WO1996026921A1 - Novel biphenyl derivatives or salts thereof, and anti-inflammatory agents containing the same - Google Patents

Abstract

Biphenyl derivatives represented by general formula (1), or salts thereof which have excellent anti-inflammatory, antipyric/analgesic and antiarthritic effects and thus are useful as medicines, wherein R1 represents lower alkyl, aryl or amino; R2 represents aryl or -Z-R5 (wherein R5 represents alkyl, alkenyl, alkylsulfonyl, aryl, etc; and Z represents oxygen, sulfur, imino, etc.); R?3 and R4¿ represent each hydroen, halogeno, cyano, azido, nitro, amino, carboxy, hydroxy, acyl, alkoxycarbonyl, alkyl, alkenyl, alkoxy, alkylthio, etc.; and n is 0, 1 or 2.

Description

 Specification

 Novel biphenyl derivative or salt thereof and anti-inflammatory agent containing them

 Technical field

 The present invention relates to the general formula [1]

Wherein R ¹ is a lower alkyl or aryl group which may be substituted with a halogen atom or an amino group which may be protected; R ² is an aryl group which may be substituted or General formula

-Z-R ⁵

(Wherein, R is an optionally substituted alkyl, alkenyl, alkylsulfonyl, cycloalkyl, aryl, aralkyl or heterocyclic group; Z is an oxygen atom, a sulfur atom, R ³ and R ⁴ may be the same or different and are a hydrogen atom, a halogen atom, a methylene group, a carbonyl group or a vinylene group which may be substituted with a hydroxyl group; A cyano group, an azide group, a nitro group, an optionally protected amino group, an optionally protected carboxyl group, an optionally protected hydroxyyl group, an acyl group, an alkoxycarbonyl group or a substituted Alkyl, alkenyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alk Sulfonyloxy, alkylsulfonylamino, amidino, guanidino, aryloxy, cycloalkyl, levavamoyl, sulfamoyl, alkylamino, acylamino, oxa mouth, alkoxyxalyl, alkoxyxylarylamino, nitrogen atom A nitrogen-containing heterocyclic carbonyl, aryl or heterocyclic group to be bonded; n represents 0, 1 or 2; "

The present invention relates to a biphenyl derivative represented by or a salt thereof, and a COX-2 selective inhibitor containing them and ^: an inflammatory agent.

Conventional technology To date, many non-steroidal anti-inflammatory drugs such as aspirin and indomethacin have been provided for the treatment of inflammatory diseases including rheumatoid arthritis. The main mechanism of action of these non-steroid acidic anti-inflammatory drugs is the inhibition of the biosynthesis of brostaglandin (PG) based on the inhibitory action of cyclooxygenase (c OX). On the other hand, clinical side effects such as gastrointestinal tract disorders and renal disorders are also due to COX inhibitory effects, and the onset of anti-inflammatory effects and the occurrence of side effects can be said to be two sides of the same coin. In recent years, COX-2 (the conventional type was named COX-11) was found as an isozyme for this COX. In other words, COX-1 is a constitutive enzyme, whereas COX-2 is an inducible enzyme, which is an enzyme that is specifically induced at the site of inflammation by inflammation. Thus, it has been suggested that drugs that selectively inhibit COX-2 may be anti-inflammatory agents with few side effects [Inflammation and Immunity, Vol. 3, No. 1, pp. 14-36 (1995) [Nature, Vol. 367, pp. 215-216 (1994)].

 Heretofore, the above-mentioned drugs have not been satisfactory because there is no large difference between the dose required for the treatment and the side effect, particularly the dose that produces an ulcer-inducing action. Therefore, the development of highly safe anti-inflammatory drugs with few side effects has been desired.

 Disclosure of the invention

 Under these circumstances, the present inventors have conducted intensive studies and as a result, have found that the compound of the general formula [1] or a salt thereof has a COX-2 selective inhibitory activity, and has extremely excellent anti-inflammatory and antipyretic properties. It has analgesic and anti-arthritic effects, and further has found that side effects such as gastrointestinal tract disorders are extremely small, thereby completing the present invention.

 Hereinafter, the compound of the present invention will be described in detail.

In the present specification, each term is, unless otherwise specified, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an acyl group is, for example, a formyl group, an acetyl or propionyl group. C ₂ _ _{| 0} Arukanoiru group, Aroiru group and Nikochinoiru such Benzoi Le or naphthoyl, Tenoiru, the Ashiru group and heterocyclic force carbonyl groups such as pyrrolidinocarbonyl or furoyl group; and Ashiruamino groups, for example, Horumiruamino, Asechiruamino , C such as propylene Oniruamino and Buchiriruami Bruno, _{| 0} a Ashiruami cyano group;. Ari Alkyl groups include, for example, phenyl and naphthyl; alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, Linear or branched C _M, such as hexyl, heptyl and octyl. An alkyl group; an alkylthio group refers to, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, heptylthio and octylthio; Linear or branched C. An alkylthio group; an alkylsulfinyl group means, for example, methylsulfinyl, ethylsulfinyl, _n -propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, ten-butylsulfinyl, pentyl Linear or branched C _M, such as sulfinyl, hexylsulfinyl, heptylsulfinyl and octylsulfinyl. Alkylsulfinyl group; alkylsulfonyl group means, for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, π-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl Linear or branched C,. _{| 0} alkylsulfonyl groups such as, hexylsulfonyl, heptylsulfonyl and octylsulfonyl; alkylsulfonyloxy groups; for example, methylsulfonyloxy, ethyl Sulfonyloxy, π-propylsulfonyloxy, isopropylsulfonyloxy, π-butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, ten-butylsulfonyloxy, pentylsulfonoxy Linear or branched C _M, such as niloxy, hexylsulfonyloxy, heptylsulfonyloxy and octylsulfonyloxy. An alkylsulfonylamino group; an alkylsulfonylamino group means, for example, methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, n-butylsulfonylamino, Linear or branched such as isobutylsulfonylamino, sec-butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, heptylsulfonylamino and octylsulfonylamino Branched C _M. Alkylsulfonylamino group; lower alkenyl The group, for example, vinyl, Ariru, Burope alkenyl, isopropenyl base alkenyl, butenyl, c ₂ straight chain and branched, such Isobuteniru and pentenyl, alkenyl group;. An alkenyl group, for example, Biel, Ariru, Burope alkenyl, isopropenyl two Le, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl and O click thenyl C ₂ straight chain or branched, such as, ₀ alkenyl group;. and alkoxy groups Is a linear or branched C _M such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy. . An alkoxycarbonyl group; an alkoxycarbonyl group is, for example, a linear or branched group such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;

The aralkyl groups such as benzyl, Jifue two Rumechiru, ar-C such as trityl and phenethyl, ₅ alkyl groups;; C alkyl O propoxycarbonyl two Le group. The cycloalkyl group, in even ', Shikurobu A C w cycloalkyl group such as mouth pill, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; a lower alkyl group is, for example, methyl, ethyl, π-propyl, isopropyl, _n -butyl, sec-butyl, isobutyl, text- butyl and linear pentyl also properly is branched C, ₅ alkyl groups;. a lower alkoxy group, for example, main butoxy, ethoxy, .eta. Purobokishi, isopropoxy, [pi —A straight chain such as butoxy, isobutoxy, sec-butoxy, tert-butoxy and pentyloxy The branched C, ₅ alkoxy group; the. The heterocyclic group, for example, Azechijiniru, thienyl, furyl, pyrrolyl, Lee Mi Dazoriru, pyrazolyl, thiazolyl, isothiazolyl, Okisazoriru, Isookisazoriru, furazanyl, pyrrolidinyl, pyrrolinyl , Imidazolidinyl, imidazolinyl, virazolidinyl, vilazolinyl, 1,3,4-year-old oxaziazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3 — Triazolyl, 1,2,4—triazolyl, tetrazolyl, thiatriazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidinyl, piperazinyl, vilanyl, morpholinyl, 1,2,4—triazinynyl, benzochenyl Naphto Chenil, Benzov Ril, isovenzofuryl, chromenil, indolinidinyl, isoindolyl, indolyl, indazolyl, pre Nil, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, phteridinyl, isochromanil, chromanyl, indolinyl, isoindolinyl, benzoxyloxyl, triazolopyridyl, tetrazolopyridazolidinyl Pyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, benzthiazolyl, 1,2,3,4-tetrahydroquinolyl, imidazo [1,2—b] [1.2] , 4] a 4- to 7-membered or condensed heterocyclic group containing at least one heteroatom atom selected from an oxygen atom, a nitrogen atom and a sulfur atom such as triazinyl and quinuclidinyl; A carbonyl group is, for example, pyrrolylca Rubonyl, pyrrolidinylcarbonyl, piperidylcarbonyl, piperazinylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl, pyridylcarbonyl, tetrahydropyridylcarbonyl, pyrimidinylcarbonyl, morpholinylcarbonyl , Thiomorpholinylcarbonyl, quinolylcarbonyl, quinolizinylcarbonyl, tetrahydroquinolinylcarbonyl, tetrahydroyloquinolinylcarbonyl, quinuclidinylcarbonyl, thiazolylcarbonyl, tetrazolylcarbonyl, thiadiazoli Carbonyl, pyrrolinylcarbonyl, imidazolinylcarbonyl, imidazolidinylcarbonyl, vilazolinylcarbonyl, vilazolidinylcarbonyl, prenylcarbonyl and indazolyl carb A 5- or 6-membered ring, a condensed ring or a bridge containing at least one nitrogen atom as a hetero atom forming the ring such as a phenyl group, and optionally containing at least one oxygen atom or sulfur atom. And a lower alkoxycarbonyl group is, for example, methoxycarbonyl, ethoxycarbonyl, π-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxy force Linear or branched C alkoxycarbonyl groups such as rubonyl, ten-butoxycarbonyl and pentoxycarbonyl; lower alkylidene groups include, for example, C alkylidene such as methylene, ethylidene, propylidene and isopropylidene; A lower alkyl group; for example, Lay methylthio, Echiruchio, n- propylthio, isopropylthio, n- butylthio, iso Chio, sec- Puchiruchio, also linear, such as ten- Puchiruchio and pentylthio The branched c, ₅ a Arukiruchio group;. The lower alkylsulfonyl group, for example, methylsulfonyl, Echirusuruhoniru, n- Bro pills sulfonyl, isopropyl sulfonyl, .pi. butylsulfonyl, iso-butylsulfonyl, sec- Buchirusuruho . sulfonyl, tert- butylsulfonyl and pentylsulfonyl straight-chain or branched C, such as, ₅ alkylsulfonyl two Le group; and halogeno-lower alkyl group, for example, Furuoromechiru, chloromethyl, bromomethyl, dichloromethyl, . Torifuruoro, trichloromethyl, Kuroroechiru, Jikuroroechiru, Harogeno C such as trichloroacetic port Echiru and black port propyl, ₅ alkyl groups; a lower alkoxy-lower alkyl group, for example, main Tokishimechiru, ethoxymethyl, n- pro . Kishime chill, C alkoxy one C such as main Tokishechiru and Etokishechiru, a ₅ alkyl Le groups; and carboxy-lower alkyl group, for example, carboxymethyl, Karubokishi C such carbonitrile Kishechiru and carboxypropyl, ₅ alkyl group;. Arsenide the Dorokishi lower alkyl group, for example, human Dorokishimechiru arsenide de π Kishi C such as human Dorokishechiru and hydroxycarboxylic propyl, ₅ alkyl group;. the § Mi-lower-§ alkyl group, e.g., aminomethyl, amino aminoethyl and Ami knob opening pill of any ami no C, ₅ alkyl groups;. a lower alkoxy force carbonyl-lower alkyl group, for example, main butoxycarbonyl methyl, ethoxycarbonylmethyl, .pi. propoxy carbonyl methyl, main butoxycarbonyl E chill And d Kishikarubo the C alkoxycarbonyl over C alkyl group such as a secondary Ruechi le;

The cyclic amino group may be, for example, either a saturated cyclic amino group or an unsaturated cyclic amino group, and may further contain one or more nitrogen atoms, oxygen atoms, sulfur atoms, etc. in the ring. It may contain atoms and a carbonyl carbon, and may be monocyclic or bicyclic, and more specifically, aziridine-11-yl, azetidine-11-yl , Pyrrolidine- 1 -yl, pyrroline-1 -yl, pyrrole-1-1 -yl, dihydropyridine-1-1 -yl, pyridino, dihydrodolazepine-1-1, and perhydroroazepine-1- A saturated or unsaturated monocyclic 3- to 7-membered cyclic amino group having one nitrogen atom such as diyl; imidazole-11-yl, imidazolidin-11-yl, imidazoline-11- Yl, villazolidine 1-yl, . Perazine 1-yl 1, 4-dihydropyrazine 1-yl, 1,2-dihydropyrazine Saturated or unsaturated monocyclic 3- to 7-membered cyclic amino groups having 2 nitrogen atoms, such as limidine-11-yl, perhydropyrazine-11-yl and homopiperazine-11-yl; 1,, 1,4-triazole-l, 1,2,3-triazo-l-yl. 1,2-dihydro-l, 2,4-triazine-l-yl and Perhydrol-S-tril Saturated or unsaturated monocyclic 317-membered cyclic amino groups having 3 or more nitrogen atoms such as azine-11-yl; oxazolidin-13-yl, isoxoxazolidine-12-yl, morpholino 1,3-oxazolidin-1-yl, thiazolidine-111-yl, isothiazolidine-111-yl, thiomorpholino, homothiomorpholine-1-1-yl and 1,2,4-thiadiazolin-2-yl Selected from oxygen and sulfur atoms in addition to nitrogen atom Saturated or unsaturated monocyclic having 1 to 4 heteroatoms

3- to 7-membered cyclic amino group; isoindolin-1-yl, indolin-11-yl, 1H-indazole-11-yl, purine-7-yl and tetrahydroquinoline Saturated or unsaturated 2- or 3-cyclic cyclic amino groups such as 11-yl; and 5-azaspiro [2,4] heptane-5-yl, 2,8-diazabicyclo [4.3.0] Nonan 8-yl, 3-azabicyclo [3.1.0] hexane-3-yl, 2-oxa-1,5,8-diazabicyclo [4.3.0] Nonan 8-yl, 2, 8-diazaspiro Four,

4] spiro- or cross-linked saturated or unsaturated 5-membered cyclic amino groups such as nonane-2-yl and 7-azabicyclo [2.2.1] heptane-7-yl; alkylamino groups; is, for example, Mechiruami Roh, Echirua Mi Roh, Puropirua Mi Roh, to Kishiruami Bruno, Hepuchiruami Bruno, Jimechiruami Bruno, Jechiruami Bruno, mono- or di-C _M such Kishiruami Bruno and Mechiruechiruami Bruno to di. The lower Arukiruami amino group, for example, Mechiruami Bruno, Echiruami Bruno, Puropiruami Bruno, Jimechiruamino, the Jechiruami Roh and methyl E chill § Mino of any mono- or di-C _M alkyl amino group; Arukiruami amino group and a lower Arukokishii amino group Is, for example, a C alkoxyamino group such as methoxyimino and ethoxyimino; a lower alkylamino lower alkyl group is, for example, methylaminomethyl, methylaminoethyl, ethylaminomethyl, methylaminobutamin. Mono or di-C alkylamino such as pill, propylaminoethyl, dimethylaminomethyl, dimethylaminomethyl, dimethylaminoethyl and dimethylaminopropyl . The Ariruokishi group, e.g., phenoxy and the groups represented by like naphthoquinone preparative alkoxy;; c, ₅ alkyl groups and the alkoxy O hexa Lil group, for example, c _M0 such main Tokisa Lil and ethoxalyl Arukiruokishio the Kisariru group; alkoxy Okisariruamino groups, e.g., C _M such main Tokisariruamino and Etokisarirua amino. Each represents an alkyloxyoxalylamino group.

The substituent of each group in R ² , R \ R ⁴ and R ′ is, for example, a halogen atom, a cyano group, a nitro group, an azide group, an optionally protected carboxyl group, an optionally protected hydroxyl An optionally protected amino group, an optionally protected carboxy lower alkyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an acyl group, a carbamoyl group, an aryl group, a cycloalkyl group, Lower alkenyl group, aralkyl group, lower alkylidene group, mercapto group, lower alkylthio group, lower alkylsulfonyl group, halogeno lower alkyl group, lower alkoxy lower alkyl group, optionally protected hydroxy lower alkyl group, protected Amino lower alkyl group, lower alkoxycarbonyl Lower alkyl group, optionally protected cyclic amino group, optionally protected lower alkylamino group, lower alkoxyamino group, hydroxyamino group, optionally protected lower alkylamino lower alkyl group And heterocyclic groups, which may be substituted with one or more substituents.

 Examples of the substituent of the imino group in Z include groups such as a lower alkyl group and an aryl group.

When the compound of the present invention and its production intermediate have a hydroxyl group, an amino group or a carboxyl group, these groups may be protected with a known protecting group. Here, the protecting group for the hydroxyl group and the hydroxy lower alkyl group includes all groups which can be usually used as a protecting group for the hydroxyl group, for example, ', benzyloxycarbonyl, 4-nitro Benzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, ten-butoxycarbonyl, 1.1 —Dimethylpropoxycarbonyl, isop or rh. Xyloxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbo Nyl, 2,2,2-trichloromouth ethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycal Bonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, aryloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-11-naphthyloxycarbonyl, 8-quino Acetyl groups such as riloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, vivaloyl and benzoyl; methyl, ten-butyl, 2, 2, 2—Trick Lower alkyl groups such as rosethyl and 2-trimethylsilylethyl; lower alkenyl groups such as aryl; lower alkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl and trityl Oxygen- and sulfur-containing heterocyclic groups such as tetrahydrofurfuryl, tetrahydroviranyl and tetrahydrothiopyranyl; methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxy Lower alkoxy- and lower-alkylthio-lower alkyl groups such as methyl, 2- (trimethylsilyl) ethoxymethyl and 1-ethoxystill; alkanes or arene-sulfonyl groups such as methanesulfonyl and p-toluenesulfonyl Substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, ten-butyldimethylsilyl, ten-butyldiphenylsilyl, diphenylmethylsilyl, and ten-butylmethoxyphenylsilyl No. Also, protecting groups for amino, lower aminoalkyl, acylamino, cyclic amino, alkylamino, lower alkylamino, alkoxyoxalylamino, alkylsulfonylamino, amidino, guanidino, carbamoyl and lower alkylamino lower alkyl groups. These include all groups that can normally be used as amino-protecting groups, for example, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, ρ-nitrobenzyloxycarbonyl, 0—Bromobenzyloxycarbonyl, (Mono, G, Tri) chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, Cyclopentanecarbonyl, benzoyl, tert-amyloxycarbonyl, ten-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl , 2 monofurfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, aranyl, leucyl, 1-adamantyloxycarbonyl and 8-quinolyloxycarbonyl Alkenyl groups such as benzyl, diphenylmethyl and trityl; arylthio groups such as 2-ditrophenylthio and 2,4-dinifluorothio; methanesulfonyl, butanesulfonyl and p Alkyno- or arylene-sulfonyl groups such as toluenesulfonyl; di-lower alkylamino-lower alkylidene groups such as Ν, Ν-dimethylaminomethylene; benzylidene, 2-hydroxybenzylidene, 2-hydroxy 5-benzylidene And lower-alkylidene groups such as 2-hydroxy-1- 1-naphthylmethylene; nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene; cyclohexylidene, 2-ethoxycarbonylcyclohexylidene Cycloalkylidene groups such as, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene and 3,3-dimethyl-5-oxocyclohexylidene; and diaryl or dialyl such as diphenylphosphoryl and dibenzylphosphoryl. one Grade alkyl one phosphoryl group; 5- methyl-2 Okiso 2 Eta - 1, such as a lower alkyl-substituted silyl group such as 3-Jiokisoru one 4- Irumechiru oxygen-containing heterocyclic alkyl groups and trimethylsilyl like can be mentioned. Further, the protecting groups for the carboxyl group and the carboxy lower alkyl group include all groups that can be used as a protecting group for a normal carboxyl group, for example, methyl, ethyl, η-propyl, lower alkyl groups such as iso-propyl, 1,1-dimethylpropyl, n-butyl and ten-butyl; aryl groups such as phenyl and naphthyl; benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl and Al-lower alkyl groups such as bis (p-methoxyphenyl) methyl; lower-alkyl groups such as acetylmethyl, benzoylmethyl, p-2-trobenzoylmethyl, p-bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl Oxygen-containing heterocyclic groups such as 2-tetrahydrobilanyl and 2-tetrahydrofuranyl; halogeno lower alkyl groups such as 2,2,2-trichloroethyl; lower alkylsilylalkyl groups such as 2- (trimethylsilyl) ethyl Alkylcarbonyloxyalkyl groups such as tert-methyl, propionyloxymethyl and bivaloyloxymethyl; nitrogen-containing hetero-lower alkyl groups such as phthalimidmethyl and succinimidomeyl; cycloalkyl such as cyclohexyl; A lower alkoxy lower alkyl group such as methoxymethyl, methoxyethoxymethyl and 2-((trimethylsilyl) ethoxymethyl); an lower alkoxy lower alkyl group such as benzyloxymethyl; methylthiomethyl and 2-methyl Lower alkylthio lower alkyl groups such as thioethyl; arylthio lower alkyl groups such as phenylthiomethyl; lower alkenyl groups such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butynyl and aryl, and trimethylsilyl, triethylsilyl, and triaryl; Substituted silyl groups such as isopropylsilyl, _tert -butyldimethylsilyl, _tert -butyldimethylsilyl, it-butyldiphenylsilyl, diphenylmethylsilyl, and ten-butylmethoxyphenylsilyl.

Examples of the salt of the compound of the general formula [1] include a commonly known salt in a basic group such as an amino group or an acidic group such as a hydroxyl or carboxyl group. Examples of the salt in the basic group include: salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; Salt strength with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.ί Examples of salts in acidic groups include sodium and potassium. Salts with alkaline metals such as lime; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, Ν, dimethylaniline, dimethyl To biperidine, Ν-methylmorpholine, getylamine, dicyclo Shi Ruami down, pro force Lee down, Jibenjiruami down, Nyu- benzyl-Fuenechirua Mi emissions, 1 Efuenami emissions and New, New '- nitrogen such dibenzylethylenediammonium § Min Motoyu And the like, and preferably, a physiologically acceptable salt.

 When isomers (eg, optical isomers, geometric isomers, tautomers, etc.) are present in the compound of the general formula [1] or a salt thereof, the present invention includes those isomers, It also includes solvates, hydrates and crystals of various shapes.

In the compound of the present invention, R ′ is a lower alkyl or amino group, and R: is a general formula—Z—R ⁵ (R ⁵ is a lower alkyl group or a substituent which may be substituted with a halogen atom, hydroxyl or oxo group. And Z represents an oxygen atom, a sulfur atom, a methylene group, a carbonyl group or a vinylene group.) Is a group represented by R ′ and Are the same or different, and each represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally protected amino group, an optionally protected carboxyl group, an acyl group, an alkoxycarbonyl group or a substituted may be alkyl, alkoxy, Cal Bamoiru is preferably a compound alkylamino or Ashiruamino group, ^R: is the formula Z- R ⁵ (R is optionally substituted with a halogen atom cycloalkyl Le, pyridyl or phenyl group the; Z is an oxygen atom, a methylene group, c indicating a carbonyl group or a vinylene group) is a group represented by , R and R ⁴ are one or more and are more preferably a hydrogen atom, a halogen atom, a cyano group, a nitro group, an acyl group or a carboxyl group or an alkyl group optionally substituted with a halogen atom. R ¹ is a methyl or amino group, R ² is a group of the general formula Z—R ⁵ (R ⁵ is a pyridyl or phenyl group optionally substituted by a halogen atom; Z is an oxygen atom .) a group represented by, R and K ⁴ are the same or different dates, hydrogen atom, Shiano group, also is properly nitro group or a carboxyl group substituted with a halogen atom Compound is a alkyl group is even more preferred.

