TW202039428A - Method for producing c-aryl hydroxy glycoxide derivatives - Google Patents

Abstract

In order to provide a method for the economical and efficient industrial production of C-aryl hydroxy glycoxide derivatives, the present invention provides a method for producing a C-aryl hydroxy glycoxide derivative represented by formula (I), the method comprising: a step for reacting a compound (II), which is represented by formula (II), with an organic zinc compound in the presence of a nickel catalyst or a palladium catalyst in order to obtain a reaction product; and a step for removing R5 from the reaction product to obtain the C-aryl hydroxy glycoxide derivative.

Description

Method for producing C-aryl hydroxyglycol compound (C-Arylhydroxyglycoxide) derivative

The present invention relates to a method for producing a C-aryl hydroxyglycolate derivative, and more specifically about a method for producing a C-aryl hydroxyglycolate derivative, the C-aryl hydroxyglycolate derivative It is useful as an intermediate product of SGLT-2 inhibitors. [Reference to related applications]

The patent application in this case is based on the Japanese Patent Application No. 2018-235903 filed on December 17, 2018 and the Japanese Patent Application No. 2019-34357 filed on February 27, 2019, with the claim of priority and quoting the aforementioned All the contents disclosed in the patent application are regarded as part of the description of the case.

Currently, there are various therapeutic drugs on the market as therapeutic drugs for diabetes. They are well known as urea drugs, Glinide drugs, biguanides, tetrahydrothiazole drugs, α-glucosidase inhibitors, dipeptidyl peptidase 4 (DPP- 4) The inhibitor, glucagon-like peptide 1 (GLP-1) is a dynamic agonist. In addition, in recent years, as a new mechanism for the treatment of diabetes, sodium-sugar cotransporter-2 (hereinafter sometimes referred to as SGLT-2) inhibitors have also been developed and paid attention to.

As an example of SGLT-2 inhibitors, canagliflozin (1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl) -2-Thienylmethyl]benzene), etc. As a method of producing these compounds, there is a proposal to add 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluoro The oxygen protecting group of the phenyl)-2-thienylmethyl]benzene precursor was deprotected, and canagliflozin was synthesized (Patent Document 1). This 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene precursor is also known as C-arylhydroxyl Glycolate derivatives are attracting attention as intermediates for the production of SGLT-2 inhibitors (see Non-Patent Document 1, Non-Patent Document 2, Non-Patent Document 3, Patent Document 1, and Patent Document 2).

There have been various proposals for the production of the above-mentioned C-aryl hydroxyglycolate derivatives. For example, it is well known that the D-gluconolactone derivative can react with aryl lithium at an ultra-low temperature of -78°C to add aryl groups. Reaction method (Non-Patent Document 1, Non-Patent Document 3), Turbo Grignard test using ArMgBr･LiCl (Ar is an aryl group) for D-gluconolactone derivatives at a low temperature of -20~-10°C Drug action, a method of aryl addition reaction (Non-Patent Document 2), and further, using a magnesium-type complex obtained from lithium tri-n-magnesite (nBu ₃ MgLi) at a temperature of about -15°C Next, a method of adding an aryl group to a D-gluconolactone derivative (Patent Document 2) and the like.

Here, there are reports that the reaction of a thioester derivative with an organozinc reagent in the presence of a nickel catalyst causes coupling to obtain a ketone derivative (Non-Patent Document 4 and Non-Patent Document 5). [Prior Technical Literature] [Patent Literature]

[Patent Document 1] WO2010/043682 Publication [Patent Document 2] WO2015/012110 Publication [Non-Patent Literature]

[Non-Patent Document 1] J.Med.Chem.2008,51,1145-1149 [Non-Patent Document 2] Org. Lett. 2014, 16, 4090-4093 [Non-Patent Document 3] J.Org.Chem.1989,54, 610-612 [Non-Patent Document 4] Tetrahedron Letters 2002,43, 1039-1042 [Non-Patent Document 5] Chem.Eur.J.2018,24,8774-8778

[The problem to be solved by the invention in this case]

In the past, the methods used in the manufacture of C-aryl hydroxyglycol derivatives were all under low temperature conditions, and high-priced reagents had to be used for implementation. The equipment cost or operating cost would become very expensive, and finally it was difficult to measure at a cheap price. Produce original medicine.

Therefore, the purpose of the present invention is to seek a method for industrially producing C-aryl hydroxyglycolate derivatives at a low price and efficiently. [Means to solve the problem]

The inventors of the present case found that, if the cross-coupling reaction is carried out with specific raw materials in the presence of nickel catalyst or palladium catalyst, and the cyclization reaction is further carried out, the C-aryl hydroxyl group can be produced inexpensively and efficiently in industry. The glycolate derivative (hereinafter also referred to as the compound (I) represented by the following formula (I)) has further completed the present invention.

[式中， R¹ 及R² 各自獨立表示羥基保護基， R³ 及R⁴ 各自獨立表示羥基保護基或氫原子，Ar表示含有芳香族烴環基或芳香族雜環基作為與式中之氧雜環鍵結之官能基之有機基，前述芳香族烴環基及前述芳香族雜環基各自亦可具有1個以上之取代基]

[式中， R¹ ~R⁴ 與前述同義， R⁵ 表示羥基保護基(惟，去除與R¹ 表示之羥基保護基相同之羥基保護基及與R² 表示之羥基保護基相同之羥基保護基)， Q表示包含脂肪族烴基、芳香族烴環基、脂肪族雜環基或芳香族雜環基作為與式中之硫原子鍵結之官能基之有機基，前述脂肪族烴基、前述芳香族烴環基、前述脂肪族雜環基及前述芳香族雜環基亦可各自具有1個以上之取代基]

[式中，Ar與前述同義，X表示鹵原子]

[式中，Ar與前述同義]

[式中，R¹ ~R⁵ 及Ar與前述同義]。 [2] 如[1]之方法，其中，前述化合物(II)與前述至少1種有機鋅化合物之反應在0~60℃下進行。 [3] 如[1]或[2]之方法，其中，前述擔持觸媒具有選自活性碳、氧化鋁、硫酸鋇、碳酸鈣、羥磷石灰及水滑石所成群中至少1種擔體，與擔持於前述擔體上之鈀觸媒。 [4] 如[1]~[3]中任一項之方法，其中，前述至少1種有機鋅化合物包含前述化合物(III-I)，前述化合物(III-I)為下述式表示之史蘭克平衡狀態，

[式中，Ar及X與前述同義]。 [5] 如[1]~[4]中任一項之方法，其中，R³ 及R⁴ 表示羥基保護基。 [6] 如[1]~[5]中任一項之方法，其中，R⁵ 表示之羥基保護基與R¹ ~R⁴ 表示之羥基保護基相異。 [7] 如[1]~[6]中任一項之方法，其中，R¹ ~R⁵ 表示之羥基保護基各自獨立選自酯型保護基、芳基烷基型保護基、烷基型保護基、芳基烷基氧基烷基型保護基、烷基氧基烷基型保護基、甲矽烷型保護基及氧基羰基型保護基所成群。 [8] 如[1]~[7]中任一項之方法，其中，Q表示之有機基包含烷基、烯基、炔基或芳基作為與式中之硫原子鍵結之官能基，前述烷基、前述烯基、前述炔基及前述芳基各自亦可具有1個以上之取代基。 [9] 如[1]~[8]中任一項之方法，其中，Q表示之有機基中包含之前述脂肪族烴基、前述芳香族烴環基、前述脂肪族雜環基或前述芳香族雜環基所亦可具有之前述1個以上之取代基各自獨立選自鹵原子、亦可經保護之羥基、亦可經保護之巰基、亦可經保護之胺基、亦可經保護之甲醯基、亦可經保護之羧基及亦可經保護之碸基所成群。 [10] 如[1]~[9]中任一項之方法，其中，Ar表示之有機基為具有碳數6~14之芳香族烴環基或碳數3~12之芳香族雜環基作為與式中之氧雜環鍵結之官能基之有機基，前述碳數6~14之芳香族烴環基及碳數3~12之芳香族雜環基各自亦可具有1個以上之取代基。 [11] 如[1]~[10]中任一項之方法，其中，Ar表示之有機基為下述式(V)表示，

[式中， R^a 各自獨立表示選自鹵原子、烷基、烯基、炔基、芳基、芳基烷基、芳基烯基、芳基炔基、烷基氧基、烯基氧基、炔基氧基、芳基氧基、芳基烷基氧基、芳基烯基氧基及芳基炔基氧基所成群之官能基，前述烷基、前述烯基、前述炔基、前述芳基、前述芳基烷基、前述芳基烯基、前述芳基炔基、前述烷基氧基、前述烯基氧基、前述炔基氧基、前述芳基氧基、前述芳基烷基氧基、前述芳基烯基氧基及前述芳基炔基氧基各自亦可具有1個以上之取代基， n為0~4之整數， Ar’表示芳香族烴環基、脂肪族雜環基或芳香族雜環基，前述芳香族烴環基、脂肪族雜環基及前述芳香族雜環基各自亦可具有1個以上之取代基]。 [12] 如[11]之方法，其中，R^a 表示之官能基各自獨立選自烷基及鹵原子，前述烷基亦可具有1個以上之取代基。 [13] 如[11]或[12]之方法，其中，Ar表示之有機基為下述式(Va)表示，

[式中， R^a 與前述同義， Ar’表示選自下述式(Va-I)、(Va-II)及(Va-III)所成群之官能基，

[式中，R^b 各自獨立表示選自脂肪族烴基、芳香族烴環基、脂肪族雜環基及芳香族雜環基所成群之官能基，前述脂肪族烴基、前述芳香族烴環基、前述脂肪族雜環基及前述芳香族雜環各自亦可具有1個以上之取代基，p表示0~5之整數]]。 [14] 如[13]之方法，其中，R^b 表示之官能基各自獨立選自碳數1~20之烷基、碳數2~20之烯基、碳數2~20之炔基、碳數6~14之芳香族烴環基、碳數2~12之脂肪族雜環基及碳數3~12之芳香族雜環基所成之群，前述烷基、前述烯基、前述炔基、前述芳香族烴環基、前述脂肪族雜環基及前述芳香族雜環基各自亦可具有1個以上之取代基。 [15] 如[1]~[14]中任一項之方法，其中，Ar表示之有機基中包含之前述芳香族烴環基或前述芳香族雜環基所亦可具有之前述1個以上之取代基各自獨立選自鹵原子、亦可經保護之羥基、亦可經保護之巰基、亦可經保護之胺基、亦可經保護之甲醯基、亦可經保護之羧基、亦可經保護之碸基、烷基、烯基及炔基所成之群。 [16] 如[1]~[15]中任一項之方法，其中，進一步包含使下述式(VI)表示之化合物(VI)與下述式(VII)表示之化合物(VII)反應，得到下述式(VIII)表示之化合物(VIII)之步驟，及將前述化合物(VIII)中之羥基以R⁵ 保護，得到前述化合物(II)之步驟，

[式中，R¹ ~R⁴ 與前述同義]

[式中，Q與前述同義]

[式中，R¹ ~R⁴ 與前述同義]。 [17] 如[16]之方法，其中，前述化合物(VI)與前述化合物(VII)之反應在-30~40℃下進行。 [18] 如[16]或[17]之方法，其中，前述化合物(VI)與前述化合物(VII)之反應在下述式(IX)表示之化合物(IX)之存在下進行，

[式中， R^c 及R^d 各自獨立表示選自鹵原子、脂肪族烴基、芳香族烴環基、脂肪族雜環基及芳香族雜環基所成群之官能基，前述脂肪族烴基、前述芳香族烴環基、前述脂肪族雜環基及前述芳香族雜環基各自亦可具有1個以上之取代基， q表示0~3之整數， r表示0~3之整數，惟，q+r=3]。 [19] 如[18]之方法，其中，R^c 及R^d 表示之官能基各自獨立選自烷基、芳基及芳基烷基所成群，前述烷基、前述芳基及前述芳基烷基各自亦可具有1個以上之取代基。 [20]一種用於製造下述式(XI)表示之化合物(XI)之試藥，其係包含下述式(II)表示之化合物(II)，

[式中，R¹ ~R⁵ 及Q與前述同義]

[式中，Ar與前述同義，R¹ ’~R⁴ ’各自獨立表示氫原子或羥基保護基]。 [21]一種下述式(II)表示之化合物(II)之使用，其係作為製造下述式化合物(XI)表示之化合物(XI)之中間產物，

[式中，Ar及R¹ ’~R⁴ ’與前述同義]

[式中，R¹ ~R⁵ 及Q與前述同義]。 [發明效果]The invention of this case can provide the following inventions. [1] A method for producing compound (I) represented by the following formula (I), which comprises one or more transition metal catalysts selected from nickel catalysts and palladium catalysts, or one or more of the foregoing In the presence of a transition metal catalyst and a supporting catalyst supporting one or more of the aforementioned transition metal catalysts, the compound (II) represented by the following formula (II) is selected from the following formula (III) -I) The compound (III-I) represented by the following formula (III-II) is reacted with at least one organozinc compound in the group of the compound (III-II) represented by the following formula (III-II) to obtain the compound represented by the following formula (IV) The step (IV), and the step of removing the hydroxyl protecting group represented by R ⁵ from the aforementioned compound (IV) to obtain the aforementioned compound (I),

[In the formula, R ¹ and R ² each independently represent a hydroxy protecting group, R ³ and R ⁴ each independently represent a hydroxy protecting group or a hydrogen atom, and Ar represents an aromatic hydrocarbon ring group or an aromatic heterocyclic group as the The organic group of the functional group to which the oxygen heterocycle is bonded, the aforementioned aromatic hydrocarbon ring group and the aforementioned aromatic heterocyclic group may each have one or more substituents]

[In the formula, R ¹ to R ^{4 have the} same meaning as above, and R ⁵ represents a hydroxyl protecting group (except that the same hydroxyl protecting group as R ^{1 and} the same hydroxyl protecting group as R ^{2 are} removed ), Q represents an organic group containing an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group or an aromatic heterocyclic group as a functional group bonded to the sulfur atom in the formula, the aforementioned aliphatic hydrocarbon group, the aforementioned aromatic The hydrocarbon ring group, the aforementioned aliphatic heterocyclic group and the aforementioned aromatic heterocyclic group may each have one or more substituents]

[In the formula, Ar has the same meaning as above, and X represents a halogen atom]

[In the formula, Ar is synonymous with the aforementioned]

[In the formula, R ¹ to R ⁵ and Ar have the same meaning as above]. [2] The method of [1], wherein the reaction between the aforementioned compound (II) and the aforementioned at least one organozinc compound is carried out at 0-60°C. [3] The method according to [1] or [2], wherein the supporting catalyst has at least one selected from the group consisting of activated carbon, alumina, barium sulfate, calcium carbonate, hydroxyphosphate lime, and hydrotalcite Body, and the palladium catalyst supported on the aforementioned support. [4] The method according to any one of [1] to [3], wherein the aforementioned at least one organozinc compound comprises the aforementioned compound (III-I), and the aforementioned compound (III-I) is represented by the following formula Rank balance state,

[In the formula, Ar and X are synonymous with the foregoing]. [5] The method according to any one of [1] to [4], wherein R ³ and R ⁴ represent hydroxyl protecting groups. [6] The method according to any one of [1] to [5], wherein the hydroxy protecting group represented by R ⁵ is different from the hydroxy protecting group represented by R ¹ to R ⁴ . [7] The method according to any one of [1] to [6], wherein the hydroxy protecting groups represented by R ¹ to R ⁵ are each independently selected from ester type protecting groups, aryl alkyl type protecting groups, and alkyl type Protective groups, arylalkyloxyalkyl-type protective groups, alkyloxyalkyl-type protective groups, silyl-type protective groups, and oxycarbonyl-type protective groups. [8] The method according to any one of [1] to [7], wherein the organic group represented by Q includes an alkyl group, an alkenyl group, an alkynyl group or an aryl group as the functional group bonded to the sulfur atom in the formula, The alkyl group, the alkenyl group, the alkynyl group, and the aryl group may each have one or more substituents. [9] The method according to any one of [1] to [8], wherein the aliphatic hydrocarbon group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group or the aromatic group contained in the organic group represented by Q The aforementioned one or more substituents that the heterocyclic group may have are each independently selected from a halogen atom, a protected hydroxyl group, a protected mercapto group, a protected amino group, and a protected methyl group. An acyl group, a protected carboxyl group, and a protected sulfonyl group are grouped. [10] The method according to any one of [1] to [9], wherein the organic group represented by Ar is an aromatic hydrocarbon ring group with 6 to 14 carbons or an aromatic heterocyclic group with 3 to 12 carbons As the organic group of the functional group bonded to the oxygen heterocyclic ring in the formula, the aforementioned aromatic hydrocarbon ring group with 6 to 14 carbon atoms and the aromatic heterocyclic group with 3 to 12 carbon atoms may each have more than one substitution. base. [11] The method as in any one of [1] to [10], wherein the organic group represented by Ar is represented by the following formula (V),

[In the formula, R ^a each independently represents selected from halogen atoms, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, arylalkyl groups, arylalkenyl groups, arylalkynyl groups, alkyloxy groups, and alkenyloxy groups , Alkynyloxy, aryloxy, arylalkyloxy, arylalkenyloxy and arylalkynyloxy group of functional groups, the aforementioned alkyl group, the aforementioned alkenyl group, the aforementioned alkynyl group, The aforementioned aryl group, the aforementioned arylalkyl group, the aforementioned arylalkenyl group, the aforementioned arylalkynyl group, the aforementioned alkyloxy group, the aforementioned alkenyloxy group, the aforementioned alkynyloxy group, the aforementioned aryloxy group, the aforementioned arylalkyl group Each of the oxy group, the aforementioned arylalkenyloxy group, and the aforementioned arylalkynyloxy group may have one or more substituents, n is an integer from 0 to 4, and Ar' represents an aromatic hydrocarbon ring group, an aliphatic hetero The cyclic group or the aromatic heterocyclic group, the aforementioned aromatic hydrocarbon ring group, the aliphatic heterocyclic group, and the aforementioned aromatic heterocyclic group may each have one or more substituents]. [12] The method of [11], wherein the functional groups represented by ^Ra are each independently selected from an alkyl group and a halogen atom, and the aforementioned alkyl group may have one or more substituents. [13] The method of [11] or [12], wherein the organic group represented by Ar is represented by the following formula (Va),

[In the formula, R ^a has the same meaning as the foregoing, and Ar' represents a functional group selected from the group consisting of the following formulas (Va-I), (Va-II) and (Va-III),

[In the formula, R ^b each independently represents a functional group selected from the group consisting of aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups and aromatic heterocyclic groups, the aforementioned aliphatic hydrocarbon groups and the aforementioned aromatic hydrocarbon ring groups , The aliphatic heterocyclic group and the aromatic heterocyclic ring may each have one or more substituents, and p represents an integer of 0 to 5]]. [14] As in the method of [13], wherein the functional groups represented by R ^b are independently selected from alkyl groups with 1 to 20 carbons, alkenyl groups with 2 to 20 carbons, alkynyl groups with 2 to 20 carbons, and A group of 6 to 14 aromatic hydrocarbon ring groups, aliphatic heterocyclic groups with 2 to 12 carbons, and aromatic heterocyclic groups with 3 to 12 carbons, the aforementioned alkyl group, the aforementioned alkenyl group, and the aforementioned alkynyl group , The aromatic hydrocarbon ring group, the aliphatic heterocyclic group, and the aromatic heterocyclic group may each have one or more substituents. [15] The method according to any one of [1] to [14], wherein the aforementioned aromatic hydrocarbon ring group or the aforementioned aromatic heterocyclic group contained in the organic group represented by Ar may have one or more of the aforementioned The substituents are each independently selected from a halogen atom, a protected hydroxyl group, a protected mercapto group, a protected amino group, a protected methyl group, a protected carboxyl group, and Groups of protected sulfonyl, alkyl, alkenyl and alkynyl groups. [16] The method of any one of [1] to [15], which further comprises reacting the compound (VI) represented by the following formula (VI) with the compound (VII) represented by the following formula (VII), The step of obtaining the compound (VIII) represented by the following formula (VIII), and the step of protecting the hydroxyl group in the aforementioned compound (VIII) with R ^{5 to} obtain the aforementioned compound (II),

[In the formula, R ¹ ~R ^{4 have the} same meaning as above]

[In the formula, Q is synonymous with the aforementioned]

[In the formula, R ¹ to R ^{4 have the} same meaning as above]. [17] The method of [16], wherein the reaction of the aforementioned compound (VI) and the aforementioned compound (VII) is carried out at -30-40°C. [18] The method of [16] or [17], wherein the reaction of the aforementioned compound (VI) and the aforementioned compound (VII) is carried out in the presence of the compound (IX) represented by the following formula (IX),

[In the formula, R ^c and ^Rd each independently represent a functional group selected from the group of halogen atoms, aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups and aromatic heterocyclic groups, the aforementioned aliphatic hydrocarbon groups, The aforementioned aromatic hydrocarbon ring group, the aforementioned aliphatic heterocyclic group, and the aforementioned aromatic heterocyclic group may each have one or more substituents, q represents an integer of 0 to 3, r represents an integer of 0 to 3, but q +r=3]. [19] The method of [18], wherein the functional groups represented by R ^c and R ^d are each independently selected from the group consisting of alkyl, aryl and arylalkyl, the aforementioned alkyl group, the aforementioned aryl group and the aforementioned aryl group Each alkyl group may have one or more substituents. [20] A reagent for the production of compound (XI) represented by the following formula (XI), which contains the compound (II) represented by the following formula (II),

[In the formula, R ¹ ~R ⁵ and Q have the same meaning as above]

[In the formula, Ar has the same meaning as described above, and R ¹ ′ to R ⁴ ′ each independently represent a hydrogen atom or a hydroxyl protecting group]. [21] The use of the compound (II) represented by the following formula (II) as an intermediate product for producing the compound (XI) represented by the following formula (XI),

[In the formula, Ar and R ¹ '~R ⁴ 'have the same meaning as above]

[In the formula, R ¹ to R ⁵ and Q have the same meaning as above]. [Invention Effect]

According to the present invention, compound (I) can be produced industrially inexpensively and efficiently. With the present invention, the equipment cost or operating cost can be reduced significantly, and it is advantageous in industrial production.

[The form of implementing the invention]

Hereinafter, the present invention will be described. In addition, in the embodiments described in this specification, when two or more embodiments can be combined, the present invention also includes the combination.

<Definition> The following describes the terms and performance used in this manual. The following definitions are applicable to the entire specification except for special provisions. For example, the definition of "alkyl" is applicable to "alkyl" or functional groups containing "alkyl" (such as alkylaryl, arylalkyl, etc.).

"Organic group" means a functional group containing more than one carbon atom. The organic group can contain one kind or two or more kinds of heteroatoms. "Heteroatom" means atoms other than hydrogen atoms and carbon atoms. Examples of heteroatoms include nitrogen atoms, oxygen atoms, sulfur atoms, halogen atoms, and silicon atoms. "Halogen atom" means fluorine atom, chlorine atom, bromine atom or iodine atom. The bonding of the organic group is preferably formed by the bonding of carbon atoms contained in the organic group.

In one embodiment, the organic group is an aliphatic hydrocarbon group which may have one or more substituents, or an aliphatic hydrocarbon group which may have one or more substituents. In this embodiment, the bonding of the organic group is preferably formed by the bonding of an aliphatic hydrocarbon group.

In another embodiment, the organic group is an aromatic hydrocarbon ring group which may have one or more substituents, or an aromatic hydrocarbon ring group which may also have one or more substituents. In this embodiment, the bonding of the organic group is preferably formed by the bonding of an aromatic hydrocarbon ring group.

In another embodiment, the organic group is an aliphatic heterocyclic group which may have one or more substituents, or an aliphatic heterocyclic group which may have one or more substituents. In this embodiment, the bonding of the organic group is preferably formed by the bonding of an aliphatic heterocyclic group.

In another embodiment, the organic group is an aromatic heterocyclic group which may have one or more substituents, or an aromatic heterocyclic group which may have one or more substituents. In this embodiment, the bonding of the organic group is preferably formed by the bonding of an aromatic heterocyclic group.

In another embodiment, the organic group includes a combination of two or more kinds selected from aliphatic hydrocarbon groups that may also have one or more substituents, aromatic hydrocarbon ring groups that may also have one or more substituents, or one The functional group formed by the aliphatic heterocyclic group of the above substituents and the aromatic heterocyclic group which may have one or more substituents. In this embodiment, the bonding of the organic group is preferably formed by a bonding of an aliphatic hydrocarbon group, aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group.

"Aliphatic hydrocarbon group" means a functional group (hydrocarbon group not having aromaticity) generated by removing a hydrogen atom from an aliphatic hydrocarbon. "Aliphatic hydrocarbon group" can mean a monovalent or divalent functional group according to the article. Hereinafter, a monovalent aliphatic hydrocarbon group may be expressed as "-aliphatic hydrocarbon group", and a divalent aliphatic hydrocarbon group may be expressed as "-aliphatic hydrocarbon group-". The aliphatic hydrocarbon group may be any of chain, cyclic, and combinations thereof. The chain shape may be linear or branched. The aliphatic hydrocarbon group is preferably linear or branched. The aliphatic hydrocarbon group may also be saturated or unsaturated. The unsaturated bond may also be a carbon-carbon double bond or a carbon-carbon triple bond.

As a monovalent aliphatic hydrocarbon group, an alkyl group, an alkenyl group, an alkynyl group, etc. are mentioned, for example. As a divalent aliphatic hydrocarbon group, an alkylene group, an alkenylene group, an alkynylene group, etc. are mentioned, for example.

"Alkyl" means a monovalent functional group generated by removing one hydrogen atom from an alkane. The alkyl group may be any of chain, cyclic, and combinations thereof. Also, cyclic alkyl has the same meaning as "cycloalkyl". The chain shape may be linear or branched. The alkyl group is preferably linear or branched. The carbon number of the linear alkyl group is usually 1-20, preferably 1-10, more preferably 1-8, still more preferably 1-6, still more preferably 1~ 4 pieces, more preferably 1 to 3 pieces. The carbon number of the branched alkyl group is usually 3-20, preferably 3-10, more preferably 3-8, still more preferably 3-6, and still more preferably 3~ 4. The carbon number of the cyclic alkyl group is usually 3-20, preferably 3-10, more preferably 3-8, and still more preferably 3-6. The carbon number of the alkyl group having a linear or branched chain part and a cyclic part is usually 4-20, preferably 4-10, more preferably 4-8, and still more preferably 4~ 6 pcs.

Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-Dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl and other linear or branched alkyl groups; cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and other cyclic alkyl groups; cyclopentyl methyl, cyclopentyl ethyl, cyclopentyl propyl, cyclohexyl methyl, cyclohexyl ethyl Such as alkyl groups with linear or branched parts and cyclic parts.

"Alkenyl" means a monovalent functional group generated by removing one hydrogen atom from an olefin. The alkenyl group has at least one carbon-carbon double bond. The alkenyl group may also be any of chain, cyclic, and combinations thereof. In addition, cyclic alkenyl has the same meaning as "cycloalkenyl". The chain shape may also be linear or branched. The alkenyl group is preferably linear or branched. The carbon number of the linear alkenyl group is usually 2-20, preferably 2-10, more preferably 2-8, still more preferably 2-6, still more preferably 2~ 4. The carbon number of the branched alkenyl group is usually 3-20, preferably 3-10, more preferably 3-8, still more preferably 3-6, still more preferably 3~ 4. The carbon number of the cyclic alkenyl group is usually 3-20, preferably 3-10, more preferably 3-8, and still more preferably 3-6. The carbon number of the alkenyl group having a linear or branched chain part and a cyclic part is usually 4-20, preferably 4-10, more preferably 4-8, and still more preferably 4~ 6 pcs. The number of double bonds in the alkenyl group is usually 1 to 9, preferably 1 to 7, more preferably 1 to 4, and still more preferably 1 to 3.

Examples of alkenyl groups include vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, and 3-hexenyl. , 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl and other linear or branched alkenyl groups; ring Cyclic alkenyl groups such as propenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl; cyclopentenyl methyl, cyclopentenyl ethyl, cyclopentenyl Alkenyl groups such as allylpropyl, cyclohexenylmethyl, cyclohexenylethyl, etc., have linear or branched parts and cyclic parts.

