JP2003327580A - 2-(substituted benzoyl)thiazine derivative, method for producing the same and herbicide - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new 2-(substituted benzoyl)thiazine derivative, to provide a method for producing the same and to obtain a selective herbicide comprising the derivative as an active ingredient. <P>SOLUTION: 4-Methyl-5,6-dihydro-1,4-thiazin-3(2)-one is reacted with 2-chloro-4- methylsulfonylbenzoic acid methyl ester in the presence of butyllithium to synthesize 2-[2-chloro-4-methylsulfonylphenyl]carbonyl]5,6-dihydro-4-methyl-1,4- thiazin-3(2H)-ol. The herbicide comprising the compound as an active ingredient is suitable for controlling dicotyledonous weeds and monocotyledonous weeds in important crops before or after germination. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 2- (substituted benzoyl) thiazine derivative, a method for producing the same and a selective herbicide containing the derivative as an active ingredient, and particularly useful as a herbicide for upland fields. Selective herbicide.

[0002]

2. Description of the Related Art Conventionally, a wide variety of chemicals have been put into practical use through many years of research and development of herbicides, and these herbicides have contributed to labor saving of weed control work and improvement of crop productivity.

In recent years, a herbicide showing a reliable herbicidal effect at a low dose, which has the advantage of reducing the amount present in the environment, and shows selectivity between crops and weeds regardless of changes in environmental conditions. There is a strong demand for herbicides having excellent herbicidal effects such as herbicides and herbicides that do not cause phytotoxicity in the double cropping.

[0004]

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned demands, and an object of the present invention is to provide a novel compound having the above-mentioned excellent herbicidal effect. , A method for producing the same, and a novel herbicide containing the compound as an active ingredient.

[0005]

The inventors of the present invention have conducted various studies to find an industrially useful 2- (substituted benzoyl) thiazine derivative for solving the above-mentioned problems, and as a result, a series of 2- ( The inventors have found that the substituted benzoyl) thiazine derivative has high herbicidal properties, and completed the present invention. The 2- (substituted benzoyl) thiazine derivative of the present invention is a novel compound which has not been reported so far to be used as an active ingredient of a herbicide.

The present invention has the following structural features. First
The invention relates to a 2- (substituted benzoyl) thiazine derivative represented by the following formula (I).

[0007]

[Chemical 6] [In the formula, X ¹ represents a hydrogen atom, a halogen atom, a nitro group,
Cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkoxyalkyl group, C1-C6 haloalkyl group, C1-C6 haloalkoxy group, C2-
C6 alkylcarbonyl group, C2-C6 alkoxycarbonyl group, aminocarbonyl group optionally substituted by 1 or 2 C1-C6 alkyl groups, C1-C
6 alkylthio group, C2-C6 alkylthioalkyl group, C1-C6 alkylsulfonyl group, or C2-C
6 represents an alkylsulfonylalkyl group. X ² is a hydrogen atom, a C1 to C6 alkoxy group, a C1 to C6 haloalkoxy group, a (C1 to C6 alkoxy) C1 to C6 alkoxy group, a (C1 to C6 haloalkoxy) C1 to C6 alkoxy group, (C1 to C6 thio). Alkoxy) C1-C6 alkoxy group, -COOR, -COO-L-OR, -COO
-LR ¹ , -COO-M, -COO-LM, -CO
O-L-O-R-R ¹ , -COO-L-S (O) _m- R,
^{-CON (R 2) (R 3} ),

[0008]

[Chemical 7] _{-CONHSO 2 CH 3, -CONHSO 2 CF} 3, -CO
_{O-L-N (R 2} ) (R 3), - COO-L-CO-R,
-COO-L-COO-R, -COO-L-CN, -C
_{OO-L-NO 2, -COOSi} (R 4) 3, -COO-N
= C (R ⁵ ) (R ⁶ ),

[0009]

[Chemical 8] -COO-LO-SO₂-R, -COO-L-O-
CO-R, -COO-L-O-L-O-R, -COO-
L-Si (R^Four)₃, -C (O) S-R, -C (S) O-
R, -C (S) S-R, -L-O-R, -L-O-L-
OR⁷, -L-O-M, -L-O-L-M, -L-NR⁷
R⁸, -LO-CH₂Ph, -L-O-L-COO
R⁸, -L-CN, -L-S (O)_m-R, -L-S-L
-OR⁸, -LO-COR⁸, -LO-SO₂R⁸,
-L-COOR⁷, -CH = CHOR ⁷, -L-O-L-
CN, or 4 or less sulfur atoms, oxygen atoms or nitrogen
By the combination of an elementary atom and one to four carbon atoms
Represents a 3- to 6-membered heterocyclic group formed.

(In the above formula, L represents a C1 to C6 alkylene group which may be substituted with a C1 to C3 alkyl group, and M is 1 to 4 sulfur atoms or oxygen atoms of 2 or less. Represents a 3- to 6-membered heterocyclic group formed by binding to a carbon atom of, R is a hydrogen atom, C1 to C
6 alkyl group, C3 to C8 cycloalkyl group, C4 to C
8 cycloalkylalkyl group, C3-C6 alkynyl group, C2-C6 alkenyl group, C1-C6 haloalkyl group, C3-C8 halocycloalkyl group, C3-C6 haloalkynyl group, C2-C6 haloalkenyl group, or
C1 to C3 alkyl group, halogen atom, nitro group or phenyl group optionally substituted with C1 to C3 alkoxy group, R ¹ is C1 to C3 alkyl group, halogen atom, nitro group or C1 to C3 alkoxy group. Represents a phenyl group which may be substituted, and R ² and R ³ are each independently a hydrogen atom, a C1 to C6 alkyl group, C3
To C8 cycloalkyl group, C4 to C8 cycloalkylalkyl group, C1 to C6 alkoxy group, C2 to C6 alkynyl group, C2 to C6 alkenyl group, C1 to C6 haloalkyl group, C3 to C8 halocycloalkyl group, C2 to C6
Haloalkynyl group, C2 -C6 haloalkenyl group, or represents a C1 to C3 alkyl group, a halogen atom, a phenyl group which may be substituted with a nitro group or a C1 to C3 alkoxy group, R ⁴ is, C1 to C3 alkyl Represents a group, R ⁵ and R ^{6, which} may be the same or different, each represents a C1 to C3 alkyl group, R ⁷ represents a hydrogen atom or a C1 to C6 alkyl group, and R ⁸ represents a C1 to C6 alkyl group. , Ph represents a phenyl group, m represents an integer of 0 to 2, and n represents an integer of 4 to 6. ) X ³ is a hydrogen atom, a halogen atom, a nitro group, C1 to C
3 represents an alkoxy group, a trifluoromethyl group, a cyano group, or —S (O) _m R ⁹ . (However, R ⁹ is C1 to C3
It represents an alkyl group or a C1-C3 haloalkyl group. m
Represents an integer of 0 to 2. ) X ⁴ is a hydrogen atom, a halogen atom, a C1 to C4 alkyl group, a C1 to C4 haloalkyl group, a C1 to C4 alkoxy group, a C2 to C6 alkoxyalkyl group, a C2 to C5 alkoxycarbonyl group, a C1 to C3 haloalkoxy group, a nitro group, a cyano group or -S (O) _m -R ¹⁰ group.
(Wherein, R ¹⁰ represents a C1 -C4 alkyl group, m. The same meaning as defined above) is X ^5, represents a hydrogen atom, a halogen atom, C1 -C4 alkyl or C1 -C4 alkoxy groups. Y ¹ , Y ² , Y
³ and Y ⁴ are each independently a hydrogen atom, C1 to C4.
It represents an alkyl group, a C1-C4 alkoxy group, or a benzyl group.

Y ⁵ is a hydrogen atom, a C1 to C6 alkyl group optionally substituted with a halogen atom, a C1 to C6 alkenyl group optionally substituted with a halogen atom, or a C1 optionally substituted with a halogen atom. To C6 alkynyl group, cyanomethyl group, or a benzyl group which may contain 1 to 5 halogen atoms, C1 to C3 alkyl group, C1 to C3 alkoxy group or nitro group as a substituent. Z represents a hydrogen atom, a C1 to C6 alkyl group optionally substituted with a halogen atom, a C1 to C6 alkenyl group optionally substituted with a halogen atom, a C1 to C6 alkynyl group optionally substituted with a halogen atom. , A cyanomethyl group, —C (O) —R ¹¹ (provided that R ¹¹ is C1 to C
6 alkyl group, C1 to C6 alkenyl group, C1 to C6 alkynyl group, C1 to C6 haloalkyl group, C1 to C6 haloalkenyl group, C1 to C6 haloalkynyl group, halogen atom, nitro group and trifluoromethyl group It represents a phenyl group, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, or a hydroxyl group which may be substituted with one or two or more same or different substituents. ), —S (O) ₂ R ¹¹ (wherein R ¹¹ has the same meaning as described above), or 1 to 5 halogen atoms as a substituent, a C 1 to C 3 alkyl group, a C 1 to C 3 alkoxy group, Alternatively, it represents a benzyl group which may contain a nitro group. The second invention relates to a method for producing a 2- (substituted benzoyl) thiazine derivative represented by the formula (I) according to the following reaction formula, wherein the thiazine compound represented by the formula (II) and the following formula: It is characterized by reacting with a benzoic acid ester represented by (III) in the presence of a Lewis base.

[0012]

[Chemical 9] (In the formula, E represents an alkyl group, X¹, X², X³, X^Four,
X^Five, Y¹, Y², Y³, Y ^Four, Y^FiveAnd Z are respectively
It has the same meaning as described above. ) A third invention is 2- (substituted benzene represented by the above formula (I).
(Zoyl) thiazine derivative as an active ingredient
Regarding agents.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
In the 2- (substituted benzoyl) thiazine derivative represented by the above formula (I) of the present invention, the substituents X ¹ , X ² , X ³ ,
^{X 4, X 5, Y 1} , Y 2, Y 3, Y 4, Y 5 and Z but is as defined above, the substituents ^{X 1, X 2, X 3} , X 4, X 5
The following substituents are preferred as Z and Z. In the following substituents, Me means a methyl group, Et means an ethyl group, Pr means a propyl group, Bu means a butyl group, Am means an amyl group, Ac means an acetyl group, and Ph means a phenyl group.

X¹: Me, Et, n-Pr, i-Pr, n-B
u, i-Bu, s-Bu, t-Bu, OMe, OEt, On-
Pr, O-i-Pr, O-n-Bu, O-i-Bu, O-s-B
u, Ot-Bu, F, Cl, Br, I, NO₂, CN,
CH₂F, CHF₂, CF₃, CH ₂CF₃, CH₂Cl, C
Cl₃, CHClMe, CH₂CH₂Cl, CHClCH₂
Cl, CH₂Br, CHBrMe, CH₂CH₂Br, C
H₂OMe, CH₂OEt, CH₂On-Pr, CH₂O-
i-Pr, CH₂On-Bu, CH₂O-i-Bu, CH₂O
-S-Bu, CH₂Ot-Bu, CHMeOMe, CHM
eOEt, CHMeO-n-Pr, CHMeO-i-Pr,
CHMeO-n-Bu, CHMeO-i-Bu, CHMeO
-S-Bu, CHMeO-t-Bu, CH₂CH₂OMe, C
H₂CH₂OEt, CH₂CH₂O-i-Pr, COMe, C
OEt, CO-n-Pr, COOMe, COOEt, CO
O-i-Pr, CONHMe, CONHEt, CONMe
₂, CONEt₂, CONEtMe, OCHF₂, OC
F₃, OCH₂CF₃, SMe, SEt, CH₂SMe, C
H₂SEt, CHMeSMe, CHMeSEt.

X ² : CH ₂ OH, CH ₂ OMe, CH ₂ OE
_{t, CH 2 O-n-} Pr, CH 2 O-i-Pr, CH 2 O-n-
_{Bu, CH 2 O-i-} Bu, CH 2 O-s-Bu, CH 2 O-t
_{-Bu, CH 2 O-n-} Am, CH 2 O-i-Am, CH 2 O-
t-Am,

[0016]

[Chemical 10] CH₂OCH = CH₂, CH₂OCH₂CH = CH₂, CH₂
OCH₂CMe = CH₂, CH₂OCHMeCH = CH₂,
CH₂OCH₂-CCH, CH₂OCHMe-CCH, C
H₂OCMe₂-CCH, CH₂OCH₂CH₂F, CH₂O
CH₂CF₃, CH ₂OCH₂CH₂Cl, CH₂OCH₂C
Cl₃, CH₂OCH₂CH₂Br,

[0017]

[Chemical 11] CH ₂ OCH ₂ CCl = CH ₂ , CH ₂ OCH ₂ CCl = C
HCl, CH ₂ OCH ₂ CH ₂ OMe, CH ₂ OCH ₂ CH _{2
OEt, CH 2 OCH 2 CH 2} O-i-Pr,

[0018]

[Chemical 12] CH ₂ OPh, CH ₂ OPh-4-Cl, CH ₂ OPh-4-
NO ₂ , CH ₂ NHMe, CH ₂ NHEt, CH ₂ NM
e ₂ , CH ₂ NEt ₂ , CH ₂ NEtMe, CH ₂ OCH ₂ P
h, CH ₂ OCH ₂ COOMe, CH ₂ OCH ₂ COOE
t, CH ₂ OCHMeCOOMe, CH ₂ OCH ₂ COO
_{-T-Bu, CH 2 OCHMeCOOEt,} CH 2 CN, C
_{H 2 SMe, CH 2 SEt,} CH 2 S-n-Pr, CH 2 S-
_{i-Pr, CH 2 S-} t-Bu, CH 2 SCH 2 CH = CH 2,
CH ₂ SCH ₂ -CCH,

[0019]

[Chemical 13] CH₂SCH₂CH₂Cl, CH₂SOMe, CH₂SOE
t, CH₂SO₂Me, CH₂SO₂Et, CH₂SO₂−n-
Pr, CH₂SO₂-I-Pr, CH₂SCH₂CH₂OM
e, CH₂SCH₂CH₂OEt, CH₂SPh, CH₂O
Ac, CH₂OCOEt, CH₂OCO-n-Pr, CH₂
OSO₂Me, CH₂OSO₂Et, CH₂OCH ₂CH₂C
N, CHMeOH, CHMeOMe, CHMeOEt,
CHMeO-n-Pr, CHMeO-i-Pr, CHMeO
-N-Bu, CHMeO-i-Bu, CHMeO-s-Bu,
  CHMeO-t-Bu,

[0020]

