Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/02—Acyclic radicals, not substituted by cyclic structures
  • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

• the present invention relates to a method for producing a C-glycoside derivative.
• the present invention includes Na + glucose cotransporter inhibitors, in particular, insulin-resistant diseases and obesity in addition to diabetes such as insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes).
• the present invention relates to a highly efficient and low-cost industrial production method of C-glycoside derivatives useful for treatment of various diabetes-related diseases and their prevention.
• C-glycoside derivatives represented by the following formula and salts thereof are used for various diabetes including insulin-resistant diseases and obesity in addition to diabetes such as insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes). It is known to be useful for treatment of related diseases and prevention thereof (Patent Document 1: International Publication No. 2004/080990 pamphlet).
• Patent Document 2 International Publication No. 2008/075736 pamphlet.
• TMS represents a trimethylsilyl group
• Me represents a methyl group
• Ac represents an acetyl group
• compound (VI) is produced from compound (I) with a total yield of 74.7% by the above method.
• an organolithium reagent for the preparation of an organolithium reagent by the reaction of compound (I) with n-butyllithium, about ⁇ 40 ° C., and for the coupling reaction of the organolithium reagent with compound (II), an ultra-low temperature of about ⁇ 70 ° C. Requires reaction conditions.
• this coupling reaction requires a reaction time as long as 6 hours or longer.
• an object of the present invention is to provide an industrially advantageous method for producing a C-glycoside derivative represented by the formula (IV) that avoids ultra-low temperature reaction conditions.
• the present inventor has made use of a coupling reaction of an arylmagnesate prepared by a reaction between a magnesium ate complex and a compound (I) and the compound (II).
• the inventors have found that a production intermediate (III) of a C-glycoside derivative represented by the formula (IV) can be produced in a high yield in a short reaction time without requiring an ultra-low temperature, and the present invention has been completed.
• the present invention includes the following aspects.
• magnesert is represented by the formula (II):
• the C-glycoside derivative represented by the formula (IV) can be produced under industrially advantageous conditions. According to the present invention, the C-glycoside derivative of the formula (IV) can be produced in a short time and in a high yield while avoiding an ultra-low temperature reaction, which is extremely advantageous industrially.
• the compound of the formula (I) can be appropriately synthesized by a method known in the art.
• the compound of the formula (I) can be synthesized by the method described in Patent Document 2 (International Publication No. 2008/075736 pamphlet).
• the magnesium ate complex can be prepared, for example, by mixing an organic magnesium reagent and an organic lithium reagent in an organic solvent.
• the molar ratio when mixing the organomagnesium reagent and the organolithium reagent is 1: 2.
• lithium tri (n-butyl) magnesate is particularly preferable.
• organic magnesium reagent examples include methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, ethyl magnesium chloride, ethyl magnesium bromide, ethyl magnesium iodide, n-propyl magnesium chloride, n-propyl magnesium bromide, n-propyl magnesium.
• Iodide isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, n-butylmagnesium chloride, n-butylmagnesium bromide, n-butylmagnesium iodide, n-pentylmagnesium chloride, n-pentylmagnesium bromide, n-pentyl Magnesium iodide or the like can be used, and preferably n-butylmagnesium bromide can be used.
• organomagnesiums can be used, for example, as a solution of diethyl ether or tetrahydrofuran, preferably as a solution of tetrahydrofuran.
• organic lithium reagent for example, methyl lithium, isopropyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, n-hexyl lithium and the like can be used, and preferably n-butyl lithium is used. it can.
• the organolithium can be used, for example, as a solution of diethyl ether, n-pentane, n-hexane or cyclohexane, preferably as a solution of n-hexane.
• the compound of formula (I) is reacted with a magnesium ate complex.
• the magnesium ate complex is preferably used in an amount of 0.33 to 2 equivalents, most preferably 1. 0 to 1.1 equivalents can be used.
• the reaction between the compound of formula (I) and the magnesium ate complex can be carried out, for example, at ⁇ 40 ° C. to room temperature, and preferably at ⁇ 20 to 0 ° C.
