TW201400495A - C-glycoside derivatives having spiro ring - Google Patents
C-glycoside derivatives having spiro ring Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
Description
本發明係關於具有SGLT活性阻礙作用之化合物或其藥學上可容許之鹽，及含有此等做為有效成分的醫藥組成物。 The present invention relates to a compound having a SGLT activity inhibitory action or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same as an active ingredient.
藉由阻礙腎臓中之糖再吸收，而使糖***至尿中增加，使血糖值降低之新機構之藥劑的研究開發正進展中(參照非專利文獻1等)。該藥劑顯示藉著阻礙存在於腎臓之近位細尿管的鈉依存性葡萄糖協同輸送體2(sodium-dependent glucose cotransporter 2；以下，稱為SGLT2)，抑制來自原尿之糖之再吸收，使糖***至體外増加而使血糖值降低(參照非專利文獻2等)。從此種背景，阻礙人類SGLT2之化合物，藉著使尿中糖***量増加，可期待使血糖值正常化，而成為1型及2型糖尿病，或伴隨高血糖發生之各種關連疾患的有效藥劑。又，藉著糖之排出，亦可期待減少過剩能量蓄積所產生的抗肥胖效果。 In the research and development of a new drug for reducing the blood sugar level by the re-absorption of the sugar in the renal pelvis, and the increase in the blood sugar level is progressing (see Non-Patent Document 1 and the like). This agent exhibits sodium-dependent glucose cotransporter 2 (hereinafter referred to as SGLT2) which inhibits the proximal ureter which is present in the renal pelvis, thereby suppressing reabsorption of sugar from the original urine. The sugar is excreted to the outside of the body to lower the blood sugar level (see Non-Patent Document 2, etc.). From such a background, the compound which inhibits human SGLT2, by increasing the amount of glucose excretion in the urine, can be expected to normalize the blood sugar level, and is an effective agent for type 1 and type 2 diabetes, or various related diseases accompanied by hyperglycemia. Moreover, by the discharge of sugar, it is also expected to reduce the anti-obesity effect caused by the accumulation of excess energy.
另一方面，為SGLT之另一種亞型之SGLT1(葡萄糖協同輸送體1；以下，稱為SGLT1)，主要於小腸表現，可發揮使糖從食物(葡萄糖、半乳糖等)吸 收至體內之輸送體之作用(參照非專利文獻3等)。已知在SGLT1先天缺損之人類中發生糖吸收不良(參照非專利文獻4等)。從此種認知研判阻礙SGLT1之藥劑藉著阻礙、延遲糖從小腸之吸收，展現食後血糖抑制作用及抗肥胖效果。再者，雖然食後之過渡性糖流入會促進胰島素分泌，然而藉由改善糖流入，可期待改善高胰島素血症。 On the other hand, SGLT1 (glucose synergistic transporter 1; hereinafter referred to as SGLT1), which is another subtype of SGLT, is mainly expressed in the small intestine and can be used to suck sugar from food (glucose, galactose, etc.). The action of the transport body in the body (see Non-Patent Document 3, etc.). It is known that sugar absorption is caused in humans whose SGLT1 is congenitally deficient (see Non-Patent Document 4, etc.). From this cognitive study, the drug that hinders SGLT1 exhibits postprandial blood glucose inhibition and anti-obesity effects by hindering and delaying the absorption of sugar from the small intestine. Furthermore, although the transitional sugar inflow after eating promotes insulin secretion, it is expected to improve hyperinsulinemia by improving the inflow of sugar.
另一方面，藉由阻礙SGLT1，可促進糖流入消化道下部以及促進GLP-1或PYY等消化道激素的分泌。其結果，可期待抗肥胖作用、胰臟保護作用、抗糖尿病作用或脂肪肝改善作用等。 On the other hand, by blocking SGLT1, it is possible to promote the inflow of sugar into the lower part of the digestive tract and promote the secretion of digestive tract hormones such as GLP-1 or PYY. As a result, anti-obesity action, pancreatic protection effect, anti-diabetic action, or fatty liver improvement action can be expected.
另一方面，藉由阻礙SGLT1，可促進糖流入消化道下部以及促進GLP-1或PYY等消化道激素的分泌。其結果，可期待抗肥胖作用、胰臟保護作用、抗糖尿病作用或脂肪肝改善作用等。 On the other hand, by blocking SGLT1, it is possible to promote the inflow of sugar into the lower part of the digestive tract and promote the secretion of digestive tract hormones such as GLP-1 or PYY. As a result, anti-obesity action, pancreatic protection effect, anti-diabetic action, or fatty liver improvement action can be expected.
從以上，抑制人類SGLT1及/或SGLT2活性之藥劑兼具増加尿中糖***之作用及阻礙糖從小腸吸收之作用，可期待此種藥劑成為伴隨1型及2型糖尿病、肥胖、高血糖發生之各種關連疾患、高胰島素血症、脂肪肝等之有效藥劑。就此種藥劑之例子而言，可列舉專利文獻1~7、非專利文獻5等所揭示之化合物。 From the above, the agent which inhibits the activity of human SGLT1 and/or SGLT2 has both the action of excreting sugar in the urine and the effect of inhibiting the absorption of sugar from the small intestine, and it is expected that such a drug will become associated with type 1 and type 2 diabetes, obesity, and hyperglycemia. It is an effective agent for various related diseases, hyperinsulinemia, fatty liver and the like. Examples of such a drug include compounds disclosed in Patent Documents 1 to 7, Non-Patent Document 5, and the like.
專利文獻1 WO2006/011502 Patent Document 1 WO2006/011502
專利文獻2 WO2006/080421 Patent Document 2 WO2006/080421
專利文獻3 WO2008/013277 Patent Document 3 WO2008/013277
專利文獻4 WO2007/140191 Patent Document 4 WO2007/140191
專利文獻5 WO2008/083200 Patent Document 5 WO2008/083200
專利文獻6 WO2008/016132 Patent Document 6 WO2008/016132
專利文獻7 WO2009/096503 Patent Document 7 WO2009/096503
非專利文獻1 J. Clin. Invest., Vol.79, pp. 1510-1515(1987) Non-Patent Document 1 J. Clin. Invest., Vol. 79, pp. 1510-1515 (1987)
非專利文獻2 J. Clin. Invest., Vol.93, pp. 397-404(1994) Non-Patent Document 2 J. Clin. Invest., Vol. 93, pp. 397-404 (1994)
非專利文獻3 Am J Clin Nutr. Vol.59(3 Suppl) pp.690S-698S(1994) Non-Patent Document 3 Am J Clin Nutr. Vol. 59 (3 Suppl) pp. 690S-698S (1994)
非專利文獻4 Nature, Vol.350, pp.354-356(1991) Non-Patent Document 4 Nature, Vol. 350, pp. 354-356 (1991)
非專利文獻5 Bioorg. Med. Chem. Lett. 19 (2009) 6877-6881 Non-Patent Document 5 Bioorg. Med. Chem. Lett. 19 (2009) 6877-6881
上述文獻中任一者均未記載或暗示本發明之化合物的具體構造。 The specific structure of the compound of the present invention is not described or suggested in any of the above documents.
因此，本發明之目的為提供具有新穎構造，副作用低，具有優良人類SGLT1及/或SGLT2阻礙活性之化合物或其藥學上可容許之鹽、以及以此等做為有效 成分，用於治療及/或預防1型糖尿病、2型糖尿病、妊娠糖尿病、或其他原因所造成之高血糖症、耐糖能力不良(impaired glucose tolerance：IGT)、糖尿病關連疾病(肥胖、高脂血症、高膽固醇血症、脂質代謝異常、高血壓症、脂肪肝、代謝症候群、水腫、心臟衰竭、狹心症、心肌梗塞、動脈硬化症、高尿酸血症、痛風等)或糖尿病合併症(網膜症、腎病、神經障礙、白內障、足壞疽、感染症、酮症等)的醫藥組成物。 Accordingly, it is an object of the present invention to provide a compound having a novel structure, low side effects, excellent human SGLT1 and/or SGLT2 inhibitory activity, or a pharmaceutically acceptable salt thereof, and the like as effective Ingredients for the treatment and/or prevention of hyperglycemia, impaired glucose tolerance (IGT), diabetes-related diseases (obesity, hyperlipemia) caused by type 1 diabetes, type 2 diabetes, gestational diabetes, or other causes Symptoms, hypercholesterolemia, abnormal lipid metabolism, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, atherosclerosis, hyperuricemia, gout, etc.) or diabetes complications ( Medical composition of omental disease, nephropathy, neurological disorders, cataracts, foot gangrene, infection, ketosis, etc.).
本發明提供：(1)一種通式(I)所示之化合物或其藥學上可容許之鹽，該通式(I)為：
(式中，R1為甲基或乙基；R2為氯原子、溴原子、C1~C3烷基或羥基C1~C3烷基；環A為選自包含以下：
之群組之1個環，該環可具有1個或2個選自取代基群α之取代基；取代基群α為鹵素原子、C1~C3烷基、C1~C3烷氧基、羥基C1~C3烷基、羥基C1~C3烷氧基或單(C1~C3烷基)胺基)；(2)如前述(1)記載之化合物或其藥學上可容許之鹽，其中環A之一價基為選自包含以下：
之群組之1個基，該基可具有1個或2個選自取代基群α之取代基；(3)如前述(1)記載之化合物或其藥學上可容許之鹽，其中環A之一價基為
依照本發明，可提供副作用低，具有優良人類SGLT1及/或SGLT2阻礙活性之化合物或其藥學上可容許之鹽，含有此等做為有效成分，而可治療及/或預防1型糖尿病、2型糖尿病、妊娠糖尿病、其他原因造成之高血糖症、IGT、糖尿病關連疾病(肥胖、高脂血症、高膽固醇血症、脂質代謝異常、高血壓症、脂肪肝、代謝症候群、水腫、心臟衰竭、狹心症、心肌梗塞、動脈硬化症、高尿酸血症、痛風等)或糖尿病合併症(網膜症、腎病、神經障礙、白內障、足壞疽、感染症、酮症等)之醫藥組成物。 According to the present invention, a compound having low side effects and excellent human SGLT1 and/or SGLT2 inhibitory activity or a pharmaceutically acceptable salt thereof can be provided, and these can be used as an active ingredient to treat and/or prevent type 1 diabetes, 2 Type 2 diabetes, gestational diabetes, other causes of hyperglycemia, IGT, diabetes related diseases (obesity, hyperlipidemia, hypercholesterolemia, abnormal lipid metabolism, hypertension, fatty liver, metabolic syndrome, edema, heart failure) , schizophrenia, myocardial infarction, atherosclerosis, hyperuricemia, gout, etc.) or a medical composition of diabetes mellitus (retinosis, kidney disease, neurological disorder, cataract, foot gangrene, infection, ketosis, etc.).
在本說明書中，「鹵素原子」意指氟原子、氯原子、溴原子或碘原子。 In the present specification, the "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
在本說明書中，「C1~C3烷基」意指甲基、乙基、丙基、異丙基或環丙基。 In the present specification, "C1 to C3 alkyl" means methyl, ethyl, propyl, isopropyl or cyclopropyl.
在本說明書中，「羥基C1~C3烷基」意指前述「C1~C3烷基」之一個氫原子被羥基置換之基。就具體例而言，可列舉：羥基甲基、羥基乙基、2-羥基乙基、羥基丙基等。 In the present specification, the "hydroxy C1 to C3 alkyl group" means a group in which one hydrogen atom of the above "C1 to C3 alkyl group" is replaced by a hydroxyl group. Specific examples thereof include a hydroxymethyl group, a hydroxyethyl group, a 2-hydroxyethyl group, and a hydroxypropyl group.
在本說明書中，「C1~C3烷氧基」意指甲氧基、乙氧基、丙氧基、異丙氧基或環丙基氧基。 In the present specification, the "C1-C3 alkoxy group" means a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group or a cyclopropyloxy group.
在本說明書中，「羥基C1~C3烷氧基」意指前述「C1~C3烷氧基」之一個氫原子被羥基置換之基。就具體例而言，可列舉：羥基甲氧基、羥基乙氧基、羥基丙氧基、羥基環丙基等。 In the present specification, the "hydroxy C1 - C3 alkoxy group" means a group in which one hydrogen atom of the above "C1 to C3 alkoxy group" is replaced by a hydroxyl group. Specific examples thereof include a hydroxymethoxy group, a hydroxyethoxy group, a hydroxypropoxy group, and a hydroxycyclopropyl group.
在本說明書中，「單或二(C1~C3烷基)胺基」意指胺基之1個或2個氫原子被前述「C1~C3烷基」置換之基。就單(C1~C3烷基)胺基而言，可列舉：甲基胺基、乙基胺基、丙基胺基、異丙基胺基等，就二(C1~C3烷基)胺基而言，可列舉：二甲基胺基、二乙基胺基、N-乙基-N-甲基胺基、二丙基胺基等。 In the present specification, the "mono or di(C1-C3 alkyl)amino group" means a group in which one or two hydrogen atoms of the amine group are replaced by the above-mentioned "C1 to C3 alkyl group". Examples of the mono(C1-C3 alkyl)amino group include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group and the like, and a di(C1-C3 alkyl)amino group. Examples thereof include a dimethylamino group, a diethylamino group, an N-ethyl-N-methylamino group, a dipropylamino group and the like.
在本說明書中，「藥學上可容許之鹽」意指藉由本發明之化合物與酸反應所形成之鹽。 In the present specification, "pharmaceutically acceptable salt" means a salt formed by reacting a compound of the present invention with an acid.
就鹽而言，可列舉：氫氟酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽等氫鹵酸鹽；硝酸鹽、過氯酸鹽、硫酸鹽、磷酸鹽等無機酸鹽；甲磺酸鹽、三氟甲磺酸鹽、乙磺酸鹽等低級烷磺酸鹽；苯磺酸鹽、對甲苯磺酸鹽等芳基磺酸鹽；乙酸鹽、蘋果酸鹽、富馬酸鹽、琥珀酸鹽、檸檬酸鹽、抗壞血酸鹽、酒石酸鹽、草酸鹽、馬來酸鹽等有機酸鹽等。 Examples of the salt include hydrohalide salts such as hydrofluoric acid salts, hydrochloride salts, hydrobromide salts, and hydroiodides; and inorganic acid salts such as nitrates, perchlorates, sulfates, and phosphates; a lower alkane sulfonate such as a methanesulfonate, a trifluoromethanesulfonate or an ethanesulfonate; an arylsulfonate such as a besylate or a p-toluenesulfonate; an acetate, a malate or a fumaric acid; Salt, succinate, citrate, ascorbate, tartrate, oxalate, maleate and other organic acid salts.
本發明之化合物有時例如藉由放置於大氣中，吸收水分而形成水合物，此種水合物亦包含於本發明之鹽中。 The compound of the present invention sometimes forms a hydrate by, for example, being placed in the atmosphere to absorb water, and such a hydrate is also included in the salt of the present invention.
本發明之化合物由於有分子內具有不對稱碳原子的情況，所以存在立體異構物。此等立體異構物、及立體異構物之混合物，全部以單一式，即通式(I)來表示。因此，本發明亦包含全部此等立體異構物、及此等立體異構物之任何比率之混合物。立體異構物之定義，如「1996 IUPAC,Pure and Applied Chemistry 68,2193-2222」所示。 Since the compound of the present invention has an asymmetric carbon atom in the molecule, a stereoisomer exists. These stereoisomers and mixtures of stereoisomers are all represented by a single formula, formula (I). Accordingly, the present invention also encompasses all such stereoisomers, and mixtures of such stereoisomers in any ratio. The definition of a stereoisomer is as shown in "1996 IUPAC, Pure and Applied Chemistry 68, 2193-2222".
本發明又可包含通式(I)所示之化合物之1個以上原子被該原子之同位素置換的化合物。同位素中存在放射性同位素及安定同位素2種，就同位素之例子而言，可列舉氫之同位素(2H及3H)、碳之同位素(11C、13C及14C)、氮之同位素(13N及15N)、氧之同位素(15O、17O及18O)、氟之同位素(18F)等。包含經同位素標識之化合物的組成物，在做為治療劑、預防劑、研究試藥、檢定試藥、診斷劑、體內圖像診斷劑等上有用。經同位素標 識之化合物及經同位素標識之化合物之任何比率的混合物亦全部包含於本發明中。經同位素標識之化合物，可依照該領域中周知之方法(例如，在後述本發明化合物之製造方法中的原料，係使用經同位素標識的原料)製造。 Further, the present invention may further comprise a compound in which one or more atoms of the compound represented by the formula (I) are substituted with an isotope of the atom. There are two kinds of radioisotopes and stable isotopes in the isotope. Examples of isotopes include hydrogen isotopes ( 2 H and 3 H), carbon isotopes ( 11 C, 13 C and 14 C), and nitrogen isotopes ( 13 N and 15 N), isotopes of oxygen ( 15 O, 17 O and 18 O), isotopes of fluorine ( 18 F), etc. A composition comprising an isotope-labeled compound is useful as a therapeutic agent, a preventive agent, a research reagent, a test reagent, a diagnostic agent, an in vivo image diagnostic agent, and the like. Mixtures of any ratios of isotopically-labeled compounds and isotopically-labeled compounds are also fully encompassed by the present invention. The isotopically-labeled compound can be produced according to a method well known in the art (for example, a raw material in the method for producing a compound of the present invention described later, using an isotope-labeled raw material).
本發明又可包含通式(I)所示之化合物的前藥(prodrug)。前藥意指通式(I)所示之化合物的衍生物，且在身體內以酵素方式或化學方式轉化為本發明化合物的化合物。 The invention may in turn comprise a prodrug of a compound of the formula (I). The prodrug means a derivative of the compound of the formula (I) and is converted to a compound of the present invention in an enzyme form or chemically in the body.
就前藥而言，可列舉分子內之胺基醯基化、烷基化或磷氧化之化合物，分子內之羥基醯基化、烷基化或磷氧化之化合物等(例如，參照Povl Krogsgaard-Larsen等，「A Textbook of Drug Design and Development」第二版，harwood academic publishers，1996年，351~385頁)。此種前藥可依照該領域中周知之方法，從通式(I)所示之化合物製造。 Examples of the prodrug include a compound in which an amino group is thiolated, alkylated or phosphorylated in a molecule, a compound in which hydroxy thiolation, alkylation or phosphorus oxidation is carried out in the molecule (for example, refer to Povl Krogsgaard- Larsen et al., "A Textbook of Drug Design and Development", second edition, harwood academic publishers, 1996, pp. 351-385). Such prodrugs can be made from the compounds of formula (I) according to methods well known in the art.
R1較佳為甲基。 R 1 is preferably a methyl group.
R2較佳為氯原子、甲基或羥基甲基。 R 2 is preferably a chlorine atom, a methyl group or a hydroxymethyl group.
環A之1價基，較佳為選自包含以下：
之群組的1個基，該基可具有1個或2個選自取代基群α之取代基；更佳為
取代基群α係以羥基丙基、羥基乙氧基、乙基或單甲基胺基為較佳。 The substituent group α is preferably a hydroxypropyl group, a hydroxyethoxy group, an ethyl group or a monomethylamino group.
本發明之化合物(I)可依照例如後述之A法製造。 The compound (I) of the present invention can be produced, for example, according to the A method described later.
A法中，各反應之目標化合物可在各反應終了後，藉由該領域中周知之方法從反應混合物中取得。例如，將反應混合物適當中和後，或於反應混合物中存在不溶物的情況，藉由過濾從反應混合物中除去不溶物後，將水及如乙酸乙酯之與水不混合之有機溶劑添加於反應混合物中，藉由將含有目標化合物的有機層分離，用水等洗淨後，以無水硫酸鈉等乾燥，然後餾去溶劑，得到目標化合物。視需要可將所得到之化合物以該領域中周知之方法，例如矽膠管柱層析，分離、精製。 In the method A, the target compound of each reaction can be obtained from the reaction mixture by a method known in the art after the end of each reaction. For example, after the reaction mixture is appropriately neutralized, or an insoluble matter is present in the reaction mixture, water and an organic solvent such as ethyl acetate which is not mixed with water are added after the insoluble matter is removed from the reaction mixture by filtration. In the reaction mixture, the organic layer containing the target compound is separated, washed with water or the like, dried over anhydrous sodium sulfate or the like, and the solvent is evaporated to give the title compound. The obtained compound can be isolated and purified by a method well known in the art, for example, a silica gel column chromatography, as needed.
再者，在A法中，於為反應基質之化合物具有胺基、羥基、羧基等阻礙目的反應之基的情況，視需要可將保護基導入此等基及除去所導入之保護基。就該保護基而言，只要為通常所使用之保護基即可，無特別限定，可列舉在T.H.Greene,P.G.Wuts,Protective Groups in Organic Synthesis,Third Edition,1999年，John Wiley & Sons,Inc.等中所記載之保護基。該保護基之導入反應及除去反應，可依照上述文獻中所記載之方法進行。 Further, in the method A, when the compound which is the reaction substrate has a group which hinders the intended reaction such as an amine group, a hydroxyl group or a carboxyl group, the protecting group may be introduced into the group and the introduced protecting group may be removed as needed. The protective group is not particularly limited as long as it is a commonly used protecting group, and is exemplified by TH Greene, PGWuts, Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. The protecting group described in the above. The introduction reaction and the removal reaction of the protective group can be carried out in accordance with the method described in the above literature.
(式中，R1、R2及環A係如前述，X1為鹵素原子或R2，R11、R12、R13、R14、R15、R16及R17分別為相同或相異之保護基)。 (wherein R 1 , R 2 and ring A are as defined above, X 1 is a halogen atom or R 2 , and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are respectively the same or a phase. Different protection base).
A1步驟係將藉由烷基鋰(正丁基鋰等)而鋰化之(2)，在惰性溶劑中附加於(1)，製造化合物(3)的步驟。 The step A1 is a step of producing a compound (3) by adding (2) to lithium (It-butyllithium or the like) and adding it to (1) in an inert solvent.
就惰性溶劑而言，可列舉：芳香族烴類、醚類等，以四氫呋喃(以下，有時稱為「THF」)、或甲苯與THF之任意比率的混合溶劑為較佳。溶劑之混合比率，以容積比計，以甲苯：THF=1：1~2：1為較佳。 The inert solvent is preferably an aromatic hydrocarbon or an ether, and a mixed solvent of tetrahydrofuran (hereinafter sometimes referred to as "THF") or a ratio of toluene to THF is preferred. The mixing ratio of the solvent is preferably from toluene:THF = 1:1 to 2:1 by volume ratio.
反應溫度雖隨原料化合物、惰性溶劑等而異，然而通常為-78℃~0℃。 The reaction temperature varies depending on the starting compound, the inert solvent, etc., but is usually -78 ° C to 0 ° C.
反應時間雖隨原料化合物、惰性溶劑、反應溫度等而異，然而通常鋰化步驟為15分鐘~2小時，後續附加反應為1小時~3小時，更佳分別為20分鐘~40分鐘、1小時~1小時半。 Although the reaction time varies depending on the starting compound, the inert solvent, the reaction temperature, etc., the lithiation step is usually 15 minutes to 2 hours, and the subsequent additional reaction is 1 hour to 3 hours, more preferably 20 minutes to 40 minutes, and 1 hour, respectively. ~1 hour and a half.
A2步驟係在惰性溶劑與醇類之混合溶劑中，於酸存在下，除去化合物(3)之R15及R16使其環化，製造化合物(4)的步驟。 The step A2 is a step of producing a compound (4) by removing R 15 and R 16 of the compound (3) in a mixed solvent of an inert solvent and an alcohol in the presence of an acid to cyclize.
就惰性溶劑而言，可列舉：烴類、醚類，較佳為THF。就醇類而言，較佳為甲醇。溶劑之混合比率，以容積比計，以惰性溶劑：醇類=約1：約1為較佳。 The inert solvent may, for example, be a hydrocarbon or an ether, preferably THF. In the case of alcohols, methanol is preferred. The mixing ratio of the solvent is preferably an inert solvent: alcohol = about 1: about 1 by volume ratio.
就酸而言，可列舉：鹽酸或硫酸，或者磺酸類等，較佳為對甲苯磺酸1水合物。 The acid may, for example, be hydrochloric acid or sulfuric acid, or a sulfonic acid or the like, and is preferably p-toluenesulfonic acid monohydrate.
反應溫度雖隨原料化合物、反應溶劑等而異，然而通常為40℃~回流溫度，較佳為約60℃。 The reaction temperature varies depending on the starting compound, the reaction solvent, etc., but is usually from 40 ° C to the reflux temperature, preferably about 60 ° C.
反應時間雖隨原料化合物、反應溶劑、反應溫度等而異，然而通常為30分鐘~6小時，較佳為2小時~3小時。 The reaction time varies depending on the starting compound, the reaction solvent, the reaction temperature, etc., but is usually 30 minutes to 6 hours, preferably 2 hours to 3 hours.
A3步驟係在惰性溶劑中，將保護基導入化合物(4)中，製造化合物(5)的步驟。 The step A3 is a step of producing a compound (5) by introducing a protective group into the compound (4) in an inert solvent.
就保護基而言，只要為通常所用之保護基即可，無特別限定，較佳為甲氧基甲基。 The protecting group is not particularly limited as long as it is a protecting group which is usually used, and is preferably a methoxymethyl group.
保護基之導入，雖隨其種類而異，然而可依照該領域中周知之方法，例如，在T.H.Greene,P.G.Wuts,Protective Groups in Organic Synthesis,Third Edition,1999年，John Wiley & Sons,Inc.中所記載之方法而進行。 The introduction of the protecting group varies depending on the type thereof, but can be carried out according to methods well known in the art, for example, in TH Greene, PGWuts, Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. The method described in the above is carried out.
A4步驟為在惰性溶劑中，過渡金屬觸媒及鹼存在下，使化合物(5)與烷基硼酸類(甲基硼酸酐等)縮合，製造化合物(6)的步驟。 Step A4 is a step of producing a compound (6) by condensing the compound (5) with an alkylboronic acid (methylboric anhydride or the like) in the presence of a transition metal catalyst and a base in an inert solvent.
就惰性溶劑而言，可列舉：芳香族烴、醚類、含水醇類等，較佳為1,4-二烷。 Examples of the inert solvent include aromatic hydrocarbons, ethers, aqueous alcohols, etc., preferably 1,4-two. alkyl.
就過渡金屬觸媒而言，可列舉：鈀錯合物等，較佳為肆(三苯膦)鈀(0)或乙酸鈀(II)。 The transition metal catalyst may, for example, be a palladium complex or the like, and is preferably ruthenium (triphenylphosphine)palladium (0) or palladium (II) acetate.
就鹼而言，可列舉：無機鹼類等，其雖隨原料化合物而異，然而較佳為碳酸鉀或碳酸鈉。 The base may, for example, be an inorganic base or the like, which varies depending on the starting compound, but is preferably potassium carbonate or sodium carbonate.
反應溫度雖隨原料化合物、反應溶劑等而異，然而通常為80℃~回流溫度，較佳為100℃~110℃。 Although the reaction temperature varies depending on the starting compound, the reaction solvent, and the like, it is usually from 80 ° C to reflux temperature, preferably from 100 ° C to 110 ° C.
反應時間雖隨原料化合物、反應溶劑、反應溫度等而異，然而通常為1小時~9小時，更佳為2小時~4小時。 Although the reaction time varies depending on the starting compound, the reaction solvent, the reaction temperature, and the like, it is usually from 1 hour to 9 hours, more preferably from 2 hours to 4 hours.
A5步驟係在惰性溶劑中，除去化合物(6)中之R17，製造化合物(7)的步驟。 The step A5 is a step of producing a compound (7) by removing R 17 in the compound (6) in an inert solvent.
就惰性溶劑而言，可列舉：醇類、醚類等，較佳為甲醇與1,4-二烷之混合溶劑。 The inert solvent may, for example, be an alcohol or an ether, preferably methanol and 1,4-two. a mixed solvent of alkane.
保護基之導入可依照與前述同樣之方法進行。 The introduction of the protecting group can be carried out in the same manner as described above.
例如，R17為甲氧基甲基之情況，可藉由在甲醇與1,4-二烷之混合溶劑中，於室溫下，使氯化氫溶液作用而進行。 For example, in the case where R 17 is a methoxymethyl group, it can be used in methanol and 1,4-two. In a mixed solvent of an alkane, a hydrogen chloride solution is allowed to proceed at room temperature.
A6步驟係藉由在惰性溶劑中將化合物(7)之羥基以溴置換，製造化合物(8)的步驟。 The step A6 is a step of producing a compound (8) by substituting a hydroxyl group of the compound (7) with bromine in an inert solvent.
就溴化劑而言，可列舉：三苯膦存在下之四溴化碳、N-溴琥珀醯亞胺等，較佳為三苯膦存在下之四溴化碳。 The brominating agent may, for example, be carbon tetrabromide or N-bromosuccinimide in the presence of triphenylphosphine, and preferably carbon tetrabromide in the presence of triphenylphosphine.
就惰性溶劑而言，可列舉：鹵化烴等，較佳為二氯甲烷。 The inert solvent may, for example, be a halogenated hydrocarbon or the like, preferably dichloromethane.
A7步驟係藉由在惰性溶劑中，於過渡金屬觸媒及鹼存在下，使化合物(7)與芳基硼酸類(1,4-苯并二烷-6-硼酸等)縮合，製造化合物(9)的步驟。 Step A7 is to compound (7) with an aryl boronic acid (1,4-benzoic acid) in an inert solvent in the presence of a transition metal catalyst and a base. The step of producing compound (9) by condensation of alkane-6-boronic acid or the like.
就惰性溶劑而言，可列舉：芳香族烴、醚類、含水醇類等，較佳為甲苯-乙醇-水之混合溶劑。 The inert solvent may, for example, be an aromatic hydrocarbon, an ether or an aqueous alcohol, and is preferably a mixed solvent of toluene-ethanol-water.
就過渡金屬觸媒而言，可列舉鈀錯合物等，較佳為肆(三苯膦)鈀(0)。 The transition metal catalyst may, for example, be a palladium complex or the like, and is preferably ruthenium (triphenylphosphine)palladium (0).
就鹼而言，可列舉無機鹼類等，較佳為碳酸鈉。 The base may, for example, be an inorganic base or the like, and is preferably sodium carbonate.
反應溫度雖隨原料化合物、反應溶劑等而異，然而通常為80℃~回流溫度，較佳為約100℃。 The reaction temperature varies depending on the starting compound, the reaction solvent, etc., but is usually from 80 ° C to the reflux temperature, preferably about 100 ° C.
反應時間雖隨原料化合物、反應溶劑、反應溫度等而異，然而通常為30分鐘~9小時，較佳為1小時~2小時。 The reaction time varies depending on the starting compound, the reaction solvent, the reaction temperature, etc., but is usually from 30 minutes to 9 hours, preferably from 1 hour to 2 hours.
A8步驟係在惰性溶劑中，除去化合物(9)中之R11、R12、R13及R14，製造化合物(I)的步驟。 The step A8 is a step of producing a compound (I) by removing R 11 , R 12 , R 13 and R 14 in the compound (9) in an inert solvent.
保護基之除去，可依照例如A3步驟中所示之文獻記載之方法而進行。 The removal of the protecting group can be carried out in accordance with, for example, the method described in the literature shown in the step A3.
例如，在R11、R12、R13及R14為苯甲基之情況，藉由在甲醇及THF之混合溶劑中，鈀碳觸媒之存在下，與氫反應，可從化合物(9)除去保護基。此時例如藉由添加1,2-二氯苯等添加劑，可加速反應，且可抑制副反應。 For example, in the case where R 11 , R 12 , R 13 and R 14 are a benzyl group, a compound (9) can be reacted with hydrogen in the presence of a palladium carbon catalyst in a mixed solvent of methanol and THF. Remove the protecting group. At this time, for example, by adding an additive such as 1,2-dichlorobenzene, the reaction can be accelerated and side reactions can be suppressed.
為A法之原料的化合物(1)，亦可藉由例如下述B法而製造，化合物(2)可藉由例如下述C法而製造，亦可依照WO2008/016132等記載之方法而製造。 The compound (1) which is a raw material of the method A can also be produced, for example, by the following B method, and the compound (2) can be produced, for example, by the following C method, or can be produced according to the method described in WO2008/016132 or the like. .
(式中，R1、R11、R12、R13及R14如前述，R18為保護基)。 (wherein R 1 , R 11 , R 12 , R 13 and R 14 are as defined above, and R 18 is a protecting group).
B1步驟係藉由將R18導入化合物(10)中，製造化合物(11)的步驟。 The step B1 is a step of producing compound (11) by introducing R 18 into compound (10).
保護基之導入，只要與A3步驟同樣方式進行即可。 The introduction of the protecting group can be carried out in the same manner as the step A3.
B2步驟係在惰性溶劑中，鹼之存在下，使化合物(10)與三氯乙腈反應，製造化合物(12)的步驟。 The step B2 is a step of producing a compound (12) by reacting the compound (10) with trichloroacetonitrile in an inert solvent in the presence of a base.
就惰性溶劑而言，可列舉鹵化烴類、醚類等，較佳為鹵化烴、更佳為二氯甲烷。 The inert solvent may, for example, be a halogenated hydrocarbon or an ether, and is preferably a halogenated hydrocarbon, more preferably dichloromethane.
就鹼而言，可列舉有機胺類等，較佳為1,8-二氮雜雙環[5.4.0]-7-十一烯。 The base may, for example, be an organic amine or the like, and is preferably 1,8-diazabicyclo[5.4.0]-7-undecene.
反應溫度雖隨原料化合物、鹼、惰性溶劑等而異，然而為-20℃~回流溫度，較佳為0℃~室溫。 The reaction temperature varies depending on the starting compound, the base, the inert solvent, etc., but is -20 ° C to reflux temperature, preferably 0 ° C to room temperature.
反應時間雖隨原料化合物、鹼、惰性溶劑、反應溫度等而異，然而為15分鐘~48小時、較佳為30分鐘~5時間。 The reaction time varies depending on the starting compound, the base, the inert solvent, the reaction temperature, and the like, but is 15 minutes to 48 hours, preferably 30 minutes to 5 minutes.
B3步驟係藉由在惰性溶劑中，於路易士酸之存在下，使化合物(12)與醇類反應，製造化合物(11)的步驟。 The step B3 is a step of producing a compound (11) by reacting the compound (12) with an alcohol in the presence of a Lewis acid in an inert solvent.
就惰性溶劑而言，可列舉：鹵化烴類、芳香族烴類、醚類、腈類等，較佳為鹵化烴、更佳為二氯甲烷。 The inert solvent may, for example, be a halogenated hydrocarbon, an aromatic hydrocarbon, an ether or a nitrile, and is preferably a halogenated hydrocarbon, more preferably dichloromethane.
就路易士酸而言，可列舉三氟化硼-二乙基醚錯合物、三氟甲磺酸三甲基矽烷酯等，較佳為三氟化硼-二乙基醚錯合物。 Examples of the Lewis acid include a boron trifluoride-diethyl ether complex and trimethylsulfonate trifluoromethanesulfonate, and a boron trifluoride-diethyl ether complex is preferable.
反應溫度雖隨原料化合物、路易士酸、惰性溶劑等而異，然而通常為-30℃~回流溫度，較佳為0℃~室溫。 Although the reaction temperature varies depending on the starting compound, Lewis acid, inert solvent, etc., it is usually from -30 ° C to reflux temperature, preferably from 0 ° C to room temperature.
反應時間雖隨原料化合物、路易士酸、惰性溶劑、反應溫度等而異，然而通常為5分鐘~24小時，較佳為10分鐘~12小時。 The reaction time varies depending on the starting compound, Lewis acid, inert solvent, reaction temperature, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 12 hours.
B4步驟係藉由除去化合物(11)之苯甲醯基，製造化合物(13)的步驟。 The step B4 is a step of producing a compound (13) by removing the benzinyl group of the compound (11).
苯甲醯基之除去，可依照該領域中周知之方法，例如，在T.H.Greene,P.G.Wuts,Protective Groups in Organic Synthesis,Third Edition,1999年，John Wiley & Sons,Inc.中所記載之方法而進行。 The removal of the benzamidine group can be carried out according to methods well known in the art, for example, in the method described in TH Greene, PGWuts, Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. get on.
B5步驟係在化合物(13)中導入R11、R12、R13及R14，製造化合物(14)的步驟。 The step B5 is a step of producing a compound (14) by introducing R 11 , R 12 , R 13 and R 14 into the compound (13).
保護基之導入，可以與A3步驟同樣之方式進行。 The introduction of the protecting group can be carried out in the same manner as the step A3.
例如，在R11、R12、R13及R14為苯甲基之情況，可藉由在惰性溶劑中，於鹼存在下，使化合物(13)與溴化苯甲基、氯化苯甲基等反應，在化合物(13)中導入保護基。 For example, in the case where R 11 , R 12 , R 13 and R 14 are a benzyl group, the compound (13) can be brominated with benzyl, benzyl chloride in an inert solvent in the presence of a base. A protecting group is introduced into the compound (13) by a reaction such as a group.
就惰性溶劑而言，可列舉醯胺類、醚類等，較佳為醯胺類、更佳為N,N-二甲基甲醯胺。 The inert solvent may, for example, be a guanamine or an ether, and is preferably a guanamine or more preferably N,N-dimethylformamide.
就鹼而言，可列舉氫化鈉、氫氧化鹼類等，較佳為氫化鈉。又，藉由添加碘化四丁基銨等之添加劑，亦可促進反應。 The base may, for example, be sodium hydride or alkali hydroxide, and is preferably sodium hydride. Further, the reaction can be promoted by adding an additive such as tetrabutylammonium iodide.
反應溫度雖隨原料化合物、惰性溶劑、鹼等而異，然而為-30℃~回流溫度，較佳為0℃~室溫。 The reaction temperature varies depending on the starting compound, the inert solvent, the base, etc., but is -30 ° C to reflux temperature, preferably 0 ° C to room temperature.
反應時間雖隨原料化合物、惰性溶劑、鹼、反應溫度等而異，然而為15分鐘~48小時，較佳為30分鐘~12小時。 The reaction time varies depending on the starting compound, the inert solvent, the base, the reaction temperature, etc., but it is from 15 minutes to 48 hours, preferably from 30 minutes to 12 hours.
B6步驟係將化合物(14)中之R18除去，製造化合物(15)的步驟。 The step B6 is a step of removing R 18 in the compound (14) to produce a compound (15).
保護基之除去，可依照前述之方法進行。 Removal of the protecting group can be carried out in accordance with the methods described above.
例如，R18為烯丙基之情況，可藉由在惰性溶劑中，於鹼存在下，使烯丙基異構化後，在惰性溶劑中，於水存在下，使N-碘琥珀醯亞胺等氧化劑與化合物(14)反應，而從化合物(14)中除去R18。 For example, in the case where R 18 is an allyl group, N-iodoammonium can be obtained by isomerization of the allyl group in an inert solvent in the presence of a base in an inert solvent in the presence of water. An oxidizing agent such as an amine is reacted with the compound (14), and R 18 is removed from the compound (14).
B7步驟係在惰性溶劑中，使化合物(12)與氧化劑反應，製造化合物(1)的步驟。 The step B7 is a step of producing a compound (1) by reacting the compound (12) with an oxidizing agent in an inert solvent.
就惰性溶劑而言，可列舉：鹵化烴類等，較佳為二氯甲烷。 The inert solvent may, for example, be a halogenated hydrocarbon or the like, and is preferably dichloromethane.
就氧化劑而言，可列舉：二甲基亞碸、鉻酸、戴斯‧馬丁‧過碘烷氧化劑(Dess-Martin periodinane)(以下，有稱為「DMP」的情況)等，較佳為DMP。 Examples of the oxidizing agent include dimethyl hydrazine, chromic acid, Dess-Martin periodinane (hereinafter referred to as "DMP"), and preferably DMP. .
反應溫度雖隨原料化合物、氧化劑、惰性溶劑等而異，然而為-30℃~回流溫度，較佳為0℃~室溫。 The reaction temperature varies depending on the starting compound, the oxidizing agent, the inert solvent, etc., but is -30 ° C to reflux temperature, preferably 0 ° C to room temperature.
反應時間雖隨原料化合物、氧化劑、惰性溶劑、反應溫度等而異，然而通常為5分鐘~24小時，較佳為10分鐘~12小時。 The reaction time varies depending on the starting compound, the oxidizing agent, the inert solvent, the reaction temperature, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 12 hours.
(式中，X1、R15及R16如前述，R19及R20相同或相異，各為保護基)。 (wherein, X 1 , R 15 and R 16 are as defined above, and R 19 and R 20 are the same or different and each is a protecting group).
C1步驟係在惰性溶劑中，使化合物(16)與還原劑反應，製造化合物(17)的步驟。 The step C1 is a step of producing a compound (17) by reacting the compound (16) with a reducing agent in an inert solvent.
就惰性溶劑而言，可列舉：醚類、醇類等，較佳為醚類，更佳為THF。 The inert solvent may, for example, be an ether or an alcohol, preferably an ether, more preferably THF.
就還原劑而言，可列舉：氫化硼鋰等氫化硼鹼金屬類；氫化鋁鋰、氫化鋰三乙氧基鋁等氫化鋁化合物；氫化碲鈉等氫化物試藥等。R19及R20為甲基之情況，較佳為氫化硼鋰。 Examples of the reducing agent include an alkali metal hydride such as lithium borohydride; an aluminum hydride compound such as lithium aluminum hydride or lithium hydride triethoxy aluminum; and a hydride reagent such as sodium hydride. In the case where R 19 and R 20 are a methyl group, lithium borohydride is preferred.
反應溫度雖隨原料化合物、還原劑、惰性溶劑等而異，然而通常為-30℃~回流溫度，較佳為0℃~室溫。 The reaction temperature varies depending on the starting compound, the reducing agent, the inert solvent, etc., but is usually -30 ° C to reflux temperature, preferably 0 ° C to room temperature.
反應時間雖隨原料化合物、還原劑、惰性溶劑、反應溫度等而異，然而通常為10分鐘~48小時，較佳為30分鐘~24小時。 The reaction time varies depending on the starting compound, the reducing agent, the inert solvent, the reaction temperature, etc., but is usually from 10 minutes to 48 hours, preferably from 30 minutes to 24 hours.
C2步驟係將R15及R16導入化合物(17)中，製造化合物(2)的步驟。 The C2 step is a step of introducing R 15 and R 16 into the compound (17) to produce the compound (2).
保護基之導入，可以與A3步驟同樣之方式進行。 The introduction of the protecting group can be carried out in the same manner as the step A3.
本發明之化合物，亦可進一步參照後述之實施例或該領域中周知之方法，從周知之化合物製造。 The compound of the present invention can also be produced from a known compound by further referring to the examples described later or methods well known in the art.
本發明之化合物或其藥學上可容許之鹽，由於具有優良降血糖作用，可做為治療及/或預防1型糖尿病、2型糖尿病、妊娠糖尿病、其他原因造成之高血糖症、IGT、肥胖、糖尿病關連疾病(高脂血症、高膽固醇血症、脂質代謝異常、高血壓症、脂肪肝、代謝症候群、水腫、心臟衰竭、狹心症、心肌梗塞、動脈硬化症、高尿酸血症、痛風等)或糖尿病合併症(網膜症、腎病、神經障礙、白內障、足壞疽、感染症、酮症等)用之醫藥組成物的有效成分。 The compound of the present invention or a pharmaceutically acceptable salt thereof can be used for treating and/or preventing type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia caused by other causes, IGT, obesity due to its excellent hypoglycemic effect. Diabetes-related diseases (hyperlipidemia, hypercholesterolemia, abnormal lipid metabolism, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, atherosclerosis, hyperuricemia, An active ingredient of a pharmaceutical composition for gout, etc. or a diabetic complication (retinosis, nephropathy, neurological disorder, cataract, foot gangrene, infection, ketosis, etc.).