[Chemical 14] CHMeOCH = CH ₂ , CHMeOCH ₂ CH = C
H ₂ , CHMeOCH ₂ -CCH, CHMeOCH ₂ C
F ₃ , CHMeOCH ₂ CH ₂ Cl, CHMeOCH ₂ CC
l ₃ , CHMeOCH ₂ CH ₂ Br,

[0021]

[Chemical 15] CHMeOCH ₂ CH ₂ OMe, CHMeOCH ₂ CH ₂ O
Et,

[0022]

[Chemical 16] CHMeOPh, CHMeNHMe, CHMeNM
e ₂ , CHMeNEt ₂ , CHMeOCH ₂ COOMe,
CHMeOCH ₂ COOEt, CHMeOCHMeCO
OMe, CHMeCN, CHMeSMe, CHMeSE
t, CHMeS-n-Pr, CHMeS-i-Pr, CHM
eSCH ₂ CH = CH ₂ , CHMeSCH ₂ -CCH,

[0023]

[Chemical 17] CHMeSCH₂CH₂Cl, CHMeSOMe, CHM
eSOEt, CHMeSO₂Me, CHMeSO₂Et,
CHMeSO₂-I-Pr, CHMeSCH₂CH₂OM
e, CHMeSPh, CHMeOAc, CHMeOCO
Et, CHMeOSO₂Me, CHMeOSO₂Et, C
HMeOCH₂CH₂CN, CMe₂OH, CMe₂OM
e, CMe₂OEt, CMe₂On-Pr, CMe₂O-i
-Pr, CMe ₂OCH = CH₂, CMe₂OCH₂CH =
CH₂, CMe₂OCH₂-CCH, CMe₂OCH₂CH₂
Cl, CMe₂OCH₂CH₂OMe,

[0024]

[Chemical 18] CMe₂NHMe, CMe₂NMe₂, CMe₂OCH₂C
OOMe, CMe₂CN, CMe₂SMe, CMe₂SE
t, CMe₂SO₂Me, CMe₂SO₂Et, CMe ₂O
Ac, CMe₂OSO₂Me, CH₂COOMe, CH₂C
OOEt, CH₂COO-i-Pr, CHMeCOOM
e, CHMeCOOEt, CHMeCOO-i-Pr, C
H₂CH₂COOMe, CH₂CH₂COOEt, CH₂C
H₂COO-i-Pr, CH = CHOMe, CH = CHO
Et, CH₂CH₂OMe, CH₂CH₂OEt, COO
H, COOMe, COOEt, COO-n-Pr, COO
-I-Pr, COO-n-Bu, COO-s-Bu, COO-
i-Bu, COO-t-Bu, COO-i-Am,

[0025]

[Chemical 19] COOCH₂CH = CH₂, COOCH₂-CCH, CO
OCH₂CMe = CH₂, COOCH₂CH₂Br, COO
CH₂CH₂Cl, COOCH₂CH₂F, COOCH₂C
F₃, COOCHMeCH₂Cl, COOCH₂CCl =
CH₂, COOCH₂CCl = CHCl, COOCH₂O
Me, COOCH₂CH₂OMe, COOCH₂CH₂OE
t, COOCH₂OEt, COOCH₂SMe, COOC
H₂CH₂SMe, COOCH₂CH₂SEt, COOCH
₂CH₂SCH₂CH₂Cl, COOCH ₂SOMe, CO
OCH₂CH₂SOMe, COOCH₂CH₂OCH₂CH₂
Cl, COOCH₂CH₂OCH₂CH₂Br, COOCH
₂CH₂OSO₂Me, COOCH₂CH₂OSO₂Ph-4-
Me, COOCH₂OCH₂CH₂OMe, COOCH₂C
H₂SO₂Me, COOCH₂CH₂SO₂Et, COOC
H₂SO₂Me, COOCH₂CN, COOCH₂CH₂C
N, COOCH₂CH₂CH₂CN, COOCH₂CH₂N
HMe, COOCH₂CH₂NMe₂, COOCH₂NMe
₂, COOCH₂CH₂NO₂, COOCH₂CH₂CH₂N
O₂, COOCH₂OH,

[0026]

[Chemical 20] COOCH₂COMe, COOCH₂CO-t-Bu, CO
OCH₂CO-i-Pr, COOCH₂COPh, COOC
H₂COOMe, COOCH₂COOEt, COOCHM
eCOOMe, COOCMe₂OMe, COOCH₂CH
₂OCH₂CH = CH₂, COOCH₂CH₂OCH₂-CC
H, COOCH₂CH₂OPh, COOCH₂OPh, C
OOCH₂CH₂OCH₂Ph, COOCH₂SiMe₃,
COOSiMe₃, COOSiEt₃, COOPh, CO
OPh-4-Cl, COOPh-4-Me, COOPh-4-
OMe, COOPh-4-NO₂, COOCH₂Ph, CO
OCH₂Ph-2-Cl, COOCH₂Ph-4-Cl, CO
OCHMePh, COOCH ₂CH₂Ph,

[0027]

[Chemical 21] C (O) SMe, C (O) SEt, C (O) S-n-P
r, C (O) S-i-Pr, C (O) S-n-Bu, C
(O) S-i-Bu, C (O) S-s-Bu, C (O) S-
t-Bu, C (S) OMe, C (S) OEt, C (S) O
-N-Pr, C (S) O-i-Pr, C (S) O-n-Bu,
C (S) O-i-Bu, C (S) O-s-Bu, C (S) O
-T-Bu, CSSMe, CSSEt, CSS-n-Pr,
CSS-i-Pr, CONHMe, CONMe 2, CON
_{HEt, CONEt 2, CONH-n} -Pr, CONH-i
-Pr, CONH-n-Bu, CONH-i-Bu, CON
H-s-Bu, CONH-t-Bu, CONH-t-Am, C
ON (n-Pr) ₂ , CON (i-Pr) ₂ , CONHPh,
CONHPh-4-Me, CONHPh- 4-NO 2,

[0028]

[Chemical formula 22] CONMeOMe, CONHCH ₂ CH = CH ₂ , CON
_{(CH 2 CH = CH 2)} 2, CONHCH 2 -CCH, C
_{ON (CH 2 -CCH) 2,} CONMePh, CONE
tPh, CON (Me) Ph-4-Me, CONHSO ₂
Me, CONHSO ₂ CF ₃ , COON = CMe ₂ ,

[0029]

[Chemical formula 23] COOCH₂OCOMe, COOCH₂OCO-t-Bu. X³: F, Cl, Br, I, NO₂, OMe, OEt, O
-N-Pr, O-i-Pr, CF₃, CN, SMe, SOM
e, SO₂Me, SCF₃, SOCF₃, SO₂CF₃. X^Four: H, F, Cl, Br, I, Me, NO₂, OMe,
OEt, On-Pr, O-i-Pr, CF₃, CN, SM
e, SOMe, SO₂Me, SCF₃, SOCF₃, SO₂
CF₃. X^Five: H, F, Cl, Br, I, Me, NO₂, OMe,
OEt, O-n-Pr, O-i-Pr. Z: H, Me, Et, n-Pr, i-Pr, n-Bu, i-B
u, s-Bu, t-Bu, CH ₂CH₂Cl, CH₂CF₃, C
HClMe, CH₂CH₂Br, CHClCH₂Cl, C
H₂CH = CH₂, CH₂CMe = CH₂, CH₂CH = C
HMe, CH₂-CCH, CH₂CCl = CH₂, CH₂C
N, CH₂Ph, CH₂Ph-2-Cl, CH₂Ph-3-C
1, CHPh-4-Cl, CH₂Ph-2-Me,

[0030]

[Chemical formula 24] CH ₂ Ph-2,4-Me ₂ , CH ₂ Ph-4-Me, CH ₂ Ph
_{-2-NO 2, CH 2 Ph} -3-CF 3, COPh, COPh
_{-4-Me, COPh-2-} NO 2, COPh-2,4-Cl 2,
Ac, COEt, CO-n-Pr, CO-i-Pr, CO-
n-Bu, CO-t-Bu, SO ₂ Me, SO ₂ Et, SO _{2
CH 2 CH = CH 2, SO} 2 Ph, SO 2 Ph-4-Me, S
_{O 2 Ph-4-Cl,} SO 2 Ph- 2,4- (NO 2) 2, SO 2
CF ₃ .

In the present invention, in the case where Z is a hydrogen atom, a metal salt or a salt with an organic base is easily formed, and these salts fall within the category of the 2- (substituted benzoyl) thiazine derivative of the present invention. Included in. Examples of the metal constituting the metal salt include sodium, potassium, calcium, lithium, barium, magnesium, iron, copper, nickel and manganese. Further, as the organic base constituting the salt, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, normal propyl amine, dinormal propyl amine, isopropyl amine, diisopropyl amine, normal butyl amine, isobutyl amine, secondary-butyl amine, Tertiary-butylamine, piperidine, pyrrolidine, morpholine, pyridine, N, N-
Examples include dimethylaniline and choline.

Specific examples of the 2- (substituted benzoyl) thiazine derivative of the present invention are shown in Table 1.

[Table 1]

Next, a method for producing the 2- (substituted benzoyl) thiazine derivative of the present invention will be described. The 2- (substituted benzoyl) thiazine derivative represented by the above formula (I) is obtained by reacting 1 mol of the thiazine represented by the formula (II) with the benzoic acid ester represented by the formula (III) in the presence of a Lewis base.
It can be produced by reacting with 7 to 1.5 mol in a reaction solvent.

Examples of the Lewis base used in this reaction include alkali metal organometallic compounds such as methyllithium, ethyllithium, butyllithium, sec-butyllithium, tert-butyllithium, and benzyllithium, methylmagnesium iodide, ethyl. Organic Grignard reagents such as magnesium bromide and n-butyl magnesium bromide, organometallic compounds of alkali metals, organocopper compounds prepared from Grignard reagents and monovalent copper salts, alkali metal amides such as lithium diisopropylamide, triethylamine, Pyridine, 4-
Dimethylaminopyridine, N, N-dimethylaniline,
1,8-diazabicyclo [5.4.0] undec-7-
Examples thereof include organic amines such as ene.

As the reaction solvent, methylene chloride,
Chlorinated hydrocarbons such as chloroform and 1,2-dichloroethane, diethyl ether, tetrahydrofuran (TH
Ethers such as F) and dioxane can be used. In the present invention, preferably, butyl lithium, lithium diisopropylamide (LDA) or the like is used as the base, and diethyl ether, tetrahydrofuran or dioxane is used as the solvent.

When a lithium compound is used as the Lewis base, a lithiated thiazine compound represented by the formula (IV) is formed as shown in the reaction formula below, which is represented by the formula (III). Reacts with benzoic acid ester
The 2- (substituted benzoyl) thiazine derivatives of the present invention are formed.

[Chemical 25]

When lithiation is carried out in the above reaction,
The reaction is usually 0 to -70 ° C, preferably -60 to -7.
It is carried out in the range of 0 ° C. Then, the benzoic acid ester is allowed to act at the same temperature, and thereafter 10 to 50 ° C., preferably 2
React at 0-30 ° C. The reaction time is 5 to 5 for lithiation.
20 minutes, preferably 10 to 15 minutes, 1 to 10 hours after addition of the benzoic acid ester, preferably,
3 to 4 hours.

Raw materials for the 2- (substituted benzoyl) thiazine derivative represented by the formula (I) of the present invention will be described. The thiazine compound represented by the above formula (II) can be synthesized by the following known synthesis method according to the following reaction formula (for example, SYNLETT: 915-916, (199).
7)).

[0039]

[Chemical formula 26]

That is, the thiazine compound represented by the above formula (II) is 1.0 to 1.7 equivalents, preferably 1.5 equivalents of methyl thioglycolate and 1.0 equivalent of 3-methyl-2-oxazolidone. And in dry n-propyl alcohol in the presence of 1.0 to 1.5 equivalents, preferably 1.3 equivalents of sodium hydride, at a temperature of 100 to 150 ° C., preferably 120 ° C. for 2 to 10 hours, It can be preferably produced by heating for 6 hours to react.

Further, the benzoic acid ester represented by the above formula (III) can be easily synthesized by various known synthesis methods (for example, Japanese Patent No. 2725274, Japanese Patent No. 2739738, and Japanese Patent No. 2739738). 29552
83, etc.).

As an example of the case where the benzene ring substituent X ³ is a benzoic acid ester represented by —SO ₂ Me or —SO ₂ R ⁹ , for example, synthesis is performed according to the steps shown in the following reaction formulas (A) to (D). can do.

[Chemical 27]

[0043]

[Chemical 28]

[0044]

[Chemical 29] (In the formula, R ¹² represents a C1 to C4 alkyl group, a methoxyethyl group, an ethoxyethyl group, a methylthioethyl group, an ethylthioethyl group, and R ¹³ represents a C1 to C3 alkyl group, X ¹ , X ² , X ⁴ , X ⁵ , and E have the meanings given above.)

In the case of the reaction formula (A), 4-methylanilines are reacted with 1.32 equivalents of t-butyl nitrite in the presence of 1.97 equivalents of dimethyl disulfide at room temperature for 7 hours. 4-Methylthiotoluenes are produced (step 1). To the obtained 4-methylthiotoluenes,
Under heating in water, excess potassium permanganate is allowed to act to obtain 4-methylsulfonylbenzoic acids (step 2). Then, thionyl chloride is allowed to act on the benzoic acids, and then alcohols are allowed to act to produce 4-methylsulfonylbenzoic acid esters via the benzoic acid chloride (step 3).

In the case of reaction formula (B), methylthiobenzenes are obtained from anilines in the same manner as in step 1 of reaction formula (A) (step 1). Next, methylthioacetophenones are derived from the obtained methylthiobenzenes by Friedel-Crafts reaction (step 2). Methylthiobenzoic acids are derived from the obtained methylthioacetophenones by the King reaction (step 3). Further, the obtained methylthiobenzoic acid is oxidized to synthesize methylsulfonylbenzoic acid (step 4). The methylsulfonylbenzoic acids can also be synthesized by subjecting the methylthioacetophenones obtained in the above Step 2 to a haloform reaction (Step 5). From the methylsulfonylbenzoic acids obtained as described above,
Methylsulfonylbenzoic acid esters are derived in the same manner as in the case of step 3 of the above reaction formula (A) (step 6).

