WO2015012110A1 - Method for manufacturing c-glycoside derivative - Google Patents

Method for manufacturing c-glycoside derivative Download PDF

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WO2015012110A1
WO2015012110A1 PCT/JP2014/068386 JP2014068386W WO2015012110A1 WO 2015012110 A1 WO2015012110 A1 WO 2015012110A1 JP 2014068386 W JP2014068386 W JP 2014068386W WO 2015012110 A1 WO2015012110 A1 WO 2015012110A1
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formula
compound
magnesium
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冨山 泰
昌幸 横田
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壽製薬株式会社
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02Acyclic radicals, not substituted by cyclic structures
    • C07H15/04Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00Processes 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.

Abstract

 The purpose of the present invention is to provide a technique for manufacturing a C-glycoside derivative with high efficiency and in commercially advantageous conditions. A C-glycoside derivatives can be manufactured in a short period of time and at high yield while avoiding ultra-low temperature reaction by using a coupling reaction in which aryl magnesate is used.

Description

C-グリコシド誘導体の製造方法Method for producing C-glycoside derivative
 本発明は、C-グリコシド誘導体の製造方法に関する。特に本発明は、Naグルコース共輸送体阻害剤、特に、インスリン依存性糖尿病(1型糖尿病)、インスリン非依存性糖尿病(2型糖尿病)等の糖尿病の他、インスリン抵抗性疾患及び肥満を含む各種糖尿病関連疾患の治療並びにこれらの予防に有用なC-グリコシド誘導体の高効率的かつ低コスト工業的製造方法に関する。 The present invention relates to a method for producing a C-glycoside derivative. In particular, 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.
 下式で示されるC-グリコシド誘導体及びその塩は、インスリン依存性糖尿病(1型糖尿病)、インスリン非依存性糖尿病(2型糖尿病)等の糖尿病の他、インスリン抵抗性疾患及び肥満を含む各種糖尿病関連疾患の治療並びにこれらの予防に有用であることが知られている(特許文献1:国際公開第2004/080990号パンフレット)。 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).
Figure JPOXMLDOC01-appb-C000008
 また、式(IV)に示されるC-グリコシド誘導体の製造方法として、以下の方法が報告されている(特許文献2:国際公開第2008/075736号パンフレット)。
Figure JPOXMLDOC01-appb-C000008
Further, the following method has been reported as a method for producing a C-glycoside derivative represented by the formula (IV) (Patent Document 2: International Publication No. 2008/075736 pamphlet).
Figure JPOXMLDOC01-appb-C000009
[式中、TMSはトリメチルシリル基、Meはメチル基、Acはアセチル基を示す]
Figure JPOXMLDOC01-appb-C000009
[Wherein, TMS represents a trimethylsilyl group, Me represents a methyl group, and Ac represents an acetyl group]
国際公開第2004/080990号パンフレットInternational Publication No. 2004/080990 Pamphlet 国際公開第2008/075736号パンフレットInternational Publication No. 2008/075736 Pamphlet
 特許文献2では、上記方法により、化合物(VI)が化合物(I)から通算収率74.7%で製造されている。しかし、化合物(I)とn-ブチルリチウムとの反応による有機リチウム試薬の調製には約-40℃、さらにその有機リチウム試薬と化合物(II)とのカップリング反応には約-70℃の超低温反応条件を必要とする。さらに、このカップリング反応は、6時間以上と長い反応時間も必要とする。 In Patent Document 2, compound (VI) is produced from compound (I) with a total yield of 74.7% by the above method. However, 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. Furthermore, this coupling reaction requires a reaction time as long as 6 hours or longer.
 超低温反応条件を達成するには特殊な冷却設備が必要となり、低温を維持するために大量の液体窒素を使用する。従って、式(IV)に示されるC-グリコシド誘導体を医薬品として製造する上で、この冷却に関わるコストが問題となる。 ∙ Special cooling equipment is required to achieve ultra-low temperature reaction conditions, and a large amount of liquid nitrogen is used to maintain a low temperature. Therefore, when the C-glycoside derivative represented by the formula (IV) is produced as a pharmaceutical, the cost related to this cooling becomes a problem.
