TW391965B - Triazole derivatives and antifungic pharmacentical compositions - Google Patents

Description

5 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

A7 B7. Description of the invention (') Field of the invention The present invention relates to a compound of formula (1) lf2,4-triazole which is effective in treating fungal diseases of humans and animals. The conventional technique is equivalent to the following formula in Japanese Patent Application Laid-Open No. 61-85369 described in Formula (1): -A- (CO) p- (R2C = CR3) q- (CsC) r- (R4C = CR5) s -Ar2 is an alkyl, cycloalkylalkyl or cycloalkyl-like compound having antifungal activity. Problems to be Solved by the Invention However, the inventors worked hard to find more excellent antifungal agents, and finally found that the compound of the present invention is an excellent antifungal agent to complete the present invention. Means for Solving the Problems The present invention is represented by the following formula U ) Compound or its pharmacological tolerance ®1 R. (O) nA- (CO) P- (R2C = CR3) q- (0Ξ〇r- (R4C = CR5) s-Ar: where Ar1 is a phenyl group or a phenyl group having a 1 to 3 値 substituent (the The substituent is halogen or trifluoromethyl),

Ar2 is a phenyl group or a 5 to 6 membered aromatic heterocyclic group having at least one value of N, 0 or S and each of which may have 1 to 3 选自 substituents selected from the group consisting of lower alkyl, lower alkane, radical, halogen, halogen Substituted lower alkyl, halogen-substituted lower alkanoyl, nitro, cyano, -S (0) mRs (Re is halogen-substituted lower alkyl, m is 0, 1 or 2) or-NHCOR7 (R7 is low alkyl); This paper size applies to China National Standard (CNS) A4 specification (210X297 mm > (Please read the precautions on the back before filling this page)

A 7-B7 V. Description of the invention (>)

Re is fluorene or lower alkyl, R1 is low alkyl, R2, R3, R4 and R5 may be the same or different, each is fluorene, and may be halogen-substituted low alkyl. When q and s are 2, R2, R3, ^ 4 and ^ 5 may be the same or different, η is 0, 1 or 2, p is 0_ or 1, q, r and s are 0, 1 or 2, and A is C4-7 aliphatic ring Or a 4- to 7-membered aliphatic heterocyclic group having at least one N, 0 or S. The aforementioned halogen may be, for example, fluorine, gas or bromine, preferably fluorine or chlorine. Lower alkyl can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second or third butyl, preferably methyl, ethyl, propyl or isopropyl. The lower alkanoyl group may be methyl, ethyl, propoxy, isopropyl, butoxy, isopropyl, second or third butoxy, methyl, ethyl Radical, propane or isopropyl.

The 5 to 6-membered aromatic heterocyclic group of Ar2 can be, for example, furyl, benzoyl, Bitrolyl, pyrazolyl, oxazolyl, oxazolyl, oxazolyl, pyridyl, pyrimidinyl, or pyridyl C4-7 aliphatic master cyclic group of A, C, F-7, C-C7, C-C7, C-C7, C-C7, C-C7, C-C7, C-C7, C-C7, C-C7, C-C7, C-C7, C-C7, C-C7, C-C7, C-C7, C-C7, C-C7, C-C7, C-C7-7, C-C7-7, C4-7 Base or cyclohexyl. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page). At least one of the 4- to 7-membered aliphatic heterocyclic groups of A, such as azetidinyl, pyrrole Pyridyl, piperidinyl, homopiperidinyl, fluorenylbutyl, tetrahydrofuryl, tetrahydropyranyl, butyl, tetrahydropyridyl, cyclopentamethylenesulfur, 1,4,5,6 -Tetrahydropyrimidine, 1,3 -dioxane, 1,3 -dibrane, dihydropyridine, tetrahydropyridine, dihydrocarbine or tetrahydrothiopyridine, especially azetidinyl, piperidyl, 1,3 -dimorphyl, 1,4,5,6 -tetrahydropyrimidine The paper size is applicable to the Chinese National Standard (CNS) M specification (210X297 mm) Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Qiu A7 B7 5 2. Description of the invention (4) group, tetrahydrocarbyl group or 1,3-dithiaalkyl group. Suitable compounds of formula (1) are:

Ar 1 is dichlorophenyl, dichlorophenyl, chlorophenyl, fluorophenyl, (trifluoromethyl) phenyl, or fluoro (trifluoromethyl) phenyl, preferably 2,4-dichlorophenyl , 2,4-difluorophenyl, 4-chlorophenyl, 4-chlorophenyl, 4- (trifluoromethyl) phenyl or 2-fluoro-4 (trifluoromethyl) phenyl, particularly preferred 2,4-difluorophenyl, 2,4-difluorophenyl, or 4- (trifluoromethyl) phenyl.

Ar2 is fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, (trifluoromethyl) phenyl, (trichloromethyl) phenyl, fluoro- (trifluoromethyl) phenyl, ( Difluoromethoxy) phenyl, (trifluoromethoxy) phenyl, (2,2,2-trifluoroethoxy) phenyl, (1,1,2,2-tetrafluoroethoxy) Phenyl, (2,2,3,3-tetrafluoropropoxy) phenyl, nitrophenyl, fluoro-nitrophenyl, cyanophenyl, chlorocyanophenyl, (methylthio) phenyl, (methyl Sulfinyl) phenyl, (methanesulfinyl) phenyl, (trifluoromethylsulfanyl) phenyl, (trifluoromethanesulfinyl) phenyl, trifluoromethanesulfinyl) phenyl, chlorine Pyridyl, (trifluoromethyl) pyridyl, (2,2,3,3-tetrafluoropropoxy) pyridyl, (trifluoromethyl) furanyl, benzoyl or (trifluoromethyl) _Panyl, 4-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 4- (trifluoromethyl) phenyl, 4- (tri Chloromethyl) phenyl, 2-fluoro-4- (trifluoromethyl) phenyl, 4- (difluoromethoxy) phenyl, 3- (trifluoromethyl) phenyl, 4- (tri Fluoromethoxy) phenyl, 4- (2,2,2-trifluoroethoxymycin) 4- (1,1,2,2-tetrafluoroethylamino) phenyl, 4- (2,2,3,3-tetrafluoropropanyl) phenyl, 2-fluoro-4- (2 , 2,3,3-tetrafluoropropoxy) phenyl, 4-nitrophenyl, 2-fluoro-4-nitrophenyl, 4-fluorophenyl, 2-gas-4-cyanophenyl, 4- This paper size applies to Chinese National Standard (CNS) A4 »(210X297mm) (Please read the notes on the back before filling this page) Order A7 B7 printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (4) (Methylthio) phenyl, 4- (methylsulfinyl) phenyl, 4- (methanesulfonyl) phenyl, 4- (trifluoromethylthio) phenyl, 4- (trifluoromethylene Sulfonyl) phenyl, 4- (trifluoromethanesulfonyl) phenyl, 6-gas-3-pyridyl, 6- (trifluoromethyl) -3-pyridyl, 5-gas.-2- Pyridyl, 6- (2,2,3,3-tetrafluoropropanyl) -3-pyridyl, 5- (trifluoromethyl) -2-furanyl, 5-gas-2-bromo, or 5- (trifluoromethyl) -2-carpanyl, especially 4-aminophenyl, 4- (trifluoromethylthio) phenyl, 4- (trifluoromethylsulfonyl) phenyl, 4- (Trifluoromethyl) phenyl, 4- (trifluoromethoxy) phenyl or 4- (2,2,3,3-tetrafluoropropanyl) phenyl. H, methyl, ethyl or propyl, preferably H, methyl or ethyl, especially hydrazone or methyl. R1 is methyl, ethyl or propyl, preferably methyl or ethyl, especially methyl. R2, R3, R4 and R5 are the same or different, each is fluorene, methyl, ethyl, propyl or trifluoromethyl, preferably H, methyl or trifluoromethyl, especially fluorene or trifluoromethyl : Η is 0, 1 or 2, especially 0. P is 0 or 1, especially 0. q is 0, 1 or 2, especially 1 is preferred. r is 0, 1 or 2, especially 0 or 1. s is 0, 1 or 2, especially 1 is preferred. A is cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetramethylpyranyl, tetrahydropyranyl, 1, 3-diamidyl, 1 The basic paper size of 1,3-di-blind alkyl, tetrahydrosulfanyl or tetrahydrothithiagen is applicable to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page) Order A7 _ B7 V. Description of the invention U), preferably cyclobutyl, fluorenyl, azetidinyl, piperidinyl, 1,3-dialkylidene, 1,3-dicarbyl, tetrahydrocarbyl Hydrocarbyl, particularly cyclohexyl, piperidinyl, 1,3-dialkyl, or 1,3-dialkyl. Examples of suitable compounds (1) are Ar1 is 4-aminophenyl, 4-difluorophenyl, 2,4-dichlorophenyl or 4- (trifluoromethyl> phenyl), and 1 ^ is 11 or methyl , R 1 is methyl and —S (O) nA- (CO) p- (R2C = CR3) q- (C = C) r- (R4C = CRS) s-Ar2 is a compound shown in Table 1 Γ n · nn ^^^ 1 HI ml — »^^ 1 ^^^ 1 ml nn m · m · J, J, 1, .¾ (Read the precautions on the back before filling this page) Central Ministry of Economic Affairs Standards Bureau's consumer cooperation'i This paper size applies Chinese National Standards (CNS) _8 4 specifications (21 OX 297 mm) A7 B7 V. Description of invention () [Table 1] Example 1 S (O) nA- (CO ) P- (R2C = CR3) q- (CEC) (R4C = CR5 > S-Ar: 2

Cl -S -S

(Please read the notes on the back before filling this page) 4

CF,

, TT 5 s < °) ^ -0

OCHF,

Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs 6 7 8 OCF, —s

2ur3 -3 < C) ^ -0

OCF.CHFn This prestige scale applies to the Chinese National Standard (CNS) A4 specification (21 OX297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (7) [Table 2] OCH2CF2CHFz 9 Factory 〇10 Ocf3 SCHo / ό 11 -s &°; // S〇2CH3 12 —A 13-< 〇 > F 1 / S〇2cf3 14 15 • Factory 〇-SO CF «/ ^ Cl / 16-< & gt -y® CF, (Please read the notes on the back before filling this page) 9- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of invention (2) [Table 3 】

Cl 17

\ · — I

18

CF, CF, -C °) \ _0

—S

twenty one

-S

twenty two

CF, printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs 23 24 -S-

-s (〇)

, S NO,

10 · (Please read the notes on the back before filling in this page)

This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of invention (9) [Table 4] 25 — S〇 K :. : V-η

OCF. 27

Cl

28 -S

S

CF,

-S < S) is

OCH2CF2CHFj Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 31 32

CF, -S

One A

OCH.

(Please read the notes on the back before filling this page)

This paper size applies to the Chinese National Standard (CNS) A4 (210X 297 mm) A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (0) [Table 5] 33 34 35 36 37 38 39 40

— ^ Nn HI in mf— nn n nn · ^ (Please read the precautions on the back before filling out this page) _12 — This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Invention Explanation (π [Table 6]

NO, 42

CN 43

OCHFo

45 -s {〇 46

-S OCF,

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

OCHnCFoCHF,

OCH.CFoCHF, -13- (Please read the notes on the back before filling this page)

This paper size applies the Chinese National Standard (CNS) A4 ^ (210X297 mm) V. Description of the invention (| >). Table 9 4 5152 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5455 ov / o 0) 0 0) 0-0} 0 · τ T II Tl IIVVVVV VVV × φ essss ·--

ο \ Λ / ο o} o 0) 0 0) 0

F OCF,

SCH,

SOoCH,

, 〇〇2cf3

CF

Cl CH,

CF,

och2cf2chf2 CH,

Cl -14- (Please read the notes on the back before filling this page) The size of the paper used for this edition applies to the Chinese National Standard (CNS) A4 (210X297 mm) A7 B7 V. Description of the invention (0) [Table 8] 57 0 CH3 CF,

58

59

N, 〇CHF2 (read the notes on the back first, then fill out this page) 60

OCH2CF2CHF2 62 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 63 64

—S

-o

och2cf2chf2 Cl • 15 · The paper size is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 5. Description of the invention (β [Table 9] 65

-S

-C A7 B7 0

0 so2cf3 66 Ο

\ CF C Fr s

-SC

CF, λ. (Please read the notes on the back before filling this page) 1 / ¾.

-S CH,

A, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 71 72 C °) >-r \

och2cf2chf2 Order -Γ!

—S

S

Cl 16 · The size of this paper applies to Chinese National Standard (CNS) A4 (210X297 mm) A7 B7 V. Description of the invention (β) [Table 1 0 73

S- < NCO

Cl

-S- < NCO

F 75

-S- < ^ NCO NO,

S- < NCO CF,

77 — S— <NCO OCHF,

One S— <NCO OCF, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

—S- 〈NCO och2cf3

—S- &lt; NCO OCFoCHF. • 17 · (Please read the precautions on the back before filling this page)

This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of invention (4) [Table 1 1]

S- &lt;, NCO

—S- &lt; NCO OCHgCFgCH1 ·, Hachiman ^) ~ S〇 2ch3

-S- &lt; (^ NCO

SOoCFr (Please read the notes on the back before filling out this page) 84

S- &lt; NCO

F

Oh-F order '85

S— &lt;, NCO

〇 &gt; -CF: CH

—S- &lt; NCO CF〇

OCF, printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

OV-OCHoCFoCHFj • 18. This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 5. Description of the invention (&lt; 7) [Table 1 2]

—S— &lt; NCO

CF, N

CH,

-s- &lt; r: nc〇 / \ / S λ NO, (Please read the notes on the back before filling this page) Order

CF, 〇cf3 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -so,

96 —S

-c NCO CF, 19- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of invention (iS [Table 1 3]

—S— <NCO

oV-ocf,

-S-k ^ NCO

F

—S—k &gt; iCO

CN --------- 61- (Please read the notes on the back before filling out this page) 100 CF, ^ 101 -S people JiCO Hachiman OCF, 102 -Sk. OCF, CHF, Central Ministry of Economic Affairs Printed by the Standards Bureau Consumer Cooperatives 103 104 —S-, “C0 OCHoCFoCHF,

—S-k ^ NCO

CF, -20- This paper size is applicable to Chinese National Standard (CNS) A4 specification (2IOX297 mm) 5. Description of the invention (, 9) [Table 1 4] 105 106 107 108 109 110 A7 B7 -S-k SCH, so2ch3

-S-k ^ NCO

-S-L -S-, Jjco

F

0 &gt; -CF,

—S-k JvICO, 〇) -〇CH2.CF2CHF2 CH,

CF, -S-k ^ NCO

O / -CF, Cl Printed by the Consumer Cooperatives, Central Standards Bureau, Ministry of Economy 111 112

-S-, JsICO

Cl N

-S-k ^ NCO

OCF, N 21. (Please read the notes on the back before filling this page)

This paper size applies the Chinese National Standard (C.NS) A4 specification (210X297 mm) V. Description of the invention (〆) [Table 1 5 113 114 115 116 117 118 A7 B7

* S ~ k ^ NCO

NO, N-

-S-C3nCO ^^ O ^ ~ CN -s- ^ Jnco ^ Y ^ V ^ 01 CH, -s-k ico ^ 's

CF, ΓΗ

-s-c

-S-k / NCO cf3 NOj Cl (Please read the notes on the back before filling in this page) Order-Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 119 120

F

-SO. Eight iC0, ^ &lt; 〇 &gt; -F CF, -22- This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) A7 B7 V. Description of the invention (&gt; 1) [Table 1 6] 121

-S-k ^ NCO

OCF〇 N

-S- &lt; NCO

Cl

-S- (. NCO NO, (Please read the notes on the back before filling this page)

124 --S- &lt; NCO

CN 125

-S— &lt; NCO CF, order

-S- (NCO OCHF, printed by Employee Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs 127 128

-S- (NCO OCF- ·

-S- (NCO / ^ X〇) -och2cf2chf2 23. This paper size applies to China National Standard (CNS) A4 (210X297 mm). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs: A7 B7 V. Description of the invention ( 》) [Table 1 7]

129 --S- &lt; ^^ N no2

F

131 &amp; -o.cf3 132 —s—nco / ^ Λ 〇 &gt;-CN cf3 133 —SN F 134 -cf3 135 .-s- (~, &gt; ιοο ^ γ ^ -OCF, CH 3 • 136 — S- &lt; ^ VlCQ / ^^ &amp; cf3 '24 This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) --- II-II-^ Λ-^ .--- 1 n 11 (Please read the precautions on the back before filling this page) A7 B7 V. Description of Invention (4) [Table 1 8

137 --S C 1 138

--S CF, 139 NO, 140

141

-s- &lt; Nco ^^ YAWT-CFs, ch3 -SO,-(: NCO \ N

Cl 142

-S- (Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, NCO 144

143 --S SJCO

〇 V-OCF, CH,

S- &lt; NCO

0 &gt; -F (Please read the notes on the back before filling this page)

This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7 V. Description of invention (pair) [Table 1 9] 146 149 150

145 -S

Cl OCF,

147 —S

F

O) -CF,

CH, 148 a S. CO

ocf2chf2

(Please read the notes on the back before filling out this page)-Ordered by the Central Ministry of Economic Affairs; printed by the Consumer Council

151 -S

CO

CF, N

152 ~ S

CH, 26- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (&lt;) [Table 2 0] CH, —s- &lt; &gt; l · CF,

—S

OV-CI —s

—S

—S

(Please read the notes on the back before filling out this page) Order Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

CF, 27 · This paper size applies to Chinese national standards (CNS> A4 size (210X 297 mm) A7 B7 V. Description of invention (4) [Table 2 1] 161

CF

OCF,

-S

S CF,

One S

0 / -NO; CF, H CH, -Ν V '〇 \ -〇CH2CF2CHF2

-S

F ------------ "2 in — (Please read the notes on the back before filling out this page) Order Central of the Ministry of Economic Affairs? I Associate Bureau employee consumer cooperative system

--C

F H CH, N \ ^; G; n

-28 · This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (&gt;?) [Table 2 2 169 H Q Ο Π Ν person

Ο CHc CF, 170

SOoCH, 171 17Z

(· Please read the notes on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

-29- Q) -och2cf2chf2 ^ SCFa .S (0) CF3 V-cf3 This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 5. Description of the invention ([Table 2 3 177

A7 B7 S- &lt; &gt; -C ^ C 0 _ / ^ 0) ~ CF3 178

s- &lt;) -c = c och2cf2chf2 179 —s

180 -s

I .-------- i clothing-(Please read the precautions on the back before filling out this page) 181 182 183 184 Printed by the Staff Consumer Cooperative of the Central Ruzhun Bureau of the Ministry of Economic Affairs 185 186 187 S (0) CF3

-sY • 30 · This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) A7 B7 Printed by the Central Government of the Ministry of Economic Affairs, Consumer Cooperatives of the Bureau of Commerce 5. Description of inventions (Qiao) The suitable compounds in Table 1 are: 4, 6, 7, 13, 16, 18, 11, 25 \ 32 Ν 36. 4 0. 43ν 44ν 47ν 52 Λ 53λ 61, 63. 7 1, 76, 96. 107. 123. 127. 142ν 174. 117 , 178. 18Κ 182, 183 are 186-substituted compounds, especially suitable: 2- (2,4-difluorophenyl) -3-[[2- [2- [4- (trifluoromethyl) phenyl ] Vinyl] -1,3-dimorphan-5-yl] thio] -1- (1H-1,2,4-triazole-butyl) -2-butanol (Example 2) 2- (2,4-difluorophenyl-triazol-1-yl) -3-[[[2- [2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane -5-yl] thio] -2-butanol (Example 11) 2- (2,4-difluorophenyl) -1- (1Η-1,2,4-triazol-1-yl)- 3- [[2- [4- [4- (trifluoromethyl) phenyl] -1,3-butadien-1-yl] -1, 3-dipaldin-5-yl] thio] 2-butanol (Example 15) 2- (2,4-difluorophenyl) -3- [[2- [4- [4- (2,2,3,3-tetrafluoropropoxy) Phenyl -1,3-butadiene-1-yl] -1,3-dioxin-5-yl] sulfanyl] -bu (1H-1,2,4-triazol-1-yl) -2- Butanol (Example 16) 2-(2, 4-difluorophenyl) -3- [[2- [4-(4-Phenylphenyl) -4,4,4-trifluoro-1,3- Pentadien-1-yl] -1,3-di-M-l-yl] thio]]-((1,1,2,4-triazol-1-yl) -2-butanol (implementation Example 18) 2- (2,4-difluorophenyl) -3-[[1-[[4- (trifluoromethoxy) cinnamoyl]] Yodo-4 -yl] thio] -1- (1H-1,2,4-trimile.-1-yl) -2-butanol (Example 21) 2- (2,4-difluorophenyl) -3- [[1- (4-nitro Cinnamyl]] piperidin-4-yl] thio]] (1H-1,2,4-triazol-1-yl) -2-butanol (Example 23) -31- This paper is applicable to China National Standard (〇 阳) 8 4 specifications (2 丨 0 乂 2.97 mm) (Please read the precautions on the back before filling this page) Order A7 B7 V. Description of the invention (V) 2- (2,4-difluoro Phenyl) -1- (1Η-1,2,4-triazole-butyl) -3-[[1- [5- [4- (trifluoromethyl) phenyl] -2,4-pentyl Dienal] piperidin-4-yl] thio] -2-butanol (Example 24) 3-methyl-1- (1H-1,2,4-tri Azol-1-yl) -2- [4- (trifluoromethyl) phenyl] -3- [[2- [4-[(trifluoromethyl) phenyl] -1,3-butanediene- 1-yl] -1,3-dioxan-5-yl] thio] -2-butanol (Example 31) 2- (2,4-difluorophenyl) -Bu (1H-1,2 , 4-triazol-1-yl) -3-[[2- [4- (trifluoromethylthio) phenyl] -1,3-butanez-1-yl] -1,3-dimer Alk-5-yl] thio] -2-butanol (Example 32) 3-[[2-[4 '-[4-(2,2,3,3-tetrafluoropropanyl) phenyl] -1, 3 -butadiene-butyl] -1,3-dioxan-5-yl] thio] -bu (1 Η-1, 2, 4, triazol-1-yl) -2- [4- (trifluoromethyl) phenyl] -2-butanol (Example 3 3) 1- (111-1,2,4-triazol-1-yl) -2- [4- (trifluoro (Methyl) phenyl] -3- [[2- [4- [4- (trifluoromethyl) phenyl] -1,3-butadiene-butyl] -1,3-dioxane-5 -Yl] thio] -2-butanol (Example 34) 2- (2,4-difluorophenyl) -1- (1Η-1,2,4-triazol-1-yl) -3- [[2- [4- [4- (trifluoromethanesulfinyl) phenyl] -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio ] -2-butanol (Example 35) Central Standard of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperatives (please read the precautions on the back before filling out this page) -3-[[4- [4- (trifluoromethyl) phenyl] -1,3-butadien-1-yl] .cyclohexyl] thio] -2-butanol (Example 36) 2 -(2,4-difluorophenyl) -1- (1Η-1,2,4-triazole-boxy) -3-[[2- [6- [4- (trimethylol) phenyl 〕 -1,3,5 -H.Three-Sens-1-Base] -1 -32- This paper size applies Chinese National Standard (CNS) A4 specification (210X: 297mm) A7 ____B7 V. Description of invention (W) *, 3-Dibenzyl-5-yl] thio] -2-butanol (Example 37) 2- (2,4-difluorophenyl) -3-methyl-1- (1H-1. , 2,4-triazol-1-yl) -3- [[2- [4- [4- (trifluorosynyl) phenyl] -1,3-butadiene_1-yl] -1,3 -Dioxan-5-yl] thio] -2-butanol (Example 38), and 2- (2,4-difluorophenyl) -1- (10-1,2,4-triazole -1-yl) -3-[[2- [4- [4- (4- (trifluoromethyl) phenyl] -1-butene-3-yn-1-yl] -1, 3-dimorpho- 5-yl] thio] j-2 -butanol (Example 39) The triazole compound (1) of the present invention has at least 2? Science and optical isomers and enantiomers exist as the hip. Optical isomers can be separated by two steps: recrystallization or chromatography using general optical separation or asymmetric synthesis to obtain two enantiomers, or diastereomers. The compound (I) of the present invention includes one or a mixture of these isomers. The triazole compound (1) of the present invention may be used as an antifungal agent as it is or a pharmacologically acceptable salt. The pharmacologically acceptable compounds of the compound (1) may be salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, such as acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, and citric acid. Salt of carboxylic acids such as malic acid, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc., or salts of amino acids such as glutamic acid, aspartic acid, etc., preferably carboxylic acid Sour hair. Printed by the Central-Associate Bureau of the Ministry of Economic Affairs Consumer Cooperatives (Please read the notes on the back before filling this page) Hydrate of Compound (1) and Salt Hydrate of Compound (1) are also included in the compounds of the present invention. The compound (1) and its pharmacologically acceptable salt of the present invention have excellent fungicidal activity, and when the compound (1) and its pharmacologically acceptable salt are used as antifungal, it can be used by itself or with a suitable pharmacologically acceptable excipient, Diluents, etc. are mixed, and taken orally, such as tablets, capsules, granules, powders or syrups, etc. -33- This paper ^ degree applies to the Chinese National Standard (€€) 8 4 specifications (210 father 297 mm) Ministry of Economic Affairs Printed by the Central Standards Bureau Shellfish Consumer Cooperative A7 B7 V. Description of Invention (&gt;), or parenteral administration such as injection. These preparations can use excipients (such as sugar derivatives such as lactose, white sugar, glucose, mannose, anisodose, etc., such as corn starch, potato starch, starch derivatives such as corn starch, dextrin, carboxymethyl starch; Crystalline vitamins, low-substituted hydroxypropyl ferritin, hydroxypropylmethylferritin, carboxy-methyl cellulose, calcium carboxymethyl cellulose, internally bridged cellulose derivatives such as sodium carboxymethyl cellulose Acacia gum; Polydextrose; Amylopectin; such as light silicic anhydride, synthetic aluminum silicate, magnesium aluminosilicate, and other silicon and acid derivatives; phosphate derivatives such as calcium phosphate; such as sulfonic acid Sulfonate derivatives; Sulfate derivatives such as calcium sulfate), binders (such as the aforementioned excipients; Mingu; polyvinylpyrrolidine polyethylene glycol, etc.), disintegrating agents (such as the aforementioned excipients; carboxylic acid Sodium methyl ether cellulose, sodium carboxymethyl starch, bridged polyvinylpyrrolidone and other chemically modified starches and pavinin derivatives, etc.), talc (such as talc; stearic acid; such as calcium stearate, stearic acid) Metal salts of stearic acid such as magnesium; colloidal silica; magnesium aluminum silicate; salamanders such as cetaceans Boric acid; ethylene glycol; carboxylic acids such as fumaric acid, adipic acid; sodium salts of carboxylic acids such as sodium benzoate; sulfates such as sodium sulfate; leucine; such as sodium dodecyl sulfate, dodecyl sulfate Dodecyl sulfate, such as magnesium; silicic acids such as silicic anhydride, silicic acid hydrate; starch derivatives in the aforementioned excipients; stabilizers (such as methyl paraben, propyl paraben, etc. Parabens; alcohols such as gas butanol, benzyl alcohol, phenethyl alcohol; benzane gasified ammonium, such as phenol, methyl alcohol, etc .; ...... Thirosalal (Thinerosal), acetic anhydride; calyx Acid, etc.), flavor corrector (such as conventional sweeteners, sour flavors, flavors, etc.), suspension emulsifiers (such as polycyanate 80, sodium carboxymethyl cellulose, etc.), diluents, solvents for formulation- 3 4-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) --------- 0W ------ 1T (Please read the precautions on the back before filling this page) A7 _________ B7 ___ Description of the invention (W) 添加 (such as water, ethanol, glycerin, etc.) and other additives are manufactured according to conventional methods. The dosage varies with symptoms, age, etc. When taken orally, 1 ~ 2000ag once a day, preferably 5 ~ 1000g, and when administered on a knee, 毎 0.1 ~ 6 0 0 bg, preferably 0 · 5 to 50 Qag, it is recommended to adults 1 to 6 times a day according to symptoms. Embodiments of the invention In the compound (1) of the present invention, r0 is Η, and n = 〇 can be prepared as follows:

(Please read the precautions on the back before filling this page.) In the formula, Ar1 and R1 are the same as before, and R8 is the aforementioned. Printed by the Central Government of the Ministry of Economic Affairs! q- (C = c) r- (R4C = CR5) S-Ar2 The ring gas compound (2) and thiol (3) or its acetate derivative (4) described in Japanese Patent Application Laid-Open No. 2-191262 under 鹾 conditions The reaction proceeds to obtain the object (1). The solvents used are preferably alcohols such as methanol, ethanol, and propanol; aprotic solvents such as dimethyl formamide, dimethyl ethylamine, dimethyl iodide, acetonitrile, and tetrahydrofuran; 4) When reacting in the above aprotic solvent, it must coexist with alcohol or water. The hydrazone used in the reaction may be sodium hydride, sodium methoxide, sodium ethoxide, lithium methoxide, potassium tert-butoxide, LiOH ^ NaOH, KOH, and 0.1 ^ 2 mole times for compound (2). The thiol (3) or its acetate derivative (4) is used at 1 to 3 mole times. The reaction temperature is from room temperature to 1〇 »〇. The reaction time is 2 to 10 hours. After the reaction, treat it in the usual way (using organic solvents -35- this paper size applies Chinese National Standard (CNS) A4 specifications (210 × 297 mm)

V. Description of the invention (W A7 B7 extraction, evaporation of the solvent, the oil obtained is purified by column chromatography or recrystallization) to obtain the compound (1). The R 8 S Η (3) or r 8 s A c (4) used can be prepared according to the following method, that is, the compound (3a &gt; or (4a) where R 8 ΨΑ is a 1,3-dioxane ring and p = 0 Known compound (5) (Document: 〇.Ε. Van Lohuizeii, PEVerfcade, Kec * trav * chim., 78,460 (1959) as raw material, manufactured by the following process

NaSCH2-

Cl

DMF ci—ch2s

HC1

MeOH C 丨 ch2s

iH R2 R3 R4 K5OHC— (C = C) q— (〇Ξ〇— (0 = 0) ~ Ar ^ ⑹ H +

Cl / -χ / -〇 R2R3 R4 R5 ~ ^ 3> —CH2S —) — (C = C) q— (C = C) — (C = C) —Ar2

Printed by mCPBA, Central Bureau of Standards, Ministry of Economic Affairs, Printed by Coconut Consumer Cooperatives r2 r3 r4 r5 2. NaHC03 aqueous solution -36 This paper size applies to China National Standard (CNS) A4 (210X2.97 mm) (3a) (Please read the back (Please fill in this page again)

A7 B7 V. Description of invention (shirt)

Ac2〇

AcS NEt3 Factory 〇R2R3 R4R5 (C = C) q- (C = C) — (C == C) —Αγς (4a) (where R2, R3, R4, R5, Ar2, q, r, s are the same as above ) (For the reaction conditions and single removal of each process, please refer to Reference Examples 3, 4, 5, 6, and 7). Among the unsaturated aldehydes (6) used, the compound with r = 0 '(6a) can generally be prepared by unsaturated ester (7a) according to the following method (for the reaction conditions and single ionization methods of each process, refer to Reference Examples 8, 9 , 10, 20, 21, 22, 23, 33, 49). R5 R4 (C = C) s-i— 《R5 OR4 R3 R2

NaH R5 R4 R3 R2 Ar 2— (C = C) — (C = C) q-COOE t (7a)

DIBAL-H

R5 R4 R3 R2 — (C = C) g — (C = C) q—CH2OH

Mn〇2 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs r5r4 r3 r2 A… .: Two w s — (C = C) q—CIIO (6a) -37 (Please read the precautions on the back before filling this page)

This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 5. Description of the invention (々Ο A7 B7 (where R 2, R 3, R 4, R 5, Ar 2, q, s are the same as before, DIBAL-Η is diisobutylaluminum hydride) 0 compound (6b) of r = 1 and 2 in unsaturated aldehyde (6)-generally obtained by unsaturated ester (7b) according to the following method (reaction conditions of each process And single ionization method, please refer to Reference Example 4 4, 4 5, 4 7, 4 8). R5R4 Ar2- (C = C) ~ Br + n3 V Pd (II)-Cu ① H (C = C) ~ CH— OH-NEt3

R5 R4 R3 Ar ^ — (C = C) ~ (C = C) —CH ~ 0H

[〇] R5 R4 r3 Ai * 2— (C = C) f (0Ξ〇 · ρ— 《(Please read the precautions on the back before filling this page) 0 R2 R3R2 (EtO) 2P ~ CH— (C = C) q_i—COOEt R5 R4 R3 R2

Ar ^-(C = C) s ~ (C = C) — (C = C) q-C00Et

DIBAL-H

Mn〇2 R5R4 R3 R2 Ar2— (C = C) s— (C = C) — (0 = 0) 0-0110 (6b) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (where R2, R3, R4 , RS, q, r, s are the same as above, DIBAL-H is diisobutylaluminum hydride). 118811 (3) 1188 eight (: (.4) of eight of 118 are 4 to 7 members containing 1}. Heterocycle (azetidine, pyrrolidine, piperidine, homopiperidine) and P = 1 compound (3b ) Or (4b) can be manufactured according to the following methods (for the reaction conditions and single ionization methods of each process, please refer to Reference Examples 16 and 17). -38 ** This paper size applies the Chinese National Standard (CNS) A4 specification (210X297) %) A7 B7 V. Description of the invention (w OH (CH2)

MeS02Cl N——Boc-； NEt3 OS〇2Me

N—Boc KSAc

DMF SAc

HC1 SAc

NH-HC1 〇 R2 R3 R4R5 Cl—C— (C = C〉 · ^ —Ar2 (10) / NEt3 (Please read the precautions on the back before filling this page) SAc

〇 R2R3 R4 R5 -C— (C = C) q— (C = C) — (C = C) s ^ Ar2 (4b)

NaOMe

MeOH

SH

N- printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 〇r2r3 r4r5 &quot; C— (C = C) q— (C = C) y— (0 = 0) —Ar ^ (3b) (where R 2 ， R 3, R 4, R s, q, Γ, s are the same as above, t is 3, 4, 5 or 6, Boc is the third butane carbonyl) β. The radon gas (10) used can convert the aforementioned unsaturated ester Ua ), (7b) is obtained by decomposing into carboxylic acid with alkali, and then treating with sulfinic sulfonium gas. In the compound (1) of the present invention, and n = 0, the following method can be used: -39- The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 5. Description of the invention (4) Manufacturing

R1SH

Ar1

(ID A7 B7 R8 —) (12)

(1) Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs (where Ar1, 111, and R8 are the same as before, x is ^ Br or I, methanesulfonyl group, benzylsulfonyl group, or tosylsulfonyl group). That is, the triazole thiol (11) described in Tokaikai 3-2 4 0 7 78 was reacted with an alkylating agent (12) under salty conditions to obtain the target product (1). The solvents used were methanol, ethanol, and propyl. Alcohol, butanol, dimethylformamide, dimethylacetamide, dimethylmethylene, acetonitrile, tetrahydrofuran, dioxane ', ether, acetone, benzene, toluene, xylene, etc. The base used can be three Ethylamine, diisopropylethylamine, sodium hydride, sodium methoxide, sodium ethoxide, lithium methoxide, potassium tert-butoxide, NaOH, KOH, etc. are used in an amount of 1 to 3 mol times for compound (11). Alkyl For the chemical agent (12), use 1 to .3 moles. The reaction temperature is -50 to 100 ° C, and the reaction time is 2 to 10 hours. After the reaction, treat it according to the usual method (take it up with an organic solvent and evaporate it). Solvent, and the obtained oil is purified by chromatography or recrystallization) to obtain compound (1). The alkylating agent R8-X (12) used can be prepared as follows. 1 {8 in which 厶 is 1, 3-2 The compound (12a) having a pinane ring and p = 0 can be obtained, for example, by reacting the diol compound (13) obtained by acid-treating the aforementioned compound (5) in methanol with an unsaturated aldehyde (6) as described above under acidic conditions. (See Example 5 6, 5 7). 40 This paper size applies to China National Standard (CNS) A4 (210X 297 mm) —I · HB1 1 ^ 1 i ^ i an —ϋ m ^ / ^ -1 »1 ^ ^ 1, a'§J (Please read the precautions on the back before filling this page) 5. Description of the invention (shirt (5) R2 R3 OIIC— (C = C) q- (C ^ C) ^ ⑹ H + A7 B7 HC1

MeOH

TsO

丨 Η (13)

OH R4R5-(C = C) ^-Ar2 / ~ 0 ff R4 R5 TsO <) (C = C) q— (C ^ C) f ~ (C = C) s ~ Ar (12a) (where R 2 , R 3, R 4, R 5, Ar 2, q, r, s are the same as above). A in R 8 is a 4- to 7-membered N-containing heterocyclic ring (azetidine, pyrrolidine, piperidine, homopiperidine) and P = 1 (12b), for example, the aforementioned cyclic amine derivative (8) can be The compound (14) obtained by the HC1 treatment is obtained by reacting the aforementioned chloro chloride (10) in the presence of a base such as triethylamine. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

HC1 OS〇2Me

NH-HC1 4 1-(Please read the notes on the back before filling this page)

This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) A7 B7 V. Description of invention (knowledge) 0 r2r3 C1—C— (C—C) 0 ~ &quot; (C = C) (10) R4 R5-(0 = έ) 5-ΛΓΣ -► NEt3 Q R2R3 NC— (C = C) q- (C = C) — (C ^ Og-Ar &quot; (12b) (where R2, R3, R4, RS , At r2, q, r, s, t same as above) (Please read the notes on the back before filling this page) R4 R5 OS〇2Me

Among the compounds (1) of the present invention, compounds in which H, n = 0, p = 0, and A is a 1,3-dioxane ring can be produced by the following method.

(17)

Ordered by the Central Bureau of Standards of the Ministry of Economic Affairs for the printing of shellfish consumer cooperatives R2 R3 R4 R5) — (C = C) q— (C = C) — (C = C) s—Ar2 R2R3 r4r5 0HC- (C = C) q -(C = C) — (C = C) s ~ Ar2 ⑹

⑴ 42 This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) Printed on the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 __— _B7__. V. Description of the Invention (β) (where Ar1, Ar2, Ιί1, R2, R3, R4, rs, p, 9 and! · Same as above). That is, the thioacetic acid derivative (15) obtained by reacting the foregoing compound (2) with the previously known compound (5) and sodium thioacetate reacts under the same reaction conditions as (2) and (4) to obtain compound (16). ), (16) is deprotected by a conventional method such as acid treatment to obtain (17), and (17) is reacted with the aldehyde compound (6) to produce the target product (1). The reaction of (17) and (6) is usually carried out under acidic conditions. The acid used may be HC1, sulfuric acid, nitric acid, boron trifluoride, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid. The amount of acid used is (17) Use Wei ~ 2 mole times, aldehyde (6) can use 1 ~ 2 mole times. The solvent can be dichloromethane, aerobic, 1,2-digas ethane, benzene, toluene, xylene, ether, Aprotic solvents such as tetrahydrofuran. The reaction takes place at a temperature of 0 ° C to the boiling point of the solvent. The β reaction time is 2 to 10 hours. The water produced by the reaction can be removed by azeotropy, or molecular sieves can be used as dehydrating agents. The reaction solution is desulfurized. After neutralization with sodium water, etc., it is processed according to a conventional method (extraction with an organic solvent, evaporation of the solvent, and the obtained oily substance is purified by chromatography or crystallization) to obtain compound (1). Among the compounds of the present invention, hydrazone, II = 0, p = i, a is 4 ~ Ί Compounds containing H heterocycles (azetidine, pyrrolidine, piperidine, homopiperazine) can be manufactured as follows: 0-43- This paper is applicable to Chinese national standards ( CNS) A4g (2 丨 〇 × 297 公 董) (Please read the back. Please note before filling in this page)

A7 B7 V. Description of the invention (Q-f &lt; 1 〇 F (2R3 (20)

NH ch2);

Cl—C— (C = C) q— (C ^ 〇- (10)

N CH2); R2 R3 R4 R5 _ ^ (¢ = 0 ^-(C = C) g—Ar2 ⑴ (Please read the precautions on the back first and fill out this page) The central standard of the Ministry of Economic Affairs is printed on the shellfish consumer cooperatives ( In the formula, Ar1, Ar2, R1, R2, R3, R4, RS, q, r, s and t are the same as above), and Boc is the third butoxycarbonyl group). That is, the aforementioned ring gas compound (2) and the aforementioned thioacetic acid derivative (9) are treated with a base to obtain a thiol compound (18), and this is reacted under the same reaction conditions as (2) and (3) to obtain compound (19 ), (19) is deprotected to form compound (20) by acid treatment according to a conventional method, and (20) is reacted with the aforementioned fermentation gas (10) to obtain the target substance (1). (20) The reaction of (10) is carried out in an inert solvent such as benzene, toluene, digasmethane, aerosol or tetrahydrofuran in the presence of an appropriate age in accordance with ordinary methods. (Reference examples 13, 14, 18, 19). Among the compounds (1) of the present invention, n = 1 or n = 2 can be produced as follows. That is, the compound (1) of the present invention where n = 0 obtained according to the above method is vaporized with 1 equivalent of a gasifying agent in a solvent to obtain a chemical compound (1) of 1. Oxidation with more than 2 equivalents of oxidant yields compound (1) with n = 2. As long as the solvent used does not hinder the reaction, but it can dissolve the starting material to a certain extent, it is not yet determined, but it is advisable to use gasifiers such as methane, chloroform and other halogenated hafnium. (210X297 mm) A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (4 彡) Peracetic acid and 3-chloroperbenzoic acid. The reaction temperature is 0 to 50 ° C, preferably room temperature, and the reaction time is generally 30 minutes to 2 hours. The reaction solution was processed in accordance with a conventional method (after washing with sodium bisulfate in water, the solvent was distilled off, and the obtained crude product was purified by layering or recrystallization) to obtain compound (l) (n = 1 or 2). Among the compounds (1) of the present invention, a compound in which R0 is a low alkyl group and n = 0 can be produced as follows.

(1) (wherein Ar1, R0 and R8 are the same as above). That is, the bromone (21) obtained by the method similar to that of JP 7-2802 is reacted with the aforementioned thiol (3) or its acetate derivative (0 to form a thioether derivative (22) under alkaline conditions, and (22) In the presence of the test, it can be reacted with trimethyl aconite and 1,2,4-triazole to obtain the target substance (1). (21) The solvent used in the reaction with (3) or (4) should be methanol, ethanol, etc. Alcohols such as propanol can be tested using NaOH, KOH, sodium methoxide, ethanol, etc. The solvent used for the reaction of thioether derivative (22) &lt; 1) is preferably methanol, ethanol, propanol, butanol, Tertiary butanol and other alcohols, dimethyl, methylformamide, dimethylacetamide, dimethylmethylene, acetonitrile, tetrahydrofuran-45- This paper size applies to Chinese National Standard (CNS) A4 (210X297) Li) (Please read the notes on the back before filling in this page)

V. Description of the invention (44 A7, B7 and other aprotic solvents. The base used may be sodium hydride, sodium methoxide, sodium ethoxide, lithium methoxide, potassium third butoxide, 1 ^ 08, 011, 1 [011, for compounds (22) Use 2 ~ 5 mole times. Trimethyl iodide iodide and 1,2,4-triazole use 1 ~ 2 mole times for (22). The reaction temperature is from room temperature to i0 (rc. Reaction. The time is 2 to 10 hours. The reaction solution is treated in the usual way (after extraction with an organic solvent, the solvent is distilled off, and the obtained crude product is purified by column chromatography or re-condensation) to obtain compound (l) (n = 0) Among the compounds (1) obtained by the above method, the compound (23) of β8 &amp; -0 &gt; -Ph) can be passed through the triol (24) as follows to obtain n = 0, p = 0 in the compound (1), A is 1,3-dioxane:

m-Λ 〇H &gt; R

) —- Ph

ArJ (23) Ο Λγ1 (24)

OH 丨 Η eeaaat I-m, I—I IK In —ϋ 1 ·-. ----n. OHC— (C == C) q— (0Ξ〇γ— (C = C) —Ar ^ 印 Printed by Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economy o R4 R5

ArJ — (~ ^) — (C = C) q—g—Ar2 0 (1) 46 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm). Five invention descriptions Ujt A7 B7 (where R0 is Low alkyl · Ar1, Ar2, Ri, R2, R3, R4, RS, q, r and s The reaction conditions of the above processes are the same as those in the above (16)-&gt; (17) -M1). Examples, reference examples, test examples, and preparation examples are described in detail below, but the scope of the present invention is not limited thereto. When the aldehyde compound used in the examples is listed in the parentheses, it can be synthesized according to the method of the document and / or the cited document. The aldehyde compounds that are not shown are commercially available and can be listed in parentheses in the examples or the aldehyde synthesis method in the cited documents or the aldehyde synthesis method that mimics the reference examples in this specification. Example Example 1 (2, 31,- 2- (2,4-difluorophenyl) &gt; -3-[[trans-2 _ [(£) _1_methyl-2- [4- (trifluoromethyl) phenyl] vinyl] yl] thio ] -1- (1H-1,2,4-triazol-1-yl) -2 · butanol (Please read the precautions on the back before filling this page) Order

F Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, trans-4- (acetamidothiomethyl_ 2- [4- (trifluorophenyl) phenyl] vinyl] -1,3 described in Reference Example 7 -Bis (0_48mffl01) and (2R, 3R) -2- (2,4-difluorophenyl) _3_methyl_2_ [(1 !!-1,2,4-triazol-1-yl ） Methyl]》 Propane ring 11〇1 ^ (〇.4411118〇1) Dissolved in dimethylformamide 2 »1, add leu methanol soda_methanol-47- under nitrogen atmosphere This paper standard applies to China Standard (CNS) A4 specification (210X297 mm) 5. Description of the invention (") A7 B7 solution 0.15nl (0.24mmol) e After stirring at 55 ° C for 6 hours, cool and dilute with ethyl acetate, and wash with saturated brine The solvent was distilled off. The obtained oil was subjected to silica gel column chromatography (hexane = ethyl hexanoate = 2: 1) to obtain the target substance 180nig (yield 74%) as an oil. NMR (60MHz, CDClg) ) δ ppm: 1.19 (3H, d, J = 7Hz), 1.90 (3H, d, J = 1.5Hz), 3.34 (1H, q, J = 7Hz), 3. 0-3. 9 (3H, m), 4. 1-4. 6 (2H, m), 4. 80 (1H, d, J = 14Hz), 4. 94 (1H, s), 5.02 (1H, d, J = lHz ), 5. 05 (1H, d, J = 14Hz), 6. 4-7. 0 (3H, m), 7. 1-7. 6 (1H, m), 7. 40 (2H, d, J = 9Hz), 7. 62 (2H, d, J = 9Hz), 7. 80 (2H, s). Example 2 (211,311) -2- (2,4-difluorophenyl) -3-[[trans-2-[(£) -2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxan-5-yl] thio] -Bu (1H-1,2,4-triazol-1-yl)- 2-butanol

S · -〇, ~ 〇 (Please read the notes on the back before filling out this page) Order the imitation example 1 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy, Order (2R, 3R) -2- (2,4- Difluorophenyl) -3 -methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] pyridine and trans-5- (ethylsulfanyl) -2- [(E) -2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane was reacted and treated to obtain the target product with a melt viscosity of 73-75 ° C. Yield: 7096 . Specific rotation [a] D25 -73. 8 ° (01.00, CHC13) NMR (270MHz, CDClg) δ ppm: 1. 19 (3H, d, J = 7.3 Hz), 3. 34 (1H, q, J = 7. 3 Hz), 3. 43 (H, tt, J = ll. 2, 4. 6 Hz), 3. 65 (1H, t, J = ll. 2 Hz), 3. 67 (1H, t, J = ll. 2Hz), 4. 33 -48- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of invention (β) (1H, ddd, J = ll. 2, 4 6, 2. OHz), 4. 46 (1H, ddd, J = ll. 2, 4. 6, 2. OHz). 4. 82 (1H, d, J = 13. 8 Hz), 5. 03 (1H, d, J = 13. 8Hz), 5. 04 (1H, br s), 5. 14 (1H, d, J = 4. 6Hz). 6. 25 (1H, dd, J = 15 .8 , 4. 6Hz), 6. 7-7. 8 (2H, in), 6. 83 (1H, d, J = 15. 8Hz), 7. 3-7. 45 (1H, in), 7. 49 (2H, d. J = 8.6 Hz), 7. 58 (2H, d, J = 8.6 Hz), 7. 79 (2H, s). Example 3 (2R, 3R) -3-. (( Trans-4-[(E) -2- (4-chlorophenyl] vinyl] cyclohexyl] thio] -2- (2,4-difluorophenyl) -1- (18-1,2, 4-three-sleep-buki) -2-butanol (Please read the precautions on the back before filling this page)

Printed in Example 1 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, Order (2R, 31〇-2- (2,4-difluorophenyl) -3-methyl-2- 2-((1H-1,2, 4-triazol-1-yl) methyl] propanyl and trans-1- (acetaldehydethio) -4-[(E) -2- (4ichlorophenyl) vinyl] cyclohexane and After treatment, the target product having a melting point of 64-66 ° C was obtained with a yield of 31%. Specific optical rotation [a] D25 -84.1 ° (C = 2.69, CHC13) NM R (270MHz, CDClg) δ ppm: 1. 16 (3H , d, J = 7.3 Hz), 1. 2-1. 6 (4H, m), 1. 9-2. 0 (2H, m), 2. 1-2. 25 (3H, m). 2 70 (1H, tt, J = ll. 2, 4. 0Hz), 3. 36 (1H, q, J = 7.3 Hz), 4. 60 (1H, s), 4. 83 (1H, d, J = 13. 9Hz). 5.10 (1H, d, J = 13. 9Hz), 6. 11 (1H, dd, J = 15. 8, 7. 3 Hz), 6. 32 (1H, d, J = 15.8Hz), 6.74 (2H, t-1 ike, J = 9Hz), 7.26 (4H, s), 7. 37 (1H, td, J = 8.6, 6.5Hz), 7.76 ( lH, s), 7.83 (lH, s) · -49- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (") Example 4 (2R, 3R)- 3-[[trans-2-[(E) -2- (4-Gaphenyl) ethyl]: yl] -1,3, dioxan-5-yl] thio] -2- (2, 4 -Difluorophenyl) -1- (1Η-1,2, 4-triazol-1-yl.)-2-butanol

S

0) 0 (A)