"Alkynyl" means a monovalent functional group generated by removing one hydrogen atom from an alkyne. The alkynyl group has at least one carbon-carbon triple bond. The alkynyl group may be any of chain, cyclic, and combinations thereof. In addition, cyclic alkynyl has the same meaning as "cycloalkynyl". The chain shape may also be linear or branched. The alkynyl group is preferably linear or branched. The carbon number of the linear alkynyl group is usually 2-20, preferably 2-10, more preferably 2-8, still more preferably 2-6, and still more preferably 2~ 4. The carbon number of the branched alkynyl group is usually 4-20, preferably 4-10, more preferably 4-8, and still more preferably 4-6. The carbon number of the cyclic alkynyl group is usually 4-20, preferably 4-10, more preferably 4-8, and still more preferably 4-6. The carbon number of the alkynyl group having a linear or branched chain part and a cyclic part is usually 5-20, preferably 5-10, more preferably 5-8, still more preferably 5~ 6 pcs. The number of triple bonds in the alkynyl group is usually 1 to 9, preferably 1 to 7, more preferably 1 to 4, and still more preferably 1 to 3.

Examples of alkynyl groups include 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2 -Heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-dodecynyl and other linear or branched alkynyl groups; cyclobutanyl Cyclic alkynyl groups such as alkynyl, cyclopentynyl, cycloheptynyl, and cyclooctynyl; cyclopentynyl methyl, cyclopentynyl ethyl, cyclopentynyl propyl, cyclopentynyl Alkynyl groups such as methyl, cyclopentynylethyl, etc., which have a linear or branched chain part and a cyclic part.

"Alkylene group" means a divalent functional group generated by removing one hydrogen atom from an alkyl group. The explanation about the alkyl group is the same as above.

The "alkenylene group" means a divalent functional group generated by removing one hydrogen atom from an alkenyl group. The description of the alkenyl group is the same as above.

The "alkynylene group" means a divalent functional group generated by removing one hydrogen atom from an alkynyl group. The description of the alkynyl group is the same as above.

"Aromatic hydrocarbon ring group" means a functional group generated by removing a hydrogen atom from an aromatic hydrocarbon ring. "Aromatic hydrocarbon ring group" can mean a monovalent or divalent functional group according to the article. Hereinafter, the monovalent aromatic hydrocarbon ring group may be expressed as "-aromatic hydrocarbon ring group", and the divalent aromatic hydrocarbon ring group may be expressed as "-aromatic hydrocarbon ring group-". A monovalent aromatic hydrocarbon ring group has the same meaning as an "aryl group", and a divalent aromatic hydrocarbon ring group has the same meaning as an "aryl group".

The aromatic hydrocarbon ring group includes, for example, a monocyclic or polycyclic (for example, bicyclic or tricyclic) aromatic hydrocarbon ring group. The aromatic hydrocarbon ring group is usually 1 to 4 ring types, preferably 1 to 3 ring types, and more preferably 1 or 2 ring types. The number of ring constituent carbon atoms in the aromatic hydrocarbon ring group is usually 6-18, preferably 6-14, and more preferably 6-10.

Examples of the monocyclic aromatic hydrocarbon ring group include phenyl.

Aromatic hydrocarbon ring groups also include condensed polycyclic aromatic hydrocarbon ring groups and partially saturated condensed polycyclic aromatic hydrocarbon ring groups. The partially saturated condensed polycyclic aromatic hydrocarbon ring group is a part of the hydrogenated condensed polycyclic aromatic hydrocarbon ring group constituting the bond of the ring. Examples of condensed polycyclic aromatic hydrocarbon ring groups include, for example, naphthyl, anthracenyl, phenanthryl, fused tetraphenyl, pyrenyl and other 2- to 4-cyclic aromatic hydrocarbon ring groups, as well as stilbene and indene. Base, acenaphthylene group, etc. Examples of the partially saturated condensed polycyclic aromatic hydrocarbon ring group include dihydronaphthyl, dihydroindenyl, and dihydroacenaphthyl groups.

The divalent aromatic hydrocarbon ring group is a divalent functional group generated by removing one hydrogen atom from a monovalent aromatic hydrocarbon ring group. The description of the monovalent aromatic hydrocarbon ring group is the same as above. Examples of the divalent aromatic hydrocarbon ring group include 1,3-phenylene and 1,4-phenylene.

"Aliphatic heterocyclic group" refers to a monocyclic or polycyclic ring containing one or more heteroatoms independently selected from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms, in addition to carbon atoms, as ring constituent atoms. The aliphatic heterocyclic ring (non-aromatic heterocyclic ring) of the formula (for example, 2-ring or 3-ring) is a functional group generated by removing a hydrogen atom. "Aliphatic heterocyclic group" can mean a monovalent or divalent functional group according to the article. Hereinafter, the monovalent aliphatic heterocyclic group may be expressed as "-aliphatic heterocyclic group", and the divalent aliphatic heterocyclic group may be expressed as "-aliphatic heterocyclic group-". In addition, in the functional group containing "aliphatic heterocyclic ring" (for example, aliphatic heterocyclic thio group, aliphatic heterocyclic oxy group, etc.), "aliphatic heterocyclic ring" means an aliphatic heterocyclic group.

The number of heteroatoms contained in the aliphatic heterocyclic group is usually 1 to 4, preferably 1 to 3, and more preferably 1 or 2. The number of members of the aliphatic heterocyclic group is usually 3-16 members, preferably 4-10 members, more preferably 5-8 members, still more preferably 5-7 members, still more preferably 5 or 6 member. The aliphatic heterocyclic group is, for example, monocyclic, bicyclic, or tricyclic, preferably monocyclic or bicyclic. The number of ring constituent carbon atoms in the aliphatic heterocyclic group can be appropriately selected according to the number of heteroatoms and the number of members of the aliphatic heterocyclic group. The number of carbon atoms constituting the ring in the aliphatic heterocyclic group is usually 2-12, preferably 2-8, and more preferably 2-5.

The monocyclic aliphatic heterocyclic group is, for example, a monocyclic saturated aliphatic heterocyclic group. The monocyclic saturated aliphatic heterocyclic group is a monocyclic aliphatic heterocyclic group formed by only a saturated bond structure. In one embodiment, the monocyclic saturated aliphatic heterocyclic group contains 1 to 2 oxygen atoms. In another embodiment, the monocyclic saturated aliphatic heterocyclic group contains 1 to 2 sulfur atoms. In another embodiment, the monocyclic saturated aliphatic heterocyclic group contains 1 to 2 oxygen atoms and 1 to 2 sulfur atoms. In another embodiment, the monocyclic saturated aliphatic heterocyclic group contains 1 to 4 nitrogen atoms. In another embodiment, the monocyclic saturated aliphatic heterocyclic group contains 1 to 3 nitrogen atoms, 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms. In a monocyclic saturated aliphatic heterocyclic group, the two carbon atoms constituting the ring can also be alkylated and crosslinked. In a monocyclic saturated aliphatic heterocyclic group, among the carbon atoms constituting the ring, two adjacent carbon atoms may also form a double bond. In the monocyclic saturated aliphatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may also be substituted by pendant oxy groups. The number of pendant oxy groups that the monocyclic saturated aliphatic heterocyclic group can have is preferably 1 or 2. When the heteroatom contained in the monocyclic saturated aliphatic heterocyclic group is a sulfur atom, the monocyclic saturated aliphatic heterocyclic group may also be a dioxide.

唑啉基、

唑啶基、吡唑基、吡唑啶基、噻唑啉基、四氫噻唑基、四氫異噻唑基、四氫噁唑基、四氫異噁唑基、哌啶基、哌

基、四氫啶基、二氫啶基、二氫硫哌喃基、四氫嘧啶基、四氫嗒

基、二氫哌喃基、四氫哌喃基、四氫硫哌喃基、嗎咻基、硫基嗎咻基(環上之硫原子亦可經氧化)、氮

基、二氮

基、氮呯基、氧雜環庚烷基、氧雜環辛烷基、二氧雜環辛烷基等之3~8員之單環式之脂肪族雜環基。Examples of monocyclic aliphatic heterocyclic groups include, for example, aziridinyl, oxiranyl, thiocyclopropyl, tetrahydroazepine, propylene oxide, thiocyclobutanyl, and tetrahydrothiophene. Group, tetrahydropyranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolinyl,

Oxazoline,

Azolidine, pyrazolyl, pyrazolidinyl, thiazolinyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piper

Group, tetrahydropyrimidinyl, dihydroimidinyl, dihydrothiopiperanyl, tetrahydropyrimidinyl, tetrahydropyridine

Group, dihydropiperanyl, tetrahydropiperanyl, tetrahydrothiopiperanyl, morphoyl, thiomorphoyl (the sulfur atom on the ring can also be oxidized), nitrogen

Radical, diazonium

3- to 8-membered monocyclic aliphatic heterocyclic groups such as nitro, azepanyl, oxepanyl, oxetanyl, dioxetanyl, etc.

The monocyclic aliphatic heterocyclic group also includes a partially saturated monocyclic aromatic heterocyclic group. The partially saturated monocyclic aromatic heterocyclic group is a monocyclic aromatic heterocyclic group in which a part of the bond constituting the ring is hydrogenated. Examples of partially saturated monocyclic aromatic heterocyclic groups include 4,5-dihydro-1H-imidazolyl, 1,2,3,6-tetrahydropyridyl, 4H-1,3-oxa Azinone group, 5,6-dihydro-4H-1,3-oxazinone group, etc. In a partially saturated monocyclic aromatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may also be substituted by pendant oxy groups. The number of pendant oxy groups that the partially saturated monocyclic aromatic heterocyclic group can have is preferably 1 or 2.

The polycyclic aliphatic heterocyclic group is, for example, a condensed polycyclic aliphatic heterocyclic group. The condensed polycyclic aliphatic heterocyclic group is, for example, a condensed polycyclic saturated aliphatic heterocyclic ring. The condensed polycyclic saturated aliphatic heterocyclic ring is a condensed polycyclic aliphatic heterocyclic group in which the ring is constituted only by a saturated bond. In one embodiment, the condensed polycyclic saturated aliphatic heterocyclic group contains 1 to 3 oxygen atoms. In another embodiment, the condensed polycyclic saturated aliphatic heterocyclic group contains 1 to 3 sulfur atoms. In another embodiment, the condensed polycyclic saturated aliphatic heterocyclic group contains 1 to 3 oxygen atoms and 1 to 3 sulfur atoms. In another embodiment, the condensed polycyclic saturated aliphatic heterocyclic group contains 1 to 5 nitrogen atoms. In another embodiment, the condensed polycyclic saturated aliphatic heterocyclic group contains 1 to 4 nitrogen atoms, 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms. In the condensed polycyclic saturated aliphatic heterocyclic group, the 2 carbon atoms constituting the ring can also be alkylated and crosslinked. In the condensed polycyclic saturated aliphatic heterocyclic group, among the carbon atoms constituting the ring, two adjacent carbon atoms may also form a double bond. In the condensed polycyclic saturated aliphatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may also be substituted by pendant oxy groups. The number of pendant oxy groups that the condensed polycyclic aliphatic heterocyclic group can have is preferably 1, 2, or 3. When the heteroatom contained in the condensed polycyclic saturated aliphatic heterocyclic group is a sulfur atom, the condensed polycyclic saturated aliphatic heterocyclic group may also be a dioxide.

As a condensed polycyclic aliphatic heterocyclic group, for example, octahydro-1H-isoindolinyl, decahydroquinolinyl, decahydroisoquinolinyl, hexahydro-2H-[1,4] two Oxinyl [2,3-c]pyrrolyl, 3-azabicyclo[3.1.0]hexa-3-yl, etc.

The aliphatic heterocyclic group also includes a spiral cyclic heterocyclic group. The helical cyclic heterocyclic group is a heterocyclic group formed by two rings with a helical carbon atom. As a combination of two rings, there are, for example, a combination of a monocyclic aliphatic heterocyclic group and a monocyclic aliphatic hydrocarbon ring group (such as cycloalkyl, cycloalkenyl, etc.), and a monocyclic aliphatic heterocyclic group Combination of cyclic group and monocyclic aliphatic heterocyclic group, etc. In a spiral ring heterocyclic group, two adjacent carbon atoms of the carbon atoms constituting the ring may also form a double bond. In the spiral ring heterocyclic group, two hydrogen atoms bonded to the same carbon atom may also be substituted by pendant oxy groups. The number of pendant oxy groups that the spirocyclic heterocyclic group can have is preferably 1, 2, or 3. When the hetero atom contained in the spiral ring heterocyclic group is a sulfur atom, the spiral ring heterocyclic group may also be a dioxide.

Examples of helical ring heterocyclic groups include 2-oxa-6-azaspiro[3.3]heptyl, 1-oxa-6-azaspiro[3.3]heptyl, 6-oxa- 1-azaspiral[3.3]heptanyl, 1-oxo-2,8-diazaspiral[4.5]decyl, 1,4-dioxa-8-azaspiral[4.5]decane Base, 2-azaspiral[3.3]heptyl, 7-oxa-2-azaspiral[3.5]nonyl, 5,8-oxa-2-azaspiral[3.4]octyl, 1,4 -Dioxa-8-azaspiral [4.5] decyl, 1-oxaspiral [4.5] decyl, etc.

"Aromatic heterocyclic group" refers to a ring constituent atom, in addition to carbon atoms, by including one or more heteroatoms independently selected from the group consisting of oxygen atoms, sulfur atoms, and nitrogen atoms. The cyclic aromatic heterocyclic ring removes the functional group generated by the hydrogen atom. "Aromatic heterocyclic group" can mean a monovalent or divalent functional group according to the article. Hereinafter, the monovalent aromatic heterocyclic group may be expressed as "-aromatic heterocyclic group", and the divalent aromatic heterocyclic group may be expressed as "-aromatic heterocyclic group-". A monovalent aromatic heterocyclic group has the same meaning as "heteroaryl", and a divalent aromatic heterocyclic group has the same meaning as "heteroaryl".

Examples of the aromatic heterocyclic group include monocyclic or polycyclic aromatic heterocyclic groups. The aromatic heterocyclic group is usually 1 to 4 ring types, preferably 1 to 3 ring types, and more preferably 1 or 2 ring types. The number of heteroatoms contained in the aromatic heterocyclic group is usually 1 to 4, preferably 1 to 3, and more preferably 1 or 2. The number of members of the aromatic heterocyclic group is preferably 5 to 14 members, and more preferably 5 to 10 members. The number of ring constituent carbon atoms in the aromatic heterocyclic group can be appropriately determined according to the number of heteroatoms and the number of members. The number of carbon atoms constituting the ring in the aromatic heterocyclic group is usually 3-12, preferably 3-8, and more preferably 3-5. In the aromatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may be substituted by pendant oxy groups. In one embodiment, the aromatic heterocyclic group is a 5- to 7-membered monocyclic aromatic heterocyclic group. In another embodiment, the aromatic heterocyclic group is a 2-ring or 3-ring aromatic heterocyclic group with 8 to 14 members.

The aromatic heterocyclic group is, for example, a monocyclic aromatic heterocyclic group. In one embodiment, the monocyclic aromatic heterocyclic group contains 1 to 2 oxygen atoms. In another embodiment, the monocyclic aromatic heterocyclic group contains 1 to 2 sulfur atoms. In another embodiment, the monocyclic aromatic heterocyclic group contains 1 to 2 oxygen atoms and 1 to 2 sulfur atoms. In another embodiment, the monocyclic aromatic heterocyclic group contains 1 to 4 nitrogen atoms. In another embodiment, the monocyclic aromatic heterocyclic group contains 1 to 3 nitrogen atoms, 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms.

基、嘧啶基、吡

基、噻吩基、吡咯基、噻唑基、異噻唑基、吡唑基、咪唑基、呋喃基、噁唑基、異噁唑基、氧雜二唑基(例如1,2,4-氧雜二唑基、1,3,4-氧雜二唑基等)、硫雜二唑基(例如1,2,4-硫雜二唑基、1,3,4-硫雜二唑基等)、三唑基(例如1,2,3-三唑基、1,2,4-三唑基等)、四唑基、三

基等之5~7員之單環式之芳香族雜環基。單環式之芳香族雜環基中，鍵結於相同碳原子之2個氫原子亦可經側氧基取代。單環式之芳香族雜環基所能夠具有之側氧基之數較佳為1或2個。As the monocyclic aromatic heterocyclic group, there are, for example, pyridyl,

Base, pyrimidinyl, pyridine

Group, thienyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl Azole, 1,3,4-oxadiazolyl, etc.), thiadiazolyl (e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, etc.), Triazolyl (e.g. 1,2,3-triazolyl, 1,2,4-triazolyl, etc.), tetrazolyl, three

A monocyclic aromatic heterocyclic group with 5 to 7 members such as a group. In a monocyclic aromatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may also be substituted by pendant oxy groups. The number of pendant oxy groups that the monocyclic aromatic heterocyclic group can have is preferably 1 or 2.

The aromatic heterocyclic group is, for example, a polycyclic aromatic heterocyclic group. The polycyclic aromatic heterocyclic group is, for example, a condensed polycyclic aromatic heterocyclic group. In one embodiment, the condensed polycyclic aromatic heterocyclic group contains 1 to 3 oxygen atoms. In another embodiment, the condensed polycyclic aromatic heterocyclic group contains 1 to 3 sulfur atoms. In another embodiment, the condensed polycyclic aromatic heterocyclic group contains 1 to 3 oxygen atoms and 1 to 3 sulfur atoms. In another embodiment, the condensed polycyclic aromatic heterocyclic group contains 1 to 5 nitrogen atoms. In another embodiment, the condensed polycyclic aromatic heterocyclic group contains 1 to 4 nitrogen atoms, 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms.

基、咪唑并嘧啶基、噻吩并嘧啶基、氟嘧啶基、氯嘧啶基、吡唑并嘧啶基、氧雜唑并嘧啶基、硫雜唑并嘧啶基、吡唑并三

基、萘[2,3-b]噻吩基、吩噻噁基、吲哚基、異吲哚啉基、1H-吲唑基、嘌呤基、異喹啉基、喹啉基、呔

基、

啶基、喹

啉基、喹唑啉基、

啉基、咔唑基、β-羰基、啡啶基、吖啶基、啡

基、啡噻

基、啡

基等之8~14員之縮合多環式(較佳為2環式或3環式)之芳香族雜環基等。多環式之芳香族雜環基中，鍵結於相同碳原子之2個氫原子亦可經側氧基取代。多環式之芳香族雜環基所能夠具有之側氧基之數較佳為1、2或3個。Examples of the condensed polycyclic aromatic heterocyclic group include, for example, benzothiophenyl, benzopyranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzene Bisisothiazolyl, benzotriazolyl, imidazopyridyl, thienopyridinyl, fluridinyl, chloropyridinyl, pyrazoloidinyl, oxazoloidyl, thiazoloidinyl, imidazo Pyridine

Group, imidazopyrimidinyl, thienopyrimidinyl, fluoropyrimidinyl, chloropyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolo three

Group, naphthalene[2,3-b]thienyl, phenothioxyl, indolyl, isoindolinyl, 1H-indazolyl, purinyl, isoquinolinyl, quinolinyl, xenoyl

base,

Pyridyl, quine

Linyl, quinazolinyl,

Linyl, carbazolyl, β-carbonyl, phenanthridinyl, acridinyl, phenanthrene

Phenanthrene

Base, brown

Condensed polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups of 8 to 14 members such as groups. In a polycyclic aromatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may also be substituted by pendant oxy groups. The number of pendant oxy groups that the polycyclic aromatic heterocyclic group can have is preferably 1, 2, or 3.

基、吲哚啉基、異吲哚啉基、四氫噻吩并[2,3-c]啶基、四氫苯并氮呯基、四氫喹

啉基、四氫啡啶基、六氫啡噻

基、六氫啡

基、四氫呔

基、四氫

啶基、四氫喹唑啉基、四氫

啉基、四氫咔唑基、四氫-β-羰基、四氫吖啶基、四氫啡

基、四氫噻噸基、八氫異喹啉基等之9~14員之縮合多環式(較佳為2環式或3環式)之芳香族雜環基等。具有部分經飽和之單環之縮合多環式之芳香族雜環基中，鍵結於相同碳原子之2個氫原子亦可經側氧基取代。具有部分經飽和之單環之縮合多環式之芳香族雜環基所能夠具有之側氧基之數較佳為1、2或3個。Aromatic heterocyclic groups also include condensed polycyclic aromatic heterocyclic groups with partially saturated monocyclic rings (such as monocyclic aromatic hydrocarbon ring groups, monocyclic aromatic heterocyclic groups, etc.) ( For example, an aromatic ring condensed an aliphatic heterocyclic ring group, etc.). A partially saturated monocyclic condensed polycyclic aromatic heterocyclic group is a partially hydrogenated monocyclic condensed polycyclic aromatic heterocyclic group which constitutes the bond of the ring. As a condensed polycyclic aromatic heterocyclic group having a partially saturated monocyclic ring, for example, dihydrobenzopyranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, and dihydrobenzothiazole Group, dihydrobenzisothiazolyl, dihydronaphthalene[2,3-b]thienyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 4H-quino

Group, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]ridinyl, tetrahydrobenzazepine, tetrahydroquine

Linyl, tetrahydrophenidinyl, hexahydrophenothi

Hexahydrophenone

Tetrahydrogen

Radical, tetrahydro

Ridinyl, tetrahydroquinazolinyl, tetrahydro

Linyl, tetrahydrocarbazolyl, tetrahydro-β-carbonyl, tetrahydroacridinyl, tetrahydrophenanthrene

Condensed polycyclic (preferably 2-ring or 3-ring) aromatic heterocyclic groups of 9 to 14 members such as tetrahydrothioxanthene, octahydroisoquinolinyl, etc. In a partially saturated monocyclic condensed polycyclic aromatic heterocyclic group, two hydrogen atoms bonded to the same carbon atom may also be substituted by pendant oxy groups. The number of pendant oxy groups that a partially saturated monocyclic condensed polycyclic aromatic heterocyclic group can have is preferably 1, 2, or 3.

基-3(4H)-酮-基、3-氧代-3,4-二氫-2H-吡啶并[3,2-b][1,4]

基-6-基、[1,3]二氧戊環[4,5-b]吡啶基、2,3-二氫苯并[b]噻吩基、2,3-二氫-1-苯并呋喃-5-基、2,3-二氫-1-苯并呋喃-6-基、1,3-二氫-2-苯并呋喃-5-基、2,3-二氫-1H-吲哚-5-基、1,3-苯并二

呃-5-基、2,3-二氫-1,4-苯并二噁英-2-基、2,3-二氫-1,4-苯并二噁英-6-基、3-氧代-3,4-二氫-2H-1,4-苯并

基-6-基、1,4-苯并二氧雜環基、2H-苯并[b][1,4]

基-3(4H)-酮-基、3,4-二氫-2H-苯并[b][1,4] 二氧雜環庚烷基、吲哚啉基、2H-異吲哚啉基、苯并二氫哌喃基、苯并哌喃酮基、異苯并二氫哌喃基、1,2,3,4-四氫異喹啉基等。Aromatic heterocyclic groups also include partially saturated condensed polycyclic aromatic heterocyclic groups. The partially saturated condensed polycyclic aromatic heterocyclic group is a partially hydrogenated monocyclic condensed polycyclic aromatic heterocyclic group which has a bond constituting the ring. Examples of partially saturated condensed polycyclic aromatic heterocyclic groups include 1,3-dihydrobenzimidazole-2-nonyl, 2-benzoxazolinenonyl, and octahydroisoindoline Group, 2H-pyrido[3,2-b]-1,4-

Group-3(4H)-keto-yl, 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]

Base-6-yl, [1,3]dioxolane [4,5-b]pyridyl, 2,3-dihydrobenzo[b]thienyl, 2,3-dihydro-1-benzo Furan-5-yl, 2,3-dihydro-1-benzofuran-6-yl, 1,3-dihydro-2-benzofuran-5-yl, 2,3-dihydro-1H-indyl Dol-5-yl, 1,3-benzobis

Er-5-yl, 2,3-dihydro-1,4-benzodioxin-2-yl, 2,3-dihydro-1,4-benzodioxin-6-yl, 3- Oxo-3,4-dihydro-2H-1,4-benzo

Group-6-yl, 1,4-benzodioxyl, 2H-benzo[b][1,4]

Group-3(4H)-keto-yl, 3,4-dihydro-2H-benzo[b][1,4]dioxepanyl, indolinyl, 2H-isoindolinyl , Chromanyl, benzopiperanone, isochromanyl, 1,2,3,4-tetrahydroisoquinolinyl, etc.

The divalent aromatic heterocyclic group means a divalent functional group generated by removing one hydrogen atom from a monovalent aromatic heterocyclic group. The description of the monovalent aromatic heterocyclic group is the same as above.

As a functional group formed by combining two or more kinds selected from aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups and aromatic heterocyclic groups, there are, for example, those formed by combining aliphatic hydrocarbon groups and aromatic hydrocarbon ring groups Functional groups, functional groups formed by combining aliphatic hydrocarbon groups and aliphatic heterocyclic groups, functional groups formed by combining aliphatic hydrocarbon groups and aromatic heterocyclic groups, etc.

The functional group formed by combining aliphatic hydrocarbon group and aromatic hydrocarbon ring group is represented by the formula: (*)-aliphatic hydrocarbon group-aromatic hydrocarbon ring group, or formula: (*)-aromatic hydrocarbon ring group-aliphatic hydrocarbon group . (*) indicates the bonding of an organic group including a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group. The aliphatic hydrocarbon group and the aromatic hydrocarbon ring group in the formula may each have one or more substituents. The aliphatic hydrocarbon group in the formula may have one or more substituents selected from, for example, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group. The aromatic hydrocarbon ring group in the formula may also have one or more substituents selected from, for example, an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group. The aliphatic hydrocarbon group selected as the substituent may have, for example, one or more substituents selected from an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group. The aromatic hydrocarbon ring group, aliphatic heterocyclic group, and aromatic heterocyclic group selected as the substituent may each have, for example, selected from aliphatic hydrocarbon group, aromatic hydrocarbon ring group, aliphatic heterocyclic group and aromatic heterocyclic ring One or more substituents of the group.

Examples of the functional group represented by the formula: (*)-aromatic hydrocarbon ring group-aliphatic hydrocarbon group include alkyl aryl groups, alkenyl aryl groups, and alkynyl aryl groups. The description of the alkyl group, alkenyl group, alkynyl group, and aryl group in "alkylaryl", "alkenylaryl" and "alkynylaryl" is the same as above.

The number of alkyl groups in the alkyl aryl group, the number of alkenyl groups in the alkenyl aryl group, and the number of alkynyl groups in the alkynyl aryl group are usually 1 to 4, preferably 1 to 3, and more preferably 1 to 2 pcs. The carbon number of the alkyl aryl group is usually 7 to 30, preferably 7 to 20, more preferably 7 to 18, still more preferably 7 to 15, still more preferably 7 to 11 . The carbon number of the alkenyl aryl group and the carbon number of the alkynyl aryl group are usually 8 to 30, preferably 8 to 20, more preferably 8 to 18, still more preferably 8 to 16, and More preferably, it is 8-12. Examples of the alkyl aryl group include o-tolyl, m-tolyl, p-tolyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-Dimethylphenyl, 2,6-Dimethylphenyl, 3,4-Dimethylphenyl, 3,5-Dimethylphenyl, 2,4,6-Trimethylbenzene Group, o-ethylphenyl, m-ethylphenyl, p-ethylphenyl, etc. Examples of alkenyl aryl groups include alkenyl aryl groups such as o-styryl, m-styryl, and p-styryl. As the alkynylaryl group, for example, an alkynylaryl group such as 2-ethynyl-2-phenyl and the like can be given.

Examples of the functional group represented by the formula: (*)-aliphatic hydrocarbon group-aromatic hydrocarbon ring group include arylalkyl groups, arylalkenyl groups, and arylalkynyl groups. The description of the alkyl group, alkenyl group, alkynyl group, and aryl group in "arylalkyl", "arylalkenyl" and "arylalkynyl" is the same as above.

The number of carbon atoms in the arylalkyl group is usually 7 to 30, preferably 7 to 20, more preferably 7 to 18, still more preferably 7 to 15, still more preferably 7 to 11 . Examples of the arylalkyl group include benzyl and 2-phenethyl. The carbon number of the arylalkenyl group is usually 8 to 30, preferably 8 to 20, more preferably 8 to 18, still more preferably 8 to 16, still more preferably 8 to 12 . Examples of the arylalkenyl group include 2-phenol vinyl group, 2-naphthalene vinyl group, and the like. The carbon number of the arylalkynyl group is usually 8 to 30, preferably 8 to 20, more preferably 8 to 18, still more preferably 8 to 16, still more preferably 8 to 12 . Examples of the arylalkynyl group include phenylethynyl group and the like.