又，本發明之化合物或其藥學上可容許之鹽，亦可與其他糖尿病治療藥、糖尿病合併症治療藥、高脂血症治療藥、高血壓症治療藥等合併使用。 Further, the compound of the present invention or a pharmaceutically acceptable salt thereof may be used in combination with other therapeutic agents for diabetes, therapeutic agents for diabetes mellitus, therapeutic agents for hyperlipemia, and therapeutic agents for hypertension.
含有本發明之化合物或其藥學上可容許之鹽的醫藥組成物，在投與至哺乳動物(人類、馬、牛、豬等，較佳為人類)之情況，可以全身性或局部性，經口或非經口之方式投與。 The pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered systemically or locally, in the case of administration to a mammal (human, horse, cow, pig, etc., preferably human). Orally or indiscriminately.
本發明之醫藥組成物，可視投與方法選擇適當之形式，並可藉由通常所用之各種製劑的調製法來調製。 The pharmaceutical composition of the present invention can be appropriately selected depending on the method of administration, and can be prepared by a modulation method of various preparations which are usually used.
就經口用之醫藥組成物的形式而言，可列舉：錠劑、丸劑、散劑、顆粒劑、膠囊劑、水劑、懸浮劑、乳劑、糖漿劑、酏劑等。此等形式之醫藥組成物，視需要可適當選擇通常用做添加劑之賦形劑、黏合劑、 崩散劑、潤滑劑、膨潤劑、膨潤補助劑、包衣劑(coating)、可塑劑、安定劑、防腐劑、抗氧化劑、著色劑、助溶劑、懸浮化劑、乳化劑、甘味劑、保存劑、緩衝劑、稀釋劑、濕潤劑等，依照一般方法來製造。 The form of the pharmaceutical composition for oral administration may, for example, be a tablet, a pill, a powder, a granule, a capsule, a liquid, a suspension, an emulsion, a syrup, an elixir or the like. In these forms of pharmaceutical compositions, if necessary, excipients, binders, and additives commonly used as additives may be appropriately selected. Disintegrating agent, lubricant, swelling agent, swelling agent, coating, plasticizer, stabilizer, preservative, antioxidant, coloring agent, solubilizing agent, suspending agent, emulsifier, sweetener, preservative A buffer, a diluent, a wetting agent and the like are produced in accordance with a general method.
就非經口用之醫藥組成物的形式而言，可列舉：注射劑、軟膏劑、凝膠劑、乳膏劑、濕布劑、貼附劑、噴霧劑、吸入劑、噴劑(spray)、點眼劑、點鼻劑、栓劑等。此等形式之醫藥組成物，視需要可適宜選擇通常用做添加劑之安定化劑、防腐劑、助溶劑、保濕劑、保存劑、抗氧化劑、著香劑、凝膠化劑、中和劑、緩衝劑、等張劑、界面活性劑、著色劑、緩衝化劑、増黏劑、濕潤劑、充填劑、吸收促進劑、懸浮化劑、黏合劑等，依照常法製造。 Examples of the form of the pharmaceutical composition for parenteral use include injections, ointments, gels, creams, wet wipes, patches, sprays, inhalants, sprays, and spots. Eye drops, nose drops, suppositories, etc. In the form of the pharmaceutical composition, if necessary, a stabilizer, a preservative, a solubilizer, a moisturizer, a preservative, an antioxidant, a flavoring agent, a gelling agent, a neutralizing agent, which are usually used as an additive, may be appropriately selected. Buffering agents, isotonic agents, surfactants, coloring agents, buffering agents, creping agents, wetting agents, fillers, absorption enhancers, suspending agents, binders, etc., are produced according to conventional methods.
本發明之化合物或其藥學上可容許之鹽之投與量，雖隨症状、年齡、體重等而異，然而在經口投與之情況，為1日1~數次，成人一人每一次化合物換算量為1~2000mg，較佳為1~400mg，在非經口投與之情況中，1日1~數次、成人一人每一次化合物換算量為0.01~500mg，較佳為0.1~300mg。 The administration amount of the compound of the present invention or a pharmaceutically acceptable salt thereof varies depending on symptoms, age, body weight, etc., but in the case of oral administration, it is 1 to several times per day, and adults are once per compound. The conversion amount is 1 to 2000 mg, preferably 1 to 400 mg. In the case of non-oral administration, the amount of the compound per adult is 0.01 to 500 mg, preferably 0.1 to 300 mg per day.
以下，列舉參考例、實施例、製劑例及試驗例，更詳細地說明本發明，然而本發明之範圍不以此等為限。 Hereinafter, the present invention will be described in more detail by way of Reference Examples, Examples, Preparation Examples and Test Examples. However, the scope of the present invention is not limited thereto.
在以下之參考例及實施例中，有時使用以下簡稱。 In the following Reference Examples and Examples, the following abbreviations are sometimes used.
Bn：苯甲基 Bn: benzyl group
Bz：苯甲醯基 Bz: benzamidine
Tf：三氟甲磺醯基 Tf: trifluoromethanesulfonyl
Ac：乙醯基 Ac: Ethyl
Me：甲基 Me: methyl
Et：乙基 Et: ethyl
Boc：三級丁氧基羰基 Boc: tertiary butoxycarbonyl
(參考例1)2,3,4,6-四-O-苯甲基-7-去氧-D-甘油-D-葡萄糖-哌喃型庚糖酸內酯 (Reference Example 1) 2,3,4,6-tetra-O-benzyl-7-deoxy-D-glycerol-D-glucose-pentanose heptanolactone
(參考例1a)烯丙基2,3,4,6-四-O-苯甲醯基-7-去氧-D-甘油-D-葡萄糖-哌喃型庚糖苷 (Reference Example 1a) Allyl 2,3,4,6-tetra-O-benzimidyl-7-deoxy-D-glycerol-D-glucose-pyloryl heptose
將2,3,4,6-四-O-苯甲醯基-7-去氧-D-甘油-α,β-D-葡萄糖-哌喃型庚糖(WO2008/016132)(30.0g，49.1mmol)溶解於二氯甲烷(100mL)中，於15℃添加三氯乙腈(15.0mL，150mmol)及1,8-二氮雜雙環[5.4.0]-7- 十一烯(0.25mL，1.68mmol)。將反應液於15℃攪拌2小時後，將其用二氯甲烷(200mL)稀釋，並以水(50mL)及飽和氯化銨水溶液(50mL)依序洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑，然後在所得到之殘餘物中添加甲苯(30mL)，並於減壓下餾去溶劑。 2,3,4,6-tetra-O-benzimidyl-7-deoxy-D-glycerol-α,β-D-glucose-pyranose heptose (WO2008/016132) (30.0g, 49.1 Methyl acetate was dissolved in dichloromethane (100 mL), and trichloroacetonitrile (15.0 mL, 150 mmol) and 1,8-diazabicyclo[5.4.0]-7- were added at 15 °C. Undecene (0.25 mL, 1.68 mmol). After the reaction mixture was stirred at 15 ° C for 2 hours, it was diluted with dichloromethane (200 mL) and washed sequentially with water (50mL) and saturated aqueous ammonium chloride (50mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated evaporated evaporated.
將所得到之殘餘物溶於二氯甲烷(200mL)，於冰冷下添加烯丙醇(6.9mL，101mmol)，繼而將三氟硼烷二乙基醚錯合物(1.9mL，15.0mmol)慢慢地滴入。將該反應液於冰冷下攪拌15分鐘後，於室溫下進一步攪拌1小時半。反應終了後，再度將反應液冰冷，並於該反應液中添加三乙基胺(2.8mL，20mmol)。將反應液用乙酸乙酯(500mL)稀釋，並以飽和食鹽水(50mL)洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。在所得到之殘餘物中添加冰冷之二氯甲烷(100mL)，過濾除去析出物(ca.5g)。於減壓下餾去溶劑，以矽膠急速管柱層析(己烷：乙酸乙酯，98：2→70：30(濃度梯度)V/V)精製，得到標題化合物(27.0g)。 The residue obtained was dissolved in dichloromethane (200 mL). <RTI ID=0.0>> Slowly drip in. The reaction solution was stirred under ice cooling for 15 minutes and then further stirred at room temperature for one and a half hours. After the reaction was completed, the reaction solution was again ice-cooled, and triethylamine (2.8 mL, 20 mmol) was added to the mixture. The reaction solution was diluted with ethyl acetate (500 mL) and washed with brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. Ice-cold dichloromethane (100 mL) was added to the obtained residue, and the precipitate (ca. 5 g) was removed by filtration. The solvent was evaporated under reduced pressure and purified mjjjlilililililililililililililililili
1H NMR(400MHz,CDCl3)：δ1.55(3H,d,J=6.6Hz),4.10-4.13(1H,m),4.18-4.24(1H,m),4.36-4.41(1H,m),4.87(1H,d,J=7.8Hz),5.10-5.15(1H,m),5.19-5.24(1H,m),5.33-5.39(1H,m),5.54(1H,dd,J=9.8Hz,8.2Hz),5.59(1H,t,J=9.8Hz),5.79-5.88(1H,m),5.89(1H,t,J=7.6Hz),7.26-7.57(12H,m),7.81-7.84(2H,m),7.90-7.93(2H,m),7.95-7.98(2H,m),8.02-8.04(2H,m). 1 H NMR (400 MHz, CDCl 3 ): δ 1.55 (3H, d, J = 6.6 Hz), 4.10-4.13 (1H, m), 4.18-4.24 (1H, m), 4.36-4.41 (1H, m) , 4.87 (1H, d, J = 7.8 Hz), 5.10-5.15 (1H, m), 5.19-5.24 (1H, m), 5.33-5.39 (1H, m), 5.54 (1H, dd, J = 9.8 Hz , 8.2 Hz), 5.59 (1H, t, J = 9.8 Hz), 5.79-5.88 (1H, m), 5.89 (1H, t, J = 7.6 Hz), 7.26-7.57 (12H, m), 7.81-7.84 (2H, m), 7.90-7.93 (2H, m), 7.95-7.98 (2H, m), 8.02-8.04 (2H, m).
(參考例1b)烯丙基7-去氧-D-甘油-D-葡萄糖-哌喃型庚糖苷 (Reference Example 1b) Allyl 7-deoxy-D-glycerol-D-glucose-pyranose heptanoside
將在參考例1a中所得到之化合物(27.0g，41.5mmol)溶於二氯甲烷(84mL)與甲醇(336mL)之混合溶劑中，於室溫下添加碳酸鉀(47.0g，0.34mol)。將該反應液攪拌4小時半後，過濾除去不溶物，在濾液中添加乙酸(30mL)。於減壓下餾去溶劑，並過濾不溶物。繼而，於減壓下餾去溶劑。將所得到之殘餘物以矽膠急速管柱層析(二氯甲烷：甲醇，99：1→85：15(濃度梯度)V/V)精製，得到標題化合物(9.2g)。 The compound obtained in Reference Example 1a (27.0 g, 41.5 mmol) was dissolved in a solvent mixture of dichloromethane (84 mL) and methanol (336 mL), and potassium carbonate (47.0 g, 0.34 mol) was added at room temperature. After the reaction mixture was stirred for 4 hours and a half, the insoluble material was removed by filtration, and acetic acid (30 mL) was added to the filtrate. The solvent was distilled off under reduced pressure, and the insoluble material was filtered. Then, the solvent was distilled off under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:
(參考例1c)烯丙基2,3,4,6-四-O-苯甲基-7-去氧-D-甘油-D-葡萄糖-哌喃型庚糖苷 (Reference Example 1c) Allyl 2,3,4,6-tetra-O-benzyl-7-deoxy-D-glycerol-D-glucose-pyloryl heptanoside
將在參考例1b中所得到之化合物(12.1g，51.6mmol)溶於N,N-二甲基甲醯胺(250mL)，於冰冷下，慢慢地添加氫化鈉(油性，63%w/w，8.3g，0.23mol)。在該反應液中，於冰冷下滴入溴化苯甲基(27.3mL，0.23 mol)，添加碘化四丁基銨(0.96g，2.6mmol)，升溫至室溫，同時攪拌9小時。將該反應液於室溫靜置整夜後，添加飽和氯化銨水溶液(200mL)中和，並用乙酸乙酯(250mL)稀釋。將其依序用10%w/v食鹽水(200mL，2次)及飽和食鹽水(50mL)洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，99：1→80：20(濃度梯度)V/V)精製，得到標題化合物(27.2g)。 The compound obtained in Reference Example 1b (12.1 g, 51.6 mmol) was dissolved in N,N-dimethylformamide (250 mL), and sodium hydride was slowly added under ice cooling (oily, 63% w/ w, 8.3 g, 0.23 mol). In the reaction solution, benzyl bromide (27.3 mL, 0.23) was added dropwise under ice cooling. Mol), tetrabutylammonium iodide (0.96 g, 2.6 mmol) was added, and the mixture was warmed to room temperature while stirring for 9 hours. After the reaction mixture was stood at room temperature overnight, a saturated aqueous solution of sodium chloride (200 mL) was then evaporated and evaporated. This was washed sequentially with 10% w/v saline (200 mL, 2 times) and saturated brine (50 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(500MHz,CDCl3)：δ1.15(3H,d,J=6.4Hz),3.39-3.47(2H,m),3.53(1H,d,J=9.8Hz),3.64-3.68(1H,m),3.83(1H,dd,J=12.9Hz,6.6Hz),4.10-4.17(1H,m),4.42-4.45(2H,m),4.56-4.59(1H,m),4.59(2H,s),4.72(1H,d,J=10.8Hz),4.77(1H,d,J=10.7Hz),4.82(1H,d,J=10.7Hz),4.95(1H,d,J=11.2Hz),4.97(1H,d,J=11.2Hz),5.21(1H,d,J=10.3Hz),5.34(1H,d,J=17.1Hz),5.91-6.01(1H,m),7.14-7.15(2H,m),7.26-7.36(18H,m). 1 H NMR (500 MHz, CDCl 3 ): δ 1.15 (3H, d, J = 6.4 Hz), 3.39 - 3.47 (2H, m), 3.53 (1H, d, J = 9.8 Hz), 3.64 - 3.68 (1H , m), 3.83 (1H, dd, J = 12.9 Hz, 6.6 Hz), 4.10-4.17 (1H, m), 4.42-4.45 (2H, m), 4.56-4.59 (1H, m), 4.59 (2H, s), 4.72 (1H, d, J = 10.8 Hz), 4.77 (1H, d, J = 10.7 Hz), 4.82 (1H, d, J = 10.7 Hz), 4.95 (1H, d, J = 11.2 Hz) , 4.97 (1H, d, J = 11.2 Hz), 5.21 (1H, d, J = 10.3 Hz), 5.34 (1H, d, J = 17.1 Hz), 5.91-6.01 (1H, m), 7.14 - 7.15 ( 2H, m), 7.26-7.36 (18H, m).
(參考例1d)2,3,4,6-四-O-苯甲基-7-去氧-D-甘油-D-葡萄糖-哌喃型庚糖 (Reference Example 1d) 2,3,4,6-tetra-O-benzyl-7-deoxy-D-glycerol-D-glucose-pentanose heptose
將在參考例1c中所得到之化合物(27.2g，45.6mmol)溶解於N,N-二甲基甲醯胺(150mL)，並於室 溫下慢慢地添加三級丁氧化鉀(15.3g，137mmol)。將該反應液升溫至80℃，並攪拌4小時半。反應終了後，將反應液冷卻至室溫，將其用乙酸乙酯(200mL)稀釋。將其依序用飽和氯化銨水溶液(100mL，2次)、10%w/v食鹽水(150mL，2次)及飽和食鹽水(50mL)洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。 The compound obtained in Reference Example 1c (27.2 g, 45.6 mmol) was dissolved in N,N-dimethylformamide (150 mL), and Three grades of potassium butoxide (15.3 g, 137 mmol) were slowly added under temperature. The reaction solution was warmed to 80 ° C and stirred for 4 and a half hours. After the reaction was completed, the reaction mixture was cooled to room temperature and then diluted with ethyl acetate (200 mL). This was washed with a saturated aqueous solution of ammonium chloride (100 mL, twice), 10% w/v brine (150 mL, twice) and brine (50 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure.
將所得到之殘餘物溶於THF(120mL)及水(30mL)，在其中於室溫下慢慢地添加N-碘琥珀醯亞胺(11.3g，50.2mmol)。將該反應液於室溫攪拌15分鐘，在其中添加乙酸乙酯(100mL)，並依序以10%w/v硫代硫酸鈉水溶液(50mL，2次)及飽和食鹽水(50mL)洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，98：2→75：25(濃度梯度)V/V)精製，得到標題化合物(21.3g)。 The residue obtained was dissolved in THF (120 mL) and water (30 mL), and N-iodosuccinimide (11.3 g, 50.2 mmol) was slowly added at room temperature. The reaction solution was stirred at room temperature for 15 min, then ethyl acetate (100 mL) was added and then washed with 10% w/v aqueous sodium thiosulfate (50 mL, twice) and brine (50 mL) . After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(400MHz,CDCl3)：δ1.14(3H,d,J=6.7Hz),3.43-3.58(3H,m),3.68(1H,t,J=9.0Hz),3.80-3.86(1H,m),4.56-4.63(5H,m),4.74(1H,d,J=10.6Hz),4.79(1H,d,J=10.9Hz),4.83(1H,d,J=11.0Hz),4.95(1H,d,J=10.5Hz),4.98(1H,d,J=10.6Hz),6.27-6.30(0H,m),7.13-7.20(3H,m),7.25-7.40(17H,m). 1 H NMR (400 MHz, CDCl 3 ): δ 1.14 (3H, d, J = 6.7 Hz), 3.43-3.58 (3H, m), 3.68 (1H, t, J = 9.0 Hz), 3.80-3.86 (1H , m), 4.56-4.63 (5H, m), 4.74 (1H, d, J = 10.6 Hz), 4.79 (1H, d, J = 10.9 Hz), 4.83 (1H, d, J = 11.0 Hz), 4.95 (1H, d, J = 10.5 Hz), 4.98 (1H, d, J = 10.6 Hz), 6.27-6.30 (0H, m), 7.13-7.20 (3H, m), 7.25-7.40 (17H, m).
(參考例1e)2,3,4,6-四-O-苯甲基-7-去氧-D-甘油-D-葡萄糖-哌喃型庚糖酸內酯 (Reference Example 1e) 2,3,4,6-tetra-O-benzyl-7-deoxy-D-glycerol-D-glucose-pentanose heptanolactone
將在參考例1d中所得到之化合物(25.2g，45.4mmol)溶解於二氯甲烷(150mL)，在其中，於冰冷下慢慢地添加DMP(25.0g，59.0mmol)。將該反應液慢慢地升溫至室溫，同時攪拌2小時，反應終了後，添加飽和碳酸氫鈉水溶液(100mL)及10%w/v硫代硫酸鈉水溶液(50mL)。將該反應液於室溫下攪拌30分鐘後，濾除不溶物，將濾液用乙酸乙酯(150mL)稀釋。將其以飽和碳酸氫鈉水溶液(100mL，2次)及飽和食鹽水(50mL，2次)依序洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，98：2→80：20(濃度梯度)V/V)精製，得到標題化合物(19.7g)。 The compound obtained in Reference Example 1d (25.2 g, 45.4 mmol) was dissolved in dichloromethane (150 mL), and DMP (25.0 g, 59.0 mmol) was slowly added under ice cooling. The reaction solution was gradually warmed to room temperature while stirring for 2 hours. After the reaction was completed, a saturated aqueous sodium hydrogen carbonate solution (100 mL) and a 10% w/v aqueous sodium thiosulfate solution (50 mL) was added. After the reaction mixture was stirred at room temperature for 30 minutes, insoluble material was filtered, and the filtrate was diluted with ethyl acetate (150 mL). This was washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate (100 mL, twice) and brine (50 mL, twice). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(400MHz,CDCl3)：δ1.20(3H,d,J=6.2Hz),2.36(1H,s),3.84-3.90(1H,m),3.92-3.98(2H,m),4.14(1H,d,J=7.4Hz),4.43(1H,d,J=11.4Hz),4.50(1H,d,J=11.7Hz),4.55-4.60(3H,m),4.72(1H,d,J=11.4Hz),4.76(1H,d,J=11.4Hz),4.95(1H,d,J=11.4Hz),7.16-7.38(20H,m). 1 H NMR (400 MHz, CDCl 3 ): δ 1.20 (3H, d, J = 6.2 Hz), 2.36 (1H, s), 3.84-3.90 (1H, m), 3.92-3.98 (2H, m), 4.14 (1H, d, J = 7.4 Hz), 4.43 (1H, d, J = 11.4 Hz), 4.50 (1H, d, J = 11.7 Hz), 4.55 - 4.60 (3H, m), 4.72 (1H, d, J = 11.4 Hz), 4.76 (1H, d, J = 11.4 Hz), 4.95 (1H, d, J = 11.4 Hz), 7.16-7.38 (20H, m).
(參考例2)2-溴-1,4-雙[(甲氧基甲氧基)甲基]苯 (Reference Example 2) 2-bromo-1,4-bis[(methoxymethoxy)methyl]benzene
在2-溴對苯二甲酸(5.00g，20.4mmol)中添加THF(60mL)，於冰冷下將硼烷四氫呋喃錯合物之THF溶液(1.0M，51.0mL，51.0mmol)慢慢地滴入其中。將該反應液於40℃攪拌1小時半，反應終了後，將反應液冰冷，慢慢地添加水(100mL)。在該反應液中添加飽和碳酸氫鈉水溶液(50mL)，並用乙酸乙酯(50mL，2次)萃取。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑，得到二醇體之粗生成物(4.30g)。 THF (60 mL) was added to 2-bromo-terephthalic acid (5.00 g, 20.4 mmol), and THF solution (1.0 M, 51.0 mL, 51.0 mmol) of borane tetrahydrofuran complex was slowly added dropwise under ice cooling. among them. The reaction solution was stirred at 40 ° C for 1 hour and a half. After the reaction was completed, the reaction mixture was ice-cooled, and water (100 mL) was slowly added. A saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added, and ethyl acetate (50 mL, twice). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give a crude product (4.30 g).
將該二醇體溶解於二氯甲烷(100mL)中，於冰冷下將二異丙基乙基胺(52.0mL，0.31mol)及氯甲基甲基醚(15.5mL，0.20mol)加入其中。將該反應液慢慢地升溫至室溫，同時攪拌5小時，靜置整夜後，在反應液中添加飽和碳酸氫鈉水溶液(50mL)，於減壓下將溶劑餾去至約半量為止。將該濃縮液以乙酸乙酯(50mL)稀釋，並用水(30mL)、飽和氯化銨水溶液(50mL，2次)及飽和食鹽水(50mL)依序洗淨。將該有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，95：5→65：35(濃度梯度)V/V)精製，得到標題化合物(5.5g)。 The diol was dissolved in dichloromethane (100 mL), and diisopropylethylamine (52.0 mL, 0.31 mol) and chloromethyl methyl ether (15.5 mL, 0.20 mol) were added thereto under ice cooling. The reaction mixture was gradually warmed to room temperature while stirring for 5 hours, and after standing overnight, a saturated aqueous sodium hydrogencarbonate solution (50 mL) was added to the reaction mixture, and the solvent was distilled off under reduced pressure to about half. The concentrate was diluted with ethyl acetate (50 mL) and washed sequentially with water (30 mL), saturated aqueous ammonium chloride (50 mL, twice) and brine (50 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(400MHz,CDCl3)：δ3.42(3H,s),3.44(3H,s),4.57(2H,s),4.67(2H,s),4.71(2H,s),4.77(2H,s),7.31(1H,dd,J=7.8Hz,1.5Hz),7.47(1H,d,J=7.8Hz),7.59(1H,d,J=1.5Hz). 1 H NMR (400MHz, CDCl 3 ): δ3.42 (3H, s), 3.44 (3H, s), 4.57 (2H, s), 4.67 (2H, s), 4.71 (2H, s), 4.77 (2H , s), 7.31 (1H, dd, J = 7.8 Hz, 1.5 Hz), 7.47 (1H, d, J = 7.8 Hz), 7.59 (1H, d, J = 1.5 Hz).
(參考例3)1-溴-4-氟-2,5-雙[(甲氧基甲氧基)甲基]苯 (Reference Example 3) 1-bromo-4-fluoro-2,5-bis[(methoxymethoxy)methyl]benzene
以2-溴-4-氟苯甲醇(2.0g，10mmol)做為原料，依照文獻記載之方法(EP2048153(A1))，得到二醇體(1.16g)，以與參考例2同樣之方式得到標題化合物(1.5g)。 Using 2-bromo-4-fluorobenzyl alcohol (2.0 g, 10 mmol) as a raw material, a diol (1.16 g) was obtained according to the method described in the literature (EP2048153 (A1)), and obtained in the same manner as in Reference Example 2. The title compound (1.5 g).
1H NMR(400MHz,CDCl3)：δ3.42(3H,s),3.43(3H,s),4.62(2H,s),4.62(2H,s),4.72(2H,s),4.77(2H,s),7.25(1H,d,J=10.5Hz),7.61(1H,d,J=6.7Hz). 1 H NMR (400MHz, CDCl 3 ): δ3.42 (3H, s), 3.43 (3H, s), 4.62 (2H, s), 4.62 (2H, s), 4.72 (2H, s), 4.77 (2H , s), 7.25 (1H, d, J = 10.5 Hz), 7.61 (1H, d, J = 6.7 Hz).
(參考例4)1-溴-4-氯-2,5-雙[(甲氧基甲氧基)甲基]苯 (Reference Example 4) 1-bromo-4-chloro-2,5-bis[(methoxymethoxy)methyl]benzene
在2-溴-5-氯對苯二甲酸二乙酯(9.2g，30.0mmol)中添加THF(150mL)，於冰冷下將氫化硼鋰(10.9g，0.45mol)慢慢地加入其中。將該反應液慢慢地升溫至室溫，同時攪拌9小時後，靜置整夜。反應終了後，將反應液冰冷，並滴入飽和氯化銨水溶液(150mL)。在該反應液中添加乙酸乙酯(100mL)，並以飽和碳酸氫鈉水溶液(100mL，3回)及飽和食鹽水(50mL)依序洗淨。將該有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。 To a solution of diethyl 2-bromo-5-chloroterephthalate (9.2 g, 30.0 mmol) was added THF (150 mL), and lithium boronhydride (10.9 g, 0.45 mol) was slowly added thereto under ice cooling. The reaction solution was slowly warmed to room temperature while stirring for 9 hours, and then allowed to stand overnight. After the reaction was completed, the reaction solution was ice-cooled, and a saturated aqueous solution of ammonium chloride (150 mL). Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate (100 mL, 3 s) and brine (50 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure.
將所得到之殘餘物溶於二氯甲烷(100mL)中，在冰冷下，將二異丙基乙基胺(77.0mL，0.45mol)及氯甲基甲基醚(23.0mL，0.30mol)加入其中。將該反應液慢慢地升溫至室溫，同時攪拌3小時後，靜置整夜。反應終了後，將反應液以乙酸乙酯(150mL)稀釋，並用飽和氯化銨水溶液(50mL，3回)及飽和食鹽水(50mL)依序洗淨。將該有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，98：2→75：25(濃度梯度)V/V)精製，得到標題化合物(6.4g)。 The residue obtained was dissolved in dichloromethane (100 mL), diisopropylethylamine (77.0 mL, 0.45 mol) and chloromethyl methyl ether (23.0 mL, 0.30 mol) among them. The reaction solution was gradually warmed to room temperature while stirring for 3 hours, and then allowed to stand overnight. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (150 mL), and washed successively with saturated aqueous ammonium chloride (50 mL, 3 s) and saturated brine (50 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(400MHz,CDCl3)：δ3.43(3H,s),3.44(3H,s),4.62(2H,s),4.65(2H,s),4.76(2H,s),4.77(2H,s),7.51(1H,s),7.70(1H,s). 1 H NMR (400MHz, CDCl 3 ): δ3.43 (3H, s), 3.44 (3H, s), 4.62 (2H, s), 4.65 (2H, s), 4.76 (2H, s), 4.77 (2H , s), 7.51 (1H, s), 7.70 (1H, s).
(參考例5)1,4-二溴-2,5-雙[(甲氧基甲氧基)甲基]苯 (Reference Example 5) 1,4-Dibromo-2,5-bis[(methoxymethoxy)methyl]benzene
在2,5-二溴對苯二甲酸(15.4g，47.5mmol)中添加THF(200mL)，於冰冷下將硼烷四氫呋喃錯合物之THF溶液(0.95M，200mL，0.19mol)慢慢地滴入。將該反應液慢慢地升溫至室溫，同時攪拌3小時後，靜置整夜。再者將該反應液於60℃攪拌2小時。反應終了後，將反應液冰冷，添加水(100mL)及1M鹽酸(500mL)，並於室溫下攪拌1小時。濾出該反應液中之析出 物，將析出物用水(50mL)、及二乙基醚(50mL)依序洗淨。將該析出物於減壓下，在40℃乾燥，得到二醇體(15.4g)。 THF (200 mL) was added to 2,5-dibromo-terephthalic acid (15.4 g, 47.5 mmol), and the borane tetrahydrofuran complex THF solution (0.95 M, 200 mL, 0.19 mol) Drop in. The reaction solution was gradually warmed to room temperature while stirring for 3 hours, and then allowed to stand overnight. Further, the reaction solution was stirred at 60 ° C for 2 hours. After the reaction was completed, the reaction solution was ice-cooled, and water (100 mL) and 1M hydrochloric acid (500 mL) was added, and the mixture was stirred at room temperature for 1 hour. Filtration of the precipitate in the reaction solution The precipitate was washed sequentially with water (50 mL) and diethyl ether (50 mL). The precipitate was dried at 40 ° C under reduced pressure to give a diol (15.4 g).
將該二醇體溶解於二氯甲烷(150mL)中，於冰冷下將二異丙基乙基胺(121mL，0.71mol)及氯甲基甲基醚(36.0mL，0.48mol)加入其中。將該反應液慢慢地升溫至室溫，同時攪拌5小時後，在反應液中加水(100mL)，於減壓下將溶劑餾去至約半量。將該濃縮液以乙酸乙酯(150mL)稀釋，並用10%w/v食鹽水(100mL)、飽和碳酸鈉水溶液(50mL，1次)、飽和氯化銨水溶液(50mL，2次)及飽和食鹽水(50mL)依序洗淨。將該有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。在所得到之殘餘物中添加己烷(300mL)及乙酸乙酯(6mL)之混合溶劑，得到標題化合物(14.5g)。 The diol was dissolved in dichloromethane (150 mL), and diisopropylethylamine (121 mL, 0.71 mol) and chloromethyl methyl ether (36.0 mL, 0.48 mol) were added thereto under ice cooling. The reaction liquid was gradually warmed to room temperature while stirring for 5 hours, and water (100 mL) was added to the reaction liquid, and the solvent was distilled off to about half amount under reduced pressure. The concentrate was diluted with ethyl acetate (150 mL), and brine (100 mL), saturated aqueous sodium carbonate (50 mL, once), saturated aqueous ammonium chloride (50 mL, twice) and saturated salt Water (50 mL) was washed sequentially. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. A mixed solvent of hexane (300 mL) and ethyl acetate (6 mL)
1H NMR(400MHz,CDCl3)：δ3.44(6H,s),4.62(4H,s),4.77(4H,s),7.68(2H,s). 1 H NMR (400 MHz, CDCl 3 ): δ 3.44 (6H, s), 4.62 (4H, s), 4.77 (4H, s), 7.68 (2H, s).
(參考例6)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-6-(溴甲基)-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 6) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-6-(bromomethyl)-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'- Piper
(參考例6a){(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲醇 (Reference Example 6a) {(1S,3'R,4'S,5'S,6'R)-3',4',5'-Phenyl(benzyloxy)-6'-[(1R)-1-( Benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-6-yl }Methanol
將在參考例4中所得到之化合物(14.0g，41.1mmol)溶解於THF(200mL)中，於氮氣環境下，在-78℃將正丁基鋰之己烷溶液(1.59M，25.8mL，41.1mmol)以15分鐘滴入。滴入終了後，將反應液於-78℃攪拌45分鐘，將在參考例1中所得到之化合物(20.6g，37.4mmol)之THF(50mL)溶液滴入，進一步攪拌1小時。反應終了後，在反應液中添加飽和氯化銨水溶液(50mL)，升溫至室溫後，以乙酸乙酯(100mL)將反應液稀釋，並用飽和食鹽水(50mL，2次)洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。 The compound obtained in Reference Example 4 (14.0 g, 41.1 mmol) was dissolved in THF (200 mL), hexane solution of n-butyllithium (1.59 M, 25.8 mL, at -78 ° C under nitrogen atmosphere. 41.1 mmol) was added dropwise over 15 minutes. After the completion of the dropwise addition, the reaction mixture was stirred at -78 ° C for 45 minutes, and a solution of the compound (20.6 g, 37.4 mmol) in THF (50 mL) was added dropwise. After the completion of the reaction, a saturated aqueous solution of ammonium chloride (50 mL) was added, and the mixture was evaporated to room temperature. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (50 mL, twice). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure.
將所得到之粗生成物(33.3g)溶解於甲醇(80mL)及THF(80mL)之混合溶劑中，於室溫下將對甲苯磺酸一水合物(21.3g，112mmol)加入反應液中。將反應液在氮氣環境下，於60℃攪拌3小時後，冷卻至室溫，並添加飽和碳酸氫鈉水溶液(80mL)。將該反應液於減壓下濃縮至約半量。將濃縮物用乙酸乙酯(100mL)稀釋，並以飽和碳酸鈉水溶液(50mL)及飽和食鹽水(50mL，2次) 依序洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑，將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，98：2→70：30(濃度梯度)V/V)精製，得到標題化合物(17.2g)。 The obtained crude product (33.3 g) was dissolved in a mixed solvent of methanol (80 mL) and THF (80 mL), and p-toluenesulfonic acid monohydrate (21.3 g, 112 mmol) was added to the reaction mixture at room temperature. The reaction solution was stirred at 60 ° C for 3 hours under a nitrogen atmosphere, and then cooled to room temperature, and a saturated aqueous sodium hydrogen carbonate solution (80 mL) was added. The reaction solution was concentrated to about half amount under reduced pressure. The concentrate was diluted with ethyl acetate (100 mL) and brine (50 mL) and brine Wash in order. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated to dryness, and the residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate, 98:2→70:30 (concentration gradient) The title compound (17.2 g) was obtained.
1H NMR(400MHz,CDCl3)：δ1.10(3H,d,J=6.6Hz),3.60(1H,dd,J=10.1Hz,9.0Hz),3.77-3.80(1H,m),3.83(1H,d,J=9.8Hz),4.16-4.22(2H,m),4.27(1H,d,J=11.4Hz),4.56(2H,dd,J=17.2Hz,12.5Hz),4.61-4.72(4H,m),4.91(1H,d,J=10.9Hz),4.91(1H,d,J=10.9Hz),4.98(1H,d,J=10.9Hz),5.18(2H,s),6.82(2H,d,J=8.2Hz),7.11-7.20(6H,m),7.25-7.35(14H,m). 1 H NMR (400 MHz, CDCl 3 ): δ 1.10 (3H, d, J = 6.6 Hz), 3.60 (1H, dd, J = 10.1 Hz, 9.0 Hz), 3.77-3.80 (1H, m), 3.83 ( 1H, d, J = 9.8 Hz), 4.16 - 4.22 (2H, m), 4.27 (1H, d, J = 11.4 Hz), 4.56 (2H, dd, J = 17.2 Hz, 12.5 Hz), 4.61-4.72 ( 4H, m), 4.91 (1H, d, J = 10.9 Hz), 4.91 (1H, d, J = 10.9 Hz), 4.98 (1H, d, J = 10.9 Hz), 5.18 (2H, s), 6.82 ( 2H,d,J=8.2Hz), 7.11-7.20(6H,m), 7.25-7.35(14H,m).
(參考例6b)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-6-(溴甲基)-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 6b) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-6-(bromomethyl)-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'- Piper
將在參考例6a中所得到之化合物溶解於二氯甲烷(170mL)中，於冰冷下添加四溴化碳(11.9g，36mmol)及三苯膦(9.5g，36mmol)。將反應液於氮氣環境下，在冰冷下攪拌2小時後，升溫至室溫，並以水(100mL，2次)洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑，將所得到之殘餘物以矽膠急速管柱層析(己 烷：乙酸乙酯，98：2→80：20(濃度梯度)V/V)精製，得到標題化合物(14.1g)。 The compound obtained in Reference Example 6a was dissolved in dichloromethane (170 mL), and carbon tetrabromide (11.9 g, 36 mmol) and triphenylphosphine (9.5 g, 36 mmol) were added under ice cooling. The reaction solution was stirred under ice cooling for 2 hours under ice-cooling, and then warmed to room temperature and washed with water (100 mL, twice). After drying the organic layer with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The title compound (14.1 g) was obtained from EtOAc (EtOAc)
1H NMR(400MHz,CDCl3)：δ1.10(3H,d,J=6.7Hz),3.60(1H,dd,J=10.2Hz,9.0Hz),3.77-3.81(2H,m),4.15-4.21(4H,m),4.46(1H,d,J=10.2Hz),4.54-4.57(2H,m),4.62(1H,d,J=11.3Hz),4.67(1H,d,J=11.0Hz),4.90(1H,d,J=11.0Hz),4.91(1H,d,J=10.8Hz),4.98(1H,d,J=10.8Hz),5.15(2H,s),6.83(2H,d,J=6.7Hz),7.11-7.19(6H,m),7.26-7.35(14H,m). 1 H NMR (400 MHz, CDCl 3 ): δ 1.10 (3H, d, J = 6.7 Hz), 3.60 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.77-3.81 (2H, m), 4.15- 4.21(4H,m), 4.46(1H,d,J=10.2Hz), 4.54-4.57(2H,m),4.62(1H,d,J=11.3Hz),4.67(1H,d,J=11.0Hz ), 4.90 (1H, d, J = 11.0 Hz), 4.91 (1H, d, J = 10.8 Hz), 4.98 (1H, d, J = 10.8 Hz), 5.15 (2H, s), 6.83 (2H, d , J = 6.7 Hz), 7.11-7.19 (6H, m), 7.26-7.35 (14H, m).
(參考例7)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-6-(溴甲基)-5-甲基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 7) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-6-(bromomethyl)-5-methyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2' -pyran
(參考例7a){(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-溴-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲醇 (Reference Example 7a) {(1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-( Benzyloxy)ethyl]-5-bromo-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-6-yl }Methanol
將在參考例5中所得到之化合物(20.0g，52.1mmol)溶解於THF(200mL)及甲苯(200mL)之混合溶劑中，於氮氣環境下，在-78℃將正丁基鋰之己烷溶液(1.59M，32.5mL，52.1mmol)以15分鐘滴入。滴入終了後，將反應液於-78℃攪拌1小時，並將在參考例1中所得到之化合物(25.0g，46.4mmol)之甲苯(100mL)溶液滴入。進一步將反應液於-78℃攪拌1小時半，並於升溫至0℃後攪拌5分鐘。反應終了後，在反應液中添加飽和氯化銨水溶液(50mL)，用乙酸乙酯(100mL)稀釋，並以飽和食鹽水(50mL，2次)洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。 The compound obtained in Reference Example 5 (20.0 g, 52.1 mmol) was dissolved in a mixed solvent of THF (200 mL) and toluene (200 mL), and n-butyllithium hexane at -78 ° C under nitrogen atmosphere. The solution (1.59 M, 32.5 mL, 52.1 mmol) was added dropwise over 15 minutes. After the completion of the dropwise addition, the reaction mixture was stirred at -78 ° C for 1 hour, and a solution of the compound (25.0 g, 46.4 mmol) in toluene (100 mL) obtained in Reference Example 1 was dropped. The reaction solution was further stirred at -78 ° C for 1 hour and a half, and stirred at 0 ° C for 5 minutes. After the completion of the reaction, a saturated aqueous solution of ammonium chloride (50 mL) was added, and the mixture was diluted with ethyl acetate (100 mL) and washed with brine (50 mL, twice). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure.
將所得到之粗生成物溶解於甲醇(150mL)及THF(150mL)之混合溶劑中，於室溫下添加對甲苯磺酸一水合物(27.0g，142mmol)。將反應液於氮氣環境下，在60℃攪拌2小時半後，於室溫下靜置整夜。反應終了後，添加飽和碳酸氫鈉水溶液(80mL)，並於減壓下濃縮至約半量。將其以乙酸乙酯(100mL)稀釋，並用飽和碳酸鈉水溶液(50mL)及飽和食鹽水(50mL，2次)依序洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑，將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，98：2→70：30(濃度梯度)V/V)精製，得到標題化合物(22.0g)。 The obtained crude product was dissolved in a mixed solvent of methanol (150 mL) and THF (150 mL), and p-toluenesulfonic acid monohydrate (27.0 g, 142 mmol) was added at room temperature. The reaction solution was stirred at 60 ° C for 2 hours and a half under a nitrogen atmosphere, and allowed to stand at room temperature overnight. After the reaction was completed, a saturated aqueous solution of sodium hydrogencarbonate (80 mL) was evaporated and evaporated. This was diluted with ethyl acetate (100 mL), and washed sequentially with saturated aqueous sodium carbonate (50 mL) and brine (50 mL, twice). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated to dryness, and the residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate, 98:2→70:30 (concentration gradient) The title compound (22.0 g) was obtained.
1H NMR(400MHz,CDCl3)：δ1.10(3H,d,J=6.7Hz),3.60(1H,dd,J=10.2Hz,9.4Hz),3.75-3.80(1H,m),3.82(1H,d,J=6.6Hz),4.15-4.22(2H,m),4.27(1H,d, J=11.3Hz),4.55-4.71(6H,m),4.90(1H,d,J=11.0Hz),4.91(1H,d,J=10.7Hz),4.97(1H,d,J=10.7Hz),5.17(2H,s),6.81(2H,d,J=7.1Hz),7.11-7.20(6H,m),7.28-7.43(14H,m)；MS(ESI)m/z：751(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.10 (3H, d, J = 6.7 Hz), 3.60 (1H, dd, J = 10.2 Hz, 9.4 Hz), 3.75-3.80 (1H, m), 3.82 ( 1H,d,J=6.6Hz), 4.15-4.22(2H,m), 4.27(1H,d,J=11.3Hz), 4.55-4.71(6H,m),4.90(1H,d,J=11.0Hz ), 4.91 (1H, d, J = 10.7 Hz), 4.97 (1H, d, J = 10.7 Hz), 5.17 (2H, s), 6.81 (2H, d, J = 7.1 Hz), 7.11-7.20 (6H , m), 7.28-7.43 (14H, m); MS (ESI) m/z: 751 (M+H) + .