Cl Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Reference Example 2 (2R, 3R) -2- (2,4-difluorophenyl) -3-C (1,3-dihydroxy-2-propyl) ) Thio] -l- (1H-1,2,4-triazole-butyl) -2-butanol 294mg (0.92fflfflOl) and trans-4-ammonium cinnamon. Wake up 19lBg (l.15uiBoli ) (Bull.Ch em Soc.Japan 5.Free 555 (1979).) Dissolved in 14 m 1 of Diqijiayuan, add p-toluene acid 1 hydrate 2 3 3 mg (1.2 3 ma ο 1) After stirring 1.5 g of molecular sieve 4A for 1 hour and 15 minutes, sodium sulfonic acid was added. After stirring for 10 minutes, the molecular sieve was filtered off. The organic layer was collected and dried, and the solvent was distilled off under reduced pressure. The obtained oily substance was subjected to 15 g of silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain the target isomer (A). 280 ag (yield 67%), oily, and then mixed with hexane: ethyl acetate = 1: 1 to obtain cis isomer (B) 35ng (yield 8% &gt; oily). Specific rotation (A), [ct] 25 -68 e (C = 1.22, CHC13) (B), [α] n25 -80 ° (C = 1.3〇, CHCl; 50 (Please read the precautions on the back before (Fill in this page)

This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (4 · 9) NMR (270MHz, CDClg) δ ppm: (A), 1. 19 (3Η, d, J = 7. 3Hz), 3. 34 (1Η, q. J = 7.3Hz), 3. 41 (1H. Tt, J = ll. 2, 4. 6Hz), 3. 64 (1H, t, J = ll. 2Hz), 3. 66 (1H, t, J = ll. 2Hz), 4. 32 (1H, ddd, J = ll. 2, 4. 6, 2. 6Hz), 4. 44 (1H, ddd , J = ll. 2, 4. 6, 2. 6Hz), 4. 82 (1H, d, J = 13. 9Hz), 5. 01 (1H, s), 5. 04 (1H, d, J = 13.9Hz), 5.11 (1H, d, J = 4.6 Hz). 6.15 (1H, dd, J = 15. 8. 4. 6Hz), 6. 7-6. 8 (2H, in), 6. 76 (1H, d. J = 15.8llz). 7. 25-7. 45 (SII. M). 7. 78 (211, s); (B), 1. 21 (3H, d, J = 7 3Hz), 3.11 (1H, s-like), 3.50 (1H, q, J = 7.3Hz), 4. 2-4. 4 (4Ht m), 4.88 (1H, J = 14. 5Hz), 4. 93 (1H, s), 5. 16 (1H, d, J = 14. 5Hz), 5. 23 (1H, d, J = 4. 6Hz), 6. 2 1 (1H, dd , J = 16. 5, 4. 6Hz), 6. 65-6. 8 (2H, m), 6. 76 (1H, d, J = 16. 5Hz), 7. 25-7. 45 (5H, m), 7.77 (lH, s), 7.80 (lH, sh) After dissolving (A) 54 ng in ethyl acetate and adding 19Bg of oxalic acid, add hexane to filter the crystals to obtain oxalic acid with a melting point of 89 ~ 2 ° 0 65mge of salt like this (B) Oxalate, melting point 94 ~ 95 ° Ce Example 5 (2 ^, 31〇-2- (2,4-difluorophenyl) -3-[[trans-2-[(£) -2- (3 -Pyridyl) vinyl] -1,3-dihenyl-5-yl] thio] -1- (1H 1,2,4-trisept-1-yl) -2 -butanol central Consumer Bureau of Standards Bureau

(Please read the precautions on the back before filling in this page) Put (2R, 3R) -2- (2,4-difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) sulfur Group] -1-[(1H-1,2,4-triazol-1-yl) -2-butanol 12OBg (0.33bbo1) and trans- (3-pyridinyl) acryl 60ng (0.45Bnol ) -51- 'This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) Printed on the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _____B7____ 5. Description of Invention (i-) (J-Med.Chen.H 839 (1975)) was dissolved in methylene chloride 5b1, and 190Bg (1.00mB0l) of p-toluenesulfonic acid monohydrate and 1.2A of molecular sieves were added. After stirring for 1 hour and 15 minutes, sodium sulfonate water was added, and the mixture was stirred for 1.0. After the separation, the molecular sieves were removed, and the mixture was dried by extraction with aerosol, and the solvent was distilled off. The obtained oil was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 4 ~ 1: 5) to obtain 82 ng of the target isomer (A) (yield 52%). β times dissolve with ethyl acetate ~ 5% methanol-ethyl acetate to obtain 28mg of cis isomer (B) (yield 15%), melting point 118 ~ 125 ° C, solid. NMR (270HHz, CDClg) 5 ppm: (A), 1 · 20 (3H, d, J = 7.3 Hz), 3. 34 (1H, q, J = 7. 3Hz), 3. 43 (1H, tt , J = ll. 2, 4. 6Hz), 3. 65 (1H, t, J = U. 2Hz), 3. 68 (1H, t, J = ll. 2Hz), 4. 33 (1H, m) , 4. 46 (1H, m), 4. 83 (1H, d, J = 13. 9Hz), 5. 04 (1H, s), 5. 04 (1H, d, J = 13. 9Hz), 5 14 (1H, d, J = 4.0 Hz), 6. 25 (1H, dd, J = 16. 5, 4. 0Hz), 6. 7-6. 8 (2H, m), 6. 81 ( 1H, d, J = 16.5Hz), 7. 29 (1H, dd, J = 7, 9, 4. 6Hz), 7. 3-7. 45 (1H, m), 7. 73 (1H, dt , J = 7. 9, 1Hz), 8. 5 KlH, dd, J = 4.6, 1Hz), 8. 62 (1H, d, J = lHz); (B), 1. 22 (3H, d , J = 7. 3Hz), 3.13 (1H, br s), 3.50 (1H, q, J = 7. 3Hz), 4. 2-4. 4 (4H, m), 4. 88 (1H, d, J = 13. 9Hz), 4. 94 (1H, s), 5.17 (1H, d, J = 13. 9Hz), 5. 26 (1H, d, J = 4.6 Hz), 6. 31 ( 1H, dd, J = 16. 5, 4. 6Hz), 6. 65-6. 8 (2H, m), 6. 81 (1H, d, J = 16. 5Hz), 7. 26 (1H, dd , J = 7. 9, 4. 6Hz), 7. 74 (1H, td, J = 7. 2, 6. 6Hz), 7. 74 (1H, br d, J = 7.9 Hz), 7. 77 (1H, s), 7. 80 (1H, ^), 8. 50 (1H, br d, J = 4.6 Hz), 8. 63 (1H, br s). Example 6 (2 ^ 311) -2- (2,4-difluorophenyl) -3-[[trans-2-[. (£) -2- [4- (trifluoromethyl) phenyl] Vinyl] -1,3-dioxane-5-yl] thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol-52- Applicable to this paper size Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling this page) Order A7 B7 V. Description of invention (in) nCn

sr ° &gt; ... ^ 〇 &gt; -CF = ν_〇 Like Example 4, let (2R, 3R) -2- (2,4-difluorophenyl) -3-[(1,3- Dihydroxy-2-propyl) thio] -1-[(1H-1,2,4-triazol-1-yl) -2-butanol and the trans-Reference of Reference Example 22-4- (trifluoromethyl ) The reaction and treatment of cinnamaldehyde gave the target product as the main product (62% yield). The physical data and spectral values were consistent with those in Example 2. Example 7 (21 ?, 3.-2- (2,4-difluorophenyl) -3-[[trans-2-[(£) -2- (4-fluorophenyl) vinyl] -1 , 3-dioxan-5-yl] thio] -1- (1H 1,2,4-triazole-butyl) -2-butanol

^ -0 s

F (Please read the notes on the back before filling out this page), 3. Order the printed example 4 printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, Order (2 R, 3 R)-2-(2, 4- Difluorophenyl) -3-[(1, 3 -dihydroxy-2-propyl) thio] -1-[(1H-1,2,4-triazole-.1-yl) methyl]- 2-Butanol and trans-4-fluorocinnamaldehyde (Arch. Pharm. 31 $ 574 (1983)) reaction and treatment, the main product is obtained as the main product, oily, yield 66% 〇-5 3-this paper size Applicable to China National Standard (CNS) A4 specification (210X297 mm)

V

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention () NM R (60MHz, CDC13) δ ppm: 1. 20 (3H, d, J = 7Hz), 3. 1-3. 9 (4H , m), 4. 1 -4.6. (2H, m), 4. 78 (1H, d, J = 14Hz), 4. 99 (1H, d, J = l. 5Hz), 5. 06 (1H , d, J = 14Hz), 5. 09 (1 H, d, J = 4Hz), 6. 07 (1H, dd, J = 16. 4Hz), 6. 79 (1H, d, J = 16Hz), 6. 5-7. 6 (7H, m), 7. 78 (2H, s). This is mixed with 1 equivalent of oxalic acid in ethyl acetate-hexane solution to obtain a melting point of 1 3 2-1 3 5'C. Crystals of oxalate. Example 8 (21 ^ 31〇-2- (2,4-difluorophenyl) -3-[[trans-2-[(£) -2- [2-fluorene-4- (trifluoromethyl) Phenyl] vinyl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol CF, imitation Example 4, Let (2R, 3R) -2- (2,4-difluorophenyl) -3-[(l, 3-dihydroxy-2-propyl) thio] -l- (lH-1, 2,4-triazol-5-yl) -2-butanol was reacted and treated with trans-2-fluoro-4- (trifluoromethyl) cinnamaldehyde, and the target product was obtained in the form of oil. %. Specific rotation [a] D 3 -72 * (C = 0.63, CHCi3) NMR (270MHz, CDClg) δ ppm: 1. 20 (3H, d, J = 7.0 Hz), 3. 34 (1H, q, J = 7. 0

Hz), 3. 43 (1H, tt, J = ll. 3, 4. 6Hz), 3. 65 (1H, t, J = li. DHz), 3. c, J = ll. 3Hz), 4. 3 4 (1H, m), 4. 46 (1H, m), 4. 83 (1H, d, J = 14. 0Hz), 5. 04 (d, J = 14. 0Hz), 5. 04 (1H , d, J = l. 1

Hz), 5. 15 (1H, d, J = 4.2 Hz), 6. 36 (1H, dd, J = 16, 3, 4.2 Hz), 6. 7-6. 8 (2H, m), 6. 97 (1H, d, J = 16. 0Hz), 7. 3-7. 45 (3H, m), 7. 58 (1H, t, J = 7. 6Hz), 7. 79 (2H, s ) e -5 4-This paper size applies to Chinese national standards (CNS &gt; A4 size (210X297 mm) (Please read the precautions on the back before filling this page)

V. Description of the invention (A7 B7 Example 9 (211,31〇-2- (2,4-difluorophenyl) -3-[[trans-2-[(£) -2- [4- (A Sulfonyl) phenyl] vinyl] -1,3-dioxan-5-yl] thio] -bu (1H-1,2,4-triazole-buyl) -2-butanol

s ^ tV ^ ~ ^ &quot; s (0) 2CH3 \ —η (read the notes on the back and then fill out this page) The Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, printed a copy of Example 4, Order (2R, 3R) -2- (2,4-difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) thio] -bu [(1H -1,2,4-triazole- Butyl) -2-butanol was reacted with trans-4- (methylsulfonyl) cinnamaldehyde to obtain the target product as an oily product with a yield of 58%. N MR (60MHz, CDCl3 + D2〇) δ ppm: 1.20 (3Η, d, J = 7Hz), 3. 00 (3Η, s), 3. 33 (1H, q, J = 7Hz), 3. 5-4. 0 (3H, m), 4. 2-4. 8 (2H, m), 4. 80 (1H, d, J = 14Hz), 5. 08 (1H, d, J = 14Hz), 5. 15 (1H, d, J = 4Hz), 6. 30 (1H, dd, J-17, 4Hz), 6. 90 (1H, d, J = 17Hz), 6. 55-7. 0 (2H , m), 7. 2-7. 6 (1H, m), 7. 58 (2H, d, J = 8Hz), 7. 80 (2H, s), 7. 94 (2H, d, J = 8Hz ). Example 1 0 (2R, 3R) -2- (2,4-difluorophenyl) -3-[[trans-2-[(E) -2- (nitrophenyl) vinyl] -1,3 -Dioxan-5-yl] thio] -1- (1H-1,2,4-triazole-butyl) -2-butanol.

N ^ \ VN

Factory 0 ^ -0 s

II II I NO. The paper size of the edition is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 55 5. Description of the invention (outside) A7 B7 Imitating Example 4 · Order (2R, 3R) -2- (2, 4-difluorophenyl) -3-[(1,3-dixiangyl-2-propyl) thio] -Γ-[(1H.-1,2,4-tri-I®-5-yl) The reaction and treatment of 2-butanol with trans-4-nitrocinnamaldehyde gave the target product as an oily product with a yield of 40%. Specific rotation [a] -64.1 ° (C = 2.43, CHC13) NMR &lt; 270MHz, CDClg) δ ppm: 1. 19 (3H, d, J = 7.3 Hz), 3. 35 (1H, q , J = 7. 3 Hz), 3. 44 (1H, tt, J = ll. 2, 4. 6Hz), 3. 66 (1H, t, J = ll. 2Hz), 3. 68 (1H, t , J = ll. 2Hz), 4. 3 4 (lH, m), 4. 46 (1H, m), 4. 83 (1H, d, J = 13. 9Hz), 5. 04 (1H, d, J = 13.9Hz), 5. 04 (1H, s), 5.16 (1H, d, J = 4.0 Hz), 6. 32 (1H, dd, J = 16. 5, 4. 0Hz), 6. 7-6. 8 (2H, ra), 6. 87 (1H, d, J = 16.5 Hz), 7. 36 (1H, m), 7. 53 (2H, d, J = 8.6 Hz ), 7. 79 (1H, s), 7. 80 (1H, s), 8. 19 (2H, d, J = 8.6 Hz). This was mixed with 1 equivalent of oxalic acid in ethyl acetate-hexane mixture. Mix to obtain oxalate crystals with a melting point of 103-1D5 ° C. Example 11 (21 ?, 31〇-2- (2,4-difluorophenyl) -Bu (111-1,2,4-triazol-1-yl) -3-[[trans-2- [ (Έ) -2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxan-5-yl] thio] -2-butanol (Please read the precautions on the back first (Fill in this page again)

、 1T Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs ◎

〇 &gt; 0 OCF, imitating Example 4, let (2R, 3R) -2- (2,4-difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) thio] -Bu [(1H-1,2,4-triazol-5-yl) -56- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) A7, B7 V. Description of the invention (rT)- The reaction of 2-butanol with 4- (tri: fluoromethylamino) cassia tincture of Reference Example 33 and treatment yielded the target product as an oily product with a yield of 43%. oc. Specific rotation [a] -77 ° (C = 0. 52, CHC13) NMR (270MHz, CDClg) 5 ppm: 1. 20 (3H, d, J = 7.3 Hz), 3. 34 (1H, q, J = 2.3 Hz), 3. 42 (1H, tt, J = ll. 2, 4. 6Hz). 3. 65 (1H, t, J = ll. 2Hz), 3. 67 (1H, t, J = ll. 2Hz), 4. 3 2 (1H, ddd, J = ll. 2, 4. 6, 2. 0Hz), 4. 45 (1H, ddd, J = ll. 2, 4. 6 , 2. 0Hz), 4. 83 (1H, d, J = 14. 5Hz), 5. 01 (1H, s), 5. 03 (1H, d, J = 14. 5Hz), 5.12 (1H, d , J = 4. 0Hz), 6. 15 (1H, dd, J = 16 .5,4. 0Hz), 6. 7-6. 8 (2H, m), 6. 79 (1H, d, J = 16.5Hz), 7. 17 (2H, d, J = 8: 6Hz), 7. 3-7. 45 (1H, m), 7. 42 (2H, d, J = 8.6Hz), 7. 79 (2H, s) e Example 12 (2R, 3R) -3-[[Trans-2-[(E) -2- (4-Gaphenyl) vinyl] -1,3-dioxane- 5-yl.] Thio] -2- (2,4-difluorophenyl) -1- (111-1,2,4-triazol-1-yl) -2-butanol (Please read the back first Note for this page, please fill out this page) Order-CH,

〇) ... ^ ~ &lt; § &gt; ~ CN The Ministry of Economic Affairs Central Standards Bureau Offshore Consumer Cooperative Co., Ltd. printed imitation Example 4, ordering (2R, 3R) -2- (2,4-diphenylphenyl) -3- [(1,3-dihydroxy-2-propyl) thio] -1-[(1H-1,2,4-triazol-5-yl) -2-butanol and trans-4-amino cinnamon Xue (Mol. Cryst. Liq. Crys.t. 123 257 (19 8 5)) reaction and treatment, the target product was obtained as the main product, oily, yield 66% 0 -57 This paper size applies to Chinese national standards (CNS ) A4 size (210X297 mm)

'sC ° &gt; Printed by the Central Government of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives, A7 B7 V. Description of invention (office) Specific rotation [a] D25 -78 ° (C = 0. 52, CHC13) NMR (270MHz, CDClg) δ ppm: 1.20 (3H, d, J = 7. 0Hz), 3.34 (1H, br q, J = 7. 0Hz), 3. 43 (1H, tt, J = ll. 3, 4. 8Hz), 3. 65 (1H, t, J = ll. 3Hz), 3. 67 (1H, t, J = ll. 3Hz), 4. 33 (1H, id), 4. 46 (1H, m) , 4. 83 (1H, d, J = 14. 2Hz), 5. 03 (1H, d, J = l. 2Hz), 5. 04 (1H, d, J = 14. 2Hz), 5.14 (1H, d, J = 4.1Hz), 6. 28 (1H, dd, J = 16.1, 4.1Hz), 6. 7-6. 8 (2H, ra), 6. 8 2 (1H, d, J = 16.1Hz ), 7. 36 (1H, m), 7. 49 (2H, d, J = 8.3 Hz), 7. 62 (2H, d, J = 8.3 Hz), 7. 79 (2 Hs). This It was mixed with 1 equivalent of oxalic acid in ethyl acetate-hexane solution to obtain 164-165 ° C fused oxalate crystal β. Example 1 3 (211,31〇-2- (2,4-difluorophenyl) -3-[[trans-2-[(£) -2-methyl-2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane-5-yl] sulfur Group] -1- (1Η-1,2,4-triazol-1-yl) -2-butanol CHn Similarly to Example 4, let (2R, 3R) -2- (2,4-difluorophenyl ) -3-[(1,3-dihydroxy-2-propyl) thio] -1-[(1H-1,2, 4-Triazol-1-yl) -2-butanol was reacted with trans-/?-Methyl-4- (trifluoromethyl) cinnamaldehyde, and the target product was obtained as an oil. Yield: 73 %. NMR (270MHz, CDClg) δ ppm: 1. 20 (3H, d, J = 7.1 Hz), 2. 16 (3H, s), 3. 36 (1H, q, J = 7.1 Hz), 3. 41 (1H, tt, J = ll. 3, 4. 6Hz), 3. 66 (1H, t, J = ll. 3Hz), 3. 68 (1H, t, J = -5 8 _ paper Standards are applicable to China National Standard (CNS) A4 specifications (210X297 mm) (Please read the precautions on the back before filling this page)

/ — * 0 &gt; 7- Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (β) Π. 3Hz), 4. 32 (1H, m), 4. 44 (1H, m), 4. 83 (1H, d, J = 13.9Hz), 5. 03 (1H, s), 5. 04 (1H, d. J = 13.9Hz), 5. 33 (1H, d, J = 6. 0Hz), 5.83 (1H, br d, J = 6.0 Hz), 6. 7-6.8 (2E, m), 7. 3-7. 45 (1H, m), 7. 51 (2H, d, J = 8.3Hz), 7.59 (2H, d, J = 8.3Hz), 7.79 (2H, s). Example 14 (2R, 3R) -3-[[反 -2- [(E BU 2- (5-Gas-2_ milepanyl) ethanyl] -1,3 -di 丨 Huang-5-yl.] Thio] -2- (2,4-difluorophenyl) -1 -(18-1,2,4-triazol-1-yl) -2-butanol

A

Cl was modeled as in Example 4, and (2R, 3 R) -2- (2,4-difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) thio] -bu [( 1H-1,2,4-triazol-5-yl) -2-butanol and trans-yS-(5-chloro-2-blapyl) acryl (Chem.Abst. 5 1 1 2 8 4 h (1 9 4 1)) Reaction and treatment to obtain the target product, oily, yield 50%. Specific rotation [a] D25 -75. 7 ° (C = 0.56, CHC13) NMR (270MHz, GDClg) 5 ppm: 1.19 (3H, d, J = 7.3 Hz). 3. 33 (1H, q , J = 7. 3 Hz), 3. 40 (1H, tt, J = ll. 2, 4. 6Hz), 3. · 62 (1H, t, J = ll. 2Hz), 3. 64 (1H, t, J = ll. 2Hz), 4. 3 6 (lH, Bi), 4.42 (lH, m), 4.82 (1H, d, J = 13. 8Hz), 5. 02 (IK, br i), d , J = 13.8Hz), 5. 06 (1H, d, J = 4.6 Hz), 5. 88 (1H, dd, J = 15. 8, 4. 6Hz), 6. 7-6. 85 (3H , m), 6. 78 (2H, s), 7.36 (1H, m), 7.87 (2H, s). -59- This paper size applies to Chinese national standards (CNS &gt; A4 size (210X297 mm) (Please read the notes on the back before filling this page)

V. Description of the invention (β) A7 B7 This is mixed with 1 equivalent of oxalic acid in a mixed solution of ethyl acetate and hexane to obtain the oxalate crystals having a melting point of 5 3 to 5 7 g. Example 15 (2R, 3R) -2- (2,4-difluorophenyl &gt; -1- (1Η-1,2,4-tri_-1-yl) -3-[[trans-2- [(1 £, 3 £) -4- [4- (trifluoromethyl) phenyl] -1,3-butadien-1-yl] -1,3-dioxan-5-yl] sulfur Yl-2-butanol

VN

(Please read the precautions on the back before filling this page) Central Ministry of Economic Affairs «Rare Bureau Employee Consumer Cooperative Co., Ltd. Prints Imitation Example 4, Order (2R, 3R) -2- (2,4-difluorophenyl) -3 -[(1,3-dihydroxy-2-propyl) thio] -l-[(1H-1,2,4-triazol-5-yl) -2-butanol and Reference Example 25 of ( 2E, 4E) -5- [4- (trifluoromethyl) phenyl] -2,4-pentadienal was reacted and treated to obtain the target product as an oily product with a yield of 67%. 0C specific rotation [a] -69.8. (C = 1.00, CHC13) NMR (270MHz, CDClg) δ ppm: 1.19 (3H, d, J = 7.3 Hz), 3. 33 (1H, q, J = 7.3 Hz), 3. 40 (1H , tt, J = ll. 2, 4. 6Hz), 3. 62 (1H, t, J = ll. 2Hz), 3. 64 (1H, t, J = ll. 2Hz), 4. 3 0 (1H , m), 4. 42 (1H, in), 4. 82 (1H, d, J = 13. 9Hz), 5. 01 (1H, s), 5. 03 (1H, d, J = 13. 9Hz ), 5. 06 (1H, d, J = 4.6 Hz), 5. 84 (1H, dd, J = 15. 2, 4. 6Hz), 6. 60 (1H, dd, J = 15. 2, 10.6Hz), 6.73 (1H, d, J = 15. 8Hz), 6. 7-6. 8 (2H, in), 6. 85 (1H, dd, J = 15. 8, 10. 6Hz ), 7. 3-7. 45 (1H, m), 7. 49 (2H, d, J = 8.6 Hz), 7. 56 (2H, d, J = 8.6 Hz), 7. 78 (2H , s). -60 &quot;

、 1T This paper size applies to Chinese National Standards (CNS) 8 4 * 1 (210X297 mm) '1 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention () Example 16 (2R, 3R) -2- (2,4-difluorophenyl) -3-[[trans-2- [(IE, 3E) -4- [4- (2,2,3,3-tetrafluoropropanyl) benzene Yl] -1,3-butadien-1-yl] -1,3-diasyn-5-yl] thio] -1- (1H-1,2,4-triazol-1-yl) 2-butanol

Following Example 4, let (2R, 3R) -2- (2,4-difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) thio-1-[(1H- 1,2,4-triazol-5-yl) -2-butanol and (2E, 4E) -5- [4- (2,2,3,3-tetrafluoropropanyl) benzene of Reference Example 32 Group] -2,4-pentadienal reaction and treatment to obtain the target product as the main product, melting point 75 ~ 85 ° C (crystallized from hexane-ether mixture), powder, yield 60% 〇Specific optical rotation [ct D-69. (C = 0.56, CHC13) NMR (270MHz, CDClg) δ ppm: 1.18 (3H, d, J = 7.0 Hz), 3. 33 (1H, q, J = 7.0 Hz), 3.39 (1H , tt, J = ll- 3, 4. 8Hz), 3. 62 (1H, t, J = ll. 3Hz), 3. 64 (1H, t, J = ll. 3Hz), 4. 3 0 (1H , m), 4. 35 (2H, br t, J = ll. 8Hz), 4. 41 (1H, m), 4. 82 (1H, d, J = 14.1Hz), 4. 99 (1H, d , J = l. 6Hz), 5. 03 (1H, d, J = 14.1Hz), 5. 04 (1H, d, J = 4. 6Hz). 5. 75 (1H, dd, J = 15. 7 , 4. 6H z), 6. 06 (1H, tt, J = 53. 0, 5. 1Hz), 6. 56 (1H, dd, J = 15. 7, 10. 2Hz), 6. 57 (1H , d, J = 15. 0Hz), 6. 68 (1H, dd, J = 15. 0, 10. 2Hz), 6. 7-6. 8 (2H, m), 6. 88 (2H, d, J = 8. 7Hz), 7. 3-7. 4 (1H, m), 7. 37 (2H, d, J = 8. 7Hz), 7. 79 (2H, s). -6 1-Paper Standards are applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) (Please read the precautions on the back before filling this page)