In the case of the reaction formula (C), methylthioanilines are diazotized with sodium nitrite and then reacted with copper halide to obtain methylthiohalogenated benzenes (step 1). A Grignard reagent and then carbon dioxide are allowed to act on the obtained methylthiohalogenated benzenes to synthesize methylthiobenzoic acids (step 2). Methylthiobenzoic acids can also be synthesized as follows. That is, the methylthiohalogenated benzenes obtained in the above step 1 are reacted with a cyanating agent to synthesize methylthiocyanobenzenes (step 3), and this is hydrolyzed to obtain methylthiobenzoic acids (step 5). . Furthermore, it can also be obtained by reacting the methylthiohalogenated benzenes obtained in step 1 with alkyllithium and then carbon dioxide gas (step 4). The methylthiobenzoic acids obtained as described above are oxidized to induce methylsulfonylbenzoic acid (step 6), and then methylsulfonylbenzoic acid esters are obtained in the same manner as in step 3 of the reaction formula (A). Is synthesized (step 7).

In the case of the above reaction formula (D), 1 molar amount of 3
Position substituted phenol with 2 moles of chlorine and a catalytic amount of C1
It is reacted with a C10 alkylamine, preferably tert-butylamine or diisopropylamine, in a solvent such as methylene chloride at a temperature between -70 ° C and 70 ° C. After the reaction, the free chlorinated phenol compound is isolated by a conventional method (step 1). 1 mol of the reaction product of the dichloro-substituted phenol obtained is reacted with a suitable alkylating agent together with a catalytic amount of potassium iodide and an excess molar amount of a base such as potassium carbonate (step 2). As the above-mentioned alkylating agent, 2-chloroethyl ethyl ether, 2-chloroethyl methyl ether, 2-
Examples thereof include chloroethyl methyl sulfide, 2-chloroethyl ethyl sulfide, and C1-C4 alkyl chloride. Alkyl iodides such as methyl iodide or ethyl iodide can also be used. In these cases, the catalyst potassium iodide is not required, and little or no heating is required. The reaction is carried out at 25 ° C to 80 ° C with stirring for 4 hours. The reaction product is isolated by a conventional method. The dichloro compound obtained in step 2 above is reacted with an equimolar amount of a C1-C4 alkyl mercaptan together with an excess molar amount of a base such as potassium carbonate in a solvent such as dimethylformamide (step 3). The reaction is carried out under an atmosphere of an inert gas such as nitrogen at a temperature of 50 ° C to 100 ° C with stirring for several hours. This reaction product is recovered by a conventional method. In addition, 1 molar amount of the 2-chloro-4-alkylthiobenzoic acid compound obtained in step 3 is treated with at least 3 moles of an oxidizing agent such as m-chloroperbenzoic acid in a suitable solvent such as methylene chloride. The reaction solution is oxidized with stirring at 20 ° C to 100 ° C. The desired intermediate is recovered by conventional methods. In this reaction, 4-
The alkylthio substituent is oxidized to the corresponding alkylsulfone (step 4).

Next, benzoic acids and their esters which can be synthesized according to the above reaction formulas (A) to (D) or in accordance therewith are exemplified in the following table.

[Table 2]

[0050]

[Table 3]

The 2- (substituted benzoyl) thiazine derivative represented by the above formula (I) of the present invention (hereinafter sometimes referred to as "the compound of the present invention") exhibits a reliable herbicidal effect at a low dose, and , Shows selectivity between crops and weeds. Therefore, a herbicide containing the compound of the present invention as an active ingredient,
For example, it is suitable for controlling dicotyledonous weeds and monocotyledonous weeds in important crops such as wheat, rice, corn and soybean before or after germination.

The dicotyledon weeds that can be controlled by the herbicide of the present invention include Amaranthus, Sengdang, Bidens, Stellaria, Abutilon, Matricaria, Examples include the genus Yamgra (Galium). In addition, as monocotyledon weeds, there are genus Echinochloa and genus Digitar.
ia), genus Alopecurus (Alopecurus), and the like.

The application range of the herbicide of the present invention includes agricultural lands such as upland fields, paddy fields and orchards, as well as non-agricultural lands such as grounds and factory sites. The compound of the present invention can be used as it is as a herbicide, but it is usually used in the form of various forms such as powders, wettable powders, granules and emulsions together with formulation auxiliary agents. When a preparation is prepared, one or more compounds of the present invention are contained in an amount of 0.1 to 95% by weight,
Preferably 0.5 to 90% by weight, more preferably 2 to
It is formulated to contain 70% by weight.

Carriers / diluents used as formulation aids,
Examples of surfactants include talc as a solid carrier,
Kaolin, bentonite, diatomaceous earth, white carbon,
Clay etc. can be mentioned. As a liquid diluent,
Water, xylene, toluene, chlorobenzene, cyclohexane, cyclohexanone, methyl sulfoxide, N, N
-Dimethylformamide, ethyl alcohol, 1-methylethyl alcohol and the like can be mentioned.

The surfactant is preferably used depending on its effect. Examples of the emulsifier include polyoxyethylene alkylaryl ether and polyoxyethylene sorbitan monolaurate. As a dispersant,
Examples thereof include lignin sulfonate and dibutyl naphthalene sulfonate. Examples of the wetting agent include alkyl sulfonates and alkyl phenyl sulfonates.

The above-mentioned preparations include those to be used as they are and those to be used after diluting to a predetermined concentration with a diluent such as water. When diluted and used, the concentration of the 2- (substituted benzoyl) thiazine derivative of the present invention is 0.001-1.
It is desirable to set it in the range of 0%. The amount of the compound of the present invention used is set within the range of 0.02 to 10 kg, preferably 0.05 to 5 kg, per ha.

The concentration and amount of the herbicide of the present invention to be used vary depending on the dosage form, time of use, method of use, place of use, target crop, etc., and it is of course possible to increase or decrease without sticking to the above range. .. Furthermore, the compound of the present invention can be used in combination with other active ingredients such as fungicides, insecticides, acaricides and herbicides.

[0058]

EXAMPLES Hereinafter, in the present invention, a synthesis example of the 2- (substituted benzoyl) thiazine derivative represented by the formula (I), the thiazine compound represented by the formula (II) and the formula (II
It will be specifically described with reference to synthesis examples of benzoic acid ester represented by I), formulation examples and test examples. The present invention is not limited to these synthetic examples, formulation examples and test examples as long as the gist thereof is not exceeded. In the synthesis examples below, the abbreviations in the NMR section have the following meanings. s (single line), d (double line), t (triple line), q (quad line), m (multiple line), dd (double line), bs (broad single line).

Example 1 2-[(2-chloro-4-methylsulfonylphenyl) carbonyl] -5,6-dihydro-4-methyl-1,4-thiazin-3 (2H) -ol [Compound No. I- 5] Synthesis of (1) 4-methyl-5,6-dihydro-1,4-thiazin-3 (2) -one [Formula (II): Y ¹ = Y ² = Y ³ = Y ⁴ = H, Y ⁵ = Me] Synthesis To 50 ml of dried n-propyl alcohol was added sodium hydride (60% in mineral oil, 2.06 g, 39.5 × 1.3 mmol). After foaming, add methyl thioglycolate (6.29
g, 39.5 × 1.5 mmol) was added and stirred for several minutes. Then
Add 3-methyl-2-oxazolidone (4g, 39.5mmol) and add
The mixture was heated and stirred at 20 ° C for 6 hours. Then, the alcohol was distilled off under reduced pressure, the residue was partitioned with water and ethyl acetate, and the organic layer was washed with saturated brine. This was dried over sodium sulfate (anhydrous), concentrated, and then purified by silica gel column chromatography to obtain a light brown liquid. Yield 3.77 g Yield 72.8% IR NaCl liq.film cm ^-1 : 2932 1668 1502 1400 1344 12
60 ¹ H-NMR (60MHz, CDCl ₃ , δ: 2.78 (2H, t, J = 6Hz) 2.93
(3H, S) 3.23 (2H, S) 3.55 (2H, t, J = 6Hz)

(2) Synthesis of 2-[(2-chloro-4-methylsulfonylphenyl) carbonyl] -5,6-dihydro-4-methyl-1,4-thiazin-3 (2H) -ol 100 ml 4-methyl-5,6-dihydro-1,4-in an eggplant-shaped flask
Thiazin-3 (2) -one (0.12g, 0.916mmol) was taken and dissolved in 5ml of dry diethyl ether. Then, a stirrer was inserted and the septum was plugged. An injection needle was inserted into the septum, suction in the flask and replacement with argon gas were repeated 3 times, and then the bath was placed at -70 ° C. To this, n-butyllithium (0.63 ml of hexane solution of 1.59 mol / l) was injected by a syringe. After stirring for about 10 minutes, argon-substituted 2-chloro-4
-Methylsulfonylbenzoic acid methyl ester (0.25 g, 0.
30 ml of a dry diethyl ether solution (916 × 1.1 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Then the solvent was evaporated and the residue was partitioned between water and ethyl acetate, the organic layer was washed with water and dried over sodium sulfate (anhydrous). After distilling off the solvent,
The residue was purified by silica gel column chromatography. Light yellow solid, mp 58-60 ° C, yield 30.8 mg, yield 10.7% IR KBr cm ^-1 : 1602 1498 1318 1156 1102 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.75 (2H, t, J = 6Hz ) 3.00
(3H, S) 3.03 (3H, S) 3.66 (2H, t, J = 6Hz) 7.43 (1H, d, J
= 8Hz) 7.63 ~ 7.96 (2H, m) OH unclear

Example 2 2-[(2,4-dichlorophenyl) carbonyl] -5,6-dihydro-
4-Methyl-1,4-thiazin-3 (2H) -ol [Compound No. I-
9] Synthesis 4-methyl-5,6-dihydro-1,4-in a 100 ml eggplant-shaped flask
Thiazin-3 (2H) -one (1 g, 7.6 mmol) was taken and dissolved in 10 ml of dry diethyl ether. Then, a stirrer was inserted and the septum was plugged. Insert the injection needle into the septum, repeat the suction and argon gas replacement in the flask 3 times, then
I put it in a 0 ° C bath. In addition to this, n-butyl lithium (1.59m
ol / l hexane solution (5.3 ml) was injected with a syringe. About 10
After stirring for 10 minutes, 10 ml of a dry diethyl ether solution of 2,4-dichlorobenzoic acid methyl ester (3.1 g, 7.6 × 2 mmol) substituted with argon was injected, and the mixture was stirred at room temperature for 2.5 hours.
Then the solvent was evaporated and the residue was partitioned between water and ethyl acetate, the organic layer was washed with water and dried over sodium sulfate (anhydrous). After the solvent was distilled off, the residue was purified by silica gel column chromatography. Light yellow solid, mp98-100 ° C, yield 0.31g, yield 13.5% IR KBr cm ^-1 : 1600 1500 1472 1446 1350 1324 1102 82
6 ¹ H-NMR (60MHz, CDCl3, δ): 2.72 (2H, t, J = 5Hz) 3.02
(3H, S) 3.61 (2H, t, J = 5Hz) 7.03 to 7.40 (3H, m) OH unclear

Example 3 2-[(2-Methyl-3-methoxymethyl-4-methylsulfonylphenyl) carbonyl] -5,6-dihydro-4-methyl-1,4-thiazin-3 (2H) -ol Synthesis of [Compound No. I-2] In a 100 ml flask, 4-methyl-5,6-dihydro-1,4-thiazin-3 (2) -one [Formula (II): Y ¹ = Y ² = Y ³ = Y ⁴ = H, Y
⁵ = Me] (0.336g, 2.57mmol) was taken and dried THF 20
dissolved in ml. This was capped with a septum, an injection needle was inserted, and vacuum suction and argon substitution were repeated 4 times. After that, it was cooled to -70 ° C, and lithium diisopropylamide (LDA) (1.5M cyclohexane solution 1.9ml, 2.57x
1.1 mmol) was injected with a syringe. After stirring for about 15 minutes, 2
-Methyl-3-methoxymethyl-4-methylsulfonylbenzoic acid methyl ester (0.7g, 2.57mmol) in dry THF
5 ml was injected with a syringe and then stirred at room temperature for 5 hours. Then, the reaction solution was distilled off, and the residue was partitioned between ethyl acetate and dilute aqueous hydrochloric acid. The organic layer was washed with saturated saline and dried over sodium sulfate (anhydrous). Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography. Viscous product, yield 0.189 g, yield 19.9% IR NaCl liq.film cm ^-1 : 2940 1598 1496 1450 1316 11
84 1154 1132 788 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.41 (3H, S, aromatic ring CH ₃ ) 2.
71 (2H, t, J = 5Hz, thiazine ring CH ₂ ) 3.05 (3H, S, SO ₂ CH ₃
or N-CH ₃ ) 3.13 (3H, S, SO ₂ CH ₃ or N-CH ₃ ) 3.43 (3H, S, O
CH ₃ ) 3.67 (2H, t, J = 5Hz, thiazine ring CH ₂ ) 4.88 (2H, S, C
H ₂ -O-) 7.33 (1H, d, J = 8Hz, aromatic ring H) 7.94 (1H, d, J = 8H
z, aromatic ring H)

Example 4 Methyl 3-[(3-hydroxy-4-methyl-5,6-dihydro-1,4-thiazin-2-yl) carbonyl] -2-methyl-6- (methylsulfonyl) benzoate Synthesis of ester [Compound No. I-3] 4-methyl-5,6-dihydro-1,4-thiazin-3 (2) -one [Formula (II): Y ¹ = Y ² = Y ^{3 was} added to a 100 ml flask. = Y ⁴ = H, Y
⁵ = Me] (0.17g, 1.3mmol) was taken and dried THF 10ml
Dissolved in. This was capped with a septum, an injection needle was inserted, and vacuum suction and argon substitution were repeated 4 times. afterwards-
Cool to 70 ℃ and add LDA (1.5M cyclohexane solution
1.0 ml, 1.3 x 1.1 mmol) was injected with a syringe. After stirring for about 15 minutes, 2-methyl-3-methoxycarbonyl-4-methylsulfonylbenzoic acid methyl ester (0.4 g, 1.3 × 1.1 mmol)
Inject 5 ml of dry THF solution of
Stir for hours. Then, the reaction solution was distilled off, and the residue was partitioned between ethyl acetate and dilute aqueous hydrochloric acid. The organic layer was washed with saturated saline and dried over sodium sulfate (anhydrous). Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography. Light yellow viscous product, yield 0.129 g, yield 25.8% IR NaCl liq.film cm ^-1 : 1738 1596 1496 1406 1324 12
76 1150 1128 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.33 (3H, S, CH ₃ ) 2.73 (2
H, t, J = 6Hz, thiazine ring CH ₂ ) 3.06 (3H, S, SO ₂ CH ₃ ) 3.1
1 (3H, S, N-CH ₃ ) 3.68 (2H, t, J = 6Hz, thiazine ring CH ₂ ) 3.
5 (3H, S, COOCH ₃ ) 7.38 (1H, d, J = 8Hz, aromatic ring H) 7.83 (1
H, d, J = 8Hz, aromatic ring H)