 Representative compounds of the compound of the present invention include, for example, the following compounds. . 2— (24-Difluorophenoxy) 1-4-methylthio 14-1-2tro 1,1,1-biphenyl

■ · 2— (24-difluorophenoxy) 1-4′-methylsulfinyl -1, 1, -biphenyl

 • 2 -— (2,4-difluorophenoxy) -14-methylsulfinyl-5-nitro-1-1,1, biphenyl

 • 4-Mono-1,4-methyl-1,2-phenoxy-1,1, -biphenyl

 · 2-cyclohexyloxy-1,4-methylsulfonyl-412 tro 1,1-biphenyl

 • 4-Acetyl-2- (2,4-difluorophenoxy) -4'-methylsulfonyl 1,1,1,1-biphenyl

 • 2 -— (2,4-difluorophenoxy) -14-methylsulfonyl-412 troth 1,1, -biphenyl

 • 2- (2,4-difluorophenoxy) 1 4'-methylsulfonyl-5-2-nitro-1,1, -biphenyl

 • 2- (2,4-difluorophenoxy) 1-4, -methylsulfonyl-5-trifluoromethyl-1,1, -biphenyl

 · 2- (2,4-difluorophenoxy) -1-5-methyl-4-methylsulfonyl-1,1,1-biphenyl

 '4 -Methylsulfonyl-1-4-nitro-2-Styryl! , 1 · biphenyl

• 4-Methylsulfonyl-4-nitro-1-phenoxy-1 1,1 · -biphenyl

• 4-—Lumbamoyl-1 -— (2,4-difluorophenoxy) -14′-methylsulfonyl-1-1,1′—biphenyl

 • 2-(2,4-difluorophenoxy) 1 5-(Phenoxydroxyiminoethyl) 1, 4,1 methylsulfonyl 1, 1'-biphenyl

 • 5-cyano-2- (2,4-difluorophenoxy) 1-4-methylsulfonyl-1,1'-biphenyl

 · 5-Amino-2- (2,4-difluorophenoxy) -14-methylsulfonyl-4-12-nitro-1,1, biphenyl

 • 2— (2,4-difluorophenoxy) -1 5— (2-ethoxycarbonyl) 1-4, -methylsulfonyl-1,1,1'-biphenyl

• 2- (2,4-difluorophenoxy) -1-5-ethoxylamino-4, _methyl Sulfonyl 1,1, -1, biphenyl

 • 5-cyano 2- (2,4-difluorophenoxy) -1,4'-methylsulfinyl-1,1,1, -biphenyl

 • 2- (2,4-difluorophenoxy) 1-4, -methylsulfinyl 4-trifluoromethyl-1,1, -biphenyl

 • 2— (2,4-difluorophenoxy) 1-4, -methylsulfonyl-5— (tetrazoyl 5-yl) 1,1,1-biphenyl

 • 2- (4-hydroxyphenoxy) 1-4, -methylsulfonyl-5-two-trough 11,1-biphenyl

 · 2- (2,4-difluorophenoxy) -1-5-fluoro-1,4-methylsulfonyl 1,1,1,1-biphenyl

 • 2- (2,4-difluorophenoxy) -1,4-methylsulfonyl-5- (2-methylsulfonylethenyl) -1,1, -biphenyl

 • 4- (2- (4-methylsulfonylphenyl) 1-412-trophenoxy) benzoic acid

 • 2 -— (2,4-difluorophenoxy) -1-5-hydroxy-4,1-methylsulfonyl-1,1,1'-biphenyl

 • 2- (2,4-difluorophenoxy) 1-4-methyl-4'-methylsulfonyl-1,1, -biphenyl

 -4-(2- (4-Methylsulfonylphenyl) 1-412-trophenoxy)

 • 4-hydroxy-4, -methylsulfonyl-1-2-phenoxy-1,1,1'-biphenyl

 • 2— (2,4-difluorophenoxy) 1 4— (piperidine;! Yl) carbo 2 4′-methylsulfonyl-1,1,1-biphenyl

 • 2- (2,4-difluorophenyl) 1-4'-methylsulfonyl-5-methylsulfonylamino 1,1,1-biphenyl

• 5-Nitro-4-methylsulfonyl-2- [2- (pyridine-3-yl) ethenyl, 1-1,1'-biphenyl • 2-(2,4-difluorophenoxy) 1 4'-methylsulfonyl-4 1,2-1,1, -biphenyl 5-carboxylic acid

 • 4, -methylsulfonyl-5-nitro-2- [2- (thiazol-5-yl) ethenyl]; [, 1-biphenyl · 2- (2,4-difluorophenoxy) 1,4,1 Methylsulfonyl-5-methylsulfonyl-1,1,1-biphenyl

 • 5-cyano 2- (2,4-difluorophenoxy) 1-4-methylsulfonyl-412 tro 1,1,1-biphenyl

 • 2- (2,4-difluorophenoxy) -14, -methylsulfonyl-41- (tetrazol-5-yl) -rubamoyl-1,1, -biphenyl

 • 2- (2,4-difluorophenoxy) -1-4'-methylsulfonyl-5-aminosulfonyl-1,1, -biphenyl

 • 5-amino-1 2- (2,4-difluorophenoxy) 1-4-methylsulfonyl-412 trough: 1,1,1-biphenyl

 '4-Methylsulfonyl-1-41- [6-methyl-6- (tetrazol-1-5-yl) heptyloxy] -2-phenoxy-1 1,1 · -biphenyl

 -2- (4- (2,4-difluorophenoxy) -1- (4-methylsulfonylphenyl) phenyl) diacid

 -4- (4- (2,4-difluorophenoxy) -13- (methylsulfonylphenyl) phenyl) butyric acid

 • 5— (4- (2,4-difluorophenoxy) 1-3- (methylsulfonylphenyl) fuunil) Valeric acid

 • 1- (4- (2,4-difluorophenoxy) -13- (methylsulfonylphenyl) phenyl) cycloprononcarboxylic acid

 ·) 1- (4- (2,4-difluorophenoxy) -3- (methylsulfonylphenyl) phenyl) Ethyl cyclopropanecarboxylate

 • 1- (4- (2,4-difluorophenoxy) -13- (methylsulfonylphenyl) phenyl) cyclohexanecarboxylic acid

• 2-(4- (2,4-difluorophenoxy)) 3- (4-methylsulfonylphen Nil) phenoxy) acetic acid

 • 2— (2,4-difluorophenoxy) 1 5— (2-methylsulfonylethyl) 1-4, -methylsulfonyl-1,1, -biphenyl

 • 5—Trifluoromethyl-4'-methylsulfonyl-2-phenoxy-1,1,1'biphenyl

 • 5-cyano 2- (2-fluorophenoxy) 1-4-methylsulfonyl; , 1, -biphenyl

 • 5-cyano 2- (4-fluorophenoxy) -1,4-methylsulfonyl-1,1, -biphenyl

 · 5-cyano-1,4-methylsulfinyl-2-phenoxy-1,1,1-biphenyl

• 4-Methylsulfonyl-5-nitro-1- (2-pyridyloxy) 1-1,1'-biphenyl

 • 5-cyano 2-cyclohexyloxy-1,4-methylsulfonyl-1,1, -biphenyl

· 4,1-Aminosulfonyl-1- (2-, 2-difluorophenoxy) -1-5-nitro-1,1'-biphenyl

 • 4'-Aminosulfonyl-2- (2.4-difluorophenoxy) -1-4-nitro-1,1, -biphenyl

 • 4'-Aminosulfonyl-2- (2,4-difluorophenoxy) -15-trifluoromethyl-1,1,1-biphenyl

 • 4'-Aminosulfonyl-1-2-cyclohexyloxy-5-trifluoromethyl-1-1,1, -biphenyl

 • 4,1-Aminosulfonyl-5-trifluoromethyl-2-phenoxy-1,1,1'-biphenyl

· 4,1-aminosulfonyl-5-cyano-2-phenoxy-1,1,1-biphenyl

• 4 * 1-aminosulfonyl-5-cyano 2- (2,4-difluorophenoxy) 1-1,1, -biphenyl

• 2- (3- (4-aminosulfonylphenyl) 1-41- (2,4-difluorophenoxy) phenyl) acetic acid • 4- (3- (4-aminosulfonylphenyl) -14- (2,4-difluorophenoxy) fuunyl) butyric acid

 • 1- (3- (4-aminosulfonylphenyl) 1-41- (2,4-difluorophenoxy) phenyl) cyclopropanecarboxylic acid

 · 1- (3- (4-aminosulfonylphenyl) -4-1 (2,4-difluorophenoxy) phenyl) cyclopentanecarboxylic acid

 • 1- (3- (4-aminosulfonylphenyl) 1-41- (2,4-difluorophenoxy) phenyl) ethyl ethyl cyclopropanecarboxylate

 • 2- (4- (4-aminosulfonylphenyl) -13- (2,4-difluorophenoxy) phenyl) acetic acid

 • 5-cyano 2- (3-hydroxycyclohexyloxy) -1-methylsulfonyl-1,1, -biphenyl

 • 4,1-Aminosulfonyl-5-cyano 2- (3-hydroxycyclohexyloxy) 1,1,1-biphenyl

 · 5-cyano 2- (4-methylphenoxy) 1,4,1-methylsulfonyl-1,1'-biphenyl

 • 4,1-Aminosulfonyl-5-cyano 2- (4-methylphenoxy) -1-1'-biphenyl

 • 5-cyano 4-methylsulfonyl-2- (2-cyclohexylpentyl) methyl-1,1, -biphenyl

 • 5-cyano 2- (2-ethyl-3-oxobutyl) -1,4-methylsulfonyl-1; 1,1, -biphenyl

 • 5-cyano 2- (2-ethyl-13-oxobutenyl) -1,4'-methylsulfonyl 1,1,1-biphenyl

 · 5-cyano 2- (2-ethyl-3-hydroxybutyl) 1,4-methylsulfonyl 1,1, -1, biphenyl

 • 2- (2-Methoxy-1- (4-methylsulfonylphenyl) -1-5-phenoxyphenyl) acetic acid

• 3— (1— (3- (4-methylsulfonylphenyl) 1-4-phenoxy) Nil) cyclobutyric acid

 • 1- (3- (4-methylsulfonylphenyl) -1-4-phenoxyphenethyl) cyclopropanecarboxylic acid

 • 4- (3- (4-methylsulfonylphenyl) -14-phenoxyphenyl) 1-2-hydroxymethylbutyric acid

 • 4- (3- (4-methylsulfonylphenyl) -1-4-phenoxyphenyl) 1-4-hydroxymethylbutyric acid

 • 4- (3- (4-methylsulfonylphenyl) -1- (phenoxyphenyl) valeric acid

 -4-(3- (4-Methylsulfonylphenyl) 1-4-phenoxyphenyl) 1-2-Methylbutyric acid

 • 4- (3- (4-methylsulfonylphenyl) 1-4-phenoxyphenyl)

 • 5-hydroxymino 4-methylsulfonyl-1- 2-phenoxy-1,1'-biphenyl

 • 5- (4-Methylbiperazin-1-yl) methyl-1,4-methylsulfonyl-2- 2-phenoxy-1,1,1-biphenyl

 • 1- (3- (4-methylsulfonylphenyl) -1-4-phenoxybenzyl) 1-4-piperidine

 · 5-cyano 2-(1-methyl-2-pyroxyl) 1-4 '-methylsulfonyl-1, 1' 1-biphenyl

 -4,1-Aminosulfonyl-5-cyano 2- (1-methyl-2-oxopropyloxy) 1,1,1-biphenyl

 -4-aminosulfonyl-5-cyano 2- (2-oxocyclopentyl) methyl 1,1-biphenyl

 Next, a method for producing the compound of the present invention will be described.

—The biphenyl derivative of the general formula [1] or a salt thereof can be produced, for example, according to the following production method. Manufacturing method Ί

SnBu,

B (OH).

R ¹ [6]

"Wherein, R ', R - \ R and R have the same meaning as described above, B _U means a blanking ethyl group."

Examples of the salts of the compounds represented by the general formulas [la], [lb], [lc] and [2] include the same salts as described for the compounds represented by the general formula [式]. —The compound of the general formula [la] can be obtained, for example, by the method described in The Chemical Society of Japan, No. 3, pp. 520-526 (1985). Specifically, for example, it can be obtained by reacting a compound of the formula [2] with a compound of the formula [3] in the presence or absence of a palladium coordination compound as a catalyst. Examples of the palladium coordination compound used in this reaction include tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) norazidium (Π), lid and benzyl (chloro) bis ( Triphenylphosphine) palladium (Π) and palladium acetate (Π). The amount of the catalyst to be used may be 0.001-1 times the molar amount of the compound of the general formula [2], preferably 0.01 to 0.05 times the molar amount. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane and tetrahydrofuran. Halogenated hydrocarbons such as chloroform and methylene chloride; alcohols such as methanol and ethanol; esters such as ethyl acetate; amides such as Ν, Ν-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used alone or in combination of two or more. This reaction is carried out usually at 40 to reflux, preferably at 70-0, for 30 minutes to 72 hours, preferably for 1 to 5 hours.

 The compound of the general formula [la] can also be obtained, for example, by the method described in Tetrahedron Letters, Vol. 28, pp. 5093-5096 (1987). Specifically, for example, it can be obtained by reacting a compound of the general formula [2] with a compound of the general formula [4]. This reaction may be usually performed using a palladium coordination compound as a catalyst in the presence of a base.

In addition, the compound of the general formula [la] in which R ^: is a styryl group is a compound of the general formula [2] in which the group corresponding to R ² is a formyl group in the same manner as the compound of the general formula [4]. Then, the formyl group corresponding to R ^: in the compound of the general formula [la] can be converted into a styryl group by a conventional method. Palladium coordination compounds used in this reaction include, for example, tetrakis (triphenylphosphine) palladium (0), bis (trifininylphosphine) palladium (II) chloride, Benji Bis (triphenylphosphine) palladium (II) and palladium sulfate (Π). The amount of the catalyst to be used may be 0.0011 to 11 times mol, preferably 0.01 to 0.05 times mol, based on the compound of the general formula [2〗] _c. Alkali carbonates such as sodium hydrogencarbonate and sodium carbonate; alkali hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal alcoholates such as sodium methoxide and sodium ethoxide; and organic bases such as triethylamine and pyridine. Can be The amount of the base to be used may be 1 to 10 times mol, preferably 2 to 4 times mol for the compound of the general formula [2]. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane and tetrahydrofuran; Halogenated hydrocarbons such as oral form and methylene chloride; alcohols such as methanol and ethanol; amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide, and water. These solvents may be used alone or in combination of two or more. This reaction is carried out usually at 40 to under reflux, preferably at 70-0 for 30 minutes to 72 hours, preferably for 1 to 5 hours.

—The compound of the formula [lc] can be obtained, for example, by the method described in The Chemical Society of Japan, No. 3, 520-526— (1985). Specifically, it can be obtained, for example, by reacting a compound of the general formula [2] with a compound of the single-arm type [5]. This reaction is usually performed using a palladium coordination compound as a catalyst. Palladium coordination compounds used in this reaction include, for example, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) no, radium () chloride, benzyl Bis (triphenylphosphine) palladium (II) and palladium (II) acetate; The amount of the catalyst used may be 0.001 to 1 times, preferably 0.01 to 0.05 times the mol of the compound of the general formula [2]. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane and tetrahydrofuran. Ethers; Halogenated hydrocarbons such as chloroform and methylene chloride; alcohols such as methanol and ethanol; esters such as ethyl acetate; amides such as Ν, Ν-dimethylformamide; and dimethyl sulfoxide These solvents may be used alone or in combination of two or more. This reaction may be carried out usually at 40 * C under reflux, preferably at 70-120, for 30 minutes-72 hours, preferably for 1-5 hours.

The compound of the general formula [lc] can also be obtained, for example, by the method described in Tetrahedron Letters, Vol. 28, pp. 5093-5096 (1987). Specifically, for example, it can be obtained by reacting a compound of the general formula [2] with a compound of the general formula [6]. This reaction may be usually carried out using a palladium coordination compound as a catalyst in the presence of a base. Palladium coordination compounds used in this reaction include, for example, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, benzyl ) Bis (triphenylphosphine) nordum (II) and palladium (II) acetate. The amount of the catalyst used may be 0.001-1 times mole, and preferably 0.01-0.05 times mole, of the compound of the single-arm type [2]. Bases used in this reaction include alkali carbonates such as sodium hydrogencarbonate and sodium carbonate; alkali hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal alcoholates such as sodium methoxide and sodium ethoxide. And organic bases such as triethylamine and pyridine. The base may be used in an amount of 1 to 10 moles, preferably 2 to 4 moles, per mole of the compound of the general formula [2]. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane and tetrahydrofuran Halogenated hydrocarbons such as chloroform and methylene chloride; alcohols such as methanol and ethanol; amides such as Ν, Ν-dimethylformamide; sulfoxides such as dimethyl sulfoxide and water. These solvents may be used alone or in combination of two or more. The reaction is usually carried out at 40 to reflux, preferably 70-120, for 30 minutes-72 hours, preferably It should be carried out for one to five hours.

 The compound of the general formula [lb] can be obtained, for example, by oxidizing the compound of the general formula [la]. The oxidizing agent to be used in this reaction is not particularly limited as long as it is a commonly used oxidizing agent. For example, oxidizing agents such as trifluoroperacetic acid, peracetic acid, perbenzoic acid and m-chloroperbenzoic acid. Acid; hydrogen peroxide; chromic acid and potassium permanganate. The amount of the oxidizing agent to be used may be 0.5 to 1.5 times mol, preferably 0.8 to 1.2 times mol, of the compound of the general formula [la]. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; and halogens such as methylene chloride and chloroform. Hydrocarbons; alcohols such as methanol and ethanol; esters such as ethyl acetate; organic acids such as formic acid and drunk acid; and water. These solvents may be used alone or in combination of two or more. May be. This reaction is usually carried out under reflux from o t :, preferably at 0 to 30 for 30 minutes to 24 hours, preferably for 30 minutes to 12 hours.

Further, the compound of the general formula [k] can be obtained, for example, by oxidizing a compound of the general formula [la] or [lb]. The oxidizing agent used in this reaction is not particularly limited as long as it is a commonly used oxidizing agent. For example, trifluoroperacetic acid, peracetic acid, perbenzoic acid and m-chloroperbenzoic acid And the like; hydrogen peroxide; chromic acid and potassium permanganate. The amount of the oxidizing agent to be used may be 1.5 to 5 times the molar amount of the compound of the general formula [la], and is preferably .5 to 2.5 times the molar amount. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride and chloroform. Halogenated hydrocarbons; alcohols such as methanol and ethanol; esters such as ethyl acetate; organic acids such as formic acid and acetic acid; water; and the like. These solvents may be used alone or in combination. Is also good. This reaction is carried out usually from 0 to under reflux, preferably from 0 to 30, for 30 minutes to 24 hours, preferably for 30 minutes to 2 hours. —In the compounds of the general formulas [la], [lb] and [lc], compounds having an amino group, a hydroxyl group or a carboxyl group should be protected with a conventional protecting group in advance, and after the reaction, If necessary, these protecting groups can be eliminated by a method known per se.

 The compound of the general formula [1] or a salt thereof obtained in this manner is subjected to, for example, an oxidation reaction using perbenzoic acid, manganese dioxide or dichromic acid, catalytic reduction, or a hydride such as lithium aluminum hydride. Reduction and reduction reactions using metals such as iron, transfer reactions such as Wolff rearrangement, alkylation, acylation, amidation, sulfonylation, cyclization, substitution such as conversion of nitrile to amidine Reaction, a halogenation reaction using carbon tetrabromide, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, or the like, a dehydration reaction or a hydrolysis reaction such as acid hydrolysis or alkali hydrolysis. Derivation to another compound of general formula [1] or a salt thereof by subjecting to a reaction or combining them as appropriate be able to. Further, it can be isolated and purified according to a conventional method such as extraction, crystallization and column chromatography.

 Next, a method for producing a raw material of the compound of the present invention will be described.

The one-branched [2] bromophenyl derivative or a salt thereof can be produced, for example, according to the following production method.

 [2]

Wherein, R ^: , R ¹ and R ⁴ have the same meanings as described above, and R is an optionally substituted lower alkyl, lower alkenyl, lower alkylsulfonyl, cycloalkyl, aryl. An aralkyl or heterocyclic group; R ^2C is a substituted or unsubstituted aryl group or a group represented by the general formula: Z′—R, wherein R ⁵ has the same meaning as described above; Z ¹ represents an oxygen atom, a sulfur atom, or an optionally substituted imino group.) R "is a group represented by the general formula: Z ² —R ⁵ (wherein, R ⁵ has the same meaning as described above, and Z ² represents an oxygen atom or a sulfur atom.) R and R "are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, an azide group, a nitro group, a carboxyl group, a hydroxyl group, an acyl group, an alkoxycarbonyl group or a substituted Alkyl, alkenyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy, alkylsulfonylamino, aryloxy, cycloalkyl, carbamoyl, sulfamoyl, acylyl, oxa mouth, alkoxyxalil, alkoxy Schoxalylamino, nitrogen-containing heterocyclic carbonyl bonded through a nitrogen atom The Ariru or heterocyclic group; R ^2e is an optionally Ariru group which may be substituted;? 1 ^ ^{3 <)} Oyobi 1 "are the same or different, a hydrogen atom, a halogen atom, Shiano group, a force Ruboxyl group, hydroxy group, acyl group, alkoxycarbonyl group or optionally substituted alkyl, alkenyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy, alkylsulfonylamino, aryloxy, cycloalkyl, cylvamoyl RR ", RR", RR, sulphamoyl, acylamino, oxa mouth, alkoxyoxalyl, alkoxyoxalylamino, a nitrogen-containing heterocyclic carbonyl, aryl or heterocyclic group bonded via a nitrogen atom; ^4f , R ^4f and R are the same or different, Hydrogen atom, halogen atom, cyano group, azide group, nitro group, carboxy group, hydroxy group, acryl group, alkoxycarbonyl group or optionally substituted alkyl, alkenyl, alkoxy, alkylthio, alkylsulfinyl, alkyl A sulfonyl, alkylsulfonylamino, arylalkyl, cycloalkyl, sulfamoyl, sulfamoyl, oxamol, nitrogen-containing heterocyclic carbonyl, aryl or heterocyclic group bonded via a nitrogen atom; R ^3f ′ and R ^4E 'is a nitro group, one of which is a hydrogen atom, a halogen atom, a cyano group, an azido group, a nitro group, a carboxyl group, a hydroxyyl group, an acyl group, an alkoxycarbonyl group or an optionally substituted alkyl group. , Alkenyl, alkoxy Alkylene thioether alkylsulfinyl, alkylsulfonyl, alkylsulfonyl A Mi Bruno Ariruokishi, cycloalkyl, force Rubamoiru, sulfamoyl, Okisa A nitrogen-containing heterocyclic carbonyl, aryl or heterocyclic group bonded via a mouth or a nitrogen atom; R "is an optionally substituted lower alkyl or cycloalkyl group; X is a halogen atom; Ac represents an acetyl group; Ms represents a mesyl group. "

 The compound of the general formula [2] can be obtained, for example, by reacting the compound of the general formula [16] with a halide such as an alkyl halide or aryl halide in the presence or absence of a base. The halide used in this reaction includes, for example, methyl iodide, cyclohexyl bromide and bromobenzene, and the amount of the halide is 115 times the molar amount of the compound of the general formula [16]. Should be fine. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction; ', for example, amides such as Ν, Ν-dimethylformamide; sulfoxides such as dimethyl sulfoxide Ketones such as acetone; alcohols such as methanol and ethanol; water; and collidine and the like. These solvents may be used alone or in combination of two or more. Bases used in this reaction include, for example, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tetrabutoxide; alkali metal alkoxides such as sodium hydride and lithium hydride. Hydrides; alkaline metal carbonates such as carbonated carbonate and sodium carbonate; alkali hydroxides such as sodium hydroxide and potassium hydroxide. The amount of the base used is the general formula

It may be 11 to 3 times the molar amount of the compound of [16]. Examples of the catalyst used in this reaction include copper powder, cuprous oxide, cuprous chloride, and 8-hydroxyquinoline-cuprous chloride. It may be 0.01 to 2 times the mole of the compound of [16]. This reaction is usually carried out at -20 to 160 for 30 minutes to 24 hours. In addition, in this reaction, when diphenyliodium bromide and diphenyl chloride are used in place of the halide, the compound of the general formula [2] in which R ² is phenoxy can be obtained.

The compound of the general formula [2] can be obtained by subjecting the compound of the general formula ⁶ ] to a Mitsunobu reaction in the presence of alcohol, triphenylphosphine, getyl azodicarboxylate and the like. The alcohol used in this reaction includes Preferably, isopropyl alcohol and cyclohexanol are exemplified. The amount of the alcohol, triphenylphosphine and getyl azodicarboxylate used in this reaction may be 1-3 times the mole of the compound of the general formula [16]. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane and tetrahydrofuran. Ethers such as; halogenated hydrocarbons such as chloroform and methylene chloride;

Amides such as Ν, Ν-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and the like. These solvents may be used alone or in combination of two or more. The reaction is usually carried out at -20 to reflux, preferably at -20 to 50, for 30 minutes to 24 hours, preferably for 30 minutes to 4 hours.

 —The compound of the general formula [16] can be prepared, for example, by the method described in Journal of Chemical. Perkin 1 (J. Chem. So Perkin I), 802-804 (1977). Can be manufactured.

 The compound of the general formula [2] can be obtained, for example, by reacting the compound of the general formula [17] with a nitrite in the presence or absence of an acid, and then converting the obtained compound to a bromide. It can be obtained by reacting with cuprous copper. Examples of the nitrite compound used in this reaction include aluminum nitrite such as sodium nitrite and potassium nitrite; and alkyl nitrite such as tertiary butyl nitrite. The amount of the nitrite compound used may be 0.5 to 5 times the mol of the compound of the general formula []. Examples of the acid used in this reaction include hydrochloric acid and sulfuric acid, and the amount of the acid used may be 150-fold molar amount to the compound of the general formula [III]. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include water, acetic acid, tetrahydrofuran, dioxane, and acetate nitrile. The solvents may be used alone or in combination of two or more. This reaction may be carried out at -20 to 50 for 30 minutes to 24 hours.

Next, the obtained compound can be reacted in the presence of an alkali metal halide such as sodium bromide and an inorganic acid with hydrobromic acid or the like. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. However, examples thereof include water, acetic acid, tetrahydrofuran, and dioxane, and these solvents may be used alone or as a mixture of two or more. The reaction, the reaction temperature, in particular not limited ^force?, For example, under cooling or warming,

It should be carried out for 30 minutes and 24 hours.

 The compound of the general formula [2] can be obtained by reacting the compound of the general formula [18] with an alcohol, phenol or thiophenol in the presence or absence of a base or in the presence or absence of a catalyst. Can be obtained. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide. Ketones such as acetone; alcohols such as methanol and ethanol; collidine; and the like. These solvents may be used alone or in combination of two or more. Bases used in this reaction include, for example, alkali metal alkoxides such as sodium methoxide, sodium methoxide and potassium ten-butoxide; alkalis such as sodium hydride and hydrogenation hydride. Metal hydrides; alkaline metal carbonates such as carbonated sodium and sodium carbonate; alkaline hydroxides such as sodium hydroxide and lithium hydroxide; and the amount of the general formula [18] 11 to 13 times that of the compound of formula (1). Examples of the alcohols, phenols and thiocyanols used in this reaction include 2,4-difluorophenol, 2,4-difluorothiophenol and ethanol. 18] with respect to the molar amount of 1 to 5 times. Examples of the catalyst used in this reaction include copper powder, cuprous oxide, cuprous chloride, and 8-hydroxyquinoline cuprous chloride. The amount of the catalyst used is expressed by the general formula [18J It may be 0.01 to 2 moles per mole of the compound. This reaction is usually carried out at -20 to 160 for 30 minutes to 24 hours.

 The compound of the general formula [18] can be found, for example, in The 'Journal' of 'Organic-Chemistry, Vol. 44, No. 11, pp. 1784-1787 (1979). It can be manufactured by the method described above.

The compound of the general formula [17] can be obtained by reducing the compound of the single-arm type [8]. This reaction can be performed using the usual method for reducing nitro groups to amino groups. For example, a method using catalytic reduction using palladium monocarbon, Raney nickel or platinum, a method using iron or tin, a method using sodium sulfide ammonium monochloride, and the like can be mentioned. For example, when iron is used, it may be used in an amount of 0.1 to 20 times the molar amount of the compound of the general formula [8], and ammonium chloride or the like is used as a reaction accelerator. Is 0.1 to 3 times the molar amount of the compound of the general formula [8]. The solvent used in this reaction, as long as it is a solvent which does not adversely adverse influence on the reaction, especially limiting force ^f, for example, alcohols such as methanol Contact and ethanol; ethers such as Jiokisan and as tetrahydrofuran; water; acetic acid And these solvents may be used alone or in combination of two or more. This reaction is usually carried out at -20 to 160t: for 30 minutes to 24 hours.

 The compound of the general formula [8] can be produced, for example, by reacting a compound of the general formula [7] with an alcohol, phenol or thiophenol in the presence or absence of a base, in the presence or absence of a catalyst. Obtainable. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, amides such as Ν, Ν-dimethylformamide; sulfoxides such as dimethyl sulfoxide Ketones such as acetone; alcohols such as methanol and ethanol; collidine; and these solvents may be used alone or in combination of two or more. Bases used in this reaction include, for example, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydrides such as sodium hydride and hydrogen hydride. Alkali metal carbonates such as carbonated sodium and sodium carbonate; alkali hydroxides such as sodium hydroxide and potassium hydroxide; and the like. The base may be used in an amount of about 13-fold the amount of the compound of the general formula [7]. The alcohols, phenols and thiophenols used in this reaction include, for example, 2,4-difluorophenol, 2,4-difluorothiophenol and ethanol. Expression

It may be 1 to 5 times the molar amount of the compound of [7]. Catalysts used in this reaction include copper powder, cuprous oxide, cuprous chloride, and 8-hydroxyquinoline monochloride. Copper may be used, and the amount of the catalyst used may be 0.01 to 2 times the molar amount of the compound of the general formula [7]. This reaction is usually carried out at -20 to 160 for 30 minutes to 24 hours.

