WO2004113258A1 - Carbon-carbon bond forming reaction - Google Patents

Abstract

A process for the production of compounds represented by the general formula (I), salts of the same, or solvate thereof from compounds represented by the general formulae (II) and (III), salts of the same, or solvates thereof, comprising the step represented by the reaction formula (A): [wherein R0 is lower alkyl or the like; R1 is lower alkyl or the like; R2 and R2’ are simultaneously hydrogen or the like; R3 is optionally substituted lower alkyl or the like; R4 is hydrogen or the like; X1 is halogeno; Y is hydroxyl or the like; Z1 is -CH=CH- or the like; Z2 is -CH=CH- or the like; m is an integer of 0 to 3; and n is an integer of 0 to 2] and characterized in that the reaction is conducted in a water-containing solvent in the presence of palladium-carbon.

Description

 Specification

 Carbon-carbon bond formation reaction

 Technical field

 [0001] The present invention relates to a Suzuki coupling suitable for an industrial process using an aqueous solvent, using economical palladium-carbon as a catalyst, considering the environment. The present invention also relates to a more versatile Suzuki coupling in an aqueous solvent to which diols are added and catalyzed by palladium on carbon. Background art

 [0002] The reaction of forming a carbon-carbon bond by reacting an aromatic halide with an aromatic boronic acid (or boronic ester) in the presence of a palladium catalyst is generally called Suzuki coupling (non- Patent Document 1). This reaction is indispensable for the synthesis of biaryl sulfide compounds useful as liquid crystals and pharmaceuticals. For example, it has been used for the synthesis of biarylsulfonamide derivatives known as MMP inhibitors such as the following aryl-heteroarylsulfonamide derivatives (Patent Documents 1 and 2, Non-Patent Documents 2 and 3)

 [Formula 1]

HCI H. N C0 ₂ Me

 THF

MeO S- C0 ₂ Me-MeO SN CO H

(72%)

 As a palladium catalyst, tetrakistriphenylphosphine

Bistriphenylphosphine palladium dichloride ((PP) PdCl) and the like are often used, and an organic solvent such as toluene is often used as a solvent. The high cost of these catalysts and the environmental impact of the use of organic solvents were often problematic.From this perspective, more inexpensive palladium catalysts and environmentally friendly A search for a solvent is performed.

 For example, it has been reported that Suzuki coupling between a phenol derivative having a phenolic hydroxyl group and phenylboronic acid proceeds in an aqueous solvent in the presence of a palladium-carbon catalyst. (Patent Document 3, Non-patent Document 4) However, the substrate is limited to a compound having a phenolic hydroxyl group.

[Formula 3]

 Non-Patent Document 5 reports Suzuki Riki coupling between a phenyl derivative having a carboxymethyl group and a phenylboronic acid derivative. However, the ratio of water: isopropanol is 8: 1, and the ratio of alcohol is high.

[Formula 4]

The substrate used in these reactions is characterized by having a hydrophilic group such as a hydroxyl group or a carboxy group as a substituent, and a substrate having only a hydrophobic group is disclosed or suggested. Not.

 On the other hand, Non-Patent Document 6 describes a reaction in which ethylene glycol is added to a toluene / water-based solvent, but there is no description of the effect of the addition of a diol on the yield. In particular, there is no description of improving the yield by adding a diol in an aqueous solvent in the presence of a palladium-carbon catalyst, or that the reaction has a wide range of applications without using a substituent.

[0004] Patent Document 1: International Publication No. 97/27174 pamphlet

 Patent Document 2: US Pat. No. 5,756,545

 Patent Document 3: JP 2003-128608 A

 Non-Patent Document 1: Norio Takaura, Akira Suzuki et al., Chemical Reviews 1995, Vol. 95, No. 7, p.2457-2483

 Non-patent Document 2: Yoshinori Tamura et al., Journal of Medicinal Chemistry (J. Med. Chem.) 1998, Vol. 41, No. 4, p. 640-649

 Non-Patent Document 3: Patrick M. O 'Brien et. Al., Journal of Medicinal Chemistry (J. Med. Chem.) 2000, Vol. 43, No. 2,

 p.156-16ο

 Non-Patent Document 4: Shunichi Hirao et al., Journal of Organic Chemistry (J. Org. Chem.) 2002, Vol. 67, No. 8, p.2721-2722

 Non-Patent Document 5: D. Gala et. Al., Organic Process Researcher! ^ Aberoffment (Organic Process Research & Development) 1997, 丄 卷, p.163-164

 Non-Patent Document 6: Christian Lieke et al., (Christian. Liek et. Al.) Zeitschrift fur Naturforschung B 1999, Vol. 54, No. 12, p. 1532 1542

 Disclosure of the invention

[0005] An industrial product that uses an economical solvent that uses an economical palladium-carbon catalyst and is environmentally friendly. Development of Suzuki coupling suitable for the law is desired. It is also desired that the coupling reaction be performed under more general reaction conditions that do not depend on the substrate.

 In view of the above points, the present inventors have conducted intensive studies, and as a result, have found a Suzuki coupling suitable for an industrial production method using an aqueous solvent using an economical palladium-carbon catalyst as a catalyst, environmentally friendly. Was. In addition, in Suzuki coupling in an aqueous solvent using palladium-carbon as a catalyst, it was found that the addition of diols dramatically improved the yield.

 That is, the present invention provides 1) a general formula (II):

[Formula 5]

(II)

(Wherein, R ¹ is lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, honolemil, acyl, acyloxy, halogen, halo-lower alkyl, halo-lower alkyloxy, nitro, carboxy, snorejo, lower alkyloxycarbonyl, Lower alkynolesulfonyl, lower alkylsulfonyloxy, optionally substituted aminocarbonyl, optionally substituted aminocarbonyl, optionally substituted aryl, or optionally substituted heteroaryl; R ² and R ² 'is simultaneously hydrogen atom or a lower alkyl, or R ² and R ^2' it may also form a 3 to 8-membered ring together with the oxygen atom connexion adjacent such together les,; Z ¹ is - Ji ^{11: .! ^ 1 -, - S} -, - 〇 -, - CR "= N-, or - N = CR" - (wherein, R ^{1 1} is as defined the hydrogen atom or R ^1, R ¹¹⁾ are selected independently of one another if there are two or more; m is an integer from 0 to 3, when the above m power ¾, the compound represented by R ¹ is selected independently), the Salts, or solvates thereof, and

General formula (III): (I'D

(Wherein R ° is lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, honolemil, acyl, acyloxy, halogen, halo-lower alkyl, halo-lower alkyloxy, nitro, carboxy, snorejo, lower alkyloxycarbonyl, Lower alkynolesulfonyl, lower alkylsulfonyloxy, optionally substituted aminyl, optionally substituted aminocarbonyl, optionally substituted aryl, or optionally substituted heteroaryl; R ³ is Hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl ; R ⁴ is hydrogen atom, lower alkyl, Ararukiru, hetero Reel alkyl or Ashiru,; Y during hydroxy or lower Arukiruokishi ¹ is a halogen or R ⁵ S_〇- (wherein, R ⁵ is lower alkyl

 Three

Or halo-lower alkyl); Z ² is — CR ¹² = CR ¹² _, — S—, —〇_, — CR ¹² = N—, or — N = CR ¹² − (where R ¹² is a hydrogen atom Or is the same as R. When two or more R ¹² are present, they are independently selected from each other); n is an integer from 0 to 2, and when n is 2, each R ° is independently A compound represented by the general formula (I): wherein the compound represented by formula (I) is reacted with a solvent containing water in the presence of palladium-carbon.

[Formula 7]

And n are the same as defined above), a salt thereof, or a solvate thereof.

More specifically, it relates to the following 2) to 10). 2) —General formula (IV)

[Formula 8]

(Wherein X ² is a halogen, R ° X ¹ Z ² and n are the same as in 1), a salt thereof, or a solvate thereof, and a compound represented by the general formula (V)

[Formula 9]

(Where R ³

And Y are the same as defined in 1)), a salt thereof, or a solvate thereof, whereby the compound represented by the general formula (III)

[Formula 10]

And n is the same as defined in 1)), the step A of obtaining a compound represented by the formula (I), a salt thereof, or a solvate thereof, and the obtained compound represented by the general formula (III), a salt thereof, or a solvate thereof ,and,

General formula (II):

[Formula 11]

 (II)

(Where:

And m are the same as defined in 1)), a salt thereof, or a solvate thereof.

By reacting in a solvent containing water in the presence of palladium-carbon, the compound of the general formula (I):

(l)

And n is the same as defined in 1), or a salt thereof, or a solvate thereof.

 3) The production method according to 1) or 2), wherein the solvent is water only.

 4) The production method according to 1) or 3), wherein the reaction in the presence of palladium-carbon is a reaction in the presence of acetic acid and palladium-carbon.

 5) Reactivity in the presence of palladium on carbon The production method according to 1) or 4), which is a reaction in the presence of a diol and palladium on carbon.

 6) The production method according to 5), wherein the diol is ethylene glycol.

