ribociclib, and relates to a preparation method and application of a pharmaceutical ribociclib intermediate compound I (6- fluoro - 5,7 - diazindole derivative). The F-substituted compound I avoids the use of a noble metal catalyst in the production process of synthesizing the ribociclib, so that the operation of removing heavy metal residues in the experiment operation is reduced, compared with the substitution reaction of A chlorine element, the method disclosed by the invention is more thorough, efficient and mild, has an important value for the production and purification and quality control of a medicine.

Description

technical field [0001] The invention relates to a preparation method and application of a pharmaceutical intermediate 6-fluoro-5,7-diazaindole derivative. Background technique [0002] Ribocoxib was approved by the FDA on March 13, 2017, and was developed by Novartis Pharmaceuticals. It is a cyclin-dependent kinase 4 / 6 (CDK4 / CDK6) inhibitor indicated for the treatment of postmenopausal women with androgen receptor (HR) positive, human epidermal growth factor receptor 2 (HER-2) negative advanced or metastatic breast cancer. [0003] Synthetic methods published by Novartis can be found in patents CN102186856 and CN103201275. The existing process route is prepared by Pd-catalyzed coupling reaction, which uses more noble metal catalysts. The coupling reaction is only two steps away from the final drug active molecule to form a chemical reaction, which has high requirements for the elimination of heavy metal residues. [0004] . Contents of the invention [0005] Since th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04Y02P20/55
Inventor 李丕旭王鹏魏强
Owner SUZHOU PENGXU PHARM TECH CO LTD
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