A7 B7

V. Description of the invention (fe.) Example 17 (2R, 3R) -3-[[trans-2- [(1Ε, 3Ε) -4- (6-fluoro-3-pyridyl) -1,3-but Dien-1-yl] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1fluorene-1,2,4-triazole -1-yl) -2-butanol

vN s ^ O Following Example 4, let (2R, 3R) -2- (2,4-difluorophenyl) -3-[(1,2-dixiangyl-2-propyl) thio]- 1- (1H-1,2,4-triazol-5-yl) -2-butanol and (2E, 4E) -5- (6-Ga-3-pyridinyl) -2 of Reference Example 38, 4-Pentadienal was reacted and treated to obtain the target product as the main product. The melting point was 88 ~ 90 ° C. The yield was 69%. Specific rotation [a] D25 -74 ° (C = 0. 59, CHC13) NMR &lt; 270MHz, CDClg) 5 ppm: 1. 19 (3H, d, J = 7.1 Hz), 3. 33 (1H, q, J = 7.1 Hz), 3. 40 (1H, tt, J = ll. 3, 4. 7Hz), 3. 62 (1H, t, J = ll. 3Hz), 3. 64 (1H, t, J = ll. 3Hz), 4. 3 0 (lH, ra), 4.42 (lH, m>, 4. 82 (lH, d, J = 14.3Hz), 5.00 (lH, s), 5.03 (1Η, d, J = 14.3Hz), 5. 05 (lHf d, J-4. 2Hz), 5. 84 (1H, dd, J = 15.1, 4.2 Hz), 6. 56 (1H , dt J = 15. 5Hz), 6. 58 (lHf dd, J = 15.1, 10.5Hz), 6. 7-6 · 8 (2H, m), 6. 80 (1H, dd · J = 15 · 5, 10. 5Hz), 7. 28 (1H, d, J = 8.3 Hz) (7. 3-7. 4 (1H, m) f7.70 (lH, ddt J = 8.3, 2.5 Hz ), 7. 79 (2H, s), 8. 37 (1H, dt J = 2.5 Hz) Example 1 8 (2R, 3R) -2- (2,4-difluorophenyl) -3- [ [Trans-2- [(1E, 3Z) -4- (4-Gaphenyl) -5,5,5-trifluoro-1,3-pentadien-1-yl] -1,3- -62 -This paper size applies Chinese National Standard (CNS) M specification (21〇 &gt; &lt; 297 mm) (Please read the notes on the back before filling out this page)-Order printed by the Staff Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs A7 _B7 _V. Description of the Invention (w) Dioxan-5-yl] thio] -1- (1H-1,2,4-triazole-1- Bu 2-butanol SVci

VN

The Central Ministry of Economic Affairs of the People's Republic of China ·· Printed the imitation example 4 of the Consumer Cooperative of the Niu Bureau. 2-propyl) thio] -1-[(111-1,2,4-triazol-5-yl) • 2-butanol and (2E, 4Z) -5- (4-gas of Reference Example 52 Phenyl) -6,6,6-trifluoro-2,4-hexadiene hydrazone was reacted and treated to obtain the target product as an oily product with a yield of 31¾. Specific rotation [a] D25 -59. 4 ° (G = 0.90, CHC13) NM R (270MHz, CDClg) δ ppm: 1.19 (3H, d, J = 7.3 Hz), 3. 33 (1H, br q , J = 7. 3Hz), 3. 40 (1H, tt, J = ll. 2, 4. 6Hz), 3. 61 (1H, t, J = ll. 2Hz), 3. 64 (1H, t, J = ll. 2Hz), 4. 31 (1H, m), 4. 43 (1H, m), 4. 82 (1H, d, J = 13. 9Hz), 5. 02 (1H, s), 5 03 (1H, d, J = 13. 9Hz), 5.09 (1H, d, J = 4.6 Hz), 5. 96 (1H, dd, J = 15. 2, 4. 6Hz), 6. 50 (1H, d, J = ll. 9Hz), 6. 7-6 .8 (2H, ro), 6. 9-7. 1 (1H, m), 7. 25-7. 4 (5H, in ), 7. 79 (2H, s). Example 1δ (2R, 3R) -2- (2,4-difluorophenyl) -3-[[trans-2-[(lE, 3E) -2-methyl-4- [4- (trifluoro (Methyl) phenyl] -1,3-butadiene M-yl] -1,3-dioxane-5-yl] thio] -Bu (1 Η-1,2,4 -Triwa-1 -base)

S / — &quot; 0 \ ^ η CF, (Please read the notes on the back before filling this page) OR-63 This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (H) Following Example 4, let (2R, 3R) -2- (2,4-difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) thio] b [( 1H-1,2,4-triazol-5-yl) -2-butanol and (2E, 4E) -3 -methyl-5- [4- (trifluoromethyl) phenyl) of Reference Example 10 -2,4-Pentadienal was reacted and treated to obtain the target product as an oily product with a yield of 70%. Specific rotation [a] D25 -68 ° (C = 0. 50, CHC13) NMR (270MHz, CDClg) δ ppm: 1. 27 (3H, d, J = 7.1 Hz), 1. 99 (3H, s ), 3. 34 (1H, q, J = 7.1 Hz), 3. 39 (1H, tt, J = ll. 3, 4. 8Hz), 3. 64 (1H, t, J = ll. 3Hz) , 3. 66 (1H, t, J = 11.3Hz), 4. 30 (1H, m), 4. 41 (1H, m), 4. 83 (1H, d, J = 14. 1Hz), 5 01 (1H, s), 5. 04 (1H, d, J = 14.1Hz), 5. 32 (1H, d, J = 6.2 Hz), 5. 66 (1H, d, J = 6 &lt; 2Hz), 6.66 (1H, d, J = 16. 1Hz), 6. 7 -6. 8 (2H, ra), 6. 86 (1H, d, J = 16. 1Hz), 7. 3- 7. 4 (1H, m), 7. 51 (2H, d, J = 8.4 Hz), 7. 57 (2H, d, J = 8.4 Hz), 7. 78 (2H, s) 20 (2I ^, 3R) -2- (2,4-difluorophenyl) -3-[[trans-2-[(lE, 3E) -3-methyl-4- [4- (trifluoromethyl )] Phenyl] -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -1- (1H-1, 2,4-triazole-b ) -2-butanol

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Copy Example 4 and make (2R, 3R) -2- (2,4-difluorophenyl) -3- [(1,3-dihydroxy-2-propyl) thio] -Bu [(1H-1,2,4-triazol-5-yl) -6 4-This paper size applies to Chinese National Standards (CNS) A4 specifications (210X297 mm) A7 B7 V. Description of the invention (w) -2-butanol and (2E, 4E) -4-methyl-5- [4- (trifluoromethyl) phenyl] -2, 4-Pentadienal was reacted and treated to obtain the target product as an oily product with a yield of 69%. Specific rotation [a] -63.4 * (C = 1.07, CHC13) NMR (270MHz, CDClg) δ ppm: 1. 19 (3H, d, J = 7.0 Hz), 2. 00 (3H, s), 3 .33 (lH, q, J = 7.0 Hz), 3. 41 (1H, tt, J = ll. 2, 4. 6Hz), 3. 64 (1H, t, J = ll. 2Hz), 3. 66 (1H, t, J = 11. 2Hz), 4. 31 (1H, m), 4. 43 (1H, m), 4. 83 (1H, d, J = 14. 2Hz), 5. 01 ( 1H, s), 5. 04 (1H, d, J = 14. 2Hz), 5. 09 (1H, d, J = 4. 6Hz), 5. 81 (1H, dd, J = 16. 0, 4 6Hz), 6.60 (1H, s), 6.63 (1H, d, J = 16.0Hz), 6. 7-6. 8 (2H, m), 7. 3-7. 4 ( 1H, m), 7.38 (2H, d, J = 8.2Hz), 7.59 (2H, d, J = 8.2Hz), 7.79 (2H, s). Example 21 (2R, 3R) -2- (2,4-difluorophenyl) -3- [[l-[((E) -4- (trifluoromethoxy) cinnamate) piperidine-4] -Yl] thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol (Please read the precautions on the back before filling this page)

N ^ \ VN

OCF, printed by the Consumer Cooperatives of the Central Mongolian Bureau of the Ministry of Economic Affairs [Method A] Reference Example 14 (2 R, 3 R)-2-(2, 4 -difluorophenyl)-3.-[(1 Η -1, 2,4-triazol-1-yl) -3-[(spectinyl-4-yl) thio] _2-butanol 2 hydrochloride 150ng (0.340 maol) and digas methane 3b1 In the nitrogen atmosphere, the mixture is added with triethylamine 142 at 0-C; ul (1.02iaaiol), and then added at 5 minutes (E) -4- -6 5-This paper size applies to China National Standard (CNS) A4 (210X297) (Centi) A7 __ ___B7__ 5. Description of the invention (w) (trifluoromethoxy) cinnamon bark gas 128ng (0.510aaol), after stirring for 30 minutes at the same temperature, evaporate the solvent I, add ethyl acetate and salt It was washed with water, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (ethyl acetate), to obtain 160 »g of the target compound, with a yield of 81%, and a colorless foam. NMR (270MHz, CDClg) δ ppm: 1.19 (3Η, d, J = 7. ΗΗζ), 1. 6-1. 8 (2Η, m), 2 • 0-2. 1 (2Η, m), 3. 0-3. 2 (2Η, m), 3. 35 (1Η, q, J = 7. 0Hz), 3. 2-3. 4 (1H, m), 4. 0-4. 1 (1H, m ), 4. 2-4. 3 (1H, m), 4. 83 (1H, s), 4. 83 (1H, d, J = 14. 0Hz), 5. 09 (1H, d, J = 14 0Hz), 6. 7-6. 8 (2H, in), 6. 87 (1H, d, J = 15. 5Hz), 7. 22 (2H, d, J = 8.5 Hz), 7. 3 -7. 4 (1H, m), 7. 55 (2H, d.J = 8.5 Hz), 7. 65 (1H, d, J = 15. 5Hz), 7. 78 (1H, s), 7 82 (1H, s) e 1 R υ maxKBl: Cffi 1: 3421,1695,1686,1617, 1591 · Mass broadcast m / e: 582, 563, 522,500,427, 359,299,258, 215, 187,144,101,82. [Preparation method B] 4- (Ethylsulfanyl) -1-[(E) -4- (trifluoromethoxy) cinnamoyl] piperidine 327mg (0.875BH01) and (2R , 3R &gt; -2- (2,4-difluorophenyl) -3 ^ methyl-2-[(1H-1, 2,4-triazol-1-yl) methyl] B alkyl, 200ng (0.796 i »mol) is dissolved in dimethylformamide 4b1, and 28% sodium methoxide-methanol 129 # 1 (〇 · 613βι» ο1) is added in the nitrogen atmosphere, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. (Please read the notes on the back before filling in this page) Stir at 50 ° C for 3 hours. After cooling, dilute with ethyl acetate, wash with water and saturated brine, and evaporate the solvent. The obtained oil is in silicone Column chromatography (ethyl acetate) yielded 275 mg of the target compound with a yield of 59% and a colorless foam. This was consistent with various spectra such as NMR, IR, and MS of the compound obtained in [Preparation Method A]. Example 2 2 (21? , 311) -2- (2,4-difluorophenyl) -3-[[Bu ((£) -4- (methyl-6 6-This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 (Mm) A7 B7 V. Description of the invention (to) Cinnamonyl]] pyridin-4-yl] thio] -1- (1H-1,2,4-triazole-1 ) -2-butanol

N ^ \ VN

CH, from (E) -4-methylcinnamon thoron (Can.J.Chea.y 1001 (1967) followed Example 21 [preparation method A]. A colorless foam was obtained. NMR (270MHz, CDClg) δ ppm: 1. 19 (3Η, d, J = 7.0 Hz), 1. 6-1. 8 (2H, ra), 2.0-2.2 (2H, m), 2. 37 (3H, s), 3. 0-3. 2 (2H, in), 3. 2-3. 4 (1H, m), 3. 35 (1H, q, J = 7. 0Hz), 4. 0-4. 2 (1H , m), 4. 4-4. 6 (1H, m), 4. 83 (1H, d, J = 13.9Hz), 4. 84 (1H, s), 5. 09 (1H, d, J = 13.9 Hz), 6. 7-6. 8 (2Hf m), 6. 85 (1H, d, J = 15. 5Hz), 7. 18 (2H, d, J = 8. 3Hz), 7. 3-7. 4 (1H, ra), 7.43 (2H, d, J = 8.3 Hz), 7. 65 (1H, d, J = 15. 5Hz), 7. 77 (1H, s), 7. 82 (1H, s). IR rn {lvKBrcm &quot; 1: 3333, 1645, 1599. [Π dX mass spectrum m / e: 512, 510, 452, 430, 425, 367, 357, 289, 229, 224, 188, 145, 117, 82. (Please read the notes on the back before filling out this page) Order printed by the Ministry of Economic Affairs central i-rr-quasi bureau employee consumer cooperatives Example 2 3 (21 ^ 31〇-2- (2 , 4-difluorophenyl) -3-[[1-((£) -4-nitrocinnamoyl) piperidin-4-yl] thio] -b (1H-1,2,4-tri Azole-butyl) 2-butanol CH.

67-This paper size applies to China National Standard (CNS) A4 size (210X297 mm) max 130, 82. B7 5. Description of the invention (M) From (E) -4-nitrocinnamaldehyde gas, Example 21 [preparation method A] was obtained, and a yellowish foam was obtained. NMR {270MHz, CDClg) δ ppm: 1.26 (3H, d, J = 6.6Hz), 1. 6-1. 9 (2H, m), 2.1-2. 3 (2Ht m), 3.1 -3. 3 (2H, ra), 3. 3-3. 5 (1H, m), 3. 42 (1H, q, J = 6.6Hz), 4. 0-4. 2 (1H, m) , 4. 4-4. 6 (1H, m), 4. 89 (1H, d, J = 13. 9Hz), 4. 92 (1H, s), 5.15 (1H, d, J = 13. 9Hz) , 6. 7-6 -9 (2H, m), 7. 10 (1H, d, J = 15. 5Hz), 7. 4-7. 5 (1H, m), 7. 73 (2H, d, J = 8. 9Hz), 7.75 (1H.d, J = 15.5Hz), 7.86 (2H, d, J = 8. 9Hz), 8.29 (1H, s), 8.32 (1H, s) e 1 R v KBrcm_1: 3361,1649,1612,1518,1345. Mass spectrum m / e: 544, 525, 513, 483,461,388, 365,284, 260,224, 219,176, 144, Example 2 4 (21 £, 3! 〇 -2- (2,4-difluorophenyl) -1- (18-1,2,4-triazol-1-yl) -3- [[l-[((3E, 4E) -5- [ 4- (trifluoromethyl) phenyl] -2,4-pentadienylfluorenyl] piperidin-4-yl] thio] -2-butanol (Please read the precautions on the back before filling this page )

Printed from (2 £, 4 £) -5- [4- (trifluoromethyl) phenyl] -2,4-pentadiene tritium gas imitation Example 21 [ Production method A] to obtain a colorless foam. , 6 8- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) A7 _B7_ V. Description of the invention (β) NMR (270MHz, CDClg) δ ppm: 1. 19 (3Η, d, J = 6.6Hz), 1. 5-1.8 (2Η, m), 2.0-2.2 (2H, in), 3. 0-3. 3 (3H, m), 3. 34 (1H, q, J = 6.6Hz), 3. 9-4. 1 (1H, in), 4. 3-4. 5 (1H, m), 4. 83 (1H, d, J = 13. 9Hz), 4. 82 (1H, s), 5. 08 (1H, d, J = 13. 9Hz), 6. 50 (1H, d, J = 14. 5Hz), 6. 7-6. 8 (2H, m), 6. 8-6. 9 (2H, m), 7. 20 (2H, d, J = 8.9Hz), 7. 3-7. 5 (2H, m), 7. 47 (2H, .d, J = 8.9 Hz), 7. 78 (1H, s), 7. 82 (1H, s), IRVK ^ cir1: 3395, 1639, 1616, 1596. (Π 3l X mass spec. In / e: 608, 589, 548, 526, 453, 433, 385, 325, 241, 224, 213, 144, 127, 82Example 25 (2R, 3R) -2- (2 , 4-difluorophenyl) -1- (1! 1-1,2,4-triazol-1-yl) -3- [[l-[((E) -3- (pyridin-4-yl ) Acrolein] piperidine- 4- ---------- ©-(Please read the precautions on the back before filling this page) Base] thio] -2-butanol

s

Order

Jts * JLbuML_u_J: .. From 4- (Ethyl-Sulfuryl)-. 1-[((E) .- 3- (Peptyl-4-yl) propanoyl]] Piperidine imitation Example 21 [Preparation method B] to obtain a colorless foam. NMR (270MHz, CDClg) δ ppm: 1. 20 (3H. D, J = 6.6 Hz). 1. 6-1.8 (2H. Οι). 2.0-2. 2 (2H. Id), 3. 0-3. 2 (2H, ni), 3. 35 (1H, q, J = 6.6 Hz), 3. 2-3. 4 (1H, m), 3. 9-4. 1 (1H, tn), 4. 3-4. 5 (1H, m), 4. 83 (1H, d. J = 14. 5Hz), 4. 86 (1H, s), 5 09 (1H, d, J = 14. 5Hz), 6. 7-6 .ο (2Γί; ...;,;. 06 (1H, d, J = 15. 2Hz), 7. 3-7 4 (1H, m), 7. 37 (2H, d, J = 5.9 Hz), 7. 57 (1H, d. J = 15. 2Hz), 7. 78 (1H, s), 7. 81 (1H, s), 8. 64 (2H, d, J = 5. 9Hz) „IR υ KBrcm_1: 3420,1651, 1615,1598. A 1V max mass m / e: 499, 439, 417, 410, 365 , 344, 307, 275, 247, 216, 144, 132. 104, 82. -69- This paper size applies to China National Standards (CNS> A4 size (210X297 mm) -1. Staff consumption of the Central Standards Bureau of the Ministry of Economic Affairs Printed by a cooperative

OCF, printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7. V. Description of Invention (P) Example 26 (211,3 "-2- (2,4-difluorophenyl) -3-[[1- ((£) -4- (trifluoromethoxy) cinnamonyl) azetidin-3-yl] thio] -1- (1H-1,2,4-triazol-1-yl) -2 -Butanol

(2R, 3R) -2- (2,4-difluorophenyl) -1- (1Η-1,2,4-tri.azol-1-yl) -3-[(BY but Ethyl-3-yl) thio] -2-butanol 2 hydrochloride was used as an example in Example 21 [Preparation Method A] to obtain a completely yellow foam. NMR (270MHz, CDClg) δ ppm: 1. 17 (3H, d, J = 7.1 Hz), 3. 32 (1H, q, J = 7. 1 Hz), 4. 0-4. 3 (3H, m), 4. 5-4. 6 (1H, m), 4. 6-4. 7 (1H, ra), 4. 86 (1H, d, J = 14. 2Hz), 5. 05 (1 H , d, J = 14. 2Hz), 5. 09 (1H, s), 6. 43 (1H, d, J = 15. 7Hz), 6. 7-6. 8 (2H, in), 7. 22 (2H, d, J = 8 .2Hz), 7. 3-7. 4 (1H, m), 7. 56 (2H, d, J = 8. 2Hz), 7. 65 (1H, d, J = 15. 7Hz), 7. 79 (1H, s), 7. 81 (lH, s) IRV max0, 1 &quot; — 1: 3376, 1656. Mass spectrum &quot; i / e: 554,535, 472,384,331,271, 224,215,187, 127,87. Example 27 (2R, 3R) -2- (2,4_ = fluorophenyl) -3-[[trans-2-((. 1Ε, 3Ε) -4- (2,4-difluoro Phenyl) -1,3-butadien-1-yl] -1,3-dioxane-5-yl] thio] -1- (1H-1,2,4-triazol-1-yl ) -2-butanol-70 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

A7 B7 V. Description of the invention

F

(Please read the precautions on the back before filling in this page) Following Example 4, let (211,3 magic-2- (2,4-difluorophenyl) -3-[(1, 3-dihydroxy-2 -Propyl) thio] -1- (1H-1,2,4-triazol-5-yl) -2-butanol and (2E, 4E) -5- (2,4-difluorophenyl) -2,4-pentadienal reaction to obtain the target product as the main product, yield 61% as oil. 〇 £; Specific optical rotation [a] D (c 1.04, CHC13) NMR (270MHz, CDC13) δ ppm : 1. 18 (3H, d, J = 7.0 Hz), 3.33 (1H, q, J = 7.0Hz), 3. 39 (1H, tt, J = ll. 3, 4. 6Hz), 3. 62 (1H, t, J = ll. 3Hz), 3. 64 (1H, t, J = ll. 3H z), 4. 30 (1H, m), 4.4l (lH, ra), 4. 82 (1H , d, J = 14. 0Hz), 5.00 (lH, s), 5.03 (lH, d, J = 14. 0Hz), 5. 05 &quot; (1H, d, J = 4.6 Hz), 5. 79 ( 1H, dd, J = 15. 2, 4. 6Hz), 6. 58 (1H, dd, J = 15. 2, 9. 5Hz), 6.65-6.9 (6H, ni), 7. 3-7. 5 (2H, m), 7.79 (2H, s). Example 2 8 (2R, 3R) -2- (2,4-difluorophenyl) -3-[[trans-2-((1Ε, 3Ε) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -4- [6- (2,2,3,3-tetrafluoropropoxy) -3-pyridinyl] -1,3-butadiene-butyl] -1,3-diB and other alkyl-5-yl] thio] -1- (1H-.1,2,4 -tri Azol-5-yl) -2-butanol

This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm). Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. A7 B7. 5. Description of the invention (π) will be (2R, 3R) -2- (2,4- Difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) thio] -1- (18-1,2,4-triazol-1-yl) -2-butanol 4 0 4 «^ (1.12 · βο1) and (2E, 4E) -5- [6- (2,2,3,3-tetrafluoropropoxy-3-pyridyl) -2,4- Pentadienal 501ag (1.73 mmol) was dissolved in digas methane 11.1, p-toluenesulfonic acid monohydrate 3200Bg (1.68inol) and molecular sieves 4A 4g were added. After stirring for 1 hour in the chamber, it was poured into ice-cold 3 % Sodium bisulfate 20nl, after stirring for 5 minutes, filter out the molecular sieve. The organic layer was separated and dried, and then the solvent was distilled off under reduced pressure. The obtained oily substance g was subjected to 19 g of silica gel column chromatography (hexane-ethyl acetate = 1: 1) to obtain 448 mg of the target substance (yield 63%) as an oil. Specific optical rotation [〇0 D 25-58. 6 ° (c 0.20, CHC13) NM R (270MHz, CDClg) δ ppm: 1. 19 (3H, J = 7. OHz), 3. 33 (1H .q, J = 7. 0Hz), 3.39 (1H, tt, J = 11.2, 4. 8Hz), 3. 62 (1H, t, J = 11. 2Hz), 3. 64 (1H, t, J = ll. 2Hz) .4. 30 (1H, ddd, J = ll. 2, 4. 7, 2.1Hz), 4. 42 (1H, ddd, J = ll. 2, 4. 7, 2. 1Hz) , 4. 74 (2H, brt, J = 12. 8Hz), 4. 82 (1H, d, J = 13. 9Hz), 5. 01 (1H, s), 5. 03 (1H, d, J = 13.9Hz). 5.0 5 (lH, d, J = 4.5 Hz), 5. 78 (1H, d, J = 15. 5, 4. 5Hz), 6. 01 (1H, tt, J = 53. 1, 4. 6Hz), 6.51 -6. 62 (2H, ni), 6. 65-6. 78 (3H, in), 6. 81 (1H, d, J = 8.6 Hz), 7. 35 ( 1H, m), 7.74 (lH, dd, J = 8.6, 2.3 Hz), 7.79 (2H.s), 8 · M (1, d, J = 2.3 Hz). Example 2 9 (211,31〇-2- (2,4-difluorophenyl) -3-[[trans-2-((1 £, 3 £) -1-methyl-4- [4- (Trifluoromethyl) phenyl] -1,3-butanedi-1-yl] -1,3-dihydroalkyl-5-yl] thio] -1- (1H-1,2,4- Triazol-1-yl) -2-butanol-72- This paper size applies to China National Standard (CNS) A4 (21 × 297 mm) (Please read the precautions on the back before filling this page).