 — The compound of the general formula [7] can be prepared, for example, by the method described in Chemical 'Pharmaceutical Bultin (Chem. Pharm. Bull), Vol. 40, No. 9, pp. 2399-2409 (1992). It can be manufactured by such as.

 —The compound of the general formula [17] can be obtained by subjecting the compound of the general formula [11] to a deacetylation reaction in the presence of an acid. Examples of the solvent used in this reaction include a mixed solvent of water and a water-organic solvent (for example, methanol, ethanol, dioxane, tetrahydrofuran and the like). Acids used in this reaction include mineral acids such as hydrochloric acid and sulfuric acid; and organic acids such as p-toluenesulfonic acid. The acid may be used in an amount of 0.1 to 50 moles per mol of the compound of the general formula [11]. This reaction is usually carried out at 0 to 150 for 30 minutes to 24 hours.

The compound of the general formula [10] can be obtained by subjecting the compound of the general formula [9] to an acetylation reaction in the presence or absence of a base, in the presence or absence of a solvent. The Asechiru agent used in this reaction include forces such as acetic anhydride and § seven Chi Rukurori de ^sigma. The acetylating agent may be used in an amount of 1 to 5 times the molar amount of the compound of the general formula [9]. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples of the solvent include halogenated hydrocarbons such as methylene chloride and chloroform-form; ,, Ν-dimethylforme Amides such as amides and ,, Ν-dimethylacetamide; alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; esters such as ethyl acetate; and amides such as acetonitrile These solvents may be used alone or in combination of two or more. Examples of the base used in this reaction include organic amines such as dimethylaminopyridine, triethylamine and pyridine; and alkali metal carbonates such as potassium carbonate and sodium carbonate. The amount of the base used may be 11 to 13 times the molar amount of the compound of the general formula [9]. The compound of the general formula [11] can be obtained by subjecting the compound of the single-armed type [10] to coupling with aryltributyltin or arylboric acid. This reaction is carried out under the same conditions as for the production of the compound of the single-arm type [la], and is usually carried out at 40 to 160 for 30 minutes to 24 hours.

 —The compound of the general formula [17] can be obtained by subjecting the compound of the general formula [12] to a demesification reaction in the presence or absence of a solvent in the presence of an acid. Acids used in this reaction include methanesulfonic acid and polyphosphoric acid. The acid may be used in an amount of 1 to 100 times the molar amount of the compound of the general formula []. Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene and toluene; and halogenated hydrocarbons such as methylene chloride and dichloroethane. This reaction is usually carried out at 0 to 150 for 30 minutes to 24 hours.

 The compound of the general formula [12] can be prepared, for example, by the method described in Chemical 'Pharmaceutical-Bultin, Vol. 40, No. 9, pp. 2399-2409 (1992), etc. Can be manufactured.

 The compound of the general formula [17] can be obtained by subjecting the compound of the general formula [15] to a deacetylation reaction in the presence of an acid. Examples of the solvent used in this reaction include a mixed solvent of water and a water-organic solvent (for example, methanol, ethanol, dioxane, tetrahydrofuran and the like). Acid catalysts used in this reaction include mineral acids such as hydrochloric acid and sulfuric acid; and organic acids such as p-toluenesulfonic acid. The amount of the acid catalyst used may be 0.1 to 50 times mol of the compound of the general formula [15]. This reaction is usually performed at 0-150 for 30 minutes and 24 hours.

—The compound of the general formula [15] can be obtained by subjecting the compound of the general formula [14] to ordinary ditrophy in the presence or absence of a solvent. Examples of the nitrifying agent used in this reaction include concentrated nitric acid, a mixed acid of nitric acid and acetic anhydride, and a mixed acid of nitric acid and sulfuric acid. The amount of the nitrating agent to be used may be 115-fold molar amount to the compound of the general formula [14]. The solvent used in this reaction, for example, be used, such as acetic force ^f, typically at 0 150, may be carried out 10 minutes a 24 hours.

The compound of the general formula [14] is obtained by converting the compound of the general formula [13] in the presence or absence of a base. It can be obtained by subjecting it to acetylation below. Examples of the acetylating agent used in this reaction include acetic anhydride and acetyl chloride. The amount of the acetylating agent to be used may be 115-fold molar amount to the compound of the general formula [13]. Examples of the base used in this reaction include organic amines such as triethylamine and pyridin; and alkali metal carbonates such as potassium carbonate and sodium carbonate. The base may be used in an amount of 11 to 13 moles based on the compound of the general formula [13]. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, halogenated hydrocarbons such as methylene chloride and chloroform; N, N-dimethylformamide And amides such as N, N-dimethylacetamide; alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; esters such as ethyl acetate; nitriles such as acetonitrile. These solvents may be used alone or as a mixture of two or more. This reaction is usually carried out at -20 to 160 for 10 minutes to 24 hours.

 The compound of the general formula [13] can be produced, for example, by the method described in JP-A-2-268.

 Examples of the salts of the compounds represented by the general formulas [2] and [7] to [18] include the same salts as described for the compound represented by the general formula [1].

 When isomers (for example, optical isomers, geometric isomers and tautomers) are present in the compounds of the general formulas [2] and [7] to [18] or salts thereof, the present invention It encompasses all isomers and extends to all crystal forms and hydrates.

 In the compounds of the general formulas [2] and [7]-[18] or salts thereof, compounds having an amino group, a hydroxyl group or a carboxyl group may be protected by a conventional protecting group. After the reaction, these protecting groups can be removed as necessary by a method known per se.

The compounds of general formulas [2] and [7]-[18] or salts thereof obtained in this way can be used, for example, in an oxidation reaction using perbenzoic acid, manganese dioxide or dichromic acid, etc. Catalytic reduction, with hydrides such as lithium aluminum hydride Reduction and reduction reactions with metals such as iron, transfer reactions such as the Wolf (WoHT) rearrangement, alkylation, acylation, amidation, sulfonylation, cyclization, substitution of nitrile to amidine, etc. Reactions known per se such as halogenation reactions using carbon tetrabromide, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or thionyl chloride, dehydration reactions or hydrolysis reactions such as acid hydrolysis and alkali hydrolysis The compound of the general formula [2] and the compound of the formula [7]-[18] or a salt thereof can be derived by subjecting the compound to or by combining them as appropriate. Further, it can be isolated and purified according to a conventional method such as extraction, crystallization, and column chromatography.

 When the compound of the present invention is used as a medicament, it may be formulated by a generally known method, and may optionally be mixed with excipients, carriers and diluents which are usually used for the formulation. These may be administered in the form of tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powders, suppositories, ointments or injections according to the usual methods. It can be administered parenterally. In addition, the administration method, dosage and number of administrations can be appropriately selected according to the age, weight, and condition of the patient. Usually, for adults, about 0.05 to 100 mg / kg orally or non-orally It may be administered orally (eg, by injection, infusion or administration to the rectal site) and may be given in one or several divided doses.

 Next, the pharmacological action of the compound of the present invention will be described.

Test Example 1 Measurement of activity inhibition rate of COX-1 and 2

As the COX-1, the microbes of the hedging gland gland microsome (manufactured by Edman Technology Co., Ltd.) are used, and as the COX-2, the purified product of the hitx placenta-derived COX-2 (manufactured by Caiman Chemical) is used. The conversion to PGE ₂ and enzymatic activity by these from Arakidon acid.

The conditions for measuring the COX-1 activity are determined according to the method of Procaccini et al. [Biochem. Pharmacol., Vol. 26, No. 105, pp. 1057 (1977)]. . That is, a test compound (final concentration 1) dissolved in 0.5 ml of 50 mM Tris buffer (pH 8.0) containing 100 μg / ml final concentration of microbeads of hedging seminal gland, 5 mM epinephrine and 5 mM glutathione was used. Or 100 μg ml), pretreat at 37 for 2 minutes. ^{0.04 Ci [l - '4 C} ] Arakido LOnmol arachidonic acid containing acid (manufactured by Amersham) is added (final concentration: 20 M).

 Conditions for measuring COX-2 activity were determined by the method of Mitchell et al. [Procedures' Ob. Natl. Acad. Sci. USA), Vol. 90, pp. 11693-111697 (1993)]. That is, 0.5 mM 50 mM Tris buffer (pH 8.0) containing a final concentration of 5 μg ml (10 units Anl) of purified placenta-derived COX-2, 5 mM epinephrine, 5 mM glutathione and 1 M hematin Then, add the test compound (final concentration 1 or 100 g / ml) dissolved in dimethyl sulfoxide, and perform pretreatment at 37 for 2 minutes. Add 3.3 nmol arachidonic acid (final concentration: 6.6 M) containing 0.04 μCi [l- "C] arachidonic acid (manufactured by Amersham) and react at 37 for 4 minutes.

The measurement of the COX activity is carried out according to the method of Yanagi and Komatsu [Biochemical Pharmacol., Vol. 25, pp. 937-941 (1976)]. That is, 2 ml of a mixture of n-hexane ethyl acetate (2: 1) is added to the reaction solution to stop the reaction, and arachidonic acid is extracted into the organic layer by centrifugation. After repeating the same extraction procedure twice, add 1 ml of ethanol to the aqueous layer, stir, and transfer the entire amount of the supernatant obtained by centrifugation to a vial for liquid scintillation counter to fractionate. . The collected organic layer is used as the arachidonic acid fraction, and 1 ml of the fraction is collected into a vial for liquid scintillation counter. Each fraction of radioactivity was measured by a liquid core guides laser Chillon counter to calculate the ratio of the radioactivity of PGE ₂ fraction of the total radioactivity. This was a PG conversion, a decrease in the conversion rate due to the test compound for controls containing only 1% final concentration of dimethyl sulfoxide, and _c the results expressed by COX activity inhibition rate shown in Table 1.

 Table 1 Example No. COX-1 suppression rate COX-2 suppression rate

+

++ 9-+++ 10 (1)-10 (3)-

10 (6)-++ 10 (7)-++

10 (9)-++ 10 (13)-10 (14)-

10 (15)-+++ 10 (18)-+++

10 (20)-+++

10 (22)-+++

11 ++

12 (4)-+++ 13-++

22-+++

25-++

26-+++

27-++ 29-+++

31-

34-*

35 (1)-*

 35 (3)-*

35 (6)-* +++ "

36-+ 37 (1)-37 (3)-

37 (5)-++ 37 (6)-++

 37 (7)-+++

 37 (8)-+++

 37 (11)-37 (12)-

37 (13)-++

 37 (17)-++

 37 (19)-+++

 37 (21)-++

 41-* +++ *

 42-+++

 44-++

 46 (2)-

46 (4)-46 (7)-* ++ *

 46 (8)-+++

 46 (11)-++

 46 (20)-* +++ '

 46 (22)-++

 46 (23)-++

 52-+++

 61-* ++ *

 62-64-70-++

78-++ The inhibition rate of each compound is-(inhibition rate less than 0-25%), + (inhibition rate less than 25-50%). ++ (inhibition rate less than 50-75%). +++ (inhibition rate Rate 75-100%). * Indicates final concentration of 1 μ The results in g / ml are shown.

Test example 2 Adjuvant arthritis inhibitory effect

 The adjuvant arthritis inhibitory effect was determined according to the method described in Araieimittel-Forschung, Vol. 42 (11), Vol. 7, No. 7, pp. 935-944.

 A group of five male rats of the Lewis-Lewis strain (weight: 190-230 g) was used. A group of 5 rats was used to suspend and dry mycobacterium tuberculosis at a rate of 6 mg / ml in liquid paraffin as an adjuvant and a biopsy. Using the resulting solution, 0.1 ml was injected intradermally into the ridge. On the 14th day after adjuvant treatment, they were divided into groups according to the swelling volume of both hind limbs (Dayl4). Oral administration at a rate of / 100g body weight. On the day after the final administration (Dayl 8), the swelling volume of both hind limbs was measured, and the inhibition rate was determined by the following formula. ♦

Inhibition rate _{(0/0) = (1} - (Day ] 4 edema rate of edema rate dose groups Dayl 8 of dose group) Bruno (edema rate Dayl4 edema rate /衬照group Dayl8 of纣照group) ) X 100

Table 2 shows the results.

Table 2 Adjuvant arthritis inhibitory effect (dose lOmgZkg) Example No. Inhibition rate (%)

30

 41

 8 (2) 39

 8 (3) 37

 8 (4) 45 *

 9 25

 10 (1 1) 22

 10 (13) 27

 10 (14) 38

10 (22) 46 34 35

 35 (1) 39

 35 (2) 62 *

 35 (3) 38

 35 (4) 57

 35 (5) 52 *

 35 (7) 57

 36 44

 37 (3) 34

 37 (6) 42

 37 (8) 48

 37 (9) 46

 37 (10) 56

 37 (1 1) 47

 37 (19) 22

 46 (2) 30

 46 (19) 25

 88 50

* Was measured at a dose of 1 mgZkg.

Test Example 3 Ulcer-inducing effect

 Using a male male rat of 7 to 8 rats / group (body weight: 180 to 230 g), the subject was suspended in 0.5% (WV) methylcellulose aqueous solution after fasting for 24 hours (water was allowed to be taken freely). The compound was orally administered at a ratio of〗 ml / 100 g body weight. After leaving for 24 hours under fasted water, the rats were killed by cervical dislocation, and their stomachs were removed and fixed with】% (V / V) formalin solution for 30 minutes. The stomach was cut open along the greater curvature, and ulcers generated on the gastric mucosa were observed under a stereoscopic microscope, and the incidence of ulcers was calculated.

The results are shown in Table 3. Table 3 Tumor-inducing effect Example No. Scene (mg / kg) Ulcer incidence

7 100 0/7

 9 100 0/7

 Control 0/8

 Indomethacin 10 8/8 The best way to carry out the invention

 Next, the ability to specifically explain the formulation examples of the compound of the present invention with specific examples The present invention is not limited to these.

 Formulation Example 1

 A hard gelatin capsule is prepared using the following ingredients.

 2- (2,4-difluorophenoxy) -1,4-methylsulfonyl

 4 12 trows 1, 1'-biphenyl 50mg

 Lactose lM.5mg

 20mg corn starch

 Hydroxypropyl cellulose 2mg

 1.5mg light caylic anhydride

 Carboxymethylcellulose calcium 10mg

 Magnesium stearate 2mg Total 200mg

The above is filled into hard capsules by a conventional method as a material for one capsule.

Formulation Example 2

 A tablet is prepared using the following ingredients.

 2- (2,4-difluorophenoxy) 1 4'-methylsulfinyl

• 4 12 trows 1, 1-biphenyl 25mg Lactose 49mg Microcrystalline cellulose 36mg Hydroxypropylcellulose lmg Potassium carboxymethylcellulose o.6mg Magnesium stearate l-2mg Talc l-2mg A total of 120mg or more is used as a tablet material to make tablets in the usual manner.

Formulation Example 3

 A tablet is prepared using the following ingredients.

 2- (2,4-difluorophenoxy) 1-4, -methylsulfinyl

4 1,2-biphenyl 50 mg Sugar 74 m e Microcrystalline cellulose 55 mg Hydroxypropyl cellulose 2 mg Carboxymethyl cellulose calcium 15 m. Magnesium stearate 2 mg Talc 2 mg A total of 200 mg or more is used as a tablet material and made into tablets in the usual manner.

Formulation Example 4

 A tablet is prepared using the following ingredients.

 2- (2,4-difluorophenoxy) 1-4-methylsulfinyl

4-Nitro 1.1 1.1-biphenyl lOOmg Lactose 49mg Microcrystalline cellulose 55mg Hydroxypropyl cellulose 2mg Power Roxy Methyl Cellulose Calcium 15mg

 Magnesium stearate 2mg

 Talc 2mg A total of 225mg or more shall be converted into tablets by the usual method using 1 tablet as an ingredient.

Formulation Example 5

 A tablet is prepared using the following ingredients.

 2- (2,4-difluorophenoxy) 1-4-methylsulfinyl

 4 12 trol 1,1, -1, -biphenyl 200mg

 Microcrystalline cellulose l OOmg

 Sodium starch glycolate 30mg

 Magnesium stearate 3 mg Total 333 mg or more is converted into tablets by the usual method using 1 tablet as the ingredient.

 Next, the method for producing the compound of the present invention will be specifically described with reference to Reference Examples and Examples. The present invention is not limited to these. The mixing ratios in the eluents were all dose ratios, and silica gel column chromatography was performed using silica gel 60, 70-230 mesh [silica gel 60, 70-230 mesh (Merck)]. The solvent described in parentheses after the melting point indicates a solvent for recrystallization of the crystal whose melting point was measured. The abbreviations used below have the following meanings.

d ₆ -DMSO: heavy dimethyl sulfoxide

Me: methyl group

Et: ethyl group

Ph: phenyl group

Example 1

Under a nitrogen atmosphere, u-bromo-1- (2,4-difluorophenoxy) -4,2-nitrobenzene 0.65 g, 4-methylthiophenenyltributyltin 0.98 g and tetrakis (Triphenylphosphine) Add 0.07 g of radium (0) to 13 ml of toluene and heat to reflux for 4 hours. After filtering off the insoluble matter, the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 20: 1] to obtain 2- (2,4-difluorophenoxy) -14'-methylthio-14 as yellow crystals. To obtain 0.26 g of 1-nitro-1,1-biphenyl.

 Melting point: 91-92 [Ethanol]

NMR (CDC1 _3): S value 2.50 (3H, s), 6.8-8.1 (10H, m)

Example 2

The following compounds are obtained in the same manner as in Example 1.

No.2 (l)

 2 — (2,4-Difluorophenoxy) -1-4'-methylthio-1, 1'-biphenyl-1-5-methyl carboxylate

IRineat ^ m ¹ : 1730, 1505

 NMR (CDC) δ value: 2.50 (3H, s), 3.90 (3H, s), 6.7-8.2 (10H, m)

Νο.2 (2)

 2- (2,4-difluorophenoxy) -1 4'-methylthio-1; I, 1-biphenyl-1-4

IR (neat) cm ': 1720,1505

 NMR (CDC1,) δ value: 2.50 (3H, s), 3.89 (3H, s), 6.8-8.0 (10H, m)

Example 3

Under a nitrogen atmosphere, 4.00 g of 1-bromo-2- (2,4-difluorophenoxy) -141nitrobenzene, 2.44 g of 4-methylthiophenenylboric acid, 12. lml of 2 M aqueous sodium carbonate solution and tetrakis ( Triphenylphosphine) 0.42 g of palladium (0) is added to a mixed solvent of 80 ml of toluene and 12 ml of ethanol, and the mixture is refluxed for 4 hours. After filtering off the insoluble matter, the filtrate is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 20: 1] to obtain yellow crystals of 2,4- (2,4-difluorophenoxy) -14,1-methylthio-14. —Nitro: Obtain 4.08 g of 1,1,1-biphenyl. Melting point: 91-92 [Ethanol]

 NMRiCDCl,): δ value 2.50 (3H, s), 6.8-8.1 (10H, m)

Example 4

Compounds in Tables 1a-c are obtained in the same manner as in Example 3,

実施例 No. R¹ n R、

Table 1a

Example No. R ¹ n R,

4 (5) CH ₃₀ NHCOCH ₃ H -0- <W>

4 (6) CH ₃ 0 H NO,

4 (7) CH ₃₀ NO '2 H -CO- ©

実施例 No. R¹ _R3 ^ R² Table 1c

Example No. R ¹ _R 3 ^ R ²

4 (15) CH ₃ o H -OH ©

4 (16) CH ₃ o H COCH ^ -O-^-j 4 (17) CH ₃ o CF ₃ H -0 ^)-F

4 (20) CH ₃ 0 H CHO-o¾H

表 1 a— cの化合物の物性を以下に示す。

The physical properties of the compounds in Table 1 ac are shown below.

No.4 (l)

Melting point: 81-82 [Ethanol]

NMR (CDCI) S value: 1, 1 -2.0 (10H, m), 2.50 (3H, s), 4.1 -4.7 (1H, m), 7.1 -8.0 (7H, m) No.4 (2)

IROieatJcm ¹ : 1585.1485,1165

NMR (CDC1 ₃₎ δ value: 2.51 (3H, s), 3.76 (3H, s), 6.5-7.6 (12H, m)

No.4 (3)

Melting point: 90-91 [ethanol] , (q))) RCDC1 (,, NM :, J7.5HZ2.935HZ2H7.6.88 ==-[¾ si690: 7Η1 "

.

ο

 DC

) (, () () ,, 68, .lH.5s24322 2.603H4. NRCDC. ョ,-] [nsC: 131 33 fτνt: αH -_- lI-.

() 5 N0.4 No.4 (13)

IRineaDcm ¹ : 1520, 1505,1345

NMR (CDC1 ₃₎ 6 value: 2.52 (3H, s), 6.7-8.4 (10H, m)

No.4 (14)

IR (nea cm ': 1505, 1335

 MR (CDC1,) δ value: 2.52 (3H, s), 6.9-7.7 (10H, m)

No.4 (15)

IRineatJcm ' ¹ : 1590, 1485

NMR (CDC1 ₃₎ δ value: 2.47 (3H, s), 6.8-7.8 (12H, m)

No.4 (16)

IRineaticm ¹ : 1680, 1505

 NMR (CDC1 δ value: 2.47 (3H, s), 2.54 (3H, s), 6.6-8.〗 (L, 0H, m)

No.4 (17)

 IRineaticm 'nSlO.nSO

NMR (CDC1,) S value: 2.52 (3H, s), 6.8-7.7 (0H, m)

No.4 (18)

 IR (neat) cni ': 1505,1250

 NMR (CDCI,) δ value: 2.34 (3H, s), 2.45 (3H, s), 6.6-7.7 (10H, m)

No.4 (19)

IR (neat) cni ¹ : 1505, 1480, 1205

 NMR (CDCI) δ value: 2.53 (3H, s), 3.84 (3H, s), 6.6-7.7 (10H, m)

No.4 (20)

 IR (neat) cm ': 1695,1505

 NMR (CDC1,) δ value: 2.50 (3H, s), 6.7-8.2 (10H, m), 10.00 (lH, s)

No.4 (21)

Melting point: 94-95 [Ethanol]

 NMRiCDCl,) δ value: 2.49 (3H, s) .6.8-7.8 (10H, m)

Example 5

(1) Under nitrogen atmosphere, 2-bromo-1-benzo-2-benzylbenzene 2.10 g and 4-medium 1.50 g of thiothiophenylborate, 9.1 ml of 2M sodium carbonate solution and 0.32 g of tetrax (triphenylphosphine) palladium (0) are added to a mixed solvent of 50 ml of toluene and 10 ml of ethanol, and heated under reflux for 2 hours. Let it. After filtering off the insoluble matter, the filtrate is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 5: 1] to give 2-formyl-14'-methylthio-14-212-row of yellow crystals; 1,1-biphenyl Get 2.00g.

Melting point: 93-95 at [ethanol]

 NMR (CDC) δ value: 2.52 (3H, s), 7.9-8.9 (7H, m), 10.1 (lH, s)

(2) Dissolve 0.87 g of benzyltriphenylphosphonium bromide in 10 ml of methanol, and add 0.35 g of 28% (WW) methanol solution of sodium methoxide and 2-formyl-14, -methylthio-14-nitro at room temperature. Add 0.5 g of 1,1,1-biphenyl and stir at the same temperature for 2 hours. Add the reaction mixture to a mixture of ice water and ethyl acetate, adjust the pH to 5.0 with 1 N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 5: 1] to give a green-yellow oil of 4, -methylthio-14-nitro-2-styrene-yl], 1'- 0.60 g of biphenyl is obtained.

IR (neaDcm ': 1515.1345

NMR (CDC1,) 5 values: 2.60 (3H, s), 6.4-8.7 (14H, m)

Example 6

Under a nitrogen atmosphere, 1-promo 2- (2,4-difluorophenylthio) -14-nitrobenzene 0.90 g, 4-methylsulfonylphenyltributyltin 1.39 g and tetrakis (triphenylphosphine) palladium ( 0) Add 0.09 g to 18 ml of xylene and heat to reflux for 5 hours. After filtering off the insoluble matter, the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography [eluent; hexane: ethyl acetate = 2: 1] to give colorless crystals of 2- (2,4-difluorophenylthio) -4, -methylsulfonyl-412. 0.27 g of 1,1,1-biphenyl trough is obtained.

Melting point: 146-147 [Ethanol-acetonitrile mixed solvent] NMR (d ₆ -DMSO): S value 3.31 (3H, s), 7.1 -8.3 (10H, m)

Example 7

 Dissolve 0.70 g of 2- (2,4-difluorophenoxy) -1,4'-methylthio-1,412 tro-1,1-biphenyl in mml of methylene chloride, and in 0-5, m-chloroperbenzoic acid 0.29 g And stirred at the same temperature for 2 hours. The reaction mixture is sequentially washed with a saturated aqueous solution of sodium hydrogencarbonate, an aqueous solution of sodium thiosulfate and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give colorless crystals of 2- (2,4-difluorophenoxy) -14, -methylsulfinyl 4-12-trough 1,1'-biphenyl 0.5 Ig Get.

Melting point: 137-138 at [ethanol]

NMR (d ₆ -DMSO) 8 value: 2.81 (3H, s), 7.1 -8.2 (10H, m)

Example 8

実施例 No. R¹ n R、

The compounds in Table 2 are obtained in the same manner as in Example 7. Table 2

Example No. R ¹ n R,

8 (2) CH H N0 ₂ -O ^ -F

表 2の化合物の物性を以下に示す _c No.8(l )

_C showing the physical properties of the compounds of Table 2 below No.8 (l)

Melting point: 125-126 [ethanol]

NMR (d ₆ -DMSO) δ value: 2.57 (3H, s), 2.80 (3H, s), 7.0-8.1 (1 OH, m)

No.8 (2)

Melting point: 165-166 [ethanol]

NMR (d ₆ -DMSO) 6 value: 2.82 (3H, s), 6.9-8.4 (10H, m)

No.8 (3)

Melting point: 79-81 [Hexane monoethyl ether mixed solvent]

NMR (CDC1 ₃₎ S value: 2.78 (3H, s), 6.7-7.8 (10H, m)

No.8 (4)

Melting point: 109-1 10 [Hexane-isopropyl ether mixed solvent]

NMR (CDC1 _? ) S value: 2.78 (3H, s), 6.7-7.8 (10H, m)

Example 9

 Dissolve 0.70 g of 2- (2,4-difluorophenoxy) -14'-methylthio-4-nitro-1,1,1-biphenyl in 14 ml of methylene chloride, and in 0-5, m-chloroperbenzoate Add 0.65 g of acid and stir at room temperature for 2 hours. The reaction mixture is washed successively with a saturated aqueous solution of sodium hydrogencarbonate, an aqueous solution of sodium thiosulfate and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained crystals were recrystallized with a mixed solvent of acetonitrile and ethanol to give colorless crystals of 2- (2,4-difluorophenoxy) -14-methylsulfonyl-4-nitro-1,1,1 -Obtain 0.62 g of biphenyl.