 このような状況に鑑み、本発明は、超低温反応条件を回避し、工業的に有利な式(IV)に示されるC-グリコシド誘導体の製造方法を提供することを目的とする。 In view of such circumstances, 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.
 本発明者は、上記課題を解決するために鋭意検討を行った結果、マグネシウムアート錯体と化合物(I)との反応により調製したアリールマグネサートと化合物(II)のカップリング反応を利用することによって、超低温を必要とせず、短い反応時間で式(IV)に示されるC-グリコシド誘導体の製造中間体(III)を高収率で製造できることを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, 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.
 すなわち、これに限定されるものでないが、本発明は以下の態様を包含する。 That is, although not limited thereto, the present invention includes the following aspects.
(1) 式(I):
Figure JPOXMLDOC01-appb-C000010
で示される化合物とマグネシウムアート錯体との臭素・マグネシウム交換反応によってマグネサートを得ること;
 得られたマグネサートを、式(II):
(1) Formula (I):
Figure JPOXMLDOC01-appb-C000010
Obtaining magnesate by bromine-magnesium exchange reaction between the compound represented by formula and magnesium ate complex;
The obtained magnesert is represented by the formula (II):
Figure JPOXMLDOC01-appb-C000011
[式中、TMSはトリメチルシリル基を示す]
 で示される化合物と反応させて、更にH+/MeOHで処理し脱TMS化とメトキシ化を行うことで、式(III):
Figure JPOXMLDOC01-appb-C000011
[Wherein TMS represents a trimethylsilyl group]
By reacting with a compound represented by formula (III):
Figure JPOXMLDOC01-appb-C000012
[式中、Meはメチル基を示す]
で示される化合物を得ること、を含む、式(III)の化合物の製造方法。
(2) 前記マグネシウムアート錯体が、リチウムトリ(n-ブチル)マグネサートである、(1)に記載の方法。
(3) 式(I):
Figure JPOXMLDOC01-appb-C000012
[Wherein Me represents a methyl group]
Obtaining a compound of formula (III).
(2) The method according to (1), wherein the magnesium ate complex is lithium tri (n-butyl) magnesate.
(3) Formula (I):
Figure JPOXMLDOC01-appb-C000013
で示される化合物とマグネシウムアート錯体との臭素・マグネシウム交換反応によってマグネサートを得ること;
 得られたマグネサートを、式(II):
Figure JPOXMLDOC01-appb-C000013
Obtaining magnesate by bromine-magnesium exchange reaction between the compound represented by formula and magnesium ate complex;
The obtained magnesert is represented by the formula (II):
Figure JPOXMLDOC01-appb-C000014
[式中、TMSはトリメチルシリル基を示す]
 で示される化合物と反応させて、更にH+/MeOHで処理し脱TMS化とメトキシ化を行うことで、式(III):
Figure JPOXMLDOC01-appb-C000014
[Wherein TMS represents a trimethylsilyl group]
By reacting with a compound represented by formula (III):
Figure JPOXMLDOC01-appb-C000015
[式中、Meはメチル基を示す]
で示される化合物を得ること;
 式(III)の化合物から-OMe基を脱離させること;
を含む、式(IV):
Figure JPOXMLDOC01-appb-C000015
[Wherein Me represents a methyl group]
To obtain a compound represented by:
Removing the -OMe group from the compound of formula (III);
Including formula (IV):
Figure JPOXMLDOC01-appb-C000016
の化合物の製造方法。
Figure JPOXMLDOC01-appb-C000016
A method for producing the compound.
 本発明によれば、式(IV)に示されるC-グリコシド誘導体を工業的に有利な条件で製造することができる。本発明によれば、超低温反応を回避しながらも短時間かつ高収率で、式(IV)のC-グリコシド誘導体を製造することができるため、工業的に極めて有利である。 According to the present invention, 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.
 本発明においては、式(I):
Figure JPOXMLDOC01-appb-C000017
で示される化合物とマグネシウムアート錯体との臭素・マグネシウム交換反応によってマグネサートを得る。
In the present invention, the formula (I):
Figure JPOXMLDOC01-appb-C000017
Magnesate is obtained by bromine / magnesium exchange reaction between the compound represented by formula (II) and a magnesium ate complex.