The functional group formed by combining aliphatic hydrocarbon group and aliphatic heterocyclic group is represented by the formula: (*)-aliphatic hydrocarbon group-aliphatic heterocyclic group, or formula: (*)-aliphatic heterocyclic group-aliphatic hydrocarbon group . (*) represents the bonding of an organic group including a functional group formed by combining an aliphatic hydrocarbon group and an aliphatic heterocyclic group. The aliphatic hydrocarbon group and the aliphatic heterocyclic group in the formula may each have one or more substituents. The aliphatic hydrocarbon group in the formula may have, for example, one or more substituents selected from aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups. The aliphatic heterocyclic group in the formula may have, for example, one or more substituents selected from the group consisting of aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups. The aliphatic hydrocarbon group selected as the substituent may have one or more substituents selected from, for example, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group. The aromatic hydrocarbon ring group, aliphatic heterocyclic group, and aromatic heterocyclic group selected as the substituent may each have, for example, selected from aliphatic hydrocarbon group, aromatic hydrocarbon ring group, aliphatic heterocyclic group and aromatic heterocyclic ring One or more substituents of the group.

The functional group represented by the formula: (*)-aliphatic heterocyclic group-aliphatic hydrocarbon group includes, for example, an alkyl aliphatic heterocyclic group, an alkenyl aliphatic heterocyclic group, and an alkynyl aliphatic heterocyclic group. The description of the alkyl group, alkenyl group, alkynyl group and aliphatic heterocyclic group in "alkyl aliphatic heterocyclic group", "alkenyl aliphatic heterocyclic group" and "alkynyl aliphatic heterocyclic group" and the above the same.

Examples of the functional group represented by the formula: (*)-aliphatic hydrocarbon group-aliphatic heterocyclic group include aliphatic heterocycloalkyl, aliphatic heterocycloalkenyl, and aliphatic heterocycloalkynyl. The description of the alkyl group, alkenyl group, alkynyl group, and aliphatic heterocyclic group in "aliphatic heterocycloalkyl", "aliphatic heterocycloalkenyl" and "aliphatic heterocycloalkynyl" is the same as above.

The functional group formed by combining aliphatic hydrocarbon group and aromatic heterocyclic group is represented by the formula: (*)-aliphatic hydrocarbon group-aromatic heterocyclic group, or formula: (*)-aromatic heterocyclic group-aliphatic hydrocarbon group . (*) indicates the bonding of an organic group including a functional group formed by combining an aliphatic hydrocarbon group and an aromatic heterocyclic group. The aliphatic hydrocarbon group and the aromatic heterocyclic group in the formula may each have one or more substituents. The aliphatic hydrocarbon group in the formula may have one or more substituents selected from, for example, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group. The aromatic heterocyclic group in the formula may have, for example, one or more substituents selected from the group consisting of aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups, and aromatic heterocyclic groups. The aliphatic hydrocarbon group selected as the substituent may have, for example, one or more substituents selected from an aromatic hydrocarbon ring group, an aliphatic heterocyclic group, and an aromatic heterocyclic group. The aromatic hydrocarbon ring group, aliphatic heterocyclic group, and aromatic heterocyclic group selected as the substituent may each have, for example, selected from aliphatic hydrocarbon group, aromatic hydrocarbon ring group, aliphatic heterocyclic group and aromatic heterocyclic ring One or more substituents of the group.

Examples of the functional group represented by the formula: (*)-aromatic heterocyclic group-aliphatic hydrocarbon group include alkyl heteroaryl, alkenyl heteroaryl, alkynyl heteroaryl and the like. The description of the alkyl group, alkenyl group, alkynyl group and heteroaryl group in "alkylheteroaryl", "alkenylheteroaryl" and "alkynylheteroaryl" is the same as above.

The number of alkyl groups in alkyl heteroaryl groups, the number of alkenyl groups in alkenyl heteroaryl groups, and the number of alkynyl groups in alkynyl heteroaryl groups are usually 1 to 4, preferably 1 to 3. More preferably, it is 1-2. The carbon number of the alkyl heteroaryl group is usually 3 to 30, preferably 3 to 20, more preferably 3 to 18, still more preferably 3 to 15, and still more preferably 3 to 11 One. The carbon number of the alkenyl heteroaryl group and the carbon number of the alkynyl heteroaryl group are usually 4 to 30, preferably 4 to 20, more preferably 4 to 18, and still more preferably 4 to 15 , And more preferably 4-11.

Examples of the functional group represented by the formula: (*)-aliphatic hydrocarbon group-aromatic heterocyclic group include heteroarylalkyl, heteroarylalkenyl, and heteroarylalkynyl. The description of the alkyl group, alkenyl group, alkynyl group and heteroaryl group in "heteroarylalkyl", "heteroarylalkenyl" and "heteroarylalkynyl" is the same as above.

The carbon number of the heteroarylalkyl group is usually 3 to 30, preferably 3 to 20, more preferably 3 to 18, still more preferably 3 to 15, and still more preferably 3 to 11 One. Examples of heteroarylalkyl groups include furylethyl, thienylmethyl, and benzothiophenylmethyl. The number of carbon atoms in the heteroarylalkenyl group is usually 4 to 30, preferably 4 to 20, more preferably 4 to 18, still more preferably 4 to 15, and still more preferably 4 to 11 One. Examples of heteroarylalkenyl groups include pyridylvinyl, thienylvinyl, and benzothiophenylvinyl. The number of carbon atoms in the heteroarylalkynyl group is usually 4 to 30, preferably 4 to 20, more preferably 4 to 18, still more preferably 4 to 15, and still more preferably 4 to 11 One. Examples of heteroarylalkynyl groups include imidazolylethynyl, thienylethynyl, and benzothiophenylethynyl.

Regarding some functional groups, the expression "may have one or more substituents" means that one or more hydrogen atoms in the functional group may be independently substituted with other atoms or atomic groups. The expression "may be substituted" is synonymous with the expression "may have more than one substituent".

The number of substituents that the aliphatic hydrocarbon group can have can be determined in accordance with the carbon number of the aliphatic hydrocarbon group and the like. The aliphatic hydrocarbon group can have, for example, 1 to 6, preferably 1 to 3, and more preferably 1 or 2 substituents at the positions that can be substituted. When the hydrocarbon group has two or more substituents, the two or more substituents may be the same or different.

When the carbon number of the alkyl group is 1 to 4, the number of substituents that the alkyl group can have is usually 1 to 3, preferably 1 or 2, and more preferably 1. When the carbon number of the alkyl group is 5-9, the number of substituents that the alkyl group can have is usually 1 to 6, preferably 1 to 5, more preferably 1 to 4, and more preferably For 1 or 2. When the carbon number of the alkyl group is 10 or more, the number of substituents that the alkyl group can have is usually 1 to 9, preferably 1 to 5, more preferably 1 to 4, and even more preferably For 1 or 2.

When the carbon number of the alkenyl group is 2 to 4, the number of substituents that the alkenyl group can have is usually 1 to 3, preferably 1 or 2, and more preferably 1. Moreover, when the carbon number of the alkenyl group is 5-9, the number of substituents that the alkenyl group can have is usually 1 to 5, preferably 1 to 4, more preferably 1 to 3, and more Preferably, it is 1 or 2. And, when the carbon number of the alkenyl group is 10 or more, the number of substituents that the alkenyl group can have is usually 1 to 8, preferably 1 to 4, more preferably 1 to 3, and still more Preferably, it is 1 or 2.

When the carbon number of the alkynyl group is 2 to 4, the number of substituents that the alkynyl group can have is usually 1 to 3, preferably 1 or 2, and more preferably 1. When the carbon number of the alkynyl group is 5-9, the number of substituents that the alkynyl group can have is usually 1 to 5, preferably 1 to 4, more preferably 1 to 3, and more preferably For 1 or 2. When the carbon number of the alkynyl group is 10 or more, the number of substituents that the alkynyl group can have is usually 1 to 8, preferably 1 to 4, more preferably 1 to 3, and even more preferably For 1 or 2.

The number of substituents that the aromatic hydrocarbon ring group can have can be appropriately determined in accordance with the carbon number and the number of members of the aromatic hydrocarbon ring group. The aromatic hydrocarbon ring group can have, for example, 1 to 5, preferably 1 to 4, more preferably 1 to 3, and still more preferably 1 or 2 substituents at the positions that can be substituted. When the aromatic hydrocarbon ring group has two or more substituents, the two or more substituents may be the same or different.

The number of substituents that the aliphatic heterocyclic group can have can be appropriately determined in accordance with the carbon number and the number of members of the aliphatic heterocyclic group. The aliphatic heterocyclic group can have, for example, 1 to 4, preferably 1 to 3, and more preferably 1 or 2 substituents at the positions that can be substituted. When the aliphatic heterocyclic group has two or more substituents, the two or more substituents may be the same or different.

The number of substituents that the aromatic heterocyclic group can have can be appropriately determined in accordance with the carbon number and the number of members of the aromatic heterocyclic group. The aromatic heterocyclic group can have, for example, 1 to 4, preferably 1 to 3, and more preferably 1 or 2 substituents at the positions that can be substituted. When the aromatic heterocyclic group has two or more substituents, the two or more substituents may be the same or different.

When the carbon number of arylalkyl or alkylaryl is 7-11, the number of substituents that arylalkyl or alkylaryl can have is usually 1 to 5, preferably 1 to 4 , More preferably 1~2. When the carbon number of arylalkyl or alkylaryl is 12-15, the number of substituents that arylalkyl or alkylaryl can have is usually 1 to 6, preferably 1 to 4 , More preferably 1~2. When the carbon number of the arylalkyl group or alkylaryl group is 16 or more, the number of substituents that the arylalkyl group or alkylaryl group can have is usually 1-8, preferably 1-6. It is more preferably 1 to 4, and still more preferably 1 to 2.

When the carbon number of the arylalkenyl or alkenylaryl group is 8-11, the number of substituents that the arylalkenyl or alkenylaryl group can have is usually 1 to 5, preferably 1 to 4 , More preferably 1~2. When the carbon number of the arylalkenyl or alkenylaryl is 12-15, the number of substituents that the arylalkenyl or alkenylaryl can have is usually 1 to 6, preferably 1 to 4 , More preferably 1~2. When the carbon number of the arylalkenyl or alkenylaryl group is 16 or more, the number of substituents that the arylalkenyl or alkenylaryl group can have is usually 1-8, preferably 1-6, It is more preferably 1 to 4, and still more preferably 1 to 2.

When the carbon number of the arylalkynyl group or alkynylaryl group is 8-11, the number of substituents that the arylalkynyl group or alkynylaryl group can have is usually 1 to 5, preferably 1 to 4 , More preferably 1~2. When the carbon number of the arylalkynyl or alkynylaryl group is 12-15, the number of substituents that the arylalkynyl or alkynylaryl group can have is usually 1 to 6, preferably 1 to 4 , More preferably 1~2. When the carbon number of the arylalkynyl group or alkynylaryl group is 16 or more, the number of substituents that the arylalkynyl group or alkynylaryl group can have is usually 1 to 8, preferably 1 to 6, It is still more preferably 1 to 4, and still more preferably 1 to 2.

The aliphatic hydrocarbon group (including monovalent and divalent) contained in the organic group can have one or more substituents, and the aromatic hydrocarbon ring group (including monovalent and divalent) contained in the organic group can have 1 More than one substituent, one or more substituents that the aliphatic heterocyclic group (including monovalent and divalent) contained in the organic group can have, and the aromatic heterocyclic group (including monovalent And divalent) can have one or more substituents each independently can be selected from the following substituent groups A to M.

[Substituent Group A] (A-1) Halogen atom (A-2) Nitro (A-3) Cyano (A-4) pendant oxy (A-5) Hydroxy which can also be protected (A-6) Sulfhydryl group that can also be protected (A-7) Amine group that can also be protected (A-8) Formaldehyde group that can also be protected (A-9) Carboxyl group that can also be protected (A-10) Amine methyl group that can also be protected (A-11) The base that can also be protected

[Substituent Group B] (B-1) Alkyl (B-2) Alkylthio (B-3) Alkyloxy (B-4) Alkylcarbonyloxy (B-5) Alkylamine formyloxy (B-6) Alkylsulfonyloxy (B-7) Alkyloxycarbonyloxy (B-8) Alkylcarbonyl (B-9) Alkyloxycarbonyl (B-10) Alkylaminocarbonyl (B-11) Alkylamine formyl (B-12) alkyl sulfonyl (B-13) Alkylsulfinyl (B-14) Mono-or di-alkylamino group (B-15) Alkylcarbonylamino group (B-16) Alkyl Amido (B-17) Alkyloxycarbonylamino group (B-18) Alkyloxyalkyloxy

[Substituent Group C] (C-1)Alkenyl (C-2)Alkenylthio (C-3)Alkenyloxy (C-4)Alkenylcarbonyloxy (C-5)Alkenylaminoformyloxy (C-6) Alkenyl sulfonyloxy (C-7)Alkenyloxycarbonyloxy (C-8)Alkenylcarbonyl (C-9)Alkenyloxycarbonyl (C-10)Alkenylaminocarbonyl (C-11)Alkenylaminomethanyl (C-12) Alkenyl Sulfonyl (C-13) Alkenylsulfinyl (C-14) Mono-or di-alkenylamino group (C-15)Alkenylcarbonylamino group (C-16) Alkenyl Amido (C-17) Alkenyloxycarbonylamino (C-18)Alkenyloxyalkyloxy

[Substituent group D] (D-1)alkynyl (D-2) Alkynylthio (D-3) Alkynyloxy (D-4) Alkynylcarbonyloxy (D-5) Alkynylaminoformyloxy (D-6)alkynyl sulfonyloxy (D-7) Alkynyloxycarbonyloxy (D-8)alkynylcarbonyl (D-9)alkynyloxycarbonyl (D-10) Alkynylaminocarbonyl (D-11) Alkynylaminoformyl (D-12)alkynyl sulfonyl (D-13) Alkynylsulfinyl (D-14) Mono-or di-alkynylamino group (D-15) Alkynylcarbonylamino group (D-16) Alkynyl Amido (D-17) Alkynyloxycarbonylamino (D-18) Alkynyloxyalkyloxy

[Substituent group E] (E-1)Aryl (E-2) Arylthio (E-3) Aryloxy (E-4) Arylcarbonyloxy (E-5) Arylaminoformyloxy (E-6) Arylsulfonyloxy (E-7) Aryloxycarbonyloxy (E-8)Arylcarbonyl (E-9) Aryloxycarbonyl (E-10) Arylaminocarbonyl (E-11) Arylaminoformyl (E-12) Aryl sulfonate (E-13) Arylsulfinyl (E-14) Mono-or di-arylamino group (E-15)Arylcarbonylamino group (E-16) Aryl Amido (E-17) Aryloxycarbonylamino group (E-18) Aryloxyalkyloxy

[Substituent Group F] (F-1) Heteroaryl (F-2) Heteroarylthio (F-3) Heteroaryloxy (F-4) Heteroarylcarbonyloxy (F-5) Heteroarylaminoformyloxy (F-6) Heteroarylsulfonyloxy (F-7) Heteroaryloxycarbonyloxy (F-8) Heteroarylcarbonyl (F-9) Heteroaryloxycarbonyl (F-10) Heteroarylaminocarbonyl (F-11) Heteroarylaminomethanyl (F-12) Heteroaryl Sulfonyl (F-13) Heteroarylsulfinyl (F-14) Mono-or di-heteroarylamino group (F-15) Heteroarylcarbonylamino group (F-16) Heteroaryl Amido (F-17) Heteroaryloxycarbonylamino (F-18) Heteroaryloxyalkyloxy

[Substituent Group G] (G-1) Aliphatic heterocyclic group (G-2) Aliphatic heterocyclic thio (G-3) Aliphatic heterocyclic oxy (G-4) Aliphatic heterocyclic carbonyloxy (G-5) Aliphatic Heterocyclic Amine Formyloxy (G-6) Aliphatic heterocyclic sulfonyloxy (G-7) Aliphatic heterocyclic oxycarbonyloxy (G-8) Aliphatic heterocyclic carbonyl (G-9) Aliphatic heterocyclic oxycarbonyl (G-10) Aliphatic heterocyclic aminocarbonyl (G-11) Aliphatic Heterocyclic Amine Formyl (G-12) Aliphatic heterocyclic ring (G-13) Aliphatic heterocyclic sulfinyl (G-14) Mono-or di-aliphatic heterocyclic amino group (G-15) Aliphatic heterocyclic carbonyl amino group (G-16) Aliphatic heterocyclic ring amine group (G-17) Aliphatic heterocyclic oxycarbonylamino group (G-18) Aliphatic heterocycloalkyloxyalkyloxy

[Substituent Group H] (H-1) Arylalkyl (H-2) Arylalkylthio (H-3) Arylalkyloxy (H-4) Arylalkylcarbonyloxy (H-5) Arylalkylamine formyloxy (H-6) Arylalkylsulfonyloxy (H-7) Arylalkyloxycarbonyloxy (H-8) Arylalkylcarbonyl (H-9) Arylalkyloxycarbonyl (H-10) Arylalkylaminocarbonyl (H-11) Arylalkylamine formyl (H-12) Arylalkyl sulfonyl (H-13) Arylalkylsulfinyl (H-14) mono-or di-arylalkylamino group (H-15) Arylalkylcarbonylamino group (H-16) Arylalkylsulfonylamino group (H-17) Arylalkyloxycarbonylamino (H-18) Arylalkyloxyalkyloxy

[Substituent Group I] (I-1) Arylalkenyl (I-2) Arylalkenylthio (I-3) Arylalkenyloxy (I-4) Arylalkenylcarbonyloxy (I-5) Arylalkenylaminoformyloxy (I-6) Arylalkenyl alkyloxy (I-7) Arylalkenyloxycarbonyloxy (I-8) Arylalkenylcarbonyl (I-9) Arylalkenyloxycarbonyl (I-10) Arylalkenylaminocarbonyl (I-11) Arylalkenylaminomethanyl (I-12) Arylalkenyl sulfonyl (I-13) Arylalkenylsulfinyl (I-14) Mono-or di-arylalkenylamino group (I-15) Arylalkenylcarbonylamino group (I-16) Arylalkenyl Amido (I-17) Arylalkenyloxycarbonylamino group (I-18) Arylalkenyloxyalkyloxy

[Substituent Group J] (J-1) Arylalkynyl (J-2) Arylalkynylthio (J-3) Arylalkynyloxy (J-4)Arylalkynylcarbonyloxy (J-5)Arylalkynylaminoformyloxy (J-6) Arylalkynyl sulfonyloxy (J-7)Arylalkynyloxycarbonyloxy (J-8)Arylalkynylcarbonyl (J-9) Arylalkynyloxycarbonyl (J-10)Arylalkynylaminocarbonyl (J-11)Arylalkynylaminoformyl (J-12) arylalkynyl sulfonyl (J-13) Arylalkynylsulfinyl (J-14) Mono-or di-arylalkynylamino group (J-15)Arylalkynylcarbonylamino group (J-16) Arylalkynyl Amido (J-17)Arylalkynyloxycarbonylamino (J-18)Arylalkynyloxyalkyloxy

[Substituent Group K] (K-1) Heteroarylalkyl (K-2) Heteroarylalkylthio (K-3) Heteroarylalkyloxy (K-4) Heteroarylalkylcarbonyloxy (K-5) Heteroarylalkylamine formyloxy (K-6) Heteroarylalkylsulfonyloxy (K-7) Heteroarylalkyloxycarbonyloxy (K-8) Heteroarylalkylcarbonyl (K-9) Heteroarylalkyloxycarbonyl (K-10) Heteroarylalkylaminocarbonyl (K-11) Heteroarylalkylamine Formyl (K-12) Heteroarylalkylsulfonyl (K-13) Heteroarylalkylsulfinyl (K-14) Mono-or di-heteroarylalkylamino group (K-15) Heteroarylalkylcarbonylamino group (K-16) Heteroarylalkylsulfonylamino (K-17) Heteroarylalkyloxycarbonylamino (K-18) Heteroarylalkynyloxyalkyloxy

[Substituent Group L] (L-1) Heteroarylalkenyl (L-2) Heteroarylalkenylthio (L-3) Heteroarylalkenyloxy (L-4) Heteroarylalkenylcarbonyloxy (L-5) Heteroarylalkenylaminoformyloxy (L-6) Heteroarylalkenyloxy (L-7) Heteroarylalkenyloxycarbonyloxy (L-8) Heteroarylalkenylcarbonyl (L-9) Heteroarylalkenyloxycarbonyl (L-10) Heteroarylalkenylaminocarbonyl (L-11) Heteroarylalkenylaminomethanyl (L-12) Heteroarylalkenyl Sulfonyl (L-13) Heteroarylalkenylsulfinyl (L-14) Mono-or di-heteroarylalkenylamino group (L-15) Heteroarylalkenylcarbonylamino group (L-16) Heteroarylalkenyl Amido (L-17) Heteroarylalkenyloxycarbonylamino (L-18) Heteroarylalkenyloxyalkyloxy

[Substituent Group M] (M-1) Heteroarylalkynyl (M-2) Heteroarylalkynylthio (M-3) Heteroarylalkynyloxy (M-4) Heteroarylalkynylcarbonyloxy (M-5) Heteroarylalkynylaminoformyloxy (M-6) Heteroarylalkynylsulfonyloxy (M-7) Heteroarylalkynyloxycarbonyloxy (M-8) Heteroarylalkynylcarbonyl (M-9) Heteroarylalkynyloxycarbonyl (M-10) Heteroarylalkynylaminocarbonyl (M-11) Heteroarylalkynylaminocarbamyl (M-12) Heteroarylalkynyl sulfonyl (M-13) Heteroarylalkynylsulfinyl (M-14) Mono-or di-heteroarylalkynylamino (M-15) Heteroarylalkynylcarbonylamino (M-16) Heteroarylalkynyl Amido (M-17) Heteroarylalkynyloxycarbonylamino (M-18) Heteroarylalkynyloxyalkyloxy

The aliphatic hydrocarbon group (including monovalent and divalent) contained in the organic group can have one or more substituents that can be independently selected from, for example, halogen atoms, nitro groups, cyano groups, pendant oxy groups, and can also be protected Hydroxyl group, sulfhydryl group that can also be protected, amine group that can also be protected, methionyl group that can also be protected, carboxyl group that can also be protected, aminomethyl group that can also be protected, and sulfonyl group that can also be protected , Aryl, aliphatic heterocyclic group, heteroaryl, alkyl aryl, alkyl aliphatic heterocyclic group, alkyl heteroaryl, aryl alkyl, aliphatic heterocycloalkyl, heteroaryl alkyl , Alkyloxy, aryloxy, aliphatic heterocyclic oxy, heteroaryloxy, alkylaryloxy, alkyl aliphatic heterocyclic oxy, alkyl heteroaryloxy, aryl Alkyloxy, aliphatic heterocycloalkyloxy, heteroarylalkyloxy, alkylthio, arylthio, aliphatic heterocyclic thio, heteroarylthio, alkylarylthio Group, alkyl aliphatic heterocyclic thio group, alkyl heteroaryl thio group, aryl alkyl thio group, aliphatic heterocycloalkyl thio group, heteroaryl alkyl thio group, alkyl carbonyl group, aryl carbonyl group , Aliphatic heterocyclic carbonyl, heteroaryl carbonyl, alkyl aryl carbonyl, alkyl aliphatic heterocyclic carbonyl, alkyl heteroaryl carbonyl, aryl alkyl carbonyl, aliphatic heterocycloalkyl carbonyl, heteroaryl Alkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aliphatic heterocyclic oxycarbonyl, heteroaryloxycarbonyl, alkylaryloxycarbonyl, alkyl aliphatic heterocyclic oxycarbonyl, alkyl Heteroaryloxycarbonyl, arylalkyloxycarbonyl, aliphatic heterocycloalkyloxycarbonyl and heteroarylalkyloxycarbonyl. Moreover, when the aliphatic hydrocarbon group (including monovalent and divalent) is a linear or branched aliphatic hydrocarbon group, the linear or branched aliphatic hydrocarbon group can have a cyclic aliphatic hydrocarbon group (for example, cycloalkane Group, cycloalkenyl, cycloalkynyl, etc.) as a substituent.

One or more substituents that the aromatic hydrocarbon ring group (including monovalent and divalent) contained in the organic group can have, and the aliphatic heterocyclic group (including monovalent and divalent) contained in the organic group can have One or more substituents and the aromatic heterocyclic group (including monovalent and divalent) contained in the organic group can have one or more substituents independently selected from, for example, halogen atoms, nitro groups, and cyano groups , Pendant groups, hydroxyl groups that can also be protected, sulfhydryl groups that can also be protected, amine groups that can also be protected, methionine groups that can also be protected, carboxyl groups that can also be protected, and carbamates that can also be protected Alkyl, alkyl, aryl, aliphatic heterocyclic group, heteroaryl, alkylaryl, alkyl aliphatic heterocyclic group, alkyl heteroaryl, arylalkyl which may also be protected , Aliphatic heterocycloalkyl, heteroarylalkyl, alkyloxy, aryloxy, aliphatic heterocyclooxy, heteroaryloxy, alkylaryloxy, alkyl aliphatic heterocycle Oxy, alkyl heteroaryloxy, arylalkyloxy, aliphatic heterocycloalkyloxy, heteroarylalkyloxy, alkylthio, arylthio, aliphatic heterocyclic sulfur Group, heteroarylthio, alkylarylthio, alkyl aliphatic heterocyclic thio, alkyl heteroarylthio, arylalkylthio, aliphatic heterocycloalkylthio, heteroaryl Alkylalkylthio, alkylcarbonyl, arylcarbonyl, aliphatic heterocyclic carbonyl, heteroarylcarbonyl, alkylarylcarbonyl, alkyl aliphatic heterocyclic carbonyl, alkyl heteroarylcarbonyl, arylalkyl Carbonyl, aliphatic heterocycloalkylcarbonyl, heteroarylalkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aliphatic heterocyclic oxycarbonyl, heteroaryloxycarbonyl, alkylaryloxy Carbonyl, alkyl aliphatic heterocyclic oxycarbonyl, alkyl heteroaryloxycarbonyl, arylalkyloxycarbonyl, aliphatic heterocycloalkyloxycarbonyl and heteroarylalkyloxycarbonyl.

Regarding some functional groups, "may be protected" means that the functional group is unsubstituted, or that the functional group is protected by a generally used protecting group.

"Protecting group" means a functional group that can change the target functional group to inert in the target reaction, and it can be removed from the target functional group after the target reaction is completed. It is not particularly limited, and can be adapted to the target functional group, The objective response and so on are appropriately selected.

The "hydroxyl group that may also be protected" is a hydroxyl group protected by a hydroxyl group or a hydroxyl protecting group, and can be represented by the formula: -OP ₁ (wherein P ₁ represents a hydrogen atom or a hydroxyl protecting group). Examples of hydroxy protecting groups include ester type protecting groups, arylalkyl type protecting groups, alkyl type protecting groups, arylalkyloxyalkyl type protecting groups, alkyloxyalkyl type protecting groups, methyl Silane type protecting group, oxycarbonyl type protecting group, etc.

As an ester-type protecting group, there are, for example, an alkylcarbonyl group with 2 to 10 carbons, which may have one or more substituents, and an arylcarbonyl group with 7 to 10 carbons, which may have one or more substituents. Wait. One or more substituents can be selected from, for example, substituent groups A to M. The substituent that the alkylcarbonyl group can have is the same as the substituent for the aliphatic hydrocarbon group. The substituents that the arylcarbonyl group can have are the same as those for the aromatic hydrocarbon ring group. The alkylcarbonyl group which may have one or more substituents includes, for example, an acetyl group, a propyl group, a buty group, an isopropyl group, and a trimethyl acetyl group. As the arylcarbonyl group which may have one or more substituents, there are, for example, benzyl, 4-nitrobenzyl, 4-methyloxybenzyl, 4-methylbenzyl Group, 4-tert-butylbenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-phenylbenzyl, 4-methyl Oxycarbonylbenzyl and the like. The ester-type protecting group is preferably an alkylcarbonyl group with 2 to 10 carbons, more preferably an alkylcarbonyl group with 2 to 5 carbons, and still more preferably an acetyl group or a trimethylacetoxy group.

As an arylalkyl-type protecting group, for example, an arylalkyl group having 7 to 11 carbons which may have one or more substituents, etc. are mentioned. One or more substituents can be selected from, for example, substituent groups A to M. The substituents that the "alkyl" in the arylalkyl group can have are the same as those for the aliphatic hydrocarbon group. The substituent that the "aryl group" in the arylalkyl group can have is the same as that of the aromatic hydrocarbon ring group. One or more substituents are preferably selected from halogen atoms, nitro groups, cyano groups, methyl groups, methyloxy groups, phenyl groups and naphthyl groups. Examples of arylalkyl groups having 7 to 11 carbon atoms that may have one or more substituents include benzyl, 1-phenylethyl, diphenylmethyl, and 1,1-diphenylethyl Group, naphthylmethyl, etc.