7) —General formula (VI):

 [Formula 13]

(Where:

And m are the same as defined in 1)), salts thereof, or solvates thereof, and

General formula (VII):

[Formula 14] ノ^(R ) p

? 2 (Where:

X ¹ and Z ² have the same meanings as in 1); p is an integer of 0 to 3, and when p is 2 or more, R ° is independently selected), a compound thereof, a salt thereof, or a salt thereof. The solvate,

Characterized by reacting in the presence of diol and palladium-carbon in a solvent containing water.

General formula (VIII):

[Formula 15]

(Where:

Z ² and m are as defined in 1), and p is as defined above), a salt thereof, or a solvate thereof.

 8) The production method according to 7), wherein the diol is ethylene glycol.

 9) The production method according to 7) or 8), wherein the amount of the diol is 0.5 to 15 equivalents to the compound represented by the general formula (VI).

 10) —General formula (IX):

[Formula 16]

(Where:

And m are the same as defined in 1), wherein R ⁶ and R ⁶ are simultaneously lower alkyl or R ⁶ and R ⁶ ′ together form a 3-8 membered ring with an adjacent oxygen atom) , A salt thereof, or a solvate thereof, and

General formula (VII):

[Formula 17]

Wherein R °, X ¹ and Z ² have the same meaning as in 1); p has the same meaning as in 7)), a salt thereof, or a solvate thereof.

The reaction is carried out in a solvent containing water in the presence of palladium-carbon, general formula (VIII):

[Formula 18]

(Where:

Z ² and m have the same meaning as in claim 1, and p has the same meaning as in 7)), a salt thereof, or a solvate thereof.

 As used herein, the term "lower alkyl" used alone or in combination with other terms includes a straight-chain or branched-chain monovalent hydrocarbon group having 118 carbon atoms. For example, methynole, ethyl, n_propyl, isopropyl, n-butyl, isobutyl, sec-butynole, tert-butynole, n-pentynole, isopentynole, neo_pentynole, n_hexynole, isohexyl, n-heptyl , N-octyl and the like. Preferably, C1-C6 alkyl is used. More preferably, C1-C4 alkyl is used. More preferably, C1-C3 alkyl is mentioned.

R. And "lower alkyl" for R ¹ is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like.

As the “lower alkyl” for R ² and R ² ′, methyl, ethyl, n-propyl, isopyryl and the like are preferable. Further, methyl is preferred.

As the “lower alkynole” for R ^3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like are preferable. Methyl, ethyl, isopropyl, isobutyl, sec-butyl are more preferred.

As the “lower alkyl” for R ^4, methyl, ethyl, n-propyl, n-butyl and the like are preferable. Masire, Further, methyl is preferred.

As the “lower alkyl” for R ^5, methyl is preferable.

As the “lower alkyl” for R ⁶ and R ⁶ ′, methyl, ethyl, n-propyl, isopyl pill and the like are preferable. Further, methyl is preferred.

[0010] In the present specification, "aryl" used alone or in combination with other terms includes a monocyclic or condensed cyclic aromatic hydrocarbon. For example, phenyl, 11-naphthine, 2-naphthyl, anthryl and the like can be mentioned.

R °,

And as "Ariru" in R ³ phenyl, 1 one-naphthyl, 2_ naphthyl. Phenyl is preferred.

 In the present specification, the term "arano quinole" is obtained by substituting the above "lower alkyl" by one or more of the above "aryl", and these may be substituted at all possible positions. For example, benzene, phenylethyl (eg, 2-phenylethyl), phenylpropyl (eg, 3_phenylpropyl), naphthylmethyl (eg, 1-naphthylmethyl, 2-naphthylmethyl, etc.), anthrylmethyl (eg, , 9-anthrylmethyl and the like).

As the “aralkyl” for R ³ and R ^4, benzyl, phenylethyl, naphthylmethyl and the like are preferable. In addition, Benginore is preferred.

[0011] In the present specification, the term "heteroaryl" used alone or in combination with other terms refers to an arbitrarily selected 5- to 6-membered ring containing one or more oxygen, sulfur or nitrogen atoms in the ring. Which may be fused with cycloalkyl, aryl, non-aromatic heterocycle, or other heteroaryl, which may be fused at all possible positions. For example, pyrrolyl (eg, 1-pyrrolyl, 2_pyrrolyl, 3-pyrrolyl), furyl (eg, 2-furyl, 3_furyl), phenyl (eg, 2_phenyl, 3_phenyl), imidazolinole (eg, 2_imidazolyl, 4-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-virazolinole), isothiazolyl (eg, 3-isothiazolyl), isoxazolyl (eg, 3-isoxazozolyl), oxazolyl (eg, 2-oxazolyl) , Thiazolyl (for example, 2-thiazolyl), pyridyl (for example, 2_pyridinole, 3_pyridinole, 4_pyridyl), pyrazur (for example, 2-pyrazuryl), pyrimidinyl (for example, 2_pyrimidyl, 4-pyrimidinyl), Pyridazinol (eg, 3_pyridazinyl), tetrazolyl (eg, 1H-tetra Zoriru), Okisajiazo Ril (for example, 1,3,4-oxaziazirolinol), thiadiazolinol (for example, 1,3,4-thiadiazolyl), indolizinyl (for example, 2 indolizinyl, 6 indolizinyl), isoindolinyl (for example, 2_isoindolyl) ), Indolyl (eg, 1 indolyl, 2_indolyl, 3-indolyl), indazolyl (eg, 3_indazolyl), purinyl (eg, 8_prinyl), quinolizinyl (eg, 2_quinolizinyl), isoquinolyl ( For example, 3_isoquinolyl), quinolyl (eg, 2_quinolyl, 5_quinolyl), phthaladur (eg, 1_phthaladur), naphthyridinyl (eg, 2_naphthyridinyl), quinoxalinyl (eg, 2_quinoxalinyl), quinazolinyl (Eg, 2-quinazolinyl), cinnolinyl (eg, 3_cinno Linyl), pteridinyl (for example, 2-pteridinyl), carbazolyl (for example, 2_carbazolyl, 3-carbazolyl), phenanthridinyl (for example, 2-phenanthridinyl, 3-phenanthrinyl), atalidinyl ( For example, 1-atalinidyl, 2-atalinidyl), dibenzofuranyl (for example, 1-dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (for example, 2 benzoimidazolinole), benzoiso Oxazolinole (for example, 3-benzoisoxazolinole), Benzoxazolyl (for example, 2-benzozozolyl), Benzoxazodazolyl (for example, 4-benzozoxazolyl) Azolyl), benzoisothiazolyl (for example, 3-benzoisothiazolyl), benzothiazolyl (for example, 2-benzothiazolyl), benzo Lil (e.g., 3-base Nzofuriru), Benzocheniru (e.g., 2-Benzocheniru), (for example, 1-benzotriazolyl) benzotriazole § benzotriazolyl and the like.

R °,

And as "Heteroariru" in R ^3, pyridyl, thienyl, furyl, indolyl, imidazolyl, etc. are preferable.

 In the present specification, the term "heteroarylalkyl" means one or more of the above "heteroaryl" substituted at any position of the above "lower alkyl", and these may be substituted at all possible positions. For example, thiazolylmethyl (for example, 4_thiazolylmethyl), thiazolylethyl (for example, 5_thiazolyl-2-ethyl), benzothiazolylmethyl (for example, (benzothiazonole_2_yl) methyl), indolylmethyl (for example, ( Indole—3—

), Imidazolylmethyl (eg, 4_imidazolylmethyl), benzothiazolylmethyl

For example, 2_ benzothiazolylmethyl), indazolylmethyl (^ the 1-noso / 々

, ΠΤ, / 1 ^ kin (10,000 il 1 _ And benzoimidazolylmethyl (for example, 2-benzoimidazolylmethyl), pyridylmethyl (for example, 2-pyridylmethyl, 3-pyridylmethyl, and 4-pyridylmethyl).

As the “heteroarylalkyl” for R ³ , indolylmethyl (eg, indolinole-3-ylmethyl), imidazolylmethyl (eg, imidazole-5-ylmethyl) and the like are preferable. Indore no_3_ylmethyl is preferred.

As the “heteroarylalkyl” for R ⁴ , indolylmethyl (eg, indole-no_3_ylmethyl) and the like are preferable.

 In the present specification, the “lower alkyloxy” includes methyloxy, ethyloxy, n-propyl pyroxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and the like. Preferably, methyloxy, ethyloxy, n-propyloxy, isopropyloxy and n-butyloxy are exemplified.

 In the present specification, the “lower alkylthio” includes methylthio, ethylthio, n-propylthio and the like.

 As used herein, the term "acyl", used alone or in combination with other terms, includes an alkylcarbonyl wherein the alkyl moiety is the above "lower alkyl" or an arylcarbonyl wherein the aryl moiety is the above "aryl". I do. For example, acetyl, propionyl, benzoyl and the like can be mentioned. “Lower alkyl” and “aryl” may be substituted by the respective substituents described below.

 In the present specification, examples of "asyloxy" include acetyloxy, propionyloxy, benzoyloxy and the like.

 As used herein, "halogen" refers to fluorine, chlorine, bromine, and iodine. Preference is given to chlorine and bromine. More preferably, chlorine is used.