 式(I)の化合物は当業界において公知の方法によって適宜合成することができる。例えば、上記の特許文献2(国際公開第2008/075736号パンフレット)に記載の方法によって式(I)の化合物を合成することができる。 The compound of the formula (I) can be appropriately synthesized by a method known in the art. For example, the compound of the formula (I) can be synthesized by the method described in Patent Document 2 (International Publication No. 2008/075736 pamphlet).
 本発明においてマグネシウムアート錯体は、例えば、有機マグネシウム試薬と有機リチウム試薬を有機溶媒中で混合することによって調製することができる。好ましい態様において、有機マグネシウム試薬と有機リチウム試薬を混合する際のモル比は1:2である。マグネシウムアート錯体としては、リチウムトリ(n-ブチル)マグネサートが特に好ましい。 In the present invention, the magnesium ate complex can be prepared, for example, by mixing an organic magnesium reagent and an organic lithium reagent in an organic solvent. In a preferred embodiment, the molar ratio when mixing the organomagnesium reagent and the organolithium reagent is 1: 2. As the magnesium ate complex, lithium tri (n-butyl) magnesate is particularly preferable.
 有機マグネシウム試薬としては、例えば、メチルマグネシウムクロリド、メチルマグネシウムブロミド、メチルマグネシウムヨージド、エチルマグネシウムクロリド、エチルマグネシウムブロミド、エチルマグネシウムヨージド、n-プロピルマグネシウムクロリド、n-プロピルマグネシウムブロミド、n-プロピルマグネシウムヨージド、イソプロピルマグネシウムクロリド、イソプロピルマグネシウムブロミド、イソプロピルマグネシウムヨージド、n-ブチルマグネシウムクロリド、n-ブチルマグネシウムブロミド、n-ブチルマグネシウムヨージド、n-ペンチルマグネシウムクロリド、n-ペンチルマグネシウムブロミド、n-ペンチルマグネシウムヨージドなどを使用でき、好ましくはn-ブチルマグネシウムブロミドを使用することができる。これらの有機マグネシウムは、例えば、ジエチルエーテルやテトラヒドロフランの溶液として使用することができ、好ましくはテトラヒドロフランの溶液として使用することができる。 Examples of the organic magnesium reagent 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. These organomagnesiums can be used, for example, as a solution of diethyl ether or tetrahydrofuran, preferably as a solution of tetrahydrofuran.
 有機リチウム試薬としては、例えば、メチルリチウム、イソプロピルリチウム、n-ブチルリチウム、sec-ブチルリチウム、tert-ブチルリチウム、n-へキシルリチウムなどを使用でき、好ましくはn-ブチルリチウムを使用することができる。有機リチウムは、例えば、ジエチルエーテル、n-ペンタン、n-ヘキサンまたはシクロヘキサンの溶液として使用することができ、好ましくはn-ヘキサンの溶液として使用することができる。 As the 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.
 本発明においては、式(I)の化合物とマグネシウムアート錯体とを反応させるが、マグネシウムアート錯体は、化合物(I)に対して0.33~2当量使用することが好ましく、最も好ましくは1.0~1.1当量使用することができる。式(I)の化合物とマグネシウムアート錯体との反応は、例えば、-40℃~室温で行うことができ、-20~0℃の範囲で行うことが好ましい。 In the present invention, 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.
 式(I)の化合物とマグネシウムアート錯体の反応における反応溶媒としては、例えば、ジエチルエーテル、イソプロピルエーテル、tert-ブチルメチルエーテル、シクロペンチルメチルエーテル、テトラヒドロフラン、1,4-ジオキサン、ベンゼン、トルエン、n-ペンタン、n-ヘキサン、シクロヘキサン、n-へプタン等を単一あるいは混合して使用することができ、好ましくは、ジエチルエーテル、テトラヒドロフランあるいはトルエンを使用することができる。 Examples of the reaction solvent in the reaction of the compound of formula (I) and the magnesium ate complex 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.