Examples of the alkyl-type protecting group include an alkyl group having 1 to 10 carbon atoms which may have one or more substituents. One or more substituents can be selected from, for example, substituent groups A to M. The substituent that the alkyl group can have is the same as the substituent for the aliphatic hydrocarbon group. One or more substituents are preferably selected from halogen atoms, nitro groups and cyano groups. The alkyl-type protecting group is preferably an alkyl group with 1 to 5 carbons that may be substituted with one or more substituents, and more preferably methyl, ethyl, tert-butyl, etc.

As the arylalkyloxyalkyl-type protecting group, there are, for example, an arylalkyloxymethyl group with 8 to 11 carbons which may have one or more substituents, and one or more substituents. The arylalkyloxyethyl group with 9-11 carbon atoms, and the arylalkyloxypropyl group with 10-11 carbon atoms, which may have more than one substituent基alkyl. One or more substituents can be selected from, for example, substituent groups A to M. The substituents that the "alkyl" in the arylalkyloxyalkyl group can have are the same as those for the aliphatic hydrocarbon group. The substituents that the "aryl group" in the arylalkyloxyalkyl group can have are the same as those for the aromatic hydrocarbon ring group. One or more substituents are preferably selected from halogen atoms, nitro groups, cyano groups, methyl groups and methyloxy groups. The arylalkyloxyalkyl-type protecting group is, for example, benzyloxymethyl which may have one or more substituents, and preferably may be halogenated, nitro, cyano, methyl or methyl The oxy-substituted benzyloxymethyl is more preferably benzyloxymethyl.

As an alkyloxyalkyl-type protecting group, there are, for example, an alkyloxymethyl group having 2 to 10 carbon atoms which may have one or more substituents, and a carbon number of one or more substituents 3-10 alkyloxyethyl groups, and alkyloxyalkyl groups such as alkyloxypropyl groups with 4-10 carbon atoms that may have more than one substituent. One or more substituents can be selected from, for example, substituent groups A to M. The substituents that the "alkyl" in the alkyloxyalkyl group can have are the same as those for the aliphatic hydrocarbon group. One or more substituents are preferably selected from halogen atoms, nitro groups, cyano groups, methyl groups and methyloxy groups. The alkyloxyalkyl-type protecting group is preferably an alkyloxymethyl group with 2 to 10 carbon atoms that may have more than one substituent, and more preferably may have a halogen atom, a nitro group, or a cyano group. The alkyloxymethyl group with 2 to 5 carbon atoms of the group, methyloxy group or ethyloxy group is more preferably methyloxymethyl group.

As the silyl-type protecting group, there are, for example, those having 1 to 10 carbon atoms selected from alkyl groups that may have one or more substituents, and those having 7 to 10 carbon atoms that may have one or more substituents. The arylalkyl group and the silyl group of the functional group of an aryl group with 6 to 10 carbons which may have more than one substituent. One or more substituents can be selected from, for example, substituent groups A to M. The substituents that the "alkyl" in the alkyl group and the arylalkyl group can have are the same as those for the aliphatic hydrocarbon group. The substituents that the "aryl" in the aryl group and the arylalkyl group can have are the same as the substituents for the aromatic hydrocarbon ring group. The silyl-type protecting group is preferably a silyl group having a functional group selected from an alkyl group having 1 to 10 carbons and an aryl group having 6 to 10 carbons, and more preferably having a functional group selected from a carbon number of 1 to 5 The silyl group of the functional group of each alkyl group and phenyl group is more preferably trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group or tert-butyldi Phenylsilyl.

As an oxycarbonyl-type protecting group, there are, for example, an alkyloxycarbonyl group with 2 to 10 carbons, which may have one or more substituents, and 3 to 10 carbons, which may have one or more substituents. The alkenyloxycarbonyl group, the arylalkyloxycarbonyl group with 8 to 11 carbon atoms and the like may also have one or more substituents. One or more substituents can be selected from, for example, substituent groups A to M. The substituents that the "alkyl" in the alkyloxycarbonyl group, the "alkenyl" in the alkenyloxycarbonyl group, and the "alkyl" in the arylalkyloxycarbonyl group can have are the same as those for the aliphatic hydrocarbon group. The substituents that the "aryl" in the arylalkyloxycarbonyl group can have are the same as those for the aromatic hydrocarbon ring group. The oxycarbonyl type protecting group is preferably an alkyloxycarbonyl group with 2 to 5 carbons, an alkenyloxycarbonyl group with 3 to 5 carbons, or benzyloxycarbonyl, and more preferably methyloxymethyl Group, allyloxycarbonyl or benzyloxycarbonyl.

The "sulfhydryl group that may also be protected" is a sulfhydryl group protected by a sulfhydryl group or a sulfhydryl protecting group, and can be represented by the formula: -SP ₂ (in the formula, P ₂ represents a hydrogen atom or a thiol protecting group). Examples of the mercapto-protecting group include ester-type protective groups, arylalkyl-type protective groups, alkyl-type protective groups, arylalkyloxyalkyl-type protective groups, alkyloxyalkyl-type protective groups, methyl Silane type protecting group, oxycarbonyl type protecting group, etc. The description of these protecting groups is the same as above.

"Amine group that may also be protected" refers to an amine group protected by an amine group or an amine protecting group, which can, for example, be of formula -NH-P ₃ , formula -N(-P ₃ )(-P ₄ ) or formula =N (-P ₃ ) (In the formula, P ₃ and P ₄ each independently represent an amine group protecting group). Examples of the amino protecting group include alkyloxycarbonyl groups having 2 to 10 carbon atoms (such as methyloxycarbonyl, tert-butyloxycarbonyl, etc.), and arylalkyloxy groups having 8 to 11 carbon atoms. Carbonyl (e.g. benzyloxycarbonyl, etc.), 9-tylmethyloxycarbonyl, benzhydryl, trityl, 2,2,2-trichloroethyloxycarbonyl, allyloxy Carbonyl and so on. In addition, the amine group also includes an alicyclic amine group and a heterocyclic amine group.

"A carboxyl group that may also be protected" is a carboxyl group protected with a carboxyl group or a carboxyl protecting group, and can be represented by, for example, the formula -C(=0)(-OP ₅ ) (in the formula, P ₅ represents a hydrogen atom or a carboxyl protecting group). Examples of carboxyl protecting groups include alkyl groups having 1 to 10 carbon atoms (for example, methyl, ethyl, propyl, etc.), arylalkyl groups having 7 to 11 carbon atoms (for example, benzyl, etc.).

"A formyl group that may also be protected" is a formyl group protected by a formyl group or a formyl group protecting group, which can be exemplified by the formula -C(Y _a P ₆ )(Y _a P ₇ ) (where Y _a represents a heteroatom, and P ₆ and P ₇ each independently represent a hydroxy protecting group, or P ₆ and P ₇ may form an alkylene group together). The hetero atom is preferably an oxygen atom or a sulfur atom. Examples of the hydroxy protecting group include an alkyl group having 1 to 5 carbon atoms, preferably methyl, ethyl, propyl, butyl and the like. In addition, the number of carbon atoms of the alkylene group formed by P ₆ and P ₇ together is preferably 2-10, preferably 2-5, and more preferably 2 or 3.

The "aminomethyl group that may also be protected" is preferably represented by the formula -OC(=0)-NH(-P ₈ ) (in the formula, P ₈ represents an amine protecting group). Examples of the amino protecting group include alkyloxycarbonyl groups having 2 to 10 carbon atoms (such as methyloxycarbonyl, tert-butyloxycarbonyl, etc.), and arylalkyloxy groups having 8 to 11 carbon atoms. Carbonyl (e.g. benzyloxycarbonyl, etc.), 9-tylmethyloxycarbonyl, benzhydryl, trityl, 2,2,2-trichloroethyloxycarbonyl, allyloxy Carbonyl and so on.

"Also protected sulfonyl group" refers to a sulfonyl group protected by a sulfonyl group or a sulfonyl protecting group, for example, an alkyl sulfonyl group that may be substituted by more than one substituent, or may be substituted by more than one substituent The aryl base and so on. One or more substituents can be selected from, for example, substituent groups A to M. The substituents that the "alkyl" in the alkyl sulfide group can have are the same as the substituents for the aliphatic hydrocarbon group. The substituents that the "aryl" in the aryl sulfide group can have are the same as those for the aromatic hydrocarbon ring group. The number of carbon atoms in the alkyl group in the alkyl group is usually 1-10, preferably 1-5, and more preferably 1-3. The alkyl sulfonyl group that may be substituted with one or more substituents is, for example, an alkyl sulfonyl group that may be substituted with a halogen atom (for example, a methyl sulfonyl group, a trifluoromethyl sulfonyl group, etc.). The carbon number of the aryl group in the aryl group is usually 6-14, preferably 6-10. The aryl sulfonyl group that may be substituted with one or more substituents is, for example, an alkyl sulfonyl group that may be substituted by a halogen atom (for example, a phenyl sulfonyl group, p-tolyl group, etc.).

The "alkyl", "alkenyl", "alkynyl", "aryl", "heteroaryl" and "aliphatic heterocyclic ring" included in the substituents in Substituent Groups A to M can also be selected separately It is substituted by one or more substituents of Substituent Group A. In order to further substitute the "alkyl", "alkenyl", "alkynyl", "aryl", "heteroaryl" or "aliphatic heterocyclic ring" contained in the substituent, one member selected from Substituent Group A The above substituents are each independently preferably selected from halogen atoms, hydroxy groups that may also be protected, sulfhydryl groups that may also be protected, amine groups that may also be protected, methylic groups that may also be protected, or protected The carboxyl group, the amine methyl group that may also be protected, and the sulfonyl group that may be substituted are more preferably selected from halogen atoms, hydroxyl groups that may be protected, amine groups that may also be protected, and methyl groups that may also be protected. The acyl group and the carboxy group which may be protected are still more preferably a halogen atom.

。化合物(I)如上述，亦稱作C-芳基羥基二醇化物衍生物，且適合作為SGLT-2抑制藥之中間產物來使用。<Compound (I)> The compound (I) of the present invention is represented by the following formula (I),

. Compound (I) is also called C-aryl hydroxyglycolate derivative as mentioned above, and is suitable for use as an intermediate product of SGLT-2 inhibitor.

In formula (I), R ¹ and R ² each independently represent a hydroxyl protecting group, and R ³ and R ⁴ each independently represent a hydroxyl protecting group or a hydrogen atom.

The protective groups for the hydroxyl groups represented by R ¹ and R ² may be the same or different, but in consideration of the effective introduction and removal of the hydroxyl protective groups, they are preferably the same.

The hydroxyl protecting group represented by R ¹ and R ² is not particularly limited, but for example, ester type protecting group, arylalkyl type protecting group, alkyl type protecting group, arylalkyloxyalkyl type protecting group, Alkyloxyalkyl type protecting group, silyl type protecting group, oxycarbonyl type protecting group, etc. These protecting groups are synonymous with the foregoing.

The hydroxy protecting group represented by R ¹ and R ² is preferably methyloxymethyl, benzyloxymethyl, acetyl, propyl, butyryl, isopropyl, trimethyl acetyl, benzene Formyl, 4-nitrobenzyl, 4-methyloxybenzyl, 4-methylbenzyl, 4-tert-butylbenzyl, 4-fluorobenzyl Group, 4-chlorobenzyl, 4-bromobenzyl, 4-phenylbenzyl, 4-methyloxycarbonylbenzyl, benzyl, 1-phenylethyl, two Phenylmethyl, 1,1-diphenylethyl, naphthylmethyl, methyl, tert-butyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl Silyl group, tert-butyldiphenylsilyl group, tert-butyloxycarbonyloxy group or benzyloxycarbonyl group, more preferably benzyl group, acetyl group, trimethylacetyl group, trimethyl Ylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

In formula (I), the functional groups represented by R ³ and R ⁴ may also be hydrogen atoms. However, from the viewpoint of efficiently forming the 6-membered ring of formula (I), the functional groups represented by R ³ and R ^{4 are} preferably hydroxyl protecting groups.

The hydroxy protecting group represented by R ³ and R ⁴ may be the same as or different from the hydroxy protecting group represented by R ¹ or the hydroxy protecting group represented by R ² , but from the viewpoint of efficiently introducing and removing the protecting group, it is the same as R ^{It is} preferred that the hydroxyl protecting groups represented by ¹ and R ^{2 are} the same.

As long as the organic group represented by Ar is an aromatic hydrocarbon ring group which may have one or more substituents or an aromatic heterocyclic group which may have one or more substituents, it is used as the oxygen heterocyclic ring in formula (I) The functional group to be bonded is sufficient, and it is not particularly limited.

In one embodiment, the organic group represented by Ar is an aromatic hydrocarbon ring group which may also have one or more substituents, or an aromatic hydrocarbon ring group which may also have one or more substituents as the formula (I) The functional group bonded to the carbon atom of the oxygen heterocycle.

In another embodiment, the organic group represented by Ar is an aromatic heterocyclic group which may also have one or more substituents, or an aromatic hydrocarbon ring group which may also have one or more substituents as a group with formula (I ) The functional group bonded to the carbon atom of the oxygen heterocyclic ring.

The organic group containing an aromatic hydrocarbon ring group which may have one or more substituents as a functional group bonded to the carbon atom of the oxygen heterocyclic ring in formula (I) can be represented by the following formula, for example.

In the above formula, J ₁ represents an aromatic hydrocarbon ring group which may have one or more substituents, J ₂ represents an aliphatic hydrocarbon group which may have one or more substituents, and J ₃ represents a The aromatic hydrocarbon ring group of the substituent, the aliphatic heterocyclic group which may have more than one substituent, or the aromatic heterocyclic group which may also have more than one substituent, (*) represents the formula (I) The bonding of the carbon atoms of the oxygen heterocycle in the middle.

In one embodiment, J ₁ is an unsubstituted aromatic hydrocarbon ring group, and J ₂ is an unsubstituted aliphatic hydrocarbon group.

In another embodiment, J ₁ is an unsubstituted aromatic hydrocarbon ring group, and J ₂ is an aliphatic hydrocarbon group having one or more substituents.

In another embodiment, J ₁ is an aromatic hydrocarbon ring group having one or more substituents, and J ₂ is an unsubstituted aliphatic hydrocarbon group.

In another embodiment, J ₁ is an aromatic hydrocarbon ring group having one or more substituents, and J ₂ is an aliphatic hydrocarbon group having one or more substituents.

In one embodiment, J ₃ is an unsubstituted aromatic hydrocarbon ring group. This embodiment can be combined with the above-mentioned embodiments regarding J ₁ and J ₂ .

In another embodiment, J ₃ is an aromatic hydrocarbon ring group having one or more substituents. This embodiment can be combined with the above-mentioned embodiments regarding J ₁ and J ₂ .

In another embodiment, J ₃ is an unsubstituted aliphatic heterocyclic group. This embodiment can be combined with the above-mentioned embodiments regarding J ₁ and J ₂ .

In another embodiment, J ₃ is an aliphatic heterocyclic group having one or more substituents. This embodiment can be combined with the above-mentioned embodiments regarding J ₁ and J ₂ .

In another embodiment, J ₃ is an unsubstituted aromatic heterocyclic group. This embodiment can be combined with the above-mentioned embodiments regarding J ₁ and J ₂ .

In another embodiment, J ₃ is an aromatic heterocyclic group having one or more substituents. This embodiment can be combined with the above-mentioned embodiments regarding J ₁ and J ₂ .

In the embodiment in which the aliphatic hydrocarbon group represented by J ₂ has one or more substituents, one or more substituents can each independently be selected from, for example, the substituent group A to M. One or more substituents of the aliphatic hydrocarbon group represented by J ₂ can be independently selected from, for example, halogen atoms, nitro groups, cyano groups, pendant oxy groups, hydroxyl groups that may be protected, mercapto groups that may also be protected, and Amino groups that can be protected, methionine groups that can also be protected, carboxyl groups that can also be protected, amine methide groups that can also be protected, sulfonyl groups, aryl groups, and aliphatic heterocyclic groups that can also be protected. Heteroaryl, alkylaryl, alkyl aliphatic heterocyclic group, alkyl heteroaryl, arylalkyl, aliphatic heterocycloalkyl, heteroarylalkyl, alkyloxy, aryloxy , Aliphatic heterocyclic oxy, heteroaryloxy, alkylaryloxy, alkyl aliphatic heterocyclic oxy, alkyl heteroaryloxy, arylalkyloxy, aliphatic heterocycloalkane Alkyloxy, heteroarylalkyloxy, alkylthio, arylthio, aliphatic heterocyclic thio, heteroarylthio, alkylarylthio, alkyl aliphatic heterocyclic thio , Alkylheteroarylthio, arylalkylthio, aliphatic heterocycloalkylthio, heteroarylalkylthio, alkylcarbonyl, arylcarbonyl, aliphatic heterocyclic carbonyl, heteroaryl Carbonyl, alkylarylcarbonyl, alkyl aliphatic heterocyclic carbonyl, alkyl heteroaryl carbonyl, aryl alkyl carbonyl, aliphatic heterocycloalkyl carbonyl, heteroaryl alkyl carbonyl, alkyloxy carbonyl, Aryloxycarbonyl, aliphatic heterocyclic oxycarbonyl, heteroaryloxycarbonyl, alkylaryloxycarbonyl, alkyl aliphatic heterocyclic oxycarbonyl, alkyl heteroaryloxycarbonyl, aryl Alkyloxycarbonyl, aliphatic heterocycloalkyloxycarbonyl and heteroarylalkyloxycarbonyl. One or more substituents are each independently selected from halogen atoms, nitro groups, cyano groups, pendant oxy groups, hydroxyl groups that can also be protected, mercapto groups that can also be protected, amine groups that can also be protected, or protected The methanoyl group, the carboxyl group that can also be protected, the aminomethionyl group that can also be protected, the sulfonyl group that can also be protected, the alkyloxy group, the alkylthio group, the alkylcarbonyl group and the alkyloxycarbonyl group are preferred . In addition, when the aliphatic hydrocarbon group represented by J ₂ is a linear or branched aliphatic hydrocarbon group, the linear or branched aliphatic hydrocarbon group can have a cyclic aliphatic hydrocarbon group (e.g., cycloalkyl, cycloalkene Group, cycloalkynyl group, etc.) as a substituent.

In the embodiment where the aromatic hydrocarbon ring group represented by J ₁ and/or the aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by J ₃ has one or more substituents, one or more substituents The groups can be each independently selected from, for example, substituent groups A to M. _One or more substituents of the aromatic hydrocarbon ring group represented by J ₁ and/or the aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by J ₃ can each be independently selected from, for example, halogen atoms , Nitro, cyano, pendant oxy groups, hydroxy groups that can also be protected, sulfhydryl groups that can also be protected, amine groups that can also be protected, methionine groups that can also be protected, carboxyl groups that can also be protected, and Protected amine methyl group, also protected sulfonyl group, alkyl group, aryl group, aliphatic heterocyclic group, heteroaryl group, alkyl aryl group, alkyl aliphatic heterocyclic group, alkyl heteroaryl group Group, arylalkyl, aliphatic heterocycloalkyl, heteroarylalkyl, alkyloxy, aryloxy, aliphatic heterocyclooxy, heteroaryloxy, alkylaryloxy, Alkyl aliphatic heterocyclooxy, alkyl heteroaryloxy, arylalkyloxy, aliphatic heterocycloalkyloxy, heteroarylalkyloxy, alkylthio, arylthio , Aliphatic heterocyclic thio group, heteroaryl thio group, alkyl aryl thio group, alkyl aliphatic heterocyclic thio group, alkyl heteroaryl thio group, aryl alkyl thio group, aliphatic heterocyclic alkane Alkylthio, heteroarylalkylthio, alkylcarbonyl, arylcarbonyl, aliphatic heterocyclic carbonyl, heteroarylcarbonyl, alkylarylcarbonyl, alkyl aliphatic heterocyclic carbonyl, alkyl heteroaryl Carbonyl, arylalkylcarbonyl, aliphatic heterocycloalkylcarbonyl, heteroarylalkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aliphatic heterocyclic oxycarbonyl, heteroaryloxycarbonyl, Alkylaryloxycarbonyl, alkyl aliphatic heterocyclic oxycarbonyl, alkylheteroaryloxycarbonyl, arylalkyloxycarbonyl, aliphatic heterocycloalkyloxycarbonyl and heteroarylalkyl Oxycarbonyl.

The organic group containing an aromatic heterocyclic group which may have one or more substituents as a functional group bonded to the carbon atom of the oxygen heterocyclic ring in formula (I) can be represented by the following formula, for example.

In the above formula, K ₁ represents an aromatic heterocyclic group which may have one or more substituents, K ₂ represents an aliphatic hydrocarbon group which may also have one or more substituents, and K ₃ represents an aromatic heterocyclic group which may also have one or more substituents. The aromatic hydrocarbon ring group of the substituent, the aliphatic heterocyclic group which may have more than one substituent or the aromatic heterocyclic group which may also have more than one substituent, (*) represents the formula (I) The bonding of the carbon atoms of the carbonyl group.

In one embodiment, K ₁ is an unsubstituted aromatic heterocyclic group, and K ₂ is an unsubstituted aliphatic hydrocarbon group.

In another embodiment, K ₁ is an unsubstituted aromatic heterocyclic group, and K ₂ is an aliphatic hydrocarbon group having one or more substituents.

In another embodiment, K ₁ is an aromatic heterocyclic group having one or more substituents, and K ₂ is an unsubstituted aliphatic hydrocarbon group.

In another embodiment, K ₁ is an aromatic heterocyclic group having one or more substituents, and K ₂ is an aliphatic hydrocarbon group having one or more substituents.

In one embodiment, K ₃ is an unsubstituted aromatic hydrocarbon ring group. This embodiment can be combined with the above-mentioned embodiments regarding K ₁ and K ₂ .

In another embodiment, K ₃ is an aromatic hydrocarbon ring group having one or more substituents. This embodiment can be combined with the above-mentioned embodiments regarding K ₁ and K ₂ .

In another embodiment, K ₃ is an unsubstituted aliphatic heterocyclic group. This embodiment can be combined with the above-mentioned embodiments regarding K ₁ and K ₂ .

In another embodiment, K ₃ is an aliphatic heterocyclic group having one or more substituents. This embodiment can be combined with the above-mentioned embodiments regarding K ₁ and K ₂ .

In another embodiment, K ₃ is an unsubstituted aromatic heterocyclic group. This embodiment can be combined with the above-mentioned embodiments regarding K ₁ and K ₂ .

In another embodiment, K ₃ is an aromatic heterocyclic group having one or more substituents. This embodiment can be combined with the above-mentioned embodiments regarding K ₁ and K ₂ .

In the embodiment where the aliphatic hydrocarbon group represented by K ₂ has one or more substituents, the one or more substituents can each independently be selected from, for example, the substituent group A to M. One or more substituents of the aliphatic hydrocarbon group represented by K ₂ can be independently selected from, for example, halogen atoms, nitro groups, cyano groups, pendant oxy groups, hydroxyl groups that may be protected, mercapto groups that may also be protected, and Amino groups that can be protected, methionine groups that can also be protected, carboxy groups that can also be protected, amine methide groups that can also be protected, sulfonyl groups, aryl groups, aliphatic heterocyclic groups that can also be protected, Heteroaryl, alkylaryl, alkyl aliphatic heterocyclic group, alkyl heteroaryl, arylalkyl, aliphatic heterocycloalkyl, heteroarylalkyl, alkyloxy, aryloxy , Aliphatic heterocyclic oxy, heteroaryloxy, alkylaryloxy, alkyl aliphatic heterocyclic oxy, alkyl heteroaryloxy, arylalkyloxy, aliphatic heterocycloalkane Alkyloxy, heteroarylalkyloxy, alkylthio, arylthio, aliphatic heterocyclic thio, heteroarylthio, alkylarylthio, alkyl aliphatic heterocyclic thio , Alkylheteroarylthio, arylalkylthio, aliphatic heterocycloalkylthio, heteroarylalkylthio, alkylcarbonyl, arylcarbonyl, aliphatic heterocyclic carbonyl, heteroaryl Carbonyl, alkyl aryl carbonyl, alkyl aliphatic heterocyclic carbonyl, alkyl heteroaryl carbonyl, aryl alkyl carbonyl, aliphatic heterocycloalkyl carbonyl, heteroaryl alkyl carbonyl, alkyloxy carbonyl, Aryloxycarbonyl, aliphatic heterocyclic oxycarbonyl, heteroaryloxycarbonyl, alkylaryloxycarbonyl, alkyl aliphatic heterocyclic oxycarbonyl, alkyl heteroaryloxycarbonyl, aryl Alkyloxycarbonyl, aliphatic heterocycloalkyloxycarbonyl and heteroarylalkyloxycarbonyl. One or more substituents are each independently selected from halogen atoms, nitro groups, cyano groups, pendant oxy groups, hydroxyl groups that may also be protected, mercapto groups that may also be protected, amine groups that may also be protected, or protected The methanoyl group, the carboxyl group that can also be protected, the amine methionyl group that can also be protected, the sulfonyl group that can also be protected, the alkyloxy group, the alkylthio group, the alkylcarbonyl group and the alkyloxycarbonyl group are preferred . And, when the aliphatic hydrocarbon group represented by K ₂ is a linear or branched aliphatic hydrocarbon group, the linear or branched aliphatic hydrocarbon group can have a cyclic aliphatic hydrocarbon group (for example, cycloalkyl, cycloalkene Group, cycloalkynyl group, etc.) as a substituent.

In the embodiment where the aromatic heterocyclic group represented by K ₁ and/or the aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by K ₃ has one or more substituents, one or more substituents The groups can be each independently selected from, for example, substituent groups A to M. _One or more substituents of the aromatic heterocyclic group represented by K ₁ and/or the aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by K ₃ can each be independently selected from, for example, halogen atoms , Nitro, cyano, pendant oxy groups, hydroxy groups that can also be protected, sulfhydryl groups that can also be protected, amine groups that can also be protected, methionine groups that can also be protected, carboxyl groups that can also be protected, and Protected amine methyl group, also protected sulfonyl group, alkyl group, aryl group, aliphatic heterocyclic group, heteroaryl group, alkyl aryl group, alkyl aliphatic heterocyclic group, alkyl heteroaryl group Group, arylalkyl, aliphatic heterocycloalkyl, heteroarylalkyl, alkyloxy, aryloxy, aliphatic heterocyclooxy, heteroaryloxy, alkylaryloxy, Alkyl aliphatic heterocyclooxy, alkyl heteroaryloxy, arylalkyloxy, aliphatic heterocycloalkyloxy, heteroarylalkyloxy, alkylthio, arylthio , Aliphatic heterocyclic thio group, heteroaryl thio group, alkyl aryl thio group, alkyl aliphatic heterocyclic thio group, alkyl heteroaryl thio group, aryl alkyl thio group, aliphatic heterocycloalkane Alkylthio, heteroarylalkylthio, alkylcarbonyl, arylcarbonyl, aliphatic heterocyclic carbonyl, heteroarylcarbonyl, alkylarylcarbonyl, alkyl aliphatic heterocyclic carbonyl, alkyl heteroaryl Carbonyl, arylalkylcarbonyl, aliphatic heterocycloalkylcarbonyl, heteroarylalkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aliphatic heterocyclic oxycarbonyl, heteroaryloxycarbonyl, Alkylaryloxycarbonyl, alkyl aliphatic heterocyclic oxycarbonyl, alkylheteroaryloxycarbonyl, arylalkyloxycarbonyl, aliphatic heterocycloalkyloxycarbonyl and heteroarylalkyl Oxycarbonyl.

The aromatic hydrocarbon ring group or aromatic heterocyclic group bonded to the oxygen heterocyclic ring in formula (I) contained in the organic group represented by Ar is preferably an aromatic hydrocarbon ring group with 6 to 14 carbons or 3 ~12 aromatic heterocyclic group, more preferably an aromatic hydrocarbon ring group with 6 to 10 carbons or an aromatic heterocyclic group with 3 to 8 carbons, still more preferably phenyl, thienyl, benzo Thiophenyl, furyl, pyrrolyl, imidazolyl, or pyridyl, more preferably phenyl, thienyl or benzothiophenyl, and still more preferably phenyl.

The organic group represented by Ar is the same as the aromatic hydrocarbon ring group or aromatic heterocyclic group possessed by the SGLT-2 inhibitor from the viewpoint of manufacturing the SGLT-2 inhibitor or its derivative, or is the aromatic hydrocarbon A cyclic group or a group derived from an aromatic heterocyclic group is preferred.

