Process for production of azulene derivatives and intermediates for the synthesis of the same

A technology of derivatives and compounds, applied in the field of production of azulene derivatives and intermediates for the synthesis of the azulene derivatives, can solve the problems of production, cost and environmental protection that are not completely satisfactory

Inactive Publication Date: 2007-06-20
ASTELLAS PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] As shown in Reference Examples 66, 67, 68 and 69 and Examples 74 and 75, in all the steps to obtain Compound (1) as the expected compound, a purification operation by column chromatography is necessary, which Not fully satisfactory industrially in terms of yield, cost and environmental protection

Method used

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  • Process for production of azulene derivatives and intermediates for the synthesis of the same
  • Process for production of azulene derivatives and intermediates for the synthesis of the same
  • Process for production of azulene derivatives and intermediates for the synthesis of the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0184] Synthesis of 1-[3-bromo-4-(methoxymethoxy)phenyl]acetone

[0185] To a solution of 1-(3-bromo-4-hydroxyphenyl)acetone (515.05 g, 2.25 mol) in acetone (2.58 L) was added potassium carbonate (466.61 g) and chloromethylmethyl ether (272.23 g). The mixture was stirred at -5°C to 5°C for 30 minutes. The reaction mixture was extracted by adding toluene (4.2 L) and water (4.2 L). The organic layer was washed with 0.1M aqueous sodium hydroxide solution (4.2 L), then washed twice with water (4.2 L). The solvent was distilled off under reduced pressure to obtain light yellow oily substance 1-[3-bromo-4-(methoxymethoxy)phenyl]acetone [605.25 g, yield=99%, purity=96% (HPLC )].

Embodiment 2

[0187] Synthesis of 1-[3-bromo-4-(methoxymethoxy)phenyl]acetone

[0188] To a solution of phosphorus pentoxide (1.70 g) in toluene (9 mL) was added methylal (3.04 g) and 1-(3-bromo-4-hydroxyphenyl)acetone (0.915 g, 3.99 mmol). The mixture was stirred at -5°C to 5°C for 17 hours. Water (9 mL) was added to extract the reaction mixture. The organic layer was washed twice with 10% potassium carbonate aqueous solution (9 mL), and then the solvent was distilled off under reduced pressure to obtain 1-[3-bromo-4-(methoxymethoxy)phenyl as a pale yellow oily substance ] Acetone [1.09 g, Yield = 100%, Purity = 94% (HPLC)].

Embodiment 3

[0190] Synthesis of 2-[3-bromo-4-(methoxymethoxy)benzyl]azulene

[0191] To a solution of 1-[3-bromo-4-(methoxymethoxy)phenyl]acetone (68.7 g, 251.54 mmol) in toluene (690 mL) was added pyrrolidine (41 mL). The mixture was subjected to atmospheric distillation, and 73 ml of the solvent was distilled off. Pyrrolidine (20 ml) was added, the mixture was subjected to atmospheric distillation, and 27 ml of the solvent was distilled off. The reaction mixture was cooled, and the solvent was distilled off under reduced pressure. To the obtained residue were added 2H-aryhepta[b]furan-2-one (40 g) and isopropanol (370 ml), and the mixture was refluxed with heating for 19 hours. The reaction mixture was concentrated. Toluene (690 ml) and 1M hydrochloric acid (690 ml) were added to the residue. After decanting the supernatant to remove the resulting insoluble precipitate, the aqueous layer and the organic layer were separated. Further 1M hydrochloric acid (690 mL) was added to the or...

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Abstract

A process for producing azulene derivatives useful as Na+-glucose cotransporter inhibitor easily and simply in high yield at a low cost which is industrially advantageous and excellent in environmental protection, characterized by subjecting at least one compound selected from among specific penta- and tetraacyl precursors of the azulene derivatives and salts of the precursors to reduction and deblocking to obtain a C-glycoside compound; and useful intermediates obtained in the above process.

Description

technical field [0001] The present invention relates to can be used as Na + - Process for the production of azulene derivatives of glucose cotransporter inhibitors, and intermediates for the synthesis of such azulene derivatives. More specifically, the present invention relates to a method for producing azulene derivatives, which is high in yield, simple in operation, low in cost, suitable for environmental protection and industrially advantageous, and the azulene derivatives obtained during the method can be used to synthesize such Intermediates of azulene derivatives. Background technique [0002] It is known that azulene derivatives and salts thereof represented by the following structural formula (6) have the ability to inhibit Na + - Action of glucose co-transporter, useful as a therapeutic agent for diabetes, etc. [See, WO 04 / 13118 pamphlet (hereinafter referred to as Patent Document 1)]. [0003] [Structural formula (6)] [0004] [0005] In structural formula ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/10C07H7/04C07H15/04C07C43/225C07C49/223
CPCC07C45/48C07C49/245C07C49/255C07C45/71C07H7/04C07C45/63C07H15/04C07C49/223C07C43/225
Inventor 冨山泰横田昌幸野田淳小林義典小笠原纯子林泰正稻越正俊中村博文小出德雄坂元健一郎山下阳平宫藤章生铃木贵之河野则征宫田淳司今村雅一菅根隆史
Owner ASTELLAS PHARMA INC
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