 上述したように、本発明では、アリールマグネサートを調製し、そのアリールマグネサートを式(II)の化合物と反応させる。ここで、アリールマグネサートの調製については、例えば、Inoue, A. et al.、J. Org. Chem.、2001, 66, 4333(参考文献1)などを参考にすることができる。参考文献1では、テトラヒドロフラン溶媒で、0℃にて、n-ブチルマグネシウムブロミドとn-ブチルリチウムから調製されるトリブチルマグネシウムリチウムで、4‐ブロモアニソールを処理しアリールマグネサートを調製した後、-78℃に冷却してベンズアルデヒドと反応させ、ジフェニルメタノール化合物を得ている。また、Iida, T. et al.、Tetrahedron Lett.、2001, 42, 4841(参考文献2)には、トルエン溶媒で、-10~0℃にてn-ブチルマグネシウムクロリドとn-ブチルリチウムから調製されるトリブチルマグネシウムリチウムで、2,6-ジブロモピリジンを処理しアリールマグネサートを調製した後、DMFと反応させ2-ブロモ-6-ホルミルピリジンを得ることが記載されており、これら文献の内容を参考にして本発明を実施することができる。 As described above, in the present invention, an aryl magnesate is prepared and the aryl magnesate is reacted with a compound of the formula (II). Here, for the preparation of arylmagnesate, for example, Inoue, A. et al., J. Org. Chem., 2001, 66, 4333 (reference document 1) can be referred to. In Reference Document 1, 4-bromoanisole was treated with tributylmagnesium lithium prepared from n-butylmagnesium bromide and n-butyllithium in a tetrahydrofuran solvent at 0 ° C. to prepare an arylmagnesate, and then −78 The diphenylmethanol compound is obtained by cooling to ℃ and reacting with benzaldehyde. Iida, idaT. Et al., Tetrahedron ettLett., 2001, 42, 4841 (reference 2) prepared with n-butylmagnesium chloride and n-butyllithium in toluene solvent at -10 ~ 0 ℃. 2,6-dibromopyridine is treated with tributylmagnesium lithium to prepare arylmagnesate, which is then reacted with DMF to give 2-bromo-6-formylpyridine. The present invention can be implemented with reference.
 本発明においては、式(I)の化合物とマグネシウムアート錯体の反応によって得られたマグネサートを、式(II): In the present invention, magnesate obtained by the reaction of a compound of formula (I) and a magnesium ate complex is represented by formula (II):
Figure JPOXMLDOC01-appb-C000018
[式中、TMSはトリメチルシリル基を示す]
 で示される化合物と反応させて、更にH+/MeOHで処理し脱TMS化とメトキシ化を行うことで、式(III):
Figure JPOXMLDOC01-appb-C000018
[Wherein TMS represents a trimethylsilyl group]
By reacting with a compound represented by formula (III):
Figure JPOXMLDOC01-appb-C000019
[式中、Meはメチル基を示す]
で示される化合物を得る。マグネサートと化合物(II)との反応は、例えば、-40℃~室温で行うことができ、-20~0℃の範囲で行うことが好ましい。反応溶媒としては、例えば、ジエチルエーテル、イソプロピルエーテル、tert-ブチルメチルエーテル、シクロペンチルメチルエーテル、テトラヒドロフラン、1,4-ジオキサン、ベンゼン、トルエン、n-ペンタン、n-ヘキサン、シクロヘキサン、n-へプタン等を単一あるいは混合して使用することができ、好ましくは、ジエチルエーテル、テトラヒドロフランあるいはトルエンを使用することができる。
Figure JPOXMLDOC01-appb-C000019
[Wherein Me represents a methyl group]
To obtain a compound represented by The 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. Examples of 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. Can be used singly or in combination, and preferably diethyl ether, tetrahydrofuran or toluene can be used.
 続くメタノール存在下、酸で処理する反応では、酸として塩化水素、硫酸、酢酸、トリフルオロ酢酸、メタンスルホン酸等が挙げられ、好ましくは、塩化水素、メタンスルホン酸が用いられる。また反応は、例えば-5~5℃で行うことができる。 In the subsequent reaction with acid in the presence of methanol, 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.