Melting point: 181-182 [Ethanol-acetonitrile mixed solvent]

NMR (d ₆ -DMSO) δ value: 3.30 (3H, s), 7.0-8.2 (10H, m)

Example 10

The compounds of Tables 3a to c are obtained in the same manner as in Example 9. Table 3a

Example No. R ¹ n R ⁴ R

10 (1) 2 NO, H-ο®

2 COCHj H -o-¾ /

10 (3)

10 (5) CH ₃ 2 NHCOCH ₃ H -0- (H)

10 (7) CH, 2 NO, H -CO- ©

Table 3c

Example No. /? 'N _R R ⁴ R ²

10 (19) CH ₃ 2 H OCH ', ₃ -o¾H

表 3 a— cの化合物の物性を以下に示す。 10 (20) CH ₃ 2 N0 ₂ H ~ CH = CH- @ 10 (21) CH ₃ 2 H COOCHs -0¾> -F

The physical properties of the compounds in Table 3 ac are shown below.

No.lO (l)

Melting point: 149-149.5T: [Ethanol]

NMR (d ₆ -DMSO) 5 values: U -2.0 (10H, m), 3.12 (3H, s), 4.2-4.7 (1 H, m) 7.3-8.2 (7H, m) Νο.10 (2)

Melting point: 159—160 [a seven tonitril]

NMR (CDC1,) δ value: 3.00 (3H, s), 3.76 (3H, s) .6.5-7.8 (12H, m) Νο.10 (3)

 Melting point: 172-173 [Ethanol-acetonitrile mixed solvent]

NMR (d ₆ -DMSO) δ value: 2.57 (3H, s), 3.27 (3H, s), 7.1-8.1 (1 OH, m)

No.10 (4)

Melting point: 166-167 [Eta'-mono-acetonitrile mixed solvent]

NMR (d ₆ -DMSO) δ value: 3.28 (3H, s), 7.8.2 (10H, m)

No.10 (5)

Melting point: 184—186 at [ethanol]

NMR (CDC1 _? ) S value: 1.3-2.l (10H, m), 2.20 (3H, s), 3.10 (3H, s), 4.24.5 (lH, m), 6.8-8.1 (8H , m)

No.10 (6)

Melting point: 145—147 [ethanol]

 NMR (CDC1,) S value: 1.3-2.2 (10H, m), 3.10 (3H, s), 4.3-4.7 (lH, m), 6.9-8.4 (7H, m)

No.10 (7)

Melting point: 170—172 [ethanol]

NMR (d ₆ -DMSO) δ value: 3.20 (3H, s), 7.5-8.6 (12H, m)

No.10 (8)

Melting point: 166-167 [acetonitrile]

NMR (CDC1,) value: 3.00 (3H, s), 3.80 (3H, s), 6.7-8.1 (10H, m)

No.10 (9)

Melting point: 182—184 [acetonitrile]

NMR (d ₆ -DMSO) δ value: 3.29 (3H, s) .4.09 (2H, s) .6.9-8.2 (I 2H, m)

No.10 (10)

Melting point: 199-201 [acetonitrile]

NMR (d ₆ -DMSO) 5 value: 3.28 (3H.s) .3.95 (3H.s), 7.6-8.3 (7H, m)

No.lO (l l)

Melting point: 219-220 [Ethanol-acetonitrile mixed solvent]

NMR (d ₆ -DMSO) δ value: 3.23 (3H, s) .7. 8.4 (1 lH, m)

Νο.10 (12) Melting point: 125-126 [ethanol]

NMR (d ₆ -DMSO) 5 values: 1.16 (3H, tJ = 7.5 Hz), 3.40 (2H, qJ = 7.5 Hz), 7.2-8.2 (1 OH.m) No. 10 (13)

Melting point:] 86-187 [Ethanol-acetonitrile mixed solvent]

NMR (d ₆ -DMSO) 5 value: 3.30 (3H, s), 6.9-8.4 (10H, m)

Νο.10 (14)

Melting point: 103.5—104.5 [Isopropyl ether]

NMR (CDC1,) δ value: 3.10 (3H, s), 6.7-8.1 (10H, m)

Νο.10 (15)

Melting point: 122.5— 125.0 [acetonitrile]

NMR (CDC1,) ^{values:. 3 .0 6 (3H,} s), 6 8 - 8 .0 (H, m)

No.10 (16)

Melting point: 153.5-154.5 [Ethanol]

NMR (CDCI,) δ value: 2.60 (3H, s), 3.09 (3H, s) '6.7-8.2 (10H, m)

No.10 (17)

Melting point: 132-133 [Ethanol]

NMR (CDCI δ value: 3.10 (3H, s), 6.8-8.2 (10H, m)

Νο.10 (18)

Melting point: 1 191-1120 [isopropyl ether]

NMR (CDCU) S value: 2.38 (3H, s), 3.06 (3H, s), 6.7-8.1 (10H, m)

Νο.10 (19)

Melting point: 128—129 [ethanol]

 NMR (CDC1,) a value: 3.08 (3H, s), 3.86 (3H, s), 6.5-8.2 (] 0H, m)

No.10 (20)

Melting point: 218—219 [acetonitrile]

NMR (d ₆ -DMSO) δ value: 3.31 (35), 6.9-8.7 (14-1, ^ 1)

No.10 (21)

Melting point: 141.5-142.0 [Ethanol]

NMR (CDC1,) δ value: 3.09 (3H, s), 3.92 (3H, s), 6.7-8.2 (1ΟΗ, τη) No.10 (22)

Melting point: 163—] 64 [ethanol]

NMR (CDC1 ₃₎ 8 value: 3.10 (3H, s), 6.8-8.2 (10H, m)

Example 1 1

(1) Dissolve 5.60 g of 2-methoxy-1,4-methylsulfonyl-4-122 tro 1,1-biphenyl in a mixture of 30 ml of acetic acid and 30 ml of 47% hydrobromic acid, and heat to reflux for 4 hours. The reaction mixture is added to a mixture of ice water and ethyl acetate, and the organic layer is separated. Ice water is added to the obtained organic layer, the pH is adjusted to 12 with a 1N aqueous sodium hydroxide solution, and the aqueous layer is separated. Ethyl acetate is added to the obtained aqueous layer, the pH is adjusted to 2.0 with 1 N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. To the obtained residue is added isopropyl ether, and the mixture is filtered to obtain 2.20 g of a pale yellow solid. The obtained solid is recrystallized from acetonitrile to obtain 2.00 g of pale yellow crystals of 2-hydroxy-14'-methylsulfonyl-14-212tro 1,1,1'-biphenyl.

Melting point: 250 or more [acetonitrile]

NMR (d ₆ -DMSO) 5 values: 3.28 (35), 7.6-8.3 (7 ^ 1,01), 11.0 (1} 1,5)

(2) In a nitrogen atmosphere, 0.06 g of 60% sodium hydrogen hydride was added to 5 ml of N, N-dimethylformamide, and then, at room temperature, 2-hydroxy-4-methylsulfonyl-412-— 1, Add 0.40 g of bifurnyl in 5 min. After stirring at the same temperature for 30 minutes, a solution of 0.17 ml of cyclopentyl bromide in 2 ml of Ν, ホ -dimethylformamide is added dropwise to the reaction mixture over 15 minutes. After stirring at the same temperature for 30 minutes, 0.05 g of 60% (W / W) sodium hydride is added at room temperature. To the reaction mixture is added dropwise a solution of 0.17 ml of cyclopentyl bromide in 2 ml of Ν, Ν-dimethylformamide over 15 minutes. After stirring at the same temperature for 1 hour, the reaction mixture is cooled, added to a mixture of ice water and ethyl acetate, and the organic layer is separated. The obtained organic layer is washed successively with water, 1N hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether is added to the obtained residue, and the residue is collected by filtration to obtain 0.38 g of a pale yellow solid. The solid obtained was recrystallized from acetonitrile to give pale yellow crystals of 2-cyclopentyloxy 4-methylsulfonyl 4-122-nitro-1,1,1'-biphenyl.

Or i (() ((H (87 ,,,. 4ii6m7.93H8.3lH NMO _J.32.48Hm32s4.5Rd DMS .------ 0 69.5 f then J Tt i-.. g .4 J = 6.0Hz), 7.6-8.2 (7H, m)

 Νο.12 (3)

 Melting point: 204.5—207 for [acetonitrile]

NMR (d ₆ -DMSO) S iit: 3.27 (3H, s), 5.34 (2H, s), 7.42 (5H, s), 7.5-8.3 (7H, m)

No.12 (4)

 Melting point: 182—184 [acetonitrile]

NMR (d ₆ -DMSO) δ value: 3.26 (35), 7.0-8.4 (12 111)

No.12 (5)

Melting point: 1 10— 1 12 "C [ethyl ether]

NMR (d ₆ -DMSO) values: 0.9-2.4O 2H, m), 3.28 (3H, s), 4.9-5.5 (lH, m), 7.5-8.3 (7H.m) Example 13

 4-cyanone 2- (2,4-difluorophenoxy) -14-methylsulfonyl; I 1, -biphenyl 0.25 g is dissolved in dimethylsulfoxide 7.5 ml and 30% hydrogen peroxide solution is added to this solution. Add 0.21 ml and potassium carbonate O.Olg and stir at 80 for 2 hours. The reaction mixture is added to a mixture of ice water and "ethyl acetate", adjusted to pH l.O with 2 N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed successively with water and saturated saline and then dried. After drying over magnesium sulfate and distilling off the solvent under reduced pressure, the residue obtained is recrystallized from acetonitrile to give colorless crystals of 4-butane 2- (2,4-diflurophenoxy). ) 0.20 g of 1,4-methylsulfonyl-1-1,1-biphenyl are obtained.

Melting point: 233—234 [a seven tonitrile]

NMR (d ₆ -DMSO) δ value: 3.27 (3H, s), 7.1 -8.2 (12H, m)

Example 14

In the same manner as in Example 13, 5-livemyl-2- (2,4-difluorophenoxy) -14′-methylsulfonyl-1 ,,]-biphenyl is obtained.

Melting point: 232—233 [acetonitrile]

NMR (d ₆ -DMSO) 8 values: 3.28 (3H, s), 6.8-8.3 (12H, m)

Example 15

2- (2,4-difluorophenoxy) 1-4,1-methylsulfonyl 4-212 0.5 g of 1, -biphenyl, 0.43 g of iron powder, 0.04 g of ammonium chloride in 5 ml of ethanol And water (2.5 ml) and heat to reflux for 1 hour. After filtering off the insoluble matter, the solvent is distilled off under reduced pressure. The obtained residue is dissolved in ethyl acetate, washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from a mixed solvent of acetonitrile and ethanol to give pale yellow crystalline 4-amino-2- (2,4-difluorophenoxy) -1-methylsulfonyl-1,1,1,1-biphenyl. 0.33 g of nil is obtained.

Melting point: 218-219 [Ethanol-acetonitrile mixed solvent]

NMR (d ₆ -DMSO) S value: 3 · 20 (3H, s), 5.52 (2H, s), 6.05 (lH, d, J = 2.0 Hz), 6.44 (lH, dd, J = 9.8 Hz, 2.0Hz), 7.0-8.0 (8H, m)

Example 16

In the same manner as in Example 15, 5-amino-2- (2,4-difluorophenoxy) -14′-methylsulfonyl-1,1, -biphenyl is obtained.

Melting point: 131- 132 [Ethanol-acetonitrile mixed solvent]

NMR (d ₆ -DMSO) δ value: 3.22 (3H, s), 5.18 (2H, s), 6.7-8.0 (10H, m)

Example 17

 4-Amino-2- (2,4-difluorophenoxy) 1,4-methylsulfonyl 0.2 g of 1,1'-biphenyl is dissolved in 4 ml of methylene chloride, and under ice-cooling, triethylamine 0.09 ml and acetic anhydride 0.06 ml and add stirring at the same temperature for 2 hours. Add the reaction mixture to ice water, adjust the pH to 1.0 with 2 N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was recrystallized from a mixed solvent of acetonitrile and ethanol to give colorless crystals of 4-acetylamino-2- (2,4-difluorophenoxy) -1,4-methylsulfonyl; ,;! To obtain 0.13 g of biphenyl.

Melting point: 215-216 [Ethanol-six tonitrile mixed solvent]

NMR (d ₆ -DMSO) δ value :: 2.02 (3H.s), 3.24 (3H, s), 7.1-8.2 (〗 0H, m), 10.12 (1 H, s)

Example) 8

In the same manner as in Example 17, 5-acetylamino-2- (2,4-difluorophenoxy) -14-methylsulfonyl-1,1′-biphenyl is obtained.

Melting point: 128-129 [Ethanol-acetonitrile mixed solvent] NMR (d ₆ -DMSO) δ value: 2.10 (3H, s), 3.30 (3H, s), 6.9-8.1 (1OH, m) .l 0.10 (1H, s)

 Example 19

 2- (2,4-difluorophenoxy) -14'-methylsulfonyl-1,1, -biphen-2-ru4 Dissolving 0.30 g of methyl rubonate in 6 ml of dioxane, then 1N aqueous sodium hydroxide solution Add 6 ml and stir at room temperature for 2 hours. The reaction mixture is adjusted to pH 1.0 with 2 N hydrochloric acid and extracted with ethyl acetate. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is recrystallized from ethanol to give 0.22 g of colorless crystalline 2- (2,4-difluorophenoxy) -14'-methylsulfonyl-1,1,1-biphenyl-2-carboxylic acid .

Melting point: 209—210 [ethanol]

NMR (d ₆ -DMSO) 5 value: 3.30 (3H, s), 7.2-8.1 (10H, m), 13.0-13.5 (lH, bs)

Example 20

In the same manner as in Example 19, 2- (2,4-difluorophenoxy) -14'-methylsulfonyl-1,1'-biphenyl-15-hydroxycarboxylic acid is obtained.

Melting point: 227—228 [ethanol]

NMR (d ₆ -DMSO) δ value: 3.28 (3H, s), 6.6-8.3 (11 Hm)

Example 21

 2-Benzoyl 4'-Methylsulfonyl 4-1-nitro-1,1'-biphenyl 1.00 g is dissolved in a mixed solvent of ethanol 5 ml, water 5 ml and tetrahydrofuran 10 ml, and ice-cooled Below, 0.10 g of sodium borohydride is added over 10 minutes, and the mixture is stirred at the same temperature for 1 hour. The reaction mixture is added to a mixed solvent of water and ethyl acetate, adjusted to pH 2.0 with 1 N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent; hexane: ethyl acetate = 10: 1] to obtain 0.74 g of a pale yellow solid. The obtained solid is recrystallized from acetonitrile to give 0.65 g of colorless crystals of 2- (c-hydroxybenzyl) 14,1-methylsulfonyl-412-trow. 1.)-Biphenyl.

Melting point: 161-163 [acetonitrile] NMR (d ₆ -DMSO) δ value: 3.30 (3H, s), 5.80 (lH, dJ = 4.5 Hz), 6.30 (lH.d, J = 4.5 Hz), 6.9-

8.5 (12H, m)

Example 22

 5-Acetyl-2- (2,4-difluorophenoxy) 1,4-methylsulfonyl-1,1,1-biphenyl 0.40 g, hydroxylamine hydrochloride 0.07 g and pyridine 0.08 ml are added to ethanol 10 ml and heated for 10 minutes Bring to reflux. The reaction mixture is added to a mixture of ice water and ethyl acetate, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent; hexane: ethyl acetate = 20: 1] to give colorless crystals of 5- (a-hydroxyiminoethyl) -2- (2,4-difluorophenyl). Enoxy) 1,4,1-methylsulfonyl-1,1′-biphenyl 0.20 g is obtained.

Melting point: 223—224 at [ethanol]

NMR (d ₆ -DMSO) 8 values: 2.20 (3H, s), 3.27 (3H, s), 6.8-8.1 (10H, m), 1 1.25 (1H, s)

Example 23

 Dissolve 2-OO (2,4-difluorophenoxy) -14'-methylsulfonyl-1,1, -biphenyl-15-butanoic acid l.OOg in methylene chloride (10 ml), and add 0.54 ml of thionyl chloride and Ν, Ν —Add 0.1 ml of dimethylformamide, reflux for 1.5 hours, and evaporate the solvent under reduced pressure. The obtained residue was added with 10 ml of tetrahydrofuran (dissolved in this solution, 1.7 ml of 25% aqueous ammonia was added dropwise under ice cooling, and the mixture was stirred at 20-25 for 24 hours. The reaction mixture was introduced into a mixture of ice water and ethyl acetate. The obtained organic layer was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.The obtained residue was recrystallized from acetonitrile Colorless ± B

 Fa says, "5-Rubamoyl 2- (2,4-difluorophenoxy) -14" -methylsulfonyl 1,1'-biphenil 0.50g.

Melting point: 232—233 [acetonitrile]

NMR (d DMSO) δ value: 3.28 (3H, s), 6.8-8.3 (H, m)

Example 24

5 · bromo-14,1 (2,4-difluorophenoxy) 1 2'-nitto under nitrogen atmosphere 1.30 g of roacetanilide, 0.62 g of 4-methylthiophenenylboric acid, 3.4 ml of 2M sodium carbonate aqueous solution and tetrakis (triphenylphosphine) palladium (0) (2 g of U mixed with 26 ml of toluene and 4 ml of ethanol The mixture was added to the solvent, and the mixture was ripened and refluxed for 2 hours After removing the insolubles, the filtrate was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent: toluene], and yellow crystals of 5- (7,7-chloroamino) -2- (2,4-difluorophenoxy) -14, -methylthio-14-212 trough: 0.95 g of I, 1, -biphenyl is obtained.

Melting point: 138-140 [ethanol]

NMR (d ₆ -DMSO) δ value: 2.12 (3H, s), 2.53 (3H, s), 6.8-7.9 (9H, m), 10.30 (1H, s)

Example 25

Dissolve 0,90 g of 5-acetylamino 2- (2,4-difluorophenoxy) -14,1-methylthio-14,2-nitro-1,1,1-biphenyl in 20 ml of methylene chloride and _m -chloro under ice-cooling Add 0.99 g of perbenzoic acid and stir the mixture at the same temperature for 1 hour. The reaction mixture is washed successively with a saturated aqueous solution of sodium hydrogen carbonate, an aqueous solution of sodium thiosulfate and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give yellow crystalline 5-acetylamino 2- (2.4-difluorophenoxy) -14-methylsulfonyl-412-nitro-1,1,1'-bi. 0.60 g of phenyl is obtained.

Melting point: 190-191.5 [ethanol]

NMR (d ₆ -DMSO) δ value: 2.1 1 (3H, s), 3.30 (3H, s), 6.8-8.4 (9H, m), 10.33 (1 H, s)

Example 26

0.55 g of 5-acetylamino-1- (2,4-difluorophenoxy) -14,1-methylsulfonyl-14,2-nitro-1,1,1'-biphenyl was added to a mixed solvent of dioxane, 0 ml and 6 N hydrochloric acid 10 ml, Heat to reflux for 1 hour. The reaction mixture is added to a mixed solvent of ethyl acetate and water, adjusted to pH 8.0 with sodium hydrogen carbonate, and the organic layer is separated. The obtained organic layer is washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was recrystallized with a mixed solvent of ethyl acetate and ethyl ether to give 5-amino-2- (2,4-difluoro) as yellow crystals. Lofenoxy) 1,4-methylsulfonyl-412 tro 1,1,1'-biphenyl 0.23 g is obtained.

 Melting point: 212-213 [Ethyl-ethyl acetate mixed solvent]

NMR (-DMSO) S ii: 3.27 (3H, s), 7.0-8.3 (l Ι Η, τη)

Example 27

 Dissolve 0.20 g of 5-amino-2- (2,4-difluorophenoxy) -14'-methylsulfonyl-412-trow 1,1, -biphenyl in 5 ml of N, N-dimethylacetamide and ice Under cooling, add 0.07 ml of ethyl oxalyl chloride, and stir at room temperature for 1 hour. The reaction mixture is added to a mixed solvent of ethyl acetate and water, and the organic layer is separated. The obtained organic layer is washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. If the residue obtained is recrystallized from ethanol,

 0.18 g of BB 2- (2,4-difluorophenoxy) -1-5-ethoxylanylamino 4'-methylsulfonyl-4-12-nitro-1,1,1-biphenyl is obtained.

Melting point: 158—159 in [ethanol]

NMR (d ₆ -DMSO) δ value: 1.35 (3H ^ J = 7.0 Hz), 3.30 (3H, s), 4.40 (2H, q, J = 7.0 Hz), 7.0-8.4 (9H, m), 11.40 (l H, bs)

Example 28

Under a nitrogen atmosphere, 0.15 g of 60% sodium hydride is suspended in 5 ml of anhydrous tetrahydrofuran, and a solution of 5 ml of anhydrous tetrahydrofuran containing 0.82 g of ethyl ethylphosphonoacetate is added dropwise at room temperature, followed by stirring at the same temperature for 30 minutes. I do. To the reaction mixture is added dropwise a solution of 1.30 g of 2- (2,4-difluorophenoxy) -15-formyl-14-methylthio-1,1′-biphenyl in 10 ml of tetrahydrofuran at room temperature, and the mixture is stirred at the same temperature for 1 hour. The reaction mixture is added to ice water, adjusted to pH 2.0 with 1 N hydrochloric acid, and extracted with ethyl acetate. The obtained organic layer is washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 10: 1] to give a colorless oily 3- (4- (2,4-difluorophenoxy) 13- (4-methylthiophenyl) phenyl) 1.50 g of ethyl acrylate are obtained.

IRineaDcm ¹ : 1710,1505, 1250 NMR (CDC1,) S value: 1.30 (3H, U = 6.0 Hz), 2.50 (3H, s), 4.20 (2H, q, J = 6.0 Hz). 6.40 (1 H, d, J = 16 Hz), 6.6 -7.9 (1 l H, m)

 Example 29

 3- (4- (2,4-difluorophenoxy) -1-3- (4-methylthiophenenyl) phenyl) Add 1.50 g of ethyl acrylate to 15 ml of methylene chloride, and use m-chloroperbenzoic acid at 15 with 1.20 g in 10 min. After stirring at the same temperature for 1 hour, the insoluble matter is removed. The filtrate is added to ice water, and the organic layer is separated. The obtained organic layer is washed successively with a saturated aqueous solution of sodium hydrogencarbonate, an aqueous solution of sodium thiosulfate and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether is added to the obtained residue, and the mixture is collected by filtration to give a colorless solid. By recrystallizing the obtained solid with ethanol, colorless crystalline 3- (4- (2,4-difluorophenyl) -13- (4-methylsulfonylphenyl) phenyl) ethyl acrylate l.OOg was obtained. obtain.

Melting point: 110— 1 12 [ethanol]

NMR (d ₆ -DMSO) δ value: 1.27 (3H, U = 6.0Hz), 3.28 (3H, s), 4.20 (2H, q, J = 6.0Hz), 6.70 (1H, d, J = 16Hz) , 6.9-8.4 (1 l H, m)

Example 30

 3- (4- (2,4-difluorophenyl) -1- (4-methylsulfonylphenyl) phenyl) 0.55 g of ethyl acrylate is dissolved in a mixed solvent of 10 ml of tetrahydrofuran and 5 ml of ethanol. Add 1.3 ml of 1N aqueous sodium hydroxide solution at room temperature and stir at 50 for 30 minutes. The reaction mixture is added to a mixture of ice water and ethyl acetate, and the aqueous layer is separated. Ethyl acetate is added to the obtained aqueous layer, the pH is adjusted to 2.0 with 1 N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether is added to the obtained residue, and the residue is collected by filtration to obtain 0.44 g of a colorless solid. The obtained solid was recrystallized from isopropyl alcohol to give colorless crystals of 3- (4- (2,4-difluorophenoxy) -13- (4-methylsulfonylphenyl) phenyl) acrylic acid 0.30 get g.

Melting point: 179—181 [isopropyl alcohol] NMR (d ₆ -DMSO) S value: 3.29 (3H, s), 6.60 (l H, d, J = 16Hz), 6.8-8.4 (12H, m)

Example 31

 Dissolve 0.58 g of 5-amino-2- (2,4-difluorophenoxy) -14-methylsulfonyl-11-biphenyl in 10 ml of methylene chloride and add 0.14 ml of pyridine under ice-cooling. Next, 0.19 ml of ethyl oxalyl chloride is added dropwise, and the mixture is stirred at the same temperature for 1 hour. Add the reaction mixture to ice water, adjust the pH to 1.0 with 2 N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was recrystallized with a mixed solvent of acetonitrile and ethanol to give colorless crystals of 2- (2,4-difluorophenyloxy) -15-ethoxylamino-4, -methylsulfonyl-1,1,1, -Obtain 0.52 g of biphenyl.

Melting point: 1 11-1 12 C [Ethanol-acetonitrile mixed solvent]

NMR (d ₆ -DMSO) δ value: 1.33 (3H, U = 7.0 Hz), 3.26 (3H, s), 4.33 (2H, qJ = 7.0 Hz), 6.9-8.2 (rat m), 10.97 () H, s)

Example 32

In the same manner as in Example 31, 2- (2,4-difluorophenoxy) -141-ethoxyarylamino 4′-methylsulfonyl-1-1,1′-biphenyl is obtained.

Melting point: 159-160 [Ethanol-acetonitrile mixed solvent]

NMR (d ₆ -DMSO) 5 value: 1.30 (3H, J = 7.0 Hz), 3.27 (3H, s), 4.32 (2H, q, J = 7.0 Hz), 7.2-8.1 (10H, m), 10.97 ( l H, s)

Example 33

The compounds in Table 8 are obtained in the same manner as in Example 3.