A7 B7 V. Description of the invention (7 /)

CF. Example 4 printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, Order (2R, 3R) -2- (2,4-diphenyl) -3-[(1,3-dihydroxy-2- Propyl) thio] -1- (1H-1,2,4-triazol-5-yl) -2-butanol and (2E, 4E) -2-methyl-5- [4- (trifluoro Methyl) phenyl) -2,4-pentadienal was reacted to obtain the target product as an oily product with a yield of 31%. , NMR (270MHz, CDClg) δ ppm: 1. 19 (3H, d, J = 7.3 Hz), 1.94 (3H, s), 3. 34 (lH, q, J = 7.3 Hz), 3. 39 (1H, tt, J = ll. 2, 4. 6Hz), 3. 36 (1H, t, J = ll. 2Hz), 3.65 (1H, t, J = ll. 2Hz), 4.33 (lH, m) , 4.44 (lH, ra), 4.83 (1H, d, J = 13.9Hz). 4.89 (lH, s), 5.02 (lH, s), 5. 04 (1H, d, J = 13. 9Hz ), 6. 41 (1H, d, J = ll. 2Hz), 6. 62 (1H, d, J = 15. 8H z), 6. 7-6. 8 (2H, in), 7. 09 ( 1H, dd, J = 15, 8, 11.2Hz), 7.36 (lH, m), 7.50 (2H, d, J = 8. 6Hz), 7.56 (2H, d, J = 8.6Hz), 7.79 (lH, s), 7.80 (lH, s) e Example 30 (RS) -3-methyl-1- (1H-1,2,4-triazol-1-yl) -2- [4- ( Difluoromethyl) phenyl) -3-[[trans-2-[(E) -2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane-5- Yl] thio] -2-butanol

} ·· OVCF, (Please read the precautions on the back before filling out this page) Order-73 This paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by A7 Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs __ ^ ____ B7 _ ^ _ V. Description of the invention () Following Example 4, let us refer to Example 55 of US) -3-[(1,3-dihydroxy-2-propyl) thio] -3 -methyl-2 -[4- (trifluoromethyl) phenyl] 1,2,4-triazol-1-yl) -2-butanol reacts with trans-4- (trifluoromethyl) cinnamaldehyde of Reference Example 22, The object was obtained as colorless foam. NM R (270MHz, CDClg) 5 ppm: 1.36 (3H, s), 1.37 (3H, s), 3.5-3.7 (3H, m), 4. 2-4. 3 (1H, m), 4. 4-4. 5 (1H, in), 5.02 (2H, s), 5.11 (1H, d, J = 4.1Hz), 5.4 4 (1H, s), 6.25 (1H, dd, J = 16.2, 4. 1Hz), 6. 84 (1H, d, J = 16. 2Hz), 7. 4-7. 6 (8H, m). 7. 70 (1H, s), 7. 93 (1H, s) e IR v (KBr) cm-1: 3404, 1618, 1508, 1328. max mass spectrum m / e: 587, 568, 331, 298, 256, 201, 159, 131. Example 3 1 Pseudo (RS &gt; -3-methyl-1- (1H-1,2,4-triazol-1-yl) &gt; -2- [4- (trifluoromethyl) phenyl-3- [[Trans- 2-((lE, 3E) -4-[(trifluoromethyl) phenyl-1,3-butadien-1-yl] -1,3-dioxan-5-yl] Thio] -2-butanolthio

3 F-Hydroxydipropyl (Please read the notes on the back before filling this page)

This paper size applies to China National Standard (CNS) A4 specification (2 丨 0 × 297 mm)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (α) (trifluoromethyl) phenyl-2,4-pentadienal was reacted to obtain the target product as a main product and a colorless foam. NMR (270MHz, CDClg) δ ppm: 1.36 (3H, s), 1.37 (3H, s), 3.4-3.7 (3H, m), 4. 2-4. 3 (1H, in), 4. 4 -4. 5 (1H, m), 5.01 (2H, s), 5. 02 (1H, d, J = 4.3 Hz), 5.3 9 (lH, s), 5. 83 (1H, dd, J = 15. 2, 4. 3 Hz), 6. 59 (1H, dd, J = 15. 2, 10. 7 Hz), 6.63 (lH, d, J = 15.8 Hz), 6. 85 (1H, dd, J = 15. 8, 10. 7 Hz), 7. 4-7. 6 (8H, m), 7. 73 (1H, s), 7.93 (1H, s). IR vmax (KBr) ¢ ^ 4: 3398, 1679, 1619, 1328, 1126. Mass spectrum m / e: 614, 541, 494, 478, 406, 348, 256, 211. Example 3 2 (2R, 3R) -2- (2,4-difluorophenyl) -1- (1Η-1,2,4-triazol-1-yl) -3-[[trans-2- ((1E, 3E) -4- [4- (trifluoromethylthio) phenyl] -1,3-butadiene-butyl] -1,3-dialkyl-5-yl] thio]- 2-butanol

F Following Example 4, let (2131〇-2- (2,4-difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) thio] -1- (1H-1 , 2,4-triazol-5-yl) -2-butanol and (2 £, 4 £) -5- [4- (trifluoromethylthio) phenyl] -2,4.-pentadiene Aldehyde reaction, the target product is the main product, colorless foam. -75- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (material), NMR (270MHz, CDClg) δ ppm: 1. 19 (3H, d, J = 7.1Hz), 3. 3-3. 5 (2H, m), 3.62 (1H, t, J = 11.4Hz), 3. 64 (1H, t, J = ll. 4Hz), 4. 31 (1H, ddd, J = ll. 4, 4. 7 , 2. 1H z), 4. 42 (1H, ddd, J = 11.4, 4. 7, 2.1.1Hz), 4. 83 (1H, d, J = 14. 1Hz), 5.01 (lH, s), 5.03 (1H, d, J = 14.1Hz), 5. 06 (1H, d, J = 4.5 Hz), 5. 83 (1H, dd, J = 15. 7, 4. 5Hz), 6.60 (1H, dd, J = 15. 7, 10. 3Hz), '6. 62 (1H, d, J = 15. 7Hz), 6. 7-6. 8 (2H, m), 6. 84 (iH, dd, J = 15. 7, 10.3Hz), 7.3-7.4 (lH, m), 7. 44 (2H, d, J = 8.3 Hz), 7. 60 (2H, d, J = 8.3 Hz), 7.79 (2H, IR vmax (KBr) cm_1: 3389, 1621, 1680, 1621, 1501, 1117. Mass spectrum m / e: 599, 580, 557, 530, 500, 438, 388, 376, 346, 284, 25 Examples 33 (2R *, 3R *)-3-[[trans-2-((1Ε, 3Ε) -4-[(2,2,3,3-tetrafluoropropoxy) phenyl] -1,3- Butadiene-butyl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2,4-triazol-1-yl) -2- [4- (tri Fluoromethyl) phenyl] -2-butanol. 〇 /-&lt; 〇) -〇ch2cf2chf2V_〇cf3 Example 4 (2 R * 3R *) -3-[(1,3-dihydroxy-2-propyl) thio] -b (1H-1,2,4-triazol-5-yl) -2- [4-(. Tri Fluoromethyl) phenyl] -2-butanol and (2E, 4E) -5- [4- (2,2,3,3-tetrafluoropropanyl) phenyl] -2,4 of Reference Example 32 -Pentadienal reaction to obtain the target product as the main product, oil. -7 6-

This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) V. Description of Invention (β) NMR (270MHz, CDClg) δ ppm: 1.22 ( 3H, d, J = 6.6Hz), 3.16 (1H, q, J = 6.6Hz), 3.34 (1H, tt, J = 11.2,4.6Hz), 3.58 (1H, t, J = ll. 2Hz), 3. 61 (1H, t, J = ll. 2Hz), 4.27 (lH, ni), 4. 35 (2H, br t, J = ll. 9Hz), 4. 39 (1H, m), 4. 57 (1H, d, J = 13.9Hz), 4.77 (lH, s), 5.02 (lH, d, J = 4.6Hz), 5. 03 (1H, d, J = 13. 9Hz) , 5. 72 (1H, dd, J = 15. 8, 4. 6Hz), 6. 05 (1H, tt, J = 52. 8, 5. 3117.), G. 5-G. 75 (311, m), G. 88 (211, d, J = 8. 6Hz), 7.36 (2H, d, J = 8. 6Hz), 7. 39 (2H, d, J = 8. 6Hz), 7. 54 ( 2H, d, J = 8.6 Hz), 7. 71 (1H, s), 7.83 (1H, s). Example 3 4 (2R *, 3R *)-1- (1Η-1, 2, 4- Triazole-butyl &gt; -2- [4- (trifluoromethyl) phenyl] -3-[[trans-2-((lE, 3E) -4- [4- (trifluoromethyl) benzene Yl] _1,3-butanes-1-yl] -1,3-diamidin-5-yl] thio] -2-butanol

(Please read the precautions on the back before filling out this page) The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed a copy of Example 1, order (2R *, 31T) -3 -methyl-2- 2-((1Η-1,2 , 4-triazole-butyl) methyl] pyridine and trans- 5- (ethylsulfanyl)-. 2-C (1E, 3Ε) -4-ί4- (trifluoromethyl) phenyl] -1,3-butadiene-butyl] -1,3 dioxane was reacted to obtain the desired product as an oil, with a yield of 71%. -77 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) A7 b! V. Description of the invention (work) NMR (270MHz, CDC1.) Δ ppm: 1. 22 (3H, dt J = 7.0Hz ), 3. 17 (1H, q (J = 7. O 0Hz), 3. 36 (1H, tt, J = ll. 3, 4. 7Hz), 3. 59 (1H, t, J = ll. 3Hz ), 3. 62 (1H, t, J = ll. 3Hz), 4. 27 (1H, ddd, J = ll. 3, 4.7, 2.2Hz), 4. 39 (1H, ddd, J = ll. 3, 4. 7, 2. 2Hz), 4.57 (1H, d, J = 14. OHz), 4.80 (lH, s), 5. 03 (1H, d, J = 14. OHz), 5. 05 ( 1H, d, J = 4.5 Hz), 5.8 3 (1H, dd, J = 15. 3, 4. 5Hz), 6. 59 (1 H, dd, J = 15. 3, 10. 7117.), G. G4 (111, d, J-113. 3110, B. 85 (1H, dd, J = 15.3, 10.7Hz), 7.39 (2H, d, J = 8.4Hz), 7. 49 (2H, d, J = 8.3 Hz), 7.54 (2H, d, J = 8.3Hz), 7. 57 (2H, d, J = 8_4Hz), 7.71 (lH, s), 7.83 (lH, s Example 35 (2R, 3R) -2- (2,4-difluorophenyl) -1- (1 (-1,2,4-triazol-1-yl) -3-[[trans-2 -((IE, 3E) -4- [4- (trifluoromethanesulfinyl) phenyl] phenyl-1,3-butadien-1-yl] -1,3-dioxan-5-yl 〕 Thio] -2-butanol (Please read the precautions on the back before filling this page)

S (0) CF, printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

F Following Example 4, let (2R, 3S) -2- (2,4-difluorophenyl) -3-[[1,3-dihydroxy-2-propyl) thio] -1- (1H -1, 2,4-triazol-5-yl) -2-butanol and (2E, .4E) -5- [4- (trifluoromethanesulfinyl) phenyl] -2,4-pentane The reaction of dienal gives the target product as the main product, which is colorless foam. NM R (270MHz, CDClg) 5 ppm: 1.19 (3H, d, J = 7.OHz), 3.3-3.5 (2H, m), 3.62 (1H, t, J = ll. 3Hz), 3 64 (1H, t, J = H. 3Hz), 4. 30 (1H, ddd, J = ll. 3, 4. 8, 2. 3H z), 4. 42 (lH, ddd, J = 11.3t4 8,2. 3Hz), 4.83 (1H, d, J-14. 1Hz), 5.01 (lH, s), 5.03 (1H, d, J = 14. 1Hz), 5. 06 (1H, d , J = 4. 5Hz), 5. 83 (1H, dd, J = 15. 9, 4. 5Hz). 6. 60 (1H, d -78 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 (Mm) A7 B7 V. Description of the invention (W) d, J = 15. 9, 10. 6 Hz), 6. 62 (1H, d, J = 15. 9 IIz), 6. 7-6. 8 (2H, m), 6. 84 (1H. dd, J = 15. 9, 10.6Hz), 7.3-7.4 (lH, in), 7. 44 (2H, d, J = 8.3 Hz), 7. 60 (2H , d, J = 8.3 Hz), 7.79 (2H, s). Mass spectrum m / e: 6 16, 600, 547, 400, 370, 342, 284, 252, 224, 183. Example 3 6 (21 {, 31〇-2- (2,4-difluorobenzene) ) -Bu (111-1,2,4-triazol-1-yl) -3-[[trans-2-[(1Ε, 3Ε) -4- [4- (trifluoromethyl) phenyl] -1, 3

I-butadiene-butyl] cyclohexyl] thio] -2-butanol

(Please read the notes on the back before filling this page) CP3

F Following Example 4, let (213 8) -2- (2,4-difluorophenyl) -3-methyl-2- (1Η-1,2,4-triazole-butyl) methyl]噚 propyl ring and the reverse of reference example 43-Ethyl (ethylsulfanyl) -4-[(1Ε, 3Ε) -4- [4- (trifluoromethyl) phenyl] -1, employee of the Central Standards Bureau of the Ministry of Economic Affairs The consumer co-operative printed the reaction of 3-butadiene-1-yl] cyclohexane to obtain the target product, melting point 74-76 ° C, yield 59%. Specific rotation (a) D 25- 83 ° (c = 0.90, CHC13) N MR (270MHz, CDClg) 5 ppm: l. 1-1. 6 (4H, m), 1. 17 (3H, d , J = 7Hz), 1 -.8-2. 0 (2H, m), 2. 0-2. 2 (2H, m), 2. 69 (1H, tt, J = 12, 3Hz), 3. 35 (III, q. J = 7Hz), 4.6 4 (lH, s, OH), 4.83 (lH, d, J = 15Hz), 5. 10 (1H, d, J = 15Hz), 5. 83 (1H , dd, J = 15, 7Hz),

6. 22 (1H, dd, J = 15, 10Hz), 6. 48 (1H, d, J = 15Hz), 6. 74 (1H, t, J = 8Hz), 6. 81 (lH, dd, J -79-This paper size applies to Chinese National Standard (CNS) grid (210 X 297 mm) A7 B7 V. Description of the invention (in) = 15, 10Hz), 7. 1-7. 5 (2H, m), 7 45 (2H, d, J = 8Hz), 7. 54 (2H, d, J = 8Hz), 7.76 (1H, s), 7.84 (1H, s) 〇IR vmax (CHCi3) cm— 1: 1615, 1500, 1325, 1125, 1068. Mass 谞 m / e: 583, 544, 340, 310, 277, 224, 159, 127. Example 3 7 (2R, 3R) -2- (2,4-difluorophenyl) -1- (1Η-1,2,4-triazole-boxy) -3-[[trans- 2- ( (1E, 3E) -6- [4- (trifluoromethyl) phenyl] -1,3,5-hexatrien-1-yl] -1,3-dioxan-5-yl] thio ] -2-butanol

(Please read the notes on the back before filling this page)

F Example 4: (2R, 3R) -2- (2,4-difluorophenyl) -3-[(1,3-dioxo-2-propyl) thio] -1- ( 1H-1,2,4-trival-1-yl) -2-butanol and Participant Example 28 of (2E, 4E, 6E) -7- [4- (trifluoromethyl) phenyl] -2 In the reaction of 4,6-heptatrienal, the target product was obtained as the main product, which was oily. The yield of 65% was printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. NMR (270MHz, CDClg) δ ppm: 1.18 (3H.d, J = 6.6Hz), 3. 33 (1H, q, J = 6.6Hz), 3. 38 (1H, tt, J = ll 2, 4, 6Hz), 3. 61 (1H, t, J = ll. 2Hz), 3. 63 (1H, t, J = ll. 2Hz), 4.29 (lH, ni), 4.40 (lH, m ), 4. 83 (1H, d, J = 14. 5Hz), 5.00 (lH, s), 5. 02 (1H, d, J = 1 -8 0 This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) A7 B7 V. Description of the invention (79) 4. 5Hz), 5. 03 (1H, d, J = 4.6 Hz), 5. 74 (1H, dd, J = 15. 2, 4. 6Hz), 6. 35-6. 55 (3H, in), 6. 59 (1H, d, J = 15. 2Hz), 6. 7-6. 8 (2H, m) t 6. 89 (1H, dd, J = 15. 2, 9. 9 Hz), 7. 35 (1H, m), 7. 48 (2H, d, J = 8. 6 Hz), 7. 56 (2H, d, J = 8.6 Hz) , 7.78 (1H, s), 7.79 (lH, s) e Example 38 (RS) -2- (2,4-difluorophenyl) -3-methyl-bu (1H-1,2, 4-triazole-boxy) -3-[[trans-2-((1Ε, 3Ε) -4- [4- (trifluoromethyl) phenyl] -1,3-butadiene-buyl] -1,3-dioxan-5-yl] thio] -2-butanol

(Please read the notes on the back before filling in the bonbon)

rx VN

F Following Example 4, let (RS) -2- (2,4-difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) thio] -3-methyl-1 -(1H-1,2,4-triazol-1-yl) -2-butanol and (2E, 4E) -5- [4- (trifluoromethyl) phenyl] -2 of Reference Example 25, The reaction of 4-pentadienal yielded the target product as the main product and a colorless foam. Printed by N MR (270MHz, CDClg) δ ppm: 1. 36 (6H, s), 3. 5-3. 6 (2H, ra), 3.6-3 .8 (2H, m), 4. 2-4. 4 (1Η, πι), 4. 4-4. 6 (1H, m), 4. 93 (1H, d, J = 14. 1Hz), 5.03 (lH, d, J = 4.3Hz), 5.23 (lH, d, J = 14.1Hz), 5.56 (lH, s), 5. 84 (1H, dd, J = 15. 4, 4. 3Hz), 6.5-6.7 (3H, m), 6. 7-6. 9 (2H, m), 7. 50 (2H, d, J = 8.4 Hz), 7. 57 (2H, d, J = 8.4 Hz), 7.6-7. 7 (lH, m), 7.74 (lH, s), 8.05 (lH, s). -8 1 ~ This paper size applies Chinese National Standard (CNS) A4 »(210X297mm) A7 B7 V. Description of the invention (withholding) Example 39 (2 ^, 31〇-2- (2,4-difluorobenzene Yl) -1- (18-1,2,4-triazole-phenyl) -3-[[trans-2-[(E) -4- [4- (trifluoromethyl) phenyl] -1 -Butene-3-yn-1-yl] -1,3-dimorphin-5-yl] thio] -2-butanolCH,

(Please read the notes on the back before filling this page) ~ ^) ~ CF3

F Example 4: (2R, 3R) -2- (2,4-difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) thio] -1- (1H -1,2,4-triazol-1-yl) -2-butanol and (E) -5- [4- (trifluoromethyl) phenyl] -3-pentene-4- of Reference Example 48 The alkynaldehyde reacted to obtain the target product as the main product and an oily substance with a yield of 70%. Specific rotation [a] D 65_ Γ (c = 0.97, CHC13) NM R (270NHz, CDClg) δ ppm: l. .19 (311, d, J = 7. OIIz), 3. 33 (111, q, J = 7. 0Hz), 3. 39 (1H, tt, J = 11.4, 4. 9Hz), 3.60 (1H, tJ = 11.4Hz), 3. 62 (1H, t, J = 11.4Hz) Economy Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Education, 4.30 (lH, m), 4.42 (lH, ni), 5. 0-5. 1 (2H, m), 5. 04 (1H, d, J = 3.2 Hz ), 6.12 (lH, d, J = 16.0Hz), 6.18 (1H, dd, J = 16. 0, 3.2Hz), 6. 7-6. 8 (2H, m), 7.36 (lH, m), 7.54 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.79 (2H, s). Example 4 0 (2R, 3'R) -2- (2,4-difluorophenyl) -3-[[trans-2-phenyl-1,3-dioxan-5-yl] thio 〕 -Triazol-1-yl) -2 -butanol-8 2-This paper size applies Chinese National Standard (CNS) (210X297mm) A7 B7 V. Description of the invention (2 丨)

0 Ph Ο N ^ \ (Please read the notes on the back before filling this page)

F (2R, 3R) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] fluorene 1.65 g (6.57 nmol) and the reverse of Reference Example 1-2.00 g (8.40 nmol) of 4- (acetaldehydethio) -2-phenyl-1,3-dihumane was dissolved in dimethylformamide 2 Bl, add 1.6M sodium methoxide-methanol solution 2.5ml (4.00Bnol) under the atmosphere. Stir at 65 ° C for 2 hours. After cooling, ethyl acetate was added, the mixture was washed with saturated brine, dried, and the solvent was distilled off under reduced pressure. Chromatography on 60 g of silica gel column (benzene-ethyl acetate = 5: 1) gave 2.53 g of the target compound ( Yield 91%) of solid β was recrystallized from ethyl acetate-hexane to obtain a pure product having a melting point of 58-60 eC. Specific optical rotation [a] D25 -88 * (01.07, CHC13) Outside 4 lines of wheat industry absorb IR (CHC1 „) cm-1: 3400,1615, 1500,1139. ΠΙαχ ο Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs NMR (270MHz, CHClg) δ ppm: 1. 21 (3Η, d, J = 7.3 Hz), 3. 36 (1Η, q, J = 7.3 Hz), 3. 48 (1H, tt, J = ll. 2, 4. 6Hz), 3. 75 (1H, t, J = ll. 2Hz), 3. 77 (1H, t, J = ll. 2Hz), 4. 4 0 (1H, ddd, J = ll. 2, 4. 6, 2. 6 Hz), 4. 51 (1H, ddd, J = ll. 2, 4. 6, 2. 6 Hz), 4. 84 (1H, d, J = 13. 9 Hz) , 5. 02 (1H, s), 5. 05 (1H, d, J = 13. 9Hz), 5. 49 (1H, s), 7. 7-7. 8 (2H, m), 7. 3 -7. 45 (4H, m), 7. 45-7. 53 (2H, m), 7. 79 (2H, s) · Reference Example 1 trans-4- (acetaldehydethio) -2-phenyl -1,3-二 丨 尊 院 -8 3-This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 5. Description of the invention (~

AcS, A7 B7) &quot; ... &quot; Ph 29.0 g (86.8 · βο1) of cis-2-phenyl-4- (p-toluenesulfonyl) &gt; -1,3-di 丨 and alkanes and sodium thioacetate ΐ7.0 g (149 lanes of "101") were dissolved in dimethylformamide 200 »11, and heated in a nitrogen atmosphere for 115-120. €: 1 hour. After the reaction, benzene was added and washed with water, and the solvent was evaporated. The brown residue was subjected to silica gel column chromatography (benzene-hexane = 2 ·· 1) and recrystallized from the benzene-hexane mixture to obtain 8.99 g (yield 43%) of the target compound having a melting point of 95 to 96 ° C. NMR (270MHz , CDClg) δ ppm: 2.37 (3H, s), 3. 79 (2H, t, J = ll. 2Hz), 4.03 (1H, tt, J = 11.2, 4.6Hz), 4. 31 (2H, dd, J = ll. 2, 4. 6Hz), 5.47 (lH, s), 7.35-7.5 (5H, m) 〇IR vmax (CHC13) cin_1: 1690, 1383, 1146, 1084. Mass spectrum m / e: 238 (M +), 237, 19.5, 162 (100%), 149, 116, 107, 73. Reference Example 2 (2R, 3R) -2- (2,4-difluorophenyl) -3-[(1, 3-dihydroxy-2-propyl) thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol --nnn-II--nn-II ^ (Please (Please read the notes on the back before filling out this page) Printed by the Central Standards Bureau of the Ministry of Economic Affairs

S

OH OH The (2R, 3R) -2- (2,4-difluorophenyl) -3-[[trans-2-phenyl-1 &gt; 3-dioxan-5-yl] thio group of Example 40 ] -1- (1H-1,2,4-triazole-8 4 _ This paper size applies to the Chinese National Standard (CNS) A4 specifications (210X297 mm) A7 B7 V. Description of the invention (w) -1-based &gt; -2-butanol 253 | ^ dissolved in methanol 3.5 | 111, add 0-11 (; 1 dioxane solution 0.35nl, stir at room temperature for 30 minutes, add NaHC03 powder 2 50 mg, stir 10 After the separation, the solution was filtered and concentrated under reduced pressure. The obtained oil was subjected to silica gel column chromatography (10% methanol-ethyl acetate) to obtain 179 ng (yield 88%) of the target substance as a viscous oil. Specific rotation [a] D25 -61 ° (C = 1.05, CHC13) infrared absorption IR v (CHC1,) cm_1: 3400, 1618, 1500. fli &amp; x ο NM R (60MHz, CDClg + DgO) δ ppm: 1.20 (3Η, d, J = 6.5Hz), 3.0-4.0 (6Η, in), 4.80 (1Η, d, J = 14Hz), 5.16 (1Η, d, J = 14Hz), 6. 6-7. 0 (2Η , m), 7. 43 (1Η, td. J = 9. 8 Hz), 7.74 (1H, s), 7.86 (1H, s). Reference Example 3 trans-5-[(4-Gabenzyl) thio 〕 -2 -phenyl-1,3-dioxane and other alkane ClHj〇 ^)-CH2Sr ^ ~ 〇) ... &quot; Ph Staff Consumption of Central Standards Bureau, Ministry of Economic Affairs # 社 印 裂(Please read the precautions on the back before filling in this page) After washing 55% NaH 240 mg (5.50 iaiD0l) in hexane, suspend it in 15 ml of dimethyl formamide, add it under nitrogen atmosphere stirring 4-chlorobenzyl mercaptan 903 mg (5.70 «η» 〇U. After 15 minutes, add cis-5-(p-toluenesulfonyl) -2-phenyl-1,3-di 1.66 g (4.96 mmol) of naphthene, stirred at 75 ° C. for 1 hour. After cooling, add benzene and wash with water and brine, evaporate the solvent, and recrystallize from the benzene-hexane mixture to obtain a melting point of 95-9. .9 °! The target 670 »^ (yield 42%), scaly crystals. NMR (60MHz, CDClg) δ ppm: 3. 02 (1H, tt, J = ll, 5Hz), 3. 67 ( 2H, t, J = 1 1Hz), 3. 72 (2H, s), 4. 2l (2H, dd, J = ll, 5Hz), 5. 39 (1H, s). 7. 30 (5H, s ), 7. 38 (4H, s). -85- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 5. Description of the invention (section) A7 B7 Reference Example 4 2-[(4- Benzyl) thio] -1,3-propanediol