 本発明によれば上記のようにして式(III)の化合物を得ることができるが、好ましい態様において、式(III)の化合物から-OMe基を脱離させることによって、式(IV): According to the present invention, 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):
Figure JPOXMLDOC01-appb-C000020
の化合物を製造することができる。まず、化合物(III)のアセチル化は、アセチル化剤を用い、適当な溶媒中、適当な塩基存在下で行われる。反応溶媒としては、例えば、アセトン、ベンゼン、トルエン、酢酸エチル、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、テトラヒドロフラン、塩化メチレン、クロロホルム、ピリジン、水等を単一あるいは混合して使用することができ、好ましくは、トルエンを使用することができる。塩基としては、例えば、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、ナトリウムメトキシド、tert-ブトキシカリウム、水素化ナトリウム、トリエチルアミン、N,N-ジイソプロピルエチルアミン、ピリジン等が挙げられ、好ましくは、ピリジンが用いられる。アセチル化剤としては、無水酢酸や塩化アセチルなどが挙げられ、好ましくは、無水酢酸が用いられる。反応条件は、例えばトルエン溶媒で、過剰量の、例えば6当量のピリジン存在下、過剰量の、例えば、5当量の無水酢酸を用いて、冷却~室温で行うことができる。また、反応を加速するために、触媒量の4-ジメチルアミノピリジンを加えることもできる。続く脱メトキシ化(還元反応)は、適当な還元剤及び酸の存在下、適当な溶媒中で行われる。還元剤としては、トリエチルシラン、トリイソプロピルシラン、tert-ブチルジメチルシラン、水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム等が挙げられ、好ましくは、tert-ブチルジメチルシランが用いられる。酸としては、三フッ化ホウ素ジエチルエーテル錯体、酢酸、トリフルオロ酢酸、トリフルオロメタンスルホン酸等が挙げられ、好ましくは、トリフルオロメタンスルホン酸が用いられる。溶媒としては、塩化メチレン、1,4-ジオキサン、アセトニトリル等が挙げられ、好ましくは、アセトニトリルが用いられる。反応条件は、例えばアセトニトリル溶媒で、例えば1~2当量のtert-ブチルジメチルシランと、例えば2当量のトリフルオロメタンスルホン酸存在下、例えば-5~5℃で行うことができる。更に、脱アセチル化は、適当な塩基存在下、適当な溶媒中で行われる。塩基としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、ナトリウムメトキシド等が挙げられ、好ましくは、水酸化ナトリウムが用いられる。溶媒としては、メタノール、エタノール、トルエン、テトラヒドロフラン、水等を単一あるいは混合して使用することができ、好ましくは、メタノールと水の混合物が用いられる。反応条件は、例えばメタノールと水の混合溶媒中、例えば5当量の水酸化ナトリウム存在下、冷却~還流で、例えば40~50℃で行うことができる。
Figure JPOXMLDOC01-appb-C000020
Can be produced. First, acetylation of compound (III) is carried out using an acetylating agent in a suitable solvent in the presence of a suitable base. As the reaction 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. Preferably, 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. Examples of the reducing agent include triethylsilane, triisopropylsilane, tert-butyldimethylsilane, sodium borohydride, sodium triacetoxyborohydride, and preferably tert-butyldimethylsilane is used. Examples of the acid include boron trifluoride diethyl ether complex, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and the like. Preferably, trifluoromethanesulfonic acid is used. Examples of 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. Furthermore, deacetylation is performed in a suitable solvent in the presence of a suitable base. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide and the like. Preferably, sodium hydroxide is used. As 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.
 下記の実施例を参照しつつ本発明をより詳しく説明するが、これらの例は単なる実例であって本発明を限定するものではなく、また本発明の範囲で変化させてもよい。 The present invention will be described in more detail with reference to the following examples, but these examples are merely illustrative and do not limit the present invention, and may be changed within the scope of the present invention.
 なお、プロトン核磁気共鳴スペクトル(1H-NMR)データの記載には次の略号を用いた。すなわち、sはシングレット、dはダブレット、tはトリプレット、qはカルテット、mはマルチプレット、bはブロードである。 The following abbreviations were used for the description of proton nuclear magnetic resonance spectrum ( 1 H-NMR) data. That is, s is a singlet, d is a doublet, t is a triplet, q is a quartet, m is a multiplet, and b is broad.