(參考例7b)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-溴-6-[(甲氧基甲氧基)甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 7b) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-5-bromo-6-[(methoxymethoxy)methyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzo Furan-1,2'-pyranose]
將在參考例7a中所得到之化合物(6.18g，8.22mmol)溶解於二氯甲烷(41mL)，於室溫下添加二異丙基乙基胺(14.0mL，82.3mmol)及氯甲基甲基醚(4.37mL，57.5mmol)。將反應液於氮氣環境下，在室溫攪拌2小時半後，冰冷並加水(10mL)，於減壓下除去溶劑至約半量。將所得到之殘餘物用乙酸乙酯(60mL)稀釋，並以飽和氯化銨水溶液(50mL)及飽和食鹽水(50mL)依序洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑，將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，100：0→80：20(濃度梯度)V/V)精製，得到標題化合物(4.63g)。 The compound obtained in Reference Example 7a (6.18 g, 8.22 mmol) was dissolved in dichloromethane (41 mL), and diisopropylethylamine (14.0 mL, 82.3 mmol) and chloromethylmethyl group were added at room temperature. Base ether (4.37 mL, 57.5 mmol). The reaction solution was stirred at room temperature for 2 hours and a half over N.sub.2, and then evaporated and evaporated. The obtained residue was diluted with ethyl acetate (60 mL) and washed successively with saturated aqueous sodium chloride (50 mL) and brine (50 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated to dryness, and the residue obtained was purified by silica gel chromatography (hexane: ethyl acetate, 100:0→80:20 (concentration gradient) The title compound (4.63 g) was obtained.
1H NMR(400MHz,CDCl3)：δ1.11(3H,d,J=6.6Hz),3.39(3H,s),3.63(1H,dd,J=10.2Hz,9.0Hz),3.77-3.83(1H,m),3.86(1H,d,J=9.4Hz),4.14-4.22(3H,m),4.53-4.69(7H,m),4.72(2H,s),4.90(2H,d,J=10.2Hz),4.97(1H,d,J=10.2Hz),5.18(2H,brs),6.67-6.82(2H,m),7.10-7.21(5H,m),7.28-7.34(14H,m),7.46(1H,brs)；MS(FAB)m/z：795(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.11 (3H, d, J = 6.6 Hz), 3.39 (3H, s), 3.63 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.77-3.83 ( 1H, m), 3.86 (1H, d, J = 9.4 Hz), 4.14 - 4.22 (3H, m), 4.53-4.69 (7H, m), 4.72 (2H, s), 4.90 (2H, d, J = 10.2 Hz), 4.97 (1H, d, J = 10.2 Hz), 5.18 (2H, brs), 6.67-6.82 (2H, m), 7.10-7.21 (5H, m), 7.28-7.34 (14H, m), 7.46 (1H, brs); MS (FAB) m/z: 795 (M+H) + .
(參考例7c)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-6-[(甲氧基甲氧基)甲基]-5-甲基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 7c) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-6-[(methoxymethoxy)methyl]-5-methyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzene And furan-1,2'-pyranose]
在參考例7b中所得到之化合物(4.63g，5.82mmol)、甲基硼酸酐(2.44mL，17.46mmol)、碳酸鉀(2.41g，17.46mmol)及肆(三苯膦)鈀(0)(672mg，0.58mmol)之混合物中，於氮氣環境下添加1,4-二烷(30mL)。將該反應液於氮氣環境下，在100℃攪拌4小時，進一步冷卻至室溫，同時靜置整夜。反應終了後，將反應液冰冷，並在其中加水(10mL)，及用乙酸乙酯(60mL)稀釋。將該反應液以飽和食鹽水(50mL)洗淨，將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑，將所得到之殘餘物 以矽膠急速管柱層析(己烷：乙酸乙酯，100：0→75：25(濃度梯度)V/V)精製，得到標題化合物(3.56g)。 The compound obtained in Reference Example 7b (4.63 g, 5.82 mmol), methyl boronic anhydride (2.44 mL, 17.46 mmol), potassium carbonate (2.41 g, 17.46 mmol), and yttrium (triphenylphosphine) palladium (0) ( In a mixture of 672 mg, 0.58 mmol), 1,4-two was added under a nitrogen atmosphere. Alkane (30 mL). The reaction solution was stirred at 100 ° C for 4 hours under a nitrogen atmosphere, and further cooled to room temperature while standing overnight. After the reaction was completed, the reaction mixture was ice-cooled, and water (10 mL), and ethyl acetate (60 mL). The reaction mixture was washed with saturated brine (50 mL), and then dried over anhydrous sodium sulfate. The solvent was evaporated. Ethyl acetate, 100:0:75:25 (concentration gradient) V/V) to give the title compound (3.56 g).
1H NMR(400MHz,CDCl3)：δ1.13(3H,d,J=7.0Hz),2.37(3H,s),3.37(3H,s),3.64(1H,dd,J=10.2Hz,9.0Hz),3.79-3.84(1H,m),3.88(1H,d,J=9.7Hz),4.14(2H,t,J=9.9Hz),4.21(1H,dd,J=10.2Hz,1.2Hz),4.50-4.63(5H,m),4.66(2H,s),4.67-4.70(1H,m),4.87(1H,d,J=10.6Hz),4.91(1H,d,J=11.0Hz),4.96(1H,d,J=11.0Hz),5.18(2H,brs),6.80(2H,d,J=6.7Hz),7.08-7.21(6H,m),7.27-7.34(14H,m)；MS(ESI)m/z：731(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.13 (3H, d, J = 7.0 Hz), 2.37 (3H, s), 3.37 (3H, s), 3.64 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.79-3.84 (1H, m), 3.88 (1H, d, J = 9.7 Hz), 4.14 (2H, t, J = 9.9 Hz), 4.21 (1H, dd, J = 10.2 Hz, 1.2 Hz) , 4.50-4.63 (5H, m), 4.66 (2H, s), 4.67-4.70 (1H, m), 4.87 (1H, d, J = 10.6 Hz), 4.91 (1H, d, J = 11.0 Hz), 4.96 (1H, d, J = 11.0 Hz), 5.18 (2H, brs), 6.80 (2H, d, J = 6.7 Hz), 7.08-7.21 (6H, m), 7.27-7.34 (14H, m); MS (ESI) m/z: 731 (M+H) + .
(參考例7d){(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-甲基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲醇 (Reference Example 7d) {(1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-( Benzyloxy)ethyl]-5-methyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-6- Methanol
將在參考例7c中所得到之化合物(3.56g，4.87mmol)溶解於甲醇(19mL)及1,4-二烷(2mL)之混合溶劑中，於室溫下慢慢地添加氯化氫之1,4-二烷溶液(4M，19mL)。將該反應液於室溫下攪拌2小時半，反應終了後，在反應液中，冰冷下添加飽和碳酸氫鈉水溶液(50mL)，進行中和。從該反應液中於減壓下除去溶 劑，將所得到之殘餘物用乙酸乙酯(50mL)稀釋，並以飽和食鹽水(50mL)洗淨2次。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑，將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，100：0→60：40(濃度梯度)V/V)精製，得到標題化合物(2.83g)。 The compound obtained in Reference Example 7c (3.56 g, 4.87 mmol) was dissolved in methanol (19 mL) and 1,4- In a mixed solvent of alkane (2 mL), slowly add 1,4-dihydrogen chloride at room temperature. Alkane solution (4M, 19 mL). The reaction mixture was stirred at room temperature for 2 hours and a half. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution (50 mL) was added to the reaction mixture, and the mixture was neutralized. The solvent was removed from the reaction mixture under reduced pressure, and ethyl acetate (50 mL) was evaporated. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated to dryness, and the residue obtained was purified by silica gel chromatography (hexane: ethyl acetate, 100:0→60:40 (concentration gradient) The title compound (2.83 g) was obtained.
1H NMR(400MHz,CDCl3)：δ1.12(3H,d,J=6.7Hz),2.36(3H,s),3.62(1H,dd,J=10.2Hz,9.0Hz),3.78-3.83(1H,m),3.86(1H,d,J=9.3Hz),4.16-4.24(3H,m),4.52-4.63(5H,m),4.68(1H,d,J=11.0Hz),4.89(1H,d,J=7.9Hz),4.92(1H,d,J=10.7Hz),4.97(1H,d,J=10.7Hz),5.18(2H,brs),6.79-6.81(2H,m),7.07-7.21(7H,m),7.26-7.35(13H,m)；MS(FAB)m/z：687(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.12 (3H, d, J = 6.7 Hz), 2.36 (3H, s), 3.62 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.78-3.83 ( 1H, m), 3.86 (1H, d, J = 9.3 Hz), 4.16-4.24 (3H, m), 4.52-4.63 (5H, m), 4.68 (1H, d, J = 11.0 Hz), 4.89 (1H) , d, J = 7.9 Hz), 4.92 (1H, d, J = 10.7 Hz), 4.97 (1H, d, J = 10.7 Hz), 5.18 (2H, brs), 6.79-6.81 (2H, m), 7.07 -7.21 (7H, m), 7.26-7.35 (13H, m); MS (FAB) m/z: 687 (M+H) + .
(參考例7e)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-6-(溴甲基)-5-甲基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 7e) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-6-(bromomethyl)-5-methyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2' -pyran
將在參考例7d中所得到之化合物(2.83g，4.12mmol)溶解於二氯甲烷(30mL)中，於冰冷下添加四溴化碳(2.46g，7.42mmol)及三苯膦(1.95g，7.42mmol)。將該反應液於氮氣環境下，在冰冷下攪拌10分 鐘。反應終了後，在反應液中添加水(20mL)及飽和食鹽水(20mL)，並以二氯甲烷(20mL)萃取2次。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑，將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，100：0→75：25(濃度梯度)V/V)精製，得到標題化合物(2.52g)。 The compound obtained in Reference Example 7d (2.83 g, 4.12 mmol) was dissolved in methylene chloride (30 mL), and carbon tetrabromide (2.46 g, 7.42 mmol) and triphenylphosphine (1.95 g, 7.42 mmol). The reaction solution was stirred under ice for 10 minutes under ice cooling. bell. After the reaction was completed, water (20 mL) and saturated brine (20 mL) were added to the mixture, and the mixture was extracted twice with dichloromethane (20 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated to dryness, and the residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate, 100:0→75:25 (concentration gradient) The title compound (2.52 g) was obtained.
1H NMR(400MHz,CDCl3)：δ1.12(3H,d,J=6.6Hz),2.45(3H,s),3.61(1H,dd,J=10.2Hz,9.0Hz),3.77-3.83(1H,m),3.83(1H,d,J=9.4Hz),4.12-4.19(2H,m),4.21(1H,dd,J=10.2Hz,1.2Hz),4.45(1H,d,J=10.2Hz),4.51(1H,d,J=10.1Hz),4.54-4.61(3H,m),4.68(1H,d,J=10.9Hz),4.88(1H,d,J=7.4Hz),4.89(1H,d,J=10.7Hz),4.98(1H,d,J=10.7Hz),5.15(2H,dd,J=16.8Hz,13.0Hz),6.81-6.84(2H,m),7.08-7.21(7H,m),7.25-7.35(13H,m)；MS(ESI)m/z：749(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.12 (3H, d, J = 6.6 Hz), 2.45 (3H, s), 3.61 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.77-3.83 ( 1H, m), 3.83 (1H, d, J = 9.4 Hz), 4.12-4.19 (2H, m), 4.21 (1H, dd, J = 10.2 Hz, 1.2 Hz), 4.45 (1H, d, J = 10.2) Hz), 4.51 (1H, d, J = 10.1 Hz), 4.54-4.61 (3H, m), 4.68 (1H, d, J = 10.9 Hz), 4.88 (1H, d, J = 7.4 Hz), 4.89 ( 1H, d, J = 10.7 Hz), 4.98 (1H, d, J = 10.7 Hz), 5.15 (2H, dd, J = 16.8 Hz, 13.0 Hz), 6.81-6.84 (2H, m), 7.08-7.21 ( 7H, m), 7.25-7.35 (13H, m); MS (ESI) m/z: 749 (M+H) + .
(參考例8)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-6-(溴甲基)-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 8) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-6-(bromomethyl)-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran]
使用在參考例2中所得到之化合物(623mg，2.04mmol)及在參考例1中所得到之化合物(1.00g，1.86mmol)，以與參考例6同樣之方式得到標題化合物(421mg)。 The title compound (421 mg) was obtained from the compound obtained from the title compound (623 mg, 2.04 mmol).
1H NMR(400MHz,CDCl3)：δ1.12(3H,d,J=6.7Hz),3.62(1H,dd,J=10.2Hz,9.0Hz),3.77-3.88(2H,m),4.10-4.26(3H,m),4.41-4.62(5H,m),4.68(1H,d,J=11.1Hz),4.90(1H,d,J=11.0Hz),4.91(1H,d,J=11.1Hz),4.98(1H,d,J=11.0Hz),5.17(1H,d,J=13.0Hz),5.21(1H,d,J=13.0Hz),6.80(2H,d,J=6.2Hz),7.09-7.43(21H,m). 1 H NMR (400MHz, CDCl 3 ): δ1.12 (3H, d, J = 6.7Hz), 3.62 (1H, dd, J = 10.2Hz, 9.0Hz), 3.77-3.88 (2H, m), 4.10- 4.26(3H,m),4.41-4.62(5H,m),4.68(1H,d,J=11.1Hz), 4.90(1H,d,J=11.0Hz),4.91(1H,d,J=11.1Hz ), 4.98 (1H, d, J = 11.0 Hz), 5.17 (1H, d, J = 13.0 Hz), 5.21 (1H, d, J = 13.0 Hz), 6.80 (2H, d, J = 6.2 Hz), 7.09-7.43 (21H, m).
(參考例9)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基-6'-[(1R)-1-(苯甲氧基)乙基]-6-(溴甲基)-5-氟-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 9) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-para (benzyloxy-6'-[(1R)-1-(phenyl) Oxy)ethyl]-6-(bromomethyl)-5-fluoro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-piperidin Mum]
使用在參考例3中所得到之化合物(659mg，2.04mmol)及在參考例1中所得到之化合物(1.00g，1.86mmol)，以與參考例6同樣之方式得到標題化合物(173mg)。 The title compound (173 mg) was obtained from the title compound ( 173 mg).
1H NMR(400MHz,CDCl3)：δ1.10(3H,d,J=6.6Hz),3.59(1H,dd,J=10.2Hz,9.0Hz),3.76-3.83(2H,m),4.13-4.23(3H,m),4.39(1H,d,J=10.7Hz),4.48(1H,d, J=10.7Hz),4.52-4.69(4H,m),4.90(2H,d,J=11.3Hz),4.98(1H,d,J=10.6Hz),5.15(2H,s),6.81-6.87(2H,m),6.94(1H,d,J=9.3Hz),7.12-7.38(19H,m). 1 H NMR (400 MHz, CDCl 3 ): δ 1.10 (3H, d, J = 6.6 Hz), 3.59 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.76-3.83 (2H, m), 4.13 4.23(3H,m), 4.39(1H,d,J=10.7Hz), 4.48(1H,d,J=10.7Hz),4.52-4.69(4H,m),4.90(2H,d,J=11.3Hz ), 4.98 (1H, d, J = 10.6 Hz), 5.15 (2H, s), 6.81-6.87 (2H, m), 6.94 (1H, d, J = 9.3 Hz), 7.12 - 7.38 (19H, m) .
(參考例10)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-6-(溴甲基)-5-乙基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 10) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-6-(bromomethyl)-5-ethyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2' -pyran
(參考例10a)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-6-[(甲氧基甲氧基)甲基]-5-乙烯基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 10a) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-6-[(methoxymethoxy)methyl]-5-vinyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzene And furan-1,2'-pyranose]
使用在參考例7b中所得到之化合物(0.36g，0.46mmol)、4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧雜硼雜環戊烷(0.17mL，1.0mmol)、碳酸鉀(0.13g，0.94mmol)及肆(三苯膦)鈀(0)(53mg，0.046mmol)，以與參考例7c同樣之方式得到標題化合物(0.30g)。 The compound obtained in Reference Example 7b (0.36 g, 0.46 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane ( 0.17 mL, 1.0 mmol), potassium carbonate (0.13 g, 0.94 mmol) and EtOAc (triphenylphosphine) palladium (0) (53 mg, 0.046 mmol).
1H NMR(400MHz,CDCl3)：δ1.12(3H,d,J=6.7Hz),3.36(3H,s),3.63(1H,dd,J=10.0Hz,9.2Hz),3.80-3.82(1H,m),3.88(1H,d,J=9.4Hz),4.10-4.20(3H,m),4.22(1H,dd,J=10.2Hz,1.2Hz),4.53-4.72(9H,m),4.89(1H,d,J=10.9Hz),4.91(1H,d,J=11.0Hz),4.97(1H,d,J=10.5Hz),5.21(1H,brs),5.38(1H,dd,J=10.9Hz,1.1Hz),5.71(1H,dd,J=17.4Hz,1.3Hz),6.78-6.81(2H,m),7.00-7.21(6H,m),7.25-7.33(14H,m)；MS(ESI)m/z：743(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.12 (3H, d, J = 6.7 Hz), 3.36 (3H, s), 3.63 (1H, dd, J = 10.0 Hz, 9.2 Hz), 3.80-3.82 ( 1H, m), 3.88 (1H, d, J = 9.4 Hz), 4.10-4.20 (3H, m), 4.22 (1H, dd, J = 10.2 Hz, 1.2 Hz), 4.53-4.72 (9H, m), 4.89 (1H, d, J = 10.9 Hz), 4.91 (1H, d, J = 11.0 Hz), 4.97 (1H, d, J = 10.5 Hz), 5.21 (1H, brs), 5.38 (1H, dd, J = 10.9 Hz, 1.1 Hz), 5.71 (1H, dd, J = 17.4 Hz, 1.3 Hz), 6.78-6.81 (2H, m), 7.00-7.21 (6H, m), 7.25-7.33 (14H, m); MS (ESI) m / z: 743 (M + H) + .
(參考例10b)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-乙基-6-[(甲氧基甲氧基)甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 10b) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-5-ethyl-6-[(methoxymethoxy)methyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzene And furan-1,2'-pyranose]
將在參考例10a中所得到之化合物(0.30g，0.40mmol)溶解於甲醇(4mL)及THF(2mL)之混合溶劑中，於氮氣環境下將鈀/絲心蛋白(fibroin)觸媒(0.030g)加入其中。將其於氫氣環境下攪拌8小時。過濾該反應液，並於減壓下餾去濾液之溶劑。將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，98：2→70：30(濃度梯度)V/V)精製，得到標題化合物(0.25g)。 The compound (0.30 g, 0.40 mmol) obtained in Reference Example 10a was dissolved in a mixed solvent of methanol (4 mL) and THF (2 mL), and palladium/fibroin catalyst (0.030) under a nitrogen atmosphere. g) Join it. This was stirred under a hydrogen atmosphere for 8 hours. The reaction solution was filtered, and the solvent of the filtrate was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(400MHz,CDCl3)：δ1.13(3H,d,J=6.6Hz),1.25(3H,t,J=7.6Hz),2.73(2H,q,J=7.4Hz),3.37(3H,s),3.63(1H,dd,J=9.9Hz,9.1Hz),3.79-3.84(1H,m),3.88(1H,d,J=9.8Hz),4.10-4.19(2H,m),4.22(1H,dd,J=10.2Hz,1.2Hz),4.52-4.72(8H,m),4.88(1H,d,J=11.0Hz),4.91(1H,d,J=10.6Hz),4.97(1H,d,J=10.6Hz),5.16(1H,d,J=12.6Hz),5.21(1H,d,J=12.1Hz),6.75-6.77(2H,m),7.08-7.15(4H,m),7.18-7.21(2H,m),7.27-7.35(14H,m)；MS(ESI)m/z：745(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.13 (3H, d, J = 6.6 Hz), 1.25 (3H, t, J = 7.6 Hz), 2.73 (2H, q, J = 7.4 Hz), 3.37 ( 3H, s), 3.63 (1H, dd, J = 9.9 Hz, 9.1 Hz), 3.79-3.84 (1H, m), 3.88 (1H, d, J = 9.8 Hz), 4.10-4.19 (2H, m), 4.22 (1H, dd, J = 10.2 Hz, 1.2 Hz), 4.52-4.72 (8H, m), 4.88 (1H, d, J = 11.0 Hz), 4.91 (1H, d, J = 10.6 Hz), 4.97 ( 1H, d, J = 10.6 Hz), 5.16 (1H, d, J = 12.6 Hz), 5.21 (1H, d, J = 12.1 Hz), 6.75-6.77 (2H, m), 7.08-7.15 (4H, m ), 7.18-7.21 (2H, m), 7.27-7.35 (14H, m); MS (ESI) m/z: 745 (M+H) + .
(參考例10c){(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-乙基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲醇 (Reference Example 10c) {(1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-( Benzyloxy)ethyl]-5-ethyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-6- Methanol
使用在參考例10b中所得到之化合物(0.66g，0.89mmol)、甲醇(4mL)及氯化氫之1,4-二烷溶液(4M，4mL)，以與參考例7d同樣之方式得到標題化合物(0.56g)。 The compound obtained in Reference Example 10b (0.66 g, 0.89 mmol), methanol (4 mL) and hydrogen chloride 1,4-di The title compound (0.56 g) was obtained.
1H NMR(400MHz,CDCl3)：δ1.12(3H,d,J=6.6Hz),1.25(3H,t,J=7.4Hz),2.72(2H,q,J=7.4Hz),3.62(1H,dd,J=10.1Hz,9.0Hz),3.79-3.84(1H,m),3.87(1H,d, J=9.8Hz),4.17-4.22(2H,m),4.24(1H,dd,J=10.3Hz,1.3Hz),4.53-4.70(6H,m),4.90(1H,d,J=11.0Hz),4.92(1H,d,J=11.3Hz),4.98(1H,d,J=10.5Hz),5.20(2H,brs),6.75-6.78(2H,m),7.08-7.21(7H,m),7.27-7.37(13H,m). 1 H NMR (400 MHz, CDCl 3 ): δ 1.12 (3H, d, J = 6.6 Hz), 1.25 (3H, t, J = 7.4 Hz), 2.72 (2H, q, J = 7.4 Hz), 3.62 ( 1H, dd, J = 10.1 Hz, 9.0 Hz), 3.79-3.84 (1H, m), 3.87 (1H, d, J = 9.8 Hz), 4.17-4.22 (2H, m), 4.24 (1H, dd, J = 10.3 Hz, 1.3 Hz), 4.53-4.70 (6H, m), 4.90 (1H, d, J = 11.0 Hz), 4.92 (1H, d, J = 11.3 Hz), 4.98 (1H, d, J = 10.5) Hz), 5.20 (2H, brs), 6.75-6.78 (2H, m), 7.08-7.21 (7H, m), 7.27-7.37 (13H, m).
(參考例10d)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-6-(溴甲基)-5-乙基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 10d) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-6-(bromomethyl)-5-ethyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2' -pyran
使用在參考例10c中所得到之化合物(0.25g，0.34mmol)，以與參考例7e同樣之方式得到標題化合物(0.16g)。 The title compound (0.16 g) was obtained from the title compound (m.
1H NMR(400MHz,CDCl3)：δ1.12(3H,d,J=6.7Hz),1.31(3H,t,J=7.6Hz),2.81(2H,q,J=7.6Hz),3.61(1H,dd,J=10.2Hz,9.0Hz),3.81(1H,dd,J=6.7Hz,1.2Hz),3.84(1H,d,J=9.4Hz),4.12-4.19(2H,m),4.22(1H,dd,J=10.3Hz,1.4Hz),4.48-4.62(5H,m),4.68(1H,d,J=11.3Hz),4.90(1H,d,J=10.9Hz),4.91(1H,d,J=11.0Hz),4.99(1H,d,J=11.0Hz),5.14(1H,d,J=12.5Hz),5.19(1H,d,J=12.5Hz),6.78-6.80(2H,m),7.09-7.21(8H,m),7.25-7.35(12H,m)； MS(ESI)m/z：763(M+H)+. 1 H NMR (400MHz, CDCl 3 ): δ1.12 (3H, d, J = 6.7Hz), 1.31 (3H, t, J = 7.6Hz), 2.81 (2H, q, J = 7.6Hz), 3.61 ( 1H, dd, J = 10.2 Hz, 9.0 Hz), 3.81 (1H, dd, J = 6.7 Hz, 1.2 Hz), 3.84 (1H, d, J = 9.4 Hz), 4.12-4.19 (2H, m), 4.22 (1H, dd, J = 10.3 Hz, 1.4 Hz), 4.48-4.62 (5H, m), 4.68 (1H, d, J = 11.3 Hz), 4.90 (1H, d, J = 10.9 Hz), 4.91 (1H) ,d,J=11.0Hz),4.99(1H,d,J=11.0Hz), 5.14(1H,d,J=12.5Hz), 5.19(1H,d,J=12.5Hz),6.78-6.80(2H , m), 7.09-7.21 (8H, m), 7.25-7.35 (12H, m); MS (ESI) m/z: 763 (M+H) + .
(參考例11)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-6-(溴甲基)-5-異丙烯基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 11) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-6-(bromomethyl)-5-isopropenyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2 '-pyran
使用在參考例7b中所得到之化合物(0.50g，0.63mmol)及2-異丙烯基-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(0.24g，1.2mmol)，以與參考例7c至參考例7e同樣之方式得到標題化合物(0.38g)。 The compound obtained in Reference Example 7b (0.50 g, 0.63 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were used. (0.24 g, 1.2 mmol).
1H NMR(400MHz,CDCl3)：δ1.12(3H,d,J=6.6Hz),2.13(3H,s),3.61(1H,dd,J=10.2Hz,9.0Hz),3.81(1H,dd,J=6.7Hz,1.2Hz),3.86(1H,d,J=9.4Hz),4.15-4.20(2H,m),4.23(1H,dd,J=10.4Hz,1.4Hz),4.52(1H,d,J=9.7Hz),4.54-4.62(4H,m),4.67(1H,d,J=10.9Hz),4.90(1H,d,J=10.9Hz),4.91(1H,d,J=10.9Hz),4.98-5.01(2H,m),5.12(1H,d,J=12.9Hz),5.18(1H,d,J=13.3Hz),5.32-5.33(1H,m),6.77-6.79(2H,m),7.03(1H,s),7.09-7.20(6H,m),7.25-7.37(13H,m)；MS(ESI)m/z：713(M+H)+. 1 H NMR (400MHz, CDCl 3 ): δ1.12 (3H, d, J = 6.6Hz), 2.13 (3H, s), 3.61 (1H, dd, J = 10.2Hz, 9.0Hz), 3.81 (1H, Dd, J = 6.7 Hz, 1.2 Hz), 3.86 (1H, d, J = 9.4 Hz), 4.15 - 4.20 (2H, m), 4.23 (1H, dd, J = 10.4 Hz, 1.4 Hz), 4.52 (1H) , d, J = 9.7 Hz), 4.54-4.62 (4H, m), 4.67 (1H, d, J = 10.9 Hz), 4.90 (1H, d, J = 10.9 Hz), 4.91 (1H, d, J = 10.9 Hz), 4.98-5.01 (2H, m), 5.12 (1H, d, J = 12.9 Hz), 5.18 (1H, d, J = 13.3 Hz), 5.32 - 5.33 (1H, m), 6.77-6.79 ( 2H, m), 7.03 (1H, s), 7.09-7.20 (6H, m), 7.25-7.37 (13H, m); MS (ESI) m/z: 713 (M+H) + .
(參考例12)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-6-(溴甲基)-5-環丙基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 12) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-6-(bromomethyl)-5-cyclopropyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2 '-pyran
使用在參考例7b中所得到之化合物(0.40g，0.50mmol)及環丙基硼酸(56mg，0.65mmol)，以與參考例7c至參考例7e同樣之方式，得到標題化合物(0.35g)。 Using the compound (0.40 g, 0.50 mmol) obtained from the title compound (b), m.p.
1H NMR(400MHz,CDCl3)：δ0.68-0.78(2H,m),1.06(2H,dd,J=8.6Hz,1.1Hz),1.11(3H,d,J=6.6Hz),2.10-2.17(1H,m),3.61(1H,dd,J=10.1Hz,9.0Hz),3.80(1H,dd,J=6.6Hz,1.2Hz),3.84(1H,d,J=9.3Hz),4.10-4.19(2H,m),4.21(1H,dd,J=10.6Hz,1.1Hz),4.54-4.58(3H,m),4.66-4.70(3H,m),4.89(1H,d,J=10.9Hz),4.91(1H,d,J=10.9Hz),4.98(1H,d,J=10.9Hz),5.11(1H,d,J=12.9Hz),5.16(1H,d,J=12.9Hz),6.77-6.79(2H,m),6.94(1H,s),7.09-7.20(6H,m),7.28-7.35(13H,m). 1 H NMR (400 MHz, CDCl 3 ): δ 0.68-0.78 (2H, m), 1.06 (2H, dd, J = 8.6 Hz, 1.1 Hz), 1.11 (3H, d, J = 6.6 Hz), 2.10- 2.17 (1H, m), 3.61 (1H, dd, J = 10.1 Hz, 9.0 Hz), 3.80 (1H, dd, J = 6.6 Hz, 1.2 Hz), 3.84 (1H, d, J = 9.3 Hz), 4.10 -4.19(2H,m), 4.21(1H,dd,J=10.6Hz,1.1Hz),4.54-4.58(3H,m),4.66-4.70(3H,m),4.89(1H,d,J=10.9 Hz), 4.91 (1H, d, J = 10.9 Hz), 4.98 (1H, d, J = 10.9 Hz), 5.11 (1H, d, J = 12.9 Hz), 5.16 (1H, d, J = 12.9 Hz) , 6.77-6.79 (2H, m), 6.94 (1H, s), 7.09-7.20 (6H, m), 7.28-7.35 (13H, m).
(參考例13)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)丙基]-6-(溴甲基)-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 13) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)propyl]-6-(bromomethyl)-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'- Piper
(參考例13a)甲基2,3,4-三-O-苯甲基-α-D-葡哌喃糖醛酸苷 (Reference Example 13a) Methyl 2,3,4-tri-O-benzyl-α-D-glucopyranuronic acid
將甲基2,3,4-三-O-苯甲基-α-D-葡哌喃糖苷(Heterocycles,2007,vol.73,165-168)(9.0g，19mmol)溶解於乙酸乙酯(45mL)及水(17mL)之混合溶劑中，於室溫下添加碳酸氫鈉(3.3g，39mmol)及溴化四正丁基銨(0.25g，0.78mmol)。將該反應液冰冷，添加2,2,6,6-四甲基哌啶-1-氧化物(60mg，0.38mmol)後，以3小時半少量逐次添加次氯酸水溶液(37.5mL)。將該反應液升溫至室溫，同時攪拌2小時，反應終了後，添加1M鹽酸(100mL)，將反應液調為酸性後，用乙酸乙酯(50mL，2次)萃取。將該有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑，在未將標題化合物之粗生成物精製下，直接使用於後續步驟。 Methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (Heterocycles, 2007, vol. 73, 165-168) (9.0 g, 19 mmol) was dissolved in ethyl acetate (45 mL) In a mixed solvent of water (17 mL), sodium hydrogencarbonate (3.3 g, 39 mmol) and tetra-n-butylammonium bromide (0.25 g, 0.78 mmol) were added at room temperature. The reaction solution was ice-cooled, and 2,2,6,6-tetramethylpiperidine-1-oxide (60 mg, 0.38 mmol) was added, and then aqueous hypochloric acid (37.5 mL) was added in a small amount of 3 hours and a half. The reaction mixture was warmed to room temperature and stirred for 2 hours. After the reaction was completed, 1M hydrochloric acid (100 mL) was added, and the reaction mixture was acidified, and then extracted with ethyl acetate (50 mL, twice). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the crude product of the title compound was purified and used in the next step.
(參考例13b)(2S,3S,4S,5R,6S)-3,4,5-參(苯甲氧基)-N,6-二甲氧基-N-甲基四氫-2H-哌喃-2-甲醯胺 (Reference Example 13b) (2S, 3S, 4S, 5R, 6S)-3,4,5-parade (benzyloxy)-N,6-dimethoxy-N-methyltetrahydro-2H-peri Norm-methylamine
將在參考例13a中所得到之化合物(9.0g)溶解於N,N-二甲基甲醯胺(60mL)中，於室溫下添加N,O-二甲基羥基胺1鹽酸鹽(2.8g，29mmol)、三乙基胺(8.0mL，57mmol)、1-羥基苯并***1水合物(3.5g，23mmol)及1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(4.4g，23mmol)。將該反應液於室溫下攪拌18小時，反應終了後，加水(50mL)並以二乙基醚(60mL，2次)萃取。將該有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑，將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，90：10→0：100(濃度梯度)V/V)精製，得到標題化合物(6.6g)。 The compound (9.0 g) obtained in Reference Example 13a was dissolved in N,N-dimethylformamide (60 mL), and N,O-dimethylhydroxylamine 1 hydrochloride was added at room temperature ( 2.8 g, 29 mmol), triethylamine (8.0 mL, 57 mmol), 1-hydroxybenzotriazole 1 hydrate (3.5 g, 23 mmol) and 1-ethyl-3-(3-dimethylaminopropyl Carbohydrated diimine hydrochloride (4.4 g, 23 mmol). The reaction mixture was stirred at room temperature for 18 hr. EtOAc (EtOAc) After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated to dryness, and the residue obtained was purified by silica gel chromatography (hexane: ethyl acetate, 90:10→0:100 (concentration gradient) Purification by V/V) gave the title compound (6.6 g).
1H NMR(400MHz,CDCl3)：δ3.24(3H,s),3.43(3H,s),3.61(1H,dd,J=9.4Hz,3.5Hz),3.66(3H,s),3.94(1H,t,J=9.4Hz),4.03(1H,t,J=9.4Hz),4.59-4.69(4H,m),4.80-4.82(2H,m),4.84(1H,d,J=10.8Hz),4.97(1H,d,J=10.8Hz),7.21-7.39(15H,m). 1 H NMR (400MHz, CDCl 3 ): δ3.24 (3H, s), 3.43 (3H, s), 3.61 (1H, dd, J = 9.4Hz, 3.5Hz), 3.66 (3H, s), 3.94 ( 1H,t,J=9.4Hz),4.03(1H,t,J=9.4Hz),4.59-4.69(4H,m),4.80-4.82(2H,m),4.84(1H,d,J=10.8Hz ), 4.97 (1H, d, J = 10.8 Hz), 7.21-7.39 (15H, m).
(參考例13c)甲基2,3,4-三-O-苯甲基-7,8-二去氧-α-D-葡萄糖-哌喃型辛-6-酮糖苷 (Reference Example 13c) Methyl 2,3,4-tri-O-benzyl-7,8-dideoxy-α-D-glucose-pyranose-oct-6-ketoglucoside
將在參考例13b中所得到之化合物(1.9g，3.6mmol)溶解於THF(20mL)中，於氮氣環境下，在-78℃將溴化乙基鎂之THF溶液(0.90M，5.2mL，4.7mmol)滴入。將該反應液在-78℃攪拌1小時，反應終了後，添加飽和氯化銨水溶液(10mL)。將該反應液用乙酸乙酯(50mL)萃取，將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，98：2→75：25(濃度梯度)V/V)精製，得到標題化合物(1.2g)。 The compound obtained in Reference Example 13b (1.9 g, 3.6 mmol) was dissolved in THF (20 mL), THF (ethyl acetate) in THF (0.90 M, 5.2 mL, 4.7 mmol) was added dropwise. The reaction solution was stirred at -78 ° C for 1 hour. After the reaction was completed, a saturated aqueous solution of ammonium chloride (10 mL) was added. The reaction mixture was extracted with ethyl acetate (50 mL). The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(400MHz,CDCl3)：δ1.03(3H,t,J=7.2Hz),2.55(2H,dd,J=14.5Hz,7.0Hz),3.40(3H,s),3.54(1H,dd,J=9.4Hz,3.5Hz),3.65(1H,dd,J=10.0Hz,8.8Hz),4.01(1H,t,J=9.4Hz),4.15(1H,d,J=9.7Hz),4.56-4.60(2H,m),4.65(1H,d,J=12.1Hz),4.79(1H,d,J=2.7Hz),4.81(1H,d,J=2.3Hz),4.83(1H,d,J=10.5Hz),4.98(1H,d,J=10.5Hz),7.20-7.40(15H,m)；MS(ESI)m/z：508(M+NH4)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.03 (3H, t, J = 7.2 Hz), 2.55 (2H, dd, J = 14.5 Hz, 7.0 Hz), 3.40 (3H, s), 3.54 (1H, Dd, J = 9.4 Hz, 3.5 Hz), 3.65 (1H, dd, J = 10.0 Hz, 8.8 Hz), 4.01 (1H, t, J = 9.4 Hz), 4.15 (1H, d, J = 9.7 Hz), 4.56-4.60(2H,m), 4.65(1H,d,J=12.1Hz), 4.79(1H,d,J=2.7Hz), 4.81(1H,d,J=2.3Hz),4.83(1H,d , J = 10.5 Hz), 4.98 (1H, d, J = 10.5 Hz), 7.20-7.40 (15H, m); MS (ESI) m/z: 508 (M + NH 4 ) + .
(參考例13d)甲基2,3,4-三-O-苯甲基-7,8-二去氧-D-甘油-α-D-葡萄糖-哌喃型辛糖苷 (Reference Example 13d) Methyl 2,3,4-tri-O-benzyl-7,8-dideoxy-D-glycerol-α-D-glucose-pyranose
將在參考例13c中所得到之化合物(1.2g，2.5mmol)溶解於THF(3mL)及乙醇(13mL)之混合溶劑中，於氮氣環境下，在-78℃添加氫化硼鈉(0.10g，2.6mmol)。將該反應液升溫至室溫，同時攪拌16小時，反應終了後，於冰冷下添加飽和氯化銨水溶液(10mL)。將該反應液用乙酸乙酯(30mL，2次)萃取，將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，98：2→60：40(濃度梯度)V/V)精製，得到標題化合物(1.1g)(cf.Can.J.Chem.,2001,79,238-255)。 The compound obtained in Reference Example 13c (1.2 g, 2.5 mmol) was dissolved in a mixed solvent of THF (3 mL) and ethanol (13 mL), and sodium borohydride (0.10 g) was added at -78 ° C under nitrogen atmosphere. 2.6 mmol). The reaction solution was warmed to room temperature while stirring for 16 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride (10 mL) was then evaporated. The reaction mixture was extracted with ethyl acetate (30 mL, twice), and the organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel flash chromatography (EtOAc: EtOAc: EtOAc EtOAc J. Chem., 2001, 79, 238-255).
1H NMR(400MHz,CDCl3)：δ0.93(3H,t,J=7.4Hz),1.37-1.44(1H,m),1.49-1.58(1H,m),2.50(1H,d,J=5.1Hz),3.38(3H,s),3.47-3.51(2H,m),3.63-3.70(2H,m),4.02(1H,t,J=9.2Hz),4.55(1H,d,J=3.5Hz),4.65(1H,d,J=11.0Hz),4.66(1H,d,J=12.1Hz),4.79(1H,d,J=12.1Hz),4.80(1H,d,J=11.0Hz),4.98(1H,d,J=11.0Hz),5.02(1H,d,J=10.9Hz),7.25-7.38(15H,m)；MS(ESI)m/z：510(M+NH4)+. 1 H NMR (400 MHz, CDCl 3 ): δ 0.93 (3H, t, J = 7.4 Hz), 1.37-1.44 (1H, m), 1.49-1.58 (1H, m), 2.50 (1H, d, J = 5.1 Hz), 3.38 (3H, s), 3.47-3.51 (2H, m), 3.63-3.70 (2H, m), 4.02 (1H, t, J = 9.2 Hz), 4.55 (1H, d, J = 3.5) Hz), 4.65 (1H, d, J = 11.0 Hz), 4.66 (1H, d, J = 12.1 Hz), 4.79 (1H, d, J = 12.1 Hz), 4.80 (1H, d, J = 11.0 Hz) , 4.98 (1H, d, J = 11.0 Hz), 5.02 (1H, d, J = 10.9 Hz), 7.25-7.38 (15H, m); MS (ESI) m/z: 510 (M+NH 4 ) + .
(參考例13e)甲基2,3,4,6-四-O-苯甲基-7,8-二去氧-D-甘油-α-D-葡萄糖-哌喃型辛糖苷 (Reference Example 13e) Methyl 2,3,4,6-tetra-O-benzyl-7,8-dideoxy-D-glycerol-α-D-glucose-pyranose
將在參考例13d中所得到之化合物(1.1g，2.2mmol)溶解於N,N-二甲基甲醯胺(11mL)中，於冰冷下添加氫化鈉(油性，55%w/w，0.13g，3.0mmol)及溴化苯甲基(0.34mL，2.9mmol)。將該反應液於氮氣環境下升溫至室溫，同時攪拌18小時，再度以冰冷卻及加水(15mL)。將該反應液用二乙基醚(30mL，2次)萃取，並將有機層以飽和食鹽水(10mL)洗淨。將該有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，98：2→80：20(濃度梯度)V/V)精製，得到標題化合物(1.2g)。 The compound (1.1 g, 2.2 mmol) obtained in Reference Example 13d was dissolved in N,N-dimethylformamide (11 mL), and sodium hydride (yield, 55% w/w, 0.13) g, 3.0 mmol) and benzyl bromide (0.34 mL, 2.9 mmol). The reaction solution was warmed to room temperature under a nitrogen atmosphere while stirring for 18 hr, and then cooled with ice and water (15 mL). The reaction mixture was extracted with diethyl ether (30 mL, EtOAc). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(400MHz,CDCl3)：δ0.83(3H,t,J=7.5Hz),1.30-1.38(1H,m),1.58-1.68(1H,m),3.39(3H,s),3.42(1H,dd,J=10.2Hz,9.0Hz),3.47-3.51(2H,m),3.94-3.97(1H,m),4.03(1H,t,J=9.2Hz),4.46(1H,d,J=11.3Hz),4.59(1H,d,J=11.0Hz),4.62(1H,d,J=3.5Hz),4.68(2H,d,J=12.1Hz),4.79(1H,d,J=12.1Hz),4.82(1H,d,J=11.0Hz),4.87(1H,d,J=10.9Hz),5.01(1H,d,J=10.9Hz),7.20-7.39(20H,m) 1 H NMR (400 MHz, CDCl 3 ): δ 0.83 (3H, t, J = 7.5 Hz), 1.30-1.38 (1H, m), 1.58-1.68 (1H, m), 3.39 (3H, s), 3.42 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.47-3.51 (2H, m), 3.94-3.97 (1H, m), 4.03 (1H, t, J = 9.2 Hz), 4.46 (1H, d, J = 11.3 Hz), 4.59 (1H, d, J = 11.0 Hz), 4.62 (1H, d, J = 3.5 Hz), 4.68 (2H, d, J = 12.1 Hz), 4.79 (1H, d, J = 12.1 Hz), 4.82 (1H, d, J = 11.0 Hz), 4.87 (1H, d, J = 10.9 Hz), 5.01 (1H, d, J = 10.9 Hz), 7.20-7.39 (20H, m)
MS(ESI)m/z：600(M+NH4)+. MS (ESI) m / z: 600 (M+NH 4 ) + .