Cl ~ &lt; g &gt; -CH2s {

on OH Dissolve 750 g of trans-5-[(4-airbenzyl) thio] -2-phenyl-1,3-dioxane in methanol 10〇1, add 4N HC1-dioxane solution InU After stirring at room temperature for 1 hour, the sodium bisulfate powder 75Qmge was added and stirred for 15 minutes, the solid was filtered off, and the solvent was distilled off. Ethyl acetate was added, the insoluble matter was filtered off, the solvent was distilled off, and recrystallization was performed from benzene-hexane to obtain 468 mg of the target compound having a melting point of 70 to 75 ", and a yield of 86%. Benzyl) thio] -2-[(E) -l-methyl-2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane C1

CH, S

1 ^ 1- ^^^ 1 1 ^ 1 n ^ in 1 ^ 1 nn In n ^ i-I (Please read the precautions on the back before filling out this page) The Central Consumers Bureau of the Ministry of Economic Affairs Employee Cooperatives will print 2 -[(4-Aminobenzyl) thio] -1,3-propanediol 341ug (1.46Bmol) and (E) -4- (trifluoromethyl)-«-methylcinnamaldehyde 375Bg (1.75mnol) Dissolve in benzene 12b1, add 3mg of p-toluenesulfonic acid, heat and reduce it under nitrogen atmosphere for 2 hours, and after cooling, wash with sodium bicarbonate and evaporate the solvent. Chromatography on a 15 g silica gel column (hexane: ethyl acetate = 9: 1). The obtained solid was washed with hexane to obtain 370 ml of the target compound having a melting point of 93-95 ° C, and a yield of 59%. -86 This paper size applies to Chinese National Standard (CNS) M specifications (2 丨 0X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 _ 5. Description of the invention (Chinese) NM R (270MHz, CDClg) δ ppm : 1. 87 (3H, s), 2. 99 (1H, tt, J = ll. 2, 4. 6Hz), 3. 58 (2H, dd, J = ll. 9, 11.1.2Hz), 3. 73 (2H. S). 4.15 (2H, dd, J = ll. 9, 4. 6Hz), 4. 87 (1H, s), 6. 68 (1H, br s), 7. 25-7. 3 (4H, m), 7. 36 (2H, d, J = 7.9 Hz), 7. 57 (2H, d, J = 7. 9 Hz). Reference Example 6 trans-5-[(4-azabenzyl ) Sulfinyl]] 2-[(E) -l-methyl- 2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane C1 2 2⑼ ~~ CF3 0 ch3 will be trans-5-[(4-heliumbenzyl) thio] -2-[(E) -1-methyl-2- [4- (trifluoromethyl) phenyl] vinyl]- 382 mg (0.89 Bmol) of 1,3-dioxane was dissolved in 10 ml of dichloromethane, and benzoic acid (purity 85%) 188Bg (0.92mniol) was added at 0 °. After stirring for 15 minutes, the acid Wash with sodium water, evaporate the solvent, and wash with ethyl acetate-hexane mixture to obtain 328 mg (83% yield) of the target compound with a melting point of 192-194 ° C. Β NMR (60MHz, CDClg) δ ppid: 1. 88 (3 H, d (J = 1.5 Hz), 2. 8-3. 3 (lH, m), 3. 8-4. 5 (4H, m), 4.01 (2H, s), 4. 95 (1H, s), 6. 73 (1H, br s), 7.15-7. 75 (8H, m). Reference Example 7 trans- 4- (acetaldehydethio) -2-[(E) -l-methyl- 2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane

AcS-F-- 0 ch3 will be trans-5-[(4-aminobenzyl) sulfinaldehyde] -2-[(E) -l-methyl-2- 2- [4- (trifluoromethyl) benzene Base] vinyl] -1,3-dioxane 3 0 9 ng (-8 Ί-gravel paper size applicable to Chinese national standard icNS) A4 size (210X297 mm) (Please read the precautions on the back before filling (This page)

Printed by A7 B7, Shellfish Consumer Cooperative of the Central Public Accreditation Bureau of the Ministry of Economic Affairs 5. Description of the invention (α) 0.696bb〇1) Dissolved in tetrahydrofuran-acetonitrile (1: 1) mixed solution 8b1, added 2,6-dimethylpyridine 500mg (4.67 mmol) e was added dropwise with 500 mg of trifluoroacetic anhydride (2.4 mmol) e at about 5 minutes under stirring at 0 ° C for 10 minutes, and then sodium nitrate water was added for about 5b 1. After stirring for 5 minutes, it was extracted with ethyl acetate, and the solvent was evaporated. The obtained oil (about 350 ng) was dissolved in digas methane 5b1, triethylamine 21〇Bg and acetone gas 109nge were added at 0 ° C for 5 minutes, washed with water, and the solvent was distilled off. Chromatography (hexane: benzene = 1: 1 ~ 1: 2), 186Bg (77% yield) of the target substance was obtained by crystallization, and recrystallization from a benzene-hexane mixture to obtain a plate crystal with a melting point of 128 ~ 129 &quot; C . NMR (270MHz, CDC1J δ ppm: 1.92 (3H, s), 2. 36 (3H, s). 3. 70 (2H. T, J = 0 11. 2Hz), 3. 96 (1H, tt, J = ll. 2, 4. 6Hz), 4. 25 (2H, dd, J = ll. 2, 4. 6Hz), 4. 94 (1H, s), 6. 7 0 (1H, br s), 7. 39 (2H, d, J = 8.2 Hz), 7. 59 (2H, d, J = 8.2 Hz). Reference Example 8 (2E, 4E) -3-methyl-5- [4- ( Trifluoromethyl) phenyl] -2,4-pentadienoate ethyl y ~~ cooc2h5 ch3 After washing 55% NaH 45ng (1.03inffl0l) in hexane, suspend in 1, 2-dimethylformate 3 ml of gaseous ethane, added 3-methyl-4-isocrotonate triethyl ester 2 7 3 mg (1.03maol) under nitrogen atmosphere stirring at 0 ° C, 15 minutes later, 4- (trifluoromethyl) 100 mg of benzaldehyde (0.57BB01), stirred for 10 minutes, added ice water, extracted with ethyl acetate, evaporated the solvent, and chromatographed ethyl acetate on a 5 g silica gel column: hexane = 4: 96) to obtain the objective (2E, 4E) isomers and (2Z, 4E) isomers -88- This paper size is applicable to China National Standard (CNS) A4 specifications (210X297 mm) (Please read the precautions on the back before filling this page) Order A7 B7 V. Description of the invention () Structure 5: 1 mixture 159Bg (yield 97%), oily. NMR (270MHz, CDC13) δ ppm: (2E, 4E) -heterosexual, 1.31 (3H, t, J = 6.6Hz), 2. 41 (3H, s), 4. 20 (2H, q, J = 6 6Hz), 5. 95 (1H, s), 6. 86 (1H, d. J = 16. 5Hz), 6. 95 (1H, d, J = 16. 5Hz), 7. 5-7 · 65 (4H, ra): (2E, 4E) -heterosexual body (Master 4 'Shi Xi Yuer), 2. 14 (3H, s), 5. 82 (1H, s), 6. 92 (1H, d, J = 16. 5Hz), 8. 49 (1H, d, J = 16. 5Hz). Reference Example 9 (2E, 4E)-3-methyl-5- [4- (trifluoromethyl) phenyl] -2, 4-pentadiene-butanol

OH will refer to (4E) -3-methyl-5- [4- (trifluoromethyl) phenyl] -2,4-pentadienoate ethyl ester of Reference Example 8 [(2 £) / (22) = 5/1] 150 ^^, (0.53 mmol) was dissolved in 2 ml of toluene, and 1.5M diisobutylaluminum hydride toluene solution 0.7ial (1.06 fmol) was added under stirring at 0 ° C. After 20 minutes, add ice water, stir for 10 minutes, filter off insoluble matter with diatomaceous earth, extract with ethyl acetate and dry, and evaporate the oily substance obtained by dissolving SK on a 5 g silica gel column chromatography (30 ~ 40% Ethyl acetate-hexane) to give 90 mg of the object, as an oil. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) NMR (270MHz, CDClg) δ ppm: 1. 34 (1H, br s), 1. 93 (3H, s) , 4. 37 (2Ht d, J = 6.5 Hz), 5. 87 (1H, t, J = 6.5 Hz), 6. 58 (1H, d. J = 16. 1Hz), 6. 88 (1H , d, J = 16. 1Hz), 7. 5 0 (2H, d, J = 8.5Ηζ), .7 · 57 (2H, d, J = 8.5Hz). / Reference example 1 0 (2 £, 4 〖)-3-methyl-5- [4- (trifluoromethyl) phenyl] -2,4-pentane _ 8 9 _ This paper size applies to Chinese national standards (CNS) A4 specification (21 × 297 mm) A7 B7 V. Description of the invention (M) enal

, ~~ CHO (please read the notes on the back before filling this page) ch3 will (2 £, 4 £) -3-methyl-5- [4- (trifluoromethyl) phenyl] -2, 460 mg (1.96 mmol) of 4-pentadien-1-ol was dissolved in 10 nl of dichloromethane, and 5 g of active digassed manganese was added. After stirring at room temperature for 30 minutes, the solid was filtered off, concentrated and subjected to silica gel chromatography (4 % Ethyl acetate-hexane) to give 460 mg of the target substance as an oil. NMR (270MHz, CDClg) δ ppm: 2. 41 (3H, s), 6. 13 (1H, d. J = 8. 0Hz), 6. 96 (1H, d, J = 16.1 Hz), 7. 09 (1H, d, J = 16. 1Hz), 7. 55-7. 7 (4H, m), 10. 19 (1H, d, J = 8. 0Hz). Reference Example 11 4- (Ethylsulfanyl) -1- (third butanecarbonyl) piperidine 〇

Ac S— ^ NCO-- Printed by the Consumer Cooperative of the Central Weng Zhun Bureau of the Ministry of Economic Affairs, dissolving 4.12 g (14.7 mmol) of 1- (third butoxycarbonyl) -4- (methanesulfonyloxy) piperidine in dimethyl ether 40 ml of methylformamide, 2.53 g (2.21 mmol) of potassium thioacetate, and stirred at 105 ° C in a nitrogen atmosphere for 4 hours. After cooling, it was diluted with ethyl acetate, washed with water and saturated brine, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 5.19 g of an oily target product (product Rate 81%). NM.R (270MHz, CDClg) δ ppm: 1.46 (9Ht s), 1. 5-1. 6 (2H, m). 1. 9-2. 0 (2 H, m), 2. 33 ( 3H, s), 3.0-3.1 (2H, m), 3 '5-3_ 7 (1H, m), 3_ 8-3. 9 (2H, tn). Mass spectrum m / e: 259, 244, 216, 202, 186, 183, 160, 144, 127, 116, 97, 84, 57. -90- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297mm) A7 B7 5. Description of the invention (approximately) Reference Example 12 1-Third butane carbonyl) -4-hydrothiopiperidine 0

520 mg (2 mi) of 4- (acetamidinethio) -1- (third butane carboxy) piperidine was dissolved in dry methanol, and 28% sodium methoxide-methanol solution 420 # 1 was added under ice-cooled and nitrogen atmosphere. 2ββ〇1). After stirring for 40 minutes, add 173 # 1 acetic acid, evaporate the solvent at room temperature, dilute with ethyl acetate, and wash with sodium bisulfate water and food water in order. The solvent was distilled off to obtain 430 mg of a red-orange oil, and the residue was purified for the next reaction. NMR (270MHz, CDC13) δ ppm: 1.46 (9Η, s), 1.5-1.6 (2H, m). 1.9-2. 0 (2 H, ra), 2. 8-3. 0 (3H, m ), 3. 9-4 · 1 (2H, m). Mass spectrum m / e: 217, 202, 184, 161,144, 127, 117,84, 82. Reference Example 13 (2R, 3R) -2- (2,4-difluorophenyl) -3- (lH-1,2,4-triazol-1-yl) -3- [[1- (third Butanylcarbonyl) pyridin-4-yl] thio] -2-butanol

ch3 HO Ι, Η F

F 0

II CO- Printed by the Central Ministry of Economic Affairs ## The Bureau ’s Consumer Cooperatives (please read the precautions on the back before filling out this page) Dissolve the result of Reference Example 12 (equivalent to 2 mol) in dimethylmetamine 6ffil Add 55% NaH 86ffig (i97mmQl) under 0 ° C nitrogen atmosphere. After 20 minutes, add (2R, 3S) -2- (2,4-difluorophenyl) -3- -91 at the same temperature and mix at the same temperature. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 (Mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

A7 B7__V. Description of the invention (90) methyl-2-C (1H-1,2,4-triazol-1-yl) methyl] propane ring 503mg (2.0〇Bla〇l), at 6 ( TC was stirred for 3 hours. After cooling, ethyl acetate was added, followed by washing with water and saturated brine, and the solvent was distilled off. The obtained oil was subjected to silica gel column chromatography (ethyl acetate) to obtain the target substance 557® g (53% yield), oily. NMR (270MHz, CDClg) 5 ppm: 1. 17 (3H, d, J = 6.6 Hz), 1. 47 (9H, s), 1. 4-1 · 6 (2H, di), 1. 9-2. 1 (2H, m), 2. 9-3. 1 (3H, m), 3. 34 (1H, q, J = 6.6 Hz), 3. 9-4.1 (2H, m), 4 • 77 (1H, s), 4. 82 (1H, d, J = 14. 2Hz), 5. 09 (1H, d, J = 14. 2Hz), 6. 7-6. 8 (2H, m), 7. 3-7. 4 (lH, m), 7.77 (lH, s), 7.82 (lH, s). IR '&amp; Guang' 1: 3401, rattan. Mass spectrum ra / e: 468, 408, 395, 365. 321. 284, 253, 224, 188, 166, 144. 127. Reference Example 1 4 (2R, 3R) -2- (2,4-difluorophenyl ) -3- (lH-1,2,4-triazole-butyl) -3-[(piperidin-4-yl) thio] -2-butanol 2 hydrochloride ch3 HO ΓλΗ F --- -： —— 1 61 — (Please read the precautions on the back before filling this page)

1T

F Dissolve 557 mg (1.05 nnol) of the product of Reference Example 13 in ethyl acetate 20 a 1, add 4 N HC1 ethyl acetate 2.63ail (10.5 minol), and stir at 40 ° C for 8 hours. After cooling, the solid was collected by filtration, and washed with hexane to obtain the target product 460Bg (yield 100%) as a colorless powder. -92- This paper size applies to Chinese National Standards (CNS) (210X297mm) Central #Ministry of Economics, Ministry of Economic Affairs, A7, B7_5. Invention Description (9 &lt;) N MR (270MHzt DMSO-dG + CDClg) δ ppm: 1. 23 (3Η, d? J = 6.6 Hz) 11. 8-2. 0 (2Hf m), 2. 3-2. 5 (2Hf m) (3. 1-3. 4 (3H ( m), 3.74 (1H, qf J = 6.6Hz), 4.79 (1H, d, J = 14. 2Hz), 5.05 (.1H, d, J = 14. 2Hz), 5 3-5.6 (lH, br s), 6.8-6 · 9 (1Η, m), 7.0-7. 1 (1H, π〇, 7. · 2-7 • 3 (lH, m) f 7.79 (lH, s), 8.28 (lH, s). 1 R ^^ / ^ (^ 4: 3366,3094,2725,2483, mass spectrum m / e: 368,308, 286, 284,253,224, 213,183, 165,144, 116, 113, 84. References Example 1 5 4- (Acetylthio) piperidine hydrochloride

AcS- ^ ΛΐΗ-HC1 Dissolve 1.25 g (4.82 mmol) of 4- (ethylsulfanyl) -1- (third butoxycarbonyl) piperidine in Reference Example 11 in 45 ml of ethyl acetate, and add 4N HC1 ethyl acetate Esters 12. 0 m 1 (4 8. 2 in m ο 1). After stirring at 50 ° C for 4 hours, β-cooling, the solid was collected by filtration, and washed with hexane to obtain 885 g of the target product, yield 94%, slightly yellow powder. NMR (270MHz, CD3〇D) δ ppm: 1. 8-2. 0 (2H, m), 2. 1-2. 3 (2H, m), 2. 35 (3 H, s), 3.1 -3. 3 (2H, m), 3. 3-3. 5 (2H, m), 3. 6-3. 8 (1H, m). Reference Example 16 4- (Ethylsulfanyl) -1-[(E) -4- (trifluoromethoxy) cinnamate] Acetyl AcS- ^ NC〇-^-&lt; 〇) -〇 ^ 3 ： -93- This paper size is applicable to China National Standard (CNS) A4 (210X297mm) (Please read the precautions on the back before filling this page)

A7 B7_ V. Description of the invention (P) 1.28 g (6.53ββο1) of 4- (acetaldehydethio) piperidine hydrochloride was suspended in digas methane 17b1, and triethylamine 2.27β1 (16.3 was added dropwise with stirring under ice cooling. Then, a solution of 1.80 g (7.18BΠ01) of cinnabarium tritium (E) -4- (trifluoromethylamino) and 6 ml of dichloromethane was added dropwise. After stirring at the same temperature for 1 hour, the solution was subjected to silica gel column chromatography ( Hexane: ethyl acetate = 2: 1 ~ 1: 1), 2.32 g (yield 95%) of the target substance was obtained, and a yellow solid was obtained. NMR (270MHz, CDClg) δ ppm: 1. 5-1. 7 (2H, m), 1. 9-2. 1 (2H, m), 2. 34 (3 H, s), 3. 1-3 3 (1H, m), 3. 3-3. 5 (1H, m), 3. 7-3. 8 (1H, m), 3. 9-4. 0 (1H, in), 4.2 -4. 4 (1H, m), 6. 85 (1H, d, J = 15. 5Hz), 7. 21 (2H, d, J = 8. 6Hz), 7. 54 (2H, d, J = 8. 6Hz), 7. 63 (1H, d, J = 15. 5Hz). Mass spectrum ra / e: 373, 330, 298, 256, 228, 215, 187, 158, 136, 116, 101 »Reference Example 1 7 3- (Ethylsulfanyl) -1- (third butane carbonyl) azetidine Ο

AcS Ό NCO — | — An orange oil was obtained from 1- (third butoxycarbonyl) -3- (methanesulfonyl) azetidine in the same manner as in Reference Example 11. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) NMR (270MHz, CDClg) 5 ppm: 1. 44 (9H, s), 2. 33 (3H, s) , 3. 81 (2H, dd, J = 9.0, 5.5 Hz), 4. 1-4. 2 (lH, m), 4. 37 (2H, t, J = 9. 0 Hz). Reference Example 18. (2R, 3R) -2- (2,4-difluorophenyl) -1- (1Η-1,2,4-triazol-1-yl) -3- [[1- ( The third butoxycarboxyl group) azetidin-3-yl] thio] -2-butanol-94- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)

F A7 B7 V. Description of the invention (") 0 SI NCO— | A light yellow foam was obtained from 3- (ethylsulfanyl) -1- (third butane carboxy) azetidine by reference examples 12 and 13. NMR (270MHz, CDClg) δ ppm: 1. 13 (3H, d, J = 7.1 Hz), 1. 45 (9H, s), 3. 27 (1H, q, J = 7.1 Hz), 3. 7-3. 9 (2H, in), 3. 9-4. 0 (1H, m), 4. 2-4. 4 (2H, m), 4. 84 (1H, d, J = 14. 1Hz ), 4. 98 (1H, s), 5. 04 (1H, d, J = 14.1Hz), 6. 7-6. 9 (2H, m), 7. 3-7. 4 (1H, in ), 7. 78 (1H, s), 7.80 (lH, s)., IRV ^ axKBrcm_1: 3405,1701. Mass m / e: 441,425, 385, 367, 341, 311,284, 252, 224 , 199, 183, 165, 141, 127, 88. Reference Example 1 9 (2R, 3R) -2- (2,4-difluorophenyl) -1- (1Η-1,2,4-triazole- 1-yl) -3-[(azetidin-3-yl) thio] -2-butanol 2 hydrochloride NH ♦ 2HC1 F. From (2R, 3R) -2- (2,4-difluoro Phenyl) -1- (1H-1,2,4-triazol-l-yl) -3-[[1- (Third-butanecarbonyl) azetidin-3-yl] thio] -2- Butanol was obtained as a slightly yellow powder after imitating Reference Example 14. -95- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back first Complete this page)

Printed by the Consumer Cooperative of the Central Mycorrhizia Bureau of the Ministry of Economic Affairs,

A7 B7 V. Description of the invention (materials) (Please read the notes on the back before filling this page) NMR-(270MHz, CDClg) 5 ppm: 1-16 (3H, d, J = 6.6 Hz), 3. 52 (1H, q, J = 6.6 Hz). 3. 9-4. 3 (3H, ra), 4. 3-4. 6 (2H, m), 4. 98 (1H, d, J = 14. 2Hz), 5. 43 (1H, d, J = 14. 2Hz), 6. 6-6. 9 (2H, m), 7. 2-7. 4 (1H, m), 8. 40 ( 1H, s), 8. 95 (1H, s), 9. 0-9. 6 (1H, br) „Reference Example 2 0 trans-4- (trifluoromethyl) ethyl cinnamate 卩 / 览 π㈣5 will 55% HaH 903ng (20.7ii »ol.) Was washed in the courtyard, suspended in 60 al of 1,2-dimethylethane, and 4.63 g of formaldehyde triethyl acetate was added dropwise with stirring at 0 ° G in the atmosphere. 20..7mnol). After 15 minutes, add 2.00 g (11.5 | 11111〇1) of 4- (trifluoromethyl) section at the same temperature. After searching for 15, add ethyl acetate. Wash with water. After drying The solvent was distilled off. The obtained oily residue was subjected to silica gel column chromatography (4% ethyl acetate-hexane) to obtain a melting point of 31 to 32.5X: the target product, a yield of 98%. NMR (270MHz, CDClg) 5 ppm: l. 35 (3H, t, J = 7.3 Hz), 4. 48 (2H, q, J = 7.3 Hz), 6-51 (lH, d, J = 16.2Hz), 7.66 (4H, s) , 7.69 (lH, d, J = 16.2Hz) Reference Example 2 1 trans-4- (trifluoromethyl) Cortisol Ministry of Economic Affairs Bureau of Standards staff printed consumer cooperatives

CH „OH Dissolve 3. 00 g (12 .3. Mmol) of ethyl 4- (trifluoromethyl) cinnamate in toluene 15b1, add 1 · 5M diisobutylaluminum hydride under TC stirring -Toluene solution 16.4 »1 (24.6bbio1). After 2Q points, add ice-water and stir to separate the insolubles, filter through diatomaceous earth, extract with ethyl acetate, dry, and steam -96- this paper Printed in Chinese National Standard (CNS) A4 (210X297 mm)

A7 B7 * -------------- ~~~:-:-V. Description of the invention (to) Remove the solvent and recrystallize from the benzene-hexane mixture to obtain a melting point of 53 ~ 55 ° C 2.36 g (96% yield). NMR (270MHz, CDClg) δ ppm: 1.55 (III, t, J-= r &gt;. Oil · /.), A. 37 (? .Ll, be t), 6-46 (lH, dt, J = 16.2,5.3Hz), 6.67 (1H, d, J = 16.2Hz), 7.46 (2H, d, J-8. 3Hz), 7.57 (2H, d, J = 8.3Hz) e Reference Example 22 Trans-4- (trifluoro.methyl) cinnamaldehyde

Dissolve 2.15 g of trans-4- (trifluoromethyl) cinnamyl alcohol in 30 ml of digas methane, add 0 g of activated manganese digas, and stir for 15 minutes, then stir at room temperature for 2 hours. The solid was filtered off and concentrated, and then recrystallized from the benzene-hexane mixed solution to obtain a product having a melting point of 60 to 6 1.0 mesh, a yield of 90%. NMR (270MHz, CDClg) δ ρριπ: 6. 78 (1Η, dd, J = 16. 2, 7. 3Hz), 7. 53 (1Η, d, J = 16. 2Ηζ), 7.69 (4Η, s ), 9. 76 (1Η, d, J = 7.3Ηζ). IR ν (KBr) cm'1: 1680, 1630, 1321, 1173, 1123, 1066. max mass m / e: 200 (M +), 199, 171, 151, 145, 131 (100%). 103, 102. Reference example 2 3 (2E, 4E) -5- [4- (trifluoromethyl) phenyl] -2,4-pentadienoate acetonitrile C02C2H5 -97- This paper size applies to China National Standards (CNS) A4 specifications (210X297 mm) H.-nn-n I-1 ^) / ^ u.-N In (Please read the notes on the back before filling out this page) A7 B7 V. Description of the invention (outside) will 55% NaH _4.51g (1〇3βπο1) was washed in his own courtyard, suspended in 1,2-dimethoxyethane, and stirred at 0 ° C cyanide atmosphere, and 25.9g of triethylbarbate was added dropwise with stirring. (10 3 ^ 〇〇1). After 15 minutes, 10-grams (57.4 mmol) of 4- (trifluoromethyl) benzaldehyde was added at the same temperature. After stirring for 10 minutes, it was poured into ice-water, extracted with ethyl acetate, and the solvent was evaporated. The oily residue was subjected to silica gel column chromatography (6% ethyl acetate-hexane) to obtain 2 g (yield 72%) of the target substance as an oil. NMR (270MHz, CDClg) 5 ppinrl. 32 (3H, t, J = 7.3 Hz), 4. 24 (2H, q, J = 7.3 Hz), 6.05 (1H, d, J = 15.2Hz), 6 85-7. 0 (2H, m), 7. 44 (1H, ddd, J = 15. 2, 7. 9, 2. 6Hz), 7.55 (2H, d, J = 8.6Hz), 7.61 ( 2H, d, J = 8.6Hz). Reference Example 24 (2 £, 4 £) -5- [4- (trifluoromethyl) phenyl] _2,4-pentadien-1-ol (Please read the precautions on the back before filling this page)