Example 5 2-[(2-chloro-3-methoxymethyl-4-methylsulfonylphenyl) carbonyl] -5,6-dihydro-4-methyl-1,4-thiazin-3 (2H) -ol Synthesis of [Compound No. I-6] 4-methyl-5,6-dihydro-1,4-thiazin-3 (2) -one in a 100 ml flask [Formula (II): Y ¹ = Y ² = Y ³ = Y ⁴ = H, Y
⁵ = Me] (0.188g, 1.43mmol) was taken and dried THF 20
dissolved in ml. This was capped with a septum, an injection needle was inserted, and vacuum suction and argon substitution were repeated 4 times. After that, it was cooled to -70 ° C., and LDA (1.56 cyclohexane solution 1.06 ml, 1.43 × 1.1 mmol) was injected into this with a syringe. About 1
After stirring for 5 minutes, 2-chloro-3-methoxymethyl-4-methylsulfonylbenzoic acid methyl ester (0.42g, 1.43mmo
5 ml of the dry THF solution of l) was injected with a syringe and then stirred at room temperature for 5 hours. Then, the reaction solution was distilled off, and the residue was partitioned between ethyl acetate and dilute aqueous hydrochloric acid. The organic layer was washed with saturated saline and dried over sodium sulfate (anhydrous). Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography. Viscous product, yield 0.176 g, yield 31.5% IR NaCl liq.film cm ^-1 : 2940 1610 1496 1320 1198 11
50 1098 798 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.75 (2H, t, J = 5Hz, thiazine ring CH ₂ ) 3.06 (3H, S, SO ₂ CH ₃ or N-CH ₃ ) 3.20 (3H , S, SO
₂ CH ₃ or N-CH ₃ ) 3.43 (3H, S, OCH ₃ ) 3.66 (2H, t, J = 5Hz,
Thiazine ring CH ₂ ) 5.05 (2H, S, CH ₂ -O-) 7.41 (1H, d, J = 8H
z, aromatic ring H) 8.03 (1H, d, J = 8Hz, aromatic ring H)

Example 6 2-Chloro-3-[(3-hydroxy-4-methyl-5,6-dihydro-
Synthesis of 1,4-thiazin-2-yl) carbonyl] -6- (methylsulfonyl) benzoic acid methyl ester [Compound No. I-7] 4-methyl-5,6-dihydro-1,4-in a 100 ml flask. Thiazin-3 (2) -one [Formula (II): Y ¹ = Y ² = Y ³ = Y ⁴ = H, Y
⁵ = Me] (0.283g, 2.163mmol) was taken and dried THF 1
It was dissolved in 0 ml. This was capped with a septum, an injection needle was inserted, and vacuum suction and argon substitution were repeated 4 times. After that, it was cooled to -70 ° C., and LDA (1.59 cyclohexane solution 1.49 ml, 2.163 × 1.05 mmol) was injected into this with a syringe. After stirring for about 15 minutes, 2-chloro-3-methoxycarbonyl-
4-Methylsulfonylbenzoic acid methyl ester (0.664g,
2.163 mmol) dry THF solution 10 ml is injected with a syringe,
Then, the mixture was stirred at room temperature for 5 hours. Then the reaction solution is distilled off,
The residue was partitioned between ethyl acetate and dilute aqueous hydrochloric acid. The organic layer was washed with saturated saline and dried over sodium sulfate (anhydrous).
Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain a solid. Yellow solid, mp: 70 to 73 ° C., yield 0.21 g, yield 23.9% IR KBr cm ⁻¹ : 3460 1740 1602 1496 1324 1274 1146 ¹ H-NMR (60 MHz, CDCl ₃ , δ): 2.78 (2H, t, J = 5Hz, thiazine ring CH ₂ ) 3.06 (3H, S, SO ₂ CH ₃ or N-CH ₃ ) 3.15 (3H, S, SO
₂ CH ₃ or N-CH ₃ ) 3.72 (2H, t, J = 5Hz, thiazine ring CH ₂ ) 4.
00 (3H, S, COOCH ₃ ) 7.60 (1H, d, J = 9Hz, aromatic ring H) 8.00
(1H, d, J = 9Hz, aromatic ring H)

Reference Example 1 Synthesis of 4-methylsulfonyl-2-chlorobenzoic acid methyl ester [Compound No. III-5] (1) Synthesis of 4-methylthio-2-chlorotoluene In a 200 ml flask equipped with a dropping funnel, Add 3-chloro-4-methylaniline (2g, 13.84mmol), dimethyldisulfide (13.15g, 136.8mmol) and 5ml chloroform,
T-Butyl nitrite (2 ml, 16.87 mmol) was added dropwise. After completion of dropping, the flask was placed in an ice water bath, and 3-chloro-4-methylaniline (8 g, 55.37 mmol) was added dropwise. Then, 10 ml
8.85 ml of t-butyl nitrite diluted with chloroform (74.6
(5 mmol) was added dropwise over 1 hour. After completion of the dropping, the ice-water bath was removed, the reaction was carried out at room temperature for 7 hours, and the mixture was allowed to stand overnight. After the reaction was completed, the reaction solution was partitioned with chloroform and 5% hydrochloric acid, and the organic layer was washed with saturated saline. The extracted organic layer was dried over sodium sulfate (anhydrous) and concentrated to obtain 8.5 g of an oily substance. This was purified by silica gel column chromatography to obtain 8.42 g of an oily compound (yield 70.5%). IR NaCl liq.film cm ^-1 : 3064 2992 2956 1598 1480 13
78 1266 1106 1050996 864 708 556 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.25 (3H, S) 2.38 (3H, S)
6.97 (1H, m) 7.01 (1H, d, J = 9.7Hz) 7.05 (1H, d, J = 9.7
Hz)

(2) Synthesis of 4-methylsulfonyl-2-chlorobenzoic acid [Compound No. VII-5] In a 300 ml flask were placed 4-methylthio-2-chlorotoluene (8 g, 46.33 mmol) and 80 ml of water. Suspended and to this was added potassium permanganate (36.86g, 0.232mol). After adding the whole amount, the mixture was made into a reflux state and reacted for 3 hours. After the reaction was completed, the reaction solution was filtered and the residue was washed with hot water. The obtained filtrate was extracted with ethyl acetate to remove unreacted compounds. The aqueous layer was then acidified with concentrated hydrochloric acid and saturated with sodium chloride. Then, the mixture was extracted with ethyl acetate, the extract was washed with saturated saline, and then dried with sodium sulfate (anhydrous). Then, the solvent was concentrated to obtain 2.27 g of solid (yield 20.9%). IR KBr cm ^-1 : 3400 to 2300 (Br) 3104 3020 1720 1600 1
480 1424 13761284 1154 1050 970 836 768 670 558 ¹ H-NMR (60MHz, CDCl ₃ , δ): 3.04 (3H, S) 7.63 ~ 8.10
(3H, m)

(3) Synthesis of 4-methylsulfonyl-2-chlorobenzoic acid methyl ester 4-methylsulfonyl-2-chlorobenzoic acid (1.64 g, 7.0 mmo
l) was suspended in 20 ml of dry benzene, thionyl chloride (4.17 g, 7.0 × 5 mmol) and 0.05 ml of dry dimethylformamide were added thereto, and the mixture was stirred under reflux for about 1 hour. Then, excess thionyl chloride and benzene were distilled off under reduced pressure, 10 ml of dry methanol was added to the residue, and then triethylamine (0.78 g, 7.0 × 1.1 mmol) was added to the residue at room temperature.
Stir for hours. Then, methanol was distilled off under reduced pressure, and the residue was partitioned with ethyl acetate and water. The organic layer was washed with saturated saline and dried over sodium sulfate (anhydrous). Then, the solvent was distilled off to obtain 1.65 g (94.8%) of a white solid. m.
p .: 106-107 ° C IR KBr cm ^-1 : 1734 1322 1264 1160 1126 1102 1050 ¹ H-NMR (60MHz, CDCl ₃ , δ): 3.06 (3H, S) 3.96 (3H, S)
7.90-8.16 (3H, m)

Reference Example 2 Synthesis of 4-methylsulfonyl-3-methoxymethyl-2-methylbenzoic acid [Compound No. VII-2] (1) Synthesis of 2-methyl-3-nitrobenzyl alcohol 2-Methyl-3- T- Methyl nitrobenzoate (39g, 0.2mol)
After dissolving in 600 ml of butanol, sodium borohydride (19 g, 0.5 mol) was added, and 150 ml of methanol was added dropwise at reflux temperature over 1 hour. The reaction was completed by refluxing for another hour. After allowing to cool, water was added and the solvent was distilled off under reduced pressure. Water and chloroform were added to the residue, the organic layer was separated, dried over sodium sulfate (anhydrous), and the solvent was distilled off to give 2-methyl-3-nitrobenzyl alcohol 3.0.
I got 7g.

(2) Synthesis of 2-methyl-3-nitrobenzyl methyl ether 2-methyl-3-nitrobenzyl alcohol (30.1g, 0.18mo
l) is dissolved in 200 ml of benzene, then tetra-n-butylammonium bromide (0.2 g) and sodium hydroxide (20.1
50% aqueous solution of g) was sequentially added. Dimethylsulfuric acid (27.2 g) was added dropwise thereto at room temperature, and the mixture was further reacted for 3 hours with stirring. Water was added to the reaction solution, and the organic layer was separated, washed successively with water, a 2% hydrochloric acid aqueous solution, water and a saturated saline solution, and then the solvent was distilled off to give 2-methyl-3-nitrobenzyl methyl ether 30.9. got g. Oil

(3) Synthesis of 3-methoxymethyl-2-methylaniline 2-methyl-3-nitrobenzyl methyl ether (30.7 g, 0.
17 mol) in 200 ml of methanol and 92 ml of concentrated hydrochloric acid
Was gradually added. After that, iron powder (30.4g) was added at reaction temperature 6
The mixture was gradually added to 0 ° C. or lower, and the reaction was continued for 1 hour. Add 300 ml of water to the reaction mixture and add sodium hydroxide to pH.
Added until> 8. Chloroform was added to the obtained slurry and stirred sufficiently, and then the organic layer was separated from the filtrate. The obtained organic layer was washed successively with water and saturated brine and then dried over sodium sulfate (anhydrous). 3-methoxymethyl-2-methylaniline by distilling off the solvent 23.
I got 1g. Oil

(4) Synthesis of 3-methoxymethyl-2-methyl-4-thiocyanoaniline 3-methoxymethyl-2-methylaniline (22.6g, 0.15mo
l) was dissolved in 300 ml of methanol and sodium thiocyanate (36.5 g) was added to obtain a homogeneous solution. 0 this solution
After cooling to 0 ° C, a solution of bromine (25.2g) in 100 ml of sodium bromide saturated methanol was added dropwise so that the reaction temperature did not exceed 5 ° C. After completion of the dropping, the reaction was completed by stirring at 5 ° C. or lower for 1 hour and further at room temperature for 1 hour. The reaction solution was added to 1 L of water, neutralized with 5% aqueous sodium carbonate solution, and chloroform was added to extract oil. The chloroform layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure to obtain 29.6 g of the desired product.

(5) Synthesis of 3-methoxymethyl-2-methyl-4-methylthioaniline 3-methoxymethyl-2-methyl-4-thiocyanoaniline (2
9.1 g, 0.14 mol) was dissolved in 200 ml of ethanol and mixed with a 100 ml aqueous solution of sodium sulfide nonahydrate (33.6 g) at room temperature. Then, methyl iodide (21.9g) was added dropwise and the mixture was stirred at room temperature for 3
Reacted for hours. After completion of the reaction, the solvent was distilled off under reduced pressure,
Partitioned with water and chloroform. Then, the organic layer was washed successively with water and saturated brine and dried over sodium sulfate (anhydrous). After distilling off the solvent, 3-methoxymethyl-2-methyl-4-
25.6 g of methylthioaniline was obtained. Oil

(6) Synthesis of 3'-iodo-2'-methyl-6'-methylthiobenzyl methyl ether 3-methoxymethyl-2-methyl-4-methylthioaniline (2
5.6g, 0.13mol) was added with 100ml of water and 33ml of concentrated hydrochloric acid to make aniline hydrochloride, and this solution was cooled to 0 ° C, and 30ml of sodium nitrite (9.3g) aqueous solution was added at reaction temperature of 5 ° C.
It was added dropwise so as not to exceed the temperature. 30 more after dropping
The diazotization was completed by stirring for a minute. 100 ml of an aqueous solution of potassium iodide (33 g) was heated to 70 ° C., and the aqueous solution of the diazonium salt obtained above was gradually added to decompose. The reaction solution was stirred at 70 ° C. for another hour, allowed to cool, and partitioned with benzene. The benzene layer was washed successively with water, saturated aqueous sodium hydrogen sulfite solution, water and saturated brine, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain 30 g of 3'-iodo-2'-methyl-6'-methylthiobenzyl methyl ether. mp: 56 ~ 59 ℃

(7) Synthesis of 3-methoxymethyl-2-methyl-4-methylthiobenzoic acid 3'-iodo-2'-methyl-6'-methylthiobenzyl methyl ether (27.7 g, 0.09 mol) was dried. Tetrahydrofuran
After dissolving in 100 ml, 63 ml of a 1.5 M solution of n-butyllithium n-hexane was added dropwise at -70 ° C or lower. After dripping, 1
After stirring at the same temperature for 5 minutes, dry carbon dioxide gas was sufficiently blown in until the reaction liquid stopped generating heat. After completion of the reaction, the reaction solution was returned to room temperature and partitioned with water and diethyl ether.
The aqueous layer was washed twice more with diethyl ether, then concentrated hydrochloric acid was added to adjust the pH to <1. The precipitated solid was collected by filtration, washed with water, and dried to give 3-methoxymethyl-2-methyl-4-methylthio. 14.4 g of benzoic acid was obtained. mp: 192-194 ℃

(8) Synthesis of 4-methylsulfonyl-3-methoxymethyl-2-methylbenzoic acid 3-methoxymethyl-2-methyl-4-methylthiobenzoic acid (1
1.3 g, 0.05 mol) was added with 120 ml of acetic acid and 120 ml of 35% hydrogen peroxide solution and reacted at 80 ° C for 1 hour. After allowing to cool, the reaction solution was added to ice water, and the precipitated solid was collected by filtration, washed with water, and dried to obtain 12.3 g of 4-methylsulfonyl-3-methoxymethyl-2-methylbenzoic acid. mp: 129-131 ℃