In the present specification, the term `` halo lower alkynole '' used alone or in combination with other terms refers to the above-mentioned `` lower alkyl '' substituted at 118 places, preferably at 115 places by the above-mentioned `` halogen ''. Is included. For example, trifluoromethyl, trichloromethyl, difluoroethyl, trifluoroethyl, dichloroethynole, trichloroethyl and the like can be mentioned. Preferably, trifluoromethyl is used. As the “halo lower alkyl” for R ⁵ , trifluoromethyl is preferable.

 In the present specification, “halo lower alkyloxy” includes trifluoromethyloxy and the like.

 In the present specification, “lower alkyloxycarbonyl” includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl and the like.

 In the present specification, the “lower alkylsulfonyl” includes methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like.

 In the present specification, the “lower alkylsulfonyloxy” includes methanesulfonyloxy, ethanesulfonylsulfonyloxy, propanesulfonyloxy and the like. As used herein, the term "optionally substituted amino" used alone or in combination with other terms refers to an unsubstituted amino or the above-mentioned "lower alkyl", "aralkyl", "heteroarylalkyl", Or amino substituted one or two times with "acyl". For example, amino, methinoleamino, dimethylamino, ethylmethylamino, getylamino, benzylamino, acetylamino, benzoylamino and the like can be mentioned. Preferably, amino, methylinoamino, dimethylamino, ethylmethylamino, getylamino, and acetylamino are exemplified.

 In the present specification, the “optionally substituted aminocarbonyl” includes aminocarbyl (forcebamoyl), methylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, getylaminocarbonyl and the like. Preferably, amino carbonyl and dimethylamino carbonyl are mentioned.

[0015] In the present specification, examples of the substituent in the "optionally substituted lower alkyl" include cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), hydroxy, and lower alkyloxy (for example, methoxy). , Ethoxy, t-butoxy), mercapto, lower alkylthio (eg, methylthio, ethylthio), halogen, nitro, cyano, carboxy, sulfo, lower alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl) ), Halo-lower alkyl (for example, triphenylenomethyl), halo-lower alkyloxy (for example, trifluoromethyloxy), lower alkyl Amino (eg, amino, methylamino, dimethylamino, ethylamino, dimethylamino, methylethylamino), rubamoyl, formyl, acyl (eg, acetyl, benzoyl), and acyloxy (eg, acetyloxy, Benzoyloxy), a non-aromatic heterocyclic group (eg, pyrrolidyl, piberidinyl, piperazur, morpholinyl, tetrahydrofuranyl, tetrahydrovinyl), aryloxy (eg, phenyloxy), aralkyloxy (eg, benzyloxy), lower alkylsulfonyl (eg, Methanesulfonyl), guanidinium-containing azo groups, ureido and the like. These may be substituted one or more times in all possible positions.

As the substituent for the “optionally substituted lower alkyl” for R ³ , hydroxy, lower alkylthio, carboxy, or rubamoyl is preferable.

"Optionally substituted aryl", "optionally substituted heteroaryl", "substituted, substituted, aralkyl", and "substituted, substituted, heteroaryl" Examples of the substituent in “reylalkyl” include lower alkyl which may be substituted, cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), lower alkenyl (eg, bier, propenyl, butenyl) , Lower alkynyl (ethynyl, propyninole), hydroxy, lower alkyloxy (eg, methoxy, ethoxy, t-butoxy), mercapto, lower alkylthio (eg, methylthio, ethylthio), halogen, nitro, cyano, carboxy, sulfo, lower alkyl Oxycarbonyl (eg, methoxycarbonyl, d Xycarbonyl, t-butoxycarbonyl), halo-lower alkyl (eg, trifluoromethyl), halo-lower alkyloxy (eg, trifluoromethyloxy), amino optionally substituted with lower alkyl (eg, amino) , Methylamino, dimethylamino, ethylamino, dimethylamino, methylethylamino), rubamoyl, formyl, acyl (eg, acetyloxy, benzoyloxy), acylyl (eg, acetyloxy, benzoyloxy), aryl, heteroaryl, non-aromatic heterocycle (For example, pyrrolidyl, pyridininole, piperazur, morpholinolinole, tetrahydrofuranyl, tetrahydrovinyl), aralkyl, aryloxy (for example, fenyloxy), and aralkyloxy (for example, Jiruokishi), lower alkylsulfonyl (e.g. methanesulfonate) yl, Guaniji Nyua zone group or ureido, and the like. These may substitute one or more at all possible positions sell.

In R ³ "is substituted, good Rere Ariru be", "substituted been, even if good records, Heteroari Le", "may be substituted Ararukiru", and "to which may be substituted Hydroxy or halogen is preferred as the substituent in “teroarylalkyl”. Also preferred are "unsubstituted aryl", "unsubstituted heteroaryl", "unsubstituted aralkyl", and "unsubstituted heteroarylalkyl".

In the present specification, "R ² and R ² 'may be taken together to form a 38-membered ring containing an adjacent oxygen atom," or "R ⁶ and R ⁶ ' are taken together. May form a 38-membered ring each containing an adjacent oxygen atom ", and includes the following rings.

 [Formula 19]

In particular, as the ring represented by “and R ⁶ ′ may be taken together to form a 3- to 8-membered ring containing an adjacent oxygen atom”, the following rings are preferred.

[Formula 20]

Or "diol" as used herein means an alcohol having two hydroxyl groups bonded to different carbon atoms in C2-C6, preferably C2-C4 alkanediyl. Examples include ethylene glycol, 2,3_butanediol, 2,3_dimethyl-2,3_butanediol, and 1,3-propanediol. Ethylene glycol is preferred. BEST MODE FOR CARRYING OUT THE INVENTION [0018] When referring to a "compound", the compound is not limited to a specific isomer, but includes all possible isomers (eg, optical isomers) and racemates. Further, a pharmaceutically acceptable salt or a solvate thereof is also included.

 The term “salt” of the compound used in the present invention refers to alkali metals (lithium, sodium, potassium, cesium, etc.), alkaline earth metals (magnesium, calcium, barium, etc.), ammonium, organic bases and amino acids. With organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) or with inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.) Contains salt. These salts can be formed by a commonly used method.

 The “solvate” of the compound used in the present invention includes, for example, solvates with organic solvents, hydrates and the like. When forming a hydrate, it may be coordinated with any number of water molecules.

 [0019] [Formula 21]

 (IV)

 (ii) (i)

(Where R °,

R ² , R ² ′, R ³ , R ⁴ , X ¹ , X ² , Y, Z ² , m, and n are as defined above (first step)

This step is a step of coupling the compound represented by the general formula (IV) and the compound represented by the general formula (V) as starting materials using the Schotten-Baumann method. Water-acetone mixed solvent, water 1,4 dioxane mixed solvent, water-tetrahydrofuran mixed solvent, water dimethoxyethane mixed solvent, water-acetonitrile mixed solvent, water-methanol mixed solvent, water Water-alcohol mixed solvent such as -ethanol mixed solvent, water-propanol mixed solvent, water-isopropanol mixed solvent, water butanol mixed solvent, water-isobutanol mixed solvent, water-sec-butanol mixed solvent, N, N-dimethyl In a solvent such as formamide, N, N_dimethylacetamide, or dimethylsulfoxide, 0.92 equivalents, preferably 1.0 equivalent to 1.2 equivalents of the compound represented by the general formula (V) is added to the compound represented by the general formula (IV). In the presence of 2 equivalents to 10 equivalents of the compound represented by, preferably 2 equivalents to 13 equivalents of a base, 1 to 20 hours at 30 ° C, preferably _5 ° C for 1 to 20 hours at 1 to 10 ° C, preferably The compound represented by the general formula (III) can be obtained by allowing the reaction to proceed for 1 hour to 13 hours and performing post-treatment usually performed.

 As the solvent, a mixed solvent of acetone and water is preferable. The mixing ratio is preferably acetone: water = 5: 1—1: 5. Further, 3: 1 to 1: 3 is preferred. In particular, 2: 1-1: 2 is preferable. Examples of the base include sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, cesium carbonate, cesium hydrogencarbonate, lithium carbonate, lithium hydrogencarbonate, rubidium carbonate, and rubidium hydrogencarbonate. And inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, norrebidium hydroxide, cesium hydroxide and ammonium carbonate, and tertiary amines such as triethylamine, tributylamine and diisopropylethylamine. Sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, triethylamine, etc. are preferred (second step).

 This step is a step of performing a coupling reaction in the presence of palladium-carbon on the compound represented by the general formula (II) and the compound represented by the general formula (III) as starting materials.

 In the solvent, in the presence of 0.001 equivalent to 0.5 equivalent, preferably 0.002 equivalent to 0.1 equivalent of the catalyst, 0.8 to 5 equivalents, preferably 0.8 to 5 equivalents of the compound represented by the general formula (III) is used. One equivalent to 1.5 equivalents of the compound represented by the general formula (II) and 0.58 equivalents, preferably 1 equivalent to 4 equivalents of the basic substance are mixed at 30 ° C. to 200 ° C., preferably 50 ° C. ° C—React at 100 ° C for 1 hour to 30 hours, preferably 1.5 hours to 5 hours, and perform the usual post-treatment to obtain the compound represented by the general formula (I). S can.