H 30N 0 lO ( ) εε

H 30N 0 lO () εε

 H awo o () εε

f00 / 96dT / XDd 9 ΙΓ69 Σ96 ΟΛΙ (oi) ee * oN

 (ui'HZl) 8'Z.-8-9 '(s'He) DD) N

 (6) εε

('ΗΖ ·) 8ΖΖ6 9'(ω'ΗΙ) Ζ. -3 '(s'H £) SS'3 ^ ϋ0ΐ) ί'Ζ-0Ί9 (ΟΟΖ ΉΡΜ S3

 (ui'HO 1) 8 .-0 · ^ '(mountain' ΗΙ) 0 · 2 · 9 '(s'H £) 0S: (: Χΐ :)) N

 0 £ 3Z:,. Uio (iB3u) ¾i

(N) εε ·. Ν οζ

（'ΟΟΖ^ΗΡΜΝΙ (ω'ΗΙΙ) 8-9

('ΟΟΖ ^ ΗΡΜΝΙ

(9) εε

('ΗΠ) 8 · -8,9 ^ U iVZ- ^ (DaD) ¾HN

(5) εε

('Ηϋε8-0'8' ('Η01) 6ΖτΖ / 9' (s'H £) 9 ^ '^ ί> h DCD) HPi

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. ΓΪ 丄 / ¾ ^^ 8mine M) 096df / XDd 89 IZ69 96 OM IR (neat) cm-': 1370, 1 150

NMR (CDC1 ₃₎ S value: 2.45 (3H, s), 3.12 (3H, s), 6.5-7.8 (10H, m)

No.33 (l l)

 IR (KBr) cm-': 1370, 1 180

NMR (CDC1,) δ value: 2.52 (3H, s), 2.58 (3H, s), 3.86 (3H, s), 6.8-7.8 (7H, m)

No.33 (12)

 IR (KBr) cm ': 1515, 1345

NMR (CDC1 ₃₎ δ value: 2.54 (3H, s), 3.47 (3H, s), 5.26 (2H, s), 7.2-8.2 (7H, m)

No.33 (13)

IR (KBr) cm ': 1710, 1520, 1350

NMR (CDC1 _? ) Value: 1 J-2.6 (8H, m), 2.53 (3H, s), 4.2-4.7 (lH, m), 4.7-5.4 (lH.m), 7.0-

8.3 (12H, m)

 No.33 (14)

 IR (KBr) cm ': 1510, 1345

NMR (CDC1 ₃₎ δ value: 2.54 (3H, s), 6.65 (2H, s), 6.9-7.5 (7H, m), 7.9-8.6 (4H.m)

Example 34

Under a nitrogen atmosphere, 1-bromo-1- (2,4-difluorophenoxy) -5-nitrobenzene 0.18 g, 4-aminosulfonylphenyltributyltin 0.22 g and tetrakis (triphenylphosphine) ) Add palladium (0) O.Olg to 4 ml of xylene and heat to reflux for 4 hours. After filtering off the insoluble matter, the solvent is distilled off under reduced pressure. The residue obtained is purified by column chromatography [eluent; hexane: ethyl acetate = 2: 1] and recrystallized from a mixed solvent of ethyl acetate-isopropyl ether to give colorless crystalline 4,1-aminosulfonyl- 2- (2,4-difluorophenoxy) -1-5-2-tro 1,1, -biphenyl 0.] 4 g is obtained.

IR (KBr) cm ': 3350, 3260. 1315, 1 165

 NMR (CDC1,) δ value: 4.98 (2H, bs), 6.6-7.6 (4H, m), 7.6-8.4 (6H, m)

Example 35

The compounds in Table 9 are obtained in the same manner as in Example 34. Table 9

Lonely example No. R ¹ n R ³ R ⁴ R ²

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(l) S £ 'ON 6tO0 / 96dT / X3d ΙΖ69Σ / 96 ΟΛ1 No.35 (10)

IR (neat) cm ¹ : 3265, 1720, 1505. 1 165

NMR (CDCI _? ) Δ value: 1.27 (3H, = 7.5Hz), 1.7-2.9 (6H, m), 4.13 (2H, qJ = 7.5Hz). 5.1 1 C2H, bs), 6.6-8.1 (10H , m)

No.35 (l l)

 IR (neat) cm-': 3380, 3255, 1700, 1 165

 NMR (CDC1,) δ value: 1.19 (3H, = 7.5Hz), 1.0-1.8 (4H, m), 4.12 (2H, q.J = 7.5Hz),

4.98 (2H, bs), 6.6-8.1 (ΙΟΗ, τη)

 No.35 (12)

IR (neat) cm ': 3350, 3265, 1720, 1340, 165

NMR (CDC1 ₃₎ δ value:... 1 18 (3H , U = 7.5Hz), 1.6-2 l (6H, m) 2.4-2.9 (2H.m).

4.10 (2H, q, J = 7.5Hz), 5.15 (2H, bs), 6.6-8.2 (10H, m)

 No.35 (13)

 IR (KBr) cm ': 3335, 3245, 1710, 1340, 1 160

NMR (CDCI,) value: 1.22 (3H, U = 7.5 Hz), 3.57 (2H, s), 4.15 (2H, q, J = 7.5 Hz), 4.60 (2H, bs), 6.6-8.2 (10H, m )

No.35 (14)

 IR (neat) cm ': 3355, 3265, 1720, 1340, 1 165

 NMR (CDCI,) δ value: 1.15 (3H, U = 7.5 Hz), 0.95-1.8 (4H, m), 4.10 (2H, q, J = 7.5 Hz), 4.95 (2H, bs), 6.7-8.2 (10H, m)

No.35 (15)

 IR (KBr) cm ': 3300, 1510, 1345, 1 165

NMR (d ₆ -DMSO + D _: 0) δ iI: 2.48 (3H, d, J = 5.5Hz), 6.9-8.4 (10H, m)

Example 36

In the same manner as in Example 7, 5-cyano-1,4-methylsulfinyl-2-phenoxy-1,1,1,1-biphenyl is obtained.

IR (KBr) cm ': 2225, 1050

NMR (d ₆ -DMSO) δ value: 2.79 (3H, s), 6.8-8.1 (12H, m)

Example 37 The compounds in Table 10 are obtained in the same manner as in Example 9.

Table 10

Example NO. R ¹ R ³ R ⁴ R ²

37 (1) CH ₃ H N0 _2- ^ OH 37 (2) CH, H N0 _2- ^ Q ^

_{37 (3) CH a H N0} 2,

37 (4) CH ₃ H N0 ₂ • ^{CH = CH} _W -J

37 (5) CH ₃ 2 H N0 ₂ O ^w

37 (6) CH, H CN,

 37 (7) CH, H CN

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() ,, IR30K) .Brcm: 329010 2- (, H 8.21-6.7- () .R IK »rs 1305c w NMR (CDC1,) 3 values: 3.14 (3H, s), 6.7-9.0 (1 lH, m)

No. 37 (22)

 IR (Br) cm ': 1515, 1350, 1300, 1 150

NMR (CDC1 ₃₎ 5 value: 3.16 (3H, s), 6.9-8.6 (13H, m)

No.37 (23)

 ΠΚΚΒΓ) οτη ': 1710, 1520, 1350, 1315, 1 150

NMR (d ₆ -DMSO) S value: 1.2-2.3 (8H, m), 3.30 (3H, s), 4.5-5.5 (2H, m), 7.4-8.2 (12H, m) No.37 (24)

 IR (KBr) cm ': 1525, 1345, 1305, 1 145

NMR (d ₆ -DMSO) 3 values: 3.29 (3H, s), 3.39 (3H, s), 5.37 (2H, s), 7.6-8.3 (7H, m)

Example 38

 2- (2,4-Difluorophenoxy) 1-4-methylsulfonyl-1,1, -biphenyl 2-ru-rubonic acid 3.20 g and a catalytic amount of N, N-dimethylformamide in 30 ml of methylene chloride Dissolve, add dropwise 0.86 ml of thionyl chloride, and heat to reflux for 1 hour. After distilling off the solvent under reduced pressure, toluene is added, and the solvent is distilled off again under reduced pressure. The obtained yellow oil is dissolved in 30 ml of methylene chloride and added to a solution of 3.32 g of diazomethane in ether under ice-cooling. After completion of the reaction, acetic acid is added, and the mixture is washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is dissolved in a mixed solvent of ethanol and tetrahydrofuran, added to a solution of 0.91 g of silver benzoate in 9.1 ml of triethylamine at room temperature, and stirred for 1 hour. The reaction mixture is added to a mixture of ice water and ethyl acetate, adjusted to pH 2.0 with 2N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue obtained is purified by column chromatography [eluent; hexane: ethyl acetate = 3:]] and recrystallized from isopropanol to give colorless crystals of 2- (4- (24-difluorophenoxy). 1) 3- (4-Methylsulfonylphenyl) phenyl) ethyl acetate].

IR (KBr) cm ': 1720, 1315, 1 150

NMR (CDC 5 values: 1.27 (3H, = 7.5Hz), 3.08 (3H, s), 3.64 (2H, s), 4.18 (2H, q, J = 7.5Hz), 6.6- 7.4 (6H, m), 7.6-8. L (4H, m)

Example 39

The following compounds were obtained in the same manner as in Example 38.

No.39 (l)

 · 2- (3- (2,4-difluorophenyl) -1- (4-methylsulfonylphenyl) phenyl) ethyl acetate

m (KBr) cm ': 1735, 1300, 1150

 NMRiCDCl,) ^ value: 1.23 (3H, tJ = 7.5Hz), 3.07 (3H, s), 3.57 (2H, s), 4.15 (2H.q.J = 7.5Hz),

6.7- 8.1 (10H, m)

No.39 (2)

 .4- (4-(2,4-difluorophenoxy) -1- (4-methylsulfonylphenyl) phenyl) ethyl butyrate

IR (neaDcm ': 1730, 1315, 1150

 NMR (CDCI,) δ value: 1.22 (3H, tJ = 7.5 Hz), 1.8-2.9 (6H, m), 3.04 (3H, s), 4.12 (2H, q, J = 7.5 Hz), 6.6-7.3 ( 6H, m), 7.5-8.2 (4H, m)

No.39 (3)

 ■ 2- (3- (4-Methylsulfonylphenyl) -1-41- (2-pyridylsulfoxy) phenyl) ethyl acetate

 IR (KBr) cm ': 1725.1300, 1155

NMR (d ₆ -DMSO) δ value: 1.21 (3H, t, J = 7.5 Hz), 3.I8 (3H, s), 3.77 (2H, s), 4.13 (2H, q, J = 7.5 Hz), 6.8-8.3 (1 lH, m)

Example 40

2- (4- (2,4-difluorophenoxy) -13- (4-methylsulfonylphenyl) phenyl) 1.80 g of ethyl acetate is dissolved in N, N-dimethylformamide and the mixture is dissolved in 0-5. Add 0.14 g of formaldehyde and 0.05 g of sodium methoxide and stir at room temperature for 1 hour. The reaction mixture is added to a mixture of water and ethyl acetate, and the organic layer is separated. The obtained organic layer is washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Purification of the resulting residue by column chromatography [eluent; toluene: ethyl acetate = 3: 1] gives a colorless solution. This gives 0.91e of 2- (4- (2,4-difluorophenoxy) -13- (4-methylsulfonylphenyl) phenyl) -13-hydroxypropionate ethyl as an oil.

NMR (CDCI ₃ ) 5 values: 1.26 (3H, U = 7.5 Hz), 3.09 (3H, s), 3.7-4.5 (5H, m), 6.6-7.4 (6H, m), 7.6-8.2 (4H, m )

Example 41

 Dissolve 0.90 g of 2- (4- (2,4-difluorophenyl) -13- (4-methylsulfonylphenyl) phenyl) -13-hydroxypropionate in methylene chloride and add 0-5 Add 0.18 ml of methanesulfonyl chloride and 0.63 ml of triethylamine with, and stir at room temperature for 30 minutes. Add the reaction mixture to a mixture of ice-water and ethyl acetate, adjust the pH to 1.0 with 2 N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether was added to the obtained residue, and the mixture was collected by filtration to give colorless crystals of 2- (4- (2,4-difluorophenoxy) -13- (4-methylsulfonylphenyl) phenyl) ethyl acrylate 0.74 g Get.

IR (Br) cm ': 1710, 1300, 1150

 NMR (CDC1,) <? Value: 1.33 (3H, t, J = 7.5 Hz), 3.08 (3H, s), 4.30 (2H, q, J = 7.5 Hz), 5.93 (lH.s), 6.38 (lH .s), 6.6-8.2 (10H, m)

Example 42

Dissolve 0.50 g of trimethylsulfonium iodide in 3 ml of dimethylsulfoxide, add 0.25 g of potassium tert-butoxide, and stir at room temperature for 1 hour. Next, 0.86 g of 2- (4- (2,4-difluorophenyl) -13- (4-methylsulfonylphenyl) phenyl) acrylate dissolved in 5 ml of dimethyl sulfoxide was added, and the mixture was added for 2 hours. Stir. The reaction mixture is added to a mixture of ice water and ethyl acetate, adjusted to pHl.O with 2N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography [eluent; hexane: ethyl acetate = 50: 1] to obtain colorless crystals of 1- (4- (2,4-difluorophenoxy)). — (4-methylsulfonylphenyl) phenyl) cyclopronocarbene Obtain 57 g of ethyl ester.

IR (KBr) cnT ': 1710, 1310, 1 145

NMR (CDC1 ₃₎ S value:. 1.0-1.4 (5H, m) , 1.4-1.8 (2H, m), 3.08 (3H, s) 4. 13 (2H, qJ = 7.5Hz), 6.6-7.5 (6H , m), 7.6-8.2 (4H, m)

Example 43

 2- (4- (2,4-Dimalolophenoxy) -3- (4-methylsulfonylphenyl) phenyl) ethyl acetate l.OOg and 1,7-dibutene mobutane 0.27 ml Ν, Ν-dimethyl Dissolve in 10 ml of formamide, add 0.09 g of sodium hydride under ice-cooling, and stir at room temperature for 1 hour. Add 0.09 g of sodium hydride again under ice cooling, and stir at room temperature for 1 hour. The reaction mixture is added to a mixture of ice water and ethyl acetate, adjusted to pH 1.0 with 2N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; toluene: ethyl acetate = 9: 1] to obtain colorless crystals of 1- (4-1 (2,4-difluorophenoxy) -1- (4 —0.54 g of methylsulfonylphenyl) phenyl) cyclopentanecarboxylate is obtained.

 IR (KBr) cm ': 1720. 1315, 1 155

 NMR (CDCU) δ value: 1.18 (3H.t, J = 7.5Hz), 1.5-2.9 (8H, m), 3.09 (3H, s) .4.12 (2H, q, J = 7.5Hz), 6.6 -7.5 (6H.m), 7.6-8.2 (4H, m)

Example 44

In the same manner as in Example 43, ethyl (4- (2,4-difluorophenoxy) -13- (4-methylsulfonylphenyl) phenyl) cyclohexylcarboxylate is obtained.

 IR (Br) cm ': 1720,1315 J 155

NMR (d ₆ -DMSO) 5 values: 1.14 (3H, t, J = 7.5 Hz), 0.9-2.2 (8H, m), 2.2-2.7 (2H, m), 3.26 (3H, s), 4.10 (2H, q, J = 7.5Hz), 6.7-7.6 (6H, m), 7.7-8.2 (4H, m)

Example 45

2-((4- (2,4-difluorophenyl))-3- (4-methylsulfonylphenyl) phenyl) Ethyl acetate 2.902 is dissolved in 15 ml of ethanol, and 1N sodium hydroxide is added. Add 15 ml of thorium aqueous solution and heat to reflux for 1 hour. The reaction mixture is added to a mixture of ice water and ethyl acetate, adjusted to pHl.O with 2N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is recrystallized from ethanol to give 1.60 g of colorless crystals of 2- (4-1 (2,4-difluorophenoxy) -13- (4-methylsulfonylphenyl) phenyl) acetic acid.

IR (KBr) cm ': 1705, 1310, 1145

NMR (d ₆ -DMSO + D ₂₀ ) δ value: 3.26 (3H, s), 3.68 (2H, s), 6.6-7.6 (6H, m), 7.6-8.3 (4H, m) Example 46

In the same manner as in Example 45, the compounds in Table 11 are obtained.

Table 11

Example No. R ¹ n R ³ R ⁴ R ²

 46 (4) 2 H-(CH ^ COOH

46 (5) 2 H -CH (CH ₂ OH) COOH

 -o¾

 ^ COOH

 46 (6) 2 H

46 (14) 2 H -OCH ₂ COOH

 -0¾ F

46 (15) CKJ 2 H -0 (CH2) * COONa

46 (16) CKJ 2 H N0 2 -CH = CH-COOH

46 (18) 2 H -CHbCOOH

 J IN

 46 (23) NH2 2 -ChtCOOH H

^ COOH

 46 (24) 2 H

-0¾ F

46 (26) 2H- (CH ^ COOH) The physical properties of the compounds in Table 11 are shown below.

46 (1)

 IR (KBr) cm ': 1710, 1300, 1150

_{NMR (CDC1, + D 2 0} ) 5 value:. 2.6-3.2 (4H, m) , 3.09 (3H.s), 6.7-7.4 (6H, m), 7.6-8 l (4H, m) 46 (2 )

 IR (KBr) cm ': 1700, 1315.1150

NMR (d ₆ -DMSO) S value: 1.7-2.9 (6H, m), 3.28 (3H, s), 6.7-8.3 (10H, m), 12.12 (lH, bs) 46 (3)

IR (KBr) cnT ': 1685, 1310, 1150 _{NMR (CDC1, + D 2 0} ) value: 3.09 (3H, s), 5.98 (1 H, d, J = 15Hz), 6.6-8.2 (13H.m)

46 (4)

m (KBr) cm ': 1725, 1150, 1295

 NMRiCDCl ^ + D ^ O) 5 values: 1.5-2.0 (4H, m), 2.2-2.8 (4H, m), 3.08 (3H, s), 6.6-7.3 (6H.m), 7.6-8.l ( 4H, m)

46 (5)

 IR (KBr) cm ': 3445, 1735, 1300, 1150

NMR (CDC1, + D ₂ 0) δ value: 3.09 (3H, s), 3.7-4.4 (3H, m), 6.6-7.5 (6H, m), 7.6-8.2 (4H, m) 46 (6)

IR (KBr) cm ': 1715, 1305, 1150

 NMRi ^ -DMSOaO) value: 3.23 (3H, s), 6.08 (lH, s), 6.32 (lH, s), 6.7-7.7 (6H.m), 7.7-

8.2 (4H, m)

 46 (7)

 IR (KBr) cm ': 1685, 1315, 1155

_{NMR (CDC1, + D 2 0} ) S Value: 1. l-1.5 (2H, m), 1.5-1.9 (2H, m), 3.08 (3H, s), 6.6-7.5 (6H, m), 7.6- 8.2 (4H, m)

46 (8)

 IR (KBr) cm ': 1735, 1685, 1310, 1150

 NMR (CDCI,) S value: 3.10 (3H, s), 6.6-7.4 (5H, m) .7.6-8.5 (5H, m)

46 (9)

 IR (Br) cm ': 3450, 1720, 1300, 1150

NMR (d ₆ -DMSO + D ₂₀ ) (Direct H: 3.26 (3H, s), 5.10 (lH, s), 6.7-8.2 (10H, m)

46 (10)

 IR (KBr) cm ': 1730, 1315, 1155

NMR (d ₆ -DMSO + D ₂₀ ) S value: 3.23 (3H, s), 6.08 (1 H, d, J = 48 Hz), 6.7-8.3 (10H, m)

46 (11)

 IR (KBr) cm ': 3450, 1315, 1150

 NMR (d-TFA) S value: 3.30 (3H, s), 5.57 (1 H, s), 6.7-8.3 (10H, m)

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66tO0 / 96df / IOd 98 IZ69Z96 OM NMR (d ₆ -DMSOD, 0) δ value: 1.4-2.8 (8H, m), 6.7-8.2 (1 OH.m)

46 (22)

 IR (KBr) cm ': 3330.3210, 1720, 1320, 1160

NMR (d ₆ -DMSO + D, 0) 5 values: 3.58 (2H, s), 6.7-8. L (lOH.m)

46 (23)

 IRCKB cm '^ SSS, 1685, 1330, 1165

NMR (d ₆ -DMSO + D ₂₀ ) 5-value: 1.0-1.6 (4H, m), 6.7-7.9 (10H, m)

46 (24)

 IR (KBr) cm ': 3365, 3265, 1715, 1335, 1160

NMR (d ₆ -DMSO) S value: 2.3-2.9 (4H, m), 6.6-8.1 (10H, m)

46 (25)

 IR (KBr) cm ': 3360.3280,】 735, 1165

NMR (d ₆ -DMSOD ₃₀ ) 5 values: 1.6-2.9 (6H, m), 6.7-8.2 (10H, m)

Example 47

3- (4- (2.4-difluorophenoxy) -1- (4-methylsulfonylphenyl) phenyl) 0.75 g of ethyl acrylate and 5%> palladium-carbon 0.25 g are converted to N, N-dimethylformamide 7.5 Stir at room temperature, under normal pressure, and in a hydrogen stream for 30 minutes. After filtering off the insoluble matter, ethyl acetate is added to the filtrate, washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether was added to the obtained residue, and the mixture was collected by filtration to give colorless crystals of 3- (4- (2,4-difluorophenyl) -13- (4-methylsulfonylphenyl) phenyl) propion 0.56 g of acid ethyl is obtained.

IR (KBr) cm ': 1720.1315, 1150

NMR (CDC1 _? ) S ii: 1.23 (3H, tJ = 7.5 Hz) 2.4-3.1 (4H, m). , m), 7.6-8. l (4H, m)

Example 48

2- (2,4-difluorophenoxy) -1-5-formyl-4'-methylthio-1,1'-biphenyl l.OOg and ((1,3-dioxolan-1-yl) methyl) triphenylphosphonyl Add 1.57 g of mubromide to 10 ml of methylene chloride, and add potassium under ice-cooling. Add 0.41 g of tert-butoxide. After stirring at the same temperature for 2 hours, further stir at room temperature for 2 hours. Add the reaction mixture to a mixture of ice-water and black-mouthed form, adjust the pH to 5.0 with〗 N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. 10 ml of 6 N hydrochloric acid and 10 ml of 1,4-dioxane are added to the obtained residue, and the mixture is stirred at room temperature for 24 hours. Add the reaction mixture to a mixture of ice water and ethyl acetate, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 4: 1] to obtain a colorless oily 2- (2,4-difluorophenoxy) -1-5- (2 —Formylethenyl) 0.90 g of 1,4′-methylthio-1,1,1-biphenyl.

IR (neat) cm ': 1670

 NMR (CDC1,) S value: 2.53 (3H, s), 6.4-7.8 (12H.m), 9.75 (1H, d, J = 8.0Hz)

Example 49

0.10 g of 60% sodium hydride is added to 5 ml of tetrahydrofuran solution containing 0.51 ml of ethyl phosphonoacetate under ice-cooling. Subsequently, 5 ml of a tetrahydrofuran solution of 0.90 g of 2- (2,4-difluorophenoxy) -15- (2-formylethenyl) -14'-methylthio-11,1-biphenyl is added dropwise, and the mixture is stirred at room temperature for 1 hour. Add the reaction mixture to a mixture of ice water and ethyl acetate, adjust the pH to 1.0 with 2 N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether was added to the obtained residue, and the residue was collected by filtration to give colorless crystals of 5- (4- (2,4-difluorophenoxy) -13- (4-methylthiophenenyl) -1,2-pentaethylate. 0.52 g is obtained.

IR (KBr) cm ': 1710, 1625

NMR (d ₆ -DMSO) δ value: 1.25 (3H, t, J = 7.5 Hz), 2.50 (3H, s), 4.18 (2H, q, J = 7.5 Hz), 6.10 (lH, d, J = 15 Hz) ), 6.7-7.8 (13H, m)

Example 50

In the same manner as in Example 47, 5— (4— (2,4-difluorophenoxy) 1-3— (4 -Methylsulfonylphenyl) phenyl) Ethyl valerate is obtained.

 NMR (CDC1,) values: 1.24 (3H, U = 7.5 Hz), 1.5-1.9 (4H, m), 2.2-2.9 (4H, m) .3.07 (3H, s) .4.14 (2H, q, J = 7.5Hz), 6.6-7.4 (6H.m), 7.6-8.2 (4H, m)

Example 51

Under a nitrogen atmosphere, dissolved methylsulfonylmethyl acid Jechiru 0.65g in Te Torahi mud furan 10 ml, cooled to -78, while stirring force ^f et dropwise hexane solution (1.68 N) 1.68 ml to the π- butyllithium Then, stir at the same temperature for 1 hour. To the reaction mixture, 10 ml of a tetrahydrofuran solution containing 2-(2,4-difluorophenoxy) -15-formyl-14-methylthio-1,1,1-biphenyl l.OOg was added dropwise, and the mixture was stirred at the same temperature for 1 hour and at room temperature. Stir for 1 hour. The reaction mixture is added to a mixture of ice water and ethyl acetate, adjusted to pHl.O with 2N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography [eluent; hexane: ethyl acetate = 3: 1] to give a colorless oil, 2- (2,4-difluorophenoxy) -5- ( 1.30 g of 1,4-methylthio-1,4'-biphenyl is obtained.

IR (KBr) cm ': 1295, 1125

 NMRfCDCI,) value: 2.51 (3H, s), 3.01 (3H, s), 6.6-7.8 (12H, m)

Example 52

In the same manner as in Example 47, 4′-methylsulfonyl-5- (2-methylsulfonylethyl) -12- (2,4-difluorophenoxy) -11,1′-biphenyl is obtained.

IR (KBr) cm ': 1305, 1150

 NMRiCDCl,) δ value: 2.89 (3H, s), 3.07 (3H, s), 2.8-3.4 (4H, m), 6.6-7.4 (6H.m) .7.6-8.2 (4H, m)

Example 53

5-Acetyl-2- (2,4-difluorophenoxy) -1-methylsulfonyl-1,1,1-biphenyl 1.35 g, trimethylsulfonium iodide 1.03 g, dimethylsulfoxide 7 ml and tetrahydrofuran Add 7 ml of the mixture under ice-cooling to potassium tert-butyl. After adding 0.57 g of toxide and stirring for 2 hours, the mixture is further stirred at room temperature for 2 hours. Add the reaction mixture to a mixture of ice water and ethyl acetate, adjust the pH to 5.0 with 2N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. After dissolving the obtained residue in 10 ml of toluene, 0.50 g of aluminum silicate is added and heated under reflux for 1 hour. After filtering off the insoluble matter and distilling off the solvent under reduced pressure, a colorless oily substance, 2- (2,4-difluorophenoxy) -15- (1-formylethyl) -14'-methylsulfonyl-1,1,1 0.80 g of -biphenyl is obtained.

 NMR (CDC1 S value: 1.50 (3H, d, J = 7.5 Hz), 3.09 (3H, s), 3.75 (lH, q, J = 7.5 Hz), 6.6-7.6 (6H, m), 7.0-8.2 ( 4H, m), 9.75 (1 H, s)

Example 54

 2- (2,4-difluorophenoxy) -1-5- (1-formylethyl) -14'-methylsulfonyl-1,1'-biphenyl 0.80 g and silver nitrate 0.98 g were added to a mixture of 80 ml of ethanol and 24 ml of water, and the mixture was added at room temperature. 9.6 ml of 1 N aqueous sodium hydroxide solution is added dropwise. After stirring at the same temperature for 30 minutes, the insoluble matter is filtered off, the filtrate is added to a mixture of ice water and ethyl acetate, the pH is adjusted to pH10 with 6N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent: ethyl acetate] to give colorless crystals 2- (4- (2,4-difluorophenoxy) -3- (4-methylsulfonylphenyl) phenyl ) 0.02 g of propionic acid is obtained.