Reference Example 3 Synthesis of 4-methylsulfonyl-3-methoxycarbonyl-2-methylbenzoic acid [Compound No. VII-3] (1) Synthesis of 3-amino-2-methylbenzoic acid methyl ester 2-methyl- Methyl 3-nitrobenzoate (40g) in methanol
It was dissolved in 120 ml and 157 g of concentrated hydrochloric acid was added. Followed by 6
Iron powder (36.8 g) was added little by little while keeping the temperature below 0 ° C. After stirring at room temperature for 4 hours, the mixture was poured into 1 L of ice water. This was neutralized with sodium carbonate and partitioned with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate (anhydrous), and then the solvent was evaporated to obtain 27.8 g of 3-amino-2-methylbenzoic acid methyl ester. Oil

(2) Synthesis of 3-amino-2-methyl-6-thiocyanobenzoic acid methyl ester 3-amino-2-methylbenzoic acid methyl ester (27.7 g),
Sodium thiocyanate (41.5g) and methanol 250
A solution of 100 ml of methanol saturated with sodium bromide and a solution of bromine (28.1 g) was slowly added dropwise thereto while keeping the solution of ml at 0 ° C or lower. After stirring at room temperature for 3 hours, the mixture was poured into 1 L of ice water. Then, after neutralizing with sodium carbonate and partitioning with chloroform, the organic layer was washed with saturated brine, sodium sulfate (anhydrous), the solvent was distilled off, and 3-amino-2-methyl-6-thiocyanobenzo was added. 34 g of acid methyl ester was obtained.
Oil

(3) Synthesis of 3-amino-2-methyl-6-methylthiobenzoic acid methyl ester To 100 ml of an aqueous solution of sodium sulfide nonahydrate (39.5 g), 3-amino-2-methyl-6-thiocyanobenzoic acid was added. A 300 ml ethanol solution of methyl ester (32.9 g) was added dropwise. At room temperature 1.
After stirring for 5 hours, methyl iodide (24 g) was added dropwise under ice cooling. After stirring at room temperature for another 2 hours, the mixture was concentrated under reduced pressure, partitioned between saturated saline and chloroform, and the organic layer was dried over sodium sulfate (anhydrous). Then, the solvent was distilled off to obtain 30.1 g of 3-amino-2-methyl-6-methylthiobenzoic acid methyl ester.

(4) Synthesis of 3-iodo-2-methyl-6-methylthiobenzoic acid methyl ester 3-Amino-2-methyl-6-methylthiobenzoic acid methyl ester (28 g) in concentrated hydrochloric acid 150 ml at room temperature Stir for hours to give the hydrochloride salt. While keeping the temperature below 0 ° C, 20 ml of an aqueous solution of sodium nitrite (11.9 g) was added dropwise to prepare a diazonium salt solution. 90m aqueous solution of potassium iodide (28.4g)
1 was kept at 80 ° C., and the diazonium salt solution prepared above was added dropwise thereto. After the dropping was completed, the mixture was stirred at 80 ° C for 15 minutes and allowed to cool. This was partitioned with chloroform, the organic layer was washed with aqueous sodium hydrogen sulfite solution, water, and dried over sodium sulfate (anhydrous). Then, the solvent was distilled off to obtain 40 g of 3-iodo-2-methyl-6-methylthiobenzoic acid methyl ester.
This was purified by silica gel column chromatography
36 g of oil was obtained.

(5) 3-methoxycarbonyl-2-methyl-4-
Synthesis of methylthiobenzoic acid 70 ml of a dry tetrahydrofuran solution of 3-iodo-2-methyl-6-methylthiobenzoic acid methyl ester (20 g) was maintained under nitrogen atmosphere at -60 ° C or lower, and n-butyllithium n
-42 ml of hexane solution (1.5M) was added dropwise. After 15 minutes, -50 ℃
Sufficient dry carbon dioxide was blown in while keeping the temperature below. Then, after removing carbon dioxide gas with nitrogen, diisopropylamine (12.7 g) was added dropwise, and the mixture was stirred until it reached room temperature. After concentration under reduced pressure, water was added and the mixture was washed with chloroform. The aqueous solution was acidified with concentrated hydrochloric acid and partitioned with chloroform. Then, the organic layer was washed with saturated saline and dried over sodium sulfate (anhydrous). Then, the solvent was distilled off to obtain 7.5 g of 3-methoxycarbonyl-2-methyl-4-methylthiobenzoic acid. mp: 178-178.5 ℃

(6) Synthesis of 4-methylsulfonyl-3-methoxycarbonyl-2-methylbenzoic acid 3-methoxycarbonyl-2-methyl-4-methylthiobenzoic acid (5 g), acetic acid 25 ml and hydrogen peroxide (35% , 25 ml) was stirred at 80 ° C. for 3 hours. After allowing the mixture to cool, it was poured into ice water and partitioned with chloroform. The organic layer was dried over sodium sulfate (anhydrous), the solvent was evaporated, and 4-methylsulfonyl-3-methoxycarbonyl-2-methylbenzoic acid 5.
I got 1g. mp: 151-152 ℃

Reference Example 4 Synthesis of 2-chloro-3-ethylthiomethyl-4-methylsulfonylbenzoic acid [VII-19] (1) Synthesis of 3-bromomethyl-2-chloro-4-methylsulfonylbenzoic acid methyl ester 2-Chloro-4-methylsulfonyl-3-methylbenzoic acid methyl ester (12.1 g) was dissolved in 250 ml of carbon tetrachloride and refluxed with stirring. Bromine (7.5 g) and benzoyl peroxide (1 g) were added to this little by little over 30 minutes, and 4 more
Heated to reflux for hours. After cooling, add 200 ml of chloroform and add 5
Washed with% aqueous sodium bisulfite. The organic layer was separated, dried over sodium sulfate (anhydrous), and the solvent was evaporated. The residue was washed with ether to obtain 13.2 g of 3-bromomethyl-2-chloro-4-methylsulfonylbenzoic acid methyl ester. mp: 77-78 ℃

(2) Synthesis of 2-chloro-3-ethylthiomethyl-4-methylsulfonylbenzoic acid methyl ester To 100 ml of tetrahydrofuran was added ethanethiol (1.3 g) and potassium carbonate (1.5 g), and then 3-bromomethyl- 2
-Chloro-4-methylsulfonylbenzoic acid methyl ester (4.4 g) was added and stirred for 1 day at room temperature. 1 hour 50
After stirring at -60 ° C, the mixture was cooled, chloroform was added, and the mixture was washed with dilute aqueous potassium carbonate. Separate the chloroform layer,
After drying over sodium sulfate (anhydrous), the solvent was distilled off to obtain 4.1 g of 2-chloro-3-ethylthiomethyl-4-methylsulfonylbenzoic acid methyl ester. Oil

(3) Synthesis of 2-chloro-3-ethylthiomethyl-4-methylsulfonylbenzoic acid 2-Chloro-3-ethylthiomethyl-4 was added to a mixture of 50 ml of 10% aqueous sodium hydroxide and 150 ml of methanol. -Methylsulfonylbenzoic acid methyl ester (3.9 g) was added, and the mixture was stirred at room temperature for 30 minutes. Methanol was distilled off under reduced pressure, and diluted hydrochloric acid was added to reprecipitate. Then, extract with ethyl acetate and dry over sodium sulfate (anhydrous), evaporate the solvent and wash with 2-chloro.
-3-ethylthiomethyl-4-methylsulfonylbenzoic acid 3.5 g
Got mp: 172-174 ℃

Reference Example 5 Synthesis of 2-chloro-4-methylsulfonyl-3-methoxymethylbenzoic acid [Compound No. VII-6] (1) 2-Chloro-4-methylsulfonyl-3-methoxymethylbenzoic acid methyl ester Synthesis of 3-bromomethyl-2-chloro-4-methylsulfonylbenzoic acid methyl ester (12 g) and methanol (100 ml) were added with a solution of sodium methoxide (1.7 g) in methanol (50 ml) and stirred at room temperature overnight. Then, after distilling off the solvent,
Dilute hydrochloric acid was added, and the mixture was partitioned with chloroform. The organic layer was washed with water and dried over sodium sulfate (anhydrous), then the solvent was distilled off to obtain 9.5 g of crude 2-chloro-4-methylsulfonyl-3-methoxymethylbenzoic acid. This was purified by silica gel column chromatography to obtain 7.5 g of the desired product. Oil

(2) Synthesis of 2-chloro-4-methylsulfonyl-3-methoxymethylbenzoic acid A solution of 2-chloro-4-methylsulfonyl-3-methoxymethylbenzoic acid methyl ester (3 g) and 20 ml of methanol in water. An aqueous solution of sodium oxide (93%, 0.57 g, water 2 ml) was added, and the mixture was stirred at room temperature for 30 minutes. After adding 10 ml of water and concentrating under reduced pressure,
Dilute hydrochloric acid was added, and the mixture was partitioned with chloroform. After drying the organic layer over sodium sulfate (anhydrous), the solvent was distilled off to give 2-
Chloro-4-methylsulfonyl-3-methoxymethylbenzoic acid
Obtained 2.6 g. mp: 137 ~ 141 ℃

Reference Example 6 Synthesis of 2-chloro-3- (methoxyethoxy) -4-ethylsulfonylbenzoic acid ethyl ester [Compound No. III-20] (1) 2,4-dichloro-3-hydroxybenzoic acid ethyl ester In a 1 liter, 3-neck flask fitted with a synthetic mechanical stirrer, condenser, thermometer and diffusion tube, 3-hydroxybenzoic acid ethyl ester (106g, 0.64
mol) and a solution of diisopropylamine (0.5 g) in 600 ml of dichloroethane were added under reflux. Chlorine (112g,
1.6 mol) was added through a diffusion tube over 6 hours and cooled to room temperature. After cooling, it was washed with 200 ml of 5% sodium bisulfite solution, then 200 ml of water and dried. Yield 9
9.6g, 66% yield

(2) Synthesis of 2,4-dichloro-3- (2-methoxyethoxy) benzoic acid ethyl ester 2,4-dichloro-3-hydroxybenzoic acid ethyl ester (18 g, 77 mmol) and 22 g (3 equivalents) ) 2-chloroethyl methyl ether and potassium carbonate (22 g, 77 × 2 mmol), about
8 in 100 ml DMF in the presence of 0.5 g sodium iodide
Heated at 0 ° C. for 1.5 hours. To the cooled solution was added 400 ml ether. 100 ml of water (twice) with 100 ml of organic layer
Wash with% sodium hydroxide and 100 ml 10% hydrochloric acid.
Then dried to obtain 20 g of product.

(3) 2-chloro-3- (methoxyethoxy) -4-
Synthesis of ethylthiobenzoic acid ethyl ester 2,4-dichloro-3- (2-methoxyethoxy) benzoic acid ethyl ester (10 g, 34 mmol) in DMF was treated with ethanethio-
(10g, 34 × 4mmol) and potassium carbonate (10g, 34 × 2mmo
l) In the presence of 100 ml of DMF, heated at 100 ° C. for 2 hours and then allowed to cool overnight. To this, add 400 ml of diethyl ether, 100 ml of water (twice) and 100 ml of 10% hydrochloric acid, then 100 ml.
Sequentially washed with 10% sodium hydroxide. Then, it dried and the oily substance was obtained. Yield 10g, yield 46%

(4) 2-chloro-3- (2-methoxyethoxy)
Synthesis of 4-Ethylsulfonylbenzoic Acid Ethyl Ester 2-Chloro-3- (methoxyethoxy) -4-ethylthiobenzoic acid ethyl ester (10 g, 31 mmol) was dissolved in 100 ml of methylene chloride and cooled on an ice bath. Then m-chloroperbenzoic acid (purity 85%, 18 g, 31 x 2.2 mmol) was added portionwise over 2 hours. The crude reaction mixture was left to warm to room temperature. After 1 hour, excess peracid was decomposed with sodium bisulfite (100 ml, 5% solution) at room temperature. The organic layer was washed twice with 5% sodium hydroxide, then sodium sulfate (anhydrous)
After drying, the solvent was distilled off to obtain a viscous oily substance.
Yield 11.3g, 72% yield

Reference Example 7 Synthesis of 4-methylsulfonyl-3-methoxymethyl-2-methylbenzoic acid methyl ester [Compound No. III-2] (1) Synthesis of 2-methyl-3-nitrobenzyl alcohol 2-methyl- Methyl 3-nitrobenzoate (39g, 0.2mol) t-
After dissolving in 600 ml of butanol, sodium borohydride (19 g, 0.2 × 1.2 mol) was added, and 150 ml of methanol was added dropwise at reflux temperature over 1 hour. The reaction was completed by refluxing for another hour. After allowing to cool, water was added and the solvent was distilled off under reduced pressure. Water and chloroform were added to the residue, the organic layer was separated, dried over sodium sulfate (anhydrous), and the solvent was distilled off to obtain 3.07 g of 2-methyl-3-nitrobenzyl alcohol.

(2) Synthesis of 2-methyl-3-nitrobenzyl methyl ether 2-methyl-3-nitrobenzyl alcohol (30.1g, 0.18mo
l) is dissolved in 200 ml of benzene, then tetra-n-butylammonium bromide (0.2 g) and sodium hydroxide (20.1
50% aqueous solution of g) was sequentially added. Then, dimethylsulfate (27.2 g) was added dropwise at room temperature, and the mixture was further reacted for 3 hours with stirring. Water was added to the reaction solution, and the organic layer was separated, washed successively with water, a 2% hydrochloric acid aqueous solution, water and a saturated saline solution, and then the solvent was distilled off to give 2-methyl-3-nitrobenzyl methyl ether 30.9. got g. Oil

(3) Synthesis of 3-methoxymethyl-2-methylaniline 2-methyl-3-nitrobenzyl methyl ether (30.7 g, 0.
17 mol) in 200 ml of methanol and 92 ml of concentrated hydrochloric acid
Was gradually added. After that, iron powder (30.4g) was added at reaction temperature 6
The mixture was gradually added to 0 ° C. or lower, and the reaction was continued for 1 hour. Add 300 ml of water to the reaction mixture and add sodium hydroxide to pH.
Added until> 8. Chloroform was added to the obtained slurry and stirred sufficiently, and then the organic layer was separated from the filtrate. The organic layer was washed successively with water and saturated saline and then dried over sodium sulfate (anhydrous). By distilling the solvent off, 23.1 g of 3-methoxymethyl-2-methylaniline was obtained.
Oil

(4) Synthesis of 3-methoxymethyl-2-methyl-4-thiocyanoaniline 3-methoxymethyl-2-methylaniline (22.6g, 0.15mo
l) was dissolved in 300 ml of methanol, and sodium thiocyanate (36.5 g) was added to make a uniform solution. The temperature is 0 ℃
After cooling to 100 ml of bromine (25.2 g) saturated with sodium bromide in 100 ml of methanol was added dropwise so that the reaction temperature did not exceed 5 ° C. After completion of the dropping, the reaction was completed by stirring at 5 ° C. or lower for 1 hour and further at room temperature for 1 hour. The reaction solution was added to 1 L of water, neutralized with 5% aqueous sodium carbonate solution, and chloroform was added to extract oil. The chloroform layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 29.6 g of the desired product.