As the solvent, water or a mixed solvent of water and an organic solvent is preferable. Water or water split A mixed solvent with an organic solvent having a high compatibility is more preferable. The mixing ratio of water and the organic solvent is preferably 100: 0-85: 15, more preferably 100: 0-90: 10, even more preferably 100: 0-93: 7, and particularly preferably. The solvent is water. In particular, water is preferred. As the organic solvent of the mixed solvent, the force due to the solubility of the substrate S, benzene, toluene, N, N-dimethylphenol, amide, dimethoxyethane, tetrahydrofuran, dioxane, methanol, ethanol, isopropanol, and the like are preferable.

 Basic substances include sodium hydroxide, sodium methoxide, potassium hydroxide, ammonia, lithium hydroxide, cesium hydroxide, rubidium hydroxide, barium hydroxide, lithium methoxide, potassium methoxide, cesium methoxide, and sodium ethoxide. , Lithium ethoxide, potassium ethoxide, cesium ethoxide, lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, norrebidium carbonate, rubidium hydrogen carbonate, cesium carbonate, cesium hydrogen carbonate, phosphorus And sodium disodium hydrogen phosphate. Sodium carbonate, potassium carbonate and disodium hydrogen phosphate are preferred.

 The palladium carbon catalyst preferably contains water. The water content is preferably 70% -30%. Further, 60% to 40% is preferable. The content of palladium carried on the palladium carbon is preferably 13% to 1%. 7% -3% is more preferred.

 In order to increase the reaction rate, it may be preferable to add 0.2 to 5 equivalents, preferably 0.8 to 2 equivalents of acetic acid to the reaction system.

 In some cases, it is preferable to add 0.1 to 5 equivalents, preferably 0.3 to 2 equivalents of a diol such as ethylene daryl to the reaction system in order to suppress a side reaction.

Solvent power W Sopropanol- 17 (main) mixed solvent, 5% palladium-carbon catalyst containing water as the catalyst, and reaction conditions in which the basic substance is potassium carbonate are preferable. In addition, the solvent contained isopropanol / water (main) mixed solvent, and the catalyst contained water5. / ₀ Reaction conditions where palladium-carbon and basic substance are sodium hydroxide, or solvent is aqueous solvent, catalyst is 5% palladium-carbon with water, basic substance is sodium hydroxide and acetic acid The reaction conditions, which are in the presence of, are preferred. [Formula 22]

• (R °) P 3rd step

ヽ-'>>, _Z 2

₍ vi) ^(VII) (viii)

(Where R °,

Z ² , m, and p are as defined above.

(3rd step)

 This step is a step of performing a coupling reaction in the presence of a diol using a compound represented by the general formula (VI) and a compound represented by the general formula (VII) as starting materials.

 In a solvent, 0.00005 equivalents to 0.1 equivalents, preferably 0.00000 equivalents to 0.05 equivalents of the compound represented by the general formula (VII), in the presence of 0.5% equivalents of a nodium radium-carbon catalyst, 0.8 equivalents — 5 equivalents, preferably 1 equivalent to 1.5 equivalents of the compound represented by the formula (VI) and 0.5 to 8 equivalents, preferably 1 to 14 equivalents of a basic substance, 0.5 to 30 equivalents The reaction is usually carried out by reacting 1 to 15 equivalents of diol at 30 ° C 200 ° C, preferably 50 ° C to 150 ° C for 1 hour to 40 hours, preferably 1.5 hours to 15 hours. By performing the post-treatment, the compound represented by the general formula (VIII) can be obtained.

 As the solvent, water or a mixed solvent of water and an organic solvent is preferable. Water or a mixed solvent with an organic solvent having a high percentage of water is more preferable. The mixing ratio of water and the organic solvent is preferably 100: 085: 15, more preferably 100: 0-90: 10, even more preferably 100: 0-93: 7, and particularly preferably a solvent. Is water. As the organic solvent of the mixed solvent, benzene, toluene, N, N-dimethylformamide, dimethoxyethane, tetrahydrofuran, dioxane, methanol, ethanol, isopropanol, etc. are preferred.

 Examples of the basic substance and the nodium-carbon catalyst include those used in the second step. The diols include ethylene glycol, 2,3_butanediol, 2,3_dimethyl-2,

3-Butanediol and 1,3-propanediol are preferred, and ethylene glycol is particularly preferred.

The pH of the reaction solution is usually pH 7-11, but the type of boronic acid represented by the general formula (VI) is Depending on the pH, pH 4-6 may be optimal. In such a case, the reaction is preferably performed in the presence of acetic acid, sodium dihydrogen phosphate or sodium monohydrogen phosphate.

 To improve the yield, it may be preferable to carry out the reaction in the presence of 0.5-10 equivalents, preferably 0.7-3 equivalents of sodium bromide.

 Preferred are reaction conditions in which the solvent is an aqueous solvent, the catalyst is 5% palladium-carbon containing water, the basic substance is disodium hydrogen phosphate, and the diol is ethylene glycol. Further, reaction conditions in which the solvent is an aqueous solvent, the catalyst is 5% palladium-carbon containing water, the basic substance is sodium hydroxide, the diol is ethylene glycol, and sodium bromide are more preferable.

[Formula 23]

XI no ( ¹ ) n

R. ) _P IT-1-(R °) p, ^{p 4th} process) I7I

In. Z ²

(IX) (VII) (VIII)

(Where R °,

Z ² , m, and p are as defined above.

(4th step)

 This step is a step of performing a coupling reaction using the compound represented by the general formula (IX) and the compound represented by the general formula (VII) as starting materials.

 In the solvent, in the presence of 0.00005 equivalent to 0.01 equivalent, preferably 0.00007 equivalent to 0.005 equivalent of the catalyst, 0.8 to 5 equivalents, preferably 0.8 to 5 equivalents of the compound represented by the general formula (VII) is used. 1 equivalent to 1.5 equivalents of the compound represented by the general formula (IX) and 0.5 to 8 equivalents, preferably 1 to 14 equivalents of a basic substance, 30 ° C to 200 ° C, preferably 50 ° The compound represented by the general formula (VIII) can be obtained by reacting at C-150 ° C for 1 hour to 40 hours, preferably 1.5 hours to 15 hours, and performing a usual post-treatment. .

As the boronic ester represented by the general formula (IX), a commercially available product can be used. References (Sudersan M. Tuladhar et. Al.), Tetrahedron Letters 1992, Vol. 33, No. 2, p. 265-268, etc. Can also be synthesized from the reaction of a boronic acid derivative with an alcohol. Further The compound can also be synthesized by the method described in the literature (Miyaura et al., Journal of Organic Chemistry (J. Org. Chem.) 1995, Vol. 60, No. 23, p. 7508-7510).

 Examples of the solvent, basic substance, catalyst and the like include the solvents, basic substances, catalysts and the like described in the second and third steps.

 Preferred are reaction conditions in which the solvent is an aqueous solvent, the catalyst is 5% palladium-carbon containing water, and the basic substance is disodium hydrogen phosphate.

 Example

 In the examples, the following abbreviations are used.

 Pd-C: Palladium-carbon

 Me: methyl

 DME: dimethoxyethane

 DMF: N, N-dimethylformamide

 DMSO: dimethyl sulfoxide

 Ph: phenyl

 THF: tetrahydrofuran

Comparative Example 1

[Formula 24]

 (1a) (2a) (3) Disodium disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 mL), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol), phenylboronic acid (2a, 0.728 g, 5.97 mmol) was added at room temperature. To the suspension was added 5% palladium-carbon (2 mg, 0.456 nmol) as a catalyst, and the mixture was stirred at 95 ° C under a nitrogen stream for 8 hours. As a result of a reaction test using HPLC, the production of the target product, 4_biphenylcarboxylic acid 3, was trace. (HPLC Peak Area% at UV 230 nm: 0.09%)

Example 1 [Formula 25]

 Disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 mL), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol) and phenylboronic acid (2a, 0.728 g, 5.97 mmol) Was added at room temperature. The suspension was mixed with ethylene glycol (3.0 ml, 53.8 mmol) and 5% palladium-carbon (2 mg, 0.456 ol) as a catalyst, and stirred at 95 ° C under a nitrogen stream for 8 hours. The reaction solution was allowed to cool to room temperature, 2 mol / L hydrochloric acid (10 ml) was added, and the mixture was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration. The obtained crude crystals were dissolved in tetrahydrofuran (100 ml), and acetonitrile was added to 1 mL of the solution to prepare a solution having a total volume of 50 ml. Using this solution, a quantitative test (UV 230 nm) was performed by HPLC. The yield of the desired product, 4-biphenylcarboxylic acid 3, was 53.2%.