(參考例13f)2,3,4,6-四-O-苯甲基-7,8-二去氧-D-甘油-D-葡萄糖-哌喃型辛糖 (Reference Example 13f) 2,3,4,6-tetra-O-benzyl-7,8-dideoxy-D-glycerol-D-glucose-pyranose
將在參考例13e中所得到之化合物(1.0g，1.7mmol)溶解於乙酸(32mL)，於室溫下添加三氟甲磺酸水溶液(2M，8mL，16mmol)。將該反應液於氮氣環境下，在80℃加熱6小時，反應終了後，添加三乙基胺(3.0mL)。將反應液之溶劑於減壓下餾去，加水(30mL)並以乙酸乙酯(30mL)萃取。將該有機層用飽和食鹽水(10mL)洗淨，以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，98：2→60：40(濃度梯度)V/V)精製，得到標題化合物(0.6g)。 The compound obtained in Reference Example 13e (1.0 g, 1.7 mmol) was dissolved in acetic acid (32 mL), and aqueous trifluoromethanesulfonic acid (2M, 8 mL, 16 mmol) was added at room temperature. The reaction liquid was heated at 80 ° C for 6 hours under a nitrogen atmosphere. After the reaction was completed, triethylamine (3.0 mL) was added. The solvent of the reaction mixture was evaporated, evaporated, evaporated. The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:
MS(ESI)m/z：586(M+NH4)+. MS (ESI) m / z: 586 (M + NH 4) +.
(參考例13g)(3R,4S,5S,6R)-3,4,5-參(苯甲氧基)-6-[(1R)-1-(苯甲氧基)丙基]四氫-2H-哌喃-2-酮 (Reference Example 13g) (3R, 4S, 5S, 6R)-3,4,5-glycol(benzyloxy)-6-[(1R)-1-(benzyloxy)propyl]tetrahydro- 2H-pene-2-one
將在參考例13f中所得到之化合物(0.60g，1.1mmol)溶解於二氯甲烷(6mL)中，於冰冷下添加DMP(0.61g，1.4mmol)。將反應液升溫至室溫，同時攪 拌2小時，反應終了後，添加飽和碳酸氫鈉水溶液(2mL)及10%w/v硫代硫酸水溶液(2mL)，進一步攪拌1小時。將該反應液用二乙基醚(10mL，2次)萃取，將有機層以飽和食鹽水(10mL)洗淨。將該有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，98：2→75：25(濃度梯度)V/V)精製，得到標題化合物(0.58g)。 The compound obtained in Reference Example 13f (0.60 g, 1.1 mmol) was dissolved in dichloromethane (6mL), and DMP (0.61 g, 1.4 mmol) was added under ice cooling. The reaction solution was warmed to room temperature while stirring After the mixture was stirred for 2 hours, a saturated aqueous sodium hydrogencarbonate solution (2 mL) and a 10% w/v aqueous solution of thiosulfuric acid (2 mL) were added and the mixture was further stirred for 1 hour. The reaction mixture was extracted with diethyl ether (10 mL, twice), and the organic layer was washed with brine (10 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(400MHz,CDCl3)：δ0.94(3H,t,J=7.5Hz),1.47-1.54(1H,m),1.67-1.75(1H,m),3.63-3.67(1H,m),3.94(1H,dd,J=7.8Hz,5.8Hz),4.00(1H,t,J=5.8Hz),4.11(1H,d,J=7.4Hz),4.48(1H,d,J=11.3Hz),4.52-4.60(5H,m),4.73(1H,d,J=11.8Hz),4.75(1H,d,J=10.9Hz),4.93(1H,d,J=11.3Hz),7.21-7.36(20H,m)；MS(ESI)m/z：567(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 0.94 (3H, t, J = 7.5 Hz), 1.47-1.54 (1H, m), 1.67-1.75 (1H, m), 3.63-3.67 (1H, m) , 3.94 (1H, dd, J = 7.8 Hz, 5.8 Hz), 4.00 (1H, t, J = 5.8 Hz), 4.11 (1H, d, J = 7.4 Hz), 4.48 (1H, d, J = 11.3 Hz) ), 4.52-4.60 (5H, m), 4.73 (1H, d, J = 11.8 Hz), 4.75 (1H, d, J = 10.9 Hz), 4.93 (1H, d, J = 11.3 Hz), 7.21 - 7.36 (20H, m); MS (ESI) m/z: 567 (M+H) + .
(參考例13h){(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)丙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲醇 (Reference 13h) {(1S,3'R,4'S,5'S,6'R)-3',4',5'-Phenyl (benzyloxy)-6'-[(1R)-1-( Benzyloxy)propyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-6-yl }Methanol
使用在參考例13g中所得到之化合物(0.58g，1.1mmol)、在參考例4中所得到之化合物(0.41g，1.2mmol)、正丁基鋰之己烷溶液(1.63M，0.75mL，1.2 mmol)、THF(14mL)、對甲苯磺酸一水合物(0.63g，3.3mmol)、及甲醇(3mL)與THF(3mL)之混合溶劑，以與參考例6a同樣之方式得到標題化合物之粗生成物。將所得到之粗生成物以矽膠急速管柱層析(己烷：乙酸乙酯，98：2→70：30(濃度梯度)V/V)精製，得到標題化合物(0.50g)。 The compound obtained in Reference Example 13g (0.58 g, 1.1 mmol), the compound obtained in Reference Example 4 (0.41 g, 1.2 mmol), hexane solution of n-butyllithium (1.63 M, 0.75 mL, 1.2 A mixed solvent of mmol, THF (14 mL), p-toluenesulfonic acid monohydrate (0.63 g, 3.3 mmol), and methanol (3 mL) and THF (3 mL) Product. The obtained crude product was purified by silica gel chromatography (hexane: ethyl acetate, 98:2: 70:30 (concentration gradient) V/V) to give the title compound (0.50 g).
1H NMR(400MHz,CDCl3)：δ0.82(3H,t,J=7.2Hz),1.37-1.46(1H,m),1.60-1.68(2H,m),3.50(1H,dd,J=9.2Hz,4.1Hz),3.70(1H,t,J=9.5Hz),3.83(1H,d,J=9.8Hz),4.17-4.24(2H,m),4.27(1H,d,J=11.3Hz),4.47(1H,d,J=11.7Hz),4.63-4.74(5H,m),4.92(2H,d,J=9.3Hz),4.98(1H,d,J=10.9Hz),5.15(1H,d,J=12.6Hz),5.19(1H,d,J=12.6Hz),6.82(2H,d,J=6.6Hz),7.11-7.18(3H,m),7.24-7.34(17H,m)；MS(ESI)m/z：721(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 0.82 (3H, t, J = 7.2 Hz), 1.37-1.46 (1H, m), 1.60-1.68 (2H, m), 3.50 (1H, dd, J = 9.2 Hz, 4.1 Hz), 3.70 (1H, t, J = 9.5 Hz), 3.83 (1H, d, J = 9.8 Hz), 4.17-4.24 (2H, m), 4.27 (1H, d, J = 11.3Hz) ), 4.47 (1H, d, J = 11.7 Hz), 4.63-4.74 (5H, m), 4.92 (2H, d, J = 9.3 Hz), 4.98 (1H, d, J = 10.9 Hz), 5.15 (1H) , d, J = 12.6 Hz), 5.19 (1H, d, J = 12.6 Hz), 6.82 (2H, d, J = 6.6 Hz), 7.11 - 7.18 (3H, m), 7.24 - 7.34 (17H, m) MS (ESI) m / z: 721 (M + H) + .
(參考例13i)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)丙基]-6-(溴甲基)-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 13i) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)propyl]-6-(bromomethyl)-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'- Piper
使用在參考例13h中所得到之化合物(0.50g，0.70mmol)、四溴化碳(0.60g，1.8mmol)、三苯膦(0.48 g，36mmol)及二氯甲烷(7mL)，以與參考例6b同樣之方式得到標題化合物之粗生成物。將所得到之粗生成物以矽膠急速管柱層析(己烷：乙酸乙酯，98：2→80：20(濃度梯度)V/V)精製，得到標題化合物(0.21g)。 The compound obtained in Reference Example 13h (0.50 g, 0.70 mmol), carbon tetrabromide (0.60 g, 1.8 mmol), triphenylphosphine (0.48) was used. g, 36 mmol) and methylene chloride (7 mL),yield of the title compound. The obtained crude product was purified by silica gel chromatography (yield: hexane: ethyl acetate, 98:2: 80:20 (concentration gradient) V/V) to give the title compound (0.21 g).
1H NMR(400MHz,CDCl3)：δ0.82(3H,t,J=7.4Hz),1.38-1.44(1H,m),1.60-1.68(1H,m),3.48-3.52(1H,m),3.71(1H,dd,J=10.2Hz,9.0Hz),3.80(1H,d,J=9.8Hz),4.15-4.23(3H,m),4.43(1H,d,J=10.2Hz),4.50(1H,d,J=12.1Hz),4.55(1H,d,J=10.6Hz),4.62(1H,d,J=11.4Hz),4.68(1H,d,J=11.7Hz),4.73(1H,d,J=11.0Hz),4.92(1H,d,J=11.0Hz),4.98(1H,d,J=10.6Hz),4.98(1H,d,J=10.6Hz),5.14(2H,brs),6.82-6.84(2H,m),7.10-7.18(4H,m),7.25-7.35(16H,m)；MS(ESI)m/z：783(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 0.82 (3H, t, J = 7.4 Hz), 1.38-1.44 (1H, m), 1.60-1.68 (1H, m), 3.48-3.52 (1H, m) , 3.71 (1H, dd, J = 10.2 Hz, 9.0 Hz), 3.80 (1H, d, J = 9.8 Hz), 4.15 - 4.23 (3H, m), 4.43 (1H, d, J = 10.2 Hz), 4.50 (1H, d, J = 12.1 Hz), 4.55 (1H, d, J = 10.6 Hz), 4.62 (1H, d, J = 11.4 Hz), 4.68 (1H, d, J = 11.7 Hz), 4.73 (1H) , d, J = 11.0 Hz), 4.92 (1H, d, J = 11.0 Hz), 4.98 (1H, d, J = 10.6 Hz), 4.98 (1H, d, J = 10.6 Hz), 5.14 (2H, brs ), 6.82-6.84 (2H, m), 7.10-7.18 (4H, m), 7.25-7.35 (16H, m); MS (ESI) m/z: 783 (M+H) + .
(參考例14)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)-2-甲基丙基]-6-(溴甲基)-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 14) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)-2-methylpropyl]-6-(bromomethyl)-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran- 1,2'-pyranose]
(參考例14a)2-甲基-1-[(2S,3S,4S,5R,6S)-3,4,5-參(苯甲氧基)-6-甲氧基四氫-2H-哌喃-2-基]丙-1-酮 (Reference Example 14a) 2-methyl-1-[(2S,3S,4S,5R,6S)-3,4,5-paran (benzyloxy)-6-methoxytetrahydro-2H-peri喃-2-yl] propan-1-one
使用在參考例13b中所得到之化合物(1.7g，3.3mmol)、氯化異丙基鎂之THF溶液(2.0M，1.8mL，3.6mmol)及THF(20mL)，以與參考例13c同樣之方式得到標題化合物(1.0g)。再者，精製係以矽膠急速管柱層析(己烷：乙酸乙酯，95：5→50：50(濃度梯度)V/V)進行。 The compound obtained in Reference Example 13b (1.7 g, 3.3 mmol), isopropylmagnesium chloride in THF (2.0 M, 1.8 mL, 3.6 mmol) and THF (20 mL) was used in the same manner as in Reference Example 13c. The title compound (1.0 g) was obtained. Further, the purification was carried out by silica gel flash column chromatography (hexane: ethyl acetate, 95:5→50:50 (concentration gradient) V/V).
1H NMR(400MHz,CDCl3)：δ1.07(3H,d,J=7.0Hz),1.12(3H,d,J=7.0Hz),2.82-2.89(1H,m),3.42(3H,s),3.55(1H,dd,J=9.4Hz,3.5Hz),3.73(1H,dd,J=9.8Hz,9.0Hz),4.02(1H,t,J=9.4Hz),4.34(1H,d,J=9.8Hz),4.53(1H,d,J=10.6Hz),4.59(1H,d,J=3.5Hz),4.65(1H,d,J=12.1Hz),4.80(1H,d,J=10.6Hz),4.81(1H,d,J=12.1Hz),4.82(1H,d,J=10.9Hz),4.98(1H,d,J=10.9Hz),7.18-7.20(2H,m),7.27-7.37(13H,m)；MS(ESI)m/z：522(M+NH4)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.07 (3H, d, J = 7.0 Hz), 1.12 (3H, d, J = 7.0 Hz), 2.82-2.89 (1H, m), 3.42 (3H, s ), 3.55 (1H, dd, J = 9.4 Hz, 3.5 Hz), 3.73 (1H, dd, J = 9.8 Hz, 9.0 Hz), 4.02 (1H, t, J = 9.4 Hz), 4.34 (1H, d, J = 9.8 Hz), 4.53 (1H, d, J = 10.6 Hz), 4.59 (1H, d, J = 3.5 Hz), 4.65 (1H, d, J = 12.1 Hz), 4.80 (1H, d, J = 10.6 Hz), 4.81 (1H, d, J = 12.1 Hz), 4.82 (1H, d, J = 10.9 Hz), 4.98 (1H, d, J = 10.9 Hz), 7.18-7.20 (2H, m), 7.27 -7.37 (13H, m); MS (ESI) m/z: 522 (M+NH 4 ) + .
(參考例14b)(1R)-2-甲基-1-[(2R,3S,4S,5R,6S)-3,4,5-參(苯甲氧基)-6-甲氧基四氫-2H-哌喃-2-基]丙-1-醇 (Reference Example 14b) (1R)-2-Methyl-1-[(2R,3S,4S,5R,6S)-3,4,5-e (phenylmethoxy)-6-methoxytetrahydrol -2H-piperidin-2-yl]propan-1-ol
使用在參考例14a中所得到之化合物(0.95 g，1.9mmol)、氫化硼鈉(80mg，2.1mmol)及乙醇(13mL)與THF(3mL)之混合溶劑，以與參考例13d同樣之方式得到標題化合物(0.80g)。再者，精製係以矽膠急速管柱層析(己烷：乙酸乙酯，95：5→60：40(濃度梯度)V/V)進行。 The compound obtained in Reference Example 14a was used (0.95 The title compound (0.80 g) was obtained from m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m Further, the purification was carried out by silica gel flash column chromatography (hexane: ethyl acetate, 95:5→60:40 (concentration gradient) V/V).
1H NMR(400MHz,CDCl3)：δ0.89(3H,d,J=6.8Hz),0.95(3H,d,J=6.8Hz),1.92-2.00(1H,m),3.00(1H,d,J=3.1Hz),3.40(3H,s),3.50(1H,dd,J=9.6Hz,3.7Hz),3.53-3.54(1H,m),3.60(1H,t,J=9.2Hz),3.68(1H,dd,J=9.3Hz,6.2Hz),4.04(1H,dd,J=9.6Hz,8.8Hz),4.53(1H,d,J=3.9Hz),4.65(1H,d,J=12.1Hz),4.70(1H,d,J=10.9Hz),4.80(1H,d,J=10.2Hz),4.80(1H,d,J=12.2Hz),5.03(1H,d,J=10.9Hz),5.05(1H,d,J=11.0Hz),7.25-7.38(15H,m)；MS(ESI)m/z：524(M+NH4)+. 1 H NMR (400 MHz, CDCl 3 ): δ 0.89 (3H, d, J = 6.8 Hz), 0.95 (3H, d, J = 6.8 Hz), 1.92-2.00 (1H, m), 3.00 (1H, d , J = 3.1 Hz), 3.40 (3H, s), 3.50 (1H, dd, J = 9.6 Hz, 3.7 Hz), 3.53-3.54 (1H, m), 3.60 (1H, t, J = 9.2 Hz), 3.68 (1H, dd, J = 9.3 Hz, 6.2 Hz), 4.04 (1H, dd, J = 9.6 Hz, 8.8 Hz), 4.53 (1H, d, J = 3.9 Hz), 4.65 (1H, d, J = 12.1 Hz), 4.70 (1H, d, J = 10.9 Hz), 4.80 (1H, d, J = 10.2 Hz), 4.80 (1H, d, J = 12.2 Hz), 5.03 (1H, d, J = 10.9 Hz) ), 5.05 (1H, d, J = 11.0 Hz), 7.25-7.38 (15H, m); MS (ESI) m/z: 524 (M + NH 4 ) + .
(參考例14c)(2R,3S,4S,5R,6S)-3,4,5-參(苯甲氧基)-2-[(1R)-1-(苯甲氧基)-2-甲基丙基]-6-甲氧基四氫-2H-哌喃 (Reference Example 14c) (2R, 3S, 4S, 5R, 6S)-3,4,5-parade (benzyloxy)-2-[(1R)-1-(benzyloxy)-2-methyl Propyl]-6-methoxytetrahydro-2H-pyran
使用在參考例14b中所得到之化合物(0.80g，1.6mmol)、氫化鈉(油性，>55%，91mg，2.1mmol)、 溴化苯甲基(0.25mL，2.1mmol)及N,N-二甲基甲醯胺(8mL)，以與參考例13e同樣之方式得到標題化合物(0.87g)。再者，精製係以矽膠急速管柱層析(己烷：乙酸乙酯，97：3→80：20(濃度梯度)V/V)進行。 The compound obtained in Reference Example 14b (0.80 g, 1.6 mmol), sodium hydride (oily, >55%, 91 mg, 2.1 mmol), The title compound (0.87 g) was obtained from the title compound (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Further, the purification was carried out by silica gel flash column chromatography (hexane: ethyl acetate, 97:3 → 80:20 (concentration gradient) V/V).
1H NMR(400MHz,CDCl3)：δ0.90(3H，d,J=6.7Hz),0.99(3H,d,J=6.7Hz),2.00-2.08(1H,m),3.20(1H,d,J=9.0Hz),3.38(3H,s),3.51(1H,dd,J=9.8Hz,3.5Hz),3.71(1H,dd,J=9.8Hz,9.0Hz),4.00(1H,t,J=9.4Hz),4.03(1H,t,J=9.4Hz),4.49(1H,d,J=11.4Hz),4.63(1H,d,J=3.5Hz),4.69(1H,d,J=12.1Hz),4.74(1H,d,J=10.9Hz),4.77(1H,d,J=11.4Hz),4.80(1H,d,J=12.9Hz),4.81(1H,d,J=10.6Hz),4.86(1H,d,J=10.6Hz),4.98(1H,d,J=10.5Hz),7.25-7.40(20H,m)；MS(ESI)m/z：614(M+NH4)+. 1 H NMR (400 MHz, CDCl 3 ): δ 0.90 (3H, d, J = 6.7 Hz), 0.99 (3H, d, J = 6.7 Hz), 2.00-2.08 (1H, m), 3.20 (1H, d , J = 9.0 Hz), 3.38 (3H, s), 3.51 (1H, dd, J = 9.8 Hz, 3.5 Hz), 3.71 (1H, dd, J = 9.8 Hz, 9.0 Hz), 4.00 (1H, t, J = 9.4 Hz), 4.03 (1H, t, J = 9.4 Hz), 4.49 (1H, d, J = 11.4 Hz), 4.63 (1H, d, J = 3.5 Hz), 4.69 (1H, d, J = 12.1 Hz), 4.74 (1H, d, J = 10.9 Hz), 4.77 (1H, d, J = 11.4 Hz), 4.80 (1H, d, J = 12.9 Hz), 4.81 (1H, d, J = 10.6 Hz) ), 4.86 (1H, d, J = 10.6 Hz), 4.98 (1H, d, J = 10.5 Hz), 7.25-7.40 (20H, m); MS (ESI) m/z: 614 (M+NH 4 ) + .
(參考例14d)(3R,4S,5S,6R)-3,4,5-參(苯甲氧基)-6-[(1R)-1-(苯甲氧基)-2-甲基丙基]四氫-2H-哌喃-2-醇 (Reference Example 14d) (3R, 4S, 5S, 6R)-3,4,5-parade (benzyloxy)-6-[(1R)-1-(phenylmethoxy)-2-methylpropane Tetrahydro-2H-piperidin-2-ol
使用在參考例14c中所得到之化合物(0.75g，1.3mmol)、三氟甲磺酸水溶液(2M，5.2mL，10.4mmol)及乙酸(26mL)，以與參考例13f同樣之方式得到標題化 合物(0.45g)。再者，精製係以矽膠急速管柱層析(己烷：乙酸乙酯，97：3→60：40(濃度梯度)V/V)進行。 Using the compound obtained in Reference Example 14c (0.75 g, 1.3 mmol), aqueous trifluoromethanesulfonic acid (2M, 5.2 mL, 10.4 mmol), and acetic acid (26 mL), the title was obtained in the same manner as in Reference Example 13f. Compound (0.45 g). Further, the purification was carried out by silica gel flash column chromatography (hexane: ethyl acetate, 97:3 → 60:40 (concentration gradient) V/V).
MS(ESI)m/z：600(M+NH4)+. MS (ESI) m / z: 600 (M+NH 4 ) + .
(參考例14e)(3R,4S,5S,6R)-3,4,5-參(苯甲氧基)-6-[(1R)-1-(苯甲氧基)-2-甲基丙基]四氫-2H-哌喃-2-酮 (Reference Example 14e) (3R, 4S, 5S, 6R)-3,4,5-parade (benzyloxy)-6-[(1R)-1-(benzyloxy)-2-methylpropane Tetrahydro-2H-pentan-2-one
使用在參考例14d中所得到之化合物(0.45g，0.78mmol)、DMP(0.43g，1.0mmol)及二氯甲烷(5mL)，以與參考例13g同樣之方法得到標題化合物(0.44g)。再者，精製係以矽膠急速管柱層析(己烷：乙酸乙酯，95：5→30：70(濃度梯度)V/V)進行。 Using the compound (0.45 g, 0.78 mmol Further, the purification was carried out by silica gel flash column chromatography (hexane: ethyl acetate, 95:5→30:70 (concentration gradient) V/V).
1H NMR(400MHz,CDCl3)：δ0.95(3H,d,J=6.9Hz),1.07(3H,d,J=6.9Hz),1.85-1.94(1H,m),3.40(1H,dd,J=8.4Hz,3.7Hz),3.94(1H,dd,J=8.2Hz,5.9Hz),4.05-4.09(2H,m),4.41(1H,d,J=11.4Hz),4.55(1H,d,J=11.7Hz),4.55(1H,d,J=11.7Hz),4.56(1H,d,J=11.3Hz),4.62-4.67(2H,m),4.74(1H,d,J=11.4Hz),4.75(1H,d,J=11.0Hz),4.89(1H,d,J=11.3Hz),7.18-7.23(4H,m),7.27-7.33(16H,m)；MS(ESI)m/z：598(M+NH4)+. 1 H NMR (400 MHz, CDCl 3 ): δ 0.95 (3H, d, J = 6.9 Hz), 1.07 (3H, d, J = 6.9 Hz), 1.85-1.94 (1H, m), 3.40 (1H, dd , J = 8.4 Hz, 3.7 Hz), 3.94 (1H, dd, J = 8.2 Hz, 5.9 Hz), 4.05-4.09 (2H, m), 4.41 (1H, d, J = 11.4 Hz), 4.55 (1H, d, J = 11.7 Hz), 4.55 (1H, d, J = 11.7 Hz), 4.56 (1H, d, J = 11.3 Hz), 4.62-4.67 (2H, m), 4.74 (1H, d, J = 11.4) Hz), 4.75 (1H, d, J = 11.0 Hz), 4.89 (1H, d, J = 11.3 Hz), 7.18-7.23 (4H, m), 7.27-7.33 (16H, m); MS (ESI) m /z:598(M+NH 4 ) + .
(參考例14f){(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)-2-甲基丙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲醇 (Reference Example 14f) {(1S,3'R,4'S,5'S,6'R)-3',4',5'-Phenyl(benzyloxy)-6'-[(1R)-1-( Benzyloxy)-2-methylpropyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran ]-6-yl}methanol
使用在參考例14e中所得到之化合物(0.44g，0.76mmol)、在參考例4中所得到之化合物(0.29g，0.85mmol)、正丁基鋰之己烷溶液(1.63M，0.52mL，0.84mmol)、THF(10mL)、對甲苯磺酸一水合物(0.44g，2.3mmol)、及甲醇(2.5mL)與THF(2.5mL)之混合溶劑，以與參考例6a同樣之方式，得到標題化合物之粗生成物。將所得到之粗生成物以矽膠急速管柱層析(己烷：乙酸乙酯，95：5→30：70(濃度梯度)V/V)精製，得到標題化合物(0.38g)。 The compound obtained in Reference Example 14e (0.44 g, 0.76 mmol), the compound obtained in Reference Example 4 (0.29 g, 0.85 mmol), hexane solution of n-butyllithium (1.63 M, 0.52 mL, 0.84 mmol), THF (10 mL), p-toluenesulfonic acid monohydrate (0.44 g, 2.3 mmol), and a mixed solvent of methanol (2.5 mL) and THF (2.5 mL) were obtained in the same manner as in Reference Example 6a. The crude product of the title compound. The obtained crude product was purified by silica gel chromatography (yield: hexane: ethyl acetate, 95:5, 30:70 (concentration gradient) V/V) to give the title compound (0.38 g).
1H NMR(400MHz,CDCl3)：δ0.91(3H,d,J=6.7Hz),0.95(3H,d,J=6.7Hz),2.01-2.08(1H,m),3.21(1H,d,J=9.8Hz),3.83(1H,d,J=9.4Hz),3.97(1H,t,J=9.5Hz),4.20(1H,t,J=9.4Hz),4.26(1H,d,J=11.8Hz),4.31(1H,d,J=10.2Hz),4.52(1H,d,J=12.1Hz),4.63-4.67(3H,m),4.78(1H,d,J=12.1Hz),4.84(1H,d,J=11.0Hz),4.90(1H,d,J=10.5Hz),4.94(1H,d,J=11.0Hz),4.95(1H,d,J=11.0Hz), 5.16(1H,d,J=13.3Hz),5.20(1H,d,J=12.9Hz),6.81-6.83(2H,m),7.08-7.18(4H,m),7.26-7.39(16H,m)；MS(ESI)m/z：735(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 0.91 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 6.7 Hz), 2.01-2.08 (1H, m), 3.21 (1H, d , J = 9.8 Hz), 3.83 (1H, d, J = 9.4 Hz), 3.97 (1H, t, J = 9.5 Hz), 4.20 (1H, t, J = 9.4 Hz), 4.26 (1H, d, J) = 11.8 Hz), 4.31 (1H, d, J = 10.2 Hz), 4.52 (1H, d, J = 12.1 Hz), 4.63-4.67 (3H, m), 4.78 (1H, d, J = 12.1 Hz), 4.84 (1H, d, J = 11.0 Hz), 4.90 (1H, d, J = 10.5 Hz), 4.94 (1H, d, J = 11.0 Hz), 4.95 (1H, d, J = 11.0 Hz), 5.16 ( 1H, d, J = 13.3 Hz), 5.20 (1H, d, J = 12.9 Hz), 6.81-6.83 (2H, m), 7.08-7.18 (4H, m), 7.26-7.39 (16H, m); MS (ESI) m/z: 735 (M+H) + .
(參考例14g)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)-2-甲基丙基]-6-(溴甲基)-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Reference Example 14g) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)-2-methylpropyl]-6-(bromomethyl)-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran- 1,2'-pyranose]
使用在參考例14f中所得到之化合物(0.37g，0.51mmol)、四溴化碳(0.34g，1.0mmol)、三苯膦(0.26g，0.99mmol)及二氯甲烷(5mL)，以與參考例6b同樣之方式得到標題化合物之粗生成物。將所得到之粗生成物以矽膠急速管柱層析(己烷：乙酸乙酯，97：3→70：30(濃度梯度)V/V)精製，得到標題化合物(0.18g)。 The compound obtained in Reference Example 14f (0.37 g, 0.51 mmol), carbon tetrabromide (0.34 g, 1.0 mmol), triphenylphosphine (0.26 g, 0.99 mmol) and dichloromethane (5 mL) The crude product of the title compound was obtained in the same manner as in the title compound. The obtained crude product was purified by silica gel chromatography (yield: EtOAc: EtOAc: EtOAc:
1H NMR(400MHz,CDCl3)：δ0.91(3H,d,J=6.7Hz),0.95(3H,d,J=6.7Hz),1.99-2.08(1H,m),3.20(1H,d,J=9.0Hz),3.77(1H,d,J=9.4Hz),3.98(1H,t,J=9.4Hz),4.17(1H,d,J=9.4Hz),4.19(1H,d,J=11.4Hz),4.29(1H,d,J=9.7Hz),4.39(1H,d,J=10.2Hz),4.54(1H,d,J=10.2Hz),4.57(1H,d,J=11.0Hz),4.62(1H,d,J=11.4Hz),4.77(1H,d,J=12.1Hz),4.85(1H,d,J=11.0Hz),4.89(1H,d,J=10.6Hz),4.95(1H,d,J=10.6Hz),4.96(1H,d,J=10.9Hz),5.15(2H, brs),6.81-6.83(2H,m),6.99(1H,s),7.10-7.18(3H,m),7.28-7.37(16H,m)；MS(ESI)m/z：797(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 0.91 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 6.7 Hz), 1.99-2.08 (1H, m), 3.20 (1H, d , J = 9.0 Hz), 3.77 (1H, d, J = 9.4 Hz), 3.98 (1H, t, J = 9.4 Hz), 4.17 (1H, d, J = 9.4 Hz), 4.19 (1H, d, J) =11.4 Hz), 4.29 (1H, d, J = 9.7 Hz), 4.39 (1H, d, J = 10.2 Hz), 4.54 (1H, d, J = 10.2 Hz), 4.57 (1H, d, J = 11.0) Hz), 4.62 (1H, d, J = 11.4 Hz), 4.77 (1H, d, J = 12.1 Hz), 4.85 (1H, d, J = 11.0 Hz), 4.89 (1H, d, J = 10.6 Hz) , 4.95 (1H, d, J = 10.6 Hz), 4.96 (1H, d, J = 10.9 Hz), 5.15 (2H, brs), 6.81-6.83 (2H, m), 6.99 (1H, s), 7.10- 7.18 (3H, m), 7.28-7.37 (16H, m); MS (ESI) m/z: 797 (M+H) + .
(參考例15)5-氟-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-2,3-二氫-1,4-苯并二英 (Reference Example 15) 5-Fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro- 1,4-benzoic acid English
(參考例15a)3-氟-4,5-二羥基苯甲醛 (Reference Example 15a) 3-Fluoro-4,5-dihydroxybenzaldehyde
將3-氟-4-羥基-5-甲氧基苯甲醛(2.0g，12mmol)於氮氣環境下溶解於二氯甲烷(36mL)中。將其冷卻至-78℃，並添加三溴化硼(17%w/v二氯甲烷溶液，約1mol/L)(36mL，36mmol)，並於-78℃攪拌1小時後，升溫至室溫，並於室溫下攪拌18小時。在該反應混合物中加水(100mL)，並以乙酸乙酯(100mL，2次)萃取。將有機層用飽和食鹽水(50mL)洗淨，以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(己烷：乙酸乙酯，90：10→100：0(濃度梯度)V/V)精製，得到標題化合物(1.7g)。 3-Fluoro-4-hydroxy-5-methoxybenzaldehyde (2.0 g, 12 mmol) was dissolved in dichloromethane (36 mL). It was cooled to -78 ° C, and boron tribromide (17% w / v dichloromethane solution, about 1 mol / L) (36 mL, 36 mmol) was added, and after stirring at -78 ° C for 1 hour, the temperature was raised to room temperature. And stirred at room temperature for 18 hours. Water (100 mL) was added to the reaction mixture and ethyl acetate (100 mL, twice). The organic layer was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc EtOAc (EtOAc)
1H NMR(400MHz,DMSO-d6)：δ7.16(1H,dd,J=2.0Hz,1.2Hz),7.24(1H,dd,J=10.6Hz,2.0Hz),9.72(1H,d,J=1.2Hz). 1 H NMR (400MHz, DMSO- d6): δ7.16 (1H, dd, J = 2.0Hz, 1.2Hz), 7.24 (1H, dd, J = 10.6Hz, 2.0Hz), 9.72 (1H, d, J =1.2Hz).
(參考例15b)8-氟-2,3-二氫-1,4-苯并二英-6-甲醛 (Reference Example 15b) 8-Fluoro-2,3-dihydro-1,4-benzoic acid English-6-formaldehyde
將在參考例15a中所得到之化合物(1.7g，11mmol)溶解於N,N-二甲基甲醯胺(11mL)，在其中添加碳酸鉀(4.6g，33mmol)，並於室溫下攪拌30分鐘。繼而，在反應混合物中添加1,2-二溴乙烷(1.1mL，13mmol)，並於60℃攪拌15小時。冷卻至室溫，並在反應混合物中加水(30mL)，將析出之固體藉由過濾回收，用水洗淨後，使其乾燥，得到標題化合物(0.19g)。 The compound (1.7 g, 11 mmol) obtained in Reference 15a was dissolved in N,N-dimethylformamide (11 mL), and potassium carbonate (4.6 g, 33 mmol) was added thereto and stirred at room temperature. 30 minutes. Then, 1,2-dibromoethane (1.1 mL, 13 mmol) was added to the reaction mixture, and stirred at 60 ° C for 15 hr. After cooling to room temperature, water (30 mL) was added to the mixture, and the precipitated solid was collected by filtration, washed with water and dried to give the title compound (0.19 g).
1H NMR(400MHz,CDCl3)：δ4.33-4.37(2H,m),4.39-4.43(2H,m),7.26-7.27(1H,m),7.24(1H,d,J=2.3Hz),9.80(1H,d,J=2.3Hz)；MS(CI)m/z：183(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 4.33-4.37 (2H, m), 4.39-4.43 (2H, m), 7.26-7.27 (1H, m), 7.24 (1H, d, J = 2.3 Hz) , 9.80 (1H, d, J = 2.3 Hz); MS (CI) m/z: 183 (M+H) + .
(參考例15c)8-氟-2,3-二氫-1,4-苯并二英-6-醇 (Reference Example 15c) 8-Fluoro-2,3-dihydro-1,4-benzoic acid English-6-alcohol
將間-氯過苯甲酸(4.0g，純度約65%w/w，約15mmol)溶解於二氯甲烷(36mL)，在其中添加氟化鉀(1.4g，24mmol)，於室溫下攪拌1小時。在該反應液中添加在參考例15b中所得到之化合物(1.6g，8.8mmol)之二氯甲烷(50mL)溶液，於室溫下攪拌20小時。將反應液中之不溶物藉由過濾除去，於減壓下餾去溶劑。將所得到之殘餘物溶解於THF(90mL)中，並添加2M氫氧化鈉水溶液(45mL，90mmol)，於室溫下攪拌3小時。在該反應液中添加2M鹽酸(60mL)，並以乙酸乙酯(200mL，2回)萃取。將有機層用5%w/v硫代硫酸鈉水溶液(50mL)、5%w/v碳酸氫鈉水溶液(50mL)及飽和食鹽水(50mL)依序洗淨，以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(己烷：乙酸乙酯，90：10→100：0(濃度梯度)V/V)精製，得到標題化合物(0.26g)。 The m-chloroperbenzoic acid (4.0 g, purity about 65% w/w, about 15 mmol) was dissolved in dichloromethane (36 mL), and potassium fluoride (1.4 g, 24 mmol) was added thereto, and stirred at room temperature. hour. A solution of the compound obtained in Reference Example 15b (1.6 g, 8.8 mmol) in dichloromethane (50 mL) The insoluble matter in the reaction liquid was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in THF (90 mL). 2M Hydrochloric acid (60 mL) was added to the mixture, and ethyl acetate (200 mL, The organic layer was washed with 5% w/v aqueous sodium thiosulfate solution (50 mL), 5% w/v aqueous sodium hydrogen carbonate (50 mL) and brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified using EtOAc EtOAc EtOAc (EtOAc)
1H NMR(400MHz,CDCl3)：δ4.23-4.30(4H,m),4.61(1H,brs),6.19(1H,dd,J=3.0Hz,2.0Hz),6.25(1H,dd,J=11.5Hz,3.0Hz)；MS(CI)m/z：171(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 4.23-4.30 (4H, m), 4.61 (1H, brs), 6.19 (1H, dd, J = 3.0 Hz, 2.0 Hz), 6.25 (1H, dd, J =11.5 Hz, 3.0 Hz); MS (CI) m/z: 171 (M+H) + .
(參考例15d)三氟甲磺酸8-氟-2,3-二氫-1,4-苯并二英-6-酯 (Reference Example 15d) 8-fluoro-2,3-dihydro-1,4-benzoic acid trifluoromethanesulfonate English-6-ester
將在參考例15c中所得到之化合物(0.26g，1.6mmol)溶解於二氯甲烷(8mL)中。於冰冷下在其中添加三乙基胺(0.45mL，3.2mmol)及三氟甲磺酸酐(0.37mL，2.4mmol)，並於0℃攪拌1小時。在反應混合物中添加飽和碳酸氫鈉水溶液(30mL)，並以乙酸乙酯(50mL，2回)萃取。將有機層用0.5M鹽酸(30mL)及飽和食鹽水(30mL)依序洗淨，以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(己烷：乙酸乙酯，95：5→50：50(濃度梯度)V/V)精製，得到標題化合物(0.40g)。 The compound obtained in Reference Example 15c (0.26 g, 1.6 mmol) was dissolved in dichloromethane (8 mL). Triethylamine (0.45 mL, 3.2 mmol) and trifluoromethanesulfonic anhydride (0.37 mL, 2.4 mmol) were added thereto under ice cooling, and stirred at 0 ° C for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate (30 mL) was evaporated. The organic layer was washed successively with 0.5 M hydrochloric acid (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc EtOAc (EtOAc)
1H NMR(400MHz,CDCl3)：δ4.34(4H,s),6.67(1H,d,J=3.1Hz),6.69(1H,dd,J=11.7Hz,3.1Hz)；MS(CI)m/z：303(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 4.34 (4H, s), 6.67 (1H, d, J = 3.1 Hz), 6.69 (1H, dd, J = 11.7 Hz, 3.1 Hz); MS (CI) m/z: 303 (M+H) + .
(參考例15e)5-氟-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-2,3-二氫-1,4-苯并二英 (Reference Example 15e) 5-Fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro- 1,4-benzoic acid English
將在參考例15d中所得到之化合物(0.40g，1.4mmol)溶解於1,4-二烷(8mL)，添加聯硼酸頻那醇酯(bis(pinacolato)diboron)(0.40g，1.5mmol)、乙酸鉀(0.42g，4.2mmol)、1,1'-雙(二苯基膦基)二茂鐵(24mg，0.042mmol)及[1,1'-雙(二苯基膦基)二茂鐵]鈀(II) 二氯化物 二氯甲烷加成物(35mg，0.042mmol)，於氮氣環境下，在80℃攪拌22小時。在反應混合物中加水(30mL)，並以乙酸乙酯(50mL，2回)萃取。將有機層以飽和食鹽水(30mL)洗淨，用無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(己烷：乙酸乙酯，95：5→50：50(濃度梯度)V/V)精製，得到標題化合物(0.29g)。 The compound obtained in Reference Example 15d (0.40 g, 1.4 mmol) was dissolved in 1,4-two. Alkane (8 mL), bis(pinacolato)diboron (0.40 g, 1.5 mmol), potassium acetate (0.42 g, 4.2 mmol), 1,1'-bis(diphenylphosphino) Ferrocene (24 mg, 0.042 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (35 mg, 0.042 mmol) in nitrogen Under the environment, stir at 80 ° C for 22 hours. Water (30 mL) was added and the mixture was evaporated. The organic layer was washed with brine (30 mL) and dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc EtOAc (EtOAc:EtOAc
1H NMR(400MHz,CDCl3)：δ1.32(12H,s),4.26-4.30(2H,m),4.31-4.36(2H,m),7.11-7.13(2H,m)；MS(FAB)m/z：281(M+H)+. 1 H NMR (400MHz, CDCl 3 ): δ1.32 (12H, s), 4.26-4.30 (2H, m), 4.31-4.36 (2H, m), 7.11-7.13 (2H, m); MS (FAB) m/z: 281 (M+H) + .
(參考例16)6-氟-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-2,3-二氫-1,4-苯并二英 (Reference Example 16) 6-Fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro- 1,4-benzoic acid English
(參考例16a)6-溴-7-氟-2,3-二氫-1,4-苯并二英 (Reference Example 16a) 6-Bromo-7-fluoro-2,3-dihydro-1,4-benzoic acid English
使用4-溴-5-氟苯-1,2-二酚(0.50g，2.4mmol)、碳酸鉀(1.0g，7.2mmol)、1,2-二溴乙烷(0.23mL、2.6mmol)及N,N-二甲基甲醯胺(2.4mL)，以與參考例15b同樣之方式得到標題化合物(0.20g)。 4-bromo-5-fluorobenzene-1,2-diphenol (0.50 g, 2.4 mmol), potassium carbonate (1.0 g, 7.2 mmol), 1,2-dibromoethane (0.23 mL, 2.6 mmol) and N,N-dimethylformamide (2.4 mL) gave the title compound (0.20 g).
1H NMR(400MHz,CDCl3)：δ4.19-4.28(4H,m),6.69(1H,d,J=8.9Hz),7.04(1H,d,J=6.7Hz)；MS(CI)m/z：233(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 4.19 - 4.28 (4H, m), 6.69 (1H, d, J = 8.9 Hz), 7.04 (1H, d, J = 6.7 Hz); MS (CI) m /z:233(M+H) + .
(參考例16b)6-氟-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-2,3-二氫-1,4-苯并二英 (Reference Example 16b) 6-Fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro- 1,4-benzoic acid English
使用在參考例16a中所得到之化合物(0.20g，0.86mmol)、聯硼酸頻那醇酯(0.24g，0.95mmol)、乙酸鉀(0.26g，2.6mmol)、1,1'-雙(二苯基膦基)二茂鐵(15mg，0.026mmol)、[1,1'-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物 二氯甲烷加成物(21mg，0.026mmol)及1,4-二烷(5mL)，以與參考例15e同樣之方式得到標題化合物(65mg)。 The compound obtained in Reference Example 16a (0.20 g, 0.86 mmol), pinacol borate (0.24 g, 0.95 mmol), potassium acetate (0.26 g, 2.6 mmol), 1,1'-bis (two) Phenylphosphino)ferrocene (15 mg, 0.026 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (21 mg, 0.026 Mm) and 1,4-two The title compound (65 mg) was obtained.
1H NMR(400MHz,CDCl3)：δ1.34(12H,s),4.19-4.23(2H,m),4.25-4.29(2H,m),6.57(1H,d,J=9.8Hz),7.21(1H,d,J=5.9Hz)；MS(FAB)m/z：319(M+K)+. 1 H NMR (400MHz, CDCl 3 ): δ1.34 (12H, s), 4.19-4.23 (2H, m), 4.25-4.29 (2H, m), 6.57 (1H, d, J = 9.8Hz), 7.21 (1H, d, J = 5.9 Hz); MS (FAB) m/z: 319 (M+K) + .