Here, canagliflozin (canagliflozin; 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene ), Empagliflozin (Empagliflozin; (1S)-1,5-anhydride-1-C-{4-chloro-3-[(4-{[(3S)-oxolane-3-yl]oxy }Phenyl)methyl]phenyl}-D-sorbitol), Ipragliflozin (Ipragliflozin; (1S)-1,5-anhydride-1-C-{3-[(1-benzothiophene- 2-yl)methyl)-4-fluorophenyl}-D-sorbitol—(2S)-pyrrolidine-2-carboxylic acid) and Dapagliflozin; (2S,3R,4R,5S,6R )-2-[4-chloro-3-(4-ethyloxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-mercapto) is representative The SGLT-2 inhibitor has an aromatic hydrocarbon ring group or aromatic heterocyclic group represented by the following formula (V) or formula (Va).

。Therefore, by one type, the organic group represented by Ar is represented by the following formula (V),

.

Formula (V), R ^a is each independently a group selected from a halogen atom, an alkyl group, alkenyl group, alkynyl group, aryl group, arylalkyl group, arylalkenyl group, arylalkynyl group, an alkyl group, an alkenyl group Functional groups consisting of oxy, alkynyloxy, aryloxy, arylalkyloxy, arylalkenyloxy and arylalkynyloxy groups, and alkyl and alkenyl groups included in the foregoing groups , Alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, arylalkyloxy, aryl Alkenyloxy and arylalkynyloxy may each have one or more substituents.

In the formula (V), the functional groups represented by ^{Ra are} preferably independently selected from halogen atoms, alkyl groups with 1 to 20 carbons, aryl groups with 6 to 14 carbons, and arylalkyls with 7 to 15 carbons. , Alkyloxy having 1-20 carbons and arylalkyloxy having 7-15 carbons, more preferably selected from halogen atoms and alkyls having 1-10 carbons.

In formula (V), n represents an integer from 0 to 4. The integer represented by n is preferably 1 to 3, more preferably 1 or 2. n is 2 or more, R ^a s n may be the same or different.

In the formula (V), Ar' represents an aromatic hydrocarbon ring group which may have one or more substituents, an aliphatic heterocyclic group which may also have one or more substituents, or one or more substituents The aromatic heterocyclic group. Ar' preferably represents an aromatic hydrocarbon ring group which may also have one or more substituents or an aromatic heterocyclic group which may also have one or more substituents.

The functional group represented by Ar' is preferably an aromatic hydrocarbon ring group with 6 to 14 carbons that may have more than one substituent or an aromatic heterocyclic group with 3 to 12 carbons that may also have more than one substituent. The ring is more preferably an aromatic hydrocarbon ring group with 6 to 14 carbon atoms which may have one or more substituents or an aromatic heterocyclic ring with carbon number 3 to 12 which may also have one or more substituents, and More preferably, it is a phenyl group which may also have one or more substituents, a thienyl group which may also have one or more substituents, a benzothiophenyl group which may also have one or more substituents, and may have 1 Furanyl with more than one substituent, pyrrolyl with more than one substituent, imidazolyl with more than one substituent, or pyridyl with more than one substituent, and more Preferably, it is a phenyl group which may also have one or more substituents, a thienyl group which may also have one or more substituents, or a benzothiophenyl group which may also have one or more substituents.

One or more substituents of the functional group represented by Ar' are preferably phenyl which can be substituted by halogen atoms, alkyloxy groups with 1 to 5 carbon atoms, and aliphatic heterocyclic oxy groups (such as tetrahydrofuran Oxy group etc.) and so on.

By a further preferred form, in formula (I), the organic group represented by Ar is represented by the following formula (Va).

The functional group represented by R ^a has the same meaning as described above.

表示。In formula (V) and formula (Va), Ar' is preferably a functional group represented by the following formulas (Va-I), (Va-II), and (Va-III).

Said.

In formulas (IVa-I), (IVa-II) and (IVa-III), R ^b each independently represents a group selected from aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups and aromatic heterocyclic groups The functional groups of the group, the aliphatic hydrocarbon group, aromatic hydrocarbon ring group, aliphatic heterocyclic group, and aromatic heterocyclic group included in the aforementioned group may each have one or more substituents.

The functional group represented by R ^b is preferably each independently selected from an alkyl group with 1 to 20 carbons that may have more than one substituent, and an alkenyl group with 2 to 20 carbons that may have more than one substituent. , Alkynyl groups with 2 to 20 carbon atoms that may have more than one substituent, aromatic hydrocarbon ring groups with 6 to 14 carbon atoms that may have more than one substituent, and more than one substituent The aliphatic heterocyclic group with 2 to 12 carbon atoms and the aromatic heterocyclic group with 3 to 12 carbon atoms that may have more than one substituent are more preferably selected from those that may have more than one substituent Alkyl with 1 to 10 carbons, alkenyl with 2 to 10 carbons that may have more than one substituent, alkynyl with 2 to 10 carbons that may also have more than one substituent, and An aromatic hydrocarbon ring group with 6 to 10 carbon atoms that may have one or more substituents and an aliphatic heterocyclic group with 2 to 5 carbon atoms that may have more than one substituent, which may have more than one The phenyl group of the substituent or the tetrahydropyranyl group which may have more than one substituent is more preferable.

One or more substituents of the functional group represented by R ^b can each independently be selected from, for example, substituent groups A to M. One or more substituents of the functional group represented by R ^b can be independently selected from, for example, halogen atoms, nitro groups, cyano groups, pendant oxy groups, hydroxyl groups that may be protected, mercapto groups that may also be protected, and Protected amine group, also protected formyl group, may be protected carboxyl group, may be protected amine formyl group, may be protected sulfonyl group, alkyl group, aryl group, aliphatic heterocyclic ring Group, heteroaryl group, alkyl aryl group, alkyl aliphatic heterocyclic group, alkyl heteroaryl group, aryl alkyl group, aliphatic heterocyclic alkyl group, heteroaryl alkyl group, alkyloxy group, aryl group Oxy, aliphatic heterocyclic oxy, heteroaryloxy, alkylaryloxy, alkyl aliphatic heterocyclic oxy, alkyl heteroaryloxy, arylalkyloxy, aliphatic hetero Cycloalkyloxy, heteroarylalkyloxy, alkylthio, arylthio, aliphatic heterocyclic thio, heteroarylthio, alkylarylthio, alkyl aliphatic heterocycle Thio, alkylheteroarylthio, arylalkylthio, aliphatic heterocycloalkylthio, heteroarylalkylthio, alkylcarbonyl, arylcarbonyl, aliphatic heterocyclic carbonyl, hetero Aryl carbonyl, alkyl aryl carbonyl, alkyl aliphatic heterocyclic carbonyl, alkyl heteroaryl carbonyl, aryl alkyl carbonyl, aliphatic heterocycloalkyl carbonyl, heteroaryl alkyl carbonyl, alkyloxy Carbonyl, aryloxycarbonyl, aliphatic heterocyclic oxycarbonyl, heteroaryloxycarbonyl, alkylaryloxycarbonyl, alkyl aliphatic heterocyclic oxycarbonyl, alkyl heteroaryloxycarbonyl, Arylalkyloxycarbonyl, aliphatic heterocycloalkyloxycarbonyl and heteroarylalkyloxycarbonyl. One or more substituents are each independently selected from halogen atoms, nitro groups, cyano groups, pendant oxy groups, hydroxyl groups that may also be protected, mercapto groups that may also be protected, amine groups that may also be protected, or protected Formyl, carboxyl which may also be protected, amineformyl which may also be protected, alkyl, alkyl, alkyloxy, alkylthio, alkylcarbonyl and alkyloxy which may also be protected The carbonyl group is preferred. One or more substituents are each independently selected from halogen atoms, nitro groups, hydroxy groups that may also be protected, sulfhydryl groups that may also be protected, methylic groups that may also be protected, amine groups that may also be protected, and A protected carboxyl group, an optionally protected sulfonyl group and an alkyloxycarbonyl group with 1 to 10 carbons are more preferred, and are selected from halogen atoms, amine groups, nitro groups, alkyloxy groups with 1 to 10 carbons, and carbon An alkyloxycarbonyl group of 1 to 10 is more preferable.

In the formula (Va-I), p represents an integer of 0-5. The integer represented by p is preferably 0-3, more preferably 0-2, and still more preferably 0 or 1. In formulas (Va-II) and (Va-III), the integer represented by p is preferably 0-5, more preferably 0-3, and still more preferably 0-2. When p is 2 or more, p R ^b may be the same or different.

In the formula (Va-I), p is preferably 1, and R ^{b is} preferably a phenyl group that may have more than one substituent, more preferably a phenyl group having a halogen atom, and still more preferably a fluorine atom. The phenyl of the atom. The position to which the phenyl group which may have one or more substituents is bonded is preferably the 2-position of the thiophene ring. In the phenyl group having a halogen atom, the position to which the halogen atom is bonded is preferably the 4-position of the benzene ring.

In formula (Va-II), p is preferably zero.

In formula (Va-III), p is preferably 1, and R ^{b is} preferably an alkyl group which may also have one or more substituents or an aliphatic heterocyclic group which may also have one or more substituents. The alkyl group that may have one or more substituents is preferably an alkyl group having 1 to 3 carbon atoms, and more preferably a methyl group or an ethyl group. The aliphatic heterocyclic group which may have one or more substituents is preferably a tetrahydropyranyl group. The position where the alkyl group which may have one or more substituents or the aliphatic heterocyclic group which may have one or more substituents is bonded is preferably the 4-position of the benzene ring.

In another preferred form, in formula (I), the organic group represented by Ar is the following (VII), (V-II-I), (V-III-I) or (V-III-II) ) Means.

。<Method for producing compound (I)> The method for producing compound (I) of the present invention includes the following steps (a) and (b). Step (a): a transition metal catalyst selected from the group consisting of more than one transition metal catalyst selected from nickel catalysts and palladium catalysts, or a transition metal catalyst with more than one transition metal catalyst mentioned above and a support for supporting more than one transition metal catalyst mentioned above In the presence of the supporting catalyst of the body, the compound (II) represented by the following formula (II) is combined with the compound (III-I) represented by the following formula (III-I) and the following formula (III- II) The step of reacting at least one organozinc compound in the group of the compound (III-II) to obtain the compound (IV) represented by the following formula (IV); Step (b): the compound (IV) The step of removing the hydroxyl protecting group represented by R ^{5 to} obtain the aforementioned compound (I),

.

The steps (a) and (b) are described in sequence below. <Step (a)>

化合物(II)之準備步驟之詳細作為步驟(a-1)來後述。<Compound (II)> In step (a), a compound (II) represented by the following formula (II) is prepared.

The details of the preparation step of compound (II) will be described later as step (a-1).

6-membered rings view hydroxy protecting group R ⁵ represents an efficient form of formula (I) of view, the removal of the R ¹ represents a hydroxyl protecting group or R ² represents the same hydroxyl-protecting group. The hydroxyl protecting group represented by R ⁵ is removed to produce a hydroxyl group, which reacts with the carbonyl group in the same molecule to form a ring of formula (I). Therefore, to maintain a hydroxy protecting group R ¹ R ² represents the same time, it is possible to selectively remove hydroxy-protecting group represented by R ^5, the selection of the type R ⁵ represents a protective group of a hydroxyl group preferred.

The hydroxy protecting group represented by R ⁵ is not particularly limited, but for example, ester type protecting group, arylalkyl type protecting group, alkyl type protecting group, arylalkyloxyalkyl type protecting group arylalkyl Alkyloxyalkyl type protecting group, silyl type protecting group, oxycarbonyl type protecting group, more preferably ester type protecting group, arylalkyloxyalkyl type protecting group alkyloxyalkyl type Protecting group, silyl type protecting group, oxycarbonyl type protecting group. More specifically, the hydroxy protecting group represented by R ⁵ is preferably methyloxymethyl, benzyloxymethyl, acetyl, propyl, butyryl, isopropyl, trimethylacetyl , Benzyl, 4-nitrobenzyl, 4-methyloxybenzyl, 4-methylbenzyl, 4-tert-butylbenzyl, 4-fluorobenzene Formyl, 4-chlorobenzyl, 4-bromobenzyl, 4-phenylbenzyl, 4-methyloxycarbonylbenzyl, benzyl, 1-phenylethyl , Diphenylmethyl, 1,1-diphenylethyl, naphthylmethyl, methyl, tert-butyl, trimethylsilyl, triethylsilyl, tert-butyldimethyl Benzyl silyl group, tert-butyldiphenylsilyl group, tert-butyloxycarbonyloxy group, benzyloxycarbonyl group, more preferably methyl group, benzyl group, acetyl group, trimethyl ethyl Acetyl, trimethylsilyl or tert-butyldimethylsilyl, tert-butyldiphenylsilyl.

Moreover, by a preferred form, the hydroxy protecting group represented by R ⁵ is an ester type protecting group, the hydroxy protecting group represented by R ^{1 and} the hydroxy protecting group represented by R ² are each independently selected from the group consisting of aryl alkyl type protecting groups, Group type protecting group, arylalkyloxyalkyl type protecting group, alkyloxyalkyl type protecting group, silyl type protecting group and oxycarbonyl type protecting group arylalkyl group. Furthermore, by a further preferred form, the hydroxy protecting group represented by R ⁵ is acetyl or trimethyl acetyl, the hydroxy protecting group represented by R ^{1 and} the hydroxy protecting group represented by R ² are each independently selected from methyl , Benzyl, trimethylsilyl or tert-butyldimethylsilyl, tert-butyldiphenylsilyl.

Moreover, according to another preferred form of the present invention, the hydroxyl protecting group represented by R ⁵ is a silyl type protecting group, and the hydroxyl protecting group represented by R ^{1 and} the hydroxyl protecting group represented by R ² are each independently selected from ester type protecting groups. Group, arylalkyl type protecting group, alkyl type protecting group, arylalkyloxyalkyl type protecting group, alkyloxyalkyl type protecting group, silyl type protecting group and oxycarbonyl type protecting group Groups of alkyl groups. Moreover, by another preferred form, the hydroxyl protecting group represented by R ⁵ is trimethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl, R The hydroxy protecting group represented by ^{1 and} the hydroxy protecting group represented by R ² are each independently selected from methyl, benzyl, acetyl or trimethyl acetyl.

In addition, from the viewpoint of more efficiently forming the 6-membered ring of formula (I), the hydroxyl protecting group represented by R ⁵ is preferably different from the hydroxyl protecting group represented by R ¹ , R ² , R ³ and R ⁴ .

In one form, the hydroxy protecting group represented by R ⁵ is an ester type protecting group, and the hydroxy protecting groups represented by R ¹ , R ² , R ³ and R ⁴ are each independently selected from aryl alkyl type protecting groups and alkyl type protecting groups. Protective groups, arylalkyloxyalkyl-type protective groups, alkyloxyalkyl-type protective groups, silyl-type protective groups, and oxycarbonyl-type protective groups. Furthermore, by a further preferred form, the hydroxy protecting group represented by R ⁵ is acetyl or trimethyl acetyl, and the hydroxy protecting groups represented by R ¹ , R ² , R ³ and R ⁴ are each independently selected from Group, benzyl, trimethylsilyl or tert-butyldimethylsilyl, tert-butyldiphenylsilyl.

Moreover, according to another preferred form of the present invention, the hydroxyl protecting group represented by R ⁵ is a silyl protecting group, and the hydroxyl protecting groups represented by R ¹ , R ² , R ³ and R ⁴ are each independently selected from aryl groups Alkyloxyalkyl type protecting group, alkyloxyalkyl type protecting group and oxycarbonyl type protecting group arylalkyl group. And, by another preferred form, the hydroxyl protecting group represented by R ⁵ is trimethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl, R ^1. The hydroxyl protecting groups represented by R ² , R ³ and R ⁴ are each independently selected from the group consisting of methyl, benzyl, acetyl and trimethyl acetyl.

In formula (II), Q represents an aliphatic hydrocarbon group that may have one or more substituents, an aromatic hydrocarbon ring group that may have one or more substituents, and an aliphatic that may have one or more substituents A heterocyclic group or an aromatic heterocyclic group which may have one or more substituents is used as an organic group for the functional group bonded to the sulfur atom in the formula (II).

In one embodiment, the organic group represented by Q is an aliphatic hydrocarbon group which may have one or more substituents, or an aliphatic hydrocarbon group which may have one or more substituents as the sulfur atom in formula (II) Bonded functional group.

In another embodiment, the organic group represented by Q is an aromatic hydrocarbon ring group which may have one or more substituents, or an aromatic hydrocarbon ring group which may also have one or more substituents as the formula (II ) The functional group bonded with the sulfur atom.

In another embodiment, the organic group represented by Q is an aliphatic heterocyclic group which may have one or more substituents, or an aliphatic heterocyclic group which may also have one or more substituents as the formula (II ) The functional group bonded with the sulfur atom.

In another embodiment, the organic group represented by Q is an aromatic heterocyclic group which may also have one or more substituents, or an aromatic heterocyclic group which may also have one or more substituents as the formula (II ) The functional group bonded with the sulfur atom.

[式中，L₁ 表示亦可具有1個以上之取代基之脂肪族烴基，L₂ 表示亦可具有1個以上之取代基之芳香族烴環基、亦可具有1個以上之取代基之脂肪族雜環基或亦可具有1個以上之取代基之芳香族雜環基，(*)表示與式(II)中之硫原子鍵結之鍵結]。An organic group containing an aliphatic hydrocarbon group which may also have one or more substituents as a functional group bonded to the sulfur atom in formula (II) can be represented by, for example, the following formula:

[In the formula, L ₁ represents an aliphatic hydrocarbon group which may also have one or more substituents, L ₂ represents an aromatic hydrocarbon ring group which may also have one or more substituents, or one which may have one or more substituents The aliphatic heterocyclic group or the aromatic heterocyclic group which may have one or more substituents, (*) represents the bond to the sulfur atom in formula (II)].

[式中，L₁ 及L₂ 與前述同義，L₃ 表示亦可具有1個以上之取代基之脂肪族烴基，(*)表示與式(II)中之硫原子鍵結之鍵結]。Furthermore, an organic group containing an aliphatic hydrocarbon group which may also have one or more substituents as a functional group bonded to the sulfur atom in formula (II) can be represented by the following formula, for example,

[In the formula, L ₁ and L _{2 have the} same meaning as described above, L ₃ represents an aliphatic hydrocarbon group that may have one or more substituents, and (*) represents a bond to the sulfur atom in formula (II)].

[式中，L₁ 、L₂ 及L₃ 與前述同義，L₄ 表示亦可具有1個以上之取代基之芳香族烴環基、亦可具有1個以上之取代基之脂肪族雜環基或亦可具有1個以上之取代基之芳香族雜環基，(*)表示與式(II)中之硫原子鍵結之鍵結]。Furthermore, an organic group containing an aliphatic hydrocarbon group which may also have one or more substituents as a functional group bonded to the sulfur atom in formula (II) can be represented by the following formula, for example,

[In the formula, L ₁ , L ₂ and L _{3 have the} same meaning as above, and L ₄ represents an aromatic hydrocarbon ring group which may have one or more substituents, or an aliphatic heterocyclic group which may have one or more substituents Or an aromatic heterocyclic group with one or more substituents, (*) represents the bond to the sulfur atom in formula (II)].

_One or more substituents that can be possessed by the aliphatic hydrocarbon group represented by L ₁ or L ₃ can each independently, for example, substituent groups A to M, and are preferably selected from substituent group A. _One or more substituents that the aliphatic hydrocarbon group represented by L ₁ or L ₃ can have are each independently selected from halogen atoms, hydroxyl groups that may also be protected, mercapto groups that may also be protected, amine groups that may also be protected, and The methanoyl group which can be protected, the carboxyl group which can also be protected, the amine methanoyl group which can also be protected, and the sulfonyl group which can also be protected are preferable. The aliphatic hydrocarbon group represented by L ₁ or L ₃ may be unsubstituted. In addition, when the aliphatic hydrocarbon group represented by L ₁ and/or L ₃ is a linear or branched aliphatic hydrocarbon group, the linear or branched aliphatic hydrocarbon group can have a cyclic aliphatic hydrocarbon group (for example, a cyclic aliphatic hydrocarbon group). Alkyl, cycloalkenyl, cycloalkynyl, etc.) as a substituent.

One or more substituents which can be possessed by the aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by L ₂ or L _{4 are} , for example, substituent group A to M, preferably substituent group A ~D and G are more preferably selected from substituent groups A, B and G. The aromatic hydrocarbon ring group, aliphatic heterocyclic group, or aromatic heterocyclic group represented by L ₂ or L ₄ can have one or more substituents independently selected from halogen atoms, or protected hydroxyl groups, or A protected sulfhydryl group, a protected amine group, a protected formyl group, a protected carboxyl group, a protected amine formyl group, a protected sulfide group, an alkyl group, Alkyloxy, aryloxy, arylalkyloxy, alkylarylalkyloxy, heteroaryloxy, heteroarylalkyloxy, alkylheteroarylalkyloxy, Aliphatic heterocyclooxy, aliphatic heterocycloalkyloxy and alkyl aliphatic heterocycloalkyloxy are preferred. The aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by L ₂ or L ₄ may be unsubstituted.

[式中，M₁ 表示亦可具有1個以上之取代基之芳香族烴環基、亦可具有1個以上之取代基之脂肪族雜環基，或亦可具有1個以上之取代基之芳香族雜環基，M₂ 表示亦可具有1個以上之取代基之脂肪族烴基，(*)表示與式(II)中之硫原子鍵結之鍵結]。An aromatic hydrocarbon ring group that may have one or more substituents, an aliphatic heterocyclic group that may have one or more substituents, or an aromatic heterocyclic group that may have one or more substituents as The organic group of the functional group bonded to the sulfur atom in formula (II) can be represented by the following formula, for example,

[In the formula, M ₁ represents an aromatic hydrocarbon ring group which may have one or more substituents, an aliphatic heterocyclic group which may have one or more substituents, or one which may have one or more substituents Aromatic heterocyclic group, M ₂ represents an aliphatic hydrocarbon group which may have more than one substituent, (*) represents a bond to the sulfur atom in formula (II)].

[式中，M₁ 及M₂ 與前述同義，M₃ 表示亦可具有1個以上之取代基之芳香族烴環基、亦可具有1個以上之取代基之脂肪族雜環基，或亦可具有1個以上之取代基之芳香族雜環基，(*)表示與式(II)中之硫原子鍵結之鍵結]。In addition, an organic group containing an aromatic hydrocarbon ring group that may have one or more substituents as a functional group bonded to the sulfur atom in formula (II) can be represented by the following formula, for example,

[In the formula, M ₁ and M _{2 have the} same meaning as above, and M ₃ represents an aromatic hydrocarbon ring group which may have more than one substituent, an aliphatic heterocyclic group which may also have more than one substituent, or also For aromatic heterocyclic groups that may have more than one substituent, (*) represents the bond to the sulfur atom in formula (II)].

[式中，M₁ 、M₂ 及M₃ 與前述同義，M₄ 表示亦可具有1個以上之取代基之脂肪族烴基，(*)表示與式(II)中之硫原子鍵結之鍵結]。In addition, an organic group containing an aromatic hydrocarbon ring group which may have one or more substituents as a functional group bonded to the sulfur atom in formula (II) can be represented by, for example, the following formula:

[In the formula, M ₁ , M ₂ and M _{3 have the} same meaning as above, M ₄ represents an aliphatic hydrocarbon group which may have more than one substituent, and (*) represents the bond to the sulfur atom in formula (II) End].

In the embodiment where the aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by M ₁ has one or more substituents, the one or more substituents can be each independently selected from, for example, substituent group A ~M. One or more substituents of the aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by M ₁ are each independently selected from a halogen atom, a protected hydroxyl group, and a protected mercapto group , Amine group that can also be protected, methionine that can also be protected, carboxyl that can also be protected, amine methionyl that can also be protected, sulfonyl, alkyl, alkenyl and alkyne that can also be protected The base is better. The aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by M ₁ may be unsubstituted.

In the embodiment where the aliphatic hydrocarbon group represented by M ₂ and/or M ₄ has one or more substituents, the one or more substituents can each independently be selected from, for example, the substituent group A to M. One or more substituents of the aliphatic hydrocarbon group represented by M ₂ and/or M ₄ are each independently selected from halogen atoms, hydroxyl groups that may be protected, mercapto groups that may be protected, and amine groups that may also be protected, The methionyl group that may also be protected, the carboxyl group that may also be protected, the amine methionyl group that may also be protected, and the sulfonyl group that may also be protected are preferred. The aliphatic hydrocarbon group represented by M ₂ or M ₄ may also be unsubstituted. In addition, when the aliphatic hydrocarbon group represented by M ₂ and/or M ₄ is a linear or branched aliphatic hydrocarbon group, the linear or branched aliphatic hydrocarbon group can have a cyclic aliphatic hydrocarbon group (for example, a cyclic aliphatic hydrocarbon group). Alkyl, cycloalkenyl, cycloalkynyl, etc.) as a substituent.

In the embodiment where the aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by M ₃ has one or more substituents, the one or more substituents can each independently be, for example, selected from the substituent group A ~M. One or more substituents of the aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by M ₃ are each independently selected from halogen atoms, hydroxyl groups that may be protected, and mercapto groups that may also be protected , Amine group that can also be protected, methionine that can also be protected, carboxyl that can also be protected, amine methionine that can also be protected, sulfonyl, alkyl, and alkyloxy that can also be protected , Aryloxy, arylalkyloxy, alkylarylalkyloxy, heteroaryloxy, heteroarylalkyloxy, alkylheteroarylalkyloxy, aliphatic heterocycle An oxy group, an aliphatic heterocycloalkyloxy group, and an alkyl aliphatic heterocycloalkyloxy group are preferred. The aromatic hydrocarbon ring group, aliphatic heterocyclic group or aromatic heterocyclic group represented by M ₃ may be unsubstituted.

The organic group represented by Q preferably includes alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl Group or heteroarylalkynyl group as the functional group bonded to the sulfur atom in formula (II), more preferably contains alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl or The arylalkynyl group serves as the functional group bonded to the sulfur atom in the formula (II). The carbon number of the alkyl group is, for example, 1-20, preferably 1-10, the carbon number of the arylalkyl group is, for example, 7-20, preferably 7-15, and the carbon number of the aryl group is, for example, 6-20. It is preferably 6-10, and the carbon number of the heteroaryl group is, for example, 5-20, preferably 5-9.

。<Reaction using organozinc compound> In step (a), one or more transition metal catalysts selected from nickel catalysts and palladium catalysts, or one or more transition metal catalysts and one type In the presence of the supporting catalyst of the above transition metal catalyst, the compound (II) is selected from the compound (III-I) represented by the following formula (III-I) and the following formula (III-II) At least one organozinc compound in the group of compound (III-II) represented by) reacts to obtain compound (IV) represented by the following formula (IV),

.

。藉由較佳型態，至少1種有機鋅化合物包含前述化合物(III-I)，且化合物(III-I)為上述平衡狀態。In step (a), the organozinc compound is used as a reagent for introducing Ar groups into compound (II). The organozinc compound can use either compound (III-I) and compound (III-II) alone, but compound (III-I) and compound (III-II) in step (a), in the reaction system, From the viewpoint that the following formula can be appropriately obtained to represent the equilibrium state, it is better to use it with compound (III-I) and compound (III-II),

. By the preferred form, at least one organozinc compound includes the aforementioned compound (III-I), and the compound (III-I) is in the above-mentioned equilibrium state.

The halogen atom represented by X is not particularly limited, but preferably a chlorine atom, a bromine atom, or an iodine atom.

The organozinc compound of the compound (III-I) and the compound (III-II) can also be commercially available, and can also be produced according to a known method as described in Non-Patent Document 5 and the like.

According to one embodiment, the organozinc compound of compound (III-I) is produced by reacting the Grignard reagent ArMgX with zinc halide ZnX ₂ in an organic solvent.

In the production of compound (III-I), the amount of zinc halide used is usually about 0.9 to 1.5 equivalents relative to 1 equivalent of Grignard reagent, preferably about 1 to 1.2 equivalents, and more preferably about 1 to 1.1 equivalents.

As the organic solvent used in the production of compound (III-I), from the viewpoint of stable production, an ether-based solvent is preferred, 2-methyltetrahydrofuran, tetrahydrofuran, etc. are more preferred, and tetrahydrofuran is still more preferred .

The reaction temperature in the production of compound (III-I) is usually -50 to 50°C, preferably 0 to 30°C.

[式中，X及Y各自獨立表示鹵原子]。鋰鹽複合物(III-Ia)在鋰鹽之存在下，能夠藉由實施化合物(III-I)之製造而適當地取得。鋰鹽複合物(III-Ia)亦可為化合物(III-I)之鋰鹽錯體。Compound (III-I) can also be used as a complex with a lithium salt (in the formula, Y is a halogen atom). The lithium salt complex of the aforementioned compound (III-I) is represented by the following formula (III-Ia),

[In the formula, X and Y each independently represent a halogen atom]. The lithium salt complex (III-Ia) can be appropriately obtained by producing the compound (III-I) in the presence of a lithium salt. The lithium salt complex (III-Ia) may also be a lithium salt complex of the compound (III-I).