• reaction solvent in the reaction of the compound of formula (I) and the magnesium ate complex examples include diethyl ether, isopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, n- Pentane, n-hexane, cyclohexane, n-heptane and the like can be used singly or in combination, and preferably diethyl ether, tetrahydrofuran or toluene can be used.
• an aryl magnesate is prepared and the aryl magnesate is reacted with a compound of the formula (II).
• arylmagnesate for example, Inoue, A. et al., J. Org. Chem., 2001, 66, 4333 (reference document 1) can be referred to.
• 4-bromoanisole was treated with tributylmagnesium lithium prepared from n-butylmagnesium bromide and n-butyllithium in a tetrahydrofuran solvent at 0 ° C.
• magnesate obtained by the reaction of a compound of formula (I) and a magnesium ate complex is represented by formula (II):
• reaction between magnesate and compound (II) can be carried out, for example, at ⁇ 40 ° C. to room temperature, and preferably at ⁇ 20 to 0 ° C.
• the reaction solvent include diethyl ether, isopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, n-pentane, n-hexane, cyclohexane, n-heptane and the like.
• examples of the acid include hydrogen chloride, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and the like, and preferably hydrogen chloride and methanesulfonic acid are used.
• the reaction can be carried out, for example, at ⁇ 5 to 5 ° C.
• the compound of the formula (III) can be obtained as described above, but in a preferred embodiment, by removing the —OMe group from the compound of the formula (III), the compound of the formula (IV):
• acetylation of compound (III) is carried out using an acetylating agent in a suitable solvent in the presence of a suitable base.
• a suitable solvent for example, acetone, benzene, toluene, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, methylene chloride, chloroform, pyridine, water, etc. are used singly or in combination.
• toluene can be used.
• Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, tert-butoxypotassium, sodium hydride, triethylamine, N, N-diisopropylethylamine, and pyridine, preferably Pyridine is used.
• Examples of the acetylating agent include acetic anhydride and acetyl chloride, and acetic anhydride is preferably used.
• the reaction conditions can be carried out, for example, in a toluene solvent, in the presence of an excess amount, for example, 6 equivalents of pyridine, with an excess amount, for example, 5 equivalents of acetic anhydride, from cooling to room temperature.
• a catalytic amount of 4-dimethylaminopyridine can also be added to accelerate the reaction.
• the subsequent demethoxylation (reduction reaction) is carried out in a suitable solvent in the presence of a suitable reducing agent and acid.
• the reducing agent include triethylsilane, triisopropylsilane, tert-butyldimethylsilane, sodium borohydride, sodium triacetoxyborohydride, and preferably tert-butyldimethylsilane is used.
• the acid include boron trifluoride diethyl ether complex, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and the like.
• trifluoromethanesulfonic acid is used.
• the solvent include methylene chloride, 1,4-dioxane, acetonitrile and the like, and preferably acetonitrile is used.
• the reaction conditions can be carried out, for example, with an acetonitrile solvent, for example, in the presence of 1 to 2 equivalents of tert-butyldimethylsilane and 2 equivalents of trifluoromethanesulfonic acid, for example at ⁇ 5 to 5 ° C.
• deacetylation is performed in a suitable solvent in the presence of a suitable base.
• the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide and the like.
• sodium hydroxide is used.
• the solvent methanol, ethanol, toluene, tetrahydrofuran, water or the like can be used singly or in combination, and preferably a mixture of methanol and water is used.
• the reaction conditions can be carried out, for example, in a mixed solvent of methanol and water, for example, in the presence of 5 equivalents of sodium hydroxide and cooled to reflux, for example, at 40 to 50 ° C.
• reaction mixture was poured into a methanol solution (10.0 mL) of methanesulfonic acid (3.0 mL) at 0 ° C. or lower and stirred at room temperature for 16 hours and 36 minutes.
• An aqueous sodium carbonate solution was added to the reaction mixture to adjust the pH to about 8, and the reaction was stopped.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Health & Medical Sciences (AREA)
• Biochemistry (AREA)
• Biotechnology (AREA)
• General Health & Medical Sciences (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Crystallography & Structural Chemistry (AREA)
• Saccharide Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=49760574

Family Applications (1)

Country Status (3)

Cited By (5)

Citations (4)

• 2013
  • 2013-07-24 JP JP2013153374A patent/JP5646706B2/ja not_active Expired - Fee Related
• 2014
  • 2014-07-10 WO PCT/JP2014/068386 patent/WO2015012110A1/ja not_active Ceased
  • 2014-07-22 TW TW103125071A patent/TW201602128A/zh unknown

Patent Citations (4)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events