(5) Synthesis of 3-methoxymethyl-2-methyl-4-methylthioaniline 3-methoxymethyl-2-methyl-4-thiocyanoaniline (2
9.1 g, 0.14 mol) was dissolved in 200 ml of ethanol and mixed with a 100 ml aqueous solution of sodium sulfide nonahydrate (33.6 g) at room temperature. Then, methyl iodide (21.9g) was added dropwise and the mixture was stirred at room temperature for 3
Reacted for hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was partitioned with water and chloroform. Then, the organic layer was washed successively with water and saturated brine and dried over sodium sulfate (anhydrous). The solvent was distilled off to obtain 25.6 g of 3-methoxymethyl-2-methyl-4-methylthioaniline. Oil

(6) Synthesis of 3'-iodo-2'-methyl-6'-methylthiobenzyl methyl ether 3-methoxymethyl-2-methyl-4-methylthioaniline (2
5.6g, 0.13mol) was added with 100ml of water and 33ml of concentrated hydrochloric acid to make aniline hydrochloride, and this solution was cooled to 0 ℃, and 30ml of sodium nitrite (9.3g) aqueous solution was added at reaction temperature of 5 ℃.
It was added dropwise so as not to exceed the temperature. 30 more after dropping
The diazotization was completed by stirring for a minute. 100 ml of an aqueous solution of potassium iodide (33 g) was heated to 70 ° C., and the aqueous solution of the diazonium salt obtained above was gradually added to decompose. The reaction solution was stirred at 70 ° C. for another hour, allowed to cool, and partitioned with benzene. The benzene layer was washed successively with water, saturated aqueous sodium hydrogen sulfite solution, water and saturated brine, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain 30 g of 3'-iodo-2'-methyl-6'-methylthiobenzyl methyl ether. mp: 56 ~ 59 ℃

(7) Synthesis of 3-methoxymethyl-2-methyl-4-methylthiobenzoic acid 3-iodo-2-methyl-6-methylthiobenzyl methyl ether (27.7 g, 0.09 mol) was dried in 100 ml of tetrahydrofuran.
Then, n-butyllithium (63 ml of 1.5 M n-hexane solution) was added dropwise at -70 ° C or lower. After completion of dropping, the mixture was stirred for 15 minutes at the same temperature. Thereafter, dry carbon dioxide gas was sufficiently blown in until the heat generation of the reaction liquid stopped. After completion of the reaction, the reaction solution was returned to room temperature and partitioned with water and diethyl ether.
The aqueous layer was washed twice more with diethyl ether, then concentrated hydrochloric acid was added to bring the pH to <1. The precipitated solid was collected by filtration, washed with water, and dried to give 3-methoxymethyl-2-methyl-4-methylthio. 14.4 g of benzoic acid was obtained. mp: 192-194 ℃

(8) Synthesis of 4-methylsulfonyl-3-methoxymethyl-2-methylbenzoic acid 3-methoxymethyl-2-methyl-4-methylthiobenzoic acid (1
1.3g, 0.05mol), acetic acid 120ml and 35% hydrogen peroxide solution 1
20 ml was added and reacted at 80 ° C. for 1 hour. After cooling, the reaction solution was added to ice water, and the precipitated solid was collected by filtration, washed with water, and dried to obtain 12.3 g of 4-methylsulfonyl-3-methoxymethyl-2-methylbenzoic acid. mp: 129-131 ℃

(9) 3- (methoxymethyl) -2-methyl-4-
(Methylsulfonyl) Synthesis of benzoic acid methyl ester 3- (methoxymethyl) -2-methyl-4- (methylsulfonyl)
Benzoic acid (1.736 g, 6.72 mmol) was mixed with 50 ml of dry benzene, and a catalytic amount of dry DMF and thionyl chloride (2.4 g, 6.72 × 3 mmol) were added thereto, and the mixture was heated under reflux for 1.5 hours. Then, benzene and excess thionyl chloride were completely distilled off. 30 ml of dry dichloromethane was added to the residue, and then excess dry methanol and triethylamine (0.71 g,
3.94 × 1.05 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. Then, the reaction solution was concentrated, and the residue was partitioned with ethyl acetate and water. The organic layer was washed with saturated saline and dried over sodium sulfate (anhydrous). Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography. Light yellow viscous substance, yield 1.46 g, yield 79.8% IR NaCl liq.film cm ^-1 : 2940 1732 1444 1310 1202 11
32 1092 1056 760 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.56 (3H, S, aromatic ring CH ₃ )
3.14 (3H, S, SO ₂ CH ₃ ) 3.45 (3H, S, OCH ₃ ) 3.86 (3H, S, COO
CH ₃ ) 4.9 (2H, S, CH ₂ ) 7.71 (1H, d, J = 8Hz, aromatic ring H) 8.
00 (1H, d, J = 8Hz, aromatic ring H)

Reference Example 8 Synthesis of 2-methyl-3- (methoxycarbonyl) -4-methylsulfonylbenzoic acid methyl ester [Compound No. III-3] (1) (3-Amino-2-methyl) benzoic acid methyl ester Synthesis of 3-nitro-2-methylbenzoic acid methyl ester (15g, 0.076
(8 mol) was dissolved in 86 ml of methanol, and 42 ml of concentrated hydrochloric acid was gradually added thereto. After that, iron powder (13.73g, 0.0768 × 3.2mo
l) is gradually added so that the reaction temperature is 60 ° C or lower,
The reaction was continued for 1 hour. 130 ml of water was added to the reaction solution, and sodium hydroxide was added until pH> 8. Chloroform was added to the obtained slurry and stirred sufficiently, and then the organic layer was separated from the filtrate. The organic layer was washed successively with water and saturated saline and then dried over sodium sulfate (anhydrous).
The target substance was obtained by distilling off the solvent. Oily substance, yield 6.87 g, yield 54.1% IR NaCl liq.film cm ⁻¹ : 3492 3404 2960 1714 1636 15
96 1472 1312 1216 1066 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.26 (3H, S, aromatic ring CH ₃ ).
3.7 (2H, S, NH ₂ ) 3.78 (3H, S, COOCH ₃ ) 6.53 ~ 7.13 (3H,
m, aromatic ring H × 3)

(2) Synthesis of (3-amino-2-methyl-6-thiocyano) benzoic acid methyl ester 3-Amino-2-methylbenzoic acid methyl ester (6.87 g, 0.
(0416 mol) was dissolved in 88 ml of methanol, and then sodium thiocyanate (10.3 g, 0.0416 × 3.06 mol) was added to make a uniform solution. After cooling the temperature to 0 ° C, bromine (6.97
g, 0.0416 x 1.048 mol) in saturated sodium bromide in methanol was added dropwise so that the reaction temperature did not exceed 5 ° C. After dropping, the mixture was stirred at room temperature for 3 hours. Then, the reaction solution was poured into ice water. Then, it was neutralized with a 5% aqueous sodium carbonate solution and extracted with chloroform. The chloroform layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography. White solid, mp: 66-8 ° C., yield 6.37 g, yield 68.9% IR KBr cm ⁻¹ : 3428 3360 3260 2160 1734 1646 1584 14
66 1322 1256 818 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.0 (3H, S, aromatic ring CH ₃ ) 3.
9 (3H, S, COOCH ₃ ) 4.16 (2H, brs, NH ₂ ) 6.56 (1H, d, J = 8H
z, aromatic ring H) 7.21 (1H, d, J = 8Hz, aromatic ring H)

(3) Synthesis of (3-amino-2-methyl-6-methylthio) benzoic acid methyl ester 18 ml of sodium sulfide nonahydrate (6.94 g, 0.0262 × 1.1 mol)
A solution of 3-amino-2-methyl-6-methylthiobenzoic acid methyl ester (5.84 g, 0.0262 mol) in 53 ml of ethanol was added dropwise to the aqueous solution. The mixture was stirred at room temperature for 1.5 hours, concentrated under reduced pressure, and partitioned with saturated brine and chloroform. Then, the organic layer was dried over sodium sulfate (anhydrous) and concentrated. The residue was purified by silica gel column chromatography to obtain a liquid. Light yellow liquid, yield 5.47 g, yield 98.9% IR NaCl liq.film cm ^-1 : 3496 3400 3256 3000 2960 29
32 1730 16361590 1472 1320 1252 1042 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.0 (3H, S, SCH ₃ or aromatic ring C
H ₃ ) 2.3 (3H, S, SCH ₃ or aromatic ring CH ₃ ) 3.86 (3H, S, COOC
H ₃ ) 3.55 to 3.93 (2H, br, NH ₄ ) 6.53 (1H, d, J = 8Hz, aromatic ring H) 7.13 (1H, d, J = 8Hz, aromatic ring H)

(4) Synthesis of (2-methyl-6-methylthio-3-iodo) benzoic acid methyl ester 3-Amino-2-methyl-6-methylthiobenzoic acid methyl ester (5.4 g, 0.0255 mol) was added to water. 19.5 ml and concentrated hydrochloric acid 6.44 ml were added, and the mixture was stirred at room temperature for 1 hour. This solution was cooled to 0 ° C., and 5.8 ml of an aqueous solution of sodium nitrite (1.83 g, 0.0255 × 1.03 mol) was added dropwise so that the reaction temperature did not exceed 5 ° C. After completion of the dropping, the mixture was stirred for additional 30 minutes to complete the diazotization. Separately, potassium iodide (6.5g, 0.0255 × 1.53mo
19.5 ml of the aqueous solution of l) was heated to 70 ° C., and the aqueous solution of the diazonium salt obtained above was gradually added to decompose. Reaction liquid 70
The mixture was stirred at 0 ° C for additional 15 minutes, allowed to cool, and partitioned with ethyl acetate and water. Next, the organic layer was washed successively with a saturated aqueous sodium hydrogen sulfite solution and saturated brine, dried over sodium sulfate (anhydrous), and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain the desired product. Light yellow liquid, yield 6.17 g, yield 75.1% IR NaCl liq. Film cm ^-1 : 1734 1434 1266 1178 1088 7
88 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.30 (3H, S, SCH ₃ or aromatic ring
CH ₃ ) 2.36 (3H, S, SCH ₃ or aromatic ring CH ₃ ) 3.86 (3H, S, COOC
H ₃ ) 6.86 (1H, d, J = 8Hz, aromatic ring H) 7.73 (1H, d, J = 8Hz,
Aromatic ring H)

(5) 2-methyl-3- (methoxycarbonyl)
Synthesis of 4-methylthiobenzoic acid A solution of (2-methyl-6-methylthio-3-iodo) benzoic acid methyl ester (6g, 18.6mmol) in dry THF (50ml) was kept under nitrogen atmosphere at -60 ° C or below. n-Butyllithium (1.59mol / L hexane solution 13.1ml, 18.6 × 1.1mmol)
Was dripped. After 15 minutes, sufficient carbon dioxide gas was blown in while keeping the temperature below -50 ° C. Then, the reaction solution was returned to room temperature and partitioned with water and ether. Unreacted raw materials were collected in the organic layer. The aqueous layer was then brought to pH <1 with concentrated hydrochloric acid and extracted with ethyl acetate. Then, it was washed with saturated saline and dried over sodium sulfate. The solvent was concentrated to give a red solid. Yield 0.83 g, 18.3% IR KBr cm ^-1 : 3000 to 2500 1734 1690 1584 1310 1258 1
188

(6) 2-Methyl-3-methoxycarbonyl-4-
Synthesis of methylsulfonylbenzoic acid 2-methyl-3- (methoxycarbonyl) -4-methylthiobenzoic acid (8g, 3.35mmol), acetic acid 6.8ml and hydrogen peroxide (35%,
6.8 ml) was stirred at 80 ° C. for 3 hours. After allowing to cool, it was poured into ice water and partitioned with chloroform. The organic layer was dried over sodium sulfate (anhydrous) and the solvent was evaporated to give 2-methyl-3-methoxycarbonyl-4-methylsulfonibenzoic acid. Light yellow solid, yield 0.585 g, yield 64.6% IR KBr cm ^-1 : 3476 1725 1710 1652 1322 1262

(7) 2-methyl-3-methoxycarbonyl-4-
Synthesis of Methylsulfonylbenzoic Acid Methyl Ester 2-Methyl-3-methoxycarbonyl-4-methylsulfonylbenzoic acid (0.585g, 2.14mmol) in 20ml of dry benzene and thionyl chloride (0.47ml, 2.14x3mmol) in catalytic amount The mixture was stirred at 85 ° C for 1 hour in the presence of dry DMF (2 to 3 drops).
Then, benzene and an excess of thionyl chloride were concentrated, dry methanol under water cooling was added to the residue in a large excess, triethylamine (0.26 g, 2.14 × 1.2 mmol) was subsequently added, and the mixture was stirred for 1 hour. Then, the methanol of the reaction solution was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated saline and dried over sodium sulfate (anhydrous),
The solvent was concentrated and the residue was purified by silica gel column chromatography. Pale yellow mucilage, yield 0.4g, yield 65.0% IR NaCl liq.film cm ^-1 : 1736 1726 1440 1248 1216 11
82 1156 11161044 980 788 760 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.53 (3H, S, aromatic ring CH ₃ )
3.11 (3H, S, SO ₂ CH ₃ ) 3.89 (3H, S, COOCH ₃ ) 3.90 (3H, S, C
OOCH ₃ ) 7.93 (2H, S, aromatic ring H × 2)