In step (a), it is better to use the lithium salt complex (III-Ia) to increase the reaction rate of the organozinc compound.

Examples of the lithium salt include lithium chloride, lithium bromide, lithium iodide, and the like, but lithium chloride is preferred. Therefore, in the lithium salt complex (III-Ia) of the organozinc compound, X and Y are preferably chlorine, bromine or iodine, and more preferably chlorine or bromine.

The lithium salt complex (III-Ia) of the organozinc compound can also be a commercially available product, or can be produced by a known method. As a preferable manufacturing method, there are Turbo Grignard reagent ArMgXa･LiY [where Ar is synonymous with the above, Xa is a halogen atom] and zinc halide ZnX ₂ [where X is a halogen atom, which may also be the same as Y Or different] The method of reaction in an organic solvent.

Turbo Grignard reagent can be replaced by inert gas (nitrogen, argon, etc.) in the reaction vessel, in the presence of lithium salt, magnesium and halogen organic compound ArXa [in the formula, Ar and Xa are synonymous with the foregoing] in an organic solvent In response to.

From the viewpoint of improving reactivity, magnesium is preferably used as a pulverized product or a shavings. In addition, from the viewpoint of improving its reactivity, in the organic solvent, relative to 1 equivalent of magnesium, a reducing agent such as diisobutyl aluminum hydride (DIBAL-H) of about 0.05 to 0.2 equivalent can also be added to the organic solvent. In magnesium.

In the manufacture of Turbo Grignard reagents, the amount of lithium salt used is usually about 1 equivalent of magnesium, usually about 0.5 to 5.0 equivalents, preferably about 0.5 to 3.0 equivalents, and more preferably about 0.5 to 2.0 equivalents. can.

In the manufacture of Turbo Grignard reagents, the amount of halogen organic compound ArXa used is about 0.5 to 3.0 equivalents relative to 1 equivalent of magnesium, preferably about 0.5 to 2.0 equivalents, and more preferably about 0.5 to 1.5 equivalents That's it.

As the organic solvent used in the manufacture of the Turbo Grignard reagent, from the viewpoint of stable manufacture, an ether-based solvent is preferred, diethyl ether, tetrahydrofuran, etc. are more preferred, and tetrahydrofuran is still more preferred. The amount of solvent used is usually 1 to 1000 times the capacity relative to the halogen organic compound ArXa, preferably 1 to 100 times the capacity.

The reaction temperature in the manufacture of Turbo Grignard reagent is usually -50~50°C, preferably -20~20°C. Moreover, the reaction time is usually 0.5 to 5 hours, preferably 1 to 3 hours.

藉由使Knochel-Hauser鹼基TMPMgXa･LiY(TMP為2,2,6,6-四甲基哌啶)與化合物Ar-H反應來製造，本案發明中亦包含相關之型態。In addition, the Turbo Grignard reagent ArMgXa･LiY may be represented by the following formula according to a known method described in Angew Chem. Int. Ed 2006, 45, 2958, etc.

It is produced by reacting the Knochel-Hauser base TMPMgXa･LiY (TMP is 2,2,6,6-tetramethylpiperidine) with the compound Ar-H. The present invention also includes related forms.

The lithium salt complex of organozinc compound can be manufactured by mixing Turbo Grignard reagent and zinc halide in a solvent. The reaction between Turbo Grignard reagent and zinc halide is preferably carried out in an ether solvent (tetrahydrofuran, etc.) in the same way as the manufacture of Turbo Grignard reagent.

The reaction between Turbo Grignard reagent and zinc halide can usually be carried out at a temperature of -30~30℃. And, the reaction time is usually 0.1 to 1 hour.

In step (a), the usage amount of the organozinc compound or its lithium salt complex can be appropriately set according to the amount of compound (II). The usage amount of the organozinc compound can be usually set to 1 to 5 equivalents, preferably 1 to 3 equivalents with respect to 1 equivalent of compound (II).

The organozinc compound or its lithium salt complex can also be added to the reaction system after mixing the migration catalyst and the compound (II), or it can be mixed with the migration catalyst at the same time as the compound (II), but mixing the migration catalyst and the compound (II) After compound (II), it is preferable to add it to the reaction system.

Moreover, in step (a), the zinc halide ZnX ₂ can also be added to the reaction system of step (a) together with the organic zinc compound or its lithium salt complex from the viewpoint of activating the organozinc compound and increasing the yield in. The amount of zinc halide added to the reaction system together with the organozinc compound or its lithium salt complex is usually 1 equivalent to the organozinc compound or its lithium salt complex, usually about 0.05 to 1.0 equivalent, preferably 0.05 to 0.3 The equivalent is about, more preferably about 0.05 to 0.2 equivalent. Zinc halide can also be added to the reaction system of step (a) separately with the organozinc compound or lithium salt complex, and can also be added at the same time with the organozinc compound or its lithium salt complex, but to mix the zinc halide and the organozinc in advance The state of the compound or its lithium salt complex is preferably added to the reaction system of step (a).

The reaction environment takes into account the activity of the aforementioned migration catalyst, and it is usually better to proceed in an inert gas environment such as argon and nitrogen. Furthermore, it may be under pressure, normal pressure, or reduced pressure.

In one embodiment, the nickel catalyst is a nickel salt or a solvent. The valence of the nickel atom contained in the nickel salt is usually divalent. Examples of nickel salts include nickel dichloride (II), nickel dibromide (II), nickel difluoride (II), nickel iodide (II) (NiI ₂ ), nickel (II) sulfate, nickel (II) Carbonate, Nickel (II) Dimethylglyoxime, Nickel Hydroxide (II), Nickel (II) Hydroxyacetate, Nickel (II) Oxalate, Nickel (II) 2-Ethyl Caproic acid ester, nickel (II) acetate, nickel (II) trifluoroacetate, nickel (II) triflate, nickel (II) acetylpyruvate (Ni(acac) ₂ ) Wait.

In another embodiment, the nickel catalyst is a nickel complex catalyst. The nickel complex catalyst includes a nickel atom and a ligand chelated to the nickel atom. The nickel complex catalyst can be advantageously used from the viewpoint of an increase in reaction yield or a decrease in by-products. The valence of the nickel atom in the nickel complex catalyst is preferably 0 or divalent, and more preferably divalent. The nickel atoms contained in the nickel complex catalyst come from, for example, nickel salts or solvents added to the reaction system. In the embodiment where the nickel catalyst is a nickel complex catalyst, a pre-formed nickel complex catalyst can also be added to the reaction system, or a nickel salt or solvent and ligand can be added to the reaction system. A nickel complex catalyst is formed in the reaction system. When a nickel complex catalyst is formed in the reaction system, the amount of ligands is, for example, about 1 to 3 equivalents relative to 1 equivalent of nickel salt, preferably about 1 to 2 equivalents.

The ligand contained in the nickel complex catalyst is a molecule or ion that is bonded to a nickel atom by coordinate bonding. The ligand can also be a single-seat ligand or a multi-seat ligand. A single coordinator is a coordinator. Multiple ligands are more than two ligands. The two ligands are ligands with 2 coordination atoms, the three ligands are ligands with 3 coordination atoms, and the four ligands are ligands with 4 coordination atoms. Coordinating atoms are atoms directly connected to the coordination bond. In the nickel complex catalyst, the ratio of ligands to nickel atoms is not particularly limited, but when the ligands are single-seat ligands, the number of ligands per nickel atom is usually 2 to 4 , Preferably two. In addition, when the ligand is a multi-seat ligand, it is preferable to coordinate at least one nickel atom per one ligand. The number of nickel atoms per 1 ligand is, for example, 1 to 3. The preferred ligand is a phosphine ligand or a nitrogen ligand.

The phosphine ligand is a ligand containing a phosphorus atom as a coordination atom. The phosphine ligand may also be a single-seat ligand or a multi-seat ligand, but a multi-seat phosphine ligand is preferred.

As the phosphine ligand, there are, for example, trimethylphosphine, tri-n-butylphosphine (P ⁿ Bu ₃ ), tricyclopentylphosphine, tricyclohexylphosphine (PCy ₃ ), trioctylphosphine (P( Oct) ₃ ), triphenylphosphine (PPh ₃ ) and other single-coordinated phosphines; 1,1'-bis(diphenylphosphino)ferrocene (dppf), 1,2-bis(diphenyl) Phosphonyl) ethane (dppe), 1,2-bis(diphenylphosphino)butane (dppb), 1,2-bis(dicyclohexylphosphino)ethane (dcype), 1,2- Bis(dimethylphosphino)ethane (dmpe), 3,4-bis(dicyclohexylphosphino)thiophene (dcypt), 1,3-bis(diphenylphosphino)propane (dppp), 2, 2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) and other two-coordinated multiple phosphines; bis(2-diphenylphosphinoethyl)phenylphosphine, Three seats of 1,1,1-ginseng (diphenylphosphinomethyl)ethane, 1,1,1-ginseng (bis(3,5-dimethylphenyl)phosphinomethyl)ethane, etc. Coordinated multiple phosphines; (2-diphenylphosphinoethyl) phosphine and other four coordinated multiple phosphines, but preferably tricyclohexylphosphine, triphenylphosphine, 1,2-bis( Diphenylphosphino)ethane, 1,2-bis(dicyclohexylphosphino)ethane, 1,2-bis(dimethylphosphino)ethane or 3,4-bis(dicyclohexylphosphino) ) Thiophene and other single-coordinated or two-coordinated phosphines, more preferably triphenylphosphine, 1,2-bis(dicyclohexylphosphino)ethane or 3,4-bis(dicyclohexylphosphine) The two coordinated phosphines such as thiophene and the like are more preferably 3,4-bis(dicyclohexylphosphino)thiophene.

Phosphine ligands also include derivatives of the aforementioned phosphine ligands. Examples of the derivation of the phosphine ligand include introduction of one or more substituents. As one or more substituents for introducing a phosphine ligand, there are, for example, alkyl, aryl, arylalkyl, alkylaryl, alkyloxy, alkyloxyalkyl, aryloxy, Aryloxyalkyl, halogen atom, dialkyl, nitro, oxycarbonyl, etc.

The nitrogen ligand is a ligand containing a nitrogen atom as a coordination atom. Nitrogen ligands are usually basic. The nitrogen ligand is, for example, an amine-based or imine-based multiple ligand.

Examples of nitrogen ligands include 2,2-bipyridine (bpy), 4,4'-dimethyl-2,2'-bipyridine (bmbpy), 4,4'-di-tert-butyl -2,2'-bipyridine (BBBPY), 4,4'-bis-(5-nonyl)-2,2'-bipyridine, 1,10-phenanthroline, N-(n-propyl)pyridine Methaneimine, N-(n-octyl)pyridylmethaneimine, N, N, N', N'-tetramethylethylenediamine (TMDTA), etc. ; N, N, N', N", N"-pentamethyldiethylene triamine (PMDTA), N-propyl-N,N-bis(2-pyridylmethyl)amine, etc. Three-coordinated multi-seat amine; hexamethylgins(2-aminoethyl)amine, N,N-bis(2-dimethylaminoethyl)-N,N'-dimethylethylene Diamine, 2,5,9,12-tetramethyl-2,5,9,12-tetraazatetradecane, 2,6,9,13-tetramethyl-2,6,9,13 -Tetraazatetradecane, 4,11-dimethyl-1,4,8,11-tetraazabicyclohexadecane, N',N''-dimethyl-N',N''- Bis((pyridin-2-yl)methyl)ethane-1,2-diamine, ginseng[(2-pyridyl)methyl]amine, 2,5,8,12-tetramethyl-2,5 ,8,12-Tetraazatetradecane and other four-coordinated polyamines; N,N,N',N'',N''', N'''',N''''-seven Five-coordinated multi-seat amines such as methyltetraethylenetetramine; N,N,N',N'-four (2-pyridylmethyl)ethylenediamine and other six-coordinated amines Polyamine; polyamine, polyethyleneimine, etc., but preferably 2,2-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 4,4 '-Di-tert-butyl-2,2'-bipyridine and other multi-seat amines with two-seat coordination of bipyridyl.

Nitrogen ligands also include derivatives of the aforementioned nitrogen ligands. Examples of the derivation of the nitrogen ligand include introduction of one or more substituents. As one or more substituents for introducing nitrogen ligands, for example, alkyl, aryl, arylalkyl, alkylaryl, alkyloxy, alkyloxyalkyl, aryloxy, Aryloxyalkyl, halogen atom, dialkyl, nitro, oxycarbonyl, etc.

Examples of other ligands included in the nickel complex catalyst include cyclooctadiene (COD), tetrahydrofuran (thf), dimethoxyethane (dme), and the like.

As the nickel catalyst used in the present invention, there are, for example, nickel(0) cyclooctadiene complex (Ni(COD) ₂ ), nickel(II) acetylpyruvate, nickel(II) dichloride or Its dimethoxyethane adduct, nickel (II) dibromide, nickel (II) dichlorobistriphenylphosphine complex, nickel (II) dibromide bistriphenylphosphine complex, nickel ( II) Dichlorotri-n-butylphosphine complex, nickel(II) dichloro1,2-diphenylphosphine complex, nickel(II)dichloro 1,3-diphenylphosphinopropane complex, Bis (tetrahydrofuran) nickel (II) dichloro complex (NiCl ₂ (thf) ₂ ) and other divalent nickel catalysts, preferably nickel (II) dichloride or its dimethoxyethane adduct, nickel (II) Dichloro 1,2-diphenylphosphinoethane complex, nickel(II) acetylpyruvate or bis(tetrahydrofuran) nickel(II) dichloro complex, more preferably nickel(II) ) Dichloro 1,2-diphenylphosphinoethane complex, nickel(II) acetylpyruvate or bis(tetrahydrofuran) nickel(II) dichloro complex, more preferably bis(tetrahydrofuran) Nickel (II) dichloro complex. These can also be used individually or in mixture of 2 or more types. In step (a), the use of a nickel catalyst is particularly advantageous in that the reaction proceeds rapidly.

As the palladium catalyst used in the present invention, for example, palladium(II) dichloride, palladium(II) dibromide, palladium(II) dichlorobistriphenylphosphine complex, palladium(0) tetraphenyl Phosphine complex, palladium(II) acetate, palladium(II), palladium(0), palladium(II) dichloride, palladium(II) dibromide, palladium(II) dichlorobistriphenylphosphine complex, Palladium(0)4-triphenylphosphine complexes, palladium(II) acetate, palladium(II) and other 0-valent or divalent palladium catalysts, but preferably palladium(0)4-triphenylphosphine complexes, Palladium (0). The use of palladium catalyst is advantageous in reducing the amount of by-products produced by the coupling reaction between Ar groups.

The migration catalyst used in the present invention can also be a uniform catalyst or a non-uniform catalyst.

When the transition metal catalyst used in the present invention is a homogeneous catalyst, the transition metal catalyst is preferably a zero-valent or divalent nickel complex or a zero-valent or divalent palladium complex. As the nickel complex, nickel(II) acetylpyruvate, nickel(II) dichloro dimethoxyethane adduct, or bis(tetrahydrofuran) nickel(II) dichloro complex is preferred. In addition, the palladium complex is preferably a palladium(0) triphenylphosphine complex or a bis(tetrahydrofuran) nickel(II) dichloro complex.

When the transition metal catalyst used in the present invention is a heterogeneous catalyst, the transition metal catalyst has one or more transition metal catalysts selected from the group consisting of nickel catalysts and palladium catalysts, and one or more transition metal catalysts supporting the foregoing one or more The supporting catalyst of the metal catalyst is better. The supporting catalyst is advantageous in that it is easy to separate the transition metal catalyst from the reaction mixture.

As the support of the supporting catalyst, there are, for example, activated carbon, alumina, barium sulfate, calcium carbonate, hydroxyphosphate lime, hydrotalcite, alumina, titanium dioxide, zirconium dioxide, silica, clay, and silicic acid. Salt, zeolite, polymer matrix, etc. The polymer matrix can also be, for example, styrene-divinylbenzene resin or phenol-formaldehyde resin. The aforementioned resins can also be bonded to chelating ligands (phosphine, 1,10-phenanthroline or 2,2'-bipyridine, etc. ). The ligand bonded to the resin can form a complex with the palladium catalyst or the nickel catalyst, and immobilize these migration catalysts as a heterogeneous catalyst.

Among the supporting catalysts, the transition metal catalyst is preferably a zero-valent or divalent palladium catalyst, and more preferably palladium(0). Moreover, when the transition metal catalyst of the supporting catalyst is a palladium catalyst, the supporting body in the supporting catalyst is preferably activated carbon, alumina, barium sulfate, calcium carbonate, hydroxyphosphate lime, hydrotalcite, and alumina , Titanium dioxide, zirconium dioxide, more preferably activated carbon. With a particularly good form, the supporting catalyst is palladium black and palladium carbon (Pd/C).

The amount of the transition metal catalyst in the supporting catalyst relative to the total weight of the supporting catalyst is, for example, 0.05-10% by weight, preferably 0.1-7% by weight, and more preferably 4-7% by weight.

The usage amount of the transition metal catalyst is usually about 0.001 to 2 mol, preferably about 0.01 to 1 mol, relative to 1 mol of the organic zinc compound.

As the solvent used in step (a), an organic solvent is preferred, for example, N,N-dimethylformamide (DMF), dimethyl sulfide (DMSO), 1,2-dimethoxy Ethane, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, cyclopentyl methyl ether (CPME), tert-butyl methyl ether, diisopropyl ether, N,N-dimethylacetamide (DMA) , Diethylene glycol dimethyl ether, methyl-tetrahydrofuran, 1,4-dioxane and other polar aprotic solvents; toluene, methylene chloride, hexane, heptane, xylene, 1,4- Non-polar solvents such as dioxane, dibutyl ether, mesitylene, p-p-isopropyl toluene, or combinations of these, but preferably THF, 2-methyl-THF, dibutyl ether, Toluene, DMF or these mixed solvents are more preferably THF.

The amount of the solvent used in step (a) is not particularly limited, but it can be, for example, a capacity of 1 to 100 times that of compound (II).

With an implementation type, in step (a), the reaction temperature can also be implemented at about 0~100°C, but it is usually 0~60°C, preferably 0~50°C, more preferably 10~50°C . Adopting such mild temperature conditions and obtaining compound (a) are better in terms of suppressing equipment costs related to temperature management and implementing industrial production.

Moreover, when the transition metal catalyst is a nickel catalyst, in step (a), the reaction temperature is preferably 0-50°C, more preferably 10-50°C, still more preferably 20-30°C, and even more preferably It is about 25°C. Moreover, when the transition metal catalyst is a palladium catalyst, in step (a), the reaction temperature is preferably 45~90°C, more preferably 45~80°C, still more preferably 50~70°C, and even more preferably It is about 60°C.

In step (a), the reaction time can also be appropriately determined corresponding to the amount of the substrate used, the amount of the catalyst, the reaction temperature, etc., and is usually 0.5 to 48 hours, preferably 1 to 24 hours.

步驟(b)中，將步驟(a)所得之化合物(IV)中R⁵ 表示之羥基保護基去除，得到化合物(I)。<Step (b)>

In step (b), the hydroxyl protecting group represented by R ⁵ in compound (IV) obtained in step (a) is removed to obtain compound (I).

The method for removing R ⁵ can be adapted to the type of hydroxyl protecting group, and can be removed by known methods described in the fifth edition of "Protective Group in Organic Synthesis" by Peter GM Wuts (published by JOHN WILEY & SONS). As a typical method, there is a method of reacting compound (II) with an acidic reagent or a basic reagent in an inactive solvent to remove R ⁵ .

Examples of acid reagents include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and hydrogen bromide, and organic acids such as trifluoroacetic acid, trichloroacetic acid, p-toluenesulfonic acid, formic acid, and phthalic acid. There are no particular limitations on the basic reagents, but fluorides such as tetra-n-butylammonium fluoride, ammonium fluoride, ammonium difluoride, and hydrogen fluoride acid, potassium carbonate, and lithium hydroxide , Water sodium oxide, water potassium oxide, sodium methyl oxide, sodium ethyl oxide, ammonia water, etc.

The usage amount of the acid reagent is usually 0.1 to 1000 equivalents, preferably 1 to 5 equivalents relative to 1 equivalent of compound (II). In addition, the usage amount of the basic reagent is usually 0.001 to 10 equivalents, preferably 0.01 to 2 equivalents relative to 1 equivalent of compound (II).

As the solvent used in the step (b), an organic solvent is preferred, for example, polar protic solvents such as methanol, ethanol, isopropanol, butanol; acetonitrile, propionitrile, THF, 2-methyl-tetrahydrofuran , 1,4-dioxane, tert-butyl methyl ether, diisopropyl ether, dimethyloxyethane, diethylene glycol dimethyl ether, acetone, methyl ethyl ketone, diethyl ketone , Methyl acetate, ethyl acetate, butyl acetate, etc. Polar aprotic solvents: methyl chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, toluene, xylene, hexane Non-polar solvents such as alkane, heptane, etc. or a combination of these, but preferably methanol, ethanol, isopropanol, or a mixed solvent of these.

The amount of solvent used in step (b) is usually 1 to 1000 times the capacity, preferably 1 to 100 times the capacity relative to compound (II).

In step (b), the reaction temperature is usually -30~100°C, preferably 0~100°C, more preferably 0~40°C, even more preferably 0~50°C. The use of such mild temperature conditions to obtain compound (I) is better in terms of suppressing equipment costs related to temperature management and implementing industrial production.

製造化合物(I)之方法中，作為出發原料使用之化合物(II)亦可購入，亦可製造，但根據步驟(a-1)製造較佳。<Step (a-1): Production of Compound (II)>

In the method for producing compound (I), compound (II) used as a starting material can also be purchased or produced, but it is preferable to produce according to step (a-1).

Step (a-1) can be divided into the following steps (a-1-1) and step (a-1-2) and implemented. Step (a-1-1): The compound (VI) represented by the following formula (VI) is reacted with the compound (VII) represented by the following formula (VII) to obtain the compound (VIII) represented by the following formula (VIII) The step, and step (a-1-2): The step of protecting the hydroxyl group in the aforementioned compound (VIII) with a hydroxyl protecting group represented by R ^{5 to} obtain the aforementioned compound (II).

步驟(a-1-1)中，實施使化合物(VI)與化合物(VII)反應，得到化合物(VIII)之步驟。<Step (a-1-1): Production of Compound (VIII)>

In step (a-1-1), a step of reacting compound (VI) with compound (VII) to obtain compound (VIII) is carried out.

The compound (VI) used as the starting material in step (a-1-1) is not particularly limited, but it may be, for example, the known method described in Non-Patent Document 1, Non-Patent Document 2, etc. or the method described in Example 1 below To manufacture, you can also use commercially available products.

The compound (VII) can also be produced by a known method, and a commercially available organic mercapto compound can also be used.

The amount of compound (VII) used is not particularly limited, but for example, it is usually 1 to 10 equivalents, preferably 1 to 5 equivalents based on 1 equivalent of compound (VI).

化合物(IX)之取得方法並無特別限定，亦可藉由公知手法來製造，亦可使用市售之鋁觸媒。The reaction conditions of compound (VI) and compound (VII) are not particularly limited as long as compound (VIII) can be obtained, but they are preferably carried out in the presence of compound (IX) represented by the following formula (IX).

The method for obtaining the compound (IX) is not particularly limited, and it may be produced by a known method, or a commercially available aluminum catalyst may be used.

R ^c and R ^d each independently represent a functional group selected from the group consisting of halogen atoms, aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups and aromatic heterocyclic groups, aliphatic hydrocarbon groups contained in the foregoing groups, The aromatic hydrocarbon ring group, the aliphatic heterocyclic group, and the aromatic heterocyclic group may each have one or more substituents.

The functional groups represented by R ^c and R ^d are each independently preferably an alkyl group, an aryl group, and an arylalkyl group, more preferably an alkyl group having 1 to 20 carbons, an aryl group having 6 to 20 carbons, and 7 carbon atoms. The arylalkyl group of ~20 is more preferably an alkyl group having 1 to 10 carbon atoms, and even more preferably a methyl group, an ethyl group, or a propyl group.

In the formula (IX), the functional group represented by R ^{c and} the functional group represented by ^Rd may be the same or different from each other, but they are preferably the same. And, with the preferred form, one of q or r represents 0, and the other represents 3.

In step (a-1-1), the amount of compound (IX) used is 1 equivalent of compound (VI), usually 1 to 5 equivalents, preferably 3 to 5 equivalents.

As the solvent used in the step (a-1-1), an organic solvent is preferred, for example, acetonitrile, propionitrile, THF, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butylmethyl Ether, diisopropyl ether, dimethyloxyethane, diethylene glycol dimethyl ether, acetone, methyl ethyl ketone, diethyl ketone, methyl acetate, ethyl acetate, butyl acetate, etc. Polar aprotic solvent; non-polar solvents such as methyl chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, toluene, xylene, hexane, heptane, etc. or a combination of these , But preferably is chlorinated methylene, toluene, hexane or a mixed solvent of these, more preferably chlorinated methylene.

The amount of solvent used in step (a-1-1) is not particularly limited, but it is usually 1 to 1000 times the capacity, preferably 1 to 100 times the capacity relative to compound (VI).

In step (a-1-1), the reaction temperature is not particularly limited, but it is usually -30 to 80°C, preferably -10 to 40°C, and more preferably 0 to 40°C. It is better to use relatively mild temperature conditions in this step to suppress the cost of equipment for temperature management.

In step (a-1-1), the reaction of the aluminum catalyst reaction is completed using water, HCl aqueous solution, ammonia chloride aqueous solution, etc., and the catalyst can be easily removed.

Therefore, after the compound (VIII) is obtained in this step (a-1), it is better to carry out the production steps of the following step (a-1-2) as soon as possible. The steps (a-1-1) and step ( a-1-2) It is better to implement in the same reaction system. Moving quickly from step (a-1-1) to step (a-1-2) is advantageous in preventing compound (VI) from regenerating due to the ring-closure reaction of compound (VIII).

<Step (a-1-2): Manufacturing Step of Compound (II)>

In step (a-1-2), the hydroxyl group in compound (VIII) represented by the following formula (VIII) is protected with a hydroxyl protecting group represented by R ^{5 to} obtain compound (II).

The introduction of the R ⁵ group of the hydroxyl group in the compound (VIII) is not particularly limited. Depending on the type of the hydroxyl protecting group represented by R ⁵ , it can be based on Peter GM Wuts "Protective Group in Organic Synthesis" 5th Edition" (JOHN WILEY&SONS Publication) and other records are implemented. As a typical method, there is a method of reacting the compound (VIII) and the protecting group-introducing reagent in the presence of an acid or basic reagent in an inert solvent to introduce R ⁵ .

The protective group introduction reagent can be appropriately determined according to the type of R ⁵ , but examples include ester-type protective group introduction agents such as acetic anhydride, trimethyl acetic anhydride, acetyl chloride, and trimethyl acetyl chloride; Introducing agent of aryl alkyl ether type protecting group such as benzyl bromide; Introducing agent of alkyl ether type protecting group such as methyl iodide; Trimethylsilyl chloride, triisopropylsilyl chloride, tert-chloride Introducing agents for silyl-type protecting groups such as butyldimethylsilane, tert-butyldiphenylsilyl chloride, etc. Oxycarbonyl-type protection of bis(tert-butyloxycarbonyloxy) oxide, etc. However, it is preferably an ester-type protecting group introducing agent such as acetic anhydride, trimethylacetic anhydride, acetyl chloride, and trimethyl acetyl chloride, and more preferably acetic anhydride.

Examples of acid reagents include inorganic acids such as acetic acid and hydrogen bromide, and organic acids such as p-toluenesulfonic acid and phthalic acid. The basic reagents are not particularly limited, but there are organic chemicals such as triethylamine, 4-dimethylaminopyridine (DMAP), diazabicycloundecene (DBU), and diethylaniline. Amine, etc., but preferably triethylamine, 4-dimethylaminopyridine (DMAP) or a mixture of these.

The amount of the acid reagent used is not particularly limited, but it is usually 0.1 to 1000 equivalents, preferably 1 to 5 equivalents relative to 1 equivalent of compound (VIII). In addition, the amount of the basic reagent used is not particularly limited, but it is usually 0.001 to 10 equivalents, preferably 0.01 to 2 equivalents relative to 1 equivalent of compound (VIII).