The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed a copy of Reference Example 21, and (2E, 4E) -5- [4- (trifluoromethyl) phenyl] -2,4-pentadienoate Isobutylaluminum treatment yields 100% in quantitative yield! . NMR (270MHz, CDClg) δ ppm: 1.47 (1Η, t, J = 5..9Hz), 4. 28 (2H, t, J = 5.9.9Hz), 6.04 (lH, dt, J = 15.2, 5. 9Hz), 6. 45 (1H, dd, J-15. 2, 10. 6Hz), 6. 57 (1H, d, J = 1 5.8Hz), 6. 87 (1H, dd, J = 15 . 8. 10. 6Hz), 7. 47 (2H, d, J = 8.6 Hz), 7. 56 (2H, d. J = 8.6 Hz). Reference example 2 5 (2E, 4E) -5- [4- (trifluoromethyl) phenyl] -2,4-pentadienal t -98- This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) A7 B7

Printed as Reference Example 22 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, using (2E, 4E) -5- [4- (trifluoromethyl) phenyl] -2,4-pentadien-1-ol as an active ingredient Manganese dioxide treatment, yield the target product, yield 92% 〇NM R. (270MHz, CDClg) 5ppm: 6.33 (lH, dd, J = 15. 2,7.3 Hz), 7.0-7.35 (3H, m) , 7.60 (2H, d, J = 8.6Hz), 7.64 (2H, d, J = 8.6Hz), 9.65 (lH, d, J = 7.3Hz). Reference example 2 6 (2 £, 4 £, 6 £) -7- [4- (trifluoromethyl) phenyl] -2,4,6-heptatrienoate ethyl ester C0Et (2E, 4E) -5- [4- (trifluoromethyl) benzyl] -2,4-heptadienal is reacted with triethyl phosphinophosphonium acetate to obtain the target product in a yield of 95%. NMR (270MHz, CDClg) δ ppm: 1. 31 (3H, t, J = 7.3 Hz), 4. 23 (2H, q, J = 7.3 Hz), 5. 96 (1H, d, J = 15 2Hz), 6. 49 (1H, dd, J = 15. 2, 11. 2Hz), 6. 72 (1H, dd, J = 15. 2, 10.6Hz), 6. 73 (1H, d, J = 15.8Hz), 6. 94 (1H, dd, J = 15. 8, 10.6Hz), 7. 37 (1H, dd, J = 15.2, 11.2Hz), 7. 51 (2H, d , J = 8.6Hz), 7. 58 (2H, d, J = 8.6Hz). Reference Example 27 (2 £, 4 £, 6 £) -7- [4- (trifluoromethyl) phenyl] -2,4,6-heptatrien-1-ol-99- This paper is for China National Standard (CNS) Α4 »(21 OX297 mm) (Read the precautions on the back before filling in this page)

A7 B7

Similarly to Reference Example 21, the product of Reference Example 26 was treated with diisobutylaluminum hydride to obtain the target product in a yield of 9 Q%. NMR (270MHz, CDClg) δ ppm: 1. 41 (1H, t, J = 5.3 Hz), 4.25 (2H, t, J = 5.3 Hz), 5.95 (lH, dt, J = 15.0, 5.3Hz) , 6. 3-6. 5 (3H, m), 6. 57 (1H, d, J = 15. 2Hz), 6.90 7. 47 (2H, d, J = 8.6 Hz), 7.55 (2H, d , J = 8.6Hz) e Reference Example 2 8 (2 £, 4 £, 6 £) -7- [4- (trifluoromethyl) phenyl] -2,4,6-heptatrienal

CHO imitates Reference Example 22, and treats the product of Reference Example 27 with active manganese dioxide to obtain the target product with a yield of 88%. NMR (270MHz, CDClg) 5 ppra: 6.23 (1H, dd, J = 15. 2, 7. 9Hz), 6. 62 (1H, dd, J = 14. 5, 11. 2Hz), 6. 82 (1H, d, J = 15. 8Hz), 6. 84 (1H, dd, J = 14. 5, 9. 9Hz), 6.98 (1 H, dd, J = 15. 8, 9. 9Hz), 7 19 (1H, dd, J = 15. 2, 11.2Hz), 7. 54 (2H, d, J = 8.6 Hz), 7.61 (2H, d, J = 8.6Hz), t62 (lH, d , J = 7.9Hz) e Reference Example 29 4- (2,2,3,3-tetrafluoropropoxy) benzaldehyde-10 0- This paper is compatible with the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling this page)

Printed by A7 B7_. _. _ V. Invention Description (99) F2CH-CF2CH2〇H〇 ^ ⑽ After washing 55% NaH 1.90 g_ (43.5 | ^ 〇1) with hexane, Suspended in 25 ml of N, N-dimethylglyoxalamine, and 5.3 g of 4-hydroxybenzaldehyde (43 · βο1) was slowly added at 0 ° C in a nitrogen atmosphere. After the hydrogen gas was allowed to stand still, 11.14 g (39mnol) of p-toluenesulfonic acid 2,2,3,3-tetrafluoropropyl ester was added, and the mixture was heated and stirred at 120 ° C for 2 hours and 15 minutes. After cooling, benzene-hexane U: 1) was added and the mixture was washed with water. After drying, the solvent was distilled off to obtain 8.85 g (yield 96%) of the target substance as an oil. NMR (270MHz, CDClg) δ ppm: 4.45 (2H, br t, J = 11.9Hz), 6. 06 (1H, tt, J = 53. 3, 4. 6Hz), 7. 06 (2H, d , J = 8. 7Hz), 7. 88 (2H, d, J = 8. 7Hz), 9. 93 (lH, s) „Reference Example 30 '(2 £, 4 £) -5- [4- ( 2,2,3,3-tetrafluoropropanyl) phenyl] -2,4-pentadienoate (read the notes on the back first and then fill out this page)

Ministry of Economics, Central Bureau of Standards, Staff Consumer Cooperative Co., Ltd., imitation reference example 23, so that 4- (2,2,3,3-tetrafluoropropoxy) benzaldehyde can be reacted with triethyl phosphonic crotonate to obtain a melting point of 65 ~ The target of 6 &quot; C, yield 74%. NMR (270MHz, CDClg) δ ppm: 1.31 (3H, t, J = 7.3 Hz), 4.23 (2H, q, J = 7.3 Hz). 4. 37 (2H, br t, J = U. 9Hz), 5.95 (1H, d, J = 15. 2Hz), 6. 06 (1H, tt, J = 53. 5, 4. 6 Hz), 6. 77 (1H, dd, J = 15. 2, 9. 9Hz), 6. 86 (1H, d, J = 15. 2Hz), 6. 91 (2H, d, J = 8. 6Hz), 7. 42 (1H, dd, J = 15. 2 , 9. 9Hz), 7. 44 (2H, d, J = 8. 611z) e Reference example 31 (2 £, 4 £) -5- [4- (2,2,3,3-tetrafluoropropane Base &gt; Phenyl] -2,4- -10 1- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7

V. Description of the invention

CH9OH F0CHCF CH 0 As in Reference Example 21, the product of Reference Example 20 was treated with diisobutylaluminum hydride to obtain the target product having a melting point of 95 to 97 ° C in a yield of 95%. NMR (270MHz, CDC13) δ ppm: 1.39 (1H, t, J = ~ 5Hz), 4. 25 (2H, t, J = 5.9 Hz), 4. 34 (2H, br t, J = ll 9Hz), 5. 94 (1H, dt, J = 15. 1, 5. 9Hz), 6. 06 (1H, tt, J = 53. 2, 4. 8Hz), 6. 40 (1H, dd, J = 15. 1, 10.3Hz), G. 50 (111, d, J-1 i3. Fill /.), (I. TilJ (JH, dil, JJ 5.5, 10. 3Hz), 6.88 (2H, d , J = 8. 7Hz), 7. 36 (2H, d, J = 8.7Hz). Reference example 3 2 (2 £, 4 £) -5- [4- (2,2,3,3-tetrafluoro Propoxy) phenyl] -2,4-pentadienal (Please read the precautions on the back before filling in this page) F2CHCF2CH2 °

Printed by the Consumers Cooperative of the Central Bureau of Standards, imitating Reference Example 22, treating the product of Reference Example 31 with active manganese dioxide to obtain the target product with a melting point of 53 to 55 ° C, and a yield of 96%. NMR (270 MHz, CDClg) δ ppra: 4. 38 (2H, br t, J = 11.9Hz), 6.06 (1H, tt, J = 52. 8, 4. 6Hz), 6. 25 (1H, dd, J = 15. 2, 7. 9Hz), 6. 90 (1H, dd, J = 15. 8, 9. 2Hz), 6.94 (2H, d, J = 8. 6Hz), 6. 97 (1H, d , J = 15. 8Hz), 7. 25 (1H, dd, J = 15. 2, 9. 2Hz), 7. 48 (2H, d, J = 8.6 Hz), 9.61 (1H, d, J = 7.9Hz). Reference Example 3 3 Trans-4- (trifluoroshenyl) cinnamaldehyde -10 2- This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) A7 B7 V. Description of the invention ("^"

CF〇0- &lt; O

Heat 4- (trifluoromethylamino) benzylhydrazone 57 ° Bg (3.0Bmol) and (triphenylsulfenyl) acetaldehyde 913Bg (3.9iBB〇l) in toluene 7.5.1 under nitrogen and heat to reflux 1 After 45 minutes, toluene was distilled off under reduced pressure, and column chromatography on 20 g of silica gel (acetic acid: hexane = 1: 10) gave 387 mg of the target compound (yield 60%). Oil LL ·. NMR (270MHz, CDC13 ) δ ppm: 6. 70 (1H, dd, J = 15. 8, 7. 3Hz). 7. 29 (2H, d, J = 8. 6Hz), 7. 47 (1H, d, J = 15.8Hz ), 7. 61 (2H, d, J = 8.6 Hz), 9. 72 (1H, d. J = 7.3 Hz) U% ax (CHC13) cm_1: 1680, 1508, 1259 e Mass m / e: 216 (M +), 215, 187, 175, 162, 131 (100%), 119, 101 ° Reference example 34 6- (2,2,3,3-tetrafluoropropanyl group)) Ester hcf2cf2ch2o -h (^)-C02C2H5 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling out this page) Wash 55% NaH 840ing (19.3 mmol) in hexane and suspend In dimethylformamide 4〇811, slowly add 2.00 g of 2,2,3,3-tetrafluoropropanol (22.7naol) in a nitrogen atmosphere of 0 °, and then stop hydrogen gas generation at about 30 at the same temperature. 3.4D g of ethyl 6-gasnicotinate (18 · 3ββο1) and dimethylformate were added dropwise.

• A solution of 15% amidine. After the dropwise addition, the mixture was stirred for 30 minutes. Pour into ice water. Extract with benzene, dry, and distill off the solvent. The oily residue was subjected to silica gel column chromatography (benzene: hexane = 1: 1) to obtain the target compound (4.22 g, yield 86%) as an oil. -103 This paper size applies to China National Standards (CNS) A4 specifications (210X297 mm) A7 B7____ V. Description of the invention (>> 〇) NMR (270MHz, CDC1 „) δ ppm: 1.40 (3Η, t, J = 7. 2Hz), 4. 39 (2H, q, J = 7. O 2Hz), 4. 81 (2H, br t, J = 12. 6Hz), 6. 00 (1H, tt, J = 53. 0 , 4. 6Hz), 6. 87 (1H, d, J = 8. 6H z), 8. 24 (1H, dd, J = 8.6, 2. 5Hz), 8.83 (lH, d, J = 2.5Hz) IR vmax (CHC13) cm-1: 1717, 1604, 1280, 1119. Mass spectrum m / e: 281 (M +), 236 (100%), 180, 152, 151, 123, 122, 93. Reference Example 35 2 -(2,2,3,3-tetrafluoropropanyl) -5- (transmethyl) pyridine N \

HCF2CF2CH2〇 — (^ 〇y-CH2〇H emulated Reference Example 21, 6- (2,2,3,3-tetrafluoropropanyl) ”ethyl alkali acid was reduced with diisobutylaluminum hydride to obtain an oily Target product, yield 1%. NMR (270MHz, CDClg) δ ppm: 1.69 (1Η, t, J = 5.8 Hz), 4. 66 (2H, d, J = 5.8 Hz), 4. 74 (2H, brt, J = 12. 8Hz), 6. 01 (1H, tt, J = 53.1, 4. 6Hz), 6. 84 (1H, d, J = 8.5 Hz), 7.69 (lH, dd , J = 8.5, 2.5Hz), 8.12 (lH, d, J = 2.5Hz) e mass spectrum ra / e: 239 (M +), 210,188, 168,138 (100%), 109, JL08, 78. Reference Example 36 6- (2, 2, 3, 3-tetrafluoropropanyl) nicotinal aldehyde HCF2CF2CH2 0— ^ 〇y-CH0 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling in (This page) Following Reference Example 22, 2- (2, 2,3, 3 -tetrafluoropropanyl) -5- (methyl) pyridine was treated with active digassed manganese to obtain the desired product as an oil. Rate 96%. NMR (270MHz, CDClg) 5 ppm: 4.86 (2H, br t, J = 12. 8Hz), 6.01 (1H, tt .J = 53. 3, 4. 4Hz), 6. 97 (1H, d, J = 8.6 Hz), 8. 15 (1H, dd, J = 8.6, 2. 3 Hz), 8.65 (lH, d, J = 2. 3 Hz) Mass spectrum m / e: 237 (M +), 186.166 · 136 (100%), 107, 10 (5. 78. -1 04 -The X degree of this paper applies the Chinese National Standard (CNS) A4 specification (21 × 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7_ V. Description of Invention (W) Reference Example 37 (2E, 4E)- 5- [6- (2,2,3,3-tetrafluoropropanyl) -3-pyridyl] -2,4-pentadienal

Similarly to Reference Examples 2, 3, 24, and 25, the target product having a melting point of 88 to 89 was obtained in 6 steps from 6- (2,2,3,3-tetrafluoropropoxy) nicotinaldehyde. NMR (270MHz, CDClg) δ ppm: 4. 78 (2H, br t, J = 12.6 Hz), 6.01 (lH, tt, J = 53. 3, 4.5 Hz), 6. 28 (1H, dd, J = 15. 2, 7. 9Hz), 6. 87 (1H, d, J = 8.7 Hz), 6.85-7.0 (2 H, m), 7. 25 (1H, ddd, J = 15. 2, 7.8, 2.5Hz), 7.85 (1H, dd, J = 8, 7, 2.5Hz), 8.23 (1H, d, J = 2.5Hz), 9. 63 (1H, d, J = 7. 9Hz). IR vmax (CHC13) cm_1: 1677, 1626, 1591, 1488, 1290, 1120. Mass spectrum m / e: 289 (M +), 260, 188, 178, 160, 145, 128, 117, 81, 69 (100%). Reference Example 38 (2 £, 4 £) -5- [6-Ga-3-pyridinyl) -2,4-pentadienal

Following Reference Examples 23, 24, and 25, the target compound was obtained from 6-gas nicotinaldehyde in 3 steps as an oil. NMR (270MHz, CDClg) δ ppm: 6. 32 (1Η, dd, J = 15.2, 7. 8Hz), 6.96 (1H, d, J = 15.4Hz), 7.0bUH, dd, J = 15.4, 9.8 Hz) t 7. 26 (1H, dd, J = 15. 2, 9. 8Hz), 7.36 (1H, d, J = 8. 3Hz), 7.80 (1H, dd, J = 8. 3, 2. 5Hz ), 8. 48 (1H, d, J = 2.5 Hz), 9. 66 (1H, d, J = 7. 8Hz) -105- This paper size is applicable to China National Standard (CNS) M specifications (210X297) Li) (Please read the notes on the back before filling in this page)

A7 _B7____ 5. Description of the Invention (· #) Reference Example 39 [4- [4-chlorobenzyl) thio] cyclohexylene] methyl methyl ether OMe (Please read the precautions on the back before filling in this page)

ci- {〇} -ch2s-QK After washing 55% iUH 146ag (3.34BB〇l) in hexane, suspend it in dimethylarene 1 «18b1, stir at 55eC for 2 hours, cool to room temperature, and add air 1.26 g of methyl triphenylmethyl scale (3.34 · ϋ〇1) β times 4-[(4-4-benzyl) thio] cyclohexanone 426 ^^ (1.67 lane 111〇1) and two After adding water to the solution of methylene sand [5 «» 1, extract with toluene, dry and evaporate the solvent, and chromatograph on a 20 g silica gel column (dichloromethane: hexane = 1: 0) to obtain 370 mg of the target compound (yield 7896), oily. NMR (270MHz, CDClg) 5 ppm: l. 2-1.5 (2H, tn), 1. 7-2. 0 (3H, m), 2.0-2.2 (lH, m), 2.5-2.8 (2H, m), 3.53 (3H, s), 3.71 (2H, s), 5.77 (lH, s), 7.27 (4H, s) IR Vmax (CHC13) cn &gt; _1: 2935, 1689, 1491 , 1443, 1123. Mass spectrum B / e: 2 8 2, 157, 124, 109. Reference Example 40 trans-4-[(4-aminobenzyl) thio] cyclohexanemethan

Cl 1 &quot; ... CH0 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs [4-[(4-Gas benzyl) thio] cycloethylene] methyl methyl ether 9 5 5 mg (3.4imol) After adding 20ml of water to country C and adding 5 継 1, add 5N_acid 1111. After stirring at 55 ° C for 20 minutes, it was concentrated under reduced pressure, extracted with ethyl acetate, dried and evaporated to remove the solvent, and subjected to 15 g of silica gel column chromatography (dichloromethane: hexane = 1: 3) to obtain the desired product. 1: 1 mixture of isomers and cis isomers-106- This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of invention (wx) 865ng, yield 95%, oily. Put this into 15 ml of 0.07N sodium methanol-methanol solution, and stir at room temperature for 2 · 3 hours, then add acetic acid 0 · 2βι1, dilute with ethyl acetate, wash with brine, and dry the solvent. 4: 1 mixture of antibody and cis body 86 5ng solid. This was recrystallized from a diethyl ether-hexane mixture to obtain a melting point of 44 to 46 T! The target compound 220nge NMR (270MHz, CDC13) δ ppm: 1.2-1.5 (4H, in), 1. 9-2. 15 (2H, m), 2.1 5-2. 35 (1H, m), 2. 35-2.55 (lH, m), 3.73 (2H, s), 7.27 (5H, s). 9.6l (lH.s) The structure at 5 3.67 (2H, s) and 59.64 (1H, S) showed a signal · IR vmax (CHC13) cm — 1: 2927, 1732, 1493, 1448, 1092. Mass spectrum m / e: 268,240,127,125,110, Reference Example 41 4-Gasbenzyl trans-4-[(1Ε, 3Ε) -4- [4- (trifluoromethyl) phenyl] -1,3-butadiene-1 -Yl] pentadiene] cyclohexylthio ci ~ {〇}-^ 2s ^ y &quot; ... Wash 55% NaH 50ng (1.14miB01) with hexane and suspend it in 7ml of dimethylarsine at 55 After stirring for 2.5 hours at ° C, it was cooled to room temperature, and [(e) -4- (trifluoromethyl) cinnamaldehyde] triphenylhydrazone] 6 0 7mg (l. 2 6 nno 1) was added.

. Added trans-4-[(4-aminobenzyl) thio] cyclohexanecarboxaldehyde 1.70 ng (0.63 maol). After stirring at room temperature for 15 minutes, it was diluted with toluene, washed with water and lithium water, dried and evaporated to remove the solvent, and subjected to 5 g of silica gel column chromatography (dichloromethane: hexane = 1: 2). Recrystallize to obtain a melting point of 142 ~ 144 eC -107- (Please read the precautions on the back before filling in this page)

This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) A7 _ B7____ V. Description of the invention: 86mg, the yield is 31%. NMR (270MHz, CDC13) 5ppra: ll-1.3 (2H, ra), l-3-1.5 (2H, m), 1.7-2. 0 (2H, ra), 2. 0-2. 2 (2H, m ), 2. 64 (1H, tt, J-12, 4Hz), 3. 74 (2H, s), 5. 81 (1H, dd, J = 15, 7Hz), 6. 20 (1H, dd, J = 15, 10Hz), 6. 47 (1H, d, J = 16Hz), 6. 81 (1H, dd, J = 16, 10Hz), 7.29 (4H, s), 7. 46 (2H, d, J = 8Hz) · 7.55 (2H, d, J = 8Hz), IR vmax (KBr) cm _1: 1641, 1612, 1490, 1326, 1167, 1127, 10 69. Mass spectrum n / e: 436,417,403,311,277,235,159,125. Reference Example 4 2 4-Chlorobenzyl trans-4-[(1Ε, 3Ε) -4- [4- (trifluoromethyl) phenyl] -1,3-butadienyl] cyclohexylsulfenyl (Please (Read the notes on the back before filling out this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, dissolving 21 lBg (0.48 nmol) of the product of Reference Example 41 in 20 ml of Erqi Jiayuan, and adding peroxybenzoic acid (purity 80%) 104Bg (〇'48mia) 〇U, after stirring for 5 minutes, add sodium sulfite water and ethyl acetate. The organic layer was washed with sodium disulfonate water and brine, dried to remove the solvent, and recrystallized from the ethyl acetate-hexane mixture The target compound, 168 l »g (yield 77%) with a melting point of 212 to 214-C was obtained.. NMR (270MHz, CDC1J δ ρρη: 1.1-1.3 (2H, m), 1. 5-1. 8 ( 2H, m), 1.9-

O 2.3 (5H, m), 2.42 (1H, tt, J = 12,4Hz), 3. 87 (1H, d, J = 13Hz), 3. 97 (1H, d, J = 13Hz), 5.80 (1H, dd, J = 15, 7Hz), 6. 22 (1H, dd, J = 15, 10Hz), 6. 48 (1H, d, J = 16Hz), 6. 80 (lH, dd, J = 16, 10Hz), 7. 25 (2H, d, J = 8Hz), 7. 36 (2H, d, J = 8Hz), 7. 45 (2H, d, J = 8Hz), 7.55 (2H, d, J = 8Hz). IR vmax (KBr) cm -1: 1612, 1492, 1325, 1168, 1128, 1069 „This paper size applies to China National Standard (CNS) A4 (2U) X297 mm) -108- Printed bags A7 B7 of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (Ic:? Mass spectrum a / e: 452,436,327,278,277,159, 125. Reference Example 43 Trans-1- (thioacetate) _4_ (1E 3E) _4_ [(三Fluoromethyl) phenyl] -1,3-butadiene-butyl] cyclohexane

178 mg (0.39 ainol) of the product of Reference Example 42 was dissolved in 11 ml of a tetraargon-acetonitrile U: 3) mixture, and 168jag (1.57BB01) of 2,6-dimethylpyridine was added. Trifluoroacetic anhydride i65lBg (.79niaol) e was added at 0 ° C for 3 minutes, and then sodium sulfonate was added, the mixture was extracted with ethyl acetate, and the solvent was evaporated. The oily residue was dissolved in dichloromethane lOail, and TC was added with triethylamine 119iiig (1.17Bmol) and acetaldehyde gas 62aig (0.779fflmol) e. After 1 hour, it was diluted with ethyl acetate and sodium bisulfate. Wash with water and brine, dry and evaporate the solvent. Chromatography on a 5 g silica gel column (dichloromethane: hexane = 1: 1), then Lro Be B, ethyl acetate: hexane = 1: 19). Chromatography yielded the target compound with a melting point of 113 ~ 115eC and a yield of 70%. NMR (270MHz, CDC13) δ ppm: l. 2-1.5 (4H, m), 1. 7-1. 9 (2H, in), 2.0-2.2 (3H, m), 2.31 (3H, s) , 3. 37 (1H, tt, J = 12, 4Hz), 5. 82 (1H, dd, J = 15, 7Hz), 6.20 (1H, dd, J = 15, 10Hz), 6. 47 (1H, d, J = 16Hz), 6. 81 (1H, dd, J = 16, 10Hz), 7. 45 (2H, d, J = 8Hz &gt;, 7. 54 (2H, d, J = 8Hz). IR v (KBr) cm _1: 1688, 1613, 1326, 1157, 1117, 1068. max mass m / e: 3 5 4, 3 3 5, 3 1 1, 2 7 7, 2 3 5, 1 5 9. Reference example 44 -109- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297): (Please read the precautions on the back before filling in this page)