Reference Example 9 2-Chloro-3- (methoxymethyl) -4- (methylsulfonyl)
Synthesis of methyl benzoate [Compound No. III-6] (1) Synthesis of 2-chloro-3-nitrobenzyl alcohol Methyl 2-chloro-3-nitrobenzoate (40g, 0.185mol)
After dissolving in 500 ml of t-butanol, sodium borohydride (17.5 g, 0.185 × 2.5 mol) was added, and further 50 ml × 2 of methanol was added dropwise at reflux temperature over 2 hours. The reaction was completed by refluxing for another hour. After cooling, water was added and the solvent was distilled off under reduced pressure. Water and chloroform were added to the residue, the organic layer was separated, dried over sodium sulfate (anhydrous), and the solvent was distilled off to obtain 37.9 g of 2-chloro-3-nitrobenzyl alcohol. This was purified by silica gel column chromatography to obtain 26.9 g (57.26%) of liquid. ¹ H-NMR (60MHz, CDCl ₃ , δ): 4.88 (2H, S, CH ₂ OH) 7.42〜
7.53 (1H, m, aromatic ring H) 7.71 to 7.81 (2H, m, aromatic ring H) OH
Ambiguous

(2) Synthesis of (2-chloro-3-nitrophenyl) methoxymethane 2-chloro-3-nitrobenzyl alcohol (15g, 0.079mo
l) was dissolved in 88 ml of benzene, and then a 50% aqueous solution of tetra-n-butylammonium bromide (0.088 g) and sodium hydroxide (8.92 g, 0.079 × 2.79 mol) was sequentially added.
Then, at room temperature, dimethylsulfate (12.1g, 0.079 × 1.19mo
l) was added dropwise, and the mixture was reacted for 3 hours with stirring. Water was added to the reaction solution, the organic layer was separated, and then water, a 2% hydrochloric acid aqueous solution,
The target product was obtained by successively washing with water and saturated saline, and then distilling off the solvent. Oily substance, crude yield 16 g, crude yield 99.4% IR NaCl liq.film cm ^-1 : 2940 2888 1602 1536 1438 13
58 1118 800 740 ¹ H-NMR (60MHz, CDCl ₃ , δ): 3.43 (3H, S, OCH ₃ ) 4.53 (2
H, S, OCH ₂ ) 7.16 to 7.81 (3H, m, aromatic ring)

(3) Synthesis of (2-chloro-3-methoxymethyl) phenylamine (2-chloro-3-nitrophenyl) methoxymethane (14.7
8 g, 0.073 mol) was dissolved in 86 ml of methanol, and 40 ml of concentrated hydrochloric acid was gradually added thereto. After that, iron powder (13.1g, 0.073 ×
3.2 mol) was gradually added so that the reaction temperature was 60 ° C. or lower, and the reaction was further performed for 1 hour. Add 130 ml of water to the reaction mixture,
Sodium hydroxide was added until pH> 8. Chloroform was added to the obtained slurry, and after sufficiently stirring,
The organic layer was separated from the filtrate. The organic layer was washed successively with water and saturated saline and then dried over sodium sulfate (anhydrous). 2-Chloro-3-methoxymethylaniline was obtained by distilling off the solvent. Red oil, yield 10.14 g, yield 80.6% IR NaCl liq.film cm ^-1 : 3496 3384 2936 1622 1474 13
20 1198 1094 1040 776 ¹ H-NMR (60MHz, CDCl ₃ , δ): 3.31 (3H, S, OCH ₃ ) 3.63〜
4.13 (2H, brs, NH ₂ ) 4.38 (2H, S, OCH ₂ ) 6.35 ~ 7.06 (3H,
m, aromatic ring H × 3)

(4) Synthesis of (2-chloro-3-methoxymethyl-4-thiocyano) phenylamine 2-chloro-3-methoxymethylaniline (10.2g, 0.0594m
ol) was dissolved in 88 ml of methanol, and sodium thiocyanate (36.5 g) was added to make a uniform solution. After cooling it to 0 ℃, add sodium bromide saturated methanol solution containing bromine (9.96g, 0.0594 × 1.048mol) to the reaction temperature of 5 ℃.
It was dropped so that it would not exceed. After dropping, the mixture was stirred at room temperature for 3 hours. Then, the reaction solution was poured into ice water. Then, the mixture was neutralized with a 5% sodium carbonate aqueous solution, chloroform was added, and the oil was extracted. The chloroform layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product. Solid, crude yield 11.28 g, yield 82.9% ¹ H-NMR (60 MHz, CDCl ₃ ,
δ): 3.38 (3H, S, OCH ₃ ) 4.06 to 4.80 (2H, bs, NH ₂ ) 4.7
1 (2H, S, OCH ₂ ) 6.73 (1H, d, J = 8Hz, aromatic ring H) 7.43 (1
H, d, J = 8Hz, aromatic ring H)

(5) Synthesis of 2-chloro-3-methoxymethyl-4-methylthiophenylamine 2-chloro-3-methoxymethyl-4-thiocyanophenylamine (11.28 g, 0.0493 mol) was dissolved in 100 ml of ethanol. ,
It was mixed with a 33 ml aqueous solution of sodium sulfide nonahydrate (13 g, 0.0493 × 1.1 mol) at room temperature for 1.5 hours. Then, methyl iodide (7.98g, 0.0493 × 1.14mol) was added dropwise under ice-cooling at room temperature.
The reaction was carried out for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was partitioned with water and chloroform. The organic layer is then water,
It was washed successively with saturated saline and dried over sodium sulfate (anhydrous). After evaporating the solvent, the desired product was obtained. Oil, crude yield 7.04 g, crude yield 65.6% IR NaCl liq.film cm ^-1 : 3496 3376 2928 1624 1468 13
16 11001 810 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.3 (3H, S, SCH ₃ ) 3.36 (3
H, S, OCH ₃ ) 3.86 to 4.28 (2H, brs, NH ₂ ) 4.71 (2H, S, OCH ₂ )
6.53 (1H, d, J = 8Hz, aromatic ring H) 7.06 (1H, d, J = 8Hz, aromatic ring H)

(6) Synthesis of (2-chloro-3-iodo-6-methylthiophenyl) methoxymethane 2-chloro-3-methoxymethyl-4-methylthiophenylamine (6.21 g, 0.0285 mol) was added to concentrated hydrochloric acid (32 ml). Was added and stirred at room temperature for 2 hours. This solution was cooled to 0 ° C., and 4 ml of an aqueous solution of sodium nitrite (2.56 g, 0.028 × 1.3 mol) was added dropwise so that the reaction temperature did not exceed 5 ° C. After the dropwise addition was completed, stirring was continued for 15 minutes to complete the diazotization. Separately
19m aqueous solution of potassium iodide (6.1g, 0.0285 × 1.29mol)
l was heated to 80 ° C., and the aqueous solution of the diazonium salt obtained above was gradually added to decompose. The reaction solution was stirred at 80 ° C. for another 15 minutes, allowed to cool, and partitioned with chloroform. Next, the organic layer was washed successively with a saturated aqueous sodium hydrogen sulfite solution and saturated brine, dried over sodium sulfate (anhydrous), and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain the desired product. Light yellow solid, mp: 50-51 ° C, yield 5.94 g, yield 63.4% IR KBr cm ^-1 : 2984 2928 1430 1374 1208 1102 1192 95
2 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.43 (3H, S, SCH ₃ ) 3.38 (3
H, S, OCH ₃ ) 4.76 (2H, S, OCH ₂ ) 6.86 (1H, d, J = 8Hz, aromatic ring H) 7.73 (1H, d, J = 8Hz, aromatic ring H)

(7) Synthesis of 2-chloro-3- (methoxymethyl) -4-methylthiobenzoic acid (2-chloro-3-iodo-6-methylthiophenyl) methoxymethane (5.44 g, 0.0165 mol) Dry tetrahydrofuran
After dissolving in 50 ml, n-butyllithium (1.5 M n-hexane solution, 63 ml, 0.0165 × 1.1 mol) was added dropwise at −70 ° C. or lower. After completion of dropping, the mixture was stirred for 15 minutes at the same temperature. afterwards,
Dry carbon dioxide was thoroughly blown in until the reaction liquid stopped generating heat. After completion of the reaction, the reaction solution was returned to room temperature and partitioned with water and diethyl ether. The aqueous layer was washed twice more with diethyl ether, then concentrated hydrochloric acid was added to adjust the pH to <1 and this was extracted with ethyl acetate. The extract layer was washed with saturated saline,
It was dried over sodium sulfate (anhydrous). Then, the solvent was distilled off to obtain a solid. White solid, mp: 157-159 ° C., yield 1.16 g, yield 28.4% IR KBr cm ⁻¹ : 2932 2816 1690 1582 1418 1310 1110

(8) 2-chloro-3- (methoxymethyl) -4-
Synthesis of (methylsulfonyl) benzoic acid 2-chloro-3- (methoxymethyl) -4-methylthiobenzoic acid (1.1 g, 4.46 mmol) in acetic acid 9.1 ml, 35% hydrogen peroxide water 9.1 m
l was added and reacted at 80 ° C. for 3 hours. After allowing to cool, the reaction solution was poured into ice water, extracted with ethyl acetate, and the extracted layer was washed with saturated saline. Then dried over sodium sulfate (anhydrous),
The solvent was concentrated. Viscous material, crude yield 1.1 g, crude yield 88.7% IR NaCl liq.film cm ^-1 : 2944 1712 1382 1314 1146 10
98

(9) 2-chloro-3- (methoxymethyl) -4-
Synthesis of (methylsulfonyl) benzoic acid methyl ester 2-chloro-3- (methoxymethyl) -4- (methylsulfonyl)
Benzoic acid (1.1 g, 3.94 mmol) was mixed with 50 ml of dry benzene, to which a catalytic amount of dry DMF and thionyl chloride (1.4 g, 3.94 × 3 mmol) were added, and the mixture was heated under reflux for 1.5 hours. Then, benzene and excess thionyl chloride were completely distilled off. To the residue was added 30 ml of dry dichloromethane, then excess dry methanol and triethylamine (0.43 g,
3.94 × 1.1 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. Then, the reaction solution was concentrated, and the residue was partitioned with ethyl acetate and water. The organic layer was washed with saturated saline and dried over sodium sulfate (anhydrous). Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography. Light yellow viscous product, yield 0.63 g, yield 54.8% IR NaCl liq.film cm ^-1 : 2940 1742 1438 1382 1310 11
46 1100 750 ¹ H-NMR (60MHz, CDCl ₃ , δ): 3.20 (3H, S, SO ₂ CH ₃ ) 3.46
(3H, S, OCH ₃ ) 3.91 (3H, S, COOCH ₃ ) 5.06 (2H, S, CH ₂ ) 7.
70 (1H, d, J = 8Hz, aromatic ring H) 8.06 (1H, d, J = 8Hz, aromatic ring H)

Reference Example 10 Synthesis of 2-chloro-3- (methoxycarbonyl) -4-methylsulfonylbenzoic acid methyl ester [Compound No. III-7] (1) of 2-chloro-3-amino-benzoic acid methyl ester Synthetic 2-chloro-3-nitrobenzoic acid methyl ester (10.3g, 4
7.7 mmol) was dissolved in 31 ml of toluene, 41 ml of water and reduced iron (7.8 g, 47.7 × 2.93 mmol) were added, and the mixture was heated to 110 ° C. To this, 0.735 ml of acetic acid was added, and the mixture was stirred with heating at the same temperature for 3 hours. Then, it was brought to room temperature and filtered through a glass filter covered with Celite. The filter cake was washed with 50 ml of toluene, and then the filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with saturated saline. Then dried over sodium sulfate (anhydrous),
The solvent was evaporated to give 2-chloro-3-aminobenzoic acid methyl ester. Pale yellow oil Yield 8.5g Yield 95.9% IR NaCl liq. Film cm ^-1 : 3500 3400 1724 1624 1460 1
330 1292 1270 1208 756 ¹ H-NMR (60MHz, CDCl ₃ , δ): 3.76 (3H, S, COOCH ₃ ) 4.0〜
4.51 (2H, bs, NH ₂ ) 6.50 ~ 7.08 (3H, m, aromatic ring H × 3)

(2) Synthesis of 3-amino-2-chloro-6-cyanothiobenzoic acid methyl ester 3-amino-2-chlorobenzoic acid methyl ester (13.5 g, 7
2.74mmol), sodium thiocyanate (18.04g, 72.74
A solution of 48 ml of methanol saturated with sodium bromide and a solution of bromine (12.2 g, 72.74 x 1.048) was slowly added dropwise while the solution of 108 ml of methanol (x3.06 mmol) and 108 ml of methanol was kept at 0 ° C or lower. After stirring at room temperature for 4 hours, the mixture was poured into 0.5 L of ice water.
Then, the mixture was neutralized with sodium carbonate, partitioned with chloroform, the organic layer was washed with saturated brine, dried over sodium sulfate (anhydrous), and the solvent was distilled off to obtain a solid. This is purified by silica gel column chromatography to give 3-amino-2-
Methyl-6-thiocyanobenzoic acid methyl ester was obtained. White solid, mp: 76-8 ° C., yield 19.7 g, yield 100% IR KBr cm ⁻¹ : 3504 3404 1730 1630 1584 1472 1270 ¹ H-NMR (60 MHz, CDCl ₃ , δ): 3.96 (3H, S, OCH ₃ ) 4.73 (2
H, S, NH ₂ ) 6.73 (1H, d, J = 8Hz, aromatic ring H) 7.36 (1H, d, J = 8
Hz, aromatic ring H)

(3) Synthesis of 3-amino-2-chloro-6-methylthiobenzoic acid methyl ester To 49 ml of an aqueous solution of sodium sulfide decahydrate (19.6 g, 72.5 × 1.1 mmol) was added 3-amino-2-chloro- 6-Cyanothiobenzoic acid methyl ester (17.6g, 72.5mmol) in ethanol 147
ml was added dropwise. After stirring at room temperature for 1.5 hours, methyl iodide (11.7 g, 72.5 × 1.14 mmol) was added dropwise under ice cooling. After stirring at room temperature for another 2 hours, the mixture was concentrated under reduced pressure, partitioned between saturated saline and chloroform, and the organic layer was dried over sodium sulfate (anhydrous). Then, the solvent was distilled off to obtain 18.3 g of a crude solid of 3-amino-2-methyl-6-methylthiobenzoic acid methyl ester. This was recrystallized from ethyl acetate to obtain 7.5 g of white crystals. Further, the recrystallized filtrate was concentrated and purified by silica gel column chromatography to obtain 7.26 g of the desired product, and a total amount of 14.76 g (yield 87.8%). White solid, mp: 69-70 ° C IR KBr cm ^-1 : 3496 3396 1716 1630 1472 1340 1262 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.31 (3H, S, SCH ₃ ) 3.91 (3
H, S, COOCH ₃ ) 4.00 to 4.36 (2H, bs, NH ₂ ) 6.70 (1H, d, J = 9H
z, aromatic ring H) 7.21 (1H, d, J = 9Hz, aromatic ring H)