 メチル1-C-[3-(1-ベンゾチオフェン-2-イルメチル)-4-フルオロフェニル]-α-グルコピラノシドの合成
 トルエン(18.0 mL)に-16℃で0.9M n-ブチルマグネシウムクロリドのテトラヒドロフラン溶液(0.9M、7.3mL)を加えた後、-12~-16℃でn-ブチルリチウムのn-ヘキサン溶液(2.66M、4.9mL)を滴下し、-12~-15℃で16分間攪拌した。
Synthesis of methyl 1-C- [3- (1-benzothiophen-2-ylmethyl) -4-fluorophenyl] -α-glucopyranoside Tetrahydrofuran of 0.9M n- butylmagnesium chloride in toluene (18.0 mL) at −16 ° C. After the solution (0.9 M, 7.3 mL) was added, n-butyllithium n-hexane solution (2.66 M, 4.9 mL) was added dropwise at −12 to −16 ° C., and −12 to −15 ° C. For 16 minutes.
 この反応液に-12~-15℃で2-(5-ブロモ-2-フルオロベンジル)-1-ベンゾチオフェン(化合物I、2.000 g)のトルエン溶液(10.0mL)を滴下した後、-12~-16℃で1時間攪拌した。この反応液に-12~-16℃で2,3,4,6-テトラキス-O-(トリメチルシリル)-D-グルコノ-1,5-ラクトン(化合物II、3.197 g)のトルエン溶液(10.0mL)を滴下した後、-12~-15℃で3時間攪拌した。反応混合物をメタンスルホン酸(3.0mL)のメタノール溶液(10.0mL)に0℃以下で注いだ後、室温で16時間36分間攪拌した。反応混合物に炭酸ナトリウム水溶液を加えてpHを約8とし、反応を停止させた。 To this reaction solution was added dropwise a toluene solution (10.0 mL) of 2- (5-bromo-2-fluorobenzyl) -1-benzothiophene (Compound I, 2.000 kg) at −12 to −15 ° C., and then −12 Stir at ~ -16 ° C for 1 hour. To this reaction solution was added a toluene solution (10.0 mL) of 2,3,4,6-tetrakis-O- (trimethylsilyl) -D-glucono-1,5-lactone (Compound II, 3.197 g) at −12 to −16 ° C. ) Was added dropwise, and the mixture was stirred at -12 to -15 ° C for 3 hours. The 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.
 酢酸エチル(50mLで2回)で抽出し、得られた有機層を飽和食塩水(10mLで1回)で洗浄後、無水硫酸ナトリウムで乾燥した。ろ過後、ろ液を減圧留去し、得られた残渣からシリカゲルカラムクロマトグラフィーで表題化合物(2.336 g、収率86.4%)を分離した。 Extraction with ethyl acetate (2 × 50 mL) was performed, and the obtained organic layer was washed with saturated brine (1 × 10 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure, and the title compound (2.336 g, yield 86.4%) was separated from the resulting residue by silica gel column chromatography.
 リチウムトリ(n-ブチル)マグネサートを使用した化合物(I)と化合物(II)のカップリング反応は、トルエン溶媒中において-12~-15℃で進行し、化合物(III)が高収率で得られた。つまり、本発明のカップリング反応を使用することによって、超低温の反応条件を回避することができ、短時間で化合物(III)を得ることができた。
1H-NMR (CD3OD) δ=3.07 (s, 3H), 3.29-3.34 (m, 1H), 3.42 (m, 1H), 3.56-3.58 (m, 1H), 3.71-3.83 (m, 2H), 3.93 (dd, J=2Hz, 12Hz, 1H), 4.22 (d, J=16Hz, 1H), 4.32 (d, J=16Hz, 1H), 7.04 (s, 1H), 7.09 (t, J=8Hz, 1H), 7.11-7.29 (m, 2H), 7.53-7.55 (m, 1H), 7.62-7.65 (m, 2H), 7.71 (d, J=8Hz, 1H).
                  
The coupling reaction of compound (I) and compound (II) using lithium tri (n-butyl) magnesate proceeds at −12 to −15 ° C. in a toluene solvent to obtain compound (III) in a high yield. It was. That is, by using the coupling reaction of the present invention, it was possible to avoid ultra-low temperature reaction conditions and obtain compound (III) in a short time.