(參考例17)5-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-2,3-二氫-1,4-苯并二英 (Reference Example 17) 5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro- 1,4-benzoic acid English
使用依照WO2008/128942記載之方法所得到之6-溴-5-氟-2,3-二氫-1,4-苯并二英(1.0g，4.3mmol)、聯硼酸頻那醇酯(1.2g，4.7mmol)、乙酸鉀(1.3g，13mmol)、1,1'-雙(二苯基膦基)二茂鐵(72mg，0.13mmol)、[1,1'-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物 二氯甲烷加成物(0.11g，0.13mmol)及1,4-二烷(25mL)，以與參考例15e同樣之方式得到標題化合物(0.49g)。 6-bromo-5-fluoro-2,3-dihydro-1,4-benzoic acid obtained by the method described in WO2008/128942 English (1.0g, 4.3mmol), pinacol borate (1.2g, 4.7mmol), potassium acetate (1.3g, 13mmol), 1,1'-bis(diphenylphosphino)ferrocene (72mg) , 0.13 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.11 g, 0.13 mmol) and 1,4-two The title compound (0.49 g) was obtained.
1H NMR(400MHz,CDCl3)：δ1.35(12H,s),4.30(4H,s),6.66(1H,dd,J=8.2Hz,1.4Hz),7.18(1H,dd,J=8.2Hz,5.9Hz)；MS(CI)m/z：281(M+H)+. 1 H NMR (400MHz, CDCl 3 ): δ1.35 (12H, s), 4.30 (4H, s), 6.66 (1H, dd, J = 8.2Hz, 1.4Hz), 7.18 (1H, dd, J = 8.2 Hz, 5.9 Hz); MS (CI) m/z: 281 (M+H) + .
(參考例18)5-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-2,3-二氫-1,4-苯并二英 (Reference Example 18) 5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro -1,4-benzoic acid English
使用6-溴-5-甲基-2,3-二氫-1,4-苯并二英(0.50g，2.2mmol)、聯硼酸頻那醇酯(0.61g，2.4mmol)、 乙酸鉀(0.65g，6.6mmol)、1,1'-雙(二苯基膦基)二茂鐵(37mg，0.066mmol)、[1,1'-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物 二氯甲烷加成物(54mg，0.066mmol)及1,4-二烷(12mL)，以與參考例15e同樣之方式得到標題化合物(0.22g)。 Using 6-bromo-5-methyl-2,3-dihydro-1,4-benzoic acid English (0.50 g, 2.2 mmol), pinacol borate (0.61 g, 2.4 mmol), potassium acetate (0.65 g, 6.6 mmol), 1,1'-bis(diphenylphosphino)ferrocene ( 37 mg, 0.066 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (54 mg, 0.066 mmol) and 1,4-two The title compound (0.22 g) was obtained.
1H NMR(400MHz,CDCl3)：δ1.33(12H,s),2.41(3H,s),4.22-4.30(4H,m),6.71(1H,d,J=8.3Hz),7.29(1H,d,J=8.3Hz)；MS(FAB)m/z：299(M+Na)+. 1 H NMR (400MHz, CDCl 3 ): δ1.33 (12H, s), 2.41 (3H, s), 4.22-4.30 (4H, m), 6.71 (1H, d, J = 8.3Hz), 7.29 (1H , d, J = 8.3 Hz); MS (FAB) m / z: 299 (M + Na) + .
(參考例19)7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-3,4-二氫-2H-1,5-苯并二氧呯 (Reference Example 19) 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1, 5-benzodioxan
(參考例19a)7-溴-3,4-二氫-2H-1,5-苯并二氧呯(benzodioxepine) (Reference Example 19a) 7-Bromo-3,4-dihydro-2H-1,5-benzodioxan (benzodioxepine)
將4-溴兒茶酚(1.9g，10mmol)溶解於乙腈(40mL)，在其中，於室溫下添加碳酸銫(9.8g，30mmol)，並攪拌30分鐘。在該反應液中添加1,3-二溴丙烷(1.0 mL、10mmol)，於氮氣環境下，在60℃攪拌14小時。將反應液用二乙基醚(40mL)稀釋，將其過濾除去不溶物後，以水(30mL)及飽和食鹽水(30mL)依序將濾液洗淨，用無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(己烷：乙酸乙酯，95：5→70：30(濃度梯度)V/V)精製，得到標題化合物(1.4g)。 4-Bromocatechol (1.9 g, 10 mmol) was dissolved in acetonitrile (40 mL), and EtOAc (EtOAc, EtOAc, EtOAc) Add 1,3-dibromopropane (1.0) to the reaction solution mL, 10 mmol) was stirred at 60 ° C for 14 hours under a nitrogen atmosphere. The reaction mixture was diluted with diethyl ether (40 mL), and filtered to remove insolubles. The filtrate was washed sequentially with water (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified using EtOAc EtOAc EtOAc (EtOAc)
1H NMR(400MHz,CDCl3)：δ2.16-2.22(2H,m),4.18-4.23(4H,m),6.85(1H,d,J=8.6Hz),7.03(1H,dd,J=8.4Hz,2.5Hz),7.13(1H,d,J=2.7Hz). 1 H NMR (400MHz, CDCl 3 ): δ2.16-2.22 (2H, m), 4.18-4.23 (4H, m), 6.85 (1H, d, J = 8.6Hz), 7.03 (1H, dd, J = 8.4 Hz, 2.5 Hz), 7.13 (1H, d, J = 2.7 Hz).
(參考例19b)7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-3,4-二氫-2H-1,5-苯并二氧呯 (Reference Example 19b) 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1, 5-benzodioxan
使用在參考例19a中所得到之化合物(0.70g，3.1mmol)、聯硼酸頻那醇酯(0.87g，3.4mmol)、乙酸鉀(0.92g，9.3mmol)、1,1'-雙(二苯基膦基)二茂鐵(52mg，0.094mmol)、[1,1'-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物 二氯甲烷加成物(76mg，0.093mmol)及1,4-二烷(20mL)，以與參考例15e同樣之方式得到標題化合物(0.61g)。 The compound obtained in Reference Example 19a (0.70 g, 3.1 mmol), boranoic acid pinacol ester (0.87 g, 3.4 mmol), potassium acetate (0.92 g, 9.3 mmol), 1,1'-bis (two) were used. Phenylphosphino)ferrocene (52 mg, 0.094 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (76 mg, 0.093 Mm) and 1,4-two The title compound (0.61 g) was obtained from m.
1H NMR(400MHz,CDCl3)：δ1.32(12H,s),2.16-2.22(2H,m),4.20(2H,t,J=5.6Hz),4.25(2H,t,J=5.6Hz),6.96(1H,d,J=7.9Hz),7.38(1H,dd,J=7.8Hz,1.6Hz),7.44(1H,d,J=1.6Hz). 1 H NMR (400MHz, CDCl 3 ): δ1.32 (12H, s), 2.16-2.22 (2H, m), 4.20 (2H, t, J = 5.6Hz), 4.25 (2H, t, J = 5.6Hz ), 6.96 (1H, d, J = 7.9 Hz), 7.38 (1H, dd, J = 7.8 Hz, 1.6 Hz), 7.44 (1H, d, J = 1.6 Hz).
(參考例20)7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-2,3-二氫[1,4]二英并[2,3-b]吡啶 (Reference Example 20) 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro[1,4] two Indolo[2,3-b]pyridine
使用7-溴-2,3-二氫[1,4]二英并[2,3-b]吡啶(432mg，2.00mmol)、聯硼酸頻那醇酯(609mg，2.40mmol)、乙酸鉀(589mg，6.00mmol)、[1,1'-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物 二氯甲烷加成物(163mg，0.20mmol)及1,2-二甲氧基乙烷(10mL)以與參考例15e同樣之方式得到標題化合物(493mg)。1H NMR(400MHz,CDCl3)：δ1.34(12H,s),4.24-4.26(2H,m),4.45-4.47(2H,m),7.54(1H,d,J=1.6Hz),8.19(1H,d,J=1.5Hz). Using 7-bromo-2,3-dihydro[1,4] Indolo[2,3-b]pyridine (432 mg, 2.00 mmol), pinacol borate (609 mg, 2.40 mmol), potassium acetate (589 mg, 6.00 mmol), [1,1'-bis(diphenyl) The title of the phosphino)ferrocene]palladium(II) dichloride methylene chloride adduct (163 mg, 0.20 mmol) and 1,2-dimethoxyethane (10 mL) was obtained in the same manner as the reference 15e. Compound (493 mg). 1 H NMR (400MHz, CDCl 3 ): δ1.34 (12H, s), 4.24-4.26 (2H, m), 4.45-4.47 (2H, m), 7.54 (1H, d, J = 1.6Hz), 8.19 (1H, d, J = 1.5Hz).
(參考例21)1-苯甲基-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-1,2,3,4-四氫喹啉 (Reference Example 21) 1-Benzyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3 4-tetrahydroquinoline
(參考例21a)1-苯甲基-7-溴-1,2,3,4-四氫喹啉 (Reference Example 21a) 1-Benzyl-7-bromo-1,2,3,4-tetrahydroquinoline
將7-溴-1,2,3,4-四氫喹啉(1.00g，4.72mmol)溶解於N,N-二甲基甲醯胺(5mL)，在其中，於冰冷下添加三級丁氧鉀(794mg，7.08mmol)及溴化苯甲基(0.84mL，7.08mmol)，升溫至室溫，同時攪拌2小時。反應終了後，在該反應液中加水，並用乙酸乙酯(30mL)稀釋。將其以10%w/v食鹽水(10mL，2次)及飽和食鹽水(20mL)依序洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，97：3→90：10(濃度梯度)V/V)精製，得到標題化合物(1.16g)。 7-Bromo-1,2,3,4-tetrahydroquinoline (1.00 g, 4.72 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then tris Potassium oxyhydroxide (794 mg, 7.08 mmol) and benzyl bromide (0.84 mL, 7.08 mmol) were warmed to room temperature and stirred for 2 hours. After the reaction was completed, water was added to the mixture and the mixture was diluted with ethyl acetate (30mL). This was washed sequentially with 10% w/v saline (10 mL, 2 times) and saturated brine (20 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(500MHz,CDCl3)：δ1.95-2.00(2H,m),2.74(2H,t,J=6.1Hz),3.33(2H,t,J=5.6Hz),4.46(2H,s),6.62(1H,d,J=1.9Hz),6.67(1H,dd,J=7.8Hz,2.0Hz),6.81(1H,d,J=7.8Hz),7.22-7.27(3H,m),7.32-7.35(2H,m). 1 H NMR (500MHz, CDCl 3 ): δ1.95-2.00 (2H, m), 2.74 (2H, t, J = 6.1Hz), 3.33 (2H, t, J = 5.6Hz), 4.46 (2H, s ), 6.62 (1H, d, J = 1.9 Hz), 6.67 (1H, dd, J = 7.8 Hz, 2.0 Hz), 6.81 (1H, d, J = 7.8 Hz), 7.22-7.27 (3H, m), 7.32-7.35(2H,m).
(參考例21b)1-苯甲基-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-1,2,3,4-四氫喹啉 (Reference Example 21b) 1-Benzyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3 4-tetrahydroquinoline
使用在參考例21a中所得到之化合物(0.58g，1.9mmol)、聯硼酸頻那醇酯(584mg，2.30mmol)、乙酸鉀(565mg，5.76mmol)、[1,1'-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物 二氯甲烷加成物(155mg，0.19mmol)及1,2-二甲氧基乙烷(10mL)，以與參考例15e同樣之方式得到標題化合物(489mg)。 The compound obtained in Reference Example 21a (0.58 g, 1.9 mmol), boranoic acid pinacol ester (584 mg, 2.30 mmol), potassium acetate (565 mg, 5.76 mmol), [1,1'-bis(diphenyl) were used. a phosphinyl)ferrocene]palladium(II) dichloride dichloromethane adduct (155 mg, 0.19 mmol) and 1,2-dimethoxyethane (10 mL) in the same manner as in Reference 15e The title compound (489 mg) was obtained.
1H NMR(400MHz,CDCl3)：δ1.60(12H,s),2.40-2.46(2H,m),3.51(2H,t,J=6.3Hz),4.04(2H,t,J=5.6Hz),5.67(2H,brs),8.74(1H,d,J=7.3Hz),8.82(1H,d,J=7.3Hz),8.88(1H,s),9.05-9.21(5H,m). 1 H NMR (400MHz, CDCl 3 ): δ1.60 (12H, s), 2.40-2.46 (2H, m), 3.51 (2H, t, J = 6.3Hz), 4.04 (2H, t, J = 5.6Hz ), 5.67 (2H, brs), 8.74 (1H, d, J = 7.3 Hz), 8.82 (1H, d, J = 7.3 Hz), 8.88 (1H, s), 9.05-9.21 (5H, m).
(參考例22)7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-2,3-二氫-4H-1,4-苯并-4-羧酸三級丁酯 (Reference Example 22) 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-1, 4-benzo 4-carboxylic acid tertiary butyl ester
(參考例22a)7-溴-3,4-二氫-2H-1,4-苯并 (Reference Example 22a) 7-Bromo-3,4-dihydro-2 H -1,4-benzo
將7-溴-2H-1,4-苯并-3(4H)-酮(0.60g，2.6mmol)溶解於THF(15mL)，在其中，於冰冷下滴入硼烷四氫呋喃錯合物之THF溶液(0.95M，4.2mL，4.9mmol)。將該反應液於氮氣環境下，在室溫攪拌30分鐘，並在70℃攪拌1小時半。反應終了後，將反應液冰冷，添加1M氫氧化鈉水溶液(10mL)，並攪拌1小時。將其以乙酸乙酯(20mL)稀釋，並用飽和食鹽水(10mL)洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑，將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，97：3→60：40(濃度梯度)V/V)精製，得到標題化合物(0.57g)。 7-bromo-2H-1,4-benzophenone -3(4H)-one (0.60 g, 2.6 mmol) was dissolved in THF (15 mL), and THF solution (0.95 M, 4.2 mL, 4.9 mmol) of borane tetrahydrofuran complex was added dropwise under ice cooling. The reaction solution was stirred at room temperature for 30 minutes under nitrogen, and stirred at 70 ° C for 1 hour and a half. After the reaction was completed, the reaction solution was ice-cooled, and then 1M aqueous sodium hydroxide (10 mL) was added and stirred for 1 hour. It was diluted with ethyl acetate (20 mL) and washed with brine (10 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated to dryness, and the residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate, 97:3→60:40 (concentration gradient) The title compound (0.57 g) was obtained.
1H NMR(400MHz,CDCl3)：δ3.41(2H,t,J=4.5Hz),3.76(1H,brs),4.22-4.24(2H,m),6.46(1H,d,J=8.6Hz),6.85(1H,dd,J=8.4Hz,2.2Hz),6.92(1H,d,J=1.9Hz). 1 H NMR (400 MHz, CDCl 3 ): δ 3.41 (2H, t, J = 4.5 Hz), 3.76 (1H, brs), 4.22-4.24 (2H, m), 6.46 (1H, d, J = 8.6 Hz ), 6.85 (1H, dd, J = 8.4 Hz, 2.2 Hz), 6.92 (1H, d, J = 1.9 Hz).
(參考例22b)7-溴-2,3-二氫-4H-1,4-苯并-4-羧酸三級丁酯 (Reference Example 22b) 7-Bromo-2,3-dihydro-4H-1,4-benzoene 4-carboxylic acid tertiary butyl ester
將在參考例22a中所得到之化合物(0.57g，2.6mmol)溶解於THF(7.8mL)，在其中，於室溫下添加二碳酸二丁酯(1.7g，7.8mmol)、N,N-二甲基-4-胺基吡啶(32mg，0.26mmol)及三乙基胺(1.08mL，7.8mmol)。將該反應液於室溫攪拌30分鐘，並於70℃攪拌8小時。 反應終了後，將反應液之溶劑於減壓下餾去，將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，97：3→70：30(濃度梯度)V/V)精製，得到標題化合物(0.70g)。 The compound (0.57 g, 2.6 mmol) obtained in Reference Example 22a was dissolved in THF (7.8 mL), and dibutyl dicarbonate (1.7 g, 7.8 mmol), N, N- Dimethyl-4-aminopyridine (32 mg, 0.26 mmol) and triethylamine (1.08 mL, 7.8 mmol). The reaction solution was stirred at room temperature for 30 minutes and at 70 ° C for 8 hours. After the completion of the reaction, the solvent of the reaction mixture was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate, 97:3 → 70:30 (concentration gradient) V/ V) purification gave the title compound (0.70 g).
1H NMR(400MHz,CDCl3)：δ1.54(9H,s),3.83-3.85(2H,m),4.22-4.25(2H,m),6.99(1H,dd,J=9.0Hz,2.4Hz),7.03(1H,d,J=2.4Hz),7.67(1H,brs). 1 H NMR (400 MHz, CDCl 3 ): δ 1.54 (9H, s), 3.83-3.85 (2H, m), 4.22-4.25 (2H, m), 6.99 (1H, dd, J = 9.0 Hz, 2.4 Hz ), 7.03 (1H, d, J = 2.4 Hz), 7.67 (1H, brs).
(參考例22c)7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-2,3-二氫-4H-1,4-苯并-4-羧酸三級丁酯 (Reference Example 22c) 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-1, 4-benzo 4-carboxylic acid tertiary butyl ester
使用在參考例22b中所得到之化合物(681mg，2.17mmol)、聯硼酸頻那醇酯(660mg，2.60mmol)、乙酸鉀(638mg，6.50mmol)、1,1'-雙(二苯基膦基)二茂鐵(120mg，0.22mmol)、[1,1'-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物 二氯甲烷加成物(177mg，0.22mmo)、及1,4-二烷(5mL)，以與參考例15e同樣之方式得到標題化合物(715mg)。 The compound obtained in Reference Example 22b (681 mg, 2.17 mmol), boranoic acid pinacol ester (660 mg, 2.60 mmol), potassium acetate (638 mg, 6.50 mmol), 1,1'-bis(diphenylphosphine) was used. Ferrocenyl (120 mg, 0.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (177 mg, 0.22 mmo), And 1,4-two The title compound (715 mg) was obtained.
1H NMR(400MHz,CDCl3)：δ1.33(12H,s),1.54(9H,s),3.84-3.87(2H,m),4.22-4.24(2H,m),7.27-7.33(2H,m),7.81(1H,brs). 1H NMR (400MHz, CDCl 3 ): δ 1.33 (12H, s), 1.54 (9H, s), 3.84-3.87 (2H, m), 4.22-4.24 (2H, m), 7.27-7.33 (2H, m ), 7.81 (1H, brs).
(參考例23)4-苯甲基-2-甲基-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-3,4-二氫-2H-1,4-苯并 (Reference Example 23) 4-Benzyl-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,4-dihydro-2H-1,4-benzoene
(參考例23a)2-(5-溴-2-硝基苯氧基)丙酸乙酯 (Reference Example 23a) 2-(5-Bromo-2-nitrophenoxy)propionic acid ethyl ester
將4-溴-2-氟-1-硝基苯(660mg，3.00mmol)溶解於THF(6ml)，在其中，於冰冷下添加氫化鈉(油性，63%w/w，137mg，3.60mmol)、及15-冠醚-5(0.03mL)。在該反應液中添加乳酸乙酯(0.36mL，3.15mmol)，升溫至室溫，同時攪拌2小時。反應終了後，在該反應液中添加甲醇(0.2mL)，並以乙酸乙酯(30mL)稀釋。將其用10%w/v食鹽水(10mL，2次)及飽和食鹽水(20mL)依序洗淨，將有機層以無水硫酸鈉乾燥後，過濾有機層。將濾液之溶劑於減壓下餾去，將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，97：3→80：20(濃度梯度)V/V)精製，得到標題化合物(681mg)。 4-Bromo-2-fluoro-1-nitrobenzene (660 mg, 3.00 mmol) was dissolved in THF (6 ml), and sodium hydride (oily, 63% w/w, 137 mg, 3.60 mmol) And 15-crown-5 (0.03 mL). Ethyl lactate (0.36 mL, 3.15 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature and stirred for 2 hours. After the reaction was completed, methanol (0.2 mL) was added and the mixture was diluted with ethyl acetate (30 mL). This was washed with 10% w/v brine (10 mL, twice) and brine (20 mL), and the organic layer was dried over anhydrous sodium sulfate. The solvent of the filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 97:3→80:20 (concentration gradient) V/V). The title compound (681 mg).
1H NMR(400MHz,CDCl3)：δ1.27(3H,t,J=7.1Hz),1.70(3H,d,J=6.7Hz),4.25(2H,q,J=7.1Hz),4.83(1H,q,J=6.7Hz),7.12(1H,d,J=1.7Hz),7.23(1H,dd,J=8.6Hz,1.7Hz),7.75(1H,d,J=8.6Hz). 1 H NMR (400 MHz, CDCl 3 ): δ 1.27 (3H, t, J = 7.1 Hz), 1.70 (3H, d, J = 6.7 Hz), 4.25 (2H, q, J = 7.1 Hz), 4.83 ( 1H, q, J = 6.7 Hz), 7.12 (1H, d, J = 1.7 Hz), 7.23 (1H, dd, J = 8.6 Hz, 1.7 Hz), 7.75 (1H, d, J = 8.6 Hz).
(參考例23b)7-溴-2-甲基-2H-1,4-苯并-3(4H)-酮 (Reference Example 23b) 7-Bromo-2-methyl-2H-1,4-benzoene -3(4H)-ketone
將在參考例23a中所得到之化合物(680mg，2.14mmol)溶解於乙酸(11mL)，在其中添加鐵粉(1.2g，21.4mmol)。將該反應液於氮氣環境下，在60℃攪拌2小時後，冷卻至室溫並以乙酸乙酯(20mL)稀釋。過濾該反應液，並於減壓下餾去濾液之溶劑。將所得到之殘餘物再度用乙酸乙酯(20mL)稀釋，並將其用水(10mL)、飽和碳酸氫鈉水溶液(20mL)、及飽和食鹽水(20mL)依序洗淨，將有機層以無水硫酸鈉乾燥。於減壓下餾去該有機層之溶劑，在未將所得到之殘餘物(483mg)精製下，直接使用於後續步驟。 The compound (680 mg, 2.14 mmol) obtained in Reference Example 23a was dissolved in acetic acid (11 mL), and iron powder (1.2 g, 21.4 mmol) was added thereto. The reaction solution was stirred at 60 ° C for 2 hr under nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate (20 mL). The reaction solution was filtered, and the solvent of the filtrate was evaporated under reduced pressure. The obtained residue was diluted with ethyl acetate (20 mL), and then washed with water (10 mL), saturated aqueous sodium hydrogen carbonate (20 mL), and brine (20 mL). Dry over sodium sulfate. The solvent of the organic layer was evaporated under reduced pressure, and the obtained residue (483 mg)
(參考例23c)7-溴-2-甲基-3,4-二氫-2H-1,4-苯并 (Reference Example 23c) 7-Bromo-2-methyl-3,4-dihydro-2H-1,4-benzo
將在參考例23b中所得到之化合物(483mg，約2.00mmol)溶解於THF(4mL)中，於冰冷下將硼烷四氫呋喃錯合物之THF溶液(0.95M，6.32mL，6.00mmol)滴入其中。將該反應液在氮氣環境下，於室溫下攪拌10分鐘，及於50℃攪拌40分鐘。反應終了後，將反應液冰冷，並將水(5mL)滴入其中。將該反應液用乙酸乙酯(10mL)稀釋，將其以水(10mL)、飽和碳酸氫鈉水溶液(20mL)、及飽和食鹽水(20mL)依序洗淨，並將有機層用無水硫酸鈉乾燥。於減壓下餾去該有機層之溶劑，在未將所得到之殘餘物(462mg)精製下，直接使用於後續步驟。 The compound obtained in Reference Example 23b (483 mg, ca. 2.00 mmol) was dissolved in THF (4 mL), and THF solution of borane tetrahydrofuran complex (0.95 M, 6.32 mL, 6.00 mmol) was added dropwise under ice cooling. among them. The reaction solution was stirred at room temperature for 10 minutes under nitrogen, and stirred at 50 ° C for 40 minutes. After the reaction was completed, the reaction solution was ice-cooled, and water (5 mL) was dropped. The reaction mixture was diluted with ethyl acetate (10 mL). EtOAc (EtOAc)EtOAc. dry. The solvent of the organic layer was evaporated under reduced pressure, and the obtained residue (462 mg)
(參考例23d)4-苯甲基-7-溴-2-甲基-3,4-二氫-2H-1,4-苯并 (Reference Example 23d) 4-Benzyl-7-bromo-2-methyl-3,4-dihydro-2H-1,4-benzoene
使用在參考例23c中所得到之化合物(462mg，約2.00mmol)、三級丁氧基鉀(337mg，3.00mmol)、溴化苯甲基(0.36mL，3.00mmol)、及N,N-二甲基甲醯胺(5mL)，以與參考例21a同樣之方式得到標題化合物(340mg)。 The compound (462 mg, about 2.00 mmol) obtained in Reference Example 23c, potassium potassium hydride (337 mg, 3.00 mmol), benzyl bromide (0.36 mL, 3.00 mmol), and N,N- The title compound (340 mg) was obtained from m.
1H NMR(500MHz,CDCl3)：δ1.34(3H,d,J=6.4Hz),3.10(1H,dd,J=11.7Hz,8.3Hz),3.25(1H,dd,J=11.7Hz,2.5Hz),4.26-4.29(1H,m),4.41(2H,brs),6.49(1H,d,J=8.5Hz),6.85(1H,dd,J=8.5Hz,2.5Hz),6.94(1H,d,J=2.5Hz),7.24-7.38(5H,m). 1 H NMR (500MHz, CDCl 3 ): δ1.34 (3H, d, J = 6.4Hz), 3.10 (1H, dd, J = 11.7Hz, 8.3Hz), 3.25 (1H, dd, J = 11.7Hz, 2.5 Hz), 4.26-4.29 (1H, m), 4.41 (2H, brs), 6.49 (1H, d, J = 8.5 Hz), 6.85 (1H, dd, J = 8.5 Hz, 2.5 Hz), 6.94 (1H) , d, J = 2.5 Hz), 7.24 - 7.38 (5H, m).
(參考例23e)4-苯甲基-2-甲基-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-3,4-二氫-2H-1,4-苯并 (Reference Example 23e) 4-Benzyl-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,4-dihydro-2H-1,4-benzoene
使用在參考例23d中所得到之化合物(340mg，1.07mmol)、聯硼酸頻那醇酯(326mg，1.28mmol)、乙酸鉀(315mg，3.21mmol)、[1,1'-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物 二氯甲烷加成物(90mg，0.11mmol)、及1,2-二甲氧基乙烷(5mL)，以與參考例15e同樣之方式得到標題化合物(252mg)。 The compound obtained in Reference Example 23d (340 mg, 1.07 mmol), pinacol borate (326 mg, 1.28 mmol), potassium acetate (315 mg, 3.21 mmol), [1,1'-bis(diphenyl) Phosphyl)ferrocene]palladium(II) dichloride methylene chloride adduct (90 mg, 0.11 mmol), and 1,2-dimethoxyethane (5 mL) in the same manner as Reference Example 15e The title compound (252 mg) was obtained.
1H NMR(400MHz,CDCl3)：δ1.30(12H,s),1.33(3H,d,J=6.3Hz),3.17(1H,dd,J=11.7Hz,7.8Hz),3.28(1H,dd,J=11.7Hz,2.7Hz),4.21-4.26(1H,m),4.48(1H,d,J=16.8Hz),4.53(1H,d,J=16.8Hz),6.67(1H,d,J=7.8Hz),7.25-7.34(7H,m). 1 H NMR (400 MHz, CDCl 3 ): δ 1.30 (12H, s), 1.33 (3H, d, J = 6.3 Hz), 3.17 (1H, dd, J = 11.7 Hz, 7.8 Hz), 3.28 (1H, Dd, J = 11.7 Hz, 2.7 Hz), 4.21-4.26 (1H, m), 4.48 (1H, d, J = 16.8 Hz), 4.53 (1H, d, J = 16.8 Hz), 6.67 (1H, d, J = 7.8 Hz), 7.25-7.34 (7H, m).
(參考例24)4-苯甲基-2,2-二甲基-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-3,4-二氫-2H-1,4-苯并 (Reference Example 24) 4-Benzyl-2,2-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Base,-3,4-dihydro-2H-1,4-benzoate
使用4-溴-2-氟-1-硝基苯(1.10g，5.00mmol)及2-羥基異丁酸乙酯(0.75mL，5.50mmol)做為原料，以與參考例23同樣之方式得到標題化合物(298mg)。 4-bromo-2-fluoro-1-nitrobenzene (1.10 g, 5.00 mmol) and ethyl 2-hydroxyisobutyrate (0.75 mL, 5.50 mmol) were used as a starting material in the same manner as in Reference Example 23. The title compound (298 mg).
1H NMR(400MHz,CDCl3)：δ1.30(3H,s),1.31(3H,s),3.09(2H,s),4.52(2H,s),6.69(1H,d,J=7.8Hz),7.25-7.35(7H,m). 1 H NMR (400 MHz, CDCl 3 ): δ 1.30 (3H, s), 1.31 (3H, s), 3.09 (2H, s), 4.52 (2H, s), 6.69 (1H, d, J = 7.8 Hz ), 7.25-7.35 (7H, m).
(參考例25)4-苯甲基-7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-3,4-二氫螺[1,4-苯并-2,1'-環丙烷] (Reference Example 25) 4-Benzyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-di Hydrogen snail [1,4-benzoate -2,1'-cyclopropane]
使用4-溴-2-氟-1-硝基苯(1.39g，6.00mmol)及、1-羥基環丙烷羧酸乙酯(954mg，6.60mmol)做為原料，以與參考例23同樣之方式得到標題化合物(626mg)。 4-bromo-2-fluoro-1-nitrobenzene (1.39 g, 6.00 mmol) and ethyl 1-hydroxycyclopropanecarboxylate (954 mg, 6.60 mmol) were used as a starting material in the same manner as in Reference Example 23. The title compound (626 mg) was obtained.
1H NMR(400MHz,CDCl3)：δ0.61-0.64(2H,m),1.01-1.04(2H,m),1.30(12H,s),3.34(2H,s),4.53(2H,s),6.68(1H,d,J=8.2Hz),7.20(1H,d,J=1.2Hz),7.26-7.35(6H,m). 1 H NMR (400 MHz, CDCl 3 ): δ 0.61-0.64 (2H, m), 1.01-1.04 (2H, m), 1.30 (12H, s), 3.34 (2H, s), 4.53 (2H, s) , 6.68 (1H, d, J = 8.2 Hz), 7.20 (1H, d, J = 1.2 Hz), 7.26-7.35 (6H, m).
(實施例1)(1S,3'R,4'S,5'S,6'R)-5-氯-6-(2,3-二氫-1,4-苯并二英-6-基甲基)-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 1) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6-(2,3-dihydro-1,4-benzoic -6-ylmethyl)-6'-[(1R)-1-hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1 , 2'-pyrano]-3',4',5'-triol
(實施例1a)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-6-(2,3-二氫-1,4-苯并二英-6-基甲基)-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Example 1a) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-5-chloro-6-(2,3-dihydro-1,4-benzoic acid Inox-6-ylmethyl)-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran]
將在參考例6中所得到之化合物(0.20g，0.26mmol)溶解於甲苯(1.1mL)-乙醇(0.78mL)-水(0.52mL)之混合溶劑中，添加(1,4-苯并二烷-6-基)硼酸(54mg，0.30mmol)、碳酸鈉(56mg，0.53mmol)、及肆三苯膦鈀(0)(30mg，0.026mmol)。將該反應液於氮氣環境下，在100℃攪拌2小時後，加水(20mL)並用乙酸乙酯(30mL，2次)萃取。將有機層用飽和食鹽水(20mL)洗淨，以無水 硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(己烷：乙酸乙酯，95：5→50：50(濃度梯度)V/V)精製，得到標題化合物(0.19g)。 The compound (0.20 g, 0.26 mmol) obtained in Reference Example 6 was dissolved in a mixed solvent of toluene (1.1 mL)-ethanol (0.78 mL)-water (0.52 mL). Alkan-6-yl)boronic acid (54 mg, 0.30 mmol), sodium carbonate (56 mg, 0.53 mmol), and triphenylphosphine palladium (0) (30 mg, 0.026 mmol). After the reaction mixture was stirred at 100 ° C for 2 hrs, then water (20mL) and ethyl acetate (30mL, twice). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc EtOAc (EtOAc)
(實施例1b)(1S,3'R,4'S,5'S,6'R)-5-氯-6-(2,3-二氫-1,4-苯并二英-6-基甲基)-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 1b) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6-(2,3-dihydro-1,4-benzoic -6-ylmethyl)-6'-[(1R)-1-hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1 , 2'-pyrano]-3',4',5'-triol
將在實施例1a中所得到之化合物(0.19g，0.23mmol)溶解於THF(8.0mL)及甲醇(4.0mL)之混合溶劑中，在其中添加1,2-二氯苯(0.13mL，1.2mmol)、及10%w/w鈀/碳(0.19g)，在氫氣環境下，於室溫攪拌1小時。將該反應液過濾後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(二氯甲烷：甲醇，98：2→80：20(濃度梯度)V/V)精製，得到標題化合物(83mg)。 The compound obtained in Example 1a (0.19 g, 0.23 mmol) was dissolved in a mixed solvent of THF (8.0 mL) and methanol (4.0 mL), and 1,2-dichlorobenzene (0.13 mL, 1.2 Methyl) and 10% w/w palladium on carbon (0.19 g) were stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtering the reaction mixture, the solvent was evaporated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(400MHz,MeOH-d4)：δ1.13(3H,d,J=6.7Hz),3.39(1H,dd,J=10.2Hz,8.2Hz),3.69(1H,d,J=9.4Hz),3.73(1H,dd,J=9.4Hz,8.2Hz),3.79(1H,dd,J=10.2Hz,3.5Hz),3.97-4.03(3H,m),4.19(4H,s),5.07(1H,d,J=12.9Hz),5.13(1H,d,J=12.9Hz),6.63-6.66(2H,m),6.72(1H,dt,J=8.8Hz,1.0Hz),7.21(1H,s),7.35(1H,s)；MS(ESI)m/z：465(M+H)+. 1 H NMR (400MHz, MeOH- d4): δ1.13 (3H, d, J = 6.7Hz), 3.39 (1H, dd, J = 10.2Hz, 8.2Hz), 3.69 (1H, d, J = 9.4Hz ), 3.73 (1H, dd, J = 9.4 Hz, 8.2 Hz), 3.79 (1H, dd, J = 10.2 Hz, 3.5 Hz), 3.97-4.03 (3H, m), 4.19 (4H, s), 5.07 ( 1H, d, J = 12.9 Hz), 5.13 (1H, d, J = 12.9 Hz), 6.63 - 6.66 (2H, m), 6.72 (1H, dt, J = 8.8 Hz, 1.0 Hz), 7.21 (1H, s), 7.35 (1H, s); MS (ESI) m/z: 465 (M+H) + .
(實施例2)(1S,3'R,4'S,5'S,6'R)-6-(2,3-二氫-1,4-苯并二英-6-基甲基)-6'-[(1R)-1-羥基乙基]-5-甲基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 2) (1S, 3'R, 4'S, 5'S, 6'R)-6-(2,3-dihydro-1,4-benzoic -6-ylmethyl)-6'-[(1R)-1-hydroxyethyl]-5-methyl-3',4',5',6'-tetrahydro-3H-spiro[2- Benzofuran-1,2'-pyrano]-3',4',5'-triol
(實施例2a)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-6-(2,3-二氫-1,4-苯并二英-6-基甲基)-5-甲基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Example 2a) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-6-(2,3-dihydro-1,4-benzoic acid Inox-6-ylmethyl)-5-methyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran]
將在參考例7中所得到之化合物(266mg，0.36mmol)、(1,4-苯并二烷-6-基)硼酸(77mg，0.43mmol)、肆三苯膦鈀(0)(41mg，0.036mmol)、及碳酸鈉(75mg，0.71mmol)溶解於甲苯(2mL)-乙醇(1.5mL)-水(0.35mL)之混合溶劑中，將其於氮氣環境下，在100℃攪拌2小時。將反應液注入水(20mL)中，並以乙酸乙酯(20mL)萃取。將有機層用飽和食鹽水(20mL)洗淨，以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘 餘物使用矽膠急速管柱層析(己烷：乙酸乙酯，97：3-75：25(濃度梯度)V/V)精製，得到標題化合物(202mg，收率71%)。 The compound obtained in Reference Example 7 (266 mg, 0.36 mmol), (1,4-benzoic acid) Alkan-6-yl)boronic acid (77 mg, 0.43 mmol), decyltriphenylphosphine palladium (0) (41 mg, 0.036 mmol), and sodium carbonate (75 mg, 0.71 mmol) dissolved in toluene (2 mL)-ethanol (1.5 mL) In a mixed solvent of water (0.35 mL), the mixture was stirred at 100 ° C for 2 hours under a nitrogen atmosphere. The reaction solution was poured into water (20 mL) The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The obtained residue was purified by EtOAc EtOAcjjjjjjjj
1H NMR(400MHz,CDCl3)：δ1.13(3H,d,J=6.7Hz),2.28(3H,s),3.63(1H,dd,J=10.0,9.2Hz),3.76-3.93(4H,m),4.04-4.26(7H,m),4.45-4.72(4H,m),4.83-4.97(3H,m),5.14(1H,d,J=12.3Hz),5.19(1H,d,J=12.3Hz),6.47(1H,dd,J=8.2,2.0Hz),6.56-6.66(2H,m),6.81(2H,dd,J=8.0,1.4Hz),7.00-7.35(20H,m)；MS(TOF MS ES+)m/z：805(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.13 (3H, d, J = 6.7 Hz), 2.28 (3H, s), 3.63 (1H, dd, J = 10.0, 9.2 Hz), 3.76-3.93 (4H , m), 4.04-4.26 (7H, m), 4.45-4.72 (4H, m), 4.83-4.97 (3H, m), 5.14 (1H, d, J = 12.3 Hz), 5.19 (1H, d, J = 12.3 Hz), 6.47 (1H, dd, J = 8.2, 2.0 Hz), 6.56-6.66 (2H, m), 6.81 (2H, dd, J = 8.0, 1.4 Hz), 7.00-7.35 (20H, m) MS (TOF MS ES+) m/z: 805 (M+H) + .
(實施例2b)(1S,3'R,4'S,5'S,6'R)-6-(2,3-二氫-1,4-苯并二英-6-基甲基)-6'-[(1R)-1-羥基乙基]-5-甲基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 2b) (1S, 3'R, 4'S, 5'S, 6'R)-6-(2,3-dihydro-1,4-benzoic -6-ylmethyl)-6'-[(1R)-1-hydroxyethyl]-5-methyl-3',4',5',6'-tetrahydro-3H-spiro[2- Benzofuran-1,2'-pyrano]-3',4',5'-triol
將在實施例2a中所得到之化合物(202mg，0.25mmol)溶解於THF(6mL)及甲醇(3mL)之混合溶劑中，於其中添加1,2-二氯苯(0.14mL，1.25mmol)、10%w/w鈀/碳(200mg)，將其在氫氣環境下，於室溫下攪拌1小時。將反應液過濾後，於減壓下餾去濾液之溶劑。將所得到之殘餘物使用矽膠急速管柱層析(二氯甲烷：甲醇， 97：3-85：15(濃度梯度)V/V)精製，得到標題化合物(97mg，收率87%)。 The compound obtained in Example 2a (202 mg, 0.25 mmol) was dissolved in a mixed solvent of THF (6 mL) and methanol (3 mL), and 1,2-dichlorobenzene (0.14 mL, 1.25 mmol), 10% w/w palladium on carbon (200 mg) was stirred under a hydrogen atmosphere at room temperature for 1 hour. After filtering the reaction mixture, the solvent of the filtrate was evaporated under reduced pressure. The obtained residue was chromatographed on silica gel (dichloromethane: methanol, 97:3-85:15 (concentration gradient) V/V) was purified to give the title compound (97 mg, yield: 87%).
1H NMR(400MHz,CD3OD)：1.14(3H,d,J=6.3Hz),2.22(3H,s),3.36-3.44(1H,m),3.70-3.76(2H,m),3.77-3.84(1H,m),3.90(2H,s),3.95-4.06(1H,m),4.18(4H,s),5.05(1H,d,J=12.1Hz),5.13(1H,d,J=12.1Hz),6.51-6.61(2H,m),6.69(1H,d,J=8.2Hz),7.08(2H,s)；MS(TOF MS ES+)m/z：445(M+H)+. 1 H NMR (400 MHz, CD 3 OD): 1.14 (3H, d, J = 6.3 Hz), 2.22 (3H, s), 3.36-3.44 (1H, m), 3.70-3.76 (2H, m), 3.77- 3.84 (1H, m), 3.90 (2H, s), 3.95-4.06 (1H, m), 4.18 (4H, s), 5.05 (1H, d, J = 12.1 Hz), 5.13 (1H, d, J = 12.1 Hz), 6.51-6.61 (2H, m), 6.69 (1H, d, J = 8.2 Hz), 7.08 (2H, s); MS (TOF MS ES+) m/z: 445 (M+H) + .