(4) Synthesis of 2-chloro-3-iodo-6-methylthiobenzoic acid methyl ester 3-Amino-2-chloro-6-methylthiobenzoic acid methyl ester (14.48 g, 62.5 mmol) in concentrated hydrochloric acid The mixture was stirred in 70 ml at room temperature for 2 hours to give a hydrochloride. While keeping this below 0 ℃,
9 ml of an aqueous solution of sodium nitrite (5.6 g, 62.5 x 1.3 mmol)
Was added dropwise to prepare a diazonium salt solution. Separately, add 42 ml of an aqueous solution of potassium iodide (13.4 g, 62.5 × 1.29 mmol) to 8
The temperature was kept at 0 ° C., and the diazonium salt solution prepared above was added dropwise thereto. After the dropping was completed, the mixture was stirred at 80 ° C for 15 minutes and allowed to cool.
This was partitioned with chloroform, the organic layer was washed with aqueous sodium hydrogen sulfite solution, water, and dried over sodium sulfate (anhydrous). Then, the solvent was distilled off to obtain 18 g of an oily substance. This was purified by silica gel column chromatography. Colorless oil, yield 14.26 g, yield 66.6% IR NaCl liq.film cm ^-1 : 1738 1426 1268 1244 1162 ¹ H-NMR (60MHz, CDCl ₃ , δ): 2.4 (3H, S, SCH ₃ ) 3.91 ( 3
H, S, COOCH ₃ ) 6.91 (1H, d, J = 9Hz, aromatic ring H) 7.80 (1H, d,
J = 9Hz, aromatic ring H)

(5) Synthesis of 2-chloro-3- (methoxycarbonyl) -4-methylthiobenzoic acid 2-chloro-3-iodo-6-methylthiobenzoic acid methyl ester (1 g, 2.9 mmol) in dry THF The solution was kept under nitrogen atmosphere at −60 ° C. or lower, and n-butyllithium (1.59
Mol / L hexane solution 1.82 ml, 2.9 mmol) was added dropwise.
After 15 minutes, sufficient carbon dioxide gas was blown in while keeping the temperature below -50 ° C. After that, the reaction solution was returned to room temperature and washed with water.
It was distributed by tell. Unreacted raw materials were collected in the organic layer. The aqueous layer was then brought to pH <1 with concentrated hydrochloric acid and extracted with ethyl acetate. Then, it was washed with saturated saline and dried over sodium sulfate. The solvent was concentrated to give a red solid. Yield 0.35g, Yield 46% IR KBr cm ^-1 : 3464 1742 1694 1584 1300 1264 1194 11
42

(6) 2-chloro-3-methoxycarbonyl-4-
Synthesis of methylsulfonylbenzoic acid 2-chloro-3-methoxycarbonyl-4-methylthiobenzoic acid (1.54 g, 5.9 mmol), acetic acid 12 ml and hydrogen peroxide (35%, 1
2 ml) was stirred at 80 ° C. for 3 hours. After allowing to cool, it was poured into ice water and partitioned with chloroform. After drying the organic layer over sodium sulfate (anhydrous), the solvent was distilled off to give 2-chloro-3.
-Methoxycarbonyl-4-methylsulfonibenzoic acid 1.48 g
Got

(7) 2-chloro-3-methoxycarbonyl-4-
Synthesis of methylsulfonylbenzoic acid methyl ester 2-chloro-3-methoxycarbonyl-4-methylsulfonylbenzoic acid (1.48g, 5.05mmol) in thionyl chloride (1.1ml, 5.053mmol) and a catalytic amount of dried chlorobenzene in 20ml of benzene. The mixture was stirred at 85 ° C for 1 hour in the presence of DMF (2 to 3 drops). Then, benzene and an excess of thionyl chloride were concentrated, dry methanol was added to the residue in a large excess under water cooling, triethylamine (0.55 g, 5.05 × 1.07 mmol) was subsequently added, and the mixture was stirred for 1 hour. Then, methanol in the reaction solution was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over sodium sulfate (anhydrous), the solvent was concentrated, and the residue was purified by silica gel column chromatography. Light red solid, mp: 63-66 ° C, yield 0.8396g, yield 54.1
6% IR NaCl liq.film cm ^-1 : 1740 1730 1456 1436 1324 12
62 1148 1200 992 ¹ H-NMR (60MHz, CDCl ₃ , δ): 3.13 (3H, S, SO ₂ CH ₃ ) 3.90
(3H, COOCH ₃ ) 3.93 (3H, S, COOCH ₃ ) 8.00 (2H, S, aromatic ring H
× 2)

Formulation examples and test examples are shown below, but the carriers (diluents) and auxiliaries, their mixing ratios and active ingredients can be varied within a wide range. In addition, "part" of each formulation example represents a weight part. Formulation Example 1 (Wettable powder) Compound (Compound No. I-2) 50 parts Sodium lignin sulfonate 5 parts Sodium alkyl sulfonate 3 parts Diatomaceous earth 42 parts The above components are mixed and pulverized to obtain a wettable powder, which is diluted with water. use. Formulation Example 2 (Emulsion) Compound (Compound No. I-2) 25 parts Xylene 65 parts Polyoxyethylene alkylaryl ether 10 parts The above components are uniformly mixed to form an emulsion, which is diluted with water before use. Formulation Example 3 (Granule) Compound (Compound No. I-2) 8 parts Bentonite 40 parts Clay 45 parts Calcium lignin sulfonate 7 parts The above components are uniformly mixed and further kneaded by adding water and using an extrusion granulator. It is processed into granules and used as granules.

Test Example 1 (Test of herbicidal effect by foliar treatment) Stem and foliage part of Aogatetou, Nogaragasi, Chickweed, Acacia catechu, Yaemgra, Inobie and Meshishiba (1 to 2 leaves for each test plant) grown in pots Then, a drug solution of the test compound prepared by adjusting the wettable powder as shown in the above formulation example to a predetermined concentration was sprayed at an amount equivalent to 1 kg / ha. 14 days after spraying, the herbicidal effect was investigated according to the following criteria.

(Survey Criteria) Less than 1: 30% inhibition 2: 30% to less than 50% inhibition 3: 50% to less than 70% inhibition 4: 70% to 90% inhibition 5: 90% or more inhibition The results are shown in Table 4.

[Table 4]

INDUSTRIAL APPLICABILITY According to the present invention, 2-
(Substituted benzoyl) thiazine derivatives show a reliable herbicidal effect at low dose and show selectivity between crops and weeds.
Therefore, the herbicide of the present invention containing this compound as an active ingredient, for example, wheat, rice, corn,
It is particularly suitable for controlling dicotyledonous and monocotyledonous weeds in important crops such as soybean before or after germination. In addition, it can be used for controlling weeds in non-agricultural lands such as grounds and factory grounds as well as agricultural lands such as upland fields, paddy fields and orchards.

Claims (3)

[Claims] 1. A 2- (substituted benzoyl) thiazine derivative represented by the following formula (I): [In the formula, X ¹ represents a hydrogen atom, a halogen atom, a nitro group,
Cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkoxyalkyl group, C1-C6 haloalkyl group, C1-C6 haloalkoxy group, C2-
C6 alkylcarbonyl group, C2-C6 alkoxycarbonyl group, aminocarbonyl group optionally substituted by 1 or 2 C1-C6 alkyl groups, C1-C
6 alkylthio group, C2-C6 alkylthioalkyl group, C1-C6 alkylsulfonyl group, or C2-C
6 represents an alkylsulfonylalkyl group. X ² is a hydrogen atom, a C1 to C6 alkoxy group, a C1 to C6 haloalkoxy group, a (C1 to C6 alkoxy) C1 to C6 alkoxy group, a (C1 to C6 haloalkoxy) C1 to C6 alkoxy group, (C1 to C6 thio). Alkoxy) C1-C6 alkoxy group, -COOR, -COO-L-OR, -COO
-LR ¹ , -COO-M, -COO-LM, -CO
O-L-O-R-R ¹ , -COO-L-S (O) _m- R,
—CON (R ² ) (R ³ ), embedded image _{-CONHSO 2 CH 3, -CONHSO 2 CF} 3, -CO
^{O-L-N (R 2} ) (R 3), - COO-L-CO-R,
-COO-L-COO-R, -COO-L-CN, -C
_{OO-L-NO 2, -COOSi} (R 4) 3, -COO-N
= C (R ⁵ ) (R ⁶ ), embedded image _{-COO-L-O-SO 2} -R ,, - COO-L-O-
CO-R, -COO-L-O-L-O-R, -COO-
_{^{L-Si (R 4) 3}} , -C (O) S-R, -C (S) O-
R, -C (S) S-R, -L-O-R, -L-O-L-
OR ⁷ , -L-O-M, -L-O-L-M, -L-NR ^{7
R 8, -L-O-CH} 2 Ph, -L-O-L-COO
^{R 8, -L-CN, -L} -S (O) m -R, -L-S-L
^{-O-R 8, -L-O} -COR 8, -L-O-SO 2 R 8,
-L-COOR ⁷ , -CH = CHOR ⁷ , -L-OL-
It represents CN or a 3 to 6 membered heterocyclic group formed by the bonding of 4 or less sulfur atoms, oxygen atoms or nitrogen atoms and 1 to 4 carbon atoms. (In the above formula, L represents a C1 to C6 alkylene group which may be substituted with a C1 to C3 alkyl group, and M represents 2 or less sulfur atoms or oxygen atoms and 1 to 4 carbon atoms. Represents a 3- to 6-membered heterocyclic group formed by combining with, and R represents a hydrogen atom, a C1 to C6 alkyl group, a C3 to C8 cycloalkyl group, a C4 to C8 cycloalkylalkyl group, a C3 to C6 alkynyl. Group, C2-C
6 alkenyl groups, C1 to C6 haloalkyl groups, C3 to C
8 halocycloalkyl group, C3-C6 haloalkynyl group, C2-C6 haloalkenyl group, or C1-C3
Alkyl group, halogen atom, nitro group or C1-C
3 represents a phenyl group which may be substituted with an alkoxy group, R ¹ represents a C1 to C3 alkyl group, a halogen atom, a nitro group or a phenyl group which may be substituted with a C1 to C3 alkoxy group, R ² and R ³ is independently a hydrogen atom, a C1 to C6 alkyl group, a C3 to C8 cycloalkyl group, a C4 to C8 cycloalkylalkyl group,
C1-C6 alkoxy group, C2-C6 alkynyl group, C
2-C6 alkenyl group, C1-C6 haloalkyl group, C
3-C8 halocycloalkyl group, C2-C6 haloalkynyl group, C2-C6 haloalkenyl group, or C1-
C3 alkyl group, halogen atom, nitro group or C1
~C3 represents a phenyl group which may be substituted by an alkoxy group, R ⁴ represents a C1~C3 alkyl group, R ⁵ and R ⁶ may be the same or different, each C1~
A C3 alkyl group, R ⁷ is a hydrogen atom or C1 to C6
Represents an alkyl group, R ⁸ represents a C1~C6 alkyl group, Ph represents a phenyl group, m represents an integer of 0 to 2, n is an integer of 4-6. ) X ³ is a hydrogen atom, a halogen atom, a nitro group, C1 to C
3 represents an alkoxy group, a trifluoromethyl group, a cyano group, or —S (O) _m R ⁹ . (However, R ⁹ is C1 to C3
It represents an alkyl group or a C1-C3 haloalkyl group. m
Represents an integer of 0 to 2. ) X ⁴ is a hydrogen atom, a halogen atom, a C1 to C4 alkyl group, a C1 to C4 haloalkyl group, a C1 to C4 alkoxy group, a C2 to C6 alkoxyalkyl group, a C2 to C5 alkoxycarbonyl group, a C1 to C3 haloalkoxy group, It represents a nitro group, a cyano group or a —S (O) _m —R ¹⁰ group.
(Wherein, R ¹⁰ represents a C1 -C4 alkyl group, m. The same meaning as defined above) is X ^5, represents a hydrogen atom, a halogen atom, C1 -C4 alkyl or C1 -C4 alkoxy groups. Y ¹ , Y ² , Y
³ and Y ⁴ are each independently a hydrogen atom, C1 to C4.
It represents an alkyl group, a C1-C4 alkoxy group, or a benzyl group. Y ⁵ is a hydrogen atom, a C1 to C6 alkyl group optionally substituted with a halogen atom, a C1 to C6 alkenyl group optionally substituted with a halogen atom, or a C1 to C6 alkynyl optionally substituted with a halogen atom. Base,
It represents a cyanomethyl group or a benzyl group which may contain 1 to 5 halogen atoms, a C1 to C3 alkyl group, a C1 to C3 alkoxy group or a nitro group as a substituent. Z represents a hydrogen atom, a C1 to C6 alkyl group optionally substituted with a halogen atom, a C1 to C6 alkenyl group optionally substituted with a halogen atom, a C1 to C6 alkynyl group optionally substituted with a halogen atom. , A cyanomethyl group, —C (O) —R ¹¹ (provided that R ¹¹ is C1 to C6.
1 selected from an alkyl group, C1-C6 alkenyl group, C1-C6 alkynyl group, C1-C6 haloalkyl group, C1-C6 haloalkenyl group, C1-C6 haloalkynyl group, halogen atom, nitro group and trifluoromethyl group Represents a phenyl group, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, or a hydroxyl group which may be substituted with one or two or more identical or different substituents. ), —S (O) ₂ R ¹¹ (wherein R ¹¹ has the same meaning as described above), or 1 to 5 halogen atoms as a substituent, a C 1 to C 3 alkyl group, a C 1 to C 3 alkoxy group, Alternatively, it represents a benzyl group which may contain a nitro group. ] 2. A thiazine compound represented by the following formula (II):
And benzoic acid ester represented by the following formula (III)
The following formula characterized by reacting in the presence of a base
The 2- (substituted benzoyl group according to claim 1, which is represented by (I).
Le) A method for producing a thiazine derivative. [Chemical 4] (In the formula, E represents an alkyl group, X¹, X², X³, X^Four,
X^Five, Y¹, Y², Y³, Y ^Four, Y^FiveAnd Z are respectively
It has the same meaning as described above. ) 3. A herbicide containing the 2- (substituted benzoyl) thiazine derivative according to claim 1 represented by the following formula (I) as an active ingredient. [Chemical 5] (In the formula, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , Y ¹ , Y ² , Y ³ , Y
⁴ , Y ⁵ and Z each have the same meaning as described above. )