IR (KBr) cm ': 1700, 1315, 1 155

_{NMR (CDC1, + D 2 0} ) 5 value: 1.55 (3H, d, J = 7.5Hz), 3.08 (3H, s), 3.80 (1 H, q, J = 7.5Hz), 6.5-

8.2 (10H, m)

Example 55

Under a nitrogen atmosphere, 0.31 ml of diisopropylamine is added to 5 ml of tetrahydrofuran, 1.33 ml of a hexane solution of n-butyllithium (1.68 N) is added dropwise at -78, and the mixture is stirred at the same temperature for 1 hour. Then, 5 ml of a solution of 2- (4- (2,4-difluorophenoxy) -3- (4-methylsulfonylphenyl) phenyl) ethyl acetate l.OOg in tetrahydrofuran was added dropwise and stirred for 1 hour. I do. Add 0.74 g of carbon tetrabromide to the reaction mixture. 5 ml of a trahydrofuran solution is added dropwise, and the mixture is stirred at the same temperature for 1 hour and then at room temperature for 1 hour. The reaction mixture is added to a mixture of ice water and ethyl acetate, adjusted to pHl.O with 2N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography [eluent; hexane: ethyl acetate = 3: 1] to give a colorless; The obtained oil is added to 20 ml of 50% acetone water, 0.42 g of silver nitrate is added at room temperature, and the mixture is stirred for 4 hours. After filtering off the insoluble matter, the filtrate is added to a mixture of water and ethyl acetate, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography [eluent; toluene: ethyl acetate =

20: 1] to give 9 g of ethyl 2- (4- (2,4-difluorophenoxy) -13- (4-methylsulfonylphenyl) phenyl) ethyl gulyoxylate as a colorless oil.

 IR (nea cm ': 1735, 1685, 1320, 1150

NMRiCDCl ^) δ value: 1.42, (3H, U = 6.5 Hz), 3.10 (3H, s), 4.45 (2H, qJ = 6.5 Hz), 6.7-7.5 (4H, m), 7.7-8.3 (6H.m )

Example 56

 2- (4- (2.4-difluorophenoxy) -1- (4-methylsulfonylphenyl) phenyl) ethyl acetate 0.20 g, N-bromosuccinic acid 0.08 g, 2.2-azobis (isobutyronitrile) O.Olg Was added to 4 ml of carbon tetrachloride, and the mixture was refluxed for one hour. The reaction mixture is added to a mixture of water and black form, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography [eluent; hexane: ethyl acetate = 3: 1] to give 2-bromo-2- (4- (2,4-difluorophenoxy) as a colorless oil. 1) 3- (4-Methylsulfonylphenyl) phenyl) Ethyl acetate 0.22 g is obtained.

IR (nea cm ": 1740.1315.1155

NMR (CDC1 value: 1.30 (3H, U = 7.5 Hz), 3.08 (3H, s), 4.26 (2H, q, J = 7.5 Hz), 5.35 (lH, s), 6.6-8.2 (10 H, m) Example 57

 2-bromo-2- (4- (2,4-difluorophenoxy) -13- (4-methylsulfonylphenyl) phenyl) 0.68 g of ethyl acetate, 2 ml of acetone I and 3 ml of water, add 0.58 g of silver nitrate to the mixture at room temperature. Stir for 5 hours. After filtering off the insoluble matter, the filtrate is added to a mixture of water and ethyl acetate, and the organic layer is separated. The obtained organic layer is washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography [eluent: toluene: ethyl acetate = 2: 1] to give a colorless oil, 2- (4- (2,4-difluorophenoxy) -13- (4- 0.23 g of methylsulfonylphenyl) phenyl) 1-2-hydroxyacetate is obtained.

IR (Br) cm '': 3480, 1735, 1305, 1150

_{NMR (CDC1 + D 2 0?} ) Δ value: 1.27 (3H, t, J = 7.5Hz), 3.08 (3H, s), 4.28 (2H, qJ = 7.5Hz), 5.20 (1 H, s), 6.6 -8.2 (10H, m)

Example 58

2-Bromo-1- (4- (2,4-difluorophenoxy) -13- (4-methylsulfonylphenyl) phenyl) Dissolve 0.59 g of ethyl acetate in 5 ml of tetrahydronitrile, and add silver fluoride at room temperature. 5 ml of acetonitrile containing 0.29 g is added dropwise and stirred for 12 hours. The insoluble material is removed by filtration, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 3: 1] to give a colorless oil, 2-fluoro-1- (4- (2,4-difluorophenol). B) 0.45 g of 1-3- (4-methylsulfonylphenyl) phenyl) ethyl acetate is obtained.

 IR (nea cm ': 1755, 1315, 1150

 NMR (CDCI,) δ value: 1.28 (3H, U = 7.5 Hz), 3.09 (3H, s), 4.28 (2H, q, J = 7.5 Hz). 5.80 (lH, dJ = 48 Hz), 6.6-8.2 ( 1 OH.m)

Example 59

2-Bromo-2- (4- (2,4-difluorophenoxy) -3- (4-methylsulfonylphenyl) phenyl) Ethyl acetate (0.60 g) was dissolved in N, N-dimethylformamide (10 ml), and dissolved at room temperature. Add 0.08 g of sodium chloride and stir for 1 hour. The reaction mixture was added to a mixture of ice water and ethyl ethyl acetate, adjusted to pH l.O with 2 N hydrochloric acid, and Separate the layers. The obtained organic layer is washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent; toluene: ethyl acetate = 9: 1] to give a colorless oil, 2-azido-2- (4- (2,4-difluorophenoxy)). 3- (4-Methylsulfonylphenyl) phenyl) 0.63 g of ethyl acetate is obtained.

IR (neat) cm-': 2nO, 1735, 1315, 1150

NMR (CDC1 ₃₎ δ value: 1.42 (3Η, J = 6.5Hz ), 3.10 (3H, s), 4.44 (2H, q, J = 6.5Hz), 6.7- 7.3 (4H, m), 7.6-8.3 ( 6H, m)

Example 60

 2-Azido 2- (4- (2,4-difluorophenoxy) -13- (4-methylsulfonylphenyl) phenyl) ethyl acetate (63 g) and 5% palladium-carbon (0.20 g) were added to ethanol, The mixture is stirred for 2 hours under a hydrogen stream at normal pressure. After removing the insoluble matter, the solvent is distilled off under reduced pressure to obtain 2-amino-2- (4- (24-difluorophenoxy) -13- (4-methylsulfonylphenyl) as a yellow oil. ) Phenyl) Obtain 0.12 g of ethyl ethate.

 IRdiea cm 'SO, 1735, 1315, 1150

 NMR (CDCI,) <5 values: 1.23 (3H, t, J = 7.5 Hz), 3.08 (3H, s), 4.20 (2H, q, J = 7.5 Hz) .4.62 (lH, s), 6.7-8.2 (12H, m)

Example 61

 2- (2,4-difluorophenoxy) 1-4'-methylsulfonyl-5-methylsulfonyloxy 1,1,1-biphenyl 4.00g, 1,4-dioxane 30ml and 1N aqueous sodium hydroxide solution 30ml The mixture is stirred at 50 for 4 hours and at 70 for 2 hours. The reaction mixture is added to a mixture of ice water and ethyl acetate, adjusted to pHl.O with 2N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is recrystallized from toluene to give 3.40 g of colorless crystals of 2- (2,4-difluorophenoxy) -15-hydroxy-4, -methylsulfonyl-1,1'-biphenyl.

IR (Br) cm ': 3460, 1300, 1150

NMR (CDC1, + D, 0) value: 3.08 (3H, s), 6.5-8.2 (1ΟΗ, τη) Example 62

 2- (2,4-difluorophenoxy) -1-hydroxy-4-methylsulfonyl-1,1,1-biphenyl l.OOg and g, Ν-dimethylformamide in a mixture of 10 ml of potassium under ice-cooling 0.33 g of tert-butoxide is added in portions. To the reaction mixture is added 0.49 g of ethyl methacrylate, and the mixture is stirred at room temperature for 6 hours. Add the reaction mixture to a mixture of ice water and ethyl acetate, adjust to pHI.O with 2N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography [eluent: toluene: ethyl acetate = io: 1] to give colorless crystals of 2- (4- (24-difluorophenoxy) -3- (4 -Methylsulfonylphenyl) phenoxy) ethyl acetate.

IR (KBr) cm ': 1745, 1315, 1150

NMR (d ₆ -DMSO) δ value: 1.22 (3H, U = 7.5 Hz), 3.25 (3H, s), 4.20 (2H, q, J = 7.5 Hz), 4.85 (2H, s), 6.7-7.5 ( 6H, m), 7.7-8.2 (4H, m)

Example 63

The following compounds were obtained in the same manner as in Example 62.

No.63 (l)

 • 5-(4- (2,4-difluorophenoxy)-(3-methylsulfonylphenyl) phenoxy) ethyl valerate

IR (neat) cm ': 1730, 1315, 1155

 NMRiCDCl,) value: 1.25 (3H, t, J = 7.5 Hz), 1.6-2.2 (4H, m), 2.2-2.6 (2H, m), 3.06 (3H, s),

3.9-4.2 (2H, m), 4.13 (2H, q.J = 7.5Hz), 6.6-7.2 (6H, m), 7.6-8.2 (4H, m)

 No.63 (2)

 • 5- (6-cyano 6-methylheptyloxy) -1-2- (2,4-difluorophenoxy) -14-methylsulfonyl-1,1, biphenyl

 IR (neat) cm ': 2235, 1315, 1150

NMR (CDC1 _? ) 5 values: ll-2.1 (14H, m), 3.06 (3H, s), 3.8-4.2 (2H, m), 6.6-7.l (6H, m), 7.6-

8.2 (4H, m)

Example 64 5- (6-cyano 6-methylheptyloxy) 1-2- (2,4-difluorophenoxy) -14-methylsulfonyl-1,1,1-biphenyl 0.40 g of concentrated sulfuric acid 2 ml, acetic acid Dissolve in a mixture of 4 mJ and 4 ml of water and ripen at reflux for 3 days. The reaction mixture is added to a mixture of ice water and * ethyl acetate, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent: toluene: ethyl acetate = 5: 1] to obtain 0.39 g of a colorless oil. The obtained oil is dissolved in 0.66 ml of 1 N aqueous sodium hydroxide solution, washed with ethyl ether, and the solvent is distilled off under reduced pressure. Ethyl ether was added to the obtained residue, and the residue was collected by filtration to give colorless crystals of 7- (3- (2,4-difluorophenoxy) -14- (4-methylsulfonylphenyl) phenoxy) -1,2,2-dimethylheptane 0.30 g of the acid is obtained as the sodium salt.

^{IR (KBr) cnT,: 3420} , 1300, 1 150

NMR (d ₆ -DMSO) value: 0.98 (6H, s), 1.2-1.9 (8H, m), 3.22 (3H, s), 3.8-4.2 (2H.m), 6.7-8.1 (10H, m)

Example 65

 2-Hydroxy-4—Methoxy-4-methylsulfonyl-1,1'-biphenyl 1.50 g, 1N aqueous sodium hydroxide solution 6.5 ml, water 8.5 ml and diphenylethanol chloride 1.71 g are heated and refluxed for 2 hours. Let it. Add the reaction mixture to a mixture of ice water and ethyl acetate, adjust the pH to 1.0 with 2 N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether is added to the obtained residue, and the residue is collected by filtration to obtain 1.75 g of colorless crystals of 4-methoxy-4,1-methylsulfonyl-2-phenoxy-11,1, -biphenyl.

IR (KBr) cm ': 1300. 1 145

NMR (d ₆ -DMSO) value: 3.23 (3H, s), 3.76 (3H, s), 6.54 (1 Hd, J = 2.0 Hz), 6.8-8.1 (1 lH, m) Example 66

1.50 g of 4-methoxy-1-methylsulfonyl-2-phenoxy-1,1'-biphenyl is dissolved in 15 ml of methylene chloride, and 0.44 ml of boron tribromide is added dropwise under ice cooling. After stirring at the same temperature for 30 minutes, leave at room temperature overnight. The reaction mixture is added to ice water, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. To the obtained residue is added isopropyl ether, and the mixture is filtered to give 1.34 g of colorless crystals of 4-hydroxy-14'-methylsulfonyl-2-phenoxy-11,1,1-biphenyl.

IR (KBr) cm ': 3425, 1300, 1 145

NMR (CDC1 ₃₎ values:. 3.05 (3H's), 5.20 (lH, bs), 6.4-8 l (12H, m)

Example 67

 4-Hydroxy-4, -methylsulfonyl-2-phenyl-1,1, -biphenyl 1.30 g, potassium iodide 0.70 g, 6-chloro-1,1,1-dimethylenanthonitrile 0.73 g and carbon dioxide lime 0.58 g Stir at 80 for 6 hours. Anti) ΐ. Add the mixture to a mixture of ice water and ethyl acetate, adjust the pH to 1.0 with 2Ν hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent: toluene: ethyl acetate = 9: 1] to obtain colorless crystals of 4- (6-cyano 6-methylheptyloxy) -14, -methylsulfonyl. 2-phenoxy-1,1,1-biphenyl l.36 g are obtained.

IR (KBr) cm ': 2230, 1310, 1 150

NMR (d ₆ -DMSO) value: 1.0-2.2 (14H, m), 3.27 (3H, s), 3.7-4.2 (2H, m), 6.48 (1 H, dJ = 2.0Hz) 6.7-8.1 (1 lH , m)

Example 68

4- (6-cyano 6-methylheptyloxy) 1-4'-methylsulfonyl-2-phenoxy 1,1,1-biphenyl 0.50 g, dimethyl sulfoxide 5 ml, potassium carbonate 0.02 g and 30% hydrogen peroxide 0 Stir 15 ml of the mixture at 80 for 12 hours. Add the reaction mixture to a mixture of ice water and ethyl acetate and separate the organic layer. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from isopropyl alcohol to give colorless crystals of 4- (6-carbamyl-6-methylheptyloxy) -14'-methylsulfonyl-2-phenoxy-1-1,1, -biphenyl 0.47 g Get. m (KBr) cm ': 3455, 1655, 1300, 1 150

_{NMR (CDC1, + D 2 0} ) value:..] 0-2 l (8H, m), 1. 18 (6H, s), 3.04 (3H, s), 3.90 (2H.U = 7.5Hz), 6.4-8. L (12H, m)

Example 69

 4- (6-cyano-6-methylheptyloxy) -1,4-methylsulfonyl-2-phenoxy-1; 1,1,1-biphenyl 0.75 g, concentrated sulfuric acid 4 ml, acetic acid 8 ml and water 8 ml Reflux for 2 days. The reaction mixture is added to a mixture of ice water and ethyl acetate, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is recrystallized from isopropyl ether to give 0.56 g of 7- (4- (4-methylsulfonylphenyl) -13- (phenoxy) phenoxy) -12,2-dimethylheptanoic acid as colorless crystals.

IR (KBr) cm ': 1685, 1310. 1 150

_{NMR (CDC1 3 + D 2 0} ) 5 value:. 1.0-2.0 (8H, m) , 1. 19 (6H, s), 3.03 (3H, s), 3.7-4 l (2H, m), 6.4- 8.1 (12H, m)

Example 70

 4- (6-cyano 6-methylheptyloxy) 1-4'-methylsulfonyl-2-phenoxy-1,1,1-biphenyl 0.50 g, tributyltin azide 1.04 g and xylene 5 ml Heat to reflux for hours. The reaction mixture is added to a mixture of ice water and toluene, adjusted to pH 10 with 2 N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent; hexane: ethyl acetate = 1: 1] to give 0.60 g of a colorless oil. The obtained product is dissolved in 1.04 ml of 1% aqueous sodium hydroxide solution, washed with ethyl ether, and the solvent is distilled off under reduced pressure. Ethyl ether was added to the obtained residue, and the residue was collected by filtration to give colorless crystals of 4-methylsulfonyl-1- (6-methyl-6- (tetrazol-5-yl) heptyloxy) 1-2-phenoxy-1 1,1 '-Obtain 0.42 g of biphenyl as sodium salt.

IRfKBr) cm-': 1305, 1 150 NMR (d ₆ -DMSO) δ value: 0.9-1.9 (14H, m), 3.20 (3H, s). 3.90 (2H, t, J = 7.5Hz), 6.45 (1H, d, J = 2.0Hz) , 6.7-8.1 (1 lH, m)

Example 71

In the same manner as in Example 69, 2- (2,4-difluorophenoxy) -14'-methylthio-1,1, -1-biphenyl-5-carboxylic acid is obtained.

IR (KBr) cm ': 1685

NMR (d ₆ -DMSO) 3 values: 2.53 (3H, s), 6.8-8.l (10H, m), 12.82 (lH, bs)

Example 72

The following compounds were obtained in the same manner as in Example 23.

No.72 (l)

 '5-(N-butylcarbamoyl) 1 2-(2,4-difluorophenoxy) 1 4' -methylthio 1, 1, 1 -biphenyl

IR (neat) cm-': 3315, 1685

 NMRiCI ^ + D ^) (5 values: 0.7-2.0 (9H, m), 2.52 (3H, s), 6.6-8.0 (10H, m)

No.72 (2)

 • 1— (4- (2,4-difluorophenoxy) -1-3- (4-methylthiophenyl) benzoyl) pyrrolidine-1—2-carboxylic acid

IR (KBr) cm ': 1735

 NMR (CDCI,) S value: 1.6-2.7 (4H, m), 2.50 (3H, s), 3.4-4.0 (2H, m), 4.5-5.0 (lH.m), 8.81 (lH, bs), 6.6 -8.2 (10H, m)

No.72 (3)

 • (4- (2,4-difluorophenoxy) -13- (4-methylsulfonylphenyl) phenyl) methyl carbonylaminoacetate

 IR (KBr) cm-': 3410, 1740, 1655. 1300, 1150

NMR (d ₆ -DMSO) 5 values: 3.28 (3H, s), 3.70 (3H, s), 3.9-4.4 (2H, m), 6.8-8.4 (10H, m), 8.9-9.3 (lH, m)

No.72 (4)

• 2— (2,4-difluorophenoxy) 1-4-methylsulfonyl-5-piveridinocarbo! ,], One bifurn IR (KBr) cm-': 1630, 1315, 1150

NMR (d ₆ -DMS 0) S value: 1.4-】. 9 (6H, m), 3.26 (3H, s), 3.0-3.7 (4H, m), 6.7-8.3 (10H, m) Example 73

In the same manner as in Example 15, 5-amino-1- (2,4-difluorophenoxy) -14'-methylthio-11,1, -biphenyl is obtained.

IR (neat) cm ' ¹ : 3455, 3370

NMR (CDC1 ₃₎ value: 2.48 (3H, s), 3.60 (2H, bs), 6.4-7.8 (10H, m)

Example 74

 5-Amino-2- (2,4-difluorophenoxy) 1-4-methylthio! ,;! Dissolve 1-biphenyl l.OOg in 10 ml of methylene chloride, add 0.49 ml of triethylamine and 0.42 ml of cyclopentanecarbonyl chloride sequentially under ice cooling, and stir at the same temperature for 2 hours. The reaction mixture is added to ice water, adjusted to pH 1 with 2 N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to give a colorless oily 5-cyclopentylcarbonylamino 2 — (2,4 —Difluorophenoxy) 1-4, -methylthio-11, u-biphenyl 1.20 g are obtained.

IR (KBr) cm ': 3290.1655

NMR (CDC1 _? + D0) 5 values: 1.5-2.3 (8H, m), 2.3-3.0 (1 Hm) 2.47 (3H, s), 6.6-7.8 (1 OH.m) Example 75

The following compounds were obtained in the same manner as in Example 74.

No.75 (l)

 • 2- (2,4-difluorophenoxy) -14-methylthio-5-propionylamino 1,1,1-biphenyl

 1 31 ': 3300.1665

NMRiCDCl,) 0 value: 1.01 (3H, U = 7.5 Hz), 1.5-2.l (2H, m), 2.35 (2H, t, J = 7.5 Hz), 2.50 (3H, s), 6.7-7.8 ( (10H, m)

No.75 (2)

• 5—Trifluoroacetylamino—2— (2,4-difluorophenoxy) -1,4′-methylsulfonyl-1,1,1-biphenyl. IR (KBr) cm ': 3335, 1735, 1295.1150

NMR (CDC1,) S value: 3.10 (3H, s), 6.6-8.6 (1 lH, m)

Example 76

 0.92 g of 5-amino-2- (2,4-difluorophenoxy) -1,4-methylthio-1,1'-biphenyl is dissolved in 10 ml of methylene chloride, and while cooling with ice, 0.45 ml of triethylamine and n-butylsulfonyl chloride are dissolved. Add 0.38 ml of the solution in succession and stir at the same temperature for 2 hours. Add the reaction mixture to ice water, adjust the pH to 1.0 with 2N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 5: 1] to give a colorless oil, 5-butylsulfonylamino_2- (2,4-difluorophenol). B) 0.64 g of 1,4-methylthio-1,1-biphenyl is obtained.

IR (neat) cm ': 3255, 1375, 1150

 NMR (CDC1,) δ value: 0.7-2.3 (7H, m), 2.52 (3H, s), 2.7-3.6 (2H, m), 6.4 (IH, bs), 6.6-7.7 (10H, m)

Example 77

In the same manner as in Example 76, 2- (2,4-difluorophenoxy) -1,4′-methylsulfonyl-1,5-methylsulfonylamino-1,1,1′-biphenyl is obtained.

IR (KBr) cm ': 3265, 1325, 1295, 1150

NMR (d ₆ -DMSO) S value: 3.04 (3H, s), 3.25 (3H, s), 6.8-8.2 (10H, m), 9.90 (1 H, s)

Example 78

 Dissolve 5-cyano-1- (2,4-difluorophenoxy) -1,4-methylsulfonyl-1,1biphenyl l.OOg in 10 ml of xylene, add 2.26 g of tributyltin azide, and heat to reflux for 5 hours. After that, the solvent is distilled off under reduced pressure. 28 ml of methanol and 20 ml of 1N hydrochloric acid are added to the obtained residue, and the mixture is stirred at room temperature for 1 hour, and the precipitated crystals are collected by filtration. The obtained crystals are washed with getyl ether and recrystallized with ethanol to give colorless crystals of 2- (2,4-difluorophenoxy) -1,4'-methylsulfonyl-5- (tetrazol-5-yl) -1 1,1'-Bifnil 0.74g is obtained.

IRiKBDcm ': 3395, 1300, 1140 NMR (d ₆ -DMSO + D ₂₀ ) 3 values: 3.29 (3H, s), 6.9-8.3 (10H, m)

Example 79

 Dissolve 0.70 g of 2- (2,4-difluorophenoxy) -14'-methylsulfonyl-5- (tetrazol-5-yl) / 1,1,1-biphenyl in 14 ml of ether and 7 ml of ethyl acetate Then, an ether solution of 0.69 g of diazomethane is added under ice-cooling. After stirring for 1 hour at room temperature, add acetic acid. The reaction mixture is washed successively with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give colorless crystals of 2- (2,4-difluorophenoxy) -1,4-methylsulfonyl-5- (1-methyl-tetrazole-5-yl) 1-1,1 '-Obtain 0.40 g of biphenyl.

IR (KBr) cm ': 1310, 1155

 NMR (CDC1,) value: 3.09 (3H, s), 4.4 (3H, s), 6.6-8.4 (10H, m)

Example 80

 (1) Dissolve 5-cyano 2- (2,4-difluorophenoxy) -1,4-methylsulfonyl 1,1'-biphenyl l.OOg in 10 ml of ethanol, and introduce hydrogen chloride gas under ice-cooling. After stirring at room temperature for 24 hours, the solvent is distilled off under reduced pressure. Isopropyl ether was added to the obtained residue, and the mixture was collected by filtration to give colorless crystals of 5-ethoxymino 2- (2,4-difluorophenoxy) -1,4'-methylsulfonyl-1,1'-biphenyl l .Mg is obtained as the hydrochloride.

 (2) 5-ethoxyimino 2- (2,4-difluorophenoxy) 1,4-, 1-methylsulfonyl 1,1,1,1-biphenyl hydrochloride l.OOg was added to 5 ml of ethanol and 2.8 N under ice-cooling Add 8 ml of a dry ammonia-ethanol solution, heat to reflux for 24 hours, and evaporate the solvent under reduced pressure. The residue obtained is added to a mixture of water and ethyl acetate, and the organic layer is separated off. The obtained organic layer is washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is recrystallized from acetonitrile to obtain 0.30 g of colorless crystalline 5-amidino-2- (2,4-difluorophenoxy) -14,1-methylsulfonyl-1,1, -biphenyl.

IR (Br) cm ': 3395, 1300, 1145

NMR (d-DMSO) value: 3.28 (3H, s) .6.8-8.3 (10H, m), 9.1-9.7 (3H, m) Example 81

 (1) Under a nitrogen atmosphere, add 0.08 g of 60% sodium hydride to 5 ml of Ν, Ν-dimethylformamide. 10 ml of N, N-dimethylformamide in which 0.80 g of bromomethyltriphenylphosphonium bromide is dissolved is added dropwise to the obtained solution at room temperature over 10 minutes. After stirring for 1 hour, 5 ml of N, N-dimethylformamide in which 0.50 g of 2-formyl-14-methylthio-14-nitro-1,1,1-biphenyl was dissolved was applied with 15 minutes for 15 minutes. And drop it. The reaction mixture is stirred at room temperature for 1 hour and then at 50 for 1 hour, then added to a mixture of ice water and ethyl ethyl acetate, adjusted to pH 5.0 with 2N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 6: 1] to obtain 2- (2-bromoethenyl) -1,4-methylthio-14-nitro-1 as yellow crystals. , l, -biphenyl 0.10 g.

IR (KBr) cm ': 1515, 1340

NMR (CDCI ₃ ) 3 values: 2.56 (3H, s), 6.8-8.5 (9H, m)

 (2) Under a nitrogen atmosphere, 0.17 g of 4-pyridyltributyltin, 0.20 g of 2- (2-promothenyl) -1,4-methylthio-14-nitro-1,1,1'-biphenyl and tetrakis (triphenylphosphine) ) 0.33 g of palladium (0) is added to 10 ml of xylene, and the mixture is refluxed for 4 hours. After filtering off the insoluble matter, the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent; hexane: ethyl acetate = 10: 1] to give 4'-methylthio-412-tlow 2- (2- (4-pyridyl) yellow crystals. (Ethenyl) 1.1,1 · -biphenyl 0.10 g is obtained.