A7 ___ B7______ V. Description of the invention (, 4) 3- [4- (trifluoromethyl) phenyl] -2-propyn-1-ol p3c ~ {〇] &gt; -c = c-ch2〇h 4-Bromo-α, α, α-trifluorotoluene 5.0 g (22bbio1) and propynol 1.25 g (22bbo1) were dissolved in diethylamine 50al, and the gasification of bis (triphenylhydrazone) harrow (II) 8〇Bg (0.11 mmol) and copper (I) iodide 40 mg (0.22 ninol), stirred at 50 ° C for 35 minutes, and then gasified bis (triphenylphosphonium) palladium (11) 4818 (O.Q6mraol), Stir for an additional 3 to 5 minutes. After cooling to room temperature, it was diluted with benzene and filtered. The filtrate was washed with water and dried, and the solvent was evaporated. The residue was chromatographed on a 50 g silica gel column (ethyl acetate: hexane = 3: 17) to obtain 2.21 g (yield 50¾) of the desired product as an oil. NMR (270MHz, CDC13) 5 ppm: 1.8 (1H, br, OH), 4.52 (2H, s), 7.54 (2H, d, J = 9Hz), 7.57 (2H, d, J = 9Hz) e IR Vmax (CHC13) cm ^ 3610, 1618, 1324, 1172, 1133, 1069, 1019, 844 »Mass spectrum m / e: 200,183,171,151,131. Reference Example 45 3- (4- (Tri-methyl) phenyl] -2-propyneac f3c- &lt; Q &gt; -csc-cho Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the note on the back first) $ Item and fill out this page) Dissolve 2.21 g of 3- [4- (trifluoromethyl) phenyl] -2-propyne-1-ol (11.0 mmo 1) in methane gas 2 0 »1, Under ice-cooling for 1 · 7 hours, 7.43 g (17.5 miaol) of Dess-Mart in reagent was added. After insoluble matter was filtered off with benzene, it was concentrated to obtain 1.83 g of the target product (yield 84%). Oily. -110- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm). Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. A7 B7. 5. Description of the Invention (I.9) NMR (270MHz, CDClg ) ^ ppm: 7-68 (2H, d, J = 9Hz), 7. 71 (2H, d, J = 9Hz), 9. 45 (1H, s) -e IR 'ax (CHC13) cm— ^ 2197 , 1664, 丄 324, 1175, 1138. Mass spectrum m / e: 198, 197, 170, 151, 120. Reference Example 4 6 (E) -5- [4- (trifluoromethyl) benzyl) _2_penteneyne Ethyl acetate g〇〇c2H5 55% NalTl81iBgU.54miiil) was washed with hexane and suspended in 10 ml of i, 2-dimethylgasethane, and then added under nitrogen atmosphere. Three B _1.〇2 g (4.54mmol). After 20 minutes, 3- [4-trifluoromethyl) phenyl] -2-propynal was added to 500 mg (2.52 ffi m ο 1). After stirring for 20 minutes, it was diluted with ethyl acetate and ice was added. The organic layer was washed with water, and the solvent was distilled off. The column was subjected to silica gel column chromatography (benzene) to obtain 488 mg (yield 72%) of the target substance as an oil. NMR (270MHz, CDClg) 5 ppm: 1.32 (3H, t, J = 7Hz), 4. 25 (2H, q, J = 7Hz), 6.35 (1H, d, J = 16Hz), 6. 97 (1H, d, J = 16Hz), 7. «5-7. 7 (4H, in) e IR vmax (CHC13) cm_1: 1712, 1622, 1316, 1174, 1134. Mass spectrum B / e: 268, 24 0, 223,195,183,175. Reference Example 47 (E) -5- [4- (trifluoromethyl) phenyl] -2-pentene-4-yn-1-ol

(E) -5- [4- (trifluoromethyl) phenyl] -2-pentene-4-ynyl ethyl ester 48 0 «1 £ (1.79111111〇1) was dissolved in toluene 41〇1, at 0 ° (: Add 1.5 ^ 1 hydrogenated under stirring 1 1 1- This paper size applies to Chinese National Standard (CNS) A4 size (210X297 mm) (Please read the precautions on the back before filling this page)

V. Description of the invention (M.) Diisobutylaluminum-toluene solution 2.38b1 (3.58bbo1). After 10 minutes, ice was added to remove insoluble matter with diatomaceous earth. After the organic layer was dried, the solvent I was distilled off, and column chromatography on 15 g of silica gel (ethyl acetate: hexane = 3: 17) was performed to obtain the target compound 3 5 3 B g (yield 87.7%. NMR (270MHz, CDClg) δ ppin: l. 60 (1J1, br.OH), 4. 31 (2H, br). 5.99 (! H, d, J = l6Hz), 6. 40 (1H, dt, J = 16, 5Hz ), 7. 54 (2H, d. J = 9Hz), 7. 57 (2H, d, J = 9Hz). Reference Example 48 (E &gt;-. 5- [4- (trifluoromethyl) phenyl]] -2-pentene-4-ynal

(E) -5- [4- (trifluoromethyl) phenyl] -2-pentene-4-yn-1-ol 3 50 mg (1.5 6 DNB ο 1) was dissolved in methane gas. 4 ml, 3.5 g of activated manganese dioxide was added, and after stirring at room temperature for 30 minutes, the solid was removed by dropping and concentrated, and then subjected to 10 g of silica gel column chromatography (ethyl acetate: hexane = 1: 24). The target substance was 245 mg (yield 70%), and it was oily. NMR &lt; 270MHz, CDClg) δ ppm: 6. 58 (111, dd. J-1G. Sliz), G. 82 (111, d, J-16Hz), 7. 63 (4H, s), 9. 65 (1H, d, J = 8Hz). (Please read the notes on the back before filling out this page) Order 1; IR vmax (CHC13) printed on the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 0 ^: 1670. 1325, 1132. 1119, 1107, 1072, 845. Mass spectrum ffl / e: 224,196,195,17 5, 170,146. Reference Example 49. (Z) -4 -Gas- (trifluoromethyl) methyl cinnamate / — '\ Π 一 COOCH3 -112- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) Economy A7 _ B7____ printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China 5. Description of the invention () The bis (2,2,2-trifluoroethyl) (methoxymethylene) phosphonate 15 0 Bg (〇.47ι · 1) Dissolved in tetrahydrofuran 10b1, and 0.5M potassium hexamethyldisilazide-toluene solvent 0.94β1 (0.47πιπο1) was added dropwise while stirring under a nitrogen stream-78 ° C. Add 18-crown-6- (622Bg, 2.36nmol) e and stir for 20 minutes, then add 4'-gas-2,2,2-trifluoroacetanilide 98 | ^ (0.47 «111〇1) and tetrahydrofuran 1 | «1 solution. The temperature was gradually raised to room temperature, and saturated gasified ammonium water was added, followed by extraction with ethyl acetate. The solvent was distilled off, and then subjected to silica gel column chromatography (4% ethyl acetate-hexane) to obtain 89 ng (yield 70%). ), Containing (E) -isomers about 1/10), oily ONM R (270MHz, CDClg) 5 ppm: 3.85 (3Hts). 6. 34 (1H, s), 7. 34 (2H, d , J = 8.6 Hz), 7. 39 (2H, d, J = 8.6Hz) „Reference Example 5 0 (Z) -4-Gas- Office- (Trifluoromethyl) Cinnamaldehyde

Cl Ma 3 followed the reference examples 21 and 22, and the target product was obtained from methyl (Z) -4-a-y8- (trifluoromethyl) cinnamate in 2 steps in the form of oil, with a yield of 81%. NMR (270MHz, CDClg) 5 ppm: 6. 36 (1H, d, J = 7.3 Hz), 7. 38 (2H, d, J = 8.6 Hz), 7. 44 (2H, d, J = 8 6Hz), 10. 21 (1H, dq, J = 7.3, 2. 0Hz). Reference Example 5 1. (2 £, 42) -5- (4-chlorophenyl) -6,6,6 -Trifluoro-2,4-hexadiene acid ester-113- This paper size applies to Chinese National Standard (CNS) A4 ^ (210X297 mm) (Please read the precautions on the back before filling this page) • Order

Employees' cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed A7 B7 V. Description of the invention (〃 ★) co2ch3 Reference Example 2 3, from (Z)-4 -chloro-yff-(trifluoromethyl) cinnamaldehyde and phosphonium croton The reaction of trimethyl acid yields the desired product as an oil, yield (refined by column chromatography). NMR (270MHz, CDClg) 5 ppm: 3.81 (3H, s), 6.15 (1H, d, J = 15. 2Hz), 6.59 (1H, d, J = 11.9Hz), 7. 31 (2H, d , J = 8. 6Hz), 7. 38 (1H, d, J = 8.6 Hz), 7. 78 (1H, ddq, J = 15. 2, 11. 9, 2. 0Hz) „. Reference Example 5 2 (2 £, 42) -5- (4-aminophenyl) -6,6,6-trifluoro-2,4-hexadienal

Trifluoro-2,4-hexadienoic acid methyl ester was obtained in 2 steps as an oil, with a yield of 7 1% 0 N MR (270MHz, CDClg) δ ppm: 6. 37 (1 Η, dd, J = 15. 2 , 7. 3Hz), 6. 72 (1Η, d, J = 11.9Hz), 7. 33 (2Η, d, J = 8.6 Hz), 7. 40 (2Η, d, J = 8.6 Hz) , 7. 64 (1Η, ddq, J = 15. 2, 11.9, 2 Hz), 9. 74 (lH, d, J = 7.3 Hz) e Reference Example 53.2 2-methyl-2-[(Trans-2 -Phenyl-1,3-dioxan-5-yl] thio] -4 三 (trifluoromethyl) propanone-114- This paper size applies to China National Standard (CNS) A4 (210X297 mm) ) (Please read the notes on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of Invention (W)

Dissolve 2-bromo-2-methyl-4 '-(trifluoromethyl) propanthene 619Bg (2.10naol) in dimethylformamide 3.8el, and add 28% sodium methoxide under nitrogen atmosphere at room temperature with stirring- Methanol 0.44 Bl (2.10 mmol). After 30 minutes, water was added and the mixture was extracted with ethyl acetate. The solvent was distilled off to obtain 860 Bg (yield: 100%) of the target substance as a solid. NMR (270MHz, CDClg) δ ppm: 1. 61 (6Η, s), 4. 42 (1H, tt, J = ll. 6, 5. OH z), 3. 64 (2H, t, J = 11.6Hz ), 4.12 (2H, dd, J = ll. 6, 5. 0Hz), 5.38 (lH, s), 7.3-7.5 (5 H, m), 7. 68 (2H, d, J = 8.2 Hz) , 8.19 (2H, d, J = 8.2Hz).

Reference Example M (RS> -3-methyl-3-[(trans-2-phenyl-1,3-dioxan-5-yl) thio] -1- (1H-1,2,4- Triazol-1-yl) -2-butanol

The product of Reference Example 53 was 680Bg (1.666nnol), iodide 4 methylamine 547n ^ (249mmol), potassium hydride 38lBg (6.79BB0l), and 1,2,4-triazole 264ug (3.82Bmol). ) Heated in 5.7 ml of tertiary butanol at 80 ° C. for 6 hours with stirring. After cooling, partition between chloroform and water. Take out the imitation layer and dry it -115- This paper size is applicable to China National Standard (CNS ') A4 (210X297mm) (Please read the precautions on the back before filling this page)

Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs CH 'A7 B7 5. After the description of the invention (), the solvent was distilled off, and the obtained oil was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1). 6D5Bg (yield 74%>, foamy. NMR (270MHz, CDClg) 5 ppm: 1.38 (3H, s), 1.39 (3H, s), 3.55-3.8 (3 H, m), 4.33 ( lH, m), 4.54 (lH, ra), 5.02 (2H; s), 5.37 (lH, s), 5.44 (lH, s), 7.3-7. 6 (5H, ra), 7. 73 (1H, s), 7. 94 (lH, s). Reference Example 5 5 (RS) -3 -Methyl-3-[(1,3-dihydroxy-2-propyl) thio] -3 -methyl- 2- [4- (trifluoromethyl) phenyl] -1- (1H-1,2,4-triazole-butyl) -2-butanol CH,

0H

0H As in Reference Example 2, the product of Reference Example 54 was treated with HC1 in methanol to obtain the target product in the form of a foam. NMR (270MHz, CDClg) δ ppm: 1.30 (3H, s), 1.42 (3H, s), 3. 35 (lH, m), 3. 55-3. 8 (3H, in), 3. 96 (1H, dd, J = 10. 9, 5. 4Hz), 4. 83 (3H, s), 5. 26 (1H, d, J = 14. 6 Hz), 5. 34 (1H, d, J = 14.6Hz), 7.53 (2H, d, J = 8.3Hz), 7.70 (lH, s), 7.75 (2H, d, J = 8.3Hz), 8.26 (1H, s) e Reference example 5 6. 2- (p-toluenesulfonyloxy) -1,3-propanediol

OH

OH -116 This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

A7 ______B7__ 5. Description of the invention (dissolve 5.00 g of cis-2-phenyl- 4- (p-toluenesulfonyl carbaldehyde 1,3 -di) in methanol 50 · 1, and add 4N HC1 dihaltane solution 5al After stirring at room temperature for 2 hours, 3.5 g of sodium osmium powder was added. After stirring for 10 minutes, it was filtered and concentrated under reduced pressure. The obtained oil was subjected to silica gel column chromatography (ethyl acetate) to obtain 3.70 g of the target substance. (Yield 100%), 状. NMR (60MHz, CDClg) δ ppm: 2.40 (311, s), 3.30 (?, H, s), 3.7,1 (411, (1, J = 4. 5HZ), 4.55 (1H, quintet, J = 4.5Hz), 7.33 (2H, d, J = 8Hz), 7.84 (2H, d, J = 8Hz) e Reference Example 57 cis-4 -(P-toluene aldehyde gas group) -2-[(IE, 3E) -4- [4- (trifluoromethyl) phenyl] -1,3-butadien-1-yl] -1, 3-Dioxane (please read the note on the back before filling this page)

Order 2- (p-toluene aldehyde gas group) -1,3-propanediol 200ng (0.8lBB0l) and (2 £, 4 £) -5- [4- (trifluoromethyl) phenyl] -2 , 4-Pentadienal 206 11 茗 (0.96! 1111〇1) was dissolved in digas methane 4.5 | 111, p-toluenesulfonic acid 15 | ^ and molecular sieve 4A 0.8g, and stirred at 0 ° C for 1 hour. After adding soda water and stirring for 10 minutes, the molecular sieve was filtered off, extracted with methane gas, and the solvent was distilled off. The obtained oily substance was subjected to thin layer chromatography on silica gel (20% ethyl acetate-hexane) to obtain 107 mg of a trans isomer having a lower polarity (yield 29%) and a cis isomer having a higher polarity The product was l53ng (yield 42%), and each was oily. Cis isomer NMR (270MHz, CDC13) δ ppni: 2.45 (3H, s), 3. 99 (2H, br d, J = 13.2Hz). 4.19 (2H, br d, J = 13. 2 Hz), 4. 45 (1H, br s), 5. 09 (1H, d, J = 4.6 Hz), 5. 82 (1H, dd, J = 15. 2, 4. 6Hz), 6. 57 (1H, dd, J = 15.2, 10.5Hz), 6. 63 (1H, d, J = 15. 2Hz). 6. 82 (1H, dd, J = 15. 2, 10. 5Hz), 7. 36 (2H, d, J = 8.6 Hz), 7. 48 (2H, d.,! ~ 8. GHz). 7. f &gt; 6 (2H, d, J = 8.6Hz), 7. 85 (2H, d, J = 8.6Hz) __-117-This paper size is applicable to Chinese National Standard (CNS) A4 secret (210X297 mm) ~~ 'MV · Printed by A7 B7, Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy Description of the Invention (w) Test Example 1 In the following, Candida albicans 4-9X 106 pups (10 mice in each group), and the drug was orally administered 20 mg / kg after 1, 4 and 24 hours To investigate the survival rate from infection to 21 days. The results of comparing the compound U) of the present invention with the commercially available Fulconazole are shown in Table 2. May have compound (1) with excellent antifungal activity "Table 2 Survival rate of compounds printed by the Consumer Cooperative of the Central Yak Bureau, Ministry of Economic Affairs, 14% 2 1st Example 2 10 0 10 0 11 10 0 10 0 15 10 0 10 0 16 10 0 10 0 18 10 0 60 2 1 10 0 10 0 3 0 10 0 10 0 3 2 10 0 10 0 3 5 10 0 10 0 37 10 0 10 0 Fulconazole 7 0 6 0 -1 1 8-(Please read the precautions on the back before filling this page) 1. This paper size applies the Chinese National Standard (CNS) A4 size (210X297 mm) 2 5 0 ng The powder of the above formula is mixed and sieved through a 6D sieve Fill in No. 3 capsule f 391965 A7 B7 V. Description of the invention (1) Formulation Example 1 Capsule Compound of Example 15 or 16 50 mg lactose 1 2 8 mg corn starch 70 mg magnesium stearate 2 mg 2 5 0 ag 〇 Formulation Example 2 Lozenge Compound of Example 15 or 16 50mg Lactose 1 2 6 rag Corn starch 23mg Magnesium stearate 1mg (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Dry and Granulated Wet Lapse Dian 00 | Rice 20 jade ingots with each, get powder, powder . Fight the side of the machine to play on the spindle 1 Alex fruit. It is effective. After mixing with Yiming, it is necessary to add sugar to dry the sugar and add T tablets. The true resistance must be different from salt. Xu Rong — 1 physical medicine and its ο 2} bacteria (1 real anti-cooperative chemical can be clarified) hairy live bacteria This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm)

Claims (1)

891965 jL. VI. Patent application fa charge Aδ B8 C8 D8 cooked _............- No. 85 1 04042 "Triazole derivative and its antifungal pharmaceutical composition" patent case (88 (Amended on November 3, 2010) Six patent applications: 1_ A three-mile compound of the following formula (1) or its pharmacologically acceptable salt S (0) nA- (CO) p— (R2C = CR3) q ~ (C = C) r-(R4C = CR5) s — Ar2 Ar1 is phenyl or Phenyl with 1 ~ 2 substituents (the substituent is F, C1, Br, "-or trifluoromethyl), Ar2 is phenyl'pyridyl or thienyl and each can have 1 ~ 2 Substituted &quot; group. It is selected from ci-3 alkyl which may have fluorine substitution, alkoxy 'F, C1, nitro' cyano which may have fluorine substitution, and -S (〇) mR6 (R6 is fluorine substituted (C, -3 alkyl, ra is 0 '1 or 2): R ° is Η or Ch alkyl' R1 is Cw alkyl, Γ. — R 2, R 3, R 4 and E 5 may be the same or the same Different, each is η, the C! _3 alkyl group which may be substituted by fluorine is η is 0'1 or 2, ρ is 〇 or ι, Γ is 〇 or 1 'q and s is 〇' 1 or 2 'A is Cyclohexane, piperidine, ργ-butidine or 1,3-dioxane, except when A is piperidine or azetidine, except for the combination of N and -S (0) n-. 2. For example, the patent application p. 1, triazole compound or its pharmacologically acceptable salt 2-(2,4-difluorophenyl) -3-[[2-[2-[4-(trifluoromethyl) Phenyl] vinyl] -1,3-diseno-5-yl] thio]]-i- (1H · :!, 2,4-triazole-1 · yl) -2-butanol, this paper Standards apply Chinese National Standard (CNS) Α4 specifications (210X297 mm), ¾—— (Please read the precautions on the back before writing this page), 1T-: i-Haaauul =: ..... 891965 jL · 6. Patent application fa charge Αδ B8 C8 D8 cooked _............- No. 85 1 04042 "Triazole derivative and its antifungal pharmaceutical composition" Patent case (November 88 (Amended on the 3rd) Six patent applications: 1_ A three-mile compound of the following formula (1) or its pharmacologically acceptable salt S (0) nA- (CO) p— (R2C = CR3) q ~ (C = C) r-(R4C = CR5) s — Ar2 Ar1 is phenyl or Phenyl with 1 ~ 2 substituents (the substituent is F, C1, Br, "-or trifluoromethyl), Ar2 is phenyl'pyridyl or thienyl and each can have 1 ~ 2 Substituted &quot; group. It is selected from ci-3 alkyl which may have fluorine substitution, alkoxy 'F, C1, nitro' cyano which may have fluorine substitution, and -S (〇) mR6 (R6 is fluorine substituted (C, -3 alkyl, ra is 0 '1 or 2): R ° is Η or Ch alkyl' R1 is Cw alkyl, Γ. — R 2, R 3, R 4 and E 5 may be the same or the same Different, each is η, the C! _3 alkyl group which may be substituted by fluorine is η is 0'1 or 2, ρ is 〇 or ι, Γ is 〇 or 1 'q and s is 〇' 1 or 2 'A is Cyclohexane, piperidine, ργ-butidine or 1,3-dioxane, except when A is piperidine or azetidine, except for the combination of N and -S (0) n-. 2. For example, the patent application p. 1, triazole compound or its pharmacologically acceptable salt 2-(2,4-difluorophenyl) -3-[[2-[2-[4-(trifluoromethyl) Phenyl] vinyl] -1,3-diseno-5-yl] thio]]-i- (1H · :!, 2,4-triazole-1 · yl) -2-butanol, this paper The dimensions are applicable to the Chinese National Standard (CNS) Α4 specification (210X297 mm), ¾ —— (Please read the precautions on the back before writing this page), 1T-: i-Haaauul =: ..... 391965 A8 B8 C8 D8 6. Scope of patent application (please read the notes on the back before filling this page) 2-(2,4-difluorobenzene)-1-(1H-1,2,4-triazole-1 -yl) -3-[[2-Γ 2-_ [4-(trifluoromethyl) phenyl] vinyl]-1, 3 -dioxane-5-yl] thio] -2-butanol, 2- (2, 4 -difluorophenyl) -1-(1 Η 1,2, 4 -triazol-1 -yl) -3-[[2-'. [4-[4-(trifluoromethyl ) Phenyl] 1,3-butadiene-1 -yl] -1, 3 -diduane-5-yl] thio] -2-butanol, '2-(2,4-difluorophenyl ) -3-[[2-[4 [4-(2,2,3,3-tetrafluoropropoxy) phenyl] -1 , 3-butadien-1-yl] -1,3-di6-alk-5-yl] thio] -1- (1fluorene-1,2,4-triazol-1-yl) -2- Butanol, 2- (2, 4-diphenylphenyl) -3-[[2- [4- (4-chlorophenyl) -4,4,4-trifluoro-.. 1, 3-pentane Alkenyl-1 -yl]-1, 3 -di 6.alkane, -1 -yl] thio]-1-(1 Η-1,2,4 -triazole-1 -yl) -2, butanol, 2-(2,4-difluorophenyl-)-. 3-[1 L-—fluorene [.4- (trifluoromethoxy) cinnamate'fluorenyl] 8.pyridine 4-yl] sulfanyl] -1-(1 Η -1, 2,4.triazole-1 -yl)-. 2 butanol, 2- (2,4-difluorophenyl) -3-[[1- (4-nitrocin Fluorenyl] piperidin-4 -... yl] thio] -1-l- (TH-i, 2,4-triazol-1-yl) -2-butanol, Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs Printed 2-(2,4-di | phenyl) -1-(1 Η-1,2,4-triazole-1 -yl) -3-[[1-[5-[4-_ (tri Fluoromethoxy) phenyl] -2,4, pentadienyl.] Piperidine JE.-4-. Yl] 1thio] -2-butanol, 3-methyl-1-(1H- 1, 2,4-triazole-1 -yl) -2- [4-(trifluoromethyl) phenylbenzene ,,] ..-. 3-[[2- [4-[(trifluoromethyl) Phenyl] -1,3-butadiene--4- 〕 -1, _ 3 -di-6-alkane-5 -yl]. Sulfur]-2-butanol (This paper size uses the Chinese National Standard (CNS) A4 specification (210X297 mm) 391965 A8 B8 C8 D8 Six Scope of patent application: printed by 2- (2,4-difluorobenzene-yl) -1- (111-1,2,4-triazole-]-yl) -3- [ [2-, [4- (trifluoromethylthio) phenyl] -1, 3-butadiene-1 -yl] -1,3-dioctane-5-yl] thio] -2-but Alcohol, 3-[[2- [4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -1,3-butadien-1-yl] -1,3- Dioxan-5-yl] thio] -1- (1H-1,2,4-triazol-1-yl) -2-[4- (trifluoromethyl) phenyl] -2-butanol , 1-U—fluorene-1,2,4-triazole-1 -yl) -2-[4-(trifluoromethyl) phenyl]; 3-. 2-—.4-. [4-( Trifluoromethyl) phenyl] -1,3-butadiene-1 --- yl] -1, 3 -1; pinane-5-yl-0thio] -2 -butanol, 2-(2, 4 -difluorophenyl) -1-(1H-1,2,4 -triazol-1 -yl) -3-[[2-C 4- [4-Eutri ,) Phenylhydrazone-1,3-butadiene-1-yl],-&quot; .'- ~. '- ..1,3, -Dioxane-5-yl] thio] -2-butanol, 2-(2,4-difluorophenyl) &gt; -4-(1Η-1, 2,4 -tri Azole 1, -yl)-3--hydrazine [4 [4-(fluorenylmethyl) phenyl-1, 3-butanesyl-1 -yl]. Cyclo, hexyl] thio]-2 -butanol ., 2-(2,4-difluorophenyl) -1-(1Η-1,2,4-triazole-1 -yl) -3-[[. 2- [6- [4-(trifluoro (Electro) phenyl] -1,3,5-.hexatriene-yl] -1,3dibifluorenosebis 5-ylJthio] -2 -butanol, 2-(2,4 -di Fluorophenyl) -3 -methyl-1-(1 Η -1,2,4-triazol-1yl) di 3di [[2-[4-[4-(trifluoromethyl) phenyl] -1,3-butadiene 1-yl]. Di 1,3-dioxan-5-yl] thio] -2-butanol, or 2- (2 ″ 4-difluoropyridyl) -1 -(1Η-1,2,4-triazole-1, yl) -3-_ [[2-, [4- [4-. (Trifluoromethyl) phenyl] -1 -butene-3- Alkyne-1 -yl] -1,3- Please read the note of \ 5 again — write 'This page applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 391965 ll D8 6. Scope of patent application III 'Alkane-5 -yl] .thio] butane Alcohols, or pharmacologically acceptable salts of these. .2. Λ antifungal medicinal composition containing triazole compounds or even permissible salts which are effective in the preparation of patents No. 1 or 2 of the patent scope. (Please read the precautions on the back before &quot; (write this page), printed by 1T Consumers' Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs. This paper size applies to Chinese national standards (CNS> Α4 specifications (210X297 mm))