(實施例3)(1S,3'R,4'S,5'S,6'R)-6-(1-苯并呋喃-5-基甲基)-5-氯-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 3) (1S, 3'R, 4'S, 5'S, 6'R)-6-(1-benzofuran-5-ylmethyl)-5-chloro-6'-[(1R)-1 -hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'-three alcohol
(實施例3a)(1S,3'R,4'S,5'S,6'R)-6-(1-苯并呋喃-5-基甲基)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Example 3a) (1S, 3'R, 4'S, 5'S, 6'R)-6-(1-benzofuran-5-ylmethyl)-3', 4', 5'-para (benzoyl) Oxy)-6'-[(1R)-1-(benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzene And furan-1,2'-pyranose]
將參考例6中所得到之化合物(0.20g，0.26mmol)、苯并呋喃-5-硼酸(50mg，0.31mmol)、肆(三苯 膦)鈀(0)(30mg，0.026mmol)、及碳酸鈉(55mg，0.52mmol)溶解於甲苯(2mL)-乙醇(1.5mL)-水(0.3mL)之混合溶劑中，於氮氣環境下，在100℃攪拌2小時。將該反應液冷卻至室溫後，注入水(10mL)中，並以乙酸乙酯(30mL)萃取。將有機層用飽和食鹽水(10mL)洗淨，以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將殘餘物使用矽膠急速管柱層析(己烷：乙酸乙酯，100：0→80：20(濃度梯度)V/V)精製，得到標題化合物(0.18g，收率85%)。 The compound obtained in Reference Example 6 (0.20 g, 0.26 mmol), benzofuran-5-boronic acid (50 mg, 0.31 mmol), hydrazine (triphenylbenzene) Palladium (0) (30 mg, 0.026 mmol) and sodium carbonate (55 mg, 0.52 mmol) were dissolved in a mixed solvent of toluene (2 mL)-ethanol (1.5 mL)-water (0.3 mL) under nitrogen atmosphere. Stir at 100 ° C for 2 hours. After the reaction mixture was cooled to room temperature, poured into water (10 mL) and ethyl acetate (30 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc
(實施例3b)(1S,3'R,4'S,5'S,6'R)-6-(1-苯并呋喃-5-基甲基)-5-氯-6'-[(1R)-1-羥基乙基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 3b) (1S, 3'R, 4'S, 5'S, 6'R)-6-(1-benzofuran-5-ylmethyl)-5-chloro-6'-[(1R)-1 -hydroxyethyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'-triol
將在實施例3a中所得到之化合物(0.18g，0.22mmol)、及1,2-二氯苯(0.12mL，1.1mmol)溶解於THF(5mL)-甲醇(2.5mL)之混合溶劑中，添加10%w/w鈀碳(0.18g)，並在氫氣環境下，於室溫下攪拌1小時30分鐘。將反應液過濾後，於減壓下餾去溶劑。將殘餘物使用矽膠急速管柱層析(二氯甲烷：甲醇、100：0→85：15(濃度梯度)V/V)精製，得到標題化合物，其為與副生成物之混合物(92mg)。 The compound obtained in Example 3a (0.18 g, 0.22 mmol), and 1,2-dichlorobenzene (0.12 mL, 1.1 mmol) were dissolved in a mixed solvent of THF (5 mL)-methanol (2.5 mL). 10% w/w palladium on carbon (0.18 g) was added and stirred at room temperature for 1 hour and 30 minutes under a hydrogen atmosphere. After filtering the reaction mixture, the solvent was evaporated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:EtOAc
(實施例3c)(1S,3'R,4'S,5'R,6'R)-6'-[(1R)-1-(乙醯基氧基)乙基]-6-(1-苯并呋喃-5-基甲基)-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三基三乙酸酯 (Example 3c) (1S, 3'R, 4'S, 5'R, 6'R)-6'-[(1R)-1-(ethylideneoxy)ethyl]-6-(1-benzene And furan-5-ylmethyl)-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3' , 4',5'-tris-triacetate
將在實施例3b中所得到之化合物(92mg，0.21mmol)溶解於乙酸乙酯(2mL)中，添加吡啶(0.20mL，2.5mmol)、乙酸酐(0.24mL，2.5mmol)、及4-二甲基胺基吡啶(3mg，0.021mmol)，並於室溫攪拌17小時。在該反應液中加水(5mL)，並以乙酸乙酯(30mL)萃取。將有機層用1M鹽酸(10mL)、飽和碳酸氫鈉水溶液(10mL)、飽和食鹽水(10mL)洗淨，以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將殘餘物使用矽膠急速管柱層析(己烷：乙酸乙酯，100：0→70：30(濃度梯度)V/V)精製，得到標題化合物(90mg，收率70%)。 The compound obtained in Example 3b (92 mg, 0.21 mmol) was dissolved in ethyl acetate (2mL), pyridine (0.20mL, 2.5mmol), acetic anhydride (0.24mL, 2.5mmol), and 4- Methylaminopyridine (3 mg, 0.021 mmol) was stirred at room temperature for 17 h. Water (5 mL) was added to the mixture, and ethyl acetate (30 mL). The organic layer was washed with 1 M hydrochloric acid (10 mL), EtOAc. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:
(實施例3d)(1S,3'R,4'S,5'S,6'R)-6-(1-苯并呋喃-5-基甲基)-5-氯-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 3d) (1S, 3'R, 4'S, 5'S, 6'R)-6-(1-benzofuran-5-ylmethyl)-5-chloro-6'-[(1R)-1 -hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'-three alcohol
將在實施例3c中所得到之化合物(90mg，0.15mmol)溶解於2-丙醇(3mL)-THF(1mL)-水(1mL)之混合溶劑中，添加5M氫氧化鈉水溶液(0.18mL，0.88mmol)，並於室溫攪拌2小時15分鐘。在該反應液中，於冰冷下，添加1M鹽酸(0.88mL，0.88mmol)中和後，添加飽和食鹽水(5mL)，並以二氯甲烷(30mL)萃取。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠急速管柱層析(二氯甲烷：甲醇，100：0→85：15(濃度梯度)V/V)精製，得到標題化合物(66mg，收率98%)。 The compound obtained in Example 3c (90 mg, 0.15 mmol) was dissolved in a mixed solvent of 2-propanol (3 mL)-THF (1 mL)-water (1 mL), 0.88 mmol) and stirred at room temperature for 2 hours and 15 minutes. In the reaction mixture, 1 M hydrochloric acid (0.88 mL, 0.88 mmol) was added to the mixture, and the mixture was stirred, and then brine (5 mL) was evaporated. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(400MHz,MeOH-d4)：δ1.11(3H,d,J=6.3Hz),3.37(1H,dd,J=10.2Hz,8.6Hz),3.67(1H,d,J=9.4Hz),3.73(1H,dd,J=9.4Hz,8.6Hz),3.79(1H,dd,J=10.2Hz,3.5Hz),3.95-4.03(1H,m),4.23(2H,s),5.08(1H,d,J=12.9Hz),5.14(1H,d,J=12.9Hz),6.75(1H,d,J=2.3Hz),7.16(1H,dd,J=8.6Hz,1.9Hz),7.24(1H,s),7.37-7.41(3H,m),7.71(1H,d,J=2.3Hz)；MS(ESI)m/z：447(M+H)+. 1 H NMR (400MHz, MeOH- d4): δ1.11 (3H, d, J = 6.3Hz), 3.37 (1H, dd, J = 10.2Hz, 8.6Hz), 3.67 (1H, d, J = 9.4Hz ), 3.73 (1H, dd, J = 9.4 Hz, 8.6 Hz), 3.79 (1H, dd, J = 10.2 Hz, 3.5 Hz), 3.95-4.03 (1H, m), 4.23 (2H, s), 5.08 ( 1H, d, J = 12.9 Hz), 5.14 (1H, d, J = 12.9 Hz), 6.75 (1H, d, J = 2.3 Hz), 7.16 (1H, dd, J = 8.6 Hz, 1.9 Hz), 7.24 (1H, s), 7.37-7.41 (3H, m), 7.71 (1H, d, J = 2.3 Hz); MS (ESI) m/z: 447 (M+H) + .
(實施例4)(1S,3'R,4'S,5'S,6'R)-6-(4-乙基苯甲基)-6'-[(1R)-1-羥基乙基]-5-(羥基甲基)-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 4) (1S, 3'R, 4'S, 5'S, 6'R)-6-(4-ethylbenzyl)-6'-[(1R)-1-hydroxyethyl]-5- (hydroxymethyl)-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'-three alcohol
(實施例4a)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-溴-6-(溴乙基)-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Example 4a) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-5-bromo-6-(bromoethyl)-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'- Piper
將在參考例7a中所得到之化合物(600mg，0.80mmol)溶解於二氯甲烷(8mL)，並在其中，於冰冷下添加三苯膦(419mg，1.60mmol)及四溴化碳(529mg，1.60mmol)，並於冰冷下攪拌10分鐘。將反應液使用矽膠急速管柱層析(己烷：乙酸乙酯，97：3-85：15，V/V)精製，得到標題化合物(608mg，收率94%)。 The compound (600 mg, 0.80 mmol) obtained in Reference Example 7a was dissolved in dichloromethane (8 mL), and triphenylphosphine (419 mg, 1.60 mmol) and carbon tetrabromide (529 mg, 1.60 mmol) and stirred for 10 minutes under ice cooling. The reaction mixture was purified by EtOAcjjjjjjjjjjj
1H NMR(400MHz,CDCl3)：δ1.10(3H,d,J=6.7Hz),3.59(1H,dd,J=10.2,9.0Hz),3.76-3.82(2H,m),4.14-4.23(3H,m),4.42-4.70(6H,m),4.86-5.01(3H,m),5.14(2H,s),6.79-6.85(2H,m),7.09-7.36(19H,m),7.45(1H,s)；MS(TOF MS ES+)m/z：813(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.10 (3H, d, J = 6.7 Hz), 3.59 (1H, dd, J = 10.2, 9.0 Hz), 3.76-3.82 (2H, m), 4.14 - 4.23 (3H, m), 4.42-4.70 (6H, m), 4.86-5.01 (3H, m), 5.14 (2H, s), 6.79-6.85 (2H, m), 7.09-7.36 (19H, m), 7.45 (1H, s); MS (TOF MS ES+) m/z: 813 (M+H) + .
(實施例4b)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-溴-6-(4-乙基苯甲基)-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Example 4b) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-5-bromo-6-(4-ethylbenzyl)-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1 , 2'-pyranose]
將實施例4a中所得到之化合物(400mg，0.49mmol)、4-乙基苯基硼酸(74mg，0.49mmol)、肆三苯膦鈀(0)(57mg，0.049mmol)、及碳酸鈉(104mg，0.98mmol)溶解於甲苯(2mL)-乙醇(1.5mL)-水(0.49mL)之混合溶劑中，於氮氣環境下，在80℃攪拌5小時。將該反應液注入水(20mL)中，並以乙酸乙酯(20mL，2次)萃取。將有機層以飽和食鹽水(40mL)洗淨，用無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠急速管柱層析(己烷：乙酸乙酯，95：5-85：15(濃度梯度)V/V)精製，得到標題化合物(326mg，收率79%)。 The compound obtained in Example 4a (400 mg, 0.49 mmol), 4-ethylphenylboronic acid (74 mg, 0.49 mmol), decyltriphenylphosphine palladium (0) (57 mg, 0.049 mmol), and sodium carbonate (104 mg) , 0.98 mmol) was dissolved in a mixed solvent of toluene (2 mL)-ethanol (1.5 mL)-water (0.49 mL), and stirred at 80 ° C for 5 hours under nitrogen atmosphere. The reaction solution was poured into water (20 mL) The organic layer was washed with brine (40 mL) and dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(400MHz,CDCl3)：δ1.08(3H,d,J=6.7Hz),1.16(3H,t,J=7.6Hz),2.55(2H,q,J=7.6Hz),3.53-3.61(1H,m),3.69-3.81(2H,m),3.99-4.20(5H,m),4.47-4.68(4H,m),4.83-4.95(3H,m),5.10-5.21(2H,m),6.77(2H,d,J=7.0Hz),6.97(1H,s),7.00(4H,s),7.12-7.35(18H,m),7.48(1H,s)；MS(TOF MS ES+)m/z：839(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.08 (3H, d, J = 6.7 Hz), 1.16 (3H, t, J = 7.6 Hz), 2.55 (2H, q, J = 7.6 Hz), 3.53- 3.61 (1H, m), 3.69-3.81 (2H, m), 3.99-4.20 (5H, m), 4.47-4.68 (4H, m), 4.83-4.95 (3H, m), 5.10-5.21 (2H, m ), 6.77 (2H, d, J = 7.0 Hz), 6.97 (1H, s), 7.00 (4H, s), 7.12-7.35 (18H, m), 7.48 (1H, s); MS (TOF MS ES+) m/z: 839 (M+H) + .
(實施例4c)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-6-(4-乙基苯甲基)-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-5-羧酸甲酯 (Example 4c) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-6-(4-ethylbenzyl)-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'- Methylpyran-5-carboxylate
將在實施例4b中所得到之化合物(326mg，0.39mmol)溶解於N,N-二甲基甲醯胺(2mL)及甲醇(2mL)之混合溶劑中，在其中添加1,3-雙(二苯基膦基)丙烷(32mg，0.078mmol)、N,N-二異丙基乙基胺(0.27mL，1.55mmol)、及乙酸鈀(17mg，0.078mmol)，於一氧化碳環境下，在80℃攪拌16小時。將該反應液用乙酸乙酯(20mL)稀釋，並以飽和食鹽水(20mL)洗淨。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠急速管柱層析(己烷：乙酸乙酯，95：5-80：20(濃度梯度)V/V)精製，得到標題化合物(276mg，收率87%)。 The compound obtained in Example 4b (326 mg, 0.39 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (2 mL) and methanol (2 mL), and 1,3-bis ( Diphenylphosphino)propane (32 mg, 0.078 mmol), N,N-diisopropylethylamine (0.27 mL, 1.55 mmol), and palladium acetate (17 mg, 0.078 mmol) in a carbon monoxide atmosphere at 80 Stir at °C for 16 hours. The reaction solution was diluted with ethyl acetate (20 mL) and evaporatedEtOAc. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by EtOAc EtOAcjjjj:
1H NMR(400MHz,CDCl3)：δ1.09(3H,d,J=6.7Hz),1.13(3H,t,J=7.6Hz),2.53(2H,q,J=7.6Hz),3.54-3.62(1H,m),3.73-3.80(2H,m),3.84(3H,s),3.97-4.69(9H,m),4.84-4.95(3H,m),5.20(2H,s),6.75(2H,d,J=7.0Hz),6.96(4H,s),7.03-7.35(19H,m),7.79(1H,s)；MS(TOF MS ES+)m/z：819(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.09 (3H, d, J = 6.7 Hz), 1.13 (3H, t, J = 7.6 Hz), 2.53 (2H, q, J = 7.6 Hz), 3.54- 3.62 (1H, m), 3.73-3.80 (2H, m), 3.84 (3H, s), 3.97-4.69 (9H, m), 4.84-4.95 (3H, m), 5.20 (2H, s), 6.75 ( 2H,d,J=7.0Hz), 6.96(4H,s), 7.03-7.35(19H,m),7.79(1H,s);MS(TOF MS ES+)m/z:819(M+H) + .
(實施例4d)(1S,3'R,4'S,5'S,6'R)-6-(4-乙基苯甲基)-3',4',5'-三羥基-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-5-羧酸甲酯 (Example 4d) (1S, 3'R, 4'S, 5'S, 6'R)-6-(4-ethylbenzyl)-3',4',5'-trihydroxy-6'-[( 1R)-1-Hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-piperane-5-carboxylic acid methyl ester
將在實施例4c中所得到之化合物(132mg，0.16mmol)溶解於THF(6mL)及甲醇(3mL)之混合溶劑中，在其中添加1,2-二氯苯(90μL，0.81mmol)、及10%w/w鈀/碳(130mg)，在氫氣環境下，於室溫攪拌1小時。過濾反應液後，將濾液於減壓下餾去溶劑。將所得到之殘餘物使用矽膠急速管柱層析(二氯甲烷：甲醇，97：3-90：10(濃度梯度)V/V)精製，得到標題化合物(66mg，收率89%)。 The compound obtained in Example 4c (132 mg, 0.16 mmol) was dissolved in a mixed solvent of THF (6 mL) and methanol (3 mL), and 1,2-dichlorobenzene (90 μL, 0.81 mmol), and 10% w/w palladium on carbon (130 mg) was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtering the reaction solution, the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography chromatography chromatography eluting
1H NMR(400MHz,CD3OD)：δ1.12(3H,d,J=6.3Hz),1.18(3H,t,J=7.6Hz),2.57(2H,q,J=7.6Hz),3.35-3.43(1H,m),3.68-3.85(6H,m),3.96-4.06(1H,m),4.30(1H,d,J=15.3Hz),4.37(1H,d,J=15.3Hz),5.12(1H,d,J=12.7Hz),5.18(1H,d,J=12.7Hz),7.01(2H,d,J=8.0Hz),7.06(2H,d,J=8.0Hz),7.27(1H,s),7.75(1H,s)；MS(TOF MS ES+)m/z：459(M+H)+. 1 H NMR (400 MHz, CD 3 OD): δ 1.12 (3H, d, J = 6.3 Hz), 1.18 (3H, t, J = 7.6 Hz), 2.57 (2H, q, J = 7.6 Hz), 3.35 -3.43 (1H, m), 3.68-3.85 (6H, m), 3.96-4.06 (1H, m), 4.30 (1H, d, J = 15.3 Hz), 4.37 (1H, d, J = 15.3 Hz), 5.12 (1H, d, J = 12.7 Hz), 5.18 (1H, d, J = 12.7 Hz), 7.01 (2H, d, J = 8.0 Hz), 7.06 (2H, d, J = 8.0 Hz), 7.27 ( 1H, s), 7.75 (1H, s); MS (TOF MS ES+) m/z: 459 (M+H) + .
(實施例4e)(1S,3'R,4'S,5'S,6'R)-6-(4-乙基苯甲基)-6'-[(1R)-1-羥基乙基]-5-(羥基甲基)-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 4e) (1S, 3'R, 4'S, 5'S, 6'R)-6-(4-ethylbenzyl)-6'-[(1R)-1-hydroxyethyl]-5- (hydroxymethyl)-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'-three alcohol
將在實施例4d中所得到之化合物(66mg，0.14mmol)溶解於THF(3.5mL)，於氮氣環境下，在0℃將1M氫化鋰鋁THF溶液(0.86mL，0.86mmol)加入其中，並於室溫攪拌1小時。在該反應液中，於冰冷下添加1M鹽酸(20mL)，並以二氯甲烷：甲醇(10：1，V/V，20mL，2次)萃取。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠急速管柱層析(二氯甲烷：甲醇，95：5-85：15(濃度梯度)V/V)精製，得到標題化合物(41mg，收率66%)。 The compound obtained in Example 4d (66 mg, 0.14 mmol) was dissolved in THF (3.5 mL), and a 1 M solution of lithium aluminum hydride (0.86 mL, 0.86 mmol) was added thereto at 0 ° C under a nitrogen atmosphere. Stir at room temperature for 1 hour. 1M Hydrochloric acid (20 mL) was added to the reaction mixture under ice-cooling, and extracted with dichloromethane: methanol (10:1, V/V, 20 mL, twice). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by EtOAc EtOAcjjjjjjj
1H NMR(400MHz,CD3OD)：δ1.13(3H,d,J=6.7Hz),1.19(3H,t,J=7.6Hz),2.59(2H,q,J=7.6Hz),3.39(1H,dd,J=10.0,8.4Hz),3.69-3.84(3H,m),3.96-4.07(3H,m),4.58(2H,s),5.10(1H,d,J=12.5Hz),5.17(1H,d,J=12.5Hz),7.03(2H,d,J=8.4Hz),7.08(2H,d,J=8.4Hz),7.12(1H,s),7.38(1H,s)；MS(TOF MS ES+)m/z：431(M+H)+. 1 H NMR (400 MHz, CD 3 OD): δ 1.13 (3H, d, J = 6.7 Hz), 1.19 (3H, t, J = 7.6 Hz), 2.59 (2H, q, J = 7.6 Hz), 3.39 (1H, dd, J = 10.0, 8.4 Hz), 3.69-3.84 (3H, m), 3.96-4.07 (3H, m), 4.58 (2H, s), 5.10 (1H, d, J = 12.5 Hz), 5.17 (1H, d, J = 12.5 Hz), 7.03 (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.4 Hz), 7.12 (1H, s), 7.38 (1H, s); MS (TOF MS ES+) m/z: 431 (M+H) + .
(實施例5)(1S,3'R,4'S,5'S,6'R)-6-(4-乙氧基苯甲基)-6'-[(1R)-1-羥基乙基]-5-(羥基甲基)-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 5) (1S, 3'R, 4'S, 5'S, 6'R)-6-(4-ethoxybenzyl)-6'-[(1R)-1-hydroxyethyl]-5 -(hydroxymethyl)-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'- Triol
以在實施例4a中所得到之化合物(0.33g，0.40mmol)、及(4-乙氧基苯基)硼酸(66mg，0.40mmol)做為原料，以與實施例4同樣之方式，得到標題化合物(65mg)。 The title compound (0.33 g, 0.40 mmol) and (4-ethoxyphenyl)boronic acid (66 mg, 0.40 mmol) were used as a starting material in the same manner as in Example 4 to obtain a title. Compound (65 mg).
1H NMR(400MHz,MeOH-d4)：δ1.13(3H,d,J=6.6Hz),1.35(3H,t,J=7.1Hz),3.38-3.42(1H,m),3.71(1H,d,J=9.4Hz),3.75(1H,d,J=8.6Hz),3.80(1H,dd,J=10.2Hz,3.5Hz),3.96-4.01(5H,m),4.59(2H,s),5.09(1H,d,J=12.9Hz),5.17(1H,d,J=12.9Hz),6.80(2H,d,J=8.6Hz),7.04(2H,d,J=8.6Hz),7.11(1H,s),7.38(1H,s)；MS(TOF MS ES+)m/z：447(M+H)+. 1 H NMR (400MHz, MeOH- d4): δ1.13 (3H, d, J = 6.6Hz), 1.35 (3H, t, J = 7.1Hz), 3.38-3.42 (1H, m), 3.71 (1H, d, J = 9.4 Hz), 3.75 (1H, d, J = 8.6 Hz), 3.80 (1H, dd, J = 10.2 Hz, 3.5 Hz), 3.96-4.01 (5H, m), 4.59 (2H, s) , 5.09 (1H, d, J = 12.9 Hz), 5.17 (1H, d, J = 12.9 Hz), 6.80 (2H, d, J = 8.6 Hz), 7.04 (2H, d, J = 8.6 Hz), 7.11 (1H, s), 7.38 (1H, s); MS (TOF MS ES+) m/z: 447 (M+H) + .
(實施例6)(1S,3'R,4'S,5'S,6'R)-6-(2,3-二氫-1,4-苯并二英-6-基甲基)-6'-[(1R)-1-羥基乙基]-5-(羥基甲基)-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 6) (1S, 3'R, 4'S, 5'S, 6'R)-6-(2,3-dihydro-1,4-benzoic Inox-6-ylmethyl)-6'-[(1R)-1-hydroxyethyl]-5-(hydroxymethyl)-3',4',5',6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyrano]-3',4',5'-triol
以在實施例4a中所得到之化合物(0.40g，0.49mmol)、及(1,4-苯并二烷-6-基)硼酸(97mg，0.54mmol)做為原料，以與實施例4同樣之方式得到標題化合物(75mg)。 The compound obtained in Example 4a (0.40 g, 0.49 mmol), and (1,4-benzoic acid) The title compound (75 mg) was obtained from m. m.
1H NMR(400MHz,CD3OD)：δ1.14(3H,d,J=6.7Hz),3.36-3.44(1H,m),3.69-3.84(3H,m),3.96(2H,s),3.97-4.04(1H,m),4.17(4H,s),4.55(1H,d,J=13.7Hz),4.59(1H,d,J=13.7Hz),5.10(1H,d,J=12.1Hz),5.17(1H,d,J=12.1Hz),6.55-6.62(2H,m),6.70(1H,d,J=8.2Hz),7.11(1H,s),7.37(1H,s)；MS(TOF MS ES+)m/z：461(M+H)+. 1 H NMR (400 MHz, CD 3 OD): δ 1.14 (3H, d, J = 6.7 Hz), 3.36-3.44 (1H, m), 3.69-3.84 (3H, m), 3.96 (2H, s), 3.97-4.04(1H,m), 4.17(4H,s),4.55(1H,d,J=13.7Hz),4.59(1H,d,J=13.7Hz),5.10(1H,d,J=12.1Hz ), 5.17 (1H, d, J = 12.1 Hz), 6.55-6.62 (2H, m), 6.70 (1H, d, J = 8.2 Hz), 7.11 (1H, s), 7.37 (1H, s); MS (TOF MS ES+) m/z: 461 (M+H) + .
(實施例7)(1S,3'R,4'S,5'S,6'R)-5-氯-6-(3,4-二氫-2H-色烯-7-基甲基)-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃-3',4',5'-三醇 (Example 7) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6-(3,4-dihydro-2H-chromen-7-ylmethyl)-6'- [(1R)-1-hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran-3',4' , 5'-triol
(實施例7a)7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-2,3-二氫-4H-色烯-4-酮 (Example 7a) 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-chromene -4-ketone
7-溴色烷-4-酮(1.13g，5.00mmol)、聯硼酸頻那醇酯(1.52g，6.00mmol)、乙酸鉀(1.47g，15.0mmol)、及[1,1’-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物二氯甲烷加成物(0.41g，0.50mmol)溶解於乙二醇二甲基醚(25mL)，於氮氣環境下，在90℃攪拌2小時。將該反應液冷卻至室溫，添加乙酸乙酯(20mL)，過濾後，將濾液注入飽和碳酸氫鈉水溶液(20mL)中，並以乙酸乙酯(50mL)萃取。將有機層用水(20mL)、飽和食鹽水(20mL)依序洗淨，以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將殘餘物使用矽膠急速管柱層析(己烷：乙酸乙酯，100：0→75：25(濃度梯度)V/V)精製，得到標題化合物(0.93g，收率68%)。 7-bromochroman-4-one (1.13 g, 5.00 mmol), pinacol borate (1.52 g, 6.00 mmol), potassium acetate (1.47 g, 15.0 mmol), and [1,1'-double ( Diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.41 g, 0.50 mmol) was dissolved in ethylene glycol dimethyl ether (25 mL) under a nitrogen atmosphere at 90 Stir at °C for 2 hours. The reaction mixture was cooled to EtOAc (EtOAc) (EtOAc) The organic layer was washed with water (20 mL) and brine (20 mL), and dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc EtOAc (EtOAc:EtOAc
(實施例7b)7-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)-2,3-二氫-4H-色烯-4-酮 (Example 7b) 7-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-Find (Benzyloxy)-6'-[(1R)- 1-(Benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran]- 6-yl}methyl)-2,3-dihydro-4H-chromen-4-one
將在參考例6中所得到之化合物(0.53g，0.69mmol)、在實施例7a中所得到之化合物(0.23g，0.83mmol)、肆(三苯膦)鈀(0)(80mg，0.069mmol)、及碳酸鈉(0.15g，1.4mmol)溶解於甲苯(6mL)-乙醇(4mL)-水 (0.7mL)之混合溶劑中，於氮氣環境下，在100℃攪拌2小時。將該反應液冷卻至室溫後，注入水(10mL)中，並以乙酸乙酯(40mL)萃取。將有機層用飽和食鹽水(10mL)洗淨，並以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠急速管柱層析(己烷：乙酸乙酯，100：0→70：30(濃度梯度)V/V)精製，得到標題化合物(0.42g，收率73%)。 The compound obtained in Reference Example 6 (0.53 g, 0.69 mmol), the compound obtained in Example 7a (0.23 g, 0.83 mmol), s(triphenylphosphine)palladium(0) (80 mg, 0.069 mmol) And sodium carbonate (0.15 g, 1.4 mmol) dissolved in toluene (6 mL)-ethanol (4 mL)-water In a mixed solvent of (0.7 mL), the mixture was stirred at 100 ° C for 2 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, poured into water (10 mL) and ethyl acetate (40 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel EtOAc (EtOAc:EtOAcHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH .
(實施例7c)7-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)-3,4-二氫-2H-色烯-4-醇 (Example 7c) 7-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-Find (Benzyloxy)-6'-[(1R)- 1-(Benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran]- 6-yl}methyl)-3,4-dihydro-2H-chromen-4-ol
將在實施例7b中所得到之化合物(0.25mg，0.30mmol)溶解於甲醇(3mL)-THF(1mL)之混合溶劑中，在其中，於冰冷下添加氫化硼鈉(18mg，0.45mmol)，並攪拌30分鐘。在該反應液中，於冰冷下添加飽和氯化銨水溶液(5mL)後，用乙酸乙酯(40mL)萃取。將有機層以飽和食鹽水(10mL)洗淨，用無水硫酸鈉乾燥後，於減壓下餾去溶劑，得到為標題化合物之粗生成物(0.25g)。 The compound obtained in Example 7b (0.25 mg, 0.30 mmol) was dissolved in methanol (3 mL)-THF (1 mL), and sodium borohydride (18 mg, 0.45 mmol) was added under ice cooling. Stir for 30 minutes. A saturated aqueous ammonium chloride solution (5 mL) was added to the mixture. The organic layer was washed with saturated brine (10 mL).
(實施例7d)乙酸7-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)-3,4-二氫-2H-色烯-4-酯 (Example 7d) Acetic acid 7-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-parade (benzyloxy)-6'-[(1R) -1-(benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran] -6-yl}methyl)-3,4-dihydro-2H-chromene-4-ester
將在實施例7c中所得到之化合物(0.25g，0.30mmol)溶解於乙酸乙酯(3mL)，在其中添加吡啶(73μL，0.90mmol)、乙酸酐(66μL，0.69mmol)、及4-二甲基胺基吡啶(4mg，0.030mmol)，並於室溫攪拌19小時。在該反應液加水(5mL)，並以乙酸乙酯(30mL)萃取。將有機層用1M鹽酸(10mL)、飽和碳酸氫鈉水溶液(10mL)、飽和食鹽水(10mL)洗淨，並以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠急速管柱層析(己烷：乙酸乙酯，100：0→70：30(濃度梯度)V/V)精製，得到標題化合物(0.23g，收率88%)。 The compound obtained in Example 7c (0.25 g, 0.30 mmol) was dissolved in ethyl acetate (3 mL), and pyridine (73 μL, 0.90 mmol), acetic anhydride (66 μL, 0.69 mmol), and 4- Methylaminopyridine (4 mg, 0.030 mmol) was stirred at room temperature for 19 h. Water (5 mL) was added to the mixture, and ethyl acetate (30 mL) was evaporated. The organic layer was washed with 1 M hydrochloric acid (10 mL), EtOAc. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc .
(實施例7e)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-6-(3,4-二氫-2H-色烯-7-基甲基)-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Example 7e) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-parade (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-5-chloro-6-(3,4-dihydro-2H-chromen-7-ylmethyl)-3',4',5',6'-tetrahydro-3H - spiro[2-benzofuran-1,2'-pyranose]
將在實施例7d中所得到之化合物(0.18g，0.21mmol)溶解於二氯甲烷(4mL)，將其冷卻至-78℃。在其中添加三乙基矽烷(0.34mL，2.1mmol)、及三氟化硼乙基醚錯合物(0.12mL，0.95mmol)，並攪拌2小時。在該反應液中添加飽和氯化銨水溶液(5mL)後，以乙酸乙酯(30mL)萃取。將有機層用飽和食鹽水(10mL)洗淨，以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠急速管柱層析(己烷：乙酸乙酯，100：0→75：25(濃度梯度)V/V)精製，得到標題化合物(0.14g，收率81%)。 The compound obtained in Example 7d (0.18 g, 0.21 mmol) was dissolved in dichloromethane (4mL), which was cooled to -78. Triethyldecane (0.34 mL, 2.1 mmol) and boron trifluoride ethyl ether complex (0.12 mL, 0.95 mmol) were added thereto and stirred for 2 hours. A saturated aqueous ammonium chloride solution (5 mL) was added to the mixture, and ethyl acetate (30 mL) was evaporated. The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The residue was purified using EtOAc (EtOAc: EtOAc (EtOAc) .
(實施例7f)(1S,3'R,4'S,5'S,6'R)-5-氯-6-(3,4-二氫-2H-色烯-7-基甲基)-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 7f) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6-(3,4-dihydro-2H-chromen-7-ylmethyl)-6'- [(1R)-1-hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4 ',5'-triol
將在實施例7e中所得到之化合物(0.18g，0.34mmol)、及1,2-二氯苯(0.19mL，1.7mmol)溶解於THF(4mL)-甲醇(2mL)之混合溶劑中，在其中添加10%鈀碳(0.18g)，並於氫氣環境下，於室溫攪拌1小時30分鐘。將反應液過濾後，於減壓下餾去溶劑。將所得到 之殘餘物使用矽膠急速管柱層析(二氯甲烷：甲醇、100：0→85：15(濃度梯度)V/V)精製，得到標題化合物(0.10g，收率63%)。 The compound obtained in Example 7e (0.18 g, 0.34 mmol), and 1,2-dichlorobenzene (0.19 mL, 1.7 mmol) were dissolved in a mixed solvent of THF (4 mL)-methanol (2 mL) 10% palladium on carbon (0.18 g) was added thereto, and the mixture was stirred at room temperature for 1 hour and 30 minutes under a hydrogen atmosphere. After filtering the reaction mixture, the solvent was evaporated under reduced pressure. Will get it The residue was purified using EtOAc EtOAc EtOAc (EtOAc:EtOAc
1H NMR(400MHz,MeOH-d4)：δ1.13(3H,d,J=6.6Hz),1.91-1.99(2H,m),2.73(2H,t,J=6.5Hz),3.39(1H,dd,J=10.2Hz,8.6Hz),3.69(1H,d,J=9.3Hz),3.74(1H,dd,J=9.3Hz,8.6Hz),3.80(1H,dd,J=10.2Hz,3.5Hz),3.96-4.05(3H,m),4.11(2H,t,J=5.1Hz),5.07(1H,d,J=12.9Hz),5.14(1H,d,J=12.9Hz),6.53(1H,d,J=1.9Hz),6.65(1H,dd,J=7.8Hz,1.9Hz),6.92(1H,d,J=7.8Hz),7.21(1H,s),7.36(1H,s)；MS(ESI)m/z：463(M+H)+. 1 H NMR (400MHz, MeOH- d4): δ1.13 (3H, d, J = 6.6Hz), 1.91-1.99 (2H, m), 2.73 (2H, t, J = 6.5Hz), 3.39 (1H, Dd, J = 10.2 Hz, 8.6 Hz), 3.69 (1H, d, J = 9.3 Hz), 3.74 (1H, dd, J = 9.3 Hz, 8.6 Hz), 3.80 (1H, dd, J = 10.2 Hz, 3.5 Hz), 3.96-4.05 (3H, m), 4.11 (2H, t, J = 5.1 Hz), 5.07 (1H, d, J = 12.9 Hz), 5.14 (1H, d, J = 12.9 Hz), 6.53 ( 1H, d, J = 1.9 Hz), 6.65 (1H, dd, J = 7.8 Hz, 1.9 Hz), 6.92 (1H, d, J = 7.8 Hz), 7.21 (1H, s), 7.36 (1H, s) MS (ESI) m / z: 463 (M + H) + .
(實施例8)(1S,3'R,4'S,5'S,6'R)-5-溴-6-(2,3-二氫-1,4-苯并二英-6-基甲基)-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 8) (1S, 3'R, 4'S, 5'S, 6'R)-5-bromo-6-(2,3-dihydro-1,4-benzoic -6-ylmethyl)-6'-[(1R)-1-hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1 , 2'-pyrano]-3',4',5'-triol
(實施例8a)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-溴-6-(2,3-二氫-1,4-苯并二英-6-基甲基)-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Example 8a) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-5-bromo-6-(2,3-dihydro-1,4-benzoic acid Inox-6-ylmethyl)-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran]
使用在實施例4a中所得到之化合物(0.40g，0.49mmol)、(1,4-苯并二烷-6-基)硼酸(0.11g，0.61mmol)、碳酸鈉(0.10g，0.94mmol)、肆三苯膦鈀(0)(57mg，0.049mmol)、及甲苯(4mL)-乙醇(3mL)-水(1mL)之混合溶劑，以與實施例1a同樣之方式得到標題化合物(0.21g)。 The compound obtained in Example 4a (0.40 g, 0.49 mmol), (1,4-benzoic acid) was used. Alkan-6-yl)boronic acid (0.11 g, 0.61 mmol), sodium carbonate (0.10 g, 0.94 mmol), triphenylphosphine palladium (0) (57 mg, 0.049 mmol), and toluene (4 mL)-ethanol (3 mL) The title compound (0.21 g) was obtained.
(實施例8b)(1S,3'R,4'S,5'S,6'R)-5-溴-6-(2,3-二氫-1,4-苯并二英-6-基甲基)-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 8b) (1S, 3'R, 4'S, 5'S, 6'R)-5-bromo-6-(2,3-dihydro-1,4-benzoic -6-ylmethyl)-6'-[(1R)-1-hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1 , 2'-pyrano]-3',4',5'-triol
將在實施例8a中所得到之化合物(100mg，0.11mmol)、及五甲基苯(179mg，1.21mmol)溶解於二氯甲烷(5mL)，在其中，於氮氣環境下，在-78℃添加三溴化硼之二氯甲烷溶液(1.0M，1.10mL，1.10mmol)。將該反應液於-78℃攪拌40分鐘後，添加甲醇(1mL)。將該反應液升溫至室溫，於減壓下餾去溶劑，並在所得到之殘餘物中添加水(3mL)及飽和食鹽水(3mL)，並用 二氯甲烷及2-丙醇(3：1)之混合溶劑萃取2次。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠急速管柱層析(二氯甲烷：甲醇、100：0→80：20(濃度梯度)V/V)精製，得到標題化合物(20mg，收率36%)。 The compound obtained in Example 8a (100 mg, 0.11 mmol), and pentamethylbenzene (179 mg, 1.21 mmol) were dissolved in dichloromethane (5 mL), and added at -78 ° C under nitrogen atmosphere. A solution of boron tribromide in dichloromethane (1.0 M, 1.10 mL, 1.10 mmol). After the reaction mixture was stirred at -78 ° C for 40 min, methanol (1 mL) was added. The reaction solution was warmed to room temperature, and the solvent was evaporated under reduced pressure. Water (3 mL) and brine (3 mL) The mixed solvent of dichloromethane and 2-propanol (3:1) was extracted twice. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel EtOAc EtOAc (EtOAc:EtOAc
1H NMR(400MHz,MeOH-d4)：δ1.13(3H,d,J=6.7Hz),3.38(1H,dd,J=10.1Hz,8.6Hz),3.68(1H,d,J=9.4Hz),3.74(1H,dd,J=9.4Hz,8.6Hz),3.80(1H,dd,J=10.1Hz,3.3Hz),3.97-4.08(3H,m),4.19(4H,s),5.07(1H,d,J=13.0Hz),5.14(1H,d,J=13.0Hz),6.62-6.67(2H,m),6.72(1H,d,J=7.8Hz),7.20(1H,s),7.55(1H,s)；MS(ESI)m/z：509(M+H)+. 1 H NMR (400MHz, MeOH- d4): δ1.13 (3H, d, J = 6.7Hz), 3.38 (1H, dd, J = 10.1Hz, 8.6Hz), 3.68 (1H, d, J = 9.4Hz ), 3.74 (1H, dd, J = 9.4 Hz, 8.6 Hz), 3.80 (1H, dd, J = 10.1 Hz, 3.3 Hz), 3.97-4.08 (3H, m), 4.19 (4H, s), 5.07 ( 1H, d, J = 13.0 Hz), 5.14 (1H, d, J = 13.0 Hz), 6.62 - 6.67 (2H, m), 6.72 (1H, d, J = 7.8 Hz), 7.20 (1H, s), 7.55 (1H, s); MS (ESI) m/z: 509 (M+H) + .
(實施例9)(1S,3'R,4'S,5'S,6'R)-5-氯-6'-[(1R)-1-羥基乙基]-6-[4-(3-羥基丙基)苯甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 9) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6'-[(1R)-1-hydroxyethyl]-6-[4-(3-hydroxypropane) Phenylmethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'- Triol
(實施例9a)3-[4-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)苯基]丙酸乙酯 (Example 9a) 3-[4-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-Find (Benzyloxy)-6'-[( 1R)-1-(benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-piperidyl Ethyl]-6-yl}methyl)phenyl]propionate
將在參考例6中所得到之化合物(0.39g，0.50mmol)溶解於甲苯(2.0mL)-乙醇(1.5mL)-水(1.0mL)之混合溶劑中，在其中添加[4-(3-乙氧基-3-側氧基丙基)苯基]硼酸(0.13g，0.59mmol)、碳酸鈉(0.11g，1.0mmol)、及肆三苯膦鈀(0)(58mg，0.050mmol)，於氮氣環境下，在100℃攪拌2小時。在該反應液中加水(20mL)，並以乙酸乙酯(30mL，2次)萃取。將有機層藉由飽和食鹽水(20mL)洗淨，以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(己烷：乙酸乙酯，95：5→50：50(濃度梯度)V/V)精製，得到標題化合物(0.35g)。 The compound (0.39 g, 0.50 mmol) obtained in Reference Example 6 was dissolved in a mixed solvent of toluene (2.0 mL)-ethanol (1.5 mL)-water (1.0 mL), and [4-(3- Ethoxy-3-oxopropyl)phenyl]boronic acid (0.13 g, 0.59 mmol), sodium carbonate (0.11 g, 1.0 mmol), and triphenylphosphine palladium (0) (58 mg, 0.050 mmol), The mixture was stirred at 100 ° C for 2 hours under a nitrogen atmosphere. Water (20 mL) was added to the mixture, and ethyl acetate (30 mL, twice). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc EtOAc (EtOAc)
(實施例9b)3-[4-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)苯基]丙-1-醇 (Example 9b) 3-[4-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-Find (Benzyloxy)-6'-[( 1R)-1-(benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-piperidyl ]]-6-yl}methyl)phenyl]propan-1-ol
將在實施例9a中所得到之化合物(0.17g，0.20mmol)在氮氣環境下溶解於THF(2.0mL)。將其冷 卻至0℃，添加氫化鋁鋰(12mg，0.32mmol)，並於0℃攪拌1小時。在該反應液中添加水(15μL)、5M氫氧化鈉水溶液(15μL)及、水(45μL)，升溫至室溫後，激烈地攪拌1小時。過濾反應液後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(己烷：乙酸乙酯、10：90→0：100(濃度梯度V/V)精製，得到標題化合物(0.15g)。 The compound obtained in Example 9a (0.17 g, 0.20 mmol) was dissolved in THF (2.0 mL). Cool it To 0 ° C, lithium aluminum hydride (12 mg, 0.32 mmol) was added and stirred at 0 ° C for 1 hour. Water (15 μL), a 5 M aqueous sodium hydroxide solution (15 μL), and water (45 μL) were added to the reaction mixture, and the mixture was warmed to room temperature, and then stirred vigorously for 1 hour. After filtering the reaction solution, the solvent was evaporated under reduced pressure. The residue was purified using EtOAc EtOAc EtOAc (EtOAc)
(實施例9c)(1S,3'R,4'S,5'S,6'R)-5-氯-6'-[(1R)-1-羥基乙基]-6-[4-(3-羥基丙基)苯甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 9c) (1S,3'R,4'S,5'S,6'R)-5-Chloro-6'-[(1R)-1-hydroxyethyl]-6-[4-(3-hydroxypropane) Phenylmethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'- Triol
將在實施例9b中所得到之化合物(0.15g，0.18mmol)溶解於THF(6.7mL)及甲醇(3.3mL)之混合溶劑中，在其中添加1,2-二氯苯(0.11mL，0.98mmol)、10%w/w鈀碳(0.15g)，並在氫氣環境下，於室溫下攪拌1小時。過濾反應液後，將濾液之溶劑於減壓下餾去。將所得到之殘餘物使用矽膠管柱層析(二氯甲烷：甲醇，98：2→80：20(濃度梯度)V/V)精製，得到標題化合物(68mg，81%)。 The compound obtained in Example 9b (0.15 g, 0.18 mmol) was dissolved in a mixed solvent of THF (6.7 mL) and methanol (3.3 mL), and 1,2-dichlorobenzene (0.11 mL, 0.98) was added thereto. Methyl), 10% w/w palladium on carbon (0.15 g), and stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtering the reaction liquid, the solvent of the filtrate was distilled off under reduced pressure. The residue was purified using EtOAc EtOAc EtOAc (EtOAc:EtOAc
1H NMR(400MHz,MeOH-d4)：δ1.12(3H,d,J=6.6Hz),1.75-1.85(2H,m),2.58-2.68(2H,m),3.35-3.42(1H,m), 3.54(1H,t,J=6.4Hz),3.67(1H,d,J=9.6Hz),3.73(1H,dd,J=9.6Hz,8.6Hz),3.79(1H,dd,J=10.2Hz,3.2Hz),3.97-4.03(1H,m),4.06-4.14(2H,m),5.07(1H,d,J=12.7Hz),5.14(1H,d,J=12.7Hz),7.11(4H,s),7.22(1H,s),7.36(1H,s)；MS(ESI)m/z：465(M+H)+. 1 H NMR (400MHz, MeOH- d4): δ1.12 (3H, d, J = 6.6Hz), 1.75-1.85 (2H, m), 2.58-2.68 (2H, m), 3.35-3.42 (1H, m ), 3.54 (1H, t, J = 6.4 Hz), 3.67 (1H, d, J = 9.6 Hz), 3.73 (1H, dd, J = 9.6 Hz, 8.6 Hz), 3.79 (1H, dd, J = 10.2) Hz, 3.2 Hz), 3.97-4.03 (1H, m), 4.06-4.14 (2H, m), 5.07 (1H, d, J = 12.7 Hz), 5.14 (1H, d, J = 12.7 Hz), 7.11 ( 4H, s), 7.22 (1H, s), 7.36 (1H, s); MS (ESI) m/z: 465 (M+H) + .