IR (Br) cm ': 1515, 1350

 NMR (CDC1) value: 2.57 (3H, s) .6.9-9.0 (13H, m)

Example 82

Example 81 In the same manner as in (2), 4'-methylthio-412-toro-2- (2- (thiazol-2-yl) ethenyl) -11,1-biphenyl is obtained.

 IR (KBr) cm ': 1510, 1345

NMR (CDC1,) δ value: 2.52 (3H, s) 7.2-8.8 (11H, m) Example 83

 2- (3-Benzyloxycyclohexyloxy) 1,4-methylsulfonyl-412 Trow 1,0,1-biphenyl 0.30 g in 1 N aqueous sodium hydroxide solution 3 ml, dioxane 3 ml and ethanol Add to 1 ml of the mixed solvent and heat to reflux for 40 minutes. The reaction mixture is added to a mixture of ice water and black form, and the organic layer is separated. The obtained organic layer is washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; toluene: ethyl acetate = 5: 1] to obtain 2- (3-hydroxycyclohexyloxy) -14, -methylsulfonyl-4-1 of yellow crystals. 1.10 g of 1,2-biphenyl is obtained.

 IR (KBr) cm ': 3385, 1520, 1345, 1315, 1155

NMR (d ₆ -DMSO) S value: 0.8-2.6 (8H, m), 3.30 (3H, s), 3.0-3.8 (lH, m), 4.2-4.9 (lH, m), 7.5-

8.2 (7H, m)

 Example 84

 Dissolve 1.00 g of 2-hydroxy-1,4-methylsulfonyl-412 tro 1,1,1-biphenyl, 0.50 g of 2-ethylthiopropanol and 0.90 g of triphenylphosphine in 10 ml of tetrahydrofuran. To the reaction mixture was added dropwise 0.77 g of getylazodoxyl oxylate at 15 and stirred at room temperature for 6 hours. The obtained reaction mixture is added to a mixture of ice water and ethyl acetate, and the organic layer is separated. The obtained organic layer is washed successively with water, a 1N aqueous solution of sodium hydroxide and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; toluene: ethyl acetate = 5: 1] to obtain 2- (2-ethylthiopropoxy) -14'-methylsulfonyl-14-dini of yellow crystals. 0.31 g of 1,1,1-biphenyl toro is obtained.

 IR (KBr) cm ': 1520.1345, 1310, 1150

NMR (d ₆ -DMSO) 5 values: 0.8-1.5 (6H, m), 2.2-2.8 (3H, m), 3.26 (3H, s), 4.22 (2H, d, J = 6.0Hz),

7.6-8.2 (7H, m)

 Example 85

■ (1) 2-Formyl-14-methylthio-5-nitro-1 'in the same manner as in Example 3. Get 1, -biphenyl.

IR KBrJcm 'r ^ SS, 1525, 1350

 NMR (CDC1,) 5 values: 2.57 (3H, s), 7.0-7.8 (4H, m), 8.0-8.7 (3H, m), 10.08 (lH.s)

(2) Dissolve 2.00 g of 2-formyl-1,4-methylthio-1-5-2,1,2-biphenyl in 20 ml of N, N-dimethylformamide and add 2.20 g of cyanomethylene triphenylphosphorane. After heating the reaction mixture at 110 for 4 hours, add to a mixture of ice water and acetic acid, adjust the pH to 5.0 with 1N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent; hexane: ethyl acetate = 5: 1] to give 2- (2-cyanoethenyl) -14,1-methylthio-1-5-nitro-1 as yellow crystals. , 1'-biphenyl 1.80g is obtained.

IR (KBr) cm ': 2220, 1520, 1350

 NMR (CDC1,) S value: 2.60 (3H, s), 5.5-6.2 (1H, m), 7.0-8.5 (8H, m) (E, ZMix)

 (3) Under nitrogen atmosphere, add 1.30 g of 2- (2-cyanoethenyl) -14-methylthio-15-nitro-1,1'-biphenyl and 3.00 g of tributyltinazide to 3 ml of xylene I, and heat to reflux for 6 hours Let it. 20 ml of methanol and 20 ml of IN hydrochloric acid are added to the reaction mixture, and the mixture is stirred at room temperature for 20 minutes. The mixture is added to a mixture of ice water and ethyl acetate, and the organic layer is separated. The obtained organic layer is washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; toluene: ethyl acetate = 10: 1] to obtain yellow crystals of 4, -methylthio-15-nitro-2- (2- (1H-tetrazole-5- Yl) ethenyl) 1,1,], 1-biphenyl 0.63 g is obtained.

IR (Br) cm ': 3450, 1520, 1345

NMR (d ₆ -DMSO + D _: 0) δ value: 2.54 (3H, s), 6.9-8.5 (9H, m)

Example 86

The following compounds were obtained in the same manner as in Example 69.

No.86 (1)

• 4- (2- (4-methylsulfonylphenyl) -1-4-nitrophenoxy) benzoic acid IR (KBr) cm ': 1685, 1525, 1345, 1305, 1150

NMR (d ₆ -DMSO) S value: 3.26 (3H, s), 7.1-7.4 (3H, m), 7.8-8.6 (8H, m)

 No.86 (2)

 • 4-Methylsulfonyl-2- (2-pyridyloxy) 1-1,1'-biphenyl-5-carubonic acid

 IR (Br) cm ': 1705, 1300, 1150

NMR (d ₆ -DMSO) δ value: 3.24 (3H, s), 7.0-7.5 (3H, m), 7.6-8.3 (8H, m)

Example 87

In the same manner as in Example 11, 2- (4-hydroxyphenoxy) -14-methylsulfonyl 5-nitro-1,1, -biphenyl is obtained.

IR (KBr) cm ': 3390, 1520, 1350, 1300, 1145

NMR (d ₆ -DMSO) S value: 3.30 (3H, s), 6.8-7.2 (5H, m), 7.8-8.4 (6H, m), 9.62 (1 H, s)

Example 88

In the same manner as in Example 11, 5-cyano 2- (1-methyl-12-oxopropyloxy) -14, -methylsulfonyl-1,1,1-biphenyl is obtained.

IR (KBr) cm ': 2225, 1720, 1300, 1150

 NMR (CDC) 5 values: 1.50 (3H.d.J = 6.8Hz), 2.13 (3H, s), 3.13 (3H, s), 4.87 (1H.q, J = 6.8Hz),

 6.90 (1 H, d, J = 9.0Hz), 7.4-8.3 (6H, m)

Reference example 1

 Add 12.0 g of 1-bromo-2-chloro-5-nitrobenzene, 7.30 g of 2,4-difluorophenol and 7.70 g of anhydrous carbon dioxide to 60 ml of Ν, Ν-dimethylformamide, and heat to reflux for 2 hours. Add the reaction mixture to ice water, adjust the pH to 1.0 with 2N hydrochloric acid, and extract with ethyl acetate. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 20: 1] to give colorless crystals of 1-bromo-12- (2,4-difluorophenoxy) -15- Obtain 14.3 g of Nitroven Zen.

Melting point: 103-104 [ethanol]

IR (KBr) cm ': 1510,1350, 1255 Reference example 2

 Add 27.0 g of 2- (2,4-difluorophenoxy) -14-nitroaniline to a mixed solvent of 110 ml of concentrated sulfuric acid, 66 ml of water and 110 ml of acetic acid, and add 0 to 5 * water containing 7.42 g of sodium nitrite. 66 ml solution is added dropwise. After stirring at the same temperature for 1 hour, the reaction mixture is added dropwise at 0-5 to a mixed solution of 17.9 g of copper (I) bromide, 12.8 g of sodium bromide, 110 ml of 47% hydrobromic acid and 66 ml of water. After stirring at 25 for 1 hour, extract with ethyl acetate. The obtained organic layer is washed successively with 6N hydrochloric acid, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 20: 1] to obtain a colorless crystal of 1-port (2-, 2,4-difluorophenoxy) -one. 4 21.7 g of nitrobenzene are obtained. Melting point: 103-104 [ethanol]

IR (Br) cm ': 1530,1505,1350,1250

Reference example 3

In the same manner as in Reference Example 2, the compounds in Table 5a and Table 5b are obtained.

Table 5a

Reference example No. R ² R ³ R ⁴

3 (1) -oR) N0 ₂ H

 Ml /

j

j

Table _p

Reference example No. R, R ⁴

3 (9) H COOCH3

3 (10) N0 ₂ H

3 (12) CF ₃ H

3 (13) -0¾> -FH OCH ₃

表 5 aおよび表 5 bの化合物の物性を以下に示す _c No.3(l) 3 (14) H CH ₃

The physical properties of the compounds of Table 5a and Table 5b are shown _below.c No.3 (l)

Melting point: 73—74 [ethanol]

IR (Br) cm ': 1520, 1340

No.3 (2)

Oil

 IR (neat) cm ': 1515.1340, 1275

No.3 (3)

Melting point: 119-120 [ethanol]

IR (KBr) cm ': 1520,1345

No.3 (4) Melting point: 72—73 "C [ethanol]

 IR (KBr) cm ': 1680,1505

 No.3 (5)

 Melting point: 118—119 [ethanol]

IR (Br) cm ': 2235,1505

No.3 (6)

Oil

No.3 (7)

Oil

IR (neat) cm ^l : 1725,1505

No.3 (8)

Melting point: 59-60 at [isopropyl ether]

IR (KBr) cm ': 1675, 1500

Νο.3 (9)

Melting point: 98.5—100 [Ethyl acetate-hexane mixed solvent]

IR (Br) cm ': 1710,1505

 No.3 (10)

Melting point: 132-133 [Ethanol]

IR (Br) cm ¹ : 1520, 1505, 1350

No.3 (ll)

Melting point: 63-65 [ethanol]

IR (KBr) cm ': 1700, 1505, 1255

No.3 (12)

Oil

IRineat ^ m ¹ : 1505, 1330

 No.3 (13)

Oil

DKneaDcm'ilSlOj OS No.3 (14)

Oil

 IR (neat) cni- ': 1505,1490, 1250

No.3 (15)

Melting point: 93-94 [ethanol]

IR (Br) cm- ': 2235, 1505

Reference example 4

To 50 ml of an aqueous solution in which 0.36 g of sodium hydroxide is dissolved, add 1.50 g of 2-bromo-5-methoxyphenol and 2.34 g of diphenyliodmonium chloride, and heat and reflux for 1 hour. The reaction mixture is added to a mixed solvent of water and ethyl acetate, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to give a colorless oily substance, 1-promo 4-methoxy-2-phenoxy. 2.10 g of benzene are obtained.

IR (neat) cm ': 1595,1490,1 170

Reference example 5

In the same manner as in Reference Example 4, 1-promo 4-fluoro-2-phenoxybenzene was used.

 IR (neat) cm ': 1580,1490.1210

Reference example 6

Add 4.60 g of 3,4,12-trifluoroacetophenone, 3.60 g of 2,4-difluorophenol and 3.82 g of anhydrous lithium carbonate to 46 ml of xylene, and heat to reflux for 2 hours. After filtering off the insoluble matter, the solvent is distilled off under reduced pressure. The obtained residue is recrystallized from ethanol to obtain 4.50 g of 3,1- (2,4-difluorophenoxy) -14'-nitroacetophenone as pale yellow crystals.

Melting point: 100—101 [ethanol]

Reference Example 7

The compounds in Table 6 are obtained in the same manner as in Example 6. Table 6 R ^2d R ^3d

R ^4d

^ Example No. R 2d R 3d R 4d

7 (1) H 7 (2)-o¾) ^ H

7 (3) H -C-CH ₃

II ³

O

7 (6) -0¾)-H -CHO 7 (7) -O ^ F H -COOC i 7 (8) -0¾-f H CH, The physical properties of the compounds in Table 6 are shown below.

 7 (1 melting point: 116-117 with [ethanol]

7 (2 yellow oil

7 (3 mp: 9 ⁴ one 95 [Etano Ichiru]

7 (4 Melting point: 99-1 100 [ethanol]

7 (5 yellow oil

7 (6 melting point: 93_94 [ethanol]

7 (7 Melting point: 88-89 at [ethanol]

7 (8 yellow oil Reference Example 8

 3,1 (2,4-difluorophenoxy) 1 4'- 12 troacetophenone 22.6 g, iron powder 22.6 g and ammonium chloride 2.27 g are added to a mixed solvent of ethanol 360 ml and water 180 ml, and heated for 1 hour Bring to reflux. After filtering off the insoluble matter, the solvent is distilled off under reduced pressure. The obtained residue is dissolved in ethyl acetate, washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue obtained is recrystallized from ethanol to give 18.5 g of colorless crystals of 4,1-amino-3,1- (2,4-difluorophenoxy) acetophenone.

Melting point: 1 15.5— 1 16.5 [ethanol]

Reference Example 9

The compounds shown in Table 7 are obtained in the same manner as in Reference Example 8.

Table VY R ^3d

R ^4d Reference example No.R ^2d R 3d R ^4d

9 (6) -O-^-p COOCHs H

表 7の化合物の物性を以下に示す。

The physical properties of the compounds in Table 7 are shown below.

No.9 (l) Melting point: 114_115 [Ethanol]

No.9 (2) yellow oil

Νο.9 (3) Melting point: 117- 118 [ethanol]

Νο.9 (4) Melting point: 102-103 [ethanol]

Νο.9 (5) Yellow oil

 Νο.9 (6) Melting point: 118-120 [Ethanol-hexane mixed solvent] Νο.9 (7) Melting point: 82-83 [Isopropyl ether]

Νο.9 (8) Melting point: 59-60Τ [Hexane] Reference Example 10

 3- (2,4-Difluorophenoxy) 14.12 Trobenzonitrile 8.00 g is added to a mixed solvent of concentrated sulfuric acid 56 ml, acetic acid 0 ml and water 40 ml, and the mixture is stirred at 130 for 1 hour. The reaction mixture was cooled to 15 and stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration to give pale yellow crystals of 3- (2,4-difluorophenoxy) -141-nitro. Obtain 8. H g of benzoic acid.

Melting point: 187—188 [ethanol]

Reference example 1 1

 3- (2,4-Difluorophenoxy) Add 4.00 g of 1,4-nitrobenzoic acid, 1.88 g of dimethyl sulfate and 2.06 g of anhydrous potassium carbonate to 40 ml of acetone, and ripen and reflux for 1 hour. The insoluble material is removed by filtration, and the solvent is distilled off under reduced pressure. The obtained residue is dissolved in ethyl acetate, washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is recrystallized from ethanol to give 3.60 g of pale yellow crystalline methyl 3- (2,4-difluorophenoxy) -14-nitrobenzoate.

Melting point: 79-81 at [ethanol]

Reference Example 12

 6.0 g of 2-bromo-4-nitroaniline and 2 g of 4-dimethylaminopyridine 0J are added to 30 ml of acetic anhydride and stirred at 40 for 24 hours. The reaction mixture is added to ice water, stirred for 1 hour, and the precipitated crystals are collected by filtration to obtain 5.02 g of 2'-promo 4'- 12-acetoanilide as yellow crystals.

Melting point: 130-131 [Ethanol-Nitonitrile mixed solvent]

Reference Example 13

Under a nitrogen atmosphere, add 3.30 g of 2, -promo 4,12 troacetanilide, 3.89 g of 4-fluorophenyltributyltin and 0.44 g of tetrax (triphenylphosphine) noradmium (0) to 33 ml of toluene, Heat to reflux for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography [eluent: hexane: ethyl acetate = 3: 1] to obtain 2 '-(4-fluorophenyl) as yellow crystals. ) 1,4,12 Obtain 3.05 g of troacetanilide. Melting point: 142.5-143.5 [Ethanol-N-tonitrile mixed solvent]

Reference Example 14

 Add 3.00 g of 2,1- (4-fluorophenyl) -14'12 troacetanilide to a mixed solvent of 7.5 ml of concentrated hydrochloric acid, 7.5 ml of water and 15 ml of dioxane, and stir at 90 * for 1 hour. The reaction mixture is added to a mixture of ice water and ethyl acetate, adjusted to pH 7.0 with a 10% aqueous sodium hydroxide solution, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue obtained is recrystallized from ethanol to give 2.34 g of 2- (4-fluorophenyl) -14-nitroaniline as yellow crystals.

Melting point:] 40-] ⁴ ] [Ethanol-acetonitrile mixed solvent]

Reference Example 15

 (2) Benzoyl (4) (12) Troaniline (3.00 g) was added to a mixed solvent of ethanol (30 ml), tetrahydrofuran (20 ml) and water (10 ml), and sodium borohydride (0.90 g) was added to the solution over 30 minutes under ice cooling I do. After stirring at room temperature for 4 hours, the reaction mixture is added to a mixed solvent of water and ethyl acetate, and the pH is adjusted to pH 1.0 with 1N hydrochloric acid. The organic layer is separated, washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to give 2- (o-hydroxybenzyl) 1-4-1 as a yellow oil. There are obtained 3.00 g of Nitroainirin.

IR (neaDcm ': 3475.3380.1625, 1505, 1490

Reference Example 16

Add 3.00 g of 2- (α-hydroxybenzyl) 1-412throaniline to a mixed solvent of 6 ml of concentrated sulfuric acid, 9 ml of water and 15 ml of drunk acid, and add water at 0-5 T containing sodium nitrite l.OOg. Add 5 ml solution dropwise. After stirring at the same temperature for 1 hour, the reaction mixture is added dropwise at 0-5 to a mixed solution of 2.30 g of copper (I) bromide, 1.60 g of sodium bromide, 15 ml of 47% hydrobromic acid and 15 ml of water. After stirring at 25 for 1 hour, extract with ethyl acetate. The obtained organic layer is washed successively with 6N hydrochloric acid, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 20: 1] to obtain 1-bromo-12- (o-hydroxybenzyl) -14-nitrobenzene as a yellow oil. Get 2.40g. ^{IR (neat) ciTT,: 3420} , 1525,1345

Reference Example 17

 1-Bromo-2- (a-hydroxylbenzyl) Dissolve 3.00 g of 1,4-tol-mouth benzene in 6.0 ml of trifluoroacetic acid, drop 4.7 ml of triethylsilane at room temperature in 20 minutes, and at the same temperature for 6 hours Stir. The reaction mixture is added to a mixed solvent of water and ethyl acetate, and the organic layer is separated. The obtained organic layer is washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, and then dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent; hexane: ethyl acetate = 10: 1] to give 1.70 g of 2-benzyl-1-bromo-4-12 trobenzene as a yellow oil.

IR (neat) cm- ¹ : 1525, 1340, 1030

Reference Example 18

 Dissolve 5.00 g of 1-bromo-2- (c-hydroxylbenzyl) -14-nitrobenzene in 50 ml of toluene, add 7.00 g of electrolytic manganese dioxide at room temperature, and stir vigorously for 2 hours. Further, add 5.00 g of electrolytic manganese dioxide and stir at the same temperature for 2 hours. The insolubles are removed by filtration through celite, and the solvent is distilled off under reduced pressure. By adding isopropyl ether to the obtained residue and removing the residue, 3.90 g of colorless crystals of 2-benzoyl-1-promo-4-12-trobenzene is obtained.

Melting point: 1 16.0— 1 18.0 [ethanol]

Reference Example 19

 2,1 (2,4 difluorophenoxy) Add 7.00 g of 1,412-methorosulfonanilide to 35 ml of methanesulfonic acid, and stir at 90 for 2 hours. Add the reaction mixture to ice water, adjust the pH to 9.0 with a 10% aqueous sodium hydroxide solution, and extract with ethyl acetate. The obtained organic layer is washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 3: 1] to give 2- (24-difluorophenoxy) -14-nitroaniline as yellow crystals. You get 4.70g.

Melting point: 120.0— 121.0 [ethanol]

IRi Br) cnT ': 3490,3355, 1505, 1295 Reference Example 20

Under ice cooling, 15.0 g of 2- (cyclohexyloxy) aniline is added in portions to 150 ml of acetic anhydride, and the mixture is stirred at the same temperature for 1 hour. The solvent is distilled off under reduced pressure, and the obtained residue is added to a mixed solvent of water and ethyl acetate, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Hexane is added to the obtained residue, and the residue is collected by filtration to obtain 4.0 g of colorless crystalline 2 '-(cyclohexyloxy) acetanilide.

Melting point: 70-71.5 [isopropyl ether]

 IR (KBr) cm ': 3290,2935, l 660,1525

Reference Example 21

 Dissolve 12.0 g of 2,1- (cyclohexyloxy) acetanilide in Oml of acetic anhydride, and add 9.4 ml of 70% nitric acid dropwise over 1 hour under ice-cooling.撹 拌 After stirring for 1 hour at the temperature, add the mixture to a mixture of ice water and ethyl acetate, and adjust the pH to 8.0 with sodium hydrogen carbonate. The organic layer is separated, washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 10: 1] to obtain 5.62 g of yellow crystalline 2'-cyclohexyloxy-14,12-trifluoroacetanilide (I). 5.30 g of yellow crystalline 2'-cyclohexyloxy 5'-nitro-2-anilide (II) is obtained.

(I) Melting point: 93.5—95 [ethanol]

(II) Melting point: 105.5—109 [ethanol]

Reference Example 22

Dissolve 3.64 g of potassium hydroxide in 90 ml of methanol, and add 9.00 g of 2,1-cyclohexyloxy-4,12-nitroacetoanilide to the solution and heat to reflux for 1 hour. The reaction mixture is added to a mixed solvent of water and ethyl acetate, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Hexane is added to the obtained residue, and the residue is collected by filtration to obtain 6,90 g of 2-cyclohexyloxy-141-troaniline.

Melting point 85.5-88 [ethanol]

Reference Example 23 In the same manner as in Reference Example 22, a yellow oily 2-hydroxyhexyloxy-5-nitroaniline is obtained.

IR (neat) cm ^l : 3490,3385,2940,1510,1340

Reference Example 24

 4- (2,4-Difluorophenoxy) 1-3-Nitrobenzaldehyde 5.00 g, ethylene glycol 20 ml, p-toluenesulfonic acid 0.38 g are added to toluene 20 ml, and azeotropic dehydration is performed for 3 hours under heating. Do. The reaction mixture is washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether is added to the obtained residue, and the solid is collected by filtration to obtain 5.70 g of pale yellow crystals of 4- (2,4-difluorophenoxy) -13-2-trobenzaldehyde ethylene acetal.

Melting point: 66-67 at [ethanol]

Reference Example 25

 4- (2,4-difluorophenoxy) 1-3-nitrobenzaldehyde ethylene tertal 5.50 g is dissolved in 80 ml of ethanol, and 0.25 g of 5% palladium-carbon is added. Stir for 2 hours. The reaction mixture is filtered and the solvent is distilled off under reduced pressure. Isopropyl ether is added to the obtained residue, and the residue is collected by filtration to obtain 3.30 g of colorless crystalline 3-amino 4- (2,4-difluorophenoxy) benzaldehyde ethylene acetal.

Melting point: 75.0-77.0 [ethanol]

 NMR (CDC1,) δ iS: 3.5-4.3 (6H, m), 5.73 (1H, s), 6.6-7.3 (6H, m)

Reference Example 26

3-Amino-4-1 (2,4-difluorophenoxy) benzaldehyde ethylene tertal l .OOg is added to a mixed solvent of concentrated sulfuric acid 1.6 ml, water 2.4 ml and acetic acid 4.0 ml, and 0-5 is sodium nitrite 0.24 g A 3.0 ml solution of water containing is added dropwise and stirred at the same temperature for 1 hour. The reaction mixture is added dropwise at 0-5 to a mixture of 0.64 g of copper (I) bromide, 0.46 g of sodium bromide, 5 ml of 47% hydrobromic acid and 10 ml of water. After stirring at 25 for 1 hour, extract with ethyl acetate. The obtained organic layer is sequentially washed with 6N hydrochloric acid, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue obtained The product is purified by column chromatography [eluent; hexane: ethyl acetate = 20: u] to give 0.48 g of 3-promo 41- (2,4-difluorophenoxy) benzaldehyde as pale yellow crystals .

Melting point: 63.0—65.0 [ethanol]

Reference Example 27

 Dissolve 5.00 g of 3,1-bromo-1,4- (2,4-difluorophenoxy) acetanilide in 50 ml of acetic anhydride, and add dropwise 1.09 ml of concentrated nitric acid with 70. After stirring at the same temperature for 1 hour, anti) v. Add the mixture to a mixture of ethyl acetate and ice water, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is recrystallized from ethanol to obtain 2.80 g of 5'-bromo-14- (2,4-difluorophenoxy) -12'-2throthrothanilide as yellow crystals.

Melting point: 159—161 in [ethanol]

Reference Example 28

The compounds in Table 12 are obtained in the same manner as in Reference Example 2.

Table 12

Example No. R ² R ³ R ⁴

28 (5)-. The physical properties of the H CN 28 (6) H CF 3 28 (7) Compound of ten H CN Table 12 below.

 No.28 (l)

 IR (neat) cm ': 2225

NMR (CDCI,) 3 values: 1 1 2.4 (10H, m), 4.2-4.7 (lH, m), 6.8-7.9 (3H, m)

No.28 (2)

IR (neat) cm ': 1330

 NMR (CDC1,) S value: 1.0-2.3 (10H, m), 4.0-4.6 (lH, m), 6.7-7.2 (lH, m), 7.3-8.2 (2H, m) No.28 (3)

IR (KBr) cm ': 2230

 NMR (CDC1,) value: 6.7-7.7 (7H, m), 7.8-8.0 (1H, m)

 No.28 (4)

IR (neat) cm ^l : 1325 NMR (CDC1,) δ value: 6.8-7.6 (7H, m), 7.8-8.0 (1H, m)

 No.28 (5)

 IR (KBr) cm ': 2225

 NMR (CDCI,) δ value: 6.6-6.9 (1H, m), 7.1-7.6 (5H, m) .7.8-8.0 (1H, m)

No.28 (6)

IRineat ^ m ¹ : 1500, 1325

 NMR (CDC1,) values: 6.7-7.7 (6H, m), 7.90 (IH, d, J = 2Hz)

 No.28 (7)

 IR (KBr) cm ': 2230

NMR (CDC1 ₃₎ S value: 6.6-7.3 (5H, m), 7.5 l (l H, dd, J = 2,8Hz), 7.92 (1 H, d, J = 2Hz)

Reference Example 29

 5.00 g of 1-bromo-2-chlorobenzene and 2.41 g of 2-hydroxypyridine are added to 35 ml of ,, Ν-dimethylformamide, and 2.85 g of potassium ten-butoxide is added in 5-10 portions. . The reaction mixture is heated under reflux for 3 hours, added to a mixture of ice water and ethyl acetate, adjusted to pH 7.0 with 2N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent; hexane: ethyl acetate = 6: 1] to give 2-80- (2-pyridyloxy) benzene 1-bromo-5-d2- 2- (2-pyridyloxy) as pale yellow crystals Get.