1 H-NMR (CD 3 OD) δ = 3.07 (s, 3H), 3.29-3.34 (m, 1H), 3.42 (m, 1H), 3.56-3.58 (m, 1H), 3.71-3.83 (m, 2H ), 3.93 (dd, J = 2Hz, 12Hz, 1H), 4.22 (d, J = 16Hz, 1H), 4.32 (d, J = 16Hz, 1H), 7.04 (s, 1H), 7.09 (t, J = 8Hz, 1H), 7.11-7.29 (m, 2H), 7.53-7.55 (m, 1H), 7.62-7.65 (m, 2H), 7.71 (d, J = 8Hz, 1H).

Claims (3)

  1.  式(I):
    Figure JPOXMLDOC01-appb-C000001
    で示される化合物とマグネシウムアート錯体との臭素・マグネシウム交換反応によってマグネサートを得ること;
     得られたマグネサートを、式(II):
    Figure JPOXMLDOC01-appb-C000002
    [式中、TMSはトリメチルシリル基を示す]
     で示される化合物と反応させて、更にH+/MeOHで処理し脱TMS化とメトキシ化を行うことで、式(III):
    Figure JPOXMLDOC01-appb-C000003
    [式中、Meはメチル基を示す]
    で示される化合物を得ること、
    を含む、式(III)の化合物の製造方法。
    Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    Obtaining magnesate by bromine-magnesium exchange reaction between the compound represented by formula and magnesium ate complex;
    The obtained magnesert is represented by the formula (II):
    Figure JPOXMLDOC01-appb-C000002
    [Wherein TMS represents a trimethylsilyl group]
    By reacting with a compound represented by formula (III):
    Figure JPOXMLDOC01-appb-C000003
    [Wherein Me represents a methyl group]
    To obtain a compound represented by
    A process for the preparation of a compound of formula (III).
  2.  前記マグネシウムアート錯体が、リチウムトリ(n-ブチル)マグネサートである、請求項1に記載の方法。 The method according to claim 1, wherein the magnesium ate complex is lithium tri (n-butyl) magnesate.
  3.     式(I):
    Figure JPOXMLDOC01-appb-C000004
    で示される化合物とマグネシウムアート錯体との臭素・マグネシウム交換反応によってマグネサートを得ること;
     得られたマグネサートを、式(II):
    Figure JPOXMLDOC01-appb-C000005
    [式中、TMSはトリメチルシリル基を示す]
     で示される化合物と反応させて、更にH+/MeOHで処理し脱TMS化とメトキシ化を行うことで、式(III):
    Figure JPOXMLDOC01-appb-C000006
    [式中、Meはメチル基を示す]
    で示される化合物を得ること;
     式(III)の化合物から-OMe基を脱離させること;
    を含む、式(IV):
    Figure JPOXMLDOC01-appb-C000007
    の化合物の製造方法。
                      
    Formula (I):
    Figure JPOXMLDOC01-appb-C000004
    Obtaining magnesate by bromine-magnesium exchange reaction between the compound represented by formula and magnesium ate complex;
    The obtained magnesert is represented by the formula (II):
    Figure JPOXMLDOC01-appb-C000005
    [Wherein TMS represents a trimethylsilyl group]
    By reacting with a compound represented by formula (III):
    Figure JPOXMLDOC01-appb-C000006
    [Wherein Me represents a methyl group]
    To obtain a compound represented by:
    Removing the -OMe group from the compound of formula (III);
    Including formula (IV):
    Figure JPOXMLDOC01-appb-C000007
    A method for producing the compound.
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WO2020129900A1 (en) * 2018-12-17 2020-06-25 株式会社トクヤマ Method for producing c-arylhydroxy glycoxide derivative
WO2020129899A1 (en) * 2018-12-17 2020-06-25 株式会社トクヤマ Method for producing c-aryl hydroxy glycoxide derivatives
WO2022107463A1 (en) 2020-11-18 2022-05-27 株式会社トクヤマ Method for producing ketone derivative

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WO2020129899A1 (en) * 2018-12-17 2020-06-25 株式会社トクヤマ Method for producing c-aryl hydroxy glycoxide derivatives
WO2022107463A1 (en) 2020-11-18 2022-05-27 株式会社トクヤマ Method for producing ketone derivative

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