(實施例10)(1S,3'R,4'S,5'S,6'R)-5-氯-6'-[(1R)-1-羥基乙基]-6-[3-(3-羥基丙基)苯甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 10) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6'-[(1R)-1-hydroxyethyl]-6-[3-(3-hydroxypropane) Phenylmethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'- Triol
以在參考例6中所得到之化合物(0.40g，0.52mmol)、及[3-(3-甲氧基-3-側氧基丙基)苯基]硼酸(0.13g)做為原料，以與實施例9同樣之方式得到標題化合物(77mg)。 The compound obtained in Reference Example 6 (0.40 g, 0.52 mmol) and [3-(3-methoxy-3-oxopropyl)phenyl]boronic acid (0.13 g) were used as a raw material. The title compound (77 mg) was obtained.
1H NMR(400MHz,MeOH-d4)：δ1.12(3H,d,J=6.6Hz),1.75-1.84(2H,m),2.63(2H,t,J=7.6Hz),3.37(1H,dd,J=10.2Hz,8.6Hz),3.54(2H,t,J=6.5Hz),3.68(1H,d,J=9.3Hz),3.74(1H,dd,J=9.3Hz,8.6Hz),3.79(1H,dd,J=10.2Hz,3.5Hz),3.97-4.05(1H,m),4.09(1H,d,J=15.4Hz),4.14(1H,d,J=15.4Hz),5.07(1H,d,J=13.1Hz),5.14(1H,d,J=13.1Hz),6.98-7.08(3H,m),7.18(1H,t,J=7.4Hz),7.21(1H,s),7.37(1H,s)； MS(ESI)m/z：465(M+H)+. 1 H NMR (400MHz, MeOH- d4): δ1.12 (3H, d, J = 6.6Hz), 1.75-1.84 (2H, m), 2.63 (2H, t, J = 7.6Hz), 3.37 (1H, Dd, J = 10.2 Hz, 8.6 Hz), 3.54 (2H, t, J = 6.5 Hz), 3.68 (1H, d, J = 9.3 Hz), 3.74 (1H, dd, J = 9.3 Hz, 8.6 Hz), 3.79 (1H, dd, J = 10.2 Hz, 3.5 Hz), 3.97-4.05 (1H, m), 4.09 (1H, d, J = 15.4 Hz), 4.14 (1H, d, J = 15.4 Hz), 5.07 ( 1H, d, J = 13.1 Hz), 5.14 (1H, d, J = 13.1 Hz), 6.98-7.08 (3H, m), 7.18 (1H, t, J = 7.4 Hz), 7.21 (1H, s), 7.37 (1H, s); MS (ESI) m/z: 465 (M+H) + .
(實施例11)(1S,3'R,4'S,5'S,6'R)-6-[4-(2-羥基乙氧基)苯甲基]-6'-[(1R)-1-羥基乙基]-5-甲基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 11) (1S, 3'R, 4'S, 5'S, 6'R)-6-[4-(2-hydroxyethoxy)benzyl]-6'-[(1R)-1-hydroxyl Ethyl]-5-methyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5 '-triol
(實施例11a)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-6-{4-[2-(甲氧基甲氧基)乙氧基]苯甲基}-5-甲基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Example 11a) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-6-{4-[2-(methoxymethoxy)ethoxy]benzyl}-5-methyl-3',4',5',6'- Tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran]
將在參考例7中所得到之化合物(0.28g，0.38mmol)溶解於甲苯(1.6mL)-乙醇(1.2mL)-水(0.8mL)之混合溶劑中，在其中添加2-{4-[2-(甲氧基甲氧基)乙氧基]苯基}-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(0.13g，0.42mmol)、碳酸鈉(81mg，0.76mmol)、及肆三苯膦鈀(0)(44mg，0.038mmol)，於氮氣環境下，在100℃攪拌2小時。在該反應液中加水(20mL)，並以乙酸乙酯(30mL、2次)萃取。將有機層用飽和食鹽水(20mL)洗 淨，以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(己烷：乙酸乙酯，95：5→50：50(濃度梯度)V/V)精製，得到標題化合物(0.28g)。 The compound (0.28 g, 0.38 mmol) obtained in Reference Example 7 was dissolved in a mixed solvent of toluene (1.6 mL)-ethanol (1.2 mL)-water (0.8 mL), and 2-{4-[ 2-(methoxymethoxy)ethoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.13 g, 0.42 mmol Sodium carbonate (81 mg, 0.76 mmol), and triphenylphosphine palladium (0) (44 mg, 0.038 mmol) were stirred at 100 ° C for 2 hours under a nitrogen atmosphere. Water (20 mL) was added to the mixture, and ethyl acetate (30 mL, twice). The organic layer was washed with saturated brine (20 mL) After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:
(實施例11b)2-[4-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-甲基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)苯氧基]乙醇 (Example 11b) 2-[4-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-parade (benzyloxy)-6'-[( 1R)-1-(benzyloxy)ethyl]-5-methyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'- Piper]-6-yl}methyl)phenoxy]ethanol
將在實施例11a中所得到之化合物(0.28g，0.38mmol)溶解於甲醇(2.0mL)中，在其中添加4M鹽酸二烷溶液(2.0mL，8.0mmol)，並於室溫下攪拌40分鐘。在反應液中添加飽和碳酸氫鈉水溶液(30mL)，並以乙酸乙酯(30mL，2次)萃取。將有機層藉由飽和食鹽水(20mL)洗淨，以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(己烷：乙酸乙酯，90：10→0：100(濃度梯度)V/V)精製，得到標題化合物(0.22g)。 The compound obtained in Example 11a (0.28 g, 0.38 mmol) was dissolved in methanol (2.0 mL), and 4 M hydrochloric acid was added thereto. A solution of the alkane (2.0 mL, 8.0 mmol) was stirred at room temperature for 40 min. A saturated aqueous solution of sodium hydrogencarbonate (30 mL) was added, and ethyl acetate (30 mL, twice). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:
(實施例11c)(1S,3'R,4'S,5'S,6'R)-6-[4-(2-羥基乙氧基)苯甲基]-6'-[(1R)-1-羥基乙基]-5-甲基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 11c) (1S, 3'R, 4'S, 5'S, 6'R)-6-[4-(2-hydroxyethoxy)benzyl]-6'-[(1R)-1-hydroxyl Ethyl]-5-methyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5 '-triol
將實施例11b中所得到之化合物(0.22g，0.17mmol)溶解於THF(10mL)及甲醇(5.0mL)之混合溶劑中，在其中添加1,2-二氯苯(0.16mL，1.4mmol)、10%w/w鈀碳(0.22g)，在氫氣環境下，於室溫攪拌1小時。過濾反應液後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(二氯甲烷：甲醇，98：2→80：20(濃度梯度)V/V)精製，得到標題化合物(0.11g)。 The compound obtained in Example 11b (0.22 g, 0.17 mmol) was dissolved in a mixed solvent of THF (10 mL) and methanol (5.0 mL), and 1,2-dichlorobenzene (0.16 mL, 1.4 mmol) was added thereto. 10% w/w palladium on carbon (0.22 g) was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtering the reaction solution, the solvent was evaporated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(400MHz,MeOH-d4)：δ1.14(3H,d,J=6.6Hz),3.42(3H,s),3.39(1H,dd,J=10.2Hz,8.4Hz),3.71(1H,d,J=9.2Hz),3.75(1H,dd,J=9.2Hz,8.4Hz),3.79(1H,dd,J=10.2Hz,3.2Hz),3.83-3.86(2H,m),3.96(2H,s),3.98-4.02(3H,m),5.07(1H,d,J=12.1Hz),5.13(1H,d,J=12.1Hz),6.84(2H,d,J=8.6Hz),7.03(2H,d,J=8.6Hz),7.09(2H,s)；MS(FAB)m/z：447(M+H)+. 1 H NMR (400MHz, MeOH- d4): δ1.14 (3H, d, J = 6.6Hz), 3.42 (3H, s), 3.39 (1H, dd, J = 10.2Hz, 8.4Hz), 3.71 (1H , d, J = 9.2 Hz), 3.75 (1H, dd, J = 9.2 Hz, 8.4 Hz), 3.79 (1H, dd, J = 10.2 Hz, 3.2 Hz), 3.83 - 3.86 (2H, m), 3.96 ( 2H, s), 3.98-4.02 (3H, m), 5.07 (1H, d, J = 12.1 Hz), 5.13 (1H, d, J = 12.1 Hz), 6.84 (2H, d, J = 8.6 Hz), 7.03 (2H, d, J = 8.6 Hz), 7.09 (2H, s); MS (FAB) m/z: 447 (M+H) + .
(實施例12)(1S,3'R,4'S,5'S,6'R)-5-氯-6'-[(1R)-1-羥基乙基]-6-[4-(甲基胺基)苯甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 12) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6'-[(1R)-1-hydroxyethyl]-6-[4-(methylamino group Benzyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'-three alcohol
(實施例12a)甲基[4-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)苯基]胺基甲酸三級丁酯 (Example 12a) Methyl [4-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-parade (benzyloxy)-6'-[( 1R)-1-(benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-piperidyl Butyl-6-yl}methyl)phenyl]carbamic acid tert-butyl butyl ester
將在參考例6中所得到之化合物(300mg，0.39mmol)、N-Boc-N-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯胺(156mg，0.47mmol)、肆三苯膦鈀(0)(45mg，0.039mmol)、及碳酸鈉(83mg，0.78mmol)溶解於甲苯(2mL)-乙醇(1.5mL)-水(0.39mL)之混合溶劑中，將其於氮氣環境下，在100℃攪拌2小時。將反應液注入水(20mL)中，並用乙酸乙酯(20mL)萃取。將有機層以飽和食鹽水(20mL)洗淨，用無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠急速管柱層析(己烷：乙酸乙酯，97：3-75：25(濃度梯度)V/V)精製，得到標題化合物(254mg，收率73%)。 The compound obtained in Reference Example 6 (300 mg, 0.39 mmol), N-Boc-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Boracyclo-2-yl)aniline (156 mg, 0.47 mmol), decyltriphenylphosphine palladium (0) (45 mg, 0.039 mmol), and sodium carbonate (83 mg, 0.78 mmol) dissolved in toluene (2 mL)-ethanol ( In a mixed solvent of 1.5 mL of water (0.39 mL), the mixture was stirred at 100 ° C for 2 hours under a nitrogen atmosphere. The reaction solution was poured into water (20 mL) The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The obtained residue was purified by EtOAc EtOAcjjjjjjjj
1H NMR(400MHz,CDCl3)：δ1.07(3H,d,J=6.7Hz),1.41(9H,s),3.14(3H,s),3.56(1H,dd,J=10.2,9.4Hz), 3.72-3.81(2H,m),4.02-4.22(5H,m),4.49-4.67(4H,m),4.85-4.96(3H,m),5.16(2H,s),6.73-6.79(2H,m),6.99-7.36(24H,m)；MS(FAB)m/z：896(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.07 (3H, d, J = 6.7 Hz), 1.41 (9H, s), 3.14 (3H, s), 3.56 (1H, dd, J = 10.2, 9.4 Hz ), 3.72-3.81(2H,m), 4.02-4.22(5H,m),4.49-4.67(4H,m),4.85-4.96(3H,m),5.16(2H,s),6.73-6.79(2H , m), 6.99-7.36 (24H, m); MS (FAB) m/z: 896 (M+H) + .
(實施例12b)(1S,3'R,4'S,5'S,6'R)-5-氯-6'-[(1R)-1-羥基乙基]-6-[4-(甲基胺基)苯甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 12b) (1S,3'R,4'S,5'S,6'R)-5-Chloro-6'-[(1R)-1-hydroxyethyl]-6-[4-(methylamino) Benzyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'-three alcohol
將在實施例12a中所得到之化合物(123mg，0.14mmol)溶解於THF(5mL)及甲醇(2.5mL)之混合溶劑中，在其中添加1,2-二氯苯(77μL，0.69mmol)、及10%w/w鈀/碳(120mg)，將其在氫氣環境下，於室溫攪拌1小時。將反應液過濾後，於減壓下餾去濾液之溶劑。 The compound obtained in Example 12a (123 mg, 0.14 mmol) was dissolved in a mixed solvent of THF (5 mL) and methanol (2.5 mL), and 1,2-dichlorobenzene (77 μL, 0.69 mmol) was added thereto. And 10% w/w palladium on carbon (120 mg), which was stirred under a hydrogen atmosphere at room temperature for 1 hour. After filtering the reaction mixture, the solvent of the filtrate was evaporated under reduced pressure.
將所得到之殘餘物溶解於甲醇(2mL)中，於冰冷下添加4N鹽酸二烷溶液(1mL)，並在室溫攪拌3小時。在反應液中，於冰冷下添加飽和碳酸氫鈉溶液(10mL)，並用氯仿：2-丙醇(3：1，V/V，20mL，2次)萃取。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。使用矽膠急速管柱層析(二氯甲烷：甲醇，95：5-88：12(濃度梯度)V/V)精製，得到標題化合物(52mg，收率87%)。 The obtained residue was dissolved in methanol (2 mL), and 4N hydrochloric acid Alkane solution (1 mL) was stirred at room temperature for 3 h. A saturated sodium hydrogencarbonate solution (10 mL) was added to the mixture, and the mixture was applied to chloroform: 2-propanol (3:1, V/V, 20 mL, twice). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The title compound (52 mg, yield: 87%) was obtained.
1H NMR(400MHz,CD3OD)：1.12(3H,d,J=6.3Hz),2.73(3H,s),3.36-3.42(1H,m),3.61-3.85(3H,m),3.92-4.07(3H,m),5.05(1H,d,J=12.9Hz),5.12(1H,d,J=12.9Hz),6.58(2H,d,J=8.6Hz),6.97(2H,d,J=8.6Hz),7.15(1H,s),7.33(1H,s)；MS(TOF MS ES+)m/z：436(M+H)+. 1 H NMR (400 MHz, CD 3 OD): 1.12 (3H, d, J = 6.3 Hz), 2.73 (3H, s), 3.36-3.42 (1H, m), 3.61-3.85 (3H, m), 3.92 4.07(3H,m), 5.05(1H,d,J=12.9Hz), 5.12(1H,d,J=12.9Hz), 6.58(2H,d,J=8.6Hz),6.97(2H,d,J = 8.6 Hz), 7.15 (1H, s), 7.33 (1H, s); MS (TOF MS ES+) m/z: 436 (M+H) + .
(實施例13)(1S,3'R,4'S,5'S,6'R)-6'-[(1R)-1-羥基乙基]-5-甲基-6-[4-(甲基胺基)苯甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 13) (1S,3'R,4'S,5'S,6'R)-6'-[(1R)-1-hydroxyethyl]-5-methyl-6-[4-(methylamine) Phenylmethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'- Triol
(實施例13a)甲基[4-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-甲基-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)苯基]胺基甲酸三級丁酯 (Example 13a) Methyl [4-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-parade (benzyloxy)-6'-[( 1R)-1-(benzyloxy)ethyl]-5-methyl-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'- Piperyl]-6-yl}methyl)phenyl]carbamic acid tert-butyl butyl ester
將在參考例7中所得到之化合物(251mg，0.34mmol)、N-Boc-N-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯胺(134mg，0.40mmol)、肆三苯膦 鈀(0)(39mg，0.034mmol)、及碳酸鈉(71mg，0.67mmol)溶解於甲苯(2mL)-乙醇(1.5mL)-水(0.33mL)之混合溶劑中，將其於氮氣環境下，在100℃攪拌2小時。將該反應液注入水(20mL)中，並用乙酸乙酯(20mL)萃取。將有機層以飽和食鹽水(20mL)洗淨，用無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠急速管柱層析(己烷：乙酸乙酯，97：3-75：25(濃度梯度)V/V)精製，得到標題化合物(212mg，收率72%)。 The compound obtained in Reference Example 7 (251 mg, 0.34 mmol), N-Boc-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Boron-2-yl)aniline (134mg, 0.40mmol), decyltriphenylphosphine Palladium (0) (39 mg, 0.034 mmol) and sodium carbonate (71 mg, 0.67 mmol) were dissolved in a mixed solvent of toluene (2 mL)-ethanol (1.5 mL)-water (0.33 mL). Stir at 100 ° C for 2 hours. The reaction solution was poured into water (20 mL) The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:
1H NMR(400MHz,CDCl3)：δ1.11(3H,d,J=6.7Hz),1.41(9H,s),2.25(3H,s),3.15(3H,s),3.60(1H,dd,J=10.2Hz,9.0Hz),3.76-3.84(2H,m),3.89-4.01(2H,m),4.08-4.25(3H,m),4.47-4.70(4H,m),4.84-4.97(3H,m),5.16(1H,d,J=12.5Hz),5.21(1H,d,J=12.5Hz),6.77-6.82(2H,m),6.92-7.35(24H,m)；MS(FAB)m/z：876(M+H)+. 1 H NMR (400 MHz, CDCl 3 ): δ 1.11 (3H, d, J = 6.7 Hz), 1.41 (9H, s), 2.25 (3H, s), 3.15 (3H, s), 3.60 (1H, dd , J = 10.2 Hz, 9.0 Hz), 3.76 - 3.84 (2H, m), 3.89 - 4.01 (2H, m), 4.08 - 4.25 (3H, m), 4.47 - 4.70 (4H, m), 4.84 - 4.97 ( 3H,m), 5.16 (1H,d,J=12.5Hz), 5.21 (1H,d,J=12.5Hz), 6.77-6.82(2H,m),6.92-7.35(24H,m);MS(FAB ) m/z: 876 (M+H) + .
(實施例13b)(1S,3'R,4'S,5'S,6'R)-6'-[(1R)-1-羥基乙基]-5-甲基-6-[4-(甲基胺基)苯甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 13b) (1S,3'R,4'S,5'S,6'R)-6'-[(1R)-1-hydroxyethyl]-5-methyl-6-[4-(methylamine) Phenylmethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'- Triol
將在實施例13a中所得到之化合物(212mg，0.24mmol)溶解於THF(5mL)及甲醇(2.5mL)之混合溶 劑中，在其中添加1,2-二氯苯(136μL，1.21mmol)、及10%w/w鈀/碳(200mg)，將其於氫氣環境下，於室溫攪拌1小時。將反應液過濾後，於減壓下餾去濾液之溶劑。 The compound obtained in Example 13a (212 mg, 0.24 mmol) was dissolved in THF (5 mL) and methanol (2.5 mL) To the mixture, 1,2-dichlorobenzene (136 μL, 1.21 mmol) and 10% w/w palladium/carbon (200 mg) were added thereto, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtering the reaction mixture, the solvent of the filtrate was evaporated under reduced pressure.
將所得到之殘餘物溶解於甲醇(2mL)，於冰冷下添加4N鹽酸二烷溶液(1mL)，並在室溫攪拌3小時。在反應液中，於冰冷下添加飽和碳酸氫鈉溶液(10mL)，並以氯仿：2-丙醇(3：1，V/V，20mL，2次)萃取。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠急速管柱層析(二氯甲烷：甲醇，97：3-85：15(濃度梯度)V/V)精製，得到標題化合物(73mg，收率73%)。 The obtained residue was dissolved in methanol (2 mL), and 4N hydrochloric acid was added under ice cooling. Alkane solution (1 mL) was stirred at room temperature for 3 h. A saturated sodium hydrogencarbonate solution (10 mL) was added and the mixture was extracted with chloroform: 2-propanol (3:1, V/V, 20 mL, twice). After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography chromatography chromatography eluting elut elut elut elut elut
1H NMR(400MHz,CD3OD)：δ1.14(3H,d,J=6.3Hz),2.23(3H,s),2.73(3H,s),3.39(1H,dd,J=10.2,8.2Hz),3.67-3.83(3H,m),3.88(2H,s),3.95-4.04(1H,m),5.05(1H,d,J=12.1Hz),5.12(1H,d,J=12.1Hz),6.56(2H,d,J=8.6Hz),6.90(2H,d,J=8.6Hz),7.06(2H,s)；MS(TOF MS ES+)m/z：416(M+H)+. 1 H NMR (400MHz, CD 3 OD): δ1.14 (3H, d, J = 6.3Hz), 2.23 (3H, s), 2.73 (3H, s), 3.39 (1H, dd, J = 10.2,8.2 Hz), 3.67-3.83 (3H, m), 3.88 (2H, s), 3.95-4.04 (1H, m), 5.05 (1H, d, J = 12.1 Hz), 5.12 (1H, d, J = 12.1 Hz) ), 6.56 (2H, d, J = 8.6 Hz), 6.90 (2H, d, J = 8.6 Hz), 7.06 (2H, s); MS (TOF MS ES+) m/z: 416 (M+H) + .
(實施例14)(1S,3'R,4'S,5'S,6'R)-5-氯-6'-[(1R)-1-羥基乙基]-6-(1,2,3,4-四氫喹啉-6-基甲基)-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 14) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6'-[(1R)-1-hydroxyethyl]-6-(1,2,3,4 -tetrahydroquinolin-6-ylmethyl)-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3', 4',5'-triol
使用在參考例6中所得到之化合物(200mg，0.26mmol)、及1-(三級丁氧基羰基)-1,2,3,4-四氫-6-喹啉基硼酸(86mg，0.31mmol)做為原料，以與實施例12同樣之方法得到標題化合物(71mg)。 The compound (200 mg, 0.26 mmol) obtained in Reference Example 6 and 1-(tertiary butoxycarbonyl)-1,2,3,4-tetrahydro-6-quinolinylboronic acid (86 mg, 0.31) were used. The title compound (71 mg) was obtained.
1H NMR(400MHz,CD3OD)：δ1.12(3H,d,J=6.7Hz),1.84-1.92(2H,m),2.68(2H,t,J=6.5Hz),3.20(2H,t,J=5.5Hz),3.37(1H,dd,J=10.2,8.6Hz),3.64-3.81(3H,m),3.88-4.04(3H,m),5.06(1H,d,J=12.9Hz),5.12(1H,d,J=12.9Hz),6.45(1H,d,J=7.8Hz),6.71-6.77(2H,m),7.15(1H,s),7.33(1H,s)；MS(TOF MS ES+)m/z：462(M+H)+. 1 H NMR (400 MHz, CD 3 OD): δ 1.12 (3H, d, J = 6.7 Hz), 1.84-1.92 (2H, m), 2.68 (2H, t, J = 6.5 Hz), 3.20 (2H, t, J = 5.5 Hz), 3.37 (1H, dd, J = 10.2, 8.6 Hz), 3.64 - 3.81 (3H, m), 3.88 - 4.04 (3H, m), 5.06 (1H, d, J = 12.9Hz) 5,5. (TOF MS ES+) m/z: 462 (M+H) + .
(實施例15)(1S,3'R,4'S,5'S,6'R)-5-氯-6-(3,4-二氫-2H-1,4-苯并-7-基甲基)-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 15) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6-(3,4-dihydro-2H-1,4-benzoene -7-ylmethyl)-6'-[(1R)-1-hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1, 2'-pyrano]-3',4',5'-triol
使用在參考例6中所得到之化合物(200mg，0.26mmol)、及7-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-2,3-二氫-4H-1,4-苯并-4-羧酸三級丁酯(113mg，0.31mmol)做為原料，以與實施例12同樣之方法得到標題化合物(68mg)。 The compound (200 mg, 0.26 mmol) obtained in Reference Example 6 and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group were used. )-2,3-dihydro-4H-1,4-benzo The title compound (68 mg) was obtained.
1H NMR(400MHz,MeOH-d4)：δ1.13(3H,d,J=6.7Hz),3.27-3.41(3H,m),3.67-3.76(2H,m),3.79(1H,dd,J=10.1Hz,3.5Hz),3.95(2H,d,J=3.5Hz),4.00(1H,dd,J=6.2Hz,3.5Hz),4.14-4.16(2H,m),5.06(1H,d,J=12.9Hz),5.13(1H,d,J=12.9Hz),6.51-6.51(1H,m),6.55-6.55(2H,m),7.18(1H,s),7.34(1H,s)；MS(TOF MS ES+)m/z：464(M+H)+. 1 H NMR (400MHz, MeOH- d4): δ1.13 (3H, d, J = 6.7Hz), 3.27-3.41 (3H, m), 3.67-3.76 (2H, m), 3.79 (1H, dd, J = 10.1 Hz, 3.5 Hz), 3.95 (2H, d, J = 3.5 Hz), 4.00 (1H, dd, J = 6.2 Hz, 3.5 Hz), 4.14 - 4.16 (2H, m), 5.06 (1H, d, J = 12.9 Hz), 5.13 (1H, d, J = 12.9 Hz), 6.51-6.51 (1H, m), 6.55-6.55 (2H, m), 7.18 (1H, s), 7.34 (1H, s); MS (TOF MS ES+) m/z: 464 (M+H) + .
(實施例16)(1S,3'R,4'S,5'S,6'R)-5-氯-6'-[(1R)-1-羥基乙基]-6-{[6-(甲基胺基)吡啶-3-基]甲基}-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 16) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6'-[(1R)-1-hydroxyethyl]-6-{[6-(methylamine Pyridin-3-yl]methyl}-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4 ',5'-triol
使用在參考例6中所得到之化合物(200mg，0.26mmol)、及6-(Boc-甲基胺基)吡啶-3-硼酸(104mg，0.31mmol)做為原料，以與實施例12同樣之方法得到標題化合物(49mg)。 The compound (200 mg, 0.26 mmol) obtained in Reference Example 6 and 6-(Boc-methylamino)pyridine-3-boronic acid (104 mg, 0.31 mmol) were used as a raw material, and were obtained in the same manner as in Example 12. Method The title compound (49 mg) was obtained.
1H NMR(400MHz,MeOH-d4)：δ1.13(3H,d,J=6.6Hz),2.83(3H,s),3.39(1H,dd,J=10.1Hz,8.2Hz),3.69-3.77(2H,m),3.80(1H,dd,J=10.0Hz,3.3Hz),3.97(2H,s),3.98-4.03(1H,m),5.07(1H,d,J=12.9Hz),5.13(1H,d,J=12.9Hz),6.45(1H,d,J=8.6Hz),7.25(1H,s),7.30(1H,dd,J=8.7Hz,2.3Hz),7.36(1H,s),7.82(1H,d,J=2.4Hz)； MS(TOF MS ES+)m/z：437(M+H)+. 1 H NMR (400MHz, MeOH- d4): δ1.13 (3H, d, J = 6.6Hz), 2.83 (3H, s), 3.39 (1H, dd, J = 10.1Hz, 8.2Hz), 3.69-3.77 (2H, m), 3.80 (1H, dd, J = 10.0 Hz, 3.3 Hz), 3.97 (2H, s), 3.98-4.03 (1H, m), 5.07 (1H, d, J = 12.9 Hz), 5.13 (1H, d, J = 12.9 Hz), 6.45 (1H, d, J = 8.6 Hz), 7.25 (1H, s), 7.30 (1H, dd, J = 8.7 Hz, 2.3 Hz), 7.36 (1H, s ), 7.82 (1H, d, J = 2.4 Hz); MS (TOF MS ES+) m/z: 437 (M+H) + .
(實施例17)(1S,3'R,4'S,5'S,6'R)-5-氯-6'-[(1R)-1-羥基乙基]-6-[3-(甲基胺基)苯甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 17) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6'-[(1R)-1-hydroxyethyl]-6-[3-(methylamino group Benzyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'-three alcohol
(實施例17a)[3-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)苯基]胺基甲酸三級丁酯 (Example 17a) [3-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-Find (Benzyloxy)-6'-[(1R) -1-(benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran] -6-yl}methyl)phenyl]carbamic acid tert-butyl butyl ester
使用在參考例6中所得到之化合物(400mg，0.52mmol)、[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯基]胺基甲酸三級丁酯(198mg，0.62mmol)、肆三苯膦鈀(0)(60mg，0.052mmol)、碳酸鈉(110mg，1.04mmol)、及甲苯(2mL)-乙醇(1.5mL)-水(0.39mL)之混合溶劑，以與實施例12a同樣之方式得到標題化合物(213mg，收率46%)。 The compound obtained in Reference Example 6 (400 mg, 0.52 mmol), [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) was used. Phenyl] carbamic acid tert-butyl butyl ester (198 mg, 0.62 mmol), decyltriphenylphosphine palladium (0) (60 mg, 0.052 mmol), sodium carbonate (110 mg, 1.04 mmol), and toluene (2 mL)-ethanol ( The title compound (213 mg, yield 46%) was obtained.
(實施例17b)甲基[3-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)苯基]胺基甲酸三級丁酯 (Example 17b) Methyl [3-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-parade (benzyloxy)-6'-[( 1R)-1-(benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-piperidyl Butyl-6-yl}methyl)phenyl]carbamic acid tert-butyl butyl ester
將在實施例17a中所得到之化合物(183mg，0.21mmol)溶解於N,N-二甲基甲醯胺(5mL)中，在其中，於冰冷下添加氫化鈉(油性，63%w/w，24mg，0.63mmol)後，升溫至室溫，同時攪拌30分鐘。在該反應液中，於冰冷下添加碘化甲基(78μL，1.3mmol)，升溫至室溫，同時攪拌1小時半。反應終了後，在該反應液中添加飽和氯化銨水溶液(1mL)，並以乙酸乙酯(10mL，2次)萃取。將有機層用10%w/v食鹽水(10mL，3次)洗淨，以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠急速管柱層析(己烷：乙酸乙酯，97：3-80：20(濃度梯度)V/V)精製，得到標題化合物(158mg，收率73%)。 The compound obtained in Example 17a (183 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride was added under ice cooling (oily, 63% w/w After 24 mg, 0.63 mmol), the mixture was warmed to room temperature while stirring for 30 minutes. In the reaction mixture, methyl iodide (78 μL, 1.3 mmol) was added under ice cooling, and the mixture was warmed to room temperature and stirred for 1 hour and a half. After the reaction was completed, a saturated aqueous solution of ammonium chloride (1 mL) was added, and ethyl acetate (10 mL, twice). The organic layer was washed with 10% w/v brine (10 mL, 3 times) and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel chromatography chromatography chromatography eluting elut elut elut elut
(實施例17c)N-甲基-3-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)苯胺 (Example 17c) N-methyl-3-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-parade(benzyloxy)-6'- [(1R)-1-(benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2' -pyrano]-6-yl}methyl)aniline
將在實施例17b中所得到之化合物(158mg，0.18mmol)溶解於二氯甲烷(2mL)中，在其中，於冰冷下慢慢地添加三氟乙酸(0.7mL)。將該反應液升溫至室溫，同時攪拌1小時後，於減壓下餾去溶劑。將所得到之殘餘物用乙酸乙酯(10mL)稀釋，並將其以飽和碳酸氫鈉水溶液(10mL)、及飽和食鹽水(10mL)依序洗淨。將該有機層以無水硫酸鈉乾燥後，及於減壓下餾去溶劑。將所得到之殘餘物使用矽膠急速管柱層析(己烷：乙酸乙酯，100：0-80：20(濃度梯度)V/V)精製，得到標題化合物(130mg，收率91%)。 The compound obtained in Example 17b (158 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.7 mL) was slowly added to ice. The reaction liquid was warmed to room temperature while stirring for 1 hour, and then the solvent was evaporated under reduced pressure. The obtained residue was diluted with ethyl acetate (10 mL), and then washed successively with saturated aqueous sodium hydrogen carbonate (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by EtOAc EtOAcjjjjjjjj
(實施例17d)(1S,3'R,4'S,5'S,6'R)-5-氯-6'-[(1R)-1-羥基乙基]-6-[3-(甲基胺基)苯甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 17d) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6'-[(1R)-1-hydroxyethyl]-6-[3-(methylamino) Benzyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'-three alcohol
將在實施例17c中所得到之化合物(130mg，0.16mmol)溶解於THF(2mL)及甲醇(2mL)之混合溶劑中，在其中，添加1,2-二氯苯(130μL，1.16mmol)、及 10%w/w鈀/碳(195mg)，並將其於氫氣環境下，在室溫下攪拌1小時。將反應液過濾後，於減壓下餾去濾液之溶劑。將所得到之殘餘物使用矽膠急速管柱層析(二氯甲烷：甲醇，95：5-80：20(濃度梯度)V/V)精製，得到標題化合物(49mg，收率70%)。 The compound obtained in Example 17c (130 mg, 0.16 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1,2-dichlorobenzene (130 μL, 1.16 mmol), and 10% w/w palladium on carbon (195 mg), and stirred under a hydrogen atmosphere at room temperature for 1 hour. After filtering the reaction mixture, the solvent of the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography chromatography eluting elut elut elut elut elut elut
1H NMR(400MHz,MeOH-d4)：δ1.12(3H,d,J=6.7Hz),2.72(3H,s),3.37(1H,dd,J=10.2Hz,8.7Hz),3.67(1H,d,J=9.4Hz),3.73(1H,dd,J=9.4Hz,8.7Hz),3.79(1H,dd,J=10.2Hz,3.6Hz),3.96-4.09(3H,m),5.07(1H,d,J=12.9Hz),5.13(1H,d,J=12.9Hz),6.46-6.52(3H,m),7.04(1H,t,J=8.0Hz),7.20(1H,s),7.35(1H,s)；MS(ESI)m/z：434(M-H)-. 1 H NMR (400MHz, MeOH- d4): δ1.12 (3H, d, J = 6.7Hz), 2.72 (3H, s), 3.37 (1H, dd, J = 10.2Hz, 8.7Hz), 3.67 (1H , d, J = 9.4 Hz), 3.73 (1H, dd, J = 9.4 Hz, 8.7 Hz), 3.79 (1H, dd, J = 10.2 Hz, 3.6 Hz), 3.96-4.09 (3H, m), 5.07 ( 1H, d, J = 12.9 Hz), 5.13 (1H, d, J = 12.9 Hz), 6.46 - 6.52 (3H, m), 7.04 (1H, t, J = 8.0 Hz), 7.20 (1H, s), 7.35 (1H, s); MS (ESI) m/z: 434 (MH) - .
(實施例18)(1S,3'R,4'S,5'S,6'R)-5-氯-6'-[(1R)-1-羥基乙基]-6-[3-甲基-4-(甲基胺基)苯甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 18) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6'-[(1R)-1-hydroxyethyl]-6-[3-methyl-4- (Methylamino)benzyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4' , 5'-triol
以在參考例6中所得到之化合物(400mg，0.52mmol)、及[2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯基]胺基甲酸三級丁酯(207mg，0.62mmol)做為原料，以與實施例17同樣之方式得到標題化合物(179mg)。 The compound obtained in Reference Example 6 (400 mg, 0.52 mmol), and [2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) The title compound (179 mg) was obtained from the title compound (m.
1H NMR(400MHz,MeOH-d4)：δ1.13(3H,d,J=6.6Hz),2.41(3H,s),3.03(3H,s),3.38(1H,dd,J=10.2Hz,8.2Hz),3.71(1H,d,J=9.7Hz),3.76(1H,dd,J=9.7Hz,8.2Hz),3.81(1H,dd,J=10.2Hz,3.5Hz),3.99-4.06(1H,m),4.16(1H,d,J=15.3Hz),4.20(1H,d,J=15.3Hz),5.09(1H,d,J=12.9Hz),5.15(1H,d,J=12.9Hz),7.21-7.28(2H,m),7.29-7.35(2H,m),7.39(1H,s)；MS(ESI)m/z：450(M+H)+. 1 H NMR (400MHz, MeOH- d4): δ1.13 (3H, d, J = 6.6Hz), 2.41 (3H, s), 3.03 (3H, s), 3.38 (1H, dd, J = 10.2Hz, 8.2 Hz), 3.71 (1H, d, J = 9.7 Hz), 3.76 (1H, dd, J = 9.7 Hz, 8.2 Hz), 3.81 (1H, dd, J = 10.2 Hz, 3.5 Hz), 3.99-4.06 ( 1H, m), 4.16 (1H, d, J = 15.3 Hz), 4.20 (1H, d, J = 15.3 Hz), 5.09 (1H, d, J = 12.9 Hz), 5.15 (1H, d, J = 12.9) Hz), 7.21-7.28 (2H, m), 7.29-7.35 (2H, m), 7.39 (1H, s); MS (ESI) m/z: 450 (M+H) + .
(實施例19)(1S,3'R,4'S,5'S,6'R)-5-氯-6-(2,3-二氫-1H-吲哚-6-基甲基)-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 19) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6-(2,3-dihydro-1H-indol-6-ylmethyl)-6'- [(1R)-1-hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4 ',5'-triol
(實施例19a)6-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)-1H-吲哚 (Example 19a) 6-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-Find (Benzyloxy)-6'-[(1R)- 1-(Benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran]- 6-yl}methyl)-1H-吲哚
使用在參考例6中所得到之化合物(0.20g，0.26mmol)、1H-吲哚-6-基硼酸(51mg，0.31mmol)、碳酸鈉(56mg，0.41mmol)、肆三苯膦鈀(0)(30mg，0.026mmol)、及水(0.52mL)-乙醇(0.78mL)-甲苯(1.1mL)之混合溶劑，以與實施例1a同樣之方式得到標題化合物(0.18g)。 The compound obtained in Reference Example 6 (0.20 g, 0.26 mmol), 1H-indole-6-ylboronic acid (51 mg, 0.31 mmol), sodium carbonate (56 mg, 0.41 mmol), yttriumtriphenylphosphine palladium (0) was used. (10 mg, 0.026 mmol), and a mixture of water (0.52 mL) and ethanol (0.78 mL) - toluene (1.1 mL).
(實施例19b)6-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)吲哚啉 (Example 19b) 6-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-Find (Benzyloxy)-6'-[(1R)- 1-(Benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran]- 6-yl}methyl)porphyrin
將在實施例19a中所得到之化合物(0.18g，0.22mmol)溶解於乙酸(1.1mL)中。將其冷卻至10℃，並在其中添加氰基氫化硼鈉(44mg，0.70mmol)，並於10℃攪拌30分鐘。在該反應液加水(20mL)，用碳酸鉀中和後，以乙酸乙酯(30mL、2次)萃取。將有機層用飽和食鹽水(20mL)洗淨，以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(己烷：乙酸乙酯，95：5→50：50(濃度梯度)V/V)精製，得到標題化合物(0.14g)。 The compound obtained in Example 19a (0.18 g, 0.22 mmol) was dissolved in acetic acid (1.1 mL). It was cooled to 10 ° C, and sodium cyanoborohydride (44 mg, 0.70 mmol) was added thereto, and stirred at 10 ° C for 30 minutes. Water (20 mL) was added to the reaction mixture, and the mixture was applied to ethyl acetate (30 mL, twice). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc EtOAc (EtOAc)
(實施例19c)(1S,3'R,4'S,5'S,6'R)-5-氯-6-(2,3-二氫-1H-吲哚-6-基甲基)-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 19c) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6-(2,3-dihydro-1H-indol-6-ylmethyl)-6'- [(1R)-1-hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4 ',5'-triol
使用在實施例19b中所得到之化合物(0.14g，0.18mmol)、1,2-二氯苯(0.10mL，0.89mmol)、10%w/w鈀碳(0.14g)、及THF(6.0mL)與甲醇(3.0mL)之混合溶劑，以與實施例1b同樣之方式得到標題化合物(54mg)。 The compound obtained in Example 19b (0.14 g, 0.18 mmol), 1,2-dichlorobenzene (0.10 mL, 0.89 mmol), 10% w/w palladium carbon (0.14 g), and THF (6.0 mL) The title compound (54 mg) was obtained from m.
1H NMR(400MHz,CDCl3)：δ2.94(2H,t,J=8.2Hz),2.95(3H,d,J=8.2Hz),3.38(1H,dd,J=10.2Hz,8.7Hz),3.44(2H,t,J=8.2Hz),3.67(1H,d,J=9.4Hz),3.73(1H,dd,J=9.4Hz,8.2Hz),3.79(1H,dd,J=10.2Hz,3.5Hz),3.96-4.01(1H,m),4.02(2H,s),5.06(1H,d,J=13.0Hz),5.13(1H,d,J=13.0Hz),6.54-6.56(2H,m),6.99(1H,d,J=6.7Hz),7.19(1H,s),7.34(1H,s)；MS(ESI)m/z：448(M+H)+. 1 H NMR (400MHz, CDCl 3 ): δ2.94 (2H, t, J = 8.2Hz), 2.95 (3H, d, J = 8.2Hz), 3.38 (1H, dd, J = 10.2Hz, 8.7Hz) , 3.44 (2H, t, J = 8.2 Hz), 3.67 (1H, d, J = 9.4 Hz), 3.73 (1H, dd, J = 9.4 Hz, 8.2 Hz), 3.79 (1H, dd, J = 10.2 Hz) , 3.5Hz), 3.96-4.01 (1H, m), 4.02 (2H, s), 5.06 (1H, d, J = 13.0 Hz), 5.13 (1H, d, J = 13.0 Hz), 6.54 - 6.56 (2H , m), 6.99 (1H, d, J = 6.7 Hz), 7.19 (1H, s), 7.34 (1H, s); MS (ESI) m/z: 448 (M+H) + .
(實施例20)(1S,3'R,4'S,5'S,6'R)-5-氯-6-(2,3-二氫-1H-吲哚-5-基甲基)-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 20) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6-(2,3-dihydro-1H-indol-5-ylmethyl)-6'- [(1R)-1-hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4 ',5'-triol
以在參考例6中所得到之化合物(0.25g，0.32mmol)、及5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-1H-吲哚(92mg，0.38mmol)做為原料，藉由與實施例19同樣之方式得到標題化合物(54mg)。 The compound obtained in Reference Example 6 (0.25 g, 0.32 mmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- The title compound (54 mg) was obtained from m.
1H NMR(400MHz,CD3OD)：δ1.12(3H,d,J=6.3Hz),2.93(2H,t,J=8.4Hz),3.36-3.46(3H,m),3.64-3.82(3H,m),3.94-4.07(3H,m),5.06(1H,d,J=12.9Hz),5.12(1H,d,J=12.9Hz),6.61(1H,d,J=7.8Hz),6.81-6.87(1H,m),6.94(1H,s),7.17(1H,s),7.33(1H,s)；MS(TOF MS ES+)m/z：448(M+H)+. 1 H NMR (400 MHz, CD 3 OD): δ 1.12 (3H, d, J = 6.3 Hz), 2.93 (2H, t, J = 8.4 Hz), 3.36 - 3.46 (3H, m), 3.64 - 3.82 ( 3H, m), 3.94-4.07 (3H, m), 5.06 (1H, d, J = 12.9 Hz), 5.12 (1H, d, J = 12.9 Hz), 6.61 (1H, d, J = 7.8 Hz), 6.81-6.87 (1H, m), 6.94 (1H, s), 7.17 (1H, s), 7.33 (1H, s); MS (TOF MS ES+) m/z: 448 (M+H) + .