Example 2

[Formula 26]

Disodium hydrogenphosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol), phenylboronic acid (2a, 0.728 g, 5.97 mmol) Was added at room temperature. Sodium bromide (0.512 g, 4.98 mmol), ethylene glycol (3.0 ml, 53.8 mmol), 5% palladium-carbon (2 mg, 0.456 nmol) were added to the suspension, and the mixture was stirred at 95 ° C for 8 hours under a nitrogen stream. Stirred. The reaction solution was allowed to cool to room temperature, 2 mol / L hydrochloric acid (10 ml) was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration. The obtained crude crystals were dissolved in tetrahydrofuran (100 ml), and a solution of acetonitrile in a total volume of 50 ml of acetonitrile was prepared in 1 mL of the solution. Using this solution, a quantitative test (UV 230 nm) was performed by HPLC. The yield of the desired product, 4-biphenylcarboxylic acid 3, was 92.8%. Also, the obtained crude crystals were treated with acetic acid: Recrystallization from xan gave 4-biphenylcarboxylic acid (3, 0.880 g, 89.2%). ¾ NMR δ (CDC1): 7.39-7.52 (m, 3H), 7.65 (ddd, J = 7.2 Hz, 1.6 Hz, 2H), 7.71

 Three

 (ddd, J = 8.8 Hz, 1.9 Hz, 2H), 8.19 (ddd, J = 8.5 Hz, 1.9 Hz, 2H)

Example 3

 [Formula 27]

 Disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol) and phenylboronic acid (2a, 0.728 g, 5.97 mmol) Was added at room temperature. 2, 3-butanediol (3.0 ml, 33.1 mmol) and 5% palladium-carbon (2 mg, 0.456 nmol) were added to the suspension, and the mixture was stirred at 95 ° C under a nitrogen stream for 8 hours. The reaction solution was allowed to cool to room temperature, 2 mol / L hydrochloric acid (10 ml) was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration. The obtained crude crystals were dissolved in tetrahydrofuran (100 ml), and acetonitrile was added to 1 ml of the solution to prepare a solution having a total volume of 50 ml. Using this solution, a quantitative test (UV 230 nm) was performed by HPLC. The yield of 4-biphenylcarboxylic acid 3 was 59.5%.

 [0028] Table 1 summarizes the results of Examples 13 and 13 and Comparative Example 1. Even when the reaction does not proceed with phenylboronic acid alone, the reaction proceeds smoothly in the presence of the diol, and the desired product is obtained in good yield. In particular, in the presence of diol and sodium bromide, the yield is significantly improved.

[0029] [Table 1] HPLC

No. Additive Yield (¾) Comparative Example 1 2a <0.1

Example 1 Ethylene glycol -B (OH) ₂ 2a 53.2 M ₂ Ethylene glycol

ΛExample 2 Sodium bromide -B (OH) ₂ 2a 92.8

Example 3 2,3-butanediol 2a 59.5

Example 4

 [Formula 28]

 Disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol) and phenylboronic acid ethylene glycol ester (2b, 0.883 g, 5.97 mmol) was added at room temperature. To the suspension was added 5% palladium-carbon (2 mg, 0.456 nmol), and the mixture was stirred at 95 ° C under a nitrogen stream for 8 hours. The reaction solution was allowed to cool to room temperature, 2 mol / L hydrochloric acid (10 ml) was added, the mixture was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration. The obtained crude crystals were dissolved in tetrahydrofuran (100 ml), and a solution in which acetonitrile was added to 1 ml of the solution and the total amount was 50 ml was prepared. Using this solution, a quantitative test (UV 230 nm) was performed by HPLC. The yield of 4_biphenylcarboxylic acid 3 was 92.7%.

Example 5

[Formula 29]

 Disodium hydrogenphosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol), phenylboronic acid 2,3 butanediol ester (2c, 1.051 g, 5.97 mmol) was added at room temperature. The suspension was quenched with 5% palladium carbon (2 mg, 0.456 nmol) and stirred at 95 ° C. for 8 hours under a nitrogen stream. The reaction solution was allowed to cool to room temperature, 2 mol / L hydrochloric acid (10 ml) was added, the mixture was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration. The obtained crude crystals were dissolved in tetrahydrofuran (100 ml), and a solution in which acetonitrile was added to 1 ml of the solution and the total amount was 50 ml was prepared. Using this solution, a quantitative test (UV 230 nm) was performed by HPLC. The yield of 4-bicarboxylic acid 3 was 86.6%.

Example 6

[Formula 30]

 Disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4-bromobenzoic acid (la, 1.00 g, 4.97 mmol), 4-acetylphenylboronic acid (2d, 0.979 g, 5.97 mmol) was added at room temperature. Sodium bromide (0.512 g, 4.98 mmol), ethylene glycol (3.0 ml, 53.8 mmol), 5% palladium on carbon (21 mg, 4.79 nmol) were added to the suspension, and the mixture was stirred at 95 ° C under a nitrogen stream for 1.5 hours. Stirred. The reaction solution was allowed to cool to room temperature, 2 mol / L hydrochloric acid (10 ml) was added thereto, and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration and recrystallized from tetrahydrofuran Z-hexane to obtain the desired product (4, 1.142 g, 95.5%).

 JH NMR δ (DMSO-d): 2.63 (s, 3H), 7.87-7.91 (m, 4H), 8.05-8.09 (m, 4H)

 6

 Example 7

[Formula 31]

 Disodium disodium hydrogen phosphate (1.786 g, 12.6 mmol) was dissolved in water (28 ml), and 4-bromoisole (lb, 0.63 ml, 5.03 mmol) and phenylboronic acid (2a, 0.736 g, 6.04 mmol) were added at room temperature. Added in. Sodium bromide (0.518 g, 5.03 mmol), ethylene glycol (2.8 ml, 50.2 mmol), 5% palladium-carbon (221 mg, 50.1 nmol) were added to the suspension, and the mixture was stirred at 95 ° C for 8 hours under a nitrogen stream. Stirred. The reaction solution was allowed to cool to room temperature, extracted twice with ethyl acetate (50 ml, 30 ml), and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was crystallized from methanol / water, and the obtained crude crystals were recrystallized from isopropanol Z water to obtain the desired product (5, 0.486 g, 52.5%). .

 'Η NMR δ (CDC1): 3.85 (s, 3H), 6.98 (ddd, J = 8.8 Hz, 2.6 Hz, 2H), 7.30 (ddd, J

= 7.3 Hz, 1.6 Hz, 1H), 7.41 (ddd, J = 7.4 Hz, 1.5 Hz, 2H), 7.51-7.56 (m, 4H) Example 8

[Formula 32]

 Disodium dihydrogen phosphate (1.783 g, 12.6 mmol) was dissolved in water (30 ml), and 4-bromoacetylethylbenzene (lc, 1.00 g, 5.02 mmol) and phenylenoboronic acid (2a, 0.735 g, 6.03 mmol) were added. Added at room temperature. To the suspension were added sodium bromide (0.517 g, 5.02 mmol), ethylene glycol (3.0 ml, 53.8 mmol), and 5% palladium on carbon (220 mg, 50.1 nmol), and the mixture was added with 95. The mixture was stirred under a nitrogen stream with C for 3 hours. The reaction solution was allowed to cool to room temperature, extracted twice (100 ml, 80 ml) with ethyl acetate, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate / hexane to obtain the desired product (6, 0.858 g, 87.0%). 'Η NMR δ (CDC1): 2.64 (s, 3H), 7.38-7.51 (m, 3H), 7.63 (ddd, J = 6.9 Hz, 1.7

Hz, 2H), 7.69 (ddd, J = 8.5 Hz, 1.9 Hz, 2H), 8.04 (ddd, J = 8.8 Hz, 1.9 Hz, 2H) Example 9

 [Formula 33]

 Disodium hydrogenphosphate (1.786 g, 12.6 mmol) was dissolved in water (28 ml), and 4-bromodisole (lb, 0.63 ml, 5.03 mmol), 4-acetylphenylboronic acid (2d, 0.990 g, 6.04 mmol) was added at room temperature. Sodium bromide (0.518 g, 5.03 mmol), ethylene glycol (2.8 ml, 50.2 mmol) and 5% palladium on carbon (221 mg, 50.1 mmol) were added to the suspension, and the mixture was stirred at 95 ° C for 8 hours under a nitrogen stream. Stirred. The reaction solution was allowed to cool to room temperature, extracted twice with ethyl acetate (100 ml), and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate / hexane to obtain the desired product (7, 0.876 g, 76.9%). 'Η NMR δ (CDC1): 2.63 (s, 3H), 3.86 (s, 3H), 7.00 (ddd, J = 9.0 Hz, 2.6 Hz, 2H),

7.58 (ddd, J = 9.0 Hz, 2.7 Hz, 2H), 7.65 (ddd, J = 9.0 Hz, 2.4 Hz, 2H), 8.01 (ddd, J = 8.4 Hz, 1.8 Hz, 2H)

Example 10

[Formula 34]

 Disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol) and 4_fluorophenylboronic acid (2e, 0.835 g, 5.97 mmol) was added at room temperature. Sodium bromide (0.512 g, 4.98 mmol), ethylene glycol (3.0 ml, 53.8 mmol) and 5% palladium on carbon (21 mg, 4.79 nmol) were added to the suspension, and the mixture was stirred at 95 ° C for 2 hours under a nitrogen stream. Stirred. The reaction solution was allowed to cool to room temperature, and the precipitated crystals were collected by filtration. The crude product was recrystallized from ethyl acetate / hexane to obtain the desired product (8, 1.015 g, 95.2%).