As the solvent used in step (a-1-2), an organic solvent is preferred, for example, acetonitrile, propionitrile, THF, 2-methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl Ether, diisopropyl ether, dimethyloxyethane, diethylene glycol dimethyl ether, acetone, methyl ethyl ketone, diethyl ketone, methyl acetate, ethyl acetate, butyl acetate, etc. Polar aprotic solvent; non-polar solvents such as methyl chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, toluene, xylene, hexane, heptane, etc. or a combination of these , But it is preferably methyl chloride, toluene or a mixed solvent of these.

The amount of the solvent used in step (a-1-2) is not particularly limited, but it is usually 1 to 1000 times the capacity, preferably 1 to 100 times the capacity relative to compound (VIII).

In step (a-1-2), the reaction temperature is not particularly limited, but it is usually -30~100°C, preferably -30~40°C, more preferably -10~40°C, and still more preferably 0~30℃. The use of relatively mild temperature conditions in this step is advantageous in inhibiting the reaction from compound (VIII)) to compound (VI). Moreover, the use of relatively mild temperature conditions in this step is better in terms of suppressing equipment costs related to temperature management and implementing industrial production.

<Production procedure of β-C-aryl glycoside derivative (Compound (XI))>

In the present invention, the compound (I) is the compound (XI) represented by the following formula (XI), that is, it can be advantageously used as a raw material for the production of β-C-aryl glycoside derivatives.

The reaction from compound (I) to compound (XI) can use a known reduction reaction. Specifically, as a reduction method, there is a method of reducing compound (I) using triethylsilane in the presence of boron trifluoride diethyl ether complex (BF ₃ ･OEt ₂ ), or a method of reducing compound (I) in the presence of triethyl In the presence of silane compounds such as methyl silane, triisopropyl silane, tetramethyldisiloxane, etc., make BF ₃ ･OEt ₂ , boron trifluoride tetrahydrofuran (BF ₃ ･THF), aluminum chloride, etc. Methods of reacting acid with compound (I), etc.

When the obtained compound (XI) directly or R ¹ ', R ² ', R ³ 'or R ⁴ ' is a hydroxyl protecting group, it can meet expectations, according to Peter GM Wuts "Protective Group in Organic Synthesis" 5th edition "(Published by JOHN WILEY & SONS), etc., to deprotect it and use it as a β-C-aryl glycoside derivative.

＜Use of compound (II)/manufacturing intermediate products＞ According to the present invention, as described above, compound (II) can be used as a production intermediate to produce compound (I), and then converted into compound (XI) corresponding to the SGLT2 inhibitor itself or its synthesis intermediate. That is, according to the present invention, compound (II) can be suitably applied as a reagent or intermediate product for producing compound (XI).

且，藉由本案發明之較佳型態，前述試藥中，式(XI)中Ar為式(V)或(Va)表示。Therefore, with the preferred form of the present invention, it is possible to provide a reagent for producing the aforementioned compound (XI) represented by the following formula (XI), which contains the compound (II) represented by the following formula (II) .

Moreover, according to the preferred form of the present invention, in the aforementioned reagent, Ar in formula (XI) is represented by formula (V) or (Va).

且，藉由本案發明之較佳型態，前述使用中，式(XI)中Ar為式(V)或(Va)表示。 [實施例]Furthermore, according to another aspect of the present invention, it is possible to provide a compound (II) represented by the following formula (II) as an intermediate for the production of the aforementioned compound (XI) represented by the following formula (XI).

Moreover, according to the preferred form of the present invention, in the aforementioned use, Ar in formula (XI) is represented by formula (V) or (Va). [Example]

The following describes embodiments of the present invention, but the present invention is not limited to these embodiments.

Example 1: Compound (2) ((3R,4S,5R,6R)-3,4,5-gin (benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran- 2-ketone) manufacturing

Put a solution containing compound (1) (2,3,4,6-tetra-O-benzyl-D-glucopyranose; 5.0g, 9.24mmol) in dimethylsulfoxide (25mL) under argon environment Stir at 20~25°C for 30 minutes. Acetic anhydride (15 mL) was added to this reaction mixture at 25°C over a period of five minutes. After the addition, the resulting reaction mixture was detected by thin layer chromatography (TLC) analysis, and stirred at 20-25°C for 20 hours. Next, the reaction mixture was diluted with toluene (100 mL), and 1N HCl aqueous solution (120 mL) was added to the resulting diluted solution to quench the excess acetic anhydride. After stirring the resulting reaction mixture at 20-25°C for 20 minutes, phase separation is performed. The obtained organic phase was washed with 1M NaHCO ₃ aqueous solution (3×50 mL). Furthermore, the organic phase was washed with water (15 mL) and brine (15 mL), and then dried with Na ₂ SO ₄ anhydride, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel tube chromatography (ethyl acetate/hexane=2/20~3/20) to obtain compound (2) ((3R, 4S, 5R, 6R)-3,4,5-ginseng(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one; 4.8g, yield 96%).

Compound (2) IR(KBr): νmax=3030, 2868, 1754, 1496, 1363, 1164, 1097, 737, 698cm ^{-1 1} H NMR(400MHz, CDCl ₃ )δ: 7.39-7.16(m, 20H), 4.97(d, J=11.4Hz, 1H), 4.73-4.44(m, 8H), 4.12(d, J=6.3Hz, 1H), 3.96-3.89(m, 2H), 3.73-3.64(m, 2H) ¹³ C NMR(101MHz, CDCl ₃ )δ: 169.38, 137.71, 137.64, 137.63, 137.06, 128.57, 128.53, 128.48, 128.19, 128.09, 128.07, 128.02, 127.91, 81.06, 78.26, 77.51, 76.20, 73.98, 73.80, 73.78 , 73.66, 68.40 HRMS[M+H] ⁺ C ₃₄ H ₃₅ O ₆ Calculated value 539.2428; Actual measurement value: 539.2420 Quality analysis [M+H] ⁺ : 539

Example 2: Compound (3) ((2R,3S,4R,5R)-S-decyl 2,3,4,6-four (benzyloxy)-5-hydroxyhexane thiol ester) manufacture

In a solution containing decanethiol (0.72g, 4.1mmol) in CH ₂ Cl ₂ anhydride (10mL) cooled to 0°C, drop trimethylaluminum (1M toluene solution; 4.1mL, 4.1mmol) over 10 minutes mmol), stirring for 20 minutes. Next, a solution containing compound (2) (2 g, 3.71 mmol) in CH ₂ Cl ₂ anhydride (12 mL) was slowly added to the resulting reaction mixture over 10 minutes, and stirred for 1 hour. The resulting reaction mixture was diluted with CH ₂ Cl ₂ (20 mL), added to a 250 mL beaker containing ice-cold water (20 mL), and then slowly poured into the beaker while stirring the 1N HCl aqueous solution (10 mL) for phase separation. The resulting aqueous phase was extracted with cold CH ₂ Cl ₂ (3×30 mL). The organic phase of the mixed organic extract was washed with water and brine, dried with Na ₂ SO ₄ , and filtered with a sudden boiling tower using CH ₂ Cl ₂ as the eluent to obtain compound (3)((2R) ,3S,4R,5R)-S-decyl 2,3,4,6-si (benzyloxy)-5-hydroxyhexane thiol ester) crude product. After that, the obtained crude product of compound (3) was used in the following steps without purification.

Example 3: Compound (4) ((2R,3R,4S,5R)-1,3,4,5-tetra(benzyloxy)-6-(decylthio)-6-oxyhexyl Alk-2-yl acetate) manufacturing

Under an argon environment, add acetic anhydride (Ac ₂ O; 0.88 mL, 9.5 mmol) to a solution containing the crude product (2.8 g, 3.71 mmol) of compound (3) in CH ₂ Cl ₂ anhydride cooled to 0°C, Furthermore, DMAP (9 mg, 2 mol%) was added. After 5 minutes, triethylamine (1.32 mL, 9.5 mmol) was added to the resulting mixture, and the mixture was stirred for 4 hours under an argon atmosphere. The resulting reaction mixture was quenched with water (30 mL), and the organic phase was extracted with CH ₂ Cl ₂ (3×30 mL). The organic phase of the mixed organic extracts was washed with water (30 mL) and brine (30 mL), dried with Na ₂ SO ₄ anhydride and concentrated. The obtained crude product was purified by silica chromatography (ethyl acetate/hexane=1/20~2/20) to obtain compound (4)((2R,3R,4S,5R)-1 as a colorless liquid ,3,4,5-Si(benzyloxy)-6-(decylthio)-6-oxyhexane-2-yl acetate; 2.6g, based on compound (2) The yield is 92%).

Compound (4) IR (KBr): νmax=3063, 3031, 2926, 2860, 1745, 1676, 1452, 1375, 1244, 1093, 1069, 745, 696cm ^{-1 1} H-NMR (400MHz, CDCl ₃ )δ: 7.40(d, J=6.5Hz, 2H), 7.36-7.15(m, 18H), 5.15(q, J=4.3Hz, 1H), 4.79(d, J=10.8Hz, 1H), 4.71(d, J =11.4Hz, 1H), 4.65-4.39(m, 6H), 4.25(d, J=4.3Hz, 1H), 4.01-3.95(m, 2H), 3.82(dd, J=10.6, 4.1Hz, 1H) , 3.65(dd, J=10.6, 5.7Hz, 1H), 2.84(t, J=7.4Hz, 2H), 1.96(s, 3H), 1.55(p, J=7.3Hz, 2H), 1.41-1.18( m, 15H), 0.88(t, J=6.7Hz, 3H) ¹³ C-NMR(101MHz, CDCl ₃ )δ: 201.90, 170.02, 138.51, 138.08, 137.98, 137.08, 128.65, 128.43, 128.39, 128.36, 128.25, 128.17, 128.04, 127.97, 127.80, 127.71, 127.59, 127.53, 85.28, 80.31, 78.45, 75.71, 74.67, 74.53, 73.23, 72.91, 68.06, 31.95, 29.61, 29.55, 29.36, 29.20, 29.05, 28.39, 22. 14.18 HRMS [M+H] ⁺ C ₄₆ H ₅₉ O ₇ S Calculated value 755.3981; Actual value: 755.3976 Quality analysis [M+H] ⁺ ：755

Example 4: Nickel (II) Acetylpyruvate (using Ni(acac) ₂ )) compound (5)((2R,3R,4S,5R)-1,3,4,5-四 (benzyl ((Phenyloxy)-6-oxo-6-phenylhexane-2-yl acetate) manufacturing

Compound (4) (0.25 mmol, 190 mg) was placed in a Schlenk tube dried in a hot oven under an argon environment, followed by Ni(acac) ₂ (0.0125 mmol, 3.2 mg) and THF (2 mL). The resulting mixed solution was stirred for 5 minutes, and then a THF solution (0.125M) of the complex of the organozinc compound and lithium chloride, PhZnCl･LiCl (0.375mmol, 3mL), was added with a syringe. The resulting reaction mixture was stirred at 25°C for 1 hour. After that, the reaction mixture was quenched with water and extracted with ethyl acetate (3×30 mL). The organic extract was washed with brine, dried with Na ₂ SO ₄ anhydride, and concentrated. The obtained crude product was purified by silica gel tube chromatography (ethyl acetate/hexane=1/20~2/20) to obtain compound (5)((2R,3R,4S,5R)-1, 3,4,5-Si (benzyloxy)-6-oxo-6-phenylhexane-2-yl acetate; 105 mg, 0.16 mmol, yield 64%). In addition, unreacted compound (4) (49 mg, 0.065 mmol, yield 26%) and by-product biphenyl Ph-Ph (10 mg, 0.064 mmol, yield 35%) were obtained simultaneously with compound (5).

Compound (5) IR (KBr): νmax=3027, 2870, 1735, 1724, 1449, 1369, 1236, 1090, 1027, 738, 696cm ^{-1 1} H-NMR(400MHz, CDCl ₃ )δ: 7.92(d, J=7.8Hz, 2H), 7.47(t, J=7.4Hz, 1H), 7.37-7.22(m, 15H), 7.21-7.11(m, 5H), 7.06-7.00(m, 2H), 5.27(q , J=5.2Hz, 1H), 4.89(d, J=4.2Hz, 1H), 4.73-4.55(m, 4H), 4.53-4.46(m, 3H), 4.31(d, J=10.8Hz, 1H) , 4.21(dd, J=6.8, 4.3Hz, 1H), 4.07(dd, J=6.8, 3.4Hz, 1H), 3.87(dd, J=10.2, 5.4Hz, 1H), 3.63(dd, J=10.2 , 5.5Hz, 1H), 1.98(s, 3H) ¹³ C-NMR(101MHz, CDCl ₃ )δ: 198.88, 169.94, 138.43, 137.88, 137.77, 137.10, 136.05, 133.06, 128.96, 128.76, 128.45, 128.35, 128.31 , 128.26, 128.19, 128.05, 127.92, 127.80, 127.73, 127.70, 127.49, 127.45, 82.68, 80.39, 79.62, 75.29, 74.62, 73.22, 73.05, 72.59, 67.87, 21.08 HRMS[M+H] ⁺ : C ₄₂ H ₄₃ O ₇ Calculated value 659.3009; Found value: 659.3004 Quality analysis [M+H] ⁺ : 659

Example 5: Compound (5)((2R,3R,4S,5R)-1,3,4,5-tetrakis(benzyloxy)-6- using nickel (II) dichloro (NiCl ₂ ) (Oxo-6-phenylhexane-2-yl acetate) manufacturing

Compound (4) (0.25 mmol, 190 mg) was placed in a Schlenk tube dried in a hot oven under an argon environment, followed by NiCl ₂ (0.0125 mmol, 3.2 mg) and THF (2 mL). The resulting mixture was stirred for 5 minutes, and then a THF solution (0.125M) of ZnCl･LiCl (0.375mmol, 3mL), a complex of Ph organozinc compound and lithium chloride, was added with a syringe. The resulting reaction mixture was stirred at 25°C for 1 hour. After that, the reaction mixture was quenched with water and extracted with ethyl acetate (3×30 mL). The organic extract was washed with brine, dried with Na ₂ SO ₄ anhydride, and concentrated. The obtained crude product was purified by silica gel tube chromatography (ethyl acetate/hexane=1/20~2/20) to obtain compound (5)((2R,3R,4S,5R)-1, 3,4,5-Si (benzyloxy)-6-oxo-6-phenylhexane-2-yl acetate; 96 mg, 0.145 mmol, yield 58%). In addition, unreacted compound (4) (60 mg, 0.08 mmol, yield 32%) and by-product biphenyl Ph-Ph (11.6 mg, 0.075 mmol, yield 40%) were obtained simultaneously with compound (5).

Example 6: Compound (5)((2R,3R,4S,5R)-1,3,4, using nickel (II) dichloro (dimethoxyethane adduct) (NiCl ₂ (dme)) Production of 5-Si (benzyloxy)-6-oxo-6-phenylhexane-2-yl acetate)

Compound (4) (0.25 mmol, 190 mg) was placed in a Schlenk tube dried in a hot oven under an argon environment, followed by NiCl ₂ (dme) (0.0125 mmol, 3 mg) and THF (2 mL). The resulting mixed solution was stirred for 5 minutes, and then a THF solution (0.125M) of the complex of the organozinc compound and lithium chloride, PhZnCl･LiCl (0.375mmol, 3mL), was added with a syringe. The resulting reaction mixture was stirred at 25°C (room temperature) for 1 hour. After that, the reaction mixture was quenched with water and extracted with ethyl acetate (3×30 mL). The organic extract was washed with brine, dried with Na ₂ SO ₄ anhydride, and concentrated. The obtained crude product was purified by silica gel tube chromatography (ethyl acetate/hexane=1/20~2/20) to obtain compound (5)((2R,3R,4S,5R)-1, 3,4,5-Four (benzyloxy)-6-oxo-6-phenylhexane-2-yl acetate; 99mg, 0.15mmol, yield 60%). In addition, unreacted compound (4) (9 mg, 0.058 mmol, yield 31%) and by-product biphenyl Ph-Ph (65 mg, 0.085 mmol, yield 34%) were obtained simultaneously with compound (5).

Example 7: Discussion on nickel catalyst

Except that the PhZnCl･LiCl of Example 6 was changed to PhZnBr and NiCl ₂ (dme) was changed to the nickel catalyst (Ni cat.) or the combination of nickel catalyst and ligand (ligand) shown in Table 1. The same procedure as in Example 6, the synthesis of compound (5) was carried out in THF (3 mL).

The results are shown in Table 1. The yield of compound (5) of test number 6 using the combination of nickel catalyst NiCl ₂ (thf) ₂ and ligand PPh ₃ is higher than the yield of test numbers 1 to 5 and 7.

In addition, the yield of the by-product biphenyl Ph-Ph in Test No. 6 was 20%, which was lower than the yield of the by-product biphenyl Ph-Ph in Test Nos. 1 to 5 and 7.

Example 8: Discussion on Ligands in Nickel Catalysts In the test numbers 7 to 11 shown in Table 2, except for changing the ligands to those shown in Table 2, the same operations as in Example 7 Test No. 6 To carry out the synthesis of compound (5). Furthermore, in test number 12, the compound (5) was synthesized by the same operation as test number 11 except that the nickel catalyst NiCl ₂ (thf) _{2 was} changed to Ni(COD) ₂ .

The results are shown in Table 2. The yield of compound (5) in test numbers 10, 11, and 12 using the diphosphine ligand was higher than that of test number 6.

In addition, the yields of the by-product biphenyl Ph-Ph in Test Nos. 8, 9, 10, 11 and 12 using the diphosphine ligand were 18%, 10%, 16%, 9% and 14%, respectively. The yield was 20% lower than that in test number 6 using a single phosphine ligand.

Example 9: Discussion on reaction temperature in reaction system using nickel catalyst In the test numbers 13 and 14 shown in Table 3, the compound (5) was synthesized by the same operation as the test number 11 in Example 8 except that the reaction temperature was changed to those shown in Table 3. In addition, in test numbers 15 and 16, the compound (5) was synthesized by the same operation as test numbers 11 and 14, except that the ligand dcype was changed to dcypt, respectively. The results are shown in Table 3.

The results are shown in Table 3. The yields of compound (5) in test numbers 11 and 15 conducted at a reaction temperature of 25°C were higher than those of test numbers 13, 14 and 16 conducted at a reaction temperature of 0°C or 50°C.

In addition, the yields of the by-product biphenyl Ph-Ph in test numbers 11 and 15 conducted at a reaction temperature of 25°C are 9% and 16%, respectively, which are higher than those of test number 13 conducted at a reaction temperature of 0°C or 50°C. The yield of biphenyl Ph-Ph, a by-product in, 14 and 16, is low.

Example 10: Discussion on ligands in nickel catalyst In the test numbers 17 to 19 shown in Table 4, the compound (5) was synthesized by the same operation as the test number 11 of Example 8 except that the ligand was changed to that shown in Table 4.

The results are shown in Table 4. In test numbers 17-19 using dipyridine-type ligands, the reaction was also confirmed to proceed.

In addition, the yields of by-product biphenyl Ph-Ph in test numbers 17, 18 and 19 were 32%, 21% and 18%, respectively.

Example 11: Compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetra(benzyloxy)-6-oxo-6-phenyl using Pd/C Hexane-2-yl acetate) manufacturing

Compound (4) (0.25 mmol, 190 mg) was placed in a Schlenk tube dried in a hot oven under an argon environment, and then Pd/C (0.0025 mmol, 3 mg) and THF (2 mL) were placed. The resulting reaction mixture was stirred for 5 minutes, and then a THF solution (0.125M) of the complex of the organozinc compound and lithium chloride PhZnCl･LiCl (0.375mmol, 3mL) was added with a syringe. The resulting reaction mixture was stirred at 25°C (room temperature) for 24 hours. After that, the reaction mixture was quenched with water (1 mL), filtered through a celite pad, and extracted with ethyl acetate (3×30 mL). The organic extract was washed with water and brine, dried with Na ₂ SO ₄ anhydride, and concentrated. The obtained crude product was purified by silica gel tube chromatography (ethyl acetate/hexane=1/20~2/20) to obtain compound (5)((2R,3R,4S,5R)-1, 3,4,5-Si (benzyloxy)-6-oxo-6-phenylhexane-2-yl acetate; 110 mg, 0.167 mmol, yield 67%). In addition, at the same time as compound (5), unreacted compound (4) (58 mg, 0.077 mmol, yield 31%) and by-product biphenyl Ph-Ph (3 mg, 0.0187 mmol, yield 10%) were obtained.

Example 12: Compound (5) ((2R,3R,4S,5R)-1,3,4,5-tetra(benzyloxy)-6-oxo-6-phenyl using Pd/C Hexane-2-yl acetate) manufacturing

Compound (4) (0.25 mmol, 190 mg) was placed in a Schlenk tube dried in a hot oven under an argon environment, and then Pd/C (0.05 mol, 6 mg) and THF (2 mL) were placed. The resulting reaction mixture was stirred for 5 minutes, and then a THF solution (0.125M) of the complex of the organozinc compound and lithium chloride, PhZnCl･LiCl (0.375mmol, 3mL), was added with a syringe. The resulting reaction mixture was stirred at 40°C for 24 hours. After that, the reaction mixture was quenched with water (1 mL), filtered through a celite pad, and extracted with ethyl acetate (3×30 mL). The organic extract was washed with water and brine, dried with Na ₂ SO ₄ anhydride, and concentrated. The obtained crude product was purified by silica gel tube chromatography (ethyl acetate/hexane=1/20~2/20) to obtain compound (5) (119 mg, 0.18 mmol, yield 72%). And, simultaneously with compound (5), unreacted compound (4) (49 mg, 0.065 mmol, yield 26%) and by-product biphenyl Ph-Ph (5 mg, 0.032 mmol, yield 17%) were obtained.

Example 13: Discussion on the reaction conditions of the reaction system using Pd/C

In the test numbers 20 to 25 in Table 5 shown below, the same operation as in Example 12 was performed except that the presence or absence of organic zinc compounds, additives, reaction temperature, and reaction time were changed to those shown in Table 5. Synthesis of compound (5). And, in test number 23 and test number 24, in the THF solution of PhZnCl･LiCl solution, the additive (DMF) was added to the reaction mixture using a syringe. In Test No. 25, the PHZnBr and ZnBr ₂ containing THE solution described in Example 20 described later was used instead of the PhZnCl·LiCl THF solution, and the additive (ZnBr ₂ ) was added to the reaction mixture.

The results are shown in Table 5. Test No. 25 using PhZnBr as the organozinc compound and adding ZnBr _{2 has a} higher yield of compound (5) compared to Test No. 20-24 using PhZnCl･LiCl as the organozinc compound.

Example 14: Discussion of reaction conditions in a reaction system using Pd/C

In the test numbers 20 to 25 in Table 6, the compound (5) was synthesized by the same operation as in Example 13 except that the organozinc compound or its amount, solvent, reaction time, and reaction temperature were changed to those shown in Table 5.

The results are shown in Table 6. Test Nos. 24 and 25 performed at a reaction temperature of 60°C have higher yields of compound (5) than Test Nos. 20-23 performed at a reaction temperature of 40-50°C. In addition, test number 25 using PhZnBr2 equivalent has a higher yield of compound (5) than test number 24 using PhZnBr1 equivalent.

Example 15: Compound (5)((2R,3R,4S,5R)-1,3,4,5-四(benzene) using palladium(0)4 triphenylphosphine complex (Pd(PPh ₃ ) ₄ ) (Methyloxy)-6-oxo-6-phenylhexane-2-yl acetate) manufacturing

Compound (4) (0.25 mmol, 190 mg) was placed in a Schlenk tube dried in a hot oven under argon, and then Pd(PPh ₃ ) ₄ (0.0125 mol, 15 mg) and THF (2 mL) were placed. The resulting reaction mixture was stirred for 5 minutes, and then a THF solution (0.125M) of the complex of the organozinc compound and lithium chloride, PhZnCl･LiCl (0.375mmol, 3mL), was added with a syringe. The resulting reaction mixture was stirred at 40°C for 24 hours. After that, the reaction mixture was quenched with water (1 mL), filtered through a celite pad, and extracted with ethyl acetate (3×30 mL). The organic extract was washed with water and brine, dried with Na ₂ SO ₄ anhydride, and concentrated. The obtained crude product was purified by silica gel tube chromatography (ethyl acetate/hexane=1/20~2/20) to obtain compound (5)((2R,3R,4S,5R)-1, 3,4,5-Four (benzyloxy)-6-oxo-6-phenylhexane-2-yl acetate; 89mg, 0.135mmol, yield 54%). And, simultaneously with compound (5), unreacted compound (4) (80 mg, 0.105 mmol, yield 42%) was obtained.

Example 16: Production of compound (6) (2,3,4,6-tetra-O-benzyl-1C-phenylglucose)

Compound (5) (0.2 mmol, 132 mg) was placed in a Schlenk tube dried in a hot oven under an argon environment, followed by sodium methoxide (0.02 mmol, 1 mg) and methanol (2 mL). The resulting reaction mixture was stirred at 25°C for 6 hours. After that, the reaction mixture was filtered through a silicon layer and washed with methanol (3×20 mL). Next, the resulting solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel tube chromatography (ethyl acetate/hexane=4/20~8/20) to obtain compound (6)(2,3,4,6-tetra-O) as a colorless liquid -Benzyl-1C-phenylglucose; 112 mg, 0.182 mmol, 91% yield).

Compound (6) IR (KBr): νmax=3411, 3027, 2923, 1590, 1494, 1452, 1361, 1212, 1093, 734, 696cm ^{-1 1} H-NMR(400MHz, CDCl ₃ )δ: 7.64(d, J=7.0Hz, 2H), 7.38-7.13(m, 21H), 6.97(d, J=6.1Hz, 2H), 4.95-4.81(m, 3H), 4.69-4.56(m, 2H), 4.51(d , J=12.3Hz, 1H), 4.38(d, J=10.4Hz, 1H), 4.17(d, J=8.2Hz, 1H), 4.07(t, J=9.2Hz, 1H), 3.84-3.79(m , 3H), 3.70(d, J=10.9Hz, 1H), 3.53(d, J=9.4Hz, 1H), 3.34(s, 1H) ¹³ C-NMR(101MHz, CDCl ₃ )δ: 142.47, 138.85, 138.58, 138.45, 137.59, 128.61, 128.47, 128.42, 128.26, 128.23, 128.03, 127.79, 127.75, 127.69, 127.62, 127.58, 126.36, 98.00, 85.28, 83.59, 78.53, 75.75, 75.53, 75, HRMS, 73.38 [MH] ^- : C ₄₀ H ₃₉ O ₆ calculated value 615.2747; measured value: 615.2743 Quality analysis [MH] ^- : 615

Example 17: Production of compound (7) (3R, 4S, 5R-tribenzyloxy-6R-benzyloxymethyl-6S-phenyltetrahydropyran)

To the acetonitrile solution (3 mL) of the compound (6) (200 mg, 0.32 mmol) obtained in Example 1, triethylsilane (76 mg, 0.65 mmol) was added. After cooling the resulting solution to -40°C in a dry ice/acetone bath, add a solution of boron trifluoride and ether complex (70mg, 0.49mmol) in methylene chloride (1mL) and stir at -40 ~-30°C 3 hours.

After the reaction solution was analyzed by HPLC, compound (6) was completely consumed, and the peak of compound (7) was confirmed.

Water (20 mL) was added to the reaction liquid, and the product was extracted with ethyl acetate (5 mL×4). Concentrate under reduced pressure with the organic extract. The concentrated solution was purified with a silica gel tube (developing solvent: hexane/ethyl acetate=10/1) to obtain compound (7) (3R, 4S, 5R-tribenzyloxy-6R-benzyloxymethyl) 6S-phenyltetrahydropyran; 110mg, yield 56%). The isomer ratio of compound (7) is β: α=82/18.