(實施例21)(1S,3'R,4'S,5'S,6'R)-5-氯-6'-[(1R)-1-羥基乙基]-6-[(5-甲氧基吡啶-2-基)甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 21) (1S,3'R,4'S,5'S,6'R)-5-Chloro-6'-[(1R)-1-hydroxyethyl]-6-[(5-methoxypyridine) -2-yl)methyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5 '-triol
(實施例21a)5-甲氧基-2-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)吡啶 (Example 21a) 5-methoxy-2-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-parade (benzyloxy)-6' -[(1R)-1-(benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2 '-pyrano]-6-yl}methyl)pyridine
於氮氣環境下，在鋅粉末(65mg，0.99mmol)中添加THF(2mL)。在該懸浮液中添加二溴乙烷(9μL，0.074mmol)，並於70℃攪拌1分鐘。冷卻至室溫，添加氯三甲基矽烷(20μL，0.16mmol)，並於室溫下攪拌10分鐘。在該懸浮液中添加在參考例6中所得到之化合物(0.39g，0.50mmol)之THF(5mL)溶液，於室溫下攪拌30分鐘。繼而，將該反應液加至預先調製之三(2-呋喃基)膦(28mg，0.12mmol)、參(二亞苄基丙酮)二鈀(0)(14mg，0.015mmol)與THF(2mL)之混合物。再者，在該反應液中添加2-溴-5-甲氧基吡啶(0.12g，0.64mmol)之THF(0.5mL)溶液，並於氮氣環境下，在80℃攪拌2小時。在反應液中加水(20mL)，並用乙酸乙酯(30mL、2次)萃取。將有機層以飽和食鹽水(20mL)洗淨，用無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(己烷：乙酸乙酯，90：10→100：0(濃度梯度)V/V)精製，得到標題化合物(0.25g)。 To a zinc powder (65 mg, 0.99 mmol) was added THF (2 mL). Dibromoethane (9 μL, 0.074 mmol) was added to the suspension, and stirred at 70 ° C for 1 minute. After cooling to room temperature, chlorotrimethylnonane (20 μL, 0.16 mmol) was added, and stirred at room temperature for 10 min. A solution of the compound (0.39 g, 0.50 mmol) in THF (5 mL) Then, the reaction mixture was added to a previously prepared tris(2-furyl)phosphine (28 mg, 0.12 mmol), bis(dibenzylideneacetone) dipalladium (0) (14 mg, 0.015 mmol) and THF (2 mL) a mixture. Further, a solution of 2-bromo-5-methoxypyridine (0.12 g, 0.64 mmol) in THF (0.5 mL) was added to the reaction mixture, and the mixture was stirred at 80 ° C for 2 hours under a nitrogen atmosphere. Water (20 mL) was added to the mixture, and ethyl acetate (30 mL, twice). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:
(實施例21b)(1S,3'R,4'S,5'S,6'R)-5-氯-6'-[(1R)-1-羥基乙基]-6-[(5-甲氧基吡啶-2-基)甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 21b) (1S,3'R,4'S,5'S,6'R)-5-Chloro-6'-[(1R)-1-hydroxyethyl]-6-[(5-methoxypyridine) -2-yl)methyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5 '-triol
使用在實施例21a中所得到之化合物(0.13g，0.16mmol)、1,2-二氯苯(92μL，0.82mmol)、10%w/w鈀碳(65mg)、THF(4.0mL)、甲醇(2.0mL)，以與實施例1b同樣之方式得到標題化合物(58mg)。 The compound obtained in Example 21a (0.13 g, 0.16 mmol), 1,2-dichlorobenzene (92 μL, 0.82 mmol), 10% w/w palladium carbon (65 mg), THF (4.0 mL), methanol The title compound (58 mg) was obtained.
1H NMR(500MHz,CDCl3)：δ1.13(3H,d,J=6.3Hz),3.39(1H,dd,J=10.2Hz,8.3Hz),3.71(1H,d,J=9.5Hz),3.75(1H,dd,J=9.5Hz,8.3Hz),3.80(1H,dd,J=10.2Hz,3.4Hz),3.84(3H,s),3.98-4.02(1H,m),4.24(2H,s),5.07(1H,d,J=13.2Hz),5.14(1H,d,J=13.2Hz),7.16(1H,d,J=8.3Hz),7.28(1H,s),7.33(1H,d,J=2.9Hz),7.37(1H,s),8.12(1H,d,J=2.9Hz)；MS(ESI)m/z：438(M+H)+. 1 H NMR (500MHz, CDCl 3 ): δ1.13 (3H, d, J = 6.3Hz), 3.39 (1H, dd, J = 10.2Hz, 8.3Hz), 3.71 (1H, d, J = 9.5Hz) , 3.75 (1H, dd, J = 9.5 Hz, 8.3 Hz), 3.80 (1H, dd, J = 10.2 Hz, 3.4 Hz), 3.84 (3H, s), 3.98-4.02 (1H, m), 4.24 (2H) , s), 5.07 (1H, d, J = 13.2 Hz), 5.14 (1H, d, J = 13.2 Hz), 7.16 (1H, d, J = 8.3 Hz), 7.28 (1H, s), 7.33 (1H) , d, J = 2.9 Hz), 7.37 (1H, s), 8.12 (1H, d, J = 2.9 Hz); MS (ESI) m/z: 438 (M+H) + .
(實施例22)(1S,3'R,4'S,5'S,6'R)-5-氯-6'-[(1R)-1-羥基乙基]-6-[(6-甲氧基吡啶-2-基)甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 22) (1S,3'R,4'S,5'S,6'R)-5-Chloro-6'-[(1R)-1-hydroxyethyl]-6-[(6-methoxypyridine) -2-yl)methyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5 '-triol
(實施例22a)2-甲氧基-6-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)吡啶 (Example 22a) 2-methoxy-6-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-parade (benzyloxy)-6' -[(1R)-1-(benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2 '-pyrano]-6-yl}methyl)pyridine
於氮氣環境下，在鋅粉末(65mg，0.99mmol)中添加THF(2mL)。在該懸浮液中添加二溴乙烷(9μL，0.074mmol)，並於70℃攪拌1分鐘。將其冷卻至室溫，並添加氯三甲基矽烷(20μL，0.16mmol)，進一步於室溫下攪拌10分鐘。在此懸浮液中添加參考例6中所得到之化合物(0.39g，0.50mmol)之THF(5mL)溶液，並於室溫下攪拌30分鐘。繼而將該反應液針對預先調製之三(2-呋喃基)膦(28mg，0.12mmol)、參(二亞苄基丙酮)二鈀(0)(14mg，0.015mmol)、及THF(2mL)之混合物添加。再者，在該反應液中添加2-溴-6-甲氧基吡啶(0.12g，0.64mmol)之THF(0.5mL)溶液，並於氮氣環境下，在80℃攪拌3小時。在反應液中加水(20mL)，並用乙酸乙酯(30mL、2次)萃取。將有機層用飽和食鹽水(20mL)洗淨，並以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物使用矽膠管柱層析(己烷：乙酸乙酯，90：10→100：0(濃度梯度)V/V)精製，得到標題化合物(0.25g)。 To a zinc powder (65 mg, 0.99 mmol) was added THF (2 mL). Dibromoethane (9 μL, 0.074 mmol) was added to the suspension, and stirred at 70 ° C for 1 minute. This was cooled to room temperature, and chlorotrimethylnonane (20 μL, 0.16 mmol) was added, and the mixture was further stirred at room temperature for 10 minutes. A solution of the compound obtained in Reference Example 6 (0.39 g, 0.50 mmol) in THF (5 mL). The reaction solution was then applied to a previously prepared tris(2-furyl)phosphine (28 mg, 0.12 mmol), bis(dibenzylideneacetone) dipalladium(0) (14 mg, 0.015 mmol), and THF (2 mL) The mixture is added. Further, a solution of 2-bromo-6-methoxypyridine (0.12 g, 0.64 mmol) in THF (0.5 mL) was added to the mixture, and the mixture was stirred at 80 ° C for 3 hours under nitrogen atmosphere. Water (20 mL) was added to the mixture, and ethyl acetate (30 mL, twice). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc:
(實施例22b)(1S,3'R,4'S,5'S,6'R)-5-氯-6'-[(1R)-1-羥基乙基]-6-[(6-甲氧基吡啶-2-基)甲基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 22b) (1S,3'R,4'S,5'S,6'R)-5-Chloro-6'-[(1R)-1-hydroxyethyl]-6-[(6-methoxypyridine) -2-yl)methyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5 '-triol
使用在實施例22a中所得到之化合物(0.26g，0.33mmol)、1,2-二氯苯(0.19mL，1.7mmol)、10%w/w鈀碳(0.26g)、及THF(6.0mL)與甲醇(3.0mL)之混合溶劑，以與實施例00同樣方式，得到標題化合物(30mg)。 The compound obtained in Example 22a (0.26 g, 0.33 mmol), 1,2-dichlorobenzene (0.19 mL, 1.7 mmol), 10% w/w palladium carbon (0.26 g), and THF (6.0 mL) The title compound (30 mg) was obtained.
1H NMR(400MHz,CDCl3)：δ1.12(3H,d,J=6.6Hz),3.38(1H,dd,J=10.2Hz,8.2Hz),3.71(1H,d,J=9.4Hz),3.75(1H,dd,J=9.4Hz,8.2Hz),3.80(1H,dd,J=10.2Hz,3.5Hz),3.86(3H,s),3.97-4.05(1H,m),4.16(1H,d,J=15.2Hz),4.22(1H,d,J=15.2Hz),5.08(1H,d,J=12.9Hz),5.14(1H,d,J=12.9Hz),6.59(1H,d,J=8.2Hz),6.72(1H,d,J=7.5Hz),7.37(2H,s),7.53(1H,dd,J=8.2Hz,7.5Hz)；MS(FAB)m/z：438(M+H)+. 1 H NMR (400MHz, CDCl 3 ): δ1.12 (3H, d, J = 6.6Hz), 3.38 (1H, dd, J = 10.2Hz, 8.2Hz), 3.71 (1H, d, J = 9.4Hz) , 3.75 (1H, dd, J = 9.4 Hz, 8.2 Hz), 3.80 (1H, dd, J = 10.2 Hz, 3.5 Hz), 3.86 (3H, s), 3.97-4.05 (1H, m), 4.16 (1H) , d, J = 15.2 Hz), 4.22 (1H, d, J = 15.2 Hz), 5.08 (1H, d, J = 12.9 Hz), 5.14 (1H, d, J = 12.9 Hz), 6.59 (1H, d , J = 8.2 Hz), 6.72 (1H, d, J = 7.5 Hz), 7.37 (2H, s), 7.53 (1H, dd, J = 8.2 Hz, 7.5 Hz); MS (FAB) m/z: 438 (M+H) + .
(實施例23)(1S,3'R,4'S,5'S,6'R)-5-氯-6-(3,4-二氫-2H-1,4-苯并-6-基甲基)-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 23) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6-(3,4-dihydro-2H-1,4-benzoene -6-ylmethyl)-6'-[(1R)-1-hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1, 2'-pyrano]-3',4',5'-triol
(實施例23a)6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-2H-1,4-苯并-3(4H)-酮 (Example 23a) 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoene -3(4H)-ketone
使用6-溴-2H-1,4-苯并-3(4H)-酮(1.14g，5.00mmol)、聯硼酸頻那醇酯(1.52g，6.00mmol)、乙酸鉀(1.47g，15.0mmol)、[1,1'-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物 二氯甲烷加成物(408mg，0.50mmol)、及1,2-二甲氧基乙烷(25mL)，以與參考例15e同樣之方式得到標題化合物(1.30g)。 Use 6-bromo-2H-1,4-benzophenone -3(4H)-one (1.14 g, 5.00 mmol), pinacol borate (1.52 g, 6.00 mmol), potassium acetate (1.47 g, 15.0 mmol), [1,1'-bis(diphenyl) Phosphyl)ferrocene]palladium(II) dichloride methylene chloride adduct (408 mg, 0.50 mmol), and 1,2-dimethoxyethane (25 mL) in the same manner as in Reference Example 15e The title compound (1.30 g) was obtained.
1H NMR(400MHz,CDCl3)：δ1.34(3H,s),4.65(2H,s),6.98(1H,d,J=7.9Hz),7.22(1H,d,J=1.5Hz),7.46(1H,dd,J=7.9Hz,1.5Hz),7.78(1H,brs). 1 H NMR (400MHz, CDCl 3 ): δ1.34 (3H, s), 4.65 (2H, s), 6.98 (1H, d, J = 7.9Hz), 7.22 (1H, d, J = 1.5Hz), 7.46 (1H, dd, J = 7.9 Hz, 1.5 Hz), 7.78 (1H, brs).
(實施例23b)6-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)-2H-1,4-苯并-3(4H)-酮 (Example 23b) 6-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-Find (Benzyloxy)-6'-[(1R)- 1-(Benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran]- 6-yl}methyl)-2H-1,4-benzoene -3(4H)-ketone
使用在參考例6中所得到之化合物(770mg，1.00mmol)、在實施例23a中所得到之化合物(330mg，1.20mmol)、碳酸鈉(212mg，2.00mmol)、肆三苯膦鈀(0)(116mg，0.10mmol)、及甲苯(15mL)-乙醇(11mL)-水(2mL)之混合溶劑，藉由與實施例1同樣之手法，得到標題化合物(660mg)。 The compound obtained in Reference Example 6 (770 mg, 1.00 mmol), the compound obtained in Example 23a (330 mg, 1.20 mmol), sodium carbonate (212 mg, 2.00 mmol), and triphenylphosphine palladium (0) A mixed solvent of (116 mg, 0.10 mmol) and toluene (15 mL)-ethanol (11 mL)-water (2 mL) was obtained.
(實施例23c)6-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-6-基}甲基)-3,4-二氫-2H-1,4-苯并 (Example 23c) 6-({(1S,3'R,4'S,5'S,6'R)-3',4',5'-Find (Benzyloxy)-6'-[(1R)- 1-(Benzyloxy)ethyl]-5-chloro-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyran]- 6-yl}methyl)-3,4-dihydro-2H-1,4-benzo
將在實施例23b中所得到之化合物(510mg，0.61mmol)溶解於THF(12mL)中，於氮氣環境下，在-78℃將氫化鋁鋰之THF溶液(1.0M，2.14mL，2.14mmol)滴入其中。將該反應液慢慢地升溫至室溫，同時攪拌2小時，進一步於50℃攪拌1小時後，靜置整夜。將該反應液冰冷，在其中添加水(1mL)、10%w/v羅謝爾 (Rochelle)鹽水溶液(2mL)、1M氫氧化鈉(2mL)、及二乙基醚(30mL)，並攪拌1小時。將該反應液用飽和食鹽水(10mL)洗淨，將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶劑。將所得到之殘餘物以矽膠急速管柱層析(己烷：乙酸乙酯，90：10→60：40(濃度梯度)V/V)精製，得到標題化合物(250mg)。 The compound obtained in Example 23b (510 mg, 0.61 mmol) was dissolved in THF (12 mL), THF, THF (1.0M, 2.14mL, 2.14mmol) Drop it into it. The reaction solution was gradually warmed to room temperature while stirring for 2 hours, and further stirred at 50 ° C for 1 hour, and then allowed to stand overnight. The reaction solution was ice-cooled, and water (1 mL) and 10% w/v Rochelle were added thereto. (Rochelle) brine solution (2 mL), 1M sodium hydroxide (2 mL), and diethyl ether (30 mL). The reaction mixture was washed with brine (10 mL). The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:
(實施例23d)(1S,3'R,4'S,5'S,6'R)-5-氯-6-(3,4-二氫-2H-1,4-苯并-6-基甲基)-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 23d) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6-(3,4-dihydro-2H-1,4-benzoene -6-ylmethyl)-6'-[(1R)-1-hydroxyethyl]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1, 2'-pyrano]-3',4',5'-triol
使用在實施例23c中所得到之化合物(130mg，0.16mmol)、10%w/w鈀碳(130mg)、1,2-二氯苯(0.09mL，0.8mmol)、及THF(4.0mL)及甲醇(2.0mL)之混合溶劑，藉由與實施例1b同樣之手法，得到標題化合物(70mg)。 The compound obtained in Example 23c (130 mg, 0.16 mmol), 10% w/w palladium carbon (130 mg), 1,2-dichlorobenzene (0.09 mL, 0.8 mmol), and THF (4.0 mL) The title compound (70 mg) was obtained.
1H NMR(400MHz,MeOH-d4)：δ1.13(3H,d,J=6.2Hz),3.34-3.43(3H,m),3.68(1H,d,J=9.8Hz),3.70-3.76(1H,m),3.79(1H,dd,J=10.1Hz,3.5Hz),3.96-4.03(3H,m),4.18-4.23(2H,m),5.06(1H,d,J=12.8Hz),5.13(1H,d,J=12.8Hz),6.57-6.62(2H,m),6.67(1H,d,J=8.6Hz),7.21(1H,s),7.35(1H,s)； MS(ESI)m/z：464(M+H)+. 1 H NMR (400MHz, MeOH- d4): δ1.13 (3H, d, J = 6.2Hz), 3.34-3.43 (3H, m), 3.68 (1H, d, J = 9.8Hz), 3.70-3.76 ( 1H, m), 3.79 (1H, dd, J = 10.1 Hz, 3.5 Hz), 3.96-4.03 (3H, m), 4.18-4.23 (2H, m), 5.06 (1H, d, J = 12.8 Hz), 5.13 (1H, d, J = 12.8 Hz), 6.57-6.62 (2H, m), 6.67 (1H, d, J = 8.6 Hz), 7.21 (1H, s), 7.35 (1H, s); MS (ESI) m/z: 464 (M+H) + .
(實施例24)(1S,3'R,4'S,5'S,6'R)-5-氯-6-(4-乙基苯甲基)-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 24) (1S, 3'R, 4'S, 5'S, 6'R)-5-chloro-6-(4-ethylbenzyl)-6'-[(1R)-1-hydroxyethyl ]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'-triol
(實施例24a)(1S,3'R,4'S,5'S,6'R)-3',4',5'-參(苯甲氧基)-6'-[(1R)-1-(苯甲氧基)乙基]-5-氯-6-(4-乙基苯甲基)-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃] (Example 24a) (1S, 3'R, 4'S, 5'S, 6'R)-3', 4', 5'-paraxyl (benzyloxy)-6'-[(1R)-1-(benzene Methoxy)ethyl]-5-chloro-6-(4-ethylbenzyl)-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1 , 2'-pyranose]
使用在參考例6中所得到之化合物(0.63g，0.82mmol)、4-乙基苯基硼酸(0.14g，0.90mmol)、碳酸鈉(0.18g，1.70mmol)、肆三苯膦鈀(0)(95mg，0.082mmol)及、甲苯(3.4mL)-乙醇(2.5mL)-水(1.7mL)之混合溶劑，以與實施例1a同樣之方式得到標題化合物(0.55g)。 The compound obtained in Reference Example 6 (0.63 g, 0.82 mmol), 4-ethylphenylboronic acid (0.14 g, 0.90 mmol), sodium carbonate (0.18 g, 1.70 mmol), yttriumtriphenylphosphine palladium (0) was used. The title compound (0.55 g) was obtained from mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
(實施例24b)(1S,3'R,4'S,5'S,6'R)-5-氯-6-(4-乙基苯甲基)-6'-[(1R)-1-羥基乙基]-3',4',5',6'-四氫-3H-螺[2-苯并呋喃-1,2'-哌喃]-3',4',5'-三醇 (Example 24b) (1S,3'R,4'S,5'S,6'R)-5-Chloro-6-(4-ethylbenzyl)-6'-[(1R)-1-hydroxyethyl ]-3',4',5',6'-tetrahydro-3H-spiro[2-benzofuran-1,2'-pyrano]-3',4',5'-triol
使用在實施例24a中所得到之化合物(0.25 g，0.32mmol)、1,2-二氯苯(0.18mL，1.6mmol)、10%w/w鈀碳(0.25g)、及THF(12mL)及甲醇(6.0mL)之混合溶劑，以與實施例1b同樣之方式，得到標題化合物(0.13g)。 The compound obtained in Example 24a (0.25) was used. a mixed solvent of g, 0.32 mmol), 1,2-dichlorobenzene (0.18 mL, 1.6 mmol), 10% w/w palladium carbon (0.25 g), and THF (12 mL) and methanol (6.0 mL) The title compound (0.13 g) was obtained.
1H NMR(400MHz,MeOH-d4)：δ1.12(3H,d,J=6.7Hz),1.20(3H,t,J=7.6Hz),2.59(2H,q,J=7.6Hz),3.37(1H,dd,J=10.1Hz,8.4Hz),3.67(1H,d,J=9.4Hz),3.73(1H,dd,J=9.4Hz,8.4Hz),3.79(1H,dd,J=10.1Hz,3.5Hz),3.97-4.03(1H,m),4.05-4.13(2H,m),5.07(1H,d,J=13.3Hz),5.13(1H,d,J=13.3Hz),7.10(4H,s),7.21(1H,s),7.36(1H,s)；MS(FAB)m/z：435(M+H)+. 1 H NMR (400MHz, MeOH- d4): δ1.12 (3H, d, J = 6.7Hz), 1.20 (3H, t, J = 7.6Hz), 2.59 (2H, q, J = 7.6Hz), 3.37 (1H, dd, J = 10.1 Hz, 8.4 Hz), 3.67 (1H, d, J = 9.4 Hz), 3.73 (1H, dd, J = 9.4 Hz, 8.4 Hz), 3.79 (1H, dd, J = 10.1) Hz, 3.5 Hz), 3.97-4.03 (1H, m), 4.05-4.13 (2H, m), 5.07 (1H, d, J = 13.3 Hz), 5.13 (1H, d, J = 13.3 Hz), 7.10 ( 4H, s), 7.21 (1H, s), 7.36 (1H, s); MS (FAB) m/z: 435 (M+H) + .
(實施例25~63) (Examples 25 to 63)
參照上述之參考例及實施例，得到實施例25~63之化合物。 The compounds of Examples 25 to 63 were obtained by referring to the above Reference Examples and Examples.
以人類SGLT1之cDNA純系(Origene公司純系編號：TC119918；GenBank登錄編號：NM_000343)做為模板，使用PCR法増幅。使用 5’-ttaagcttaccatggacagtagcacctggagccc-3’(引子1：序列表之序列編號1)做為PCR法之正義‧寡聚核苷酸‧引子；使用5’-ttctcgagtcaggcaaaatatgcatggcaa-3’(引子2：序列表之序列編號2)做為反義‧寡聚核苷酸‧引子。將PCR反應產物進行瓊脂糖電泳後，從相當於2013鹼基之單一帶回收目標DNA斷片，用限制酵素HindIII、XhoI切斷後，導入載體pCMV-Script(Stratagene公司)之HindIII/XhoI部位，形成SGLT1表現質體pCMV-SGLT1。從pCMV-SGLT1切出HindIII/XhoI片段，導入pENTR1A(Gateway、Invitrogen公司)之BamHI/XhoI部位，製成pENTR-SGLT1。以導入有Gateway載體轉換系統篋A(Gateway Vector Conversion System Cassette A)(Invitrogen公司)之反轉錄‧病毒‧載體pLPCX(Clontech公司)做為目標質體(destination plasmid)，製成SGLT1表現反轉錄‧病毒‧載體pLPCX-SGLT1。 The cDNA pure line of human SGLT1 (Origene pure line number: TC119918; GenBank accession number: NM_000343) was used as a template, and the PCR method was used. use 5'-ttaagcttaccatggacagtagcacctggagccc-3' (introduction 1: sequence number 1 of the sequence listing) as a sense of justice for the PCR method ‧ primers; use 5'-ttctcgagtcaggcaaaatatgcatggcaa-3' (introduction 2: sequence number of the sequence listing) 2) As an antisense ‧ oligonucleotide ‧ primer After the PCR reaction product was subjected to agarose electrophoresis, the target DNA fragment was recovered from a single band corresponding to the 2013 base, cut with restriction enzymes HindIII and XhoI, and introduced into the HindIII/XhoI site of the vector pCMV-Script (Stratagene) to form SGLT1. Express the plastid pCMV-SGLT1. The HindIII/XhoI fragment was excised from pCMV-SGLT1 and introduced into the BamHI/XhoI site of pENTR1A (Gateway, Invitrogen) to prepare pENTR-SGLT1. The retroviral ‧ virus ‧ vector pLPCX (Clontech), which was introduced with the Gateway Vector Conversion System C (Avitrogen), was used as the destination plasmid to produce reverse transcription of SGLT1. Virus ‧ vector pLPCX-SGLT1.
將1)中所得到之反轉錄‧病毒pLPCX-SGLT1轉染於整合素αvβ3表現HEK-293細胞後，以抗生物質G418(商品名：遺傳黴素(geneticin)，Invitrogen公司製)、嘌呤黴素(puromycin)(Clontech公司製)處理細胞，取得具有耐性之目標載體的安定表現細胞HEK-SGLT1。安定表現細胞之培養、維持係使用含有250μg/ml G418、1μg/ml嘌呤黴素、3μM KGT-1075、10%FBS之DMEM培養基來進行。 The trans-transcription ‧ virus pLPCX-SGLT1 obtained in 1) was transfected into integrin αvβ3 to express HEK-293 cells, and then anti-biomass G418 (trade name: geneticin, manufactured by Invitrogen), puromycin (puromycin) (manufactured by Clontech Co., Ltd.) treats cells and obtains a stable expression cell HEK-SGLT1 of a target vector having tolerance. The culture and maintenance of diazepam cells were carried out using DMEM medium containing 250 μg/ml G418, 1 μg/ml puromycin, 3 μM KGT-1075, and 10% FBS.
將HEK-SGLT1細胞在含有250μg/ml G418、1μg/ml嘌呤黴素、10%FBS之DMEM培養基中，以106細胞/ml之密度懸浮，然後以每孔100μl之量播種在塗覆類型I膠原之96孔培養盤(Corning公司製)之各孔中。次日，將培養基更換為糖攝取緩衝液(10mM HEPES(pH7.5)、5mM Tris-HCl(pH7.5)、140mM NaCl、2mM KCl、1mM CaCl2、1mM MgCl2)，將1mM[14C]-α-甲基-D-葡哌喃糖苷(0.1m Ci)及評價化合物一起於37℃培養30分鐘後，以洗淨緩衝液(10mM HEPES(pH7.5)、5mM Tris-HCl(pH7.5)、140mM氯化膽鹼、2mM KCl、1mM CaCl2、1mM MgCl2)洗淨3次。在96孔培養盤之各孔中，每孔各添加100μl液體閃爍雞尾酒混液(商品名：Supermix，Perkin Elmer公司製)，攪拌10分鐘後，藉由為液體閃爍計數器之一之Micro β(Perkin Elmer公司製) 測定放射活性。以過剩量之SGLT1阻礙化合物存在下之放射活性做為背景值，將從各測定值減去該背景值之值做為糖攝取活性，從未使用試驗化合物而求得之對照糖攝取活性，及使用一定濃度之試驗化合物時之糖攝取活性，求取阻礙率(%)，調查阻礙50%糖攝取活性之試驗化合物之濃度。將其結果示於表11。 HEK-SGLT1 cells were suspended in DMEM medium containing 250 μg/ml G418, 1 μg/ml puromycin, 10% FBS at a density of 10 6 cells/ml, and then seeded at a dose of 100 μl per well in coating type I. Each well of a 96-well culture plate of collagen (manufactured by Corning) was used. The next day, the medium was changed to a sugar uptake buffer (10 mM HEPES (pH 7.5), 5 mM Tris-HCl (pH 7.5), 140 mM NaCl, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 ), 1 mM [ 14 C ]-α-Methyl-D-glucopyranoside (0.1 m Ci) and the evaluation compound were incubated at 37 ° C for 30 minutes, followed by a washing buffer (10 mM HEPES (pH 7.5), 5 mM Tris-HCl (pH 7). .5), washed with 140 mM choline chloride, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 ). In each well of a 96-well culture plate, 100 μl of a liquid scintillation cocktail mixture (trade name: Supermix, manufactured by Perkin Elmer Co., Ltd.) was added to each well, and after stirring for 10 minutes, Microβ (Perkin Elmer, which is one of liquid scintillation counters) Company system) Determination of radioactivity. Taking the radioactivity of the excess amount of SGLT1 in the presence of the compound as a background value, the value of the background value is subtracted from each measured value as the sugar uptake activity, and the control sugar uptake activity obtained without using the test compound, and The glucose uptake activity at a certain concentration of the test compound was used to determine the inhibition rate (%), and the concentration of the test compound which inhibits the 50% sugar uptake activity was investigated. The results are shown in Table 11.
以人類SGLT2之cDNA純系(Origene公司純系編號：TC303267；GenBank登錄編號：NM_003041)做為模板，使用PCR法増幅。使用5’-ttaagcttaccatggaggagcacacagaggcagg-3’(引子3：序列表之序列編號3)做為PCR法之正義‧寡聚核苷酸‧引子；使用5’-ttctcgagttaggcatagaagccccagagg-3’(引子4：序列表之序列編號4)做為反義‧寡聚核苷酸‧引子。將PCR反應產物進行瓊脂糖電泳後，從相當於2037鹼基之單一帶回收目標之DNA斷片，以限制酵素HindIII、XhoI切斷後，導入載體pCMV-Script(Stratagene公司)之HindIII/XhoI部位。形成SGLT2表現質體pCMV-SGLT2。從pCMV-SGLT2切出HindIII/XhoI片段，導入pENTR1A(Gateway，Invitrogen公司)之BamHI/XhoI部位，製成pENTR-SGLT2。將導入有Gateway載體轉 換系統篋A(Invitrogen公司)之反轉錄‧病毒‧載體pLPCX(Clontech公司)當做目標質體，製成SGLT2表現反轉錄‧病毒‧載體pLPCX-SGLT2。 The cDNA pure line of human SGLT2 (Origene pure line number: TC303267; GenBank accession number: NM_003041) was used as a template, and the PCR method was used. Use 5'-ttaagcttaccatggaggagcacacagaggcagg-3' (introduction 3: sequence number 3 of the sequence listing) as the sense of justice for the PCR method ‧ primers; use 5'-ttctcgagttaggcatagaagccccagagg-3' (introduction 4: sequence of the sequence listing) No. 4) as an antisense ‧ oligonucleotide ‧ primer After the PCR reaction product was subjected to agarose electrophoresis, the target DNA fragment was recovered from a single band corresponding to 2037 bases, and the restriction enzymes HindIII and XhoI were cleaved, and then introduced into the HindIII/XhoI site of the vector pCMV-Script (Stratagene). The formation of SGLT2 expresses the plastid pCMV-SGLT2. The HindIII/XhoI fragment was excised from pCMV-SGLT2, and introduced into the BamHI/XhoI site of pENTR1A (Gateway, Invitrogen) to prepare pENTR-SGLT2. Will be imported with Gateway carrier The system 箧A (Invitrogen) reverse transcription ‧ virus ‧ vector pLPCX (Clontech) as the target plastid, made SGLT2 expressed reverse transcription ‧ virus ‧ vector pLPCX-SGLT2
用在1)中所得到之反轉錄‧病毒pLPCX-SGLT2轉染表現整合素αvβ3之HEK-293細胞後，以抗生物質G418(商品名：遺傳黴素(geneticin)，Invitrogen公司製)、嘌呤黴素(Clontech公司製)處理細胞，取得具有耐性之目標載體之安定表現細胞HEK-SGLT2。安定表現細胞之培養、維持係使用含有250μg/ml G418、1μg/ml嘌呤黴素、3μM KGT-1075、10%FBS之DMEM培養基來進行。 After transfecting HEK-293 cells expressing integrin αvβ3 with the reverse transcription ‧ virus pLPCX-SGLT2 obtained in 1), anti-biomass G418 (trade name: geneticin, manufactured by Invitrogen), fungus The cells (manufactured by Clontech Co., Ltd.) were treated with cells to obtain a stable expression cell HEK-SGLT2 of a target vector having tolerance. The culture and maintenance of diazepam cells were carried out using DMEM medium containing 250 μg/ml G418, 1 μg/ml puromycin, 3 μM KGT-1075, and 10% FBS.
將HEK-SGLT2細胞以106細胞/ml之密度懸浮在含有250μg/ml G418、1μg/ml嘌呤黴素、10%FBS之DMEM培養基中，並以每孔100μl之量播種於被覆類型I膠原之96孔培養盤(Corning公司製)之各孔中。次日，將培養基更換為糖攝取緩衝液(10mM HEPES(pH7.5)、5mM Tris-HCl(pH7.5)、140mM NaCl、2mM KCl、1mM CaCl2、1mM MgCl2)，將1mM[14C]-α-甲基-D-葡哌喃糖苷(0.1m Ci)及評價化合物一起於37℃培養30分鐘後，用洗淨緩衝液(10mM HEPES(pH7.5)、5mM Tris-HCl(pH7.5)、140mM膽鹼氯化物、2mM KCl、1mM CaCl2、1mM MgCl2)洗淨3次。在96孔培養盤之各孔中以每孔100μl之量添 加液體閃爍雞尾酒混液(商品名：Supermix，Perkin Elmer公司製)，攪拌10分鐘後，藉由為液體閃爍計數器之一之Micro β(Perkin Elmer公司製)測定放射活性。以過剩量之SGLT2阻礙化合物存在下之放射活性做為背景值，將從各測定值減去該背景值之值做為糖攝取活性，從未使用試驗化合物而求得之對照糖攝取活性，及使用一定濃度之試驗化合物時之糖攝取活性，求取阻礙率(%)，調查阻礙50%糖攝取活性之試驗化合物之濃度。將其結果示於表11。 HEK-SGLT2 cells were suspended at a density of 10 6 cells/ml in DMEM medium containing 250 μg/ml G418, 1 μg/ml puromycin, 10% FBS, and seeded in coated I type collagen in an amount of 100 μl per well. In each well of a 96-well culture plate (manufactured by Corning). The next day, the medium was changed to a sugar uptake buffer (10 mM HEPES (pH 7.5), 5 mM Tris-HCl (pH 7.5), 140 mM NaCl, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 ), 1 mM [ 14 C ]-α-Methyl-D-glucopyranoside (0.1 m Ci) and the evaluation compound were incubated at 37 ° C for 30 minutes, followed by washing buffer (10 mM HEPES (pH 7.5), 5 mM Tris-HCl (pH 7). .5), washed with 140 mM choline chloride, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 ) 3 times. A liquid scintillation cocktail mixture (trade name: Supermix, manufactured by Perkin Elmer Co., Ltd.) was added in an amount of 100 μl per well in each well of a 96-well culture plate, and after stirring for 10 minutes, Microβ (Perkin) which is one of liquid scintillation counters Radioactivity was measured by Elmer. Taking the radioactivity of the excess amount of SGLT2 in the presence of the compound as a background value, the value of the background value is subtracted from each measured value as the sugar uptake activity, and the control sugar uptake activity obtained without using the test compound, and The glucose uptake activity at a certain concentration of the test compound was used to determine the inhibition rate (%), and the concentration of the test compound which inhibits the 50% sugar uptake activity was investigated. The results are shown in Table 11.
以主要阻礙SGLT2結果引起之尿糖***為指標，檢討活體中之SGLT2阻礙活性。將各受檢化合物以使投與體積成為1~10mL/kg之方式懸浮或溶解於溶劑(0.5%甲基纖維素液或丙二醇與Tween80以4：1混合而成之溶液等)中，將複數用量(以包含在0.03~10mg/kg之範圍內為較佳)經口投與至各種動物(小鼠、大鼠、犬或猴等)。對照群方面係將溶劑以同量經口投與。經時地採取尿，從尿量及葡萄糖濃度計算尿糖***量，評價各受檢化合物於活體中之SGLT2阻礙活性。 The SGLT2 inhibitory activity in the living body was reviewed by taking the urine glucose excretion caused by the SGLT2 result as an indicator. Each test compound is suspended or dissolved in a solvent (0.5% methylcellulose solution or a solution of propylene glycol and Tween 80 mixed at 4:1) so that the administration volume is 1 to 10 mL/kg, and the plural is The dosage (preferably in the range of 0.03 to 10 mg/kg is preferred) is orally administered to various animals (mouse, rat, dog or monkey, etc.). In the control group, the solvent was orally administered in the same amount. Urine was taken over time, and the amount of urinary glucose excretion was calculated from the urine volume and the glucose concentration, and the SGLT2 inhibitory activity of each test compound in the living body was evaluated.
藉由評價各受檢化合物對於糖負荷後或食後之高血糖之抑制效果，可檢測出基於阻礙SGLT1及SGLT2而抑制血糖上升之綜合表現。再者，藉由檢討於選擇性SGLT2阻礙劑(dapagliflozin等)存在下受檢化合物所產生之血糖上升抑制效果，可評價SGLT1特異性阻礙活性。就用於試驗之動物而言，以小鼠、大鼠、犬或猴為較佳。 By evaluating the inhibitory effect of each test compound on hyperglycemia after sugar load or after eating, it is possible to detect a comprehensive expression that inhibits blood glucose rise by inhibiting SGLT1 and SGLT2. Furthermore, the SGLT1 specific inhibitory activity can be evaluated by examining the effect of suppressing the increase in blood glucose produced by the test compound in the presence of a selective SGLT2 inhibitor (dapagliflozin or the like). For the animal to be tested, a mouse, a rat, a dog or a monkey is preferred.
列舉一例：將達格列淨(dapagliflozin)，以使投與體積成為1~10mL/kg之方式懸浮於溶劑(0.5%甲基纖維素液)中，並將其經口投與至已絕食一晚之C57BL/6NCrlCrlj小鼠(7~10週齡、雄性)。再者，將各受檢化合物以使投與體積成為1~10mL/kg之方式懸浮或溶 解於溶劑(0.5%甲基纖維素液或丙二醇與Tween80以4：1混合而成之溶液等)中，並經口投與複數用量(以包含在0.03~10mg/kg之範圍內為較佳)。對照群方面，係將溶劑以同量經口投與。經過一定時間後(例如30分後)，將葡萄糖以一定量(2g/10mL/kg等)經口投與。再者，於一定時間(例如30分鐘後)測定血糖值。以對照群之血糖上升的降低率做為指標，評價在小鼠中各受檢化合物之活體內SGLT1阻礙活性。 For example, dapagliflozin is suspended in a solvent (0.5% methylcellulose solution) so that the administration volume becomes 1 to 10 mL/kg, and it is orally administered to a hunger strike. Late C57BL/6NCrlCrlj mice (7-10 weeks old, male). Furthermore, each test compound is suspended or dissolved in such a manner that the administration volume becomes 1 to 10 mL/kg. Solve in a solvent (0.5% methylcellulose solution or a solution of propylene glycol and Tween80 in a 4:1 mixture), and orally and in a plurality of doses (including in the range of 0.03 to 10 mg/kg is preferred). ). In the case of the control group, the solvent was orally administered in the same amount. After a certain period of time (for example, after 30 minutes), glucose is orally administered in a certain amount (2 g/10 mL/kg, etc.). Furthermore, the blood glucose level is measured at a certain time (for example, after 30 minutes). The in vivo SGLT1 inhibitory activity of each test compound in mice was evaluated by using the decrease rate of blood glucose rise in the control group as an index.
藉由將5g之實施例之化合物，90g之乳糖，34g之玉米澱粉，20g之結晶纖維素及1g之硬脂酸鎂以摻和機(blender)混合後，用打錠機打錠，可得到錠劑。 5g of the compound of the example, 90g of lactose, 34g of corn starch, 20g of crystalline cellulose and 1g of magnesium stearate are mixed by a blender and then ingot by a tableting machine. Lozenges.
本發明之化合物，呈現優良的人類SGLT1及/或SGLT2阻礙活性，做為治療或預防1型糖尿病、2型糖尿病、妊娠糖尿病、其他原因造成之高血糖症、IGT、糖尿病關連疾病(肥胖、高脂血症、高膽固醇血症、脂質代謝異常、高血壓症、脂肪肝、代謝症候群、水腫、心臟衰竭、狹心症、心肌梗塞、動脈硬化症、高尿酸血症、痛風等)、或糖尿病合併症(網膜症、腎病、神經障礙、白內障、足壞疽、感染症、酮症等)用之醫藥組成物之有效成分上有用。 The compound of the present invention exhibits excellent human SGLT1 and/or SGLT2 inhibitory activity, and is used for treating or preventing type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia caused by other causes, IGT, diabetes related diseases (obesity, high Lipemia, hypercholesterolemia, abnormal lipid metabolism, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, atherosclerosis, hyperuricemia, gout, etc., or diabetes It is useful as an active ingredient of a pharmaceutical composition for comorbidities (retinopathy, nephropathy, neurological disorders, cataracts, foot gangrene, infectious diseases, ketosis, etc.).
序列編號1：人類SGLT1之PCR正義引子 Sequence number 1: PCR justice primer for human SGLT1
序列編號2：人類SGLT1之PCR反義引子 SEQ ID NO: 2: PCR antisense primer for human SGLT1
序列編號3：人類SGLT2之PCR正義引子 Sequence number 3: PCR justice primer for human SGLT2
序列編號4：人類SGLT2之PCR反義引子 SEQ ID NO: 4: PCR antisense primer for human SGLT2
<110> 第一三共股份有限公司 <110> First Three Co., Ltd.
<120> 具有螺環之C-醣苷衍生物 <120> C-glycoside derivatives having a spiro ring
<130> FP1317 <130> FP1317
<150> JP 2012-084469 <150> JP 2012-084469
<151> 2012-04-03 <151> 2012-04-03
<160> 4 <160> 4
<170> PatentIn版本3.5 <170> PatentIn version 3.5
<210> 1 <210> 1
<211> 34 <211> 34
<212> DNA <212> DNA
<213> 人造序列 <213> Artificial sequence
<220> <220>
<223> 人類SGLT1之PCR正義引子 <223> PCR justice primer for human SGLT1
<400> 1 <400> 1
<210> 2 <210> 2
<211> 30 <211> 30
<212> DNA <212> DNA
<213> 人造序列 <213> Artificial sequence
<220> <220>
<223> 人類SGLT1之PCR反正義引子 <223> PCR anti-righteous primer for human SGLT1
<400> 2 <400> 2
<210> 3 <210> 3
<211> 34 <211> 34
<212> DNA <212> DNA
<213> 人造序列 <213> Artificial sequence
<220> <220>
<223> 人類SGLT2之PCR正義引子 <223> PCR justice primer for human SGLT2
<400> 3 <400> 3
<210> 4 <210> 4
<211> 30 <211> 30
<212> DNA <212> DNA
<213> 人造序列 <213> Artificial sequence
<220> <220>
<223> 人類SGLT2之PCR反正義引子 <223> PCR anti-sense primer for human SGLT2
<400> 4 <400> 4
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| JP5230613B2 (en) * | 2006-05-23 | 2013-07-10 | テラコス・インコーポレイテッド | Glucose transporter inhibitor and method of use thereof |
| TWI403516B (en) * | 2006-07-27 | 2013-08-01 | Chugai Pharmaceutical Co Ltd | To replace spirocyclic alcohol derivatives, and its use as a therapeutic agent for diabetes |
| TW200817424A (en) * | 2006-08-04 | 2008-04-16 | Daiichi Sankyo Co Ltd | Benzylphenyl glucopyranoside derivatives |
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