^{J H NMR δ (DMSO-d} ): 7.34 (dd, J = 9.0 Hz, 2.1 Hz, 2H), 7.77-7.82 (m, 4H), 8.02 (ddd, J = 8.5 Hz, 1.9 Hz, 2H)

Example 11

[Formula 35]

 (1d) (2a) (9) Disodium hydrogen phosphate (1.760 g, 12.4 mmol) was dissolved in water (24 ml), and 2-bromothienephen (Id, 0.48 ml, 4.96 mmol), phenylboronic acid (2a , 0.725 g, 5.95 mmol) at room temperature. Sodium bromide (0.510 g, 4.96 mmol), ethylene glycol (2.4 ml, 43.0 mmol), 5% palladium-carbon (218 mg, 49.7 nmol) were added to the suspension, and the mixture was stirred at 95 ° C for 8 hours under a nitrogen stream. Stirred. The reaction solution was allowed to cool to room temperature, extracted twice (150 ml, 100 ml) with ethyl acetate, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from acetone / water to obtain the desired product (9, 0.502 g, 63.2%).

 'Η NMR δ (DMSO-d): 7.08 (dd, J = 3.6 Hz, 4.9 Hz, 1H), 7.27-7.32 (m, 3H),

 6

 7.35-7.40 (m, 2H), 7.62 (d, J = 7.2 Hz, 2H)

Example 12

 [Formula 36]

HOOC

Disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4-bromobenzoic acid (la, 1.00 g, 4.97 mmol) and 4-methylthiophenenylboronic acid (2f, 1.00 mmol) were dissolved. g, 5.97 mmol) at room temperature. Sodium bromide (0.512 g, 4.98 mmol), ethylene glycol (3.0 ml, 53.8 mmol) and 5% palladium on carbon (221 mg, 50.1 nmol) were added to the suspension, and the mixture was stirred at 95 ° C for 28 hours under a nitrogen stream. Stirred. The reaction solution was allowed to cool to room temperature, extracted twice with ethyl acetate (150 ml, 100 ml), and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate / hexane to give the desired product (10, 0.268 g, 22.1%).

 'Η NMR δ (DMSO-d): 2.53 (s, 3H), 7.38 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz,

 6

 2H), 7.79 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 8.2 Hz)

Example 13

 [Formula 37]

■

HOOC

 Disodium hydrogen phosphate (1.765 g, 12.4 mmol) was dissolved in water (30 ml), and 4_bromobenzoic acid (la, 1.00 g, 4.97 mmol) and 4_tolylboronic acid (2 g, 0.812 g, 5.97 g) were dissolved. mmol) at room temperature. Sodium bromide (0.512 g, 4.98 mmol), ethylene glycol (3.0 ml, 53.8 mmol), 5% palladium-carbon (21 mg, 4.79 nmol) were added to the suspension, and the mixture was stirred at 95 ° C for 3 hours under a nitrogen stream. Stirred. The reaction solution was allowed to cool to room temperature, and 2 mol / L hydrochloric acid (10 ml) was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate / hexane to obtain the desired product (11, 0.969 g, 91.8%).

 'Η NMR δ (DMSO-d): 2.36 (s, 3H), 7.31 (d, J = 7.7 Hz, 2H), 7.64 (d, J = 8.2 Hz,

 6

 2H), 7.78 (ddd, J = 8.8 Hz, 1.8 Hz, 2H), 8.01 (ddd, J = 8.5 Hz, 1.9 Hz, 2H)

Example 14

 [Formula 38]

Disodium hydrogenphosphate (1.777 g, 12.5 mmol) was dissolved in water (26 ml), and 4-bromophenololebenzene (If, 0.55 ml, 5.01 mmol) and phenylboronic acid (2a, 0.733 g, 6.01 mmol) were added at room temperature. added. To the suspension were added sodium bromide (0.515 g, 5.01 mmol), ethylene glycol (2.6 ml, 46.6 mmol), and 5% palladium on carbon (220 mg, 50.1 nmol). Stirred for hours. The reaction solution was allowed to cool to room temperature and twice with ethyl acetate (200 ml, 100 ml), and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from methanol / water to obtain the desired product (12, 0.613 g, 71.1%).

¾ NMR δ (CDC1): 7.12 (ddd, J = 8.8 Hz, 2.2 Hz, 2H), 7.34 (ddd, J = 7.3 Hz, 1.4

Hz, 1H), 7.43 (ddd, J = 7.6 Hz, 1.8Ηζ, 2H), 7.51-7.59 (m, 4H)

Example 15

[Formula 39]

 (14) (15) (16) First step

 Under a nitrogen atmosphere, 4-bromothioanisole (13, 10.63 g, 52.3 mmol) in tetrahydrofuran (74 mL) in n-butyllithium (1.57 mol / L in hexane, 40 mL, 1.2 eq) in tetrahydrofuran (32 mL) solution was added dropwise at -73--65 ° C over 8 minutes. After stirring at -67-75 ° C for 1 hour, triisopropyl borate (18.1 mL, d 0.815, 1.5 eq) was added to this mixed solution at once. The resulting pale yellow solution was stirred at −38—15 ° C. for 33 minutes. After water (27 mL) was added to the reaction solution at -15 to 9 ° C over 9 minutes, the mixed solution was stirred for 1 hour and 20 minutes. The pH of the mixture was adjusted to 3.7 with concentrated hydrochloric acid (about 1.4 mL) and 1 mol / L HCl (30 mL). The desired product was extracted with ethyl acetate (2 X 60 mL), and the organic layers were washed with water (30 mL) and brine (20 mL), dried together, concentrated under reduced pressure, and concentrated in slurry (15.6 mL). g) was obtained. The resulting slurry was diluted with n-hexane (90 mL), and left overnight at 5 ° C. The precipitate was filtered, washed with hexane (2 × 15 mL), and dried to give the compound (2f, 8.01 g, 91.0% yield) as a white solid.

Melting point: 202-209. C

 'Η NMR δ (CDC1 -DMSO-d), 2.49 (s, 3H), 6.49 (s, 2H), 7.22 (d, 2H, J = 8.4 Hz),

7.76 (d, 2H, J = 8.4 Hz)

Elemental analysis (as CH BO S) Calculated: C, 50.04; H, 5.40; S, 19.08

 Found: C, 49.24; H, 5.32; S, 18.74

[0042] Second step

 To a mixed solution of potassium carbonate (13.13 g, 2.5 eq) and D_parin (15, 4.90 g, 1.1 eq) in water (68 mL) —acetone (57 mL), add 4_bromobenzenesulfoylcu-oride (14, 9.71 g, 38.0 mmol) is divided into 5 times, and calories can be obtained at 4-5 ° C for 11 minutes. The resulting suspension was stirred at 3-5 ° C for 1 hour, and then gradually heated to 20 ° C over 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained slurry (108.4 g) was extracted with water (59 mL), acetone (2.8 mL), and ethyl acetate (57 mL). After the organic layer was extracted with water (13 mL), the aqueous layers were combined, acidified with concentrated hydrochloric acid (13 mL), and extracted with ethyl acetate (60 mL). The organic layer is washed with water (20 mL) and concentrated under reduced pressure. After dissolving the residue in isopropanol (26 mL), the solution was concentrated once more to obtain an isopropanol solution of compound 16 (25.0 g), and this solution was directly used in the next step. Purified samples for analysis were obtained by crystallization of acetone tonoleenca. Melting point: 123-125 ° C

^J H NMR δ (CDC1), 0.88 (d, 3H, J = 6.9Hz), 0.99 (d, 3H, J = 6.6Hz), 2.15 (m, 1H),

 Three

 3.83 (dd, 1H, J = 9.9, 4.5 Hz), 7.61-7.72 (m, 4H)

 Elemental analysis (as C H NBrO S)

 11 14 4

 Calculated: C, 39.30; H, 4.20; N, 4.17; Br, 23.77; S, 9.54

 Found: C, 39.18; H, 3.93; N, 4.13; Br, 23.51; S, 9.40.

 [0043] Third step

Carbonic acid was added to a suspension of Compound 16 (25.0 g, Compound 14; isopropanol solution obtained from 38.0 mol) and Compound 2f (6.38 g, 1.0 eq) in isopropanol (7.8 mL) and water (128 mL). Potassium (13.1 g, 2.5 eq) was added in portions. Wet 5% palladium on carbon (51.5%, 2.5 g, 0.015 eq) was added to the suspension and the mixture was degassed by purging three times with vacuum-nitrogen. The mixture was heated at 7580 ° C for 5 hours, and then cooled to room temperature. The reaction mixture with concentrated hydrochloric acid (13.6 mL) was adjusted to _P H 1.9, followed by stirring for 30 minutes. The precipitate was filtered and washed with water (2 × 30 mL) to obtain a water-containing solid containing the desired product (29.5 g). This wet solid was dissolved in acetone (137 mL) at 50 ° C. Insoluble matter is removed by filtration And washed with acetone / water (9/1, 13.2 mL). The filtrate and the washing solution were combined and treated with activated carbon (0.64 g). After filtering the activated carbon, it was washed with acetone / water (9/1, 13.2 mL). Water (60 mL) was slowly added to the combined solution of the filtrate and the washings. After further stirring at 22 ° C for 20 minutes, water (84 mL) was added to the slurry at 22-24 ° C. The slurry was cooled to 18 ° C, filtered, washed with water (20 mL), and dried to obtain a crude product (13.3 g). When the crude product was recrystallized from tetrahydrofuran / acetone, the first crystal (9.08 g, 62.9%), the second crystal (1.25 g, 8.7%) and the third crystal (0.50 g, 3.5%) of the target product IA were obtained. Got.