IR (KBr) cm ': 1510,1345

 NMR (CDCI,) δ value: 6.9-7.5 (3H, m), 7.6-8.3 (3H, m), 8.4-8,6 (lH, m)

Reference Example 30

The following compound was obtained in the same manner as in Reference Example 29.

No.30 (l)

 1-bromo-5-cyano 2- (2-pyridyloxy) benzene

IR (KBr) cm ': 2235

 NMR (CDC1,) δ value: 6.9-8.3 (7Η, τη)

Νο.30 (2)

] Mouth-mouth 2-(4-methoxyphenoxy) 1-5-nitrobenzene IR (KBr) cm-': 1505,1345

 NMR (CDC1,) δ value: 3.81 (3H, s), 6.6-7.3 (5H, m), 7.9-8.2 (1H, m), 8.3-8.6 (1H.m)

 No.30 (3)

 1-bromo-2- (4-cyanophenoxy) -1-5-nitrobenzene

 IR (KBr) cm ': 2220, 1515,1345

NMR (CDC1 _? ) $ Value: 7.0-7.3 (3H, m), 7.71 (2H, d, J = 9Hz), 8.21 (lH, dd.J = 9,2Hz),

8.57 (lH, d, J = 2Hz)

 Reference Example 31

The compounds shown in Table 13 are obtained in the same manner as in Reference Example 6.

Table 13

Example No. R ² R ³ R ⁴

The physical properties of the compounds in Table 13 are shown below.c

No. 31 (l)

IR (Br) cnT ': 2235, 1535.1360

呦 ^ Oblique I J? 8 Γι ^ ζ

 Ζί

 (ZHJ: = f 'Ρ'Η [) Sr8' (ZH6 = rPP'H I) '(HS' -69: Army 2 (DaD) HW

('θαθ)ΉΙΛΙΝ Si οςίνοίςνςίζζ-

('θαθ) ΉΙΛΙΝ Si

 Scer? I:,. Io (jB3u) Hi

 (9) 1 £ ΌΝ

('ΗΠ 8ζζ (' ΗΙ) 669 · '(Η)-P'n' (Mountain 'ΗΙ) 1'-6'9: 1} (' lDaD) H

 09ε roesi

 (i'H l · 8_ `` 8 Η £) 6 · 6 · 9: ¾ 9: ΧΟ) ΗΝΝ

 () ΐε0Ν

('ΗΙ) 1τ8-Γ8' ('Η) 6-6.9: ¾ S DdD) Ν

 osei'oesr mountain 3 (· »8) ΉΙs

(・ Ηε) 9 ・ 8_6 ・ 9 '(* Η I) 6 ε (' Η01) ε · Γ I · 3 DOD) ¾WN

(ω'Ηε) ς8-0 '.' (ωΗ1) Γς-εΚ (ω'Η01) VZ- Hi οα: »ΗΝΝ 刚 / 96dT / XD <I ^ίζι IZ69V96 ΟΛλ

Reference example No. R ³ R ⁴

 32 (4) H CR 32 (5) H CN

表 14の化合物の物性を以下に示す。 -o 32 (6) H CF ₃

The physical properties of the compounds in Table 14 are shown below.

No.32 (l)

 IR (KBr) cm ': 3480,3375,2220

NMR (CDC1 ₃₎ S value: 1.0-2.3 (10H, m), 4.0 (2H, bs), 4.2-4.6 (1 H, m), 6.6-7.7 (3H, m) No.32 (2)

IRineaDcm ¹ : 3485,3385

 NMR (CDC1,) S value: 1.1 -2.2 (10H, m), 3.6-4.2 (2H.m), 4.0-4.5 (1H, m), 6.8-7.3 (3H, m) No.32 ( 3)

lR (Br) cm ': 3480,3380,2225

 NMR (CDC1 S value: 4.12 (2H, bs), 6.6-7.6 (8H, m)

No.32 (4)

IRineaDcm ¹ : 3490,3390,1340

_{NMR (CDC1 3) d ii:} 3.8-4.2 (2H, m) .6.8-7.6 (8H.m) No.32 (5)

 IR (Br) cm- ': 3490,3365,2215

NMR (CDC1 _? ) Δ value: 4.20 (2H, bs), 6.5-7.9 (7H, m)

No.32 (6)

IRineaDcm ': 3490,3400

NMR (CDC1 ₃₎ δ value: 4.10 (2H, bs), 6.6-7.5 (7H, m)

No.32 (7)

 IR (KBr) cm ': 3480,3380,2230

NMR (CDCU) δ value: 4.10 (2H, bs), 6.5-7.2 (7H, m)

Reference Example 33

 4 Dissolve l.Og in 1 ml of anhydrous bromotetrahydrofuran, add 8.00 g of 25% aqueous ammonia under ice-cooling, and stir at the same temperature for 30 minutes and at room temperature for 24 hours. Add the reaction mixture to a mixture of water and ethyl acetate, adjust the pH to 2.0 with 2N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether is added to the obtained residue, and the residue is collected by filtration to obtain 7.93 g of colorless crystalline 4-aminosulfonyl-1-bromobenzene.

IR (neat) cm '; 3330,3240.1330,1 150

NMR (d ₆ -DMSO) δ value: 7.44 (2H, bs), 7.68 (4H, m)

Reference example 34

As in Reference Example 33

 4-Bu π-mo 1- (N-methylaminosulfonyl) benzene is obtained.

 IR (neat) cm '; 3295,1325,1 165

Reference Example 35

Under a nitrogen atmosphere, 0.50 g of 4-aminosulfonyl-1-bromobenzene, 4.85 ml of bistriptyrutin and 0.04 g of tetrakis (triphenylphosphine) palladium (0) are added to 10 ml of xylene, and the mixture is heated under reflux for 14 hours. After filtering off the insoluble matter, the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography [eluent; hexane: ethyl acetate = 5: 1] to give 4-aminosulfonylphenyl as a colorless oil. 0.52 g of niltributyltin are obtained.

 IR (neat) ση '; 3345,3270, 1340, 1 165

 Reference Example 36

 As in Reference Example 35

 4-(-Methylaminosulfonyl) phenyl tributyltin is obtained.

IR (neat) cm '; 3295, 1325,1 165

 NMR (CDC1,) 5 values: 0.6-1.9 (27H, m), 2.65 (3H, cU = 5.5Hz), 4.4-4.9 (lH, m), 7.4-8.0 (4H, m) Reference Example 37

The following compounds were obtained in the same manner as in Example 38.

No.37 (l)

 • 2- (4-bromo-13- (2,4-difluorophenoxy) phenyl) ethyl acetate

NMR (CDCU) δ value: 1.20 (3H, = 7.5Hz), 3.49 (2H, s), 4.12 (2H, q, J = 7.5Hz), 6.7-7.7 (6H, m)

No.37 (2)

 • 2- (3-bromo-41- (2,4-difluorophenoxy) phenyl) ethyl acetate

 IRineaDcm ^ nSS

NMR (CDCI,) δ value: 1.26 (3H, t, J = 7.5 Hz), 3.55 (2H, s), 4.17 (2H, q, J = 7.5 Hz), 6.6-7.7 (6H, m) Νο37 (3)

 • 4- (3-bromo-1- (2,4-difluorophenoxy) phenyl) severe acid

 IR (neat) cm ': 1735

NMR (CDC1 _? ) Δ value: 1.26 (3H, tJ = 7.5Hz), 1.7-2.8 (6H, m), 4.15 (2H, q, J = 7.5Hz), 6.6-7.6 (6H, m)

Reference Example 38

The following compounds were obtained in the same manner as in Example 40.

No.38 (l) • 2- (3-bromo-41- (2,4-difluorophenoxy) phenyl) 1-3-hydroxyethyl ethion pionate

NMR (CDC1 _? ) Δ value: 1.23 (3H, U = 7.5 Hz), 1.64.1 (3H.m) .4.22 (2H.qJ = 7.5 Hz) .6.6-7.7 (6H, m)

IRineaDcm ¹ : 3425, 1735

No.38 (2)

 • 2- (4-bromo-1--3- (2,4-difluorophenoxy) phenyl) -1-ethyl ethyl propionate

Reference example 39

The following compounds were obtained in the same manner as in Example 41.

No.39 (l)

 • 2- (3-bromo-1- (2,4-difluorophenoxy) phenyl) ethyl acrylate

 NMR (CDC1,) δ value: I · 29 (3Η, = 7.5Ηζ), 4.23 (2Η, ς,】 = 7.5Ηζ), 6.8-7.8 (7Η, πι)

IR (neat) cm ': 1715

No.39 (2)

 -2- (4-bromo-3- (2,4-difluorophenoxy) phenyl) acrylate

Reference example 40

The following compounds were obtained in the same manner as in Example 42.

No.40 (l)

 • 1- (3-bromo-1- (2,4-difluorophenoxy) phenyl) cyclopropyl, ethyl carboxylate

IR (neat) cm ': 1715

NMR (CDC1,) o value: 1.18 (3H, t, J = 7.5 Hz), 1.0-1.8 (4H, m), 4.10 (2H, q, J = 7.5 Hz), 6.6-7.7 (6H, m)

No.40 (2)

• 1- (4-bromo-3- (2,4-difluorophenoxy) phenyl) ethyl cyclocyclocarboxylate

NMR (CDC1 ₃₎ δ values:. I 13 (3H, U = 7.5Hz), 0.95-1.35 (2H, m), 1.35-1.70 (2H.m), 4.08 (2H, q, J = 7.5Hz), 6.7-7.7 (6H, m)

Reference Example 41

In the same manner as in Example 43, 11- (3-promo 41- (2,4-difluorophenoxy) phenyl) ethyl ethyl cyclopentanecarboxylate is obtained.

IR (neat) cm ^l : 1720

 NMR (CDC1,) δ value: 1.15 (3H, U = 7.5 Hz), 1.6-2.2 (6H, m), 2.3-2.9 (2H.m), 4.09 (2H, q, J = 7.5 Hz), 6.6- 7.7 (6H, m)

Reference Example 42

The following compounds were obtained in the same manner as in Example 45.

No.42 (l)

 • 3— (3-bromo-4- (2,4-difluorophenoxy) phenyl) propionic acid

IR (neat) cm ': 1710

_{NMR (CDC1 3 + D 2 0} ) δ value: 2.4-3.1 (4H, m), 6.4-7.9 (6H, m)

No.42 (2)

 • 3-Bromo-1- 4- (2,4-difluorophenoxy) benzoic acid

IR (Br) cm ': 1685

NMR (CDC1, + D _; 0) δ value: 6.6-7.4 (4H, m), 7.95 (1H, dd, J = 2,8Hz), 8.40 (1H, d, J = 2Hz) No.42 ( 3)

 • 4 one-promote 3— (2,4-difluorophenoxy) benzoic acid

IR (Br) cm ': 1690

_{NMR (CDC1 + D 2 0?} ) Δ value: 6.8-7.9 (6H, m)

Reference Example 43

4.2 ml of ethyl phosphonoacetate was dissolved in 40 ml of tetrahydrofuran, 0.85 g of sodium hydride was added under ice-cooling, and then 1-bromo-2- (2,4-difluorophenoxy) -1 5-formylbenzene dissolved in 20 ml of tetrahydrofuran Add 6.00g and stir at room temperature for 1 hour. The reaction mixture was added to a mixture of ice water and ethyl acetate. In addition, adjust the pH to 1.0 with 2 N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is mixed with isopropyl ether and collected by filtration to give a colorless mixture.

5.00 g of 3- (3-bromo-4- (2,4-difluorophenoxy) phenyl) ethyl acrylate of BBB is obtained.

NMR (CDC) _? ) Δ value: 1.33 (3H, t, J = 7.5Hz), 4.23 (2H, q, J = 7.5Hz), 6.1 -7.9 (8H, m)

Reference example 44

 Dissolve 5.00 g of 3- (3-bromo-4-1 (2,4-difluorophenoxy) phenyl) ethyl acrylate in 50 ml of N, N-dimethylformamide, add 5% palladium-carbon l.OOg, Stir at room temperature, under normal pressure, and under a hydrogen stream for 4 hours. The insoluble material is removed by filtration, and the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography [eluent; hexane: ethyl acetate = 10: 1] to give a colorless oil, 3- (3-bromo-141- (2,4-difluorophenoxy). ) Phenyl) 4.00 g of ethyl propionate are obtained.

 IR (neaDcm ': 1735

NMR (CDC1 _? ) Δ value: 1.23 (3H, U = 7.5 Hz), 2.4-3.1 (4H, m), 4.13 (2H, q, J = 7.5 Hz), 6.6-

7.9 (6H, m)

Reference example 45

 Add 3.00 g of 1-bromo-1-methyl-5-nitrobenzene, 3.20 g of N-bromosuccinic acid and 0.1 g of 2,2, azobis (isobutyronitrile) to 30 ml of carbon tetrachloride and heat to reflux for 2 hours. The reaction mixture is added to ice water, and the organic layer is separated. The obtained organic layer is washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. As a result, 1-bromo-2-bromomethyl-5-nitrobenzene as an orange oil is obtained. 4.00g is obtained.

 NMR (CDCU) S value: 4.65 (2H, s), 7.0-8,5 (3H, m)

Reference Example 46

1-bromo-2-Buromomechiru 5 two preparative port benzene 4.00g was dissolve in Toruen 30 ml, then added triphenyl phosphinite down 3.30 g, reacted for 2 hours at 60 _c The precipitated crystals are collected and washed with ethyl acetate to obtain 2.00 g of 2-promo 4-nitrobenzyltriphenylphosphonium bromide as yellow crystals.

 IR (KBr) cm ': 1525, 1345

Reference Example 47

 1 Dissolve 6.8 g of 1-bromo-1-bromomethyl-5-nitrobenzene in 35 ml of Ν, Ν-dimethylformamide, add 4.50 g of potassium acetic anhydride, and react at 100 for 1 hour. The reaction mixture is added to a mixture of ice water and ethyl acetate, adjusted to pH 5.0 with 1 N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent; hexane: ethyl acetate = 5: 1] to obtain 3.3 g of 2-acetoxymethyl-1-bromo-5-nitrobenzene as yellow crystals. .

IR (KBr) cm ': 1740, 1525, 1345

NMR (CDC1 ₃₎ δ value: 2.18 (3H, s), 5.30 (2H, s), 7.64 (lH, d, J = 8.0Hz), 8.20 (1 H, dd, J = 8.0Hz, J = 2.0Hz ), 8.44 (1 H, d, J = 2.0Hz)

Reference Example 48

 Dissolve 4.50 g of ubromo-1-acetoxymethyl-5-nitrobenzene in 22.5 ml of ethanol. Add 18 ml of 1 N aqueous sodium hydroxide solution under ice-cooling, and stir at room temperature for 30 minutes. The reaction mixture is added to ice water and ethyl acetate, adjusted to pH 5 with 1N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed first with water and saturated saline, then dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Π-Hexane is added to the obtained residue, and the residue is collected by filtration to obtain 3.40 g of colorless crystalline 1-promo 2-hydroxymethyl-15-nitrobenzene.

IR (KBr) cm ': 3260,1530.1345

NMR (CDCK) o value: 2.40 (lH, s), 4.84 (2H, s), 7.81 (lH, d.J = 8.0Hz),

8.24 (1 H.dd, J = 8.0Hz, J = 2.0Hz). 8.43 (1 H, d, J = 2.0Hz)

Reference 49

Dissolve 3.30 g of 1-bromo-2-hydroxymethyl-5-nitrobenzene in 50 ml of toluene. At room temperature, add 3.70 g of electrolytic manganese dioxide and stir vigorously. 3 O'clock After a short time, 3.70 g of electrolytic manganese dioxide is further added, and the mixture is stirred at the same temperature for 3 hours. _C Insolubles are removed by filtration, and the solvent is distilled off under reduced pressure. Isopropyl ether was added to the obtained residue, and the residue was collected by filtration to obtain 2.80 g of 1-promo 2-formyl-5-nitrobenzen as colorless crystals.

IR (KBr) cm ¹ : 1690.1525, 1350

 NMR (CDC10 value: 8.14 (lH, d, J = 8.0 Hz), 8.38 (lH, dd, L = 8.0 Hz, J = 2.0 Hz) .8.57 (1 H, d, J = 2.0 Hz), 10.48 ( lH, s)

Reference example 50

Under a nitrogen atmosphere, add 0.20 g of 60% sodium hydride to 10 ml of Ν, Ν-dimethylformamide, and at room temperature, contain 2.90 g of 2-bromo-412-trobenzyltriphenylphosphonium bromide Ν, Ν Add 15 ml of dimethylformamide solution dropwise and stir at the same temperature for 30 minutes. Add 0.50 g of isonicotinaldehyde to the reaction mixture and stir at 80 for 2 hours. The reaction mixture is added to a mixture of ice water and ethyl acetate, adjusted to pH 2.0 with 1 N hydrochloric acid, and the organic layer is separated. The obtained organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Purification of the resulting residue by column chromatography [eluent: toluene: ethyl acetate = 10: 1] yields yellow crystals of 3-promo 41- (2- (4-pyridyl) ethenyl) nitrobenzene. 0.15 g is obtained.

IR (KBr) cm ': 1520.1350

NMR (CDC) 8 values: 6.7-7.3 (5 111), 8.0 (, € 11, ”= 8.0 ^^,” = 2. (^ 2), 8.3-8.8 (301) Reference Example 51

Add 5.00 g of 2-hydroxy-4-nitroaniline to a mixed solvent of 10 ml of concentrated sulfuric acid, 15 ml of water and 25 ml of acetic acid, and add 0 to 5 drops of 10 ml of an aqueous solution containing 2,70 g of sodium nitrite. After stirring at the same temperature for 1 hour, the reaction mixture is added dropwise at 0-5 to a mixture of 6.00 copper bromide, 4.30 g of sodium bromide, 25 ml of 47% hydrobromic acid and 50 ml of water. After stirring at 25 for 1 hour, ethyl acetate is added and the organic layer is separated. The obtained organic layer is washed successively with 6N hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: vinegar ethyl = 10: 1] to obtain yellow crystals of 1-bromo-2-hydroxy. 4.70 g of hydroxy benzene are obtained.

IR (KBr) cm ' ¹ : 3460, 1510.1345

NMR (CDC1,) δ value: 6.0 (〗 H, s), 7.5-8.2 (3H, m)

Reference Example 52

1 Buromo 2- arsenide Dorokishi 4 twelve preparative port benzene 3.30g and to 3-Benzoiru Okishishikuro dissolving hexanol ⁴ .00G anhydrous Te Torahi Dorofuran 30 ml. At room temperature, 4.00 g of triphenyl phosphine is added, and then 4.00 g of getyl azodicarboxylate is added dropwise. After stirring the reaction mixture at the same temperature for 4 hours, the mixture is added to a mixture of ice water and ethyl acetate, and the organic layer is separated. The obtained organic layer is washed successively with water, a saturated aqueous sodium carbonate solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography [solvent; hexane: ethyl acetate = 10: 1] to give 1-promo 2- (3-benzoyloxycyclohexyloxy) -14-nitro as yellow crystals. 2.00 g of benzene are obtained.

IR (KBr) cm ¹ : 1715, 1525, 1350

 NMR (CDC1,) δ value: 1.32.8 (8Η, πι), 4.2-4.8 (1H, m), 4.8-5.4 (1Hm), 7.2-8.5 (8H, m) Reference Example 53

 Dissolve 1-bromo-2-hydroxy-14-nitrobenzene lO.Og in 10 ml of methylene chloride. To the reaction mixture, under ice-cooling, add 5.00 g of tritylamine, and then add dropwise a 10 ml solution of methylene chloride containing 4.00 g of methyl methyl ether at the same temperature over 20 minutes. After stirring at room temperature for 4 hours, heat to reflux for 3 hours. The reaction mixture is added to ice water, and the organic layer is separated. The obtained organic layer is washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether is added to the obtained residue, and the residue is collected by filtration to obtain 9.70 g of 1-bromo-2-methoxymethyloxy-4-nitrobenzene as yellow crystals.

IR (Br) cm ': 1520,1345

 NMR (CDCIJ δ value: 3.55 (3H, s); 5.36 (2H, s), 7.5-8.3 (3H, m)

Reference example 54

1-bromo-2- (2,4-difluorophenoxy) -1-5-methoxybenzene 15.0g Was added to 150 ml of methylene chloride, 4.95 ml of boron tribromide was added dropwise under ice cooling, and the mixture was stirred for 30 minutes and left at room temperature overnight. The reaction mixture is added to ice water, and the organic layer is separated. The obtained organic layer is washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography [eluent; hexane: ethyl acetate = 9: 1] to give a colorless oily 3-promo 4- (2,4-difluorophenoxy) phenol 14.3 get g.

IR (neat) cm ': 3375

NMR (CDC1 _? ) Δ value: 647 (1 H.bs), 6.6-7.5 (6H, m)

Reference Example 55

 Dissolve 14.5 g of 3-bromo-1- (2,4-difluorophenoxy) phenol and 7.39 ml of triethylamine in 150 ml of methylene chloride, stir under ice-cooling, and add 4.10 ml of methanesulfonyl chloride dropwise. The reaction mixture is stirred for 1 hour, added to ice water, adjusted to pH 10 with 2 N hydrochloric acid, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 3: 1] to obtain 1-promo 2- (2,4-difluorophenoxy) -1,5-mesylo as a colorless oil. 17.7 g of xylene are obtained.

IRineaDcm ¹ : 1375, 1 160

 NMRiCDC !,) δ value: 3.16 (3H, s), 6.4-7.7 (6H, m)

Reference Example 56

 Dissolve 8.20 g of 2-bromo-5-methoxyphenol and 6.19 ml of triethylamine in 80 ml of methylene chloride, and dropwise add 3.44 ml of methanesulfonyl chloride under ice-cooling. After allowing the reaction mixture to stand at room temperature overnight, add the mixture to ice water, adjust the pH to 10 with 2 N hydrochloric acid, and separate the organic layer. The obtained organic layer is washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Hexane is added to the obtained residue, and the residue is collected by filtration to give colorless crystals of 1-bromo-12-mesyloxy-14-methoxybenzene lO.Og.

IR (Br) cm ': 1380, 1 185

NMR (CDCI,) δ value: 3.24 (3H, s), 3.8 (3H, s), 6.76 (1H, dd, J = 9.0Hz, J = 2.0Hz), 7.02 (1 Hd, J = 2.0Hz), 7.50 (1 Hd, J = 9.0Hz)

 Industrial applicability

The biphenyl derivative of the compound of the present invention or a salt thereof has excellent anti-inflammatory, antipyretic analgesic, anti-clinical effects and the like, and is useful as a pharmaceutical.

Claims

The scope of the claims 1. General formula

Wherein R ¹ is a lower alkyl or aryl group optionally substituted with a halogen atom or an amino group which may be protected; R ² is an aryl group which may be substituted or a general formula -Z-R ⁵ (Wherein, R ⁵ represents an optionally substituted alkyl, alkenyl, alkylsulfonyl, cycloalkyl, aryl, aralkyl or heterocyclic group; Z represents an oxygen atom, a sulfur atom, R ¹ and R ⁴ are the same or different, and each represents a hydrogen atom, a halogen atom, or an imino group, a methylene group, a carbonyl group or a vinylene group which may be substituted with a hydroxy group. , A cyano group, an azide group, a nitro group, an optionally protected amino group, an optionally protected carboxyl group, an optionally protected hydroxyyl group, an acyl group, an alkoxycarbonyl group or a substituted May be alkyl, alkenyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alk Sulfonyloxy, alkylsulfonylamino, amidino, guanidino, aryloxy, cycloalkyl, rubamoyl, sulfamoyl, alkylamino, acylamino, oxa-mouth, alkoxyoxalyl, alkoxyoxalylamino, nitrogen atom A nitrogen-containing heterocyclic carbonyl, aryl or heterocyclic group bonded through a group; n represents 0, 1 or 2;  The bifuninyl derivative represented by these, or its salt. 2. The biphenyl derivative or a salt thereof according to claim ¹ , wherein R ¹ is a lower alkyl or amino group. 3. 1¾ ^{'mosquitoes?,} Biphenyl derivative according to claim 1, wherein a methyl or amino group Or its salt. 4. R ² is a general formula One Z-R ⁵ (Wherein, R ⁵ is a lower alkyl group which may be substituted with a halogen atom, a hydroxyl or oxo group, or a cycloalkyl, aryl, aralkyl or heterocyclic group which may be substituted; z is an oxygen atom An atom, a sulfur atom, a methylene group, a carbonyl group or a vinylene group.) 4. The biphenyl derivative or a salt thereof according to 2 or 3. 5. R and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group which may be protected, a carboxyl group which may be protected, an acyl group, an alkoxycarbonyl group or a substituent. The biphenyl derivative or a salt thereof according to any one of claims 1 to 4, which is an optionally substituted alkyl, alkoxy, carbamoyl, alkylamino or acylamino group. 6. R ² is a general formula  -Z-R- (In the formula, represents a cycloalkyl, pyridyl or phenyl group optionally substituted with a halogen atom; Z represents an oxygen atom, a methylene group, a carbonyl group or a vinylene group.) 6. The biphenyl derivative or a salt thereof according to any one of claims 1, 2, 3, and 5. 7.R Claims 1 to 4 wherein R and R ⁴ are the same or different and are a hydrogen atom, a halogen atom, a cyano group, a nitro group, an acyl group or a carboxyl group or an alkyl group optionally substituted with a halogen atom. 7. The biphenyl derivative or a salt thereof according to any one of 6. 8. R ² is a general formula  -Z-R ' (Wherein, R ⁵ is a optionally substituted pyridyl or phenyl group with a halogen atom; Z represents an oxygen atom.) The group represented ^by;? R and R ⁴ are taken identical or different, A hydrogen atom, a cyano group, a nitro group, or a carboxyl group or an alkyl group optionally substituted with a halogen atom. A biphenyl derivative or a salt thereof according to any of the above.  9.5-Cyanol 4-methylsulfonyl-2-phenoxy-1.1-biphenyl or a salt thereof.  0.4,1-Aminosulfonyl-5-cyano-2-phenoxy-1,1,1-biphenyl or a salt thereof.  1 1. An anti-inflammatory agent comprising the biphenyl derivative according to any one of claims 1 to 10 as an active ingredient.  12. A C0X-2 selective inhibitor containing the biphenyl derivative according to any one of claims 1 to 10 as an active ingredient.  1 3. Use as an anti-inflammatory agent comprising the biphenyl derivative or a salt thereof according to any one of claims 1 to 10 as an active ingredient.  14. Use as a COX-2 selective inhibitor containing the biphenyl derivative or a salt thereof according to any one of claims 1 to 10 as an active ingredient.  15. A pharmaceutical composition comprising the biphenyl derivative or a salt thereof according to any one of claims 1 to 10 as an active ingredient.