HPLC conditions: Measurement wavelength: 210nm Flow rate: 1.0mL/min Mobile phase: acetonitrile: water=90/10→100/0 (0→10, 20min) Column temperature: 20℃ Filling agent: X Bridge, C18, 5mm, 4.8mmx150mm) Holding time: β body 5.64min; α body 5.31min

Compound (7) ¹ H-NMR(CDCl ₃ )δ: 3.50-3.55(m, 1H), 3.60-3.61(m, 1H), 3.73-3.82(m, 5H), 4.25(d, J=9.3Hz, 1H), 4.36(d, J=10.3 Hz, 1H), 4.55-4.68(m, 3H), 4.86-4.98(m, 3H), 6.91-6.93(m, 2H), 7.14-7.53(m, 23H)

Example 18: Production of PhZnCl･LiCl, a compound of organic zinc compound and lithium chloride

Put scraped Mg (372 mg, 15.3 mmol, 1.5 equivalents) and lithium chloride (LiCl; 540 mg, 12.75 mmol, 1.25 equivalents) into a 50 mL dried Shrank tube with a magnetic stirring rod, and put Put it into the sterile glove box and dry it with a heat gun. Then, after pouring argon 3 times into the warm flask, add dried THF (8mL) and diisobutylaluminum hydride (DIBAL-H; 1.0M THF solution 0.1mL, 1mol%) at room temperature, and stir for 5 ~10 minutes. Next, the Schlenk tube was cooled to 0°C, and bromobenzene (1.1 mL, 10.2 mmol, 1.0 equivalent) was added. The resulting reaction mixture was stirred at 0°C for 10 minutes, and then stirred at room temperature for 2 hours to obtain a complex of Grignard reagent and lithium chloride (PhMgBr･LiCl). Dilute the complex of Grignard reagent and lithium chloride (PhMgBr･LiCl) with an appropriate amount of dry THF, titrate with LiCl and iodine, and adjust to a concentration of about 1M. Add the solution containing the obtained Grignard reagent and lithium chloride complex to the dry THF solution containing ZnCl ₂ (1 equivalent relative to Grignard reagent) at room temperature, and stir for 15 minutes to obtain 0.125M content Solution of complex PhZnCl･LiCl. Moreover, the solution concentration is adjusted according to the titration concentration of the corresponding Grignard reagent and the dilution rate after methylation.

Example 19: Production of phenyl zinc bromide (PhZnBr)

Dilute phenylmagnesium bromide (Grignard reagent) with dry THF, titrate with LiCl and iodine, and adjust to a THF solution of Grignard reagent with a concentration of about 0.5M. Add the obtained THF solution of Grignard reagent to a dry THF solution containing ZnBr ₂ (1 equivalent relative to Grignard reagent) at 25°C, stir for 1 hour, perform transmethylation, and obtain 0.25M containing PhZnBr的THF solution. Moreover, the solution concentration is adjusted according to the titration concentration of the corresponding Grignard reagent and the dilution rate after methylation.

Example 20: Preparation of THF solution containing phenyl zinc bromide (PhZnBr) and zinc bromide (ZnBr ₂ ). Add 0.5M phenyl magnesium bromide (Grignard reagent) in THF solution at 25°C. In the dry THF solution of ZnBr ₂ , stir for 1 hour to perform transmethylation to obtain a 0.25 M THF solution containing PhZnBr and ZnBr ₂ (0.1 equivalent excess with respect to PhZnBr). And, the solution concentration is adjusted according to the titration concentration of the corresponding Grignard reagent and the dilution rate after transmethylation.

Example 21: Production of compound (9) (aryl zinc bromide)

Under argon atmosphere, add a solution of i-propyl magnesium chloride in THF (0.8 mL, 1.6 mmol, 1.06 equivalent) to a solution of lithium chloride anhydride (65 mg, 1.53 mmol, 1.02 equivalent) in THF anhydride (2 mL) at 0°C 2.0M. Compound (8) (2-(5-iodo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene; 612 mg, 1.5 mmol, 1 equivalent) in THF anhydride (5 mL) was heated at 0°C The mixture was dropped into the reaction mixture under argon, and the reaction solution was returned to room temperature and stirred for 1 hour. The resulting reaction solution was added to a dry THF solution of ZnBr ₂ (372 mg, 1.65 mmol, 1.1 equivalents) in THF anhydride (5 mL) to perform transmethylation to obtain a solution of compound (9), which was used in the following Mentioned steps.

Example 22: Compound (10)((2R,3R,4S,5R)-1,3,4,5-tetra(benzyloxy)-6-(3-((5-(4-fluorophenyl) (Thien-2-yl)methyl)-4-methylphenyl)-6-oxyhexane-2-yl acetate)

The solution of compound (9) obtained in Example 21 was dropped into a Schlenk tube containing compound (4) (566 mg, 0.75 mmol, 0.5 equivalent) in THF (5 mL). The reaction solution was stirred at 25°C for 36 hours, then the reaction solution was quenched with water (1 mL), the reaction mixture was filtered with Celite (trademark), and washed with ethyl acetate (3×100 mL). The filtrate was washed with water and brine, dried with Na ₂ SO ₄ anhydride, and evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/hexane=1/20 to 3/20) to obtain compound (10) (492 mg, 0.57 mmol, 76%).

Compound (10) ¹ H-NMR(400MHz, CDCl ₃ )δ: 7.50(d, J=1.3Hz, 1H), 7.43(dd, J=7.8, 1.6Hz, 1H), 7.41-7.14(m, 21H) , 7.07-7.04(m, 2H), 7.00-6.93(m, 3H), 6.60(d, J=3.5Hz, 1H), 4.95-4.84(m, 3H), 4.70-4.59(m, 3H), 4.42 (d, J=10.4Hz, 1H), 4.19-4.14(m, 2H), 4.04(d, J=16.0Hz, 1H), 3.91(d, J=10.4Hz, 1H), 3.89-3.74(m, 4H), 3.40(d, J=9.6Hz, 1H), 3.16(s, 3H), 2.34(s, 3H) ¹³ C-NMR(101MHz, CDCl ₃ )δ: 198.51, 170.08, 162.2(d, J= 245.3Hz), 142.69, 142.60, 141.79, 138.64, 138.55, 138.06, 137.99, 137.36, 134.54, 130.84(d, J=3.4Hz), 130.68, 130.31, 128.76, 128.53, 128.42, 128.38, 128.29, 128,17, 127.98 127.91, 127.88, 127.79, 127.58, 127.55, 127.22(d, J=8.0Hz), 126.24, 122.83, 115.82(d, J=21.8Hz), 82.94, 80.68, 79.52, 75.51, 74.64, 73.26, 73.15, 72.72, 68.12, 34.14, 21.21, 19.88 HRMS [M+Na] ⁺ C ₅₄ H ₅₁ FO ₇ SNa calculated value 885.3237; measured value 885.3229.

Example 23: Production of compound (11)

The Schlenk tube dried in a hot oven was cooled to room temperature, and compound (10) (173 mg, 0.2 mmol) in MeOH (5 mL) was placed in the Schlenk tube. NaOMe (11 mg, 0.2 mmol) was added to the resulting solution under an argon atmosphere, and the reaction solution was stirred at 25°C for 6 hours. Then the reaction solution was neutralized with 1N HCl (2 mL) aqueous solution. Next, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by silica chromatography (ethyl acetate/hexane=2/20~8/20) to obtain compound (11) (142 mg, 0.172 mmol, 86%) as a yellow solid.

¹ H-NMR(400MHz, CDCl ₃ )δ: 7.52(s, 1H), 7.47-7.43(m, 1H), 7.39-7.09(m, 21H), 7.03-6.89(m, 5H), 6.61(d, J=3.5Hz, 1H), 4.89-4.86(m, 3H), 4.68-4.62(m, 2H), 4.53(d, J=12.3Hz, 1H), 4.38(d, J=10.6Hz, 1H), 4.19-4.03(m, 4H), 3.94(d, J=10.5Hz, 1H), 3.87-3.82(m, 2H), 3.71(d, J=11.1Hz, 1H), 3.60(d, J=9.3Hz) , 1H), 3.08(s, 1H), 2.33(s, 3H) ¹³ C-NMR(101MHz, CDCl ₃ )δ: 162.18(d, J=246.6Hz), 143.59, 141.58, 140.59, 138.86, 138.75, 138.50 , 138.13, 137.77, 136.95, 130.94(d, J=3.3Hz), 130.59, 128.52, 128.50, 128.44, 128.38, 128.28, 128.08, 127.87, 127.82, 127.73, 127.67, 127.57, 127.20(d, J=8.0Hz) , 125.94, 124.97, 122.78, 115.77(d, J=21.6Hz), 98.03, 85.55, 83.63, 78.53, 77.48, 77.16, 76.84, 75.84, 75.68, 75.18, 73.52, 72.39, 69.11, 34.48, 19.37 HRMS [M+ Na] ⁺ ：C ₅₂ H ₄₉ FO ₆ SNa Calculated value 843.3132, measured value 843.3123

Example 24: Compound (12)((2R,3R,4R,5S,6S)-3,4,5-ginseng(benzyloxy)-2-(benzyloxymethyl)-6-(3- ((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran)

Add Et ₃ SiH (88 μL, 0.55 mmol) to a solution of compound (11) (150 mg, 0.18 mmol) in acetonitrile/dichloromethane (3:2) (10 mL) under argon, and then cool the reaction solution At -40°C, drop BF ₃ ･Et ₂ O (70 μL, 0.56 mmol) in the reaction solution. Next, the reaction solution was stirred for 6 hours, and an aqueous NaHCO ₃ solution (20 mL) was slowly added to the reaction solution at 0°C, and the aqueous phase was extracted with dichloromethane (3×40 mL). After phase separation, the aqueous phase was discarded, the organic phase was washed with brine, dried with Na ₂ SO ₄ anhydride, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel tube chromatography (ethyl acetate/hexane=2/20~6/20) to obtain compound (12) (133 mg, 0.164 mmol, 90%) as a colorless gum ), directly used in the following steps. HRMS [M+Na] ⁺ : C ₅₂ H ₄₉ FO ₅ SNa Calculated value 827.3182, measured value 827.3176

Example 25: Compound (13) ((2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl-4-methylbenzene Yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; canagliflozin)

Under an argon environment, iodotrimethylsilane (0.110 ml, 0.744 mmol) was slowly added to a solution (100 mg, 0.124 mmol) of compound (12) in dichloromethane (5 mL) at 0°C. After the addition, the reaction solution was heated to 25°C and stirred for 8 hours. The reaction solution was concentrated. The obtained crude product was purified by silica gel column chromatography (MeOH/DCM=1/30~1/20) to obtain compound (13) (51 mg, 93%).

¹ H-NMR(400MHz, DMSO-d ₆ )δ: 7.61-7.57(m, 2H), 7.27 (d, J=4.4Hz, 1H), 7.22-7.10(m, 5H), 6.79(d, J= 3.6Hz, 1H), 4.99(br, 2H, OH), 4.79(br, 1H, OH), 4.45(br, 1H, OH), 4.15(d, J=16Hz, 1H), 4.09(d, J= 16Hz, 1H), 3.96(d, J=9.6Hz, 1H), 3.69(d, J=11.2Hz, 1H), 3.46-3.41(m, 1H), 3.29-3.14(m, 4H), 2.26(s , 3H) ¹³ C-NMR(101MHz, DMSO-d ₆ )δ: 161.4(d, J=243Hz), 143.63, 140.22, 138.21, 137.35, 134.93, 130.53(d, J=3.1Hz), 129.65, 129.05, 126.95(d, J=8Hz), 126.34, 126.23, 123.38, 115.86(d, J=21.6Hz), 81.31, 81.17, 78.48, 74.68, 70.44, 61.45, 33.44, 18.79 HRMS[M+Na] ⁺ ：C ₂₄ H ₂₅ FO ₅ SNa calculated value 467.1304; measured value: 467.1299

Example 26: Production of compound (15) (aryl zinc bromide)

The Schlenk tube dried in a hot oven was cooled under an argon environment, and compound (14) (4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene: 0.163g, 0.5mmol) and Cut magnesium (0.1g, 4.1mmol), then put THF anhydride (5mL) and 1,2-dibromoethane (0.05mL). The reaction liquid is heated to the back flow, and the reaction is started. After the reaction started, the additional compound (8) (0.49 g, 1.5 mmol) in THF anhydride (10 mL) was dropped into the reaction solution under an argon atmosphere, and the reaction solution was left to flow for 3 hours. Next, the reaction mixture was cooled to room temperature. The Grignard reagent immediately obtained was added to a solution of ZnBr ₂ (773 mg, 3.43 mmol, 1.1 equivalents) in dry THF at 25° C. and stirred for 1 hour to obtain compound (9), which was used in the following steps.

Example 27: Compound (10) ((2R,3R,4S,5R)-1,3,4,5-(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl) (Yl)phenyl)-6-oxyhexane-2-yl acetate) production

The solution of compound (9) was dropped into a Schlenk tube containing a solution of compound (4) (756 mg, 1 mmol) in THF (5 mL), and then 10 wt% Pd/C (22 mg, 0.02 mmol) was placed. The reaction solution was stirred at 40°C for 48 hours, quenched with water (1 mL), the reaction solution was filtered with Celite (trademark), and washed with ethyl acetate (3×100 mL). The filtrate was washed with water and brine, dried with Na ₂ SO ₄ anhydride, and distilled off under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/hexane=1/20~3/20) to obtain compound (16)((2R,3R,4S,5R)-1,3,4,5-400 (Benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-oxyhexane-2-yl acetate; 588mg, 0.71mmol, 71% ).

Compound (16) ¹ H-NMR(400MHz, CDCl ₃ )δ: 7.82(d, J=1.3Hz, 1H), 7.68(dd, J=8.3, 1.6Hz, 1H), 7.33-7.12(m, 19H) , 6.99(d, J=6.8Hz, 2H), 6.95(d, J=8.5Hz, 2H), 6.71(d, J=8.5Hz, 2H), 5.24(q, J=4.9Hz, 1H), 4.73 (d, J=4.5Hz, 1H), 4.62-4.42(m, 7H), 4.31(d, J=10.8Hz, 1H), 4.13-4.09(m, 1H), 4.02-3.99(m, 1H), 3.94-3.88(m, 4H), 3.84(dd, J=10.4, 5.0Hz, 1H), 3.63(dd, J=10.4, 5.5Hz, 1H), 1.97(s, 3H), 1.34(t, J= 7.0Hz, 3H) ¹³ C-NMR(101MHz, CDCl ₃ )δ: 198.56, 170.09, 157.66, 139.53, 138.42, 138.00, 137.78, 137.12, 134.76, 131.85, 130.70, 129.98, 129.56, 128.72, 128.57, 128.45, 128.40 , 128.38, 128.32, 128.20, 128.07, 127.93, 127.87, 127.83, 127.68, 127.62, 114.65, 83.59, 80.59, 79.21, 77.36, 75.49, 74.60, 73.35, 72.71, 68.15, 63.46, 38.45, 21.21, 14.96 HRMS [ Na] ⁺ : C ₅₁ H ₅₁ ClO ₈ Na calculated value 849.3170; measured value 849.3165

Example 28: Production of compound (17)

The Schlenk tube dried in a hot oven was cooled to room temperature, and compound (16) (166 mg, 0.2 mmol) in MeOH (5 mL) was placed. NaOMe (11 mg, 0.2 mmol) was added to the solution under an argon atmosphere, and the reaction solution was stirred at 25°C for 6 hours. After that, the reaction solution was neutralized with 1N HCl (2 mL) aqueous solution. The solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by silica gel tube chromatography (ethyl acetate/hexane=2/20-8/20) to obtain compound (17) (145 mg, 0.184 mmol, 92%) as a colorless solid.

¹ H-NMR(400MHz, CDCl ₃ )δ: 7.44(d, J=1.9Hz, 1H), 7.37(dd, J=8.3, 2.0Hz, 1H), 7.32-7.12(m, 19H), 7.01(d , J=8.5Hz, 2H), 6.91(d, J=6.7Hz, 2H), 6.71(d, J=8.6Hz, 2H), 4.86(s, 2H), 4.85(d, J=10.1Hz, 1H ), 4.63(d, J=10.9Hz, 1H), 4.58(d, J=12.3Hz, 1H), 4.49(d, J=12.3Hz, 1H), 4.42(d, J=10.7Hz, 1H), 4.14-3.85(m, 7H), 3.83-3.74(m, 2H), 3.68-3.65(m, 1H), 3.48(d, J=9.3Hz, 1H), 3.12(s, 1H), 1.35(t, J=7.0Hz, 3H) ¹³ C-NMR(101MHz, CDCl ₃ )δ: 157.53, 141.37, 138.89, 138.72, 138.59, 138.38, 137.43, 134.50, 131.43, 129.82, 129.44, 129.03, 128.53, 128.46, 128.31, 128.07 , 127.86, 127.84, 127.79, 127.72, 127.69, 127.64, 125.72, 114.64, 97.77, 84.88, 83.66, 78.46, 75.84, 75.57, 75.17, 73.48, 72.36, 69.00, 63.45, 38.60, 14.98 H RMS [M+Na] ⁺ C ₄₉ H ₄₉ ClO ₇ Na calculated value 807.3065; measured value 807.3060

Example 29: Production of compound (18)

Under an argon environment, add Et ₃ SiH (88 μL, 0.55 mmol) to a solution of compound (17) (142 mg, 0.18 mmol) in acetonitrile/dichloromethane (3:2) (10 mL), and then cool the reaction solution To -30°C, drop BF ₃ ･Et ₂ O (70 μL, 0.56 mmol). After the dripping, the reaction solution was stirred for 4 hours, NaHCO ₃ aqueous solution (20 mL) was slowly added at 0° C., and the aqueous phase was extracted with dichloromethane (3×40 mL). After phase separation, the aqueous phase was discarded, the organic phase was washed with brine, dried with Na ₂ SO ₄ anhydride, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel tube chromatography (ethyl acetate/hexane=2/20~6/20) to obtain compound (18) (105 mg, 0.137 mmol, 76%) as a colorless gum ), directly used in the following steps. HRMS [M+Na] ⁺ : C ₄₉ H ₄₉ ClO ₆ Na calculated value 791.3115; actual value 791.3109

Example 30: Compound (19) ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetra Hydrogen-2H-pyran-3,4,5-triol: dapagliflozin) manufacturing

Under an argon environment, 5 wt% Pd/C (1.5 mg, 0.014 mmol, 11 mol% based on metal) was added to a solution (100 mg, 0.13 mmol) of compound (18) in EtOAc (4 mL), and the hydrogenation flask was Replace with argon. The argon environment was replaced with a hydrogen environment, and the reaction solution was stirred at 30°C for 24 hours. Next, the reaction solution was filtered with Celite, washed with EtOAc (3×40 mL), all the volatiles of the filtrate were distilled off under reduced pressure and concentrated to obtain a crude product. Next, the crude product was purified by PTLC chromatography (hexane/EtOAc/MeOH, 10:10:1) to obtain compound (19) (42 mg, 79%).

Compound (19) ¹ H-NMR (400MHz, methanol-d ₄ )δ: 7.35-7.22(m, 3H), 7.09 (d, J=8.4Hz, 2H), 6.79(d, J=8.5Hz, 2H) , 4.09(d, J=9.5Hz, 1H), 4.03-3.95(m, 3H), 3.87(d, J=12.6Hz, 1H), 3.69(dd, J=11.9, 4.8Hz, 1H), 3.48- 3.26(m, 5H), 1.35(t, J=7.0Hz, 3H) ¹³ C-NMR(101MHz, MeOD)δ: 158.81, 139.97, 139.89, 134.45, 132.91, 131.91, 130.80, 130.11, 128.19, 115.47, 82.86 , 82.16, 79.73, 76.42, 71.86, 64.46, 63.10, 39.21, 15.18 HRMS [M+Na] ⁺ : C ₂₁ H ₂₅ ClO ₆ Na calculated value 431.1237; measured value 431.1231

Claims (21)

A method for producing compound (I) represented by the following formula (I),

[In the formula, R ¹ and R ² each independently represent a hydroxy protecting group, R ³ and R ⁴ each independently represent a hydroxy protecting group or a hydrogen atom, and Ar represents an aromatic hydrocarbon ring group or an aromatic heterocyclic group as the The organic group of the functional group to which the oxygen heterocycle is bonded, the aforementioned aromatic hydrocarbon ring group and the aforementioned aromatic heterocyclic group may each have more than one substituent], which is contained in a nickel catalyst and a palladium catalyst In the presence of one or more transition metal catalysts, or a supporting catalyst having one or more transition metal catalysts and a support supporting one or more transition metal catalysts, the following formula ( The compound (II) represented by II) is at least selected from the group consisting of the compound (III-I) represented by the following formula (III-I) and the compound (III-II) represented by the following formula (III-II) The step of reacting an organozinc compound to obtain the compound (IV) represented by the following formula (IV), and the step of removing the hydroxyl protecting group represented by R ⁵ from the aforementioned compound (IV) to obtain the aforementioned compound (I),

[In the formula, R ¹ to R ^{4 have the} same meaning as above, and R ⁵ represents a hydroxy protecting group (except for the same hydroxy protecting group as R ^{1 and} the same hydroxy protecting group as R ² ), Q represents an organic group containing an aliphatic hydrocarbon group, an aromatic hydrocarbon ring group, an aliphatic heterocyclic group or an aromatic heterocyclic group as a functional group bonded to the sulfur atom in the formula, the aforementioned aliphatic hydrocarbon group, the aforementioned aromatic The hydrocarbon ring group, the aforementioned aliphatic heterocyclic group and the aforementioned aromatic heterocyclic group may each have one or more substituents]

[In the formula, Ar has the same meaning as above, and X represents a halogen atom]

[In the formula, Ar is synonymous with the aforementioned]

[In the formula, R ¹ to R ⁵ and Ar have the same meaning as above]. The method of claim 1, wherein the reaction between the aforementioned compound (II) and the aforementioned at least one organozinc compound is carried out at 0 to 80°C. The method of claim 1 or 2, wherein the supporting catalyst has at least one support selected from the group consisting of activated carbon, alumina, barium sulfate, calcium carbonate, hydroxyphosphate lime, and hydrotalcite, and the supporting catalyst Palladium catalyst on the aforementioned support. The method according to any one of claims 1 to 3, wherein the aforementioned at least one organozinc compound comprises the aforementioned compound (III-I), and the aforementioned compound (III-I) is in the Schlenk equilibrium state represented by the following formula ,

[In the formula, Ar and X are synonymous with the foregoing]. The method according to any one of claims 1 to 4, wherein R ³ and R ⁴ represent a hydroxyl protecting group. The method according to any one of claims 1 to 5, wherein the hydroxy protecting group represented by R ⁵ is different from the hydroxy protecting group represented by R ¹ to R ⁴ . The method according to any one of claims 1 to 6, wherein the hydroxyl protecting groups represented by R ¹ to R ⁵ are each independently selected from ester-type protecting groups, arylalkyl-type protecting groups, alkyl-type protecting groups, and aryl groups Alkyloxyalkyl type protecting group, alkyloxyalkyl type protecting group, silyl type protecting group and oxycarbonyl type protecting group are grouped. The method according to any one of claims 1 to 7, wherein the organic group represented by Q includes an alkyl group, an alkenyl group, alkynyl group or an aryl group as a functional group bonded to the sulfur atom in the formula, the aforementioned alkyl group, the aforementioned The alkenyl group, the aforementioned alkynyl group, and the aforementioned aryl group may each have one or more substituents. The method according to any one of claims 1 to 8, wherein the aliphatic hydrocarbon group, the aromatic hydrocarbon ring group, the aliphatic heterocyclic group or the aromatic heterocyclic group contained in the organic group represented by Q is also The aforementioned one or more substituents that may be possessed are each independently selected from halogen atoms, hydroxyl groups that may also be protected, sulfhydryl groups that may also be protected, amino groups that may also be protected, methylamino groups that may also be protected, or The protected carboxyl group and the protected carboxyl group are grouped together. Such as the method of any one of claims 1 to 9, wherein the organic group represented by Ar contains an aromatic hydrocarbon ring group with 6 to 14 carbons or an aromatic heterocyclic group with 3 to 12 carbons as the The organic group of the functional group to which the oxygen heterocycle is bonded, the aforementioned aromatic hydrocarbon ring group with 6 to 14 carbon atoms and the aromatic heterocyclic group with 3 to 12 carbon atoms may each have one or more substituents. Such as the method of any one of claims 1 to 10, wherein the organic group represented by Ar is represented by the following formula (V),

[In the formula, R ^a each independently represents selected from halogen atoms, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, arylalkyl groups, arylalkenyl groups, arylalkynyl groups, alkyloxy groups, alkenyloxy groups , Alkynyloxy, aryloxy, arylalkyloxy, arylalkenyloxy, and arylalkynyloxy group of functional groups, the aforementioned alkyl group, the aforementioned alkenyl group, the aforementioned alkynyl group, The aforementioned aryl group, the aforementioned arylalkyl group, the aforementioned arylalkenyl group, the aforementioned arylalkynyl group, the aforementioned alkyloxy group, the aforementioned alkenyloxy group, the aforementioned alkynyloxy group, the aforementioned aryloxy group, the aforementioned arylalkyl group Each of the oxy group, the aforementioned arylalkenyloxy group and the aforementioned arylalkynyloxy group may have one or more substituents, n is an integer from 0 to 4, and Ar' represents an aromatic hydrocarbon ring group, an aliphatic hetero The ring or aromatic heterocyclic group, the aforementioned aromatic hydrocarbon ring group, the aforementioned aliphatic heterocyclic group, and the aforementioned aromatic heterocyclic group may each have one or more substituents]. The method according to claim 11, wherein the functional groups represented by ^Ra are each independently selected from an alkyl group and a halogen atom, and the aforementioned alkyl group may have one or more substituents. Such as the method of claim 11 or 12, wherein the organic group represented by Ar is represented by the following formula (Va),

[In the formula, R ^a is synonymous with the foregoing, and Ar' represents a functional group selected from the group of the following formulas (Va-I), (Va-II) and (Va-III),

[In the formula, R ^b each independently represents a functional group selected from the group consisting of aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups and aromatic heterocyclic groups, the aforementioned aliphatic hydrocarbon groups and the aforementioned aromatic hydrocarbon ring groups , The aliphatic heterocyclic group and the aromatic heterocyclic ring may each have one or more substituents, and p represents an integer of 0 to 5]]. Such as the method of claim 13, wherein the functional groups represented by R ^b are each independently selected from alkyl groups with 1 to 20 carbons, alkenyl groups with 2 to 20 carbons, alkynyl groups with 2 to 20 carbons, and 6 to carbon atoms. A group of 14 aromatic hydrocarbon ring groups, aliphatic heterocyclic groups with 2 to 12 carbons, and aromatic heterocyclic groups with 3 to 12 carbons, the aforementioned alkyl group, the aforementioned alkenyl group, the aforementioned alkynyl group, and the aforementioned aromatic The hydrocarbon ring group, the aliphatic heterocyclic group, and the aromatic heterocyclic group may each have one or more substituents. The method according to any one of claims 1 to 14, wherein the aforementioned aromatic hydrocarbon ring group or the aforementioned aromatic heterocyclic group contained in the organic group represented by Ar may have one or more substituents independently Selected from halogen atoms, hydroxyl groups that can also be protected, sulfhydryl groups that can also be protected, amine groups that can also be protected, methanoyl groups that can also be protected, carboxyl groups that can also be protected, and sulfhydryl groups that can also be protected , Alkyl, alkenyl and alkynyl groups. The method according to any one of claims 1 to 15, which further comprises reacting the compound (VI) represented by the following formula (VI) with the compound (VII) represented by the following formula (VII) to obtain the following formula ( VIII) the step of compound (VIII), and the step of protecting the hydroxyl group in the aforementioned compound (VIII) with R ^{5 to} obtain the aforementioned compound (II),

[In the formula, R ¹ ~R ^{4 have the} same meaning as above]

[In the formula, Q is synonymous with the aforementioned]

[In the formula, R ¹ to R ^{4 have the} same meaning as above]. The method of claim 16, wherein the reaction of the aforementioned compound (VI) and the aforementioned compound (VII) is carried out at -30 to 40°C. The method of claim 16 or 17, wherein the reaction of the aforementioned compound (VI) and the aforementioned compound (VII) is carried out in the presence of the compound (IX) represented by the following formula (IX),

[In the formula, R ^c and ^Rd each independently represent a functional group selected from the group consisting of halogen atoms, aliphatic hydrocarbon groups, aromatic hydrocarbon ring groups, aliphatic heterocyclic groups and aromatic heterocyclic groups, the aforementioned aliphatic hydrocarbon groups, The aforementioned aromatic hydrocarbon ring group, the aforementioned aliphatic heterocyclic group and the aforementioned aromatic heterocyclic group may each have one or more substituents, q represents an integer of 0 to 3, r represents an integer of 0 to 3, but q +r=3]. The method of claim 18, wherein the functional groups represented by R ^c and R ^d are each independently selected from the group consisting of alkyl, aryl, and arylalkyl, and the aforementioned alkyl group, the aforementioned aryl group and the aforementioned arylalkyl group are each independently It may have more than one substituent. A reagent for producing compound (XI) represented by the following formula (XI), which contains compound (II) represented by the following formula (II),

[In the formula, Ar has the same meaning as above, and R ¹ '~R ⁴ 'each independently represents a hydrogen atom or a hydroxyl protecting group]

[In the formula, R ¹ to R ⁵ and Q have the same meaning as above]. A use of compound (II) represented by the following formula (II) as an intermediate in the manufacture of compound (XI) represented by the following formula (XI),

[In the formula, Ar and R ¹ '~R ⁴ 'have the same meaning as above]

[In the formula, R ¹ to R ⁵ and Q have the same meaning as above].