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Synthesis of substituted 1h-pyrazolo[3,4-d]pyrimidines

A compound, unsubstituted technology, applied in the field of synthesis of substituted 1H-pyrazolo[3,4-d]pyrimidine compounds, can solve the problems of chiral piperidinylhydrazine derivatives such as expensive chiral chromatography steps

Inactive Publication Date: 2017-05-31
SANDOZ LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the preparation of chiral piperidinylhydrazine derivatives requires an expensive chiral chromatography step
Furthermore, the final step has the same disadvantages as described in WO 2008 / 039218

Method used

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  • Synthesis of substituted 1h-pyrazolo[3,4-d]pyrimidines
  • Synthesis of substituted 1h-pyrazolo[3,4-d]pyrimidines
  • Synthesis of substituted 1h-pyrazolo[3,4-d]pyrimidines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] Example 1: Synthesis of 4,6-dichloropyrimidine-5-formyl chloride

[0128]

[0129] In a three-necked round bottom flask with nitrogen inlet, 4,6-dichloropyrimidine-5-carboxylic acid (3.80 g, 1 eq.) was dissolved in diethyl ether (Et 2 (0) (60 mL), followed by the addition of dimethylformamide (DMF) (0.030 mL). After adding oxalyl chloride (2.03 mL, 1.2 eq.), the mixture was stirred at room temperature for 30 minutes. During this period, the escape of gas gradually ceased. The solvent was evaporated under reduced pressure to give the crude product, which was pure enough for the next step.

Embodiment 2

[0130] Embodiment 2: Synthesis of (4,6-dichloropyrimidin-5-yl) (4-phenoxyphenyl) ketone

[0131]

[0132] In a three-necked round bottom flask with nitrogen inlet, the acid chloride prepared in Example 1 was dissolved in CH 2 Cl 2 (220mL). Add AlCl 3 (7.25g, 2.5eq.) and diphenyl ether (8.97mL, 2.6eq.), a pale yellow suspension was obtained. The reaction mixture was stirred overnight at 50 °C, then poured into 400 mL of ice water. The phases were separated and the aqueous layer was washed with CH 2 Cl 2 (1x) extraction. The combined organic layers were washed with H 2 Washed with O (2x), saturated NaCl solution (2x), dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography (cyclohexane / ethyl acetate 25:1) to give the product as a colorless crystalline solid. pass 1 The product was identified by H NMR and the following peaks were obtained:

[0133] 1 H NMR (500MHz, d 6 -DMSO)=9.14(s,1H),8.01(d,J=8.85Hz,...

Embodiment 3

[0134] Example 3: Synthesis of (4-amino-6-chloropyrimidin-5-yl) (4-phenoxyphenyl)-methanone

[0135]

[0136] In a Schlenk type flask, the ketone prepared in Example 2 (1.0 g, 1 eq.) was dissolved in toluene (70 mL). The reaction vessel was evacuated, backfilled three times with nitrogen, then finally evacuated and filled with NH 3 (airbag) refill. The reaction mixture was vigorously stirred overnight at 60 °C. Then, the solvent was evaporated under reduced pressure to give the product as an almost colorless crystalline solid. pass 1 The product was identified by H NMR and the following peaks were obtained:

[0137] 1 H NMR (500MHz, C 6 D. 6 )=8.10(s,1H),7.37(d,J=8.85Hz,2H),6.82(t,J=7.93Hz,2H),6.68(t,J=7.43Hz,1H),6.64–6.61(m , 2H), 6.50 (d, J=8.85Hz, 2H), 4.65 (br s, 2H).

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Abstract

The present invention refers to the synthesis and intermediates of substituted bicyclic compounds by using a central 1H- pyrazolo[3,4-d]pyrimidine of formula (I), which is assembled starting from 4,6-dichloropyrimidine carboxylic acid. The invention in particular refers to the synthesis of the Bruton's tyrosine kinase (Btk) inhibitor 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-l-yl)prop-2-en-l-one(ibrutinib) and its synthesis intermediates.

Description

technical field [0001] The present invention relates to the synthesis of substituted bicyclic compounds and intermediates by using a central 1H-pyrazolo[3,4-i]pyrimidine prepared starting from 2,6-dichloropyrimidinecarboxylic acid. In particular, the present invention relates to the synthesis of Bruton's tyrosine kinase (Btk) inhibitor 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 -d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one (ibrutinib) and its synthetic intermediates. Background technique [0002] Inhibitors of kinases involved in mediating or maintaining disease states represent new therapies for various diseases such as hyperproliferative diseases and cancer. Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. Btk plays an important role in the B cell signaling pathway, which can connect the cell surfa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94C07D487/04C07D239/86
CPCC07D239/86C07D239/94C07D487/04
Inventor C·罗斯H·希尔伯格E·施赖纳W·费尔曼N·马拉斯
Owner SANDOZ LTD
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