Melting point: 207.5 ° C

 'Η NMR δ (CDC1-DMSO-d), 0.89 (d, 3H, J = 6.9Hz), 1.00 (d, 3H, J = 6.6Hz), 2.11

 3 6

 (m, 1H), 2.53 (s, 3H), 3.75 (dd, 1H, J = 9.3, 4.5 Hz), 5.53 (d, 1H, J = 9.3 Hz), 7.34 (d, 2H, J = 8.1 Hz) , 7.55 (d, 2H, J = 8.4 Hz), 7.67 (d, 2H, J = 8.4 Hz), 7.90 (d, 2H, J = 8.1

Hz)

Elemental analysis (as C H NO S)

 18 21 4 2

Calculated: C, 56.97; H, 5.58; N, 3.69; S, 16.90

Found: C, 56.82; H, 5.53; N, 3.73; S, 16.83

Example 16

[Formula 40]

 (2d).

(First step)

Potassium carbonate (34.6 g, 250 mmol, 2.5 eq) was dissolved in water (235 mL), and D_valine (15, 12.9 g, 110 mmol, 1.1 eq) was added at around 25 ° C. After dissolving D-valine at the same temperature, acetone (210 mL) was added, and the mixture was cooled to 0-5 ° C. The compound (17, 26.2 g, 100 mmol) was charged in 5 portions at 0_5 ° C and stirred at the same temperature for 1.5 hours. Ethyl acetate (250 mL) and water (200 mL) were added to the reaction solution, and after liquid separation, the organic layer was back-extracted with 0.6% saline (100 mL). Acetic acid in the combined aqueous layer The ethyl (200 mL) was caloried, and the compound 18 was acid-converted with 6 mol / L hydrochloric acid (100 mL). After liquid separation, the organic layer was washed twice with 5% saline (100 mL). After concentration of the solvent, the residue was crystallized from toluene to give the desired product (18, 25.7 g, 75.1%).

 mp. 197.0-197.5 ° C (dec.)

 'Η NMR δ (CDC1), 0.91 (d, J = 6.9 Hz, 3H), 1.03 (d, J = 6.6 Hz, 3H), 2.11-2.25

 Three

 (m, 1H), 3.88-3.93 (m, 1H), 5.33 (d, d, J = 4.8, 9.9 Hz, 1H), 7.03 (m, 1H), 7.34 (m, 1H), 7.60 (br, 1H )

(Second step)

 Sodium hydroxide (2.9 g, 73.1 mmol, 2.5 eq) was dissolved in water (80 mL), and isopropanol (10 mL) was added. Compound (18, 10 g, 29.2 mmol), compound (2d, 5.7 g, 35.0 mmol, 1.2 eq), 5% palladium-carbon (51.5% wet) (6.0 g, 1.5 mmol, 0.05 eq), The temperature was raised to 90 ° C. The reaction solution was stirred at the same temperature for 8 hours, and after filtering palladium-carbon, the palladium-carbon was washed with tetrahydrofuran / water (50 mL / 50 mL). The filtrate was washed sequentially with ethyl acetate (50 mL, 30 mL), and the organic layer was back-extracted with water (30 mL). To the combined aqueous layer, 35% hydrochloric acid (3.8 mL) was added dropwise at about 25 ° C, and the pH was adjusted to 2.2. After stirring at about 25 ° C for 1 hour, the precipitated crystals were collected by filtration and washed with isopropanol / water (50 mL / 50 mL). The crystals were dried to obtain crude IB (8.26 g). The crystals were dissolved in tetrahydrofuran (50 mL), activated carbon (500 mg) was added, and the mixture was filtered. After concentrating the solvent, the precipitated crystals were collected by filtration and washed with cold isopropyl. Dried and purified I-B (8.2 g, 73.6%) was obtained.

 Elemental analysis (as C H NO S)

 1 19 5 2

 Calculated: C, 53.53; H, 5.02; N, 3.67; S, 16.81,

 Found: C, 53.46; Η, 5 · 08; Ν, 3 · 61; S, 16.70; Η Ο 0.1%

 2,

 'Η NMR δ (DMSO-d), 0.83, 0.88 (d, J = 6.6 Hz, 6H), 1.95-2.06 (m, 1H), 2.61 (s,

 6

 3H), 3.62-3.67 (m, 1H), 7.57-8.04 (m, 6H), 8.42 (d, J = 9.0 Hz, 1H),

IR v (Nujol),: 3229, 1714, 1650, 1439, 1341, 1168 cm— ¹ ,

 UV (THF), v max: 235.0 nm (ε 6,900), 320.5 nm (ε 27,300),

 mp: 233.3 ° C

[0046] Non-isolated method for intermediate D-valine (15, 8.4 g, 71.7 mmol, 1.1 eq) was dissolved in a 2% aqueous sodium hydroxide solution (129.6 g, 1.0 eq), and isopropanol (102 mL) was obtained. Compound 6 (17 g, 65.0 mmol) was added at about 7 ° C, and the pH was maintained at 11 to 12 by adding a 17% aqueous sodium hydroxide solution (17.3 g, 1.1 eq). The reaction solution was stirred at around 7 ° C for 5 hours. The reaction solution was concentrated to 127.9 g to distill off isopropanol, and a 3.7% aqueous sodium hydroxide solution (69.4 g, l.Oeq) was added. Compound 2d (11.6 g, 70.6 mmol, 1.1 eq), acetic acid (5.84 g, 96.4 mmol, 1.5 eq), 5% palladium-carbon (51.6% wet) (7.07 g, 1.6 mmol, 0.025 eq) were added sequentially. 90. The temperature rose to C. The reaction solution was stirred at the same temperature for 4 hours. A 6.4% aqueous sodium hydroxide solution (98 was added, the mixture was filtered at about 60 ° C., and the radium monocarbon was washed with a 4% aqueous sodium hydroxide solution (23.1 g.) The reaction filtrate was diluted with isopropanol (52.3 g). Then, the temperature was raised to about 55 ° C, and 9.9% hydrochloric acid (76 mL) was added dropwise over 1 hour to adjust the pH to 3.5. After stirring at about 25 ° C for 1 hour, the precipitated crystals were collected by filtration, and water (66 After washing with wet crude B (102.9 g), 5.2% aqueous sodium hydroxide solution (64.0 g) and isopropanol (185 mL) were added to wet crude B (102.9 g), and the mixture was dissolved. After filtration with activated carbon, the activated carbon was washed with water / isopropanol (28 mL / 35 mL), the filtrate was heated to around 55 ° C, and 9.9% hydrochloric acid was added dropwise over 1 hour to pH. After stirring for 1 hour at around 25 ° C, the precipitated crystals were collected by filtration, washed with water / isopropanol (28 mL / 35 mL), and dried and purified IB (20.5 g, 82.6%) Got.

Example 17

[Formula 41]

(2g) (16) ₍ l_c) Compound 16 (1.25 g, Compound 14; 1.90 mm (isopropanol solution obtained from ^) and Compound 2 g (0.288 g, 1.0 eq) in isopropanol (1.56 mL ) And water (25.6 m), add potassium carbonate (0.657 g, 2.5 eq) separately, and add 5% palladium-carbon with water (51.5%, 0.125 g, 0.015 eq) to this suspension. The mixture is degassed by purging with vacuum nitrogen three times, heating the mixture at 75-80 ° C for 5 hours, and then cooling to room temperature. Adjust the volume to near and stir for 30 minutes. After washing twice with water and water, the desired product and a solid containing water are obtained. The moist solid is dissolved in acetone at 50 ° C. Filter off insolubles and wash with acetone / water (9/1). The filtrate and the washing solution are combined and treated with activated carbon. After filtering the activated carbon, it is washed with acetone / water (9/1). Slowly add water to the combined solution of filtrate and washings. After further stirring at 22 ° C for 20 minutes, water is added to the slurry at 22-24 ° C. After cooling the slurry to 18, filtration, washing with water and drying, a crude product is obtained. The crude product is recrystallized with tetrahydrofuran / acetone power to obtain the desired crystal (g).

Example 18

 [Formula 42] OOH

 Suspension of Compound 16 (1.25 g, Compound 14; 1.90 mm (isopropanol solution obtained from ^) and Compound 2e (0.269 g, 1.0 eq) in isopropanol (1.56 mL) and water (25.6 mL) Potassium carbonate (0.657 g, 2.5 eq) is added to the suspension, 5% palladium-carbon with water (51.5%, 0.125 g, 0.015 eq) is added to the suspension, and the mixture is vacuum-nitrogen The mixture is heated at 75-80 ° C for 5 hours and cooled to room temperature.The reaction mixture is adjusted to pH 2 with concentrated hydrochloric acid (0.682 mL). After stirring the precipitate for 30 minutes, the precipitate is filtered and washed with water to obtain the desired product and a solid containing water.The solid containing water is dissolved in acetone at 50 ° C. Acetone / water

 Wash with (9/1). The filtrate and the washing solution are combined and treated with activated carbon. After filtering the activated carbon, wash it with acetone / water (9/1). Slowly add water to the combined solution of filtrate and washings.

 After further stirring for 20 minutes at 22 ° C, water is added to the slurry at 22-24 ° C. The slurry is cooled to 18 ° C, filtered, washed with water, and dried to obtain a crude product (0.66 g). The crude product is recrystallized from tetrahydrofuran / acetone to obtain the target crystal (I-D,).

Example 19

[Formula 43] -B (OH) ₂

 (2a) (18) (1-E) Dissolve sodium hydroxide (0.29 g, 7.31 mmol, 2.5 eq) in water (8.0 mL) and add isopropanol (1.0 mL). Compound 18 (1.0 g, 2.92 mmol), compound 2a (0.43 g, 3.53 mmol, 1.2 eq) and 5% palladium on carbon (51.5% wet) (0.60 g, 0.145 mmol, 0.05 eq) were added sequentially, and 90 ° C Heat up to The reaction solution is stirred at the same temperature for 8 hours, and after filtering palladium-carbon, palladium-carbon is washed with tetrahydrofuran / water (1/1). After washing the filtrate twice with ethyl acetate, the organic layer is back-extracted with water. To the combined aqueous layer, add 35% hydrochloric acid dropwise at around 25 ° C, and adjust the pH to around 2. After stirring at about 25 ° C for 1 hour, the precipitated crystals are collected by filtration and washed with isopropanol / water (1/1). The crystals are dried to obtain crude E. After dissolving the crystals in tetrahydrofuran, activated carbon is added and filtered. After concentrating the solvent, the precipitated crystals are collected by filtration and washed with cold isopropanol. Dry to obtain the purified IE.

Example 20

[Formula 44]

Dissolve sodium hydroxide (0.29 g, 7.31 mmol, 2.5 eq) in water (8.0 mL) and add isopropanol (1.0 mL).匕 合 18 (1.0 g, 2.92 mmol), 匕 合 2 g (0.4.3 g, 3.53 mmol, 1.2 eq), 5% palladium on carbon (51.5% wet) (0.60 g, 0.145 mmol, 0.05 eq) ), And raise the temperature to 90 ° C. The reaction solution is stirred at the same temperature for 8 hours, and after filtering palladium-carbon, the palladium-carbon is washed with aqueous tetrahydrofuran Z (1/1). After the filtrate was sequentially washed twice with ethyl acetate, the organic layer was back-extracted with water. To the combined aqueous layer, add 35% hydrochloric acid dropwise at around 25 ° C, and adjust the pH to around 2. After stirring at about 25 ° C for 1 hour, the precipitated crystals are collected by filtration and washed with isopropanol / water (1/1). The crystals are dried to obtain crude F. After dissolving the crystals in tetrahydrofuran, activated carbon is added and filtered. After concentrating the solvent, the precipitated crystals were collected by filtration and cooled. Wash with sopropanol. Dry to obtain purified IF.

Industrial applicability

 An economical Suzuki coupling suitable for an industrial process using an aqueous solvent can be performed using palladium-carbon as a catalyst, considering the environment. In addition, by adding diols, it is possible to improve the yield of Suzuki coupling in a nodium-carbon catalyst and aqueous system.

Claims

The scope of the claims

 [1] General formula (π):

[Formula 1]

(Wherein, R ¹ is lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, honolemil, acyl, acyloxy, halogen, halo-lower alkyl, halo-lower alkyloxy, nitro, cyano, carboxy, snorejo, lower alkyloxycarbonyl, Lower alkynolesulfonyl, lower alkylsulfonyloxy, optionally substituted aminocarbonyl, optionally substituted aminocarbonyl, optionally substituted aryl, or optionally substituted heteroaryl; R ² and R ² ′ may be a hydrogen atom or lower alkyl at the same time, or R ² and R ² ′ may be taken together to form a 3-8 membered ring with an adjacent oxygen atom; Z ¹ is —CR ^{11 : ^^ 11 - - S -,} - 〇 _, - CR "= N-, or - N = CR" _ (wherein, R ^{1 1} is as defined the hydrogen atom or R ^1, R ¹¹ If there are two or more are selected independently of one another); m is an integer from 0 to 3, when the above m forces, the compound represented by R ¹ is selected independently), a salt thereof or, Its solvates, and

 General formula (III):

[Formula 2] H)

(Where R ° is lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, honolemil, acyl, acyloxy, halogen, halo-lower alkyl, halo-lower alkyloxy, nitro, carboxy, snorejo, lower alkyloxycarbonyl, Lower alkynolesulfonyl, lower alkylsulfonyloxy, optionally substituted amino group, optionally substituted aminocarbonyl, optionally substituted aryl, or substituted An optionally substituted heteroaryl; R ³ is a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, or a substituted R ⁴ is hydrogen atom, lower alkyl, aralkyl, heteroarylalkyl, or acyl; Y is hydroxy or lower alkyloxy ¹ is halogen or R ⁵ S〇— R ⁵ is lower alk

 Three

Or Z ² is — CR ¹² = CR ¹² _, — S—, —〇_, — CR ¹² = N—, or — N = CR ¹² — (where R ¹² is a hydrogen atom) Or is the same as R °, and when two or more R ¹² are present, they are independently selected from each other); n is an integer from 0 to 2, and when n is 2, R ° is each independently A compound represented by the general formula (I): wherein the compound represented by formula (I) is reacted with a solvent containing water in the presence of palladium-carbon.

 [Formula 3]

(

And n is as defined above), a salt thereof, or a solvate thereof.

[2] General formula (IV):

 [Formula 4]

Wherein X ² is halogen, X ¹ , Z ² and n are as defined in claim 1, a salt thereof, or a solvate thereof, and a compound represented by the general formula (V):

[Formula 5] (V)

(Wherein R ³ and Y have the same meanings as in claim 1), a salt thereof, or a solvate thereof, to give a compound of the general formula (III):

[Formula 6]

()

(

Wherein R °, R ³ , R ⁴ , Y, and n have the same meanings as in claim 1), a step A of obtaining a compound thereof, a salt thereof, or a solvate thereof, and the obtained compound represented by the general formula (III ), A salt thereof, or a solvate thereof, and

General formula (II):

[Formula 7]

(

Wherein R ² , R ² ′, Z ¹ and m are the same as defined in claim 1), a salt thereof, or a solvate thereof.

By reacting in a solvent containing water in the presence of palladium-carbon, the compound of the general formula (I):

, And n are as defined in claim 1) 2. The method according to claim 1, comprising a step B of producing a compound, a salt thereof, or a solvate thereof.

 [3] The production method according to claim 1 or 2, wherein the solvent is water only.

 [4] The production method according to any one of claims 13 to 13, wherein the reaction in the presence of palladium-carbon is a reaction in the presence of acetic acid and palladium-carbon.

[5] The production method according to any one of claims 14 to 14, wherein the reaction is a reaction in the presence of diol and palladium-carbon.

6. The method according to claim 5, wherein the diol is ethylene glycol.

[7] General formula (VI):

 [Formula 9]

(VI)

(

m is the same as defined in claim 1), a salt thereof, or a solvate thereof, and

 General formula (VII):

 [Formula 10]

(Wherein R °, X ¹ and Z ² have the same meaning as in claim 1; p is an integer of 0 to 3, and when p is 2 or more, R ° is independently selected) A compound, a salt thereof, or a solvate thereof,

 Characterized by reacting in the presence of diol and palladium-carbon in a solvent containing water.

 General formula (VIII):

[Formula 11]

(Where:

Z ² and m have the same meanings as in claim 1, and p has the same meaning as described above), a salt thereof, or a solvate thereof.

[8] The production method according to claim 7, wherein the diol is ethylene glycol.

[9] The production method according to claim 7, wherein the amount of the diol is 0.5 to 15 equivalents to the compound represented by the general formula (VI).

[10] General formula (IX):

 [Formula 12]

(Where R ¹

And m are the same as defined in claim 1, and R ⁶ and R ⁶ ′ are simultaneously lower alkyl or R ⁶ and R ⁶ ′ are taken together to form a 3- to 8-membered ring together with an adjacent oxygen atom. Compound, a salt thereof, or a solvate thereof, and

 General formula (VII):

 [Formula 13]

(Where:

X ¹ and Z ² are the same as in claim 1; P is the same as in claim 7), a salt thereof, or a solvate thereof.

 The reaction is carried out in a solvent containing water in the presence of palladium-carbon, general formula (VIII):

[Formula 14] (VIII)

(Where:

Z ² and m are as defined in claim 1, and p is as defined in claim 7), a salt thereof, or a solvate thereof.